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    Clinical Trial Results:
    REPLACE (Randomized evaluation of fibrinogen versus placebo in complex cardiovascular surgery): a prospective, multinational, multicenter, randomized, double-blind, placebo-controlled, phase III study for the use of Fibrinogen Concentrate (Human) (FCH) in complex cardiovascular surgery

    Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
    Summary
    EudraCT number
    		 2011-002685-20
    Trial protocol
    		 DE   GB   FI   IT   AT   CZ   PL   DK  
    Global end of trial date
    11 Sep 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Jul 2016
    First version publication date
    29 Jul 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    BI3023_3002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01475669
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    CSL Behring GmbH
    Sponsor organisation address
    Emil-von-Behring-Strasse 76, Marburg, Germany, 35041
    Public contact
    Trial Registration Co-ordinator, CSL Behring GmbH, clinicaltrials@cslbehring.com
    Scientific contact
    Trial Registration Co-ordinator, CSL Behring GmbH, 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
    16 Oct 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Sep 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of FCH treatment in controlling microvascular bleeding during complex cardiovascular surgery.
    Protection of trial subjects
    This study was carried out in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines, and standard operating procedures for clinical research and development at CSL Behring. The study protocol and all amendments, the Subject Information Sheet, and the Informed Consent Form were reviewed and approved by the independent ethics committee / and Institutional Review Boards of the participating centers. Before undergoing screening procedures for possible enrollment into the study, subjects were informed, in an understandable form, about the nature, scope, and possible consequences of the study. The investigator was responsible for obtaining a subject’s written informed consent to participate in the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Jan 2012
    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
    Poland: 6
    Country: Number of subjects enrolled
    United Kingdom: 24
    Country: Number of subjects enrolled
    Austria: 5
    Country: Number of subjects enrolled
    Czech Republic: 19
    Country: Number of subjects enrolled
    Denmark: 6
    Country: Number of subjects enrolled
    Finland: 12
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    Canada: 21
    Country: Number of subjects enrolled
    Japan: 48
    Worldwide total number of subjects
    152
    EEA total number of subjects
    83
    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)
    72
    From 65 to 84 years
    77
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 This multinational study enrolled subjects undergoing elective open surgical procedures on any part of the aorta requiring cardiopulmonary bypass. Subjects were enrolled at 34 sites in 11 countries.

    Pre-assignment
    Screening details
    		 Screening took place up to 4 weeks before administration of IMP. A total of 579 patients provided written informed consent and 519 eligible subjects were randomized at the start of surgery. Of the 519 randomized subjects, 152 (29.3%) met all intraoperative eligibility criteria and were treated with IMP (FCH arm: n = 78; placebo arm: n = 74).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 FCH arm
    Arm description
    		 Subjects were administered fibrinogen concentrate, human (FCH).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fibrinogen concentrate, human
    Investigational medicinal product code
    FCH
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects who met the the intraoperative eligibility criteria were to receive a single intravenous dose within 5 minutes of the completion of the measurement of the 5-minute bleeding mass. The FCH dose was determined individually based on the maximum clot firmness measured 20 to 30 minutes prior to discontinuation of cardiopulmonary bypass and subject body weight.

    Arm title
    		 Placebo arm
    Arm description
    		 Subjects were administered placebo (0.9% sodium chloride solution).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    0.9% sodium chloride solution
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single dose of 0.9% sodium chloride solution infused intravenously within 5 minutes at a volume equivalent to that needed for FCH.

    Number of subjects in period 1
    		FCH arm Placebo arm
    Started
    78
    74
    Completed
    74
    68
    Not completed
    4
    6
         Adverse event, serious fatal
    1
    5
         Consent withdrawn by subject
    1
    -
         Surgical intervention due to bleeding
    -
    1
         Adverse event, non-fatal
    1
    -
         Moved to another facility, too unwell to complete
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    FCH arm
    Reporting group description
    		 Subjects were administered fibrinogen concentrate, human (FCH).

    Reporting group title
    Placebo arm
    Reporting group description
    		 Subjects were administered placebo (0.9% sodium chloride solution).

    Reporting group values
    		 FCH arm Placebo arm Total
    Number of subjects
    		 78 74 152
    Age categorical
    Units: Subjects
        < 65 years
    		 38 34 72
        >= 65 years
    		 40 40 80
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.9 ± 12.96 64.2 ± 13.53 -
    Gender categorical
    Units: Subjects
        Female
    		 18 23 41
        Male
    		 60 51 111
    Surgical stratum
    Units: Subjects
        Primary procedure
    		 71 70 141
        Reoperation
    		 7 4 11
    Surgery type
    Units: Subjects
        Thoracic aortic aneurysm repair with proximal arch
    		 32 36 68
        Thoracic aortic aneurysm repair, no proximal arch
    		 43 34 77
        Thoracoabdominal aortic aneurysm repair
    		 3 4 7
    First 5-minute bleeding mass
    First 5-minute bleeding mass:the difference in weight of surgical swabs after 5 minutes of surgical packing of the aortic surgical site
    Units: gram
        median (full range (min-max))
    		 107 (60 to 242) 91 (60 to 233) -

    End points

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    End points reporting groups
    Reporting group title
    FCH arm
    Reporting group description
    		 Subjects were administered fibrinogen concentrate, human (FCH).

    Reporting group title
    Placebo arm
    Reporting group description
    		 Subjects were administered placebo (0.9% sodium chloride solution).

    Subject analysis set title
    FCH - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The intention-to treat (ITT) population (all randomized subjects who received any quantity of investigational medicinal product [IMP]) who were treated with FCH.

    Subject analysis set title
    Placebo - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population (all randomized subjects who received any quantity of IMP) who were treated with placebo.

    Subject analysis set title
    FCH - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per-protocol (PP) population (all subjects in the ITT population, excluding subjects who had at least 1 major protocol deviation), who were treated with FCH.

    Subject analysis set title
    Placebo - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP population (all subjects in the ITT population, excluding subjects who had at least 1 major protocol deviation), who were treated with placebo.

    Primary: Total units of allogeneic blood products

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    End point title
    		 Total units of allogeneic blood products
    End point description
    Number of units administered of all allogeneic blood products combined (fresh frozen plasma [FFP], platelets, and red blood cells [RBCs]).
    End point type
    Primary
    End point timeframe
    Up to 24 hours after IMP administration
    End point values
    		 FCH - ITT Placebo - ITT FCH - PP Placebo - PP
    Number of subjects analysed
    78
    74
    60
    64
    Units: units
        median (full range (min-max))
    5 (0 to 72)
    3 (0 to 25)
    5 (0 to 72)
    3.5 (0 to 25)
    Statistical analysis title
    		 FCH arm vs Placebo arm - ITT population
    Comparison groups
    FCH - ITT v Placebo - ITT
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.026 [1]
    Method
    		 van Elteren test
    Confidence interval
    Notes
    [1] - P value of van Elteren test (stratification by pooled study center).
    Statistical analysis title
    		 FCH arm vs Placebo arm - PP population
    Comparison groups
    FCH - PP v Placebo - PP
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.15 [2]
    Method
    		 van Elteren test
    Confidence interval
    Notes
    [2] - P value of van Elteren test (stratification by pooled study center).

    Secondary: Total avoidance of allogeneic blood transfusions

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    End point title
    		 Total avoidance of allogeneic blood transfusions
    End point description
    Number of subjects who are alive and do not have any administration of platelets, FFP, and RBCs during the first 24 hours after administration of IMP
    End point type
    Secondary
    End point timeframe
    During the 24 hours after IMP administration
    End point values
    		 FCH - ITT Placebo - ITT FCH - PP Placebo - PP
    Number of subjects analysed
    78
    74
    60
    64
    Units: subjects
    12
    21
    9
    19
    Statistical analysis title
    		 FCH arm vs Placebo arm - ITT population
    Comparison groups
    FCH - ITT v Placebo - ITT
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.047 [3]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [3] - Cochran-Mantel-Haenszel (CMH) test, stratified by pooled center
    Statistical analysis title
    		 FCH arm vs Placebo arm - PP population
    Comparison groups
    FCH - PP v Placebo - PP
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.058 [4]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [4] - Cochran-Mantel-Haenszel (CMH) test, stratified by pooled center

    Secondary: Quantity of blood loss

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    End point title
    		 Quantity of blood loss
    End point description
    Blood drainage volume from the chest
    End point type
    Secondary
    End point timeframe
    At 6, 12 and 24 hours after skin closure
    End point values
    		 FCH - ITT Placebo - ITT FCH - PP Placebo - PP
    Number of subjects analysed
    76
    74
    59
    64
    Units: mL
    median (full range (min-max))
        6 hours after skin closure
    260 (51 to 3125)
    297.5 (75 to 1340)
    255 (51 to 3125)
    297.5 (75 to 1340)
        12 hours after skin closure
    405 (101 to 3740)
    447.5 (140 to 1680)
    352 (101 to 3740)
    443 (140 to 1680)
        24 hours after skin closure
    590 (170 to 4420)
    682.5 (195 to 2115)
    590 (176 to 4420)
    695 (195 to 2115)
    Statistical analysis title
    		 FCH arm vs Placebo arm - ITT population, 6 hours
    Comparison groups
    Placebo - ITT v FCH - ITT
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.241 [5]
    Method
    		 van Elteren test
    Confidence interval
    Notes
    [5] - P-value of van Elteren test, stratified by pooled center
    Statistical analysis title
    		 FCH arm vs Placebo arm - ITT population, 12 hours
    Comparison groups
    Placebo - ITT v FCH - ITT
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.137 [6]
    Method
    		 van Elteren test
    Confidence interval
    Notes
    [6] - P-value of van Elteren test, stratified by pooled center
    Statistical analysis title
    		 FCH arm vs Placebo arm - ITT population, 24 hours
    Comparison groups
    FCH - ITT v Placebo - ITT
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.12 [7]
    Method
    		 van Elteren test
    Confidence interval
    Notes
    [7] - P-value of van Elteren test, stratified by pooled center
    Statistical analysis title
    		 FCH arm vs Placebo arm - PP population, 6 hours
    Comparison groups
    FCH - PP v Placebo - PP
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.106 [8]
    Method
    		 van Elteren test
    Confidence interval
    Notes
    [8] - P-value of van Elteren test, stratified by pooled center
    Statistical analysis title
    		 FCH arm vs Placebo arm - PP population, 12 hours
    Comparison groups
    FCH - PP v Placebo - PP
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.075 [9]
    Method
    		 van Elteren test
    Confidence interval
    Notes
    [9] - P-value of van Elteren test, stratified by pooled center
    Statistical analysis title
    		 FCH arm vs Placebo arm - PP population, 24 hours
    Comparison groups
    FCH - PP v Placebo - PP
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.103 [10]
    Method
    		 van Elteren test
    Confidence interval
    Notes
    [10] - P-value of van Elteren test, stratified by pooled center

    Secondary: Change in bleeding mass

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    End point title
    		 Change in bleeding mass
    End point description
    The 5-minute bleeding mass is measured as the difference in weight of surgical swabs after 5 minutes of surgical packing of the aortic surgical site immediately before and 5 minutes after completion of IMP administration.
    End point type
    Secondary
    End point timeframe
    Immediately before and 5 minutes after completion of IMP administration
    End point values
    		 FCH - ITT Placebo - ITT FCH - PP Placebo - PP
    Number of subjects analysed
    77
    74
    59
    64
    Units: grams
        median (full range (min-max))
    -20 (-153 to 40)
    -19.5 (-174 to 97)
    -19 (-153 to 40)
    -18.5 (-126 to 97)
    Statistical analysis title
    		 FCH arm vs Placebo arm - ITT population
    Comparison groups
    FCH - ITT v Placebo - ITT
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.319 [11]
    Method
    		 van Elteren test
    Confidence interval
    Notes
    [11] - P-value of van Elteren test, stratified by pooled center
    Statistical analysis title
    		 FCH arm vs Placebo arm - PP population
    Comparison groups
    FCH - PP v Placebo - PP
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.23 [12]
    Method
    		 van Elteren test
    Confidence interval
    Notes
    [12] - P-value of van Elteren test, stratified by pooled center

    Secondary: Mortality

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    End point title
    		 Mortality
    End point description
    Mortality with adjudicated cause of death (thrombotic/thromboembolic event [TEE] or non-TEE event) during the first 24 hours after administration of IMP, and up to 10 days and 30 days after surgery.
    End point type
    Secondary
    End point timeframe
    Within 24 hours after IMP administration, up to 10 days after surgery, and up to 30 days after surgery
    End point values
    		 FCH arm Placebo arm
    Number of subjects analysed
    78
    74
    Units: subjects
        Overall, within 24 hours after IMP
    0
    0
        TEE, within 24 hours after IMP
    0
    0
        Non-TEE, within 24 hours after IMP
    0
    0
        Overall, up to 10 days after surgery
    1
    1
        TEE, up to 10 days after surgery
    1
    1
        Non-TEE, up to 10 days after surgery
    0
    0
        Overall, up to 30 days after surgery
    1
    4
        TEE, up to 30 days after surgery
    1
    2
        Non-TEE, up to 30 days after surgery
    0
    2
    No statistical analyses for this end point

    Secondary: Consumption of blood products

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    End point title
    		 Consumption of blood products
    End point description
    Consumption of each individual blood product administered (FFP, platelets, and RBCs).
    End point type
    Secondary
    End point timeframe
    Up to 24 hours, and up to 10 days after IMP administration
    End point values
    		 FCH - ITT Placebo - ITT FCH - PP Placebo - PP
    Number of subjects analysed
    78
    74
    60
    64
    Units: units
    median (full range (min-max))
        FFP, within 24 hours after IMP administration
    4 (0 to 28)
    0 (0 to 14)
    4 (0 to 28)
    0 (0 to 14)
        Platelets within 24 hours after IMP administration
    1 (0 to 16)
    1 (0 to 6)
    1 (0 to 16)
    1 (0 to 6)
        RBCs, within 24 hours after IMP administration
    1 (0 to 28)
    0 (0 to 6)
    1 (0 to 28)
    0 (0 to 6)
        FFP, up to 10 days after IMP administration
    4 (0 to 31)
    0 (0 to 14)
    4 (0 to 31)
    0 (0 to 14)
        Platelets, up to 10 days after IMP administration
    1 (0 to 23)
    1 (0 to 6)
    1 (0 to 23)
    1 (0 to 6)
        RBCs, up to 10 days after IMP administration
    2 (0 to 33)
    2 (0 to 10)
    2 (0 to 33)
    1.5 (0 to 8)
    Statistical analysis title
    		 FCH vs Placebo, ITT population, FFP, 24 hours
    Comparison groups
    FCH - ITT v Placebo - ITT
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.017 [13]
    Method
    		 van Elteren test
    Confidence interval
    Notes
    [13] - P-value of van Elteren test, stratified by pooled center
    Statistical analysis title
    		 FCH vs Placebo, ITT population, FFP, 10 days
    Comparison groups
    FCH - ITT v Placebo - ITT
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.021 [14]
    Method
    		 van Elteren test
    Confidence interval
    Notes
    [14] - P-value of van Elteren test, stratified by pooled center
    Statistical analysis title
    		 FCH vs Placebo, PP population, FFP, 24 hours
    Comparison groups
    FCH - PP v Placebo - PP
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.114 [15]
    Method
    		 van Elteren test
    Confidence interval
    Notes
    [15] - P-value of van Elteren test, stratified by pooled center
    Statistical analysis title
    		 FCH vs Placebo, PP population, FFP, 10 days
    Comparison groups
    FCH - PP v Placebo - PP
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.137 [16]
    Method
    		 van Elteren test
    Confidence interval
    Notes
    [16] - P-value of van Elteren test, stratified by pooled center
    Statistical analysis title
    		 FCH vs Placebo, ITT population, platelets, 24 hour
    Comparison groups
    FCH - ITT v Placebo - ITT
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.089 [17]
    Method
    		 van Elteren test
    Confidence interval
    Notes
    [17] - P-value of van Elteren test, stratified by pooled center
    Statistical analysis title
    		 FCH vs Placebo, ITT population, platelets, 10 days
    Comparison groups
    FCH - ITT v Placebo - ITT
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.126 [18]
    Method
    		 van Elteren test
    Confidence interval
    Notes
    [18] - P-value of van Elteren test, stratified by pooled center
    Statistical analysis title
    		 FCH vs Placebo, PP population, platelets, 24 hours
    Comparison groups
    FCH - PP v Placebo - PP
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.232 [19]
    Method
    		 van Elteren test
    Confidence interval
    Notes
    [19] - P-value of van Elteren test, stratified by pooled center
    Statistical analysis title
    		 FCH vs Placebo, PP population, platelets, 10 days
    Comparison groups
    FCH - PP v Placebo - PP
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.266 [20]
    Method
    		 van Elteren test
    Confidence interval
    Notes
    [20] - P-value of van Elteren test, stratified by pooled center
    Statistical analysis title
    		 FCH vs Placebo, ITT population, RBCs, 24 hours
    Comparison groups
    FCH - ITT v Placebo - ITT
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.101 [21]
    Method
    		 van Elteren test
    Confidence interval
    Notes
    [21] - P-value of van Elteren test, stratified by pooled center
    Statistical analysis title
    		 FCH vs Placebo, ITT population, RBCs, 10 days
    Comparison groups
    FCH - ITT v Placebo - ITT
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.553 [22]
    Method
    		 van Elteren test
    Confidence interval
    Notes
    [22] - P-value of van Elteren test, stratified by pooled center
    Statistical analysis title
    		 FCH vs Placebo, PP population, RBCs, 24 hours
    Comparison groups
    FCH - PP v Placebo - PP
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.354 [23]
    Method
    		 van Elteren test
    Confidence interval
    Notes
    [23] - P-value of van Elteren test, stratified by pooled center
    Statistical analysis title
    		 FCH vs Placebo, PP population, RBCs, 10 days
    Comparison groups
    FCH - PP v Placebo - PP
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.93 [24]
    Method
    		 van Elteren test
    Confidence interval
    Notes
    [24] - P-value of van Elteren test, stratified by pooled center

    Secondary: Total units of all allogeneic blood products

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    End point title
    		 Total units of all allogeneic blood products
    End point description
    Number of units of all allogeneic blood products combined (FFP, platelets, and/or RBCs) administered during the first 6 hours after administration of IMP, and during 12 hours after administration of IMP.
    End point type
    Secondary
    End point timeframe
    During the 6 hours and 12 hours after IMP administration
    End point values
    		 FCH - ITT Placebo - ITT FCH - PP Placebo - PP
    Number of subjects analysed
    78
    74
    60
    64
    Units: units
    median (full range (min-max))
        6 hours after IMP administration
    5 (0 to 67)
    3 (0 to 24)
    4.5 (0 to 67)
    2.5 (0 to 24)
        12 hours after IMP administration
    5 (0 to 69)
    3 (0 to 24)
    5 (0 to 69)
    3.5 (0 to 24)
    Statistical analysis title
    		 FCH vs Placebo, ITT population, 6 hours
    Comparison groups
    FCH - ITT v Placebo - ITT
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.052 [25]
    Method
    		 van Elteren test
    Confidence interval
    Notes
    [25] - P-value of van Elteren test, stratified by pooled center
    Statistical analysis title
    		 FCH vs Placebo, PP population, 6 hours
    Comparison groups
    FCH - PP v Placebo - PP
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.147 [26]
    Method
    		 van Elteren test
    Confidence interval
    Notes
    [26] - P-value of van Elteren test, stratified by pooled center
    Statistical analysis title
    		 FCH vs Placebo, ITT population, 12 hours
    Comparison groups
    FCH - ITT v Placebo - ITT
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.037 [27]
    Method
    		 van Elteren test
    Confidence interval
    Notes
    [27] - P-value of van Elteren test, stratified by pooled center
    Statistical analysis title
    		 FCH vs Placebo, PP population, 12 hours
    Comparison groups
    FCH - PP v Placebo - PP
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.149 [28]
    Method
    		 van Elteren test
    Confidence interval
    Notes
    [28] - P-value of van Elteren test, stratified by pooled center

    Secondary: Volume of all allogeneic blood products

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    End point title
    		 Volume of all allogeneic blood products
    End point description
    Volume of all allogeneic blood products combined (FFP, platelets, and/or RBCs) administered during the first 6, 12, and 24 hours after administration of IMP
    End point type
    Secondary
    End point timeframe
    During the 6, 12, and 24 hours after administration of IMP
    End point values
    		 FCH - ITT Placebo - ITT FCH - PP Placebo - PP
    Number of subjects analysed
    78
    74
    60
    64
    Units: mL
    median (full range (min-max))
        6 hours after IMP administration
    1120 (0 to 20050)
    787.5 (0 to 6500)
    1105 (0 to 20050)
    715 (0 to 6500)
        12 hours after IMP administration
    1190 (0 to 20650)
    800 (0 to 6500)
    1120 (0 to 20650)
    800 (0 to 6500)
        24 hours after IMP administration
    1190 (0 to 21550)
    850 (0 to 6800)
    1120 (0 to 21550)
    880 (0 to 6800)
    Statistical analysis title
    		 FCH vs Placebo, ITT population, 6 hours
    Comparison groups
    FCH - ITT v Placebo - ITT
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.049 [29]
    Method
    		 van Elteren test
    Confidence interval
    Notes
    [29] - P-value of van Elteren test, stratified by pooled center
    Statistical analysis title
    		 FCH vs Placebo, PP population, 6 hours
    Comparison groups
    FCH - PP v Placebo - PP
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.138 [30]
    Method
    		 van Elteren test
    Confidence interval
    Notes
    [30] - P-value of van Elteren test, stratified by pooled center
    Statistical analysis title
    		 FCH vs Placebo, ITT population, 12 hours
    Comparison groups
    FCH - ITT v Placebo - ITT
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.05 [31]
    Method
    		 van Elteren test
    Confidence interval
    Notes
    [31] - P-value of van Elteren test, stratified by pooled center
    Statistical analysis title
    		 FCH vs Placebo, PP population, 12 hours
    Comparison groups
    FCH - PP v Placebo - PP
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.163 [32]
    Method
    		 van Elteren test
    Confidence interval
    Notes
    [32] - P-value of van Elteren test, stratified by pooled center
    Statistical analysis title
    		 FCH vs Placebo, ITT population, 24 hours
    Comparison groups
    FCH - ITT v Placebo - ITT
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.038 [33]
    Method
    		 van Elteren test
    Confidence interval
    Notes
    [33] - P-value of van Elteren test, stratified by pooled center
    Statistical analysis title
    		 FCH vs Placebo, PP population, 24 hours
    Comparison groups
    FCH - PP v Placebo - PP
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.17 [34]
    Method
    		 van Elteren test
    Confidence interval
    Notes
    [34] - P-value of van Elteren test, stratified by pooled center

    Secondary: Time from administration of study drug to completion of skin closure

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    End point title
    		 Time from administration of study drug to completion of skin closure
    End point description
    End point type
    Secondary
    End point timeframe
    Average 2 hours
    End point values
    		 FCH - ITT Placebo - ITT FCH - PP Placebo - PP
    Number of subjects analysed
    78
    74
    60
    64
    Units: minutes
        median (full range (min-max))
    84.5 (16 to 329)
    77 (20 to 192)
    83.5 (16 to 300)
    71.5 (20 to 192)
    Statistical analysis title
    		 FCH arm vs Placebo arm - ITT population
    Comparison groups
    FCH - ITT v Placebo - ITT
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.19 [35]
    Method
    		 van Elteren test
    Confidence interval
    Notes
    [35] - P-value of van Elteren test, stratified by pooled center
    Statistical analysis title
    		 FCH arm vs Placebo arm - PP population
    Comparison groups
    FCH - PP v Placebo - PP
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.263 [36]
    Method
    		 van Elteren test
    Confidence interval
    Notes
    [36] - P-value of van Elteren test, stratified by pooled center

    Secondary: Observed peak plasma concentration of fibrinogen (Cmax)

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    End point title
    		 Observed peak plasma concentration of fibrinogen (Cmax)
    End point description
    Fibrinogen levels were determined using the Clauss assay.
    End point type
    Secondary
    End point timeframe
    At the end of IMP administration
    End point values
    		 FCH - ITT Placebo - ITT FCH - PP Placebo - PP
    Number of subjects analysed
    77
    74
    60
    64
    Units: g/L
        median (full range (min-max))
    2.41 (0.47 to 3.7)
    1.105 (0.31 to 2.23)
    2.415 (0.47 to 3.7)
    1.12 (0.36 to 2.23)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From screening up to 45 days after the administration of IMP, for subjects who were treated.
    Adverse event reporting additional description
    The safety population comprised all randomized subjects who received any quantity of IMP. Adverse Event data are treatment-emergent data unless otherwise noted.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    FCH arm
    Reporting group description
    		 Subjects were administered fibrinogen concentrate, human (FCH).

    Reporting group title
    Placebo arm
    Reporting group description
    		 Subjects were administered placebo (0.9% sodium chloride solution).

    Serious adverse events
    		 FCH arm Placebo arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    27 / 78 (34.62%)
    25 / 74 (33.78%)
         number of deaths (all causes)
    1
    5
         number of deaths resulting from adverse events
    0
    1
    Vascular disorders
    Haemodynamic instability
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphorrhoea
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial haemorrhage
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Endotracheal intubation
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 74 (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
    Asthenia
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    2 / 78 (2.56%)
    4 / 74 (5.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    5 / 78 (6.41%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    2 / 78 (2.56%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chylothorax
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mediastinal haemorrhage
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Platelet count decreased
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Procedural haemorrhage
         subjects affected / exposed
    4 / 78 (5.13%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anastomotic haemorrhage
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endotracheal intubation complication
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac tamponade
         subjects affected / exposed
    1 / 78 (1.28%)
    6 / 74 (8.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pericardial effusion
         subjects affected / exposed
    2 / 78 (2.56%)
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 78 (2.56%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 74 (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 / 78 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Low cardiac output syndrome
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right ventricular dysfunction
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sick sinus syndrome
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    0 / 78 (0.00%)
    3 / 74 (4.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Brain injury
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Convulsion
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic cerebral infarction
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Ischaemic stroke
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 74 (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 haemorrhage
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 74 (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
    Renal failure acute
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Compartment syndrome
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Bronchitis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal infection
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incision site infection
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 74 (1.35%)
         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 / 78 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Malnutrition
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 FCH arm Placebo arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    70 / 78 (89.74%)
    61 / 74 (82.43%)
    Investigations
    C-reactive protein increased
         subjects affected / exposed
    4 / 78 (5.13%)
    3 / 74 (4.05%)
         occurrences all number
    4
    3
    White blood cell count increased
         subjects affected / exposed
    0 / 78 (0.00%)
    4 / 74 (5.41%)
         occurrences all number
    0
    4
    Injury, poisoning and procedural complications
    Wound complication
         subjects affected / exposed
    9 / 78 (11.54%)
    8 / 74 (10.81%)
         occurrences all number
    9
    8
    Procedural pain
         subjects affected / exposed
    8 / 78 (10.26%)
    5 / 74 (6.76%)
         occurrences all number
    8
    5
    Post procedural haemorrhage
         subjects affected / exposed
    4 / 78 (5.13%)
    2 / 74 (2.70%)
         occurrences all number
    4
    2
    Procedural haemorrhage
         subjects affected / exposed
    5 / 78 (6.41%)
    1 / 74 (1.35%)
         occurrences all number
    5
    1
    Vascular disorders
    Hypotension
         subjects affected / exposed
    10 / 78 (12.82%)
    11 / 74 (14.86%)
         occurrences all number
    10
    11
    Hypertension
         subjects affected / exposed
    2 / 78 (2.56%)
    6 / 74 (8.11%)
         occurrences all number
    2
    6
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    33 / 78 (42.31%)
    30 / 74 (40.54%)
         occurrences all number
    35
    31
    Pericardial effusion
         subjects affected / exposed
    4 / 78 (5.13%)
    6 / 74 (8.11%)
         occurrences all number
    4
    6
    Tachycardia
         subjects affected / exposed
    1 / 78 (1.28%)
    4 / 74 (5.41%)
         occurrences all number
    1
    4
    Ventricular tachycardia
         subjects affected / exposed
    4 / 78 (5.13%)
    0 / 74 (0.00%)
         occurrences all number
    4
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    15 / 78 (19.23%)
    18 / 74 (24.32%)
         occurrences all number
    15
    19
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    9 / 78 (11.54%)
    5 / 74 (6.76%)
         occurrences all number
    9
    5
    Oedema peripheral
         subjects affected / exposed
    5 / 78 (6.41%)
    3 / 74 (4.05%)
         occurrences all number
    5
    3
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    9 / 78 (11.54%)
    2 / 74 (2.70%)
         occurrences all number
    9
    2
    Diarrhoea
         subjects affected / exposed
    5 / 78 (6.41%)
    3 / 74 (4.05%)
         occurrences all number
    5
    3
    Constipation
         subjects affected / exposed
    2 / 78 (2.56%)
    5 / 74 (6.76%)
         occurrences all number
    2
    5
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    18 / 78 (23.08%)
    16 / 74 (21.62%)
         occurrences all number
    18
    17
    Pneumothorax
         subjects affected / exposed
    3 / 78 (3.85%)
    4 / 74 (5.41%)
         occurrences all number
    3
    4
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    10 / 78 (12.82%)
    11 / 74 (14.86%)
         occurrences all number
    10
    11
    Delirium
         subjects affected / exposed
    6 / 78 (7.69%)
    4 / 74 (5.41%)
         occurrences all number
    6
    4
    Renal and urinary disorders
    Oliguria
         subjects affected / exposed
    4 / 78 (5.13%)
    5 / 74 (6.76%)
         occurrences all number
    4
    5
    Renal failure acute
         subjects affected / exposed
    2 / 78 (2.56%)
    5 / 74 (6.76%)
         occurrences all number
    2
    5
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    4 / 78 (5.13%)
    2 / 74 (2.70%)
         occurrences all number
    4
    2
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    7 / 78 (8.97%)
    8 / 74 (10.81%)
         occurrences all number
    7
    8
    Hypokalaemia
         subjects affected / exposed
    4 / 78 (5.13%)
    5 / 74 (6.76%)
         occurrences all number
    4
    6
    Hypovolaemia
         subjects affected / exposed
    3 / 78 (3.85%)
    5 / 74 (6.76%)
         occurrences all number
    3
    5
    Dehydration
         subjects affected / exposed
    4 / 78 (5.13%)
    2 / 74 (2.70%)
         occurrences all number
    4
    3
    Hypocalcaemia
         subjects affected / exposed
    4 / 78 (5.13%)
    2 / 74 (2.70%)
         occurrences all number
    4
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Feb 2013
    The primary purpose of Amendment 1 of the clinical protocol was to allow the enrolment of subjects undergoing reoperation (resternotomy or rethoracotomy). The following main changes were made in this amendment: • Modification of an exclusion criterion to allow the inclusion of subjects undergoing reoperative aortic procedures (ie, resternotomy and rethoracotomy). Subjects undergoing reoperative aortic surgery at the same anatomic site as the original procedure, such as replacement of a previously placed aortic graft, were to continue to be excluded. • Reduction in the number of assessments requiring blood samples from study subjects. • Inclusion of additional biochemistry assessments. • Addition of health care resource utilization exploratory endpoints. • Clarification of the definition of unblinding, particularly in reference to access by study personnel to the results of fibrinogen assessments. • To clarify statements regarding: clinical procedures and assessments, concomitant medications and analysis populations.

    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.
    Markers of coagulopathic bleeding (eg, plasma fibrinogen level, platelet count) are likely to be more appropriate indicators of the need for allogeneic blood product transfusion than the 5-minute bleeding mass assessment used in this study.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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