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    Clinical Trial Results:
    RETIC trial: Reversal of Trauma Induced Coagulopathy by using Coagulation factor concentrates or Fresh frozen Plasma

    Summary
    EudraCT number
    		 2011-004139-29
    Trial protocol
    		 AT  
    Global end of trial date
    20 Feb 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Oct 2020
    First version publication date
    25 Oct 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RETIC
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01545635
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Medical University Innsbruck
    Sponsor organisation address
    Christoph-Probst-Platz 1, Innrain 52 A, Innsbruck, Austria, 6020
    Public contact
    Univ.Doz. Dr. Petra Innerhofer, Medical University Innsbruck, University Hospital for Anaesthesia and Intensive Care, +43 (0)50504-28503, petra.innerhofer@tirol-kliniken.at
    Scientific contact
    Univ.Doz. Dr. Petra Innerhofer, Medical University Innsbruck, University Hospital for Anaesthesia and Intensive Care, +43 (0)50504-28503, petra.innerhofer@tirol-kliniken.at
    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
    20 Feb 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Feb 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Feb 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To assess the difference in incidence of multi organ failure (MOF) after treatment of trauma induced coagulopathy with Fresh frozen plasma (FFP) or Coagulation factor concentrates (CFC).
    Protection of trial subjects
    Fibrinogen administration is calculated and aimed to maintain fibrinogen concentration and polymerization within the lower normal levels of healthy adults. In addition, ROTEM assays are performed following each therapeutic step and enable detection of hypercoagulability. Several cases of thrombembolismn have been reported after PCC administration. However the majority of data refers to patients receiving huge doses and continuous administration such as needed in patients with haemophilia and antibody formation. The doses used in the present study will be low and are aimed to raise factors levels up to 50% which is the lower normal level. Furthermore patients are closely monitored by ROTEM and a shortened ExTEM CT value should warrant against overdosing. Regarding FXIII concentrate no cases of thrombembolism following FXIII administration have been reported so far. Finally the amount of blood loss (120ml total, about 2% of calculated blood volume in a 70kg patient) due to study related blood sampling should not harm the patient.
    Background therapy
    		 TXA will be administered to all included study patients as a single bolus of 20mg/kg immediately after inclusion. Additional doses will be administered if indicated by ROTEM assays. Red blood cells will be transfused to maintain haemoglobin between 8-10mg/dl. Autologous salvaged red cells will be re-transfused irrespective of actual hemoglobin levels. Platelet concentrates (1-2 U PC) will be administered if clot firmness remains poor to maintain platelet count between 50-100 G/L or (ExTEM A10 <35mm) albeit sufficient fibrinogen polymerization (FibTEm A10 >10mm). Crystalloid fluids and 4% modified gelatin solution should be used preferently to maintain normovolemia in amounts disrected by the treating anaesthesist. Because of the profound effect of HES solutions on haemostasis HES should be avoided and only used if gelatin is contraindicated (known or new allergy). The use of HES will be documented and explained. All patients receive prewarmed iv fluids. In both groups pH, Ca++, BE and temperature are monitored and corrected as possible (targets pH>7.2, Ca++ >1mmol/L, BE >-4, temperature >35°C).
    Evidence for comparator
    		 We hypothesize that the exclusively use of CFC improves outcome of severely traumatized patients. The administration of CFC should effectively and timely raise coagulation factor levels, thereby limiting coagulopathic bleeding. Because volume expansion and dilution can be avoided with use of CFC the numbers of red cell and platelet transfusion should be reduced. As all types of blood components increase susceptibility to nosocomiale infection and sepsis a reduction in allogeneic transfusions and avoidance of FFP should result in a lower incidence of sepsis and multi organ failure. To test the hypothesis we will conduct a prospective study in adult patients with major trauma and coagulopathy randomly receiving CFC or FFP for correcting TIC.
    Actual start date of recruitment
    01 Mar 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
    Austria: 100
    Worldwide total number of subjects
    100
    EEA total number of subjects
    100
    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)
    1
    Adults (18-64 years)
    88
    From 65 to 84 years
    11
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Adult patients (aged 18–80 years) with trauma exhibiting an Injury Severity Score (ISS) greater than 15 and clinical signs or risk of substantial haemorrhage were screened for trauma-induced coagulopathy, which was defined as abnormally low fibrin polymerisation (measured with FibTEM assay) and/or prolonged initiation of coagulation (ExCT).

    Pre-assignment
    Screening details
    		 Between March 3, 2012, and Feb 20, 2016, 292 trauma patients with an expected ISS greater than 15 were screened for eligibility, of whom 192 were found ineligible. 100 patients were enrolled and randomly assigned to receive either FFP (n=48) or CFC (n=52).

    Period 1
    Period 1 title
    Treatment period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject
    Blinding implementation details
    Enrolled patients were randomly assigned (1:1) to FFP or CFC. An independent statistician determined random codes using permuted blocks with varying block size and Stata/MP 10.1 for Windows Statistical Software. Randomisation was stratified for presence or absence of brain injury, and patients were stratified into three ISS groups (ISS 16–30, 31–50, or >50).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 CFC group
    Arm description
    		 We started bleeding management with CFC immediately after randomisation and during surgical or radiological interventions, and continued study-specific coagulation management during the first 24 h at the intensive care unit (ICU). Considering that coagulopathy might reoccur, one or several treatment loops were administered during the entire study period (lasting from admission to the emergency department until 24 h at the ICU). In total 50 patients completed the treatment period, of which 38 patients received a single dose of CFC, 10 patients recieved a double dose of CFC and 2 patients received a double dose of CFC and in a crossover fashion rescue medication.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Haemocomplettan P
    Investigational medicinal product code
    Other name
    Blutgerinnungsfaktor 1, Human Fibrinogen
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    The used dosage of fibrinogen (50mg/kg), refer to he European Guidelines of trauma management (published 2010, 2013, 2016).

    Investigational medicinal product name
    Fibrogammin P 250E
    Investigational medicinal product code
    Other name
    FACTOR XIII
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    The FXIII concentrate were administered at 20IU/kg.

    Investigational medicinal product name
    Beriplex P/N 500 I.E
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    The 4 factor-PCC and FXIII concentrate were administered at 20IU/kg.

    Arm title
    		 FFP group
    Arm description
    		 We started bleeding management with FFP immediately after randomisation and during surgical or radiological interventions, and continued study-specific coagulation management during the first 24 h at the intensive care unit (ICU). Considering that coagulopathy might reoccur, one or several treatment loops were administered during the entire study period (lasting from admission to the emergency department until 24 h at the ICU). In total 44 patients completed the treatment period, of which 12 patients received a single dose of FFP, 9 patients recieved a double dose of FFP and 23 patients received a double dose of FFP and in a crossover fashion rescue medication.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Octaplas SD Blutgruppe A
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    For the FFP group, transfusion of FFP (Octapharma, Vienna, Austria) delivered by the local blood bank was done in a single dose of 15 mL/kg of bodyweight. Octaplas shows activity that is comparable to that of normal fresh-frozen human plasma. The final product contains 45-70 mg/mL of plasma protein.

    Number of subjects in period 1
    		CFC group FFP group
    Started
    52
    48
    Completed
    50
    44
    Not completed
    2
    4
         age < 18 years
    1
    -
         fatal injury
    1
    3
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CFC group
    Reporting group description
    		 We started bleeding management with CFC immediately after randomisation and during surgical or radiological interventions, and continued study-specific coagulation management during the first 24 h at the intensive care unit (ICU). Considering that coagulopathy might reoccur, one or several treatment loops were administered during the entire study period (lasting from admission to the emergency department until 24 h at the ICU). In total 50 patients completed the treatment period, of which 38 patients received a single dose of CFC, 10 patients recieved a double dose of CFC and 2 patients received a double dose of CFC and in a crossover fashion rescue medication.

    Reporting group title
    FFP group
    Reporting group description
    		 We started bleeding management with FFP immediately after randomisation and during surgical or radiological interventions, and continued study-specific coagulation management during the first 24 h at the intensive care unit (ICU). Considering that coagulopathy might reoccur, one or several treatment loops were administered during the entire study period (lasting from admission to the emergency department until 24 h at the ICU). In total 44 patients completed the treatment period, of which 12 patients received a single dose of FFP, 9 patients recieved a double dose of FFP and 23 patients received a double dose of FFP and in a crossover fashion rescue medication.

    Reporting group values
    		 CFC group FFP group Total
    Number of subjects
    		 52 48 100
    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)
    		 1 0 1
        Adults (18-64 years)
    		 45 43 88
        From 65-84 years
    		 6 5 11
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 42.60 ± 16.724 42.26 ± 16.748 -
    Gender categorical
    Units: Subjects
        Female
    		 12 13 25
        Male
    		 40 35 75

    End points

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    End points reporting groups
    Reporting group title
    CFC group
    Reporting group description
    		 We started bleeding management with CFC immediately after randomisation and during surgical or radiological interventions, and continued study-specific coagulation management during the first 24 h at the intensive care unit (ICU). Considering that coagulopathy might reoccur, one or several treatment loops were administered during the entire study period (lasting from admission to the emergency department until 24 h at the ICU). In total 50 patients completed the treatment period, of which 38 patients received a single dose of CFC, 10 patients recieved a double dose of CFC and 2 patients received a double dose of CFC and in a crossover fashion rescue medication.

    Reporting group title
    FFP group
    Reporting group description
    		 We started bleeding management with FFP immediately after randomisation and during surgical or radiological interventions, and continued study-specific coagulation management during the first 24 h at the intensive care unit (ICU). Considering that coagulopathy might reoccur, one or several treatment loops were administered during the entire study period (lasting from admission to the emergency department until 24 h at the ICU). In total 44 patients completed the treatment period, of which 12 patients received a single dose of FFP, 9 patients recieved a double dose of FFP and 23 patients received a double dose of FFP and in a crossover fashion rescue medication.

    Primary: Multiple organ failure

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    End point title
    		 Multiple organ failure
    End point description
    End point type
    Primary
    End point timeframe
    Day 0- day 30
    End point values
    		 CFC group FFP group
    Number of subjects analysed
    50
    44
    Units: MOF
        number (not applicable)
    25
    29
    Statistical analysis title
    		 Multiple organ failure
    Comparison groups
    CFC group v FFP group
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.15
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 4.86

    Secondary: Massive transfusions of RBC

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    End point title
    		 Massive transfusions of RBC
    End point description
    As further secondary efficacy endpoint, we also addressed frequency of massive transfusions of RBC during the first 24 h.
    End point type
    Secondary
    End point timeframe
    Day 0
    End point values
    		 CFC group FFP group
    Number of subjects analysed
    50
    44
    Units: Number of patients
        number (not applicable)
    6
    13
    Statistical analysis title
    		 Massive tranfusions of RBC
    Comparison groups
    CFC group v FFP group
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.042
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.95
         upper limit
    		 10.87

    Secondary: Frequency of transfusions of platelet concentrates

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    End point title
    		 Frequency of transfusions of platelet concentrates
    End point description
    As further secondary efficacy endpoint, we also addressed frequency of transfusions of platelet concentrates during the first 24 h.
    End point type
    Secondary
    End point timeframe
    Day 0
    End point values
    		 CFC group FFP group
    Number of subjects analysed
    50
    44
    Units: Number of patients
        number (not applicable)
    10
    21
    Statistical analysis title
    		 Frequency of tranfusions of platelet concentrate
    Comparison groups
    FFP group v CFC group
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0078
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.35
         upper limit
    		 10.18

    Secondary: Bleeding score of 2 or 3

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    End point title
    		 Bleeding score of 2 or 3
    End point description
    Bleeding score is defined as number fom 0-3, dependent on severity of bleeding. A coagulopathic bleeding score of 2 or 3 after first study drug administration was more frequently observed in the FFP group.
    End point type
    Secondary
    End point timeframe
    Day 0
    End point values
    		 CFC group FFP group
    Number of subjects analysed
    50
    44
    Units: Patients
        number (not applicable)
    14
    31
    Statistical analysis title
    		 Bleeding score of 2 or 3
    Comparison groups
    CFC group v FFP group
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Bleeding score of 2 or 3 and massive transfusion
    Comparison groups
    CFC group v FFP group
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Rescue therapy

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    End point title
    		 Rescue therapy
    End point description
    20 (87%) of the 23 patients in the FFP group who required rescue medication needed rescue already in the first treatment loop, whereas three other patients in the FFP group and the two patients in the CFC group received rescue therapy in later treatment loops.
    End point type
    Secondary
    End point timeframe
    Day 0
    End point values
    		 CFC group FFP group
    Number of subjects analysed
    50
    44
    Units: Patients
        number (not applicable)
    2
    23
    Statistical analysis title
    		 Rescue medication
    Comparison groups
    CFC group v FFP group
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    25.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.47
         upper limit
    		 240.03

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 0- day 30
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.03
    Reporting groups
    Reporting group title
    CFC group
    Reporting group description
    		 We started bleeding management with CFC immediately after randomisation and during surgical or radiological interventions, and continued study-specific coagulation management during the first 24 h at the intensive care unit (ICU). Considering that coagulopathy might reoccur, one or several treatment loops were administered during the entire study period (lasting from admission to the emergency department until 24 h at the ICU). In total 50 patients completed the treatement period, of which 38 patients received a single dose of CFC, 10 patients recieved a double dose of CFC and 2 patients received a double dose of CFC and rescue medication. In these patients, rescue therapy was initiated, meaning FFP was administered to patients in the CFC group.

    Reporting group title
    FFP group
    Reporting group description
    		 We started bleeding management with FFP immediately after randomisation and during surgical or radiological interventions, and continued study-specific coagulation management during the first 24 h at the intensive care unit (ICU). Considering that coagulopathy might reoccur, one or several treatment loops were administered during the entire study period (lasting from admission to the emergency department until 24 h at the ICU). In total 44 patients completed the treatement period, of which 12 patients received a single dose of FFP, 9 patients recieved a double dose of FFP and 23 patiens received a double dose of FFP and rescue medication.

    Serious adverse events
    		 CFC group FFP group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 52 (28.85%)
    18 / 48 (37.50%)
         number of deaths (all causes)
    5
    2
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    DVT
         subjects affected / exposed
    5 / 52 (9.62%)
    8 / 48 (16.67%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 52 (5.77%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial thrombosis
         subjects affected / exposed
    2 / 52 (3.85%)
    2 / 48 (4.17%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Delir
         subjects affected / exposed
    1 / 52 (1.92%)
    2 / 48 (4.17%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute renal failure
         subjects affected / exposed
    5 / 52 (9.62%)
    7 / 48 (14.58%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 CFC group FFP group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 52 (9.62%)
    3 / 48 (6.25%)
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 48 (2.08%)
         occurrences all number
    2
    2
    Tachycardia
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 48 (0.00%)
         occurrences all number
    1
    1
    Nervous system disorders
    Dysphagia
         subjects affected / exposed
    0 / 52 (0.00%)
    2 / 48 (4.17%)
         occurrences all number
    2
    2
    Vocal cord paralysis
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 48 (0.00%)
         occurrences all number
    1
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 48 (0.00%)
         occurrences all number
    1
    1
    Skin and subcutaneous tissue disorders
    Exanthema
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 48 (2.08%)
         occurrences all number
    2
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Mar 2012
    substantial amendments: another trial monitor, another member in study team (a medical doctor for transfusion medicine), definition for platelet transfusion trigger (50.000-100.000)
    14 Jul 2012
    Substantial amendment of an inclusion criterium: Limit of FibTEM was changed from <7mm to <9mm

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/28457980
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