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    Clinical Trial Results:
    Pilot Randomized trial of Fibrinogen in Trauma Haemorrhage (PRooF-iTH).

    Summary
    EudraCT number
    		 2014-003978-16
    Trial protocol
    		 DK  
    Global end of trial date
    15 Nov 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 May 2022
    First version publication date
    28 May 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PRooF-iTH
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02344069
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Rigshospitalet, Section for Transfusion Medicine, Capitol Region Blood Bank
    Sponsor organisation address
    Blegdamsvej 9, Copenhagen, Denmark, DK-2100
    Public contact
    Jakob Stensballe, Section for Transfusion Medicine, Capitol Region Blood Bank, 45 35458587, jakob.stensballe@regionh.dk
    Scientific contact
    Jakob Stensballe, Section for Transfusion Medicine, Capitol Region Blood Bank, 45 35458587, jakob.stensballe@regionh.dk
    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
    15 Nov 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Nov 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Nov 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective is to assess the efficacy and safety of an immediate pre-emptive first-line treatment with fibrinogen concentrate in patients with trauma haemorrhage in need of haemostatic resuscitation.
    Protection of trial subjects
    All patients are included upon admission to the trauma center and is receiving the best possible care and monitoring to treat their injury. The dose of fibrinogen concentrate in the present trial is 60-70 mg/kg and this is in alignment with the recommended dose stated in the summary of product characteristics (SPC) from CSL Behring
    Background therapy
    		 Standard of care at the trauma center
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Nov 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 46
    Worldwide total number of subjects
    46
    EEA total number of subjects
    46
    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)
    42
    From 65 to 84 years
    2
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patient were recruited upon admisssion to the trauma center at Rigshospitalet. Informed consent were obtained by an independed scientific guardian before inclusion in the trail. Afterwards informed consent is obtained from next of kin and/or the patient when able to concent.

    Pre-assignment
    Screening details
    		 A this i an emergency trial, patients were screening for inclusion immediatly after arrival to the trauma center. The primary inclusion criteria are: age at 18 or above, requiring blood transfusion,

    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
    Blinding implementation details
    This is a single-centre, randomized (1:1, active:placebo), placebo-controlled, double-blinded trial. The randomization is done in blocks of six, and the randomization sequence and envelopes are generated and validated by two persons that are otherwise not involved in the trial. Randomization was performed using Microsoft Excel software. Two identical sets of envelopes are generated - one set for randomization of patients, and an “emergency” set for code breaking if necessary.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intervention arm
    Arm description
    		 The active treatment consists of intravenous injection of fibrinogen concentrate (Riastap®) of 60–70 mg/kg (dose of 4 g for patients with body weight 55–69 kg, 5 g for 70–85 kg or 6 g for >85 kg) as a bolus dose when haemostatic resuscitation is deemed necessary by the clinician. Fibrinogen is administered as an immediate single intravenous injection (bolus dose) as early as possible during the initial resuscitation.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Riastap
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Riastap® is given as a intervenous bolus dose of 60–70 mg/kg (dose of 4 g for patients with body weight 55–69 kg, 5 g for 70–85 kg or 6 g for >85 kg)

    Arm title
    		 Placebo arm
    Arm description
    		 Patients in the placebo group will receive 0.9 % saline infusions in equal volume to active treatment and will be treated exactly as active patients. The volume of placebo administered is equal to the volume of active drug administered, again as a bolus dose when haemostatic resuscitation is deemed necessary by the clinician.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Saline 0.9%
    Investigational medicinal product code
    Other name
    sodium chloride
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients in the placebo group will receive 0.9 % saline infusions in equal volume to active treatment and will be treated exactly as active patients. The volume of placebo administered is equal to the volume of active drug administered

    Number of subjects in period 1
    		Intervention arm Placebo arm
    Started
    23
    23
    Completed
    21
    19
    Not completed
    2
    4
         Died before intervention
    -
    1
         No need for blood transfusion
    1
    -
         Missed allokation
    -
    1
         Protocol deviation
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Intervention arm
    Reporting group description
    		 The active treatment consists of intravenous injection of fibrinogen concentrate (Riastap®) of 60–70 mg/kg (dose of 4 g for patients with body weight 55–69 kg, 5 g for 70–85 kg or 6 g for >85 kg) as a bolus dose when haemostatic resuscitation is deemed necessary by the clinician. Fibrinogen is administered as an immediate single intravenous injection (bolus dose) as early as possible during the initial resuscitation.

    Reporting group title
    Placebo arm
    Reporting group description
    		 Patients in the placebo group will receive 0.9 % saline infusions in equal volume to active treatment and will be treated exactly as active patients. The volume of placebo administered is equal to the volume of active drug administered, again as a bolus dose when haemostatic resuscitation is deemed necessary by the clinician.

    Reporting group values
    		 Intervention arm Placebo arm Total
    Number of subjects
    		 23 23 46
    Age categorical
    all patients at 18 or above is eligiable
    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)
    		 20 22 42
        From 65-84 years
    		 2 0 2
        85 years and over
    		 1 1 2
    Gender categorical
    Both men and women were incluted
    Units: Subjects
        Female
    		 3 4 7
        Male
    		 20 19 39

    End points

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    End points reporting groups
    Reporting group title
    Intervention arm
    Reporting group description
    		 The active treatment consists of intravenous injection of fibrinogen concentrate (Riastap®) of 60–70 mg/kg (dose of 4 g for patients with body weight 55–69 kg, 5 g for 70–85 kg or 6 g for >85 kg) as a bolus dose when haemostatic resuscitation is deemed necessary by the clinician. Fibrinogen is administered as an immediate single intravenous injection (bolus dose) as early as possible during the initial resuscitation.

    Reporting group title
    Placebo arm
    Reporting group description
    		 Patients in the placebo group will receive 0.9 % saline infusions in equal volume to active treatment and will be treated exactly as active patients. The volume of placebo administered is equal to the volume of active drug administered, again as a bolus dose when haemostatic resuscitation is deemed necessary by the clinician.

    Primary: Thrombelastograph (TEG) functional fibrinogen (FF)

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    End point title
    		 Thrombelastograph (TEG) functional fibrinogen (FF)
    End point description
    Primary endpoint is thrombelastograph (TEG) functional fibrinogen (FF) maximun amplitude (MA) at 15 minuts after the intervention TEG FF MA ws significant higher in the fibrinogen group as compared to placebo (P<0.00001)
    End point type
    Primary
    End point timeframe
    15 minuts after the intervention
    End point values
    		 Intervention arm Placebo arm
    Number of subjects analysed
    23
    23
    Units: mm
    median (inter-quartile range (Q1-Q3))
        FF MA
    24 (23 to 26)
    19 (16 to 22)
    Statistical analysis title
    		 Primary endpoint
    Statistical analysis description
    TEG FF MA at 15 min was significant higher in the fibrinogen group as compared to the placebo group
    Comparison groups
    Intervention arm v Placebo arm
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 < 0.05 [2]
    Method
    		 ANCOVA
    Parameter type
    		 Cox proportional hazard
    Confidence interval
    Notes
    [1] - Numeric variable was presented as medians with interquartile range analysed by Mann-Whitney U test
    [2] - Primary endpoint were analysed with ANCOVA, adjusted for baseline values to increase statistical power

    Secondary: Mortality at 24 hours

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    End point title
    		 Mortality at 24 hours
    End point description
    ITT population Number of death within 24-hours post intervention. There were no statistical difference between the groups.
    End point type
    Secondary
    End point timeframe
    "4 hours post intervention
    End point values
    		 Intervention arm Placebo arm
    Number of subjects analysed
    21
    19
    Units: number
        Death
    0
    1
    No statistical analyses for this end point

    Secondary: Mortality day 30

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    End point title
    		 Mortality day 30
    End point description
    ITT population Numbers of deaths from baseline to day 30 There were no statistical difference between the groups.
    End point type
    Secondary
    End point timeframe
    Day 30
    End point values
    		 Intervention arm Placebo arm
    Number of subjects analysed
    21
    19
    Units: numbers
        Death
    4
    2
    No statistical analyses for this end point

    Secondary: Transfusion requirements

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    End point title
    		 Transfusion requirements
    End point description
    ITT population The transfusion requirements in the fibrinogen group was significant lower in the first 2 hours after the intervention (p=0.048)
    End point type
    Secondary
    End point timeframe
    at 2 hours post intervention
    End point values
    		 Intervention arm Placebo arm
    Number of subjects analysed
    23
    23
    Units: units
    median (inter-quartile range (Q1-Q3))
        Transfusion units
    2 (1 to 4)
    5 (3 to 13)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Adverse events are collected from baseline to day 30. Only SAE and SAR are recorded in the study as these patients are severily ill upon admission to the trauma center
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 none
    Dictionary version
    0
    Reporting groups
    Reporting group title
    Overall trail
    Reporting group description
    		 -

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: AE and AR is not reported in this trial as this trial is in trauma patients which per definition are seriously ill and therefore will have several AE without any value for the safety reporting in this trial
    Serious adverse events
    		 Overall trail
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 46 (8.70%)
         number of deaths (all causes)
    9
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Trombose
    Additional description: 4 events of trombosis were seen (1 of 23 in the fibrinogen group and 3 of 23 in the placebo group)
         subjects affected / exposed
    4 / 46 (8.70%)
         occurrences causally related to treatment / all
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Overall trail
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 46 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Feb 2016
    Extension of trial period

    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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    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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