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    Clinical Trial Results:
    A randomized, active-controlled, multicenter, phase III study investigating efficacy and safety of intra-operative use of BT524 (human fibrinogen concentrate) in subjects undergoing major spinal or abdominal surgery (AdFIrst).

    Summary
    EudraCT number
    		 2017-001163-20
    Trial protocol
    		 DE   BE   ES   CZ   GB  
    Global end of trial date
    21 Nov 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Nov 2024
    First version publication date
    29 Nov 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Study No. 995
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03444324
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Biotest AG
    Sponsor organisation address
    Landsteinerstr. 5, Dreieich, Germany, 63303
    Public contact
    Corporate Clinical Research, Biotest AG, 0049 61038016395, 995@biotest.com
    Scientific contact
    Corporate Clinical Research, Biotest AG, 0049 61038016395, 995@biotest.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
    06 Feb 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Nov 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Nov 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main purpose of this phase III trial was to demonstrate the efficacy of fibrinogen concentrate (BT524) as a complementary therapy for the management of uncontrolled severe hemorrhage in subjects with acquired hypofibrinogenemia undergoing elective major spinal or abdominal surgery. The primary objective of this study was to demonstrate that BT524 is non-inferior, that means not worse than fresh frozen plasma (FFP)/cryoprecipitate with a non-inferiority margin of 150 mL in reducing intra-operative blood loss by intravenous (IV) administration in subjects with acquired hypofibrinogenemia undergoing elective major spinal or abdominal surgery. If therapeutical equivalence (non-inferiority) had been demonstrated, therapeutic superiority of BT524 compared with FFP/cryoprecipitate was also to be assessed.
    Protection of trial subjects
    The trial was conducted in accordance with the ICH-GCP guidelines, the most recent version of the Declaration of Helsinki, with local regulatory requirements, and in accordance with standard operating procedures for clinical research at Biotest AG and the contract research organization. A Data Safety Monitoring Board (DSMB) independently reviewed and assessed the unblinded safety data throughout the entire trial at regular intervals. The DSMB members were unblinded during the evaluation periods and were provided with the following information: reports of Serious Adverse Events and Adverse Events, data on markers of coagulation and coagulation factors, clinical laboratory assessments of hematology, clinical chemistry and urinalysis, and vital signs. The DSMB were provided with data covering the screening visit, the day of surgery plus 4 additional follow-up visits and evaluated the subjects’ risks at formal DSMB meetings with regards to the relevant parameters and outcome criteria. In addition, subject's data from the closing visit were also be evaluated if data already available at the time of the DSMB meeting. The DSMB members could propose to stop the trial at any time after a scheduled or unscheduled meeting in case of major safety concerns related to trial treatment.
    Background therapy
    		 None
    Evidence for comparator
    		 FFP was used as active comparator to BT524 in subjects undergoing major spinal surgery. FFP is the standard of care in many European countries for replacement of coagulation factors during major bleeding in clinical settings such as surgery and trauma. Standard FFP contains 2-5 mg fibrinogen per mL. Cryoprecipitate was used as active comparator to BT524 in subjects undergoing cytoreductive PMP surgery at one site in the UK. Cryoprecipitate is produced in the UK, USA, Canada, Australia, and New Zealand, where it is mainly used as a concentrated source of fibrinogen for treatment of acquired hypofibrinogenemia. Cryoprecipitate is available as single units or as pools of five. A single unit contains a mean of approximately 400 to 460 mg fibrinogen.
    Actual start date of recruitment
    03 Apr 2018
    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
    Belgium: 1
    Country: Number of subjects enrolled
    Switzerland: 24
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    Spain: 53
    Country: Number of subjects enrolled
    United Kingdom: 109
    Country: Number of subjects enrolled
    Czechia: 67
    Country: Number of subjects enrolled
    Germany: 84
    Worldwide total number of subjects
    339
    EEA total number of subjects
    206
    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)
    167
    From 65 to 84 years
    169
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment was based on the surgeons’ clinical assessments during physical examinations and personal consultations prior to spinal or abdominal surgery (Day -42 to Day -1), which were conducted at the respective hospitals where surgeries were scheduled to take place.

    Pre-assignment
    Screening details
    		 Eligible subjects were those scheduled for elective major spinal or abdominal surgery with an expected major blood loss. While the type of spinal surgery was not restricted, the abdominal surgery was limited to cytoreductive surgery for pseudomyxoma peritonei (PMP). Screening occurred during a dedicated visit within 42 days before surgery.

    Pre-assignment period milestones
    Number of subjects started
    		 339
    Number of subjects completed
    		 222

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Adverse event, non-fatal: 2
    Reason: Number of subjects
    		 Consent withdrawn by subject: 10
    Reason: Number of subjects
    		 Physician decision: 21
    Reason: Number of subjects
    		 Eligibility criteria prior surgery not met: 11
    Reason: Number of subjects
    		 Intra-operative eligibility criteria not met: 69
    Reason: Number of subjects
    		 Technical reason: 3
    Reason: Number of subjects
    		 Other: 1
    Period 1
    Period 1 title
    Intra-operative, from decision to treat (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject
    Blinding implementation details
    This trial was partially blinded; surgeon, surgical staff, and subjects were blinded to treatment allocation throughout the entire surgery. The anesthesiologist who administered the IMP was not blinded to treatment allocation because of the inherent characteristics of the IMPs (BT524, FFP, and cryoprecipitate).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BT524
    Arm description
    		 BT524 is a lyophilized, heat-treated, virus and prion safe human fibrinogen concentrate manufactured from human plasma used as complementary therapy to management of uncontrolled severe hemorrhage in acquired hypofibrinogenemia.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BT524
    Investigational medicinal product code
    BT524
    Other name
    Human fibrinogen concentrate
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Infusion , Intravenous use
    Dosage and administration details
    For subjects who underwent spinal surgery, BT524 dose was calculated based on the subject’s body weight (BW) and the functional fibrinogen levels (FIBTEM A10) measured by ROTEM thromboelastometry with the aim of restoring the individual baseline FIBTEM A10 value, using a given formula. First dose was at least 2g and the maximum dose of fibrinogen concentrate during surgery should not exceed 8g. For subjects who underwent cytoreductive PMP surgery, the dose of BT524 infused was a fixed dose of 4g with the aim of restoring the fibrinogen plasma level per guidelines. The first BT524 dose was administered pre-emptively. Subjects randomized to the BT524 group received 4g BT524 each time fibrinogen supplementation was ordered. BT524 was administered intravenously.

    Arm title
    		 FFP/Cryo
    Arm description
    		 Conventional replacement therapy with fresh frozen plasma or cryoprecipitate, used during surgery to supplement fibrinogen in case of bleeding.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Fresh Frozen Plasma
    Investigational medicinal product code
    FFP
    Other name
    Pharmaceutical forms
    Sterile concentrate
    Routes of administration
    Infusion , Intravenous use
    Dosage and administration details
    Dosage was based on local standards and depended on the extent of bleeding and the subject's clinical condition. The recommended dose of FFP was 15 mL per kg body weight (BW). Subsequent intra-operative infusions were given as required. FFP was administered intravenously.

    Investigational medicinal product name
    Cryoprecipitate
    Investigational medicinal product code
    Cryo
    Other name
    Pharmaceutical forms
    Sterile concentrate
    Routes of administration
    Infusion , Intravenous use
    Dosage and administration details
    The therapeutic cryoprecipitate dose was two pools, each pool consisting of 5 units (10 units, dose-equivalent to 4g fibrinogen concentrate). The first cryoprecipitate dose was administered pre-emptively. Subjects randomized to the cryoprecipitate group received two pools cryoprecipitate each time fibrinogen supplementation was ordered. Cryo was administered intravenously.

    Number of subjects in period 1 [1]
    		BT524 FFP/Cryo
    Started
    110
    112
    Randomization
    110
    112
    Completed
    105
    106
    Not completed
    5
    6
         Consent withdrawn by subject
    -
    1
         Other
    -
    1
         Lack of Study Compliance
    1
    1
         Lost to follow-up
    4
    2
         Protocol deviation
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The group 'All subjects enrolled' includes all subjects who provided informed consent during the screening visit (n=339). Of these, n=117 were screening failures. Intraoperatively, at the time of the 'decision to treat,' n=222 subjects were deemed eligible and were randomised. Baseline data were analyzed only for this group of randomised subjects. The intraoperative period, starting from the decision to treat, is considered the baseline period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BT524
    Reporting group description
    		 BT524 is a lyophilized, heat-treated, virus and prion safe human fibrinogen concentrate manufactured from human plasma used as complementary therapy to management of uncontrolled severe hemorrhage in acquired hypofibrinogenemia.

    Reporting group title
    FFP/Cryo
    Reporting group description
    		 Conventional replacement therapy with fresh frozen plasma or cryoprecipitate, used during surgery to supplement fibrinogen in case of bleeding.

    Reporting group values
    		 BT524 FFP/Cryo Total
    Number of subjects
    		 110 112 222
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 62 58 120
        From 65-84 years
    		 48 54 102
        85 years and over
    		 0 0 0
    Age continuous
    Adults aged ≥ 18
    Units: years
        arithmetic mean (standard deviation)
    		 61.2 ( 12.52 ) 60.8 ( 14.07 ) -
    Gender categorical
    Units: Subjects
        Female
    		 67 64 131
        Male
    		 43 48 91
    Subject analysis sets

    Subject analysis set title
    Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Analysis Set (SAF) comprises all subjects who have received at least one dose of IMP.

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomized subjects receiving IMP post randomization and with data collected post randomization were included in the FAS.

    Subject analysis set title
    Modified Full Analysis Set
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All randomized subjects who met the following conditions were included in the Modified Full Analysis Set (mFAS): Subjects who received at least one dose of IMP prior to the ‘end of surgery’ and have at least one postdose efficacy assessment. This included all subjects whose IMP infusion started prior to the end of surgery, irrespective of the amount of IMP infused.

    Subject analysis set title
    Per-Protocol Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per-Protocol Set is a subset of FAS and included all subjects who were compliant with the clinical trial protocol without any major protocol deviations thought to have the potential to impact the results of the efficacy analysis, e.g., no treatment with IMP, incomplete treatment with IMP (administration of the first IMP dose was not completed if the end of the first IMP administration was after the end of surgery), treatment with IMP after the ‘end of surgery’, no postdose efficacy assessment for the primary endpoint.

    Subject analysis sets values
    		 Safety Set Full Analysis Set Modified Full Analysis Set Per-Protocol Set
    Number of subjects
    222
    222
    211
    201
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
    0
        Adults (18-64 years)
    120
    120
    114
    110
        From 65-84 years
    102
    102
    97
    91
        85 years and over
    0
    0
    0
    0
    Age continuous
    Adults aged ≥ 18
    Units: years
        arithmetic mean (standard deviation)
    61.0 ( 13.29 )
    61.0 ( 13.29 )
    61.2 ( 12.82 )
    60.9 ( 12.95 )
    Gender categorical
    Units: Subjects
        Female
    131
    131
    121
    115
        Male
    91
    91
    90
    86

    End points

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    End points reporting groups
    Reporting group title
    BT524
    Reporting group description
    		 BT524 is a lyophilized, heat-treated, virus and prion safe human fibrinogen concentrate manufactured from human plasma used as complementary therapy to management of uncontrolled severe hemorrhage in acquired hypofibrinogenemia.

    Reporting group title
    FFP/Cryo
    Reporting group description
    		 Conventional replacement therapy with fresh frozen plasma or cryoprecipitate, used during surgery to supplement fibrinogen in case of bleeding.

    Subject analysis set title
    Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Analysis Set (SAF) comprises all subjects who have received at least one dose of IMP.

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomized subjects receiving IMP post randomization and with data collected post randomization were included in the FAS.

    Subject analysis set title
    Modified Full Analysis Set
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All randomized subjects who met the following conditions were included in the Modified Full Analysis Set (mFAS): Subjects who received at least one dose of IMP prior to the ‘end of surgery’ and have at least one postdose efficacy assessment. This included all subjects whose IMP infusion started prior to the end of surgery, irrespective of the amount of IMP infused.

    Subject analysis set title
    Per-Protocol Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per-Protocol Set is a subset of FAS and included all subjects who were compliant with the clinical trial protocol without any major protocol deviations thought to have the potential to impact the results of the efficacy analysis, e.g., no treatment with IMP, incomplete treatment with IMP (administration of the first IMP dose was not completed if the end of the first IMP administration was after the end of surgery), treatment with IMP after the ‘end of surgery’, no postdose efficacy assessment for the primary endpoint.

    Primary: Intra-operative blood loss

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    End point title
    		 Intra-operative blood loss
    End point description
    Intra-operative blood loss after decision to treat the subject with IMP until the end of surgery as measured by amount of blood from the blood suction unit and amount of blood from swabs, surgical cloths and compresses.
    End point type
    Primary
    End point timeframe
    After decision to treat the subject with IMP until the end of surgery.
    End point values
    		 BT524 FFP/Cryo
    Number of subjects analysed
    103 [1]
    98 [2]
    Units: mL
        least squares mean (confidence interval 95%)
    1380.70 (1187.09 to 1574.31)
    1660.13 (1460.65 to 1895.61)
    Notes
    [1] - Per-Protocol Set
    [2] - Per-Protocol Set
    Statistical analysis title
    		 Primary Non-inferiority Analysis
    Statistical analysis description
    Primary Non-inferiority Analysis of Intra-operative Blood Loss after Decision to Treat with IMP until the End of Surgery - Per-protocol Set
    Comparison groups
    FFP/Cryo v BT524
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    P-value
    		 < 0.001 [4]
    Method
    		 Van Elteren test
    Parameter type
    		 Difference in LSM
    Point estimate
    -279.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -552.38
         upper limit
    		 -6.48
    Notes
    [3] - The primary efficacy analysis of this endpoint was to test non-inferiority in the Per-protocol Set (PPS). The final analysis was performed using a two-way analysis of variance (ANOVA). Non-inferiority was to be demonstrated if the upper confidence limit of the two-sided 95 % confidence interval (CI) for the difference in the least squares mean (LSM) was less than the non-inferiority margin (150 mL).
    [4] - p-value from Van Elteren test, stratified by predictive blood loss (> 1,000 mL to = 2,000 mL and > 2,000 mL).

    Secondary: Subjects with successful correction of fibrinogen level

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    End point title
    		 Subjects with successful correction of fibrinogen level
    End point description
    The proportion (%) of subjects with a successful correction of fibrinogen level (by FIBTEM A10) 15 minutes after start of first IMP administration will be compared between the treatment arms using a Cochran-Mantel-Haenszel (CMH) approach stratified by predictive blood loss (> 1,000 mL to ≤ 2,000 mL and > 2,000 mL).
    End point type
    Secondary
    End point timeframe
    15 minutes after the start of the first IMP administration
    End point values
    		 BT524 FFP/Cryo
    Number of subjects analysed
    104 [5]
    102 [6]
    Units: Number of subjects
    59
    19
    Notes
    [5] - mFAS
    [6] - mFAS
    Statistical analysis title
    		 Correction of Fibrinogen Level
    Statistical analysis description
    The proportion (%) of subjects with a successful correction of fibrinogen level (by FIBTEM A10) 15 minutes after start of first IMP administration will be compared between the treatment arms using a Cochran-Mantel-Haenszel (CMH) approach stratified by predictive blood loss (> 1,000 mL to ≤ 2,000 mL and > 2,000 mL).The number and percentage of subjects with a successful correction of fibrinogen level 15 minutes after start of first IMP administration will be presented for both treatment arms.
    Comparison groups
    BT524 v FFP/Cryo
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [7]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in response rate
    Point estimate
    38.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 26
         upper limit
    		 50.3
    Notes
    [7] - P-value is from a Cochran-Mantel-Haenszel model stratified by predictive blood loss (> 1,000 mL to ≤ 2,000 mL and > 2,000 mL).

    Secondary: Time to first successful correction of fibrinogen level

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    End point title
    		 Time to first successful correction of fibrinogen level
    End point description
    The 4 categories were compared between the two treatment arms using a Chi-square test. For the above Chi-square test, the number and percentage of subjects in each category were presented for each treatment arm, together with an overall p-value for the difference between the two treatment arms.
    End point type
    Secondary
    End point timeframe
    Within 15 minutes after IMP start, >15 and <= 90 minutes after IMP start, >90 minutes after IMP start, unsuccessful correction.
    End point values
    		 BT524 FFP/Cryo
    Number of subjects analysed
    107 [8]
    104 [9]
    Units: Number of subjects
        <=15 minutes after IMP start
    59
    19
        >15 and <= 90 minutes after IMP start
    17
    11
        >90 minutes after IMP start
    11
    16
        Unsuccessful correction
    20
    58
    Notes
    [8] - mFAS
    [9] - mFAS
    Statistical analysis title
    		 Time to first Correction of Fibrinogen level
    Statistical analysis description
    The two treatment arms were compared using a Chi-Square test.
    Comparison groups
    BT524 v FFP/Cryo
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Amount of transfusion products

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    End point title
    		 Amount of transfusion products
    End point description
    Total amount (volume) of transfusion products (allogeneic blood products) or autologous blood transfusion infused after start of first IMP administration until end of surgery. The end of surgery is defined as time of last suture.
    End point type
    Secondary
    End point timeframe
    After start of first IMP administration until end of surgery.
    End point values
    		 BT524 FFP/Cryo
    Number of subjects analysed
    107 [10]
    104 [11]
    Units: mL
    arithmetic mean (standard deviation)
        Cell salvage
    95.6 ( 244.57 )
    78.0 ( 234.77 )
        Allogeneic platelets
    3.0 ( 30.94 )
    3.6 ( 36.38 )
        Allogeneic RBCs
    455.5 ( 492.19 )
    488.4 ( 547.72 )
        Allogeneic FFP
    60.5 ( 217.68 )
    14.8 ( 110.94 )
        Cryoprecipitate
    0 ( 0 )
    0 ( 0 )
    Notes
    [10] - mFAS
    [11] - mFAS
    No statistical analyses for this end point

    Secondary: Amount of Red Blood Cells

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    End point title
    		 Amount of Red Blood Cells
    End point description
    Amount (volume) of red blood cells (RBCs) (allogeneic and autologous) infused after start of first IMP administration until end of surgery. The end of surgery is defined as time of last suture.
    End point type
    Secondary
    End point timeframe
    After start of first IMP administration until end of surgery.
    End point values
    		 BT524 FFP/Cryo
    Number of subjects analysed
    107 [12]
    104 [13]
    Units: mL
        least squares mean (confidence interval 95%)
    543.4 (441.99 to 644.77)
    558.9 (456.08 to 661.62)
    Notes
    [12] - mFAS
    [13] - mFAS
    Statistical analysis title
    		 Amount of RBCs
    Statistical analysis description
    An ANOVA analysis will be performed with the amount of RBCs required as the dependent variable and the predictive blood loss (> 1,000 mL to ≤ 2,000 mL and > 2,000 mL) as a covariate. The least square means and difference in least square means will be presented with the corresponding 95% confidence intervals and 2-sided p-value.
    Comparison groups
    FFP/Cryo v BT524
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 other [14]
    P-value
    		 < 0.831 [15]
    Method
    		 ANOVA
    Parameter type
    		 Difference in LSM
    Point estimate
    -15.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -157.83
         upper limit
    		 126.88
    Notes
    [14] - Difference of LS Mean (BT524-FFP/Cryo)
    [15] - LS means, confidence intervals, difference, and p-values are from an ANOVA model with the amount of RBCs required as the dependent variable and the predictive blood loss (> 1,000 mL to ≤ 2,000 mL and > 2,000 mL) as a covariate.

    Secondary: Post-operative Blood Loss

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    End point title
    		 Post-operative Blood Loss
    End point description
    Post-operative blood loss in the first 24 hours after end of surgery.
    End point type
    Secondary
    End point timeframe
    From end of surgery until 24 hours after the end of surgery.
    End point values
    		 BT524 FFP/Cryo
    Number of subjects analysed
    107 [16]
    104 [17]
    Units: mL
        least squares mean (confidence interval 95%)
    306.3 (234.15 to 378.38)
    293.9 (220.76 to 366.95)
    Notes
    [16] - mFAS
    [17] - mFAS
    Statistical analysis title
    		 Post-operative Blood Loss
    Statistical analysis description
    The post-operative blood loss is the blood loss from end of surgery until 24 hours after end of surgery. This endpoint was descriptively summarized by treatment arm. An ANOVA analysis was performed with the post-operative blood loss in the first 24 hours as the dependent variable and the predictive blood loss (> 1,000 mL to ≤ 2,000 mL and > 2,000 mL) as a covariate. The LSM and difference between groups was presented with corresponding 95% confidence intervals and 2-sided p-value.
    Comparison groups
    BT524 v FFP/Cryo
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.809
    Method
    		 ANOVA
    Parameter type
    		 Difference in LSM
    Point estimate
    12.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -88.84
         upper limit
    		 113.66

    Secondary: Subjects with Rebleeds

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    End point title
    		 Subjects with Rebleeds
    End point description
    Proportion (%) of subjects with rebleeds after the end of surgery until day 8.
    End point type
    Secondary
    End point timeframe
    After the end of surgery until day 8.
    End point values
    		 BT524 FFP/Cryo
    Number of subjects analysed
    107 [18]
    104 [19]
    Units: Number of subjects
    0
    5
    Notes
    [18] - mFAS
    [19] - mFAS
    Statistical analysis title
    		 Subjects with Rebleeds
    Comparison groups
    BT524 v FFP/Cryo
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 other [20]
    P-value
    		 = 0.022 [21]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in proportion
    Point estimate
    -4.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.9
         upper limit
    		 -0.7
    Notes
    [20] - The proportion of subjects with rebleeds is compared between the treatment arms using a CMH approach stratified by predictive blood loss. The number and percentage of subjects with a rebleed were presented and the estimated treatment effect (difference in rebleed rate between treatment arms), corresponding 95% confidence interval, and 2-sided p-value for the difference is presented.
    [21] - p-value is from a CMH model stratified by predictive blood loss

    Secondary: Hospital length of stay after surgery

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    End point title
    		 Hospital length of stay after surgery
    End point description
    Length of stay after surgery (days) = date of hospital discharge – date of surgery. Where date of discharge is the date of discharge following the IMP treated surgery.
    End point type
    Secondary
    End point timeframe
    From date of surgery until date of hospital discharge.
    End point values
    		 BT524 FFP/Cryo
    Number of subjects analysed
    107 [22]
    104 [23]
    Units: Number of subjects
        > 36 days
    7
    4
        29-36 days
    4
    10
        22-28 days
    13
    12
        15-21 days
    34
    17
        8-14 days
    39
    49
        1-7 days
    10
    12
    Notes
    [22] - mFAS
    [23] - mFAS
    No statistical analyses for this end point

    Secondary: In-hospital mortality

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    End point title
    		 In-hospital mortality
    End point description
    The number and percentages of subjects who died during their hospital stay presented with corresponding 95% confidence intervals of death rate by treatment arm using the Clopper-Pearson Method.
    End point type
    Secondary
    End point timeframe
    From day of surgery until hospital discharge.
    End point values
    		 BT524 FFP/Cryo
    Number of subjects analysed
    107 [24]
    104 [25]
    Units: Number of subjects
    0
    0
    Notes
    [24] - mFAS
    [25] - mFAS
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment emergent Adverse Events (TEAEs): during or after administration of IMP until the subject’s last trial visit. Non-TEAEs: after signing the ICF and prior administration of IMP.
    Adverse event reporting additional description
    Analyses were focused on TEAEs, defined as any AEs with start during or after administration of IMP until the subject’s last trial visit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    BT524
    Reporting group description
    		 BT524 is a lyophilized, heat-treated, virus and prion safe human fibrinogen concentrate manufactured from human plasma used as complementary therapy to management of uncontrolled severe hemorrhage in acquired hypofibrinogenaemia.

    Reporting group title
    FFP/Cryo
    Reporting group description
    		 Conventional replacement therapy with fresh frozen plasma or cryoprecipitate, used during surgery to supplement fibrinogen in case of bleeding.

    Serious adverse events
    		 BT524 FFP/Cryo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    28 / 110 (25.45%)
    41 / 112 (36.61%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    1
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 110 (0.91%)
    3 / 112 (2.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurogenic shock
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Impaired healing
         subjects affected / exposed
    2 / 110 (1.82%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical failure
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    3 / 110 (2.73%)
    7 / 112 (6.25%)
         occurrences causally related to treatment / all
    1 / 3
    4 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Injury, poisoning and procedural complications
    Seroma
         subjects affected / exposed
    1 / 110 (0.91%)
    3 / 112 (2.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia postoperative
         subjects affected / exposed
    0 / 110 (0.00%)
    3 / 112 (2.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dural tear
         subjects affected / exposed
    3 / 110 (2.73%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    2 / 110 (1.82%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    1 / 110 (0.91%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder injury
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal stoma complication
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural complication
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound complication
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural haemorrhage
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stoma site haemorrhage
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound haematoma
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrospinal fluid leakage
         subjects affected / exposed
    2 / 110 (1.82%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraparesis
         subjects affected / exposed
    2 / 110 (1.82%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraplegia
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 110 (0.00%)
    2 / 112 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic diathesis
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    2 / 110 (1.82%)
    2 / 112 (1.79%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    2 / 110 (1.82%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 110 (0.91%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric perforation
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileal perforation
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia strangulated
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 112 (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
    Joint range of motion decreased
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Postoperative wound infection
         subjects affected / exposed
    1 / 110 (0.91%)
    3 / 112 (2.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 110 (0.91%)
    2 / 112 (1.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis bacterial
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 112 (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
    		 BT524 FFP/Cryo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    92 / 110 (83.64%)
    93 / 112 (83.04%)
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    5 / 110 (4.55%)
    8 / 112 (7.14%)
         occurrences all number
    5
    8
    Oxygen saturation decreased
         subjects affected / exposed
    2 / 110 (1.82%)
    7 / 112 (6.25%)
         occurrences all number
    2
    8
    Injury, poisoning and procedural complications
    Anaemia postoperative
         subjects affected / exposed
    15 / 110 (13.64%)
    6 / 112 (5.36%)
         occurrences all number
    15
    6
    Vascular disorders
    Hypotension
         subjects affected / exposed
    23 / 110 (20.91%)
    10 / 112 (8.93%)
         occurrences all number
    29
    14
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    19 / 110 (17.27%)
    14 / 112 (12.50%)
         occurrences all number
    22
    14
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    12 / 110 (10.91%)
    13 / 112 (11.61%)
         occurrences all number
    12
    19
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    6 / 110 (5.45%)
    2 / 112 (1.79%)
         occurrences all number
    6
    2
    Nausea
         subjects affected / exposed
    10 / 110 (9.09%)
    4 / 112 (3.57%)
         occurrences all number
    11
    4
    Hepatobiliary disorders
    Hypertransaminasaemia
         subjects affected / exposed
    13 / 110 (11.82%)
    11 / 112 (9.82%)
         occurrences all number
    13
    11
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax
         subjects affected / exposed
    4 / 110 (3.64%)
    6 / 112 (5.36%)
         occurrences all number
    5
    6
    Psychiatric disorders
    Hallucination
         subjects affected / exposed
    29 / 110 (26.36%)
    26 / 112 (23.21%)
         occurrences all number
    30
    26
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    10 / 110 (9.09%)
    10 / 112 (8.93%)
         occurrences all number
    10
    10
    Urinary tract infection
         subjects affected / exposed
    10 / 110 (9.09%)
    10 / 112 (8.93%)
         occurrences all number
    10
    10
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    5 / 110 (4.55%)
    6 / 112 (5.36%)
         occurrences all number
    5
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Apr 2018
    The amendment clarified the treatment algorithm for allogeneic or autologous blood products (ABPs) administration and specified the need for repeated tests at screening and baseline visits. The prior version lacked clarity on whether the IMP infusion must be finished before ABPs can be given. The amendment specified that certain ABPs and hemostatic agents cannot be administered prior to or during IMP treatment, except for red blood cells.
    07 Jun 2019
    The amendment adjusted the intra-operative inclusion criterion, changing the trigger for IMP treatment from > 1000 mL blood loss to approximately 1 L based on the clinical need for fibrinogen supplementation. Blood loss estimation, not measurement, should trigger treatment. Dosage was revised to avoid under-dosing with BT524 and to allow repeated IMP dosing.
    04 Dec 2019
    The amendment expanded the trial's scope to include UK-based abdominal surgery cases, introducing cryoprecipitate as a BT524 comparator. Biostatistical changes encompassed three interim analyses and post Data Monitoring adjustments to standard deviation and power.

    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
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