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    Clinical Trial Results:
    Evaluation of postoperative administration of tranexamic acid on reducing blood loss after hip prothesis surgery.

    Summary
    EudraCT number
    		 2013-000791-15
    Trial protocol
    		 FR  
    Global end of trial date
    27 Jan 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Sep 2019
    First version publication date
    05 Sep 2019
    Other versions
    Summary report(s)
    		 PORTO_Anesthesiology

    Trial information

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    Trial identification
    Sponsor protocol code
    1308015
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02252497
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    CHU SAINT-ETIENNE
    Sponsor organisation address
    Boulevard Pasteur, LILLE, France,
    Public contact
    FORT, CHU de Saint-Etienne, 33 0477828374, j.noel.fort@chu-st-etienne.fr
    Scientific contact
    FORT, CHU de Saint-Etienne, 33 0477828374, j.noel.fort@chu-st-etienne.fr
    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
    19 Aug 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Jan 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Jan 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective is to compare the blood loss during a hip replacement surgery and during the next 4 days, between 2 groups. First group will receive 1g of tranexamic acid (Exacyl) before the surgery. Second group will receive 1g of tranexamic acid (Exacyl) before the surgery, and 1g in a 8h-perfusion during the surgery.
    Protection of trial subjects
    The safety of both groups will be assessed by comparing the number of expected and unexpected serious adverse events that occur in each of the two groups.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Sep 2013
    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
    France: 168
    Worldwide total number of subjects
    168
    EEA total number of subjects
    168
    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)
    75
    From 65 to 84 years
    81
    85 years and over
    12

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were only recruited in France, at chu St-Etienne between April 2014 and December 2015

    Pre-assignment
    Screening details
    		 No screenig in this study

    Period 1
    Period 1 title
    Treatment (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    The study was conducted in double-blind: - the syringes was prepared by another service - tranexamic acid and NaCl were indistinguishable As a result, neither investigators nor patients were aware of the treatment administered. In addition, the dosages of tranexamic acid concentrations were performed blindly in the randomization group.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Exacyl group
    Arm description
    		 Patients received 1g of tranexamic acid (Exacyl) before the surgery then 1g of tranexamic acid for 8 hours.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tranexamic acid
    Investigational medicinal product code
    Other name
    Exacyl
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous infusion of 1g of tranexamic acid for 8 hours.

    Arm title
    		 Control group
    Arm description
    		 Patients received 1g of tranexamic acid (Exacyl) before the surgery then physiological serum (NACL) for 8 hours.
    Arm type
    		 Placebo

    Investigational medicinal product name
    NACL
    Investigational medicinal product code
    Other name
    Physiological serum
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous infusion of physiological serum (NACL) for 8 hours.

    Number of subjects in period 1
    		Exacyl group Control group
    Started
    84
    84
    Completed
    84
    83
    Not completed
    0
    1
         Consent withdrawn by subject
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Exacyl group
    Reporting group description
    		 Patients received 1g of tranexamic acid (Exacyl) before the surgery then 1g of tranexamic acid for 8 hours.

    Reporting group title
    Control group
    Reporting group description
    		 Patients received 1g of tranexamic acid (Exacyl) before the surgery then physiological serum (NACL) for 8 hours.

    Reporting group values
    		 Exacyl group Control group Total
    Number of subjects
    		 84 84 168
    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)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
        Adults
    		 84 83 167
        Not recorded
    		 0 1 1
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 65.5 (58.7 to 73.0) 68.2 (56.8 to 78.4) -
    Gender categorical
    Units: Subjects
        Female
    		 47 39 86
        Male
    		 37 44 81
        Not recorded
    		 0 1 1
    Subject analysis sets

    Subject analysis set title
    Final analysis
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The statistical analysis was done using sAS-Windows software® version 9.4 installed on PC. The graphical representations were made using the R version 3.2.1 software. No interim analysis was performed. The protocol provided for a safety analysis for half of the patients included to assess by a monitoring committee the frequency of expected and unexpected SAE occurring in each treatment group. After the inclusion of 80 patients, only 3 SAE were registered that did not require a supervisory committee meeting. The final analysis was performed on the 167 patients included in the study, with 1 patient withdrawing consent on the day of surgery, according to the principle of intention-to-treat (ITT).

    Subject analysis sets values
    		 Final analysis
    Number of subjects
    167
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    75
        From 65-84 years
    81
        85 years and over
    11
        Adults
    167
        Not recorded
    1
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    66.2 (58.0 to 75.6)
    Gender categorical
    Units: Subjects
        Female
    86
        Male
    81
        Not recorded
    1

    End points

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    End points reporting groups
    Reporting group title
    Exacyl group
    Reporting group description
    		 Patients received 1g of tranexamic acid (Exacyl) before the surgery then 1g of tranexamic acid for 8 hours.

    Reporting group title
    Control group
    Reporting group description
    		 Patients received 1g of tranexamic acid (Exacyl) before the surgery then physiological serum (NACL) for 8 hours.

    Subject analysis set title
    Final analysis
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The statistical analysis was done using sAS-Windows software® version 9.4 installed on PC. The graphical representations were made using the R version 3.2.1 software. No interim analysis was performed. The protocol provided for a safety analysis for half of the patients included to assess by a monitoring committee the frequency of expected and unexpected SAE occurring in each treatment group. After the inclusion of 80 patients, only 3 SAE were registered that did not require a supervisory committee meeting. The final analysis was performed on the 167 patients included in the study, with 1 patient withdrawing consent on the day of surgery, according to the principle of intention-to-treat (ITT).

    Primary: Calculated volume of blood loss since the start of the intervention at Day 4 (in ml)

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    End point title
    		 Calculated volume of blood loss since the start of the intervention at Day 4 (in ml)
    End point description
    End point type
    Primary
    End point timeframe
    The primary endpoint is the calculated blood loss between the beginning of the surgery (day 1) and day 4.
    End point values
    		 Exacyl group Control group Final analysis
    Number of subjects analysed
    84
    83
    167
    Units: millilitre(s)
        arithmetic mean (standard deviation)
    918.6 ± 337.8
    888.4 ± 366.4
    903.6 ± 351.6
    Statistical analysis title
    		 Primary Endpoint
    Statistical analysis description
    A description of the included population was conducted using the following statistical methods: - Quantitative data: number of data available, average, standard deviation, median, 1st and 3rd quartiles (Q1 and Q3), minimum and maximum. - Qualitative data: absolute and relative frequencies (expressed in %). The comparability of the two treatment groups to inclusion was verified on demographics and initial characteristics.
    Comparison groups
    Exacyl group v Control group
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.58
    Method
    		 Student test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    30.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -76.7
         upper limit
    		 137.2
    Notes
    [1] - No statistical tests were conducted, with differences to be evaluated in clinical terms. In order to compare the two treatment groups on perioperative blood loss, total blood loss volumes were calculated. They were compared by a Student t test or in the case of a non-normal distribution variable, by a rank test. Normality was pre-verified by a Shapiro-Wilk test. The difference in averages was also presented with its 95% confidence interval (IC 95%).

    Secondary: The blood loss during the surgery

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    End point title
    		 The blood loss during the surgery
    End point description
    End point type
    Secondary
    End point timeframe
    Hemoglobin at the beginning of the surgery D1, at the end of the surgery D1.
    End point values
    		 Exacyl group Control group Final analysis
    Number of subjects analysed
    84
    83
    167
    Units: millilitre(s)
        arithmetic mean (standard deviation)
    166.6 ± 206.0
    165.4 ± 222.8
    166.0 ± 213.9
    Statistical analysis title
    		 The blood loss during the surgery
    Statistical analysis description
    The blood loss since the beginning of the surgery until the end of the surgery. With regard to secondary objectives, if the variables were quantitative, tests identical to those used for the main criterion were implemented. For qualitative variables, the two groups were compared using Fisher's exact test. Relative risk (RR) and 95% confidence interval (IC 95%) were also estimated.
    Comparison groups
    Exacyl group v Control group
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.97
    Method
    		 Student test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -64
         upper limit
    		 66.2
    Notes
    [2] - For the determination of risk factors for blood loss, a multivariate linear regression was performed. Initially, univariate analyses adjusted to the treatment group were implemented on each of these factors: for quantitative factors, which were continuously tested, univariate analyses by linear regression were qualitative factors, univariate analyses of variance have been implemented.

    Secondary: The postoperative blood loss, between the end of the surgery and the day after

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    End point title
    		 The postoperative blood loss, between the end of the surgery and the day after
    End point description
    The postoperative blood loss, between the end of the surgery and the day after.
    End point type
    Secondary
    End point timeframe
    Since the end of surgery until 24 hours later.
    End point values
    		 Exacyl group Control group Final analysis
    Number of subjects analysed
    84
    83
    167
    Units: millilitre(s)
        median (inter-quartile range (Q1-Q3))
    288.7 (111.5 to 436.9)
    236.4 (38.4 to 386.9)
    265.3 (73.6 to 422.0)
    Statistical analysis title
    		 The postoperative blood loss until 24 hours
    Statistical analysis description
    The blood loss between the end of the surgery and 24 hours later.
    Comparison groups
    Exacyl group v Control group
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.4
    Method
    		 Logrank
    Parameter type
    		 Mean difference (final values)
    Point estimate
    26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -61.8
         upper limit
    		 113.7
    Notes
    [3] - With regard to secondary objectives, if the variables were quantitative, tests identical to those used for the main criterion were implemented. For qualitative variables, the two groups were compared using Fisher's exact test. Relative risk (RR) and 95% confidence interval (IC 95%) were also estimated.

    Secondary: Blood loss from the end of surgery to Day 4

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    End point title
    		 Blood loss from the end of surgery to Day 4
    End point description
    The postoperative blood loss, between the end of the surgery (day 1) and day 4.
    End point type
    Secondary
    End point timeframe
    Between the end of the surgery (day 1) and day 4.
    End point values
    		 Exacyl group Control group Final analysis
    Number of subjects analysed
    84
    83
    167
    Units: millilitre(s)
        median (inter-quartile range (Q1-Q3))
    480.9 (221.1 to 687.7)
    398.0 (137.9 to 634.8)
    418.2 (174.4 to 683.7)
    Statistical analysis title
    		 Blood loss from the end of surgery to Day 4
    Statistical analysis description
    With regard to secondary objectives, if the variables were quantitative, tests identical to those used for the main criterion were implemented. For qualitative variables, the two groups were compared using Fisher's exact test. Relative risk (RR) and 95% confidence interval (IC 95%) were also estimated
    Comparison groups
    Exacyl group v Control group
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.53
    Method
    		 Logrank
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -128.2
         upper limit
    		 133.4
    Notes
    [4] - No comment.

    Secondary: Hemoglobin since the beginning of the intervention until Day 4

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    End point title
    		 Hemoglobin since the beginning of the intervention until Day 4
    End point description
    Hemoglobin since the beginning of the intervention until Day 4
    End point type
    Secondary
    End point timeframe
    hemoglobin at the beginning of the surgery D1, at the end of the surgery D1, at the day after the surgery (D2) and at D4.
    End point values
    		 Exacyl group Control group Final analysis
    Number of subjects analysed
    84
    83
    167
    Units: g/dl
    arithmetic mean (standard deviation)
        pre-operative hemoglobin
    14.2 ± 1.5
    14.2 ± 1.5
    14.2 ± 1.5
        Hemoglobin at the biginning ot the surgery
    13.1 ± 1.4
    13.2 ± 1.4
    13.1 ± 1.4
        Hemoglobin at the end of the surgery
    12.6 ± 1.5
    12.7 ± 1.4
    12.7 ± 1.5
        Hemoglobin at Day 1
    11.9 ± 1.5
    12.1 ± 1.2
    12.0 ± 1.4
        "Corrected" hemoglobin at Day 1
    11.9 ± 1.5
    12.1 ± 1.3
    12.0 ± 1.4
        Hemoglobin at Day 4
    11.4 ± 1.4
    11.5 ± 1.3
    11.5 ± 1.3
        "Corrected" hemoglobin at Day 4
    11.4 ± 1.5
    11.5 ± 1.3
    11.4 ± 1.4
        loss of hemoglobin at D4 compared to pre-operative
    2.8 ± 1.0
    2.7 ± 1.1
    2.8 ± 1.1
    Statistical analysis title
    		 Pre-operative hemoglobin
    Statistical analysis description
    With regard to secondary objectives, if the variables were quantitative, tests identical to those used for the main criterion were implemented. For qualitative variables, the two groups were compared using Fisher's exact test. Relative risk (RR) and 95% confidence interval (IC 95%) were also estimated.
    Comparison groups
    Exacyl group v Control group
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.88
    Method
    		 Student test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.45
         upper limit
    		 0.45
    Notes
    [5] - No comment.
    Statistical analysis title
    		 Hemoglobin at the biginning ot the surgery
    Statistical analysis description
    With regard to secondary objectives, if the variables were quantitative, tests identical to those used for the main criterion were implemented. For qualitative variables, the two groups were compared using Fisher's exact test. Relative risk (RR) and 95% confidence interval (IC 95%) were also estimated.
    Comparison groups
    Exacyl group v Control group
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.32
    Method
    		 Student test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.49
         upper limit
    		 0.35
    Statistical analysis title
    		 Hemoglobin at the end of the surgery
    Statistical analysis description
    With regard to secondary objectives, if the variables were quantitative, tests identical to those used for the main criterion were implemented. For qualitative variables, the two groups were compared using Fisher's exact test. Relative risk (RR) and 95% confidence interval (IC 95%) were also estimated.
    Comparison groups
    Exacyl group v Control group
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 = 0.58
    Method
    		 Student test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.52
         upper limit
    		 0.37
    Notes
    [6] - No comment.
    Statistical analysis title
    		 Hemoglobin at Day 1
    Statistical analysis description
    With regard to secondary objectives, if the variables were quantitative, tests identical to those used for the main criterion were implemented. For qualitative variables, the two groups were compared using Fisher's exact test. Relative risk (RR) and 95% confidence interval (IC 95%) were also estimated.
    Comparison groups
    Exacyl group v Control group
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.15
    Method
    		 Student test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.62
         upper limit
    		 0.22
    Notes
    [7] - No comment.
    Statistical analysis title
    		 "Corrected" hemoglobin at Day 1
    Statistical analysis description
    With regard to secondary objectives, if the variables were quantitative, tests identical to those used for the main criterion were implemented. For qualitative variables, the two groups were compared using Fisher's exact test. Relative risk (RR) and 95% confidence interval (IC 95%) were also estimated.
    Comparison groups
    Exacyl group v Control group
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.38
    Method
    		 Student test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.61
         upper limit
    		 0.24
    Notes
    [8] - No comment.
    Statistical analysis title
    		 Hemoglobin at Day 4
    Statistical analysis description
    With regard to secondary objectives, if the variables were quantitative, tests identical to those used for the main criterion were implemented. For qualitative variables, the two groups were compared using Fisher's exact test. Relative risk (RR) and 95% confidence interval (IC 95%) were also estimated.
    Comparison groups
    Exacyl group v Control group
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.23
    Method
    		 Student test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.54
         upper limit
    		 0.28
    Notes
    [9] - No comment.
    Statistical analysis title
    		 "Corrected" hemoglobin at Day 4
    Statistical analysis description
    With regard to secondary objectives, if the variables were quantitative, tests identical to those used for the main criterion were implemented. For qualitative variables, the two groups were compared using Fisher's exact test. Relative risk (RR) and 95% confidence interval (IC 95%) were also estimated.
    Comparison groups
    Exacyl group v Control group
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 = 0.54
    Method
    		 Student test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.55
         upper limit
    		 0.29
    Notes
    [10] - No comment.
    Statistical analysis title
    		 Loss of hemoglobin at D4 compared to pre-operative
    Statistical analysis description
    With regard to secondary objectives, if the variables were quantitative, tests identical to those used for the main criterion were implemented. For qualitative variables, the two groups were compared using Fisher's exact test. Relative risk (RR) and 95% confidence interval (IC 95%) were also estimated.
    Comparison groups
    Exacyl group v Control group
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.44
    Method
    		 Student test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2
         upper limit
    		 0.45
    Notes
    [11] - No comment.

    Secondary: Transfusion between the beginning of the surgery and day 4

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    End point title
    		 Transfusion between the beginning of the surgery and day 4
    End point description
    Transfusion between the beginning of the surgery and day 4.
    End point type
    Secondary
    End point timeframe
    Between the beginning of the surgery and day 4.
    End point values
    		 Exacyl group Control group Final analysis
    Number of subjects analysed
    84
    83
    167
    Units: Number
        Since the beginning ot the surgery until day 4
    1
    1
    2
        Beginning of the surgery until - end of study
    3
    3
    6
        During the surgery
    0
    0
    0
        Since the recovery room until 24 hours
    0
    1
    1
        Since 24 hours until Day 4
    1
    0
    1
        Since Day 4 until the exit from the hospital
    1
    1
    2
        Exit from the hospital until- End of the follow-up
    1
    2
    3
    Statistical analysis title
    		 Since the beginning of the surgery an day 4
    Statistical analysis description
    At least one transfusion since the beginnig of the surgery and post-operative day 4. With regard to secondary objectives, if the variables were quantitative, tests identical to those used for the main criterion were implemented. For qualitative variables, the two groups were compared using Fisher's exact test. Relative risk (RR) and 95% confidence interval (IC 95%) were also estimated.
    Comparison groups
    Exacyl group v Control group
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 = 1
    Method
    		 Chi-squared
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.06
         upper limit
    		 15.5
    Notes
    [12] - No comment.
    Statistical analysis title
    		 Beginning of the surgery until - end of study
    Statistical analysis description
    At least one transfusion since the beginning of the surgery until the end of the study. With regard to secondary objectives, if the variables were quantitative, tests identical to those used for the main criterion were implemented. For qualitative variables, the two groups were compared using Fisher's exact test. Relative risk (RR) and 95% confidence interval (IC 95%) were also estimated.
    Comparison groups
    Exacyl group v Control group
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 = 1
    Method
    		 Chi-squared
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.21
         upper limit
    		 4.76
    Notes
    [13] - No comment.
    Statistical analysis title
    		 During the surgery
    Statistical analysis description
    Transfusion during the surgey. With regard to secondary objectives, if the variables were quantitative, tests identical to those used for the main criterion were implemented. For qualitative variables, the two groups were compared using Fisher's exact test. Relative risk (RR) and 95% confidence interval (IC 95%) were also estimated
    Comparison groups
    Control group v Exacyl group
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 Since the recovery room until 24 hours
    Statistical analysis description
    Transfusion since the recovery room until 24 hours. With regard to secondary objectives, if the variables were quantitative, tests identical to those used for the main criterion were implemented. For qualitative variables, the two groups were compared using Fisher's exact test. Relative risk (RR) and 95% confidence interval (IC 95%) were also estimated.
    Comparison groups
    Exacyl group v Control group
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 Since 24 hours until Day 4
    Statistical analysis description
    Transfusion since 24 hours until Day 4. With regard to secondary objectives, if the variables were quantitative, tests identical to those used for the main criterion were implemented. For qualitative variables, the two groups were compared using Fisher's exact test. Relative risk (RR) and 95% confidence interval (IC 95%) were also estimated.
    Comparison groups
    Exacyl group v Control group
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 Since Day 4 until the exit from the hospital
    Statistical analysis description
    Transfusion since Day 4 until the exit from the hospital. With regard to secondary objectives, if the variables were quantitative, tests identical to those used for the main criterion were implemented. For qualitative variables, the two groups were compared using Fisher's exact test. Relative risk (RR) and 95% confidence interval (IC 95%) were also estimated.
    Comparison groups
    Exacyl group v Control group
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Chi-squared
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.06
         upper limit
    		 15.5
    Statistical analysis title
    		 Exit from the hospital until- End of the follow-up
    Statistical analysis description
    Transfusion since the exit from the hospital until the end of the follow-up. With regard to secondary objectives, if the variables were quantitative, tests identical to those used for the main criterion were implemented. For qualitative variables, the two groups were compared using Fisher's exact test. Relative risk (RR) and 95% confidence interval (IC 95%) were also estimated.
    Comparison groups
    Exacyl group v Control group
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.62
    Method
    		 Chi-squared
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.05
         upper limit
    		 5.34

    Secondary: Incidence of symptomatic thromboembolic events and death at 6 weeks

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    End point title
    		 Incidence of symptomatic thromboembolic events and death at 6 weeks
    End point description
    The endpoint is a composite endpoint consisting venous events (deep vein thrombosis or pulmonary embolism), arterial events (acute coronary syndrome, stroke ischemic acute lower limb ischemia) and death from all causes.
    End point type
    Secondary
    End point timeframe
    At 6 weeks after the surgery.
    End point values
    		 Exacyl group Control group Final analysis
    Number of subjects analysed
    84
    83
    167
    Units: Number
        symptomatic thromboembolic events-death at 6 weeks
    0
    2
    2
        thromboembolic venous events at 6 weeks
    0
    2
    2
        thromboembolic aterial events at 6 weeks
    0
    0
    0
        Death at 6 weeks
    0
    0
    0
    Statistical analysis title
    		 Symptomatic thromboembolic events and death
    Statistical analysis description
    Symptomatic thromboembolic events and death at 6 weeks. With regard to secondary objectives, if the variables were quantitative, tests identical to those used for the main criterion were implemented. For qualitative variables, the two groups were compared using Fisher's exact test. Relative risk (RR) and 95% confidence interval (IC 95%) were also estimated.
    Comparison groups
    Exacyl group v Control group
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 = 0.25
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [14] - No comment.
    Statistical analysis title
    		 Venous thromboembolic events at 6 weeks
    Statistical analysis description
    With regard to secondary objectives, if the variables were quantitative, tests identical to those used for the main criterion were implemented. For qualitative variables, the two groups were compared using Fisher's exact test. Relative risk (RR) and 95% confidence interval (IC 95%) were also estimated.
    Comparison groups
    Exacyl group v Control group
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 = 0.25
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [15] - No comment.

    Secondary: The postoperative blood loss in the surgical drain until the 24th postoperative hour

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    End point title
    		 The postoperative blood loss in the surgical drain until the 24th postoperative hour
    End point description
    To evaluate the effect of blood levels of blood loss, the criterion will be the postoperative blood loss measured in the surgical drain placed intraarticular until the 24th postoperative hour.
    End point type
    Secondary
    End point timeframe
    Since the surgery until the 24th post-operative hour.
    End point values
    		 Exacyl group Control group Final analysis
    Number of subjects analysed
    84
    83
    167
    Units: millilitre(s)
    median (inter-quartile range (Q1-Q3))
        Blood loss in the drain at 1 hour
    60.0 (35.0 to 100.0)
    60.0 (30.0 to 80.0)
    60.0 (30.0 to 90.0)
        Blood loss in the drain at 2 hours
    80.0 (40.0 to 125.0)
    80.0 (40.0 to 100.0)
    80.0 (40.0 to 120.0)
        Blood loss in the drain at 3 hours
    90.0 (50.0 to 150.0)
    100.0 (50.0 to 120.0)
    100.0 (50.0 to 140.0)
        Blood loss in the drain at 4 hours
    100.0 (60.0 to 170.0)
    110.0 (50.0 to 150.0)
    110.0 (60.0 to 160.0)
        Blood loss in the drain at 8 hours
    150.0 (100.0 to 235.0)
    155.0 (90.0 to 220.0)
    150.0 (100.0 to 230.0)
        Blood loss in the drain at 12 hours
    180.0 (120.0 to 270.0)
    200.0 (100.0 to 270.0)
    190.0 (120.0 to 270.0)
        Blood loss in the drain at 16 hours
    205.0 (140.0 to 310.0)
    230.0 (130.0 to 300.0)
    210.0 (140.0 to 310.0)
        Blood loss in the drain at 20 hours
    230.0 (170.0 to 350.0)
    260.0 (150.0 to 340.0)
    250.0 (170.0 to 350.0)
        Blood loss in the drain at 24 hours
    265.0 (200.0 to 390.0)
    300.0 (170.0 to 390.0)
    290.0 (190.0 to 390.0)
    Statistical analysis title
    		 Blood loss in the drain at 1 hour
    Statistical analysis description
    With regard to secondary objectives, if the variables were quantitative, tests identical to those used for the main criterion were implemented. For qualitative variables, the two groups were compared using Fisher's exact test. Relative risk (RR) and 95% confidence interval (IC 95%) were also estimated.
    Comparison groups
    Exacyl group v Control group
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [16]
    P-value
    		 = 0.34
    Method
    		 Logrank
    Parameter type
    		 Mean difference (final values)
    Point estimate
    9.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.98
         upper limit
    		 24.55
    Notes
    [16] - No comment.
    Statistical analysis title
    		 Blood loss in the drain at 2 hours
    Statistical analysis description
    With regard to secondary objectives, if the variables were quantitative, tests identical to those used for the main criterion were implemented. For qualitative variables, the two groups were compared using Fisher's exact test. Relative risk (RR) and 95% confidence interval (IC 95%) were also estimated.
    Comparison groups
    Exacyl group v Control group
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 = 0.64
    Method
    		 Logrank
    Parameter type
    		 Mean difference (final values)
    Point estimate
    7.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.55
         upper limit
    		 24.86
    Notes
    [17] - No comment.
    Statistical analysis title
    		 Blood loss in the drain at 3 hours
    Statistical analysis description
    With regard to secondary objectives, if the variables were quantitative, tests identical to those used for the main criterion were implemented. For qualitative variables, the two groups were compared using Fisher's exact test. Relative risk (RR) and 95% confidence interval (IC 95%) were also estimated.
    Comparison groups
    Exacyl group v Control group
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6
    Method
    		 Logrank
    Parameter type
    		 Mean difference (final values)
    Point estimate
    8.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.77
         upper limit
    		 28.45
    Statistical analysis title
    		 Blood loss in the drain at 4 hours
    Statistical analysis description
    With regard to secondary objectives, if the variables were quantitative, tests identical to those used for the main criterion were implemented. For qualitative variables, the two groups were compared using Fisher's exact test. Relative risk (RR) and 95% confidence interval (IC 95%) were also estimated.
    Comparison groups
    Exacyl group v Control group
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.58
    Method
    		 Logrank
    Parameter type
    		 Mean difference (final values)
    Point estimate
    11.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.68
         upper limit
    		 33.5
    Statistical analysis title
    		 Blood loss in the drain at 8 hours
    Statistical analysis description
    With regard to secondary objectives, if the variables were quantitative, tests identical to those used for the main criterion were implemented. For qualitative variables, the two groups were compared using Fisher's exact test. Relative risk (RR) and 95% confidence interval (IC 95%) were also estimated.
    Comparison groups
    Exacyl group v Control group
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.95
    Method
    		 Logrank
    Parameter type
    		 Mean difference (final values)
    Point estimate
    6.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22.03
         upper limit
    		 35.4
    Statistical analysis title
    		 Blood loss in the drain at 12 hours
    Statistical analysis description
    With regard to secondary objectives, if the variables were quantitative, tests identical to those used for the main criterion were implemented. For qualitative variables, the two groups were compared using Fisher's exact test. Relative risk (RR) and 95% confidence interval (IC 95%) were also estimated.
    Comparison groups
    Exacyl group v Control group
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [18]
    P-value
    		 = 0.92
    Method
    		 Logrank
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -31.01
         upper limit
    		 36.12
    Notes
    [18] - No comment.
    Statistical analysis title
    		 Blood loss in the drain at 16 hours
    Statistical analysis description
    With regard to secondary objectives, if the variables were quantitative, tests identical to those used for the main criterion were implemented. For qualitative variables, the two groups were compared using Fisher's exact test. Relative risk (RR) and 95% confidence interval (IC 95%) were also estimated.
    Comparison groups
    Exacyl group v Control group
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 = 0.77
    Method
    		 Logrank
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -39.9
         upper limit
    		 34.13
    Notes
    [19] - No comment.
    Statistical analysis title
    		 Blood loss in the drain at 20 hours
    Statistical analysis description
    With regard to secondary objectives, if the variables were quantitative, tests identical to those used for the main criterion were implemented. For qualitative variables, the two groups were compared using Fisher's exact test. Relative risk (RR) and 95% confidence interval (IC 95%) were also estimated.
    Comparison groups
    Exacyl group v Control group
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [20]
    P-value
    		 = 0.99
    Method
    		 Logrank
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -38.08
         upper limit
    		 42.78
    Notes
    [20] - No comment.
    Statistical analysis title
    		 Blood loss in the drain at 24 hours
    Statistical analysis description
    With regard to secondary objectives, if the variables were quantitative, tests identical to those used for the main criterion were implemented. For qualitative variables, the two groups were compared using Fisher's exact test. Relative risk (RR) and 95% confidence interval (IC 95%) were also estimated.
    Comparison groups
    Exacyl group v Control group
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [21]
    P-value
    		 = 0.89
    Method
    		 Logrank
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -41.03
         upper limit
    		 45.55
    Notes
    [21] - No comment.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    At 6 weeks. The investigator was required to report to the promoter: - any unexpected SAE within 24 hours of its appearance, - any SAE expected within 8 days of its appearance. whether or not this SAE was related to the experimental drug.
    Adverse event reporting additional description
    Any serious adverse event/effect (SAE) contained in the Summary of product characteristics was considered as an expected SAE. The following events were also considered as expected SAE: - hemorrhage, hematoma regardless of the site - venous or arterial thromboembolic complication - infectious complications - post-op operative complication
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    Exacyl group
    Reporting group description
    		 Non-serious adverse events: A total of 22 patients (13.2%) had at least one non-serious adverse event, 12 (14.3%) in the Exacyl group . Serious adverse events: A total of 6 patients (3.6%) had at least one serious adverse event (SAE), 2 (2.4%) in the Exacyl group . In this group one patient presented a vascular condition and an other one presented gastrointestinal problems.

    Reporting group title
    Placebo group
    Reporting group description
    		 Non-serious adverse events: A total of 22 patients (13.2%) had at least one non-serious adverse event, 10 (12.0%) in the placebo group. Serious adverse events: A total of 6 patients (3.6%) had at least one serious adverse event (SAE), 4 (4.8%) in the placebo group. In this group: - two patients presented a vascular condition - one patient presented a heart condition - and an other one presented musculoskeletal and connective tissue disorders.

    Serious adverse events
    		 Exacyl group Placebo group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 84 (2.38%)
    4 / 83 (4.82%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    vascular condition
    Additional description: - Stitches hemorrhage for the patient of the Exacyl group - Hemorrhagic duodenal ulcer for one of the patients of the placebo group - Deep Vein Thrombosis for the other patient of the placebo group
         subjects affected / exposed
    1 / 84 (1.19%)
    2 / 83 (2.41%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    heart condition
    Additional description: Bradycardia
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    gastrointestinal problems
    Additional description: Obstruction of the small intestine
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 83 (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
    musculoskeletal and connective tissue disorders
    Additional description: mixed infection
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1.19%
    Non-serious adverse events
    		 Exacyl group Placebo group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 84 (14.29%)
    10 / 83 (12.05%)
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 84 (1.19%)
    4 / 83 (4.82%)
         occurrences all number
    5
    5
    Surgical and medical procedures
    Wall hematoma
         subjects affected / exposed
    8 / 84 (9.52%)
    6 / 83 (7.23%)
         occurrences all number
    14
    14
    Complication of the prosthesis
         subjects affected / exposed
    3 / 84 (3.57%)
    2 / 83 (2.41%)
         occurrences all number
    5
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Oct 2013
    This amendment is a substantial change in the protocol because it concerns: - The accuracy of the second sample for the dosage of tranexamic acid, which will be 20 minutes after the Exacyl bolus. - The accuracy of the timing of the samples for dosages of tranexamic acid and hemoglobin at the end of the procedure, which will be done after plugging in the drains - The accuracy of the time of the 4th sample for the dosage of tranexamic acid, which will take place 3 hours after the exacyl bolus - The accuracy of the time of the 5th and final sample for the dosage of tranexamic acid, which will take place at the end of the infusion of Exacyl or placebo
    16 Jun 2014
    This amendment is a substantial change in the protocol because it concerns: - the modification of a non-inclusion criterion. Indeed, following an update of the Summary of characteristics of the Exacyl , the contraindications have been modified, including the "history of confirmed arterial or venous thrombotic accident" which has become "Acute Venous or Arterial Thrombosis". This criterion has therefore been updated in the protocol. - The addition of 2 co-investigators: o Dr Pierre LAMBERT o Dr Nicolas BARBE - The addition of an experimenter: Julien LANOISELE
    09 Feb 2015
    This amendment is a substantial change in the protocol because it concerns: - The addition of a co-investigator: o Dr Jean-Yves BIEN
    07 Sep 2015
    This amendment constitutes a substantial change in the protocol as it relates to the extension of the inclusion period for a period of 1 year, until 31 August 2016, bringing the end of the follow-up to 31 October 2016. The purpose of this extension is to allow for the inclusion of all planned patients. To date 120 patients have been included out of the 168 planned.

    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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