<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03023189</url>
  </required_header>
  <id_info>
    <org_study_id>P150959</org_study_id>
    <secondary_id>2016-002677-35</secondary_id>
    <nct_id>NCT03023189</nct_id>
  </id_info>
  <brief_title>Efficacity and Safety of Tranexamic Acid in Cirrhotic Patients Presenting With Acute Upper Gastrointestinal Bleeding</brief_title>
  <acronym>EXARHOSE</acronym>
  <official_title>Efficacy and Safety of Early Administration of Tranexamic Acid in Cirrhotic Patients Presenting With Acute Upper Gastrointestinal Bleeding: a Multicenter, Randomized, Double Blind, Placebo-controlled Trial (Modified by amendment1)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Assistance Publique - Hôpitaux de Paris</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Assistance Publique - Hôpitaux de Paris</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Upper digestive bleeding. Upper gastrointestinal haemorrhage is a common cause of&#xD;
      decompensated cirrhosis and is associated with a high mortality rate among cirrhotic&#xD;
      patients. Its leading cause is the rupture of gastro-esophageal varices due to portal&#xD;
      hypertension. In cirrhotic patients, the management of acute gastrointestinal haemorrhage is&#xD;
      challenging as they often present with coagulation (or haemostasis abnormalities)&#xD;
      abnormalities such as hyperfibrinolysis, especially when the cirrhosis is decompensated.&#xD;
      Beyond life support measures, therapeutic modalities of upper gastrointestinal bleeding rely&#xD;
      on both endoscopic and pharmacological interventions. Tranexamic acid (TA) is an&#xD;
      antifibrinolytic that may help control the bleeding in this setting, as it showed an&#xD;
      unquestionable benefit in other indications. TA has previously been studied in both upper&#xD;
      gastrointestinal haemorrhage from any causes and in liver transplantation of cirrhotic&#xD;
      patients. However, there is a lack of data to conclude on its effectiveness (or efficiency)&#xD;
      in the early treatment of acute bleeding in cirrhotic patients.&#xD;
&#xD;
      Investigators hypothesize that, when given early, TA would be beneficial for cirrhotic&#xD;
      patients presenting with acute upper gastrointestinal haemorrhage , by controlling the&#xD;
      haemorrhage, avoiding rebleeding episodes and reducing mortality within 5 days after its&#xD;
      administration. Moreover, TA could prevent early cirrhosis complications (such as hepatic&#xD;
      encephalopathy, sepsis and ascites liquid infection, hepatorenal syndrome), could reduce&#xD;
      indications to transjugular portosystemic shunt (TIPS), shorten the length of stay in&#xD;
      intensive care unit and the length of hospitalization, and decrease late relapses and&#xD;
      one-year mortality.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Acute Upper gastrointestinal haemorrhage (UGIH) is frequent, with an estimated annual&#xD;
      incidence of 150/100 000 in France. Its second etiology is the rupture of portal&#xD;
      hypertension-related gastro-esophageal varices, accounting for 20 % of the patients and&#xD;
      responsible for more than 50 % of the hospitalizations in intensive care unit (ICU) for UGIH.&#xD;
&#xD;
      In cirrhotic patients, variceal bleeding is the main cause of UGIH (over 70 %) and death (30&#xD;
      %), which occurs in the most severe patients (Child-Pugh score B or C and/or high MELD score,&#xD;
      and high levels of portal hypertension).&#xD;
&#xD;
      Acute UGIH is directly responsible for 50 % of the deaths, either because it remains&#xD;
      uncontrolled during the acute phase (within 5 days), or because of early relapses (within 6&#xD;
      weeks). Every episode of acute UGIH worsens the middle and long-term vital prognosis: about&#xD;
      60 % of the patients present with UGIH recurrence within one year and the survival rate is&#xD;
      only 30 % 3 years after the first episode.&#xD;
&#xD;
      Moreover, acute UGIH is a triggering factor for several severe cirrhosis-specific&#xD;
      complications (such as hepatic encephalopathy, sepsis and ascites liquid infection,&#xD;
      hepatorenal syndrome), which themselves lead to high mortality rates. Despite the improvement&#xD;
      of preventive, diagnostic and therapeutic strategies, UGIH remains stable in France.&#xD;
&#xD;
      The haemostasis of cirrhotic patients is often abnormal at baseline : thrombopenia, decrease&#xD;
      of factors II, V, VII, IX, X and XI, decrease of fibrinolytic proteins, increase of factor&#xD;
      VIII and spontaneous fibrinolysis. When compensated, the cirrhotic's haemostasis remains&#xD;
      globally preserved, due to the balance of pro and anticoagulant alterations.&#xD;
&#xD;
      Every cause of cirrhosis decompensation, such as acute PHT-UGIH, can increase hemostatic&#xD;
      disorders, leading to hyperfibrinolysis. This could slow down or inhibit the clotting, thus&#xD;
      disrupting pharmacological control of acute UGIH.&#xD;
&#xD;
      TA could be efficient in acute UGIH of cirrhotic patients. It is a simple antifibrinolytic&#xD;
      which showed clinical benefits on haemorrhage and/or mortality in several other indications&#xD;
      (surgical, obstetrical and traumatic). It is now widely used according to recommendations.&#xD;
&#xD;
      Early administration of TA seems to be beneficial in UGIH haemorrhage. Despite theoretical&#xD;
      efficiency, 4 recent Cochrane meta-analysis concluded to the lack of significant data (poor&#xD;
      overall trials quality). The benefit of the use of TA in acute UGIH (and acute PHT-UGIH)&#xD;
      remains uncertain.&#xD;
&#xD;
      At this day, TA has still not been studied in acute UGIH of cirrhotic patients, although it&#xD;
      showed benefits on blood transfusion's requirements and on haemorrhagic complications during&#xD;
      liver transplantation (for which cirrhosis most frequent cause).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">April 3, 2017</start_date>
  <completion_date type="Anticipated">April 2020</completion_date>
  <primary_completion_date type="Anticipated">April 2019</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>The main outcome is a composite criterion and includes: control on acute bleeding, absence of re-bleeding episodes at day 5 and absence of death at day 5 (modified by amendment 1)</measure>
    <time_frame>5 days after randomisation</time_frame>
    <description>Specifically, the composite criterion is defined by all the following criteria:&#xD;
Immediate control of the hemorrhage after initial patient management using splanchnic vasoconstrictors and/or proton pump inhibitors, potentially including volume expander, transfusion and/or prescription of vasopressor amines :&#xD;
Achievement of the transfusion target (Hb ≥ 7 g/dL) 24 hours after initial patient management and then until day 5&#xD;
Absence of initiation or increase in vasopressor amines, until day 5&#xD;
Absence of recourse to the transfusion of 2 or more red cells packs within 24h to maintain the transfusion target (Hb ≥ 7 g/dL)&#xD;
Absence of persistence or evolution towards haemorrhagic shock (systolic blood pressure &lt; 100 mmHg and/or mean arterial pressure &lt; 60 mmHg and/or heart rate &gt; 100 bpm)&#xD;
Absence of re-bleeding episodes at day 5, assessed by the medical team on the bases of clinical, biological or endoscopic elements&#xD;
Absence of death at day 5</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Control of the bleeding</measure>
    <time_frame>Within 5 days after randomisation</time_frame>
    <description>At least 1 criterion present :&#xD;
Persistence of the bleeding (regardless of the volume), 2 hours after initiation of medical or endoscopic treatment&#xD;
And/Or blood transfusion needed within 24 hours after treatment initiation (≥ 2 red cells units)&#xD;
And/Or hemorrhagic shock installation (systolic blood pressure &lt; 100 mmHg and/or mean arterial pressure &lt; 60 mmHg and/or heart rate &gt; 100 bpm)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Re-bleeding episodes</measure>
    <time_frame>At day 6, day 28, day 42, 3 months, 6 months and 1 year after randomisation</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Death</measure>
    <time_frame>At day 6, day 28, day 42, 3 months, 6 months and 1 year after randomisation</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fluid infusion volume (in mL)</measure>
    <time_frame>At day 6, day 28 and day 42 after randomisation</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood transfusion volume (in mL)</measure>
    <time_frame>At day 6, day 28 and day 42 after randomisation</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood transfusion quantity (number of units)</measure>
    <time_frame>At day 6, day 28 and day 42 after randomisation</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Nature of blood transfusion: - Red cells units - Platelets units - Fresh frozen plasma - Fibrinogen - Other</measure>
    <time_frame>At day 6, day 28 and day 42, after randomisation</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>TIPS procedure (in Child-Pugh B patients)</measure>
    <time_frame>At day 6, day 28, day 42 after randomisation</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Visceral and systemic complications</measure>
    <time_frame>At day 6, day 28 and day 42, after randomisation (or until discharge)</time_frame>
    <description>Complications, defined as:&#xD;
Acute organ failure (using CLIF-C ACLF and CLIF-SOFA scores)&#xD;
Hepatic encephalopathy&#xD;
Hepatic failure&#xD;
Hepatorenal syndrome&#xD;
Renal failure (using grades 2 and 3 of the KDIGO classification)&#xD;
Sepsis&#xD;
Ascites liquid infection</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Need for organ substitution - Renal replacement therapy (dialysis) - Liver replacement therapy - Mechanical ventilation</measure>
    <time_frame>At day 6, day 28 and day 42, after randomisation (or until discharge)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Liver transplantation</measure>
    <time_frame>At day 6, day 28, day 42, 3 months, 6 months and 1 year after randomisation</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Length of stay in ICU (in days)</measure>
    <time_frame>At day 6, day 28, day 42, 3 months, 6 months and 1 year after randomisation</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of hospitalization (in days)</measure>
    <time_frame>At day 6, day 28, day 42, 3 months, 6 months and 1 year after randomisation</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of participants with treatment-related adverse events as assessed by the ANSM notice of Exacyl®</measure>
    <time_frame>up to 5 days</time_frame>
    <description>Adverse events as assessed by the ANSM notice of Exacyl® are :&#xD;
Allergy&#xD;
Thrombotic events&#xD;
Seizures&#xD;
Acute renal failure (KDIGO grades 2 and 3)&#xD;
Death&#xD;
Or any other adverse event suspected to be treatment-related&#xD;
Adverse effects will be systematically searched for and collected in the electronic Case Report Form (eCRF) during the acute phase (within 5 days after randomization), as assessed by the AP-HP notification form. When present, investigators will have to send a notification to the promoter (by fax). Patients with severe adverse effects (leading to death, life-threatening condition, hospitalization and pursuit of hospitalization, incapacity or handicap, congenital malformation) will be followed until disappearance of these. Every document related to the patient during the protocol should be transmitted to the promoter. Investigators are supposed to answer every inquiry of the promoter.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Delay between the beginning of the haemorrhage and the initiation of the AT treatment</measure>
    <time_frame>At day 1</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">500</enrollment>
  <condition>Upper Digestive Bleeding</condition>
  <condition>Cirrhosis</condition>
  <arm_group>
    <arm_group_label>Tranexamic acid</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>At randomisation : loading dose of 1g of intravenous tranexamic acid for 10 min, immediately followed by an intravenous infusion of 3g of TA over 24h</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>At randomisation : loading dose of 10 mL of intravenous isotonic saline for 10 min, immediately followed by an intravenous infusion of 30 mL of isotonic saline over 24h</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tranexamic acid</intervention_name>
    <description>At randomisation : loading dose of 1g of intravenous tranexamic acid for 10 min, immediately followed by an intravenous infusion of 3g of TA over 24h.&#xD;
Total dose : 4 g of TA</description>
    <arm_group_label>Tranexamic acid</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>At randomisation : loading dose of 10 mL of intravenous isotonic saline for 10 min, immediately followed by an intravenous infusion of 30 mL of isotonic saline over 24h Total dose : 40 mL of Placebo</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria (modified by amendment1)&#xD;
&#xD;
          -  Age ≥ 18&#xD;
&#xD;
          -  Patient treated by a prehospital physician-staffed SMUR team, a firefighter&#xD;
             physician-staffed ambulance (ARBSPP), an hospital EMS or an ICU&#xD;
&#xD;
          -  Acute upper digestive bleeding (&lt; 24h) in the shape of hematemesis, described either&#xD;
             by the physician, the patient, a relative or a member of the medical team&#xD;
&#xD;
          -  Known or suspected cirrhosis (based on clinical/biological/radiographic/anamnestic&#xD;
             data)&#xD;
&#xD;
          -  Affiliated or recipient of the French social security&#xD;
&#xD;
          -  Written consent (or under emergency procedures)&#xD;
&#xD;
        Exclusion Criteria (modified by amendment1)&#xD;
&#xD;
          -  Known ongoing pregnancy or breastfeeding&#xD;
&#xD;
          -  TA already given (if inter-hospital transfer)&#xD;
&#xD;
          -  Endoscopy already performed for the current haemorrhagic episode&#xD;
&#xD;
          -  Hospitalization for over 24h in an intensive care unit or a routine care unit&#xD;
&#xD;
          -  Exclusive lower digestive bleeding or melena only&#xD;
&#xD;
          -  Patient in cardiac arrest at the arrival of the prehospital medical team, whether&#xD;
             recovered or not&#xD;
&#xD;
          -  Patient already randomised once in EXARHOSE study&#xD;
&#xD;
          -  TA Counter-indications&#xD;
&#xD;
               -  creatininemia &gt; 500 μmol/L or documented clearance &lt; 30 mL/min&#xD;
&#xD;
               -  documented ongoing CIVD (prior to UDB)&#xD;
&#xD;
               -  ongoing seizures&#xD;
&#xD;
               -  ongoing arterial or venous thrombosis&#xD;
&#xD;
               -  allergy&#xD;
&#xD;
          -  Known participation of the patient to another therapeutic study&#xD;
&#xD;
          -  Known linguistic inability of the patient to understand the study&#xD;
&#xD;
          -  Patient under known guardianship&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Matthieu HEIDET</last_name>
    <role>Principal Investigator</role>
    <affiliation>Assistance Publique - Hôpitaux de Paris</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Matthieu HEIDET, MD</last_name>
    <email>matthieu.heidet@aphp.fr</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Roland AMATHIEU, MD</last_name>
    <email>roland.amathieu@aphp.fr</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Jean Verdier Hospital</name>
      <address>
        <city>Bondy</city>
        <zip>93140</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Roland Amathieu, MD</last_name>
      <email>roland.amathieu@aphp.fr</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Henri Mondor Hospital</name>
      <address>
        <city>Creteil</city>
        <zip>94010</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Matthieu HEIDET, MD</last_name>
      <email>matthieu.heidet@aphp.fr</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Marc Jacquet Hospital</name>
      <address>
        <city>Melun</city>
        <zip>77000</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Line JACOB, MD</last_name>
      <email>line.jacob@ch-melun.fr</email>
    </contact>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>April 2018</verification_date>
  <study_first_submitted>December 23, 2016</study_first_submitted>
  <study_first_submitted_qc>January 13, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 18, 2017</study_first_posted>
  <last_update_submitted>April 10, 2018</last_update_submitted>
  <last_update_submitted_qc>April 10, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">April 11, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Upper digestive bleeding</keyword>
  <keyword>Haemorrhage</keyword>
  <keyword>Cirrhosis</keyword>
  <keyword>Antifibrinolytic</keyword>
  <keyword>Tranexamic acid</keyword>
  <keyword>Emergency</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Gastrointestinal Hemorrhage</mesh_term>
    <mesh_term>Hemorrhage</mesh_term>
    <mesh_term>Fibrosis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tranexamic Acid</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03023189
org study id: P150959
secondary id: 2016-002677-35
nct id: NCT03023189
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Upper digestive bleeding. Upper gastrointestinal haemorrhage is a common cause of
      decompensated cirrhosis and is associated with a high mortality rate among cirrhotic
      patients. Its leading cause is the rupture of gastro-esophageal varices due to portal
      hypertension. In cirrhotic patients, the management of acute gastrointestinal haemorrhage is
      challenging as they often present with coagulation (or haemostasis abnormalities)
      abnormalities such as hyperfibrinolysis, especially when the cirrhosis is decompensated.
      Beyond life support measures, therapeutic modalities of upper gastrointestinal bleeding rely
      on both endoscopic and pharmacological interventions. Tranexamic acid (TA) is an
      antifibrinolytic that may help control the bleeding in this setting, as it showed an
      unquestionable benefit in other indications. TA has previously been studied in both upper
      gastrointestinal haemorrhage from any causes and in liver transplantation of cirrhotic
      patients. However, there is a lack of data to conclude on its effectiveness (or efficiency)
      in the early treatment of acute bleeding in cirrhotic patients.

      Investigators hypothesize that, when given early, TA would be beneficial for cirrhotic
      patients presenting with acute upper gastrointestinal haemorrhage , by controlling the
      haemorrhage, avoiding rebleeding episodes and reducing mortality within 5 days after its
      administration. Moreover, TA could prevent early cirrhosis complications (such as hepatic
      encephalopathy, sepsis and ascites liquid infection, hepatorenal syndrome), could reduce
      indications to transjugular portosystemic shunt (TIPS), shorten the length of stay in
      intensive care unit and the length of hospitalization, and decrease late relapses and
      one-year mortality.
Acute Upper gastrointestinal haemorrhage (UGIH) is frequent, with an estimated annual
      incidence of 150/100 000 in France. Its second etiology is the rupture of portal
      hypertension-related gastro-esophageal varices, accounting for 20 % of the patients and
      responsible for more than 50 % of the hospitalizations in intensive care unit (ICU) for UGIH.

      In cirrhotic patients, variceal bleeding is the main cause of UGIH (over 70 %) and death (30
      %), which occurs in the most severe patients (Child-Pugh score B or C and/or high MELD score,
      and high levels of portal hypertension).

      Acute UGIH is directly responsible for 50 % of the deaths, either because it remains
      uncontrolled during the acute phase (within 5 days), or because of early relapses (within 6
      weeks). Every episode of acute UGIH worsens the middle and long-term vital prognosis: about
      60 % of the patients present with UGIH recurrence within one year and the survival rate is
      only 30 % 3 years after the first episode.

      Moreover, acute UGIH is a triggering factor for several severe cirrhosis-specific
      complications (such as hepatic encephalopathy, sepsis and ascites liquid infection,
      hepatorenal syndrome), which themselves lead to high mortality rates. Despite the improvement
      of preventive, diagnostic and therapeutic strategies, UGIH remains stable in France.

      The haemostasis of cirrhotic patients is often abnormal at baseline : thrombopenia, decrease
      of factors II, V, VII, IX, X and XI, decrease of fibrinolytic proteins, increase of factor
      VIII and spontaneous fibrinolysis. When compensated, the cirrhotic's haemostasis remains
      globally preserved, due to the balance of pro and anticoagulant alterations.

      Every cause of cirrhosis decompensation, such as acute PHT-UGIH, can increase hemostatic
      disorders, leading to hyperfibrinolysis. This could slow down or inhibit the clotting, thus
      disrupting pharmacological control of acute UGIH.

      TA could be efficient in acute UGIH of cirrhotic patients. It is a simple antifibrinolytic
      which showed clinical benefits on haemorrhage and/or mortality in several other indications
      (surgical, obstetrical and traumatic). It is now widely used according to recommendations.

      Early administration of TA seems to be beneficial in UGIH haemorrhage. Despite theoretical
      efficiency, 4 recent Cochrane meta-analysis concluded to the lack of significant data (poor
      overall trials quality). The benefit of the use of TA in acute UGIH (and acute PHT-UGIH)
      remains uncertain.

      At this day, TA has still not been studied in acute UGIH of cirrhotic patients, although it
      showed benefits on blood transfusion's requirements and on haemorrhagic complications during
      liver transplantation (for which cirrhosis most frequent cause).
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: The main outcome is a composite criterion and includes: control on acute bleeding, absence of re-bleeding episodes at day 5 and absence of death at day 5 (modified by amendment 1)
time frame: 5 days after randomisation
description: Specifically, the composite criterion is defined by all the following criteria:
Immediate control of the hemorrhage after initial patient management using splanchnic vasoconstrictors and/or proton pump inhibitors, potentially including volume expander, transfusion and/or prescription of vasopressor amines :
Achievement of the transfusion target (Hb ≥ 7 g/dL) 24 hours after initial patient management and then until day 5
Absence of initiation or increase in vasopressor amines, until day 5
Absence of recourse to the transfusion of 2 or more red cells packs within 24h to maintain the transfusion target (Hb ≥ 7 g/dL)
Absence of persistence or evolution towards haemorrhagic shock (systolic blood pressure < 100 mmHg and/or mean arterial pressure < 60 mmHg and/or heart rate > 100 bpm)
Absence of re-bleeding episodes at day 5, assessed by the medical team on the bases of clinical, biological or endoscopic elements
Absence of death at day 5
measure: Control of the bleeding
time frame: Within 5 days after randomisation
description: At least 1 criterion present :
Persistence of the bleeding (regardless of the volume), 2 hours after initiation of medical or endoscopic treatment
And/Or blood transfusion needed within 24 hours after treatment initiation (≥ 2 red cells units)
And/Or hemorrhagic shock installation (systolic blood pressure < 100 mmHg and/or mean arterial pressure < 60 mmHg and/or heart rate > 100 bpm)
measure: Re-bleeding episodes
time frame: At day 6, day 28, day 42, 3 months, 6 months and 1 year after randomisation
measure: Death
time frame: At day 6, day 28, day 42, 3 months, 6 months and 1 year after randomisation
measure: Fluid infusion volume (in mL)
time frame: At day 6, day 28 and day 42 after randomisation
measure: Blood transfusion volume (in mL)
time frame: At day 6, day 28 and day 42 after randomisation
measure: Blood transfusion quantity (number of units)
time frame: At day 6, day 28 and day 42 after randomisation
measure: Nature of blood transfusion: - Red cells units - Platelets units - Fresh frozen plasma - Fibrinogen - Other
time frame: At day 6, day 28 and day 42, after randomisation
measure: TIPS procedure (in Child-Pugh B patients)
time frame: At day 6, day 28, day 42 after randomisation
measure: Visceral and systemic complications
time frame: At day 6, day 28 and day 42, after randomisation (or until discharge)
description: Complications, defined as:
Acute organ failure (using CLIF-C ACLF and CLIF-SOFA scores)
Hepatic encephalopathy
Hepatic failure
Hepatorenal syndrome
Renal failure (using grades 2 and 3 of the KDIGO classification)
Sepsis
Ascites liquid infection
measure: Need for organ substitution - Renal replacement therapy (dialysis) - Liver replacement therapy - Mechanical ventilation
time frame: At day 6, day 28 and day 42, after randomisation (or until discharge)
measure: Liver transplantation
time frame: At day 6, day 28, day 42, 3 months, 6 months and 1 year after randomisation
measure: Length of stay in ICU (in days)
time frame: At day 6, day 28, day 42, 3 months, 6 months and 1 year after randomisation
measure: Duration of hospitalization (in days)
time frame: At day 6, day 28, day 42, 3 months, 6 months and 1 year after randomisation
measure: Number of participants with treatment-related adverse events as assessed by the ANSM notice of Exacyl®
time frame: up to 5 days
description: Adverse events as assessed by the ANSM notice of Exacyl® are :
Allergy
Thrombotic events
Seizures
Acute renal failure (KDIGO grades 2 and 3)
Death
Or any other adverse event suspected to be treatment-related
Adverse effects will be systematically searched for and collected in the electronic Case Report Form (eCRF) during the acute phase (within 5 days after randomization), as assessed by the AP-HP notification form. When present, investigators will have to send a notification to the promoter (by fax). Patients with severe adverse effects (leading to death, life-threatening condition, hospitalization and pursuit of hospitalization, incapacity or handicap, congenital malformation) will be followed until disappearance of these. Every document related to the patient during the protocol should be transmitted to the promoter. Investigators are supposed to answer every inquiry of the promoter.
measure: Delay between the beginning of the haemorrhage and the initiation of the AT treatment
time frame: At day 1
arm group label: Tranexamic acid
arm group type: Active Comparator
description: At randomisation : loading dose of 1g of intravenous tranexamic acid for 10 min, immediately followed by an intravenous infusion of 3g of TA over 24h
arm group label: Placebo
arm group type: Placebo Comparator
description: At randomisation : loading dose of 10 mL of intravenous isotonic saline for 10 min, immediately followed by an intravenous infusion of 30 mL of isotonic saline over 24h
intervention type: Drug
intervention name: Tranexamic acid
description: At randomisation : loading dose of 1g of intravenous tranexamic acid for 10 min, immediately followed by an intravenous infusion of 3g of TA over 24h.
Total dose : 4 g of TA
arm group label: Tranexamic acid
intervention type: Drug
intervention name: Placebo
description: At randomisation : loading dose of 10 mL of intravenous isotonic saline for 10 min, immediately followed by an intravenous infusion of 30 mL of isotonic saline over 24h Total dose : 40 mL of Placebo
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Matthieu HEIDET
role: Principal Investigator
affiliation: Assistance Publique - Hôpitaux de Paris
last name: Matthieu HEIDET, MD
email: matthieu.heidet@aphp.fr
last name: Roland AMATHIEU, MD
email: roland.amathieu@aphp.fr
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
country: France
responsible party type: Sponsor
mesh term: Gastrointestinal Hemorrhage
mesh term: Hemorrhage
mesh term: Fibrosis
mesh term: Tranexamic Acid