<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/NCT02203968</url>
  </required_header>
  <id_info>
    <org_study_id>064-2014</org_study_id>
    <nct_id>NCT02203968</nct_id>
  </id_info>
  <brief_title>Fibrinogen in the Initial Resuscitation of Severe Trauma (FiiRST)</brief_title>
  <acronym>FiiRST</acronym>
  <official_title>Fibrinogen in the Initial Resuscitation of Severe Trauma (FiiRST): a Randomized Feasibility Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sunnybrook Health Sciences Centre</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Sunnybrook Health Sciences Centre</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Trauma is the leading cause of death in people 44 years of age or younger. After major&#xD;
      trauma, such as following high-speed motor vehicle collision, bleeding coupled with clotting&#xD;
      defects is responsible for most of deaths in the first hours of hospital admission. Of note,&#xD;
      these bleeding-related deaths are potentially preventable. Accordingly, the initial&#xD;
      in-hospital management of severely injured patients focuses on stopping bleeding, replacing&#xD;
      blood loss and correcting clotting defects.&#xD;
&#xD;
      Recently, animal and human research demonstrated that one of the major clotting defects&#xD;
      following injury and bleeding is the drop in blood levels of fibrinogen (a clotting factor),&#xD;
      which is detected on hospital admission in severely injured patients. These low fibrinogen&#xD;
      levels are associated with increased blood transfusion and death. However, in North America,&#xD;
      the standard of care for replacing low fibrinogen requires the use of cryoprecipitate, which&#xD;
      is a frozen blood product with long preparation time, and similarly to other blood products,&#xD;
      carries the risk of viral transmission and transfusion complications. Alternately, many&#xD;
      Europeans countries where cryoprecipitate has been withdrawn from the market due to safety&#xD;
      concerns, use fibrinogen concentrate. Fibrinogen concentrate undergoes pathogen inactivation,&#xD;
      which is a process to eliminate the risk of transmitting viruses, bacteria and parasites, is&#xD;
      likely a safer and faster alternative to cryoprecipitate. In Canada, fibrinogen concentrate&#xD;
      is licensed for congenital low fibrinogen only.&#xD;
&#xD;
      Although preliminary data suggest that fibrinogen supplementation in trauma is associated&#xD;
      with reduced bleeding, blood transfusion, and death, the feasibility, safety and efficacy of&#xD;
      early fibrinogen replacement remains unknown. We proposed to conduct a feasibility randomized&#xD;
      trial to evaluate the use of early fibrinogen concentrate against placebo in injured patients&#xD;
      at our trauma centre.&#xD;
&#xD;
      A pilot trial is necessary to demonstrate the feasibility of rapidly preparing, delivering,&#xD;
      and infusing fibrinogen concentrate as an early therapy to prevent excessive bleeding in&#xD;
      trauma. This feasibility trial will provide preliminary safety and clinical outcome data to&#xD;
      inform the design of larger trials; which ultimately aims to prevent bleeding-related deaths&#xD;
      in the trauma population.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>October 2014</start_date>
  <completion_date type="Actual">December 2015</completion_date>
  <primary_completion_date type="Actual">December 2015</primary_completion_date>
  <phase>Phase 1/Phase 2</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>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Feasibility</measure>
    <time_frame>One year</time_frame>
    <description>1.Feasibility endpoint: 1.1Proportion of patients receiving study intervention (Fibrinogen Concentrate [FC] or placebo) within first hour of hospital admission. Based on the trial's sample size of 50 patients, feasibility is defined by 85% (96% confidence interval (CI) [72% - 98%]) of study participants receiving the study intervention within the first hour of hospital admission</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Other feasibility endpoints and physiologic endpoints</measure>
    <time_frame>one year</time_frame>
    <description>Other feasibility endpoints:1.2.Proportion of patients receiving study intervention prior to any blood transfusion; 1.3.Times to randomization, issue, and start of infusion; 1.4.Duration of infusion; 1.5.Wastage of study intervention; 1.6.Proportion of patients with blood tests performed for all time points; 1.7.Proportion of missed patients (eligible but not randomized); 1.8.Randomization errors.&#xD;
Physiologic endpoints: Plasma fibrinogen levels; Rotational Thromboelastometry/ Thromboelastography parameters (functional fibrinogen, fibtem, fibtem plus); plasmin anti-plasmin complex; tissue plasminogen activator; plasminogen activator inhibitor-1; d-dimer levels; international normalized ratio [INR]; partial thromboplastin time; complete blood count; endogenous thrombin potential; factor XIII; factor V; and activated protein C will be obtained on admission; and +1h, +3h, +11h, +23h &amp; +47h following start time of study infusion</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Clinical Parameters</measure>
    <time_frame>one year</time_frame>
    <description>Rates of symptomatic thromboembolic complications in both study arms defined by the evidence of any of the following any time during hospital stay: deep venous thrombosis; myocardium infarction; cerebral vascular accident; pulmonary embolism; and arterial thrombosis&#xD;
Rates of asymptomatic deep venous thrombosis by leg doppler at day 7 of hospital stay&#xD;
Mortality by exsanguination&#xD;
All-cause mortality at 28 days (mainly due to exsanguination; mainly neurological/ due to traumatic brain injury/ withdrawal of care; or mainly due to multiple organ failure/sepsis)&#xD;
Incidence of acute lung injury/ acute respiratory distress syndrome before day 28&#xD;
Multiple organ failure&#xD;
Total amount of crystalloids used in 24h&#xD;
Units of blood and blood products transfused in 24h of hospitalization</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">50</enrollment>
  <condition>Trauma</condition>
  <condition>Injury</condition>
  <condition>Bleeding</condition>
  <condition>Haemorrhage</condition>
  <condition>Coagulopathy</condition>
  <arm_group>
    <arm_group_label>Normal saline</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo (normal saline) will be administered intravenously as a single 300ml rapid infusion (less than 3min) via level I automated pressure pump within one hour of hospital admission.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Fibrinogen concentrate</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Fibrinogen concentrate (RiaSTAP™) is a freeze-dried lyophilised plasma product presented in powdered form. The powder is reconstituted with water for intravenous injection at a concentration of 20 mg fibrinogen per ml. The concentrate is formulated with human albumin, L-arginine, sodium citrate and sodium chloride. RiaSTAP™ is supplied as a purified lyophilisate in a 1g dosage form and is reconstituted in 50 ml of sterile water. The final volume of RiaSTAP™ to be infused in this study will therefore be 300 ml.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fibrinogen concentrate</intervention_name>
    <description>Six grams of fibrinogen concentrate (RiaSTAP™) will be administered intravenously as a single 300ml rapid infusion (less than 3min) via level I automated pressure pump within one hour of hospital admission.</description>
    <arm_group_label>Fibrinogen concentrate</arm_group_label>
    <other_name>RiaSTAP™</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo Comparator</intervention_name>
    <description>Placebo Comparator: Normal saline Placebo (normal saline) will be administered intravenously as a single 300ml rapid infusion (less than 3min) via level I automated pressure pump within one hour of hospital admission.</description>
    <arm_group_label>Normal saline</arm_group_label>
    <other_name>Normal saline</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        1. Injured trauma (penetrating or blunt) patients who are at risk of significant bleeding,&#xD;
        defined as: i. Systolic blood pressure (SBP) ≤ 100mmHg at any time from the injury scene&#xD;
        until 30min after hospital admission AND ii. Red blood cell transfusion has been ordered by&#xD;
        the trauma team leader (or delegate)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patients in shock which the etiology is purely not related to bleeding:&#xD;
&#xD;
             i. Cardiogenic (myocardial or valvular dysfunction); ii. Distributive (septic,&#xD;
             anaphylactic, acute adrenal insufficiency and neurogenic) and iii. Obstructive&#xD;
             (cardiac tamponade, tension pneumothorax and massive pulmonary emboli).&#xD;
&#xD;
          2. Severe head injury, defined as any of the following:&#xD;
&#xD;
             i. Glasgow coma scale (GCS) of 3 due to severe traumatic brain injury (TBI); ii. TBI&#xD;
             with clear indication of immediate neurosurgical intervention based on clinical&#xD;
             findings (mechanism of trauma associated with focal signs such as anisocoria with&#xD;
             fixed pupil) or on CT results (bleeding causing mass effect); iii. Unsalvageable head&#xD;
             injury such as through-through gunshot wound to the head, open skull fracture with&#xD;
             exposure/loss of brain tissue; as per the trauma team or neurosurgery initial clinical&#xD;
             assessment or as per initial CT of the head findings;&#xD;
&#xD;
          3. Known complete or incomplete spinal cord injury;&#xD;
&#xD;
          4. Known hereditary or acquired coagulopathies unrelated to the trauma resuscitation&#xD;
             (e.g. known hepatic dysfunction);&#xD;
&#xD;
          5. Use of anticoagulant medications such as warfarin, low-molecular weight heparin, and&#xD;
             direct thrombin and factor Xa inhibitors;&#xD;
&#xD;
          6. Moribund with evidence of unsalvageable injuries and withdrawal of care, as per the&#xD;
             trauma team;&#xD;
&#xD;
          7. Received blood products prior to admission;&#xD;
&#xD;
          8. Patients with estimated body weight under 50Kg;&#xD;
&#xD;
          9. Patients with known or suspected pregnancy;&#xD;
&#xD;
         10. Patients arriving more than 6hr after injury.&#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>Barto Nascimento, MD MSc</last_name>
    <role>Principal Investigator</role>
    <affiliation>Sunnybrook Health Sciences Centre, University of Toronto</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Sunnybrook Health Sciences Centre</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M4N3M5</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>April 2016</verification_date>
  <study_first_submitted>July 8, 2014</study_first_submitted>
  <study_first_submitted_qc>July 29, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 30, 2014</study_first_posted>
  <last_update_submitted>April 13, 2016</last_update_submitted>
  <last_update_submitted_qc>April 13, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">April 14, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Fibrinogen replacement</keyword>
  <keyword>Trauma coagulopathy</keyword>
  <keyword>Hypofibrinogenemia</keyword>
  <keyword>Early trauma coagulopathy</keyword>
  <keyword>Haemorrhage</keyword>
  <keyword>Fibrinogen concentrate</keyword>
  <keyword>Feasibility trial</keyword>
  <keyword>Clinical trials</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hemostatic Disorders</mesh_term>
    <mesh_term>Blood Coagulation Disorders</mesh_term>
    <mesh_term>Hemorrhage</mesh_term>
    <mesh_term>Wounds and Injuries</mesh_term>
  </condition_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/NCT02203968
org study id: 064-2014
nct id: NCT02203968
lead sponsor: 
has dmc: Yes
Trauma is the leading cause of death in people 44 years of age or younger. After major
      trauma, such as following high-speed motor vehicle collision, bleeding coupled with clotting
      defects is responsible for most of deaths in the first hours of hospital admission. Of note,
      these bleeding-related deaths are potentially preventable. Accordingly, the initial
      in-hospital management of severely injured patients focuses on stopping bleeding, replacing
      blood loss and correcting clotting defects.

      Recently, animal and human research demonstrated that one of the major clotting defects
      following injury and bleeding is the drop in blood levels of fibrinogen (a clotting factor),
      which is detected on hospital admission in severely injured patients. These low fibrinogen
      levels are associated with increased blood transfusion and death. However, in North America,
      the standard of care for replacing low fibrinogen requires the use of cryoprecipitate, which
      is a frozen blood product with long preparation time, and similarly to other blood products,
      carries the risk of viral transmission and transfusion complications. Alternately, many
      Europeans countries where cryoprecipitate has been withdrawn from the market due to safety
      concerns, use fibrinogen concentrate. Fibrinogen concentrate undergoes pathogen inactivation,
      which is a process to eliminate the risk of transmitting viruses, bacteria and parasites, is
      likely a safer and faster alternative to cryoprecipitate. In Canada, fibrinogen concentrate
      is licensed for congenital low fibrinogen only.

      Although preliminary data suggest that fibrinogen supplementation in trauma is associated
      with reduced bleeding, blood transfusion, and death, the feasibility, safety and efficacy of
      early fibrinogen replacement remains unknown. We proposed to conduct a feasibility randomized
      trial to evaluate the use of early fibrinogen concentrate against placebo in injured patients
      at our trauma centre.

      A pilot trial is necessary to demonstrate the feasibility of rapidly preparing, delivering,
      and infusing fibrinogen concentrate as an early therapy to prevent excessive bleeding in
      trauma. This feasibility trial will provide preliminary safety and clinical outcome data to
      inform the design of larger trials; which ultimately aims to prevent bleeding-related deaths
      in the trauma population.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Feasibility
time frame: One year
description: 1.Feasibility endpoint: 1.1Proportion of patients receiving study intervention (Fibrinogen Concentrate [FC] or placebo) within first hour of hospital admission. Based on the trial's sample size of 50 patients, feasibility is defined by 85% (96% confidence interval (CI) [72% - 98%]) of study participants receiving the study intervention within the first hour of hospital admission
measure: Other feasibility endpoints and physiologic endpoints
time frame: one year
description: Other feasibility endpoints:1.2.Proportion of patients receiving study intervention prior to any blood transfusion; 1.3.Times to randomization, issue, and start of infusion; 1.4.Duration of infusion; 1.5.Wastage of study intervention; 1.6.Proportion of patients with blood tests performed for all time points; 1.7.Proportion of missed patients (eligible but not randomized); 1.8.Randomization errors.
Physiologic endpoints: Plasma fibrinogen levels; Rotational Thromboelastometry/ Thromboelastography parameters (functional fibrinogen, fibtem, fibtem plus); plasmin anti-plasmin complex; tissue plasminogen activator; plasminogen activator inhibitor-1; d-dimer levels; international normalized ratio [INR]; partial thromboplastin time; complete blood count; endogenous thrombin potential; factor XIII; factor V; and activated protein C will be obtained on admission; and +1h, +3h, +11h, +23h & +47h following start time of study infusion
measure: Clinical Parameters
time frame: one year
description: Rates of symptomatic thromboembolic complications in both study arms defined by the evidence of any of the following any time during hospital stay: deep venous thrombosis; myocardium infarction; cerebral vascular accident; pulmonary embolism; and arterial thrombosis
Rates of asymptomatic deep venous thrombosis by leg doppler at day 7 of hospital stay
Mortality by exsanguination
All-cause mortality at 28 days (mainly due to exsanguination; mainly neurological/ due to traumatic brain injury/ withdrawal of care; or mainly due to multiple organ failure/sepsis)
Incidence of acute lung injury/ acute respiratory distress syndrome before day 28
Multiple organ failure
Total amount of crystalloids used in 24h
Units of blood and blood products transfused in 24h of hospitalization
arm group label: Normal saline
arm group type: Placebo Comparator
description: Placebo (normal saline) will be administered intravenously as a single 300ml rapid infusion (less than 3min) via level I automated pressure pump within one hour of hospital admission.
arm group label: Fibrinogen concentrate
arm group type: Active Comparator
description: Fibrinogen concentrate (RiaSTAP™) is a freeze-dried lyophilised plasma product presented in powdered form. The powder is reconstituted with water for intravenous injection at a concentration of 20 mg fibrinogen per ml. The concentrate is formulated with human albumin, L-arginine, sodium citrate and sodium chloride. RiaSTAP™ is supplied as a purified lyophilisate in a 1g dosage form and is reconstituted in 50 ml of sterile water. The final volume of RiaSTAP™ to be infused in this study will therefore be 300 ml.
intervention type: Drug
intervention name: Fibrinogen concentrate
description: Six grams of fibrinogen concentrate (RiaSTAP™) will be administered intravenously as a single 300ml rapid infusion (less than 3min) via level I automated pressure pump within one hour of hospital admission.
arm group label: Fibrinogen concentrate
other name: RiaSTAP™
intervention type: Drug
intervention name: Placebo Comparator
description: Placebo Comparator: Normal saline Placebo (normal saline) will be administered intravenously as a single 300ml rapid infusion (less than 3min) via level I automated pressure pump within one hour of hospital admission.
arm group label: Normal saline
other name: Normal saline
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Barto Nascimento, MD MSc
role: Principal Investigator
affiliation: Sunnybrook Health Sciences Centre, University of Toronto
facility: 
country: Canada
responsible party type: Sponsor
mesh term: Hemostatic Disorders
mesh term: Blood Coagulation Disorders
mesh term: Hemorrhage
mesh term: Wounds and Injuries