Evaluation of the Safety and Efficacy of the Second Dose of Tranexamic Acid
Condition: Tranexamic Acid
Study type: Interventional
Phase: Phase 3

Summary: 
      TXA is currently administered pre-hospital in Canada, Germany, United Kingdom and Israel .
      These studies demonstrated that TXA use did not result in any detectable complications or
      adverse events. It is considered an ideal pre-hospital treatment because: (a) patients with
      severe hemorrhage die early more often than patients without hemorrhage; (b) it seems that
      the earlier treatment is administered, the better; (c) it is stable and easily stored; and
      (d) it is easily administered by paramedics. Herein, the study aimed to evaluate the effect
      of administration of second dose of Tranexamic acid infusion in the hospital setting in
      comparison to not receiving the second dose on the outcomes of trauma patients with an
      evidence of significant hemorrhage.

      Recently, HGH ambulance service has included pre-hospital administration of TXA in trauma
      patients with significant hemorrhage. So, all eligible trauma patients will receive
      pre-hospital TXA (first dose) slowly over 10 minutes by the critical care paramedics as
      standard of care.

      Inclusion Criteria: All adult trauma male and female patients (≥18 or <90 years) with
      evidence of significant hemorrhage (systolic blood pressure <90 mmHg or heart rate >110 beats
      per minutes, or both) or had Capillary Refill Time 3-4 seconds and received first dose of
      prehospital TXA will be included in the study.

      Exclusion criteria:

        1. Age > 90 or < 18 years of age

        2. Inability to obtain intravenous access (intraosseous access not sufficient)

        3. Documented cervical cord injury with motor deficit

        4. Known prisoner

        5. Known pregnancy

        6. Traumatic arrest with > 5 minutes CPR without return of vital signs

        7. Penetrating cranial injury

        8. Traumatic brain injury with brain matter exposed

        9. Isolated drowning or hanging victims

       10. Wearing an opt out bracelet. Patient data will include demographics, time since injury,
           type of injury (blunt or penetrating), Glasgow Coma Score(GCS), Injury severity score
           (ISS), systolic blood pressure, respiratory rate, central capillary refill time,
           estimated number of hours since injury, laboratory findings, blood transfusion, units of
           transfused blood, management, complications and outcome.

      The primary outcome will be death in hospital within 4 weeks of injury. Secondary outcomes
      will be morbidity (thromboembolic events, sepsis, Acute respiratory distress syndrome and
      organ failure), and number of blood transfusions (Massive transfusion protocol) and hospital
      length of stay.
    

Detailed description: 
      Study design It is a single-center, prospective, double-blind, randomized, placebo-controlled
      trial.

      Study population All severely injured male and female patients with evidence of significant
      hemorrhage (systolic blood pressure <90 mmHg or heart rate >110 beats per minutes, or both)
      or had Capillary Refill Time 3-4 seconds will be administered TXA slowly over 10 minutes at
      the prehospital settings by critical care paramedics as standard of care are eligible for
      participation in this trial.

      Sample size estimation:

      The present clinical trial is based on CRASH-2 study [2] in which the sample size was more
      than 20,000 using the followings primary outcomes estimates such as all-cause-mortality 14.5%
      (TXA) vs. 16% (Placebo) and bleeding: 4.9% (TXA) vs. 5.7% (Placebo). According to CRASH-2
      study approximately 30% of all patients randomized presented with significant hypotension
      (blood pressure < 90 mm Hg) considered to have significant hemorrhage.

      This is a unique study to assess the effect of second dose of tranexamic acid in the hospital
      setting and there are no precise estimates available on the primary outcome particularly in
      our population. According to CRASH-2 trial, approximately 30% of all randomized patients
      presented with significant hypotension (BP <90mmHg) indicated hemorrhagic shock. Therefore,
      taking the prevalence of hemorrhage to be 30% with 5% confidence limit and 80% power; a total
      of 335 trauma patients need to be included in the study.

      There will be three arms in this trial; Group-1 will include 110 patients with initial
      pre-hospital TXA administered slowly over 10 minutes followed by in-hospital intravenous
      infusion of 1 g TXA administer over 8 h; Group-2 will include 110 patients with initial
      pre-hospital TXA administered slowly over 10 minutes but will receive placebo over 8 h in the
      hospital and Group-3 will include 110 age and injury severity score (ISS) matched historical
      controls without TXA administration identified from hospital database (January 1, 2016 till
      December 31, 2016).

      Each study package will be labelled with the study protocol number, unique randomization
      code, and name of the principal investigator. All study treatment pack will contain two
      ampules of either tranexamic acid 500 mg or placebo, one 100 ml bag of 0.9% saline, a syringe
      and needle, stickers with the trial details and randomization number (for attaching to
      infusion bags, data forms, and patient medical records), and instructions. Each box contained
      information leaflets for patients and their representatives, consent forms, and data
      collection forms. The stickers, instructions, leaflets, and forms will be available in
      English and Arabic. A small number of details will be completed on the wristband and label
      (Patient's initials, Date and time of randomization). The label will be placed in the
      patient's hospital medical record. The wristband and label in the patient's medical record
      will alert hospital staff to the patient's enrollment in the study. The principal
      investigator or their designee is responsible for ensuring the drug or placebo is
      administered according to the study protocol and they will be unaware of whether the patient
      was assigned to the TXA or placebo group.

      The research team including research coordinator will be notified by the treating physician
      about the recruitment. Detailed interventions are mentioned in study procedures below.

      10 ml blood specimen will be drawn for coagulation profile (INR, PT, PTT, Fibrinogen, and
      D-Dimer); 5 ml before and 5 ml after starting TXA. The data will be collected prospectively
      with the help of a predesigned data collection form. Patient data included sex, age,
      nationality, time since injury, type of injury (blunt or penetrating), Glasgow Coma
      Score(GCS), Injury severity score (ISS), systolic blood pressure, respiratory rate, central
      capillary refill time, estimated number of hours since injury, laboratory findings, blood
      transfusion, units of transfused blood, management, complications and outcome.

      The primary outcome will be death in hospital within 4 weeks of injury. Secondary outcomes
      will be morbidity (thromboembolic events, sepsis, Acute respiratory distress syndrome and
      organ failure), and number of blood transfusions (Massive transfusion protocol) and hospital
      length of stay.

      Study Population Pre-hospital administration of TXA in trauma patients with evidence of
      significant hemorrhage is being included in the HGH ambulance service. So, all eligible
      trauma patients with risk of bleeding will receive pre-hospital TXA slowly over 10 minutes by
      the critical care paramedics as standard of care. In the hospital, subjects will be assessed
      by study trained treating physician and if they fulfill the inclusion criteria and have no
      exclusion criteria they will be randomized to give second 8-hour infusion of TXA or placebo
      by opening the next opaque envelope in the randomization series. The envelopes will contain a
      wristband to be placed on the patient & a label which designates the study number and
      treatment allocation. A small number of details will be completed on the wristband and label
      (patient's initials, date and time of randomization). The label will be placed in the
      patient's hospital medical record. The wristband and label in the patient's medical record
      will alert hospital staff to the patient's enrollment in the study.

      The research team including research coordinator will be notified by the treating physician
      about the recruitment.

      The information regarding patient's enrollment will be kept confidential and all study
      related steps (explanation of study procedures and consenting) with the next of kin will be
      done in isolated room in the emergency area to maintain complete privacy. No one outside the
      research team and next of kin will be aware about the patient's participation in the study.

      Recruited subjects will receive a specific study number. The research coordinator will
      compile a study enrollment log which will link the study number to the patient's details.
      Subsequent data will be identified by the study number. The enrollment log and study data
      will be kept separately. All data collected for the assessment will be identified by the
      study code. Study data will be entered into a password protected computer with study
      documents will be kept in a locked office with principal investigator at HMC.

      Study drug Each 5 mL ampule contains 500 gm (×2) tranexamic acid and 10 mL water for
      injection as the inactive ingredient. Tranexamic acid solution for injection is a sterile,
      clear, colorless solution. The pH is 6.5 to 8.0. The placebo is identical in appearance and
      packaging but contains sodium chloride 0.9% w/v in a 10 mL ampule.

      It is a randomized double blind placebo controlled single center trial. Eligible subjects
      will be screened and enrolled in the hospital by the treating physician. If they fulfill the
      inclusion criteria and have no exclusion criteria they will be randomized into either of the
      group (Group-1 or group-2) by opening the next opaque envelope in the randomization series
      kept in the trauma room. The envelopes will contain a wristband to be placed on the patient &
      a label which designates the study number and treatment. A small number of details will be
      completed on the wristband and label (Patient's initials, Date and time of randomization).
      The label will be placed in the patient's hospital electronic medical record. The wristband
      and label in the patient's medical record will alert hospital staff to the patient's
      enrollment in the study.

      Blinding Blinding will be done through pharmacy department where both tranexamic acid and
      normal saline will be placed in similar bags in IV admixture room, both are colorless. Total
      of 220 bags will be numbered, the codes will be kept confidential and not broken unless
      emergency case.

      The emergency physicians will be unable to determine whether a trial pack contains the active
      study drug or placebo as they are both identical in appearance. The unique study ID number
      printed on the trial pack and the contents within the pack is the only way to determine
      whether a pack contains active drug or placebo. The coded list of study ID numbers is only
      accessible to the independent study coordinator and will not be accessible to researchers
      involved in the trial until after the trial is completed (individual cases may be unblinded
      in exceptional circumstances as per emergency unblinding mentioned below). Both participants
      and study staff (investigators and trial staff) will be masked to treatment allocation.

      Emergency unblinding

      The treating physician at emergency department will ask for unblinding for the sake of
      patient care, if unblinding is needed based on the clinical progress of the patient following
      steps will be followed:

      Procedure for emergency unblinding:

        1. In case of emergency, the treating physician will contact the trial coordinator to break
           the code.

        2. The trial coordinator will provide with the information as requested.

        3. The study code should only be broken when the treating physician believes that clinical
           management depends importantly upon knowledge of whether the patient received
           antifibrinolytic or placebo. In those few cases only, unblinding will be allowed to know
           whether the patient received antifibrinolytic or placebo.

        4. On receipt of the treatment allocation details, treating physician deals with the
           participant's medical emergency as appropriate.

        5. If the treating physician is not the PI, the treating physician must inform the PI of
           the code break and the reasons for the actions taken as soon as possible.

        6. The PI documents the breaking of the code and the reasons for doing so on the data
           collection sheet.

        7. The PI documents the breaking of the codes in a separate file. Discontinuation of
           treatment Study medication will be ceased permanently for any occurrence of serious
           adverse event such as seizure, cardiac arrest or anaphylaxis. Ultimately the treating
           clinician will have the right to decide whether to discontinue treatment, ideally this
           should be discussed with the principal investigator where feasible. All patients with
           discontinued treatment of the study drug will be followed for outcomes.

      Significance This trial aims to determine the overall benefits and harms of giving second
      infusion of TXA for severely injured patients in the emergency room. Importantly, it aims to
      determine whether TXA infusion as compared to single dose will affect the outcomes of the
      trauma patients with significant bleeding. It is timely that it will objectively resolve
      current uncertainty about whether the benefits of TXA infusion versus single dose will
      outweigh any potential harm for severely injured patients in prehospital setting in our
      region. The potential benefit of TXA to significantly improve mortality rates and secondary
      outcomes for patients could result in significant savings in lifetime costs and improved
      quality of life following severe injury. If this trial proves a beneficial effect of early
      TXA infusion of second dose of TXA in hospital setting in terms of outcomes, than it will be
      used for all trauma patients with significant bleeding. On the other hand, if single dose
      shows similar benefit in terms of outcomes than it can mitigate the side effects that could
      be raised with the second dose of TXA infusion and would recommend using only single dose of
      TXA in the prehospital settings. Finally, this trial will demonstrate the ability of our
      trauma services to appropriately select patients and administer a time-critical drug
      treatment to minimize harmful consequences of hemorrhage in major trauma.
    

Intervention name(s): Tranexamic Acid; Placebo
Intervention type(s): Drug; Other
Intervention description(s): intravenous infusion of 1 g infusion to be given and completed over 8 h in the hospital; placebo (normal saline) infusion to be given and completed over 8 h in the hospital
Other intervention name(s): TXA; normal saline
Intervention MeSH terms: Tranexamic Acid
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Trauma, Mortality, Tranexamic , Prehospital