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| ID | Type | Description | Link |
|---|---|---|---|
| 5U01HL077863-09 | U.S. NIH Grant/Contract | View source | |
| TATRC Log No. 13335004-A | Other Grant/Funding Number | US Army Medical Research Acquisition Activity (USAMRAA) |
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| Name | Class |
|---|---|
| National Heart, Lung, and Blood Institute (NHLBI) | NIH |
| U.S. Army Medical Research and Development Command | FED |
| Canadian Institutes of Health Research (CIHR) | OTHER_GOV |
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Primary aim: To determine the efficacy of two dosing regimens of TXA initiated in the prehospital setting in patients with moderate to severe TBI (GCS score ≤12).
Primary hypothesis: The null hypothesis is that random assignment to prehospital administration of TXA in patients with moderate to severe TBI will not change the proportion of patients with a favorable long-term neurologic outcome compared to random assignment to placebo, based on the GOS-E at 6 months.
Secondary aims: To determine differences between TXA and placebo in the following outcomes for patients with moderate to severe TBI treated in the prehospital setting with 2 dosing regimens of TXA:
Inclusion: Blunt and penetrating traumatic mechanism consistent with TBI with prehospital GCS ≤ 12 prior to administration of sedative and/or paralytic agents, prehospital SBP ≥ 90 mmHg, prehospital intravenous (IV) access, age ≥ 15yrs (or weight ≥ 50kg if age is unknown), EMS transport destination based on standard local practices determined to be a participating trauma center.
Exclusion: Prehospital GCS=3 with no reactive pupil, estimated time from injury to start of study drug bolus dose >2 hours, unknown time of injury, clinical suspicion by EMS of seizure activity, acute MI or stroke or known history, to the extent possible, of seizures, thromboembolic disorders or renal dialysis, CPR by EMS prior to randomization, burns > 20% TBSA, suspected or known prisoners, suspected or known pregnancy, prehospital TXA or other pro-coagulant drug given prior to randomization, subjects who have activated the "opt-out" process when required by the local regulatory board.
A multi-center double-blind randomized controlled trial with 3 treatment arms:
Overview This multi-center, Phase II trial is designed to determine if Tranexamic Acid (TXA) initiated in the prehospital setting improves long-term neurologic outcome compared to placebo in patients with moderate to severe TBI who are not in shock. This study protocol will be conducted as part of the Resuscitation Outcomes Consortium (ROC) at trauma centers in the United States and Canada. ROC is funded by the National Heart Lung and Blood Institute (NHLBI) in partnership with the US Army Medical Research and Materiel Command (USAMRMC), Canadian Institutes of Health Research, the Heart & Stroke Foundation of Canada, the American Heart Association (AHA), and the Defense Research and Development Canada. ROC is a clinical trials network focusing on research primarily in the area of prehospital cardiopulmonary arrest and severe traumatic injury. The mission of ROC is to provide infrastructure and project support for clinical trials and other outcome-oriented research in the areas of cardiopulmonary arrest and severe traumatic injury that lead to evidence-based change in clinical practice.
Specific Aims/Hypothesis Statement
2.1 Clinical Hypotheses and Aims
Specific aim 1: To compare 6-month neurologic outcome between subjects who are randomly assigned to TXA to subjects who are randomly assigned to placebo by evaluating the Glasgow Outcome Scale Extended score (GOS-E) at 6 months post-injury.
Primary Hypotheses: We will perform a one-sided test of the following null hypothesis: The proportion of subjects who have a favorable neurologic outcome (GOS-E > 4) at six months post injury who are randomly assigned to TXA is not different from the proportion of subjects who have a favorable neurologic outcome (GOS-E > 4) who are randomly assigned to placebo. This hypothesis will be tested versus the alternative that the proportion of subjects with a favorable neurologic outcome who are randomly assigned to TXA is higher than in subjects who are randomly assigned to placebo at the .1 level and versus the alternative that the proportion of subjects with a favorable neurologic outcome who are randomly assigned to TXA is lower than it is in the placebo group at the .025 level
Specific aim 2: To assess differences in morbidity and mortality measured from randomization through 28 days or initial hospital discharge and differences in neurologic outcomes at 6 months between subjects in the bolus/maintenance arm, bolus only arm, and placebo arm.
Secondary Hypotheses: The null hypotheses are that there will be no difference between subjects who are randomly assigned to TXA and subjects who are randomly assigned to placebo in the following: both absolute and relative volume of intracranial hemorrhage (ICH) progression, proportion of subjects with ICH progression, frequency of neurosurgical interventions, GOS-E measured at discharge and 6 months, Disability Rating Scale score (DRS) measured at discharge and 6 months, 28-day survival, and ventilator-free, intensive care unit (ICU)-free, and hospital-free days.
Specific aim 3: To assess differences in adverse events measured from randomization to initial hospital discharge between subjects in the bolus/maintenance arm, bolus only arm, and placebo arm.
Tertiary Hypotheses: The null hypotheses are that there will be no difference between subjects who are randomly assigned to TXA and subjects who are randomly assigned to placebo in the following: proportion of subjects experiencing seizures, cerebral ischemic events, myocardial infarction (MI), deep venous thrombosis (DVT), or pulmonary thromboembolism (PE) post randomization through 28 days or discharge, whichever occurs first.
2.2 Laboratory Hypotheses and Aims
Specific aim 1: To compare coagulation profiles over time using kaolin activated thrombelastography (TEG) results between subjects who are randomly assigned to TXA and subjects who are randomly assigned to placebo.
Primary hypothesis: The null hypothesis is that there will be no difference in the degree of fibrinolysis as assessed by percentage of clot lysis determined 30 minutes after the maximum amplitude is reached (LY30) between subjects who are randomly assigned to TXA and subjects who are randomly assigned to placebo.
Specific aim 2: To explore the underlying mechanism of TXA by comparing fibrinolytic pathway mediator activity between subjects who are randomly assigned to TXA and subjects who are randomly assigned to placebo.
Secondary hypothesis: The null hypothesis is that there will be no change in fibrinolytic pathway mediators between subjects who are randomly assigned to TXA and subjects who are randomly assigned to placebo.
Specific aim 3: To estimate the association between the degree of fibrinolysis based on kaolin activated TEG results and fibrinolytic pathway mediators on primary and secondary clinical outcomes.
Tertiary hypothesis: The null hypothesis is that no association will exist between the degree of fibrinolysis and fibrinolytic pathway mediators and primary and secondary clinical outcomes.
Study Enrollment
EMS agencies will carry blinded sealed study drug kits. Once the seal is broken in the presence of the patient, the patient is randomized. The EMS study drug kit will contain a vial of either 1 gram TXA, 2 grams TXA, or placebo. EMS will mix the study drug in a 250 mL bag of 0.9% sodium chloride and administer the bolus infusion as soon as life-saving interventions are performed. After randomization, EMS will provide the study drug kit ID# to the receiving pharmacy. The hospital pharmacist will obtain the randomization assignment from the coordinating center and prepare the appropriate drug to be administered in the hospital.
Sample Size and Statistical Analysis
The total sample size is 963 (321 per group) starting treatment, which will allow for 80% power to detect a 7.1% absolute difference in favorable long-term neurological outcome as determined by the GOS-E 6 months after injury comparing the combined TXA treatment groups to placebo, using a one-sided, level 0.1 test.
Statistical analysis of primary hypothesis: Modified intention-to-treat analysis using logistic regression to test for association and estimate the strength of the association of treatment group with a favorable 6-month outcome (defined as a GOS-E > 4), after adjustment for study site.
Human subjects protection
This study qualifies for the exception from informed consent (EFIC) required for emergency research outlined in FDA regulation 21CFR50.24. EFIC applies because of life-threatening situation, intervention must be administered before consent is feasible, no reasonable way to identify prospectively individuals at risk, patients have the prospect of benefit from the treatment, and the research could not practically be carried out without the waiver of consent.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 1 gram Tranexamic Acid (TXA) | Experimental | Loading dose of 1 gram TXA given prior to hospital arrival followed by a 1 gram TXA infusion over 8 hours after hospital arrival |
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| 2 grams TXA | Experimental | Loading dose of 2 gram TXA given prior to hospital arrival followed by a placebo of 0.9% Sodium Chloride solution infusion over 8 hours after hospital arrival |
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| 0.9% Sodium Chloride injectable | Placebo Comparator | Loading dose of 0.9% Sodium Chloride solution given prior to hospital arrival followed by a placebo of 0.9% Sodium Chloride solution infusion over 8 hours after hospital arrival |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 1 gram Tranexamic Acid (TXA) | Drug | TXA produces an antifibrinolytic effect by competitively inhibiting the activation of plasminogen to plasmin. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Dichotomized Glasgow Outcome Scale Extended (GOS-E) at 6 Months | GOS-E subdivides the categories of severe and moderate disability and good recovery using a scale of 1 to 8 where 1 = death, 2 = vegetative state, 3 = lower severe disability, 4 = upper severe disability, 5 = lower moderate disability, 6 = upper moderate disability, 7 = lower good recovery, and 8 = upper good recovery. Structured telephone interviews have been developed and validated for the GOS-E and these questions were incorporated into the follow-up survey. GOS-E was dichotomized into unfavorable (1 to 4) and favorable (5 to 8) outcomes. | 6 months post-injury |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants Who Died Within 28 Days | The counts of patients who died on or before day 28 are reported. | 28 days after hospital arrival |
| Disability Rating Scale (DRS) at 6 Months | The DRS is designed to classify patients based on their degree of function after brain injury. The DRS consists of 8 items that fall into 4 categories: (a) arousability, awareness and responsivity, (b) cognitive ability for self-care activities, (c) dependence on others, and (d) psychosocial adaptability. The score ranges from 0 (no disability) to 30 (death). |
| Measure | Description | Time Frame |
|---|---|---|
| Fibrinolysis at Hospital Admission | Alterations in fibrinolysis based on fibrinolytic pathway mediators and degree of clot lysis based on kaolin-activated thromboelastography (TEG) and defined as LY30 or the per cent lysis that occurs 30 minutes after maximum amplitude (MA) is achieved. LY30 is categorized as <0.8% (fibrinolysis shutdown), 0.8-3% (normal), and >3% (hyperfibrinolysis). | First blood draw (average of 1.6 hours post-injury) |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Susanne May, PhD | University of Washington | Principal Investigator |
| Martin Schreiber, MD FACS | Oregon Health and Science University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Alabama Resuscitation Center | Birmingham | Alabama | 35249 | United States | ||
| Hennepin County Medical Center |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 40490870 | Derived | Minoza KG, Brito AM, Loss L, McLoud S, Kenny JEH, McLean WJ, Papa L, Rowell S, Schreiber M. Association between coagulation biomarkers, intracranial hemorrhage types, and tranexamic acid treatments in early traumatic brain injury. J Trauma Acute Care Surg. 2025 Sep 1;99(3):468-476. doi: 10.1097/TA.0000000000004669. Epub 2025 Jun 10. | |
| 39226704 | Derived | Newman ZC, Ogbeifun VO, Barbosa CE, McKinley WI, Benjamin AJ, Munar MY, Pramuka PE, McGovern KD, Nordgren RK, Schreiber MA, Rowell SE. Intravenous Versus Intraosseous Use of Tranexamic Acid in Patients With Traumatic Brain Injury. J Surg Res. 2024 Oct;302:798-804. doi: 10.1016/j.jss.2024.08.003. Epub 2024 Sep 2. |
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Public use data set will be shared with NHLBI. It will include individual patient data that are de-identified. It will be available 3 years after study completion. This is currently expected for the end of 2020. The data should then be available at <https://biolincc.nhlbi.nih.gov/studies/\>.
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Some persons for whom the blinded study kit was opened did not actually receive any of the study drug. These persons are not included in the enrollment numbers. However, they are enumerated in the first section of the patient flow tables.
Between May 2015 and March 2017, participants were enrolled by 39 emergency management service (EMS) agencies and transported to 20 trauma centers within 12 regional sites in North America.
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| ID | Title | Description |
|---|---|---|
| FG000 | Placebo | Placebo IV bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours. |
| FG001 | Bolus-Maintenance |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Intervention Started |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP_ICF | Yes | Yes | Yes | Study Protocol, Statistical Analysis Plan, and Informed Consent Form: Protocol in force at beginning of enrollment |
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| Heart and Stroke Foundation of Canada |
| OTHER |
| American Heart Association | OTHER |
| Defence Research and Development Canada | INDUSTRY |
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| 2 grams TXA | Drug | TXA produces an antifibrinolytic effect by competitively inhibiting the activation of plasminogen to plasmin. |
|
|
| 0.9% Sodium Chloride injectable | Drug | Loading dose of 0.9% Sodium Chloride solution given prior to hospital arrival followed by a placebo of 0.9% Sodium Chloride solution infusion over 8 hours after hospital arrival. No active drug is added to the solution. |
|
|
| 6 months post-injury |
| Number of Participants With Unfavorable Outcome on Dichotomized Glasgow Outcome Scale Extended (GOS-E) at Discharge | GOS-E subdivides the categories of severe and moderate disability and good recovery using a scale of 1 to 8 where 1 = death, 2 = vegetative state, 3 = lower severe disability, 4 = upper severe disability, 5 = lower moderate disability, 6 = upper moderate disability, 7 = lower good recovery, and 8 = upper good recovery. Structured telephone interviews have been developed and validated for the GOS-E and these questions were incorporated into the follow-up survey. GOS-E was dichotomized into unfavorable (1 to 4) and favorable (5 to 8) outcomes. The number of subjects with unfavorable outcome is reported. | At the end of the hospital stay (average of 9 days post injury) |
| Disability Rating Scale (DRS) at Discharge | The DRS is designed to classify patients based on their degree of function after brain injury. The DRS consists of 8 items that fall into 4 categories: (a) arousability, awareness and responsivity, (b) cognitive ability for self-care activities, (c) dependence on others, and (d) psychosocial adaptability. The score ranges from 0 (no disability) to 30 (death). | At the end of the hospital stay (average of 9 days post injury) |
| Number of Participants With Intracranial Hemorrhage (ICH) Progression | All clinically indicated head computed tomography (CT) scans obtained during the initial hospitalization or within the first 28 days were assessed for ICH. Parenchymal (IPH), subdural (SDH) and epidural (EDH) hemorrhage volumes were measured and quantified using volumetric software and verified by manual calculations based on the previously validated ABC/2 technique. The sum of the IPH, SDH, and EDH volumes were compared across scans. A relative increase of 33% (and at least a 1 ml increase) on any subsequent scan compared to the initial scan was defined as a progression. | From hospital admission through 28 days or the end of the hospital stay if sooner (average of 13 days among patients with multiple scans) |
| Marshall Computed Tomography (CT) Score on Initial Head CT | The Marshall classification categorizes patients into one of six categories (I to VI) of increasing severity on the basis of findings on non-contrast CT scan of the brain. Higher categories have worse prognosis and survival. | Initial head CT (average of 1.9 hours post-injury) |
| Rotterdam Computed Tomography (CT) Score Among Subjects With Intracranial Hemorrhage (ICH) on Initial Head CT | The Rotterdam classification includes four independently scored elements: degree of basal cistern compression, degree of midline shift, presence of epidural hematomas, and presence of intraventricular or subarachnoid blood. The elements are combined to form an overall score from 1 to 6 with higher scores having worse prognosis and survival. | Initial head CT (average of 1.9 hours post-injury) |
| Number of Participants With One or More Neurosurgical Interventions | Neurosurgical interventions include craniotomy, craniectomy, and placement of a neuromonitoring or drainage device. Counts are of subjects with one or more neurosurgical interventions. | From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days) |
| Hospital-free Days | Hospital-free days count any day from hospital admission through day 28 that the patient is alive and out of the hospital. | From hospital admission through day 28 |
| Intensive Care Unit (ICU)-Free Days | ICU-free days count any day from hospital admission through day 28 that the patient is alive and not in the ICU. Subjects who die prior to discharge (even if after 28 days) are assigned a value of 0. | From hospital admission through day 28 |
| Ventilator-free Days | Ventilator-free days count any day from hospital admission through day 28 that the patient is alive and does not require mechanical ventilatory support. Subjects who die prior to discharge (even if after 28 days) are assigned a value of 0. | From hospital admission through day 28 |
| Number of Participants With Seizure | Seizures may cause involuntary changes in body movement or function, sensation, awareness, or behavior. Seizures are often associated with a sudden and involuntary contraction of a group of muscles and loss of consciousness. Seizures or episodes of seizure-like activity were reported by medics in the field following the start of study drug infusion through hand-off to the trauma center and by trauma center staff through discharge. Reported events were included if providers gave anti-seizure medication and/or the event was confirmed by EEG. | From start of study drug infusion through 28 days or the end of the hospital stay if sooner (average of 9 days) |
| Number of Participants With Cerebral Ischemic Event | Diagnosis of cerebral ischemic event | From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days) |
| Number of Participants With Myocardial Infarction (MI) | Diagnosis of an acute myocardial infarction | From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days) |
| Number of Participants With Deep Vein Thrombosis (DVT) | Diagnosis of DVT | From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days) |
| Number of Participants With Pulmonary Embolus (PE) | Diagnosis of PE | From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days) |
| Number of Participants With Any Thromboembolic Event | Diagnosis of one or more of the following: cerebral ischemic event, myocardial infarction (MI), deep vein thrombosis (DVT), pulmonary embolism (PE), or any other thromboembolic event | From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days) |
| Minneapolis |
| Minnesota |
| 55415 |
| United States |
| Mayo Clinic Rochester | Rochester | Minnesota | 55905 | United States |
| St Paul Regions Hospital | Saint Paul | Minnesota | 55101 | United States |
| University of Cincinnati Medical Center | Cincinnati | Ohio | 45267 | United States |
| Oregon Health & Sciences University | Portland | Oregon | 97239-3098 | United States |
| Dallas Center for Resuscitation Research | Dallas | Texas | 75390 | United States |
| Memorial Hermann Hospital - Texas Medical Center | Houston | Texas | 77030 | United States |
| Harborview Medical Center | Seattle | Washington | 98104 | United States |
| Milwaukee Resuscitation Research Center | Milwaukee | Wisconsin | 53226 | United States |
| British Columbia Regional Coordinating Center | Vancouver | British Columbia | V5Z 1 M9 | Canada |
| Toronto RescuNet | Toronto | Ontario | M5B 1W8 | Canada |
| 38685481 | Derived | Rowell S, Meier EN, Hoyos Gomez T, Fleming M, Jui J, Morrison L, Bulger E, Sopko G, Weisfeldt M, Christenson J, Klotz P, McMullan J, Callum J, Sheehan K, Tibbs B, Aufderheide T, Cotton B, Gandhi R, Idris A, Frascone RJ, Ferrara M, Richmond N, Kannas D, Schlamp R, Robinson B, Dries D, Tallon J, Hendrickson A, Gamber M, Garrett J, Simonson R, McKinley WI, Schreiber M. The effects of prehospital TXA on mortality and neurologic outcomes in patients with traumatic intracranial hemorrhage: A subgroup analysis from the prehospital TXA for TBI trial. J Trauma Acute Care Surg. 2024 Oct 1;97(4):572-580. doi: 10.1097/TA.0000000000004354. Epub 2024 Apr 30. |
| 37807179 | Derived | Hoefer LE, Benjamin AJ, Polcari AM, Schreiber MA, Zakrison TL, Rowell SE. TXA does not affect levels of TBI-related biomarkers in blunt TBI with ICH: A secondary analysis of the prehospital TXA for TBI trial. J Trauma Acute Care Surg. 2024 Jan 1;96(1):94-100. doi: 10.1097/TA.0000000000004130. Epub 2023 Oct 9. |
| 35358154 | Derived | Harmer JW, Dewey EN, Meier EN, Rowell SE, Schreiber MA. Tranexamic acid is not inferior to placebo with respect to adverse events in suspected traumatic brain injury patients not in shock with a normal head computed tomography scan: A retrospective study of a randomized trial. J Trauma Acute Care Surg. 2022 Jul 1;93(1):98-105. doi: 10.1097/TA.0000000000003635. Epub 2022 Mar 28. |
| 32897344 | Derived | Rowell SE, Meier EN, McKnight B, Kannas D, May S, Sheehan K, Bulger EM, Idris AH, Christenson J, Morrison LJ, Frascone RJ, Bosarge PL, Colella MR, Johannigman J, Cotton BA, Callum J, McMullan J, Dries DJ, Tibbs B, Richmond NJ, Weisfeldt ML, Tallon JM, Garrett JS, Zielinski MD, Aufderheide TP, Gandhi RR, Schlamp R, Robinson BRH, Jui J, Klein L, Rizoli S, Gamber M, Fleming M, Hwang J, Vincent LE, Williams C, Hendrickson A, Simonson R, Klotz P, Sopko G, Witham W, Ferrara M, Schreiber MA. Effect of Out-of-Hospital Tranexamic Acid vs Placebo on 6-Month Functional Neurologic Outcomes in Patients With Moderate or Severe Traumatic Brain Injury. JAMA. 2020 Sep 8;324(10):961-974. doi: 10.1001/jama.2020.8958. |
1 gram IV TXA bolus in the prehospital setting followed by a 1 gram IV maintenance infusion initiated on hospital arrival and infused over 8 hours.
| FG002 | Bolus Only | 2 grams IV TXA bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours. |
| COMPLETED |
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| NOT COMPLETED |
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| Prehospital Study Drug Infusion |
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| In-Hospital Study Drug Infusion |
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| 6-Month Follow-up |
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Subjects for whom study drug administration was started minus one Bolus Only arm subject who was mistakenly enrolled while in police custody.
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| ID | Title | Description |
|---|---|---|
| BG000 | Placebo | Placebo IV bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours. |
| BG001 | Bolus-Maintenance | 1 gram IV TXA bolus in the prehospital setting followed by a 1 gram IV maintenance infusion initiated on hospital arrival and infused over 8 hours. |
| BG002 | Bolus Only | 2 grams IV TXA bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours. |
| BG003 | Total | Total of all reporting groups |
| Units | Counts |
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| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median | Inter-Quartile Range | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Ethnicity was not reported at Canadian sites. | Count of Participants | Participants |
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| Race (NIH/OMB) | Race was not reported at Canadian sites. | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Penetrating injury | Count of Participants | Participants |
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| Cause of injury | Cause of injury missing on 1 placebo participant and 5 bolus only participants. | Count of Participants | Participants |
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| Prehospital Glasgow Coma Scale | Neurological scale used to assess the level of consciousness following traumatic brain injury. Scores range from 3 to 15. Scores of 3-8 are generally considered severe, 9-12 moderate, and 13-15 minor. | Count of Participants | Participants |
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| Injury Severity Score (ISS) | The Injury Severity Score is a measure used to assess trauma severity. It is correlated with mortality, morbidity, and hospital length of stay. The score ranges between 0 (no injury) and 75 (unsurvivable injury). Scores greater than 15 are defined as major trauma. | ISS is sometimes not available if the patient dies early or there is insufficient information about injuries in specific body regions. The measure is missing for 7 placebo, 8 bolus-maintenance, and 3 bolus only participants. | Median | Inter-Quartile Range | score on a scale |
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| Head Abbreviated Injury Score (AIS) | The Abbreviated Injury Scale is an anatomical-based coding system used to classify and describe the severity of injuries. The scores for a particular region range from 0 (no injury) to 6 (unsurvivable injury). | Head AIS is sometimes not available if the patient dies early or there is insufficient information about injuries to the head. The measure is missing for 8 placebo, 6 bolus-maintenance, and 1 bolus only participants. | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Dichotomized Glasgow Outcome Scale Extended (GOS-E) at 6 Months | GOS-E subdivides the categories of severe and moderate disability and good recovery using a scale of 1 to 8 where 1 = death, 2 = vegetative state, 3 = lower severe disability, 4 = upper severe disability, 5 = lower moderate disability, 6 = upper moderate disability, 7 = lower good recovery, and 8 = upper good recovery. Structured telephone interviews have been developed and validated for the GOS-E and these questions were incorporated into the follow-up survey. GOS-E was dichotomized into unfavorable (1 to 4) and favorable (5 to 8) outcomes. | Subjects for whom study drug administration was started minus one Bolus Only arm subject who was mistakenly enrolled while in police custody. | Posted | Count of Participants | Participants | 6 months post-injury |
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| Secondary | Number of Participants Who Died Within 28 Days | The counts of patients who died on or before day 28 are reported. | Subjects for whom study drug administration was started and 28-day vital status was definitively obtained. Patients excluded from the counts include subjects who withdrew from the study prior to day 28 and subjects who were lost to follow-up. | Posted | Count of Participants | Participants | 28 days after hospital arrival |
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| Secondary | Disability Rating Scale (DRS) at 6 Months | The DRS is designed to classify patients based on their degree of function after brain injury. The DRS consists of 8 items that fall into 4 categories: (a) arousability, awareness and responsivity, (b) cognitive ability for self-care activities, (c) dependence on others, and (d) psychosocial adaptability. The score ranges from 0 (no disability) to 30 (death). | Subjects for whom study drug administration was started and DRS questions were obtained at 6 months. Excluded subjects include those who withdrew prior to 6 months after injury and those lost to follow-up. | Posted | Mean | Standard Deviation | score on a scale | 6 months post-injury |
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| Secondary | Number of Participants With Unfavorable Outcome on Dichotomized Glasgow Outcome Scale Extended (GOS-E) at Discharge | GOS-E subdivides the categories of severe and moderate disability and good recovery using a scale of 1 to 8 where 1 = death, 2 = vegetative state, 3 = lower severe disability, 4 = upper severe disability, 5 = lower moderate disability, 6 = upper moderate disability, 7 = lower good recovery, and 8 = upper good recovery. Structured telephone interviews have been developed and validated for the GOS-E and these questions were incorporated into the follow-up survey. GOS-E was dichotomized into unfavorable (1 to 4) and favorable (5 to 8) outcomes. The number of subjects with unfavorable outcome is reported. | Subjects for whom study drug administration was started and for whom Glasgow Outcome Score Extended was obtained at discharge. Subjects who withdrew prior to discharge make up most of the subjects who were excluded from this analysis. | Posted | Count of Participants | Participants | At the end of the hospital stay (average of 9 days post injury) |
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| Secondary | Disability Rating Scale (DRS) at Discharge | The DRS is designed to classify patients based on their degree of function after brain injury. The DRS consists of 8 items that fall into 4 categories: (a) arousability, awareness and responsivity, (b) cognitive ability for self-care activities, (c) dependence on others, and (d) psychosocial adaptability. The score ranges from 0 (no disability) to 30 (death). | Subjects for whom study drug administration was started and for whom discharge Disability Rating Scale was obtained. Subjects who withdrew prior to discharge make up most of the subjects who were excluded from this analysis. | Posted | Mean | Standard Deviation | score on a scale | At the end of the hospital stay (average of 9 days post injury) |
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| Secondary | Number of Participants With Intracranial Hemorrhage (ICH) Progression | All clinically indicated head computed tomography (CT) scans obtained during the initial hospitalization or within the first 28 days were assessed for ICH. Parenchymal (IPH), subdural (SDH) and epidural (EDH) hemorrhage volumes were measured and quantified using volumetric software and verified by manual calculations based on the previously validated ABC/2 technique. The sum of the IPH, SDH, and EDH volumes were compared across scans. A relative increase of 33% (and at least a 1 ml increase) on any subsequent scan compared to the initial scan was defined as a progression. | Subjects for whom study drug administration was started and for whom two or more analyzable head CT scans were obtained prior to a hematoma evacuation. Excluded subjects primarily include those who died or withdrew before an initial or second CT scan was taken, who had a hematoma evacuation prior to a second scan, or who had only one negative CT. | Posted | Count of Participants | Participants | From hospital admission through 28 days or the end of the hospital stay if sooner (average of 13 days among patients with multiple scans) |
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| Secondary | Marshall Computed Tomography (CT) Score on Initial Head CT | The Marshall classification categorizes patients into one of six categories (I to VI) of increasing severity on the basis of findings on non-contrast CT scan of the brain. Higher categories have worse prognosis and survival. | Subjects who received an initial head computed tomography scan with sufficient information to be scored. | Posted | Count of Participants | Participants | Initial head CT (average of 1.9 hours post-injury) |
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| Secondary | Rotterdam Computed Tomography (CT) Score Among Subjects With Intracranial Hemorrhage (ICH) on Initial Head CT | The Rotterdam classification includes four independently scored elements: degree of basal cistern compression, degree of midline shift, presence of epidural hematomas, and presence of intraventricular or subarachnoid blood. The elements are combined to form an overall score from 1 to 6 with higher scores having worse prognosis and survival. | Subjects determined by the central image reviewer to have an intracranial hemorrhage (ICH) on the initial head computed tomography (CT) scan and sufficient information to assign the Rotterdam score. | Posted | Count of Participants | Participants | Initial head CT (average of 1.9 hours post-injury) |
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| Secondary | Number of Participants With One or More Neurosurgical Interventions | Neurosurgical interventions include craniotomy, craniectomy, and placement of a neuromonitoring or drainage device. Counts are of subjects with one or more neurosurgical interventions. | Subjects for whom study drug administration was started minus one Bolus Only arm subject who was mistakenly enrolled while in police custody. | Posted | Count of Participants | Participants | From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days) |
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| Secondary | Hospital-free Days | Hospital-free days count any day from hospital admission through day 28 that the patient is alive and out of the hospital. | Subjects for whom study drug administration was started and for whom discharge status was known. Subjects who withdrew prior to discharge make up most of the subjects who were excluded from this analysis. | Posted | Mean | Standard Deviation | days | From hospital admission through day 28 |
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| Secondary | Intensive Care Unit (ICU)-Free Days | ICU-free days count any day from hospital admission through day 28 that the patient is alive and not in the ICU. Subjects who die prior to discharge (even if after 28 days) are assigned a value of 0. | Subjects for whom study drug administration was started and for whom number of ICU days through 28 days was known. Subjects who withdrew prior to discharge make up most of the subjects who were excluded from this analysis. | Posted | Mean | Standard Deviation | days | From hospital admission through day 28 |
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| Secondary | Ventilator-free Days | Ventilator-free days count any day from hospital admission through day 28 that the patient is alive and does not require mechanical ventilatory support. Subjects who die prior to discharge (even if after 28 days) are assigned a value of 0. | Subjects for whom study drug administration was started and for whom number of ventilator days through 28 days was known. Subjects who withdrew prior to discharge make up most of the subjects who were excluded from this analysis. | Posted | Mean | Standard Deviation | days | From hospital admission through day 28 |
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| Secondary | Number of Participants With Seizure | Seizures may cause involuntary changes in body movement or function, sensation, awareness, or behavior. Seizures are often associated with a sudden and involuntary contraction of a group of muscles and loss of consciousness. Seizures or episodes of seizure-like activity were reported by medics in the field following the start of study drug infusion through hand-off to the trauma center and by trauma center staff through discharge. Reported events were included if providers gave anti-seizure medication and/or the event was confirmed by EEG. | Subjects for whom study drug administration was started minus one Bolus Only arm subject who was mistakenly enrolled while in police custody. | Posted | Count of Participants | Participants | From start of study drug infusion through 28 days or the end of the hospital stay if sooner (average of 9 days) |
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| Secondary | Number of Participants With Cerebral Ischemic Event | Diagnosis of cerebral ischemic event | Subjects for whom study drug administration was started minus one Bolus Only arm subject who was mistakenly enrolled while in police custody. | Posted | Count of Participants | Participants | From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days) |
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| Secondary | Number of Participants With Myocardial Infarction (MI) | Diagnosis of an acute myocardial infarction | Subjects for whom study drug administration was started minus one Bolus Only arm subject who was mistakenly enrolled while in police custody. | Posted | Count of Participants | Participants | From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days) |
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| Secondary | Number of Participants With Deep Vein Thrombosis (DVT) | Diagnosis of DVT | Subjects for whom study drug administration was started minus one Bolus Only arm subject who was mistakenly enrolled while in police custody. | Posted | Count of Participants | Participants | From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days) |
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| Secondary | Number of Participants With Pulmonary Embolus (PE) | Diagnosis of PE | Subjects for whom study drug administration was started minus one Bolus Only arm subject who was mistakenly enrolled while in police custody. | Posted | Count of Participants | Participants | From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days) |
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| Secondary | Number of Participants With Any Thromboembolic Event | Diagnosis of one or more of the following: cerebral ischemic event, myocardial infarction (MI), deep vein thrombosis (DVT), pulmonary embolism (PE), or any other thromboembolic event | Subjects for whom study drug administration was started minus one Bolus Only arm subject who was mistakenly enrolled while in police custody. | Posted | Count of Participants | Participants | From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days) |
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| Other Pre-specified | Fibrinolysis at Hospital Admission | Alterations in fibrinolysis based on fibrinolytic pathway mediators and degree of clot lysis based on kaolin-activated thromboelastography (TEG) and defined as LY30 or the per cent lysis that occurs 30 minutes after maximum amplitude (MA) is achieved. LY30 is categorized as <0.8% (fibrinolysis shutdown), 0.8-3% (normal), and >3% (hyperfibrinolysis). | Subjects with an LY30 measurement at hospital admission are included. Subjects who were transported to trauma centers without a TEG machine, who died prior to the initial blood draw, or who withdrew or refused a blood draw were excluded. Additional exclusions included blood draw missed by study staff and technical difficulties with processing. | Posted | Count of Participants | Participants | First blood draw (average of 1.6 hours post-injury) |
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Adverse events data were captured from the beginning of study drug infusion on day 0 through day 28. While follow-up time varies by patient due to withdrawals, transfers to non-participating hospitals, deaths, and participants lost to follow-up, all analysis patients were "at risk" for adverse events during at least some period of time and are thus included in all adverse event denominators.
Chart reviews were made daily. Events prespecified as possibly related to study drug were categorized for seriousness by site PIs and are listed in both the "Serious" and "Other" AE sections below. Other events (marked with "^") were monitored and reported but not considered adverse events of the study drug. These are listed in the "Other" AE section since they were not assessed for seriousness. One Bolus Only arm subject who was mistakenly enrolled while in police custody is excluded.
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Placebo | Placebo IV bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours. | 50 | 309 | 25 | 309 | 81 | 309 |
| EG001 | Bolus-Maintenance | 1 gram IV TXA bolus in the prehospital setting followed by a 1 gram IV maintenance infusion initiated on hospital arrival and infused over 8 hours. | 53 | 312 | 13 | 312 | 74 | 312 |
| EG002 | Bolus Only | 2 grams IV TXA bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours. | 40 | 345 | 24 | 345 | 92 | 345 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Disseminated intravascular coagulation | Blood and lymphatic system disorders | Systematic Assessment |
| ||
| Myocardial infarction (MI) | Cardiac disorders | Systematic Assessment |
| ||
| Cerebrovascular accident - hemorrhagic | Nervous system disorders | Systematic Assessment |
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| Cerebrovascular accident - thrombotic | Nervous system disorders | Systematic Assessment |
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| Seizures | Nervous system disorders | Systematic Assessment |
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| Pulmonary embolism (PE) | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| Cerebral vascular emboli | Vascular disorders | Systematic Assessment |
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| Cerebral venus sinus thrombosis | Vascular disorders | Systematic Assessment |
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| Deep vein thrombosis (DVT) | Vascular disorders | Systematic Assessment |
| ||
| Embolic infarcts | Vascular disorders | Systematic Assessment |
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| Inferior vena cava thrombus | Vascular disorders | Systematic Assessment |
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| Internal jugular vein thrombus | Vascular disorders | Systematic Assessment |
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| Left ventricular thrombus | Vascular disorders | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Cardiac arrest (non-fatal)^ | Cardiac disorders | Systematic Assessment |
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| Cardiac failure^ | Cardiac disorders | Systematic Assessment |
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| Myocardial infarction (MI) | Cardiac disorders | Systematic Assessment |
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| Pseudomembranous colitis^ | Gastrointestinal disorders | Systematic Assessment |
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| Abdominal Compartment Syndrome^ | General disorders | Systematic Assessment |
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| Central diabetes insipidus^ | General disorders | Systematic Assessment |
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| Cerebral vasospams^ | General disorders | Systematic Assessment |
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| Extremity Compartment Syndrome^ | General disorders | Systematic Assessment |
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| Cholecystitis^ | Hepatobiliary disorders | Systematic Assessment |
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| Liver failure^ | Hepatobiliary disorders | Systematic Assessment |
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| Bloodstream infection^ | Infections and infestations | Systematic Assessment |
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| Empyema^ | Infections and infestations | Systematic Assessment |
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| Intra-abdominal abscess^ | Infections and infestations | Systematic Assessment |
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| Meningitis^ | Infections and infestations | Systematic Assessment |
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| Pneumonia^ | Infections and infestations | Systematic Assessment |
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| Sepsis^ | Infections and infestations | Systematic Assessment |
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| Urinary tract infection (UTI)^ | Infections and infestations | Systematic Assessment |
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| Wound infection^ | Infections and infestations | Systematic Assessment |
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| Hypernatremia^ | Metabolism and nutrition disorders | Systematic Assessment |
| ||
| Cerebrovascular accident - hemorrhagic | Nervous system disorders | Systematic Assessment |
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| Cerebrovascular accident - thrombotic | Nervous system disorders | Systematic Assessment |
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| Seizures | Nervous system disorders | Systematic Assessment |
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| Acute kidney injury (AKI)^ | Renal and urinary disorders | Systematic Assessment |
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| Renal failure^ | Renal and urinary disorders | Systematic Assessment |
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| Acute Respiratory Distress Syndrome (ARDS)^ | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
| ||
| Pulmonary embolism (PE) | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
| ||
| Cerebral venus sinus thrombosis | Vascular disorders | Systematic Assessment |
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| Deep vein throbosis (DVT) | Vascular disorders | Systematic Assessment |
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| Superficial venus thrombosis | Vascular disorders | Systematic Assessment |
|
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Susanne May | University of Washington, Resuscitation Outcomes Consortium | 206-685-1302 | rochelp@uwctc.org |
| Apr 3, 2015 |
| Jul 26, 2018 |
| Prot_SAP_ICF_000.pdf |
| Prot_SAP_ICF | Yes | Yes | Yes | Study Protocol, Statistical Analysis Plan, and Informed Consent Form: Protocol after Amendment 2 | Jul 29, 2015 | Jul 26, 2018 | Prot_SAP_ICF_001.pdf |
| Prot_SAP_ICF | Yes | Yes | Yes | Study Protocol, Statistical Analysis Plan, and Informed Consent Form: Protocol after Amendment 2.1 | Aug 2, 2016 | Jul 26, 2018 | Prot_SAP_ICF_002.pdf |
| ID | Term |
|---|---|
| D000070642 | Brain Injuries, Traumatic |
| D020300 | Intracranial Hemorrhages |
| ID | Term |
|---|---|
| D001930 | Brain Injuries |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D006259 | Craniocerebral Trauma |
| D020196 | Trauma, Nervous System |
| D014947 | Wounds and Injuries |
| D002561 | Cerebrovascular Disorders |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D006470 | Hemorrhage |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
Not provided
Not provided
| ID | Term |
|---|---|
| D014148 | Tranexamic Acid |
| D000077330 | Saline Solution |
| ID | Term |
|---|---|
| D003509 | Cyclohexanecarboxylic Acids |
| D000146 | Acids, Carbocyclic |
| D002264 | Carboxylic Acids |
| D009930 | Organic Chemicals |
| D000077324 | Crystalloid Solutions |
| D007552 | Isotonic Solutions |
| D012996 | Solutions |
| D004364 | Pharmaceutical Preparations |
Not provided
Not provided
| Required CPR |
|
| Other safety concern |
|
| Death |
|
| Discharged |
|
| Withdrawal by Subject |
|
| Emergency unblinding |
|
| Unknown if completed |
|
| Withdrawal by Subject |
|
| Death or comfort care |
|
| Emergency unblinding |
|
| Seizure or concern for seizure |
|
| CVA/thrombotic event or concern for one |
|
| Required CPR |
|
| Other safety concern |
|
| Taken into police custody |
|
| Found not to be injured |
|
| Transfer to non-participating facility |
|
| Other procoagulant administered |
|
| Unknown if completed |
|
| No contact information |
|
| Homeless |
|
| Prisoner at time of enrollment |
|
| Prisoner at time of follow-up |
|
| Patient at psychiatric hospital |
|
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|
|
|
| United States |
|
|
|
|
|
|
|
| Favorable GOS-E (>4) |
|
| Missing GOS-E |
|
Odds ratio for unfavorable GOS-E (<=4) for the Combined TXA Arms (numerator) vs. Placebo (denominator)
| Superiority |
| Units |
|---|
| Counts |
|---|
| Participants |
|
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|
|
| OG002 | Bolus Only | 2 grams IV TXA bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours. |
|
|
|
|
| OG002 | Bolus Only | 2 grams IV TXA bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours. |
|
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| Units | Counts |
|---|
| Participants |
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| Units | Counts |
|---|---|
| Participants |
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| Units |
|---|
| Counts |
|---|
| Participants |
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| Units | Counts |
|---|---|
| Participants |
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| Units | Counts |
|---|---|
| Participants |
|
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2 grams IV TXA bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours. |
|
|
| Participants |
|
|
| Participants |
|
|
| Participants |
|
|
| Participants |
|
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| Units | Counts |
|---|---|
| Participants |
|
|
2 grams IV TXA bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.
|
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