TXA: Prehospital Tranexamic Acid Use for Traumatic Brain Injury

• Sponsor: University of Washington (Other)
• Overall Status: Completed
• CT.gov ID: NCT01990768
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH), U.S. Army Medical Research and Development Command (U.S. Fed), Canadian Institutes of Health Research (CIHR) (Other), Heart and Stroke Foundation of Canada (Other), American Heart Association (Other), Defence Research and Development Canada (Industry)
• Enrollment: 967
• Locations: 12
• Arms: 3
• Duration (Months): 30.3
• Patients Per Site: 80.6
• Patients Per Site Per Month: 2.7

Study Details

Study Description

Brief Summary

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:

• Clinical outcomes: ICH progression, Marshall and Rotterdam CT classification scores, DRS at discharge and 6 months, GOS-E at discharge, 28-day survival, frequency of neurosurgical interventions, and ventilator-free, ICU-free, and hospital-free days.

• Safety outcomes: Development of seizures, cerebral ischemic events, myocardial infarction, deep venous thrombosis, and pulmonary thromboembolism.

• Mechanistic outcomes: Alterations in fibrinolysis based on fibrinolytic pathway mediators and degree of clot lysis based on TEG.

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:

• 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.

• 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.

• Placebo: Placebo IV bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.

Condition or Disease	Intervention/Treatment	Phase
Traumatic Brain Injury	Drug: 1 gram Tranexamic Acid (TXA); Drug: 2 grams TXA; Drug: 0.9% Sodium Chloride injectable	Phase 2

Detailed Description

1. 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.

2. 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.

1. 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.

1. 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.

1. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 967 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Prehospital Tranexamic Acid Use for Traumatic Brain Injury
• Study Start Date: May 1, 2015
• Actual Primary Completion Date: Nov 7, 2017
• Actual Study Completion Date: Nov 7, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 gram Tranexamic Acid (TXA) Loading dose of 1 gram TXA given prior to hospital arrival followed by a 1 gram TXA infusion over 8 hours after hospital arrival	Drug: 1 gram Tranexamic Acid (TXA); TXA produces an antifibrinolytic effect by competitively inhibiting the activation of plasminogen to plasmin.; Other Names: Cyklokapron
Experimental: 2 grams TXA 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	Drug: 2 grams TXA; TXA produces an antifibrinolytic effect by competitively inhibiting the activation of plasminogen to plasmin.; Other Names: Cyklokapron
Placebo Comparator: 0.9% Sodium Chloride injectable 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	Drug: 0.9% Sodium Chloride injectable; 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.; Other Names: Normal saline solution

Outcome Measures

Primary Outcome Measures

1. Dichotomized Glasgow Outcome Scale Extended (GOS-E) at 6 Months [6 months post-injury]

   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.

Secondary Outcome Measures

1. Number of Participants Who Died Within 28 Days [28 days after hospital arrival]

   The counts of patients who died on or before day 28 are reported.

2. Disability Rating Scale (DRS) at 6 Months [6 months post-injury]

   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).

3. Number of Participants With Unfavorable Outcome on Dichotomized Glasgow Outcome Scale Extended (GOS-E) at Discharge [At the end of the hospital stay (average of 9 days post injury)]

   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.

4. Disability Rating Scale (DRS) at Discharge [At the end of the hospital stay (average of 9 days post injury)]

   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).

5. Number of Participants With Intracranial Hemorrhage (ICH) 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)]

   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.

6. Marshall Computed Tomography (CT) Score on Initial Head CT [Initial head CT (average of 1.9 hours post-injury)]

   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.

7. Rotterdam Computed Tomography (CT) Score Among Subjects With Intracranial Hemorrhage (ICH) on Initial Head CT [Initial head CT (average of 1.9 hours post-injury)]

   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.

8. Number of Participants 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)]

   Neurosurgical interventions include craniotomy, craniectomy, and placement of a neuromonitoring or drainage device. Counts are of subjects with one or more neurosurgical interventions.

9. Hospital-free Days [From hospital admission through day 28]

   Hospital-free days count any day from hospital admission through day 28 that the patient is alive and out of the hospital.

10. Intensive Care Unit (ICU)-Free Days [From hospital admission through day 28]

    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.

11. Ventilator-free Days [From hospital admission through day 28]

    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.

12. Number of Participants With Seizure [From start of study drug infusion through 28 days or the end of the hospital stay if sooner (average of 9 days)]

    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.

13. Number of Participants With Cerebral Ischemic Event [From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days)]

    Diagnosis of cerebral ischemic event

14. Number of Participants With Myocardial Infarction (MI) [From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days)]

    Diagnosis of an acute myocardial infarction

15. Number of Participants With Deep Vein Thrombosis (DVT) [From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days)]

    Diagnosis of DVT

16. Number of Participants With Pulmonary Embolus (PE) [From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days)]

    Diagnosis of PE

17. Number of Participants With Any Thromboembolic Event [From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days)]

    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

Other Outcome Measures

1. Fibrinolysis at Hospital Admission [First blood draw (average of 1.6 hours post-injury)]

   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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 15 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Blunt or penetrating traumatic mechanism consistent with traumatic brain injury

2. Prehospital Glasgow Coma Score (GCS) score ≤ 12 at any time prior to randomization and administration of sedative and/or paralytic agents

3. Prehospital systolic blood pressure (SBP) ≥ 90 mmHg prior to randomization

4. Prehospital intravenous (IV) or intraosseous (IO) access

5. Estimated Age ≥ 15 (or estimated weight > 50 kg if age is unknown)

6. Emergency Medicine System (EMS) transport to a participating trauma center

Exclusion Criteria:

1. Prehospital GCS=3 with no reactive pupil

2. Estimated time from injury to hospital arrival > 2 hours

3. Unknown time of injury - no known reference times to support estimation

4. Clinical suspicion by EMS of seizure activity or known history of seizures, acute myocardial infarction (MI) or stroke

5. Cardio-pulmonary resuscitation (CPR) by EMS prior to randomization

6. Burns > 20% total body surface area (TBSA)

7. Suspected or known prisoners

8. Suspected or known pregnancy

9. Prehospital TXA given prior to randomization

10. Subjects who have activated the "opt-out" process when required by the local regulatory board

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Alabama Resuscitation Center	Birmingham	Alabama	United States	35249
2	Hennepin County Medical Center	Minneapolis	Minnesota	United States	55415
3	Mayo Clinic Rochester	Rochester	Minnesota	United States	55905
4	St Paul Regions Hospital	Saint Paul	Minnesota	United States	55101
5	University of Cincinnati Medical Center	Cincinnati	Ohio	United States	45267
6	Oregon Health & Sciences University	Portland	Oregon	United States	97239-3098
7	Dallas Center for Resuscitation Research	Dallas	Texas	United States	75390
8	Memorial Hermann Hospital - Texas Medical Center	Houston	Texas	United States	77030
9	Harborview Medical Center	Seattle	Washington	United States	98104
10	Milwaukee Resuscitation Research Center	Milwaukee	Wisconsin	United States	53226
11	British Columbia Regional Coordinating Center	Vancouver	British Columbia	Canada	V5Z 1 M9
12	Toronto RescuNet	Toronto	Ontario	Canada	M5B 1W8

Sponsors and Collaborators

• University of Washington
• National Heart, Lung, and Blood Institute (NHLBI)
• U.S. Army Medical Research and Development Command
• Canadian Institutes of Health Research (CIHR)
• Heart and Stroke Foundation of Canada
• American Heart Association
• Defence Research and Development Canada

Investigators

• Principal Investigator: Susanne May, PhD, University of Washington
• Principal Investigator: Martin Schreiber, MD FACS, Oregon Health and Science University

Study Documents (Full-Text)

• Study Protocol, Statistical Analysis Plan, and Informed Consent Form: Protocol in force at beginning of enrollment - Apr 3, 2015
• Study Protocol, Statistical Analysis Plan, and Informed Consent Form: Protocol after Amendment 2 - Jul 29, 2015
• Study Protocol, Statistical Analysis Plan, and Informed Consent Form: Protocol after Amendment 2.1 - Aug 2, 2016

More Information

Publications

None provided.

• Responsible Party: Susanne May, Associate Professor, University of Washington
• ClinicalTrials.gov Identifier: NCT01990768
• Other Study ID Numbers: 47114; 5U01HL077863-09; TATRC Log No. 13335004-A
• First Posted: Nov 21, 2013
• Last Update Posted: Jan 14, 2019
• Last Verified: Dec 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Susanne May, Associate Professor, University of Washington: tranexamic acid; traumatic brain injury; intracranial hemorrhage; prehospital; neurologic outcome; glasgow outcome scale extended; disability rating scale
• Additional relevant MeSH terms: Brain Injuries; Brain Injuries, Traumatic; Wounds and Injuries; Tranexamic Acid

Study Results

Participant Flow

Recruitment Details	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.
Pre-assignment Detail	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.

Arm/Group Title	Placebo	Bolus-Maintenance	Bolus Only
Arm/Group Description	Placebo IV bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.	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.	2 grams IV TXA bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.
Period Title: Intervention Started
STARTED	345	345	373
COMPLETED	309	312	346
NOT COMPLETED	36	33	27
Period Title: Intervention Started
STARTED	309	312	346
COMPLETED	290	285	327
NOT COMPLETED	19	27	19
Period Title: Intervention Started
STARTED	309	312	346
COMPLETED	214	229	266
NOT COMPLETED	95	83	80
Period Title: Intervention Started
STARTED	309	312	346
COMPLETED	270	261	288
NOT COMPLETED	39	51	58

Baseline Characteristics

Arm/Group Title	Placebo	Bolus-Maintenance	Bolus Only	Total
Arm/Group Description	Placebo IV bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.	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.	2 grams IV TXA bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.	Total of all reporting groups
Overall Participants	309	312	345	966
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	36	39	40	38
Sex: Female, Male (Count of Participants)
Female	76 24.6%	85 27.2%	90 26.1%	251 26%
Male	233 75.4%	227 72.8%	255 73.9%	715 74%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	40 12.9%	40 12.8%	43 12.5%	123 12.7%
Not Hispanic or Latino	225 72.8%	224 71.8%	251 72.8%	700 72.5%
Unknown or Not Reported	44 14.2%	48 15.4%	51 14.8%	143 14.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	2 0.6%	4 1.3%	4 1.2%	10 1%
Asian	7 2.3%	13 4.2%	10 2.9%	30 3.1%
Native Hawaiian or Other Pacific Islander	1 0.3%	1 0.3%	1 0.3%	3 0.3%
Black or African American	46 14.9%	50 16%	53 15.4%	149 15.4%
White	213 68.9%	202 64.7%	227 65.8%	642 66.5%
More than one race	2 0.6%	3 1%	0 0%	5 0.5%
Unknown or Not Reported	38 12.3%	39 12.5%	50 14.5%	127 13.1%
Region of Enrollment (participants) [Number]
Canada	24 7.8%	28 9%	36 10.4%	88 9.1%
United States	285 92.2%	284 91%	309 89.6%	878 90.9%
Penetrating injury (Count of Participants)
Count of Participants [Participants]	16 5.2%	12 3.8%	5 1.4%	33 3.4%
Cause of injury (Count of Participants)
Motor vehicle occupant	113 36.6%	103 33%	115 33.3%	331 34.3%
Motor vehicle motorcycle	33 10.7%	32 10.3%	44 12.8%	109 11.3%
Motor vehicle bicycle/pedestrian	56 18.1%	61 19.6%	62 18%	179 18.5%
Fall at ground level	37 12%	44 14.1%	45 13%	126 13%
Fall at more than 1 meter	32 10.4%	40 12.8%	38 11%	110 11.4%
Assault	24 7.8%	20 6.4%	25 7.2%	69 7.1%
Suicide	9 2.9%	8 2.6%	5 1.4%	22 2.3%
Other	4 1.3%	4 1.3%	6 1.7%	14 1.4%
Prehospital Glasgow Coma Scale (Count of Participants)
3-8	186 60.2%	169 54.2%	177 51.3%	532 55.1%
9-12	115 37.2%	129 41.3%	159 46.1%	403 41.7%
13-15	8 2.6%	14 4.5%	9 2.6%	31 3.2%
Injury Severity Score (ISS) (score on a scale) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [score on a scale]	17	17	17	17
Head Abbreviated Injury Score (AIS) (Count of Participants)
0-1	76 24.6%	86 27.6%	103 29.9%	265 27.4%
2	46 14.9%	48 15.4%	48 13.9%	142 14.7%
3	61 19.7%	64 20.5%	66 19.1%	191 19.8%
4	67 21.7%	56 17.9%	71 20.6%	194 20.1%
5-6	51 16.5%	52 16.7%	56 16.2%	159 16.5%

Outcome Measures

1. Primary Outcome

Title	Dichotomized Glasgow Outcome Scale Extended (GOS-E) at 6 Months
Description	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.
Time Frame	6 months post-injury

Outcome Measure Data

Analysis Population Description

Subjects for whom study drug administration was started minus one Bolus Only arm subject who was mistakenly enrolled while in police custody.

Arm/Group Title	Placebo	Bolus-Maintenance	Bolus Only	Combined TXA Arms
Arm/Group Description	Placebo IV bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.	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.	2 grams IV TXA bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.	Includes both the 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) and 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) treatment arms.
Measure Participants	309	312	345	657
Unfavorable GOS-E (<=4)	107 34.6%	108 34.6%	110 31.9%	218 22.6%
Favorable GOS-E (>4)	163 52.8%	153 49%	178 51.6%	331 34.3%
Missing GOS-E	39 12.6%	51 16.3%	57 16.5%	108 11.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Combined TXA Arms
	Comments	This study was designed with an asymmetric boundary for tests for treatment harm and benefit. The conventional 0.025 level was used to test for harm while a 0.1 level was used to determine benefit for this Phase II trial. Statistical significance for the primary analysis was conducted under a group-sequential design that included a single, interim futility analysis using a Wang-Tsiatis boundary with parameter 0.8 based on outcome data from the first 200 subjects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.1809
	Comments	Based on an interim futility analysis, a one-sided P-value less than .1028 was required to declare benefit.
	Method	Regression, Logistic
	Comments	Analysis was adjusted for regional site. Missing outcomes were multiply imputed.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.87
	Confidence Interval	(1-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio for unfavorable GOS-E (<=4) for the Combined TXA Arms (numerator) vs. Placebo (denominator)

2. Secondary Outcome

Title	Number of Participants Who Died Within 28 Days
Description	The counts of patients who died on or before day 28 are reported.
Time Frame	28 days after hospital arrival

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo	Bolus-Maintenance	Bolus Only
Arm/Group Description	Placebo IV bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.	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.	2 grams IV TXA bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.
Measure Participants	285	285	318
Count of Participants [Participants]	50 16.2%	53 17%	40 11.6%

3. Secondary Outcome

Title	Disability Rating Scale (DRS) at 6 Months
Description	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).
Time Frame	6 months post-injury

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo	Bolus-Maintenance	Bolus Only
Arm/Group Description	Placebo IV bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.	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.	2 grams IV TXA bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.
Measure Participants	266	261	287
Mean (Standard Deviation) [score on a scale]	8.0 (11.8)	8.1 (11.9)	6.6 (10.8)

4. Secondary Outcome

Title	Number of Participants With Unfavorable Outcome on Dichotomized Glasgow Outcome Scale Extended (GOS-E) at Discharge
Description	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.
Time Frame	At the end of the hospital stay (average of 9 days post injury)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo	Bolus-Maintenance	Bolus Only
Arm/Group Description	Placebo IV bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.	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.	2 grams IV TXA bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.
Measure Participants	292	294	329
Count of Participants [Participants]	196 63.4%	193 61.9%	228 66.1%

5. Secondary Outcome

Title	Disability Rating Scale (DRS) at Discharge
Description	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).
Time Frame	At the end of the hospital stay (average of 9 days post injury)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo	Bolus-Maintenance	Bolus Only
Arm/Group Description	Placebo IV bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.	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.	2 grams IV TXA bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.
Measure Participants	291	294	329
Mean (Standard Deviation) [score on a scale]	9.0 (11.1)	9.4 (11.0)	8.1 (9.8)

6. Secondary Outcome

Title	Number of Participants With Intracranial Hemorrhage (ICH) Progression
Description	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.
Time Frame	From hospital admission through 28 days or the end of the hospital stay if sooner (average of 13 days among patients with multiple scans)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo	Bolus-Maintenance	Bolus Only
Arm/Group Description	Placebo IV bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.	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.	2 grams IV TXA bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.
Measure Participants	148	154	178
Count of Participants [Participants]	30 9.7%	26 8.3%	27 7.8%

7. Secondary Outcome

Title	Marshall Computed Tomography (CT) Score on Initial Head CT
Description	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.
Time Frame	Initial head CT (average of 1.9 hours post-injury)

Outcome Measure Data

Analysis Population Description

Subjects who received an initial head computed tomography scan with sufficient information to be scored.

Arm/Group Title	Placebo	Bolus-Maintenance	Bolus Only
Arm/Group Description	Placebo IV bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.	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.	2 grams IV TXA bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.
Measure Participants	291	290	332
Diffuse injury I	120 38.8%	115 36.9%	134 38.8%
Diffuse injury II	106 34.3%	117 37.5%	135 39.1%
Diffuse injury III	12 3.9%	12 3.8%	12 3.5%
Diffuse injury IV	7 2.3%	4 1.3%	5 1.4%
Mass lesion V/VI	46 14.9%	42 13.5%	46 13.3%

8. Secondary Outcome

Title	Rotterdam Computed Tomography (CT) Score Among Subjects With Intracranial Hemorrhage (ICH) on Initial Head CT
Description	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.
Time Frame	Initial head CT (average of 1.9 hours post-injury)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo	Bolus-Maintenance	Bolus Only
Arm/Group Description	Placebo IV bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.	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.	2 grams IV TXA bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.
Measure Participants	158	161	187
1	2 0.6%	1 0.3%	5 1.4%
2	32 10.4%	28 9%	36 10.4%
3	81 26.2%	91 29.2%	98 28.4%
4	17 5.5%	24 7.7%	28 8.1%
5	21 6.8%	12 3.8%	17 4.9%
6	5 1.6%	5 1.6%	3 0.9%

9. Secondary Outcome

Title	Number of Participants With One or More Neurosurgical Interventions
Description	Neurosurgical interventions include craniotomy, craniectomy, and placement of a neuromonitoring or drainage device. Counts are of subjects with one or more neurosurgical interventions.
Time Frame	From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days)

Outcome Measure Data

Analysis Population Description

Subjects for whom study drug administration was started minus one Bolus Only arm subject who was mistakenly enrolled while in police custody.

Arm/Group Title	Placebo	Bolus-Maintenance	Bolus Only
Arm/Group Description	Placebo IV bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.	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.	2 grams IV TXA bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.
Measure Participants	309	312	345
Count of Participants [Participants]	54 17.5%	62 19.9%	75 21.7%

10. Secondary Outcome

Title	Hospital-free Days
Description	Hospital-free days count any day from hospital admission through day 28 that the patient is alive and out of the hospital.
Time Frame	From hospital admission through day 28

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo	Bolus-Maintenance	Bolus Only
Arm/Group Description	Placebo IV bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.	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.	2 grams IV TXA bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.
Measure Participants	295	292	331
Mean (Standard Deviation) [days]	13.6 (10.7)	13.6 (10.7)	14.1 (10.4)

11. Secondary Outcome

Title	Intensive Care Unit (ICU)-Free Days
Description	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.
Time Frame	From hospital admission through day 28

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo	Bolus-Maintenance	Bolus Only
Arm/Group Description	Placebo IV bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.	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.	2 grams IV TXA bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.
Measure Participants	295	293	331
Mean (Standard Deviation) [days]	18.5 (10.6)	18.1 (10.8)	19.1 (9.7)

12. Secondary Outcome

Title	Ventilator-free Days
Description	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.
Time Frame	From hospital admission through day 28

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo	Bolus-Maintenance	Bolus Only
Arm/Group Description	Placebo IV bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.	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.	2 grams IV TXA bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.
Measure Participants	295	293	331
Mean (Standard Deviation) [days]	20.2 (10.5)	19.9 (10.8)	20.9 (9.7)

13. Secondary Outcome

Title	Number of Participants With Seizure
Description	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.
Time Frame	From start of study drug infusion through 28 days or the end of the hospital stay if sooner (average of 9 days)

Outcome Measure Data

Analysis Population Description

Subjects for whom study drug administration was started minus one Bolus Only arm subject who was mistakenly enrolled while in police custody.

Arm/Group Title	Placebo	Bolus-Maintenance	Bolus Only
Arm/Group Description	Placebo IV bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.	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.	2 grams IV TXA bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.
Measure Participants	309	312	345
Count of Participants [Participants]	7 2.3%	5 1.6%	17 4.9%

14. Secondary Outcome

Title	Number of Participants With Cerebral Ischemic Event
Description	Diagnosis of cerebral ischemic event
Time Frame	From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days)

Outcome Measure Data

Analysis Population Description

Subjects for whom study drug administration was started minus one Bolus Only arm subject who was mistakenly enrolled while in police custody.

Arm/Group Title	Placebo	Bolus-Maintenance	Bolus Only
Arm/Group Description	Placebo IV bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.	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.	2 grams IV TXA bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.
Measure Participants	309	312	345
Count of Participants [Participants]	10 3.2%	3 1%	13 3.8%

15. Secondary Outcome

Title	Number of Participants With Myocardial Infarction (MI)
Description	Diagnosis of an acute myocardial infarction
Time Frame	From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days)

Outcome Measure Data

Analysis Population Description

Subjects for whom study drug administration was started minus one Bolus Only arm subject who was mistakenly enrolled while in police custody.

Arm/Group Title	Placebo	Bolus-Maintenance	Bolus Only
Arm/Group Description	Placebo IV bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.	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.	2 grams IV TXA bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.
Measure Participants	309	312	345
Count of Participants [Participants]	1 0.3%	3 1%	2 0.6%

16. Secondary Outcome

Title	Number of Participants With Deep Vein Thrombosis (DVT)
Description	Diagnosis of DVT
Time Frame	From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days)

Outcome Measure Data

Analysis Population Description

Subjects for whom study drug administration was started minus one Bolus Only arm subject who was mistakenly enrolled while in police custody.

Arm/Group Title	Placebo	Bolus-Maintenance	Bolus Only
Arm/Group Description	Placebo IV bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.	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.	2 grams IV TXA bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.
Measure Participants	309	312	345
Count of Participants [Participants]	9 2.9%	3 1%	10 2.9%

17. Secondary Outcome

Title	Number of Participants With Pulmonary Embolus (PE)
Description	Diagnosis of PE
Time Frame	From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days)

Outcome Measure Data

Analysis Population Description

Subjects for whom study drug administration was started minus one Bolus Only arm subject who was mistakenly enrolled while in police custody.

Arm/Group Title	Placebo	Bolus-Maintenance	Bolus Only
Arm/Group Description	Placebo IV bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.	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.	2 grams IV TXA bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.
Measure Participants	309	312	345
Count of Participants [Participants]	5 1.6%	3 1%	6 1.7%

18. Secondary Outcome

Title	Number of Participants With Any Thromboembolic Event
Description	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
Time Frame	From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days)

Outcome Measure Data

Analysis Population Description

Subjects for whom study drug administration was started minus one Bolus Only arm subject who was mistakenly enrolled while in police custody.

Arm/Group Title	Placebo	Bolus-Maintenance	Bolus Only
Arm/Group Description	Placebo IV bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.	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.	2 grams IV TXA bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.
Measure Participants	309	312	345
Count of Participants [Participants]	30 9.7%	13 4.2%	31 9%

19. Other Pre-specified Outcome

Title	Fibrinolysis at Hospital Admission
Description	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).
Time Frame	First blood draw (average of 1.6 hours post-injury)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo	Bolus-Maintenance	Bolus Only
Arm/Group Description	Placebo IV bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.	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.	2 grams IV TXA bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.
Measure Participants	240	246	261
<0.8 (fibrinolysis shutdown)	148 47.9%	157 50.3%	165 47.8%
0.8-3% (normal)	56 18.1%	61 19.6%	65 18.8%
>3% (hyperfibrinolysis)	36 11.7%	28 9%	31 9%

Adverse Events

Time Frame	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.
Adverse Event Reporting Description	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.
Arm/Group Title	Placebo		Bolus-Maintenance		Bolus Only
Arm/Group Description	Placebo IV bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.		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.		2 grams IV TXA bolus in the prehospital setting followed by a placebo maintenance infusion initiated on hospital arrival and infused over 8 hours.
All Cause Mortality
	Placebo		Bolus-Maintenance		Bolus Only
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	50/309 (16.2%)		53/312 (17%)		40/345 (11.6%)
Serious Adverse Events
	Placebo		Bolus-Maintenance		Bolus Only
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	25/309 (8.1%)		13/312 (4.2%)		24/345 (7%)
Blood and lymphatic system disorders
Disseminated intravascular coagulation	0/309 (0%)	0	1/312 (0.3%)	1	1/345 (0.3%)	1
Cardiac disorders
Myocardial infarction (MI)	1/309 (0.3%)	1	2/312 (0.6%)	2	1/345 (0.3%)	1
Nervous system disorders
Cerebrovascular accident - hemorrhagic	2/309 (0.6%)	2	3/312 (1%)	3	0/345 (0%)	0
Cerebrovascular accident - thrombotic	9/309 (2.9%)	10	1/312 (0.3%)	1	11/345 (3.2%)	11
Seizures	2/309 (0.6%)	2	3/312 (1%)	3	6/345 (1.7%)	6
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism (PE)	3/309 (1%)	3	2/312 (0.6%)	2	4/345 (1.2%)	4
Vascular disorders
Cerebral vascular emboli	1/309 (0.3%)	1	0/312 (0%)	0	1/345 (0.3%)	1
Cerebral venus sinus thrombosis	4/309 (1.3%)	4	0/312 (0%)	0	4/345 (1.2%)	4
Deep vein thrombosis (DVT)	4/309 (1.3%)	5	1/312 (0.3%)	1	5/345 (1.4%)	5
Embolic infarcts	0/309 (0%)	0	0/312 (0%)	0	1/345 (0.3%)	1
Inferior vena cava thrombus	0/309 (0%)	0	0/312 (0%)	0	1/345 (0.3%)	1
Internal jugular vein thrombus	1/309 (0.3%)	1	0/312 (0%)	0	0/345 (0%)	0
Left ventricular thrombus	1/309 (0.3%)	1	0/312 (0%)	0	0/345 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		Bolus-Maintenance		Bolus Only
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	81/309 (26.2%)		74/312 (23.7%)		92/345 (26.7%)
Cardiac disorders
Cardiac arrest (non-fatal)^	5/309 (1.6%)	5	5/312 (1.6%)	5	2/345 (0.6%)	2
Cardiac failure^	1/309 (0.3%)	1	0/312 (0%)	0	1/345 (0.3%)	1
Myocardial infarction (MI)	0/309 (0%)	0	1/312 (0.3%)	1	1/345 (0.3%)	1
Gastrointestinal disorders
Pseudomembranous colitis^	3/309 (1%)	3	3/312 (1%)	3	0/345 (0%)	0
General disorders
Abdominal Compartment Syndrome^	0/309 (0%)	0	1/312 (0.3%)	1	0/345 (0%)	0
Central diabetes insipidus^	5/309 (1.6%)	5	0/312 (0%)	0	4/345 (1.2%)	4
Cerebral vasospams^	4/309 (1.3%)	4	2/312 (0.6%)	2	4/345 (1.2%)	4
Extremity Compartment Syndrome^	1/309 (0.3%)	1	0/312 (0%)	0	1/345 (0.3%)	1
Hepatobiliary disorders
Cholecystitis^	0/309 (0%)	0	1/312 (0.3%)	1	0/345 (0%)	0
Liver failure^	0/309 (0%)	0	0/312 (0%)	0	1/345 (0.3%)	1
Infections and infestations
Bloodstream infection^	1/309 (0.3%)	1	4/312 (1.3%)	4	3/345 (0.9%)	3
Empyema^	0/309 (0%)	0	0/312 (0%)	0	2/345 (0.6%)	2
Intra-abdominal abscess^	1/309 (0.3%)	1	1/312 (0.3%)	1	0/345 (0%)	0
Meningitis^	2/309 (0.6%)	2	0/312 (0%)	0	0/345 (0%)	0
Pneumonia^	29/309 (9.4%)	29	36/312 (11.5%)	36	45/345 (13%)	45
Sepsis^	6/309 (1.9%)	6	11/312 (3.5%)	11	9/345 (2.6%)	9
Urinary tract infection (UTI)^	9/309 (2.9%)	9	15/312 (4.8%)	15	9/345 (2.6%)	9
Wound infection^	3/309 (1%)	3	0/312 (0%)	0	5/345 (1.4%)	5
Metabolism and nutrition disorders
Hypernatremia^	10/309 (3.2%)	10	8/312 (2.6%)	8	14/345 (4.1%)	14
Nervous system disorders
Cerebrovascular accident - hemorrhagic	1/309 (0.3%)	1	1/312 (0.3%)	1	2/345 (0.6%)	2
Cerebrovascular accident - thrombotic	1/309 (0.3%)	1	2/312 (0.6%)	2	2/345 (0.6%)	2
Seizures	5/309 (1.6%)	5	2/312 (0.6%)	2	11/345 (3.2%)	11
Renal and urinary disorders
Acute kidney injury (AKI)^	13/309 (4.2%)	13	17/312 (5.4%)	17	16/345 (4.6%)	16
Renal failure^	0/309 (0%)	0	0/312 (0%)	0	5/345 (1.4%)	5
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Distress Syndrome (ARDS)^	12/309 (3.9%)	12	8/312 (2.6%)	8	5/345 (1.4%)	5
Pulmonary embolism (PE)	2/309 (0.6%)	2	1/312 (0.3%)	1	2/345 (0.6%)	2
Vascular disorders
Cerebral venus sinus thrombosis	1/309 (0.3%)	1	0/312 (0%)	0	3/345 (0.9%)	3
Deep vein throbosis (DVT)	5/309 (1.6%)	5	2/312 (0.6%)	2	5/345 (1.4%)	5
Superficial venus thrombosis	1/309 (0.3%)	1	0/312 (0%)	0	2/345 (0.6%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.