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Prehospital Tranexamic Acid Use for Traumatic Brain Injury (TXA)

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ClinicalTrials.gov Identifier: NCT01990768
Recruitment Status : Completed
First Posted : November 21, 2013
Results First Posted : January 14, 2019
Last Update Posted : January 14, 2019
Sponsor:
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
U.S. Army Medical Research and Materiel Command
Canadian Institutes of Health Research (CIHR)
Heart and Stroke Foundation of Canada
American Heart Association
Defence Research and Development Canada
Information provided by (Responsible Party):
Susanne May, University of Washington

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Traumatic Brain Injury
Interventions Drug: 1 gram Tranexamic Acid (TXA)
Drug: 2 grams TXA
Drug: 0.9% Sodium Chloride injectable
Enrollment 967
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 Details 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
Hide 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
Reason Not Completed
Found to be ineligible             14             13             11
Study drug issue or kit malfunction             9             6             7
Patient became ineligible due to vitals             5             5             2
Not enough time for EMS to enroll             4             3             0
Patient care priority             1             2             3
IV lost             2             2             2
Required CPR             1             1             0
Seizure or hx of seizure             0             0             2
Discovered to be pregnant             0             1             0
Period Title: Prehospital Study Drug Infusion
Started 309 312 346
Completed 290 285 327
Not Completed 19 27 19
Reason Not Completed
Protocol non-compliance             4             11             10
Seizure or concern for seizure             4             3             4
Required CPR             2             6             0
Other safety concern             2             1             1
Death             3             1             1
Discharged             2             1             0
Withdrawal by Subject             1             0             0
Emergency unblinding             0             0             1
Unknown if completed             1             4             2
Period Title: In-Hospital Study Drug Infusion
Started 309 312 346
Completed 214 229 266
Not Completed 95 83 80
Reason Not Completed
Discharged             19             18             13
Protocol non-compliance             14             17             10
Withdrawal by Subject             13             7             12
Death or comfort care             12             11             6
Emergency unblinding             11             4             7
Seizure or concern for seizure             8             9             17
CVA/thrombotic event or concern for one             5             5             4
Required CPR             3             7             1
Other safety concern             4             2             3
Taken into police custody             4             0             3
Found not to be injured             1             1             1
Transfer to non-participating facility             1             1             0
Other procoagulant administered             0             1             2
Unknown if completed             0             0             1
Period Title: 6-Month Follow-up
Started 309 312 346
Completed 270 261 288
Not Completed 39 51 58
Reason Not Completed
Withdrawal by Subject             25             25             26
Calls unreturned or refused contact             4             15             20
No contact information             5             6             5
Homeless             4             3             6
Prisoner at time of enrollment             0             0             1
Prisoner at time of follow-up             0             2             0
Patient at psychiatric hospital             1             0             0
Arm/Group Title Placebo Bolus-Maintenance Bolus Only Total
Hide 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 Number of Baseline Participants 309 312 345 966
Hide Baseline 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.
Age, Continuous  
Median (Inter-Quartile Range)
Unit of measure:  Years
Number Analyzed 309 participants 312 participants 345 participants 966 participants
36
(25 to 55)
39
(26 to 57)
40
(26 to 56)
38
(25 to 56)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 309 participants 312 participants 345 participants 966 participants
Female
76
  24.6%
85
  27.2%
90
  26.1%
251
  26.0%
Male
233
  75.4%
227
  72.8%
255
  73.9%
715
  74.0%
Ethnicity (NIH/OMB)   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 309 participants 312 participants 345 participants 966 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%
[1]
Measure Description: Ethnicity was not reported at Canadian sites.
Race (NIH/OMB)   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 309 participants 312 participants 345 participants 966 participants
American Indian or Alaska Native
2
   0.6%
4
   1.3%
4
   1.2%
10
   1.0%
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
  16.0%
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
   0.0%
5
   0.5%
Unknown or Not Reported
38
  12.3%
39
  12.5%
50
  14.5%
127
  13.1%
[1]
Measure Description: Race was not reported at Canadian sites.
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Canada Number Analyzed 309 participants 312 participants 345 participants 966 participants
24 28 36 88
United States Number Analyzed 309 participants 312 participants 345 participants 966 participants
285 284 309 878
Penetrating injury  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 309 participants 312 participants 345 participants 966 participants
16
   5.2%
12
   3.8%
5
   1.4%
33
   3.4%
Cause of injury   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 308 participants 312 participants 340 participants 960 participants
Motor vehicle occupant
113
  36.7%
103
  33.0%
115
  33.8%
331
  34.5%
Motor vehicle motorcycle
33
  10.7%
32
  10.3%
44
  12.9%
109
  11.4%
Motor vehicle bicycle/pedestrian
56
  18.2%
61
  19.6%
62
  18.2%
179
  18.6%
Fall at ground level
37
  12.0%
44
  14.1%
45
  13.2%
126
  13.1%
Fall at more than 1 meter
32
  10.4%
40
  12.8%
38
  11.2%
110
  11.5%
Assault
24
   7.8%
20
   6.4%
25
   7.4%
69
   7.2%
Suicide
9
   2.9%
8
   2.6%
5
   1.5%
22
   2.3%
Other
4
   1.3%
4
   1.3%
6
   1.8%
14
   1.5%
[1]
Measure Analysis Population Description: Cause of injury missing on 1 placebo participant and 5 bolus only participants.
Prehospital Glasgow Coma Scale   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 309 participants 312 participants 345 participants 966 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%
[1]
Measure Description: 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.
Injury Severity Score (ISS)   [1] [2] 
Median (Inter-Quartile Range)
Unit of measure:  Score on a scale
Number Analyzed 302 participants 304 participants 342 participants 948 participants
17
(9 to 27)
17
(8 to 27)
17
(8 to 27)
17
(9 to 27)
[1]
Measure Description: 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.
[2]
Measure Analysis Population Description: 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.
Head Abbreviated Injury Score (AIS)   [1] [2] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 301 participants 306 participants 344 participants 951 participants
0-1
76
  25.2%
86
  28.1%
103
  29.9%
265
  27.9%
2
46
  15.3%
48
  15.7%
48
  14.0%
142
  14.9%
3
61
  20.3%
64
  20.9%
66
  19.2%
191
  20.1%
4
67
  22.3%
56
  18.3%
71
  20.6%
194
  20.4%
5-6
51
  16.9%
52
  17.0%
56
  16.3%
159
  16.7%
[1]
Measure Description: 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).
[2]
Measure Analysis Population Description: 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.
1.Primary Outcome
Title Dichotomized Glasgow Outcome Scale Extended (GOS-E) at 6 Months
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 309 312 345 657
Measure Type: Count of Participants
Unit of Measure: Participants
Unfavorable GOS-E (<=4)
107
  34.6%
108
  34.6%
110
  31.9%
218
  33.2%
Favorable GOS-E (>4)
163
  52.8%
153
  49.0%
178
  51.6%
331
  50.4%
Missing GOS-E
39
  12.6%
51
  16.3%
57
  16.5%
108
  16.4%
Show Statistical Analysis 1 Hide 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 [Not Specified]
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
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
Hide Description The counts of patients who died on or before day 28 are reported.
Time Frame 28 days after hospital arrival
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 285 285 318
Measure Type: Count of Participants
Unit of Measure: Participants
50
  17.5%
53
  18.6%
40
  12.6%
3.Secondary Outcome
Title Disability Rating Scale (DRS) at 6 Months
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 266 261 287
Mean (Standard Deviation)
Unit of Measure: 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
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 292 294 329
Measure Type: Count of Participants
Unit of Measure: Participants
196
  67.1%
193
  65.6%
228
  69.3%
5.Secondary Outcome
Title Disability Rating Scale (DRS) at Discharge
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 291 294 329
Mean (Standard Deviation)
Unit of Measure: 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
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 148 154 178
Measure Type: Count of Participants
Unit of Measure: Participants
30
  20.3%
26
  16.9%
27
  15.2%
7.Secondary Outcome
Title Marshall Computed Tomography (CT) Score on Initial Head CT
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 291 290 332
Measure Type: Count of Participants
Unit of Measure: Participants
Diffuse injury I
120
  41.2%
115
  39.7%
134
  40.4%
Diffuse injury II
106
  36.4%
117
  40.3%
135
  40.7%
Diffuse injury III
12
   4.1%
12
   4.1%
12
   3.6%
Diffuse injury IV
7
   2.4%
4
   1.4%
5
   1.5%
Mass lesion V/VI
46
  15.8%
42
  14.5%
46
  13.9%
8.Secondary Outcome
Title Rotterdam Computed Tomography (CT) Score Among Subjects With Intracranial Hemorrhage (ICH) on Initial Head CT
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 158 161 187
Measure Type: Count of Participants
Unit of Measure: Participants
1
2
   1.3%
1
   0.6%
5
   2.7%
2
32
  20.3%
28
  17.4%
36
  19.3%
3
81
  51.3%
91
  56.5%
98
  52.4%
4
17
  10.8%
24
  14.9%
28
  15.0%
5
21
  13.3%
12
   7.5%
17
   9.1%
6
5
   3.2%
5
   3.1%
3
   1.6%
9.Secondary Outcome
Title Number of Participants With One or More Neurosurgical Interventions
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 309 312 345
Measure Type: Count of Participants
Unit of Measure: Participants
54
  17.5%
62
  19.9%
75
  21.7%
10.Secondary Outcome
Title Hospital-free Days
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 295 292 331
Mean (Standard Deviation)
Unit of Measure: days
13.6  (10.7) 13.6  (10.7) 14.1  (10.4)
11.Secondary Outcome
Title Intensive Care Unit (ICU)-Free Days
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 295 293 331
Mean (Standard Deviation)
Unit of Measure: days
18.5  (10.6) 18.1  (10.8) 19.1  (9.7)
12.Secondary Outcome
Title Ventilator-free Days
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 295 293 331
Mean (Standard Deviation)
Unit of Measure: days
20.2  (10.5) 19.9  (10.8) 20.9  (9.7)
13.Secondary Outcome
Title Number of Participants With Seizure
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 309 312 345
Measure Type: Count of Participants
Unit of Measure: Participants
7
   2.3%
5
   1.6%
17
   4.9%
14.Secondary Outcome
Title Number of Participants With Cerebral Ischemic Event
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 309 312 345
Measure Type: Count of Participants
Unit of Measure: Participants
10
   3.2%
3
   1.0%
13
   3.8%
15.Secondary Outcome
Title Number of Participants With Myocardial Infarction (MI)
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 309 312 345
Measure Type: Count of Participants
Unit of Measure: Participants
1
   0.3%
3
   1.0%
2
   0.6%
16.Secondary Outcome
Title Number of Participants With Deep Vein Thrombosis (DVT)
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 309 312 345
Measure Type: Count of Participants
Unit of Measure: Participants
9
   2.9%
3
   1.0%
10
   2.9%
17.Secondary Outcome
Title Number of Participants With Pulmonary Embolus (PE)
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 309 312 345
Measure Type: Count of Participants
Unit of Measure: Participants
5
   1.6%
3
   1.0%
6
   1.7%
18.Secondary Outcome
Title Number of Participants With Any Thromboembolic Event
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 309 312 345
Measure Type: Count of Participants
Unit of Measure: Participants
30
   9.7%
13
   4.2%
31
   9.0%
19.Other Pre-specified Outcome
Title Fibrinolysis at Hospital Admission
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 240 246 261
Measure Type: Count of Participants
Unit of Measure: Participants
<0.8 (fibrinolysis shutdown)
148
  61.7%
157
  63.8%
165
  63.2%
0.8-3% (normal)
56
  23.3%
61
  24.8%
65
  24.9%
>3% (hyperfibrinolysis)
36
  15.0%
28
  11.4%
31
  11.9%
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
Hide 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 (%) Affected / at Risk (%) Affected / at Risk (%)
Total   50/309 (16.18%)      53/312 (16.99%)      40/345 (11.59%)    
Show Serious Adverse Events Hide Serious Adverse Events
Placebo Bolus-Maintenance Bolus Only
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   25/309 (8.09%)      13/312 (4.17%)      24/345 (6.96%)    
Blood and lymphatic system disorders       
Disseminated intravascular coagulation   0/309 (0.00%)  0 1/312 (0.32%)  1 1/345 (0.29%)  1
Cardiac disorders       
Myocardial infarction (MI)   1/309 (0.32%)  1 2/312 (0.64%)  2 1/345 (0.29%)  1
Nervous system disorders       
Cerebrovascular accident - hemorrhagic   2/309 (0.65%)  2 3/312 (0.96%)  3 0/345 (0.00%)  0
Cerebrovascular accident - thrombotic   9/309 (2.91%)  10 1/312 (0.32%)  1 11/345 (3.19%)  11
Seizures   2/309 (0.65%)  2 3/312 (0.96%)  3 6/345 (1.74%)  6
Respiratory, thoracic and mediastinal disorders       
Pulmonary embolism (PE)   3/309 (0.97%)  3 2/312 (0.64%)  2 4/345 (1.16%)  4
Vascular disorders       
Cerebral vascular emboli   1/309 (0.32%)  1 0/312 (0.00%)  0 1/345 (0.29%)  1
Cerebral venus sinus thrombosis   4/309 (1.29%)  4 0/312 (0.00%)  0 4/345 (1.16%)  4
Deep vein thrombosis (DVT)   4/309 (1.29%)  5 1/312 (0.32%)  1 5/345 (1.45%)  5
Embolic infarcts   0/309 (0.00%)  0 0/312 (0.00%)  0 1/345 (0.29%)  1
Inferior vena cava thrombus   0/309 (0.00%)  0 0/312 (0.00%)  0 1/345 (0.29%)  1
Internal jugular vein thrombus   1/309 (0.32%)  1 0/312 (0.00%)  0 0/345 (0.00%)  0
Left ventricular thrombus   1/309 (0.32%)  1 0/312 (0.00%)  0 0/345 (0.00%)  0
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Placebo Bolus-Maintenance Bolus Only
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   81/309 (26.21%)      74/312 (23.72%)      92/345 (26.67%)    
Cardiac disorders       
Cardiac arrest (non-fatal)^   5/309 (1.62%)  5 5/312 (1.60%)  5 2/345 (0.58%)  2
Cardiac failure^   1/309 (0.32%)  1 0/312 (0.00%)  0 1/345 (0.29%)  1
Myocardial infarction (MI)   0/309 (0.00%)  0 1/312 (0.32%)  1 1/345 (0.29%)  1
Gastrointestinal disorders       
Pseudomembranous colitis^   3/309 (0.97%)  3 3/312 (0.96%)  3 0/345 (0.00%)  0
General disorders       
Abdominal Compartment Syndrome^   0/309 (0.00%)  0 1/312 (0.32%)  1 0/345 (0.00%)  0
Central diabetes insipidus^   5/309 (1.62%)  5 0/312 (0.00%)  0 4/345 (1.16%)  4
Cerebral vasospams^   4/309 (1.29%)  4 2/312 (0.64%)  2 4/345 (1.16%)  4
Extremity Compartment Syndrome^   1/309 (0.32%)  1 0/312 (0.00%)  0 1/345 (0.29%)  1
Hepatobiliary disorders       
Cholecystitis^   0/309 (0.00%)  0 1/312 (0.32%)  1 0/345 (0.00%)  0
Liver failure^   0/309 (0.00%)  0 0/312 (0.00%)  0 1/345 (0.29%)  1
Infections and infestations       
Bloodstream infection^   1/309 (0.32%)  1 4/312 (1.28%)  4 3/345 (0.87%)  3
Empyema^   0/309 (0.00%)  0 0/312 (0.00%)  0 2/345 (0.58%)  2
Intra-abdominal abscess^   1/309 (0.32%)  1 1/312 (0.32%)  1 0/345 (0.00%)  0
Meningitis^   2/309 (0.65%)  2 0/312 (0.00%)  0 0/345 (0.00%)  0
Pneumonia^   29/309 (9.39%)  29 36/312 (11.54%)  36 45/345 (13.04%)  45
Sepsis^   6/309 (1.94%)  6 11/312 (3.53%)  11 9/345 (2.61%)  9
Urinary tract infection (UTI)^   9/309 (2.91%)  9 15/312 (4.81%)  15 9/345 (2.61%)  9
Wound infection^   3/309 (0.97%)  3 0/312 (0.00%)  0 5/345 (1.45%)  5
Metabolism and nutrition disorders       
Hypernatremia^   10/309 (3.24%)  10 8/312 (2.56%)  8 14/345 (4.06%)  14
Nervous system disorders       
Cerebrovascular accident - hemorrhagic   1/309 (0.32%)  1 1/312 (0.32%)  1 2/345 (0.58%)  2
Cerebrovascular accident - thrombotic   1/309 (0.32%)  1 2/312 (0.64%)  2 2/345 (0.58%)  2
Seizures   5/309 (1.62%)  5 2/312 (0.64%)  2 11/345 (3.19%)  11
Renal and urinary disorders       
Acute kidney injury (AKI)^   13/309 (4.21%)  13 17/312 (5.45%)  17 16/345 (4.64%)  16
Renal failure^   0/309 (0.00%)  0 0/312 (0.00%)  0 5/345 (1.45%)  5
Respiratory, thoracic and mediastinal disorders       
Acute Respiratory Distress Syndrome (ARDS)^   12/309 (3.88%)  12 8/312 (2.56%)  8 5/345 (1.45%)  5
Pulmonary embolism (PE)   2/309 (0.65%)  2 1/312 (0.32%)  1 2/345 (0.58%)  2
Vascular disorders       
Cerebral venus sinus thrombosis   1/309 (0.32%)  1 0/312 (0.00%)  0 3/345 (0.87%)  3
Deep vein throbosis (DVT)   5/309 (1.62%)  5 2/312 (0.64%)  2 5/345 (1.45%)  5
Superficial venus thrombosis   1/309 (0.32%)  1 0/312 (0.00%)  0 2/345 (0.58%)  2
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Dr. Susanne May
Organization: University of Washington, Resuscitation Outcomes Consortium
Phone: 206-685-1302
Responsible Party: Susanne May, University of Washington
ClinicalTrials.gov Identifier: NCT01990768     History of Changes
Other Study ID Numbers: 47114
5U01HL077863-09 ( U.S. NIH Grant/Contract )
TATRC Log No. 13335004-A ( Other Grant/Funding Number: US Army Medical Research Acquisition Activity (USAMRAA) )
First Submitted: October 30, 2013
First Posted: November 21, 2013
Results First Submitted: November 7, 2018
Results First Posted: January 14, 2019
Last Update Posted: January 14, 2019