Trial Outcomes & Findings for Tranexamic Acid Mechanisms and Pharmacokinetics in Traumatic Injury (NCT NCT02535949)

Last Updated: 2021-08-31

Results Overview

Blood was drawn from patients at baseline (0 h, just before placebo or drug administration) and at 72 hours post placebo or drug administration. Leukocytes in these blood samples were stained with fluroescent antibodies specific for CD45, CD14, and HLA-DR, analyzed by flow cytometry, and the median fluorescen intensity (MFI) of HLA-DR signal was recorded for monocytes (CD45+CD14+). The fold change in HLA-DR expression from prior to placebo/drug administration to 72 h after placebo/drug administration ("0 h : 72 h") was calculated as HLA-DR MFI72hours ÷ HLA-DR CD14 MFI0hours. Non-paramteric one-way ANOVA (Kruskal-Wallis test) was performed between each treatment group at the given time pont, and the p-value reported.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

150 participants

Primary outcome timeframe

Samples Drawn through 72 hours after study initiation

Results posted on

2021-08-31

Participant Flow

Participant milestones

Participant milestones
Measure	Tranexamic Acid 2 Gram One time dose IV TXA 2 Grams given over 10 minutes within 2 hours of initial injury Tranexamic Acid: Tranexamic acid is a man-made form of an amino acid (protein) called lysine. Tranexamic acid prevents enzymes in the body from breaking down blood clots.	Tranexamic Acid 4 Gram One time dose IV TXA 4 Grams given over 10 minutes within 2 hours of initial injury Tranexamic Acid: Tranexamic acid is a man-made form of an amino acid (protein) called lysine. Tranexamic acid prevents enzymes in the body from breaking down blood clots.	Placebo Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury Placebo: Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury
Overall Study STARTED	50	50	50
Overall Study COMPLETED	49	50	50
Overall Study NOT COMPLETED	1	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Tranexamic Acid Mechanisms and Pharmacokinetics in Traumatic Injury

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Tranexamic Acid 2 Gram n=49 Participants One time dose IV TXA 2 Grams given over 10 minutes within 2 hours of initial injury Tranexamic Acid: Tranexamic acid is a man-made form of an amino acid (protein) called lysine. Tranexamic acid prevents enzymes in the body from breaking down blood clots.	Tranexamic Acid 4 Gram n=50 Participants One time dose IV TXA 4 Grams given over 10 minutes within 2 hours of initial injury Tranexamic Acid: Tranexamic acid is a man-made form of an amino acid (protein) called lysine. Tranexamic acid prevents enzymes in the body from breaking down blood clots.	Placebo n=50 Participants Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury Placebo: Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury	Total n=149 Participants Total of all reporting groups
Age, Categorical <=18 years	1 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	2 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	47 Participants n=5 Participants	46 Participants n=7 Participants	49 Participants n=5 Participants	142 Participants n=4 Participants
Age, Categorical >=65 years	1 Participants n=5 Participants	3 Participants n=7 Participants	1 Participants n=5 Participants	5 Participants n=4 Participants
Sex: Female, Male Female	5 Participants n=5 Participants	8 Participants n=7 Participants	5 Participants n=5 Participants	18 Participants n=4 Participants
Sex: Female, Male Male	44 Participants n=5 Participants	42 Participants n=7 Participants	45 Participants n=5 Participants	131 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	42 Participants n=5 Participants	43 Participants n=7 Participants	44 Participants n=5 Participants	129 Participants n=4 Participants
Race (NIH/OMB) White	7 Participants n=5 Participants	6 Participants n=7 Participants	5 Participants n=5 Participants	18 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Region of Enrollment United States	49 participants n=5 Participants	50 participants n=7 Participants	50 participants n=5 Participants	149 participants n=4 Participants

PRIMARY outcome

Timeframe: Samples Drawn through 72 hours after study initiation

Population: Change in HLA-DR Expression on Monocytes 72 hours after administration. Leukocytes stained with antibodies and analyzed by flow cytometry. The median fluorescen intensity of HLA-DR signal was measured for monocytes at 0 and 72 hours. Non-paramteric one-way ANOVA was performed and the p-value reported.

Outcome measures

Outcome measures
Measure	Tranexamic Acid 2 Gram n=49 Participants One time dose IV TXA 2 Grams given over 10 minutes within 2 hours of initial injury Tranexamic Acid: Tranexamic acid is a man-made form of an amino acid (protein) called lysine. Tranexamic acid prevents enzymes in the body from breaking down blood clots.	Tranexamic Acid 4 Gram n=50 Participants One time dose IV TXA 4 Grams given over 10 minutes within 2 hours of initial injury Tranexamic Acid: Tranexamic acid is a man-made form of an amino acid (protein) called lysine. Tranexamic acid prevents enzymes in the body from breaking down blood clots.	Placebo n=50 Participants Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury Placebo: Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury
Change in HLA-DR Expression on Monocytes 72 Hours After Drug or Placebo Administration in Patient Groups (0g TXA (Placebo); 2g TXA; 4g TXA)."	0.503 fold change Interval 0.0 to 0.717	0.509 fold change Interval 0.336 to 0.733	0.532 fold change Interval 0.371 to 0.736

SECONDARY outcome

Timeframe: Samples Drawn through 72 hours after study initiation

Population: Cytokine Levels at 0 and 72 hours after drug or placebo administration in patient groups. Blood was drawn, serum isolated, and frozen. Frozen sera were thawed and the listed cytokines measured uisng a multiplexed platform. Non-paramteric one-way ANOVA was performed between each treatment group, and the p- value reported.

To evaluate the effects of TXA on immune function parameters we will, in a RCT, analyze samples from 150 patients (50 in each study group), at multiple time points. Parameters are: a. Cytokines measured from time 0 to 72 hours.

Outcome measures

Outcome measures
Measure	Tranexamic Acid 2 Gram n=49 Participants One time dose IV TXA 2 Grams given over 10 minutes within 2 hours of initial injury Tranexamic Acid: Tranexamic acid is a man-made form of an amino acid (protein) called lysine. Tranexamic acid prevents enzymes in the body from breaking down blood clots.	Tranexamic Acid 4 Gram n=50 Participants One time dose IV TXA 4 Grams given over 10 minutes within 2 hours of initial injury Tranexamic Acid: Tranexamic acid is a man-made form of an amino acid (protein) called lysine. Tranexamic acid prevents enzymes in the body from breaking down blood clots.	Placebo n=50 Participants Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury Placebo: Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury
Differences in Cytokine Profiles Between the Three Study Groups IL-6 hour 72	73.97 pg/mL Interval 35.27 to 156.11	67.95 pg/mL Interval 32.83 to 149.24	41.9 pg/mL Interval 21.71 to 70.01
Differences in Cytokine Profiles Between the Three Study Groups ITAC hour 0	34.24 pg/mL Interval 25.02 to 55.19	32.75 pg/mL Interval 21.34 to 49.41	29.34 pg/mL Interval 17.92 to 44.44
Differences in Cytokine Profiles Between the Three Study Groups ITAC hour 72	25.67 pg/mL Interval 20.76 to 41.14	21.69 pg/mL Interval 13.98 to 34.58	21.58 pg/mL Interval 13.8 to 33.24
Differences in Cytokine Profiles Between the Three Study Groups GM-CSF hour 0	67.79 pg/mL Interval 46.73 to 111.19	67.58 pg/mL Interval 43.91 to 125.74	64.69 pg/mL Interval 39.83 to 97.43
Differences in Cytokine Profiles Between the Three Study Groups GM-CSF hour 72	69.22 pg/mL Interval 34.07 to 107.56	52.88 pg/mL Interval 38.41 to 94.83	61.41 pg/mL Interval 46.09 to 96.77
Differences in Cytokine Profiles Between the Three Study Groups Factalkine hour 0	223.61 pg/mL Interval 94.4 to 328.9	146.23 pg/mL Interval 103.15 to 210.32	141.8 pg/mL Interval 75.83 to 223.7
Differences in Cytokine Profiles Between the Three Study Groups Factalkine hour 72	174.91 pg/mL Interval 116.22 to 239.2	124.23 pg/mL Interval 83.71 to 183.81	100.51 pg/mL Interval 74.7 to 187.04
Differences in Cytokine Profiles Between the Three Study Groups IFNgamma hour 0	23.46 pg/mL Interval 13.25 to 38.08	17.59 pg/mL Interval 14.16 to 38.95	17.47 pg/mL Interval 9.49 to 25.81
Differences in Cytokine Profiles Between the Three Study Groups IFNgamma hour 72	17.89 pg/mL Interval 12.22 to 30.44	14.79 pg/mL Interval 10.89 to 29.69	12.98 pg/mL Interval 9.06 to 28.48
Differences in Cytokine Profiles Between the Three Study Groups IL-10 hour 0	115.98 pg/mL Interval 41.93 to 235.6	84.39 pg/mL Interval 46.77 to 127.73	105.07 pg/mL Interval 39.75 to 250.02
Differences in Cytokine Profiles Between the Three Study Groups IL-10 hour 72	31.76 pg/mL Interval 14.47 to 46.13	42.39 pg/mL Interval 16.48 to 64.75	32.38 pg/mL Interval 19.7 to 44.71
Differences in Cytokine Profiles Between the Three Study Groups MIP-3a hour 0	22.95 pg/mL Interval 14.03 to 29.38	21.94 pg/mL Interval 17.4 to 27.98	22.95 pg/mL Interval 12.36 to 31.03
Differences in Cytokine Profiles Between the Three Study Groups MIP-3a hour 72	38.49 pg/mL Interval 23.43 to 132.02	27.61 pg/mL Interval 23.66 to 54.31	31.54 pg/mL Interval 17.89 to 50.33
Differences in Cytokine Profiles Between the Three Study Groups IL-12p70 hour 0	9.5 pg/mL Interval 6.81 to 17.61	8.64 pg/mL Interval 6.04 to 12.65	8.78 pg/mL Interval 4.89 to 13.58
Differences in Cytokine Profiles Between the Three Study Groups IL-12p70 hour 72	9.67 pg/mL Interval 5.86 to 14.06	9.45 pg/mL Interval 5.72 to 11.9	7.58 pg/mL Interval 3.78 to 17.51
Differences in Cytokine Profiles Between the Three Study Groups IL-13 hour 0	11.8 pg/mL Interval 5.7 to 26.86	11.11 pg/mL Interval 5.37 to 23.82	9.08 pg/mL Interval 5.31 to 16.27
Differences in Cytokine Profiles Between the Three Study Groups IL-13 hour 72	11.11 pg/mL Interval 5.78 to 27.37	10.27 pg/mL Interval 5.24 to 20.28	10.28 pg/mL Interval 4.42 to 18.9
Differences in Cytokine Profiles Between the Three Study Groups IL -17A hour 0	21.51 pg/mL Interval 11.46 to 30.35	15.05 pg/mL Interval 9.9 to 24.01	18.73 pg/mL Interval 11.45 to 28.43
Differences in Cytokine Profiles Between the Three Study Groups IL-17A hour 72	20.06 pg/mL Interval 11.0 to 38.72	16.67 pg/mL Interval 11.07 to 26.89	14 pg/mL Interval 9.35 to 29.42
Differences in Cytokine Profiles Between the Three Study Groups IL-1beta hour 0	4.17 pg/mL Interval 2.49 to 6.63	3.75 pg/mL Interval 2.75 to 6.11	3.9 pg/mL Interval 2.77 to 5.7
Differences in Cytokine Profiles Between the Three Study Groups IL-1beta hour 72	4.15 pg/mL Interval 2.75 to 5.34	3.44 pg/mL Interval 2.32 to 4.77	3.11 pg/mL Interval 2.4 to 6.01
Differences in Cytokine Profiles Between the Three Study Groups IL-2 hour 0	4.17 pg/mL Interval 2.82 to 7.36	4.29 pg/mL Interval 2.62 to 7.07	4.01 pg/mL Interval 3.05 to 5.63
Differences in Cytokine Profiles Between the Three Study Groups IL-2 hour 72	4.26 pg/mL Interval 2.4 to 8.62	3.49 pg/mL Interval 2.21 to 5.77	4.12 pg/mL Interval 2.74 to 7.07
Differences in Cytokine Profiles Between the Three Study Groups IL-21 hour 0	6.28 pg/mL Interval 3.51 to 9.74	6.13 pg/mL Interval 3.64 to 9.75	7.02 pg/mL Interval 3.22 to 10.96
Differences in Cytokine Profiles Between the Three Study Groups IL-21 hour 72	6.44 pg/mL Interval 3.89 to 13.59	6.95 pg/mL Interval 3.61 to 9.5	5.51 pg/mL Interval 2.79 to 10.92
Differences in Cytokine Profiles Between the Three Study Groups IL-4 hour 0	69.45 pg/mL Interval 45.42 to 94.71	58.24 pg/mL Interval 41.97 to 79.64	58.16 pg/mL Interval 37.97 to 95.79
Differences in Cytokine Profiles Between the Three Study Groups IL-4 hour 72	49.99 pg/mL Interval 29.39 to 73.91	40.5 pg/mL Interval 24.45 to 75.08	35.53 pg/mL Interval 23.24 to 68.29
Differences in Cytokine Profiles Between the Three Study Groups IL-23 hour 0	724.45 pg/mL Interval 445.25 to 1105.5	428.26 pg/mL Interval 244.36 to 875.62	406.46 pg/mL Interval 244.04 to 773.56
Differences in Cytokine Profiles Between the Three Study Groups IL-23 hour 72	589.73 pg/mL Interval 388.72 to 893.66	351.47 pg/mL Interval 258.99 to 811.79	399.74 pg/mL Interval 248.94 to 971.77
Differences in Cytokine Profiles Between the Three Study Groups IL-5 hour 0	9.3 pg/mL Interval 4.12 to 15.79	9.48 pg/mL Interval 5.17 to 15.28	9.06 pg/mL Interval 5.72 to 13.27
Differences in Cytokine Profiles Between the Three Study Groups IL-5 hour 72	8.68 pg/mL Interval 6.31 to 17.87	8.05 pg/mL Interval 6.12 to 15.22	8.32 pg/mL Interval 6.94 to 13.44
Differences in Cytokine Profiles Between the Three Study Groups IL-6 hour 0	54.48 pg/mL Interval 23.0 to 182.07	39.7 pg/mL Interval 18.27 to 97.99	63.56 pg/mL Interval 28.05 to 110.6
Differences in Cytokine Profiles Between the Three Study Groups IL-7 hour 0	18.53 pg/mL Interval 12.67 to 30.56	15.33 pg/mL Interval 11.47 to 24.3	16.52 pg/mL Interval 10.19 to 23.65
Differences in Cytokine Profiles Between the Three Study Groups IL-7 hour 72	18.47 pg/mL Interval 11.19 to 27.49	16.24 pg/mL Interval 11.0 to 22.19	16.8 pg/mL Interval 10.93 to 19.66
Differences in Cytokine Profiles Between the Three Study Groups IL-8 hour 0	15.25 pg/mL Interval 10.43 to 31.68	13.59 pg/mL Interval 9.62 to 24.65	13.78 pg/mL Interval 8.03 to 26.45
Differences in Cytokine Profiles Between the Three Study Groups IL-8 hour 72	26.9 pg/mL Interval 18.0 to 42.11	23.05 pg/mL Interval 17.14 to 38.97	17.64 pg/mL Interval 13.78 to 23.71
Differences in Cytokine Profiles Between the Three Study Groups MIP-1alpha hour 0	32.57 pg/mL Interval 22.77 to 42.48	30.98 pg/mL Interval 20.36 to 42.9	27.85 pg/mL Interval 21.99 to 41.89
Differences in Cytokine Profiles Between the Three Study Groups MIP-1alpha hour 72	28.57 pg/mL Interval 20.69 to 43.98	27.24 pg/mL Interval 18.05 to 39.23	25.47 pg/mL Interval 17.29 to 43.96
Differences in Cytokine Profiles Between the Three Study Groups MIP-beta hour 0	44.91 pg/mL Interval 31.8 to 54.57	37.66 pg/mL Interval 13.55 to 48.35	35.44 pg/mL Interval 24.74 to 50.11
Differences in Cytokine Profiles Between the Three Study Groups MIP-beta hour 72	36.78 pg/mL Interval 25.72 to 45.65	29.02 pg/mL Interval 23.15 to 39.4	28.15 pg/mL Interval 22.23 to 36.19
Differences in Cytokine Profiles Between the Three Study Groups TNFa hour 0	19.16 pg/mL Interval 13.34 to 23.46	16.4 pg/mL Interval 13.3 to 20.5	16.4 pg/mL Interval 12.3 to 21.17
Differences in Cytokine Profiles Between the Three Study Groups TNFa hour 72	19.38 pg/mL Interval 17.57 to 25.85	20.09 pg/mL Interval 15.82 to 25.62	16.16 pg/mL Interval 12.37 to 21.36

SECONDARY outcome

Timeframe: Samples Drawn through 72 hours after study initiation

Population: Change in CD11b and CD16 Expression on neutrophils 72 hours after. Leukocytes stained with antibodies specific and analyzed by flow cytometry. The median fluorescen intensity of CD11b or CD16 signal was measured on neutrophils. The fold change was measured, MFI72hours/MFI0hours. Non-paramteric one-way ANOVA was performed and the p-value reported.

Outcome measures

Outcome measures
Measure	Tranexamic Acid 2 Gram n=49 Participants One time dose IV TXA 2 Grams given over 10 minutes within 2 hours of initial injury Tranexamic Acid: Tranexamic acid is a man-made form of an amino acid (protein) called lysine. Tranexamic acid prevents enzymes in the body from breaking down blood clots.	Tranexamic Acid 4 Gram n=50 Participants One time dose IV TXA 4 Grams given over 10 minutes within 2 hours of initial injury Tranexamic Acid: Tranexamic acid is a man-made form of an amino acid (protein) called lysine. Tranexamic acid prevents enzymes in the body from breaking down blood clots.	Placebo n=50 Participants Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury Placebo: Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury
Differences in Leukocyte Function Parameters Between the Three Study Groups CD 16+	0.917 Fold Change Interval 0.733 to 0.994	0.870 Fold Change Interval 0.731 to 0.994	0.817 Fold Change Interval 0.703 to 0.942
Differences in Leukocyte Function Parameters Between the Three Study Groups CD 11b+	0.875 Fold Change Interval 0.667 to 1.11	0.967 Fold Change Interval 0.802 to 1.207	0.844 Fold Change Interval 0.713 to 1.02

SECONDARY outcome

Timeframe: 24 hours

Population: Of the 99 participants analyzed, 49 received the 2 gram dose and 50 received the 4 gram dose.

Pharmacokinetic data was analyzed with NONMEM, using both the first-order and conditional non-Laplacian (with centering) estimation techniques. We considered two- and three-compartment models, parameterized in terms of both compartment volumes and clearances (distribution and elimination). We compared a basic model (in which pharmacokinetic parameters were independent of weight) to a model in which the pharmacokinetic parameters were assumed to be proportional to weight. The optimal model was selected on the basis of the objective function logarithm of the likelihood of the results) using standard criteria (NONMEM guide). Equations from optimal model: CL=109\*((WT/70)\*\*0.75) \* (SCRint\^-0.084) \* ((NIRSInt)/96)\^ -0.27 ) \* ((PLTint)/130)\^0.45) V1=1,160\*(WT/70) \* (TxTot)\^0.03) Q=174\*((WT/70)\*\*0.75) V2=1080 \*(WT/70) "Total Transfusion Volume CL" equals clearance (CL) affected by the covariate of Total Transfusion Volume (TxTot). This value is unitless per NONMEM reporting.

Outcome measures

Outcome measures
Measure	Tranexamic Acid 2 Gram n=99 Participants One time dose IV TXA 2 Grams given over 10 minutes within 2 hours of initial injury Tranexamic Acid: Tranexamic acid is a man-made form of an amino acid (protein) called lysine. Tranexamic acid prevents enzymes in the body from breaking down blood clots.	Tranexamic Acid 4 Gram One time dose IV TXA 4 Grams given over 10 minutes within 2 hours of initial injury Tranexamic Acid: Tranexamic acid is a man-made form of an amino acid (protein) called lysine. Tranexamic acid prevents enzymes in the body from breaking down blood clots.	Placebo Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury Placebo: Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury
Total Transfusion Volume CL	0.03 unitless Interval 0.007 to 0.05	—	—

SECONDARY outcome

Timeframe: Hospital Discharge (average 10 days)

Population: The incidence of thromboembolic events (DVT, MI, PE, Stroke) in all three study groups are given based on events per group.

The number of events per group for the incidence of thromboembolic events (DVT, MI, PE, Stroke) in all three study groups.

Outcome measures

Outcome measures
Measure	Tranexamic Acid 2 Gram n=49 Participants One time dose IV TXA 2 Grams given over 10 minutes within 2 hours of initial injury Tranexamic Acid: Tranexamic acid is a man-made form of an amino acid (protein) called lysine. Tranexamic acid prevents enzymes in the body from breaking down blood clots.	Tranexamic Acid 4 Gram n=50 Participants One time dose IV TXA 4 Grams given over 10 minutes within 2 hours of initial injury Tranexamic Acid: Tranexamic acid is a man-made form of an amino acid (protein) called lysine. Tranexamic acid prevents enzymes in the body from breaking down blood clots.	Placebo n=50 Participants Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury Placebo: Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury
Determine the Incidence of Thromboembolic Events (DVT, MI, PE, Stroke) in All Three Study Groups.	13 events	16 events	6 events

SECONDARY outcome

Timeframe: 24 hours following TXA

Population: The incidence of seizures at 24 hours in all three study groups. This was done by totaling the number of participants with reported seizures.

The incidence of seizures at 24 hours in all three study groups. Number of participants with seizures are reported

Outcome measures

Outcome measures
Measure	Tranexamic Acid 2 Gram n=49 Participants One time dose IV TXA 2 Grams given over 10 minutes within 2 hours of initial injury Tranexamic Acid: Tranexamic acid is a man-made form of an amino acid (protein) called lysine. Tranexamic acid prevents enzymes in the body from breaking down blood clots.	Tranexamic Acid 4 Gram n=50 Participants One time dose IV TXA 4 Grams given over 10 minutes within 2 hours of initial injury Tranexamic Acid: Tranexamic acid is a man-made form of an amino acid (protein) called lysine. Tranexamic acid prevents enzymes in the body from breaking down blood clots.	Placebo n=50 Participants Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury Placebo: Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury
Determine the Incidence of Seizures at 24 Hours in All Three Study Groups.	0 Participants	1 Participants	0 Participants

SECONDARY outcome

Timeframe: Hospital Discharge (average 10 days)

Population: The number of incidents were totaled for the three study groups.

All adverse events were totaled for each of the three study groups based on the number of incidents.

Outcome measures

Outcome measures
Measure	Tranexamic Acid 2 Gram n=49 Participants One time dose IV TXA 2 Grams given over 10 minutes within 2 hours of initial injury Tranexamic Acid: Tranexamic acid is a man-made form of an amino acid (protein) called lysine. Tranexamic acid prevents enzymes in the body from breaking down blood clots.	Tranexamic Acid 4 Gram n=50 Participants One time dose IV TXA 4 Grams given over 10 minutes within 2 hours of initial injury Tranexamic Acid: Tranexamic acid is a man-made form of an amino acid (protein) called lysine. Tranexamic acid prevents enzymes in the body from breaking down blood clots.	Placebo n=50 Participants Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury Placebo: Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury
Determine the Incidence of All Adverse Events in All Three Study Groups	168 events	264 events	138 events

SECONDARY outcome

Timeframe: 24 hours

Population: Of the 99 participants analyzed, 49 received the 2 gram dose and 50 received the 4 gram dose.

Pharmacokinetic data was analyzed with NONMEM, using both the first-order and conditional non-Laplacian (with centering) estimation techniques. We considered two- and three-compartment models, parameterized in terms of both compartment volumes and clearances (distribution and elimination). We compared a basic model (in which pharmacokinetic parameters were independent of weight) to a model in which the pharmacokinetic parameters were assumed to be proportional to weight. The optimal model was selected on the basis of the objective function logarithm of the likelihood of the results) using standard criteria (NONMEM guide). Equations from optimal model: CL=109\*((WT/70)\*\*0.75) \* (SCRint\^-0.084) \* ((NIRSInt)/96)\^ -0.27 ) \* ((PLTint)/130)\^0.45) V1=1,160\*(WT/70) \* (TxTot)\^0.03) Q=174\*((WT/70)\*\*0.75) V2=1080 \*(WT/70) "Platelet Count CL" equals clearance (CL) affected by the covariate of Platelet Count (PLTint). This value is unitless per NONMEM reporting.

Outcome measures

Outcome measures
Measure	Tranexamic Acid 2 Gram n=99 Participants One time dose IV TXA 2 Grams given over 10 minutes within 2 hours of initial injury Tranexamic Acid: Tranexamic acid is a man-made form of an amino acid (protein) called lysine. Tranexamic acid prevents enzymes in the body from breaking down blood clots.	Tranexamic Acid 4 Gram One time dose IV TXA 4 Grams given over 10 minutes within 2 hours of initial injury Tranexamic Acid: Tranexamic acid is a man-made form of an amino acid (protein) called lysine. Tranexamic acid prevents enzymes in the body from breaking down blood clots.	Placebo Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury Placebo: Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury
Platelet Count CL	0.45 unitless Interval 0.28 to 0.61	—	—

SECONDARY outcome

Timeframe: 24 hours

Population: Of the 99 participants analyzed, 49 received the 2 gram dose and 50 received the 4 gram dose.

Pharmacokinetic data was analyzed with NONMEM, using both the first-order and conditional non-Laplacian (with centering) estimation techniques. We considered two- and three-compartment models, parameterized in terms of both compartment volumes and clearances (distribution and elimination). We compared a basic model (in which pharmacokinetic parameters were independent of weight) to a model in which the pharmacokinetic parameters were assumed to be proportional to weight. The optimal model was selected on the basis of the objective function logarithm of the likelihood of the results) using standard criteria (NONMEM guide). Equations from optimal model: CL=109\*((WT/70)\*\*0.75) \* (SCRint\^-0.084) \* ((NIRSInt)/96)\^ -0.27 ) \* ((PLTint)/130)\^0.45) V1=1,160\*(WT/70) \* (TxTot)\^0.03) Q=174\*((WT/70)\*\*0.75) V2=1080 \*(WT/70) "Near Infrared Spectroscopy CL" equals clearance (CL) affected by the covariate of Near Infrared Spectroscopy (NIRSint). This value is unitless per NONMEM reporting.

Outcome measures

Outcome measures
Measure	Tranexamic Acid 2 Gram n=99 Participants One time dose IV TXA 2 Grams given over 10 minutes within 2 hours of initial injury Tranexamic Acid: Tranexamic acid is a man-made form of an amino acid (protein) called lysine. Tranexamic acid prevents enzymes in the body from breaking down blood clots.	Tranexamic Acid 4 Gram One time dose IV TXA 4 Grams given over 10 minutes within 2 hours of initial injury Tranexamic Acid: Tranexamic acid is a man-made form of an amino acid (protein) called lysine. Tranexamic acid prevents enzymes in the body from breaking down blood clots.	Placebo Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury Placebo: Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury
Near Infrared Spectroscopy CL	-0.27 unitless Interval -0.38 to -0.15	—	—

SECONDARY outcome

Timeframe: 24 hours

Population: Of the 99 participants analyzed, 49 received the 2 gram dose and 50 received the 4 gram dose.

Pharmacokinetic data was analyzed with NONMEM, using both the first-order and conditional non-Laplacian (with centering) estimation techniques. We considered two- and three-compartment models, parameterized in terms of both compartment volumes and clearances (distribution and elimination). We compared a basic model (in which pharmacokinetic parameters were independent of weight) to a model in which the pharmacokinetic parameters were assumed to be proportional to weight. The optimal model was selected on the basis of the objective function logarithm of the likelihood of the results) using standard criteria (NONMEM guide). Equations from optimal model: CL=109\*((WT/70)\*\*0.75) \* (SCRint\^-0.084) \* ((NIRSInt)/96)\^ -0.27 ) \* ((PLTint)/130)\^0.45) V1=1,160\*(WT/70) \* (TxTot)\^0.03) Q=174\*((WT/70)\*\*0.75) V2=1080 \*(WT/70) "Creatinine Count CL" equals clearance (CL) affected by the covariate of Creatinine levels (SCRint). This value is unitless per NONMEM reporting.

Outcome measures

Outcome measures
Measure	Tranexamic Acid 2 Gram n=99 Participants One time dose IV TXA 2 Grams given over 10 minutes within 2 hours of initial injury Tranexamic Acid: Tranexamic acid is a man-made form of an amino acid (protein) called lysine. Tranexamic acid prevents enzymes in the body from breaking down blood clots.	Tranexamic Acid 4 Gram One time dose IV TXA 4 Grams given over 10 minutes within 2 hours of initial injury Tranexamic Acid: Tranexamic acid is a man-made form of an amino acid (protein) called lysine. Tranexamic acid prevents enzymes in the body from breaking down blood clots.	Placebo Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury Placebo: Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury
Creatinine Count CL	-0.084 unitless Interval -0.13 to -0.03	—	—

SECONDARY outcome

Timeframe: 24 hours

Population: Of the 99 participants analyzed 49 received the 2 gram dose and 50 received the 4 gram dose.

Outcome measures

Outcome measures
Measure	Tranexamic Acid 2 Gram n=99 Participants One time dose IV TXA 2 Grams given over 10 minutes within 2 hours of initial injury Tranexamic Acid: Tranexamic acid is a man-made form of an amino acid (protein) called lysine. Tranexamic acid prevents enzymes in the body from breaking down blood clots.	Tranexamic Acid 4 Gram One time dose IV TXA 4 Grams given over 10 minutes within 2 hours of initial injury Tranexamic Acid: Tranexamic acid is a man-made form of an amino acid (protein) called lysine. Tranexamic acid prevents enzymes in the body from breaking down blood clots.	Placebo Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury Placebo: Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury
V2- Peripheral Volume (L/70kg)	1080 L/70kg Interval 959.0 to 1200.0	—	—

SECONDARY outcome

Timeframe: 24 hours

Population: Of the 99 participants analyzed, 49 received the 2 gram dose and 50 received the 4 gram dose.

Outcome measures

Outcome measures
Measure	Tranexamic Acid 2 Gram n=99 Participants One time dose IV TXA 2 Grams given over 10 minutes within 2 hours of initial injury Tranexamic Acid: Tranexamic acid is a man-made form of an amino acid (protein) called lysine. Tranexamic acid prevents enzymes in the body from breaking down blood clots.	Tranexamic Acid 4 Gram One time dose IV TXA 4 Grams given over 10 minutes within 2 hours of initial injury Tranexamic Acid: Tranexamic acid is a man-made form of an amino acid (protein) called lysine. Tranexamic acid prevents enzymes in the body from breaking down blood clots.	Placebo Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury Placebo: Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury
Q- Intercompartmental Clearance (L/70kg)	174 L/70kg Interval 128.0 to 220.0	—	—

SECONDARY outcome

Timeframe: 24 hours

Population: Of the 99 participants analyzed, 49 received the 2 gram dose and 50 received the 4 gram dose.

Outcome measures

Outcome measures
Measure	Tranexamic Acid 2 Gram n=99 Participants One time dose IV TXA 2 Grams given over 10 minutes within 2 hours of initial injury Tranexamic Acid: Tranexamic acid is a man-made form of an amino acid (protein) called lysine. Tranexamic acid prevents enzymes in the body from breaking down blood clots.	Tranexamic Acid 4 Gram One time dose IV TXA 4 Grams given over 10 minutes within 2 hours of initial injury Tranexamic Acid: Tranexamic acid is a man-made form of an amino acid (protein) called lysine. Tranexamic acid prevents enzymes in the body from breaking down blood clots.	Placebo Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury Placebo: Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury
V1- Central Volume (L/70kg)	1160 L/70kg Interval 968.0 to 1350.0	—	—

SECONDARY outcome

Timeframe: 24 hours

Population: Of the 99 participants analyzed, 49 received the 2 gram dose and 50 received the 4 gram dose.

Outcome measures

Outcome measures
Measure	Tranexamic Acid 2 Gram n=99 Participants One time dose IV TXA 2 Grams given over 10 minutes within 2 hours of initial injury Tranexamic Acid: Tranexamic acid is a man-made form of an amino acid (protein) called lysine. Tranexamic acid prevents enzymes in the body from breaking down blood clots.	Tranexamic Acid 4 Gram One time dose IV TXA 4 Grams given over 10 minutes within 2 hours of initial injury Tranexamic Acid: Tranexamic acid is a man-made form of an amino acid (protein) called lysine. Tranexamic acid prevents enzymes in the body from breaking down blood clots.	Placebo Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury Placebo: Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury
CL- Clearance of TXA (mL/(Min*70kg))	109 mL/(min*70kg) Interval 100.0 to 118.0	—	—

Adverse Events

Tranexamic Acid 2 Gram

Serious events: 14 serious events

Other events: 25 other events

Deaths: 5 deaths

Tranexamic Acid 4 Gram

Serious events: 18 serious events

Other events: 39 other events

Deaths: 4 deaths

Placebo

Serious events: 13 serious events

Other events: 26 other events

Deaths: 9 deaths

Serious adverse events

Serious adverse events
Measure	Tranexamic Acid 2 Gram n=49 participants at risk One time dose IV TXA 2 Grams given over 10 minutes within 2 hours of initial injury Tranexamic Acid: Tranexamic acid is a man-made form of an amino acid (protein) called lysine. Tranexamic acid prevents enzymes in the body from breaking down blood clots.	Tranexamic Acid 4 Gram n=50 participants at risk One time dose IV TXA 4 Grams given over 10 minutes within 2 hours of initial injury Tranexamic Acid: Tranexamic acid is a man-made form of an amino acid (protein) called lysine. Tranexamic acid prevents enzymes in the body from breaking down blood clots.	Placebo n=50 participants at risk Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury Placebo: Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury
Vascular disorders Deep Vein Thrombosis	10.2% 5/49 • 28 days	14.0% 7/50 • 28 days	2.0% 1/50 • 28 days
Blood and lymphatic system disorders acute blood loss/anemia	4.1% 2/49 • 28 days	4.0% 2/50 • 28 days	2.0% 1/50 • 28 days
Respiratory, thoracic and mediastinal disorders Acute desaturation	0.00% 0/49 • 28 days	0.00% 0/50 • 28 days	2.0% 1/50 • 28 days
Renal and urinary disorders Acute Kidney Injury	0.00% 0/49 • 28 days	6.0% 3/50 • 28 days	0.00% 0/50 • 28 days
Respiratory, thoracic and mediastinal disorders Acute Respiratory Distress Syndrome	2.0% 1/49 • 28 days	2.0% 1/50 • 28 days	2.0% 1/50 • 28 days
Blood and lymphatic system disorders Anastomatic Bleeding	0.00% 0/49 • 28 days	4.0% 2/50 • 28 days	0.00% 0/50 • 28 days
Blood and lymphatic system disorders Arterial Bleeding	4.1% 2/49 • 28 days	0.00% 0/50 • 28 days	0.00% 0/50 • 28 days
Injury, poisoning and procedural complications Death	8.2% 4/49 • 28 days	6.0% 3/50 • 28 days	18.0% 9/50 • 28 days

Other adverse events

Other adverse events
Measure	Tranexamic Acid 2 Gram n=49 participants at risk One time dose IV TXA 2 Grams given over 10 minutes within 2 hours of initial injury Tranexamic Acid: Tranexamic acid is a man-made form of an amino acid (protein) called lysine. Tranexamic acid prevents enzymes in the body from breaking down blood clots.	Tranexamic Acid 4 Gram n=50 participants at risk One time dose IV TXA 4 Grams given over 10 minutes within 2 hours of initial injury Tranexamic Acid: Tranexamic acid is a man-made form of an amino acid (protein) called lysine. Tranexamic acid prevents enzymes in the body from breaking down blood clots.	Placebo n=50 participants at risk Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury Placebo: Matching Volume Normal Saline Placebo given IV over 10 minutes within 2 hours of initial injury
Injury, poisoning and procedural complications Pain	0.00% 0/49 • 28 days	0.00% 0/50 • 28 days	4.0% 2/50 • 28 days
Gastrointestinal disorders Nausea	12.2% 6/49 • 28 days	32.0% 16/50 • 28 days	12.0% 6/50 • 28 days
Infections and infestations Sepsis	12.2% 6/49 • 28 days	12.0% 6/50 • 28 days	4.0% 2/50 • 28 days
Cardiac disorders Hypotension	8.2% 4/49 • 28 days	6.0% 3/50 • 28 days	12.0% 6/50 • 28 days
Blood and lymphatic system disorders Anemia	16.3% 8/49 • 28 days	18.0% 9/50 • 28 days	16.0% 8/50 • 28 days
Infections and infestations Urinary tract infection	2.0% 1/49 • 28 days	2.0% 1/50 • 28 days	4.0% 2/50 • 28 days
Cardiac disorders SVT	0.00% 0/49 • 28 days	4.0% 2/50 • 28 days	0.00% 0/50 • 28 days
Blood and lymphatic system disorders Hyperphosphatemia	0.00% 0/49 • 28 days	4.0% 2/50 • 28 days	0.00% 0/50 • 28 days

Additional Information

Dr. Philip Spinella

Washington University School of Medicine

Phone: 314-286-0858

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place