Study of Tranexamic Acid During Air and Ground Medical Prehospital Transport Trial For Trauma Patients At Risk Of Hemorrhage (STAAMP Trial); Phase III Multicenter, Prospective, Randomized, Double Blind, Interventional Trial
Phase: PHASE3
Conditions: Traumatic Hemorrhage
Sponsor: Jason Sperry

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C. Clinical Protocol 
University of Pittsburgh 
Departments of Critical Care, Surgery and Emergency Medicine 
MACRO (Multidisciplinary Acute Care Research Organization) 
 
Study of Tranexamic acid during Air and ground Medical Prehospital transport (STAAMP) trial 
Phase 3 Multi-center, Prospective, Randomized, Blinded, Controlled Interventional Trial  
Protocol Version 2.7 date: January 11, 2019 
 
 
 
 
This study is being funded by the Department of Defense (DOD) Telemedicine and Advanced 
Technology Research Center (TATRC). 
 
 
 
 
 
 
IND Sponsor: 
Jason L. Sperry MD, MPH 
Associate Professor of Surgery and Critical Care Medicine  
University of Pittsburgh 
3500 Fifth Avenue, Suite 303 
Pittsburgh, PA 15213 
412 802 8270 
sperryjl@upmc.edu 
 

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Table of Contents 
PROTOCOL SYNOPSIS ........................................................................................................................................................... 5 
A. Statement of Work .......................................................................................................................................................... 6 
B. Investigators .................................................................................................................................................................... 7 
Sub-Investigators and Key Study Personnel: ...................................................................................................................... 7 
Collaborating Centers and Site Principal Investigators: ...................................................................................................... 7 
C. Background and Significance ........................................................................................................................................... 8 
C.1. Uncontrolled hemorrhage and coagulopathy remain leading causes of mortality post-injury: ................................. 8 
C.2. Coagulopathy occurs early and is a complex, primary process following injury: ........................................................ 8 
C.3. Hyperfibrinolysis is associated with poor outcome following traumatic injury: ......................................................... 9 
C.4. Rapid-thromboelastography (TEG) and hyperfibrinolysis: .......................................................................................... 9 
C.5. Early tranexamic acid reduces mortality post-injury: .................................................................................................. 9 
C.6. Mechanisms responsible for the beneficial effects of tranexamic acid following injury remain inadequately 
characterized: ................................................................................................................................................................... 10 
C.7. Plasmin and its pro-inflammatory effects: ................................................................................................................ 10 
C.8. Safety and dosing of tranexamic acid: ....................................................................................................................... 10 
C.9. Delay to definitive hemorrhage control: ................................................................................................................... 11 
D. Preliminary Studies ........................................................................................................................................................ 11 
D.1. Addressing coagulopathy is associated with improved survival and reduction in blood transfusion requirements:
 .......................................................................................................................................................................................... 11 
D.2. Early attention to coagulopathy is associated with a reduction in massive transfusion: ......................................... 12 
D.3. Prehospital interventions and management practice are associated with outcome differences following traumatic 
injury: ................................................................................................................................................................................ 12 
D.4. Feasibility of the trial: ................................................................................................................................................ 13 
D.5. Feasibility of air medical service intervention at the University of Pittsburgh: ........................................................ 13 
D.6. Clinical research infrastructure and coordinating center expertise of the University of Pittsburgh: ....................... 13 
D.7. Feasibility of patient recruitment for the trial: ......................................................................................................... 14 
E. Objectives/Hypotheses .................................................................................................................................................. 14 
E.1. Study Rationale: ......................................................................................................................................................... 14 
E.2. Primary Objective: ...................................................................................................................................................... 14 
E.3. Secondary Objectives ................................................................................................................................................. 14 
F. Project Milestones: ........................................................................................................................................................ 16 
G. Military Significance/Public Purpose: ............................................................................................................................ 16 
H. Research Design and Methods ...................................................................................................................................... 16 
H.1. Study Design/Setting: ................................................................................................................................................ 16 

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H.2. Study Population: ...................................................................................................................................................... 17 
H.3. Interventional Arm: ................................................................................................................................................... 18 
H.4. Placebo/Control Arm: ................................................................................................................................................ 20 
H.5. Randomization: .......................................................................................................................................................... 20 
H.6. Blinding ...................................................................................................................................................................... 20 
H.7. Prehospital Standard Operating Procedures ............................................................................................................. 20 
H.8. In-hospital Standard Operating Procedures .............................................................................................................. 21 
I. Outcome Variables/Definitions ...................................................................................................................................... 21 
I.1. Primary Outcome ........................................................................................................................................................ 21 
I.2 Secondary Clinical Outcomes ....................................................................................................................................... 21 
I.3. Secondary Laboratory/Mechanistic Outcomes: ......................................................................................................... 21 
I.4. Clinical Outcomes Methods/Definitions: .................................................................................................................... 21 
I.5. Laboratory/Mechanistic Outcome Methods/Definitions ........................................................................................... 23 
J. Analysis Plan: .................................................................................................................................................................. 24 
J.1. Data Analysis for Primary Outcome ............................................................................................................................ 24 
J.2. Analysis of Prehospital Randomized Secondary Outcomes ....................................................................................... 24 
J.3. Analysis for Second Stage In-hospital Randomized Dosage Regimens....................................................................... 25 
J.4. Predefined Subgroup Analyses ................................................................................................................................... 25 
J.5. Randomization of Ineligible Subjects: ......................................................................................................................... 25 
J.6. Non-adherence ........................................................................................................................................................... 25 
J.7. Missing Data ............................................................................................................................................................... 25 
K. Sample Size Justification and Power Analysis: ............................................................................................................... 25 
K.1. Primary Outcome 30 day mortality ........................................................................................................................... 25 
L. Human Subjects: ............................................................................................................................................................ 26 
M. Screening, Enrollment and Notification: ...................................................................................................................... 26 
N. Data ............................................................................................................................................................................... 27 
N.1. Sources ...................................................................................................................................................................... 27 
N.2. Prehospital Resuscitation Elements .......................................................................................................................... 27 
N.3. In-Hospital Resuscitation Elements ........................................................................................................................... 27 
N.4. Data Entry .................................................................................................................................................................. 28 
N.5. Database Management ............................................................................................................................................. 28 
N.6. Mortality Outcome Data (30 day) ............................................................................................................................. 28 
O. Training and Participating Site Coordination ................................................................................................................ 28 
P. Safety Monitoring .......................................................................................................................................................... 28 

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P.1. Data Safety Monitoring Board (DSMB) ...................................................................................................................... 28 
P.2.  Research Monitor ...................................................................................................................................................... 29 
P.3. Assessing and Reporting Adverse Events (AEs) ......................................................................................................... 29 
P.4. Interim Analyses ......................................................................................................................................................... 29 
P.5  IP Stopping Rules: ....................................................................................................................................................... 31 
Q. Quality Control and Assurance...................................................................................................................................... 31 
Q.1. Protocol Compliance and Reporting ......................................................................................................................... 31 
Q.2. Investigator Responsibilities ...................................................................................................................................... 31 
R. Study Limitations: .......................................................................................................................................................... 32 
Bibliography ....................................................................................................................................................................... 32 
Clinical Protocol Appendix 2 .............................................................................................................................................. 36 
Clinical Protocol Appendix 3 – Data Safety Monitoring Board (DSMB) Charter ................................................................ 38 
Clinical Protocol Appendix 4 – Stopping Rules .................................................................................................................. 49 
 

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PROTOCOL SYNOPSIS 
Study of Tranexamic acid during Air and ground Medical Prehospital transport (STAAMP) trial 
PI – Jason L. Sperry MD, MPH, Co-PI- Frank X. Guyette MD, MS, MPH 
Background: Traumatically injured patients continue to be plagued with uncontrolled hemorrhage resulting in 
significant morbidity and early mortality. A primary driving force for this unbridled hemorrhage is known to be 
the early coagulopathy which complicates severe injury. Trauma induced coagulopathy has been postulated to 
be an equilibrium imbalance between pro and anticoagulant factors, platelets, endothelium and fibrinolysis soon 
after injury. Recent evidence demonstrates that the early use of the antifibrinolytic agent tranexamic acid (TXA) 
after trauma center arrival results in improved survival in patients at risk for bleeding. Bringing this proven 
treatment to the prehospital arena and intervening earlier in those patients who would otherwise not be 
candidates for treatment has the real potential to further reduce or prevent the vicious hemorrhagic cascade, 
improve clinical outcomes and provide insight into the underlying mechanisms responsible for and which 
maximize its benefit. 
Objective/Hypothesis: The primary hypothesis will be that prehospital infusion of tranexamic acid in patients 
at risk for bleeding will reduce the incidence of 30 day mortality. The secondary hypotheses include that 
prehospital tranexamic acid will reduce the incidence of hyperfibrinolysis, acute lung injury, multiple organ 
failure, nosocomial infection, mortality, early seizures, pulmonary embolism and early resuscitation needs, 
reduce or prevent the early coagulopathy as demonstrated by improving presenting INR and rapid 
thromboelastography parameters, reduce the early inflammatory response, plasmin levels, leukocyte, platelet 
and complement activation, and determine the optimal dosing of tranexamic acid post-injury. 
Specific Aims: 
Aim#1: Determine whether prehospital tranexamic acid as compared to placebo results in a lower incidence of 
30 day mortality, 24 hour mortality, acute lung injury, multiple organ failure, nosocomial infection and 
improved shock parameters and early resuscitation and transfusion requirements.  
Aim#2: Determine whether prehospital tranexamic acid as compared to placebo reduces hyperfibrinolysis, 
lowers the incidence of acute traumatic coagulopathy and improves early markers of coagulopathy. 
Aim#3: To explore novel mechanisms by which prehospital tranexamic acid alters the inflammatory response 
independent of effects on hyperfibrinolysis including analysis of platelet and leukocyte activation, plasmin 
levels and plasmin mediated complement activation and the early cytokine response to trauma. 
Aim#4: Determine whether different dosing regimens of tranexamic acid upon arrival in the hospital are 
associated with improvements in hyperfibrinolysis, coagulopathy, clinical outcomes and the early inflammatory 
response. 
Study Design: Multi-center, prospective, randomized, blinded, controlled interventional trial over 3 years 
focusing on patients with concern for bleeding who are transported via emergency medical transport to 
definitive care. 
Population: Blunt or penetrating injured patients transported via emergency medical transport within two hours 
of estimated time of injury with concern for bleeding with 1.) a documented systolic blood pressure < 90 mmHg 
at the scene, en route, or at outside/referral facility OR 2.) documented tachycardia (> 110 bpm) at the scene, en 
route, or at outside/referral facility. Stage 1 Intervention: 1gm of tranexamic acid or placebo will be infused in a 
100ml saline bag by emergency medical staff over approximately 10 minutes once inclusion criteria are met. 
Prehospital providers and trauma center arrival staff will be blinded to the treatment given. Stage 2 Intervention: 
After arrival enrolled patients who received tranexamic acid will undergo a second randomization to one of 
three different arms: 1.) repeat tranexamic acid dosing, 2.) standard dosing or 3.) abbreviated dosing. Placebo 
infusion bags will be used for blinding in all arms including those who received placebo for the Stage 1 
Intervention. Patients and all treatment staff will be blinded to the intervention arm given for both stages. 
Randomization: Predetermined randomized allocation sequences using block sizes of 8 and 9 respectively for 
stage 1 and stage 2 interventions will be utilized. 
Relevance: Few interventions exist that alter the morbidity and mortality that inherently follows traumatic 
injury. By extrapolating the beneficial effects of tranexamic acid found in the hospital to the prehospital setting 
will allow intervention at an earlier point promoting a cascade of consequences with positive effects, in a cohort 

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of patients who otherwise would not benefit due to the early administration requirement for tranexamic acid. 
The results provided by the successful completion of this proposal will have paramount implications for both 
civilian and military injured patients as control of coagulopathy and hemorrhage and delay to definitive care 
represent major impediments. The current proposal will add needed understanding and insight into improving 
outcomes when these impediments exist and will promote focus on the mechanisms responsible and the dosing 
requirements of tranexamic acid that maximize its benefit. 
 
 
CLINICAL PROTOCOL 
 
A. Statement of Work 
Principal Investigators (PIs): Dr. Jason L. Sperry and Dr. Frank X. Guyette will oversee all planning and 
execution of the Study of Tranexamic acid during Air Medical Prehospital transport (STAAMP) trial which is a 
3 year, multi-center, randomized, double blinded, placebo controlled clinical trial. For patients at risk of 
bleeding who are transported by emergency medical transport, a 1 gram bolus of prehospital tranexamic acid 
and subsequent in hospital tranexamic acid dosing regimens will be compared to placebo for clinical, 
coagulation, inflammatory and dosing regimen endpoints. 
Coordinating Center: The University of Pittsburgh will be both the clinical outcome and data coordinating 
center. The University of Pittsburgh under the auspices of the Principal Investigators will be responsible for the 
education and training of participating center research staff and will oversee education and training of 
prehospital providers and research staff for participating centers. The University of Pittsburgh under the 
auspices of the Principal Investigators will be responsible for sample acquisition, sample storage, data 
acquisition and entry via web based platform, and maintenance of data integrity. 
Participating Centers: Site Investigators from participating centers will oversee the planning and execution of 
the trial at their respective centers. 
The Principal Investigators, the University of Pittsburgh and participating centers will thru the execution of the 
trial: 
1. Determine whether prehospital tranexamic acid as compared to placebo reduces 30 day mortality, 
reduces the incidence of hyperfibrinolysis, Acute Traumatic Coagulopathy and improves early markers 
of coagulopathy and hyperfibrinolysis. (r-TEG parameters, D-dimers, activated protein C, and plasmin-
anti-plasmin complexes)  
2. Determine whether prehospital tranexamic acid as compared to placebo results in a lower incidence of 
24 hour mortality, acute lung injury, multiple organ failure, nosocomial infection, shock parameters, 
early resuscitation and transfusion needs, early seizures and pulmonary embolism. 
3. To explore potential novel mechanisms by which tranexamic acid alters the inflammatory response to 
injury independent of effects on hyperfibrinolysis including effects on platelet and leukocyte activation 
via flow cytometry, measurements of plasmin levels and subsequent plasmin mediated complement 
activation and the early inflammatory cytokine response to trauma. 
4. Determine whether different dosing regimens of tranexamic acid upon arrival in the hospital are 
associated with improvements in hyperfibrinolysis, markers of coagulopathy, clinical outcomes, and the 
early inflammatory response. 
Pre Trial Start Period: The PIs and Site investigators will obtain FDA approval followed by approval for 
exception from consent for emergency research from their respective IRBs. The University of Pittsburgh as 
coordinating center will create a web based data entry platform for the trial. 
 
Year 1: Following a 1 month training period for participating centers on enrollment procedures and TEG 
analysis, trial enrollment will begin with an estimated 330 patients enrolled by years end. Blood samples will be 
batched for plate assay analysis at the University of Pittsburgh and prospective outcomes data will be obtained, 

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entered and integrity verified. First interim analysis will occur at 1/3 of total patient enrollment. Those 
exploratory aim measurements that require fresh blood samples will occur at the University of Pittsburgh alone. 
 
Year 2: An estimated additional 330 patients will be enrolled (total=660) by end of the second year and blood 
samples will again be batch analyzed for plate assay analysis. Continued prospective data collection and 
integrity verification for clinical outcomes will occur. A second interim analysis will occur after 2/3 of total 
patient enrollment. Exploratory aim measurements which require fresh blood samples will occur at the 
University of Pittsburgh alone. 
 
Year 3: An estimated additional 334 patients will be enrolled (total=994) by end of third year, blood samples 
will be batched for analysis. Continued prospective data collection and integrity verification for clinical 
outcomes will occur. Exploratory aim measurements which require fresh blood samples will occur at the 
University of Pittsburgh alone. Study completion, final manuscript preparation will soon follow. 
 
B. Investigators 
 
 
Principal Investigator: 
Jason L. Sperry MD, MPH, Associate Professor of Surgery and Critical Care 
Medicine, Co-Director of Acute Care Fellowship, University of Pittsburgh 
 
Sub-Investigators and Key Study Personnel: 
 
Co-Investigators:  
Frank X. Guyette MD, MS, MPH; Brian S. Zuckerbraun MD; Clifton 
Callaway, MD, PhD;  Graciela Bauza, MD; Raquel Forsythe, MD; Juan C. 
Puyana, MD; Gregory Watson, MD; Ankur Doshi, MD; Scott Gunn, MD; 
Christian Martin-Gill, MD; Paul Phrampus, MD; Matthew Rosengart, MD; 
Matthew Neal, MD; Barbara Early, RN, BSN, Adam Janicki, MD; Joseph 
Yanta, MD; Adam Frisch, MD; Aaron Brown, MD; Anthony Pizon, MD;  
Joshua Shulman, MD; Adam Tobias, MD, MPH; Julie McCausland, MD; 
Alexandra Castro, MD; Charissa Pacella, MD; Amy Talley, MD; Ross 
McCormack, MD                                                                                                                            
 
Consultant:  
Mazen Zenati MD, MPH, PhD, Assistant Professor of Surgery and 
Epidemiology, University of Pittsburgh 
Consultant:  
 
Derek C. Angus MD, MPH, The Mitchell P. Fink Professor and Chair,   
 
 
 
 
Department of Critical Care Medicine, University of Pittsburgh 
Consultant: 
Timothy R. Billiar MD, George Vance Foster Professor and Chair, Department 
of Surgery, University of Pittsburgh 
Consultant: 
Alan D. Murdock MD, Chief of Acute Care Surgery, Department of Surgery, 
University of Pittsburgh, Consultant to the Surgeon General for Trauma/Critical 
Care, Air Force Medical Operations Agency 
Consultant: 
Andrew B. Peitzman MD, Mark M. Ravitch Professor and Vice-Chair, 
Chief, Division of General Surgery, University of Pittsburgh 
Research Monitor:  
Louis Alarcon, MD, Medical Director, Trauma Surgery; Associate Professor of  
 
 
 
 
Surgery and Critical Care, University of Pittsburgh 
 
Collaborating Centers and Site Principal Investigators: 
 

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University of Arizona: 
Gary Vercruysse, MD, Medical Director, Burn Care Program, 
Associate Professor of Surgery, University of Arizona 
University of Texas, San Antonio:   
Brian J. Eastridge MD, Chief of Trauma Services, Professor-
Clinical, Department of Surgery, University of Texas at San 
Antonio 
University of Utah: 
Raminder Nirula MD, MPH, Associate Professor of Surgery, 
Surgical Critical Care Fellowship Director, University of Utah 
C. Background and Significance 
C.1. Uncontrolled hemorrhage and coagulopathy remain leading causes of mortality post-injury: 
Hemorrhage is estimated to be responsible for over 40% of all trauma-related deaths, nearly half of which occur 
in the pre-hospital setting.1,2 Uncontrolled bleeding remains the leading cause of early in hospital mortality.3,4 
Ongoing hemorrhage is complicated by the well-known ‘lethal triad’ of coagulopathy, hypothermia and acidosis 
(Fig 1.).5-8 It has been demonstrated that persistent hypothermia and progressive metabolic acidosis are 
associated with severe recalcitrant coagulopathy and resultant unbridled hemorrhage.9-12 Although multiple 
mechanisms which promote or result in coagulopathy post-injury have been proposed and studied, interventions 
that reduce the morbidity and mortality associated with hemorrhage and coagulopathy in the clinical arena 
remain limited.13,14  
C.2. Coagulopathy occurs early and is a complex, primary 
process following injury: Coagulopathy has been shown to be 
present in over 25% of patients at the time of trauma admission 
and has been determined to be an independent predictor of 
mortality with an associated 4-fold higher risk of mortality in 
both civilian and military settings.15-19 Those injured who 
arrive with coagulopathy also have been shown to have longer 
ICU stays and ventilator requirements, are more likely to 
develop acute renal injury, multiple organ failure, and have a 
trend towards a greater incidence of acute lung injury.18,20 Prior 
literature has suggested that the coagulopathy which 
complicates injury is a secondary event driven by physiologic derangements and abnormalities.7,9,21,22 Evolving 
evidence suggests that these prior mechanisms individually, which drive dysfunction or consumption of 
coagulation factors, may be too simplistic.23 More recent evidence demonstrates the importance of shock and 
tissue hypoperfusion as principle drivers of coagulopathy following injury which results in an imbalance of the 
equilibrium between procoagulant factors, anticoagulation factors, platelet and leukocyte activation, and 
fibrinolysis.12,20,23-26 (Fig 2.) As our understanding has increased regarding the mechanisms responsible for the 
acute coagulopathy of trauma, a new paradigm where early coagulopathy post-injury is considered a complex, 
multi-factorial, primary event has developed.22,23,27  
It is with this understanding that the scope and magnitude of morbidity due to uncontrolled 
hemorrhage is demonstrated, highlighting the importance of the potential benefits of prehospital 
tranexamic acid which may have a greatly magnified effect by intervening during the earliest time 
period and in those patients who would otherwise not be candidates for treatment due to the early 
time requirements for its administration . 
Ongoing 
Hemorrha
ge 
‘Lethal 
Acidosis 
Hypothermia 
Coagulopathy 
Fig 1. Adapted from Jansen JO, et al. BMJ. 2009 Jun 5;338:b1778 

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C.3. Hyperfibrinolysis is associated with poor outcome 
following traumatic injury: Hyperfibrinolysis has been 
identified as an integral component of acute traumatic 
coagulopathy.28,29 The incidence of hyperfibrinolysis as 
measured by thromboelastography (TEG) has been 
identified in 2% to 34% of trauma patients, with those 
patients who require large volume transfusion (>10 units 
in first 6 hours) having the highest incidence.29-31 It has 
been shown to occur early, following traumatic injury and 
significantly associated with an independent greater risk 
of mortality, the need for massive transfusion, higher 
injury and shock severity, and greater prehospital 
crystalloid resuscitation.29-32 Importantly, recent evidence 
suggests moderate fibrinolysis,  as measured by elevated 
plasmin-antiplasmin complexes in serum, may be 
apparent in over 50% of patients.32 This more common, subclinical measurement of fibrinolytic activity is not 
able to be assessed using standard TEG analysis, but is associated again with significantly greater 28-day 
mortality, greater ICU requirements and longer length of stay. 
C.4. Rapid-thromboelastography (TEG) and hyperfibrinolysis: As we continue to expand our 
understanding of the acute coagulopathy of trauma, emphasis has also been placed on diagnosing coagulopathy 
which complicates injury to allow real time assessment to guide 
evolving blood component transfusion requirements.33 Increasing 
evidence suggests that historic reliance on prothrombin time (PT), 
and international normalized ratio (INR) is time exclusive and 
provides insufficient information relative to the complexity which 
drives this coagulopathic process.34-36 Needed for the appropriate 
evaluation of an acutely injured patient’s coagulation status is a 
rapid, reliable assessment of the thrombosis and fibrinolysis arms 
of the hemostatic cascade. Thromboelastography (TEG) is a 
technology which provides a real time, viscoelastic analysis of 
these blood clotting processes.33 (Fig 3.) Point-of-care rapid 
thromboelastography (POC r-TEG) differs from standard TEG 
because the clotting process and subsequent analysis is accelerated 
by the addition of tissue factor to a whole blood sample.37 POC r-
TEG is limited, however, by the requirement that the analysis be performed within minutes of blood draw to 
prevent clot formation unless the addition of citrate occurs.37 It has been demonstrated the TEG can assess 
coagulopathy, platelet dysfunction and most importantly, hyperfibrinolysis at an early stage following injury 
and is the most rapid available test for providing reliable information on coagulopathy in significantly injured 
patients.38,39 If not more important, the technology has been deemed feasible for use in a deployed military 
setting as well as for civilian use.40 
C.5. Early tranexamic acid reduces mortality post-injury: 
In a large, civilian, multicenter, randomized, controlled trial (CRASH-2 trial) on the use of tranexamic acid in 
patients at risk of bleeding, a significant reduction in mortality was found with its use.41 Tranexamic acid is a 
lysine analog that is known to interfere with binding sites on plasminogen and inhibit fibrinolysis.42 Inclusion 
criteria for the trial included hypotension SBP <90 mm Hg or tachycardia (> 110 beats per min), in patients at 
risk of significant hemorrhage within 8 hours from injury. Dosing of tranexamic acid was given in a bolus 1 
gram dose over approximately 10 minutes followed by an infusion dose (additional 1 gram) over eight hours. 
This therapy was subsequently found in exploratory analysis to be beneficial in those who received tranexamic 
acid in the first 3 hours from injury and strongest in those patients who received it in the first hour following 
injury.43 Pre-specified analysis of the trial data demonstrated that the mortality benefit attributable to tranexamic 
Fig 3. Standard TEG parameters. Reaction (R) time, clot 
formation (K) time, fibrin cross-linking (angle = α), clot 
strength (maximal amplitude [MA]), and estimated percent lysis 
(EPL). Harr JN,et al. J Surg Res. 2011 Oct;170(2):319-24. 
Fig 2. Nascimento B. et al. Crit Care. 2010; 14(1): 202.  

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acid remained consistent across patients with low thru high predicted mortality in those enrolled in the first 3 
hours from injury, suggesting its use should not be limited to the most severely injured.44  Importantly, 
subgroup analysis on patients with brain injury revealed neither moderate benefits nor moderate detrimental 
effects and provides grounds for further evaluation in those patients with traumatic brain injury.45 Military 
experience with tranexamic also has demonstrated beneficial effects in a large retrospective analysis 
(MATTERs) study.46 The use of tranexamic acid within 1 hour of injury was associated with a lower mortality 
despite higher injury severity, and a lower incidence of coagulopathy as measured by standard laboratory testing 
(prothrombin time or activated partial thromboplastin time). Importantly, no information regarding the potential 
benefits of pre-hospital tranexamic acid currently exists. 
C.6. Mechanisms responsible for the beneficial effects of tranexamic acid following injury remain 
inadequately characterized: Tranexamic acid is known to inhibit fibrinolysis and has most commonly been 
used to decrease blood loss during cardiac and orthopedic surgeries.47-50 Its hypothetical benefit following 
traumatic injury would be derived from reducing blood loss and hyperfibrinolysis and the attributable 
independent morbidity associated with blood transfusion and coagulopathy. The CRASH-2 trial, despite 
showing a mortality benefit in over 20,000 enrolled patients, provides little insight into the mechanisms 
responsible for its beneficial effect.41 Early coagulopathy measurements or TEG analysis to measure fibrinolysis 
were not performed while only 50% of enrolled patients required blood transfusion at all.46 In the trial, total 
blood transfusion was recorded along with operative procedures, with neither of these important outcomes 
being different across treatment groups (tranexamic acid vs. placebo). Early blood transfusion requirements in 
the first 6 hour and 24 hours when tranexamic acid may have its greatest affect, were not recorded. In the 
retrospective military study (MATTERs) tranexamic acid was associated with greater 24 hour blood and blood 
component transfusion requirements and despite higher injury severity, the tranexamic acid group remained 
associated with lower mortality.46 The current evidence suggest that in addition to altering fibrinolysis,  
tranexamic acid may also effect outcome via a non-antifibrinolytic mechanism.  
The successful completion of the proposed aims of the current proposal will provide needed insight 
into the mechanisms responsible for the mortality benefit attributable to tranexamic acid in patients 
at risk for hemorrhage including those with brain injury, allowing focus on specific pathways and 
future therapeutic targets that will further improve care of the injured patient.  
C.7. Plasmin and its pro-inflammatory effects: Tranexamic acid is a lysine analogue that interferes with 
binding of plasminogen to fibrin, which is required for plasmin activation.42 Plasmin has pro-inflammatory 
effects by activating monocytes, neutrophils, platelets, endothelial and dendritic cells and induces pro-
inflammatory genes.51,52 Plasmin also induces chemotaxis of monocytes and dendritic cells and in-vitro and in-
vivo studies have demonstrated the ability of plasmin to stimulate the production reactive oxygen species and 
promote the release of lipid mediators and cytokines via complement activation.51,53 Tranexamic acid benefits in 
cardiac surgery have been hypothesized to be secondary to a reduction in the inflammatory response, possibly 
via a reduction of plasmin activation.53-55 The mortality benefit associated with tranexamic acid may occur 
secondary to an anti-inflammatory effect due to a reduction in plasmin activation. (Fig 4.) 
C.8. Safety and dosing of tranexamic acid: Tranexamic acid has been most commonly used in cardiac surgery 
and orthopedic surgery for its blood transfusion reduction effects with the risks of thrombotic complications and 
post-operative seizures being the most common complications 
reported with its use.49,50,56,57 It has been retrospectively compared 
to other anti-fibrinolytics used in cardiac surgery and shown to 
have a similar or better safety profile in most studies. Post-
operative seizures, due to a GABA receptor antagonist effect, 
have also been documented following cardiac surgery and this 
complication is thought to be a dose dependent effect.58,59 An 
orthopedic meta-analysis demonstrated no higher risk of venous 
thromboembolism following hip and knee replacement, surgeries 
typically thought to be at increased risk of thromboembolism.49  
The literature does suggest that further higher level studies are 
Fig 4. Pro-inflammatory and coagulation system effects of 
plasmin. Levy JH. Lancet. 2010 Jul 3;376(9734):3-4 

11 
 
required to verify the safety profile of lysine analogue anti-fibrinolytics in the non-injured patient 
population.49,60 The CRASH-2 trial, which looked at over 20,000 patients demonstrated no differences in deaths 
from vascular occlusive events including myocardial infarction, stroke, and pulmonary embolism and concluded 
the tranexamic acid safely reduced the risk of death in bleeding trauma patients.41 Importantly, the trial 
demonstrated that mortality due to bleeding was increased in patients who received tranexamic acid beyond 3 
hours from injury.43  In the retrospective military study (MATTERs, 896 patients) an increased incidence of 
deep vein thrombosis and pulmonary thromboembolism was demonstrated. These results were, however, 
confounded by higher injury severity in the tranexamic acid group.46  
The dosages used in the trauma population studies have been 1 to 2 grams either in loading and/or infusion 
route, all within the first 8 hours from injury. For the CRASH-2 trial, the dosage regimen was selected to 
provide a fixed dose within the range shown to inhibit fibrinolysis in larger patients and safe in smaller patients 
(10 mg/kg loading and 1mg/kg/hr infusion dose).41 For the military MATTERs study, 1 gram of tranexamic 
acid was given as a loading dose with the potential for repeat loading dosages.46 Based upon these prior studies, 
the most safe and optimal dosing regimen in trauma patients at risk for bleeding remains obscure.60 
C.9. Delay to definitive hemorrhage control: Definitive control of ongoing hemorrhage remains a 
fundamental principle in trauma management. Increasing attention has been paid to the significance of delay 
and the timing of definitive control of hemorrhage. Clarke and colleagues have previously shown that delays to 
operative intervention in patients with significant abdominal injuries are associated with a higher mortality risk, 
demonstrating a 1% higher risk of mortality for every 3 minute delay in getting patients from the ED to 
laparotomy.61 Additional studies documenting relationships between delay and poor outcome following injury 
have been demonstrated for interventional radiology procedures and by excessive radiographic imaging post-
injury in the hospital setting.62,63 Prehospital air medical transport has been shown to be associated with 
improved outcome following severe injury, however, scene time and overall transport times are consistently 
longer as compared to ground transportation in both civilian and military setting.64-68  
The results provided by the successful completion of this proposal will 
have paramount implications for both civilian and military injured 
patients as control of hemorrhage and delay to definitive care 
represent major impediments for both populations. This proposal will 
provide needed insight into the consequences of early tranexamic acid 
intervention following injury, the mechanisms responsible for its 
beneficial effects and the dosage regimen that maximizes its benefit 
when these impediments exist. 
 
D. Preliminary Studies 
D.1. Addressing coagulopathy is associated with improved survival 
and reduction in blood transfusion requirements: Secondary to the 
University of Pittsburgh’s participation with the Inflammation and the Host 
Response to Injury Large Scale 
Collaborative Program prospective 
cohort trial, (www.gluegrant.org), we 
have previously characterized the 
relationships of addressing the early 
coagulopathy following acute injury 
and the outcomes associated with its 
presence.69-74 We have documented 
the relationship between high fresh 
frozen plasma:packed red blood cell 
(FFP:PRBC) transfusion ratios in 
Fig 5. Kaplan-Meier Survival Analysis comparing 
survival across different transfusion ratio groups. 
0.03
24HR Mortality
12HR Mortality
6HR Mortality
PLT:PRBC
24HR Mortality
12HR Mortality
6HR Mortaltiy
FFP:PRBC
1.0
 Independent Risks Of Mortality
For 6hr HIGH vs. LOW
Transfusion Ratios
Fig 7. Mortality risks for 6hr High and Low transfusion ratios 
over the first 24hrs post injury. 
Fig 6. Transfusion requirements across High and 
Low FFP:PRBCs groups 

12 
 
massive transfusion patients and outcome.74 We verified a dose response relationship revealing as the 
FFP:PRBC increased toward 1:1.5, a significant reduction in mortality occurred. (Fig 5.) Equally important, 
there were significant reductions in blood and blood component transfusion requirements in those with High vs. 
Low FFP:PRBC transfusion ratios. (Fig 6.) More recent analyses aimed to debunk any question of survival bias 
regarding high plasma transfusion ratios in the glue grant cohort.71 Cox-Hazard regression was used to 
determine the independent mortality risks at 6hr, 12hr, and 24hrs while controlling for important confounders. 
FFP:PRBC and platelet:PRBC ratios were also analyzed as time-dependent covariates  accounting for 
fluctuation over time. We found that despite similar degrees of early shock and coagulopathy, HIGH 
FFP:PRBC and platelet:PRBC ratios are associated with a survival benefit as early as 6hrs and throughout the 
first 24hrs, even when time dependent fluctuations of component transfusion were accounted for. (Fig 7.) We 
concluded that the observed mortality benefit associated with high component transfusion ratios was unlikely 
due to survivor bias and that early attainment of high transfusion ratios may significantly lower the risk of 
mortality in MT patients. This prior work demonstrates that addressing the coagulopathy following significant 
injury is associated with improved outcome. 
D.2. Early attention to coagulopathy is associated with a reduction in massive transfusion: We have 
recently characterized changes in resuscitation practice which have occurred over time in a cohort severely 
injured patients requiring massive transfusion.73 We demonstrated that the incidence of massive transfusion 
(>10 units blood) 
significantly decreased over time, 
despite the median ISS of 
the cohort increasing. (Fig 8.) 
When the recent time 
period (2007-current) was 
compared to the early time 
period (2004-2006) of enrollment 
for the study, there was a 
significant increase in the 
FFP:PRBC and 
platelet:PRBC transfusion ratios 
as early as 6 hours post 
injury, and the proportion of each 
blood component that was 
given in first 6hrs relative to the 
total give at 24 hours 
significantly increased. (Fig. 9.) 
This occurred in patients 
who required 7-10 units of blood, 
just below the definition of 
massive transfusion. The data 
suggests that early, more 
aggressive attainment of high 
transfusions ratios may 
reduce the requirement for 
massive transfusion and 
may shift overall blood 
requirements below those 
which currently define massive 
transfusion. This previous 
work suggests that early attention to 
coagulopathy is associated 
with improved outcome, highlighting 
the importance of prehospital 
interventions known to have a 
beneficial effect. 
D.3. Prehospital 
interventions and 
management practice are 
associated with outcome 
differences following 
traumatic injury: 
Secondary to the University 
of Pittsburgh’s participation with the Resuscitation Outcomes Consortium 
(https://roc.uwctc.org/), prior work has demonstrated the importance of 
interventions in the prehospital arena.75-79 We have also previously 
demonstrated the expertise the air medical service has with air medical 
interventions in injured patients.80-82 A recent analysis demonstrates the 
importance of prehospital serum lactate measurement during air medical transport for traumatic injury and its 
role as an independent predictor of in-hospital death, need for emergent operative intervention and the 
2004
2006
2008
4.0
5.0
6.0
7.0
20
25
30
35
MT (% patients)
ISS
*
*
Median 24hr PRBC (unit)
*
Year
Fig 8. Decreasing incidence of massive transfusion  over time 
with increasing injury severity  
FFP
PLT
30
40
50
60
70
80
EARLY
RECENT
*
*
SUB-MT 6HR/24HR %
Fig 9. Comparing the proportion of component 
transfusion in the first 6 hours relative to 24 hours 
in early and recent time periods. 
Fig 10. Logistic regression results for prehospital 
lactate predicting risks for in-hospital death, need 
for emergent operation and multiple organ failure. 

13 
 
development of multiple organ failure.83 (Figure 10.) More recent work demonstrates the utility of air medical 
tissue oximetry and the ability it has to predict operative intervention or blood transfusion in the first 24 hours 
following injury.84 (Figure 11.) A recent study which was presented at the 2012 AAST annual meeting utilizing 
Gluegrant dataset demonstrated that overly aggressive prehospital crystalloid use was associated with an 
independent greater risk of early coagulopathy and mortality in patients who were normotensive (SBP> 
90mmHg) while a trend towards benefit and lower risks of poor outcome were found in patients with 
prehospital hypotension (SBP<90mmHg). (Journal of Trauma and Acute Care Surgery. In Press, 2013, Figure 
12.)  
D.4. Feasibility of the trial: The collaborative environment between the 
Departments of Surgery and Emergency Medicine at the University of 
Pittsburgh unifies prehospital clinical research expertise with hospital 
based acute care research expertise and will provide the main impetus for 
the successful execution of the current proposal.  The principal 
investigators participation and involvement in the Inflammation and the 
Host Response to Injury Program, (Glue grant), the Resuscitation 
Outcomes Consortium (ROC) and recent funding (proposal #11152002, 
W81XWH-12-2-0023) from the Department of Army for the ‘Prehospital 
Use of Plasma for Traumatic Hemorrhage (PUPTH) Program’ documents 
and verifies the robust nature of the University of Pittsburgh’s multi-center 
research collaborations and expertise in prehospital investigations, the 
clinical research infrastructure that is available and the institutional and 
departmental support to promote and allow the successful execution and 
completion of the proposed aims that will provide important knowledge 
into the mechanisms and appropriate dosing of tranexamic acid that 
maximize its beneficial effects. 
D.5. Feasibility of air medical service intervention at the University 
of Pittsburgh: Under the direction of Dr. Frank Guyette, Co-Principal 
Investigator of this proposal, the air medical service at the University of 
Pittsburgh is the busiest non-profit flight service in the country and has a 
significant track record of prospective trials and interventions in the 
prehospital arena.76,78,79,82-86  The air medical service at the University 
of Pittsburgh has 14 air medical bases which have flown over 1,600 injured patients to Presbyterian 
Hospital, the busiest level 1 trauma center in the state of Pennsylvania, over the last 12 months (2012 
data). The DOD funded PAMPer trial (Prehospital Air Medical Plasma trial) under the auspices of the 
PUPTH Program will utilize only 4 out of the 14 air medical bases which reside closest to blood banking 
affiliates due to the requirement of thawed plasma for the multi-center trial. The remaining 10 helicopter 
bases will be utilized for the current proposal providing one of largest patient populations available 
across the country for an air medical prehospital intervention. It is this extensive prehospital investigation 
expertise and experience that will promote and allow the successful completion of the aims of the proposal. 
D.6. Clinical research infrastructure and coordinating center expertise of the University of Pittsburgh: 
The Department of Surgery at the University of Pittsburgh has interdepartmental research affiliations with the 
Department of Critical Care Medicine and the Department of Emergency Medicine and has spearheaded the 
Multidisciplinary Acute Care Clinical Research Organization (MACRO). MACRO is a unique, 
interdepartmental resource with laboratory facilities, an experienced and professionally-trained staff of 11 
clinical research coordinators, 15 research associates and 24 hour around the clock screening capabilities. They 
have extensive experience with data entry, multi-center data coordination, training, IRB liaison needs, web-
based data entry platform creation and specimen management and storage. MACRO follows a cost center model 
and provides ‘cost-neutral’ services to clinical investigators from diverse specialties in order to conduct clinical 
and translational research. Currently, Over 71 principal investigators and co-investigators from 9 different 
departments currently utilize MACRO services. Thru 2012 alone, MACRO’s services were utilized for 14 
Fig 12. Forest plot depicting independent mortality 
risks associated with high volume prehospital 
crystalloid in hypotensive and non-hypotensive 
Fig 11. ROC curve revealing ability of prehospital tissue 
oximetry to predict operative intervention or blood 
transfusion in first 24 hours post-injury 

14 
 
interventional trials and 11 observational trials. MACRO has been the clinical research infrastructure utilized 
for the institutions involvement in the Gluegrant and ROC studies and is the infrastructure that is being utilized 
for the multi-center coordination of the DOD funded PAMPer trial. It is with the dedicated clinical research 
infrastructure provided by MACRO at the University of Pittsburgh that the aims of the current proposal can 
successfully be completed. 
D.7. Feasibility of patient recruitment for the trial: As demonstrated by being essential participants of both 
the Gluegrant and ROC studies, the departments of Surgery and Emergency Medicine at the University of 
Pittsburgh have a significant track record of successful patient recruitment and enrollment in large prehospital 
and in hospital prospective trials for traumatic injury. Regarding the specifics of the current proposal, over the 
last 12 months, the air medical services that will be utilized for this trial has transported > 150 patients meeting 
the specific inclusion and exclusion criteria for this proposal (SBP < 90mmHg and tachycardia - > 110 bpm). 
Participating centers have been chosen with similarly busy air medical services and with a history of 
involvement with the Gluegrant, ROC or with other multi-institutional clinical research experience. It is under 
the auspices of the collaborative clinical research environment of the University of Pittsburgh and these busy 
participating trauma centers that the specific objectives and aims of the current proposal can successfully be 
accomplished. 
 
E. Objectives/Hypotheses 
E.1. Study Rationale: Traumatic injured patients continue to be plagued with uncontrolled hemorrhage 
resulting in significant morbidity and early mortality. A primary driving force for this unbridled hemorrhage is 
known to be the early coagulopathy which complicates severe injury. Trauma induced coagulopathy has been 
postulated to be an equilibrium imbalance between pro and anticoagulant factors, platelets, endothelium and 
fibrinolysis soon after injury. Recent evidence demonstrates that the early use of the antifibrinolytic agent 
tranexamic acid after trauma center arrival results in improved survival in patients at risk for bleeding. Bringing 
this proven treatment to the prehospital arena and intervening earlier in those patients who would otherwise not 
be candidates for treatment has the real potential to further reduce or prevent the vicious hemorrhagic cascade, 
improve clinical outcomes and provide insight into the underlying mechanisms responsible for and which 
maximize its benefit. 
E.2. Primary Objective: To determine the effect of prehospital tranexamic acid infusion (1 gram over 
approximately 10 minutes) as compared to placebo during emergency medical transport in patients at risk of 
traumatic hemorrhage on 30 day mortality. 
E.2.1. Primary Aim#1: Determine whether prehospital tranexamic acid as compared to placebo reduces 
30 day mortality in patients at risk for traumatic hemorrhage. 
Primary Hypothesis 1: Prehospital tranexamic acid as compared to placebo will reduce 30 day mortality 
in patients at risk of traumatic hemorrhage 
E.3. Secondary Objectives: To determine the effect of prehospital tranexamic acid infusion (1 gram over 
approximately 10 minutes) as compared to placebo during emergency medical transport in patients at risk of 
traumatic hemorrhage on the incidence of hyperfibrinolysis (estimated percent lysis > 7.5%, first 30 minutes by 
rapid-thromboelastography) acute traumatic coagulopathy (ATC), early markers of coagulopathy, the incidence 
of 24 hour mortality, acute lung injury, multiple organ failure and development of nosocomial infection, shock 
parameters and resuscitation/transfusion requirements, platelet and leukocyte activation and the early 
inflammatory response and to determine whether different dosing regimens of tranexamic acid upon arrival in 
the hospital are associated with improvements in hyperfibrinolysis, coagulopathy, clinical outcomes  and the 
early inflammatory response. 
E3.1. Secondary Aim#1: Determine whether prehospital tranexamic acid as compared to placebo 
reduces the incidence of hyperfibrinolysis (estimated percent lysis > 7.5%), acute traumatic 
coagulopathy (ATC, presenting INR > 1.4), improves PT measurements and additional r-TEG 
parameters, D-dimer levels, activated Protein C levels, and plasmin-antiplasmin complexes. 

15 
 
Secondary Hypothesis 1: Prehospital tranexamic acid as compared to placebo will reduce the incidence 
hyperfibrinolysis (estimated percent lysis > 7.5%), reduce the incidence of patients with an arrival INR 
> 1.4, improve PT and additional presenting r-TEG parameters of coagulopathy including ACT, r-value, 
k-time, α-angle, maximal amplitude (MA) and G-values and D-dimer levels, activated Protein C levels 
and plasmin-antiplasmin complexes. 
E.3.2. Secondary Aim#2: Determine whether prehospital tranexamic acid as compared to placebo 
results in a lower incidence of 24 hour mortality, acute lung injury, multiple organ failure, nosocomial 
infection, early seizures, pulmonary embolism, shock parameters and early resuscitation and transfusion 
requirements. 
Secondary Hypothesis 2A: Prehospital tranexamic acid as compared to placebo will reduce the 
incidence of 24 hour and 30 day mortality, acute lung injury, multiple organ failure, nosocomial 
infection, early (24hr) seizures and in-hospital pulmonary embolism. 
Secondary Hypothesis 2B: Prehospital tranexamic acid as compared to placebo will improve presenting 
base deficit, 24 hour crystalloid requirements and reduce 6 hour and 24 hour blood and blood 
component transfusion requirements (PRBC, FFP and platelets).  
E.3.3. Secondary Aim #3: To investigate potential novel mechanisms by which tranexamic acid alters 
the inflammatory response to injury independent of effects on hyperfibrinolysis. Investigations of the 
effects of tranexamic acid on inflammation will include analysis of platelet and leukocyte activation via 
flow cytometry, measurements of plasmin levels and subsequent plasmin mediated complement 
activation and the early inflammatory cytokine response to trauma. 
Secondary Hypothesis 3A: Prehospital tranexamic acid as compared to placebo will reduce plasmin 
levels and markers of platelet and leukocyte activation measured by flow cytometry (FACS) and result 
in a plasmin mediated reduction of complement activation as measured by C3a and Factor B levels. 
Secondary Hypothesis 3B: Prehospital tranexamic acid as compared to placebo will attenuate trauma-
induced pro-inflammatory changes and immunosuppression by reducing the early inflammatory 
cytokine response (GM-CSF, IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10 and TNF-α), HMGB1 
levels and early inflammatory gene responses as measured by RT-PCR. 
E.3.4. Secondary Aim#4: Determine whether different dosing regimens of tranexamic acid upon arrival 
in the hospital are associated with improvements in hyperfibrinolysis, markers of coagulopathy, clinical 
outcomes, platelet and leukocyte activation and the early inflammatory response. 
Secondary Hypothesis 4A: Repeat dosing of 1 gram of tranexamic acid followed by 1 gram over 
approximately 8 hours after hospital arrival in patients who have already received 1 gram of prehospital 
tranexamic acid will lower the incidence of 12 hour (from arrival) hyperfibrinolysis (estimated percent 
lysis > 7.5%), coagulopathy (INR > 1.4) and improve r-TEG markers of coagulopathy, D-dimer levels, 
activated protein C levels and plasmin-antiplasmin complex levels as compared to standard dosing of 
tranexamic acid (1 gram over approximately 8 hours) or abbreviated dosing (no additional tranexamic 
acid). 
Secondary Hypothesis 4B: Repeat dosing of 1 gram of tranexamic acid followed by 1 gram over 
approximately 8 hours after hospital arrival in patients who already received prehospital tranexamic acid 
will lower the incidence of 24 hour and 30 day mortality, acute lung injury, multiple organ failure and 
nosocomial infection as compared to standard dosing or abbreviated dosing.  
Secondary Hypothesis 4C: Repeat dosing of 1 gram of tranexamic acid followed by 1 gram over 
approximately 8 hours after hospital arrival in patients who already received prehospital tranexamic acid 
will reduce 12 hour (from arrival) base deficit, 24 hour crystalloid requirements and 6 hour and 24 hour 
blood and blood component transfusion requirements (PRBC, FFP and platelets) as compared to 
standard dosing or abbreviated dosing. 
Secondary Hypothesis 4D: Repeat dosing of 1 gram of tranexamic acid followed by 1 gram over 
approximately 8 hours after hospital arrival in patients who already received prehospital tranexamic acid 
will reduce 12 hour and 24 hour (from arrival) markers for platelet and leukocyte activation, plasmin 

16 
 
levels, markers of complement activation, HMGB1 levels and the early inflammatory cytokine response 
as compared to standard dosing or abbreviated dosing. 
 
F. Project Milestones:  
The proposal is for a 3 year trial. The FDA approval process will be initiated after notification of proposal 
funding.  Community notification and other procedures associated with exception from consent for emergency 
research will be initiated and completed prior to IRB approval at all institutions. Following final IRB approval a 
1.5 month startup period will be utilized to verify and educate all centers prior to beginning enrollment. A data 
entry web based platform will be created during this same time period. Enrollment will occur for 33 months 
(2.75 years) with prospective data entry of laboratory and TEG measurements, clinical outcomes, transfusion 
requirements and demographic and injury characteristics. Serum for cytokine and ELISA measurements will be 
batched and sent to the University of Pittsburgh on an annual basis. We expect approximately 70 patients per 
year per institution on average. Flow cytometry for platelet and leukocyte activation and RT-PCR may be 
performed at the University of Pittsburgh prospectively on a subset of patient samples. Enrollment will be 
monitored on a semi-annual basis for each participating center. Data safety and monitoring over the course of 
the clinical trial will fall under the responsibility of an independent data safety and monitoring board (DSMB). 
Interim analysis will occur at 33% and 66% of patient enrollment. A 1.5 month data cleaning and wind down 
will occur once enrollment has been completed, allowing data analysis and manuscript preparation. 
 
G. Military Significance/Public Purpose:  
Despite the significant advances in trauma care delivery and post-injury management practices which have 
occurred over the last decade, uncontrolled hemorrhage remains one of the leading causes of trauma related 
deaths.4,5,87,88 Recent evidence demonstrates that the early use of the antifibrinolytic agent tranexamic acid after 
trauma center arrival results in improved survival in patients at risk for bleeding.41 Bringing this proven 
treatment to the prehospital arena and intervening earlier in those patients who would otherwise not be 
candidates for treatment has the real potential to further reduce or prevent the vicious hemorrhagic cascade, 
improve clinical outcomes and provide insight into the underlying mechanisms responsible for and which 
maximize its benefit. This potential knowledge base would be dramatically beneficial to both military and 
civilian trauma systems. It is in both these settings where the prehospital phase of treatment represents a 
relatively novel arena for new interventions. The results provided by the successful completion of this proposal 
will have paramount implications for both military and civilian injured patients as control of hemorrhage and 
delay to definitive care represent major impediments for both populations. This proposal will provide needed 
insight into the consequences of early tranexamic acid intervention in these significantly injured patients when 
these impediments exist. 
 
H. Research Design and Methods 
H.1. Study Design/Setting: The study will be a 3 year, multi-center, blinded, randomized trial utilizing level-1 
trauma centers with busy emergency medical transport services with a clinical research track record. For 
patients at risk of hemorrhage being transported by emergency medical transport, the infusion of 1 gram of 
tranexamic acid over approximately 10 minutes in the prehospital setting will be compared to placebo.  The 
University of Pittsburgh Medical Center (UPMC) will be both the clinical outcome and data coordinating 
center. Each individual institution will perform point of care rapid TEG analysis and coagulation measurements 
on site. UPMC presbyterian is the busiest level-1 trauma center in the state of Pennsylvania and is affiliated 
with the largest non-profit air medical service in the country with an extensive track record of multi-center, in-

17 
 
hospital and prehospital clinical trials. All enrolling centers and respective investigators similarly have busy 
emergency medical services and significant experience with multi-center trials, the research infrastructure to 
allow them to successfully occur and have no other clinical investigations that would preclude participation in 
the current proposal. Participating Institutions include: University of Pittsburgh, University of Arizona, 
University of Texas at San Antonio, and the University of Utah. The University of Tennessee at Memphis will 
be utilized as an alternate/additional site if required. 
H.2. Study Population: The study population will include blunt or penetrating injured patients at risk of 
hemorrhage being transported via emergency medical services from the scene of injury or from referring 
hospital to a definitive trauma center that is participating in the trial. We have selected similar inclusion criteria 
as the prior large, prospective study41 (CRASH-2).   This represents a similar level of acuity than the CRASH-2 
study and additionally allows the mechanism of tranexamic acid’s benefit to be characterized across a spectrum 
of injury severity since the pre-specified analysis of the CRASH-2 trial demonstrated that the mortality benefit 
attributable to early tranexamic acid remained consistent across patients with low thru high predicted mortality, 
suggesting its use should not be limited to the most severely injured.44  The study group may also contain 
traumatic brain injured patients who represent a subgroup that may also benefit from early tranexamic 
intervention. 45 Based upon our own current data (2011-2012) in injured patients that require air medical 
transport, these inclusion criteria are associated with over a 65% blood transfusion rate in the first 24 hours 
from admission and represents the most pertinent population for the trial. 
H.2.1. Specific Inclusion Criteria: 
1. Blunt or penetrating injured patients at risk of hemorrhage being transported via emergency medical 
services from the scene of injury or from referring hospital to a definitive trauma center that is 
participating in the trial 
AND 
2. Within 2 hours of estimated time of injury 
AND 
3A. Hypotension (Systolic Blood Pressure (SBP) < 90mmHg) 
 
 
i. At scene of injury or during emergency medical transport 
 
ii. Documented at referring hospital prior to emergency medical transport arrival 
OR 
3B. Tachycardia (heart rate >110 beats per minute) 
 
 
i. At scene of injury or during emergency medical transport 
 
 
ii. Documented at referring hospital prior to emergency medical transport arrival 
 
 
 
      
H.2.2 Specific Exclusion Criteria: 
1. Age > 90 or < 18 years of age; 2. Inability to obtain intravenous or intraosseous access;3. 
Documented (radiographic evidence) cervical cord injury with motor deficit; 4. Known prisoner; 5. 
Known pregnancy; 6. Traumatic arrest with > 5 minutes CPR without return of vital signs; 7. 
Penetrating cranial injury 8. Traumatic brain injury with brain matter exposed; 9. Isolated drowning or 
hanging victims  10. Wearing an opt out bracelet. 11. Objection to study voiced by subject or family 
member at the scene. 12.  Isolated fall from standing 
 
Inclusion and exclusion criteria will be assessed based on available information at the time of enrollment.  
Although all reasonable efforts will be made by the emergency medical crew to either directly witness or obtain 
documentation of inclusion criteria, including qualifying vitals, due to the nature of the emergency pre-hospital 
setting, there may be occasions where the emergency medical crew must rely on verbal report of qualifying 
vitals from the referring hospital or ground crew.  In these instances, if, after subsequent review of outside 
hospital and/or ground crew documentation, it is determined that the subject did not meet inclusion criteria 

18 
 
and/or met exclusion criteria, the subject will remain enrolled in the study based on the intention-to-treat 
principle.  
 
In the event that a verbal report must be used in lieu of physical documentation or directly witnessing the 
qualifying vitals, documentation of the verbal report will serve as the source documentation for determining 
eligibility.  Verbal reports will be documented in the emergency medical record and will detail the information 
reported and by whom.  
 
H.3. Interventional Arm: The Intervention will have both a prehospital phase and in-hospital phase. 
Investigational Drug Services (IDS) at the University of Pittsburgh will be utilized to supply and organize both 
tranexamic acid and placebo along with respective normal saline bolus and infusion bags to all participating 
trial sites. IDS at the University of Pittsburgh has a long track record of managing large multicenter trials and is 
currently executing and responsible for over 150 inpatient and outpatient clinical trials. 
H.3.1. Prehospital Phase Intervention: Once inclusion and exclusion are verified while the patient is 
being transported via emergency medical transport to a STAAMP trial participating center, in a 
randomized, double blinded fashion, either 1 gram bolus of tranexamic acid diluted in 100cc of normal 
saline (pre-prepared on emergency vehicle) or placebo of identical volume will be infused intravenously 
or intraosseously (if IO access was obtained due to a clinical need per standard of care) into the patient 
over approximately 10 minutes (“Bag A”). After receiving the prehospital phase intervention, standard 
operating procedures utilizing goal directed crystalloid infusion will be followed (see H.7. Prehospital 
Standard Operating Procedures below) 
H.3.2. In-hospital Phase Intervention: Upon arrival, patient blood and labs will be sampled and arrival 
rapid-TEG analysis will be performed within first 6 hours. After inclusion and exclusion criteria 
verification by research staff, in a double blinded, randomized fashion, those patients who received 
tranexamic acid in the prehospital phase will receive 1 of 3 different dosage regimens: 
 
1. Standard Tranexamic acid Dosing:  
1 gram infusion over approximately 8 hours 
2. Repeat Tranexamic acid Dosing:  
1 gram bolus and 1 gram infusion over approximately 8 
hours 
3. Abbreviated Tranexamic acid Dosing: 
No further tranexamic acid to be given 
 
For intervention blinding purposes, each patient will receive both a bolus dose (either tranexamic acid or 
placebo), “Bag B,” and 8 hour infusion (either tranexamic acid or placebo), “Bag C,” depending on the 
randomized dosing regimen. (Figure 13. below) 
 
H.3.2.1 Adjustment For Renal Insufficiency: Subjects with a known or suspected history of 
renal insufficiency will receive a renal dose adjustment for the 8 hour repeat infusion (Bag C).  
The Estimated Body Weight Table will be used to determine the dose (Figure 12).  The dose will 
be capped at 1000 mg. 
 
1. Standard  Dosing:       
 bolus- no dose adjustment / infusion- 1.25 mg/kg/hr x 8hrs 
2. Repeat Dosing: 
       
 bolus- no dose adjustment / infusion- 1.25 mg/kg/hr x 8hrs 
3. Abbreviated Dosing:   
 bolus- no dose adjustment / infusion- 1.25 mg/kg/hr x 8hrs 
 
Renal adjustment will be based upon the most current tranexamic acid Product 
Information/Package Insert (Cyklokarpon package insert. West Ryde NSW: Pfizer Inc. 2010 
October) where renal dosing adjustment is recommended for cardiac bypass surgery patients, 
whose eGFRis below 29 (< 29 mL/min/1.73m2).  
 

19 
 
 
 
 
 
 
Figure 12. Dose adjustment 
 
 
 
 
 
 
 
 
 
 
 
 
       Intervention        Phase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Estimated Body Weight 
Dose 
>100 kg 
1000 mg (10 ml from vial) 
90-99.9 kg 
900 mg (9 ml from vial) 
80-89.9 kg 
800 mg (8 m1 from vial) 
70-79.9 kg 
700 mg (7 ml from vial) 
60-69.9 kg 
600 mg (6 ml from vial) 
50-59.9 kg 
500 mg (5 ml from vial) 
40-49.9 kg 
400 mg (4 ml from vial) 
30-39.9 kg 
300 mg (3 ml from vial) 
20-29.9 kg 
200 mg (2 ml from vial) 
1
2
3
            In-Hospital 
                   In-Hospital                       In-Hospital 
             Standard  
 
   Repeat  
 Abbreviated 
 
         Placebo Bolus                     TXA Bolus                     Placebo Bolus 
 
         TXA Infusion  
                 TXA Infusion                Placebo Infusion 
              (8hrs) 
 
  (8hrs) 
 
     (8hrs) 
In-Hospital Placebo 
 
 
Placebo Bolus 
 
Placebo Infusion 
(8hrs) 
Received 
Prehospital TXA 
Received  
Prehospital Placebo 
Blinded 
In-Hospital 
Prehospital 
Blinded 
Meets Inclusion and 
Exclusion Criteria 
Prehospital Intervention 
TXA vs Placebo bolus (10 min)
Prehospital Goal 
Directed Resuscitation 
SOP 
Trauma Center Arrival 
Blood, Labs, rapid-TEG 
Injury 
In-Hospital Intervention 

20 
 
 
 
 
 
 
 
H.4. Placebo/Control Arm: Prehospital phase patients randomized to placebo will receive identical placebo 
diluted in 100cc of normal saline and infused over approximately 10 minutes. Patients who received prehospital 
phase placebo will receive in-hospital identical placebo bolus and approximately 8 hour placebo infusion for 
blinding purposes.  
H.5. Randomization: The randomization scheme will have both a prehospital phase and in-hospital phase.  
H.5.1. Prehospital Phase Randomization: Individual patients meeting criteria while en route via 
emergency medical transport will be randomized using an allocation sequence block size of 8 to either 1 
gram of tranexamic acid or placebo diluted in 100cc of normal saline given over approximately 10 
minutes. A single prehospital treatment box containing ascending numerically labeled (1-8) treatment 
packs (randomized with a computer random number generator) will be distributed to each respective 
helicopter base (or station in the case of ground ambulance). In an ascending numerical order fashion 
treatment packs will be utilized for enrolled patients. The box and treatment pack # will be recorded by 
research staff upon arrival for all randomized patients. The patient and all treatment and research staff 
will be blinded to the treatment arm. All intervention vials will be covered to obscure view of vial 
contents to prehospital staff giving the intervention and amber colored syringes will be utilized to 
maintain blinding. IDS at the University of Pittsburgh will be unblinded to the prehospital intervention. 
Additionally, the pharmacy at each respective participating center will have access to the prehospital 
randomization/assignment scheme once the prehospital intervention box and treatment # are provided to 
them by the accepting research staff at each participating center.  
H.5.2. In-hospital Phase Allocation: Using a web based, randomization assignment program built 
specifically for the trial, research staff will provide and input the prehospital intervention box # and 
treatment pack # into the web based platform at each site and be provided the In-hospital treatment 
allocation to be utilized for the second phase intervention. IDS at the University of Pittsburgh and each 
respective pharmacy at the participating sites will be provided with the random allocation sequence and 
will be unblinded to the in-hospital allocation assignment. The accepting research staff and pharmacy 
will verify they have the same in-hospital phase treatment assignment as an additional check to the 
allocation assignment.  An allocation sequence based upon a block size of 9 again generated with a 
computer random number generator will be utilized for those who received prehospital Tranexamic 
Acid.  Each respective IDS or pharmacy will prepare the inhospital phase treatment (approximate 10 
minute and 8 hour infusion). The patient and all treatment and research staff will be blinded to the 
treatment that is received. 
H.6. Blinding: The trial is a double blinded trial for both the prehospital phase and in-hospital phase 
interventions. The participants, investigators, research coordinators and staff, and persons having any contact 
with the patients will be blinded to study treatment assignments. The IDS at the University of Pittsburgh will be 
unblinded to the prehospital phase treatment arm and the respective pharmacy at each center will be unblinded 
once the treatment prehospital treatment information is provided to them by research staff. Both IDS at the 
University of Pittsburgh and the respective IDS or pharmacy at each center will be unblinded to the in hospital 
treatment assignment. 
H.7. Prehospital Standard Operating Procedures: To minimize over exuberant crystalloid resuscitation 
during the prehospital phase of treatment after enrollment, further crystalloid resuscitation post-intervention will 
follow a ‘goal directed’ standard operating procedure (SOP). Crystalloid infusion following the intervention 
will be based upon hemodynamic status (SBP < 90mmHg) with infusion of 500cc boluses of crystalloid for 
those patients with persistent hypotension. Normotensive patients will receive crystalloid infusion at 
maintenance rate. (Figure 13. above) All crystalloid volumes will be monitored relative to transport time for all 
Figure 13. 2-phase Intervention Schematic. 
12hr, 24hr and 72hr blood, labs, TEG, 

21 
 
patients and across enrolling sites. To minimize important differences for the early pre-hospital management of 
each patient, scene time, referral hospital time and definitive transport times for emergency medical services 
will be obtained, recorded and monitored including pre-hospital interventions.  
H.8. In-hospital Standard Operating Procedures: We have selected level I, academic, trauma centers with 
busy emergency medical transport services that are recognized for providing high level care of the injured 
patient. As the intervention begins in the pre-hospital setting, there exists the potential for in-hospital 
management differences to occur across centers as in any multi-center study which does increase the study 
results applicability. However, to minimize those differences where high level evidence exists for the early in-
hospital management of each patient, and throughout a patients’ admission, SOPs for resuscitation and 
transfusion will be employed over the initial 24 hours and throughout a patients’ admission. SOPs for patients 
who are at risk of massive transfusion will target an FFP:PRBC ratio of at least 1:2 based upon currently 
available data. Once 48 hours has passed without ongoing blood transfusion requirements, standard transfusion 
practice evidence in the ICU will be followed including standard restrictive transfusion guidelines for each 
respective institution in line with the TRICC trial recommendations (transfusion trigger of hgb- 7.0).89 
I. Outcome Variables/Definitions 
I.1. Primary Outcome: The primary outcome which will be utilized to power the study will be 30 day 
mortality. We anticipate that this study will be conducted with an exception from consent for emergency 
research and will require FDA approval. We will power the study using 30-day mortality as the primary 
outcome variable.  
I.2 Secondary Clinical Outcomes: Secondary clinical outcomes will include the incidence of hyperfibrinolysis 
(EPL > 7.5% by rapid-TEG analysis) upon arrival to the trauma bay within the first 6 hours, the incidence of 
acute traumatic coagulopathy (INR > 1.4), 24 hour mortality, acute lung injury, multiple organ failure, the 
development of nosocomial infection, early (24hr) seizures, in-hospital pulmonary embolism, presenting base 
deficit, 24 hour crystalloid requirements and 6 hour and 24 hour blood and blood component transfusion 
requirements (PRBC, FFP and platelets). These same clinical outcomes will similarly be used for the 
randomized tranexamic acid dosage regimen comparison. 
I.3. Secondary Laboratory/Mechanistic Outcomes: All laboratory/mechanistic outcomes will be measured 
during the first 6 hours from trauma center arrival and at 12 and 24 hours (+/- 12 hours) out from injury. Those 
laboratory/mechanistic outcomes including flow cytometry which require fresh blood samples will be 
performed only at the University of Pittsburgh on a subset of patient samples unless participating centers have 
specific capabilities and following appropriate training for standardization. These same laboratory/mechanistic  
outcomes will similarly be used for the randomized tranexamic acid dosage regimen comparison at 12 and 24 
hours post-injury. 
I.4. Clinical Outcomes Methods/Definitions: All clinical outcomes will be prospectively evaluated for 
throughout ICU and hospital admission and the timing from the day of initial injury will be recorded for time-
to-event statistical analysis. 
I.4.1. 30 day and 24 hour mortality: 30 day mortality will be prospectively recorded from the day of 
trauma bay arrival. Over the first 24 hours we will document and record the time of death in hours. We 
suspect that patients enrolled will have a significant percentage of mortality that occurs in the first 24hrs.  
I.4.2. Acute lung injury: Development of acute lung injury will be assessed utilizing the 1992 
American-European Consensus Conference definition90 which includes: 1) bilateral infiltrates on cxray, 
2) a capillary wedge pressure < 18mmHg, and 3) Pao2/Fio2 ratio < 300 via blood gas analysis. In those 
patients without a Swan-Ganz catheter (vast majority) to determine capillary wedge pressure, the 
absence of signs of or clinical concern for elevated left sided atrial pressures will be used for the 
diagnosis. All patients who remain intubated beyond the first 24 hours post injury will be evaluated 
using blood gas analysis and cxray evaluation. Those patients who remain intubated at 48 hours thru 7 
days will be reevaluated for this outcome at these time points. All time variables to the respective 

22 
 
outcome event will be determined from the day of initial injury for time-to-event analysis and 
multivariate Cox proportional hazard regression analysis. 
 I.4.3. Nosocomial infection: Infectious outcomes of interest will include ventilator associated 
pneumonia, blood stream infection and urinary tract infections. Surgical site infections and post-
operative intra-abdominal collections will also be recorded but excluded as a principal secondary 
outcome event to reduce the confounding effects of operative interventions which not all patients 
require. The development of these nosocomial infections will be based upon positive culture evidence 
during hospital admission. Infections will be monitored until post injury day 30 or ICU discharge. 
Diagnosis of ventilator associated pneumonia requires a quantitative culture threshold of ≥ 104 CFU/ml 
from broncho-alveolar lavage specimens in addition to standard x-ray and clinical criteria. Diagnosis of 
catheter-related blood stream infections requires  positive peripheral cultures with an identical organism 
obtained from either a positive semi-quantitative culture (>15 CFU/segment), or positive quantitative 
culture (>103 CFU/segment) from a catheter segment specimen. Urinary tract infections required > 105 
organisms/ml of urine. All time variables to the respective outcome event will be determined from the 
day of initial injury, while the time to the first nosocomial infection will be used in those patients with 
multiple infections for time-to-event analysis and multivariate Cox proportional hazard regression 
analysis. 
I.4.4. Multiple organ failure: Organ dysfunction will be evaluated via a well-validated scoring system 
referred to as the Denver Postinjury Multiple Organ Failure Score.91-93  Patients who are never admitted 
to the ICU or those with a length of ICU stay of less than 48 hrs will be considered to have a Denver 
score of 0. A summary of the Denver score may be calculated by summing the worst scores of each of 
the individual systems over the course of the ICU stay. A summary Denver score > 3 will be classified 
as multiple organ failure (MOF). Scores will be determined daily up until post injury day 30 or ICU 
discharge. All time variables to the respective outcome event will be determined from the day of initial 
injury, for time-to-event analysis and multivariate Cox proportional hazard regression analysis. 
I.4.5. Early seizures: Seizures will be prospectively monitored for over the first 24 hours from injury. 
Whether the seizures occurred post-operatively or in those patients who did not require operative 
intervention will be documented. Neurology consultation will be sought in those patients with seizure 
activity. Classification of seizure type and management will be based upon formal neurology 
consultation. Repeat occurrence and outcomes associated with seizure will similarly be documented. 
I.4.6. In-hospital pulmonary embolism: Pulmonary embolism that occurs during the primary 
admission hospital stay will be documented for all enrolled patients. Radiographic confirmation via CT 
imaging, transthoracic or trans-esophageal echo, or ventilation/perfusion scanning will be required.  
I.4.7. Blood and blood component transfusion and resuscitation requirements: 6 and 24-hour 
transfusion requirements for blood, fresh frozen plasma and platelet transfusion will be determined by 
recording the number of units transfused for each component from the time of trauma bay arrival. 
Transfusion components which are initiated will be considered transfused irrespective of completion. 
Similar determinations for crystalloid requirements (volume in cc’s) over the first 24hrs of injury will 
occur.  
I.4.8. Adverse Events: An adverse event (AE) is defined as any untoward medical occurrence in a trial 
subject undergoing a study procedure or administration of a study drug. Thus, an AE is an unfavorable 
sign, symptom, or disease temporally associated with the study intervention, irrespective of whether it is 
considered related to the study intervention. A reportable AE is defined as an unexpected, serious event 
related or possibly related to the study intervention or procedures. 
I.4.9. Unexpected Adverse Events: Unexpected adverse events will be defined as any serious 
unexpected adverse effect on health or safety or any unexpected life-threatening problem caused by, or 
associated with the interventions if that effect or problem was not previously identified in nature, 
severity, or degree of incidence in the investigation plan or application (including a supplementary plan 
or application), or any other unexpected serious problem that relates to the rights, safety or welfare of 
subjects.  

23 
 
I.4.10. Expected Adverse Events: Expected adverse events are commonly observed in patients who are 
at risk of hemorrhage following traumatic injury and may or may not be attributable to the tranexamic 
acid intervention. These will be monitored and reported throughout the time period for the trial. Clinical 
diagnoses of pneumonia, sepsis, cerebral bleeding, stroke, seizures, surgical interventions, complications 
due to specific injuries as well as other major medical or surgical complications are commonly observed 
in these patients. They will be recorded as noted in the hospital discharge summary.  
I.5. Laboratory/Mechanistic Outcome Methods/Definitions: All measurements will be performed within 6 
hours of arrival and at 12 and 24 hours post injury (+/- 12 hours) for the randomized dosage regimen 
comparison. One more additional blood sample will be collected at 72 hours (± 12 hrs) for D-dimer, activated 
Protein C levels and plasmin-antiplasmin complexes measurements.Excluding r-TEG analysis and PT/ INR 
measurements, all blood and serum samples will be spun, stored and batched at their respective institution and 
delivered to the University of Pittsburgh where formal ELISA immunoassay measurements will be undertaken. 
Those laboratory/mechanistic outcomes including flow cytometry which require fresh blood samples will be 
performed only at the University of Pittsburgh on a subset of patient samples unless participating centers have 
specific capabilities and following appropriate training for standardization. 
I.5.1. Coagulopathy and TEG parameters (Aim#2): To appropriately characterize differences in 
coagulopathy between tranexamic acid and placebo, in addition to r-TEG measurements of 
hyperfibrinolysis, presenting PT/ INR and additional TEG parameters will also be measured (ACT, r-
value, k-time, α-angle, maximal amplitude, and G-values ). All rapid TEG measurements will be 
performed within 6 hours of arrival and at 12 and 24 (+/- 12 hours) hours post injury. TEG analysis will 
be performed on a TEG® 5000 Thromboelastograph® Hemostasis Analyzer which will reside within the 
emergency department of each participating site. Standard laboratory INR will be drawn and measured 
at each institution within 6 hours of arrival and at 12 and 24 hours (+/- 12 hours). To further quantify the 
coagulopathy and hyperfibrinolysis post injury in these patients, D-dimer, activated Protein C levels and 
plasmin-antiplasmin complexes will be measured by ELISA plate assay. (ANIARA, USCN Life Science 
Inc., DRG International, Inc.) Plasmin-antiplasmin complexes may represent a more common, 
subclinical measurement of fibrinolytic activity that is not able to be assessed using standard TEG 
analysis, but elevated levels are associated with significantly worse outcome post injury and may be a 
marker than demonstrates the mechanism by which tranexamic acids has it beneficial effects. 
I.5.2. Exploratory Inflammatory Response Outcomes (Aim#3): Plasmin has pro-inflammatory 
effects by activating monocytes, neutrophils, platelets, endothelial and dendritic cells and induces pro-
inflammatory genes.51,52 Plasmin also induces chemotaxis of monocytes and dendritic cells and in-vitro 
and in-vivo studies have demonstrated the ability of plasmin to stimulate the production reactive oxygen 
species and promote the release of lipid mediators and cytokines via complement activation.51,53 To 
appropriately characterize the potential non-antifibrinolytic mechanisms responsible for the mortality 
benefit attributable to tranexamic acid, serum plasmin levels, and plasmin mediated compliment 
activation (C3a and Factor B) and HMGB1 levels will be measured by ELISA plate assay for all 
enrolled patients (MyBioSource, BD Biosciences). A Cytokine 10-plex Panel for the Luminex® 
platform will be utilized for all early inflammatory cytokine measurements. (Novex®) These same 
inflammatory response measurements will be utilized for the randomized dose regimen comparison at 
12 and 24 hours post injury. 
I.5.3. Platelet, Leukocyte and Inflammatory Gene Expression Measurements (Aim#3): To further 
characterize an anti-inflammatory effect of tranexamic acid mediated thru reduced plasmin activation, 
for those patients enrolled at the University of Pittsburgh, whole fresh blood will be obtained and 
platelet and leukocyte activation will be measured on a subset of patient samples using flow cytometry 
(FACS) analysis utilizing platelet activation specific antibodies (CD41 and CD62P, Molecular Probes®) 
and Leukocyte activation specific antibodies (CD11a and CD35, Molecular Probes®). Inflammatory 
gene expression will be assessed via RT-PCR with a focus on evidence based gene targets including 
those identified as being most dramatically perturbed following severe injury from the Glue Grant study 
cohort including CD177, MMP8, lactotransferrin, haptoglobin, S100A8 (calgranulin), MYBL1 

24 
 
(myeloblastosis viral homologue, v-myb), KLRF1 (Killer cell lectin like receptor subfamily F, member 
1), TGFBR3 (TGF-β receptor III subunit), and TCRA (T cell receptor α subunit).94 These studies will be 
performed at a University of Pittsburgh FACS and RT-PCR core facilities which will be available 24 
hours/day over the three years of the study.  
 
J. Analysis Plan:  
The overarching goal of the study proposal is to assess the efficacy of prehospital tranexamic acid as compared 
to placebo for injured patients at risk for traumatic hemorrhage who require emergency medical transport. 
Additional goals include dose regimen comparison and characterization of the mechanisms responsible for 
tranexamic acid’s beneficial effects. All primary and secondary analyses will be performed based on the Intent-
to-Treat principle for the prehospital randomization and analyses will include all enrolled patients grouped by 
randomization assignment. 
J.1. Data Analysis for Primary Outcome: We follow an intent-to-treat approach in analyzing our primary 
outcome of 30 day mortality. 
J.1.1. Primary Primary Outcome (30 Day Mortality): All randomized subjects will be included in the 
analysis to test the differences in 30 day mortality. 30 day mortality will be computed at the end of study and 
stated as a dichotomous variable.  For subjects who have not been reported as deceased by day 30 following 
admission from any of the sources queried we will use multiple imputation under the assumption that the 
missing data are not missing at random. The process for determining whether or not a subject is deceased at 30 
days is described in detail in section (N.6.). If more than 15% of the subjects are missing the 30 day outcome, 
we will consider this outcome as descriptive only. We will analyze this endpoint as a fixed point in time using a 
two-sided Mantel-Haenszel (M-H) test taking site, the stratifying variable (strata), into account. The M-H test is 
robust to lack of homogeneity of odds ratio although power would be reduced. This approach has more power 
than the survival analysis described below given the potential for crossing hazard functions. We will also test 
homogeneity of the odds ratios across sites using the Breslow-Day test. We will compute 95% confidence 
intervals on mortality by treatment group at 30 days. We will also conduct a sensitivity analysis of 30 day 
mortality to assess the effect of imputation ‘as alive’ on the treatment group comparisons and confidence limits 
for the 30 day outcome. To provide further insight we will compute 30-day survival curves. Survival time will 
be compared between treatment arms using Cox proportional hazards model with site as a covariate.  If the 
proportional hazards assumption is violated we will include a time treatment interaction in the model and 
choose the appropriate approach. As an additional analysis, we will use the same Cox proportional hazards 
approach to adjust for baseline covariates such as demographics, injury severity, presenting vital signs, and 
prehospital time. Since site is a stratifying variable it will be included as a random effect. We will do pre-
screening of covariates other than site at the 0.20 level before fitting the final model if our sample size is not 
sufficient to include all covariates in the model. We would follow the approach above to test for and take 
crossing hazards into account if applicable. As an additional exploratory analysis we will compare 30-day 
survival in the two groups adjusting for the covariates listed above and any additional baseline covariates that 
are imbalanced between treatment groups (p<0.10) using the same screening approach to decrease the number 
of covariates included in the model, if necessary. 
J.2. Analysis of Prehospital Randomized Secondary Outcomes: Unless there is sufficient power 
(predetermined before the analysis is begun), the approach to analysis of secondary endpoints will generally be 
calculation of confidence limits on intervention group differences or model parameters rather than formal tests 
of significance at a specified critical level as the trial will not have sufficient power to detect difference in all of 
these outcomes. However, these comparisons will add to the knowledge of the benefits and risks of the 
interventions. Parametric and nonparametric comparisons will be applied according to normalcy. All tests used 
will be two-tailed tests at significance level (alpha) of 0.05. For prehospital randomized clinical outcomes we 
will use Chi-square with 95% confidence intervals for dichotomous outcomes and parametric or non-parametric 
testing for continuous variable with 95% confidence intervals. For prehospital randomized laboratory or 
exploratory outcomes we will use parametric or non-parametric testing for continuous variable with 95% 
confidence intervals. 

25 
 
J.3. Analysis for Second Stage In-hospital Randomized Dosage Regimens: Chi-square test will be able to 
test the effect of different tranexamic dosage regimens on hyperfibrinolysis.  Similarly, chi-square will be used 
to detect any differences between dosage groups for 30 day mortality. To detect a trend in dosage response, test 
for trend will be implemented.  As additional analysis and to account for site and to adjust for some important 
covariates, we will use logistic regression to test the effect of dosage on hyperfibrinolysis. Similarly Cox 
proportional hazards regression can be used for 30 day mortality. For In-hospital randomized dosage regimen 
comparison for clinical outcomes we will use Chi-square with 95% confidence intervals for dichotomous 
outcomes and parametric or non-parametric testing for continuous variable with 95% confidence intervals. For 
In-hospital randomized dosage regimen comparison for laboratory or exploratory outcomes we will use 
parametric or non-parametric testing for continuous variable with 95% confidence intervals. 
J.4. Predefined Subgroup Analyses: Predefined subset analyses will be performed looking at 1.) patients who 
ultimately did or did not required blood transfusion 2.) those patients with significant traumatic brain injury 
(Head AIS >2) versus those without significant brain injury (Head AIS ≤ 2), 3.) those patients enrolled from the 
scene of injury versus those enrolled from a referral hospital, 4.) those patients that require operative 
intervention in the first 24 hours, 5.) those patients with a preinjury history of vitamin K antagonist medication 
history versus those without,  6.) those patients with preinjury history of antiplatelet medication history. 7.) 
those patients who ultimately did or did not require massive transfusion (≥ 10 units blood in first 24hrs).  It is 
recognized that the study is not appropriately powered for these subgroup comparisons and the results and 
conclusions formulated from these subgroup analyses will be considered exploratory in nature and will not be 
used as a basis for treatment recommendations. 
J.5. Randomization of Ineligible Subjects: It is anticipated that there will be a small proportion of 
patients enrolled who receive either tranexamic acid or placebo that in retrospect will not have met the 
entry criteria and are thus ineligible. In this circumstance, patients will be analyzed according to the 
group to which they were randomized. Subgroup analyses based on eligibility criteria will be performed 
if the number of patients so affected is large. However, based on the relatively limited inclusion and 
exclusion criteria it is anticipated that the frequency of this event will be low.   
J.6. Non-adherence: In some circumstances, patients may receive the incorrect treatment packet. Non-
adherence is most likely to occur in the case of the exsanguinating patient when time is limited and the 
wrong treatment pack is utilized. Fortunately, this event is relatively rare. In keeping with the intention-
to-treat analytic design, these patients will be analyzed with the group to which they were to be 
randomized to. 
J.7. Missing Data: For 30-day mortality, given the transient nature of many of the subjects, extensive efforts 
will be made to ascertain vital status (see N.6.). Batch searches of the mortality databases will continue every 
quarter for subjects with unknown status, until trial closeout. For interim and final analyses, subjects who have 
not been reported as deceased by day 30 following ED admission from any of these sources we will use 
multiple imputation for the final value. As sensitivity analyses we will report the data with and without 
imputation. We will also report an analysis consistent with that used in other studies counting those missing as 
alive on day 30. 
 
K. Sample Size Justification and Power Analysis:  
We have determined the sample size for this proposal and powered the analysis based upon the primary 
outcome, 30 day mortality. 
K.1. Primary Outcome 30 day mortality: Assuming a baseline mortality risk of 16% as was demonstrated in 
the Crash-2 study41,43 with 30 day mortality as the primary outcome, using a two-sided Z test with pooled 
variance and a 2 sided alpha of 0.05 the study will have a 90% power to detect a 7% or greater difference in 30 

26 
 
day mortality. The study will have 80% power to detect a 6% or greater difference in 30 day mortality. Using 
this power analysis, 497 patients in each arm, 994 total patients will be required, with a power of 0.85 and 
2 sided alpha of 0.05. This will require on average each center to enroll 80 patients per year or 1 to 2 per 
week.  As busy, level 1 trauma centers with robust emergency medical programs were screened using the 
proposed inclusion criteria over 2012 data and selected for participation based upon this information, this 
sample size estimate is appropriate and attainable. 
 
 
Sample Sample 
Prop|H1 
Prop 
 
 
 
 
 
 
Size 
Size 
Grp 1 or 
Grp 2 or 
Diff 
Diff 
 
 
 
 
Grp 1 
Grp 2 
Trtmnt 
Control 
if H0 
if H1 
Target 
Actual 
 
Power 
N1 
N2 
P1 
P2 
D0 
D1 
Alpha 
Alpha 
Beta 
0.9000 
497 
497 
0.0919 
0.1600 
0.0000 
-0.0681 
0.0500 
 
0.1000 
0.8500 
497 
497 
0.0965 
0.1600 
0.0000 
-0.0635 
0.0500 
 
0.1500 
0.8000 
497 
497 
0.1003 
0.1600 
0.0000 
-0.0597 
0.0500 
 
0.2000 
 
L. Human Subjects:  
We anticipate that this study would be conducted with an exception from consent for emergency research, 
including community consultation, public notification, as well as notification of patients or their legally-
authorized representative as soon as feasible after enrollment. The latter shall include provision of an 
opportunity to opt out from ongoing participation that will be given through oral and written communication. 
 
Community consultation as outlined by the local IRB will be undertaken prior to IRB approval. Since the 
population eligible for enrollment includes all citizens in the study regions it will not be possible to target any 
particular small group. Feedback from the community will be obtained by research personnel regarding any 
concerns they may have about potential enrollment. If requested, bracelets will be made available that could be 
worn by members of the community who do not want to participate. Public notification and community 
consultation will be performed as directed by the local IRB and may include such methods as using random 
digit dialing telephone surveys of the proposed study community, targeted small group meetings or consultation 
with community leaders. Due to ongoing participation in large multicenter research organizations, our 
institution and participating centers have significant experience with community consultation and notification 
practices.  
 
Benefits of participation in the STAAMP trial for both interventional and control subjects: 
A unique benefit regarding participation in the STAAMP trial is that all research results for both Tranexamic 
acid and control arms of the study may be used to further inform clinical care decisions throughout a 
participants hospital stay.  Participation in the trial may also aid in early recognition of trauma induced 
coagulopathy due to the early measurements of INR and thrombelastography (TEG) which will be performed 
on all enrolled subjects. TEG is an FDA approved tool, however, currently it is not standard of care and only a 
small proportion of trauma centers across the country routinely obtain early INR and point of care rapid-TEG 
analysis in the emergency department, soon after arrival in patients in hemorrhagic shock.  Early recognition of 
coagulopathy for all enrolled subjects may lead to earlier intervention and in hospital mechanisms that improve 
clinical outcome.    
 
M. Screening, Enrollment and Notification:  
The Department of Surgery at the University of Pittsburgh has interdepartmental research affiliations with the 
Department of Critical Care Medicine and the Department of Emergency Medicine and has spearheaded the 
Multidisciplinary Acute Care Clinical Research Organization (MACRO). MACRO is a unique, 

27 
 
interdepartmental resource with laboratory facilities, an experienced and professionally-trained staff of clinical 
research coordinators, and 24 hour around the clock screening capabilities. They have extensive experience with 
data entry, multi-center data coordination, training, IRB liaison needs, web-based data entry platforms and 
specimen management and storage. MACRO follows a cost center model and provides ‘cost-neutral’ services to 
clinical investigators from diverse specialties in order to conduct clinical and translational research. The 
University of Pittsburgh will be the data and specimen coordinating center for the proposal. MACRO research 
coordinators and participating site research coordinators will document and verify all trauma arrivals via 
emergency medical transport for enrollment. Those patients who met inclusion and exclusion criteria en route 
via emergency medical transport that were enrolled will be verified and enrolled patients will undergo initial 
laboratory and blood sampling and will have point of care rapid thromboelastography (TEG) performed for 
coagulation parameter measurements within 6 hours of patient arrival. All guidelines and requirements for 
notification for exception of consent for emergency research will be followed. Patients at risk for 
hemorrhage during or directly preceding emergency medical transport represents an immediate life threatening 
condition with the patient commonly intubated, unconscious, or not responsive, it will not be possible to contact 
legal representatives at the time of study entry. Research coordinators will make every effort to contact legal 
representatives after admission to the hospital to notify them that the patient was enrolled in a randomized trial. 
Research personnel will attempt to contact the subject’s legally authorized representative as soon as feasible for 
notification of enrollment and will provide an opportunity to opt out from ongoing participation. Summary of 
these efforts will be documented in the patient’s chart. If the subject becomes competent during the study period 
then he/she will be approached by research personnel for notification of enrollment and a similar provision of 
an opportunity to opt out from ongoing participation. 
 
We will inform the family member or LAR at the earliest feasible opportunity of the subject’s inclusion in the 
clinical trial, the details of the trial, other information contained in the informed consent document, and that he 
or she may discontinue the subject’s participation at any time without penalty or loss of benefits to which the 
subject is otherwise entitled. The therapeutic window for this trial is zero due to prehospital nature of this trial. 
Such notification is not usually feasible before or at the actual time of treatment or trial enrollment and must be 
deferred until after resuscitation efforts have been completed. Such notification will be in person wherever 
possible and as soon as feasible (unless otherwise directed by a local IRB). A log will be kept to document the 
attempts made to contact the LAR/family member. The log will be included in the paper data collection forms. 
 
The investigators will utilize social workers and law enforcement personnel to try to locate the patient's legally 
authorized representative. If that search is unsuccessful, a notification letter will be sent to the subject's 
authorized representative explaining the study and providing contact information for answering questions. The 
letter will be sent via registered mail or by UPS and documentation of the addressee and date of mailing will be 
kept. 
N. Data  
N.1. Sources: Data will be collected prospectively as patient care progresses. This will include a review of the 
emergency medical patient care report(s), Emergency Department and electronic/ paper hospital records.  
N.2. Prehospital Resuscitation Elements: Demographics, emergency medical response times (call receipt to 
arrival, arrival at patient side,) injury characteristics, vital signs, prehospital resuscitation characteristics, 
(plasma volume, crystalloid volume, blood transfusion volume, starting at referring hospital or scene) 
prehospital interventions (needle decompression, chest tubes) referring hospital vitals, and interventions. 
N.3. In-Hospital Resuscitation Elements: Demographics, shock severity (base deficit, lactate), injury 
characteristics, ED vitals, ED interventions (chest tubes, intubation),  operative interventions and timing of 
interventions, injury severity score, ICU days, ventilator days, length of stay, multiple organ dysfunction scores 
(daily), nosocomial infectious outcomes, blood gas results, cxray reads, transfusion of blood and blood 
components, resuscitation requirements, all primary and secondary outcomes. 

28 
 
N.4. Data Entry: MACRO and associated internet technology affiliates at the University of Pittsburgh will 
create web-based data entry platform to collect necessary information from all participating sites which will 
also be utilized for randomization assignment. Web entry forms will have dynamic features such as immediate 
checks on data and relationships within a form and between forms. Details and clarification about data items 
will be provided using pop-up windows and links to appropriate sections of the on-line version of the Manual of 
Operations. Data encryption and authentication methods will be used. Additional features will be built into the 
web entry forms including: forms transmission history, access to past forms, tracking of data corrections, and 
the capability to save and re-load incomplete forms. 
N.5. Database Management: A two-tiered database structure will be created. A front-end database will serve 
the web entry needs, using a database management system well-suited to handling updates from multiple 
interactive users. The data from this database will be transferred periodically (e.g. weekly) to a data repository 
that can be used by statistical software packages. These data sets will be the basis for data queries, analyses and 
monitoring reports. Various versions of this database will be kept as needed, e.g. for quarterly performance 
reports. Backup of data and programs will be performed at frequent intervals. Access to data will be limited to 
those who need access to perform their tasks. The database management system is able to manage large 
quantities of data, to merge data from multiple databases as required, to handle complex and possibly changing 
relationships, and to produce analysis datasets that can be imported into a variety of statistical packages. 
N.6. Mortality Outcome Data (30 day): If discharge occurs before hospital day 30 and the subject is 
discharged to a hospice, nursing home or other healthcare provider, research staff will contact the facility to 
ascertain the subject’s vital status. If the subject is discharged to his/her usual residence before day 30, the 
research staff will contact the subject or their family/legally authorized representative (LAR). If vital status 
remains unknown the clinical site will request periodic searches for the subject’s social security number in the 
Social Security Master Death Index, the respective State Health Department’s vital statistics/mortality database, 
and the mortality databases of a credit reporting agency, e.g., Experian. For subjects not reported as deceased by 
these sources by day 30 following ED admission, batch searches of the mortality databases will continue every 
quarter until trial close-out. Date (and cause of death when available) for out-of-hospital deaths will be 
documented; however, underlying and contributing causes of death may not be available from these sources. 
Clinical sites will follow local and state HIPPA guidelines for release of PHI for research. 
 
O. Training and Participating Site Coordination:  
As the coordinating center for the proposed trial, the University of Pittsburgh will be responsible for all research 
coordinator training, prehospital provider training, sample and data collection, and maintenance of data 
integrity. Research coordinators, prehospital providers and associated staff will be trained during the months 
prior to the trial start date regarding the scientific basis for the study, specific inclusion and exclusion criteria, 
sample collection and processing, prehospital procedures and SOPs, and rapid thromboelastography (TEG) 
performance. Training verification and retraining will occur at yearly intervals or more commonly if new staff 
is hired at individual participating sites. Trial enrollment and maintenance of data integrity will be assessed 
monthly using the web based data platform. Trial screening, enrollment and data completeness and accuracy 
will be accessed at 6 months via site visit and random patient audit and then annually. 
 
P. Safety Monitoring 
P.1. Data Safety Monitoring Board (DSMB): Data safety and monitoring over the course of the clinical trial 
will fall under the responsibility of an independent data safety and monitoring board.  The DSMB will consist 
of at a minimum, a hematologist with expertise in transfusion medicine, a trauma/critical care surgeon, an 
epidemiologist with expertise in clinical trial design, and a biostatistician all of whom will have no proprietary 
interest in the outcome of the trial. The responsibilities of the DSMB will fall under several domains.  Prior to 
beginning the accrual of subjects, the DSMB will review the research protocol and identify logistic problems 
that may pose problems with randomization schemes and distribution of Tranexamic acid.  At this early phase, 

29 
 
the DMSB will also review the plans for data and safety monitoring. At the time of interim analyses, the DMSB 
will aid in identifying problems surrounding patient accrual and randomization, data collection and follow-up.  
At this time, the DMSB will also perform an assessment of safety through the comparison of adverse events 
across both study arms.  Lastly, it will fall under the domain of the DMSB to establish whether further conduct 
of the trial is unnecessary due to strong evidence of benefit or futility.  
     Although the DSMB will make the final decision about the interim monitoring plan, we anticipate that the 
DSMB will evaluate the rate of adverse events between the treatment and control arms at 6 months and then 
annually during enrollment. The DSMB will also monitor primary, secondary study outcomes between the 
treatment and control groups including main effects and a priori subgroups as specified elsewhere in the 
protocol. The DSMB will advise the investigators if a change in the protocol is warranted based on this interim 
monitoring.  
P.2.  Research Monitor 
 The Research Monitor is responsible to oversee the safety of the research subjects and report 
observations/findings to the IRB or a designated institutional official. The Research Monitor will review all 
unanticipated problems involving risks to subjects or others associated with the protocol and provide an 
independent report of the event. The Research Monitor may discuss the research protocol with the investigators; 
shall have authority to stop a research protocol in progress, remove individual human subjects from a research 
protocol, and take whatever steps are necessary to protect the safety and well-being of human subjects until the 
IRB can assess the monitor's report; and shall have the responsibility to promptly report their observations and 
findings to the IRB or other designated official and the HRPO. 
P.3. Assessing and Reporting Adverse Events (AEs): All Adverse Events will be documented and assessed 
for relationship to the study intervention. Reporting forms will be submitted to the DSMB and IRB. All 
potential adverse events will be reviewed as to treatment arm and further classified by: a) Severity (life-
threatening, serious, non-serious); and b) Expected vs. Unexpected. For serious adverse events, the coordinating 
center will notify the DSMB as well as appropriate regulatory agencies, site, and sponsor promptly. The 
coordinating center will tabulate and report compliance, data quality, and non-serious adverse events on a 
regular basis. Life-threatening or fatal unexpected AE associated with the study intervention or procedure 
should be reported within 24 hours of discovery with subsequent follow-up submission of a detailed written 
report. Serious AEs and unexpected AEs associated with the use of the study intervention or procedure must be 
reported to the DSMB and IRB within 5 working days with follow up submission of a detailed written report. 
The DSMB will determine if the event merits an immediate review.  
A summary report of the DSMB’s findings will be submitted to regulatory agencies. At least one specialized 
clinician from the Data Safety Monitoring committee will be responsible for monitoring data safety. All related 
unanticipated problems will be directly handled by study’s PIs and reported accordingly. We will also follow 
Department Of Defense Unique requirements documentation. The University of Pittsburgh and each 
participating center will have an AE logbook to record and to assure adequate attention for continuous 
assessment, analysis, and reporting of adverse effects using a standardized report form. The coordinating center 
will be responsible for all oversight of these risk assessments with monthly evaluations. 
P.4. Interim Analyses: In concert with the DSMB, prior to initiation of the trial, the final monitoring plan will 
be developed to serve as the guide to the DSMB’s decision-making process concerning early stopping of the 
trial. We will recommend interim analyses as 1/3 and 2/3 of patient enrollment. In making the decision to 
recommend termination of the study, the DSMB shall be guided by several types of information: (i) a formal 
stopping rule based on the primary analysis (comparison of treatment groups on the in-hospital mortality and 24 
hour blood transfusion requirements), (ii) information on safety outcomes by treatment group, (iii) consistency 
between results for primary and secondary outcomes, and (iv) consistency of treatment effects across 
subgroups. Formal interim analyses will be performed at 6 months and then annually throughout enrollment 
. The DSMB will use the results of implementing the stopping rule as a guideline in evaluating the evidence for 
treatment effects. In making a recommendation to terminate the study, the DSMB will also consider information 
on safety outcomes, as well as consistency of outcomes for secondary outcomes and consistency of outcomes 
within important subgroups as described previously. The group sequential method described by O’Brien and 

30 
 
Fleming will be used to develop stopping rules to limit the impact of repeated testing on the probability of a 
Type I error.95 
 
Based on our power analysis, sample sizes of 497 in interventional group and 497 in control group can achieve 
80% power to detect a difference of 0.06 between the group proportions of 0.10 and 0.16 at a significance level 
(alpha) of 0.05 using a two-sided z-test.   
 
We have proposed two interim analyses in this trial. We have based our testing on group sequential design that  
dividing patient entry into a fixed number of equal-sized groups and provides ethical and practical ways to make 
decision to stop the trial or continue based on repeated significance tests of the accumulated data after each group 
 is evaluated.  
 
According to the above power calculation and following the group sequential method described by O’Brien and 
Fleming in developing stopping rules to limit the impact of repeated testing on the probability of a Type I error, 
we will have equally spaced looks at 33%, 67% and 100% of patient accruals. This is equal to 166, 332, and 
497 subjects in each group at these three looks. The following table and graph provide in details information in 
relation to alpha spending functions to determine the test boundaries according to O’Brien-Fleming method.    
 
Details when Spending = O'Brien-Fleming, N1 = 497, N2 =497, P1 = 0.10, P2 = 0.16 
 
 
Lower 
Upper 
Nominal 
Inc 
Total 
Inc 
Total 
Look Time 
Bndry 
Bndry 
Alpha 
Alpha 
Alpha 
Power 
Power 
1 
0.33 
-3.71030 
3.71030 
0.000207 
0.000207 
0.000207 
0.018687 
0.018687 
 
2 
0.67 
-2.51142 
2.51142 
0.012025 
0.011890 
0.012097 
0.399207 
0.417894 
 
3 
1.00 
-1.99302 
1.99302 
0.046259 
0.037903 
0.050000 
0.382494 
0.800388 
 
Drift 2.82089 
 
 
Look: These are the sequence numbers of the interim tests. 
 
Time: These are the time points at which the interim tests are conducted. This is also related to proportion of subject accruals 
 
Lower and Upper Boundary: These are the test boundaries. If the computed value of the test statistic z is between these values, the trial should 
continue. Otherwise, the trial can be stopped. 
 
Nominal Alpha:  This is the value of alpha for these boundaries if they were used for a single, standalone test. Hence, this is the significance level 
that must be found for this look in a standard statistical package that does not adjust for multiple looks.  
 
Inc Alpha: This is the amount of alpha that is spent by this interim test. It is close to, but not equal to, the value of alpha that would be achieved if 
only a single test was conducted. The difference is due to the correction that must be made for multiple tests.  
 
Total Alpha: This is the total amount of alpha that is used up to and including the current test.  
 
Inc Power: These are the amounts that are added to the total power at each interim test. They are often called the exit probabilities because they give 
the probability that significance is found and the trial is stopped, given the alternative hypothesis. 
 
O’Brien-Fleming boundary values are inversely proportional to the square root of information levels on the standardized Z scale 
(O’Brien and Fleming 1979). The O’Brien-Fleming boundary is conservative in the early stages and tends to stop the trials early only 
with a small P-value. But the nominal value at the final stage is close to the overall P-value of the design. 
 

31 
 
 
The above plot shows the interim boundaries for each look. This plot shows very dramatically that the results must be 
extremely significant at early looks, but that they are near the single test boundary (1.96 and -1.96) at the last look. 
 
 
Interim Analysis References 
1. Chow, S.C.; Shao, J.; Wang, H. 2003. Sample Size Calculations in Clinical Research. Marcel Dekker. New York. 
2. Lan, K.K.G. and DeMets, D.L. 1983. 'Discrete sequential boundaries for clinical trials.' Biometrika, 70, pages 659-663. 
3. O'Brien, P.C. and Fleming, T.R. 1979. 'A multiple testing procedure for clinical trials.' Biometrics, 35, pages 549-556 
4. Pocock, S.J. 1977. 'Group sequential methods in the design and analysis of clinical trials.' Biometrika, 64, pages 191-199 
5. Reboussin, D.M., DeMets, D.L., Kim, K, and Lan, K.K.G. 1992. 'Programs for computing group sequential boundaries using 
the Lan-DeMets Method.' Technical Report 60, Department of Biostatistics, University of Wisconsin-Madison. 
 
P.5 IP Stopping Rules:  Study product administration should not be stopped except for in the rare instance that 
necessary treatment or clinical condition would be contraindicated to TXA administration, patient has a confirmed (as 
determined by an attending physician) seizure during administration, or if the patient is experiencing a suspected 
allergic reaction to the study product. 
Q. Quality Control and Assurance 
Q.1. Protocol Compliance and Reporting: The PI or participating site investigators will not deviate from the 
protocol for any reason without prior written approval from the IRB except in the event of medical emergency. 
In that event, the PI will notify the IRB immediately and request approval of protocol deviation. The PI will 
inform the IRB about all protocol deviations, safety information and other changes. Persistent or serious 
noncompliance may result in termination of the study. The PI is responsible for reporting all deviations to the 
University of Pittsburgh IRB and their respective IRB for participating sites. If changes to the design of the 
study are made by the PI, a protocol amendment must be submitted to the University of Pittsburgh IRB. 
Changes in the protocol cannot be instituted until appropriate approval has been given by the IRB. 
Q.2. Investigator Responsibilities: The PI and site investigators will agree to implement the IRB approved 
protocol and conduct the study in accordance with Section 9 (Commitments) of FDA form 1572, Title 21 of the 
US CFR, and the ICH GCP Guidelines (E6, Section 5) as well as all national, state and local laws of applicable 
O'Brien-Fleming Boundaries with Alpha = 0.05
Upper
Lower
Z Value
Look
-1
-2
-3
-4
0
1
2
3
4
0.5
1.0
1.5
2.0
2.5
3.0

32 
 
Regulatory Authorities. The study will be performed in accordance with ethical principles that have their origin 
in the Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, and applicable requirements. 
 
R. Study Limitations:  
The study is a multi-center trial with the potential for variation in prehospital standard of care and in-hospital 
variation in post-injury care potentially affecting the primary and secondary outcomes for the proposal. We 
elected to standardize prehospital emergency medical standard of care to minimize any prehospital variability. 
Importantly, we selected similar academic, level 1, participating centers based upon their patient and emergency 
medical transport volumes, there prior experience with clinical research and prior participation in prior multi-
center trials, and who practice up-to-date evidence based trauma care, in attempts to minimize significant 
variation in post injury care. 
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mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med. Mar 1994;149(3 Pt 
1):818-824. 
91. 
Sauaia A, Moore FA, Moore EE, Lezotte DC. Early risk factors for postinjury multiple organ failure. World J 
Surg. May 1996;20(4):392-400. 
92. 
Moore FA, Sauaia A, Moore EE, Haenel JB, Burch JM, Lezotte DC. Postinjury multiple organ failure: a bimodal 
phenomenon. J Trauma. Apr 1996;40(4):501-510; discussion 510-502. 
93. 
Sauaia A, Moore EE, Johnson JL, Ciesla DJ, Biffl WL, Banerjee A. Validation of postinjury multiple organ failure 
scores. Shock. May 2009;31(5):438-447. 
94. 
Xiao W, Mindrinos MN, Seok J, et al. A genomic storm in critically injured humans. J Exp Med. Dec 19 
2011;208(13):2581-2590. 
95. 
O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics. Sep 1979;35(3):549-556. 
 
 
 Clinical Protocol Appendix 2 
 
Proposed Community Consultation and Public Disclosure Plan STAAMP Trial 
 
I. 
Community Consultation 
 
A.      City of Pittsburgh 
1.        Consultation with representatives of the communities in which the clinical investigation will be conducted 
and from which the subjects will be drawn 
B.      Website 
Information about the current STAAMP Trial will be posted on a website which has been developed for 
this purpose.  Contact information will be provided for questions and comments. All multimedia material 
will have the following website listed: www.acutecareresearch.org 
There will be information on how to get more information about the trial and how to obtain on “opt out 
bracelet” if desired.  
C.     Surveys 
Paper surveys will be placed in the Trauma Service outpatient clinic. They will also include the web 
address and contact information.  A detailed telemarketing survey will be performed over a four-week 
period with approximately 500 households in the zip codes we intend to conduct this study. 
D.     Presentation to Pennsylvania Emergency Health Services Counsel 
        We will schedule to present at one of their meetings 
 
 
II. 
Public disclosure 
 
A.      Multi-Media 
   The UPMC Media Office will issue a press release describing the upcoming study and locations of public 
forums.   
B.      Notifications will be posted on our local Pittsburgh Authority public transportation buses. The website 
address will be posted.  Contact information will be provided for questions and comments. This will 

37 
 
include information regarding how to obtain an opt-out bracelet. This has been the most effective means 
of getting feedback in our area.  
C.     Flyers 
 
We will distribute flyers directing traffic to our local website.  Flyers will be provided in hospital waiting 
areas and community bulletin boards. 
D. 
Presentation to local paramedics, emergency physicians, and medical directors 
E. 
E-mail listserv 
 
We will create an e-mail listserv using Campaign Monitor and will add community members that express 
interest in our research based on e-mails, calls, inquiries, and referrals. 
 
F. Opt out bracelets will be made available upon request. They will be orange and state “NO STAAMP”. 
 
 
 

38 
 
Clinical Protocol Appendix 3 – Data Safety Monitoring Board (DSMB) Charter 
DSMB Charter 
 
Study of Tranexamic acid during Air and ground Medical Prehospital transport (STAAMP) trial 
 
August 03, 2017 
 
Version 1.3 

 
 
 
39 
Data Safety Monitoring Board (DSMB) Overview 
Trial Description and Study Design 
• Trial name: Study of Tranexamic acid during Air and ground Medical Prehospital transport 
(STAAMP) trial 
• Principal investigator (PI): Jason Sperry, MD, MPH 
• Funding agency: Department of Defense 
• Trial design: Multi-center, prospective, randomized, blinded, controlled interventional trial.   
• Phase: III 
• Number of patients: 994  
• Number of sites: 4 
 
DSMB Description  
• This DSMB will be coordinated by the PI, Jason Sperry, MD, MPH. 
• This DSMB will be independent of the investigators, funding agency, regulatory agencies, and 
institutional review boards. 
• This charter will be approved by its DSMB members as attested to by signature of the 
chairperson. 
 
DSMB Membership 
• Members will disclose conflicts of interest and will be cleared of significant conflicts of interest 
and potential conflicts of interest in accordance with provisions in this charter.  
• DSMB members will sign confidentiality agreements covering DSMB activities. 
• Composition of membership will be researchers with the following expertise:  hematology 
(transfusion medicine), surgery (trauma/critical care), prehospital emergency medicine, 
epidemiology (clinical trial design), and biostatistician.  
• Remuneration will be provided any expenses related to DSMB activities. 
 
Reporting 
• Unblinded data to be reviewed by the DSMB will be provided by an independent statistician.  
Issues and recommendations identified by the DSMB will be provided to the principal 
investigator by the DSMB chairperson in accordance with this charter.  
• Details of closed session deliberations (e.g., minutes) will be considered privileged and not 
subject to disclosure except as required by law.  

 
 
 
40 
Introduction 
The purpose of this charter is to define the roles and responsibilities of the DSMB, delineate 
qualifications of the membership, describe the purpose and timing of meetings, provide the 
procedures for ensuring confidentiality and proper communication, and outline the content of the 
reports.   
 
The DSMB will function in accordance with the principles of the following documents: FDA document 
“Guidance for Clinical Trial Sponsors: On the Establishment and Operation of Clinical Trial Data 
Monitoring Committees”.  
 
Study Overview/Summary 
Objective/Hypothesis: The primary hypothesis will be that prehospital infusion of tranexamic acid in 
patients at risk for bleeding will reduce the incidence of 30 day mortality. The secondary hypotheses 
include that prehospital tranexamic acid will reduce the incidence of hyperfibrinolysis, acute lung 
injury, multiple organ failure, nosocomial infection, mortality, early seizures, pulmonary embolism and 
early resuscitation needs, reduce or prevent the early coagulopathy as demonstrated by improving 
presenting INR and rapid thromboelastography parameters, reduce the early inflammatory response, 
plasmin levels, leukocyte, platelet and complement activation, and determine the optimal dosing of 
tranexamic acid post-injury.. 
 
Specific Aims: 
Aim#1: Determine whether prehospital tranexamic acid as compared to placebo results in a lower 
incidence of 30 day mortality, 24 hour mortality, acute lung injury, multiple organ failure, nosocomial 
infection and improved shock parameters and early resuscitation and transfusion requirements. 
 
Aim#2: Determine whether prehospital tranexamic acid as compared to placebo reduces 
hyperfibrinolysis, lowers the incidence of acute traumatic coagulopathy and improves early markers of 
coagulopathy. 
 
Aim#3: To explore novel mechanisms by which prehospital tranexamic acid alters the inflammatory 
response independent of effects on hyperfibrinolysis including analysis of platelet and leukocyte 
activation, plasmin levels and plasmin mediated complement activation and the early cytokine 
response to trauma. 
 
Aim#4: Determine whether different dosing regimens of tranexamic acid upon arrival in the hospital 
are associated with improvements in hyperfibrinolysis, coagulopathy, clinical outcomes and the early 
inflammatory response. 
 
Study Design: Multi-center, prospective, randomized, blinded, controlled interventional trial over 3 
years focusing on patients with concern for bleeding who are transported via air medical transport to 
definitive care. 
 
Population: Blunt or penetrating injured patients transported via emergency medical transport within 
two hours of injury with concern for bleeding with 1.) a documented systolic blood pressure < 90 
mmHg en route at outside/referral facility AND 2.) documented tachycardia (> 110 bpm) en route or at 
outside/referral facility.. 
 
Inclusion Criteria: 

 
 
 
41 
1. Blunt or penetrating injured patients being transported via emergency medical services from the 
scene of injury or from referring hospital to a definitive trauma center that is participating in the trial 
AND 
2. Within 2 hours of time of injury 
AND 
3A. Hypotension (Systolic Blood Pressure (SBP) < 90mmHg) 
i. At scene of injury or during emergency medical transport 
ii. Documented at referring hospital prior to emergency medical transport arrival 
OR 
3B. Tachycardia (heart rate >110 beats per minute) 
i. At scene of injury or during emergency medical transport 
ii. Documented at referring hospital prior to emergency medical transport arrival 
Inclusion criteria #3. and #4. not required to be simultaneous 
 
Exclusion Criteria: 
1. Age > 90 or < 18 years of age;  
2. Inability to obtain intravenous or intraosseous access ; 
3. Documented cervical cord injury with motor deficit;  
4. Known prisoner;  
5. Known pregnancy; 
6. Traumatic arrest with > 5 minutes CPR without return of vital signs;  
7. Penetrating cranial injury 
8. Traumatic brain injury with brain matter exposed;  
9. Isolated drowning or hanging victims 
10. Wearing an opt out bracelet. 
11. Isolated fall from standing 
12. Objection by patient or family member 
 
Interventional Arm: The Intervention will have both a prehospital phase and in-hospital phase. 
Investigational Drug Services (IDS) at the University of Pittsburgh will be utilized to supply and 
organize both tranexamic acid and placebo along with respective normal saline bolus and infusion 
bags to all participating trial sites. IDS at the University of Pittsburgh has a long track record of 
managing large multicenter trials and is currently executing and responsible for over 150 inpatient 
and outpatient clinical trials. 
Prehospital Phase Intervention: Once inclusion and exclusion are verified while the patient is 
being transported via emergency medical transport to a STAAMP trial participating center, in a 
randomized, double blinded fashion, either 1 gram bolus of tranexamic acid diluted in 100cc of 
normal saline (preprepared on helicopter) or placebo of identical volume will be infused into the 
patient over approximately 10 minutes. After receiving the prehospital phase intervention, 
standard operating procedures utilizing goal directed crystalloid infusion will be followed  
 
In-hospital Phase Intervention: Upon arrival, patient blood and labs will be sampled and arrival 
rapid-TEG analysis will be performed within first 60 minutes. After inclusion and exclusion 
criteria verification by research staff, in a double blinded, randomized fashion, those patients 
who received tranexamic acid in the prehospital phase will receive 1 of 3 different dosage 
regimens: 
 
1. Standard Tranexamic acid Dosing:  1 gram infusion over 8 hours 

 
 
 
42 
2. Repeat Tranexamic acid Dosing:  1 gram bolus and 1 gram infusion over 8 hours 
3. Abbreviated Tranexamic acid Dosing: No further tranexamic acid to be given  
 
For intervention blinding purposes, each patient will receive both a bolus dose (either 
tranexamic acid or placebo) and 8 hour infusion (either tranexamic acid or placebo) depending 
on the randomized dosing regimen. 
 
Placebo/Control Arm: Prehospital phase patients randomized to placebo will receive identical placebo 
diluted in 100cc of normal saline and infused over 10 minutes. Patients who received prehospital 
phase placebo will receive in-hospital identical placebo bolus and 8 hour placebo infusion for blinding 
purposes 
 
Randomization: The randomization scheme will have both a prehospital phase and in-hospital phase. 
Prehospital Phase Randomization: Individual patients meeting criteria while en route via 
emergency medial transport will be randomized using an allocation sequence block size of 8 to 
either 1 gram of tranexamic acid or placebo diluted in 100cc of normal saline given over 10 
minutes. A single prehospital treatment box containing ascending numerically labeled (1-8) 
treatment packs (randomized with a computer random number generator) will be on board 
each respective emergency transport vehicle. In an ascending numerical order fashion 
treatment packs will be utilized for enrolled patients. The box and treatment pack # will be 
recorded by research staff upon arrival for all randomized patients. The patient and all 
treatment and research staff will be blinded to the treatment arm. All intervention vials will be 
covered to obscure view of vial contents to prehospital staff giving the intervention and amber 
colored syringes will be utilized to maintain blinding. IDS at the University of Pittsburgh will be 
unblinded to the prehospital intervention. Additionally, the pharmacy at each respective 
participating center will have access to the prehospital randomization/assignment scheme 
once the prehospital intervention box and treatment # are provided to them by the accepting 
research staff at each participating center. 
In-hospital Phase Allocation: Using a web based, randomization assignment program built 
specifically for the trial, research staff will provide and input the prehospital intervention box # 
and treatment pack # into the web based platform at each site and be provided the In-hospital 
treatment allocation to be utilized for the second phase intervention. IDS at the University of 
Pittsburgh and each respective pharmacy at the participating sites will be provided with the 
random allocation sequence and will be unblinded to the in-hospital allocation assignment. The 
accepting research staff and pharmacy will verify they have the same in-hospital phase 
treatment assignment as an additional check to the allocation assignment. An allocation 
sequence based upon a block size of 9 again generated with a computer random number 
generator will be utilized for those who received prehospital Tranexamic Acid. Each respective 
IDS or pharmacy will prepare the inhospital phase treatment (10 minute and 8 hour infusion). 
The patient and all treatment and research staff will be blinded to the treatment that is 
received. 
 
Blinding: The trial is a double blinded trial for both the prehospital phase and in-hospital phase 
interventions. The participants, investigators, research coordinators and staff, and persons having 
any contact with the patients will be blinded to study treatment assignments. The IDS at the 
University of Pittsburgh will be unblinded to the prehospital phase treatment arm and the respective 
pharmacy at each center will be unblinded once the treatment prehospital treatment information is 

 
 
 
43 
provided to them by research staff. Both IDS at the University of Pittsburgh and the respective IDS or 
pharmacy at each center will be unblinded to the in hospital treatment assignment. 
 
Roles and Responsibilities 
DSMB Roles and Responsibilities 
This DSMB will 
• Meet periodically (see DSMB Meetings) to review aggregate and individual subject data 
related to safety, data integrity and overall conduct of the trial. 
• Review specific interim analyses for efficacy (see Study Review Criteria/Stopping Rules 
and Guidelines).  
• Provide recommendations to continue or terminate the trial depending upon these 
analyses.   
• Communicate other recommendations or concerns as appropriate. 
• Operate according to the procedures described in this charter and all procedures of the 
DSMB.    
• Follow conflict of interest guidelines as detailed below (see DSMB Membership). 
• Comply with confidentiality procedures as described below (see Confidentiality). 
• Maintain documentation and records of all activities as described below (see DSMB 
Meetings, DSMB Reports). 
 
Principal Investigator (or Designees) Roles and Responsibilities 
The PI will directly or through delegation:  
• Assure the proper conduct of the study. 
• Assure collection of accurate and timely data (monitoring and data management). 
• The PI will designate an independent statistician to compile and report SAEs to the DSMB. 
• Promptly report potential safety concern(s) to the DSMB. 
• Prepare summary reports of relevant data for the DSMB. (This may include analyses not 
otherwise outlined in this charter based upon findings.) 
• Provide an independent facilitator for presentation of results during DSMB meetings if 
requested by the DSMB. 
• Communicate with regulatory authorities, IRB, and investigators, in a manner that 
maintains integrity of the data, as necessary. (This communication is not the responsibility 
of the DSMB.) 
• Provide funding for the study and DSMB. 
• PI will not attend the closed session of the DSMB Meeting.  
 
DSMB Membership 
The DSMB will consist of at least 4 members.  The DSMB members have been selected by the PI in 
consultation with the investigators. 
As characteristic qualifications, members will:  
• Work professionally and meet qualifications for their respective professions. 
• Comply with accepted practices of their respective professions. 
• Comply with the conflict of interest policies specified by the standard operating procedures 
(SOPs) of the PI to ensure that members do not have serious scientific, financial, personal, or 
other conflicts of interest related to the conduct, outcome, or impact of the study according to 

 
 
 
44 
the guidelines specified below (e.g., engaged in any simultaneously occurring competitive trials 
in any role that could pose a conflict of interest for this study).  
• Be independent from the PI, IRB, regulatory agencies, principal investigator, co-principal or 
sub-principal investigator, site investigator, site sub-investigator, clinical care of the study 
subjects, or any other capacity related to trial operations. 
• Not be on the list of Notice of Initiation of Disqualification Proceedings and Opportunity to 
Explain (NIDPOE) (http://www.fda.gov/foi/nidpoe/default.html) and/or debarred list of 
investigators (http://www.fda.gov/ora/compliance_ref/debar). 
Although each DSMB member will be expected to serve for the duration of the trial, in the unlikely 
event that a member is unable to continue participation, the reason will be documented and a 
replacement will be selected by the PI. 
 
The DSMB will follow conflict of interest guidelines referenced by the Department of Health and 
Human Services, Financial Relationships and Interests in Research Involving Human Subjects: 
Guidance for Human Subject Protection (http://www.hhs.gov/ohrp/humansubjects/finreltnn/fguid.pdf). 
DSMB members will sign a non-conflict of interest statement in regard to this study which will be on 
file with the PI. As determined by the PI, conflicts of interest and/or potential conflicts of interest (as 
determined by SOPs) will be reduced to the greatest extent that is consistent with assembling a 
highly competent DSMB. Any questions or concerns that arise regarding conflicts of interest will be 
addressed by the DSMB chairperson with input from other DSMB members and PI as necessary. 
 
DSMB Meetings 
Projected Schedule of Meetings  
An initial meeting of the DSMB will be held prior to any subject enrollment in the study in order for the 
members to review the charter, to form an understanding of the protocol and definitions being used, 
to establish a meeting schedule, and to review the study modification and/or termination guidelines. 
Subsequent interim and final review meetings will be held to review and discuss interim and final 
study data (adverse events, protocol deviations, enrollment summary and tables for overall primary 
and secondary endpoints).  Frequency of meetings will be every six months, unless the board 
determines otherwise.  
 
Meeting Format 
DSMB meetings will generally be conducted by teleconference and coordinated by the PI. A quorum, 
defined as 2 out of 4 members will be required to hold a DSMB meeting. Critical decisions of the 
DSMB should be made by unanimous vote. However, if this is not possible, majority vote will decide. 
 
Open and Closed Sessions  
The open session may be attended by the PI and study investigators or their designees. Data 
presented in the open session may include enrollment data, individual adverse event data, baseline 
characteristics, overall data accuracy and compliance data or issues, and other administrative data. 
Minutes of the open session will be recorded by the Chair of the DSMB. Minutes will be finalized upon 
signature of the chairperson and maintained by the DSMB in accordance with applicable statutory 
regulation.   
 
The closed session will be restricted to the DSMB members. A facilitator or recorder may be 
requested by the DSMB. Data which may compromise the integrity of the study (e.g., comparative 

 
 
 
45 
data) will be analyzed and discussed only in the closed session. The minutes of the closed session 
will be recorded by the DSMB Chair. Minutes from the closed session will be recorded separately 
from the minutes of the open session and stored securely by the DSMB Chair. Closed session 
minutes, finalized by signature of the chairperson, will be maintained in confidence and retained until 
discarded in accordance with applicable statutory regulation. 
 
Following each meeting, a report separate from the minutes of the open and closed sessions will be 
sent to the PI describing the DSMB recommendations and rationale for such (see DSMB 
Communication of Findings and Recommendations). 
 
Study Review Criteria/Stopping Rules and Guidelines 
Guidance for the conduct of safety and efficacy analyses, and guidelines / stopping rules will be 
established prior to the DSMB’s first evaluation of data. 
 
Safety Analyses 
The primary safety endpoint is mortality as observed during interim analysis.  In addition to the 
primary safety endpoint, the DSMB will monitor the following adverse events:  
1. 
Acute Lung Injury 
2. 
Nosocomial infection 
3. 
MOF (multiple organ failure) 
4. 
Early seizures 
5. 
In-hospital pulmonary embolism 
6. 
Blood and blood component transfusion and resuscitation requirements 
7. 
Adverse Events 
8. 
Unexpected Adverse Events 
9. 
Expected Adverse Events 
 
Stopping Guidelines / Stopping Rules: Safety 
Termination or modification may be recommended for any perceived safety concern based on clinical 
judgment, including but not limited to a higher than anticipated rate for any component of the primary 
endpoint resulting in adverse events, or unexpected SAEs. 
 
Efficacy Analyses 
The primary outcome variable 30 day mortality will be utilized to access for efficacy of the trial. 
Accessing this primary outcome variable at each interim analysis will allow early termination of the 
trial for either lack of efficacy or excessive efficacy. 
 
Adaptive Protocol Modification 
There is no planned sample size re-estimation; however if the DSMB reveals a need, the sample size 
calculation can be re-evaluated.  
 
Consideration of External Data 
The DSMB will also consider data from other studies or external sources during its deliberations, if 
available, as these results may have a profound impact on the status of the patients and design of the 
current study. 
 
DSMB Reports 
Monitoring for Safety 

 
 
 
46 
The primary charge of the DSMB is to monitor the study for patient safety. Formal DSMB safety 
reviews will occur as specified above (see Study Review Criteria/Stopping Rules and Guidelines).   
 
Monitoring for Efficacy 
The DSMB will monitor efficacy outcomes to determine relative risk/benefit, futility, or for early 
termination due to overwhelming efficacy.  Interim analyses efficacy reports sent to the DSMB will 
occur as specified above (see Study Review Criteria/Stopping Rules and Guidelines).  
 
Monitoring for Study Conduct 
The DSMB will review data related to study conduct. Data to be reviewed and listed in the DSMB 
reports includes: enrollment rates over time, time from last patient enrolled to date of report 
(indication of delay between treatment or follow-up and reporting), summary of protocol violations, 
and completeness of treatment and follow-up visit data. 
 
Data Flow for Adverse Events 
The DSMB will carefully monitor adverse events periodically throughout the duration of the study. 
This process will be dynamic to include quarterly reviews of all reported SAEs by the DSMB 
chairperson. The investigators will be expected to report Serious Adverse Events (SAEs) to the PI 
within 24 hours of knowledge of the event. The PI will then report it to the DSMB within 7 days.  
 
Preparation of Reports to the DSMB 
At the scheduled 6 month DSMB meetings, the study statistician will prepare results for the closed 
session that show outcomes by treatment effect but with the blinds intact.    An independent 
statistician will prepare and distribute reports to the DSMB electronically approximately 7 days prior to 
the date of each DSMB meeting. 
 
In order to provide the maximum amount of information to the DSMB, the analyses will employ the 
most recent data (recognizing limitations thereof) available at the time of the analysis. Requests for 
additional data by the DSMB members will be made to the DSMB chairperson or his or her designee, 
who will be responsible for communicating the request with the PI. 
 
The DSMB will review the data and discuss the analyses during the closed portion of the scheduled 
meeting.  If in the closed session the DSMB finds blinded results that are concerning, the meeting will 
be ended and the DSMB will reconvene in closed session within 1 week to be given the same data 
unblinded.  If the meeting is necessary, an additional interim analysis will be added to the two 
scheduled interim analyses resulting in the need to recalculate alpha spent.  We will be cognizant of 
the logistical and scientific costs associated with this plan when we are considering any unscheduled 
analysis. 
 
For the interim analyses at 1/3 and 2/3 enrollment points, the biostatistician will create two reports for 
the DSMB closed session meeting: one with the treatment arms blinded and one with the blinds 
broken.  The biostatistician will first present to the DSMB data with the blinds intact in closed session.  
If no point estimates are within the range of the a priori stopping rules, the statistician will be asked to 
proceed at that time with presenting a report with the blinds broken.  As the alpha accounting for 
these two interim looks has already been calculated, it will not need to be recalculated. 
 
DSMB Communication of Findings and Recommendations 

 
 
 
47 
Following each meeting and within 14 days of the meeting, the chairperson will send findings and 
recommendations of the DSMB in writing to the PI.  
 
These findings and recommendations can result from both the open and closed sessions of the 
DSMB. If these findings include serious and potentially consequential recommendations that require 
immediate action, the chairperson will also promptly notify the PI by phone and/or by email. 
 
PI’s Response to DSMB Findings and Recommendations 
The PI and co-investigators will review and respond to the DSMB recommendations. The 
recommendations of the DSMB will not be legally binding but require professional consideration by 
the recipients. If the DSMB recommends continuation of the study without modification, no formal 
response will be required. However, if the recommendations request action, such as a 
recommendation for termination of the study or modification of the protocol, the DSMB will request 
that the PI provide a formal written response stating whether the recommendations will be followed 
and the plan for addressing the issues. 
 
It is recognized that the PI may need to consult with regulatory agencies or other consultants before 
finalizing the response to the DSMB. Upon receipt, the DSMB will consider the PI response and will 
attempt to resolve relevant issues, resulting in a final decision. Appropriate caution will be necessary 
during this process to avoid compromising study integrity or the ability of the PI to manage the study, 
should the study continue. The PI will agree to disseminate the final decision to the appropriate 
regulatory agencies, IRB, and investigators within an appropriate time. 
 
In the unlikely event of irreconcilable differences, especially regarding study termination or other 
substantial study modifications, the DSMB may decide to discontinue monitoring the current study 
and disband. This decision will be communicated to the PI, FDA, and IRBs. 
 
Public disclosure of the PI’s final decision or DSMB recommendations will be at the discretion of the 
PI or their designee. The DSMB will not make any public announcements either as a group or 
individually.   
 
DSMB Closeout 
This study may be terminated under a variety of circumstances including, but not limited to, 
termination for overwhelming effectiveness, futility, or safety issues per protocol or DSMB monitoring 
guidelines. Responsibilities of the DSMB with regard to closeout will be to review the final study report 
to ensure study integrity. The DSMB may recommend continuing action items to the PI based upon 
the final review. 
 
Confidentiality 
All data provided to the DSMB and all deliberations of the DSMB will be privileged and confidential. 
The DSMB will agree to use this information to accomplish the responsibilities of the DSMB and will 
not use it for other purposes without written consent from the study PI and co-investigators. No 
communication of the deliberations or recommendations of the DSMB, either written or oral, will occur 
except as required for the DSMB to fulfill its responsibilities. Individual DSMB members must not have 
direct communication regarding the study outside the DSMB (including, but not limited to the 
investigators, IRB, regulatory agencies, or PI) except as authorized by the DSMB. 
 

 
 
 
48 
Amendments to the DSMB Charter 
This DSMB charter can be amended as needed during the course of the study. Information to be 
included as amendments will be any modifications or supplements to the reports prepared for the 
DSMB, as well as amendments to other information addressed in this charter. All amendments will be 
documented with sequential version numbers and revision dates, and will be recorded in the minutes 
of the DSMB meetings. Each revision will be reviewed and agreed upon by both the study PI and the 
DSMB. All versions of the charter will be archived in accordance with this document and maintained 
by the PI.  
 
 
 

 
 
 
49 
Clinical Protocol Appendix 4 – Stopping Rules 
STAAMP Trial Stopping Rule and Data Monitoring 
In concert with the DSMB, prior to initiation of the trial, the final monitoring plan will be developed to serve as the guide 
to the DSMB’s decision-making process concerning early stopping of the trial monitoring safety and efficacy.  In making 
the decision to recommend termination of the study, the DSMB shall be guided by several types of information: (i) a 
formal stopping rule based on the primary analysis (comparison of treatment groups on the 30 day mortality), (ii) 
information on safety outcomes by treatment group, (iii) consistency between results for primary and secondary 
outcomes, and (iv) consistency of treatment effects across subgroups. 
1. O'Brien-Fleming spending (z-values and related alpha) of interim boundaries for each look 
We have designed this trial with a two interim look before the final analysis. Our power analysis generated assuming a 
total of 3 sequential tests based on O'Brien-Fleming spending function to determine alpha spending and test boundaries. 
We will use test of proportions differences, two sided z-test with continuity correction applied and other adjusting 
techniques. The level of significance will maintain an overall p value of 0.05 according to O’Brien-Fleming stopping 
boundaries leaving a p value of 0.038; two sided, for the final analysis with a final z-value of 1.993. An independent data 
and safety monitoring board (DSMB) will periodically review the efficacy and safety data. DSMB will issue related 
recommendations based on comprehensive data monitoring and substantiated evidences. Two formal interim analyses of 
efficacy will be performed when 33% and 67% of the expected number of primary events had accrued (about one month 
after 1/3 and 2/3 of subject accruals). The purpose of our sequential tests is to detect early sign of superior efficacy and 
detect further apparent futility in the intervention group. This kind of futility monitoring and testing could cause this trial 
to be stopped as soon as a negative outcome of 30-days mortality is inevitable and thus it is no longer worthwhile 
continuing the trial to its completion. Such early termination for futility could reduce the enormous expenditures of 
resources, human and financial, involved in the conduct of trials that ultimately provides negative answers regarding the 
value of the study medical intervention. 
 
Our trial’s lower and upper stopping boundaries have been computed to ensure that the trial Type I and Type II error 
probabilities of the group sequential plan are according to the study assumptions and design. The upper boundaries are 
related to the formal efficacy testing at each assigned sample size (expected number of primary events completion at 
33%, 67%, and 100%). The lower boundaries are related to the formal futility (safety) testing at each assigned sample 
size (expected number of primary events completion at 33%, 67%, and 100%). Upper and lower boundaries will be 
provided to DSMB as a guideline and could be modified by DSMB prior to the trial upon reasonable justifications. With this 
sequential testing plan based on O'Brien-Fleming spending function, only an absolutely overwhelming treatment 
intervention can justify the termination of our clinical trial after a third of the subjects have been enrolled and completed 
a one month of follow up. If the trial has been ordered to stop early because of interim analysis, adjusted p-values will be 
computed based on the described analysis of our main clinical outcome. Unadjusted p-value will not be considered for 
final results interpretations.  
Our interim analysis is part of our three sequential testing as we have mentioned above. At each of the two interim looks, 
30 days-mortality will be pooled across participated centers comparing between the two study groups. Based on the 
assumed power analysis at each interim look, the z-value will be calculated and checked against the upper and lower 
values guide lines for that specific check.  We have illustrated z-values for the upper and lower boundaries across interim 
two analyses and final analysis of a total accumulated alpha of 0.05. (Figure and Table below) 
Details when Spending = O'Brien-Fleming, N1 = 497, N2 =497, P1 = 0.10, P2 = 0.16 
 
 
Lower 
Upper 
Nominal 
Inc 
Total 
Inc 
Total 
Look Time 
Bndry 
Bndry 
Alpha 
Alpha 
Alpha 
Power 
Power 
1 
0.33 
-3.71030 
3.71030 
0.000207 
0.000207 
0.000207 
0.018687 
0.018687 
 
2 
0.67 
-2.51142 
2.51142 
0.012025 
0.011890 
0.012097 
0.399207 
0.417894 
 

 
 
 
50 
3 
1.00 
-1.99302 
1.99302 
0.046259 
0.037903 
0.050000 
0.382494 
0.800388 
 
Drift 2.82089 
 
Look: These are the sequence numbers of the interim tests. 
 
Time: These are the time points at which the interim tests are conducted. This is also related to proportion of subject accruals 
 
Lower and Upper Boundary: These are the test boundaries. If the computed value of the test statistic z is between these values, the trial should 
continue. Otherwise, the trial can be stopped. 
 
Nominal Alpha:  This is the value of alpha for these boundaries if they were used for a single, standalone test. Hence, this is the significance level 
that must be found for this look in a standard statistical package that does not adjust for multiple looks.  
 
Inc Alpha: This is the amount of alpha that is spent by this interim test. It is close to, but not equal to, the value of alpha that would be achieved if 
only a single test was conducted. The difference is due to the correction that must be made for multiple tests.  
 
Total Alpha: This is the total amount of alpha that is used up to and including the current test.  
 
Inc Power: These are the amounts that are added to the total power at each interim test. They are often called the exit probabilities because they give 
the probability that significance is found and the trial is stopped, given the alternative hypothesis. 
 
 
O’Brien-Fleming boundary values are inversely proportional to the square root of information levels on the standardized Z scale 
(O’Brien and Fleming 1979). The O’Brien-Fleming boundary is conservative in the early stages and tends to stop the trials early only 
with a small P-value. But the nominal value at the final stage is close to the overall P-value of the design. 
 
 
The above plot shows the interim boundaries for each look. This plot shows very dramatically that the results must be 
extremely significant at early looks, but that they are near the single test boundary (1.96 and -1.96) at the last look. 
References 
1. Chow, S.C.; Shao, J.; Wang, H. 2003. Sample Size Calculations in Clinical Research. Marcel Dekker. New York. 
2. Lan, K.K.G. and DeMets, D.L. 1983. 'Discrete sequential boundaries for clinical trials.' Biometrika, 70, pages 659-663. 
3. O'Brien, P.C. and Fleming, T.R. 1979. 'A multiple testing procedure for clinical trials.' Biometrics, 35, pages 549-556 
4. Pocock, S.J. 1977. 'Group sequential methods in the design and analysis of clinical trials.' Biometrika, 64, pages 191-199 
O'Brien-Fleming Boundaries with Alpha = 0.05
Upper
Lower
Z Value
Look
-1
-2
-3
-4
0
1
2
3
4
0.5
1.0
1.5
2.0
2.5
3.0

 
 
 
51 
5. Reboussin, D.M., DeMets, D.L., Kim, K, and Lan, K.K.G. 1992. 'Programs for computing group sequential boundaries using the Lan-
DeMets Method.' Technical Report 60, Department of Biostatistics, University of Wisconsin-Madison. 
. 
2. Eligibility, recruitment, and accrual reporting  
Our periodic reports to DSMB will include as well data on recruitment, data completion, data quality, etc. Data will be 
summarized in tables as listed below of simplicity and clarity. For simplicity and clarity in reading information, data on 
eligibility, recruitment, and accrual reporting will be summarized in table 1 and figure 1 and 2. 
 
    Table 1 Recruitment and Accrual 
 
Center1 
Center2 
Center3 
Center4 
Center5 
Total 
Study treatment 
A 
B 
A 
B 
A 
B 
A 
B 
A 
B 
A 
B 
Duration of time 
in weeks since 
start going life 
 
 
 
 
 
 
 
 
 
 
 
 
Number of 
Patients 
screened 
 
 
 
 
 
 
 
 
 
 
 
 
Number of 
patient eligible 
for study 
 
 
 
 
 
 
 
 
 
 
 
 
Eligible but not 
entered in the 
study 
 
 
 
 
 
 
 
 
 
 
 
 
Drop off / not 
able to follow up 
 
 
 
 
 
 
 
 
 
 
 
 
Total patient 
“randomized” 
 
 
 
 
 
 
 
 
 
 
 
 
Average accrual 
per month 
 
 
 
 
 
 
 
 
 
 
 
 
Data completion 
(✓) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data Quality (✓) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
52 
 
 
Figure 2  Overall Accrual 
 
Figure 3 Accrual by intervention and centers 
 
 
 
 
0
20
40
60
80
100
120
140
160
180
200
Center 1
Center 2
Center 3
Center 4
Center 5
Total
Example for Overall accrual for STAAMP
Overall accrual
0
10
20
30
40
50
60
70
80
90
100
Intervention A
Intervention B
Patient numbers
Example for  at First Interim Analysis

 
 
 
53 
3. Information on subjects’ demographics and illnesses 
In details information on subjects’ demographics and illnesses will be summarize in table 2 
Table 2 Demographics and Baseline Disease Characteristics 
 
Center1 
Center2 
Center3 
Center4 
Center5 
Total 
 
A 
B 
A 
B 
A 
B 
A 
B 
A 
B 
A 
B 
Patients 
numbers 
 
 
 
 
 
 
 
 
 
 
 
 
Age, median and 
range 
 
 
 
 
 
 
 
 
 
 
 
 
Sex (male) n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
Race, N (%) 
White 
Black 
Other 
 
 
 
 
 
 
 
 
 
 
 
 
Average Lowest 
pre hospital SBP 
 
 
 
 
 
 
 
 
 
 
 
 
Average Heart 
rate 
 
 
 
 
 
 
 
 
 
 
 
 
Average 
Perspiration 
Rate 
 
 
 
 
 
 
 
 
 
 
 
 
Median ISS 
 
 
 
 
 
 
 
 
 
 
 
 
Mechanism of 
Injury (blunt) 
(%) 
 
 
 
 
 
 
 
 
 
 
 
 
CPR (%) 
 
 
 
 
 
 
 
 
 
 
 
 
Pre hospital 
Blood 
transfusion (%) 
 
 
 
 
 
 
 
 
 
 
 
 
!!! 
 
 
 
 
 
 
 
 
 
 
 
 
 
4. Monitoring Safety and efficacy 
Further and in relation to interim safety analysis, safety data by study groups labeled as Interventional group (Early 
using of tranexamic acid) and Control group (Standard of care) will be provided periodically to DSMB. These processed 
data will provide information on safety outcomes by treatment group, ascertain the consistency between results for 
primary and secondary outcomes, and inspect the consistency of treatment effects across subgroups.  Safety data of the 
study include serious adverse events regarding frequency, anticipated or unanticipated, individual description for each 
event and dates. Other data will be provided as well as any additional safety analysis upon DSMB request. Mortality will 
be reported as an overall in our periodic reports (every 6-9 months depends on accrual rate) to DSMB however we will 
report mortality individually as treatment A and B at each of the trial two formal interim analyses. Data will be 
summarized in tables (3-6) 
 

 
 
 
54 
 
Table 3 Possible Adverse effects 
 
Center1 
Center2 
Center3 
Center4 
Center5 
Total 
 
A 
B 
A 
B 
A 
B 
A 
B 
A 
B 
A 
B 
Patients 
numbers 
 
 
 
 
 
 
 
 
 
 
 
 
Transfusion 
related lung 
injury n, (%) 
 
 
 
 
 
 
 
 
 
 
 
 
Allergic/anaphyl
actic reaction 
 
 
 
 
 
 
 
 
 
 
 
 
Circulatory 
overload 
 
 
 
 
 
 
 
 
 
 
 
 
Infection 
 
 
 
 
 
 
 
 
 
 
 
 
Febrile reaction 
 
 
 
 
 
 
 
 
 
 
 
 
Hemolytic 
reaction 
 
 
 
 
 
 
 
 
 
 
 
 
!!! 
 
 
 
 
 
 
 
 
 
 
 
 
!!! 
 
 
 
 
 
 
 
 
 
 
 
 
!!!! 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 4 Unexpected Adverse Effects 
 
Center1 
Center2 
Center3 
Center4 
Center5 
Total 
 
A 
B 
A 
B 
A 
B 
A 
B 
A 
B 
A 
B 
Patients 
numbers 
 
 
 
 
 
 
 
 
 
 
 
 
1.                  n,(%)  
 
 
 
 
 
 
 
 
 
 
 
2. 
 
 
 
 
 
 
 
 
 
 
 
 
3. 
 
 
 
 
 
 
 
 
 
 
 
 
4. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 5 Primary outcomes for patients in the Study 
 
Center1 
Center2 
Center3 
Center4 
Center5 
Total 
 
A 
B 
A 
B 
A 
B 
A 
B 
A 
B 
A 
B 
Number of 
Patients  
 
 
 
 
 
 
 
 
 
 
 
 
24 hr Mortality 
n, (%) 
 
 
 
 
 
 
 
 
 
 
 
 
30 day Mortality 
n, (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 6 Secondary outcomes for patients in the Study 
 
Center1 
Center2 
Center3 
Center4 
Center5 
Total 

 
 
 
55 
 
A 
B 
A 
B 
A 
B 
A 
B 
A 
B 
A 
B 
Number of Patients  
 
 
 
 
 
 
 
 
 
 
 
 
Hyperfibrinolysis 
 
 
 
 
 
 
 
 
 
 
 
 
Acute lung injury (%) 
 
 
 
 
 
 
 
 
 
 
 
 
Multiple organ failure 
(%) 
 
 
 
 
 
 
 
 
 
 
 
 
Nosocomial infection (%) 
 
 
 
 
 
 
 
 
 
 
 
 
Improved shock 
parameters (%) 
 
 
 
 
 
 
 
 
 
 
 
 
Early resuscitation need 
(%) 
 
 
 
 
 
 
 
 
 
 
 
 
Transfusion 
requirements (%) 
 
 
 
 
 
 
 
 
 
 
 
 
Early seizures (%) 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary embolism (%) 
 
 
 
 
 
 
 
 
 
 
 
 
Reduce or prevent the 
early coagulopathy as 
demonstrated by 
improving presenting 
INR (%) 
 
 
 
 
 
 
 
 
 
 
 
 
and Rapid 
thromboelastography 
parameters (%) 
 
 
 
 
 
 
 
 
 
 
 
 
Reduce the early 
inflammatory response, 
plasmin levels, leukocyte, 
platelet and complement 
activation (%) 
 
 
 
 
 
 
 
 
 
 
 
 
ICU days 
 
 
 
 
 
 
 
 
 
 
 
 
Ventilation days 
 
 
 
 
 
 
 
 
 
 
 
 
Hospital LOS 
 
 
 
 
 
 
 
 
 
 
 
 
!!!