Conditions: Trauma Hemorrhagic Shock
Keywords: coagulopathy hemorrhagic shock plasma blood product transfusion
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 144
Healthy volunteers: no

Brief summary:
Bleeding is the most avoidable cause of death in trauma patients. Up to one-third of severely injured trauma patients are found to be coagulopathic and forty percent of the mortality following severe injury is due to uncontrollable hemorrhage in the setting of coagulopathy. It has been established that early administration of fresh frozen plasma decreases mortality following severe injury, replacing lost coagulation factors, improving the coagulopathy and restoring blood volume. This study will determine if giving plasma to severely injured trauma patients during ambulance transport versus after arrival to the hospital will help reduce hemorrhage, thus decreasing both total blood product administration and mortality.

Detailed description:
Study Design: Severely injured trauma patients with a systolic blood pressure (SBP) ≤ 70 or SBP ≤ 90 with a heart rate ≥ 108 bpm at the scene will be enrolled and randomized to receive either 2 units of frozen plasma thawed in the field or normal saline (the current standard of care), as the initial resuscitation fluid. After this initial resuscitation fluid, both groups will receive the same standard of care, including packed red blood cells, additional normal saline, or plasma as needed based on laboratory and clinical evidence of coagulopathy. Blood samples and clinical information will be collected throughout the hospital stay up to 28 days after injury.

Arms:
arm 1: If the patient is randomized to experimental arm, 2 units of frozen type AB plasma (FP24) will be thawed in the Plasmatherm Dry Thawing and Warming Device according to the operator manual as approved by the FDA in the ambulance and infusion will commence as soon as the type AB plasma is ready, and will continue during transport to the emergency department (ED). After infusion of 2 units of type AB plasma is completed, subsequent care will proceed per institutional, Advanced Trauma Life Support (ATLS) guided resuscitation with acute packed red blood cells (pRBC) administration determined by the hemodynamic response and additional blood component administration guided by rapid thrombelastography (rTEG) and coagulation panel assessment in conjunction with clinical scenario. arm 2: If the patient is randomized to the standard arm, the patient will be given intravenous crystalloid fluid (normal saline) as the initial resuscitation fluid with 2 large bore IVs based on the current ATLS guidelines, the standard of care. Subsequent care will proceed per institutional, ATLS guided resuscitation with acute packed red blood cells pRBC administration determined by the hemodynamic response and additional blood component administration guided by rTEG and coagulation panel assessment in conjunction with clinical scenario.

Interventions: intervention 1: Type AB plasma intervention 2: Crystalloid fluid (standard of care for resuscitation)
Intervention descriptions: intervention 1: The plasma is thawed and administered to subjects in the experimental (plasma) arm. intervention 2: Normal saline will be give to subjects in the standard arm as the current standard of care for an initial resuscitation fluid

Protocol document:
Prot_SAP_000.pdf: 
On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 1
CF-146, Effective 4-26-2010
COMIRB Protocol
PROTOCOL #:
12-1349
VERSION DATE:       12/27/2016
(Use Protocol Manager on the COMIRB Website)
COLORADO MULTIPLE INSTITUTIONAL REVIEW BOARD
CAMPUS BOX F-490    TELEPHONE:  303-724-1055  Fax:  303-724-0990
Project Title:
Control Of Major Bleeding After Trauma (COMBAT): A prospective, 
randomized comparison of fresh frozen plasma versus standard crystalloid 
intravenous fluid as initial resuscitation fluid
Principal Investigator: Ernest E. Moore, M.D.
 
This study is sponsored by the DOD’s Telemedicine & Advanced Technology Research 
Center (TATRC).  
I.
Study Main Objective:  The main objective of the study is to determine the efficacy of 
administering plasma (specifically AB-FP24) during field resuscitation compared to current 
treatment policy or standard of care (SOC) in which normal saline is infused in the pre-ED 
phase. This Phase 2 trial will provide preliminary evidence to potentially support Phase 3 
trials with large study populations. 
Study aims:
1)
To determine if plasma-first resuscitation of severe hemorrhagic shock attenuates the 
acute coagulopathy of trauma.
2)
To determine if plasma-first resuscitation of severe hemorrhagic shock improves 
metabolic recovery. 
3)
To determine if plasma-first resuscitation of severe hemorrhagic shock decreases overall 
blood product transfusion and reduces the incidence of acute lung injury, multiple organ 
failure, and mortality. In relation to the efficacy of plasma-first resuscitation, we will 
assess whether waveform information can help predict activation of the massive 
transfusion protocol. 
II.
Background and Significance: 
A.
Background: Hemorrhage is the most preventable cause of death in trauma patients.  
However, despite improvements in patient transport via EMS, survival in the first hour 
post-injury has changed little over the past 40 years.1-4  Epidemiologic studies at trauma 
centers have revealed hemorrhage to be responsible for up to 50% of trauma related 
mortality.1-4  In parallel, military trauma data from the current war on terror, and extending 
back to Vietnam, identify hemorrhage as a leading cause of preventable death in combat 
casualties, estimated to represent >80% of potentially survivable injuries.5-8  Recent 
studies have documented coagulopathy in up to a third of trauma patients upon arrival to 
the emergency department (ED) prior to resuscitation, which correlates with the severity 
of tissue injury and magnitude of hemorrhagic shock.9-12  Collectively, these findings have 
COMIRB
APPROVED
24-Mar-2017


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 2
CF-146, Effective 4-26-2010
stimulated a resurgent interest in developing an improved resuscitation fluid for severe 
hemorrhagic shock.13 
The pathogenesis of the acute coagulopathy of trauma is undergoing intense 
worldwide investigation, but is undoubtedly multi-factorial and, at this moment, remains 
largely ill-defined.14-19  The most recent emphasis has been on the complex interactions 
between post-injury inflammation and coagulation.20-24 Irrespective of the ongoing debate, 
most authorities agree there is a component of disseminated intravascular coagulation 
(DIC), as well as thrombin generation for tissue hemostasis, that depletes circulating 
clotting factors.16-19 The existence of DIC was recognized from Vietnam combat data and 
verified experimentally,25-27 but its potential role in depleting coagulation factors was not 
evident until whole blood transfusion was abandoned in favor of component therapy in 
the early 1980s. This policy change stimulated several trauma centers to recommend 
presumptive administration of fresh frozen plasma (FFP) with initial packed red blood cell 
(pRBC) transfusion.28-30 In fact, as far as we can ascertain, our report to the American 
Association for the Surgery of Trauma (AAST) in 198129 was the first to advocate pre-
emptive FFP in the severely injured patient.  
Furthermore, by the late 1980s, 
anesthesiologists documented clotting factor deficiency associated with pRBC 
transfusion during elective surgery.31, 32
B.
Current Advanced Trauma Life Support guidelines: Current guidelines from the 
American College of Surgeons recommend two liters of crystalloid, such as normal saline 
or lactated ringers, as the initial resuscitation fluid. DHMC paramedic protocol for 
traumatic shock states that IV NS bolus should be given. (See Appendix 0-DHMC 
Paramedic Prehospital Care)  If the patient remains hemodynamically unstable with 
SBP<90 and HR>100 after the two liters of crystalloid fluid in the ED, the trauma team 
will start blood transfusion with “trauma blood,” which is group O, and Rhesus D negative 
if female.  The Massive Transfusion Protocol is initiated by the attending trauma surgeon 
when a) a severely injured patient arrives in profound shock believed to be due to acute 
blood loss, b) when a severely injured patient remains in shock (SBP<90 mmHg) despite 
crystalloid resuscitation and is believed to have acute major blood loss, or c) a severely 
injured patient who requires massive RBC transfusion (>2 units PRBC per 30 minutes) to 
maintain hemodynamic stability and is believed to have ongoing acute blood loss. Once 
AB plasma is available, it is sent from the blood bank and infused. The Massive 
Transfusion protocol at DHMC is initiated at a 1:2 FFP: pRBC ratio (See Appendix 1 for 
DHMC Massive Transfusion Protocol).    
III. Preliminary Studies/Progress Report: 
A.
Preliminary studies: As outlined in the background, the need for early infusion of FFP in 
patients requiring pRBC transfusion has been recognized from the time of blood 
component use in the early 1980’s. Retrospective studies have shown increased survival 
with early transfusion of FFP in combat patients.33, 34 Furthermore, there are now multiple 
retrospective clinical studies showing an increased ratio of FFP to pRBC during massive 
transfusion is warranted.35-39 We initially suggested on a ratio of 1:4 in 198229, and 
consequently others have shown improved 30-day mortality with ratios greater than 2:3.35 
Furthermore, retrospective studies from European trauma registries have shown that FFP 


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 3
CF-146, Effective 4-26-2010
to pRBC ratios closer to 1:1 improved 24-hour mortality.37 This has been further 
demonstrated in the US with patients receiving higher FFP: pRBC ratios (mean, 1:1.3) 
within the first 24 hours of admission had a 63% lower risk of death than those with a 
lower ratio (mean, 1:3.7),40 and our most recent clinical investigation suggested 
presumptive FFP: pRBC ratios of 1:2 improves survival and coagulopathy of trauma.36, 41  
Early and aggressive FFP administration at a ratio of 1:1 in severely injured patients, 
even in patients that are not massively transfused has also been reported to improve 
mortality.42  A recent multi-institutional preclinical trial in a large animal model of severe 
polytrauma supports this concept.43   Using an established swine model, it was shown 
that the animals developed coagulopathy after inducing a femur fracture, hemorrhagic 
shock, and hypothermia.  Treatment with whole blood, FFP only, and FFP with pRBC all 
attenuated the coagulopathy, suggesting that FFP alone can effectively correct the 
coagulopathy.  
The infusion of FFP in severe trauma patients with coagulopathy is further 
supported in the concept of damage control resuscitation (DCR).44, 45  DCR occurs during 
damage control surgery where the goal of surgery is to minimize blood loss and 
contamination, with the plan to return to the operating room for definitive repair when the 
patient is resuscitated and hemodynamically stable, and hemostatically secure.  DCR 
involves minimizing the use of crystalloid, infusion of blood products, especially plasma, 
and permissive hypotension to limit blood loss, yet maintain perfusion to critical organs.  
In a retrospective study comparing outcomes of a cohort after the implementation of a 
DCR protocol to a historical cohort, patients in the DCR period received less crystalloid 
and more FFP with a FFP: pRBC ratio of 1:1.4, but had significantly improved 30 day 
survival and significantly shorter ICU and hospital stays.46
 In a review article evaluating the available data on the effects of resuscitation 
fluids, including isotonic crystalloids and plasma, Rhee et al. concluded that isotonic 
crystalloids, such as normal saline and lactated ringer, led to activation of neutrophils and 
increased markers of cellular injury.  They also concluded that plasma had favorable 
effects on immune function.47  
Recent studies are showing improved outcomes with plasma-first resuscitation.  
In a trauma/hemorrhagic shock rabbit model with uncontrolled bleeding, initial 
resuscitation with plasma had improved coagulation function, as measured by 
thrombelastography, compared to Hextend (the standard initial resuscitation fluid in the 
military).48 Another study demonstrated that having thawed plasma available in the 
emergency department lead to a faster infusion of plasma on arrival to the emergency 
department, a reduction in overall blood product use, and a 60% increase in 30-day 
survival.49
In a retrospective review recently accepted for publication, Kim et al. examined 
the effects of helicopter transport, pre-hospital plasma first resuscitation protocol in 
patients with hemorrhagic shock.50 There were 9 who received plasma first, of 59 patients 
who met criteria for the pre-hospital massive transfusion protocol. Patients that received 
plasma first had greater baseline and post plasma INR values, but the decrease in INR 
was greater in those who received plasma first. Regarding the FFP:pRBC resuscitation 
ratio, the plasma first group received a ratio near 1:1 compared to a ratio of 0.45:1 in the 
control group.  


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 4
CF-146, Effective 4-26-2010
Based on the current literature and despite no previous prospective clinical trials, 
the University of Texas at Houston has adopted early FFP administration in their trauma 
protocol and is currently administering thawed FFP in the field for critically injured 
patients transported by helicopter. (J. Holcomb personal communication with E.E. Moore)
B.
Description of Plasma: Fresh frozen plasma (FFP) is defined in the United States as 
plasma that is obtained from whole blood and frozen within eight hours of collection (or 
six hours if acid-citrate-dextrose is the anticoagulant/preservative) per AABB Standard 
5.7.5.9 and FDA 21CFR640.34 (b).51 Interestingly, FFP is regulated by the FDA under 
21CFR640,51 but unlike other blood products, there is no quality control requirement for 
FFP in the USA regarding the contents, especially coagulation factors and protein 
concentrations. However, to decrease the burden on blood centers to process blood 
rapidly and freeze the blood within 6-8 hours, the vast majority of the fresh frozen plasma 
is frozen within 24 hours and denoted FP24. Additionally, the use of FP24 allows the 
blood center to confirm which plasma units meet criteria of antibody negative or type AB, 
potentially reducing adverse transfusion reactions such as transfusion-related acute lung 
injury (TRALI). Plasma represents a third generation resuscitation fluid.  Like first 
generation crystalloids, FP24 is iso-osmolar with blood and contains all of the cations 
(e.g. Na, K, Mg, Ca) and anions (e.g. Cl, PO4) present in blood.  Like the second-
generation colloid resuscitation fluids based on albumin alone, or non-human 
polysaccharides such as large dextrans and starches, it has high oncotic pressure 
(28mmHg vs. 3mmHg in 0.9% saline).  Furthermore, FP24 contains hundreds of proteins 
at concentrations of mg/L.  In fact, after albumin (40gm/L), the top 10 proteins add 
another 9.6g/L, when measured biochemically.  
Although FP24 does contain 
carbohydrate, these are glyco-conjugates to proteins and structurally quite different and 
more complex that dextrans or starches.13, 52, 53 As summarized in Table 1, there are only 
small differences in the coagulation factors between thawed FFP and FP24 and similar 
concentrations of these proteins are present in the freeze-dried preparations (LysoPlas 
N-W, Resusix).54-56


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 5
CF-146, Effective 4-26-2010
Recent proteomic analyses of injured patients have demonstrated that following 
injury these patients have decreased levels of circulating anti-proteases and increased 
levels of intracellular enzymes, which may directly affect coagulation and influence organ 
injury through the protease-activated receptors on endothelial cells, and common 
intracellular proteins, like actin, which, if polymerized, may cause acute lung injury 
(ALI).57-59  
Interestingly, our recent proteomic analysis of FP24 demonstrates an 
abundance of numerous anti-proteases, α2-macroglobulin and α1-antitrypsin, which have 
the ability to oppose protease effects of coagulation and PARS as well as gelsolin, an 
extracellular protein that “solubilizes” actin filaments that could induce endothelial 
injury.57, 58, 60
Overall, there is, however, a limited supply of AB type plasma. AB plasma is the 
universal plasma donor for patients that have not yet had blood typing and will be the 
only type of plasma used for this study regardless if it is FFP or FP24.  According to the 
DHMC adult transfusion guidelines, thawed plasma is given in patients with massive 
transfusion or life threatening bleeding with clinical evidence of coagulopathy, regardless 
of PT/PTT levels and only AB plasma will be infused.  
The Circular of Information for the Use of Human Blood and Blood Components, 
prepared by the AABB, American Red Cross, America’s Blood Centers, and the Armed 
Services Blood Program and approved by the FDA, states the indications for infusion of 
FP24 are the same as FFP except for treatment of deficiencies of Factor VIII and Factor 
V.61 Under the section for Dosage and Administration, “FFP must be thawed in a water 
bath at 30 to 37 degrees Celsius or in an FDA-cleared device.” 
In the traditional method of thawing plasma, the blood bank often uses a water 
bath at 37 degrees Celsius and takes an average of 20 minutes for 2 units.62 After 
thawing, the thawed plasma must be kept at 4 degrees Celsius up to 24 hours. It has 


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 6
CF-146, Effective 4-26-2010
been shown that plasma thawed and refrigerated for more than 24 hours are not 
considered to be equivalent to thawed FFP or FP24 due to loss of labile proteins.  
Relying on the water bath method would make the plasma unavailable at the time of 
initial resuscitation or we would have to discard refrigerated frozen plasma every 24 
hours, regardless of use.  We plan to use an FDA –approved dry thaw device called 
Plasmatherm (510K#  BK100063)  to thaw the AB plasma. In order to use the AB plasma 
in a timely manner, we  plan to store the plasma in a larger bag to increase the surface 
area to volume ratio.  After extensive testing, we determined that utilizing a 2L bag to 
store the plasma allows for a thaw time that is faster than the microwave plasma 
defroster due to an increase in the surface area for a given volume   
In the trauma setting, we have determined that an independent risk factor for 
mortality is the number of blood products received in the first 12 hours post-injury.63 The 
acute coagulopathy of trauma perpetuates the need for blood products during 
resuscitation and may lead to increased organ failure and mortality.  It has been 
recommended to give FFP earlier in resuscitation to correct coagulopathy during massive 
transfusion.41 Furthermore, the war in Iraq prompted the military to refocus on 
presumptive plasma for resuscitation of soldiers with severe blast injuries and 
retrospective data analysis produced compelling evidence of its merit.33, 34, 64 These 
results and associated discussions at academic meetings stimulated a worldwide 
resurgent interest in the role of pre-emptive plasma replacement at the time of pRBC 
transfusion.35, 37-39, 41, 42, 65, 66
FP24 and FFP are FDA approved and regulated as biologics under 21 CFR 640 
Subpart D and G and The Circular of Information for the Use of Human Blood and Blood 
Components.51, 61  In this study, we are not altering the plasma in any way.  Rather, it is 
the infusion in the field with the exception from informed consent that requires an 
Investigational New Drug application, and not the product itself. 
The AB-FP24 that will be used is from never transfused male donors, and never 
pregnant female donors.  Most of the AB plasma is FP24 in order to verify the donors and 
the AB type of plasma as a universal donor to increase the supply of AB Plasma for 
transfusion for those who have not yet been blood typed. This is the standard used for 
plasma transfusion in the emergent setting for America’s Blood Centers. The DHMC 
Adult Transfusion Guidelines specifies the universal plasma donor is AB and indications 
for plasma transfusion include patients with massive transfusion or life-threatening 
bleeding with clinical evidence of coagulopathy regardless of PT/PTT values. (See 
Appendix 2.  
IV.  Study Design and Research Methods  
A.
Overview of Study Design: This Phase 2 trial is a randomized, controlled trial in which 
eligible injured patients will be randomized in the field into two groups, an experimental 
group who will receive plasma (AB-FP24) first or a control group who will receive SOC 
resuscitation with normal saline first. Randomization will be determined by trained 
paramedics assisting the patient in the field, as described below in IV.A.1. From this point 
forward in this document, the names Experimental group and Control group will be 
used to designate these two groups.  


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 7
CF-146, Effective 4-26-2010
1.
Rationale for Study Design:  The DOD contract specifically requires the study to 
emphasize testing in the field. The Denver Health Paramedic system uses the 
dynamic dispersal model such that ambulances are placed at certain locations and 
then mobilized according to shortest distance to the accident4. As a result, one 
ambulance in a given shift may cover various regions of the city and are mobilized 
randomly based on need. Seven to twenty eight ambulances may be deployed to 
cover the city depending on the time of day and day of the week.  Regardless, to 
minimize all possible sources of confounding and bias, thus all ambulances will be 
equipped with Plasmatherm devices, coolers, and AB-FP24 in all ambulances.  
For randomization, half of the coolers will contain AB-FP24 (experimental)  the 
other half will contain frozen water in a ziplock bag (or similar) that is incompatible 
with IV tubing (control).  We chose this method of randomization for several reasons. 
First, it will avoid protocol violation if the randomization group is determined by the 
product that is in the cooler.   It also does not require paramedics to open an 
envelope and read the randomization, allowing for faster enrollment, randomization 
and transport to the hospital for definitive care. This method also reduces the number 
of AB-FP24 units that can expire and be discarded; thus conserving the valuable 
resources of the blood bank.  The units of AB-FP24 and frozen water will be placed in 
an opaque wrap or case.  Only study personnel will know the type of fluid placed in 
each cooler prior to randomization. We chose frozen water that cannot be infused to 
be a dummy weight for the control coolers because we did not want to infuse cold 
saline that had been in a cooler for an extended period of time as this may cause 
further coagulopathy. If the subject is randomized to the standard group, paramedics 
will continue with the standard of care and begin infusing normal saline.  If the subject 
is randomized to the experimental group, paramedics will proceed with thawing the 
plasma as described in Procedures involving plasma. (Section IV.K.1)  Once the 
cooler has been opened, the paramedics will return to the Vehicle Support 
Technician (where paramedic equipment and medications are typically stored and 
distributed as well as the coolers) and obtain a fresh, unopened randomized cooler. If 
the cooler is not opened for the shift, it will be returned to the VST. The coolers will 
be assigned to paramedic teams at random. Our paramedic workforce has previous 
experience with field enrollment and randomization with the Polyheme study and is 
already on board with this study. Of note, our institution had only 4 protocol violations 
of the 128 patients enrolled during the Polyheme study, which relied heavily on 
participation of the paramedic team. (EE Moore, MD, personal communication, July 
17, 2012) 


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 8
CF-146, Effective 4-26-2010
COMBAT Study: Step-by-Step algorithm


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 9
CF-146, Effective 4-26-2010
Blinding is not possible because AB-FP24 is processed separately by a blood 
center through specific procedures. AB-FP24 is opaquely distinctly different.  Colored 
bags would not suffice because tubing would also have to be colored, and it would 
interfere with urgent care.  It could complicate the logistics of the clinical scenario 
since pre-hospital personnel and nurses use the drip chamber to ensure that the fluid 
is infusing thus they must be able to see the fluid, which will appear different.
2.
Exception of Informed Consent: This study will require a waiver of consent under 
21 CFR 50.24 for patient enrollment as described in the section Special Consent 
Issues (Section IV.M)
3.
Duration of study: 5 years.
4.
Description of population to be enrolled: Enrollment will include acutely injured 
trauma patients in severe, presumed hemorrhagic shock. Patients will be enrolled 
based on initial field vital signs. Inclusion criteria:  Age>18 years, acutely injured, 
with presumed hemorrhagic shock from acute blood loss defined as SBP<70 mmHg 
or SBP 71-90 mmHg with HR>108 beats per minute. Exclusion criteria: Visibly or 
verbally reported pregnant women, age<18 years, known prisoners, unsalvageable 
injuries (defined as asystolic or CPR prior to randomization), isolated GSW to the 
head with a GSW < 5 (a highly lethal injury that is not primarily due to acute blood 
loss), known or religious objection to blood products, the patient has an opt-out 
bracelet or necklace, or a family member present at the scene objects to the patient’s 
enrollment in research. Pregnant Women: It is not feasible to perform a pregnancy 
test after determination of eligibility because of life threatening injuries.  In the 
community consultation, we will advise nonvisibly pregnant women opt out of the 
study.  We will exclude any women of childbearing age that is visibly pregnant. 
Prisoners:  Only known prisoners at the time of enrollment will be excluded.  
Patients who are under a police hold or become a prisoner during hospitalization will 
be included in the study.  In the acute trauma setting, patients may be placed on a 
police hold at any time during hospitalization. The hold may be temporary for a short 
time or for an indeterminant length of time. Paramedics may not know who will be 
placed under a police hold.  Thus, ethically, these patients cannot be coerced for 
enrollment,. Patients placed on a police hold during hospitalization have already 
been randomized to the standard or experimental group. The study team would 
collect serial blood samples and follow up with the patient at 28 days.   Rationale for 
hemorrhagic shock entry criteria: The criteria were based on the last ROC trial67, 
which in turn were chosen based on a previous trial68 that showed that 
SBP≤90mmHG was not as “specific marker of hypovolemic shock”, while the 
alternative criteria led to a larger proportion of patients requiring massive transfusion. 
Thus, although the traditional marker of severe shock, SBP<90, we plan to use the 
same entry criteria as the ROC trauma trial so the populations of the two studies may 
be compared, which will enhance generalizability of the findings. 
Table 2 below shows the number of patients received by our trauma center from 
Jan 2009-Dec 2010, by different eligibility criteria and respective mortality rates. 
These numbers exclude patients who died within 10 minutes of arrival (a group of 
patients with potentially unsalvageable injuries). These are conservative estimates; 


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 10
CF-146, Effective 4-26-2010
our trauma volume has increased over 20% in 2012 and we anticipate maintaining 
this growth. 
5.
Gender, race, ethnic origin restrictions: There are no subject restrictions based 
upon gender, race, or ethnic origin unless the patient has a known objection to blood 
products. The research design will include sufficient enrollment of persons of both 
genders and diverse racial/ethnic backgrounds to ensure that the benefits and 
burdens of research participation are distributed in an equitable manner.  There are 
no religious restrictions, but people of the faith of Jehovah’s Witnesses typically 
object to transfusion of blood products and will be excluded from the study. 
B.
Detailed description of study design: 
1.
Procedure for enrollment, randomization and intervention:
a) Determination of eligibility of enrollment in this stage is based on initial 
vital signs from EMS in the field. (See Population to be Enrolled-Section 
IV.A.4 and Paramedic Training-Section IV.J) 
b) Trained paramedics will look for opt out specific bracelets or necklace 
ID.  If any of these opt out items are found or there is evidence of 
refusal of blood products, then the patient will not be enrolled.  
c) If a family member is present at the scene and not in shock or severely 
injured, easily accessible to paramedics, and the patient is not in 
imminent danger of death, the paramedics will state "We are enrolling 
him/her in a study where we are giving plasma for its clotting factors.  
We cannot explain the study at this time.  Is this okay?"  The 
paramedics will not be able to look for family members among a crowd 
of bystanders given the acute setting and the importance of transporting 
the patient to the hospital as soon as possible.
d) Once determined to be eligible, the paramedics will open the cooler, 
remove the two cassettes from the sealed bag, and open both cassettes 
to determine their contents. Once the cassettes are opened, the patient 
will be randomized to one of the 2 arms. If the cooler contains two units 
of AB-FP24, the patient is randomized to the experimental group.  If the 
cooler contains non-infusable frozen water, the patient is randomized to 
the control group. All ambulances will be equipped with a Plasmatherm 
and a cooler storage box containing either plasma or noninfusable 
Table 2. Trauma registry data Jan 2009-Dec 2011 (3 years), excludes DOA (patients who 
died within 10 minutes of arriving at ED)
Field Entry Criteria
N
Mortality
SBP<90
241
24%
SBP<80
175
32%
SBP≤70  OR (SBP 71-90 + HR≥108)
172
31%
SBP<70 
109
44%


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 11
CF-146, Effective 4-26-2010
frozen water. Before transfusing any fluids (likely immediately before 
drawing blood so as not to hinder patient care), paramedics will apply 
the noninvasive device for recording continuous waveform data. This 
device will remain on the patient for 24 hours and will begin obtaining 
critical physiological information as soon as the monitoring begins. 
Since this is an observational component of the study, there will be no 
changes made to the patient’s care during this portion. Waveform data 
will not be used in the provision of subsequent care. 
e) If the patient is randomized to the control arm, the patient will be given 
intravenous normal saline as the initial resuscitation fluid with 2 large 
bore IVs based on the current ATLS guidelines. Subsequent care will 
proceed per institutional, ATLS guided resuscitation with acute pRBC 
administration determined by hemodynamic response and additional 
blood component administration guided by rTEG and coagulation panel 
assessment in conjunction with clinical scenario. The Massive 
Transfusion Protocol may be initiated using the ABC score69 and 
heuristic evaluation of uncontrolled hemorrhage of the attending 
surgeon (See Appendix 1 for DHMC Massive Transfusion Protocol)
f) If the patient is randomized to experimental arm, 2 units of frozen AB-
FP24 will be thawed in the Plasmatherm thawing device according to the 
operator manual as approved by the FDA (see Plasmatherm- section 
IV.L.2) in the ambulance and infusion will commence as soon as the AB-
FP24 is ready, and will continue during transport to the ED.   If the AB-
FP24 is not ready, but IV access is acquired, normal saline will be 
infused and the volume recorded. Once the AB-FP24 is ready, the 
normal saline infusion will be stopped and the AB-FP24 will be started. If 
the patient has 2 lines, both lines will be used for AB-FP24.  If only 1 IV 
is available, one unit of AB-FP24 will be infused until it either is 
completed or another line is available for infusion. The experimental 
group will receive at least the standard of a resuscitation fluid, regardless 
if the AB-FP24 is ready for infusion.  After infusion of 2 units of AB-FP24 
is completed, subsequent care will proceed per institutional, ATLS 
guided resuscitation with acute pRBC administration determined by 
hemodynamic response and additional blood component administration 
guided by rTEG and coagulation panel assessment in conjunction with 
clinical scenario.  The Massive Transfusion Protocol may be initiated 
using the ABC score72 and heuristic evaluation of uncontrolled 
hemorrhage of the attending surgeon, similar to the standard arm. (See 
Appendix 1 for DHMC Massive Transfusion Protocol)
g) Both groups will be managed based on the critical care guidelines for 
trauma patients as published in the Journal of Trauma, which is the 
routine hospital care for trauma patients at DHMC.70-78 These are 
Standard 
Operating 
Procedures 
for 
critical 
care 
management 
specifically developed and peer-reviewed during our NIH sponsored 
Glue Grant studies


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 12
CF-146, Effective 4-26-2010
h) In the unlikely event multiple patients are enrolled in this study, all 
patients will be maintained as study patients despite the fact that there 
will be logistic barriers to obtaining a complete laboratory assessment. 
The rationale for this policy is the primary endpoint of this study is 
mortality; whereas, laboratory assessments are secondary endpoints.
i) There will be no ceiling dose for the total amount of intravenous fluids 
that will be administered in the field. Based on our experience, no more 
than 700cc of normal saline on average is infused prior arrival to the 
ED. 
C.
Data Collection and Storage
1.
Data Collection:  Each patient enrolled will be given a unique patient identifier 
that will be kept in a separate database to protect heath information.  
a.Laboratory studies will be performed to evaluate the acute coagulopathy 
of trauma from blood samples collected in the field, upon ED arrival, at 2, 
4, 6, 12, 24, 48 and 72 hours, and day 5 and day 7 post-injury as shown 
below in the figure titled “Biological Sampling and Study Timeline." 
Standard coagulation assays (prothrombin time/INR, activated partial 
thromboplastin time, fibrinogen levels, and platelet counts),  ROTEM 
(rotational theomboelastography) and TEGs, [rapid, tissue factor-
activated thrombelastograms (r-TEG), classic kaolin-activated TEGs with 
platelet mapping of the response to arachidonic acid (AA) and adenosine 
di-phosphate (ADP)] will all be completed in the Clinical Laboratories or 
Trauma Research Laboratory at Denver Health Medical Center in 
addition to CBC, serum chemistries, hepatic profile, lactate, and arterial 
blood gases.  Crystalloid volume, resuscitation fluids and number of 
blood products infused will be recorded hourly. 
b. In the event that multiple patients are enrolled in the study at the same 
time, due to logistical restrictions, samples may be delayed or not 
collected. Sample collection and processing will be resumed according 
to the protocol at the earliest opportunity. 
c. The clinical data both at presentation and throughout hospitalization will 
be obtained and recorded in the COMBAT/Trauma Activation Database.  
Additional clinical information specific to the study including blood 
product transfusion will be recorded in the REDCap data collecting 
system.  Clinical data entered will include a summary of injuries on 
admission, illness during the index admission, medical history, 
medications, and infectious and non-infectious complications as well as 
time and cause of death. Patient data entry will end with the index 
hospital stay. Outpatient information will not be included.  
d.Patients will be contacted after hospital discharge on day 28 primarily for 
28-day mortality.  
e.Each field, ED arrival, 2, 4, 6, 12, 24, 48, 72 hour, day 5 and day 7 time 
point blood samples obtained will be banked by a unique patient 
identifier for further research and for determination of proteomics and 


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 13
CF-146, Effective 4-26-2010
cytokines. These blood samples will also be used for panomics, such as 
metabolomics. Clinical data will also be kept for future research to 
correlate clinical outcomes with banked samples. 
f.
Samples from a limited data set including dates and times of events 
will be sent to TACTIC (Trans-Agency Consortium for Trauma-Induced 
Coagulopathy) for validation of inflammatory cytokine and chemokine 
data and to Children’s Hospital of Colorado for measurements of 
coagulation factors. 
g. Admission laboratory values obtained more than 60 minutes from 
ambulance arrival to the scene will be considered a missing value. 
h. We will do our best to obtain blood samples at the time points indicated 
in this protocol. However, due to events outside of research team’s 
control (e.g. urgent surgeries, delays in obtaining central venous access, 
etc.), samples may need to be collected within a 1 hour window of each 
time point at 2, 4, 6, and 12 hours and within a 2 hour window of each 
time point at hours 24, 48, 72, Day 5, and Day 7.
Time Point
Amount Drawn
Total Volume
Field
29.5 mL
29.5 mL
ED
40.5 mL
40.5 mL
Hour 2, 4, 6, 12, 24, 48
33.0 mL
198.0 mL
Hour 72
37.0 mL
37.0 mL
Day 5, Day 7
33.0 mL
66.0 mL
TOTAL AMOUNT DRAWN
371.0 mL


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 14
CF-146, Effective 4-26-2010
2.
Data Storage: Electronic case report forms and study data management will be 
performed using the REDCap Study Data Management System through the 
CCTSI Informatics Core.  
REDCap is a HIPAA compliant research data 
management system developed at Vanderbilt University and deployed at over 52 
institutions. All study data are stored on a secure database server, which is 
separate from the web-facing server - a best practices for internet-based 
security. All user access requires user accounts and passwords.  All user actions 
are recorded in a secure audit log.  The database server is routinely backed-up.  
All security patches and application updates are applied immediately upon 
release. Any paper records, which will be a minimum, will be kept in a locked 
location, only accessible by study personnel. Investigators, wishing to develop 
separate studies, not described above, using these data, will be required to 
submit a new IRB approval to allow the use of the data. Accurate and complete 
study records will be maintained and made available to representatives of the 
U.S. Army Medical Research and Materiel Command. These representatives are 
authorized to review research records as part of their responsibility to protect 
human research volunteers. Research records will be stored in a secure manner 
to protect the confidentiality of subject information.  
3.
Banked blood samples will be de-identified and kept for future research only for 
subjects who regain cognitive capacity and provide written consent or their LAR 
has given written consent if subjects do not regain cognitive capacity. No blood 
samples or data will be banked for those who withdraw from the study. 
4.
A limited data set will be uploaded to the edcCloudShare system. The 
edcCloudShare is a communication tool and vehicle used for secure and timely 
information exchange across participating centers. It is a proprietary service that 
operates locally on the Epidemiology Data Center's (EDC) LAN, and it is a subset 
of the University of Pittsburgh network. Several security features are utilized, 
such as named user accounts, user roles (i.e. Viewer/Reader, Editor/Manager, 
Owner/Administrator), and 2048-bit AES encryption to protect the privacy and 
confidentiality of the information being exchanged. The edcCloudShare system 
uses a Windows Server 2008 R2 Enterprise VM Server. It is protected by the 
University of Pittsburgh's enterprise firewall system in addition to a local firewall 
and Symantec Endpoint protection. Updates are applied as needed, and other 
updates are applied quarterly during the standard change management.The data 
destruction plan for paper and electronic data will be per COMIRB protocol.
5.
CRI Devices Data Collection
a.
Continuous waveform data will not contain any patient identifiers or 
protected health information (PHI).  Clinical data that is collected will 
be de-identified prior to data analysis. Data will be locked up and will 
only be accessed by members of the research team.  Data will be 
backed up to a secure server using secure transfer protocols such as 
the Secure Copy Protocol, which uses Secure Shell (SSH) for data 
transfer and utilizes the same mechanisms for authentication to ensure 
authenticity and confidentiality of the data in transit. 
b.
Paper documents (the case report forms and data collection sheets) 
will be locked up with the data collection equipment and will only be 


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 15
CF-146, Effective 4-26-2010
accessed by members of the research team.  The medical record 
number (MRN) will be written on one of these documents, but upon 
completion of these documents, the MRN will be blacked out to de-
identify the document and, thus, is confidential.  These documents will 
be scanned as PDF’s and uploaded to a secure server along with each 
subject’s waveform data.  
c.
The waveform data will be synchronized and subject to data analysis 
at a later time, looking specifically at waveform changes in response to 
fluid resuscitation types, rates and volumes, response to fluid therapy, 
types of injuries, operative timing and management, length of ICU and 
hospital stay, as well as survival.  These results will be compared to 
existing LBNP waveform data. LBNP is a laboratory model of human 
hemorrhage that redistributes intravascular volume to the pelvis and 
lower extremities, thereby inducing central hypovolemia
D.
Data Analysis 
1.
All analyses will be conducted using SAS for Windows vs. 9.3 (SAS Institute Inc., 
Cary NC, USA) on de-identified data.  Outcome and effect variables that are not 
normally distributed will be either categorized or analyzed using non-parametric 
methods.  Missing data will be managed during analysis using the method 
proposed by Sauaia et al.4
2.
Randomization effectiveness:  Effectiveness of randomization will be examined 
by comparing the two groups regarding demographic variables (age, gender), 
injury severity (Injury Severity Score, blunt versus penetrating mechanism), 
degree of shock (Field SBP, Field Heart rate, Field Hematocrit), and a field 
coagulation measure (Field INR). We will adjust all analyses of endpoints for the 
covariates showing different distribution (either statistically significant difference 
at p<0.05 or clinically significant difference as determined by the DSMB). 
Specifically, adjustment for these pre-specified, potential confounders will be 
performed using three different methods according to the type of endpoint: 
a.
Categorical variables: we will use multiple logistic regression 
(polytomous logistic regression will be used for non-binary variables);
b.
Continuous normally distributed endpoints: we will utilize mixed linear 
models to adjust for confounders, assuming an unstructured 
covariance structure. 
c.
Continuous non-normally distributed endpoints: if the endpoint is non-
normally distributed, we will attempt first to transform the variable to 
approximate normality (e.g., log transformation), and if this fails, we will 
resort to categorization based on previously determined, clinically 
relevant cutoffs.79-83
3.
Intent to treat analysis: primary and secondary outcome data will be collected 
in all patients regardless of treatment received.84 An “intent-to-treat” approach will 
be used for all primary/secondary outcome analyses, i.e., we will compare the 
outcomes of the two groups according to the group assignment at time of 
randomization, regardless of what treatment participants actually received. 
Phase 2 trial, this approach will allow a preliminary evaluation of the 


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 16
CF-146, Effective 4-26-2010
effectiveness of the proposed treatment (in addition to the efficacy assessment), 
since the health care of the subjects reflects the health care available to civilian 
trauma. More details are given in the sections describing statistical analysis as 
well as the missing data prevention and treatment.84 
In addition to the “intent to treat” approach, this study design also 
supports that exploratory analyses assess the association between the dose of 
plasma received in the field and the primary/secondary outcomes, an equivalent 
to the estimand  “Outcome Improvement in Tolerators” described by the  Panel 
on Handling Missing Data in Clinical Trials.84 This will provide information on 
possible “dose-response” patterns for Phase 3 trials. 
4.
Power analysis: Power analyses for each primary endpoint in Stage I and II 
were performed using Pass 11 (Hintze, J. (2011). PASS 11. NCSS, LLC. 
Kaysville, Utah, USA. www.ncss.com). All power analyses account for two 
interim analyses for a total of three sequential, equally spaced analyses, 
assuming attrition rates of 0%, 10%, and 20%. 
5.
Interim analyses: We planned 5 analyses (4 interim, 1 final), equally spaced, 
using the O’Brien-Fleming method to calculate two-sided boundaries, assuming a 
95% confidence and 80% power.  Spacing will be defined by number of enrolled 
patients. The first look at the data will be done when one third of the predicted 
total enrollment has been reached and all patients accrued have been observed 
for the total 28-day period or till death, whatever occurs earlier. The first interim 
analysis will be conducted when n=50, the second at n=100, the third at n=150, 
the fourth at n=200 and the final at end of the 5-year period of accrual.   
Boundaries will be used to declare a statistically significant difference 
between the two groups at an earlier stage without inflating the overall 
experiment errors. These interim analyses will be conducted by Dr. Sauaia and 
Dr. Chin using SAS vs. 9.3 data and reported to the DSMB, both in table format 
and in user-friendly graphs illustrating the test score, rejection and acceptance 
regions, as in the example below:  


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 17
CF-146, Effective 4-26-2010
At each interim stage, if the test statistic falls into a rejection zone, the 
null hypothesis may be rejected and the DSMB will use this as one of the criteria 
for recommending early interruption of the trial. Otherwise, the trial continues to 
the next stage. At the final stage, the null hypothesis is rejected if Z falls into a 
rejection region. Otherwise, the null hypothesis is not rejected. In the example 
illustrated in the figure, the test statistic does not fall into the rejection regions for 
looks 1 and 2, and so the trial continued to the final analysis 3 when the test 
statistic fell into the rejection region, and the null hypothesis was rejected. 
The results of the interim analyses described above will be just one of 
the criteria used by the DSMB to recommend early interruption of the trial as 
explained in more detailed later in this document. 
6.
Covariates for analysis:  Please see description of randomization effectiveness 
for more details.  
(Section IV.D.2) In brief, potential covariates include: 
demographic variables (age, gender), injury severity (Injury Severity Score, blunt 
versus penetrating mechanism), degree of shock (Field SBP, Field Heart rate, 
Field Hematocrit), and a field coagulation measure (Field INR). We will adjust the 
analyses of endpoints only for the above-mentioned covariates showing different 
distribution (either statistically significant difference at p<0.05 or clinically 
significant difference as determined by the DSMB).
7.
Waveform Data: We would like to collect more CRI data from very sick 
individuals to see how the algorithm captures their clinical presentation and 
resuscitation. We also want to see if a certain minimal CRI or low CRI for a 
period time triggers the acute coagulopathy of trauma. Just as other vital signs 
can be used to indicate certain medical conditions, we would analyze the data to 
see if the acute coagulopathy of trauma correlates with either a minimal CRI or 
low CRI for a certain period of time. We will also collate the CRI data with the 
clinical timeline of interventions, medications and fluids given.  This will help us 
correlate the effects of the interventions, medications and fluids with changes in 
CRI. 
a.
Data analytics will be used to analyze the waveform data in relation to 
fluid resuscitation types, rates and volumes, response to fluid therapy, 
types of injuries, operative timing and management, length of ICU and 
hospital stay, as well as overall outcomes. We will compare the 
waveform features from trauma patients to those features collected 
from research subjects with analogous levels of LBNP applied.
E.
Primary Study  Objectives and Endpoints
1.
Primary Study Objective: to determine the efficacy, as measured by 28-day 
mortality reduction, of using postinjury field-resuscitation with plasma first 
compared to standard of care (SOC). 
Primary Endpoint: 28-day mortality
a.
Definition: 28-day mortality is defined as death within 28 days post 
injury (death of any cause except for death due to a second, clearly 
unrelated traumatic injury suffered after discharge). Research 
coordinators will verify the vital status of all patients at day 28. Patients 


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 18
CF-146, Effective 4-26-2010
discharged home before day 28 will be reached using contact 
information obtained at discharge.  In case of transfer or discharge to 
another facility before day 28, research coordinators will coordinate 
with the other facility to ascertain vital status, verify contact information 
at discharge or determine patient disposition at day 28 postinjury
b.
Hypothesis: 28-day mortality will be significantly higher* in control 
patients compared to experimental patients.
c.
Statistical Analysis:  The Fisher Exact test will be use to compare 28-
day mortality in the two groups. Statistical significance will be 
determined according to the interim analyses procedures describe 
below. If adjustment for pre-defined confounders is needed, we will use 
the above-defined method for categorical, binary variables. 
d.
Interim analyses: We planned 5 analyses (4 interim, 1 final), equally 
spaced, using the O’Brien-Fleming method to calculate two-sided 
boundaries, assuming a 95% confidence and 80% power. All patients 
entered in each interim analyses will have complete data on 28-day 
mortality (i.e., the analyses will be conducted only once the 28-day 
observation period for all survivors have been completed). 
e.
Sample Size and Power: This is a Phase 2 trial and is powered to 
detect large (17 to 19 percent-point) differences in mortality between 
the two groups.  
Primary endpoint power calculations: 28-day mortality
Assumptions: 80% power, 95% confidence, 2-tailed test, P2=mortality in control group, P1=mortality in 
experimental group; 3 equally spaced data analyses, as determined by number of patients enrolled (2 
interim when 1/3 and 2/3 of the predicted sample or 20 and 40 patients were enrolled, and a final when 60 
to 75 patients were enrolled), using the O’Brien-Fleming method; control group 30-day mortality of 26% 
(based on control arm of ROC HS trial67) and three attrition rates (0, 10%, 20%)
Power
N1
N2
Alpha
Beta
P1
P2
Difference
Attrition 
Rate
0.800000
60
60
0.050000
0.200000
0.07
0.26
0.19
20%
0.800000
68
68
0.050000
0.200000
0.08
0.26
0.18
10%
0.800000
75
75
0.050000
0.200000
0.09
0.26
0.17
0%
Sample size of 60 and 60 achieves 80% power to detect a difference of 0.19 between the group 
proportions at a significance level (alpha) of 0.05 using a two-sided test. These results assume that 3 
sequential tests are made using the O'Brien-Fleming spending function to determine the test boundaries, 
as seen below.
Boundaries (Bndry) for data looks
Details when Spending = O'Brien-Fleming, N1 = 60, N2 =60, P1 = 0.07, P2 = 0.26
Lower
Upper
Nominal
Inc
Total
Inc
Total
* Although the hypothesis is worded as “higher”, all tests will be two-tailed to control for differences in 
either direction (higher or lower than the other group). 


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 19
CF-146, Effective 4-26-2010
Look
Bndry
Bndry
Alpha
Alpha
Alpha
Power
Power
1
-3.71030
3.71030
0.000207
0.000207
0.000207
0.018650
0.018650
2
-2.51142
2.51142
0.012025
0.011890
0.012097
0.398801
0.417451
3
-1.99302
1.99302
0.046259
0.037903
0.050000
0.382549
0.800000
Details when Spending = O'Brien-Fleming, N1 = 68, N2 =68, P1 = 0.08, P2 = 0.26
Lower
Upper
Nominal
Inc
Total
Inc
Total
Look
Bndry
Bndry
Alpha
Alpha
Alpha
Power
Power
1
-3.71030
3.71030
0.000207
0.000207
0.000207
0.018650
0.018650
2
-2.51142
2.51142
0.012025
0.011890
0.012097
0.398801
0.417451
3
-1.99302
1.99302
0.046259
0.037903
0.050000
0.382549
0.800000
Details when Spending = O'Brien-Fleming, N1 = 75, N2 =75, P1 = 0.09, P2 = 0.26
Lower
Upper
Nominal
Inc
Total
Inc
Total
Look
Bndry
Bndry
Alpha
Alpha
Alpha
Power
Power
1
-3.71030
3.71030
0.000207
0.000207
0.000207
0.018650
0.018650
2
-2.51142
2.51142
0.012025
0.011890
0.012097
0.398801
0.417451
3
-1.99302
1.99302
0.046259
0.037903
0.050000
0.382549
0.800000
Addendum Nov 16, 2016
At the second interim analyses, we had enrolled 100 patients (2/3 of the 150 total sample size), of 
whom 88 (12% attrition rate) patients were eligible for analysis (please, see Interim Analyses 
report for details). This attrition rate was similar to the lowest anticipated attrition rate (see first 
table above). Yet we noticed several important differences regarding the assumptions used to 
estimate the sample size. In brief, the cohort enrolled based on the entry criteria (field systolic 
blood pressure, SBP<70mmHg or SBP <90mmHg AND heart rate>108bpm) was less severely 
injured than anticipated (as measured by base deficit, INR and TEG G) and had lower mortality 
than anticipated. 
Variable
Anticipated (sample 
size/power analyses 
assumptions)
COMBAT 
group A
COMBAT 
group B
INR
1.47
1.32
1.38
INR>1.5
24% to 36%  *
18%
16%
Base deficit (mEq/L)
5.15
11.2
9.2
TEG G dynes/cm2
4.9
7.3
7.5
Mortality
26%
12%
13%
* {MacLeod, 2003 #1415;Maegele, 2007 #905;Niles, 2008 #4410}
In addition, a slightly lower proportion of patients required transfusions (55% of group A, 61% of 
group B) compared to our anticipated proportion based on trauma registry data encompassing 
the period of January 2009-December 2011 (3 years) and excluding patients who died within 10 
minutes of arriving at ED (64%). 
Although we enrolled a cohort with less physiologic and coagulation derangement than 
anticipated, which decreased our statistical power to detect differences in the primary and 
secondary outcomes, we detected some promising trends, as follows:
1) Group B experienced larger improvement in coagulopathy as measured by fibrinolysis from 
Field to ED (one of our secondary objectives, see below): as demonstrated by a repeated 
measures mixed linear model, the interaction between time and randomization approached 
significance, suggesting that group assignment modified the temporal trends of fibrinolysis as 


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 20
CF-146, Effective 4-26-2010
measured by rTEG Ly30. Limiting the model to patients who presented in the Field in severe 
shock further increased the significance. 
2) Toleration of longer time to RBC without any adverse event, which was another of our 
secondary objectives (an objective of major importance to the military, and consequently to our 
funder, the Dept. of Defense)
There seemed to be a difference in time from injury and from ED arrival to the first required RBC 
favoring group B, who tolerated longer time without increasing mortality or any other adverse 
event. A survival analysis, however, did not reach significance. 
More important, there has been no increase in adverse events or any suggestion of harm to 
enrollees and enrollment has been on target. 
Linear Models for Repeated Measures including only Field and ED times for TEGs
Model for LY30
ALL PATIENTS
SEVERE SHOCK ONLY
(Field SBP<=70mmHg)
Beta
SE
P-VALUE
Beta
SE
P-VALUE
Intercept
6.7484
2.8959
6.2593
3.7915
Time (ED, Field)
1.5018
2.9601
0.2528
4.9843
4.1149
0.5087
Randomization
(groups A, B)
3.3722
4.165
0.8321
7.0309
5.9547
0.9767
Randomization*time 
(Interaction)
-8.1625
4.4787
0.0721
-14.3628
6.5971
0.0348
Group A
Group B


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 21
CF-146, Effective 4-26-2010
There are several explanations for the differences in the expected and observed values. First, for 
the most common injury mechanisms, the case-fatality rate is decreasing in our trauma center 
(Sauaia et al. JAMA, 2016). Second, the wide use of TEG-guided hemostatic resuscitation in our 
institution has been associated with a dramatic decrease in post-injury mortality (Gonzalez, Ann 
Surg, 2016). In addition, our findings are not isolated. A recent multicenter RCT (Connelly et al., 
JAMA Surgery, 2016) also noted that the patients enrolled were less severely injured than 
anticipated based on previous experiences. Given the time required to establish such intense 
trials, usually one to two years, the assumptions used in the calculation of the sample size can 
understandably become outdated. This has prompted proposals of alternative designs for RCTs, 
such as adaptive and Bayesian RCTs as recently described by an NIH-funded workshop (Coffey 
et al. Clinical trials, 2012). 
Based on the explanations above, we propose a continuation of the trial to increase sample size 
and make it adequate to detect differences in the proposed outcomes (mortality, admission 
acidosis and coagulation, hemorrhage as well as requirement for blood products), as follows:
Hypothesis for primary endpoint above: 28-day mortality will be significantly higher in control 
patients compared to experimental patients.
With 80% power, 95% confidence and assuming 12% mortality rate in the control group (based 
on the second interim analyses data), with 5 interim analyses (4 interim and 1 final, of which 3 
already occurred), we will require 112 patients in each group (assuming the attrition rate 
observed in this RCT of 12%) to detect a difference of 10 percent points. This results in a total of 
224 patients, which corresponds to an increase of 74 patients over the current sample size of 150 
patients. See below the significance level for the 5 analyses. 
Spending = O'Brien-Fleming, N1 = 112, N2 =112, P1 = 0.12, P2 = 0.02, Continuity Correction.
Lower
Upper
Nominal
Inc
Total
Inc
Total
Look
Time
Bndry
Bndry
Alpha
Alpha
Alpha
Power
Power
1
0.20
-4.87688
4.87688
0.000
0.000
0.000
0.00015
0.000
2
0.40
-3.35695
3.35695
0.001
0.001
0.001
0.05885
0.059
3
0.60
-2.68026
2.68026
0.007
0.007
0.008
0.25750
0.317
4
0.80
-2.28979
2.28979
0.022
0.017
0.024
0.28890
0.605
5
1.00
-2.03100
2.03100
0.042
0.026
0.050
0.19460
0.800
Hypothesis 5: Admission clot strength (as measured by TEG G) will be significantly lower in 
control patients compared to experimental group patients
With 80% power, 95% confidence and assuming mean admission TEG G = 7 dynes/cm2 with 
standard deviation of 3 in the control group (based on the second interim analyses data), with 5 
interim analyses (4 interim and 1 final, of which 3 already occurred), we will require 112 patients 
in each group (assuming the attrition rate observed in this RCT of 12%) to detect a difference of 
1.1 dynes/cm2 (from 7 to 5.9 dynes/cm2) between the two mean TEG Gs. This results in a total of 
224, which corresponds to an increase of 74 patients over the current sample size of 150 
patients.
F.
Secondary Study Objectives and Endpoints
1.
Secondary Objective 1: To determine the efficacy of postinjury field –
resuscitation with plasma first compared to the current standard of care on 


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 22
CF-146, Effective 4-26-2010
decreasing the incidence of adverse outcomes (as measured by a composite 
outcome including multiple organ failure and/or 28-day death). 
Secondary Endpoint 1:  Composite outcome of 28-day in-hospital mortality and 
postinjury multiple organ failure (MOF) incidence 
a.
Definition: This outcome is defined as the occurrence of in-hospital 
death or MOF within the first 28 days postinjury. MOF is defined using 
the validated Denver MOF score (Denver MOF score>3 of 
simultaneously obtained scores after 48 hours postinjury).80 Postinjury 
MOF remains the leading cause of late death among trauma patients, 
thus having a strong association with mortality.85 
b.
Hypothesis 1: The incidence of the composite outcome (28-day in-
hospital death or MOF) will be significantly higher† in control patients 
compared to experimental group patients.
c.
Statistical Analysis:  Fisher Exact Test will be used to compare the 
incidence of this composite outcome in the two groups. Statistical 
significance will be determined according to the interim analyses 
procedures describe below. If adjustment for the pre-defined 
confounders (see Randomization Effectiveness in Section IV.D.2) is 
needed, we will use the above-defined method for categorical, binary 
variables. 
d.
Interim analyses: We planned 5 analyses (4 interim, 1 final), equally 
spaced, using the O’Brien-Fleming method to calculate two-sided 
boundaries, assuming a 95% confidence and 80% power. All patients 
entered in each interim analyses will have complete data on 28-day 
outcomes (i.e., the analyses will be conducted only once the 28-day 
observation period for all survivors have been completed).
e.
Sample size and Power calculations: This is a Phase 2 trial, 
powered to detect differences in this outcome as follows:
Power calculations: composite 28-day in-hospital death or MOF incidence 
Assumptions 1: 80% power, 95% confidence, 2-tailed test, 3 equally spaced data analyses (2 interim, 1 
final), using the O’Brien-Fleming method; control group 28-day composite outcome of mortality or MOF of 
46% (based on control arm of ROC HS trial67 and Denver MOF database data from 2005-2008).
Power
N1
N2
Alpha
Beta
P1
P2
Difference
Attrition Rate
0.800000
60
60
0.050000
0.200000
0.22
0.46
0.24
20%
0.800000
68
68
0.050000
0.200000
0.23
0.46
0.23
10%
0.800000
75
75
0.050000
0.200000
0.24
0.46
0.22
0
Sample sizes of 60 and 60 achieve 80% power to detect a difference of 0.24 between the group proportions of 0.22 
and 0.46 at a significance level (alpha) of 0.05 using a two-sided test. These results assume that 3 sequential tests are 
made using the O'Brien-Fleming spending function to determine the test boundaries.
Boundaries (Bndry) for data looks 
Details when Spending = O'Brien-Fleming, N1 = 60, N2 =60, P1 = 0.22, P2 = 0.46
Lower
Upper
Nominal
Inc
Total
Inc
Total
† Although the hypothesis is worded as “higher”, all tests will be two-tailed to control for differences in 
either direction (higher or lower than the other group).


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 23
CF-146, Effective 4-26-2010
Look
Bndry
Bndry
Alpha
Alpha
Alpha
Power
Power
1
-3.71030
3.71030
0.000207
0.000207
0.000207
0.018650
0.018650
2
-2.51142
2.51142
0.012025
0.011890
0.012097
0.398801
0.417451
3
-1.99302
1.99302
0.046259
0.037903
0.050000
0.382549
0.800000
Details when Spending = O'Brien-Fleming, N1 = 68, N2 =68, P1 = 0.23, P2 = 0.46
Lower
Upper
Nominal
Inc
Total
Inc
Total
Look
Bndry
Bndry
Alpha
Alpha
Alpha
Power
Power
1
-3.71030
3.71030
0.000207
0.000207
0.000207
0.018650
0.018650
2
-2.51142
2.51142
0.012025
0.011890
0.012097
0.398801
0.417451
3
-1.99302
1.99302
0.046259
0.037903
0.050000
0.382549
0.800000
Details when Spending = O'Brien-Fleming, N1 = 75, N2 =75, P1 = 0.24, P2 = 0.46
Lower
Upper
Nominal
Inc
Total
Inc
Total
Look
Bndry
Bndry
Alpha
Alpha
Alpha
Power
Power
1
-3.71030
3.71030
0.000207
0.000207
0.000207
0.018650
0.018650
2
-2.51142
2.51142
0.012025
0.011890
0.012097
0.398801
0.417451
3
-1.99302
1.99302
0.046259
0.037903
0.050000
0.382549
0.800000
Addendum November 16, 2016
Using the results of the first and second interim analyses, a new calculation for the sample size 
demonstrates: with 80% power, 95% confidence and assuming a 14% rate of the composite 
outcome in the control group (based on the second interim analyses data), with 5 interim 
analyses (4 interim and 1 final, of which 3 already occurred), we will require 112 patients in each 
group (assuming the attrition rate observed in this RCT of 12%) to detect a difference of 11 
percent points. This results in a total of 224 patients, which corresponds to an increase of 74 
patients over the current sample size of 150 patients. 
2.
Secondary Objective 2: To determine if early administration of plasma in the 
field will improve the incidence of early postinjury coagulopathy on admission 
compared to the current standard of care. 
Secondary Endpoint 2:   Admission coagulopathy.  This is an endpoint for 
which there is ample evidence of a strong association with mortality.11, 86, 87
a.
Definition: Admission coagulopathy will be measured by the 
admission international normalized ratio for pro-thrombin time (INR). 
INR will be defined as the first INR obtained upon ED arrival. The 
target time point is 30 minutes after ambulance arrival to injury scene. 
Our institution’s average time from arrival of ambulance to scene till 
arrival in ED is 28 minutes 88. INR obtained more than 60 minutes from 
arrival of ambulance to scene will not be used as the endpoint.
b.
Hypothesis 2.1: Admission INR will be significantly higher‡ in control 
patients compared to experimental group patients.
c.
Statistical test 2.1: Linear regression will be used to compare the 
mean admission INR of the two groups. Statistical significance will be 
determined according to the interim analyses procedures describe 
‡ Although the hypothesis is worded as “higher”, all tests will be two-tailed to control for differences in 
either direction (higher or lower than the other group).


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 24
CF-146, Effective 4-26-2010
below. If adjustment for pre-defined confounders is needed, we will use 
the above-defined method for continuous, normally distributed 
variables.
d.
Sample size and Power calculations: This is a Phase 2 trial, 
powered to detect differences in this outcome as follows:
Addendum November 16, 2016
Based on the interim analyses, a proposed new sample size is: with 80% power, 95% confidence 
and assuming mean admission INR = 1.32 with standard deviation of 0.5 in the control group 
(based on the second interim analyses data), with 5 interim analyses (4 interim and 1 final, of 
which 3 already occurred), we will require 112 patients in each group (assuming the attrition rate 
observed in this RCT of 12%) to detect a difference of 0.19 (from 1.32 to 1.13) between the two 
mean INRs. This results in a total of 224, which corresponds to an increase of 74 patients over 
the current sample size of 150 patients. 
Power calculations: Admission INR
Assumptions 1: 80% power, 95% confidence, 2-tailed test, 3 equally spaced data analyses (2 interim, 1 
final), using the O’Brien-Fleming method; control group mean admission INR=1.47 and standard 
deviation (SD) =1.0 (based on ROC trial control arm67).
Power
N1
N2
Alpha
Beta
Mean 1
Mean 2
SD
Difference
Attrition Rate
0.800000
60
60
0.050000
0.200000
1.50
1.00
1.00
0.50
20%
0.800000
68
68
0.050000
0.200000
1.50
1.02
1.00
0.48
10%
0.800000
75
75
0.050000
0.200000
1.50
1.04
1.00
0.46
0
Sample sizes of 60 and 60 achieve 80% power to detect a difference of 0.50 between the two means, a clinically 
relevant difference, at a significance level (alpha) of 0.05 using a two-sided test. These results assume that 3 
sequential tests are made using the O'Brien-Fleming spending function to determine the test boundaries.
Boundaries (Bndry) for data looks
Details when Spending = O'Brien-Fleming, N1 = 60, N2 =60, S1 = 1.00, S2 = 1.00, Diff = 0.50
Lower
Upper
Nominal
Inc
Total
Inc
Total
Look
Bndry
Bndry
Alpha
Alpha
Alpha
Power
Power
1
-3.71030
3.71030
0.000207
0.000207
0.000207
0.018650
0.018650
2
-2.51142
2.51142
0.012025
0.011890
0.012097
0.398801
0.417451
3
-1.99302
1.99302
0.046259
0.037903
0.050000
0.382549
0.800000
Details when Spending = O'Brien-Fleming, N1 = 68, N2 =68, S1 = 1.00, S2 =1.00 , Diff = 0.48
Lower
Upper
Nominal
Inc
Total
Inc
Total
Look
Bndry
Bndry
Alpha
Alpha
Alpha
Power
Power
1
-3.71030
3.71030
0.000207
0.000207
0.000207
0.018650
0.018650
2
-2.51142
2.51142
0.012025
0.011890
0.012097
0.398801
0.417451
3
-1.99302
1.99302
0.046259
0.037903
0.050000
0.382549
0.800000
Details when Spending = O'Brien-Fleming, N1 = 75, N2 =75, S1 = 1.00, S2 = 1.00, Diff = 0.46
Lower
Upper
Nominal
Inc
Total
Inc
Total
Look
Bndry
Bndry
Alpha
Alpha
Alpha
Power
Power
1
-3.71030
3.71030
0.000207
0.000207
0.000207
0.018650
0.018650
2
-2.51142
2.51142
0.012025
0.011890
0.012097
0.398801
0.417451
3
-1.99302
1.99302
0.046259
0.037903
0.050000
0.382549
0.800000


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 25
CF-146, Effective 4-26-2010
e.
Hypothesis 2.2: The incidence of admission coagulopathy as 
measured by INR>1.5 will be significantly higher§ in control patients 
compared to experimental group patients. 
f.
Statistical test 2.2: Logistic regression will be used to compare the 
incidence of admission coagulopathy between the two groups. 
Statistical significance will be determined according to the interim 
analyses procedures describe below. If adjustment for pre-defined 
confounders is needed, we will use the above-defined method for 
categorical, binary variables. 
g.
Sample size and Power calculations: this is a Phase 2 trial, powered 
to detect differences in this outcome as follows:
Power calculations: Admission coagulopathy
Assumptions 1: 80% power, 95% confidence, 2-tailed test, 3 equally spaced data analyses (2 interim, 1 
final), using the O’Brien-Fleming method; control group admission coagulopathy incidence 24%, 28% and 
36% (based on  11, 86, 87).
Power
N1
N2
Alpha
Beta
P1
P2
Difference
Attrition Rate
0.800000
60
60
0.050000
0.200000
0.06
0.24
0.18
20%
0.800000
68
68
0.050000
0.200000
0.07
0.24
0.17
10%
0.800000
75
75
0.050000
0.200000
0.07
0.24
0.17
0
0.800000
60
60
0.050000
0.200000
0.08
0.28
0.18
20%
0.800000
68
68
0.050000
0.200000
0.09
0.28
0.17
10%
0.800000
75
75
0.050000
0.200000
0.10
0.28
0.16
0
0.800000
60
60
0.050000
0.200000
0.14
0.36
0.22
20%
0.800000
68
68
0.050000
0.200000
0.15
0.36
0.21
10%
0.800000
75
75
0.050000
0.200000
0.16
0.36
0.20
0
Sample sizes of 60 and 60 achieve 80% power to detect a difference of 0.18 between the group proportions at a 
significance level (alpha) of 0.05 using a two-sided test. These results assume that 3 sequential tests are made using 
the O'Brien-Fleming spending function to determine the test boundaries.
Boundaries (Bndry) for data looks (worst case scenario)
Details when Spending = O'Brien-Fleming, N1 = 60, N2 =60, P1 = 0.14, P2 = 0.36
Lower
Upper
Nominal
Inc
Total
Inc
Total
Look
Bndry
Bndry
Alpha
Alpha
Alpha
Power
Power
1                       -3.71030
3.71030
0.000207
0.000207
0.000207
0.018650
0.018650
2
-2.51142
2.51142
0.012025
0.011890
0.012097
0.398801
0.417451
3
-1.99302
1.99302
0.046259
0.037903
0.050000
0.382549
0.800000
Details when Spending = O'Brien-Fleming, N1 = 68, N2 =68, P1 = 0.15, P2 = 0.36
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
0.018650
0.018650
2
0.67
-2.51142
2.51142
0.012025
0.011890
0.012097
0.398801
0.417451
3
1.00
-1.99302
1.99302
0.046259
0.037903
0.050000
0.382549
0.800000
Details when Spending = O'Brien-Fleming, N1 = 75, N2 =75, P1 = 0.16, P2 = 0.36
Lower
Upper
Nominal
Inc
Total
Inc
Total
Look
Bndry
Bndry
Alpha
Alpha
Alpha
Power
Power
1
-3.71030
3.71030
0.000207
0.000207
0.000207
0.018650
0.018650
2
-2.51142
2.51142
0.012025
0.011890
0.012097
0.398801
0.417451
3
-1.99302
1.99302
0.046259
0.037903
0.050000
0.382549
0.800000
§ Although the hypothesis is worded as “higher”, all tests will be two-tailed to control for differences in 
either direction (higher or lower than the other group).


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 26
CF-146, Effective 4-26-2010
Addendum November 16, 2016
Based on the interim analyses, a proposed new sample size is: with 80% power, 95% confidence 
and assuming a 18% rate of INR>1.5 in the control group (based on the second interim analyses 
data), with 5 interim analyses (4 interim and 1 final, of which 3 already occurred), we will require 
112 patients in each group (assuming the attrition rate observed in this RCT of 12%) to detect a 
difference of 13 percent points. This results in a total of 224 patients, which corresponds to an 
increase of 74 patients over the current sample size of 150 patients.
3.
Secondary Objective 3: To determine if early administration of plasma in the 
field will improve postinjury clot strength upon admission compared to the current 
standard of care. 
Secondary Endpoint 3: Admission clot strength. This is an endpoint for which 
there is evidence of association with postinjury mortality, coagulopathy and use 
of blood products 79, 83, 89, 90.    
a.
Definition: 
Admission 
clot 
strength 
will 
be 
measured 
by 
thrombelastography G-value upon ED arrival. The target time point 
is 30 minutes after ambulance arrival to injury scene. Our institution’s 
average time from arrival of ambulance to scene till arrival in ED is 28 
minutes.88 If value is obtained more than 60 minutes from arrival of 
ambulance to scene, it will not be used to define the endpoint. 
b.
Hypothesis 3.1: Admission clot strength will be significantly lower** in 
control patients compared to experimental group patients.
c.
Statistical test 3.1: Multiple linear regression will be used to compare 
the mean clot strength in the two groups. Statistical significance will be 
determined according to the interim analyses procedures describe 
below. If adjustment for pre-defined confounders is needed, we will use 
the above-defined method for continuous, normally distributed 
variables.
d.
Interim analyses: We planned 5 analyses (4 interim, 1 final), equally 
spaced, using the O’Brien-Fleming method to calculate two-sided 
boundaries, assuming a 95% confidence and 80% power. 
e.
Sample size and Power calculations: This is a Phase 2 trial, 
powered to detect differences in this outcome as follows:
** Although the hypothesis is worded as “lower”, all tests will be two-tailed to control for differences in 
either direction (higher or lower than the other group).
Power calculations: Admission Clot Strength (TEG G-Value)
Assumptions 1: 80% power, 95% confidence, 2-tailed test, 3 equally spaced data analyses (2 interim, 1 
final), using the O’Brien-Fleming method; control group admission clot strength (based on Pezold et al. 
83).
Power
N1
N2
Alpha
Beta
P1
P2
S1
S2
Difference
Attrition 
Rate
0.800000
60
60
0.050000
0.200000
4.90
3.72
2.30
2.30
1.18
20%
0.800000
68
68
0.050000
0.200000
4.90
3.79
2.30
2.30
1.11
10%
0.800000
75
75
0.050000
0.200000
4.90
3.84
2.30
2.30
1.06
0
Sample sizes of 60 and 60 achieve 80% power to detect a difference of 1.18 dynes/cm2 between the two groups, 


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 27
CF-146, Effective 4-26-2010
f.
Hypothesis 3.2: The incidence of admission high clot strength defined 
as TEG G-value>5.0 dynes/cm2 will be significantly lower†† in control 
patients compared to experimental group patients.
g.
Statistical test 3.1: Multiple logistic regression will be used to 
compare the incidence of high clot strength (TEG G-value 
>5.0dynes/cm2) in the two groups. Statistical significance will be 
determined according to the interim analyses procedures describe 
below. If adjustment for pre-defined confounders is needed, we will use 
the above-defined method for continuous, normally distributed 
variables.
h.
Interim analyses: We planned 5 analyses (4 interim, 1 final), equally 
spaced, using the O’Brien-Fleming method to calculate two-sided 
boundaries, assuming a 95% confidence and 80% power.
i.
Sample size and Power calculations: This is a Phase 2 trial, 
powered to detect differences in this outcome as follows:
†† Although the hypothesis is worded as “lower”, all tests will be two-tailed to control for differences in 
either direction (higher or lower than the other group).
which is smaller than a clinically relevant difference based on previous clinical trials aiming at addressing early 
postinjury coagulopathy 79, 89, 90 at a significance level (alpha) of 0.05 using a two-sided test. These results assume 
that 3 sequential tests are made using the O'Brien-Fleming spending function to determine the test boundaries.
Boundaries (Bndry) for data looks 
Details when Spending = O'Brien-Fleming, N1 = 60, N2 =60, S1 = 2.30, S2 = 2.30, Diff=1.18
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
0.018650
0.018650
2
0.67
-2.51142
2.51142
0.012025
0.011890
0.012097
0.398801
0.417451
3
1.00
-1.99302
1.99302
0.046259
0.037903
0.050000
0.382549        0.800000
Details when Spending = O'Brien-Fleming, N1 = 68, N2 =68, S1 = 2.30, S2 = 2.30, Diff=1.11
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
0.018650
0.018650
2
0.67
-2.51142
2.51142
0.012025
0.011890
0.012097
0.398801
0.417451
3
1.00
-1.99302
1.99302
0.046259
0.037903
0.050000
0.382549
0.800000
Details when Spending = O'Brien-Fleming, N1 = 75, N2 =75, S1=2.30, S2 = 2.30, Diff=1.06
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
0.018650
0.018650
2
0.67
-2.51142
2.51142
0.012025
0.011890
0.012097
0.398801
0.417451
3
1.00
-1.99302
1.99302
0.046259
0.037903
0.050000
0.382549
0.800000
Power calculations: Admission High Clot Strength (TEG G-value>5dynes/cm2)
Assumptions 1: 80% power, 95% confidence, 2-tailed test, 3 equally spaced data analyses (2 interim, 1 
final), using the O’Brien-Fleming method; control group admission acidosis (based on 83).
Power
N1
N2
Alpha
Beta
P1
P2
Difference
Attrition Rate
0.800000
60
60
0.050000
0.200000
0.25
0.50
0.25
20%
0.800000
68
68
0.050000
0.200000
0.27
0.50
0.23
10%
0.800000
75
75
0.050000
0.200000
0.28
0.50
0.22
0


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 28
CF-146, Effective 4-26-2010
Addendum November 16, 2016
Based on the interim analyses, a proposed new sample size is: with 80% power, 95% confidence 
and assuming mean admission TEG G = 7 dynes/cm2 with standard deviation of 3 in the control 
group (based on the second interim analyses data), with 5 interim analyses (4 interim and 1 final, 
of which 3 already occurred), we will require 112 patients in each group (assuming the attrition 
rate observed in this RCT of 12%) to detect a difference of 1.1 dynes/cm2 (from 7 to 5.9 
dynes/cm2) between the two mean TEG Gs. This results in a total of 224, which corresponds to 
an increase of 74 patients over the current sample size of 150 patients.
4.
Secondary Objective 4: To determine if early administration of plasma in the 
field will improve the incidence of early postinjury acidosis compared to the 
current standard of care. 
Secondary Endpoint 4:  Admission acidosis. This is an endpoint for which 
there is ample evidence of a strong association of postinjury mortality and 
serious complications. 91-100
a.
Definition: Admission acidosis will be defined through base deficit 
(BD) or lactate levels upon ED arrival. The target time point is 30 
minutes after ambulance arrival to injury scene. Our institution’s 
average time from arrival of ambulance to scene till arrival in ED is 28 
minutes. 88 If both base deficit and lactate are obtained more than 60 
minutes from arrival of ambulance to scene, they will not be used to 
define the endpoint.
Sample sizes of 60 and 60 achieve 80% power to detect a difference of 0.25 between the group proportions at a 
significance level (alpha) of 0.050000 using a two-sided test. These results assume that 3 sequential tests are made 
using the O'Brien-Fleming spending function to determine the test boundaries.
Boundaries (Bndry) for data looks 
Details when Spending = O'Brien-Fleming, N1 = 60, N2 =60, P1 = 0.25, P2 = 0.50
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
0.018650
0.018650
2
0.67
-2.51142
2.51142
0.012025
0.011890
0.012097
0.398801
0.417451
3
1.00
-1.99302
1.99302
0.046259
0.037903
0.050000
0.382549
0.800000
Details when Spending = O'Brien-Fleming, N1 = 68, N2 =68, P1 = 0.27, P2 = 0.50
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
0.018650
0.018650
2
0.67
-2.51142
2.51142
0.012025
0.011890
0.012097
0.398801
0.417451
3
1.00
-1.99302
1.99302
0.046259
0.037903
0.050000
0.382549
0.800000
     
Details when Spending = O'Brien-Fleming, N1 = 75, N2 =75, P1 = 0.28, P2 = 0.50
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
0.018650
0.018650
2
0.67
-2.51142
2.51142
0.012025
0.011890
0.012097
0.398801
0.417451
3
1.00
-1.99302
1.99302
0.046259
0.037903
0.050000
0.382549
0.800000


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 29
CF-146, Effective 4-26-2010
b.
Hypothesis 4.1: Admission BD will be higher‡‡ among control patients 
compare to the experimental group patients.
c.
Statistical test 4.1: Linear regression will be used to compare the 
mean admission base deficit of the two groups. Statistical significance 
will be determined according to the interim analyses procedures 
describe below. If adjustment for pre-defined confounders is needed, 
we will use the above-defined method for continuous, normally 
distributed variables.
d.
Interim analyses: We planned 5 analyses (4 interim, 1 final), equally 
spaced, using the O’Brien-Fleming method to calculate two-sided 
boundaries, assuming a 95% confidence and 80% power.
e.
Sample size and Power calculations: This is a Phase 2 trial, 
powered to detect differences in this outcome as follows:
Power calculations: Admission Base Deficit
Assumptions 1: 80% power, 95% confidence, 2-tailed test, 3 equally spaced data analyses (2 interim, 1 
final), using the O’Brien-Fleming method; control group mean admission BD=5.15 and standard 
deviation (SD) =5.1 (based on92)
Power
N1
N2
Alpha
Beta
Mean 1
Mean 2
SD
Difference
Attrition Rate
0.800000
60
60
0.050000
0.200000
5.15
2.52
5.10
2.63
20%
0.800000
68
68
0.050000
0.200000
5.15
2.68
5.10
2.47
10%
0.800000
75
75
0.050000
0.200000
5.15
2.80
5.10
2.35
0
Sample sizes of 60 and 60 achieve 80% power to detect a difference of 2.63 between the two means, a clinically 
relevant difference, at a significance level (alpha) of 0.05 using a two-sided test. These results assume that 3 
sequential tests are made using the O'Brien-Fleming spending function to determine the test boundaries.
Boundaries (Bndry) for data looks
Details when Spending = O'Brien-Fleming, N1 = 60, N2 =60, S1 = 5.10, S2 = 5.10, Diff = 2.63
Lower
Upper
Nominal
Inc
Total
Inc
Total
Look
Bndry
Bndry
Alpha
Alpha
Alpha
Power
Power
1
-3.71030
3.71030
0.000207
0.000207
0.000207
0.018650
0.018650
2
-2.51142
2.51142
0.012025
0.011890
0.012097
0.398801
0.417451
3
-1.99302
1.99302
0.046259
0.037903
0.050000
0.382549
0.800000
Details when Spending = O'Brien-Fleming, N1 = 68, N2 =68, S1 = 5.10, S2 = 5.10, Diff = 2.47
Lower
Upper
Nominal
Inc
Total
Inc
Total
Look
Bndry
Bndry
Alpha
Alpha
Alpha
Power
Power
1
-3.71030
3.71030
0.000207
0.000207
0.000207
0.018650
0.018650
2
-2.51142
2.51142
0.012025
0.011890
0.012097
0.398801
0.417451
3
-1.99302
1.99302
0.046259
0.037903
0.050000
0.382549
0.800000
Details when Spending = O'Brien-Fleming, N1 = 75, N2 =75, S1 = 5.10, S2 = 5.10, Diff = 2.35
Lower
Upper
Nominal
Inc
Total
Inc
Total
Look
Bndry
Bndry
Alpha
Alpha
Alpha
Power
Power
1
-3.71030
3.71030
0.000207
0.000207
0.000207
0.018650
0.018650
2
-2.51142
2.51142
0.012025
0.011890
0.012097
0.398801
0.417451
3
-1.99302
1.99302
0.046259
0.037903
0.050000
0.382549
0.800000
‡‡ Although the hypothesis is worded as “higher”, all tests will be two-tailed to control for differences in 
either direction (higher or lower than the other group).


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 30
CF-146, Effective 4-26-2010
Addendum November 16, 2016
Based on the interim analyses, a proposed new sample size is: with 80% power, 95% confidence 
and assuming mean admission BD = 11mEq/L with standard deviation of 6.3 in the control group 
(based on the second interim analyses data), with 5 interim analyses (4 interim and 1 final, of 
which 3 already occurred), we will require 112 patients in each group (assuming the attrition rate 
observed in this RCT of 12%) to detect a difference of 2mEq/L (from 11 to 9mEq/L) between the 
two mean BDs. This results in a total of 224, which corresponds to an increase of 74 patients 
over the current sample size of 150 patients. 
f.
Hypothesis 4.2: Admission lactate will be higher§§ among control 
patients compare to the experimental group patients. Statistical test 
3.2: Linear regression will be used to compare the mean admission 
lactate of the two groups. Statistical significance will be determined 
according to the interim analyses procedures describe below. If 
adjustment for pre-defined confounders is needed, we will use the 
above-defined method for continuous, normally distributed variables. 
g.
Interim analyses: We planned 5 analyses (4 interim, 1 final), equally 
spaced, using the O’Brien-Fleming method to calculate two-sided 
boundaries, assuming a 95% confidence and 80% power.
h.
Sample size and Power calculations: This is a Phase 2 trial, 
powered to detect differences in this outcome as follows:
Power calculations: Admission Lactate
Assumptions 1: 80% power, 95% confidence, 2-tailed test, 3 equally spaced data analyses (2 interim, 1 
final), using the O’Brien-Fleming method; control group mean admission lactate=2.0 mmol/L and 
standard deviation (SD) =2.0 (based on 67, 81, 91)
Power
N1
N2
Alpha
Beta
Mean 1
Mean 2
SD
Difference
Attrition Rate
0.800000
60
60
0.050000
0.200000
2.00
0.97
2.00
1.03
20%
0.800000
68
68
0.050000
0.200000
2.00
1.03
2.00
0.97
10%
0.800000
75
75
0.050000
0.200000
2.00
1.08
2.00
0.92
0
Sample sizes of 60 and 60 achieve 80% power to detect a difference of 1.03 mmol/L between the two means, a 
clinically relevant difference, at a significance level (alpha) of 0.05 using a two-sided test. These results assume 
that 3 sequential tests are made using the O'Brien-Fleming spending function to determine the test boundaries.
Boundaries (Bndry) for data looks
Details when Spending = O'Brien-Fleming, N1 = 60, N2 =60, S1 = 2.00, S2 = 2.00, Diff = 1.03
Lower
Upper
Nominal
Inc
Total
Inc
Total
Look
Bndry
Bndry
Alpha
Alpha
Alpha
Power
Power
1
-3.71030
3.71030
0.000207
0.000207
0.000207
0.018650
0.018650
2
-2.51142
2.51142
0.012025
0.011890
0.012097
0.398801
0.417451
3
-1.99302
1.99302
0.046259
0.037903
0.050000
0.382549
0.800000
Details when Spending = O'Brien-Fleming, N1 = 68, N2 =68, S1 = 2.00, S2 = 2.00, Diff = 0.97
§§ Although the hypothesis is worded as “higher”, all tests will be two-tailed to control for differences in 
either direction (higher or lower than the other group).


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 31
CF-146, Effective 4-26-2010
Lower
Upper
Nominal
Inc
Total
Inc
Total
Look
Bndry
Bndry
Alpha
Alpha
Alpha
Power
Power
1
-3.71030
3.71030
0.000207
0.000207
0.000207
0.018650
0.018650
2
-2.51142
2.51142
0.012025
0.011890
0.012097
0.398801
0.417451
3
-1.99302
1.99302
0.046259
0.037903
0.050000
0.382549
0.800000
Details when Spending = O'Brien-Fleming, N1 = 75, N2 =75, S1 = 2.00, S2 = 2.00, Diff = 0.92
Lower
Upper
Nominal
Inc
Total
Inc
Total
Look
Bndry
Bndry
Alpha
Alpha
Alpha
Power
Power
1
-3.71030
3.71030
0.000207
0.000207
0.000207
0.018650
0.018650
2
-2.51142
2.51142
0.012025
0.011890
0.012097
0.398801
0.417451
3
-1.99302
1.99302
0.046259
0.037903
0.050000
0.382549
0.800000
Addendum November 16, 2016
Based on the interim analyses, a proposed new sample size is: with 80% power, 95% confidence 
and assuming mean admission lactate=5 mg/dL with standard deviation of 2 in the control group 
(based on the second interim analyses data), with 5 interim analyses (4 interim and 1 final, of 
which 3 already occurred), we will require 112 patients in each group (assuming the attrition rate 
observed in this RCT of 12%) to detect a difference of 1 mg/dL between the two mean lactates. 
This results in a total of 224, which corresponds to an increase of 74 patients over the current 
sample size of 150 patients.
G. Exploratory analyses
1.
Exploratory analysis 1: 24-hour mortality Based on the control arm of the 
recent ROC trial67 and our trauma registry data, the control group 24-hours 
mortality is estimated to be between 19% and 26%.
a.
Definition: 24-hours mortality is defined as death within 24 hours post 
injury (death of any cause). Research coordinators will verify the vital 
status of all patients 24 hours postinjury and determine the time of 
death in relationship to injury. 
b.
Hypothesis: 24-hour mortality will be significantly higher*** in control 
patients compared to experimental group patients.
c.
Statistical test: Logistic regression will be used to compare the 24-
hour mortality in the two groups. Statistical significance will be 
evaluated at each interim analyses for the primary outcomes and p-
values, as well as 95% and 99% confidence intervals will be reported 
to the DSMB for analyses. If adjustment for pre-defined confounders is 
needed, we will use the above-defined method for categorical, binary 
variables. Time from injury to death will be evaluated using the Kaplan 
Meyer curves, which will be compared using SAS PROC LIFETEST. 
We will use the Wilcoxon test (which places more weight on shorter 
survival times) and the log-rank test (which privileges longer survival 
times). SAS PROC LIFETEST also constructs statistics to test for 
*** Although the hypothesis is worded as “lower”, all tests will be two-tailed to control for differences in 
either direction (higher or lower than the other group).


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 32
CF-146, Effective 4-26-2010
association between covariates and the lifetime variable through rank 
tests for the association of survival time with covariates, if there are 
potential confounders detected using the above-described procedures.
2.
Pre-planned subgroup analyses:
a.
Blunt trauma mechanism: There is evidence to suggest that the 
coagulation and inflammatory responses to injury differ by trauma 
mechanism, as they cause different tissue damage.101, 102
1.
Hypothesis: Blunt trauma patients will have different effect sizes 
than penetrating trauma victims regarding the primary endpoint 
and secondary endpoints
2.
Statistical tests: Same tests described for primary and 
secondary endpoints stratified by mechanism of injury (blunt vs. 
penetrating). We will compare the 95% confidence intervals to 
determine overlap between the blunt and penetrating groups for 
each endpoint.
b.
Absence vs. presence of serious traumatic brain injury (TBI): 
there is evidence to suggest a differential coagulation and 
inflammatory response by the presence of TBI.101, 103, 104
1.
Hypothesis: 
Patients 
with 
associated 
TBI 
(defined 
as 
Abbreviated Injury Score, AIS, for Head >3) will have different 
effect sizes than their counterparts without TBI regarding the 
primary endpoint and secondary endpoints.
2.
Statistical tests: Same tests described for primary and 
secondary endpoints stratified by presence of TBI. We will 
compare the 95% confidence intervals to determine overlap 
between the two groups for each endpoint.
c.
Presence of very severe hemorrhagic shock (HS, defined as 
SBP≤70 mmHg) versus severe HS (defined as SBP 71-90mmHg + 
Heart rate>=108bpm): There is evidence that the patients with very 
severe HS shock are more likely to require massive transfusion and 
present severe coagulopathy, thus potentially having differential 
mortality.105
1.
Hypothesis: Patients with very severe hemorrhagic shock 
(defined as SBP≤70mmHg) will have different effect sizes than 
their counterparts with severe hemorrhagic shock (defined as 
SBP 71-90mmHg +heart rate>=108bpm) regarding the primary 
endpoint and secondary endpoints.
2.
Statistical tests: Same tests described for primary and 
secondary endpoints stratified by degree of hemorrhagic shock. 
We will compare the 95% confidence intervals to determine 
overlap between the two groups for each endpoint. Overall 
experiment error will be adjusted for the number of subgroups 
being analyzed using the Bonferroni method.


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 33
CF-146, Effective 4-26-2010
3.
Adverse-outcome free days: There is ample evidence suggesting a strong 
association with these outcomes and mortality. These outcomes were devised by 
the ARDS Net group to overcome survivor bias, initially for mechanical ventilation 
and quickly expanded to include other outcomes potentially biased by 
survivorship. Outcome-free-days (OFD) as proposed by the NIH sponsored 
ARDSnet trials,106 takes the observation time into account. We apologize for not 
providing more information on this measure; we assumed the reviewers were 
familiar with it as it is so often used in recent clinical trials. Indeed, ALI-free days, 
MOF-free days and ventilator-free days (VFD) were proposed exactly to deal with 
the survivor –bias stated by the reviewers. 
a.
Definition: VFDs can be arbitrarily defined as the number of days 
between successful weaning from mechanical ventilation and day 28 
after study enrollment. The 28-day landmark was suggested both 
because interventional trials in acute lung injury typically involve a 28-
day treatment/follow-up period after the patient enrolls in the trial and 
because most, but not all, patients with acute lung injury have either 
died or been successfully weaned from mechanical ventilation by day 
28. VFDs are defined as follows:
VFDs = 0: If the patient dies before 28 days.   
VFDs = (28 - x): If the patient is successfully weaned from 
mechanical ventilation within 28 days, where x is the number of 
days spent receiving mechanical ventilation.   
VFDs = 0: If the patient requires mechanical ventilation for 28 
days or more. 
For example, VFD=2 means that the patient spent at least 26 
days on the ventilator or, less likely, died within 2 days without 
being on a ventilator, both of which are considered poor 
outcomes. 
b.
We will assess two adverse-outcome-free days measured over 28 
days, as follows: 
1.
Ventilation free days
2.
Acute Lung Injury (ALI) free days (as defined by the 
validated Denver  Lung Dysfunction score)
c.
Hypothesis: Experimental group patients will have longer †††adverse-
outcome-free-days than control patients.
d.
Statistical test: these outcomes are often skewed and non-normally 
distributed. Log transformation has been shown to be a good 
alternative to approximate normality for them. Thus, we will utilize 
linear regression to examine differences between the two groups. If 
adjustment for covariates is needed, we will proceed with the method 
for continuous normally distributed variables. In the case, normality 
cannot be achieved (as determined by the Shapiro-Wilk test for 
††† Although the hypothesis is worded as longer, the tests will be two-tailed to examine association in either 
direction.


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 34
CF-146, Effective 4-26-2010
normality), and there is no need to adjust for confounders, we will 
report median and interquartile ranges as measures of data central 
tendency and dispersion and use the Wilcoxon test to evaluate 
differences. If adjustment for covariates is needed, then we will resort 
to categorization of the outcomes, based on previously established, 
clinically meaningful cutoffs.80  
Overall experiment error will be 
adjusted for the number of adverse-outcomes-free-days parameters 
being analyzed using the Bonferroni method.
4.
Temporal trends: 
a.
Coagulation Profile: We will assess temporal trends from pre-hospital 
coagulation variables (as described below) at 2, 4, 6, 12, 24, 72 hours 
and 28 days post-injury.  The proposed coagulation measurements will 
also test the efficacy of plasma first resuscitation, since plasma is 
primarily employed for restoring levels of Factors II, V, VII, X and 
possibly XIII with a goal of greater than 20%, which is known to be 
effective for the cessation of surgical bleeding107.  In addition, there are 
major changes in the post-shock plasma affecting levels of proteins 
involved in regulating proteolysis, membrane lipid binding and 
stabilizing potentially cytotoxic intracellular components released after 
tissue injury.  
Our recent investigations of the proteome of three patients with 
significant hyperfibrinolysis, two who had ALI but survived and one 
who developed ARDS and did not, were compared to healthy controls 
of the same gender.  The hyperfibrinolytic state of these injured 
patients was confirmed by thrombelastograms (TEG) prior to blood 
component resuscitation (results not shown).  
The proteins that 
significantly increase in the patient plasma vs. normal males include: 
actin (15-28-fold), a cytoplasmic protein that has been implicated in ALI 
when free in the circulation, von Willebrand Factor (15-24-fold), a 
necessary coagulation factor, α-enolase (10-28-fold)59 a lyase with 
protease activity, perioxiredoxins 2 & 6 (7-14-fold), proteins which are 
atypical phospholipases, adiponectin (8-19-fold), which is a hormone 
from adipocytes that is important in glucose uptake & insulin sensitivity, 
lipid 
oxidation 
and 
is 
a 
PPAR1/PPAR2 
ligand, 
matrix 
metalloproteinase-9 (MMP-9) (3-5-fold) that is also known as 
gelatinase, which breaks down the extracellular matrix and is a 
sensitive indicator of leukocyte activation and, lastly, carboxypeptidase 
β2, also known as TAFI.  Plasma contains many proteins which can 
oppose the actions of these proteins, including: anti-proteases (α1-
antitrypsin, α2-macroglobulin, and other globulins), lipid carriers 
(albumin), and gelsolin which solubilizes and inhibits actin induced 
ALI.57, 58, 60, 108
1.
Hypothesis: Experimental group patients will demonstrate 
earlier and larger improvement in coagulation variables 
compared to control patients. 


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 35
CF-146, Effective 4-26-2010
2.
Statistical analysis: variables will be examined for normality 
through the Shapiro-Wilk test and log-transformed if necessary 
to approximate normality. Statistical analyses will be performed 
by using mixed linear models (SAS Proc Mixed), with an 
unstructured covariance structure between the different time 
measures, and if needed, adjustment for potential confounders in 
case randomization fails to account for differences. Overall 
experiment error will be adjusted for the number of coagulation 
parameters being analyzed using the Bonferroni method. 
Multiple comparison adjustment within each coagulation variable 
temporal trend will be done using the Tukey’s method. 
Mixed linear modeling with SAS Proc Mixed allows for 
incomplete data, thus all observed points will be used in the 
analysis. Missing data in temporal trends will be dealt with 
differently depending on the reason for missing. If MAR (loss to 
followup, withdrawn from study), multiple imputation methods will 
be used, as recommended by the Panel on Handling Missing 
Data in Clinical Trials. However, as described in previous 
sections, a major reason for missing data in these cases is early 
death, resulting in data MNAR, for which we will use the same 
approach to deal with the missing data as described for the 
secondary endpoints. 
A similar analysis will be carried out for temporal trends 
in Proteomic Profile, Actin and Neutrophil Elastase inhibitors.
5.
Blood components transfusion in the first 12 hours postinjury
a.
Packed Red Blood Cells (RBC) volume
1.
Hypothesis: The volume of RBC transfused in the first 12 hours 
postinjury will be larger among control patients compared to the 
experimental group patients. 
b.
Plasma volume
1.
Hypothesis: The volume of plasma transfused in the first 12 
hours postinjury will be larger among control patients compared 
to the experimental group patients. 
2.
Statistical test for a.1 and b.2: These variables are usually 
non-normally distributed, thus the Wilcoxon non-parametric test 
will be used to compare the two groups and median/interquartile 
range will be used to express data central tendency and 
dispersion. If adjustment for covariates is needed, we will follow 
the procedure described for continuous, not normally distributed 
variables. Overall experiment error will be adjusted for the 
number of blood transfusion parameters being analyzed using 
the Bonferroni method.
c.
Time to first RBC: This is a variable of high importance for DOD, 
which leads to direct application in war theater trauma.


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 36
CF-146, Effective 4-26-2010
1.
Hypothesis: Time to the first RBC will be longer among patients 
in the experimental group compared to control patients. 
2.
Statistical test: Kaplan Meyer curves will be compared using 
SAS PROC LIFETEST, which provides nonparametric k-sample 
tests based on weighted comparisons of the estimated hazard 
rate of the individual population under the null and alternative 
hypotheses. A variety of tests can be specified, of which we will 
use the Wilcoxon test (which places more weight on shorter 
survival times) and the log-rank test (which privileges longer 
survival times). SAS PROC LIFETEST also constructs statistics 
to test for association between covariates and the lifetime 
variable through rank tests for the association of survival time 
with covariates
H.
Missing data prevention and treatment procedures: 
We will follow the recommendations for prevention and treatment procedures 
outlined in the recent report by the National Research Council Panel on Handling Missing 
Data in Clinical Trials.84 Missing data prevention is crucial in the primary endpoint to 
avoid any reduction in statistical power and the need for statistical analyses to account 
for the missing data.  To minimize bias by missing data, research coordinators will collect 
data on the primary and secondary endpoints of all patients who were randomized in the 
field (including vital status at day 28 postinjury), including data on those patients who did 
not complete the protocol or were excluded for protocol violations or other reasons. 
Patients who withdraw from the study will be asked to allow research coordinators to 
collect SOC data from their medical record and, at a minimum, to provide contact 
information (and permission to be contacted) for verification of the primary endpoint 
mortality. 
Based on previous trials in our institution, we predict that mortality will be missing 
due to loss of follow up in less than 2% of the sample. This is comparable to the loss to 
follow-up observed in the ROC trial (2 out 895 field-randomized patients). Several 
prevention procedures are in place to prevent missing data in our institution. At least two 
other data collection mechanisms (in addition to the COMBAT trial) will be capturing data 
from these patients: the Trauma Registry and the COMBAT/Trauma Activation database, 
which include information on the primary and secondary endpoints for COMBAT-eligible 
patients.  
However, we are aware that avoiding missing data completely is not always 
possible. Thus, as in the ROC trial, we will assume that patients for whom vital status (the 
primary endpoint) could not be verified despite reasonable efforts to ascertain it were 
alive at day 28.67 Patients lost to follow up will be fully described in terms of group 
assignment and covariates. Mortality data will most likely be “missing at random” (MAR). 
This is a reasonable assumption since patients with missing data on day 28 vital were 
those discharged alive before day 28 and lost to follow-up. Mortality in this group is most 
likely unrelated to the trial group assignment. In the unlikely event that vital status data 
are missing in over 5% of the sample, we will conduct a sensitivity analysis assuming 


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 37
CF-146, Effective 4-26-2010
extreme case scenarios (i.e., all missing vital status did not survive, all missing survived). 
84
For the secondary endpoint 1, missing data in the composite outcome of 28-day 
mortality or MOF incidence will be dealt with by using the method proposed by the 
authors of the validated Denver MOF score for scoring patients with missing data.80, 81
Because the secondary endpoints 2, 3 and 4 (admission coagulopathy, acidosis 
and clot strength) are obtained at 30 minutes postinjury in all trauma activation patients, 
we anticipate very few missing data. The main and most complicated reason for missing 
data in these secondary endpoints is death before test was obtained. These data are 
clearly “missing not at random” (MNAR), as they are likely to represent the most injured 
patients and those more likely to have abnormal test values. This survivor-bias plagues 
emergency and trauma research and it is difficult to manage in the analysis period. 109-111 
As recommended by the Panel on Handling Missing Data in Clinical Trials, missing data 
both due to death and related to death must be treated as a special case. 84 We will 
proceed as follows for these analyses: 1) the primary analysis will focus on all patients 
with complete data; 2) the second analysis will focus on those who remained alive in 
either group; 3) a third approach will fold death occurring within 1-hour between 
ambulance arrival at scene into the two binary endpoints 2, 3 and 4 to form composite 
outcomes (admission coagulopathy or 1-hour death; admission acidosis or 1-hour death). 
For the continuous secondary endpoints 2, 3, and 4, we will limit the analyses to 
approaches 1 and 2 and as a third approach, multiple imputations will be used.
Missing data for the variables chosen to assess effectiveness of randomization 
are anticipated to be less than 5% given the mechanisms described above. For the 
variables MAR with >5% missing data, we will use the multiple imputation method. 81, 84 If 
the variable is MNAR, the missing indicator method, as proposed by Sauaia et al., which 
is equivalent to the inverse probability weighting method, will be employed. In brief, the 
variable is categorized in missing, normal value and abnormal value, using established 
cutoffs for normal and abnormal values.
Missing data procedures for exploratory analysis 1: By the very nature of the 
study, missing data for this outcome (24-hour mortality) as a binary outcome (death yes 
or no) is likely to be null; while missing data for time from injury to death within 24 hours 
can be missing, which will be censored in the above-described survival analysis.
I.
Trial assessment
1.
Assessing Phase 2 trial results for promising benefits of the therapy: 
Because the trial has low power for the primary endpoint and some of the 
secondary endpoints, it is unlikely that we can detect a statistical significant 
difference. Thus, it is important to pre-determine the findings that we believe will 
indicate promising results that must be further investigated in larger Phase 3 
trials. We will specifically look at the following measures to declare that the 
therapy is promising:
a.
Statistical significant difference in primary endpoint or secondary 
endpoints
b.
Strong, yet not statistically significant association (e.g., p-value = 0.10 
to 0.05) with improved primary and secondary endpoints. The direction 


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 38
CF-146, Effective 4-26-2010
of the association must indicate therapy benefit in ALL primary and 
secondary endpoints. Associations indicating harm will be reviewed by 
the DSMB for possible early termination.
c.
Exploratory analyses of variables with supporting evidence for 
association with improved patient outcomes with statistically significant 
results (respecting the boundaries determined by the interim analyses 
methods, and adjusted for multiple comparisons as detailed in the 
description of the exploratory analyses). 
The DSMB will also be in charge to making recommendations regarding the 
promising nature of the therapy and whether Phase 3 trials are warranted. 
2.
Interrupting the trial early: 
The DSMB will be responsible for making a recommendation for early stopping of 
the trial. The DSMB will be asked to address early termination during each and 
every time they are activated, as described in the DSMB roles and 
responsibilities. In brief, the DSMB will be activated in case of a unanticipated 
problem, or during the interim analyses. Drs. Sauaia and Chin will prepare the 
materials for DSMB review containing:
a.
blinded results (experimental and control groups will be referred as A 
and B) of effectiveness of randomization, primary and secondary 
outcomes, as well as exploratory analyses (most especially the two 
subgroup analyses regarding blunt versus penetrating mechanism, 
presence of traumatic brain injury and Field SBP≤70mmHg versus 
SBP 71-90mmHg), any potential adverse events, and missing data 
description (to include number missing and their characteristics 
regarding outcomes and covariates). 
b.
predicted probabilities of all previous events and outcomes based on 
the Denver MOF database, the ROC trial, the National Trauma Data 
Bank and the Trauma registry: these statistics will assist the DSMB in 
determining harm based on larger numbers than those provided by the 
comparisons between control and experimental groups
c.
graphs containing the statistical scores, interim analyses boundaries 
and prediction of future statistical scores based on observed data.
d.
pertinent studies published since the initiation of the trial.
e.
any feedback received from community members, enrolled patients, 
paramedics, research coordinators and attending health care 
providers.
Based on the above elements, the DSMB will make a recommendation on early 
termination of the trial. 
J.
Paramedic training and ambulance equipment
1.
Paramedics will be trained utilizing a PowerPoint presentation that emphasizes 
the protocol, study background, inclusion-exclusion criteria and transfusion 
reactions. All trainees will have ample opportunity to ask questions and offer 
comments.  Commencement of study enrollment will begin only after training is 
concluded. Paramedics authorized to perform study related procedures will be 


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 39
CF-146, Effective 4-26-2010
required to not only have completed and documented this mandatory training, but 
must provide certification of their credentials, prior to study initiation. All 
documentation will be reviewed and stored by the study coordinator. In addition, 
paramedics hired after this training has been completed will be required to review 
study training material and will be guided by veteran paramedics as well as the 
previously mentioned study staff.  
Study staff will meet with the trainees 
specifically to discuss the study and answer any questions. 
2.
As requested by the Jehovah’s Witness Hospital Liaison (JWHL) Committee 
during the Community Consultation, the JWHL Committee will have the 
opportunity to educate and train the paramedics how to seek Jehovah’s 
Witnesses.  
3.
For the study, all the DHMC paramedic ambulances will be equipped with 
validated coolers, (See Section IV.L.1 Dry Ice Plasma Storage Box) to store the 2 
units of AB-FP24.  
The Thermal Isolation Chamber (TIC) panels will be 
exchanged every 48 hours and the AB-FP24, if not used, will be replaced every 
11.5 months. According to the 28th Edition of the AABB Standards for Blood 
Banks and Transfusion Services, plasma frozen within 24 hours of phlebotomy 
expires at 12 months from collection. (See Appendix 12)  Type AB plasma is a 
valuable resource that we do not want to waste or discard unless it is expired by 
the AABB standards.  To be conservative, we will replace AB-FP24 at 11.5 
months from collection. This method was deemed to be the most cost effective 
and logistically feasible in the ambulances.  When the frozen AB-FP24 is 
needed, it will be rapidly thawed in a FDA approved dry warming device called 
Plasmatherm powered by a 12V to 120V AC inverter (see section IV.L.2 
Plasmatherm).  
4.
The AB-FP24 will be infused once ready with the standard Y-set with blood 
transfusion filter (170-260 micron).  If IV access has been obtained and the AB-
FP24 is not ready to be infused, fluid resuscitation will not be withheld and 
crystalloid fluid will be infused until the AB-FP24 is thawed.  This will minimize 
the possibility that subjects in the study group will receive inferior care if the AB-
FP24 is not ready for infusion.
5.
Paramedics will briefly look for necklace ID or bracelet. If the patient has any of 
these, he/she will not be enrolled. 
6.
If the patient has a durable power of attorney that reports Jehovah’s Witnesses 
or no blood products, regardless if fractions are accepted, we will not enroll the 
patient in the study.  The degree that fractions will be accepted varies among 
members of the Jehovah’s Witnesses congregation.  Thus to be conservative 
and minimize the chance of enrolling patients that do not accept plasma 
fractions, we will not enroll these patients.
7.
If a family member is present at the scene and not in shock or severely injured, 
easily accessible to paramedics, and the patient is not in imminent danger of 
death, the paramedics will state "We are enrolling him/her in a research study 
where we are giving a blood product.  We don’t have time to explain the study at 
this time.  Is this okay?"  The paramedics will not look for family members among 
a crowd of bystanders given the acute setting and the importance of transporting 


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 40
CF-146, Effective 4-26-2010
the patient  to the hospital as soon as possible. Paramedics cannot assess 
competency of family members in this time-sensitive setting; thus family 
members that are not in shock or severely injured will be assumed to be 
competent. 
8.
 It will be assumed that patients will not be competent to give an assent since by 
nature of the eligibility criteria, the patient will be in severe shock.  
9.
If the patient will not be transported to Denver Health, he/she will not be enrolled.  
If the patient is enrolled, but due to unforeseen circumstances (such as 
impending airway), must be transported to a nearby facility that is not Denver 
Health, then the patient will be unenrolled.  If possible, every effort will be made 
to contact the family and follow the patient for any adverse effects. The consent 
form will be used to verify that the patient (or family) was informed. 
K.
Procedures involving plasma
1.
Procedure for thawing frozen AB-FP24: AB-FP24 will be thawed in the 
Plasmatherm (see section IV.L.2) and in accordance to the instructions 
accompanying the product and as approved by the FDA. 
Plasma is thawed but not transfused: If the AB-FP24 is thawed but not transfused 
for unforeseen reasons, such as discovery of Jehovah’s Witnesses, then the 
unit(s) will be discarded or used for research purposes. It will not be transfused 
into humans.
2.
Procedure for Issuing 2 units of AB-FP24:  Bonfils Blood Center will be 
providing the AB plasma for the study..  This is modified from the DHMC policy 
for Blood Transfusions to be applicable to this study. 
a.
AB-FP24 will be administered through the standard Y-set with blood 
transfusion filter (170-260 micron). 
b.
Vital signs are required before the transfusion of all components and 
again after 15 minutes and at the completion of the transfusion. 
Transfusion rate will be compatible with the patient’s condition. The 
patient will be monitored closely during the entire transfusion. The 
documented start and stop times are directly related to the actual 
transfusion of the component. Paramedics will document vital signs 
and start times in the field.  
Study coordinators will assume 
responsibility of additional vital signs and stopping time of the AB-
FP24.  
c.
The patient medical record shall include the following: 
1.
Name of the components transfused 
2.
Donor identification number of components
3.
Date and time of transfusion (Start and Stop time) 
4.
Pre and post transfusion vital signs 
5.
The volume transfused 
6.
The transfusionist’s name (paramedic) 
7.
Documentation of related adverse events 
3.
Rescue procedure for transfusion reactions: This is modified from the DHMC 
policy for Blood Transfusions to be applicable for this study. 


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 41
CF-146, Effective 4-26-2010
a.
Careful observation throughout the transfusion allows for early 
detection of adverse reactions and optimal treatment, if necessary. All 
reactions should be handled initially as possible hemolytic reactions 
and the transfusion must be stopped. Any adverse events associated 
with the transfusion of blood or blood components should be 
documented in the patient’s Medical Record and reported to the Blood 
Bank. 
b.
The most common clinical events accompanying or announcing 
transfusion reactions are, in order of decreasing frequency: 
1.
Fever, with or without chills 
2.
Skin symptoms, hives and/or itching or rash 
3.
Chest pain 
4.
Hypotension 
5.
Nausea 
6.
Flushing 
7.
Respiratory Distress (wheezing, coughing or dyspnea) 
8.
Bleeding at infusion site 
9.
Hemoglobinuria 
10. Circulatory overload 
11. Anaphylaxis 
c.
If an adverse reaction is suspected, follow the procedure below:
1.
Stop the transfusion 
2.
Maintain IV access with Normal Saline and change the tubing. 
3.
Notify the patient’s physician upon arrival to the ED and initiate 
immediate treatment as ordered. 
4.
For all other blood products involved in a reaction, the 
transfusion shall be stopped and a Transfusion Reaction 
Investigation (F20-251) shall be initiated. This form can be 
obtained from the Blood Bank. 
5.
Notify the Blood Bank (303) 436-6929 of the suspected 
transfusion reaction. 
6.
Collect a sample drawn from the patient as soon after the 
reaction was detected. Send a 6 mLs pink top tube, labeled with 
a new Blood Bank armband to the Blood Bank along with the 
unused blood, blood bag with attached hard back copy of the 
transfusion tag, the IV tubing used and the top 2 copies of the 
Transfusion Reaction Investigation 3 part form. The back copy of 
the Transfusion Reaction Investigation form should remain in the 
patient’s chart as the initial report. A post transfusion reaction 
Urinalysis with Microscopic may also be ordered by the patient’s 
physician. 
7.
The Blood Bank will complete the Transfusion Reaction initial 
report and notify the caregiver of the critical results. Pathology 


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 42
CF-146, Effective 4-26-2010
will evaluate the patient’s reactions, Blood Bank’s initial report, 
culture when indicated, and report will be documented in the 
patient’s medical record. Consultation between the Medical 
Director of the Transfusion Service, the patient’s physician and 
Risk Management is required when a fatal hemolytic transfusion 
reaction occurs. Further evaluation and FDA notification may be 
indicated. The Hospital Transfusion Committee is responsible for 
peer review and blood utilization practice.
4.
Look back procedures: Since the plasma will be tracked through the DHMC 
Blood Bank, look back/product recall procedures will be conducted as per DHMC 
standard protocol. (See appendix 3: Look Back Procedures/Product Recall)
L.
Devices used in this study: 
1.
Cooler box: Bonfils Blood Center, US License #0166, CFN#1723428, validated 
a cooler box, an army surplus ammo can with 2” foam insulation and phase 
change material (PCM) for temperature control, has undergone intensive in-
house validation such that the summer temperature test proved that the above 
mentioned container would maintain a temperature of -18°C or colder for 27.8 
hours.  Therefore two units of plasma will remain frozen for at least 24 hours 
when properly packed with PCM as also mentioned in the validation report 
(appendix 12).  Furthermore, this precise packing methodology per Bonfils Blood 
Center standard operating procedures will be implemented without deviation.  In 
addition, the PCM will be changed at least every 24 hours to ensure that the 
plasma remains frozen.
a.
2 units of frozen AB-FP24 will be stored in the half of the cooler boxes.   
PCM bottles will be exchanged every 24 hours. If the stored frozen AB-
FP24 is not used within 11.5 months of collection, it will be replaced. 
This allows a wide buffer to ensure plasma that is beyond 12 months of 
collection is not infused. If there is any possibility of compromise to the 
plasma, study personnel and Dr. Tuan Le, who is responsible for 
maintaining the supply of frozen AB-FP24, will be notified and the unit 
will be removed and labeled for research purposes or discarded.  The 
cooler will be inspected and replaced if there is any concern of the 
integrity of the cooler.  
2.
PlasmaTherm by Barkey (510K# BK100063,) is approved for thawing plasma 
by the FDA.  It is distributed by Genesis BPS. (65 Commerce Way, Hackensack, 
NJ 07601  Phone: 866-712-5663  201-708-1400;  Fax: 201-708-1104; email: 
info@genesisbps.com) The device will be used as approved by the FDA (see 
appendix 4 for operating manual). 
a.
Plasmatherm functions similarly to the typical water bath, however, the water 
does not contact the plasma, reducing the potential for contamination in the 
event of back breakage. If a bag breaks, Plasmatherm is easier to clean up than 
a typical water bath. 


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 43
CF-146, Effective 4-26-2010
b.
Monthly, the Plasmatherm will be inspected for damage and cleaned. If there is 
any concern regarding the use of the Plasmatherm, the PI will be notified.  Before 
each shift, the display will be tested
3.
CipherOx M1 by Flashback Technologies is a non-FDA approved device 
consisting of an FDA-approved Nonin OEM III pulse-oximeter integrated with an 
ARM III processors, memory, a mini-USB port for charging and data off-load, as 
well as a high-resolution screen for indoor and outdoor use. The device collects 
non-invasive waveform data from acutely injured, potentially bleeding trauma 
patients. The device displays the date/time and an image of a finger with a 
sensor that is displayed in “green” if the data collection is “good.” The providers 
are blinded to all physiological data collection by the device.
M. Special Consent Issues  
1.
We have requested an exception from informed consent for emergency research 
under 21 CFR §50.24 as the patients selected for enrollment in this clinical study 
will be unable to provide prospective informed consent due to the extent of their 
injuries and their immediate need for resuscitation from life-threatening 
hemorrhagic shock. These patients are often unable to give consent upon arrival, 
and this study cannot be carried out without an exception from informed consent. 
a.
The therapeutic window dedicated to obtaining prospective informed 
consent from the patient or a legally authorized representative is very 
brief. On average, line-placement has been accomplished by 
experienced field care personnel in approximately one minute, and 
therefore, 
the 
process 
of 
patient 
assessment, 
scene 
care, 
randomization, enrollment, thawing of plasma, and the start of AB 
plasma infusion can be expected to occur in less than 8 min.  The 
opportunity to obtain prospective informed consent from the patient or 
a legally authorized representative or to provide an opportunity for a 
family member to object to the subject’s imminent enrollment in the 
study may not be possible prior to the commencement of study 
procedures.
b.
Once the patient arrives at the hospital, the admissions department 
and social workers in the ED attempt to locate family members of the 
patient using every resource available, including several databases, 
previous medical records, and cellular phones.  Within the trauma 
population, few of the patients have advance medical directives 
identifying a legally authorized representative (LAR).  If no LAR was 
previously identified and there are several interested parties, per 
Colorado law, the social worker meets with all interested parties to 
select a proxy decision maker (See Appendix 5: Proxy Decision 
Maker).  Continued diligent attempts by social workers to contact a 
legally authorized representative or family member of the patient will 
continue if the patient remains incapacitated. 
c.
Prisoners: If the patient becomes a prisoner during the study, they will 
be treated similar to non-prisoner subjects in accordance with DH 
policy of hospital care of patient-inmates. (see appendix 13)


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 44
CF-146, Effective 4-26-2010
d.
Procedure for consent
1.
Once a LAR/PDM is available, a member of the study team will 
inform him/her of the study and obtain consent for continued 
collection of blood samples up to day 7 and clinical data up to 
day 28. 
2.
If a LAR/PDM does not consent for continued data collection, 
no further blood draws and/or data collection will occur.  The 
LAR/PDM will be asked if he/she would like the patient 
withdrawn from the study. 
3.
If a patient becomes competent to consent, a member of the 
study team will inform and re-obtain consent from the patient 
for continued data collection. 
4.
If a family member has consented for continued data 
collection, but when competent, the patient does not consent 
for continued data collection, no further blood draws and/or 
data collection will occur. The patient will be asked if he/she 
would like to be withdrawn from the study.
5.
The LAR/PDM or the patient may withdraw from the study at 
any time, including at the time of consent. If the patient is 
withdrawn from the study, previously collected blood samples 
and data will be destroyed. 
6.
If a patient never regains decisional capacity and no 
LAR/proxy can be found, data and samples may be used since 
the subject has been enrolled under Exception for consent for 
emergency research. In this situation, all attempts at 
consenting will be documented.  
e.
Procedure to inform family of patients who died before consent is 
obtained
1.
After patient death, if applicable, social work and decedent 
affairs/coroner will be contacted for information about the social 
situation and family contact information.
2.
In 2-4 days after patient death, call next of kin or family contact. 
If family members are met in person at any time after death and 
the timing is appropriate, inform the family in person. 
3.
During the call, verify address and mail information letter as 
follow-up or give the letter to family if met in person. 
4.
If no one answers the call, leave a message, if possible. If no 
response in 24 hours, call back. Repeat up to 3 times.
5.
The rationale of this procedure is that 21 CFR 50.24 requires 
that information about the clinical investigation be provided to the 
LAR or family member of patients who died before consent is 
obtained, if feasible. In certain clinical situations, the family may 
not be local and may not come to the hospital, thus, we will call 


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 45
CF-146, Effective 4-26-2010
the family members after a brief period of grieving. However, 
given the sensitive situation, we prefer in-person communication, 
and will engage family if appropriate. We will follow up with the 
information letter, either by mail or in person as appropriate, 
allowing family members to read it at a later date. If we are 
unable to contact family after 3 tries, we will consider informing 
the family as not feasible. 
2.
Community Consultation and Public Disclosure (CCPD): Protection of the 
rights and welfare of patients is necessary in all clinical studies and is paramount 
in studies involving vulnerable populations.  Because this study involves victims 
of trauma who likely will not be able to provide informed consent or actively 
refuse enrollment, patients are placed in particularly vulnerable circumstances.  
This lack of autonomy creates a special need for FDA, sponsors, IRBs, and 
clinical investigators to work closely together to ensure that the interests of this 
vulnerable patient population are protected to the maximum extent possible.  For 
such studies to be conducted, investigators must provide an opportunity for 
dialogue with the community in which a study will be conducted and from where 
subjects will be drawn.  The IRB, Department of Defense, and the investigators 
will coordinate these efforts using the plan outlined in Appendix 6 Community 
Consultation and Public Disclosure Plan and Appendix 7 List of Neighborhoods 
and HOAs around Denver Metro Area.  
Discussion with the information 
disseminated to the community will adhere to 21 CFR §50.24 and 56.115. 
a.
In brief, the community consultation and public disclosure plan required 
by the 21 CFR §50.24 will include feedback from community meetings, 
online and social media feedback as well as paid advertisements, 
media news releases to TV, radio and newspapers, and women’s 
health and community clinics. In addition, prior to initiation of the study, 
the clinical investigators and IRB will make arrangements for public 
disclosure of the plans for the investigation and a balanced disclosure 
of the risks and potential benefits to patients enrolled in the study.  This 
disclosure will also include background information about the study, a 
synopsis of the protocol and study design, risks and benefits of fresh 
frozen plasma versus the standard crystalloid fluid, the selection of 
subjects, the use of provisions for exception from informed consent 
requirements and the process for attempting to contact a legally 
authorized representative, and the ways in which subjects can 
communicate their desire not to participate. Following the completion 
of the study, a summary of the findings of the clinical trial will be 
disseminated to the community.  This information, presented to the 
community, is in language that is understandable and does not 
promote fresh frozen plasma, and will include the results of the trial 
and demographics of the patients enrolled.
b.
Under 21 CFR §50.24, we submitted an Investigational New Drug 
Application  (IND# 15216) for the use of thawed plasma in the 
resuscitation of severely injured trauma patients in an emergency 


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 46
CF-146, Effective 4-26-2010
research protocol, which is necessary to obtain a waiver of consent in 
emergency research. 
3.
Under Title 10 US Code Section 980, Department of Defense funds may not be 
used for human research unless an informed consent of the subject or a legally 
authorized representative of the subject is obtained in advance for human 
subjects research.  The Secretary of Defense may waive this prohibition for a 
specific research project to advance the development of a medical product 
necessary to the armed forces if the research project may directly benefit the 
subject and is carried out in accordance with all other applicable laws.  
The contract with the Department of Defense is specific to the evaluation of the 
use of plasma in the field.  As described above, the majority of potentially 
survivable injuries are due to hemorrhage. If administering plasma earlier in the 
field decreases hemorrhage from acute coagulopathy of trauma, injured 
members of the armed forces may have more time to reach a facility to be better 
stabilized and resuscitated.  
Although some institutions have adopted the 
principle of early plasma administration in the management of severe trauma and 
the acute coagulopathy of trauma, there are no prospective studies measuring 
the benefit and risks of administering plasma early.  
Although this is a greater than minimal risk study, subjects are likely to 
receive direct benefit from this clinical trial from closer evaluation and testing of 
coagulation status. Based on the previous retrospective studies and preclinical 
studies described in the Section II.A. (Background) and Section III.A. (Preliminary 
studies) as well as our current understanding of administering plasma earlier and 
more frequently in the resuscitation of patients in severe hemorrhagic shock, 
patients receiving early plasma are likely to directly benefit from this study.  
This study will be carried out in accordance with 21 CFR §50.24 Exception from 
Informed Consent for Emergency Research. 
N.
Description of Risks, Benefits and Justification
1.
Risk of blood transfusion:  These risks apply to any patient that receives blood 
products regardless of group assignment.  Both the standard and experimental 
groups are likely to receive blood products during the resuscitation period, but 
the study group will receive at 
a minimum 2 units of AB 
plasma. In this study, all 
plasma used as an initial 
resuscitation fluid will be AB 
and 
hence 
universally 
infusible 
without 
the 
requirement for patient blood 
typing.  This is the usual type 
of fresh frozen plasma used in 
acute trauma setting prior to 
obtaining 
type 
and 
cross 
match (see appendix 9 for adult transfusion guidelines).  
Risks of blood 


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 47
CF-146, Effective 4-26-2010
transfusion include febrile non-hemolytic transfusion reaction (1.1% to 2.5%), 
hemolytic transfusion reactions (1:1,250,000), transmission of blood borne 
pathogens (See Table 2), transfusion-related lung injury (TRALI) (8.1 per 
100,000), transfusion associated circulatory overload (TACO) (2-3 per 100).112   
A blood transfusion may also result in a reaction that includes fever, chills, or 
hives. Although uncommon, the patient may experience this type of reaction as 
the result of receiving the incorrect type of blood. By using AB type of plasma, 
this risk is minimized. This risk is minimized in the blood bank by a questionnaire 
to exclude donors who are at risk of having a blood borne pathogen as regulated 
by the FDA under 21CFR 640 subpart G. The donated blood is also tested in the 
laboratory for infectious diseases. 
A blood transfusion may increase the likelihood of developing an infection 
while the patient is in the hospital, may exaggerate how the patient’s body 
responds to injury, and may increase the patient’s risk of internal organ failure 
after his/her injury. 
Excessive transfusions place patients at higher risk of hypervolemia, and 
pulmonary edema, but this risk also exists for patients who receive excessive 
intravenous fluids. The risk of 2 units of AB-FP24 as initial resuscitation leading 
to cardiac failure, hypervolemia and pulmonary edema is low as it is a smaller 
volume (500ml) than the standard 2 liters of crystalloid intravenous fluid.  These 
risks exist with transfusions of any blood products
2.
Risk of Inadvertent Release of Protected Health Information (PHI): This risk 
is minimized by using a unique patient identifier and role based security for the 
database. All hard copies will be kept locked in the research office or be 
destroyed.
3.
Venipuncture risk: In most cases blood will be drawn from an intravenous line 
(I.V.) already placed as part of the patient’s standard medical care. In the event 
the patient does not have an I.V., blood will be drawn using a method known as 
venipuncture.  This procedure consists of placing a small needle in a vein in the 
patient’s arm to withdraw blood.  Risks associated with drawing blood from the 
patient’s arm include pain, bruising, lightheadedness, and rarely infection.
4.
Potential Scientific Problems:  
Potential scientific problems include the 
possibility our hypothesis will not increase survival, improve MOF, and decrease 
the need to blood products.  We feel this possibility is low given the background 
and preliminary studies that have been done, however, we will evaluate the 
outcomes at each interim analysis to detect early if our hypothesis is incorrect.   
Another potential scientific problem may be the enrollment of patients who are 
nonvisibly pregnant, or younger than 18 years of age, during the hospital stay. 
Age is often estimated at the time paramedics arrive to the scene and some 
patients may appear to be 18 years of age or older but may truly be younger. We 
plan to minimize the potential to enroll pregnant or potentially pregnant women 
and patients less than 18 years, by recommending they opt out with the bracelet 
and necklace ID. Other potential scientific problems include the risk of 
unforeseen events such as thrombotic events of myocardial infarction, stroke, 
and venous thromboembolism. We will monitor for these events in the study 


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 48
CF-146, Effective 4-26-2010
patients and determine if administration of plasma leads to increased thrombotic 
events. Upon discovery of these events, it will be reported to the Data Safety 
Monitoring Board. The risk of this is low since these patients are hypocoagulable 
and at risk for bleeding. Finally, the study is not blinded to clinicians.  Thus, there 
may be a treatment bias to withhold blood transfusions for borderline values in 
the study arm for a longer time or to transfuse those in the standard arm quicker.  
However, the initial resuscitation occurs in the ambulance, where the patient is 
randomized.  The majority of the resuscitation occurs in the Operating Room, 
often driven by the anesthesia team or the Surgical Intensive Care Unit, driven by 
the ICU team, who may have no knowledge which study arm the patient is 
enrolled in or if the patient is enrolled at all.  
5.
Risk to Investigator or Institution. There is no known direct risk to the 
Investigator or Institution.  However, the transmission of viruses may occur 
through contact with contaminated needles and blood or blood products. 
Accordingly, all study personnel involved in the collection of blood and/or 
handling of specimens will employ appropriate blood and body fluid precautions 
in the both the clinical and laboratory settings.
6.
Benefits: Utilizing AB plasma as the initial resuscitation fluid may increase the 
likelihood of survival, decrease multiple organ failure, and decrease the overall 
need for blood products, especially in the setting of activation of the massive 
transfusion protocol. Furthermore, implementation of this study may help patients 
in the future by giving important information about the treatment of acute blood 
loss and initial resuscitation in trauma. Benefits for patients in the control arm 
include intensive surveillance of the acute coagulopathy of trauma that may 
result in further appropriate medical treatment
7.
Risk-Benefit analysis: Risks to the subject include reaction to risk of 
transmission of blood-borne pathogens, which is minimal, risk of reaction to 
blood transfusion, venipuncture, inadvertent release of PHI, or unforeseen 
happenings.  Benefits include the potential to improve outcome in the critically 
injured with acute coagulopathy of trauma as well as decreased need for blood 
products.   
The risks of blood transfusion is small, but this specific trauma 
population that is severely injured and in hemorrhagic shock will likely receive 
transfusion of multiple blood products, including plasma, regardless of the type of 
initial resuscitation fluid. By transfusing AB plasma early as a resuscitation fluid, 
we may be able to slow down the ACoT, leading to a decreased number of 
transfused blood products.  As stated above, transfusion of blood products in the 
first 12 hours is an independent risk factor of mortality.63 Furthermore, using the 
same inclusion criteria as in the recent ROC hypertensive HTS trial,67 mortality in 
this study is expected to exceed one in four. At the same time, massive pRBC 
infusion remains a major risk factor for MOF36, 38, 99 while plasma transfusion 
does not.
8.
Adverse Events
a.
The PRA team will be responsible for identifying and documenting 
adverse reactions. They will ask the principal investigator and the 
attending physician for the relatedness of the adverse reaction to study 


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 49
CF-146, Effective 4-26-2010
and if they should be reported to the appropriate agencies.  The DSMB 
as well as the RM will evaluate the relatedness of adverse reactions.  
All product related SAE’s will be reported to the FDA within 15 
calendar days.
b.
The definitions of serious adverse events are from our MOF database 
and the Glue Grant study and in Table 4: 
Table 4: Definitions of Serious Adverse Events
Serious Adverse Events
Presentation and Treatment
Bloodstream Infections
Bacteriologic confirmation of a recognized pathogen from one 
or more blood cultures and organism cultured is not related to 
an infection at another site. If a skin contaminant is cultured 
(diptheroids, Bacillus sp, Propionobacterium sp, coagulase-
negative staphylococci), the organism must be cultured from at 
least two cultures within a 48 hour period and the patient has at 
least one of: fever>38.5oC, WBC>10,000 or <3,000/mm3, 
SBP<90 mmHg or >25% drop in SBP.
Myocardial infarction
Acute, irreversible myocardial injury documented by both: 1) 
abnormal increase in CK-MB or troponin, and 2) new, serial T-
wave, S-T segment or Q wave EKG abnormalities.
Cerebral infarction
New neurologic deficit not present on admission which is 
sudden or rapid in onset and last >24 hours or until death and 
confirmed as an infarction by CT or MRI.  
Lung dysfunction
Denver lung dysfunction score ≥2* (P/F ratio adjusted for 
altitude≤165)
Renal dysfunction
Denver renal dysfunction score ≥ 2* (serum creatinine 
≤2.5mg/dL)
Multiple Organ Failure (MOF)
Denver MOF score ≥3 for 1 day*
Febrile non-hemolytic reaction
A temperature elevation of ≥ 1oC or 2oF occurring during or 
shortly after a transfusion and in the absence of any other 
pyrexic stimulus. Symptoms treated with antipyretics
Allergic reactions
Mild or self-limiting urticaria or wheezing that usually respond to 
antihistamines. 
Anaphylactoid/anaphylactic 
reactions
Hypotension, tachycardia, nausea, vomiting and/or diarrhea, 
abdominal pain, severe dyspnea, pulmonary and/or laryngeal 
edema, and bronchospasm and or laryngospasm. Immediately 
treated with epinephrine. 
Transfusion-related 
acute 
lung injury (TRALI)
Acute onset of hypoxemia within 6 hours of a blood component 
transfusion, bilateral infiltrates on chest x-ray, and the exclusion 
of preexisting acute lung disease or transfusion-associated 
circulatory overload (TACO) in a patient without clinical risk 
factors for the development of ALI.  
Bacterial sepsis
High fever (≥2oC or ≥3.5oF increase in temperature), severe 
chills, hypotension, or circulatory collapse during or shortly after 
transfusion suggests possible bacterial contamination and/or 
endotoxin reaction. Treated with discontinuation of the 
transfusion and aggressive therapy with broad-spectrum 
antimicrobials and vasopressor agents, if necessary. 
*Denver postinjury MOF Score80


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 50
CF-146, Effective 4-26-2010
 
c.
Data Safety Monitoring Board (DSMB):  The DSMB will include 
Martin Schreiber, MD, Professor of Surgery, Chief of Division of 
Trauma, Critical Care and Acute Care Surgery of Oregon Health and 
Science University; Arthur Derse, MD, JD, Professor of Bioethics and 
Medical Humanities, and Emergency Medicine, Director for Medical 
and Legal Affairs, and Director, Center for Bioethics and Medical 
Humanities, Director, MCW Medical Humanities Program of the 
Medical College of Wisconsin;Kirk Bol, MSPH, Vital Statistics Program, 
Colorado Department of Public Health and Environement; and Jeannie 
Callum, MD, FRCPC, Associate scientist, biological sciences-Trauma, 
Emergency, and Critical Care Program, Sunnybrook Research 
Institute, 
Associate 
staff, 
department 
of 
laboratory 
hematology/transfusion medicine, University Health Network, Director 
of transfusion medicine and tissue banks, department of clinical 
pathology, Sunnybrook Health Sciences Centre, and Assistant 
professor, department of laboratory medicine and pathobiology, 
University of Toronto. Dr. Schreiber will serve as the chairperson of the 
DSMB.  He previously served on the DSMB for the ROC clinical trial.   
1.
Role and Responsibilities:  The role and responsibilities of the 
follow FDA Guidance for Establishment and Operation of Clinical 
Trial Data Monitoring Committees.113  A draft DSMB charter is in 
Appendix 10. 
d.
Research Monitor: Per DOD requirements, Michael Wang, MD, 
Assistant Professor of Pediatrics and Head of the Mountain States 
Regional Hemophilia and Thrombosis Center, will serve as the 
Research Monitor (RM), whose purpose is to be involved in 
Department of Defense (DOD)-supported research studies that are 
determined to pose more than minimal risk to subjects (DOD 
Instruction 3216.02, Nov 2011).  The RM is not a member of the study 
team and is not affiliated with the Department of Defense.  The RM's 
duties should be based on specific risks or concerns about the 
research and in relation to scrutinizing the research effort on behalf of 
interests of the research participants.
1.
 The RM may perform oversight functions and report their 
observations and findings to the IRB, DSMB, investigators, 
DOD’s HRPO, or the FDA.  Functions could include observing 
recruitment and enrollment procedures and the consent process 


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 51
CF-146, Effective 4-26-2010
for individuals, groups or units, overseeing study interventions 
and interactions, reviewing monitoring plans; and overseeing 
data matching, data collection, and analysis. 
2.
There may be more than one research monitor (e.g., if different 
skills or experiences are necessary). The monitor may be an 
ombudsman or a member of the data safety monitoring board.  
The research monitor may discuss the research protocol with the 
investigators, interview human subjects, and consult with the 
IRB, DOD HRPO and the FDA; 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, DSMB, investigators, DOD’s HRPO or the FDA. 
3.
The research monitor is authorized to review research records 
as part of their responsibility to protect human research 
volunteers. Research records will be stored in a secure manner 
so as to protect the confidentiality of subject information  
e.
All unanticipated problems involving risk to subjects or others must be 
promptly 
reported 
by 
phone 
(301-619-2165), 
by 
email 
(Usarmy.detrick.medcom-usamrmc.other.hrpo@mail.mil), 
or 
by 
facsimile (301-619-7803) to the HRPO.  A complete written report will 
follow the initial notification.  In addition to the methods above, the 
complete report can be sent to the US Army Medical Research and 
Materiel Command, ATTN:  MCMR-RP, 810 Schreider Street, Fort 
Detrick, Maryland  21702-5012.. 
f.
Any deviation to the protocol that may have an adverse effect on the 
safety or rights of the subject or the integrity of the study must be 
reported to the HRPO and the IRB as soon as the deviation is 
identified.
g.
A summary of the safety monitoring schedule in Table 5: 
Table 5: Monitoring Schedule
Equipment
Frequency
Responsible 
Party
Product
Exchange 
of 
PCM 
bottles
Every 24 hours
Paramedics
Log of coolers
Inspection of cooler box
every shift
Paramedics
Log of coolers
Plasma replaced if not 
used
11.5 months from time of collection
PRA
Plasmatherm inspection 
Every shift
Paramedics
Log 
of 
checklists
Clinical Lab TEG
-Manufacturer 
calibration
-Quality control
- every 6 months
- every shift
Clinical Lab
Clinical Lab
Documented 
in Clinical Lab 
log
Research Lab TEG
Documented 


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 52
CF-146, Effective 4-26-2010
-Manufacturer 
calibration
-Quality control
- every 6 months
- every week
PRAs
log
Freezer 
for 
sample 
storage
Connected to Sensaphone alarm system at 
all times and physically checked once a day 
M-F. 
Data Monitoring
Evaluation 
of 
data 
quality
Data collectors will be fully trained and 
observed in the first two patients to assure 
correct data obtention; data entry will be 
verified by cross checking with the medical 
record the data entered for the first 5 
patients. Discordances between medical 
record (which will be considered the "gold 
standard") 
and data 
entry 
will 
be 
adjudicated by Dr. Chin. In the case there is 
any 
discordance 
in 
the 
primary 
or 
secondary endpoints, data collectors will be 
re-trained 
to 
ensure 
data 
reliability. 
Discordances over 5% in the variables used 
in the exploratory analyses will trigger re-
training. At the end of the study, a random 
sample of 10% of the patients will have their 
data 
cross-checked 
with 
the 
medical 
records and if there are discordances with 
primary endpoints, all records will be 
reviewed 
to 
ascertain 
the 
primary 
endpoints. 
Secondary 
endpoints 
and 
exploratory analyses will follow the same 
procedure if over 5% discordance is found. 
Laboratory 
measurements 
defined 
in 
exploratory analyses 4, 5, and 6 follow 
standard procedures in the lab to ensure 
data integrity
Theresa Chin, 
Research 
Fellows, PRAs
Evaluating 
data 
for 
adverse events
Daily
Theresa 
Chin,Research 
Fellows, PRAs
Verify training of newly 
hired paramedics
Every 4 months
Research 
Fellows, PRAs
DSMB meeting
Every 6 months or sooner
DSMB
DSMB report
Interim Analysis
Per analysis plan
Angela Sauaia 
Theresa Chin
Interim Report
9.
Medical Care for Research Related Injury: In the event of a research related 
injury, medical care will be arranged, and the patient or the patient’s insurance 
company will cover the cost. 
O. Roles and Responsibilities of Study Personnel: 
1.
Dr. Ernest E. Moore: As Vice Chairman of Surgery for research at the University 
of Colorado and Principal Investigator of this study, Dr. Moore will be responsible 
for overall progress of the study, especially critical aspects and in apportioning 
responsibilities to other senior investigators involved in the study. Dr. Moore will 
see identifiable data and interact with subjects. 


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 53
CF-146, Effective 4-26-2010
2.
Dr. Anirban Banerjee: As the Program Director of the NIH/NIGMS funded 
Trauma Research Center, Dr. Banerjee will be responsible for overall 
administration and financial oversight of the study as well as data processing and 
reporting.  Dr. Banerjee will not see identifiable data or interact with subjects. 
3.
Dr. Kirk Hansen:  As Assistant Professor and an internationally acclaimed expert 
in advanced Mass Spectrometric methods deciphering the proteomics of post-
shock blood and lymph, he will have primary responsibility for quantitatively 
identifying proteins in blood samples. Dr. Hansen will not see identifiable data or 
interact with the subjects. 
4.
Dr. Xiayuan Liang: As an Associate Professor of pathology, and the 
hematopathologist at Colorado Children’s Hospital, Dr. Liang will ensure that all 
measurements of soluble coagulation factors, anti-coagulant and the thrombolytic 
system are done appropriately and will aid in the analysis of these data. She is 
also an expert in processing very small volumes of blood to obtain the most 
comprehensive panel of coagulation factors using the powerful STARR 
instrument at nominal costs. Dr. Liang will not see identifiable data or interact 
with subjects. 
5.
Dr. Angela Sauaia: As an expert epidemiologist and biometrician, she will be 
responsible for coordinating data collection and quality, database management, 
and blinded interim data analyses and relations with IRB.  Dr. Sauaia may see 
identifiable data. 
6.
Dr. Christopher Silliman: As a Professor of Pediatrics and Surgery and a board 
certified pediatric hematologist, Dr. Silliman will review all hematological data, 
coagulative proteomics data, and perform the ELISAs and other assays in his 
laboratory including Quality Controlled analyses and presentation.  Along with Dr. 
Moore, he will be responsible for analysis of the TEG data. Dr. Silliman may see 
identifiable data. 
7.
Dedicated study PRAs will be responsible for providing coverage of the ER in 
response to trauma alerts.  They will provide coverage 24/7 with available back 
up, especially over holiday and weekend nights when historically most such 
alerts occur.  All will be thoroughly cross trained in specimen processing and 
banking; data abstraction, entry and reporting; regulatory reporting; and patient 
consenting. These PRAs will also be trained to conduct viscoelastic assays on 
sequentially obtained samples, as well as helping perform other assays 
(cytokines, ELISAs etc.). All PRAs will be required to undergo CITI human 
research training prior to viewing identifiable information and/or having interaction 
with subjects.
8.
Dr. Chris Colwell: As the Director of Emergency Medicine at Denver Health 
Medical Center, he will oversee the logistics of delivering AB-FP24 to patients. 
Dr. Colwell will see identifiable data and may interact with subjects. 
9.
Dr. Tuan Lee: As the Medical Director of Bonfils Blood Center and Medical 
Director for Transfusion Services at Denver Health, , Dr. Lee will provide 
scientific and medical direction that supports high-quality blood products and 
components, laboratory testing, donor collections and counseling, hospital 
relations, product management and clinical research. .  


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 54
CF-146, Effective 4-26-2010
10. Dr. Theresa Chin is a consultant on the project and a current surgical resident.
11. Arsen Ghasabyan is the safety officer of the project. He is responsible for 
overseeing the PRA’s.
12. Dr. Steven Moulton: Will oversee aspects of the study related to the collection of 
waveform data. 
P.
Accurate and complete study records will be maintained and made available to 
representatives of the U.S. Army Medical Research and Materiel Command. These 
representatives are authorized to review research records as part of their responsibility to 
protect human research volunteers. Research records will be stored in a confidential 
manner so as to protect the confidentiality of subject information
Q. Summary of Knowledge to be Gained:
1.
Public Purpose: Hemorrhage is the most preventable cause of death in trauma 
patients.  
Epidemiologic studies at civilian trauma centers have revealed 
hemorrhage as responsible for up to 50% of trauma related mortality.  But 
despite improvements in patient transport via EMS, survival in the first hour 
postinjury has changed little over the past 40 years.  Crystalloids remain the 
mainstay of treatment without a convincing reduction of mortality due to blood 
loss.  Thawed plasma, as a third generation fluid for initial resuscitation, appears 
logical and promising, but has not been evaluated. While many urban trauma 
centers can provide various blood products, including thawed plasma, as 
required in the ED and in the field, the vast majority of rural trauma centers 
cannot resemble the austere conditions of the military frontline environment.  
Stage I will allow this study to be generalizable to the most typical scenario in the 
U.S., i.e., thawed plasma only available in the ED. Moreover, as we have 
witnessed, natural disasters and acts of terrorisms cause mass casualties that 
can overwhelm labile blood product resources.  A stable plasma preparation that 
can be stored for longer periods is necessary for these situations. Civilian trauma 
victims will benefit from longer time for transportation as well as more time for 
blood banks to prepare and deploy specific blood components. Blood products, 
especially pRBCs have been associated with increased morbidity and mortality 
among civilian trauma victims who will likely experience improved outcomes with 
decreased blood product utilization.  In addition, our already depleted blood 
supplies will benefit from decreased utilization. 
2.
Military Significance: Traumatic blood loss due to combat related injuries is the 
primary cause of death in field combatants. While significant advances have 
been made in the prevention and treatment of hemorrhage with the introduction 
of novel hemostatic dressings and tourniquets, little progress has been made in 
developing new resuscitation strategies. Primary resuscitation using crystalloids 
is the current standard of care.  Crystalloids only provide a means to temporarily 
increase intravascular volume to maintain blood pressure and may not be the 
optimal initial resuscitation fluid in traumatic hemorrhagic shock. The proposed 
study will elucidate the use of plasma in the pre-hospital setting as an initial 
resuscitation fluid for traumatic hemorrhage.  This project will also be the 


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 55
CF-146, Effective 4-26-2010
gateway study to examine and compare the use of long shelf-life and more 
logistically accessible resuscitation fluids, such as lyophilized plasma, and, in 
development, the multifunctional resuscitation fluids.  This study will provide an 
exponential leap forward in the care and development of future therapies for the 
wounded war fighter in the field.  The data generated from this study will provide 
i. an evaluation of the safety and efficacy of the early use of plasma, ii. 
information on the mechanism(s) of acute traumatic coagulopathy, and iii. a 
functional and proteomic baseline to gauge the desired composition of future 
plasma-based products, such as lyophilized plasma and multifunctional 
resuscitation fluids. Delaying the requirement of pRBC transfusion will allow 
longer transport times to combat support units stocked with pRBC in the military 
theater. In addition, there will be more time to adequately array blood 
components for transfusion. Decreasing blood products transfusion in the initial 
postinjury period has implications for decreased need of precious blood products, 
as well as a decrease in the deleterious effects of blood products in the postinjury 
period including increased rates of MOF, ARDS, infections and death as well as 
hospital resources utilization (ICU stay and mechanical ventilation time)
3.
Waveform Data: Previous research supports the notion that LBNP is a well 
tested and safe model that can be used to simulate severe hemorrhage 
approaching cardiovascular collapse in humans. However, data from LBNP 
experiments have not been directly compared to data collected from bleeding 
and hemodynamically unstable trauma patients in a hospital setting. If our main 
hypothesis is proven correct, that the physiologic changes that occur with the 
application of LBNP mimic those observed in bleeding and hemodynamically 
unstable trauma patients, then the LBNP model could be used to further explore 
the human response to severe hemorrhage secondary to trauma. This 
knowledge would facilitate future research investigating the relationship between 
continuous physiologic waveform features and central volume loss, and may in 
the future reveal additional early indicators of hemodynamic instability, 
cardiovascular collapse and risk of death secondary to traumatic hemorrhage.
R.
Changes to the Protocol: Substantive modifications to the research protocol and any 
modifications that could potentially increase risk to subjects must be submitted to the 
HRPO for approval prior to implementation.  The USAMRMC ORP HRPO defines a 
substantive modification as a change in Principal Investigator, change or addition of an 
institution, elimination or alteration of the consent process, change to the study population 
that has regulatory implications (e.g. adding children, adding active duty population, etc.), 
significant change in study design (i.e. would prompt additional scientific review), or a 
change that could potentially increase risks to subjects.
S.
Continuing Review and Final Report:  A copy of the continuing review report and the 
re-approval notification by the IRB must be submitted to the HRPO as soon as possible 
after receipt of approval Please note that the HRPO also conducts random audits at the 
time of continuing review and additional information and documentation may be 
requested at that time. 


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 56
CF-146, Effective 4-26-2010
T.
The final study report submitted to the IRB, including a copy of any acknowledgement 
documentation and any supporting documents must be submitted to the HRPO as soon 
as all documents become available. DOD Funded Research Guidelines: The protocol 
will not be initiated until written notification of approval of the research project is issued by 
the HRPO.  
Suspensions, clinical holds (voluntary or involuntary), or terminations of this research by the IRB, 
the institution, the sponsor, or regulatory agencies will be promptly reported to the USAMRMC 
ORP HRPO. The knowledge of any pending compliance inspection/visit by the Food and Drug 
Administration (FDA), Office for Human Research Protections, or other government agency 
concerning this research; the issuance of inspection reports, FDA Form 483, warning letters, or 
actions taken by any regulatory agencies including legal or medical actions; and any instances of 
serious or continuing noncompliance with the regulations or requirements must be reported 
immediately to the HRPO.
References
1.
Demetriades D, Kimbrell B, Salim A, et al. Trauma deaths in a mature urban trauma 
system: is "trimodal" distribution a valid concept? J Am Coll Surg 2005;201:343-8.
2.
Dutton RP, Stansbury LG, Leone S, Kramer E, Hess JR, Scalea TM. Trauma mortality in 
mature trauma systems: are we doing better? An analysis of trauma mortality patterns, 1997-
2008. J Trauma 2010;69:620-6.
3.
Potenza BM, Hoyt DB, Coimbra R, Fortlage D, Holbrook T, Hollingsworth-Fridlund P. The 
epidemiology of serious and fatal injury in San Diego County over an 11-year period. J Trauma 
2004;56:68-75.
4.
Sauaia A, Moore FA, Moore EE, et al. Epidemiology of trauma deaths: a reassessment. J 
Trauma 1995;38:185-93.
5.
Bellamy RF. The causes of death in conventional land warfare: implications for combat 
casualty care research. Mil Med 1984;149:55-62.
6.
Holcomb JB, McMullin NR, Pearse L, et al. Causes of death in U.S. Special Operations 
Forces in the global war on terrorism: 2001-2004. Ann Surg 2007;245:986-91.
7.
McNamara JJ, Stremple JF. Causes of death following combat injury in an evacuation 
hospital in Vietnam. J Trauma 1972;12:1010-2.
8.
Pruitt BA, Jr. Combat casualty care and surgical progress. Ann Surg 2006;243:715-29.
9.
Brohi K, Singh J, Heron M, Coats T. Acute traumatic coagulopathy. J Trauma 
2003;54:1127-30.


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 57
CF-146, Effective 4-26-2010
10.
Floccard B, Rugeri L, Faure A, et al. Early coagulopathy in trauma patients: An on-scene 
and hospital admission study. Injury 2010.
11.
Maegele M, Lefering R, Yucel N, et al. Early coagulopathy in multiple injury: an analysis 
from the German Trauma Registry on 8724 patients. Injury 2007;38:298-304.
12.
Moore EE, Moore FA, Fabian TC, et al. Human polymerized hemoglobin for the treatment 
of hemorrhagic shock when blood is unavailable: the USA multicenter trial. J Am Coll Surg 
2009;208:1-13.
13.
Santry HP, Alam HB. Fluid resuscitation: past, present, and the future. Shock 
2010;33:229-41.
14.
Brohi K, Cohen MJ, Ganter MT, Matthay MA, Mackersie RC, Pittet JF. Acute traumatic 
coagulopathy: initiated by hypoperfusion: modulated through the protein C pathway? Ann Surg 
2007;245:812-8.
15.
Brohi K, Cohen MJ, Ganter MT, et al. Acute coagulopathy of trauma: hypoperfusion 
induces systemic anticoagulation and hyperfibrinolysis. J Trauma 2008;64:1211-7; discussion 7.
16.
Gando S, Sawamura A, Hayakawa M. Trauma, shock, and disseminated intravascular 
coagulation: lessons from the classical literature. Ann Surg 2011;254:10-9.
17.
Hayakawa M, Sawamura A, Gando S, et al. Disseminated intravascular coagulation at an 
early phase of trauma is associated with consumption coagulopathy and excessive fibrinolysis 
both by plasmin and neutrophil elastase. Surgery 2011;149:221-30.
18.
Johansson PI, Ostrowski SR. Acute coagulopathy of trauma: balancing progressive 
catecholamine induced endothelial activation and damage by fluid phase anticoagulation. Med 
Hypotheses 2010;75:564-7.
19.
Kashuk JL, Moore EE, Sawyer M, et al. Primary fibrinolysis is integral in the pathogenesis 
of the acute coagulopathy of trauma. Ann Surg 2010;252:434-42; discussion 43-4.
20.
Levi M, van der Poll T. Inflammation and coagulation. Crit Care Med 2010;38:S26-34.
21.
Lissauer ME, Johnson SB, Siuzdak G, et al. Coagulation and complement protein 
differences between septic and uninfected systemic inflammatory response syndrome patients. J 
Trauma 2007;62:1082-92; discussion 92-4.
22.
Loof TG, Schmidt O, Herwald H, Theopold U. Coagulation systems of invertebrates and 
vertebrates and their roles in innate immunity: the same side of two coins? J Innate Immun 
2011;3:34-40.
23.
Ruf W, Ruggeri ZM. Neutrophils release brakes of coagulation. Nat Med 2010;16:851-2.
24.
Van de Wouwer M, Collen D, Conway EM. Thrombomodulin-protein C-EPCR system: 
integrated to regulate coagulation and inflammation. Arteriosclerosis, thrombosis, and vascular 
biology 2004;24:1374-83.
25.
Miller RD, Robbins TO, Tong MJ, Barton SL. Coagulation defects associated with 
massive blood transfusions. Ann Surg 1971;174:794-801.
26.
Rutherford RB, West RL, Hardaway RM, 3rd. Coagulation changes during experimental 
hemorrhagic shock. Clotting activity, contribution of splanchnic circulation and acidosis as 
controlled by THAM. Ann Surg 1966;164:203-14.
27.
Simmons RL, Collins JA, Heisterkamp CA, Mills DE, Andren R, Phillips LL. Coagulation 
disorders in combat casualties. I. Acute changes after wounding. II. Effects of massive 
transfusion. 3. Post-resuscitative changes. Ann Surg 1969;169:455-82.
28.
Harrigan C, Lucas CE, Ledgerwood AM. The effect of hemorrhagic shock on the clotting 
cascade in injured patients. J Trauma 1989;29:1416-21; discussion 21-2.
29.
Kashuk JL, Moore EE, Millikan JS, Moore JB. Major abdominal vascular trauma--a 
unified approach. J Trauma 1982;22:672-9.
30.
Phillips TF, Soulier G, Wilson RF. Outcome of massive transfusion exceeding two blood 
volumes in trauma and emergency surgery. J Trauma 1987;27:903-10.
31.
Murray DJ, Olson J, Strauss R, Tinker JH. Coagulation changes during packed red cell 
replacement of major blood loss. Anesthesiology 1988;69:839-45.
32.
Murray DJ, Pennell BJ, Weinstein SL, Olson JD. Packed red cells in acute blood loss: 
dilutional coagulopathy as a cause of surgical bleeding. Anesth Analg 1995;80:336-42.
33.
Borgman MA, Spinella PC, Perkins JG, et al. The ratio of blood products transfused 
affects mortality in patients receiving massive transfusions at a combat support hospital. J 
Trauma 2007;63:805-13.


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 58
CF-146, Effective 4-26-2010
34.
Spinella PC, Perkins JG, Grathwohl KW, et al. Effect of plasma and red blood cell 
transfusions on survival in patients with combat related traumatic injuries. J Trauma 2008;64:S69-
77; discussion S-8.
35.
Gunter OL, Jr., Au BK, Isbell JM, Mowery NT, Young PP, Cotton BA. Optimizing 
outcomes in damage control resuscitation: identifying blood product ratios associated with 
improved survival. J Trauma 2008;65:527-34.
36.
Kashuk JL, Moore EE, Johnson JL, et al. Postinjury life threatening coagulopathy: is 1:1 
fresh frozen plasma:packed red blood cells the answer? J Trauma 2008;65:261-70; discussion 
70-1.
37.
Maegele M, Lefering R, Paffrath T, Tjardes T, Simanski C, Bouillon B. Red-blood-cell to 
plasma ratios transfused during massive transfusion are associated with mortality in severe 
multiple injury: a retrospective analysis from the Trauma Registry of the Deutsche Gesellschaft 
fur Unfallchirurgie. Vox Sang 2008;95:112-9.
38.
Moore FA, Nelson T, McKinley BA, et al. Is there a role for aggressive use of fresh frozen 
plasma in massive transfusion of civilian trauma patients? Am J Surg 2008;196:948-58; 
discussion 58-60.
39.
Teixeira PG, Inaba K, Shulman I, et al. Impact of plasma transfusion in massively 
transfused trauma patients. J Trauma 2009;66:693-7.
40.
Snyder CW, Weinberg JA, McGwin G, Jr., et al. The relationship of blood product ratio to 
mortality: survival benefit or survival bias? J Trauma 2009;66:358-62; discussion 62-4.
41.
Gonzalez EA, Moore FA, Holcomb JB, et al. Fresh frozen plasma should be given earlier 
to patients requiring massive transfusion. J Trauma 2007;62:112-9.
42.
Wafaisade A, Maegele M, Lefering R, et al. High plasma to red blood cell ratios are 
associated with lower mortality rates in patients receiving multiple transfusion (4</=red blood cell 
units<10) during acute trauma resuscitation. J Trauma 2011;70:81-8; discussion 8-9.
43.
Alam HB, Bice LM, Butt MU, et al. Testing of blood products in a polytrauma model: 
results of a multi-institutional randomized preclinical trial. J Trauma 2009;67:856-64.
44.
Duchesne JC, McSwain NE, Jr., Cotton BA, et al. Damage control resuscitation: the new 
face of damage control. J Trauma 2010;69:976-90.
45.
Dutton RP. Resuscitative strategies to maintain homeostasis during damage control 
surgery. Br J Surg 2012;99 Suppl 1:21-8.
46.
Duchesne JC, Barbeau JM, Islam TM, Wahl G, Greiffenstein P, McSwain NE, Jr. 
Damage control resuscitation: from emergency department to the operating room. Am Surg 
2011;77:201-6.
47.
Rhee P, Koustova E, Alam HB. Searching for the optimal resuscitation method: 
recommendations for the initial fluid resuscitation of combat casualties. J Trauma 2003;54:S52-
62.
48.
Kheirabadi BS DK, Terrazas I, Callego HL, Dubick MA, Blackbourne LH. Is limited 
prehospital resuscitation with plasma or albumin more advantageous than hextend, the standard 
resuscitation fluid on the battlefield? . Presented at the 70th Annual American Association for the 
Surgery of Trauma conference on September 14, 2011.
49.
Radwan ZA MN, Podbielski J, Del Junco D, McCarthy JJ, Bai Y, Wade CE, Holcomb JB, 
Cotton BA. An emergency department thawed plasma (TP) protocol decreases blood component 
utilization and improves survival in severely injured patients. Presented at the 70th Annual 
American Association for the Surgery of Trauma conference on September 14, 2011.
50.
Kim BD, Zielinski MD, Jenkins DH, Schiller HJ, Berns KS, Zietlow SP. The effects of 
prehospital plasma on patients with injury: A prehospital plasma resuscitation. Journal of Trauma 
and Acute Care Surgery 2012;73(2) Supplement 1:p S49–S53.
51.
Additional Standards for Human Blood and Blood Products, Title 21 Code of Federal 
Regulations 
Part 
640. 
(Accessed 
May 
31, 
2012, 
at 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=640.)
52.
Farrah T, Deutsch EW, Omenn GS, et al. A high-confidence human plasma proteome 
reference set with estimated concentrations in PeptideAtlas. Mol Cell Proteomics 2011.
53.
Liu T, Qian WJ, Gritsenko MA, et al. High dynamic range characterization of the trauma 
patient plasma proteome. Mol Cell Proteomics 2006;5:1899-913.


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 59
CF-146, Effective 4-26-2010
54.
Horowitz B, Busch M. Estimating the pathogen safety of manufactured human plasma 
products: application to fibrin sealants and to thrombin. Transfusion 2008;48:1739-53.
55.
Scott E, Puca K, Heraly J, Gottschall J, Friedman K. Evaluation and comparison of 
coagulation factor activity in fresh-frozen plasma and 24-hour plasma at thaw and after 120 hours 
of 1 to 6 degrees C storage. Transfusion 2009;49:1584-91.
56.
Yazer MH, Cortese-Hassett A, Triulzi DJ. Coagulation factor levels in plasma frozen 
within 24 hours of phlebotomy over 5 days of storage at 1 to 6 degrees C. Transfusion 
2008;48:2525-30.
57.
Maniatis NA, Harokopos V, Thanassopoulou A, et al. A critical role for gelsolin in 
ventilator-induced lung injury. Am J Respir Cell Mol Biol 2009;41:426-32.
58.
Peltz ED, Moore EE, Zurawel AA, et al. Protease inhibitors are depleted in postshock 
mesenteric lymph. Shock 2009;31.
59.
Tucker N, Dzieciatkowska M, Hansen K, et al. a-enolase from injured patients and stored 
packed red blood cells activates pulmonary endothelium and serves as the first event in a two-
event model of neutrophil cytotoxicity. Blood 2010;116:1374.
60.
Silliman CC, Dzieciatkowska M, Moore EE, et al. Proteomic analyses of human plasma: 
Venus versus Mars. Transfusion 2012;52:417-24.
61.
Guidance for Industry: An Acceptable Circular of Information for the Use of Human Blood 
and 
Blood 
Components. 
October 
2009. 
(Accessed 
at 
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformati
on/Guidances/Blood/UCM187348.pdf.)
62.
Gibson BE, Todd A, Roberts I, et al. Transfusion guidelines for neonates and older 
children. Br J Haematol 2004;124:433-53.
63.
Moore FA, Moore EE, Sauaia A. Blood transfusion. An independent risk factor for 
postinjury multiple organ failure. Arch Surg 1997;132:620-4; discussion 4-5.
64.
Ketchum L, Hess JR, Hiippala S. Indications for early fresh frozen plasma, 
cryoprecipitate, and platelet transfusion in trauma. J Trauma 2006;60:S51-8.
65.
Cotton BA, Gunter OL, Isbell J, et al. Damage control hematology: the impact of a trauma 
exsanguination protocol on survival and blood product utilization. J Trauma 2008;64:1177-82; 
discussion 82-3.
66.
Geeraedts LM, Jr., Demiral H, Schaap NP, Kamphuisen PW, Pompe JC, Frolke JP. 
'Blind' transfusion of blood products in exsanguinating trauma patients. Resuscitation 
2007;73:382-8.
67.
Bulger EM, May S, Kerby JD, et al. Out-of-hospital hypertonic resuscitation after 
traumatic hypovolemic shock: a randomized, placebo controlled trial. Ann Surg 2011;253:431-41.
68.
Bulger EM, Jurkovich GJ, Nathens AB, et al. Hypertonic resuscitation of hypovolemic 
shock after blunt trauma: a randomized controlled trial. Arch Surg 2008;143:139-48.
69.
Nunez TC, Voskresensky IV, Dossett LA, Shinall R, Dutton WD, Cotton BA. Early 
prediction of massive transfusion in trauma: simple as ABC (assessment of blood consumption)? 
J Trauma 2009;66:346-52.
70.
Cuschieri J, Freeman B, O'Keefe G, et al. Inflammation and the host response to injury a 
large-scale collaborative project: patient-oriented research core standard operating procedure for 
clinical care X. Guidelines for venous thromboembolism prophylaxis in the trauma patient. J 
Trauma 2008;65:944-50.
71.
Evans HL, Cuschieri J, Moore EE, et al. Inflammation and the host response to injury, a 
Large-Scale Collaborative Project: patient-oriented research core standard operating procedures 
for clinical care IX. Definitions for complications of clinical care of critically injured patients. J 
Trauma 2009;67:384-8.
72.
Harbrecht BG, Minei JP, Shapiro MB, et al. Inflammation and the host response to injury, 
a large-scale collaborative project: patient-oriented research core-standard operating procedures 
for clinical care: VI. Blood glucose control in the critically ill trauma patient. J Trauma 
2007;63:703-8.
73.
Minei JP, Nathens AB, West M, et al. Inflammation and the Host Response to Injury, a 
Large-Scale Collaborative Project: patient-oriented research core--standard operating procedures 
for clinical care. II. Guidelines for prevention, diagnosis and treatment of ventilator-associated 
pneumonia (VAP) in the trauma patient. J Trauma 2006;60:1106-13; discussion 13.


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 60
CF-146, Effective 4-26-2010
74.
Moore FA, McKinley BA, Moore EE, et al. Inflammation and the Host Response to Injury, 
a large-scale collaborative project: patient-oriented research core--standard operating procedures 
for clinical care. III. Guidelines for shock resuscitation. J Trauma 2006;61:82-9.
75.
Nathens AB, Johnson JL, Minei JP, et al. Inflammation and the Host Response to Injury, 
a large-scale collaborative project: Patient-Oriented Research Core--standard operating 
procedures for clinical care. I. Guidelines for mechanical ventilation of the trauma patient. J 
Trauma 2005;59:764-9.
76.
O'Keefe GE, Shelton M, Cuschieri J, et al. Inflammation and the host response to injury, 
a large-scale collaborative project: patient-oriented research core--standard operating procedures 
for clinical care VIII--Nutritional support of the trauma patient. J Trauma 2008;65:1520-8.
77.
West MA, Moore EE, Shapiro MB, et al. Inflammation and the host response to injury, a 
large-scale collaborative project: patient-oriented research core--standard operating procedures 
for clinical care VII--Guidelines for antibiotic administration in severely injured patients. J Trauma 
2008;65:1511-9.
78.
West MA, Shapiro MB, Nathens AB, et al. Inflammation and the host response to injury, a 
large-scale collaborative project: Patient-oriented research core-standard operating procedures 
for clinical care. IV. Guidelines for transfusion in the trauma patient. J Trauma 2006;61:436-9.
79.
Kashuk JL, Moore EE, Wohlauer M, et al. Point Of Care (Poc) Rapid 
Thrombelastography Improves Management Of Life Threatening Postinjury Coagulopathy. Ann 
Surg 2009.
80.
Sauaia A, Moore EE, Johnson JL, Ciesla DJ, Biffl WL, Banerjee A. Validation of 
postinjury multiple organ failure scores. Shock 2009;31:438-47.
81.
Sauaia A, Moore FA, Moore EE, Norris JM, Lezotte DC, Hamman RF. Multiple organ 
failure can be predicted as early as 12 hours after injury. J Trauma 1998;45:291-301; discussion -
3.
82.
Cosgriff N, Moore EE, Sauaia A, Kenny-Moynihan M, Burch JM, Galloway B. Predicting 
life-threatening coagulopathy in the massively transfused trauma patient: hypothermia and 
acidoses revisited. J Trauma 1997;42:857-61.
83.
Pezold M, Moore EE, Wohlauer M, et al. Viscoelastic clot strength predicts coagulation-
related mortality within 15 minutes. Surgery 2012;151:48-54.
84.
National Research Council. Panel on Handling Missing Data in Clinical Trials,Committee 
on National Statistics, Division of Behavioral and Social Sciences and Education. The Prevention 
and Treatment of Missing Data in Clinical Trials. Washington, DC; 2010.
85.
Ciesla DJ, Moore EE, Johnson JL, Burch JM, Cothren CC, Sauaia A. A 12-year 
prospective study of postinjury multiple organ failure: has anything changed? Arch Surg 
2005;140:432-8.
86.
Niles SE, McLaughlin DF, Perkins JG, et al. Increased mortality associated with the early 
coagulopathy of trauma in combat casualties. J Trauma 2008;64:1459-63; discussion 63-5.
87.
MacLeod JB, Lynn M, McKenney MG, Cohn SM, Murtha M. Early coagulopathy predicts 
mortality in trauma. J Trauma 2003;55:39-44.
88.
Johnson TL. Denver Emergency Medical Services (EMS) System available at 
emsgarage.com/wp-content/uploads/2008/11/denver_ems_white_paper.pdf. In. Denver: Health 
Policy Solutions; 2008.
89.
Kashuk JL, Moore EE, Sabel A, et al. Rapid thrombelastography (r-TEG) identifies 
hypercoagulability and predicts thromboembolic events in surgical patients. Surgery 
2009;146:764-74.
90.
Kashuk JL, Moore EE, Sawyer M, et al. Postinjury Coagulopathy Management: Goal 
Directed Resuscitation via POC Thrombelastography. Annals of Surgery 2010;251:604-14.
91.
Ouellet JF, Roberts DJ, Tiruta C, et al. Admission base deficit and lactate levels in 
Canadian patients with blunt trauma: Are they useful markers of mortality? J Trauma Acute Care 
Surg 2012;72:1532-5.
92.
Hodgman EI, Morse BC, Dente CJ, et al. Base deficit as a marker of survival after 
traumatic injury: consistent across changing patient populations and resuscitation paradigms. J 
Trauma Acute Care Surg 2012;72:844-51.


On the Web at http://comirbweb.uchsc.edu
Protocol Template
Page 61
CF-146, Effective 4-26-2010
93.
Cancio LC, Galvez E, Jr., Turner CE, Kypreos NG, Parker A, Holcomb JB. Base deficit 
and alveolar-arterial gradient during resuscitation contribute independently but modestly to the 
prediction of mortality after burn injury. J Burn Care Res 2006;27:289-96.
94.
Rixen D, Raum M, Bouillon B, Lefering R, Neugebauer E. Base deficit development and 
its prognostic significance in posttrauma critical illness: an analysis by the trauma registry of the 
Deutsche Gesellschaft fur unfallchirurgie. Shock 2001;15:83-9.
95.
Eberhard LW, Morabito DJ, Matthay MA, et al. Initial severity of metabolic acidosis 
predicts the development of acute lung injury in severely traumatized patients. Crit Care Med 
2000;28:125-31.
96.
Davis JW, Kaups KL, Parks SN. Base deficit is superior to pH in evaluating clearance of 
acidosis after traumatic shock. J Trauma 1998;44:114-8.
97.
Kincaid EH, Miller PR, Meredith JW, Rahman N, Chang MC. Elevated arterial base deficit 
in trauma patients: a marker of impaired oxygen utilization. J Am Coll Surg 1998;187:384-92.
98.
Davis JW, Parks SN, Kaups KL, Gladen HE, O'Donnell-Nicol S. Admission base deficit 
predicts transfusion requirements and risk of complications. J Trauma 1996;41:769-74.
99.
Sauaia A, Moore FA, Moore EE, Haenel JB, Read RA, Lezotte DC. Early predictors of 
postinjury multiple organ failure. Arch Surg 1994;129:39-45.
100.
Rutherford EJ, Morris JA, Reed GW, Hall KS. Base deficit stratifies mortality and 
determines therapy. J Trauma 1992;33:417-23.
101.
Neher M, Weckbach S, Flierl M, Huber-Lang M, Stahel P. Molecular mechanisms of 
inflammation and tissue injury after major trauma-is complement the "bad guy"? Journal of 
Biomedical Science 2011;18:90.
102.
Dente CJ, Shaz BH, Nicholas JM, et al. Improvements in early mortality and 
coagulopathy are sustained better in patients with blunt trauma after institution of a massive 
transfusion protocol in a civilian level I trauma center. J Trauma 2009;66:1616-24.
103.
Schirmer-Mikalsen K, Vik A, Gisvold SE, Skandsen T, Hynne H, Klepstad P. Severe head 
injury: control of physiological variables, organ failure and complications in the intensive care unit. 
Acta AnaesthesiolScand 2007;51:1194-201.
104.
Morganti-Kossmann MC, Satgunaseelan L, Bye N, Kossmann T. Modulation of immune 
response by head injury. Injury 2007;38:1392-400.
105.
Bulger EMMD, May SP, Kerby JDMDP, et al. Out-of-hospital Hypertonic Resuscitation 
After Traumatic Hypovolemic Shock: A Randomized, Placebo Controlled Trial. Ann Surg 
2011;253:431-41.
106.
Schoenfeld DA, Bernard GR. Statistical evaluation of ventilator-free days as an efficacy 
measure in clinical trials of treatments for acute respiratory distress syndrome. Crit Care Med 
2002;30:1772-7.
107.
Hathaway WE, Goodnight SH. Disorders of hemostasis and thrombosis : a clinical guide. 
New York: McGraw-Hill, Health Professions Division; 1993.
108.
Jordan JR, Moore EE, Damle SS, et al. Gelsolin is depleted in post-shock mesenteric 
lymph. J Surg Res 2007;143:130-5.
109.
Spinella PC, Perkins JG, Grathwohl KW, et al. Effect of plasma and red blood cell 
transfusions on survival in patients with combat related traumatic injuries. J Trauma 2008;64:S69-
S77.
110.
Holcomb JB, Jenkins D, Rhee P, et al. Damage control resuscitation: directly addressing 
the early coagulopathy of trauma. J Trauma 2007;62:307-10.
111.
Ho AM, Dion PW, Yeung JH, et al. Prevalence of survivor bias in observational studies 
on fresh frozen plasma:erythrocyte ratios in trauma requiring massive transfusion. Anesthesiology 
2012;116:716-28.
112.
Carson JL, Grossman BJ, Kleinman S, et al. Red Blood Cell Transfusion: A Clinical 
Practice Guideline From the AABB. Ann Intern Med 2012.
113.
Establishment and Operation of Clinical Trial Data Monitoring Committees. In: Services 
UDoHaH, Administration FaD, Research CfBEa, Research CfDEa, Health CfDaR, eds.; March 
2006.

ICF_001.pdf: 
Consent and Authorization Form Approval
Combined Biomedical Consent and HIPAA authorization
CF-151, Effective 8-31-11
Page 1 of 17
Initials______
Study Title:  
Control Of Major Bleeding After Trauma (COMBAT): A prospective, 
randomized comparison of fresh frozen plasma versus standard crystalloid 
intravenous fluid as initial resuscitation fluid
Principal Investigator:
Ernest E. Moore, M.D.
COMIRB No: 12-1349
Version Date: 02/07/2017
Version #: 10
This study is sponsored by the Department of Defense’s Telemedicine & Advanced 
Technology Research Center (TATRC). 
 
This consent form may have words that you do not understand. Please ask the study 
doctor or the study staff to explain any words or information that you do not clearly 
understand. 
Some people in this study cannot make decisions for themselves because of their 
injuries. If you have been asked to decide for someone else whether they should be 
in this study, please read this consent form carefully.  In this form, we use the words 
“you” and “your.”  If you are deciding for someone else, the words ‘you’ and ‘your’ 
refer to that other person, not to you. 
You were placed in this research study based on your injuries or condition. You were 
not able to consent for placement in this study when it began due to your injuries. You 
were placed in this study under exception to informed consent rules. These rules were 
created by the FDA (U.S. Food and Drug Administration) and written in the 21 Code of 
Federal Regulations Section 50.24. In order, to obtain a Waiver of Consent, Federal 
Regulations require that 1) The study must look at a life-threatening health problem 
that needs urgent treatment. 2)The patient cannot give informed consent to be in the 
study due to their condition. 3) Because the dangerous health problem needs to be 
treated quickly, the treatment being studied must be given before a legally authorized 
representative (LAR) can be contacted. 4) The treatment being studied must also 
have potential for helping the patient. 
Before starting this study, the researcher met the requirements to do this type of 
research. The study team talked with community groups throughout the Denver area 
and tried to inform as many people as possible through the media, advertisements, 
and social media. 
At the time of this consent, you have already been placed into a group. With your 
permission, we will continue to test your blood and record your clinical measures. No 
other treatments will be given to you, only standard medical care. When you were 
COMIRB
APPROVED
For Use
10-Feb-2017
07-Apr-2017


Consent and Authorization Form Approval
Combined Biomedical Consent and HIPAA authorization
CF-151, Effective 8-31-11
Page 2 of 17
Initials______
placed in this study, you were in a life-threatening condition that needed care right 
away and could not give your permission due to your injuries.  Placement into the 
study and treatment happened before you or a family member could give 
permission.  We could not obtain your permission before the trauma happened.  This 
study could only be done with an exception from informed consent. 
You are now being told that you are a part of this study. This is the earliest time we 
could inform you of this study. From this point forward, anytime during the study, you 
may stop being a part of the study.  You will not lose any benefits, normal care, 
and/or assistance if you decide to stop being in this study. 
Study Description
Thawed plasma is given to severe trauma patients in the hospital as the standard of 
care to treat bleeding. The purpose of this study is to see if giving thawed plasma 
earlier in the ambulance to trauma patients will help slow or stop bleeding. Usually 
we give trauma patients plasma in the hospital, but we want to see if giving plasma 
in the ambulance will help to slow or stop their bleeding. 
One form of thawed plasma that is given to trauma patients is called AB-FP24. This 
study looks to see if giving AB-FP24 to severe trauma patients in the ambulance will 
limit blood loss compared to giving plasma in the hospital.  
Despite advances in science, patients continue to die from bleeding because their 
blood will not clot. Severely injured patients, who are in shock after trauma, often 
have bleeding that is hard to stop, known as coagulopathy. Normally, we have 
proteins in the blood to form a clot and stop bleeding.  One reason that trauma 
patients continue to bleed is that these proteins in the bloodstream are used up from 
the trauma. Plasma is a part of donated blood that contains these proteins. Plasma 
is often given to slow or stop bleeding. 
You would get the standard of care if you were not enrolled in the study. The current 
standard of care for severe trauma patients begins with giving salt water to replace 
blood that was lost. Then, in the hospital, blood transfusions, thawed plasma, and 
more salt water are given as needed to support the body and help the blood to clot. 
Salt water does not help clotting and only replaces lost blood. 
The doctors conducting the study hope that thawed AB-FP24 that is given during the 
ambulance ride will slow down or stop bleeding in severe trauma patients. In this 
study, the thawed AB-FP24 is given as soon as possible after the severe injury. After 
the thawed AB-FP24, we would give salt water, blood transfusions and more thawed 
AB-FP24 in the hospital as needed.    
You are being asked to continue in this research study because you were severely 
injured in a traumatic event and your heart rate and critically low blood pressure 
(both signs of severe shock) met the criteria to place you in the study. 


Consent and Authorization Form Approval
Combined Biomedical Consent and HIPAA authorization
CF-151, Effective 8-31-11
Page 3 of 17
Initials______
Procedures
Since you were placed in this study, your care has been changed in the following 
ways: 
Starting at the scene of injury, you received the usual treatment for shock that 
occurs following trauma, including finding your vital signs and protection of your 
airway and spinal cord. Since you were placed in the study, your care had the 
following differences: 
1. Before patients get to the hospital, patients are given intravenous (I.V.) fluid into 
their veins to support blood pressure. Since you are in this study, you were given 
either salt water or thawed AB-FP24 as the first I.V fluid. To decide which 
treatment you would get, we used a method of chance.  This method is like 
flipping a coin.  You were randomized to either the standard (salt water solution) 
or experimental (thawed AB-FP24) group. You had an equal chance of being in 
either group.
2. If you were assigned to the standard group, you received salt water as the first 
fluid in the ambulance. You were then treated as all trauma patients are treated 
at the hospital. The doctors who saw you at the hospital may have decided to 
give you a blood transfusion or thawed AB-FP24. If you were transfused, you 
received donated blood products. If you need further blood products, you will be 
given donated blood products.  This is the standard of care for all patients who 
come into the hospital after a severe injury.
3. If you were assigned to the experimental group, you received 2 units AB-FP24 as 
the first fluid in the ambulance.  After the thawed AB-FP24, the doctors at the 
hospital may have decided that you needed a blood transfusion, salt water or 
more plasma.  If you needed or continue to need blood transfusions or thawed 
AB-FP24, donated blood products were and will be given.
4. At the time of this consent, you have been assigned to the standard or 
experimental group. There will be no more differences in treatment between the 
two groups. For both groups, blood samples were collected in the ambulance, in 
the emergency room, 2, 4, 6, 12, 24, 48, and 72 hours after injury and on days 5 
and 7 of your hospital treatment. 
5. We also put body sensors on your skin. Participating in this study will permit us to 
use the data from additional body sensors that you wore in the first 24 hours at 
the hospital. The sensors (pulse oximeters) recorded information about how your 
body was responding to bleeding. You will also allow us to use data from your 
medical records about how you were treated for this hospital visit. 
If you agree to continue to be in this study, we will continue to collect blood samples 
as scheduled above.  The laboratory tests done as part of the study are the same for 
both the standard and experimental groups. We will collect blood samples up to 10 
times during your hospital stay, but some of them are already done.  The most 


Consent and Authorization Form Approval
Combined Biomedical Consent and HIPAA authorization
CF-151, Effective 8-31-11
Page 4 of 17
Initials______
amount of blood drawn for any one sample for research only  will be approximately 8 
teaspoons, for a total of 75 teaspoons of blood.  
The study continues for 28 days after your injury. As with any part of this study, you 
do not have to have your blood drawn and can withdraw from the study anytime. The 
portion of the study involving the body sensor devices is for 24 hours only.
Continuation in this study
If you continue to be in the study, we will continue to watch you closely and record 
pertinent information during your hospital course for 28 days after your injury or until 
you leave the hospital. If you are discharged before 28 days after injury, we will 
contact you 28 days after your injury to see how you are doing.  
Other people in this study 
Up to  224 people from your area will be entered in the study over 5 years. 


Consent and Authorization Form Approval
Combined Biomedical Consent and HIPAA authorization
CF-151, Effective 8-31-11
Page 5 of 17
Initials______
Discomforts and risks
Transfusion risks: In this study, AB-FP24 was the product transfused.  Type AB 
plasma is the universal donor type. This means that the plasma and the blood type 
of the patient getting the transfusion do not have to match. Fresh Frozen Plasma 
(FFP) is taken from donors and frozen within 8 hours. We use AB plasma, called 
AB-FP24, that is frozen within 24 hours. AB-FP24 is almost the same as AB-FFP 
and works for trauma patients who need the clotting proteins after severe injury.  
After receiving any blood products, patients may have a small increased risk of 
infection. They may also have a small increased risk of a transfusion related 
reaction. Both the thawed AB-FP24 in the experimental group and all blood products 
given as the standard of care in the standard group have these small increased 
risks. Most patients with severe injuries will require thawed plasma without being in 
this study. After getting any sort of blood product, the risk of infection is: 

1 in 1,467,000 chance of HIV infection (human immunodeficiency virus),

1 in 8,300,000 chance of hepatitis A infection,

1 in 282,000 chance of hepatitis B infection,

1 in 1,149,000 chance of hepatitis C infection,

1 in 4,000,000 chance of malaria infection, and

1 in 2,990,000 chance of getting a human T-cell lymphotrophic virus infection 
(A virus that can cause leukemia or lymphoma)  
Other risks of blood transfusion include: 

Fever, chills, or hives (1.1% to 2.5%),

hemolytic transfusion reactions that occurs when the immune system of the 
patient receiving the blood transfusion attacks the cells in the transfusion of 
donated blood (1:1,250,000),

transfusion-related lung injury (8.1 per 100,000), and 

transfusion associated circulatory overload, which occurs with rapid 
transfusion of a large volume of blood (2-3 per 100). 
If you are enrolled and found to be pregnant and got thawed AB-FP24 from the 
study, there may be risks to the embryo or fetus. These risks are currently unclear. 
The thawed plasma (AB-FP24) that is given in the experimental group is the same 
plasma that is given in the standard treatment. Again, the experimental group 
receives the AB-FP24 in the ambulance. The standard group receives salt water 
solution in the ambulance.


Consent and Authorization Form Approval
Combined Biomedical Consent and HIPAA authorization
CF-151, Effective 8-31-11
Page 6 of 17
Initials______
Venipuncture risk: In most cases, blood can be drawn from a line in your vein (I.V.) 
already placed as part of your standard medical care. In the event you do not have 
an I.V., blood will be drawn by placing a small needle in a vein in your arm to remove 
blood. Blood is typically drawn this way if there is no I.V. Risks related with drawing 
blood from your arm include slight pain, bruising, lightheadedness, and a very low 
risk of infection. In this study we will need to get about 75 teaspoons of blood from 
you over the entire study period. You may feel some pain when the needle goes into 
your vein.  A day or two later, you may have a small bruise where the needle went 
under the skin. 
Risk of unplanned release of protected health information (PHI): There is also a 
risk that people outside of the study team will see your personal information. We will 
do all that we can to protect your personal information.
Risk of unexpected events: Your condition may not improve or may worsen while 
being a part of this study. You will be told of any major new findings that may affect 
your decision to remain in the study.   
It is not expected that patients placed in this study will have a reaction to plasma 
transfusion.  Plasma is usually given to severe trauma patients as the standard of 
care. This study focuses on the time period it is given. 
Body Sensors Risks: There are no known risks to wearing sensors, but there may 
be some discomfort. The discomforts associated with a pulse oximeter may be felt if 
the sensor is on too tight. We can reapply the sensor so it doesn’t feel too tight. It 
may leave small marks on your skin. These marks should go away after removing 
the sensor. We may use something sticky to keep the sensor on you which could 
make your skin itch. These sensors are made to be used on patients and don’t 
bother most people’s skin.
The study may include risks that are unknown at this time. 
Benefits of the study
This study is intended to benefit you, but we cannot guarantee that your health will 
improve if you join this study or continue in this study. You have either received 
usual medical care or you have received the experimental treatment that includes 
early thawed AB-FP24. If you are in the experimental group, we hoped to decrease 
the amount of blood lost. In the end, we hoped to decrease the amount of blood 
products given to you.  If you get less blood products, your risk of infection from 
donated blood may be lowered. 
In both groups, we have tested your blood’s ability to clot normally in the first 24 
hours after your injury. We also monitored the amount of blood transfusions that you 
need. By doing these things, we may be able to treat you better by reducing the 


Consent and Authorization Form Approval
Combined Biomedical Consent and HIPAA authorization
CF-151, Effective 8-31-11
Page 7 of 17
Initials______
amount of blood you lose. Other possible benefits include a decreased risk of organ 
failure and infection, a decreased number of days in the intensive care unit, and a 
decreased risk of death.
By taking part in this study, there is no guarantee that your health will improve. Also, 
there are risks as mentioned in the Discomforts and Risk section. 
Wearing the body sensor devices is a procedure designed for the researchers 
involved in the study to learn more about how our bodies respond to bleeding. 
Allowing us to collect data is not designed to treat any illness or to improve your 
health. Also, there may be risks, as discussed in the section describing the 
discomforts or risks.
Alternative treatments 
At the time of this consent, you have already been given the standard or 
experimental treatment. From now on, you will receive the standard treatment given 
to all trauma patients.  However, we will continue to collect blood samples for up to 7 
days after your admission to the hospital. We will collect clinical data up to 28 days 
after injury. As an alternative, you may refuse to continue follow up in this study.  If 
you refuse to continue follow-up, you will still get the standard medical care. 
Who is paying for this study?
The COMBAT Study is being paid for by the Department of Defense. The use of the 
body sensors is being paid by a separate grant to Flashback Technologies from the 
Department of Defense.  The data gathered from this device may be used to develop 
a commercial product. Currently, this device is not approved by the FDA. The 
product would be based on technology invented by Dr. Moulton, a co-investigator of 
this project, and assigned to the Regents of the University of Colorado. Flashback 
Technologies Inc. has licensed the technology from the University of Colorado, and 
Dr. Moulton has an equity interest in Flashback Technologies. If a commercial 
product is developed, Dr. Moulton, Flashback Technologies Inc., and the University 
of Colorado could gain financially by selling the product.
One of the investigators in this study (Dr. Moore) as well as the University of Colorado own 
intellectual property that is related to this study. As this may represent potential or perceived 
conflicts of interest (COI), management plans have been put into place to minimize the 
possibility that any COI will influence the outcome of the study.
Payment for being in the study  
You will not be paid to be in the study. 


Consent and Authorization Form Approval
Combined Biomedical Consent and HIPAA authorization
CF-151, Effective 8-31-11
Page 8 of 17
Initials______
Cost to you
It will not cost you anything to be in the study and you will not be charged for 
laboratory tests done only for this study.
Continuing participation
Continuing to take part in this study is up to you. You have the right to choose not to 
continue in this study. If you decide to withdraw, you will not lose any benefits or 
rights. You will also still get the standard medical care given to all trauma patients. At 
this point, study treatments are done. Your continued participation would mean that 
blood samples will be collected from you if you are still in the hospital. Your clinical 
results would be monitored until 28 days after injury. 
You were enrolled in the study under the federal rules for emergency research, 21 
CFR Section 50.24.  These rules require the study team to inform the public about 
the study and get feedback from the community before the study begins. People 
have the choice to “opt out” or not be placed in the study. They can do this by 
wearing a study bracelet or study necklace. This tells the ambulance crew at the 
time of your injury to not to place you into the study. Since this study is being done 
on severely injured patients, there is a chance these things may not be found on the 
patient.  To the best of our knowledge, you were wearing neither a study bracelet 
nor a study necklace when you were enrolled in the study. 
If you do choose to continue to be in the study, you have the right to stop at any 
time.  The only treatment that you will lose is the care you are getting as part of this 
study.
If there are any new findings during the study that may affect whether you want to 
continue to participate, you will be notified about them.
Removal from this study 
The study doctor may decide to take you out of the study without your permission. 
The infusion of the AB-FP24 may have been stopped if the study team found out you 
did not want to be enrolled, you refused blood products, or you had a major 
transfusion reaction. Also, the sponsor, Department of Defense’s Telemedicine & 
Advanced Technology Research Center (TATRC), may stop the study at any time. 
Injury from the study   
If you have an injury while you are in this study, you should call Ernest E. Moore, MD 
immediately.  His phone number is 303-602-1820.  We will explore to see if the 
injury was due to the study.  We will arrange to get you medical care if you have an 
injury that is caused by this research.  However, you or your insurance company will 
have to pay for that care. 


Consent and Authorization Form Approval
Combined Biomedical Consent and HIPAA authorization
CF-151, Effective 8-31-11
Page 9 of 17
Initials______
If you have questions
You may have questions about your rights as a patient in this study. If you have 
questions, concerns, or complaints, you may call Ernest E. Moore, M.D. at (303) 602-
1820. You will be given a copy of this form to keep.  
You can also call the Institutional Review Board who approved this study (COMIRB) 
at 303-724-1055.  COMIRB (Colorado Multiple Institutional Review Board) is a group 
of people not related to the study. They make sure the patients placed in the study 
have the lowest risk of harm from the study as possible.  
 
A description of this study will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This website will not include information that can identify you. 
At most, the website will include a summary of the results. You can access this 
website at any time. 
You may also access a website specific to the COMBAT study. It will provide 
information as well as a forum for comments and questions.  Links to this website will 
be 
accessible 
via 
the 
Denver 
Health 
website 
(http://denverhealth.org/COMBATStudy).
Optional Consent and Authorization for Data and Blood Banking for Future 
Research 
Dr. Ernest E. Moore would like to keep some of the data and blood that is taken 
during the study but is not used for other tests. If you agree, the data and blood will 
be kept and may be used in future research to learn more about trauma related 
illnesses. The research that is done with your data and blood is not designed to 
especially help you. However, it might help people who have a traumatic injury in the 
future. Reports about research done with your data and blood will not be given to 
you or your doctor. These reports will not be put in your health records. The 
research using your data and blood will not affect your care in any way.
The choice to let Dr. Moore keep the data and blood for future research is up to you. 
No matter what you decide to do, it will not affect the care that you will receive as 
part of the study. If you decide now that your data and blood can be kept for 
research, you can change your mind at any time and contact Dr. Moore to let him 
know that you do not want your data or blood used any longer, and they will no 
longer be used for research. Otherwise, they may be kept until they are used up, or 
until Dr. Moore decides to destroy them. 
When your data and blood are given to other researchers in the future, Dr. Moore 
will not give them your name, address, phone number or any other information that 
will let the researchers know who you are. 


Consent and Authorization Form Approval
Combined Biomedical Consent and HIPAA authorization
CF-151, Effective 8-31-11
Page 10 of 17
Initials______
Sometimes data and blood are used for genetic research (about diseases that are 
passed on in families). Even if your data and blood are used for this kind of 
research, the results will not be told to you and will not be put in your health records. 
Your data and blood will only be used for research and will not be sold. The research 
done with your data and blood may help to develop new products in the future, but 
there is no plan for you to be paid.
The possible benefits of research from your data and blood include learning more 
about what causes illnesses in trauma patients, how to prevent them and how to 
treat them. The greatest risk to you is the release of your private information.  Dr. 
Moore will protect your records so that your name, address and phone number will 
be kept private. The chance that this information will be given to someone else is 
very small. There will be no cost to you for any data or blood collection and storage 
by Dr. Moore.  
The data and blood collected from you during this study are important to this study 
and to future research.  If you join this study:
The data or blood are given by you to the investigators for this research and 
therefore no longer belong to you.  However, if you take back your 
permission to use your data and blood, we will no longer use your data or 
blood in research. 
Both the investigators and any sponsor of this research may study your data 
and blood collected from you.
If data or blood are in a form that identifies you, UCD or the hospitals 
involved in this study may use them for future research only with your 
consent or IRB approval.
Any product or idea created by the researchers working on this study will not 
belong to you.
There is no plan for you to get any financial benefit from the creation, use or 
sale of such a product or idea. 


Consent and Authorization Form Approval
Combined Biomedical Consent and HIPAA authorization
CF-151, Effective 8-31-11
Page 11 of 17
Initials______
Storage of Data and Blood
Please read each sentence below and think about your choice.  After reading 
each sentence, circle “yes” or “no.” If you have questions, please talk to your 
doctor or nurse. Remember, no matter what you decide to do about the storage 
and future use of your data and blood, you may still take part in the study.
I give my permission for my data and blood to be stored in a central tissue bank 
at DHMC for future use by the study investigators:
1.
I give my permission for my data and blood to be kept by Dr. Moore for use 
in future research to learn more about how to prevent, detect, or treat trauma-
related illnesses.
☐  Yes
☐   No
________Initials
2.
I give my permission for my data and blood to be used for research about 
other health problems (for example: causes of heart disease, osteoporosis, 
diabetes).
☐   Yes
☐   No
_________Initials
3.
I give my permission for my study doctor (or someone he or she chooses) 
to contact me in the future to ask me to take part in more research.
☐   Yes
☐   No
_________Initials
Who will see my research information?
The University of Colorado Denver and the hospital(s) it works with have rules to 
protect information about you.  
Federal and state laws including the Health 
Insurance Portability and Accountability Act (HIPAA) also protect your privacy.   This 
part of the consent form tells you what information about you may be collected in this 
study and who might see or use it.  
The institutions involved in this study include: 
University of Colorado Denver
The Children’s Hospital


Consent and Authorization Form Approval
Combined Biomedical Consent and HIPAA authorization
CF-151, Effective 8-31-11
Page 12 of 17
Initials______
Denver Health and Hospital Authority
The Children’s Hospital of Colorado shares a medical record system with the 
Barbara Davis Center and PedsConnect; therefore, it is also possible that your 
information could be viewed by healthcare professionals at these organizations. 
We cannot do this study without your permission to see, use and give out your 
information.  You do not have to give us this permission.  If you do not, then you may 
not join this study.  
We will see, use and disclose your information only as described in this form and in 
our Notice of Privacy Practices; however, people outside the University of Colorado 
Denver and its affiliate hospitals may not be covered by this promise.
We will do everything we can to keep your records a secret.  It cannot be 
guaranteed. 
The use and disclosure of your information has no time limit.  You can cancel your 
permission to use and disclose your information at any time by writing to the study’s 
Primary Investigator, at the name and address listed below.  If you do cancel your 
permission to use and disclose your information, your part in this study will end and 
no further information about you will be collected.  Your cancellation would not affect 
information already collected in this study.  
Ernest E. Moore, MD
655 Broadway, Suite 365
MC 1655
Denver, CO 80203
(303) 602-1820
Both the research records that identify you and the consent form signed by you may 
be looked at by others who have a legal right to see that information.  

Federal offices such as the Food and Drug Administration (FDA) that protect 
research subjects like you.

People at the Colorado Multiple Institutional Review Board (COMIRB)

The study doctor and the rest of the study team.

Officials at the institution where the research is being conducted and officials at 
other institutions involved in this study who are in charge of making sure that we 
follow all of the rules for research

Representatives of the U.S. Army Medical Research and Materiel Command, 
who are authorized to review research records as part of their duty to protect 
human research volunteers. Research records will be stored in a way to protect 
your information and keep it confidential. 


Consent and Authorization Form Approval
Combined Biomedical Consent and HIPAA authorization
CF-151, Effective 8-31-11
Page 13 of 17
Initials______

Naval Medical Research Center to test samples without information that can 
identify you.

Officials identified by the DoD, called the research monitor,  who are in charge of 
making sure that we follow all rules for research.
We might talk about this research study at meetings.  We might also print the results 
of this research study in relevant journals.  But we will always keep the names of the 
research subjects, like you, private. 
You have the right to request access to your personal health information from the 
Investigator. To ensure proper evaluation of test results, your access to these study 
results may not be allowed until after the study has been completed.
Information about you that will be seen, collected, used and disclosed in this 
study: 
Name and Demographic Information (age, sex, ethnicity, address, phone 
number, etc.).
Portions of any previous and current Medical Records that are related to this 
study, including but not limited to Diagnoses, History and Physical, laboratory or 
tissue studies, radiology studies, procedure results, and clinical measures
Hospital stay and Research Test records 
Blood samples and the data with the samples. 
What happens to Data and Blood that are collected in this study? 
Scientists at the University of Colorado Denver and the hospitals involved in this study 
work to find the causes and cures of disease.  The data and blood collected from you 
during this study are important to this study and to future research.  If you join this 
study:
The data and blood are given by you to the investigators for this research and 
so no longer belong to you.  
Both the investigators and any sponsor of this research may study your data or 
blood collected from you.
If data or blood are in a form that identifies you, UCD or the hospitals involved 
in this study may use them for future research only with your consent or IRB 
approval.
Any product or idea created by the researchers working on this study will not 
belong to you.
There is no plan for you to receive any financial benefit from the creation, use 
or sale of such a product or idea. 
The investigator (or staff acting on behalf of the investigator) will also make all 


Consent and Authorization Form Approval
Combined Biomedical Consent and HIPAA authorization
CF-151, Effective 8-31-11
Page 14 of 17
Initials______
or some of the following health information collected from the body sensors 
about you available to:

Flashback Technologies

The Department of Defense
This information may include a limited data set consisting of:
Portions of your previous and current Medical Records that are relevant 
to this study, including but not limited to Diagnosis(es), History and 
Physical, laboratory or tissue studies, radiology studies, procedure 
results
Research Visit and Research Test records
Waveform data collected by the body sensors


Consent and Authorization Form Approval
Combined Biomedical Consent and HIPAA authorization
CF-151, Effective 8-31-11
Page 15 of 17
Initials______
NOTIFICATION OF PARTICIPATION AND OPTION TO CONTINUE
The investigator has placed you in this study without your consent using a process 
called, “Exception from Informed Consent Requirement for Emergency Research” (21 
Code of Federal Regulations Section 50.24). These rules give us guidelines to study 
life-threatening health problems in human subjects who cannot give informed consent 
because of their life-threatening medical condition. These medical conditions require a 
treatment to be given to the patient before informed consent can be obtained from the 
patient or a legally authorized representative.
☐ Option #1: I have been informed of the details of this study, have had the 
opportunity to ask questions about this study and have my questions answered.  
I choose to continue my participation in this research study and authorize the 
continued release of my medical records as stated in this consent. 
Initials_________
☐ Option #2: I have been informed of the details of this study, have had the 
opportunity to ask questions about this study and have my questions answered. I 
choose to withdraw from this study and do not agree to any further data 
collection. 
Initials_________
HIPAA Authorization for Optional Additional Study Procedures 
In this form, you were given the option to agree to additional, optional research 
procedures.  You must also give us your permission, under HIPAA rules, to use and 
disclose the information collected from these optional procedures, as described above.  
If you decline to give us permission to use and disclose your information, you cannot 
take part in these optional procedures, but you can still participate in the main study.  
Please initial next to your choice:
_____ I give permission for my information, from the optional procedures I have agreed 
to above, to be used and disclosed as described in this section.
_____ I do not give permission for my information for any optional procedures to be 
used and disclosed; I understand that I will not participate in any optional 
procedures.


Consent and Authorization Form Approval
Combined Biomedical Consent and HIPAA authorization
CF-151, Effective 8-31-11
Page 16 of 17
Initials______
Agreement to be in this study and use my data
I have read this paper about the study or it was read to me. I understand the possible 
risks and benefits of this study. I understand and authorize the access, use and 
disclosure of my information as stated in this form. I know that being in this study is 
voluntary. If choose to continue to be in this study, I will get a signed and dated copy of 
this consent form.
_________________________________________________
Printed Name of Patient
_________________Date/Time:
____
Patient Signature:
___________________________________________________
Printed Name of Legally Authorized Representative/ Proxy Decision Maker
__________________Date/Time:
____
LAR/Proxy Signature:
Note: Proxy decision makers cannot consent for future research because there is no 
treatment decision involved in this portion of the study. 
Consent form explained by:
__Date/Time:
Signature:
___
Witness Name: _____________________________________
__________________________________________________Date/Time:_________
Witness of Signature

Witness of consent process
 
Check (if applicable):
Use of Short-form 
Non-English speaking 

Non-reading 
Investigator: ________________________________________Date/Time: _______
Investigator must sign within 30 days  


Consent and Authorization Form Approval
Combined Biomedical Consent and HIPAA authorization
CF-151, Effective 8-31-11
Page 17 of 17
Initials______
☐This section applies if the patient is in police custody or incarcerated after study enrollment and 
before 28 days. 
You have a choice about being in this study.  Being in this study will not change your release date, 
your parole status, or your living conditions. 
The federal government requires us to keep your information private.   But if you give us information 
about child abuse, we will have to report that.  If you give us information about someone hurting 
someone else, we will have to report that.  If a court orders us to hand over your study records, we will 
have to hand them over to the court.
☐Option #1: I choose to continue my participation in this research study and authorize the continued 
release of my medical records as stated in this consent.           
☐Option #2: I choose to withdraw from this study and do not agree to any further data collection.     
___________________________________________________
Printed Name 
_________________Date/Time:
____
Signature:
Consented by:
_________
Date/Time: