Prehospital Air Medical Plasma (PAMPer) Phase III Multicenter, Prospective, Randomized, Open-label, Interventional Trial A Four Year Multicenter Open Label Randomized Trial
Phase: PHASE3
Conditions: Hemmorhagic Shock During Air Medical Transport
Sponsor: Jason Sperry

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Clinical Protocol  
 
                                            University of Pittsburgh 
 
            Departments of Critical Care, Surgery and Emergency Medicine 
MACRO (Multidisciplinary Acute Care Research Organization) 
 
 
 
Prehospital Air Medical Plasma (PAMPer)  
Phase III Multicenter, Prospective, Randomized, Open-label, Interventional Trial 
Protocol Version 3 date: January 17, 2017 
 
 
 
 
Funding for the study is provided by the Department of Defense (DOD) Telemedicine and Advanced 
Technology Research Center (TATRC). 
 
IND Sponsor: 
Jason L. Sperry MD, MPH 
Assistant Professor of Surgery and Critical Care Medicine  
University of Pittsburgh Medical Center 
3500 Fifth Avenue, Suite 303 
Pittsburgh, Pa. 15213 
412 802 8270 
sperryjl@upmc.edu 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                                                                                                                                           
  
 
 
 
 
 
 

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Table of Contents  
I. Study Site Investigator Information ........................................................................................................................................ 4 
Investigator, University of Pittsburgh/UPMC ................................................................................................................................. 4 
Sub-Investigators, University of Pittsburgh/UPMC ....................................................................................................................... 4 
Investigators at other participating institutions/study sites ............................................................................................................. 4 
Medical Monitor ............................................................................................................................................................................. 4 
 
II. Scope of Work .......................................................................................................................................................................... 5 
 
III. Roles and Responsibilities...................................................................................................................................................... 5 
Study timelines ................................................................................................................................................................................ 5 
Pre-trial and Year one ..................................................................................................................................................................... 5 
Year Two ........................................................................................................................................................................................ 6 
Year Three ...................................................................................................................................................................................... 6 
Year Four ........................................................................................................................................................................................ 6 
 
IV. Study Site Information ........................................................................................................................................................... 6 
 
V. Study Information .................................................................................................................................................................... 7 
 
VI. Study Design ............................................................................................................................................................................ 7 
Background and significance .......................................................................................................................................................... 7 
Preliminary studies ........................................................................................................................................................................ 10 
Objectives and hypothesis ............................................................................................................................................................. 12 
 
VII. Research Design and Methods ........................................................................................................................................... 15 
Study design and setting ............................................................................................................................................................... 15 
Study population ........................................................................................................................................................................... 15 
Inclusion and exclusion criteria .................................................................................................................................................... 15 
Randomization .............................................................................................................................................................................. 15 
Intervention ................................................................................................................................................................................... 16 
Standard of Care ........................................................................................................................................................................... 17 
Standard Operating Procedures (SOPs) ........................................................................................................................................ 17 
Blinding......................................................................................................................................................................................... 18 
Outcome Variables ........................................................................................................................................................................ 19 
Primary Outcomes ........................................................................................................................................................................ 19 
Secondary Outcomes .................................................................................................................................................................... 19 
Clinical Outcomes ......................................................................................................................................................................... 19 
Twenty four hour blood transfusion requirements ........................................................................................................................ 19 
In-hospital Mortality ..................................................................................................................................................................... 19 
Multiple Organ Failure.................................................................................................................................................................. 19 
Nosocomial Infection .................................................................................................................................................................... 20 
Acute Lung Injury ......................................................................................................................................................................... 20 
Blood component transfusion requirements.................................................................................................................................. 20 
Coagulation Parameters ................................................................................................................................................................ 21 
Cytokine and Protein C pathway measures ................................................................................................................................... 21 
 
VIII. Human Subjects ................................................................................................................................................................. 21   
Screening and enrollment.............................................................................................................................................................. 22 
Informed consent and notification ................................................................................................................................................ 22 
HIPAA .......................................................................................................................................................................................... 23 
 

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IX. Sample Storage ..................................................................................................................................................................... 23 
 
X. Data ......................................................................................................................................................................................... 23 
 
XI. Analysis plan ......................................................................................................................................................................... 24 
Primary hypothesis ........................................................................................................................................................................ 24 
Secondary hypothesis .................................................................................................................................................................... 25 
Predefined subgroup analysis ........................................................................................................................................................ 26 
Randomization of ineligible subjects ............................................................................................................................................ 26 
Non- adherence ............................................................................................................................................................................. 26 
Sample size justification and power analysis ................................................................................................................................ 26 
 
XII. Safety monitoring ................................................................................................................................................................ 29 
Adverse events .............................................................................................................................................................................. 29 
Data Safety Monitoring Board (DSMB) ....................................................................................................................................... 32 
Interim analysis ............................................................................................................................................................................. 33 
Quality control, assurance and confidentiality .............................................................................................................................. 35 
 
XIII. Study limitations ................................................................................................................................................................ 35 
 
XIV. Timetable ............................................................................................................................................................................ 36 
 
XV. Additional regulatory requirements USAMRMC ............................................................................................................ 36 
 
XVI. Literature Review .............................................................................................................................................................. 36 
 
Clinical Protocol -Appendix 1:  Response to Requirements for Exception From Consent For Emergency Research ...... 43 
 
Clinical Protocol -Appendix 2: Reporting Requirements for USAMRMC HRPO............................................................... 46 
 
Clinical Protocol -Appendix 3: Call Tracker for LAR – Incoming/Outgoing ....................................................................... 47 
 
Clinical Protocol -Appendix 4: Blood Product Maintenance .................................................................................................. 49 
 
Clinical Protocol -Appendix 5: Donor-Patient “Lookback” ................................................................................................... 54 
 
Clinical Protocol -Appendix 6: Data Safety Monitoring Board (DSMB) Overview ............................................................. 60 
 
Clinical Protocol -Appendix 7: Reporting Requirements ....................................................................................................... 67 
 
Clinical Protocol - Appendix 8: Harmonized Protocol ............................................................................................................ 68 
 
Clinical Protocol - Appendix 9: PAMPer Roles and Responsibilities .................................................................................... 85 
 
 
 
 
 
 
 
 
 
 

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I. Investigator Information 
 
A. Investigators at the University of Pittsburgh/UPMC: 
 
Jason L. Sperry MD, MPH 
                       Assistant Professor of Surgery and Critical Care Medicine  
                       University of Pittsburgh Medical Center 
                       3500 Fifth Avenue, Suite 303 
Pittsburgh, PA 15213 
412 802 8270 
sperryjl@upmc.edu  
 
B. Sub-Investigators and Key Study Personal at the University of Pittsburgh/UPMC: 
Frank X. Guyette MD, MS, MPH, Assistant Professor of Emergency Medicine, University of Pittsburgh 
Darrell J. Triulzi MD, Professor of Pathology and Medicine, University of Pittsburgh  
Mazen Zenati MD, MPH, PhD, Assistant Professor of Surgery and Epidemiology, University of Pittsburgh 
Timothy R. Billiar MD, Chair, Department of Surgery, University of Pittsburgh  
Derek Angus MD, MPH, Chair, Department of Critical Care Medicine, University of Pittsburgh 
Andrew B. Peitzman MD, Vice-Chair,Chief, Division of General Surgery, University of Pittsburgh 
Clifford Calloway MD, PhD, Associate Professor of Emergency Medicine, University of Pittsburgh 
Mark Yazer, MD, Medical Director Centralized Transfusion Service; University of Pittsburgh 
Barbara Early, RN, BSN, CCRC, MACRO CRC Director, University of Pittsburgh 
A. Tyler Putnam, MD, Trauma and Acute Care Surgeon, Trauma and Emergency Services, UPCM Altoona 
 
C. Investigators at other participating institutions: 
 
Case Western University -   
 Jeffrey A. Claridge, MD, MS 
University of Louisville - 
 
 Brian G. Harbrecht, MD 
University of Texas Southwestern- Herb Phelan, MD 
University of Tennessee-   
 Brian M. Daley, MD 
Vanderbilt University-  
 
 Richard S. Miller, MD, FACS 
Harris Methodist Hospital-  
 William Witham, MD 
John Peter Smith Hospital-  
 Therese Duane, MD 
 
D. Research Monitor (Coordinating Center – University of Pittsburgh): 
 
Louis Alarcon, MD 
Medical Director, Trauma Surgery 
F 1264 PUH 
200 Lothrop St. 
University of Pittsburgh 
Pittsburgh, Pa 15213 
412 647 1158 
alarconl@upmc.edu 
 
 
 
 
 
II. Scope of Work 
 
A. The IND Sponsor and study site Investigators will through the execution of the trial: 
1. Determine whether prehospital infusion of 2 units of AB plasma or low titer anti-B A plasma as compared to 
standard air medical care results in a reduction in 30 day mortality 

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2. Determine whether prehospital infusion of AB plasma or low titer anti-B A plasma  as compared to standard 
air medical care results in a lower incidence of 24 hour transfusion requirements, in-hospital mortality, multiple 
organ failure, nosocomial infection and acute lung injury. 
3. Determine whether prehospital infusion of AB plasma or low titer anti-B A plasma  as compared to standard 
air medical care results in a reduction of blood component transfusion and resuscitation requirements over the 
first 24 hours post-injury. 
4. Determine whether prehospital infusion of AB plasma or low titer anti-B A plasma  as compared to standard 
air medical care results in improved coagulation measurements as determined by INR, PT, and 
thromboelastography (TEG) parameters. 
5. Determine whether prehospital infusion of AB plasma or low titer anti-B A plasma  as compared to standard 
air medical care results in lower levels of early IL-6 cytokine expression, reduced thrombomodulin and 
increased protein C levels. 
 
III. Roles and Responsibilities 
 
A. IND Sponsor: Dr. Jason L. Sperry will oversee all planning and execution of the Prehospital Air Medical 
Plasma (PAMPer) trial, which is a 4 year, multi-center, randomized, open label, clinical trial, and will assume 
the responsibilities of the IND Sponsor as addressed under 21 CFR Part 312, Subpart D.   
B. Study Site Investigators: The study site Investigators will oversee the conduct of the PAMPer trial at their 
respective study sites, and will assume the responsibilities of Investigators as addressed under 21 CFR Part 
312, Subpart D.  
C. Coordinating Center: The University of Pittsburgh will serve as both the clinical outcome and data-
coordinating center. The University of Pittsburgh Coordinating Center, under the auspices of the IND Sponsor, 
will be responsible for the education and training of participating center research staff and will oversee 
education and training of prehospital providers from participating centers. The University of Pittsburgh 
Coordinating Center, under the auspices of the IND Sponsor, will be responsible for sample acquisition, 
sample storage, data entry via web based platform, and maintenance of data integrity. 
D. Study Timeline Responsibilities: 
1.  Pre-Trial Start Period and Year One:  
University of Pittsburgh Coordinating Center: The IND Sponsor, participating study site Investigators, 
consultants, research staff and data management team will develop the clinical trial protocol, Investigator’s 
Brochure, informed consent documents and notification letters, data collection forms, database, and manual of 
operations. An IND application will be submitted to the FDA in accordance with the provisions governing the 
conduct of this clinical trial under the Exception from the Requirement for Informed Consent for Emergency 
Research.  A coordinating center protocol and separate study site clinical protocol will be initially submitted for 
review and approval by the University of Pittsburgh IRB, and the USAMRMC Office of Research Protections 
Human Research Protections Office. Once approved at these levels, the University of Pittsburgh Coordinating 
Center will send materials to subcontracted study sites for submission to their respective IRBs.  Study sites will 
be added to the clinical trial protocol following approval by their responsible IRB, and the IND application and 
Coordinating Clinical Center protocol will be amended accordingly.     
 
Participating Study Sites: Study site Investigators will coordinate and oversee the execution of the clinical 
trial at their respective institutions. They will finalize plans with each of their respective blood banks for the 
obtaining and rotation of plasma to and from the helicopter bases. They will each submit their plasma plan to 
the University of Pittsburgh Coordinating Center for approval. Once they have received an approved master 
clinical trial protocol, the study site investigators and their research team will submit the protocol to their 
respective IRB’s and follow local and federal regulations and guidelines relevant to this research; i.e.: 21 CFR 
50.24, Exception from Informed Consent Requirements for Emergency Research, the harmonized U.S. 
Department of Health and Human Services (HHS) regulations; 21 CFR Part 312, Investigational New Drug 
Application; and DOD Directive DODD 3216.02. No research at any site will commence until approval from the 
responsible IRB and the USAMRMC ORP HRPO has been received.  
 
2. Year Two: 
 

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University of Pittsburgh Coordinating Center staff will conduct a study site initiation visit subsequent to 
responsible IRB approval of the clinical trial protocol and approval of the study site by the USAMRMC ORP 
HRPO. The Coordinating Center research staff will verify that the study team has received and reviewed the 
protocol, and also understands the relevant scientific background information.  We will go over the study time 
line and accrual rate. Roles and responsibilities of all key personnel will be reviewed, along with a site 
delegation of duties log. We will review their ability to conduct the study according to the written protocol, 
federal and DOD regulations. We will ascertain their understanding of adverse event reporting and serious 
adverse event reporting. So as to address the training of study site staff who were unavailable at the time of 
the site initiation visit or who become involved at a later date, the Coordinating Center will implement a web-
based training module.  This will include testing which will serve as documentation that training requirements 
have been met. 
     Following a training period for participating study sites on enrollment procedures and TEG analysis, trial 
enrollment at the study site will begin. Blood samples will be batched for analysis, and prospective outcomes 
data will be entered and integrity verified. It is anticipated that 110 subjects will be enrolled in the first year.  
After the first 100 subjects have completed the clinical trial protocol, an initial interim analysis with be 
completed with a focus on safety. 
     Phase system analysts at the University of Pittsburgh Coordinating Center will create a web-based secure 
server to link sites with relevant information; a pass-word protected, electronic Case Report Form for data 
entry; and training modules for the conduct of the clinical trial protocol including electronic data entry.   
Personnel will need to pass a test on the portal as evidence of their training and knowledge of the protocol and 
procedures.   
     Each enrolling study site will be monitored on an annual basis by the research staff of the University of 
Pittsburgh Coordinating Center.  Study sites having difficulty with addressing the provisions associated with the 
Exception from the Requirement for Informed Consent for Emergency Research, underperforming sites, or 
sites with multiple protocol deviations will be reassessed for ability to continue. If unable to improve, they may 
be replaced. 
Two formal interim analyses of efficacy will be performed when 33% and 67% of the expected number of 
primary events had accrued (about one month after 1/3 and 2/3 of subject accruals). 
 
An estimated additional 150 patients will be enrolled (total=260) by end of second year, and blood samples will 
be batch analyzed for cytokine and protein C constituents. Continued prospective data collection and integrity 
verification for clinical outcomes will occur.  
 
3. Year Three: 
An estimated additional 150 patients will be enrolled (total=410) by end of third year, and blood samples will be 
batched analyzed for cytokine and protein C constituents. Continued prospective data collection and integrity 
verification for clinical outcomes will occur. 
 
4. Year Four: 
An estimated additional 120 patients will be enrolled (estimated total= 530) by 9 months into the fourth year, 
with completion of analyses for cytokine and protein C constituents once we meet our enrollment. Prospective 
data collection will be completed and final integrity verification for all data will occur. Final data analysis will be 
completed in the final 3 months after data integrity is verified. Manuscript preparation will follow soon after. 
 
IV. Study Site Information 
 
It is anticipated that the participating study sites/institutions will include: University of Pittsburgh/UPMC, 
University of Texas Southwestern, University of Tennessee, Case Western Reserve University, University of 
Louisville and Vanderbilt University. These institutions have busy air medical transport services and existing 
affiliations with local blood banks. The actual intervention will take place en route to the trauma center, and 
follow up data will be collected up to 30 days, independent of discharge disposition. 
 
 
V. Study Information 

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The study will be a 4 year, multi-center, open-label, randomized trial conducted at level-1 trauma centers. For 
patients with evidence of hemorrhagic shock being transported by air medical transport, the pre-hospital 
infusion of two units of AB plasma or low titer anti-B A plasma (<1:50 dilution or titer <50) will be compared to 
air medical standard of care.   
 
VI.  Study Design 
 
A. Background and Significance: 
 
1.  Uncontrolled hemorrhage and coagulopathy remain 
leading causes of mortality post-injury: Hemorrhage is 
estimated to be responsible for over 40% of all trauma-related 
deaths, nearly half of which occur in the pre-hospital setting.[1, 2] 
In addition, uncontrolled bleeding remains the leading cause of 
early in-hospital mortality.[3, 4] Ongoing hemorrhage is 
complicated by the well-known ‘lethal triad’ of coagulopathy, 
hypothermia and acidosis (Fig 1.).[5-8] It has been demonstrated 
that persistent hypothermia and progressive metabolic acidosis 
are associated with severe recalcitrant coagulopathy and 
resultant unbridled hemorrhage.[9-12] Although multiple 
mechanisms which promote or result in coagulopathy post-
injury have been proposed and studied, interventions that 
reduce the morbidity and mortality associated with 
hemorrhage and coagulopathy in the clinical arena remain 
limited.[13, 14]  
 
2. Coagulopathy is common, occurs early and is a 
complex, primary process following injury: Coagulopathy 
has been shown to be present in over 25% of patients at the 
time of trauma admission and has been determined to be an 
independent predictor of mortality with an associated 4-fold 
higher risk of mortality in both civilian and military 
settings.[15-19] Those injured who arrive with coagulopathy 
also have been shown to have longer ICU stays and 
ventilator requirements, are more likely to develop acute renal 
injury and multiple organ failure, and have a trend towards a 
greater incidence of acute lung injury.[18, 20] Prior literature 
has suggested that the coagulopathy which complicates injury is a secondary event driven by physiologic 
derangements and abnormalities.[7, 9, 21] Postulated mechanisms for this post-injury coagulopathy include 
dilution, depletion, and disseminated intravascular coagulation 
(DIC).[22] Dilution is thought to arise secondary to excessive 
crystalloid or colloid, or due to transfusion of blood products 
devoid of coagulation factors; with depletion resulting from 
ongoing bleeding where factor replacement lags behind 
utilization.[22] In a smaller subgroup of trauma patients, DIC 
has been shown to occur and is associated with the systemic 
inflammatory 
response 
syndrome 
and 
multiple 
organ 
failure.[23] Evolving evidence suggests that these prior 
mechanisms, which drive dysfunction or consumption of 
coagulation factors, may be individually too simplistic.[24] 
More recent evidence demonstrates the importance of shock 
and tissue hypoperfusion as principal drivers of coagulopathy 
following injury which may be required for coagulation factor 
Ongoing 
Hemorrha
ge 
Acidosis 
Hypothermia 
Coagulopathy 
Fig 1. Adapted from Jansen JO, et al. BMJ. 2009 Jun 5;338:b1778 
Fig 3. Standard TEG parameters. Reaction (R) time, clot 
formation (K) time, fibrin cross-linking (angle = α), clot strength 
(maximal amplitude [MA]), and estimated percent lysis (EPL). 
Harr JN,et al. J Surg Res. 2011 Apr 17 [Epub ahead of print] 
Fig 2. Nasciento B. et al. Crit Care. 2010; 14(1): 202.  

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dilution and depletion to become evident.[12, 20, 24, 25] (Fig 2.) These processes may in part be modulated by 
the thrombomodulin-protein C pathway.[20] As our understanding has increased regarding the mechanisms 
responsible for the acute coagulopathy of trauma, a new paradigm where early coagulopathy post-injury is 
considered a complex, multi-factorial, primary event has developed.[22, 24, 26]  
It is with this understanding that the scope and magnitude of morbidity due to uncontrolled 
hemorrhage is demonstrated, highlighting the importance of the potential benefits of prehospital 
administration of plasma which may improve both tissue hypoperfusion and lessen or prevent the 
early coagulopathy and resultant transfusion requirements which complicates severe injury and lower 
30 day mortality. 
 
3. Diagnosis of the acute coagulopathy of trauma: As we continue to expand our understanding of the 
acute coagulopathy of trauma, emphasis has also been placed on diagnosing coagulopathy which complicates 
injury to allow real time assessment to guide evolving blood component transfusion requirements.[27] 
Increasing evidence suggests that historic reliance on prothrombin time (PT) and international normalized ratio 
(INR) is time exclusive and provides insufficient information relative to the complexity which drives this 
coagulopathic process.[28-30] What is needed for the appropriate evaluation of an acutely injured patient’s 
coagulation status is a rapid, reliable assessment of the thrombosis and fibrinolysis arms of the hemostatic 
cascade. Thrombelastography (TEG) is a technology which provides a real time, viscoelastic analysis of these 
blood clotting processes.[27] (Fig 3.) Point-of-care rapid thrombelastography (POC r-TEG) differs from 
standard TEG because the clotting process and subsequent analysis is accelerated by the addition of tissue 
factor to a whole blood sample.[31] POC r-TEG is limited, however, by the requirement that the analysis be 
performed within 4 minutes of blood draw to prevent clot formation unless the addition of citrate occurs.[31] It 
has been demonstrated that TEG can assess coagulopathy, platelet dysfunction and hyperfibrinolysis at an 
early stage following injury and is the most rapid available test for providing reliable information on 
coagulopathy in significantly injured patients.[32, 33] If not more important, the technology has been deemed 
feasible for use in a deployed military setting as well as for civilian use.[34] 
 
4. Aggressive blood component transfusion is associated with improved outcomes in massive 
transfusion: Both allogeneic blood and FFP transfusions have been shown to be independent risk factors for 
poor outcome in the critically ill. [35-39] Despite these inherent risks, the acutely exsanguinating, injured 
patient at times requires large volumes of these transfusion components until definitive control of bleeding and 
hemostasis can be obtained.[40-42] A significant amount of recent attention has focused on the prevention and 
treatment of the early coagulopathy which complicates severe injury and massive transfusion.[42-45]  Since 
2007, a large amount of both military and civilian evidence has accumulated suggesting that ratio-based 
transfusion strategies targeting high fresh frozen plasma: packed red blood cell and platelet: packed red blood 
cell transfusion ratios reduces the morbidity and mortality associated with unbridled hemorrhage and massive 
transfusion post injury. [46-53] These same studies revealed significantly lower overall blood transfusion 
requirements with shorter time intervals to receiving individual component transfusion, when these 
resuscitation protocols were employed in the hospital setting.[47, 50, 54, 55] Controversy remains regarding 
the exact proportion of plasma or other blood components these patients with hemorrhagic shock should 
receive and the potential for survival bias when analyzing retrospective data[56-59]; however, consistent 
evidence suggests that addressing the acute coagulopathy of trauma is associated with improved outcome.[60] 
This evidence demonstrates that plasma transfusion plays an intricate role in addressing the early 
coagulopathy which is present at the time of admission following injury and that intervening early in 
the prehospital setting has the potential to further reduce overall transfusion requirements and 
significantly improve outcomes associated with hemorrhagic shock. 
 
5. Predicting high volume transfusion requirements: With the demonstrated benefit of targeting high 
plasma and platelet transfusion ratios in those patients that ultimately require massive transfusion (defined as 
transfusion of >10 units of pack red blood cells in the first 24 hours from injury), it is essential that massive 
transfusion can be predicted relatively early, soon after presentation to the trauma center in a large proportion 
of patients.[61] There exists an increasing pool of literature suggesting that this can be done relatively easily 
soon after (or before) trauma center arrival. The majority of these massive transfusion scoring systems 
incorporate laboratory values in addition to vital signs upon admission in both civilian and military settings.[61-

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65] Consistently, these scoring systems include hypotension (<90mmHg) as one of the primary predictors of 
large volume transfusion requirements. The ABC scoring system consists of 4 non-weighted parameters and 
include hypotension (<90mmHg), penetrating mechanism, positive focused assessment sonography of trauma, 
and a heart rate >120 bpm.[66] This score had an area under the curve of 0.84 via receiver operation 
characteristic curve analysis and is devoid of any laboratory measurements or requirements. 
These analyses suggest that the vital sign parameters of hypotension and tachycardia have the ability 
to predict with a high likelihood the requirement for those patients who ultimately require large volume 
transfusion, with a corresponding high propensity to develop early coagulopathy. It is this cohort of 
patients where the benefits of early plasma intervention may have its strongest clinical effect.  
 
6. Risks associated with plasma transfusion: Both allogeneic blood and blood components have been 
shown to be independent risk factors for morbidity in the critically ill. [35-39, 47, 67] With their use a risk of 
allergic reactions, transfusion-associated acute lung injury, transfusion-associated cardiac overload, and acute 
respiratory distress syndrome, has been documented.[39, 60] These are hypothesized to be secondary to 
transfer of antileukocyte antibodies from allo-immunized donors or a resultant biological response to 
accumulated by-products associated with blood and blood component storage.[39] Consistently, these studies 
which have characterized the risks associated with plasma transfusion find no association with greater 
mortality. It is in those patients with hemorrhagic shock and early coagulopathy where the documented survival 
benefit likely far exceeds any complication risks attributable to component transfusion.[47, 60, 67, 68]  
The risks associated with plasma transfusion may inherently be minimized secondary to addressing 
and intervening with the development of acute coagulopathy post injury early in the prehospital setting 
and by reducing overall blood transfusion requirements may result in a reduction of 30 day mortality. 
 
7.  Universal donor ‘AB- plasma’:  
For this clinical trial, the early, pre-
hospital administration of non-cross-
matched plasma will utilize a rare 
resource, ‘universal donor plasma’ or AB 
plasma represents approximately 3-5% 
of all plasma available and is typically 
considered in chronic shortage.[25] It is 
sometimes referred to as ‘liquid gold’. 
Due to the precious nature of universal 
donor plasma, the NIH blood bank has developed 
and maintains a special AB plasma donor program. 
(http://clinicalcenter.nih.gov/blooddonor/donationtypes/ab_plasma.html) 
It is the precious nature of universal donor plasma which highlights the importance of utilizing air 
medical transport in this proposal. Air medical services cover large geographical areas and provide 
care at both the scene of injury and to those critically injured patients who are initially evaluated at 
outside facilities and require transfer to definitive care trauma centers. By utilizing air medical services 
as the site of universal donor plasma administration, the most efficient use of a rare resource can be 
accomplished with minimization of waste. Utilizing trauma centers with busy air medical services, who 
have relationships with their respective blood bank affiliates, will allow the successful completions of 
the aims and objectives proposed with minimization of blood bank resources due to the logistical 
considerations relative to ground prehospital transport. 
 
8. Delay to definitive hemorrhage control: Definitive control of ongoing hemorrhage remains a fundamental 
principle in trauma management. Increasing attention has been paid to the significance of delay and the timing 
of definitive control of hemorrhage. Clarke and colleagues have previously shown that delays to operative 
intervention in patients with significant abdominal injuries are associated with a higher mortality risk, 
demonstrating a 1% higher risk of mortality for every 3 minute delay in getting patients from the ED to 
laparotomy.[69] Additional studies documenting relationships between delay and poor outcome following injury 
have been demonstrated for interventional radiology procedures and by excessive radiographic imaging post-
injury in the hospital setting.[70, 71] Prehospital air medical transport has been shown to be associated with 
Fig 4. http://www.redcrossblood.org/learn-about-blood/blood-types 

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improved outcome following severe injury, however, scene time and overall transport times are consistently 
longer as compared to ground transportation in both civilian and military setting.[72-76]   
The results provided by the successful completion of this proposal will have paramount implications 
for both civilian and military injured patients as control of hemorrhage and delay to definitive care 
represent major impediments for both populations. This proposal will provide needed insight into the 
consequences of early plasma intervention in these critically injured patients when these impediments 
exist.   
 
B. Preliminary Studies: 
1. High plasma: blood transfusion ratios improve survival and 
reduce blood transfusion requirements: Secondary to the 
University of Pittsburgh’s participation in the Inflammation and the 
Host Response to Injury Large Scale Collaborative Program or ‘glue 
grant’ prospective cohort trial, (www.gluegrant.org), we have 
previously characterized the relationship between high fresh frozen 
plasma:packed red blood cell (FFP:PRBC) transfusion ratios in 
massive transfusion patients.[47] We verified a dose response 
relationship revealing that as the FFP:PRBC increased toward 
1:1.5, a significant reduction in mortality occurred. (Fig 5.) These 
findings remained 
significantly robust after 
controlling for important differences in injury severity, temperature, 
shock parameters and operative interventions. Equally important, 
there were significant reductions in blood and blood component 
transfusion requirements in those with High vs. Low FFP:PRBC 
transfusion ratios. (Fig 6.) In a more recent analysis (unpublished, 
submitted to 2012 EAST) aimed to debunk any question of survival 
bias regarding high plasma transfusion ratios, Cox-Hazard regression 
was used to determine the independent mortality risks at 6hr, 12hr, 
and 24hrs while controlling for important confounders. FFP:PRBC 
and platelet:PRBC ratios were also analyzed as time-dependent 
covariates accounting for 
fluctuation over time. We found that despite similar degrees of 
early shock and coagulopathy, high FFP:PRBC and platelet:PRBC 
ratios are associated with a survival benefit as early as 6hrs and 
throughout the first 24hrs, even when time dependent fluctuations 
of component transfusion were accounted for (Fig 7). We 
concluded that the observed mortality benefit associated with high 
component transfusion ratios was unlikely due to survivor bias and 
that early attainment of high transfusion ratios may significantly 
lower the risk of mortality in massive transfusion patients.  
This previous work demonstrates that in patients who 
ultimately require large volume transfusion, targeted high 
proportions of plasma improves outcome. 
2. Earlier more aggressive blood component 
transfusion is associated with a reduction in massive 
transfusion: We have recently characterized changes in 
resuscitation practice which have occurred over time in a 
cohort of severely injured patients requiring massive 
transfusion (in press, Journal of Trauma, presented at 
Western Trauma Association, 2011).  We demonstrated 
that the incidence of massive transfusion (>10 units blood) 
significantly decreased over time, despite the median ISS 
of the cohort increasing. (Fig 8). When the recent time 
Cumulative % Survival
1.0
0.9
0.8
0.7
0.6
0.5
Days From Injury
30
25
20
15
10
5
0
1: 5 or less
1: 3-4 ratio
1: 2 ratio
1: 1 ratio
Fig 5. Kaplan-Meier Survival Analysis comparing survival across 
different transfusion ratio groups. 
Fig 6. Transfusion requirements across High and Low 
FFP:PRBCs groups 
0.03
24HR Mortality
12HR Mortality
6HR Mortality
PLT:PRBC
24HR Mortality
12HR Mortality
6HR Mortaltiy
FFP:PRBC
1.0
 Independent Risks Of Mortality
For 6hr HIGH vs. LOW
Transfusion Ratios
Fig 7. Mortality risks for 6hr High and Low transfusion 
ratios over the first 24hrs post injury.
2004
2006
2008
4.0
5.0
6.0
7.0
20
25
30
35
MT (% patients)
ISS
*
*
Median 24hr PRBC (unit)
*
Year
Fig 8. Decreasing incidence of massive transfusion over time 
with increasing injury severity  

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period (2007-current) was compared to the early time period (2004-2006) of enrollment for the study, there was 
a significant increase in the FFP: PRBC and platelet: PRBC transfusion ratios as early as 6 hours post injury, 
and the proportion of each blood component that was given in first 6 hours relative to the total given at 24 
hours significantly increased (Fig. 9). This occurred in patients 
who required 7-10 Units of blood, just below the definition of 
massive transfusion. The data suggests that early, more 
aggressive attainment of high transfusion ratios may reduce the 
requirement for massive transfusion and may shift overall blood 
requirements below those which currently define massive 
transfusion.  
This previous work suggests that early and aggressive 
plasma administration may be associated with improved 
outcomes and reduced overall blood transfusion 
requirements and mortality. 
 
1. The potential risks associated with plasma transfusion: We 
have previously documented the independent risks associated 
with blood component transfusion (per/Unit) in a cohort of significantly injured patients.[67] Using Cox hazard 
regression and controlling for all important confounders, we found no association between plasma 
administration and the development of nosocomial infection. There was a relationship between plasma and 
multiple organ failure and acute respiratory distress syndrome. A dose response relationship was documented 
with the risk of these complications significantly increasing after 3 Units of plasma (Fig. 10). Overall, taking into 
account all patients in the analysis, plasma was associated with a significantly lower independent risk of 
mortality. For every Unit of plasma given (in-hospital) the independent risk of mortality was estimated to be 
reduced by 3% (HR 0.97, p=0.02, 95%C.I. 0.94-0.99, Fig. 11 
This prior work suggests the mortality benefit may outweigh 
the potential risks associated with plasma transfusion; with 
the early administration of plasma having the potential to 
reduce overall blood transfusion requirements and further 
improve outcomes. These results are similar to prior military 
experience which documented improved survival for every 
unit of plasma a patient receives.[68]  
 
3. Feasibility of air medical service intervention: The air 
medical service at the University of Pittsburgh/UPMC is the 
busiest non-profit flight service in the country and has a significant 
track record of prospective trials and interventions.[77-80] The 
Department of Emergency Medicine’s participation in the 
Resuscitation Outcomes Consortium (https://roc.uwctc.org/) 
further demonstrates the expertise and capabilities this service 
has with air medical interventions. A recent analysis 
demonstrates the importance of prehospital serum lactate 
measurement during air medical transport for traumatic injury and 
its role as an independent predictor of in-hospital death, need for 
emergent operative intervention and the development of multiple 
organ failure[80] More recent work (submitted, Journal of Trauma, 
2011) demonstrates the utility of air medical tissue oximetry and the ability it has to predict operative 
intervention or blood transfusion in the first 24 hours following injury.  
Additional anticipated participating centers for this clinical trial, which include the University of Texas 
Southwestern, University of Louisville, University of Tennessee at Knoxville, Vanderbilt University and Case 
Western Reserve University, have been selected for their relationships with their respective air medical 
transport team, their experience with air medical interventional trials and their clinical research infrastructure to 
allow an interventional trial as described to occur. Air bases that will be utilized for the trial will be selected to 
maximize patient enrollment, minimize their distance from the trauma center and blood bank facility and to 
Fig 10.  Dose dependent relationship between plasma 
transfusion and organ failure and acute respiratory 
distress syndrome. 
0.6
1.9
> 6 units
3-6 units
1-3 units
FFP 
1.0
 Independent Hazard Ratios For
Development of ARDS
1.3
1.6
2.0
2.5
> 6 units
3-6 units
1-3 units
FFP 
1.0
 Independent Hazard Ratios For
Development of MOF
FFP
PLT
30
40
50
60
70
80
EARLY
RECENT
*
*
SUB-MT 6HR/24HR %
Fig 9. Comparing the proportion of component transfusion in 
the first 6 hours relative to 24 hours in early and recent time 
periods. 

Protocol Version 3                                                                                                                      January 17, 2017 
 
Page 12 of 86 
 
provide the widest geographic distribution of patients. The anatomy of each respective institution will vary 
according to these variables and will each be individually maximized. Dr. Herb Phelan and Dr. Joseph Minei 
from the University of Texas Southwestern are also investigators in the Resuscitation Outcomes Consortium 
where pre-hospital interventional trials are the focus of the consortium. Similarly Dr. Harbrecht from the 
University of Louisville was the lead site investigator of the Inflammation and the Host Response to Injury 
Large Scale Collaborative Program.  Dr. Harbrecht was previously at the University of Pittsburgh prior to 
becoming director of the division of Trauma at the University of Louisville. He leads a trauma division with a 
busy air medical service and with a research infrastructure already in place for the execution of this trial. 
Similarly, Dr. Brian Daley is the division leader of a large and busy air medical transport service at the 
University of Tennessee, which has a clinical research infrastructure already in place with the air medical 
service to allow the smooth execution of this trial. Dr. Richard Miller from Vanderbilt University leads one of the 
busiest air medical services in the Southeast which is operated by the Vanderbilt Hospital system itself, with 
the appropriate research infrastructure already in place for the execution of this trial. Finally, Dr. Jeffrey 
Claridge leads the trauma division at Metro Health hospital at Case Western Reserve University and is the air 
medical director for the entire Northern Ohio area with similar research infrastructure to allow the execution of 
this clinical trial. 
 
4. Feasibility of the AB plasma or low titer anti-B A plasma intervention: The collaborative environment 
between the Departments of Surgery, Emergency Medicine and Transfusion Medicine at the University of 
Pittsburgh/UPMC unifies prehospital clinical research expertise with hospital based acute care research 
expertise and will provide the main impetus for the successful execution of the current proposal.  The 
leadership and direction provided by University of Pittsburgh/UPMC clinicians and investigators will also 
promote the successful execution of the trial at the other participating centers. Dr. Triulzi, as the Medical 
Director of the Institute of Transfusion at the University of Pittsburgh, has the buy-in and support of Pittsburgh 
Central blood Bank and our transfusion service in ensuring the availability of 6 Units of AB thawed plasma at 
all times. This plasma will be exchanged prior to day 5 to be utilized as standard hospital supply; thereby 
minimizing any waste of this valuable resource. This will allow 3 out of 6 air transport bases to have 2 units of 
AB plasma or low titer anti-B A plasma per month at any one time. If we need to increase number of 
participating bases, we will work closely with Dr. Triulzi to minimize waste. Similar exchange procedures of AB 
plasma or low titer anti-B A plasma have been prearranged at the other participating centers where similar 
collaborative relationships were required to be considered as a participating center for this trial. The 
relationships already in place and the prior experience of each of the participating centers will allow the smooth 
execution of the current trial. 
     Thawed plasma which will be distributed to the air medical bases and returned if unused has the potential to 
increase the average age of the thawed plasma depending on how quickly thawed plasma is utilized at each 
respective center for trauma and non-trauma transfusion needs during different time periods of enrollment. 
Transfusion practice, due to the relative scarcity of universal donor AB plasma, dictates the use of the oldest 
thawed plasma available (up to 5 days) when required. As no clinically significant differences have been 
documented regarding the safety or efficacy secondary to the age of thawed plasma (1-5 days old), the 
potential for increasing the average age is possible but not clinically significant in regards to the safety of 
transfusion practice at each center or the execution of the proposed trial.  The storage logs will be with the 
plasma product at all times recording age and temperature of storage. The respective transfusion services at 
each participating center will have full and complete access to the storage records to verify that the plasma 
products have been properly stored prior to their exchange. Blood bank staff will verify age and proper storage 
before reissuing plasma. 
 
C. Objectives/Hypotheses: 
1. Study Rationale: The effects of coagulopathy, hypothermia and acidosis are well known markers for 
mortality following traumatic hemorrhage. Increasing attention has recently been paid to the correction of the 
coagulopathy which complicates damage control resuscitation. Importantly, coagulopathy has been shown to 
be present very early after injury, at the time of trauma admission, even further substantiating the importance 
of early initiation of treatment. It is with this understanding that the magnitude of importance of the current 
proposal becomes apparent. Air medical transport is utilized for both civilian and military injured victims where 
delay to definitive care and hemorrhage control is exceedingly common. Delay to definitive care and 
hemorrhage control has been shown to be associated with poor outcome. It is in this cohort of patients where 

Protocol Version 3                                                                                                                      January 17, 2017 
 
Page 13 of 86 
 
interventions that improve or prevent coagulopathy may have their greatest positive effect. The successful 
completion of the proposed aims will provide needed insight into the potential consequences of early 
intervention in these critically injured patients. 
 
2. Primary Objective: To determine the effect of the prehospital infusion (i.e., during air medical transport) of 
AB plasma or low titer anti-B A plasma (2 units) on 30 day mortality in patients with hemorrhagic shock as 
compared to standard air medical care.  
a. Primary Aim #1: Determine whether prehospital infusion of AB plasma or low titer anti-B A plasma (2 units) 
as compared to standard air medical care results in a reduction in 30 day mortality 
Hypothesis Primary Aim #1: Patients in hemorrhagic shock who receive AB plasma or low titer anti-B A 
plasma during air medical transport will have a reduced 30 day mortality as compared to patients who receive 
standard air medical care. 
3. Secondary Objectives: To determine the effect of the prehospital infusion (i.e., during air medical transport) 
of AB plasma or low titer anti-B A plasma (2 units) in patients with hemorrhagic shock on clinical outcomes 
including 24 hour blood transfusion requirements, the development of multiple organ failure, nosocomial 
infection, acute lung injury (ALI) and transfusion related acute lung injury (TRALI).  To determine the effect of 
prehospital infusion (i.e., during air medical transport) of AB plasma or low titer anti-B A plasma (2 Units) in 
patients with hemorrhagic shock on blood component transfusion and resuscitation requirements in the first 24 
hours; on presenting coagulation parameters including INR, PT and thromboelastography measurements; and 
on IL-6 cytokine levels and markers of Protein C activation. 
a. Secondary Aim #1: Determine whether prehospital infusion of AB plasma or low titer anti-B A plasma as 
compared to standard air medical care results in a lower 24 hour blood transfusion requirement, a lower 
incidence of multiple organ failure, nosocomial infection, acute lung injury and TRALI. 
Hypothesis Secondary Aim #1: Patients in hemorrhagic shock who receive AB plasma or low titer anti-B A 
plasma  during air medical transport will have a lower 24 hour blood transfusion requirement, a lower incidence 
of multiple system organ failure, nosocomial infection, acute lung injury and TRALI as compared to patients 
who receive standard air medical care. 
 
b. Secondary Aim #2: Determine whether prehospital infusion of AB plasma or low titer anti-B A plasma as 
compared to standard air medical care results in a reduction of blood component transfusion and resuscitation 
requirements over the first 24 hours post-injury. 
Hypothesis Secondary Aim #2: Patients in hemorrhagic shock who receive AB plasma or low titer anti-B A 
plasma during air medical transport will have a reduced fresh frozen plasma and platelet transfusion 
requirement, a reduced crystalloid and colloid requirement in the first 24 hours post-injury and will less 
commonly require vasopressor support in the first 24 hours post injury as compared to patients who receive 
standard air medical care. 
 
c. Secondary Aim #3: Determine whether prehospital infusion of AB plasma or low titer anti-B A plasma as 
compared to standard air medical care results in improved coagulation measurements as determined by INR, 
PT, and thromboelastography parameters.  
Hypothesis Secondary Aim #3: Patients in hemorrhagic shock who receive AB plasma or low titer anti-B A 
plasma during air medical transport will have improved coagulation measurements as determined by INR, PT 
and thromboelastography parameters as compared to patients who receive standard air medical care. 
 
d. Secondary Aim #4: Determine whether prehospital infusion of AB plasma or low titer anti-B A plasma as 
compared to standard air medical care results in lower levels of early IL-6 cytokine expression, reduced 
thrombomodulin and increased protein C levels. 
Hypothesis Secondary Aim #4: Patients in hemorrhagic shock who receive AB plasma or low titer anti-B A 
plasma during air medical transport will have reduced early IL-6 cytokine expression, reduced thrombomodulin 
and increased protein C levels as compared to patients who receive standard air medical care. 
 
4. Project Milestones: Following final IRB approval for the University of Pittsburgh/UPMC and all participating 
centers, a 3 month start up period will be utilized to verify and educate all study sites prior to beginning 

Protocol Version 3                                                                                                                      January 17, 2017 
 
Page 14 of 86 
 
enrollment. Community notification and other procedures associated with the provisions for  Exception from 
Informed Consent for Emergency Research will be initiated commensurate with IRB approval at all institutions. 
A data entry web based platform will be created. Enrollment will occur for 3.5 years with prospective data entry 
of laboratory and TEG measurements, clinical outcomes, transfusion requirements and demographic and injury 
characteristics. Serum for cytokine, protein C and thrombomodulin measurements will be batched and sent to 
the University of Pittsburgh on an annual basis. We expect approximately 25 patients per year per institution 
on average. Enrollment will be monitored on a semi-annual and annual basis for each participating center. 
Data safety and monitoring over the course of the clinical trial will fall under the responsibility of an 
independent data safety and monitoring board (DSMB). Interim analysis will occur when 1/3 and 2/3 of patients 
are enrolled. A 3 month data cleaning and wind down will occur once enrollment has been completed, allowing 
data analysis and manuscript preparation.   
 
5. Military Significance/Public Purpose: Despite the significant advances in trauma care delivery and post-
injury management practices which have occurred over the last decade, uncontrolled hemorrhage remains one 
of the leading causes of trauma related deaths.[4, 5, 81, 82]  
To intervene early in the cascade of events which promotes and drives ongoing hemorrhage and the early 
coagulopathy that complicates injury has the potential to reduce overall transfusion requirements, alter the 
early systemic inflammatory response, and reduce the morbid clinical outcomes which are common in patients 
requiring large volume transfusion. It remains unknown the magnitude of effects associated with early 
intervention into this process. Importantly, the risks associated with early, prehospital administration of plasma 
remain unknown. In those patients who ultimately would not require large volume blood component 
transfusion, early plasma may be associated with a greater risk of acute lung injury or an exaggerated 
systemic inflammatory response in addition to any beneficial survival effect. The results and conclusions of the 
current proposal will allow and promote understanding of both the potential benefits and risks attributable to 
this type of intervention and this knowledge would have a direct impact on both military and civilian injured 
patients. 
 
Due to the sparse nature of AB plasma processes and distribution procedures which efficiently allow and 
promote the availability of this product for prehospital providers has the potential to dramatically change the 
way our trauma systems are designed and currently function. The potential for additional blood transfusion 
components to be made available would open the possibilities of a flying or driving prehospital blood bank all 
with transfusion interventions in this setting. This potential knowledge base would be dramatically beneficial to 
both military and civilian trauma systems. It is in both these settings where the prehospital phase of treatment 
represents a relatively novel arena for new interventions.  
It is anticipated that the results provided by the successful completion of this proposal will have paramount 
implications for both military and civilian injured patients as control of hemorrhage and delay to definitive care 
represent major impediments for both populations. This proposal will provide needed insight into the 
consequences of early plasma intervention in these critically injured patients when these impediments exist. 
 
6.  Patient Benefit: The potential benefit of 2 units of plasma in the prehospital period irrespective of transport 
time to the hospital is based upon the premise that intervening early in the viscous cycle of hemorrhagic shock 
and coagulopathy will be beneficial to patients. Plasma will provide needed coagulation factors to begin to 
interrupt the coagulopathy that is occurring which represents the mainstay of treatment in the hospital setting 
(once arriving at the hospital) Currently, standard of care at the vast majority of prehospital provider services is 
the use of crystalloid infusion. Longer transport times typically are associated with greater crystalloid volumes 
at our own centers. There are trauma centers and their respective prehospital services that have the ability to 
transfuse uncrossmatched packed red blood cells following persistent, unresponsive hypotension. [83] It is 
know that hypotension in the prehospital period is associated with a higher independent risk of mortality and 
worse outcome.[84-86] It is in these patients where the benefits of early prehospital plasma may be of greatest 
benefit.  Improved outcomes have been demonstrated the earlier plasma is given after arrival to a trauma 
center.[87] Recent, published evidence has documented the feasibility and potential benefits of a 
prehospital plasma resuscitation protocol similar to the current proposed trial. The small study 
demonstrates that patients who receive prehospital plasma, (as part of a plasma first resuscitation 
strategy) in patients with average transport times of 40 minutes, benefit by having an in hospital 
improved plasma: PRBC transfusion ratio throughout the first 24 hours, a reduction in crystalloid in 

Protocol Version 3                                                                                                                      January 17, 2017 
 
Page 15 of 86 
 
the prehospital setting, and  early treatment of trauma-induced coagulopathy which is a known 
independent predictor of mortality.[83] (see Attached Manuscript) This prior and recent evidence 
suggests the current trial has significant potential to provide benefit to patients. 
 
VII. Research Design and Methods 
A. Study Design/Setting: The study will be a 4 year, multi-center, open label, randomized trial utilizing level-1 
trauma centers with busy air medical transport services where affiliations with local blood bank institutions 
exist. For patients with evidence of hemorrhagic shock being transported by air medical transport, the pre-
hospital infusion of two Units of AB plasma or low titer anti-B A plasma  will be compared to air medical 
standard of care.  The University of Pittsburgh will serve as both the clinical outcome and data coordinating 
center for this multi-center clinical trial. Each individual institution will perform point of care rapid TEG analysis 
and coagulation measurements on site. UPMC Presbyterian is the busiest level-1 trauma center in the state of 
Pennsylvania and is affiliated with the largest non-profit air medical service in the country with an extensive 
track record of multi-center, in-hospital and prehospital clinical trials. All enrolling centers and respective 
investigators similarly have significant experience with multi-center trials and the research infrastructure to 
allow them to successfully participate in this research study. It is anticipated that participating Institutions 
will include: University of Pittsburgh/UPMC, University of Texas Southwestern, University of 
Tennessee, Case Western Reserve University, University of Louisville and Vanderbilt University. 
 
B. Study Population: Blunt or penetrating injured patients with hemorrhagic shock being transported via air 
medical services from the scene of injury or from referring hospital to a definitive care trauma center 
participating in the trial.  
 
Inclusion Criteria: 
1. Blunt or penetrating injured patients being transported from scene or referral hospital to PAMPer site 
AND 
2. Systolic blood pressure below 90mmHg AND tachycardia>108 at scene, or at outside hospital or during 
transport. 
OR 
3. Systolic blood pressure below 70mmHg at scene, or outside hospital or during transport. 
 
 
 
Exclusion Criteria: 
1. Wearing NO PAMP opt –out bracelet 
2. Age > 90 or < 18 years of age 
3. Inability to obtain intravenous or interosseous access 
4. Isolated fall from standing injury mechanism 
5. Documented (radiographic evidence) cervical cord injury with motor deficit 
6. Known prisoner or known pregnancy 
7. Traumatic arrest with > 5 minutes of CPR without return of vital signs 
8. brain matter exposed or penetrating brain injury (GSW) 
9. Isolated drowning or hanging victims 
10. Isolated burns > estimated 20% total body surface area 
11. Referral Hospital In-patient admission  
12. Objection to study voiced by subject or family member at scene 
 
Inclusion and exclusion criteria will be assessed based on available information at the time of enrollment.  
Although all reasonable efforts will be made by the air medical crew to either directly witness or obtain 
documentation of qualifying vitals, due to the nature of the emergency pre-hospital setting, there may be 
occasions where the air medical crew must rely on verbal report of inclusion criteria, including qualifying vitals, 
from the referring hospital or ground crew.  In these instances, if, after subsequent review of outside hospital 

Protocol Version 3                                                                                                                      January 17, 2017 
 
Page 16 of 86 
 
and/or ground crew documentation, it is determined that the subject did not meet inclusion criteria and/or met 
exclusion criteria, the subject will remain enrolled in the study based on the intention-to-treat principle.  
 
In the event that a verbal report must be used in lieu of physical documentation or directly witnessing the 
qualifying vitals, documentation of the verbal report will serve as the source documentation for determining 
eligibility.  Verbal reports will be documented in the air medical record and will detail the information reported 
and by whom.  
 
C. Randomization:  A single stage cluster randomization scheme will be utilized. Air medical services at each 
respective participating institution (2 to 6 bases or helicopters at each center) will be block randomized and 
assigned to the plasma arm or standard care (control) arm for 1 month at a time. The cluster design will be at 
the level of the helicopter.  The block scheme will vary randomly between 2, 4, and 6 month block sizes over 
the period of enrollment for the trial at each participating center. Examples of a 4 month block randomized 
possibilities for a single helicopter or air base every month would be: PPSS, PSPS, PSSP, SPSP, SPPS, or 
SSPP (P=plasma, S=standard care.)  
 
Randomization assignments for each center will be determined prior to the start of enrollment following the 
above single stage cluster design using standard computerized randomization software. Communication with 
the blood bank transportation services and each respective air base will occur and an annual schedule of 
randomization assignment will be distributed to all air base sites by the coordinating center. This specific 
randomization scheme is required due to the limited supply of AB universal donor plasma and also due to the 
logistics of the intervention. AB plasma or low titer anti-B A plasma is required to be delivered to and available 
at each institution’s respective air base and on board the appropriate helicopter which is randomized to plasma 
intervention. Due to these factors, patients are not feasibly able to be randomized individually as this would 
require excessive amount of AB plasma or low titer anti-B A plasma  to be on board at all air base or helicopter 
services. Similarly, due to plasma distribution requirements, monthly random assignments of air base of 
helicopter services to plasma or standard of care reduces logistical demands for blood bank services and 
prehospital providers. Importantly, prehospital care providers or in-hospital physician teams will not be formally 
blinded to whether a patient receives plasma or standard air medical care. However, we will attempt to 
minimize ED and staff treatment bias by utilizing sham plasma transfusion bags which will be brought in to the 
trauma bay by the air medical crew in those patients who meet inclusion criteria during randomized months 
where plasma is not given. Additionally, all steps will be undertaken so that data analysis will be performed in a 
blinded fashion. Sham bags will be distributed to all participating helicopters and air bases for the entire 
duration of the study and will be utilized in those months where plasma is not on board and in patients who 
meet inclusion criteria.  
 
D. Intervention: 2 units of thawed AB plasma or low titer anti-B A plasma not older than 5 days will be infused 
in eligible patients who are randomized to the plasma arm of the clinical trial.  The AB plasma or low titer anti-B 
A plasma  will be that which is routinely used clinically; as collected, tested and stored by established (FDA-
registered) blood collection and banking laboratories.  Those air medical transport bases randomized to 
prehospital plasma infusion will be routinely (i.e., for the month of randomized assignment to the plasma arm) 
stocked with 2 Units of thawed AB plasma or low titer anti-B A plasma, which will be transported in a cooler 
with a temperature between 1 to 10 degrees centigrade and stored in a monitored refrigerator between 1 to 6 
degrees centigrade.  To minimize waste of AB plasma or low titer anti-B A plasma, local blood bank affiliates in 
coordination with each participating center will exchange unused plasma before the end of the fifth day thereby 
allowing subsequent clinical use by the respective blood bank facility. This will also be accomplished in a 
cooler with a temperature between 1 and 10 degrees Centigrade. The respective transfusion services at each 
participating center will have full and complete access to the storage records to verify that the plasma products 
have been properly stored prior to their exchange. A blood bank technician at each respective center will be in 
charge of monitoring all units of plasma at each air base, the age of each unit of plasma and the timing of 
transport services used to transport unused plasma back to the blood bank facility. Storage records at that time 
will verify appropriate storage and age of the plasma prior to placing it back in the blood bank plasma pool.   

Protocol Version 3                                                                                                                      January 17, 2017 
Page 17 of 86 
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YES 
Figure 11. Intervention Schematic. 
NO 
Continuation       
in-hospital 
resuscitation/care 
Completion of 
2
nd Unit of 
prehospital 
plasma 
Goal Directed 
Prehospital 
resuscitation SOP: 
Hypotension 
(SBP< 90)? 
Meets Inclusion 
and Exclusion 
Criteria
Initiation of 1
st 
and 2
nd unit of 
pre hospital 
plasma 
Completion of 
initiated 
prehospital 
plasma 
Trauma 
Center Arrival 
Trauma 
Center Arrival 
 
 Crystalloid Bolus or 
Blood Transfusion 
 Maintenance 
crystalloid infusion 
only 

Protocol Version 3                                                                                                                      January 17, 2017 
 
Page 18 of 86 
 
overall study PI (Dr. Sperry). The individual pre-hospital times will be controlled for in our primary and 
secondary endpoint model analyses. 
     Evidence has accumulated regarding the potential negative effects of excessive crystalloid particularly in 
patients with hemorrhagic shock. A standard operating procedure (SOP) for crystalloid/resuscitation 
management for enrolled patients in the pre-hospital setting has been created to limit excessive crystalloid 
administration during the window of plasma intervention completion and trauma center arrival based upon 
hemodynamic status (SBP < 90mmHg) for a ‘goal directed resuscitation. (Figure 11. above) These crystalloid 
volumes will be monitored relative to transport time for all patients and across enrolling sites. 
Some of the participating centers for the proposed study have the ability to carry uncrossmatched blood 
routinely on their air medical services to be initiated during flight. The air medical protocols for these institutions 
to transfuse blood en route occurs when greater than 2 liters of crystalloid/ resuscitation are infused with 
ongoing hypotension. The air medical services carry only 2 units of PRBCs (‘O’ negative) carried in approved 
coolers, with appropriate recordings to comply with blood banking standards, with similar look back procedures 
as is being proposed for the current trial for plasma. These protocols are already up and running at each 
respective institution and will not be altered by the current trial. This has become standard of care for these air 
medical services. For the proposed intervention to be most applicable across the majority of trauma air medical 
systems across the country, we will continue this practice. The inclusion criteria for the PAMPer trial will enroll 
patients based upon the proposed inclusion and exclusion criteria well before this blood transfusion threshold 
is met.  In those patients who remain hypotensive after the 2 units of AB plasma or low titer anti-B A 
plasma, the respective institutions will follow their own air medical transfusion guidelines (transfusion 
initiation if continued hypotension with concern for bleeding after 2L of resuscitation or following 
discussion with their respective medic command). Any additional blood en route will occur following 
completion of the 2 units of AB plasma or low titer anti-B A plasma following each respective institutions 
current guidelines which are both following 2 liters of resuscitation with direction from their medic command 
center. We will control and adjust for prehospital blood transfusion (# of units) in all of our primary and 
secondary analyses and will further characterize this prehospital variable in our predefined subgroup 
analysis. 
     At the initial writing of the proposal, 2 month data were collected during the busy months for each of the 
centers looking at crystalloid and transport times from the projected air medical bases that could be used for 
the trial. Transport times vary with the distance the helicopter base is from the trauma center as flights are 
dispatched by their starting location and who is closest to the scene or referral hospital in most cases. There 
will be some variance depending on the air medical bases which are utilized at the formal initiation of the trial. 
Importantly, those patients with in hemorrhagic shock typically receive larger volumes of crystalloid volume. As 
only 20-30 patients are projected to be enrolled per year there were not enough that would meet inclusion 
criteria to include only likely eligible patients for the 3 month sampling. We will control and adjust for 
individual prehospital crystalloid and transport times in all of our primary and secondary analyses and 
will further characterize these prehospital variables in  our predefined subgroup analyses. 
      
 
Tabular Historic Data for transferred patients from potential air bases over a 2 month period: 
 
 
 
 
 
  n       Crystalloid 
 
 Time (helicopter landing to trauma bay arrival) 
Pittsburgh 
 
42 
235cc±321cc  
40min±15min 
Dallas  
 
33 
331cc±390cc  
36min±19min 
Louisville 
 
40 
290cc±400cc  
35min±21min 
Tennessee 
 
29 
352cc±290cc  
34min±23min 
Vanderbilt 
 
35 
270cc±231cc  
36min±17min 
Cleveland 
 
31 
257cc±302cc  
39min±15min 
 
 
 
2.  In Hospital SOPs: We have selected level 1, academic, trauma centers with busy air medical transport 
services that are recognized for providing high level care of the injured patient. As the intervention is solely in 
the pre-hospital setting, there exists the potential for in-hospital management differences to occur across 
centers as in any multi-center study which does increase the study results applicability. However, to minimize 

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those differences where high level evidence exists for the early in-hospital management of each patient, and 
throughout a patients’ admission, local SOPs for resuscitation and transfusion will be employed and monitored 
over the initial 24 hours and throughout a patients’ admission. SOPs for patients who are at risk of massive 
transfusion (MT) will target an FFP: PRBC ratio of at least 1:2 based upon currently available data. Similar 
local SOPs for PLT transfusion ratios (1:2) will be employed and monitored during the initial 24 hours out from 
injury. Once 48 hours has passed without ongoing blood transfusion requirements, standard transfusion 
practice evidence in the ICU will be followed including standard restrictive transfusion guidelines for each 
respective institution in line with the TRICC trial recommendations (transfusion trigger of hgb- 7.0 in the ICU, 
non-bleeding patient).[88]  
 
G.  Blinding: Because of the pre-hospital setting of the intervention, the precious nature of AB plasma and all 
attempts to minimize waste of this resource, the transportation required to have thawed plasma at varied 
helicopter bases, and to minimize the air medical flight crews’ requirements for the trial, the current 
randomization scheme at the level of the helicopter base was selected on a monthly basis and the intervention 
was unable to be blinded since transfusion of blood products requires documentation. However, we will 
attempt to minimize ED and staff treatment bias by adding sham plasma transfusion bags which will be brought 
in to the trauma bay by the air medical crew in those patients who meet inclusion criteria during randomized 
months where plasma is not given.  
 
 
 
 
H.  Outcome Variables/Definitions: 
 
1. Primary Outcomes: Our primary outcome for the proposal will be 30 day mortality. It is this outcome 
variable for which the study will be powered.  
 
2. Secondary Outcomes: Our secondary outcomes for the proposal will include clinical outcomes, 24 hour 
blood component transfusion and resuscitation requirements, coagulation parameters, and cytokine and 
protein C pathway measurements. 
 
 
3. Clinical Outcomes: All clinical outcomes will be prospectively evaluated throughout ICU and hospital 
admission, and the timing from the day of initial injury will be recorded for time-to-event statistical analysis. 
 
a. Twenty Four-Hour Blood Transfusion Requirements: 24-hour blood transfusion requirements will be 
determined by recording blood and number of Units transfused from the time of trauma bay arrival or upon 
completion of pre-hospital initiated plasma infusion. For survival bias analysis, number of blood transfusion 
Units received at 3, 6, 12, and 18 hours will also be recorded. Any initiation of blood transfusion will be 
considered completed. 
 
b. In-hospital Mortality: In hospital mortality will be prospectively recorded from the time of trauma bay arrival. 
Over the first 24 hours we will document and record the time of death in hours, while after the 24 hour time 
point, we will document and record the time of death in days from arrival. We suspect that patients in 
hemorrhagic shock will have a significant percentage of mortality occurring in the first 24 hour period. 
 
c. Multiple Organ Failure: Organ dysfunction will be evaluated via a well-validated scoring system 
referred to as the Denver Postinjury Multiple Organ Failure Score.  Patients who are never admitted 
to the ICU or those with a length of ICU stay of less than 48 hours will be considered to have a 
Denver Score of 0. The Denver score rates the dysfunction of four organ systems (pulmonary, renal, hepatic, 
and cardiac), which are evaluated daily throughout the patient’s intensive care unit stay and graded on a scale 
from 0 to 3 with the total score ranging from 0-12. Daily WORST laboratorial and physiologic values are used 
for the score. MOF scores are calculated as the sum of the simultaneously obtained individual organ scores on 
each hospital day and MOF status is defined as a score >3 occurring any day after 48 hours postinjury. 
 

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A determined from the day of initial injury for time-to-event analysis and multivariate Cox proportional hazard 
regression analysis.  
Dysfunction 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Pulmonary 
  PaO2/FiO2 ratio 
 
 > 208 
 
208 - 165 
 
165 - 83 
 
< 83  
Renal  
  Creatinine       
  (umol/L) 
 
<159 
 
160 - 210 
 
211 - 420 
 
> 420 
Hepatic 
Total Bilirubin 
(umol/L) 
 
< 34 
 
34 – 68 
 
69 - 137 
 
> 137 
Cardiac 
  Inotropes 
No 
inotropes 
Only one 
inotrope at a 
small dose * 
Any inotrope at 
moderate dose or 
>1 agent, all at 
small doses * 
Any inotrope at large 
dose or > 2 agents at 
moderate doses * 
• 
Inotrope doses (in  ug/ Kg / min):  
 
 
Small 
Moderate  
Large  
Milrinone          
<0.3 
0.4 -0.7  
>0.7   
Vasopressin       
<0.03 
0.03 -0.07 
>0.07   
 
 
 
 
 
    
Dopamine           
<6 
6 - 10 
 
>10 
Dobutamine        
<6 
6 - 10 
 
>10 
Epinephrine        
<0.06 
0.06 -0.15 
>0.15 
Norepinephrine     <0.11 
0.11 -0.5   
>05 
Phenylephrine      <0.6 
0.6 - 3 
 
>3    
 
 
 
 
d. Nosocomial Infection: Infectious outcomes of interest will include ventilator associated pneumonia, blood 
stream infection and urinary tract infections. Surgical site infections and post-operative intra-abdominal 
collections will also be recorded but excluded as a principal secondary outcome event so as to reduce the 
confounding effects of operative interventions which not all patients require. The development of these 
nosocomial infections will be based upon positive culture evidence during hospital admission. Infections will be 
monitored until post-injury day 28 or ICU discharge. Diagnosis of a ventilator associated pneumonia requires a 
quantitative culture threshold of ≥ 104 CFU/ml from broncho-alveolar lavage specimens in addition to standard 
x-ray and clinical criteria. Diagnosis of catheter-related blood stream infections requires positive peripheral 
cultures with an identical organism obtained from either a positive semi-quantitative culture (>15 
CFU/segment), or positive quantitative culture (>103 CFU/segment) from a catheter segment specimen. 
Urinary tract infections require > 105 organisms/ml of urine. All time variables to the respective outcome event 
will be determined from the day of initial injury, while the time to the first nosocomial infection will be used in 
those patients with multiple infections for time-to-event analysis and multivariate Cox proportional hazard 
regression analysis. 
 
e. Acute Lung Injury (ALI) and Transfusion Related Acute Lung Injury (TRALI): Development of ALI will 
be assessed utilizing the 1992 American-European Consensus Conference definition [92] which includes: 1) 
bilateral infiltrates on chest x-ray, 2) a capillary wedge pressure < 18mmHg, and 3) Pao2/Fio2 ratio < 300 via 
blood gas analysis. In those patients without a Swan-Ganz catheter to determine capillary wedge pressure, the 
absence of signs of, or clinical concern, for elevated left sided atrial pressures will be used for the diagnosis.  
All patients who remain intubated beyond the first 24 hours post-injury will be evaluated using blood gas 
analysis and chest x-ray evaluation. Those patients who remain intubated at 48 hours through 7 days will be 
reevaluated for this outcome at these time points. All time variables to the respective outcome event will be 
determined from the day of initial injury for time-to-event analysis and multivariate Cox proportional hazard 
regression analysis.  The diagnosis of TRALI will be defined as when ALI occurs within the first 6 hours from 
arrival at the trauma center as it is clinically defined. 
 

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     Toy et al. reported a TRALI risk of 1:12,731 across all blood components including plasma. The most recent 
FDA mortality data for 2011 reports 4 TRALI related deaths due to plasma. These data suggest that the overall 
risk of TRALI is low. There are no definitive data on the risk of TRALI from an AB plasma or low titer anti-B A 
plasma  unit from a multiparous female. The specific unit of thawed plasma which a patient would receive in 
the pre-hospital setting as the intervention would be the potential same thawed unit at the definitive trauma 
center and thus would inherently contain the same risks of complications as those transfused in the hospital. 
The risk of complications including TRALI are required to be specifically monitored for, recorded and 
investigated by every transfusion service at each enrolling center. Any transfusion complication in the pre-
hospital setting will be similarly monitored. As the intervention is specific to the pre-hospital setting and since 
transfusion complications are temporally related to the specific transfusion, all transfusion related 
complications will be assessed during the initial 24 hours from arrival and recorded. All participating blood 
centers will minimize multiparous female donor plasma as is current standard of practice for blood banks. 
 
f. Blood component transfusion and resuscitation requirements: 24-hour blood component transfusion 
requirements for fresh frozen plasma and platelet transfusion will be determined by recording blood component 
number of Units transfused for fresh frozen plasma and platelets from the time of trauma bay arrival or upon 
completion of prehospital initiated plasma infusion. Similar determinations for crystalloid requirements, colloid 
requirements (albumin, hetastarch) and whether the patient requires vasopressors (yes/no; norepinephrine, 
epinephrine, vasopressin or phenylephrine) in the first 24 hours post-injury will occur. For survival bias 
analysis, number of Units will also be determined at 3, 6, 12, and 18 hours for each transfusion and 
resuscitation component. 
 
g. Coagulation Parameters: During the first 60 minutes (+ 12 hours) of the initial in-hospital resuscitation in 
the trauma bay or in the operating room (for those patients taken directly to the OR), but after transfusion of 
thawed plasma if hanging,  blood for PT, INR and point of care rapid-TEG analysis will be obtained. These 
measurements will be repeated as close to  24 hours (+/- 12 hours) from the time of injury as feasible, to 
coordinate with other lab draws and staffing patterns. We will also be performing additional coagulation 
biomarker assays at these time points. Tissue factor will be added to a citrated whole blood collection tube and 
rapid TEG parameters including activated clotting time (ACT, seconds), angle (α, degrees), coagulation time 
(K, seconds), maximum amplitude (MA, mm), clot strength (G, dynes/cm2), and estimated percent lysis (EPL, 
%) will be measured for each patient .  
 
h. Cytokine and Protein C pathway measurements: During the first 60 minutes (+ 12 hours) of the initial in-
hospital resuscitation in the trauma bay or in the operating room (for those patients taken directly to the OR), 
but after transfusion of thawed plasma if hanging,  blood for IL-6 cytokine levels, thrombomodulin and protein C 
levels will be drawn along with blood for coagulation analysis. These measurements will be repeated at 24 
hours (+/- 12 hours) from the time of injury as feasible, to coordinate with other lab draws and staffing patterns. 
An additional blood draw will be performed at 72 hours (+/- 12) for additional coagulation biomarkers.  IL-6 
levels rather than a large panel of early inflammatory cytokines will be measured; as IL-6 is one of the few 
cytokine markers shown to be associated with the development of multiple organ failure post injury.[93, 94] 
Altered thrombomodulin and protein C levels have similarly been shown recently to be associated with 
increased mortality, blood transfusion requirements, acute renal injury and greater ventilator requirements 
post-injury.[20] These outcome markers will provide information and insight into the mechanisms responsible 
for any beneficial effects of addressing hemorrhagic shock early in the prehospital setting. IL-6 will be 
measured using an ELISA immunoassay kit (Human IL-6 ELISA Kit, Antigenix America Inc., USA). 
Thrombomodulin and protein C levels will also be determined utilizing ELIZA immunoassay techniques 
(Asserachrom Thrombomodulin EIA, Diagnostica Stago, USA) and (Staclot Protein C clot-based activity assay, 
Diagnositca Stago, USA), respectively. All cytokine and Protein C pathway samples will be stored and batched 
at their respective institution and delivered to the University of Pittsburgh Coordinating Center where formal 
ELISA immunoassay measurements will be undertaken. 
 
VIII. Human Subjects  
We anticipate that this study will be conducted under the federal provisions governing Exception from the 
Requirement for Informed Consent for Emergency Research, including community consultation, public 

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notification, as well as notification of patients or their legally-authorized representative as soon as feasible after 
enrollment. The latter shall include provision of an opportunity to opt out from ongoing participation that will be 
given through oral and written communication. 
Community consultation as determined by the local IRB will be undertaken prior to final IRB approval. Since 
the population eligible for enrollment includes all citizens in the study regions it will not be possible to target 
any particular small group. Feedback from the community will be obtained by research personnel regarding 
any concerns they may have about potential enrollment. If requested, bracelets will be made available that 
could be worn by members of the community who do not want to participate. Public notification and community 
consultation will be performed as directed by the local IRB and may include such methods as using random 
digit dialing telephone surveys of the proposed study community, targeted small group meetings or 
consultation with community leaders. Due to ongoing participation in numerous multicenter research studies 
involving emergency research, our institution and the other participating institutions have significant experience 
with community consultation and notification practices. The requirements for Exception from the Requirement 
for Informed Consent for Emergency Research and our proposal’s characteristics regarding these can be 
found in the Clinical Protocol Appendix 1. Once a participating institution completes the processes for 
obtaining IRB approval of the research protocol, the IND will be amended to include the institution as a study 
site.  The respective information submitted to the IND application will include a summary of the community 
consultation process accepted by the reviewing IRB. Community Consultation Plan (appendix 2) attached. 
 
Benefits of participation in the PAMPer trial for both plasma and standard of care subjects: 
     A unique benefit regarding participation in the PAMPer trial is that all research results for both plasma and 
control arms of the study may be used to further inform clinical care decisions throughout a participants 
hospital stay. We have recently presented research currently in press (Brown et al. Journal of Trauma and 
Acute Care Surgery, 2013) documenting the potential benefits of goal directed prehospital crystalloid 
resuscitation. Based upon this knowledge for all trial participants, a prehospital standard operating procedure 
(SOP) utilizing a goal directed crystalloid resuscitation guideline will be followed. Due to the variability of 
prehospital crystalloid resuscitation that currently exists across injured patients, this will potentially benefit 
participants in either arm of the study. 
     Participation in the trial may also aid in early recognition of trauma induced coagulopathy due to the early 
measurements of INR and thrombelastography (TEG) which will be performed on all enrolled subjects. TEG is 
an FDA approved tool, however, currently it is not standard of care and only a small proportion of trauma 
centers across the country routinely obtain early INR and point of care rapid-TEG analysis in the emergency 
department, soon after arrival in patients in hemorrhagic shock.  Early recognition of coagulopathy for all 
enrolled subjects may lead to earlier intervention and in hospital mechanisms that improve clinical outcome.    
     For all participants in the trial, early and continual screening and assessment for clinical outcomes including 
multiple organ failure (MOF), nosocomial infection (NI) and acute respiratory distress syndrome (ARDS) will 
occur and will have the potential to again benefit all participants, irrespective of which arm of the study they are 
randomized to, as early surveillance for these clinical outcome may lead to beneficial effects.  It is the layering 
of standardization of prehospital resuscitation, early diagnosis of trauma induced coagulopathy and additional 
early assessment and screening for important clinical outcomes including MOF, NI, and ARDS that highlights 
the benefits of participation in the PAMPer trial for both plasma and control arms of the study.  
1. Screening and Enrollment: Subjects will be identified prospectively by air medical transport personnel 
familiar with the inclusion and exclusion criteria. The intervention takes place on board the air medical transport 
vehicle by personnel trained in blood product administration. Site research coordinators will document and 
verify all trauma arrivals via air medical transport for enrollment. Those patients who met inclusion and no 
exclusion criteria will have been assigned to AB plasma / low titer anti-B A plasma or standard of care (i.e., 
based on the study site randomization code). Subjects not enrolled by prehospital personnel may be identified 
and enrolled by research personnel as control subjects upon arrival to the ED. Once in the emergency 
department, the subjects will undergo initial blood sampling for our secondary outcomes of interest, and will 
have point of care rapid thromboelastography (TEG) performed for coagulation parameter measurements 
within 60 minutes of patient arrival and again the next day. 

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2. Informed Consent and Notification: If any subject or family member voice objections to being included in 
research at the scene, the subject will not be included.  Once subjects have arrived at the hospital, they will be 
approached for informed consent as soon as possible, or their legally authorized representative, if available, 
will be approached if subject is unable to consent. We expect most of these subjects to be unable to 
prospectively provide consent due to the critical nature of their injuries. We also anticipate that, in many cases, 
the subject’s legally authorized representative will not be readily available at the injury scene to prospectively 
provide informed consent. The subject’s capacity to consent will be determined by the treating physician at the 
hospital.  All consenting and notification will be accomplished by research team members trained in informed 
consent processes, HIPAA laws, and the protocol.  For those subjects that expire due to their injuries, next of 
kin will be notified of their involvement in the trial. 
In our experience, there is no single time-line that is appropriate for all subjects or families who are dealing with 
the end-of-life or social issues surrounding resuscitation from traumatic injury. The treating healthcare team 
can guide appropriate timing of discussions about our research.   When a family member refuses to provide 
consent for the subject’s participation in the study, they will be provided with a notification form approved by 
the IRB. Additionally, for subjects that do not survive we will send a certified letter, also approved by the IRB.   
     We will keep a log that reflects the required steps for contacting the LAR or family member. The checklist 
will be completed for each subject enrolled and included in the subject’s research records. See Appendix 3 
We will attempt to notify the family as soon as possible in person. In the event that they cannot be contacted in 
person (for example, if they are outside of the state), we will notify them by registered mail.  Subjects (or their 
legally authorized representatives) may refuse follow-up and/or access to medical record review  as stated in 
the notification form. This will be documented in the subject’s case history, along with the date and reason for 
withdrawal. The study investigators may examine data that have already been collected in order to determine 
safety. Subjects who wish to withdraw also will be reminded that total withdrawal will prevent the investigators 
from identifying any potential adverse events. Outcomes for subjects who withdraw or who decline consent to 
the follow-up portion of the study will be assessed by use of existing public databases such as obituaries or the 
Social Security Death Index (SSDI). 
     The original informed consents will be kept in a binder in a locked secure cabinet at each study site. Copies 
of all notifications will also be kept in a binder in a locked cabinet. These documents will be kept for a minimum 
of 7 years after study analysis is completed. Then they will be destroyed. 
 
3. HIPAA: language is included in our informed consent which contains adequate written assurances that 
protected health information (PHI) will not be disclosed to any person or entity other than those listed on the 
informed consent. This research could not practically be conducted without access and use of PHI for safety 
reasons.  
 
 
IX. Sample Storage 
 
     Detailed instructions beyond what is presented here regarding blood sample collection, processing, storage, 
packaging, and shipping will be provided in a separate manual of procedures.  Samples will be kept for at least 
7 years. 
     Future uses of blood samples obtained in this study will not include DNA or genetic testing.  Future testing 
by members of the PAMPer team may include additional physiological markers that may indicate mechanisms 
of early coagulopathy of trauma that have not yet been identified. 
     Upon receiving all specimens, research lab personnel will inspect the sample integrity and document the 
conditions (for example: thawed, vial broken, clotted, etc.).  The plasma samples obtained during PAMPer will 
be maintained by the University of Pittsburgh Coordinating Center in a -80°C freezer. 
 
X. Data  
 
1. Sources: Data will be collected prospectively as patient care progresses. This will include a review of the air 
medical patient care report(s), Emergency Department and electronic/ paper hospital records.  
 

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2. Prehospital Resuscitation Elements: Demographics, air medical response times, injury characteristics, 
vital signs, prehospital resuscitation characteristics, (plasma volume, crystalloid volume, blood transfusion 
volume, starting at referring hospital or scene) prehospital interventions (needle decompression, chest tubes) 
referring hospital vitals, and interventions. 
 
3. In-Hospital Resuscitation Elements: Demographics, shock severity (base deficit, lactate), injury 
characteristics, ED vitals, ED interventions (chest tubes, intubation), injury severity, operative interventions and 
timing of interventions, injury severity score, ICU days, ventilator days, length of stay, multiple organ 
dysfunction scores (daily), nosocomial infectious outcomes, blood gas results, chest x-ray reads, transfusion of 
blood and blood components, resuscitation requirements. 
 
4. Data Entry: MACRO and associated internet technology affiliates at the University of Pittsburgh will create 
web-based HTML forms to collect necessary information from all participating sites. Web entry forms will have 
dynamic features such as immediate checks on data and relationships within a form and between forms. 
Details and clarification about data items will be provided using pop-up windows and links to appropriate 
sections of the on-line version of the Manual of Operations. Data encryption and authentication methods will be 
used. Additional features will be built into the web entry forms including: forms transmission history, access to 
past forms, tracking of data corrections, and the capability to save and re-load incomplete forms. The subjects 
will be identified by a study number only. All clinical interventions will become part of the patient’s medical 
records including plasma transfusion.  All hard copy source documentation will be kept in a secured, locked 
cabinet in the site‘s research coordinator‘s office. All study documents will be maintained in a secure location 
for the time frame designated by each participating site‘s requirements. The electronic data will be entered and 
maintained on a password protected SSL website designed for this trial. 
     The data entered for the PAMPer trial will be maintained at the University of Pittsburgh on a relational 
database. The database would be housed in a virtual environment so in the event of a hardware failure it would 
migrate to a new host. The data will be backed up 4 times a day with full transaction log files in use and copies 
of the data will be stored offsite with a secure service, Iron Mountain. In addition to the data server, the 
production web server will also be backed up routinely and as a virtual machine can be transitioned to different 
hardware automatically in case of hardware failure.  All Servers are behind an enterprise firewall and access 
has to be granted through the firewall even within the University Network.  Research laboratory results will also 
be downloaded to the study designated program. 
 
5. Database Management: A two-tiered database structure will be created. A front-end database will serve the 
web entry needs, using a database management system well-suited to handling updates from multiple 
interactive users. The data from this database will be transferred periodically (e.g. weekly) to a data repository 
that can be used by statistical software packages. These data sets will be the basis for data queries, analyses 
and monitoring reports. Various versions of this database will be kept as needed, e.g. for quarterly 
performance reports. Backup of data and programs will be performed at frequent intervals. Access to data will 
be limited to those who need access to perform their tasks. The database management system is able to 
manage large quantities of data, to merge data from multiple databases as required, to handle complex and 
possibly changing relationships, and to produce analysis datasets that can be imported into a variety of 
statistical analysis packages. 
 
XI. Analysis Plan  
 
The over arching goal of the study proposal is to assess the efficacy and safety of prehospital plasma infusion 
as compared to standard of care for injured patients in hemorrhagic shock who require air medical transport. 
All primary and secondary analyses will be performed based on the Intent-to-Treat principle and will include all 
enrolled patients grouped by randomization. 
 
1. Data Analysis For Primary Hypothesis: 
 

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a. Hypothesis Primary Aim #1: Using the hypothesis patients in hemorrhagic shock who receive AB 
plasma or low titer anti-B A plasma during air medical transport will have a reduced 30 day mortality as 
compared to patients who receive standard air medical care. 
 
In this phase III clinical trial our primary outcome of 30-days mortality will be analyzed on the basis of intent-to-
treat. All subjects within all 32 clusters randomized will be included for the primary clinical outcome analysis. 30 
day mortality will be computed based on our data collection and follow up using all available sources including 
social security death records. Subjects who have not been reported as deceased by day 30 following ED 
admission from any of the sources used for query, multiple imputation will be used under the assumption that 
the missing data are  not missing at random. Further details concerning the determination a subject death is 
included in the data collection section of this protocol. If more than 15% of the subjects are missing the 30 days 
mortality data, our primary outcome will be analyzed descriptively without inferential testing. The proportion of 
mortality within each cluster (level of randomization) will be computed and pooled for both intervention and 
control groups. For our cluster design, the primary clinical outcome of 30-day mortality will be assessed as a 
fixed end point of time using test of proportions differences, pooled z-test with continuity correction applied. 
Our statistical testing is part of 3 sequential tests that determined using the O'Brien-Fleming spending function 
to determine the test boundaries at each look including the final analysis as described in our power 
analysis.[95] P value and related effect size with 95% confident interval for 30 days mortality differences will be 
computed. Cluster size variation will be checked and consequently a weighted analysis to account for related 
variation will be performed. We will take advantage of the advanced method in accounting for intra-cluster 
correlation in which will help in increasing the statistical power of our analysis. Accounting for cluster effect can 
be accomplished by dividing z-value on the square root of the design effect in this study.[96] The revised z-
value adjusting for clustering is calculated with following equation:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
𝑧𝑧−𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉
ඥ(𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒)
 
 
 
 
     As an extension for the above analysis, multiple regression including generalized estimating equations 
(GEE) will be used as well to adjust for cluster level covariates and to incorporate patient level covariates 
through a two-stage process.[97] This approach of modeling techniques allows the inherent correlation within 
clusters to be modeled explicitly and a more satisfactory model can be obtained.[98, 99] For this regard in 
utilizing a statistical modeling we will be able to identify the main factors that explain variation in the outcome. 
Our analysis plan is to adjust for the effect of related covariates before testing the effect of our intervention 
(pre-hospital plasma) rather than to maximize the proportion of variation explained. Ensuring that our modeling 
is hypothesis-led rather than data driven, we have considered the most covariates which are to be included in 
our model with the intervention variable fitted last (pre-hospital plasma). Of these covariates: prehospital 
transporting time, pre-hospital blood transfusion and crystalloid, mechanism of injury, head injury/GCS, age, 
and gender. The priority will be for base line covariates which reveal imbalance in between clusters or 
treatment groups.  Site as a stratifying variable will be included as a random effect .[100]  The number of 
variables that we may adjust our main effect for will be according to related relevancy and sample size 
adequacy. We are also aware that we should avoid the extended enthusiasm in over adjusting to avoid diluting 
the intervention main effect of our trial. Sensitivity analysis of 30 days mortality will be performed to check the 
effect of imputation as alive on the treatment group for comparisons and related confident intervals. Additional 
statistical technique may be added based on DSMB recommendations. STATA software, StataCorp, College 
Station, TX, will be used in our analysis. Interim and final analyses of the primary outcome will be the same, 
and both adjusted and unadjusted p-values will be presented for all analyses.  
 
2. Secondary Hypotheses: 
 
a. Hypothesis Secondary Aim #1: Using the hypothesis patients in hemorrhagic shock who receive 
prehospital AB plasma or low titer anti-B A plasma during air medical transport (Ppp) will have a lower 24hour 
blood transfusion requirement, a lower incidence of multiple system organ failure, nosocomial infection, acute 
lung injury and TRALI as compared to patients who receive standard air medical care (Psc), we will test the 

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null hypothesis of Ppp=Psc versus the alternative hypothesis that Ppp<Psc. In testing the significance for our 
secondary aims, data will be checked for equal variance across clusters and adjustment for fixed effects and 
random effects will be incorporated in any modeling when needed. Assuming equal variance, we will utilize the 
two-sided Mann-Whitney U or Fishers Exact test for these secondary clinical outcome comparisons. Time-to-
event analysis using Kaplan-Meier and log rank comparison will also be performed utilizing the timing of the 
secondary outcome event in days and censoring patients who suffer mortality prior to any outcome event. 
Regression analysis of individual level data using methods for clustered data (adjusting the standard errors for 
the design effect) will be used in order to analyze the effect of intervention on the outcome variables adjusting 
for all confounding, covariates and expected interactions. Models will be compared with the likelihood ratio test.  
 
b. Hypothesis Secondary Aim #2: Using the hypothesis patients in hemorrhagic shock who receive 
prehospital AB plasma or low titer anti-B A plasma during air medical transport (Ppp) will have a reduced fresh 
frozen plasma and platelet transfusion requirement, a reduced crystalloid and colloid requirement in the first 24 
hours post-injury and will less commonly require vasopressor support in the first 24 hours post injury as 
compared to patients who receive standard air medical care (Psc), we will test the null hypothesis of Ppp=Psc 
versus the alternative hypothesis that Ppp<Psc. In testing the significance for our secondary aims, data will be 
checked for equal variance across clusters and adjustment for fixed effects and random effects will be 
incorporated in any modeling when needed. Assuming equal variance, we will utilize an independent samples 
Mann-Whitney U test for these secondary hypothesis comparisons of resuscitation volumes across 
randomization groups as they will not be normally distributed. We will utilize the two-sided Fisher Exact test for 
vasopressor requirement (yes/no) in the intial 24 hours post-injury across randomization groups. Similar 
analyses controlling for possible survival bias will be performed as proposed for our primary outcome, 24 hour 
blood transfusion requirements.  
 
c. Hypothesis Secondary Aim #3: Using the hypothesis patients in hemorrhagic shock who receive 
prehospital AB plasma or low titer anti-B A plasma during air medical transport (Ppp) will have improved 
coagulation measurements as determined by INR, PT and thromboelastography parameters as compared to 
patients who receive standard air medical care (Psc), we will test the null hypothesis of Pp=Psc versus the 
alternative hypothesis that Ppp<Psc for each coagulation parameter. In testing the significance for these 
secondary aims, data will be checked for equal variance across clusters and adjustment for fixed effects and 
random effects will be incorporated in any modeling when needed. Assuming equal variance, we will utilize an 
independent samples Mann-Whitney U test for these secondary hypothesis comparisons of coagulation 
parameters as they will not be normally distributed. We will additionally control for mulitple comparisons. 
Similiar analyses for the two time points will be performed (first 60 minutes (+12 hours) and 24 hours).  
 
d. Hypothesis Secondary Aim #4: Using the hypothesis patients in hemorrhagic shock who receive 
prehospital AB plasma or low titer anti-B A plasma during air medical transport (Ppp) will have reduced early 
IL-6 cytokine expression, reduced thrombomodulin and increased protein C levels as compared to patients 
who receive standard air medical care (Psc), we will test the null hypothesis of Ppp=Psc versus alternative 
hypotheses (Ppp<Psc for IL-6 and thrombomodulin and Ppp>Psc for protein C levels). In testing the 
significance for these secondary aims, data will be cheeked for equal variance across clusters and adjustment 
for fixed effects and random effects will be incorporated in any modeling when needed. Assuming equal 
variance, we will utilize an independent samples Mann-Whitney U test for these secondary hypothesis 
comparisons of cytokine and protein C pathway moeities as they will not be normally distributed. Similiar 
analyses for the two time points will be performed (first 60 minutes (+12 hours) and 24 hours). 
 
3. Predefined Subgroup Analyses: Predefined subset analyses will be performed looking at 1a.) patients 
who ultimately did or did not required massive transfusion in the first 24 hours (≥ 10 Units PRBCs) 1b.) patients 
who ultimately required ≥  than 4 Units of  PRBC’s 2.) those patients who received or did not receive 
prehospital PRBC transfusion, 3.) those patients with significant traumatic brain injury (Head AIS >2) versus 
those without significant brain injury (Head AIS ≤ 2), 4.) those patients enrolled from the scene of injury versus 
those enrolled from a referral hospital, 5.) those patients with a preinjury history of vitamin K antagonist 
medication versus those without,  6.) those patients with preinjury history of antiplatelet medication, 7.) those 
patients who suffered blunt injury as compared to those who suffered penetrating injury,  and 8.) those patients 
with high versus low field to ED transport times (median split subgroups) .  It is recognized that the study is not 

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appropriately powered for these subgroup comparisons and the results and conclusions formulated from these 
subgroup analyses will be considered exploratory in nature and will not be used as a basis for treatment 
recommendations. 
 
4. Randomization of Ineligible Subjects: It is anticipated that there will be a small proportion of patients 
enrolled who receive either AB plasma/low titer anti-B A plasma or standard of care that in retrospect will not 
have met the entry criteria and are thus ineligible. In this circumstance, patients will be analyzed according to 
the group to which they were randomized. Subgroup analyses based on eligibility criteria will be performed if 
the number of patients so affected is large. However, based on the relatively limited inclusion and exclusion 
criteria it is anticipated that the frequency of this event will be low.   
 
5. Non-adherence: In some circumstances, patients may receive standard care instead of AB plasma/low titer 
anti-B A plasma intervention when randomized to AB plasma /low titer anti-B A plasma for that month. Non-
adherence is most likely to occur in the case of the exsanguinating patient when AB plasma or low titer anti-B 
A plasma despite being available is not used. Fortunately, this event is relatively rare. In keeping with the 
intention-to-treat analytic design, these patients will be analyzed with the group to which they were 
randomized. 
 
6. Sample Size Justification and Power Analysis: We have determined the sample size for this proposal 
and powered the analysis based upon our primary outcome (30 day mortality) as this is a traditional trauma 
trial standard for evaluating delayed complications and safety of trial interventions, the benefit is 
durable, the outcome is important to scientists and patients and provides evidence to support the 
most efficient use of the nation’s blood supply. All subjects will be tracked for vital statistics for a full 
30 days, whether or not they have left the hospital. 
 
7. Blood Transfusion at 24 hours Secondary Outcome: Baseline references for the average 24 hour blood 
transfusion requirement in injured patients with hemorrhagic shock vary in the literature and depends on 
multiple factors including shock severity, injury severity, age, mechanism of injury and transfusion practice at 
the institutions being analyzed.[36, 45, 47, 68, 101-105] From these baseline references we determined that 
the average requirement for blood in initial 24 hours for patients in hemorrhagic shock is 15.0±12 Units. Based 
upon the sample size estimate for our primary outcome of 30 day mortality, we will have 80% power to detect 
at least a 20% reduction in 24 hour blood transfusion requirements. 
 
8. Sample Size Calculation for a Cluster Design: To appropriately power the study for 30 day mortality, we 
have utilized, as of yet, unpublished prospective data from the Inflammation and the Host Response to Injury 
Large Scale Collaborative Program, (www.gluegrant.org) supported by the National Institute of General 
Medical Sciences (NIGMS) or more commonly termed ‘Glue Grant’ study and additional published literature to 
estimate our baseline mortality and effect size for the study. In hemorrhagic shock patients enrolled in the Glue 
Grant, patients who require at least 3-4 units of blood within the first 6 hours of injury had a in hospital 21.3% to 
22.4% mortality, respectively. This is similar and in conjunction with prior published literature in hemorrhagic 
shock patients.[51, 105-108] Based upon these point estimates we will use a baseline mortality of 22% for our 
power calculations.  By intervening early into the coagulopathy which complicates significant traumatic injury 
and hemorrhagic shock, the intent of the trial would be to improve outcomes (30 mortality) by reducing 
transfusion requirements, reducing the need for massive transfusion (> 10 units of blood in 24 hours post 
injury) and reducing the inflammatory response which blood transfusion has been shown to be an independent 
risk factor for. Again, using the Glue Grant dataset, for those patients who required between  at least10 units 
and 15 units of blood transfusion over the initial 24 hours following injury, the mortality rate was 7.6% and 
8.3%, respectively. 
For our sample size estimation for the 30 day mortality outcome, we chose a difference of 14% (22% to 8%, 
see Glue Grant point estimates above) from a baseline mortality of 22% when comparing patients randomized 
to plasma versus standard of care. The trial will be powered at 88% with a two-sided alpha level of 0.05, 
adjusted for interim analyses to 0.037 (interim analyses at 1/3 and 2/3 enrollment). The additional power will 
allow adjustment of potential unequal cluster sizes as this could decrease the statistical power of the study. We 
considered a between group difference in 30 day mortality of 14% or greater to be clinically meaningful and of 

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O'Brien-Fleming Boundaries with Alpha = 0.05
Upper
Lower
Z Value
Look
-1
-2
-3
-4
0
1
2
3
4
0.5
1.0
1.5
2.0
2.5
3.0
sufficient magnitude to influence clinical practice. Adjusting for site generally should increase power unless 
there is a lack of homogeneity of treatment effects across sites.  
The required sample size is 144 patients in each group multiplied by 1.75 to adjust for cluster design 
(average 16 patients per cluster) and addition of 12% for missing data giving a needed number of patients of 
282 for each group and 564 patients total. We will have 80% power to detect a 13% difference from baseline 
and 75% power to detect a 12% difference. Our sample size will provide additional power to overcome the 
possibility of within cluster variation due to cluster design. 
 
 
 
 
Power 
N1 
N2 
Alpha 
Beta 
P1 
P2 
 
0.883804 
144 
144 
0.050000 
0.116196 
0.22 
0.08 
 
0.874007 
140 
140 
0.050000 
0.125993 
0.22 
0.08 
 
0.863480 
136 
136 
0.050000 
0.136520 
0.22 
0.08 
 
0.855080 
133 
133 
0.050000 
0.144920 
0.22 
0.08 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
Assuming 0.038 alpha level, two sided, test of proportions differences, z-test with continuity correction applied.   
(Power analysis performed using PASS statistical software, Number Cruncher Statistical System, Kaysville, Utah).  
 
The above power analysis generated assuming 3 sequential tests are made using the O'Brien-Fleming 
spending function to determine the test boundaries and depicted in the following table and graph: 
 
Details when Spending = O'Brien-Fleming, N1 = 144, N2 =144, P1 = 0.22, P2 = 0.08, Continuity Correction. 
 
 
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 
0.030172 
0.030172 
 
2 
0.67 
-2.51142 
2.51142 
0.012025 
0.011890 
0.012097 
0.501816 
0.531988 
 
3 
1.00 
-1.99302 
1.99302 
0.046259 
0.037903 
0.050000 
0.351816 
0.883804 
 
Drift 
3.17317 
 
 
      
 
 
 
 
 
 
 
 
 
 
 
Assumption 
Control group 
Intervention 
group 
Absolute 
differences 
(effect size) 
Estimated Power* 
1 
22% 
10% 
12% 
75% 
2 
22% 
9% 
13% 
80% 
3 
22% 
8% 
14% 
88.4% 

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The used multiplier of 1.75 has been determined based on the equation of (1 + (ň - I) Ƿ), where ň = average 
cluster size) and (Ƿ = estimated intra-cluster correlation coefficient). Assuming a 1:1 randomization of equal 
cluster sizes, with 32 clusters of 16 patients each, with an estimated intra-cluster correlation coefficient (ICC) of 
0.05, (as recommended when no previous literature or similar trials involving patient-level outcomes exist, 
[109-111]. With a total of 564 patients needed for this trail, on average, over the 3.5 years of enrollment for the 
trial, each participating center of will need to enroll 20-30 patients per year.  We will enroll 564 subjects in order 
to ensure that we reach our goal of 504 evaluable subjects for our per-protocol analysis. 
 
9. Missing Data: As a general strategy for missing data in this study we will concentrate highly on tactical 
approach rather than only analytical. Our goal is to focus on preventing missing data as much as possible. 
There is no methodology that can recover the robustness and unbiased character of estimates derived from a 
complete set of data.  
     We expect very little missing data due to the nature of our study design and with related heavy preparation 
and efforts from our parts to have a well-conducted clinical trial. The study intervention in this study will span a 
short duration in mostly prehospital phase therefore we do not expect a considerable drop out during that 
treatment phase.  We expect about 2.5%-3% on average. We have inflated our sample size by 5% to reduce 
related effect on power adequacy.  
     In this study we will be attempting to maximize the number of participants according to the study protocol 
until all outcome data are collected. Our outcome measurements will be attempted in all subjects who initially 
are enrolled into the study including those who did not complete the study and in a full ‘intention to treat’ basis 
for our statistical analysis.  
     For 30-day mortality, given the transient nature of many of the subjects, extensive efforts will be made to 
ascertain vital status. Batch searches of mortality databases will continue annually for subjects with unknown 
status, until 30 days post trial closeout. If discharge occurs before hospital day 30 and the subject is 
discharged to a hospice, nursing home or other healthcare provider, research staff will contact the facility to 
ascertain the subject’s vital status. If the subject was discharged to his/her usual residence before day 30, the 
research staff will contact the subject or their family/legally authorized representative (LAR). If vital status 
remains unknown the clinical site will request periodic searches for the subject’s social security number in the 
Social Security Master Death Index. For subjects not reported as deceased by these sources by day 30 
following ED admission, batch searches of the mortality database will continue annually until trial close-out. 
Date (and cause of death when available) for out-of-hospital deaths will be documented; however, underlying 
and contributing causes of death may not be available from these sources. For interim and final analyses, 
subjects who have not been reported as deceased by day 30 following ED admission from any of these 
sources, we will use multiple imputation for the final value. For sensitivity analyses we will report the data with 
and without imputation. We also will report an analysis consistent with that used in other trauma studies 
counting those missing as ‘alive’ and ‘dead’ on day 30. 
     Data missing will be accurately documented with related causes, continuously monitored and mitigated 
accordingly. We are not expecting missing baseline data as prehospital data collection will be protocolled and 
complete, therefore no problem should be expected in the precision of our analysis.  We are setting a minimum 
rate of completion for the study primary outcomes data equal to 80%.  A rate above 15% of missing primary 
outcome data is unacceptable for our data analysis and will be reported as a descriptive outcome only. Single 
imputation methods will not be used as the primary approach in the treatment of missing data.   
     We will assume data missing is not at random in our trial and we will use all baseline covariates and some 
of missing data might be determined by some observed outcome as trial progress. A likelihood-based analysis 
including regression multiple imputations and random-effects regression models could be implemented in this 
regard. Missing outcome can be predicted from individuals’ observed data using model based on observed 
individuals. In our final analysis we will explicitly state the assumptions underlying treating missing outcomes 

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and justifying those using compressive data descriptions and sensitivity analysis.  Our sensitivity analysis will 
allow us to explore the robustness of conclusions to alternative plausible assumptions. We will follow 
CONSORT statement in reporting the number of clusters/objects with missing outcome data by treatment 
arm.[112] All methods used in treating missing data will be adequately reported.  
 
 
 
 
XII. Safety Monitoring 
 
1. Adverse Event definitions:   
 
a. Adverse event means any untoward medical occurrence associated with the use of the drug in humans, 
whether or not considered drug related. 
 
b. Adverse reaction means any adverse event caused by a drug. 
 
c. Suspected adverse reaction means any adverse event for which there is a reasonable possibility that the 
drug caused the adverse event.  Suspected adverse reaction implies a lesser degree of certainty about 
causality than “adverse reaction” 
 
d. Reasonable possibility.  For the purpose of IND safety reporting, “reasonable possibility” means there is 
evidence to suggest a causal relationship between the drug and the adverse event. 
 
e. Life-threatening, suspected adverse reaction.  A suspected adverse reaction is considered “life-threatening” 
if, in the view of either the Investigator (i.e., the study site principal investigator) or Sponsor, its occurrence 
places the patient or research subject at immediate risk of death.  It does not include a suspected adverse 
reaction that had it occurred in a more severe form, might have caused death. 
 
f. Serious, suspected adverse reaction. A suspected adverse reaction is considered “serious” if, in the view of 
the Investigator (i.e., the study site principal investigator) or Sponsor, it results in any of the following 
outcomes: death, a life-threatening adverse reaction, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions, or a congenital anomaly/birth defect. 
 
Important drug-related medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered “serious” when, based upon appropriate medical judgment, they may 
jeopardize the research subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in the emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
g. Unexpected, suspected adverse reaction.  A suspected adverse reaction is considered “unexpected” if it is 
not listed in the general investigational plan, clinical protocol, or elsewhere in the current IND application; or is 
not listed at the specificity or severity that has been previously observed and/or specified. 
 
 
2. Assessing and Reporting Adverse Events (AEs): All adverse events will be documented by the study 
sites and assessed for relationship to the study intervention. Reporting forms will be submitted to the 
Coordinating Center (to include the IND Sponsor) and Data Safety Monitoring Board (DSMB). All reported 
adverse events will be reviewed as to treatment arm and further classified by: a) Severity (serious or non-
serious); and b) Expected vs. Unexpected. For serious, unexpected adverse events felt to be associated with 
the research intervention, the Coordinating Center will notify the reviewing IRBs and the FDA/IND application 
in accordance with requisite reporting time frames.  

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     Investigators and study team will determine daily if any clinical adverse experiences occur during the period 
from enrollment. The investigator will evaluate any changes in laboratory values and physical signs and will 
determine if the change is clinically important and different from what is expected in the course of treatment. If 
reportable adverse experiences occur, they will be recorded on the adverse event case report form. The study 
population is expected to have a large number of unrelated, expected serious adverse events including death 
from trauma related injuries. The SAE will be recorded on the subject’s AE/SAE log and follow local reporting 
requirements. 
     SAE reporting for the PAMPer study will follow the FDA guidance on safety reporting requirements for IND 
and Department of Defense guidelines as well as local IRB reporting guidelines. SAE’s will be reported within 
15 calendar days of receiving the site report. 
          Transfusion services at each respective enrolling center will rely upon their respective central blood bank 
to provide them universal donor ‘AB’ plasma. All participating blood centers will minimize multiparous female 
donor plasma as is current standard of practice for blood banks. The risk of complications including TRALI and 
are required to be specifically monitored for, recorded and investigated by every transfusion service at each 
enrolling center. Any transfusion complication including any transfusion of blood products in the pre-hospital 
setting will be similarly monitored and documented. As the intervention is specific to the pre-hospital setting 
and since transfusion complications are temporally related to the specific transfusion, all transfusion related 
complications will be assessed during the initial 24 hours from arrival and recorded. The admitting hospital and 
their respective blood bank transfusion service, which will be the service which provides the plasma for the trial 
and is a participating center, will be responsible for investigating and documenting any adverse reaction or 
fatality due to plasma that was transfused during transport.  
 
     Prehospital SOPs for blood storage, temperature monitoring, administration, and adverse event reporting 
will be followed across all participating trauma centers. (see Appendix 4) 
     A summary report of the DSMB’s findings will be submitted to regulatory agencies. At least one specialized 
clinician from the Data Safety Monitoring committee will be responsible for monitoring data safety. All related 
unanticipated problems will be directly handled by study site Investigators and reported accordingly. We will 
also follow Department Of Defense Unique requirements documentation. The University of Pittsburgh and 
each participating center will have an AE logbook to record and to assure adequate attention for continuous 
assessment, analysis, and reporting of adverse effects using a standardized report form (i.e., Form FDA 
3500A). The Coordinating Center will be responsible for all oversight of these risk assessments with monthly 
evaluations. 
  
 
3. Prehospital Blood Product Adverse Events and Look Back SOP: 
a.. 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 plasma. 
b. 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 volumeor # of units transfused 
6. The transfusionist’s name (paramedic) 
7. Documentation of related adverse events 
     c. Procedure for transfusion reactions:  
This is modified from UPMC policy for Blood Transfusions to be applicable for this study. 
1. 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/ transfusion service. Prehospital providers initiating transfusion of blood products will monitor 
vitals throughout transport. If clinical concern for a transfusion reaction occurs, the transfusion will be 
stopped, and supportive care will continue. The concern for a transfusion reaction will then be 
communicated to the trauma center staff. 

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2. The most common clinical events accompanying or announcing transfusion reactions are, in order of 
decreasing frequency: 
a. Fever, with or without chills 
b. Skin symptoms, hives and/or itching or rash 
c. Chest pain 
d. Hypotension 
e. Nausea 
f. Flushing 
g. Respiratory Distress (wheezing, coughing or dyspnea) 
h. Bleeding at infusion site 
i. Hemoglobinuria 
j. Circulatory overload 
k. Anaphylaxis 
3. If an adverse reaction is suspected, the procedure below will be followed: 
a. Stop the transfusion 
b. Maintain IV access with Normal Saline and change the tubing. 
c. 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 shall be initiated per standard blood bank guidelines 
5. Notify the Blood Bank 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 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 participating centers Transfusion Service is responsible for peer review and blood 
utilization practice. 
8. Look back procedures: Since the plasma will be tracked through the participating centers Blood 
Bank/Transfusion service look back/product recall procedures will be conducted as per standard 
protocol. (See Appendix 5) 
 
4. Data Safety Monitoring Board (DSMB): A Data and Safety Monitoring Board (DSMB) will be created to 
review this study and provide recommendations re. study continuation to the IND Sponsor.  After initial 
approval and at periodic intervals (to be determined by the committee) during the course of the study, the 
DSMB responsibilities are to: 
 
a. Review the research protocol, informed consent documents and plans for data and safety monitoring; 
 
b. Evaluate the progress of the study, including periodic assessments of data quality and timeliness, participant 
recruitment, accrual and retention, participant risk versus benefit, adverse events, unanticipated problems, 
performance of the trial sites, and other factors that can affect study outcome; 
 
c. Consider factors external to the study when relevant information becomes available, such as scientific or 
therapeutic developments that may have an impact on the safety of the participants or the ethics of the study; 
 
d. Review clinical center performance, make recommendations and assist in the resolution of problems 
reported by the IND Sponsor or study site Investigators; 
 

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e. Protect the safety of the study participants; 
 
f. Report on the safety and progress of the study; 
 
g. Make recommendations to the IND Sponsor, and if required, to the FDA concerning continuation, 
termination or other modifications of the study based on the observed beneficial or adverse effects of the 
treatment under study; 
 
h. Monitor the confidentiality of the study data and the results of monitoring;  
 
i. Assist the IND Sponsor by commenting on any problems with study conduct, enrollment, sample size and/or 
data collection. 
 
j. The DSMB will include experts in emergency medicine, surgery (trauma/critical medicine),bioethics and 
biostatistics.  As a condition of Department of Defense funding, a Medical Monitor will be appointed and 
approved by the IRB.  The Medical Monitor may or may not be a DSMB member. Members will consist of 
persons independent of the investigators who have no financial, scientific, or other conflict of interest with the 
study.  Written documentation attesting to absence of conflict of interest will be required.   
 
k. The University of Pittsburgh Office of Clinical Research, Health Sciences will provide the logistical 
management and support of the DSMB.  A safety officer (chairperson) will be identified at the first meeting.  
This person will be the contact person for serious adverse event reporting.  Procedures for this will be 
discussed at the first meeting. 
 
l. The first meeting will take place before initiation of the study to discuss the protocol, approve the 
commencement of the study, and to establish guidelines to monitor the study. The follow-up meeting frequency 
of the DSMB will be determined during the first meeting.  An emergency meeting of the DSMB will be called at 
any time by the Chairperson should questions of patient safety arise. DSMB charter is attached (Appendix 6). 
   
5.  Research Monitor 
The research monitor is required to review all unanticipated problems involving risk to subjects or others, 
serious adverse events and all subject deaths and provide an unbiased written report of the event. At a 
minimum, the medical monitor must comment on the outcomes of the event or problem and in case of a 
serious adverse event or death, comment on the relationship to participation in the study. The medical monitor 
must also indicate whether he concurs with the details of the report provided by the principal investigator. The 
research monitor may also discuss the research protocol with the investigators, interview human subjects, and 
consult with others outside of the study about the research.  The research monitor shall have authority to stop 
a research protocol in progress, remove individual human subjects from a research protocol, and take 
whatever steps necessary to protect the safety and well-being of human subjects until the IRB can assess the 
monitor’s report.  Reports for events determined by either the investigator or research monitor to be possibly or 
definitely related to participation and reports of events resulting in death must be promptly forwarded to the 
U.S. Army Medical Research and Materiel Command Office of Research Protections Human Research 
Protections Office (USAMRMC ORP HRPO). 
 
6. Interim Analyses: In concert with the DSMB, prior to initiation of the trial, the final monitoring plan                    
will be developed to serve as the guide to the DSMB’s decision-making process concerning early stopping of 
the trial. In making the decision to recommend termination of the study, the DSMB shall be guided by several 
types of information: (i) a formal stopping rule based on the primary analysis (comparison of treatment groups 
on the 30 day mortality), (ii) information on safety outcomes by treatment group, (iii) consistency between 
results for primary and secondary outcomes, and (iv) consistency of treatment effects across subgroups. 
     We have designed this trial with a two interim look before the final analysis. Our power analysis generated 
assuming a total of 3 sequential tests based on O'Brien-Fleming spending function to determine alpha 
spending and test boundaries. We will use test of proportions differences, z-test with continuity correction 
applied and other adjusting techniques. The level of significance will maintain an overall p value of 0.05 
according to O’Brien-Fleming stopping boundaries leaving a p value of 0.038; two sided, for the final analysis 

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with a final z-value of 1.993. An independent data and safety monitoring board (DSMB) will periodically review 
the efficacy and safety data. DSMB will issue related recommendations based on comprehensive data 
monitoring and substantiated evidences. Two formal interim analyses of efficacy will be performed when 33% 
and 67% of the expected number of primary events had accrued (about one month after 1/3 and 2/3 of subject 
accruals). The purpose of our sequential tests is to detect early sign of superior efficacy and detect further 
apparent futility in the intervention group. This kind of futility monitoring and testing could cause this trial to be 
stopped as soon as a negative outcome of 30-days mortality is inevitable and thus it is no longer worthwhile 
continuing the trial to its completion. Such early termination for futility could reduce the enormous expenditures 
of resources, human and financial, involved in the conduct of trials that ultimately provides negative answers 
regarding the value of the study medical intervention.[113]  
     Our trial’s lower and upper 
stopping boundaries have been 
computed to ensure that the trial 
Type I and Type II error 
probabilities of the group 
sequential plan are according to 
the study assumptions and design. 
The upper boundaries are related 
to the formal efficacy testing at 
each assigned sample size 
(expected number of primary 
events completion at 33%, 67%, 
and 100%). The lower boundaries 
are related to the formal futility 
(safety) testing at each assigned 
sample size (expected number of 
primary events completion at 33%, 
67%, and 100%). Upper and lower 
boundaries will be provided to 
DSMB as a guideline and could be modified by DSMB prior to the trial upon reasonable justifications. With this 
sequential testing plan based on O'Brien-Fleming spending function, only an absolutely overwhelming 
treatment intervention can justify the termination of our clinical trial after a third of the subjects have been 
enrolled and completed a one month of follow up. If the trial has been ordered to stop early because of interim 
analysis, adjusted p-values will be computed based on the described analysis of our main clinical outcome. 
Unadjusted p-value will not be considered for final results interpretations.  
Our interim analysis is part of our three sequential testing as we have mentioned above. At each of the two 
interim looks, 30 days-mortality will be pooled across clusters comparing between the two study groups. Based 
on the assumed power analysis at each interim look, the z-value will be calculated and adjusted for cluster size 
and other adjustments (including within-clusters correlation) similar of what we have described on the analysis 
of our primary clinical outcome and as much as the accrued sample size at that specific check may allowed.  
We have illustrated z-values for the upper and lower boundaries across interim two analyses and final analysis 
of a total accumulated alpha of 0.05. (Figure and Table below) 
     Further and in relation to interim safety analysis, safety data by study groups labeled as Plasma group and 
Control group will be provided periodically to DSMB. Data will be remained completely unblinded unless the 
DSMB call for otherwise. The safety data of the study include serious adverse events regarding frequency, 
anticipated or unanticipated, individual description for each event and dates. Our periodic reports to DSMB will 
include as well data on recruitment, data completion, data quality, etc.  Other data will be provided as well as 
any additional safety analysis upon DSMB request. Mortality will be reported as an overall in our periodic 
reports to DSMB however we will report mortality individually as treatment A and B at each of the trial two 
formal interim analyses. Secondary to limited funding, complex cluster design and multicenter nature of the 
trial, we are unable use adaptive design due to the possibility of substantial increase in sample size, however 
based upon a DSMB recommendation during our interim analysis if our mortality rate is lower than expected 
and requires less than a 10% increase in our pre-determined sample size required, we will attempt to increase 
our enrollment utilizing those centers with highest enrollment, limited by budgetary feasibility, and taking into 
consideration the needed adjustment for type I error. 
O'Brien-Fleming Boundaries with Alpha = 0.05
Upper
Lower
Z Value
Look
-1
-2
-3
-4
0
1
2
3
4
0.5
1.0
1.5
2.0
2.5
3.0

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Sequential tests based on O'Brien-Fleming spending function, alpha spending and test boundaries 
Look 
time 
Lower 
Boundary 
Upper 
boundary 
Nominal 
Alpha 
Inc Alpha 
Spent Alpha 
Total 
Alpha 
Inc Power          
Exit probabilities 
Total 
Power 
1 
0.33 
-3.71030 
3.71030 
0.000207 
0.000207 
0.000207 
0.030172 
0.030172 
2 
0.67 
-2.51142 
2.51142 
0.012025 
0.011890 
0.012097 
0.501816 
0.531988 
3 
1.00 
-1.99302 
1.99302 
0.046259 
0.037903 
0.05000 
0.351816 
0.883804 
 
As an alternative to the above methods to monitor futility, the DSMB might want to terminate our trial when the 
results of the interim analysis are unlikely to change after accruing more patients based on conditional power. 
Conditional power is defined as the approach that quantifies the statistical power to yield an answer different 
from that seen at the interim analysis. If this quantity is really small, then we can conclude that it would be futile 
to continue with the investigation. 
For such a conditional power calculation, we will use z to determine if we can reject our H0 with related interim 
alpha according to the following: 
If the current trend continues, what is the chance that we will have a positive study (Final Z ≥ 1.96) 
𝑧𝑧= Actual mortality at this current interim − 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑎𝑎𝑎𝑎 𝑡𝑡ℎ𝑖𝑖𝑖𝑖 𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎
ඥTotal calculated sample size (𝑒𝑒𝑥𝑥𝑥𝑥𝑥𝑥𝑥𝑥𝑥𝑥𝑥𝑥𝑥𝑥 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 𝑜𝑜𝑜𝑜 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚)(expected rate of survival)
≥1.96 
We will be able to tell how many remaining subjects should survive in order to reject H0.  Also we can be able 
to determine if the probability is so small to reject the H0 according to accumulated data. Using the above 
information we can decide that if it is futile to continue because there is such a small chance of rejecting the 
trial H0.    
For futility assessment based on conditional power we will be able to use SAS programs (FindZa.sas and 
FindZaBI.sas) at each interim analysis to compute the properties of a futility assessment based on a 
conditional power computation. 
Based on the above analysis the study DSMB might provide recommendations at interim analysis for early 
discontinuation of the trial because of futility and related conditional power. Such conclusion is based on a fact 
that even further subject enrollments to a full sample size or even additional increase in sample size will 
unlikely proves effectiveness. Possible additional confirmatory analysis can be applied to consider any other 
efficacy measures and to provide subsets analysis based on centers and other considerations.    
 
 
7. Quality Control, Assurance and Confidentiality: 
 
a. Protocol Compliance: 
The participating study site Investigators will not deviate from the protocol for any reason without prior written 
approval from the IRB except in the event of the safety of the research subject. In that event, the study site 
Investigator will notify the IND Sponsor and reviewing IRB immediately, if possible, and request approval of the 
protocol deviation, or, if prospective IND Sponsor and IRB approval is not possible, the study site Investigator 
will notify the IND Sponsor and reviewing IRB promptly following the respective protocol deviation. The study 
site Investigator will inform the reviewing IRB of all protocol deviations and unanticipated events involving risks 
to the research subjects and others, and will obtain prospective IRB approval for all proposed protocol 
changes. Persistent or serious noncompliance may result in termination of the study site’s participation in the 
research study. 
 
Protocol Deviations: Due to the prehospital setting of the intervention, the relative focused inclusion criteria, 
and the short intervention period, we expect few protocol deviations as compared to other large multicenter 
trials. If monitoring reports demonstrate evidence of continuing protocol deviations, we will analyze them to 

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determine if they are site specific or common across the study. We will note if specific inclusion or exclusion 
criteria are being misinterpreted, if a certain time point in testing is being omitted, or if a common set of data 
elements are missing. If the deviations are site specific, retraining will be done at the site. If the problems are 
study wide, we will discuss them with the other investigators, the DOD and the FDA to see if the protocol 
needs amended or recruitment put on hold. 
 
b. Privacy and Confidentiality: 
The study site Investigator’s and members of their research team will make reasonable effort to ensure the 
research subjects’ confidentiality. Subject name and other identifiable information will be kept in a secure, 
locked, limited access area. 
 
c. Investigator Responsibilities: 
The study site Investigators will agree to implement the IRB approved protocol and conduct the study in 
accordance with Section 9 (Commitments) of Form FDA 1572, 21 CFR Part 312, Subpart D, and the ICH GCP 
Guidelines (E6, Section 5) as well as all applicable national, state and local laws. The study will be performed 
in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with 
ICH/Good Clinical Practice, and applicable regulatory requirements. 
 
XIII. Study Limitations  
Due to the scarce nature of universal donor AB plasma or low titer anti-B A plasma and logistics of the air 
medical transport intervention, randomization for the proposal will be assigned in a 2, 4, or 6 month block 
fashion for helicopters or airbases at each respective participating institution. Individual patient randomization, 
requiring AB plasma or low titer anti-B A plasma to be aboard or available at every helicopter or airbase 
constantly throughout enrollment, remains the optimal randomization method, however is not feasible. This will 
bring in the potential for disparities in enrollment to either the intervention arm or standard care arm as we will 
not be able to assure equal numbers in each arm of the study. 
The study is a multi-center trial with the potential for variation in prehospital standard of care and in-hospital 
variation in post-injury care potentially affecting the primary and secondary outcomes for the proposal. To 
maximize the generalizability of the trial results and to minimize procedural requirements in the prehospital 
setting, we elected not to standardize prehospital air medical standard of care except for crystalloid infusion. 
Importantly, we selected similar academic, level 1, participating centers based upon their patient and air 
medical transport volumes, their prior experience with clinical research and prior participation in prior multi-
center trials, and who practice up-to-date evidence based trauma care, in attempts to minimize significant 
variation in post injury care. 
 
XIV. Timetable  
Wind Down 
3 months
IRB approval, 
Community 
Consent, 
Web Based 
Data Entry 
Year 1 
Year 2 
Year 3 
Year 4 
Pre-study 
period 
Site 
Training 
1st 3 
Months 
Enrollment 
Interim 
Analysis 
6 month 
Enrollment 
Interim 
Analysis 
Interim 
Analysis 

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XV. Additional Regulatory and Reporting Requirements Of The USAMRMC  
Additional reporting requirements and responsibilities of the Principal Investigator to the United States Army 
Medical Research and Materiel Command’s (USAMRMC) Office of Research Protections (ORP), Human 
Research Protection Office (HRPO) that will be employed can be found in the Appendices. (Clinical Protocol 
Appendix 7) 
 
XVI. Bibliography and References/ Literature Review 
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38. 
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Carrico, C.J., et al., Multiple-organ-failure syndrome. Arch Surg, 1986. 121(2): p. 196-
208. 
90. 
Marshall, J.C., Organ dysfunction as an outcome measure in clinical trials. Eur J Surg 
Suppl, 1999(584): p. 62-7. 
91. 
Marshall, J.C., et al., Multiple organ dysfunction score: a reliable descriptor of a 
complex clinical outcome. Crit Care Med, 1995. 23(10): p. 1638-52. 

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92. 
Bernard, G.R., et al., The American-European Consensus Conference on ARDS. 
Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J 
Respir Crit Care Med, 1994. 149(3 Pt 1): p. 818-24. 
93. 
Cuschieri, J., et al., Early elevation in random plasma IL-6 after severe injury is 
associated with development of organ failure. Shock, 2010. 34(4): p. 346-51. 
94. 
Sperry, J.L., et al., Male gender is associated with excessive IL-6 expression following 
severe injury. J Trauma, 2008. 64(3): p. 572-8; discussion 578-9. 
95. 
O'Brien, P.C. and T.R. Fleming, A multiple testing procedure for clinical trials. 
Biometrics, 1979. 35(3): p. 549-56. 
96. 
Murray, D.M., ed. The Design and Analysis of Group Randomized Trials. Oxford 
University Press: Oxford. 
97. 
Zucker, D.M., et al., Statistical design of the Child and Adolescent Trial for 
Cardiovascular Health (CATCH): implications of cluster randomization. Control Clin 
Trials, 1995. 16(2): p. 96-118. 
98. 
Burton, P., L. Gurrin, and P. Sly, Extending the simple linear regression model to 
account for correlated responses: an introduction to generalized estimating equations 
and multi-level mixed modelling. Stat Med, 1998. 17(11): p. 1261-91. 
99. 
Murray, D.M., S.P. Varnell, and J.L. Blitstein, Design and analysis of group-randomized 
trials: a review of recent methodological developments. Am J Public Health, 2004. 
94(3): p. 423-32. 
100. Hedeker, D., R.D. Gibbons, and B.R. Flay, Random-effects regression models for 
clustered data with an example from smoking prevention research. J Consult Clin 
Psychol, 1994. 62(4): p. 757-65. 
101. Dutton, R.P., et al., Safety of uncrossmatched type-O red cells for resuscitation from 
hemorrhagic shock. J Trauma, 2005. 59(6): p. 1445-9. 
102. Murthi, S.B., et al., Transfusion medicine in trauma patients. Expert Rev Hematol, 
2008. 1(1): p. 99-109. 
103. Murray, D.J., et al., Packed red cells in acute blood loss: dilutional coagulopathy as a 
cause of surgical bleeding. Anesth Analg, 1995. 80(2): p. 336-42. 
104. Velmahos, G.C., et al., Is there a limit to massive blood transfusion after severe 
trauma? Arch Surg, 1998. 133(9): p. 947-52. 
105. Gonzalez, E.A., et al., Fresh frozen plasma should be given earlier to patients requiring 
massive transfusion. J Trauma, 2007. 62(1): p. 112-9. 
106. Heckbert, S.R., et al., Outcome after hemorrhagic shock in trauma patients. J Trauma, 
1998. 45(3): p. 545-9. 
107. Cales, R.H., Trauma mortality in Orange County: the effect of implementation of a 
regional trauma system. Ann Emerg Med, 1984. 13(1): p. 1-10. 
108. Teixeira, P.G., et al., Impact of plasma transfusion in massively transfused trauma 
patients. J Trauma, 2009. 66(3): p. 693-7. 
109. Lancaster, G.A., et al., Trials in primary care: statistical issues in the design, conduct 
and evaluation of complex interventions. Stat Methods Med Res, 2010. 19(4): p. 349-
77. 
110. Littenberg, B. and C.D. MacLean, Intra-cluster correlation coefficients in adults with 
diabetes in primary care practices: the Vermont Diabetes Information System field 
survey. BMC Med Res Methodol, 2006. 6: p. 20. 

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111. Elley, C.R., et al., Intraclass correlation coefficients from three cluster randomised 
controlled trials in primary and residential health care. Aust N Z J Public Health, 
2005. 29(5): p. 461-7. 
112. Campbell, M.K., D.R. Elbourne, and D.G. Altman, CONSORT statement: extension to 
cluster randomised trials. BMJ, 2004. 328(7441): p. 702-8. 
113. Ware, J.H., J.E. Muller, and E. Braunwald, The futility index. An approach to the cost-
effective termination of randomized clinical trials. Am J Med, 1985. 78(4): p. 635-43. 
 
 
 
 

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Clinical Protocol Appendix 1 
Requirements for Exception From Consent For Emergency Research 
 
We have outlined below each criterion stipulated in the regulations for this exception and how our study design applies to 
these criteria.  
 
(1) The human subjects are in a life-threatening situation, available treatments are unproven or unsatisfactory, 
and the collection of valid scientific evidence, which may include evidence obtained through randomized 
placebo-controlled investigations, is necessary to determine the safety and effectiveness of particular 
interventions.  
 
The proposed trial is a randomized trial comparing the use of prehospital plasma versus standard of care in patients in 
hemorrhagic shock following injury requiring air medical transport to a definitive trauma center. These patients are in an 
life-threatening situation with a mortality before discharge approaching 25% despite all efforts. The standard of care for 
management of these patients includes intravenous crystalloid while en route to definitive care. As reviewed in this 
proposal, prior studies have demonstrated that injured patients who require large volume blood transfusion have improved 
survival if transfusion of plasma in high or equal ratios to blood occurs. Evidence suggests that early blood component 
transfusion may reduce overall blood transfusion requirements and that addressing the coagulopathy which occurs early 
after injury improves outcome. Controversy remains regarding the specific ratio of plasma and other blood components 
relative to blood that is beneficial. It is known that plasma is associated with a greater risk of pulmonary complications, 
including acute lung injury and adult respiratory distress syndrome; however, whether these risks outweigh the survival 
benefit associated with early plasma in hemorrhagic shock patients remains unknown. Prehospital plasma use has never 
been characterized in civilian or military patient cohorts.  
     We propose a randomized trial focused on evaluation of prehospital plasma with sufficient statistical power to detect 
changes in clinical outcomes. Furthermore, we have developed the current proposal with also places an emphasis on the 
mechanism by which plasma may have any beneficial effect.  
 
(2) Obtaining informed consent is not feasible because:  
i. The subjects will not be able to give their informed consent as a result of their medical condition;  
ii. The intervention under investigation must be administered before consent from the subjects' legally 
authorized representatives is feasible; and  
iii. There is no reasonable way to identify prospectively the individuals likely to become eligible for participation 
in the clinical investigation.  
 
The study intervention needs to be administered en route to a definitive trauma center from the injury scene or from a 
referring hospital (see discussion of therapeutic window below). In this uncontrolled setting, the hemorrhagic shock patient 
is unable to provide consent for study enrollment, is commonly unconscious or in extremis, and legal next-of-kin are often 
not immediately available at the scene, nor is it practical for the hospital provider to explain the study and receive consent 
while caring for the patient. Since we are studying patients with hemorrhagic shock following injury, there is no way to 
prospectively identify individuals who are likely to become eligible for this trial. 
 
(3) Participation in the research holds out the prospect of direct benefit to the subjects because:  
i. Subjects are facing a life-threatening situation that necessitates intervention;  
ii. Appropriate animal and other preclinical studies have been conducted, and the information derived from those 
studies and related evidence support the potential for the intervention to provide a direct benefit to the individual 
subjects; and  
iii. Risks associated with the investigation are reasonable in relation to what is known about the medical 
condition of the potential class of subjects, the risks and benefits of standard therapy, if any, and what is known 
about the risks and benefits of the proposed intervention or activity.  
 
(i) As defined, these patients are injured and in hemorraghic shock and are facing a potentially life-threatening situation 
that requires immediate intervention.  
(ii) Previous animal and human studies have been conducted, and suggest the potential for a direct benefit to individual 
patients who require large volume blood transfusion.  
(iii) Plasma has been evaluated in patients who require large volume blood transfusion following injury and has been 
shown to provide a survival advantage. Plasma has also been independently shown to be associated with pulmonary 
complications but no higher risk of mortality. As discussed above, there are potential risks to subjects that may have not 

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been observed in previous trials. We contend that these risks are reasonable in light of the potential benefits outlined in 
this proposal and the current poor outcome for patients with hemorrhagic shock. 
 
(4) The clinical investigation could not practicably be carried out without the waiver.  
 
This study could not be conducted without the waiver of consent due to the need to administer the intervention in the 
prehospital setting en route to a definitive trauma center.  
 
(5) The proposed investigational plan defines the length of the potential therapeutic window based on scientific 
evidence, and the investigator has committed to attempting to contact a legally authorized representative for 
each subject within that window of time and, if feasible, to asking the legally authorized representative contacted 
for consent within that window rather than proceeding without consent. The investigator will summarize efforts 
made to contact legally authorized representatives and make this information available to the IRB at the time of 
continuing review. 
 
Patients in hemorrhagic shock following injury have been shown to develop progressive hypothermia, coagulopathy and 
acidosis leading to further recalcitrant hemorrhage and multisystem organ failure and death. The potential therapeutic 
window for addressing this process is during the initial resuscitation period, which occurs from arrival of the air medical 
transport provider on scene or at a referral hospital up until trauma center arrival. Since this is an immediately life-
threatening situation, it will not always be possible to contact legal representatives at the time of study entry. We will make 
every effort to contact legal representatives after admission to the hospital to notify them that the patient was enrolled in a 
randomized trial. Research personnel will attempt to contact the subject’s legal authorized representative as soon as 
feasible and a summary of these efforts will be documented in the patient’s chart. If the subject becomes competent 
during the study period then he/she will be approached by research personnel for notification of enrollment.   
 
(6) The IRB has reviewed and approved informed consent procedures and an informed consent document 
consistent with Sec. 50.25. These procedures and the informed consent document are to be used with subjects 
or their legally authorized representatives in situations where use of such procedures and documents is feasible. 
The IRB has reviewed and approved procedures and information to be used when providing an opportunity for a 
family member to object to a subject's participation in the clinical investigation consistent with paragraph 
(a)(7)(v) of this section. 
 
All procedures and consent forms will be approved by the Institutional Review Board (IRB) of the study site prior to the 
onset of the trial.  
 
(7) Additional protections of the rights and welfare of the subjects will be provided, including, at least:  
i. Consultation (including, where appropriate, consultation carried out by the IRB) with representatives of the 
communities in which the clinical investigation will be conducted and from which the subjects will be drawn;  
ii. Public disclosure to the communities in which the clinical investigation will be conducted and from which the 
subjects will be drawn, prior to initiation of the clinical investigation, of plans for the investigation and its risks 
and expected benefits;  
iii. Public disclosure of sufficient information following completion of the clinical investigation to apprise the 
community and researchers of the study, including the demographic characteristics of the research population, 
and its results;  
iv. Establishment of an independent data monitoring committee to exercise oversight of the clinical investigation; 
and  
v. If obtaining informed consent is not feasible and a legally authorized representative is not reasonably 
available, the investigator has committed, if feasible, to attempting to contact within the therapeutic window the 
subject's family member who is not a legally authorized representative, and asking whether he or she objects to 
the subject's participation in the clinical investigation. The investigator will summarize efforts made to contact 
family members and make this information available to the IRB at the time of continuing review. 
 
(i) Community consultation as outlined by the local IRB will be undertaken prior to IRB approval. Since the population 
eligible for enrollment includes all citizens in the study region it will not be possible to target any particular small group. 
Feedback from the community will be obtained by research personnel regarding any concerns they may have about 
potential enrollment. If requested, bracelets will be made available that could be worn by members of the community who 

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do not want to participate. Public notification and community consultation will be performed as directed by the local IRB 
and may include such methods as using random digit dialing telephone surveys of the proposed study community, 
targeted small group meetings or consultation with community leaders. Our institution has significant experience with 
community consultation and notification practices.  
(ii) & (iii) Public disclosures will be performed both prior to study enrollment and at the completion of the study in the form 
of multimedia press releases organized by the investigators. These will include plans for the study including potential risks 
and benefits and a summary of the results of the study upon completion. In the event that the press releases are not 
widely circulated, advertisements will also be placed in local papers describing the study.  
(iv) The Data Safety Monitoring Board will function as an independent data monitoring committee who will exercise 
oversight of the study.  
 
(v) We expect that all patients who meet the enrollment criteria will be unconscious or in critical state that does not allow 
appropriate consent to occur. Any delay in medical care that would be required for the care provider to attempt to obtain 
consent from the patient’s legal guardian would be life threatening. Thus it will not be feasible to attempt to obtain 
informed consent during the initial therapeutic window. Requiring consent to review a hospital chart to determine the 
presence or absence of serious adverse events is likely to be associated with a biased estimate of the safety and efficacy 
of the intervention. Therefore we will use exception from consent for emergency research which includes public 
notification, community consultation, patient notification of enrollment, and provision of an opportunity to opt out from 
ongoing participation. 
 
 
 
 
 

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Clinical Protocol Appendix 2 
 
Proposed Community Consultation and Public Disclosure Plan PAMPer Trial 
 
I. 
Community Consultation 
 
A.      City of Pittsburgh 
1.      Pittsburgh Human Relations Committee    
B.      Website 
Information about the current PAMPer Trial will be posted on a website which has been developed for 
this purpose.  Contact information will be provided for questions and comments. All multimedia material 
will have the following website listed: www.acutecareresearch.org 
There will be information on how to get more information about the trial and how to obtain on “opt out 
bracelet” if desired.  
C.     Surveys 
Surveys will be placed in the Trauma Service outpatient clinic. They will also include the web address 
and contact information.  
 
II. 
Public disclosure 
 
A.      Multi-Media 
1.      The UPMC Media Office will issue a press release describing the upcoming study and locations of public 
forums.   
B.      Notifications will be posted on our local Pittsburgh Authority public transportation buses. The website 
address will be posted.  Contact information will be provided for questions and comments. This will 
include information regarding how to obtain an opt-out bracelet. This has been the most effective means 
of getting feedback in our area.  
 
C. Opt out bracelets will be made available upon request. They will be PINK and state “NO PANPER”. 
 
 

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Clinical Protocol Appendix 3 
Telephone Conversation Tracker 
for LAR Calls 
Date 
Start 
time 
End 
time 
Name 
Phone 
Number 
Subject ID 
Notes 
Action Items 
Follow-
up 
Needed? 
Y/N 
 
 
 

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Telephone Conversation 
Tracker for Outgoing Calls 
Date 
Start 
time 
End 
time 
Name 
Phone 
Number 
Subject 
Notes 
Action Items 
Follow-
up 
Needed? 
Y/N 
 
 
 

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Clinical Protocol Appendix 4 
CENTER FOR EMERGENCY MEDICINE OF WESTERN PENNSYLVANIA,INC. 
STAT MEDEVAC 
 
Policy Number: 220 
Effective Date: January 1, 2012 
CAMTS Reference: None 
Subject: 
Blood Product Maintenance 
 
                               1. 
 Base site blood products will be inspected daily for adequate temperature 
maintenance in the blood product storage refrigerator. Daily temperature checks will 
be documented in conjunction with the weekly circular graph temperature recording.   
Blood products will also be properly signed out of the blood refrigerator when indicated 
for missions and maintained at proper temperature  until transfused or returned to the 
refrigerator. 
2. 
Inventory/Expiration Tracking Log 
a.  All PRBC units must be logged on this sheet when received from the 
designated distribution  point: 
1.   STAT MedEvac 1- Washington Hospital Transfusion 
Services Lab 
2. STAT MedEvac 2 -Johnstown American Red Cross 
3.   STAT MedEvac 3- UPMC Passavant Cranberry Blood Bank 
4. 
STAT MedEvac 4- UPMC McKeesport Transfusion Services 
Lab 
5. STAT MedEvac 5- Uniontown Hospital Blood Bank 
6. STAT MedEvac 6- Clarion Hospital Blood Bank 
7. STAT MedEvac 7- UPMC Horizon Transfusion Services 
Lab 
8. STAT MedEvac 8- UPMC Passavant Cranberry 
9. STAT MedEvac 9- American Red Cross 
10. STAT MedEvac 10- John Hopkins Hospital 
11. STAT MedEvac 11 -Altoona Hospital Blood Bank 
12. STAT MedEvac 13- Baltimore American Red Cross 
13. STAT MedEvac 14- UPMC Passavant Cranberry Blood Bank 
14. STAT MedEvac 15- Washington Hospital Transfusion Services Lab 
15.  STAT MedEvac 16- UPMC Passavant Cranberry Blood Bank 
16. STAT MedEvac 17- UPMC Hamot 
17. STAT MedEvac 18- Children's National Medical Center Blood Bank 
 
b. 
Record the following information: 
1.   Unit Number 
2.   Date placed in service 
3.   Date unit will expire 
4.   Date unit is to be returned (minimum of 10 days prior to expiration 
date on blood products) 
5.   Initials of person confirming ABO type and placing units into service. 
6.   Disposition of units (transfused, wasted, or returned) 
7.   Location: - Note the receiving facility where patient receiving 
PRBCs transfusion was admitted. 
8.   Paperwork: Check that all appropriate paperwork is completed. 
9.   Comments:  As needed, and list flight number associated with blood 
product transfusion. 
10. Initials of person completing log regarding unit disposition. 
 
______________________________________________________________________________________________________ 
Page 1 of 5 
Original Policy Date: June 20, 1994 
Revision Date: June 25, 1998; June 2011; February 2003; May 2004; April 2007; December 2011 
 

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CENTER FOR EMERGENCY MEDICINE OF WESTERN PENNSYLVANIA,INC. 
STAT MEDEVAC 
 
Policy Number: 220 
Effective Date: January 1, 2012 
CAMTS Reference: None 
 
3.  
Daily Checks I Shift Responsibilities:  In order to prevent any problems with the 
recording chart to potentially go undetected for as long as 24 hours, check the chart 
midway through the shift for accurate documentation of current day and time every 
shift. Any problems should be corrected immediately and documented on the recording 
chart. 
a.   Temperature and Visual Inspection to be completed on every shift recording the 
following information on the Temperature 
Check and Visual Inspection Sheet: 
1.   Date of inspection 
2.   Temperatures as indicated 
a. Make sure temperature reading on recording chart corresponds 
with current day, time. 
b. Make sure stylus is making contact with recording chart. 
c. Notify Base Site Manager of any problems,  i.e.: possibility of 
contamination,  temperature  not maintained between 1o  C to 
6° C, inability to get recording chart to function properly. 
3.   Refrigerator graph:  Confirm accurate documentation of current day and 
time on the circular graph. Internal refrigerator temperatures and chart 
temperatures must both be within acceptable range (1-6° C) and agree 
with each other: t1° 
a.   Any gaps or fluctuations in temperature on recording chart must 
have explanation documented on chart followed by your initials. 
b.   A copy of all temperature documentation will be sent to the 
appropriate blood bank by the Base Site Coordinator or base 
representative. 
4.   Contamination: Check each unit of blood for contamination and expiration 
date- i.e., if the red cell mass appears purple; if there is a zone of 
hemolysis: visible clots; if the plasma is murky; if plasma has a purple, 
brown,  or red discoloration; if there are signs of leakage or inadequate  
sealing. 
a. 
PRBC units that are questionable must be quarantined and recorded 
as such in the comments section. 
b. Notify the appropriate blood bank immediately of quarantined 
blood. 
c. 
 Exchange quarantined units for replacement  units as soon as 
possible. 
5.   Confirm that blood is ''0" negative or positive. 
6.   Confirm that blood is not due to expire by checking the inventory and 
expiration tracking log.  If blood is to be returned, follow blood 
product return/transfer procedure. 
7.   Confirm ice or commercial ice packs are available for transport. 
8.   Comments as needed 
9.   Initials of person doing inspection. 
b.   Ensure refrigerator is clean and in working order. 
 
Page 2 of 5 
Original Policy Date: June 20, 1994Revision Date: June 25, 1998; June 2011; February 2003; May 2004; April 2007; 
December 2011 
 
 
 

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CENTER FOR EMERGENCY MEDICINE OF WESTERN PENNSYLVANIA,INC. 
STAT MEDEVAC 
 
Policy Number: 220 
Effective Date: January 1, 2012 
CAMTS Reference: None 
4.  
Weekly Recording Chart Change 
a. Every Monday the circular graph recording chart on top panel of the blood 
product storage refrigerator must be changed. 
Instructions to remove graph: 
1.  Open the latch and door. 
2. Push the number "3" button on the interior panel to reposition the 
stylus. 
3.  Unscrew center nut on graph. 
 4.   Remove graph paper. 
5.  Write in the current date, in the appropriate space, in which the circular 
graph paper was removed and then initial (the graph will have been 
stamped when the new circular graph paper was placed). 
6.   Examine the circular graph and ensure that any fluctuations in 
temperature on the graph or any corrective action to correct fluctuations 
in temperature are explained on the graph and initialed. 
7.   Place completed circular graph in the Base Site Manager's or base 
representative's mail box. All graphs must be kept for a minimum of 5 
years. 
8.   Utilizing the commercial stamp mark the new circular graph along the outer  
       edge of the paper and note in pen the Unit (listed as GEM), Location (listed  
      as STAT X), Date in and initials of the person completing the form. 
9.   Insert new graph into the receptacle and replace central nut. 
10. Push the number "3" button on the interior panel to return the stylus to the 
recording position. 
11. Ensure that the stylus is touching graph at the appropriate spot for 
current day and time. 
12. Close door and engage latch. 
13. Any problems existing after trouble shooting proves unsuccessful should 
be reported to the Base Site Manager. 
5. 
Blood tracking log 
a.   Columns 1-5 must be filled out when removing blood products from the 
refrigerator 
1.   Date: Current date entered. 
2. Unit number:  List all units available. 
3.  Issued Time and Temperature: Current time and temperature 
when blood is being removed. 
4.   Visual inspection: Check appearance, type, and expiration 
date to ensure it is correct and it is not expired.  Record as satisfactory 
or unsatisfactory. Any units that appear unsatisfactory are not to be 
taken out on a mission but immediately placed out of service 
5. Initials:  Your initials. 
b.   Columns 6-10 must be filled out as indicated when returning blood products to the 
refrigerator. 
1.  Disposition: If no units are transfused, list as returned. If units are 
transfused, indicate the specific units transfused and receiving hospital 
of patient transfer. If units are to be quarantined, indicate the specific 
units quarantined. 
2.   Returned time: Time blood returned to blood product refrigerator. 
__________________________________________________________________________________________________ 
Page 3 of 5Original Policy Date: June 20, 1994 
Revision Date: June 25, 1998; June 2011; February 2003; May 2004; April 2007; December 2011 
 
 

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CENTER FOR EMERGENCY MEDICINE OF WESTERN PENNSYLVANIA,INC. 
STAT MEDEVAC 
Policy Number: 220 
Effective Date: January 1, 2012 
CAMTS Reference: None 
3. Visual Inspection: Check appearance for contamination, clots, 
discoloration, etc.  List as satisfactory or unsatisfactory. 
4. Initials: Your initials. 
5. Comments: Insert flight number and patient name if blood product was 
transfused. 
7. 
Packing blood products for a mission 
a. 
Blood products are to be taken on every mission. 
b. 
Each unit should be in the plastic blood product bags 
c. 
 Place in the insulated cooler with commercial ice packs or ice and an appropriate 
thermometer. The units should be "sandwiched" between the ice using appropriate 
barriers to prevent the units from coming in direct contact with the ice. 
d. 
 If blood is not transfused, return it to the blood product refrigerator upon 
returning to base. Fill out remaining Columns 6-10 of Blood Tracking Log 
8. 
Administration of blood products is to be carried out in strict accordance with STAT 
MedEvac Critical Care Protocols. 
9. 
Documentation of transfusion 
a.   When a unit is transfused during a mission make sure the appropriate 
information is relayed to the receiving facility including type and unit 
number. 
b.   Fill out appropriate blood bank forms for transfused products per Central Blood 
Bank I American Red Cross instructions. 
c. Upon return to the base, fill out the Blood Tracking Log for 
Columns 6-10 as instructed. 
10. 
Replacement of transfused blood products 
a.   Notify appropriate blood bank that you have transfused blood and specify 
the number of replacements needed. 
i. 
Notify STAT Com and the Medical Director on call of any delay in receiving 
replacement units of blood and document the delay via special report. 
11. 
Transfusion Complications 
a. Notify the receiving facility of the patient's signs and symptoms immediately 
upon arrival. 
b.  Upon returning to base, an Adverse Reaction special report should be 
completed. 
11. 
Blood refrigerator alarms 
a.   Monthly Check- High and low temperature alarms to be checked on 
the first of every month. 
i.   Remove blood from refrigerator and place on ice in cooler. 
ii.     Remove probe from glycerol solution and place the probe on ice.  
Temperature of probe will register below 1c  C within several minutes to 
activate alarm. 
iii.  The designated operator should call to advise of the Alarm. 
Activate the silence button on the blood product storage refrigerator 
after receiving phone call. 
iv.  Then place probe in tepid water to test high temperature alarm (>6°). 
v.   Again, the designated operator should call to confirm alarm 
activation. Activate the silence button on the blood product storage 
refrigerator after receiving phone call. 
vi.   Initial and note "Alarm Test" on Temperature Graph. 
 
__________________________________________________________________________________________________ 
Page 4 of 5 
Original Policy Date: June 20, 1994 
Revision Date: June 25, 1998; June 2011; February 2003; May 2004; April 2007; December 2011 
 

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CENTER FOR EMERGENCY MEDICINE OF WESTERN PENNSYLVANIA,INC. 
STAT MEDEVAC 
Policy Number: 220 
Effective Date: January 1, 2012 
CAMTS Reference: None 
vii. Document "Alarms Checked/Operational or Non­ Operational" in 
comment section of Daily Temperature Checks and Visual Inspection 
Logs. 
viii. If alarms fail or no phone call is received from the designated operator keep 
blood on ice in cooler and notify the Base Site Manager immediately for 
guidance. 
c.   Alarm Activation 
i. 
The blood bank refrigerator will alarm any time the temperature in it rises 
above 6°C or below 1 oc or electrical power is shut off to the refrigerator. 
ii. 
At the same time, the remote alarm will be activated at the 
Communications Specialist's switch board, the Communications Specialist 
will notify you by phone when the alarm activates. 
iii. 
When alarm goes off, try to find any obvious causes, i.e., door is open to 
refrigerator, refrigerator is unplugged, circuit breaker is off, or circulating 
fan is not working. 
iv. 
If cause cannot be found or corrected, removed blood and place it on 
ice in the cooler. 
v. 
Notify the Base Site Manager immediately of problem. The Base Site 
Manager will instruct you as to what to do with the units of blood. 
12. 
Quarterly Temperature Monitoring 
a. 
 Every quarter (March, June, September, and December) a verification of 
temperature maintenance of blood during emergency flights must be 
performed. 
b. 
The following steps are to be performed when testing the 
temperatures: 
1.  Store the bottle in your refrigerator along with the units of blood until 
needed. 
2.   When packing units for an emergency, record the thermometer reading, 
time packed, date and initials on the card provided. 
3.   Place the bottle into the cooler along with the blood. 
4.   Assure that all the blood units and the bottle are covered with ice. 
5.  Upon return to base after flight, record the thermometer reading, time 
unpacked, date, and initials on the bottom of the card provided. 
6.  The acceptable range during transport is 1-10. 
c. 
A record of all results will be maintained at the base 
 
 
President: 
 
 
Medical Director: 
 
 
 
 
 
Page 5 of 5 
Original Policy Date: June 20, 1994 
Revision Date: June 25, 1998; June 2011; February 2003; May 2004; April 2007; December 2011 
 

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Clinical Protocol Appendix 5 
 
 
  
Pittsburgh, PA & Chicago, IL 
Donor-Patient “Lookback” 
Pg.  1 of 6 
Doc #:  ITxM-CS-00795 
Revision:  7 
Department:  Patient Transfusion Service 
 
 
DONOR-PATIENT “LOOKBACK” 
 
 
 
APPROVALS
 
All Approvals are maintained and controlled via Document Control Systems’ MC3 Portal™ Software. Please Refer to MC3 
Portal™ for the current controlled revision and approval records. 
 
 
 
SUMMARY OF THE MODIFICATIONS – See MASTERControl™ InfoCard Release Date 
 
List a summary of the modifications below.  Bullet outline is recommended. 
 
 
   Addition of UPMC East 
UPMC EAST – Patients transfused after July 2, 2012 are in SafeTrace Tx.  UPMC East has no 
transfusion records prior to this date. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Copyright© ITxM 2006.  All rights reserved.  May not be reproduced without permission.  All hard copies should be checked against the current electronic version 
within MASTERControl™ prior to use and destroyed promptly thereafter.  All hard copies are considered unco ntrolled documents except when issued by Quality 
Assurance as an official hard copy for use in lieu of MASTERCon trol™. 

Protocol Version 3                                                                                                                      January 17, 2017 
 
Page 56 of 86 
 
 
 
Pittsburgh, PA & Chicago, IL 
Donor-Patient “Lookback” 
Pg.  2 of 6 
Doc #:  ITxM-CS-00795 
Revision:  7 
Department:  Patient Transfusion Service 
 
PROCESS  
SYSTEM 
Investigation of Adverse Transfusion Effects, Information Management 
CRITICAL CONTROL POINT 
Documentation/Record Keeping, Supplier Qualification, Error/Accident Review, Internal Assessment, Process Improvement 
 
PRINCIPLE 
Regulatory agencies require notification of recipients of blood products from a donor who subsequently tests confirmed 
positive for HIV1,2, HCV or HTLV-I/II, or is at risk for transmitting Creutzfeldt-Jakob disease (CJD). 
 
POLICY 
I.          IDENTIFICATION OF INFECTED DONORS 
          PROSPECTIVE LOOKBACK - Units implicated in the lookback process are identified by Central 
Blood Bank or LifeSource and CTS or RCRL is notified in writing of the units and their shipping date. For 
HIV, HCV, and HBV lookback cases, CBB or LifeSource will recall all indate products within 3 days of a 
repeat reactive screening test and will notify the transfusion service in writing within 30 days of a positive 
Western blot for HIV or 45 days for a RIBA positive HCV test. 
          RETROSPECTIVE LOOKBACK - Units implicated in the retrospective HCV lookback         
process are identified by CBB or LifeSource and the transfusion service is notified in writing of the units and 
their shipping date within 6 months of the September 23, 1998 publication of the FDA guidance document. 
          CENTRALIZED TRANSFUSION SERVICE RECIPIENT IDENTIFICATION - The    
transfusion service must identify the recipient of any of the implicated units.  The                              
method of recipient tracing varies with the date of transfusion and the hospital. 
PUH/E&E/CHP - After May 21, 1999 - SafeTrace Tx contains all units receipts received. 
Between mid-October 1988 and May 20, 1999 - the PTS computer system or microfiche                      
contains all units recipients received. 
Prior to PTS computer (1988) - unit inventory cards (3 x 5) were used to record each                                  
unit, to whom it was issued and the hospital.  Cards are stored in boxes stored in a                               
warehouse at National Business Records Management (NBRM).  There are cards dating                               
back at least to 1977. (see Notes for retrieving cards) 
MUH -  Patients transfused after May 11, 1991 are in the PTS system.  MUH has no transfusion               records 
prior to this date. 
ALLEGHENY GENERAL HOSPITAL - Patients transfused after May 21, 1999 are in SafeTrace Tx.  Patients 
transfused between August 20, 1994 and May 20, 1999 are in the PTS system.  Patients transfused prior to this 
date must be retrieved by AGH staff.  From September 17, 1988 to August 19, 1994 records are at AGH 
Information Systems (SunQuest System).  From March 14, 1979 to September 16, 1988, records are in log 
books stored at AGH Stat lab.  Any additional records are stored at Iron Mountain.  A request for the required 
records should be sent to the medical director of the department of pathology and the LIS manager. 
 
 
 
 
 
 
 
 
Copyright© ITxM 2006.  All rights reserved.  May not be reproduced without permission.  All hard copies should be checked against the current electronic 
version within MASTERControl™ prior to use and destroyed promptly thereafter.  All hard copies are considered unco ntrolled documents except when issued 
by Quality Assurance as an official hard copy for use in lieu of MASTERCon trol™. 

Protocol Version 3                                                                                                                      January 17, 2017 
 
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Pittsburgh, PA & Chicago, IL 
Donor-Patient "Lookback" 
Pg.  3 of 6 
Doc#: ITxM-CS-00795    I  Revision:  7 
Department:  Patient Transfusion Service 
 
SHADYSIDE  HOSPITAL- Patients transfused after May 21, 1999 are in SafeTrace  Tx.  Patients transfused 
between October 7, 1994 and May 20, 1999 are in the PTS system. Patients transfused on or prior to this 
date must be extracted by SSH staff. A request for the required records should be sent to the medical 
director of the department of pathology and the laborat01y administrative director. 
WASHINGTON  HOSPITAL- Patients transfused after May 21, 1999 are in SafeTrace Tx. 
Patients transfused between July 7, 1995 and May 20, 1999 are in the PTS system. Patients transfused 
prior to this date are in card files and will be retrieved by WH staff. A request for the required records 
should be sent to the medical director of the department of pathology and the lab manager. 
MCKEESPORT  HOSPITAL -Patients transfused after May 21, 1999 are in SafeTrace  Tx. 
Patients transfused between March 2, 1997 and May 20, 1999 are in the PTS system. Patients transfused 
on or prior to this date are in card files and will be retrieved by McK staff. A request for the required 
records should be sent to the medical director of the department of pathology and the lab manager. 
UPMC, SOUTH SIDE HOSPITAL- Patients transfused after May 21, 1999 are in SafeTrace Tx. 
Patients transfused between February 28, 1997 and May 20, 1999 are in the PTS system. Patients 
transfused on or prior to this date are in card files and will be retrieved by SOSH staff. A request for the 
required records should be sent to the medical director of the department of pathology and the lab 
manager. 
COMMUNITY MEDICAL CENTER- Patients transfused on or after October 5, 1999 are in the 
SafeTrace Tx system.  Patients transfused prior to this date are referred to the medical director/lab 
manager to obtain the required information. 
UPMC, ST. MARGARETS -Patients transfused after July 31, 2000 are in the SafeTrace Tx system.  Patients 
transfused on or prior to this date are referred to the medical director/lab manager to obtain the 
required information. 
MAGEE HOSPITAL- Patients transfused after December 10, 2000 are in SafeTracc  Tx. 
Patients transfused on or prior to this date are referred to the medical director/lab manager of the 
hospital. 
WEST PENN HOSPITAL- Patients transfused after November 19, 2000 are in SafeTrace Tx. 
Patients transfused on or prior to this date are referred to the medical director/lab manager of the 
hospital. 
LIFECARE HOSPITAL- Patients transfused after January 17, 2000 are in SafeTrace Tx. 
Patients transfused on or prior to this date arc referred to the medical director/lab manager of the 
hospital. 
K INDRED HOSPITAL - Patients transfused after December 31, 1999 are in SafeTrace Tx. 
Patients transfused on or prior to this date are referred to the medical director/lab manager of the 
hospital. 
RCRL CHICAGO- Patient's  transfused after June 1, 2000 are in SafeTrace  Tx.  For patient's 
transfused prior to this date, LifcSource will contact the transfusing facility directly. UPMC-
BRA    DDOCK HOSPITAL- Patients transfused  after September 16, 2001 are in 
SafeTrace Tx.  Patients transfused prior to this date are rcfcned to the lab manager of the hospital. 
FORBES REGIONAL HOSPITAL- Patients transfused after March 24, 2002 arc in SafeTrace 
Tx.  Patients transfused prior to this date arc referred to the lab manager of the hospital. 
 
 
 
 
 
Copyright© ITxM 2006.  All rights reserved.  May not be reproduced without permission.  All hard copies should be checked against the current electronic 
version within MASTERControl™ prior to use and destroyed promptly thereafter.  All hard copies are considered unco ntrolled documents except when issued 
by Quality Assurance as an official hard copy for use in lieu of MASTERCon trol™. 

Protocol Version 3                                                                                                                      January 17, 2017 
 
Page 58 of 86 
 
  
Pittsburgh, PA & Chicago, IL 
Donor-Patient "Lookback" 
Pg.  4 of 6 
Doc#: ITxM-CS-00795    I  Revision:  7 
Department:  Patient Transfusion Service 
 
UPMC PASSAV ANT AND UPMC PASSAVANT  CRANBERRY  HOSPITAL- Patients transfused after October 
31, 2004 are in SafeTrace Tx.  Patients transfused prior to this date are referred to the lab manager of the 
hospital. 
AGH-SUBURBAN CAMPUS- Patients transfused after March 15, 2006, are in SafeTrace Tx. Patients transfused 
prior to this date are referred to the lab manager of the hospital.  
UPMC MERCY- Patients transfused after December 1, 2008 are in SafeTrace  Tx.  Patients transfused prior to 
this date are referred to the lab manager of the hospital. 
 LIFELINE- Patients transfused after December 1, 2009 are in SafeTrace  Tx.  
ADVANCED SURGICAL -Patients transfused after May 1 , 201I 0 are in SafeTrace  Tx. 
MEADVILLE MEDICAL CENTER - Patients transfused after March 15, 2012 are in SafeTrace Tx.  Patients 
transfused prior to this date are referred to the lab manager of the hospital. 
UPMC EAST- Patients transfused after July 2, 2012 are in SafeTrace  Tx.  UPMC East has no transfusion records 
prior to this date. 
 
II.          CONFIRMING THE PATIENT AND IDENTIFYING THE PHYSICIAN 
Pittsburgh- For patients since October 1988, the SafeTrace  Tx has the patient's name, hospital number, birth date 
and sometimes the physician.  If the physician's name is not available in the computer, this must be obtained from 
the medical record.  For transfusions in the pre-computer era, the transfusion, the recipient, and the physician are 
verified by review of the medical record or by the PTS patient card.  Patient cards are stored in boxes stored in a 
warehouse at National Business Records Management (NBRM). 
Chicago -Patients transfused after June I, 2000 are in SafeTrace  Tx.  If physician information is not in SafeTrace 
Tx, the transfusion entity will receive only the information available  prior to this time. 
 
III.        RECIPIENTS PHYSICIAN NOTIFICATION OF POSSIBLE VIRAL INFECTION 
The CTS or RCRL Chicago physician will send the patient's physician, the physician who ordered the blood product, 
or the transfusing entity a letter notifying him/her of the lookback. All correspondence is sent by certified mail or by 
UPS. For HIV, HCV and HBV lookback, the physician must promptly return an enclosed confirmation letter to the 
transfusion service indicating that they accept responsibility for patient notification. In the case of HIV and HCV, 
patient notification includes the need for HIV or HCV testing and counseling. If the transfusion service cannot locate 
the physician, does not receive the confirmatory documentation from the physician or the physician refuses to accept 
responsibility for notification, then the transfusion service is responsible for notifying the patient.  This is done by the 
CTS physician at CTS hospitals.  The FDA requires that the process of notification be completed within 8 weeks for 
HIV and 12 weeks for HCV (prospective) and 1 year for HCV (retrospective). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Copyright© ITxM 2006.  All rights reserved.  May not be reproduced without permission.  All hard copies should be checked against the current electronic version 
within MASTERControl™ prior to use and destroyed promptly thereafter.  All hard copies are considered unco ntrolled documents except when issued by Quality 
Assurance as an official hard copy for use in lieu of MASTERCon trol™. 
 

Protocol Version 3                                                                                                                      January 17, 2017 
 
Page 59 of 86 
 
  
Pittsburgh, PA & Chicago, IL 
Donor-Patient "Lookback" 
Pg.  5 of 6 
Doc#: ITxM-CS-00795    I  Revision:  7 
Department:  Patient Transfusion Service 
 
IV.        RECORDS 
• The following documents are maintained in the look back file: 
-Notification letter from CBB or LifeSource (HIV, HCV, HBV, HTLV-I, CJD) 
-Copy of certified letter notifying recipient's physician (HIV, HCV, HBV,                     
HTLV-1, CJD) 
- Documentation indicating physician's acceptance of responsibility for                    
patient notification (HIV, HCV only) 
- Certified mail receipts 
-Documentation of patient notification if performed by the transfusion service medical                  
director.  Three attempts will be made to notify the patient by letter for HCV or HIV                     
lookback.  If the first attempt is returned because the address is not valid, no further letters will be sent. 
•  Documentation of notification of the patient by his/her physician is maintained in the patient's medical record. 
•  Lookback records arc maintained at CTS. 
 
PROCEDURE NOTES 
1.          STORED INVENTORY CARDS AND PATIENT RECORD CARDS FOR UPMC/CHP 
The inventory-card boxes are listed, along with other stored PTS records, on a computer printout from NBRM 
labeled ("CBB- LAB PTS").  Photocopies of this computer printout are held by Central Records, Donor 
Counseling, and the Associate Medical Director.  Each box is listed according to the first and last card (e.g., 
RIOOOO-Rl4000), and there are often more than one letter series in the same box.  Some box records have the 
year; most do not.  Some box numbers have a very broad span; often this is because frozen RBCs from years 
before were used and put into the current box with the same letter series.  This means that there is usually more 
than one box on the list which could contain a given card.  The end number of the box is closer to most of the 
cards in it. 
2.          POOLED COMPONENTS 
Pools are given unique unit numbers in the computer.  In SafeTrace Tx, the unique pool number can be found in 
the additional information tab of the component profile of the original unit.  This pool number can then be queried 
to get final disposition information.   In the PTS computer system, the blood unit inquiry for the original unit 
number will give P-number, and then this can be entered to yield the patient.  Pre-computer, when a platelet was 
pooled, the P-number was put on the platelet's original inventory card and a new P-number inventory card was 
made.  The P­ series card has the recipient's name, so if only the original unit number is given, both cards must be 
sought sequentially for pre-1984 searches.  After the BOS mainframe computer system began in 1984, pools in 
PTS were entered.  Donor Counseling will provide the P-number or individual unit IDs from the mainframe. 
3.          OBTAINING INVENTORY CARDS/PATIENT RECORD CARDS 
The Quality Department secretary provides forms for requesting stored boxes from NBRM. 
After identifying the boxes needed from the computer list above, the request forms are completed and sent to the 
Quality Department secretary.  They arrange for the boxes to be picked up by CBB drivers and brought to the 
requester in a few days. 
 
REFERENCES 
Federal Register Vol61, No. 175 September 9, 1996 page 47423-34. 
 
 
 
 
 
Copyright© ITxM 2006.  All rights reserved.  May not be reproduced without permission.  All hard copies should be checked against the current electronic 
version within MASTERControl™ prior to use and destroyed promptly thereafter.  All hard copies are considered unco ntrolled documents except when issued 
by Quality Assurance as an official hard copy for use in lieu of MASTERCon trol™. 

Protocol Version 3                                                                                                                      January 17, 2017 
 
Page 60 of 86 
 
  
Pittsburgh, PA & Chicago, IL 
Donor-Patient "Lookback" 
Pg.  6 of 6 
Doc#: ITxM-CS-00795    I  Revision:  7 
Department:  Patient Transfusion Service 
 
AUTHOR 
Darrell J. Triulzi, M.D., and Linda F. Hahn, MPM, MT(ASCP)SBB 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Copyright© ITxM 2006.  All rights reserved.  May not be reproduced without permission.  All hard copies should be checked against the current electronic version 
within MASTERControl™ prior to use and destroyed promptly thereafter.  All hard copies are considered unco ntrolled documents except when issued by Quality 
Assurance as an official hard copy for use in lieu of MASTERCon trol™. 
 

Protocol Version 3                                                                                                                      January 17, 2017 
 
Page 61 of 86 
 
Clinical Protocol Appendix 6 
 
 
 
 
 
 
 
 
 
DSMB Charter 
 
Prehospital Air Medical Plasma (PAMPer) trial 
 
October 24, 2013 
Version 5.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Data Safety Monitoring Board (DSMB) Overview 
Trial Description and Study Design 
• 
Trial name: Prehospital Air Medical Plasma (PAMPer) trial 
• 
Principal investigator (PI): Jason Sperry, MD, MPH 
• 
Funding agency: Department of Defense 
• 
Trial design: Multi-center, prospective, randomized, open label interventional trial.   
• 
Phase: III 
• 
Number of patients: 550  
• 
Number of sites: 6 
 
DSMB Description  
• 
This DSMB will be coordinated by the PI, Jason Sperry, MD, MPH. 
• 
This DSMB will be independent of the investigators, funding agency, regulatory agencies, and institutional review 
boards. 
• 
This charter will be approved by its DSMB members as attested to by signature of the chairperson. 
 
DSMB Membership 
• 
Members will disclose conflicts of interest and will be cleared of significant conflicts of interest and potential 
conflicts of interest in accordance with provisions in this charter.  
• 
DSMB members will sign confidentiality agreements covering DSMB activities. 
• 
Composition of membership will be researchers with the following expertise:  emergency medicine, surgery 
(trauma/critical medicine), biostatistics and a bioethicist.  
• 
Remuneration will be provided any expenses related to DSMB activities. 
 
Reporting 
 
• 
Unblinded data to be reviewed by the DSMB will be provided by an independent statistician.  Issues and 
recommendations identified by the DSMB will be provided to the principal investigator by the DSMB chairperson 
in accordance with this charter.  
• 
Details of closed session deliberations (e.g., minutes) will be considered privileged and not subject to disclosure 
except as required by law.  
 

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Introduction 
The purpose of this charter is to define the roles and responsibilities of the DSMB, delineate qualifications of the 
membership, describe the purpose and timing of meetings, provide the procedures for ensuring confidentiality and proper 
communication, and outline the content of the reports.   
 
The DSMB will function in accordance with the principles of the following documents: FDA document “Guidance for 
Clinical Trial Sponsors: On the Establishment and Operation of Clinical Trial Data Monitoring Committees”.  
 
Study Overview/Summary 
Objective/Hypothesis: The primary hypothesis will be that prehospital infusion of plasma during air medical transport in 
patients with hemorrhagic shock will reduce overall blood transfusion requirements in the first 24 hours post injury. The 
secondary hypotheses include that prehospital infusion of plasma will reduce the incidence of mortality, multiple organ 
failure, nosocomial infection, and acute lung injury; reduce or prevent the early coagulopathy as demonstrated by 
improvements in presenting coagulation and thromboelastography parameters; and reduce the early inflammatory 
cytokine response, thrombomodulin and increase protein C levels. 
 
Specific Aims: 
Aim#1: Determine whether prehospital infusion of plasma as compared to standard air medical care results in a reduction 
in 24 hour blood transfusion requirements.  
Aim#2: Determine whether prehospital infusion of plasma as compared to standard air medical care results in a reduction 
in the incidence of in-hospital mortality, multiple organ failure, nosocomial infection, acute lung injury and 24 hour blood 
component transfusion and resuscitation requirements. 
Aim#3: Determine whether prehospital infusion of plasma as compared to standard air medical care results in an 
improvement in the acute coagulopathy of trauma, lower early IL-6 cytokine levels, reduced thrombomodulin and 
increased protein C levels. 
 
Study Design: Multi-center, prospective, randomized, open label, interventional trial over 4yrs focusing on patients with 
concern for hemorrhagic shock being transported via air ambulance to definitive trauma care. 
 
Population: Blunt or penetrating injured patients with hemorrhagic shock being transported via air medical services from 
the scene of injury or from referring hospital to a definitive care trauma center participating in the trial. 
 
Inclusion Criteria: 
1. Blunt or penetrating injured patients being transported from scene or referral hospital to PAMPer site 
AND 
2. Systolic blood pressure below 90mmHg AND tachycardia>108 at scene, or at outside hospital or during transport 
OR 
3. Systolic blood pressure below 70mmHg at scene, or outside hospital or during transport 
 
Exclusion Criteria: 
1. 
Wearing NO PAMP opt –out bracelet 
2. 
Age > 90 or < 18 years of age 
3. 
Inability to obtain intravenous or interosseous access 
4.  
Isolated fall from standing injury mechanism 
5 
Documented cervical cord injury with motor deficit 
6 
Known prisoner or known pregnancy 
7. 
Traumatic arrest with > 5 minutes of CPR without return of vital signs 
8. 
Brain matter exposed or penetrating brain injury (GSW) 
9. 
Isolated drowning or hanging victims 
10. 
Isolated burns > estimated 20% total body surface area 
11. 
Referral Hospital In-patient admission  
12. 
Objection to study voiced by subject or family member at scene 
 
Intervention: Eligible patients will be randomized to receive 2 units of AB thawed plasma, not older than 5 days, vs. 
standard air medical care. To minimize waste of AB plasma or low titer anti-B A plasma, local blood bank affiliates in 
coordination with each participating center will exchange unused, ≤ 5 day-old AB thawed plasma allowing its subsequent 
clinical use.  
 

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Randomization scheme: Respective air medical services will be randomly divided into 2 groups by either air base or 
helicopter, depending on each service’s organizational characteristics. These groups will then be 4-month, block 
randomized to either AB plasma or low titer anti-B A plasma or standard care. 
 
Roles and Responsibilities 
DSMB Roles and Responsibilities 
This DSMB will 
• 
Meet periodically (see DSMB Meetings) to review aggregate and individual subject data related to safety, data 
integrity and overall conduct of the trial. 
• 
Review specific interim analyses for efficacy (see Study Review Criteria/Stopping Rules and Guidelines).  
• 
Provide recommendations to continue or terminate the trial depending upon these analyses.   
• 
Communicate other recommendations or concerns as appropriate. 
• 
Operate according to the procedures described in this charter and all procedures of the DSMB.    
• 
Follow conflict of interest guidelines as detailed below (see DSMB Membership). 
• 
Comply with confidentiality procedures as described below (see Confidentiality). 
• 
Maintain documentation and records of all activities as described below (see DSMB Meetings, DSMB 
Reports). 
 
Principal Investigator (or Designees) Roles and Responsibilities 
The PI will directly or through delegation:  
• 
Assure the proper conduct of the study. 
• 
Assure collection of accurate and timely data (monitoring and data management). 
• 
The PI will designate an independent statistician to compile and report SAEs to the DSMB. 
• 
Promptly report potential safety concern(s) to the DSMB. 
• 
Prepare summary reports of relevant data for the DSMB. (This may include analyses not otherwise outlined in 
this charter based upon findings.) 
• 
Provide an independent facilitator for presentation of results during DSMB meetings if requested by the 
DSMB. 
• 
Communicate with regulatory authorities, IRB, and investigators, in a manner that maintains integrity of the 
data, as necessary. (This communication is not the responsibility of the DSMB.) 
• 
Provide funding for the study and DSMB. 
• 
PI will not attend the closed session of the DSMB Meeting.  
 
DSMB Membership 
The DSMB will consist of at least 4 members.  The DSMB members have been selected by the PI in consultation with the 
investigators. 
As characteristic qualifications, members will:  
• 
Work professionally and meet qualifications for their respective professions. 
• 
Comply with accepted practices of their respective professions. 
• 
Comply with the conflict of interest policies specified by the standard operating procedures (SOPs) of the PI to 
ensure that members do not have serious scientific, financial, personal, or other conflicts of interest related to the 
conduct, outcome, or impact of the study according to the guidelines specified below (e.g., engaged in any 
simultaneously occurring competitive trials in any role that could pose a conflict of interest for this study).  
• 
Be independent from the PI, IRB, regulatory agencies, principal investigator, co-principal or sub-principal 
investigator, site investigator, site sub-investigator, clinical care of the study subjects, or any other capacity 
related to trial operations. 
• 
Not be on the list of Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE) 
(http://www.fda.gov/foi/nidpoe/default.html) and/or debarred list of investigators 
(http://www.fda.gov/ora/compliance_ref/debar). 
Although each DSMB member will be expected to serve for the duration of the trial, in the unlikely event that a member is 
unable to continue participation, the reason will be documented and a replacement will be selected by the PI. 
 
The DSMB will follow conflict of interest guidelines referenced by the Department of Health and Human Services, 
Financial Relationships and Interests in Research Involving Human Subjects: Guidance for Human Subject Protection 
(http://www.hhs.gov/ohrp/humansubjects/finreltnn/fguid.pdf). DSMB members will sign a non-conflict of interest statement 

Protocol Version 3                                                                                                                      January 17, 2017 
 
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in regard to this study which will be on file with the PI. As determined by the PI, conflicts of interest and/or potential 
conflicts of interest (as determined by SOPs) will be reduced to the greatest extent that is consistent with assembling a 
highly competent DSMB. Any questions or concerns that arise regarding conflicts of interest will be addressed by the 
DSMB chairperson with input from other DSMB members and PI as necessary. 
 
DSMB Meetings 
Projected Schedule of Meetings  
An initial meeting of the DSMB will be held prior to any subject enrollment in the study in order for the members to review 
the charter, to form an understanding of the protocol and definitions being used, to establish a meeting schedule, and to 
review the study modification and/or termination guidelines. Subsequent interim and final review meetings will be held to 
review and discuss interim and final study data (adverse events, protocol deviations, enrollment summary and tables for 
overall primary and secondary endpoints).  Frequency of meetings will be every six months, unless the board determines 
otherwise.  
Meeting Format 
DSMB meetings will generally be conducted by teleconference and coordinated by the PI. A quorum, defined as 2 out of 4 
members will be required to hold a DSMB meeting. Critical decisions of the DSMB should be made by unanimous vote. 
However, if this is not possible, majority vote will decide. 
 
Open and Closed Sessions  
The open session may be attended by the PI and study investigators or their designees. Data presented in the open 
session may include enrollment data, individual adverse event data, baseline characteristics, overall data accuracy and 
compliance data or issues, and other administrative data. Minutes of the open session will be recorded by the Chair of the 
DSMB. Minutes will be finalized upon signature of the chairperson and maintained by the DSMB in accordance with 
applicable statutory regulation.    
 
The closed session will be restricted to the DSMB members. A facilitator or recorder may be requested by the DSMB. 
Data which may compromise the integrity of the study (e.g., comparative data) will be analyzed and discussed only in the 
closed session. The minutes of the closed session will be recorded by the DSMB Chair. Minutes from the closed session 
will be recorded separately from the minutes of the open session and stored securely by the DSMB Chair. Closed session 
minutes, finalized by signature of the chairperson, will be maintained in confidence and retained until discarded in 
accordance with applicable statutory regulation. 
 
Following each meeting, a report separate from the minutes of the open and closed sessions will be sent to the PI 
describing the DSMB recommendations and rationale for such (see DSMB Communication of Findings and 
Recommendations). 
 
Study Review Criteria/Stopping Rules and Guidelines 
Guidance for the conduct of safety and efficacy analyses, and guidelines / stopping rules will be established prior to the 
DSMB’s first evaluation of data. 
 
Safety Analyses 
The primary safety endpoint is mortality as observed during interim analysis.  In addition to the primary safety endpoint, 
the DSMB will monitor the following adverse events:  
1. ARDS (adult respiratory distress syndrome) 
2. TRALI (transfusion related acute lung injury) 
3. MOF (- multiple organ failure) 
4. Transfusion reactions 
5. Surgical interventions 
6. Complications due to specific injuries 
7. Other major medical or surgical complications are commonly observed in these patients 
  
Stopping Guidelines / Stopping Rules: Safety 
Termination or modification may be recommended for any perceived safety concern based on clinical judgment, including 
but not limited to a higher than anticipated rate for any component of the primary endpoint resulting in adverse events, or 
unexpected SAEs. 
 
Efficacy Analyses 
The primary outcome variable 30 day mortality will be utilized to access for efficacy of the trial. Accessing this  primary 
outcome variable at each interim analysis will allow early termination of the trial for either lack of efficacy or excessive 
efficacy or benefit provided by early prehospital plasma. 

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Adaptive Protocol Modification 
There is no planned sample size re-estimation; however if the DSMB reveals a need, the sample size calculation can be 
re-evaluated.  
 
Consideration of External Data 
The DSMB will also consider data from other studies or external sources during its deliberations, if available, as these 
results may have a profound impact on the status of the patients and design of the current study. 
 
DSMB Reports 
Monitoring for Safety 
The primary charge of the DSMB is to monitor the study for patient safety. Formal DSMB safety reviews will occur as 
specified above (see Study Review Criteria/Stopping Rules and Guidelines).   
 
Monitoring for Efficacy 
The DSMB will monitor efficacy outcomes to determine relative risk/benefit, futility, or for early termination due to 
overwhelming efficacy.  Interim analyses efficacy reports sent to the DSMB will occur as specified above (see Study 
Review Criteria/Stopping Rules and Guidelines).  
 
Monitoring for Study Conduct 
The DSMB will review data related to study conduct. Data to be reviewed and listed in the DSMB reports includes: 
enrollment rates over time, time from last patient enrolled to date of report (indication of delay between treatment or 
follow-up and reporting), summary of protocol violations, and completeness of treatment and follow-up visit data. 
 
Data Flow for Adverse Events 
The DSMB will carefully monitor adverse events periodically throughout the duration of the study. This process will be 
dynamic to include quarterly reviews of all reported SAEs by the DSMB chairperson. The investigators will be expected to 
report Serious Adverse Events (SAEs) to the PI within 24 hours of knowledge of the event. The PI will then report it to the 
DSMB within 7 days.  
 
Preparation of Reports to the DSMB 
The University of Pittsburgh Coordinating Center will generate unblinded data for DSMB review.  The PI will prepare and 
distribute reports to the DSMB electronically approximately 7 days prior to the date of each DSMB meeting. 
 
In order to provide the maximum amount of information to the DSMB, the analyses will employ the most recent data 
(recognizing limitations thereof) available at the time of the analysis. Requests for additional data by the DSMB members 
will be made to the DSMB chairperson or his or her designee, who will be responsible for communicating the request with 
the PI. 
 
The DSMB will review the data and discuss the analyses during the closed portion of the scheduled meeting.  
 
DSMB Communication of Findings and Recommendations 
Following each meeting and within 7 days of the meeting, the chairperson will send findings and recommendations of the 
DSMB in writing to the PI.  
 
These findings and recommendations can result from both the open and closed sessions of the DSMB. If these findings 
include serious and potentially consequential recommendations that require immediate action, the chairperson will also 
promptly notify the PI by phone and/or by email. 
 
PI’s Response to DSMB Findings and Recommendations 
The PI and co-investigators will review and respond to the DSMB recommendations. The recommendations of the DSMB 
will not be legally binding but require professional consideration by the recipients. If the DSMB recommends continuation 
of the study without modification, no formal response will be required. However, if the recommendations request action, 
such as a recommendation for termination of the study or modification of the protocol, the DSMB will request that the PI 
provide a formal written response stating whether the recommendations will be followed and the plan for addressing the 
issues. 
 
It is recognized that the PI may need to consult with regulatory agencies or other consultants before finalizing the 
response to the DSMB. Upon receipt, the DSMB will consider the PI response and will attempt to resolve relevant issues, 
resulting in a final decision. Appropriate caution will be necessary during this process to avoid compromising study 

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integrity or the ability of the PI to manage the study, should the study continue. The PI will agree to disseminate the final 
decision to the appropriate regulatory agencies, IRB, and investigators within an appropriate time. 
 
In the unlikely event of irreconcilable differences, especially regarding study termination or other substantial study 
modifications, the DSMB may decide to discontinue monitoring the current study and disband. This decision will be 
communicated to the PI, FDA, and IRBs. 
 
Public disclosure of the PI’s final decision or DSMB recommendations will be at the discretion of the PI or their designee. 
The DSMB will not make any public announcements either as a group or individually.   
 
DSMB Closeout 
This study may be terminated under a variety of circumstances including, but not limited to, termination for overwhelming 
effectiveness, futility, or safety issues per protocol or DSMB monitoring guidelines. Responsibilities of the DSMB with 
regard to closeout will be to review the final study report to ensure study integrity. The DSMB may recommend continuing 
action items to the PI based upon the final review. 
 
Confidentiality 
All data provided to the DSMB and all deliberations of the DSMB will be privileged and confidential. The DSMB will agree 
to use this information to accomplish the responsibilities of the DSMB and will not use it for other purposes without written 
consent from the study PI and co-investigators. No communication of the deliberations or recommendations of the DSMB, 
either written or oral, will occur except as required for the DSMB to fulfill its responsibilities. Individual DSMB members 
must not have direct communication regarding the study outside the DSMB (including, but not limited to the investigators, 
IRB, regulatory agencies, or PI) except as authorized by the DSMB. 
 
Amendments to the DSMB Charter 
This DSMB charter can be amended as needed during the course of the study. Information to be included as 
amendments will be any modifications or supplements to the reports prepared for the DSMB, as well as amendments to 
other information addressed in this charter. All amendments will be documented with sequential version numbers and 
revision dates, and will be recorded in the minutes of the DSMB meetings. Each revision will be reviewed and agreed 
upon by both the study PI and the DSMB. All versions of the charter will be archived in accordance with this document 
and maintained by the PI.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Clinical Protocol Appendix 7 
 
Reporting Requirements 
 
Reporting Requirements and Responsibilities of the Principal Investigator to the United States Army Medical 
Research and Materiel Command’s (USAMRMC), Office of Research Protections (ORP), Human Research 
Protection Office (HRPO). 
 
    a. The protocol will not be initiated until written notification of approval of the research project is issued by the HRPO.   
 
    b. The Principal Investigator has a duty and responsibility to foster open and honest communication with research 
subjects. The USAMRMC strongly encourages the Principal Investigator to provide subjects with a copy of the research 
protocol, if requested, with proprietary and personal information redacted as needed. 
 
    c. The Principal Investigator must comply with the following minimum reporting requirements.  Specific reporting 
requirements for the protocol will be included in the HRPO Approval Memorandum.  Failure to comply could result in 
suspension of funding. 
 
        (1)  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.   
 
        (2)  Any changes of the IRB used to review and approve the research will be promptly reported to the USAMRMC 
ORP HRPO.   
 
        (3)  All unanticipated problems involving risk to subjects or others must be promptly reported by telephone (301-619-
2165), by email (HRPO@amedd.army.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 U.S. Army Medical 
Research and Materiel Command, ATTN:  MCMR-RP, 504 Scott Street, Fort Detrick, Maryland  21702-5012.   
        (4)  Suspensions, clinical holds (voluntary or involuntary), or terminations of this research by the Institutional Review 
Board (IRB), the institution, the Sponsor, or regulatory agencies will be promptly reported to the USAMRMC ORP HRPO. 
 
        (5)  A copy of the continuing review approval notification by the IRB of Record must be submitted to the HRPO as 
soon as possible after receipt.  For greater than minimal risk research, a copy of the continuing review report approved by 
the IRB must also be provided.  Please note that the HRPO also conducts random audits at the time of continuing review.  
Additional information and documentation may be requested at that time. 
 
        (6)  The final study report, including any acknowledgement documentation and supporting documents, must be 
submitted to the HRPO when available. 
 
        (7)  The knowledge of any pending compliance inspection/visit by the FDA, DHHS Office of Human Research 
Protections (OHRP), 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 promptly reported to the 
HRPO.   
 
Please Note: The USAMRMC ORP HRPO conducts site visits as part of its responsibility for compliance oversight.  
Accurate and complete study records must be maintained and made available to representatives of the USAMRMC as a 
part of their responsibility to protect human subjects in research.  Research records must be stored in a confidential 
manner so as to protect the confidentiality of subject information.   
 
For questions regarding the HRPO human research protocol review requirements email hrpo@amedd.army.mil or leave a 
voicemail at 301-619-2165 and a staff member will contact you. 
 
 

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Clinical Protocol Appendix 8 
 
Harmonization Protocol for Prehospital Use of Plasma for Traumatic Hemorrhage Clinical Studies 
Date: 22 October 2013 
Point of Contact and Principal Investigator for Harmonization Protocol: Anthony E. Pusateri, PhD 
1. Introduction 
This harmonization protocol describes two phases for harmonizing three clinical studies that examine the prehospital 
use of plasma for traumatic hemorrhage.  The primary harmonization plan is effective immediately and harmonizes the 
key study components that are critical to the primary unifying hypotheses and to the preplanned meta-analysis related 
to those primary unifying hypotheses.  The secondary harmonization plan will be developed later, and will address 
secondary hypotheses and exploratory analyses.  In this document, the primary harmonization will be described in 
detail.  The approach and components related the secondary harmonization plan will be identified but will not be 
discussed in detail. 
Currently, there is great interest in the potential use of plasma as the initial resuscitation fluid for traumatic 
hemorrhage.  Traditionally, initial resuscitation has included fluids such as crystalloids.  Plasma has been used as part of 
transfusion during the in-hospital phase of care.  Recent evidence suggests both that earlier transfusion and that a 
higher ratio of transfused plasma with respect to red cells improve outcomes.  These findings suggest that earlier use of 
plasma may be beneficial in trauma patients; however, there are little clinical data on the use of plasma in the pre-
hospital environment.  The question of the utility of plasma in the prehospital environment is especially significant in 
combat casualty care because of the challenges of the battlefield that may result in unpredictable and often prolonged 
evacuation times.  Therefore, the US DoD has sponsored three clinical trials to study the potential beneficial or negative 
effects of plasma in the prehospital setting.   
The approach taken in the overarching research program was to fund three separate studies, as opposed to funding a 
single very large study for licensure.  This approach was taken because of the limited information available on the 
prehospital use of plasma.  The approach was designed to provide information on prehospital plasma use under the 
different conditions and approaches provided by three separate studies.  To obtain the maximum amount of 
information possible, the three clinical studies will be harmonized to provide the most effective possible meta-analysis 
addressing the most important outcomes.  Harmonization is not meant to significantly alter the objectives or success of 
any individual study.  An additional reason for harmonization is to facilitate an interface with the NHLBI-DoD Trans-
agency Consortium on Coagulopathy in Trauma (TACTIC).  
2. Purpose of this document 
This document is a Harmonization Protocol.  It identifies the specific points of harmonization among the three separate 
clinical studies.  This document also identifies the unifying hypotheses, approach to data integration, and the meta-
analysis plan, as well as relevant coordination procedures.  Specific details about clinical protocol procedures are 
included within each separate study protocol (Appendices 1-3).  This harmonization protocol does not replace or negate 
any planned analyses described for each individual site, nor does it detract from the unique characteristics of each 
study.  This document describes procedures and analyses that will bring together the three studies with the purpose of 
capitalizing on the increased statistical power made possible by combining selected, harmonized data and by conducting 
meta-analyses according to a pre-planned, statistically valid approach. 

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3. This document brings together three separate clinical studies. 
a. 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., Denver Health Medical Center, Denver, CO  
 
b. Study Title: Prehospital Air Medical Plasma (PAMPer) Phase III Multicenter, Prospective, Randomized, Open-label, 
Interventional Trial 
Principle Investigator: Jason L. Sperry MD, MPH, University of Pittsburgh Medical Center, Pittsburgh, PA  
 
c. Study Title: Pre-Hospital Use of Plasma for Traumatic Hemorrhage – (PUPTH_Study) 
Principle Investigator: Bruce D. Spiess, MD, Virginia Commonwealth University Medical School, Richmond, VA 
 
The scientific and clinical backgrounds and rationales for each study are thoroughly reviewed in the individual clinical 
protocols (Appendices 1-3). 
4. Unifying Hypotheses 
The following hypotheses will be addressed by the combined study harmonization plan and meta-analysis. 
Primary Outcome 
1. Prehospital administration of 2 units of plasma will reduce mortality at 30 days after ED arrival 
Secondary Outcomes 
2. Prehospital administration of 2 units of plasma will reduce mortality 
a. Prehospital administration of 2 units of plasma will reduce mortality at time of emergency department (ED) arrival 
b. Prehospital administration of 2 units of plasma will reduce mortality at 24 hours after ED arrival 
3. Prehospital administration of 2 units of plasma will reduce 24 hour transfusion requirements4. Prehospital 
administration of 2 units of plasma will improve standard coagulation parameters at the time of ED arrival 
5. Prehospital administration of 2 units of plasma will improve clot viscoelastic properties (thromboelastograph (TEG) 
parameters) at the time of ED arrival 
6. Prehospital administration of 2 units of plasma will improve hemodynamic parameters (systolic blood pressure (SBP) 
and heart rate (HR)) at the time of ED arrival 
7. Prehospital administration of 2 units of plasma will improve cellular hematologic parameters (hematocrit, red cells, 
platelet count) at the time of ED arrival 
8. Prehospital administration of 2 units of plasma will improve metabolic status (lactate, blood gases, pH, base deficit) at 
the time of ED arrival 
9. Prehospital administration of 2 units of plasma will improve International Society on Thrombosis and Haemostasis 
Disseminated Intravascular Coagulation Score (ISTH DIC Score) at the time of ED arrival and at 24 hours after ED arrival 

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5. Clinical Protocol Harmonization Approach 
This protocol harmonization will be conducted in two stages, Primary Harmonization and Secondary Harmonization.  
Primary Harmonization will be accomplished prior to the start of patient enrollment with the purpose to support the 
unifying hypotheses stated in this document.  This will include such key aspects as experimental treatments and 
inclusion/exclusion criteria, among others.  Secondary harmonization will be accomplished later and will include specific 
assay methodology and other aspects of the study.  The approach to harmonization will be to attain agreement among 
site principal investigators and then to obtain local IRB, USAMRMC Human Use Review Office, Secretary of the Army, 
and FDA approval for any required protocol modifications.  Ideally, all changes that require FDA and/or Secretary of the 
Army approval will be accomplished as part of primary harmonization.  It is hoped that items harmonized during 
secondary harmonization will require only IRB notification or, at most, IRB concurrence for approval. 
Primary harmonization will include the following aspects of each clinical study: 
1. Experimental Treatment Groups 
2. Inclusion and Exclusion Criteria 
3. Timing of blood samples and identification of key parameters and assays  
4. Adverse events 
5. Methods to account for patient transport time 
6. Enabling language and permissions for secondary harmonization.  
Secondary Harmonization will include the following aspects of each clinical study: 
1. Assay procedures and reagents 
2. Blood sampling and handling procedures 
3. Sample processing and storage procedures 
4. Timing and number of blood samples (additional harmonization beyond that stated for primary harmonization)  
5. Consolidation of procedures and laboratories to run assays 
1. Experimental Treatment Groups 
Across the three individual studies (Combined Study), the experimental treatment groups will be: 
Control: Prehospital standard of care crystalloid resuscitation or fluid infusion 
Treatment: Prehospital administration of 2 units of plasma 
The individual study sites differ somewhat with respect to the specific plasma component and preparation procedures 
to be used (Table 1).  These are dictated by local blood bank policy and it will not be possible to change these 
parameters.  However, we believe that the procedures to be used for each individual study are similar enough to enable 
the overarching analyses described in the preplanned meta-analysis section.  The volume of blood products 
administered will be recorded in units or volume.  Randomization will be accomplished as described in each individual 
site protocol (Appendices1-3). 

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Table 1. Treatment Groups at Individual Sites 
Parameter 
Colorado (COMBAT) 
Pittsburgh (PAMPer) 
Virginia (PUPTH) 
Blood Component 
Type AB FP24 thawed 
plasma 
Type AB thawed plasma 
Type A thawed plasma 
Handling Procedures 
Plasma will be carried 
frozen and will be 
thawed in the 
ambulance using FDA 
approved microwave or 
other approved method 
Thawed plasma (TP) will 
be carried as 
refrigerated thawed 
plasma.  Thawed 
plasma will not be older 
than 5 days (post-thaw), 
and will be rotated 
every 5 days.   
Thawed plasma will be 
carried as refrigerated 
thawed plasma in EMS 
supervisor vehicles. 
How administered 
Gravity feed with 
manual compression.  
TP will be administered 
by a paramedic or 
higher level care 
provider via a dedicated 
large bore line.  If not 
randomized to TP, then 
standard crystalloid will 
be administered in the 
same manner. A limited 
amount of crystalloid 
may be administered 
prior to TP.  The volume 
administered will be 
documented. 
Crystalloid will not be 
warmed in field.   
Gravity feed with 
manual compression.  
TP will be administered 
by a paramedic or 
higher level care 
provider via a dedicated 
large bore line.  If not 
randomized to TP, then 
standard crystalloid will 
be administered in the 
same manner. A limited 
amount of crystalloid 
may be administered 
prior to TP.  The volume 
or units administered 
will be documented. 
Plasma and crystalloid 
will not be warmed in 
field.   
Gravity feed with 
manual compression.  
TP will be administered 
by EMS supervisor via a 
dedicated large bore 
line.  If not randomized 
to TP, then standard NS 
resuscitation will be 
administered in the 
same manner  A limited 
amount of crystalloid 
may be administered 
prior to TP.  The volume 
administered will be 
documented. Plasma 
and crystalloid will not 
be warmed in field.   
Procedure 
Patients randomized to 
the plasma group will 
receive 2 units of 
plasma before 
crystalloids.  If the 
plasma is not ready and 
a patient needs fluids, 
Normal saline (NS) will 
be administered until 
plasma is ready.  There 
Patients that are 
randomized to the 
plasma group will 
receive 2 units of 
plasma prior to 
administration of any 
other fluids or blood 
components.  .  The 
volume or units of 
crystalloid administered 
Patients randomized to 
the plasma group will 
receive 2 units of 
plasma before 
crystalloids.  If the 
plasma is not ready and 
a patient needs fluids, 
NS will be administered 
until plasma is ready.  
There is no limit to 

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is no limit to crystalloid 
volume.  The volume of 
crystalloid administered 
and when it is 
administered (before or 
after plasma) will be 
documented for all 
patients in both 
treatment groups. 
and when it is 
administered (before or 
after plasma) will be 
documented for all. 
patients in both 
treatment groups.  The 
volume or units and 
timing of red cell 
administration will also 
be documented. 
crystalloid volume.  The 
volume of crystalloid 
administered and when 
it is administered 
(before or after plasma) 
will be documented for 
all patients in both 
treatment groups. 
Control Group 
Normal saline will be 
used for resuscitation.  
There will be no limit to 
total NS administered. 
The volume of 
crystalloid administered 
will be documented for 
each patient. 
Crystalloid resuscitation 
will be performed using 
(NS or lactated Ringer’s 
solution (LR)) as needed 
(no upper limit).   
Those patients with 
persistent hypotension 
(SBP>90mmHg) with 
completion of the 2 
units of plasma or initial 
crystalloid treatment 
will follow a goal 
directed prehospital 
crystalloid resuscitation 
standard operation 
procedure which 
includes crystalloid 
bolus infusion or 
uncrossmatched blood 
depending on the 
particular air medical 
service for patients who 
remain hypotensive 
after the plasma 
intervention. 
The volume or units and 
timing of both 
crystalloid and red cells 
will be documented. 
Normal saline will be 
used for resuscitation  
The volume of 
crystalloid administered 
will be documented for 
each patient. 
Standard of care 
Normal saline as 
needed (no upper 
Crystalloid (NS ro LR) as 
needed (no upper 
limit).  Some 
Normal saline as 
needed (no upper 

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limit). 
participating sites also 
administer packed red 
cells during aero-
medical transport. 
limit). 
 
2. Inclusion and Exclusion Criteria 
Inclusion and exclusion criteria are compatible among the three individual studies.  Inclusion and exclusion criteria are 
phrased differently among the three individual protocols (Appendices 1-3).  There are differences in specific wording and 
details of the inclusion and exclusion criteria as written.  These are summarized in Tables 2 and 3.  For purposes of the 
combined harmonization protocol, simplified inclusion and exclusion criteria have been developed (Tables 4-5).  We 
believe that these simplified inclusion and exclusion criteria reflect the primary features and intent identified in each 
protocol and describe, for the combined protocol, valid criteria that identify the harmonized patient population for 
purposes of the harmonized analysis and interpretation of the combined studies.  Although there may remain slight 
differences in inclusion and exclusion criteria, it is expected that the number of enrolled patients that fall outside of the 
simplified, harmonized criteria will be so small as to not appreciably affect the projected power of the planned analyses 
through exclusion of these patients from the harmonized dataset.  Exclusion would only be required for the primary and 
secondary unified hypotheses.. 
Table 2. Inclusion Criteria For Each Clinical Study 
Criteria 
COMBAT 
PAMPer 
PUPTH 
Type of injury 
 Acutely injured trauma 
patients in severe, 
presumed hemorrhagic 
shock. 
Blunt or penetrating 
injured patients with 
hemorrhagic shock 
 
Blunt or penetrating 
trauma 
Age 
Age >/= 18 years 
Age 18 to 90 years 
Age>/=18 years 
Gender 
Either sex 
Either sex 
Either sex 
Hemorrhagic Shock 
Status 
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. 
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. 
BP systolic </=70 mmHg 
or BP systolic 70-90 
mmHg with HR >/=108 
BPM 
 
 
 
 
 
 
Major, ongoing 
hemorrhage, expected 
unstable vital signs 

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consistent with above 
Transport 
 
Air medical transport to 
tertiary definitive care 
trauma center 
participating in the trial 
 
Consent 
 
 
If lucid, able to consent (if 
feasible LAR/next of kin 
available and provides 
consent (abbreviated)), 
otherwise exception from 
informed consent 
 
Table 3. Exclusion Criteria For Each Clinical Study 
Criteria 
COMBAT 
PAMPer 
PUPTH 
Age 
Age<18 years 
Age >90 or <Age 18 
years of age 
Age <18 years 
Not expected to 
survive 
Unsalvageable injuries 
(defined as asystolic or 
CPR prior to 
randomization) 
 
Not expected to survive 
transport to VCUMC 
Head or CNS injury 
Isolated gunshot wound 
to the head (a highly 
lethal injury that is not 
primarily due to blood 
loss) 
Penetrating cranial 
injury 
Penetrating head trauma 
 
 
Traumatic brain injury 
with brain matter 
exposed 
 
 
 
Documented  cervical 
cord injury with motor 
deficit 
 
 
Pregnancy 
Visibly or verbally 
reported pregnant 
woman 
Known pregnancy 
Known/obvious 
pregnancy 

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Prisoner 
Known prisoner 
Known prisoner 
Prisoner 
Cardiac activity 
Unsalvageable injuries 
(defined as asystolic or 
CPR prior to 
randomization) 
Trauma arrest with >5 
minutes of CPR without 
return of vital signs 
Cardiac arrest or CPR prior 
to randomization 
Decline 
participation 
Patient has an opt-out 
bracelet or necklace  
 
Wearing an opt out wrist 
band 
 
Family member present 
at the scene objects to 
the patient’s 
participation 
 
Refusal to participate  
Objections to Blood 
Products 
Known or religious 
objection to blood 
products 
 
Wearing medical alert 
jewelry/bracelet, etc. 
found to indicate 
Jehovah’s Witness or 
similar with objections to 
blood transfusions 
IV access 
 
Inability to obtain 
intravenous or 
interosseous access 
Inability to obtain IV 
access to administer TP 
Other 
 
Isolated fall from 
standing injury 
mechanism 
Arrival of EMS supervisor 
at the time ambulance 
transport is underway 
 
 
Isolated drowning or 
hanging victims 
Not English or Spanish-
speaking 
 
 
Isolated burns > 
estimated 20% total 
body surface area 
Communication barrier at 
the time of eliciting 
refusal (non-English or 
non-Spanish speaking) 
 
 
Referral hospital In-
patient admission 
Documented “Do not 
resuscitate” (DNR) order 
found/known 
 
Table 4. Harmonized Inclusion Criteria 
Acutely injured patients with blunt or penetrating trauma in severe hemorrhagic shock  

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Transported by ground or air ambulance 
Presence of electrical activity and/or measureable or palpable blood pressure at time of randomization 
Age>/=18 years 
Shock definition: Acutely injured, with presumed hemorrhagic shock from acute blood loss defined as 
SBP</=70 mmHg or with SBP 71-90 mmHg and HR>/=108 beats per minute  
Either sex 
Volume or units of crystalloid administered prior to randomization can be documented 
 
Table 5. Harmonized Exclusion Criteria 
Age <18 years 
Inability to obtain intravenous or interosseous access 
Penetrating cranial injury. 
Traumatic brain injury with brain matter exposed. 
Visibly or verbally reported pregnant woman 
Cardiac arrest or CPR prior to randomization 
Known prisoner 
Unsalvageable injuries 
Known religious objection to blood products 
Patient has an opt-out bracelet, necklace or wallet card 
Patient (if lucid) or family member at scene declines participation in the study 
 
3. Timing of blood samples and identification of key parameters and assays 
Timing of collection of data for key parameters that support the unifying hypotheses will be standardized across studies 
to the following times: 1) Emergency Department arrival (within 1 hour of arrival and prior to in-hospital transfusion of 
fluid administration; 2) 24 hours after ED arrival; and 3) 28-30 days after ED arrival.  This represents the minimum that 
will be performed.  Data will also be collected at other time points as described in each individual site protocol. 
Additional assays are included as specified in each site specific protocol (Appendices 1-3). 
The clinical data both at presentation and throughout hospitalization will be obtained and recorded in individual 
databases established at each study site (Table 6).  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 

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as time and cause of death. Patient data entry will end with the index hospital stay. Outpatient information will not be 
included.  A combined data base will be established for the combined study that will minimize need for manual data 
entry.  This will be established and validated prior to the first interim data analysis. The ClinPortal web-based data 
collection tool at Washington University in Saint Louis will be used to compile and integrate data from each clinical study 
site. 
Table 6. Key data collection will include the following 
Parameter 
Time 
ED 
Arrival 
24 Hr 
30 d 
Mortality (Documented by telephone contact if discharged before 30 days) 
x 
x 
x 
24 Hour Blood Transfusion Requirements (total and by blood component) 
 
x 
 
Standard coagulation assays: prothrombin time (PT), international 
normalization ratio (INR), and fibrinogen concentration (Clauss Method) 
x 
x 
 
Thromboelastography (TEG): Tissue factor activated rapid TEG (r-TEG) will be 
used. Parameters will include activated clotting time (ACT, seconds), angle 
(alpha, degrees), coagulation time (K, seconds), maximum amplitude (MA, 
mm), clot strength (G, dynes/cm2), and estimated percent lysis (EPL, %).  
x 
x 
 
D-dimer 
x 
x 
 
Multiple Organ Failure (Using standard MOF checklist/criteria (TBD)) 
 
x 
x 
Nosocomial Infection (number of events, organism and antibiotic sensitivity) 
 
x 
x 
Acute Lung Injury (Using standard ALI checklist/criteria (Appendix 5 TBD) 
 
x 
x 
Transfusion Related Acute Lung Injury (Using standard TRALI checklist/criteria 
(Appendix 6 TBD) 
 
x 
x 
Resuscitation Fluid Requirements 
x 
x 
x 
Lactate 
x 
x 
 
Arterial Blood Gases 
x 
x 
 
Platelet Count 
x 
x 
 
Hematocrit 
x 
x 
 
Red Blood Cell Count 
x 
x 
 
Hemodynamic Parameters (SBP and HR) 
x 
 
 

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Transport Time 
x 
 
 
Time from 911 call (estimate of time of injury) to ED arrival 
x 
 
 
Injury Severity Score (Calculated within 14 days of entry into study) 
 
 
 
 
Timing of data and sample collection for each study and for the harmonized approach is depicted in Figure 1. 
Scene
ED
2h
4h
6h
8h
12h
24h
72h
5d
7d
30d
Colorado Study
Pittsburgh Study
Virginia Study
Primary Harmonization Time Points for Primary and Secondary Outcomes 
(Mortality Only)
 
4. Adverse Events 
Adverse events will be reported according to the reporting procedures established for each individual study, as 
described within each protocol (Appendices 1-3) 
5. Methods to account for patient transport time 
Time of injury will be estimated based on the time of the initial 911 call.  Transport time will be calculated as the time 
from EMS arrival on scene to time of arrival at the ED 
Figure 1. Timing of blood samples (black arrows) and data collection times for each study and for the combined 
harmonized study.  Harmonization time points (red arrows) indicate the time points that will be harmonized across the 
three studies.  These are the time points that support the unifying hypotheses and primary and secondary outcomes 
identified in the harmonization protocol. 
6. Enabling language and permissions for secondary harmonization.  

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Each site protocol will include language that will provide permission to: archive samples, share samples with other 
laboratories, perform additional assays on samples, store data, transfer and share data, and perform future data 
analyses beyond the scope of the specific approved study and specifically delineated procedures.  In addition, a 
maximum blood volume approval will be sought for each individual site protocol to facilitate planning for any future 
additional blood samples that may be included.  For additional blood samples, or for any other change related to 
secondary harmonization or other reason, appropriate approvals will be sought.  It is anticipated that each of the three 
studies will be included as the DoD component of the NHLBI/DoD Trans-Agency Research Consortium for Trauma-
Induced Coagulopathy (TACTIC) grant program.  This program will likely require the collection of samples for analysis of 
genetically-related parameters.  Therefore, permissions will be specifically sought for collection of these types of 
samples.  These may include additional consent procedures.  
Secondary Harmonization will include the following aspects of each clinical study: 
1. Selected assay procedures and reagents 
2. Blood sampling and handling procedures 
3. Timing of interim reviews 
4. Sample processing and storage procedures 
5. Timing and number of blood samples (additional harmonization beyond that stated for primary harmonization)  
6. Consolidation of procedures and laboratories to run selected assays 
Details for secondary harmonization will be determined later. 
7. Coordinating Procedures  
Communication plan.  Coordination of the three separate studies will be facilitated by monthly conference calls, periodic 
site visits by USAMRMC personnel, and twice yearly in-person meetings.  In addition, procedures will be established to 
report progress and for transfer data.  Additional communications will be established as needed to address specific 
topics.  Study sites will share full protocols, manuals of operations, and specific details of assays and other procedures as 
needed to facilitate coordination of studies.  In cases where it is determined that assays or other procedures will be 
standardized among the three study sites, detailed procedures will be exchanged, technicians will be cross-trained, and 
assays (or other procedures) will be validated at each individual site. 
Data consolidation plan.  A specific, detailed data consolidation plan will be developed well in advance of the first 
interim data analysis that is planned for each study site.  The time of the first interim analysis will also be the time of the 
first full test of the consolidated data set and all associated data transfer procedures. 
Study monitoring will be conducted in accordance with USAMRMC standard procedures for monitoring human use 
protocols.  This will include periodic site visits by study monitors, periodic progress reports, and other communications. 
Data Safety Monitoring Board (DSMB) Procedures.  Each individual study site will be responsible for its DSMB.  Reporting 
will be in accordance with FDA and USAMRMC requirements.  
Local protocol approvals will be the responsibility of each individual study site.  All study sites will share lessons-learned 
with the overall team. 

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Investigational New Drug (IND) applications will be the responsibility of each individual study site.  All study sites will 
share lessons-learned with the overall team. 
Community consultation procedures will be the responsibility of each individual study site.  All study sites will share 
lessons-learned with the overall team. 
Secretary of the  Army Approval.  Each individual site protocol will require approval from the Office of the Secretary of 
the Army.  The approvals will be facilitated by the USAMRMC Human Research Protections Office.  Each individual site 
protocol will be submitted along with the Combined Study Harmonization Protocol to demonstrate that the studies are 
part of a coordinated program and to facilitate approval. 
8. Data Meta-Analysis Plan 
Unifying Hypotheses 
The following hypotheses will be addressed by the combined study harmonization plan and meta-analysis. 
It is expected that all patients enrolled in the COMBAT and PUPTH studies  will be included in the meta-analyses that 
address the primary and secondary unifying hypotheses.  The PAMPer Study includes five enrolling sites. Two of these 
sites will have a slightly different prehospital treatment.  Procedures at these two sites include the possibility of initiating 
transfusion of packed red blood cells enroute, prior to ED arrival.  It is anticipated that for some parameters, this will 
require sub-analysis.  For the purpose of addressing the primary and secondary outcomes,  these sites will be excluded.  
Overall sample size projections, with and without PAMPer sites allowing prehospital packed red blood cells, are shown 
in Table 7. 
Primary Outcome 
1. Prehospital administration of 2 units of plasma will reduce mortality at 30 days after ED arrival 
Secondary Outcomes 
2.  Prehospital administration of 2 units of plasma will reduce mortality at time of emergency department (ED) arrival 
3. Prehospital administration of 2 units of plasma will reduce mortality at 24 hours after ED arrival 
4. Prehospital administration of 2 units of plasma will reduce 24 hour transfusion requirements 
5. Prehospital administration of 2 units of plasma will improve standard coagulation parameters at the time of ED arrival 
6. Prehospital administration of 2 units of plasma will improve clot viscoelastic properties (thromboelastograph (TEG) 
parameters) at the time of ED arrival 
7. Prehospital administration of 2 units of plasma will improve hemodynamic parameters (systolic blood pressure (SBP) 
and heart rate (HR)) at the time of ED arrival 
8. Prehospital administration of 2 units of plasma will improve cellular hematologic parameters (hematocrit, red cells, 
platelet count) at the time of ED arrival 
9. Prehospital administration of 2 units of plasma will improve metabolic status (lactate, blood gases, pH, base deficit) at 
the time of ED arrival 

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10. Prehospital administration of 2 units of plasma will improve International Society on Thrombosis and Haemostasis 
Disseminated Intravascular Coagulation Score (ISTH DIC Score) at the time of ED arrival and at 24 hours after ED arrival 
Table 7. Sample Size Projections 
Site 
Total Sample Size 
Sample Size Excluding Sites That 
Transfuse Red Cells Enroute 
Colorado 
150 
150 
Pittsburgh 
545 
375 
Virginia 
270 
270 
Total 
965 
795 
Meta-analysis objectives: 
Table 8 shows the various planned primary (P), secondary (S), and exploratory (E) outcome measures across the three 
studies. Analysis of ED arrival and 24 hour mortality will provide a more fine-grained look at the mortality and may 
provide insights into trends in other variables (time dependency, survivor bias, etc.).  In addition, analyses will be 
performed to support each of the secondary hypotheses (hypotheses 2-10) described above. 
Table 8. Pre-planned Primary and Secondary Outcome Measures 
Outcome 
PAMPer 
COMBAT 
PUPTH 
30/28 Day Mortality 
P 
P 
S6 
Multiple Organ Failure 
S1 
S1 
S6 
Post Admission Coagulopathy 
S3 
S2 
S3 
Clot Strength 
S3 
S3 
S3 
Acidosis/Shock 
S4 
S4 
24 Hour Mortality 
E1 
Blood Product Use 
S1, S2 
E5 
S5 
Nocosomial Infection 
S1 
S6 
Lung Injury 
S1 
E3 
TRALI 
S1 
1st 24hr Vasopressor Support 
S2 
 
 
Inflammation 
S4 
Ventilator (Free) Days 
E3 
S6 
Statistical Analysis Plan 
For all primary and secondary endpoints the null hypothesis that Plasma=Standard of Care (SOC) will be tested against 
the alternative hypothesis that Plasma<SOC (Plasma>SOC for Clot Strength) using the appropriate independent sample 
test at a significance cutoff of 0.05. For normally distributed continuous variables, or those which can be log transformed 
to normality (e.g. transfusion requirement), a t-test will be used.  For non-normally distributed continuous variables the 
Mann-Whjtney U test will be used.  Binary endpoints (e.g. 30 day mortality) will be tested using the Fisher Exact Test.  
For all secondary endpoints and exploratory subgroup analysis, the significance cutoff will be Bonferroni corrected. If 
warranted by highly correlated endpoints which are individually significant but do not meet Bonferroni corrected 

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significance cutoffs, exploratory Westfall-Young Bootstrap (sampled permutation) minP based p-values and step-down 
null hypothesis rejection decisions will also be presented.   
Size and power of pooled data analysis: 
Individual participant data (IPD) from the three studies will be pooled for meta-analysis using a one-step approach.  
Potential study specific clustering effects will be accounted for by adding study membership as a random effects 
covariate. This constitutes a two level grouped design which will allow covariate analysis and adjustment at the patient 
and study levels. Any study terminated at or after the first interim analysis, but before planned completion due to 
adverse events will be included in the meta-analysis. 
Figures 2 provides the power estimates for a range of potential pooled sample sizes for 30 day survival.  An estimated 
control mortality of 22% from the PAMPer study was chosen over the slightly less conservative 26% estimate from the 
COMBAT study.  The combined study power curves represent a best case scenario which assumes a negligible effect 
from covariates and an interclass correlation (ICC) of 0.  We expect a low ICC based on our high degree of harmonization 
and demonstrated equivalency of primary treatments.  Adjusting for covariates at the patient and study levels will 
reduce their negative impact on grouped power.  The unequal number of patients expected across the three studies will, 
with a non-0 ICC, work to slightly decrease expected power.   
 
 
  
 
 
 
 
 
Subgroup analysis: 
Figure 2.  Power (a) and detectable effect size (b) as a function of sample size for 30 day mortality.  The 
curved black line in each plot represents a 30 day control mortality estimate of 22% (PAMPer study).  
Vertical lines represent the expected number of total patients for the PAMPer (red), COMBAT (blue), 
and PUPTH (green) studies.  Patient estimates for the PAMPer study exclude sites which allow 
administration of prehospital packed red blood cells and are taken before the 1.75 multiplication 
adjustment for grouped design. The black vertical line gives the pooled sum of these patient values. The 
intersection of the curved and vertical black lines represents the upper limit of meta-analysis power (a) 
and effect size (b). Power calculations use a two tailed test of proportions differences.   
a   
b   

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Table 9 shows planned subgroup analyses for the three studies. Trauma type (blunt vs. penetrating), head injury, and 
shock are shared across two of the three studies and will be conducted for the primary and secondary meta-analysis 
outcomes. Additionally, any subgroup analysis which shows treatment effects in an individual study will be repeated in 
the meta-analysis if permitted by collected data. Where differing metrics are planned for a single subgroup (e.g. 
lactate/BE vs. systolic blood pressure + heart rate for shock), the metric used for meta-analysis will be that which is 
present in, and most directly comparable across, the three studies.  
Table 9. Pre-planned Subgroup Analysis 
Subgroup 
PAMPer COMBAT PUPTH 
Blunt vs. Penetrating Trauma 
yes 
yes 
Brain Injury/TBI 
yes 
yes 
Shock/hypoperfusion 
yes 
yes 
24hr Transfusion Req. 
yes 
yes 
Scene vs. Hospital Referral 
yes 
Number of Surgeries 
 
 
yes 
Vit. K Antagonist Medication 
yes 
PRBC Req. 
yes 
yes 
Antiplatelet Medication 
yes 
Transport Time 
yes 
Injury Severity 
yes 
 
Covariate adjustment and missing data etc: 
Table 10 shows the planned covariate adjustments for the three studies. A similar approach will be taken as for 
subgroup analysis, using multiple regression to adjust for covariates which are planned in at least 2/3 studies or those 
which show significant treatment significant group imbalance in at least one study. For this analysis, a single SBP/HR 
shock metric will be used.  
Table 10. Pre-planned Covariate Adjustment 
  
Covariate 
PAMPer COMBAT PUPTH 
Demographic Age 
yes 
yes 
  
Gender 
yes 
yes 
  
  
Injury 
Severity Score 
yes 
yes 
  
Blunt vs. Penetrating  
yes 
yes 
  
Brain: TBI/GCS 
yes 
yes 
  
  
Shock 
Field SBP 
yes 
  
Field HR 
yes 
  
Field Hemocrit 
yes 
  
Lactate+BE 
yes 
  
  
Coagulation 
INR 
yes 
  
  

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Blood 
Blood Transfusion Units 
yes 
yes 
  
Pre-Hospital Crystalloid 
yes 
  
  
Other 
Site 
yes 
  
Transport Times 
yes 
 
As mentioned above, we plan to account for major study cite differences by treating study membership as a random 
effects covariate.  In addition, we will assess study site heterogeneity of all potential covariates from table 10 including 
pre-hospital crystalloid volume.  While not conclusive, this analysis in conjunction with planned covariate analysis may 
suggest predominant causes for any study cite treatment differences.   
For the primary and secondary meta-analysis outcomes, missing data is expected to be very rare and will be imputed 
using multiple imputation. One potential issue related to missing data is that of the effect of early mortality on additive 
metrics such as total 24 hour blood product use. While not a longitudinal variable as such, 24 hour blood product use is 
likely to be correlated with time of early death. We will treat blood product use between death and 24hours as “non-
ignorable missing data with known mechanism” and use a maximum likelihood modeling approach to impute the 
“missing” portion.  
Intent to treat analysis: primary and secondary outcome data will be collected in all patients regardless of treatment 
received.  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.  In addition to the “intent to treat” approach, the harmonized combined data 
will also support exploratory analyses, which may incorporate analysis based on the treatment received including red 
blood cell transfusion. 
9. Annexes  
a. Each site protocol 
c. Timeline of harmonized protocol events (TBD) 
d. Combined dataset format (TBD) 
e. Coordination plan with TACTIC (TBD) 
 
 
 
 
 
 
 

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Clinical Protocol Appendix 9 
PAMPer Roles and Responsibilities at UPMC January 2013 
e
Research Assistants, 
Clinical Research 
Coordinators:
Verify eligibility 
assessment; collect blood 
for TEG analysis, etc., 
attempt to contact familiy
if not present; collect data; 
review AEs , SAE's
Monitor  randomization 
and age of plasma in 
Prehospital personnel: 
Eligibility criteria assessment ; 
administer plasma or sham 
bag;  continue resusitative 
efforts; provide clinical care
Emergency Department:
continue resuscitative efforts; 
provide clinical care
Investigators:
Verify eligibility;protocol adherence; 
informed consent process; monitor for AE's 
and SAE's 
Blood Bank:
Provide 
Plasmato 
bases; 
contact 
courier for 
restock and