Type O Whole Blood and Assessment of Age During Prehospital Resuscitation (TOWAR) Trial
Phase: PHASE3
Conditions: Hemorrhagic Shock, Traumatic Injury
Sponsor: Jason Sperry

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Task Order 0007 
 
 
Type O Whole blood and assessment of AGE 
during prehospital Resuscitation (TOWAR) 
Trial 
 
Protocol v8_8.23.2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Linking Investigations in Trauma and Emergency Services 

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Contents 
Protocol Synopsis .......................................................................................................................................... 4 
I. 
Specific Aims ......................................................................................................................................... 5 
II. 
Background and Significance ................................................................................................................ 7 
Study Population ....................................................................................................................................... 7 
Study Intervention ................................................................................................................................ 8 
Study Intervention Arm......................................................................................................................... 8 
Standard Care Arm ................................................................................................................................ 8 
Randomization and Masking ................................................................................................................. 8 
III. 
Outcomes .......................................................................................................................................... 9 
Primary Outcome ...................................................................................................................................... 9 
Secondary Outcomes ................................................................................................................................ 9 
Secondary Outcome Definitions ........................................................................................................... 9 
Classification of Mortality ....................................................................................................................... 11 
Predefined Subgroups ............................................................................................................................. 11 
IV. 
Screening and Enrollment ............................................................................................................... 12 
V. 
Potential Risks and Benefits ................................................................................................................ 12 
Potential Risks ......................................................................................................................................... 12 
Potential Benefits/Safety ........................................................................................................................ 13 
VI. 
Statistical Analysis Plan ................................................................................................................... 13 
Analysis for Trial Clinical Outcomes ........................................................................................................ 13 
Sample Size Justification and Power Analysis: ........................................................................................ 16 
Randomization of Ineligible Subjects ...................................................................................................... 16 
Non-adherence ....................................................................................................................................... 17 
Interim Analyses ..................................................................................................................................... 17 
Data Sources ........................................................................................................................................... 17 
Data Entry ............................................................................................................................................... 17 
Database Management ........................................................................................................................... 18 
Surveillance for Outcomes and Data Elements ...................................................................................... 18 
VII. 
Clinical Coordinating Center (CCC) .................................................................................................. 18 
VIII. 
Data Coordinating Center (DCC) ..................................................................................................... 19 
IX. 
Human Subjects .............................................................................................................................. 19 
Institutional Review Board ...................................................................................................................... 19 

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Training and Participating Site Coordination .......................................................................................... 19 
X. 
Safety Monitoring ............................................................................................................................... 20 
Adverse Event and Non-compliance Definitions .................................................................................... 20 
Assessing and Reporting Adverse Events (AEs) and Non-compliance .................................................... 20 
Data Safety Monitoring Board (DSMB) ................................................................................................... 21 
XI. 
Quality Control, Assurance and Confidentiality .............................................................................. 22 
Protocol Compliance ............................................................................................................................... 22 
Protocol Deviations ................................................................................................................................. 22 
Privacy and Confidentiality ..................................................................................................................... 23 
Investigator Responsibilities ................................................................................................................... 23 
Timetable ................................................................................................................................................ 23 
XII. 
References ...................................................................................................................................... 23 
Appendix I Requirements for Exception From Consent For Emergency Research ..................................... 25 
Appendix II Donor -Patient LOOKBACK ....................................................................................................... 28 
Appendix III Abbreviations .......................................................................................................................... 33 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Protocol Synopsis 
 
Protocol Title: 
Type O Whole blood and assessment of AGE during prehospital 
Resuscitation (TOWAR) Trial 
Protocol Number: 
STUDY20110430 
NCT Number: 
NCT04684719 
Version # and Date: 
Version 8.0 dated 8/23/2022 
Investigational Drug: 
Low titer whole blood  
Trial Sites: 
Clinical Coordinating Center 
• 
University of Pittsburgh, University of Pittsburgh Medical 
Center, PI Jason Sperry, Co-PI Frank Guyette 
Additional Sites: 
• 
University of Alabama at Birmingham 
• 
University of Washington/ Harborview Medical Center 
• 
University of Tennessee Medical Center Knoxville 
• 
University of Texas Houston 
• 
University of Louisville 
• 
Vanderbilt University 
• 
University of Mississippi 
• 
University of Cincinnati 
• 
MetroHealth 
 
Funding Agency 
Department of Defense 
IND Sponsor: 
Jason L Sperry, MD, MPH 
Study Aims: 
AIM#1: Determine whether prehospital low titer whole blood as 
compared to standard prehospital resuscitation results in lower 
30-day mortality in patients at risk of hemorrhagic shock. 
AIM#2: Determine whether prehospital whole blood (age > 14 days) 
as compared to young whole blood (age ≤ 14 days) is associated with 
equivalent clinical outcomes, hemostasis, prevention of 
coagulopathy, and platelet function in patients at risk of hemorrhagic 
shock.   
AIM#3: Determine whether prehospital low titer whole blood as 
compared to standard prehospital resuscitation results in lower early 
mortality, blood and blood component transfusion requirements, 
incidence of coagulopathy, improved hemostasis and platelet 
function in patients at risk of hemorrhagic shock. 
Study Design: 
Open label, multi-center, pre-hospital randomized trial utilizing 10 
level-1 trauma centers designed to determine the efficacy and safety 
of low titer whole blood resuscitation as compared to standard of care 

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resuscitation in patients at risk of hemorrhagic shock and to 
appropriately characterize the hemostatic competency of whole blood 
relative to its age. 
Planned Sample Size:  
1020 patients 
Planned Study Time: 
6-year, multi-center study; 4-year enrollment 
Major Inclusion Criteria:  
             1.) Injured patients at risk of hemorrhagic shock being 
transported from scene or referral hospital to a 
participating TOWAR trial site that meet requirements for 
initiation of blood or blood component transfusion 
 
AND 
              2A.) Systolic blood pressure ≤90mmHg and tachycardia 
(HR ≥108) at scene, at outside hospital or during transport 
  
OR 
 
 2B.) Systolic blood pressure ≤ 70mmHg at scene, at outside 
hospital or during transport 
 
Major Exclusion Criteria: 
1. Wearing “NO TOWAR” opt–out bracelet 
2. Age > 90 or < 18 years of age 
3. Isolated fall from standing injury mechanism 
4. Known prisoner or known pregnancy 
5. Traumatic arrest with > 5 consecutive minutes of CPR 
without return of vital signs 
6. Brain matter exposed or penetrating brain injury (GSW) 
7. Isolated drowning or hanging victims 
8. Objection to study voiced by subject or family member at 
the scene 
9. Inability to obtain IV or intraosseous access 
10. Isolated burns without evidence of traumatic injury 
Primary Endpoint: 
30-day mortality 
I. 
Specific Aims 
Resuscitation strategies for the acutely injured patient in hemorrhagic shock have evolved.  
Patients benefit from receiving less crystalloid and early red blood cell transfusion with balanced 
ratios of plasma and platelets.1-3 These resuscitation practices are termed Damage Control 
Resuscitation and are incorporated into massive transfusion protocols in level 1 trauma centers 
across the country.2-4 This reconstituted strategy has also been coined ‘whole blood-like’ 
resuscitation despite being inferior compositionally to whole blood.5,6  
     Despite these changes, deaths from traumatic hemorrhage continue to occur in the first hours 
following trauma center arrival, underscoring the importance of early interventions which 
provide benefit.1-3,7 Due to the time sensitive nature of the treatment of hemorrhage, the ideal 
resuscitation intervention would entail use of blood products containing all essential hemostatic 

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components, administration closest to time of injury, and mitigation of the devastating 
downstream consequences of shock and coagulopathy.  
     Whole blood transfusion following traumatic injury represents the ‘essential next step’ for the 
management of hemorrhagic shock post-injury. Prehospital whole blood is significant in that it 
brings this lifesaving hospital intervention to those patients who need it most, at a time before 
hemorrhagic shock and coagulopathy begin to have their detrimental consequences. We 
hypothesize that the initiation of whole blood resuscitation in the prehospital setting will 
significantly reduce the morbidity and mortality attributable to hemorrhagic shock post-injury as 
compared to standard prehospital resuscitation practice. Thus, a large pragmatic clinical trial is 
needed to definitively establish the efficacy and safety of whole blood resuscitation initiated in 
the prehospital setting. Only a high-quality clinical trial will provide the evidence to justify the 
use of this limited resource early post-injury.  
     Whole blood is a precious resource. The shelf life of the whole blood product depends on 
separation procedures and ranges from 21 to 35 days. The storage of whole blood leads to 
platelet dysfunction, cell lysis, and release of potassium and free heme which may reduce the 
resuscitative capacity of whole blood or contribute to end organ injury. The safety and efficacy 
of whole blood as a resuscitation fluid as it approaches its shelf life remains poorly characterized. 
The aims of the current Type O Whole blood and assessment of Age during prehospital 
Resuscitation (TOWAR) trial are to determine the efficacy and safety of whole blood 
resuscitation as compared to standard care resuscitation in patients at risk of hemorrhagic shock 
and to appropriately characterize the hemostatic competency of whole blood relative to its age. 
      
AIM#1: Determine whether prehospital low titer whole blood as compared to standard 
prehospital resuscitation results in lower 30-day mortality in patients at risk of hemorrhagic 
shock. 
AIM#2: Determine whether old prehospital whole blood (age > 14 days) as compared to young 
prehospital whole blood (age ≤ 14 days) is associated with equivalent clinical outcomes, 
hemostasis, prevention of coagulopathy, and platelet function in patients at risk of hemorrhagic 
shock. 
AIM#3: Determine whether prehospital low titer whole blood as compared to standard 
prehospital resuscitation results in lower early mortality endpoints, blood and blood component 
transfusion requirements, lower incidence of coagulopathy, and improved hemostatic and platelet 
function in patients at risk of hemorrhagic shock. 
 

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II. 
Background and Significance  
Initiation of the tenets of damage control 
resuscitation early, in the prehospital setting, has 
the potential to reduce downstream complications 
attributable to hemorrhage by intervening closer 
to the time of injury, prior to the development of 
coagulopathy, irreversible shock, and the ensuing 
inflammatory response.8-11 Thawed plasma 
transfusion has been shown to safely reduce 
30-day mortality when infused early, in the 
prehospital setting, in patients at risk of 
hemorrhagic shock and this separation of survival 
occurs within the first 3 hours.12 (Figure 1.)  
     A recent secondary analysis from the PAMPer 
trial demonstrated that patients who received both 
plasma and red cells (an independent predictor of 
mortality in the cohort) in the prehospital setting, 
had the best adjusted survival. Patients receiving   
crystalloid resuscitation only, had the highest 
mortality.13 (Figure 2.) 
     We hypothesize that the initiation of low titer 
whole blood (LTWB O) resuscitation in the 
prehospital setting is the most effective 
resuscitation for those at risk of hemorrhage and 
significantly reduces the morbidity and mortality 
attributable to hemorrhagic shock post-injury as 
compared to standard prehospital resuscitation 
practice. A large pragmatic clinical trial is needed 
to definitively establish the efficacy and safety of 
whole blood resuscitation initiated in the prehospital setting and to characterize its effectiveness 
as a function of storage time. Only a high-quality clinical trial will provide the evidence to justify 
the use of this precious blood banking resource early post-injury.  
 
Study Design/Setting: The current proposed trial will be a 6-year (4-year enrollment), multi-
center, open label, prehospital randomized trial utilizing 10 level-1 trauma centers from within 
the LITES network and will enroll approximately 1020 patients. The University of Pittsburgh 
will be the Clinical Coordinating Center and the Data Coordinating Center for the study. 
 
Study Population: Injured patients at risk of hemorrhagic shock requiring blood transfusion in 
prehospital phase of care. 
 
Inclusion Criteria:  
  
1.) Injured patients at risk of hemorrhagic shock being transported from scene or 
referral hospital to a participating TOWAR trial site that meet requirements 
for initiation of blood or blood component transfusion 
Figure 1. 30-day survival analysis 
Log-rank chi-square 5.57, p=0.02 
Figure 2. Pamper Prehospital Blood Component 
Secondary Analysis 

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AND 
 
2A.) Systolic blood pressure ≤ 90mmHg and tachycardia (HR ≥ 108) at scene, at     
        outside hospital or during transport 
OR 
 
2B.) Systolic blood pressure ≤ 70mmHg at scene, at outside hospital or during      
        transport 
 
Exclusion Criteria: 
1. Wearing NO TOWAR opt–out bracelet 
2. Age > 90 or < 18 years of age 
3. Isolated fall from standing injury mechanism 
4. Known prisoner or known pregnancy 
5. Traumatic arrest with > 5 consecutive minutes of CPR without return of vital signs 
6. Brain matter exposed or penetrating brain injury (GSW) 
7. Isolated drowning or hanging victims 
8. Objection to study voiced by subject or family member at the scene 
9. Inability to obtain IV or intraosseous access 
10. Isolated burns without evidence of traumatic injury 
 
Study Intervention: Two units of low titer whole blood, group O (LTWB O) will be collected 
using local site approved blood banking protocols and will be stored at each respective EMS 
base or stocking facility for each EMS unit/service. Low titer will be defined as anti-A and anti-
B antibody titers <256 and only units meeting this threshold or lower will be issued for 
prehospital study use. Whole blood will be collected and kept to either 21 days or 35 days based 
upon which preservation process is employed at each respective participating site (CPD-21 days 
shelf life, CPDA-1-35 days shelf life). 
 
Study Intervention Arm: Patients will receive up to two units of whole blood as collected by local 
blood bank procedures and stored at 1-6 degrees Celsius initiated in the prehospital phase of care 
when available once all inclusion criteria and no exclusion criteria are met. Once TOWAR trial 
site arrival occurs and prehospital initiated intervention transfusions are completed, randomized 
patients will receive standard in-hospital trauma care. 
 
Standard Care Arm: Patients will receive prehospital crystalloid infusion or blood component 
transfusion resuscitation per site standard care for the respective EMS unit/service once all 
inclusion criteria and no exclusion criteria are met. Once the patient arrives at a participating site 
and prehospital initiated standard care transfusions are completed, patients will receive standard 
in-hospital trauma care. 
 
Randomization and Masking: A single stage cluster randomization scheme will be utilized. 
Participating EMS services/agencies at each site will follow a fixed randomization approach of 
(LTWB O), (LTWB O), (Standard Care), with the initial treatment being randomly assigned.  
Thus an EMS service/agency will be randomly assigned to one of three three-month repeated 

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sequences: (1) LTWB O), (LTWB O), (Standard Care); (2) LTWB O), (Standard Care), (LTWB 
O); and (3) (Standard Care), LTWB O), (LTWB O) 
 
Communication with the blood bank transportation services and each respective air base or EMS 
unit/service will occur and an annual schedule of randomization assignment will be distributed to 
each study site and respective EMS base/service. This specific randomization scheme is required 
due to the limited supply, goal of minimization of wastage of LTWB O, and the logistics and 
delivery of the intervention in the prehospital setting. The proposed trial will be an open label 
trial as blood product transfusion requires appropriate documentation and essential look back 
procedures. 
 
III. 
Outcomes 
 
Primary Outcome: The primary outcome for the clinical trial will be all cause 30-day mortality. 
 
30-day mortality will be checked by calling the participant directly with the phone number they 
provided. If there is no response from the patient, 30-day mortality will be checked by searching 
public databases such as the National Death Index. 
 
Secondary Outcomes: Our principal secondary outcome for the trial will be age of whole 
blood and its association with all primary and additional secondary outcomes. Additional 
secondary outcomes for the proposal will include 3-hour mortality, 6-hour mortality, 24-hour 
mortality, in hospital mortality, death from hemorrhage, death from brain injury, blood and blood 
component transfusion requirements in the initial 24 hours, incidence of Multiple Organ Failure 
(MOF), incidence of nosocomial infection, incidence of acute respiratory distress syndrome 
(ARDS), time to hemostasis, incidence of coagulopathy by TEG, incidence of 
allergic/transfusion reaction and measurements of platelet and overall patient hemostatic 
function. 
 
Secondary Outcome Definitions: 
 
Age of whole blood: Age of the LTWB O blood products transfused will be recorded as 
designated by the respective blood banking service at each respective site from the time 
of donation. Based upon the separation procedures utilized at the respective blood bank, 
LTWB O units will have a defined maximum shelf life out to 21 days or 35 days. 
Specific sites may have the capability to recycle LTWB O units to packed red blood cells 
and standard site-specific protocols will be utilized for this. When the age of 2 units of 
LTWB O are disparate, an average age of LTWB O transfusion will be calculated. We 
will stratify Age of LTWB O into YOUNG (1-14 days) and OLD (>14 days). We will 
similarly bin age or average age of LTWB O by week (1-7days), (8-14days), (15-
21days), (22-28days), and > 28 days and allow comparison across all primary and 
secondary outcomes. 
 
3-hour, 6-hour, 24-hour, and In-hospital mortality: 3-hour, 6-hour, 24-hour, and in 
hospital mortality will be recorded from the time of randomization. Over the first 

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24 hours, we will document and record the time of death in hours, while after the 24-hour 
time period, 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. 
 
Time to death:  Time to death will be based on the documented and recorded time of 
death in days from arrival.  Those surviving up to 30-days post enrollment will be 
censored.   
 
Mortality from hemorrhage and brain injury: Cause of death will be adjudicated by a 
site investigator 
 
Twenty four-hour blood and blood component transfusion requirements: 24-hour 
blood and blood component transfusion requirements will be determined by recording the 
type of product, the number of units transfused, and the time of transfusion. Any 
initiation of blood transfusion will be considered completed. 
 
Multiple Organ Failure (MOF): Organ dysfunction will be evaluated via the Denver 
Post-injury Multiple Organ Failure Score, a well-validated scoring system in injured 
patients and characterized as an incidence rate (%) and as MOF free days.14,15 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. A summary of the Denver score 
may be calculated by summing the worst scores of each of the individual systems. A 
summary Denver score > 3 will be classified as MOF. Scores will be determined daily up 
until Day 7 or ICU discharge, whichever comes first.15  
 
Nosocomial Infection (NI): The CDC criteria for the diagnosis of hospital acquired 
pneumonia and blood stream infection will be utilized (www.cdc.gov/nhsn) and recorded 
over 30 days. 
 
Acute Respiratory Distress Syndrome (ARDS): The Berlin definition for mild ARDS 
(PaO2/FIO2, ≤ 300 mm Hg + timing, imaging and origin criteria) will be utilized as a 
threshold value to determine the incidence of ARDS and will be further stratified into 
Moderate (PaO2/FIO2, ≤ 200 mm Hg) and Severe (PaO2/FIO2, ≤ 100 mm Hg).16 
 
Coagulation parameters: During the first 60 minutes from arrival to the TOWAR trial 
site, blood for PT, INR and point of care rapid-TEG or conventional TEG analysis will be 
obtained. These measurements will be repeated as close to 24 hours (+/- 12 hours) from 
the time of arrival as feasible, to coordinate with other lab draws and staffing patterns. 
For those sites with rapid TEG capabilities, tissue factor will be added to a citrated whole 
blood collection tube and rapid TEG parameters including activated clotting time (ACT, 
seconds or R time), angle (α, degrees), coagulation time (K, seconds), maximum 
amplitude (MA, mm), clot strength (G, dynes/cm2), and estimated percent lysis (LY30, 
%) will be measured for each patient. 
 

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Time to hemostasis: The time to hemostasis outcome variable will be determined by the ability 
to reach a nadir transfusion requirement of 1 unit of red blood cells in a 60-minute time period in 
the first 4 hours following arrival to the TOWAR trial site. Surgeon directed time to hemostasis 
will also be collected during the case when feasible. In the absence of the ability to obtain 
hemostasis by either of these criteria within the first 4 hours, the patient will be designated a 
‘non-hemostasis’ patient. 
 
Allergic/Transfusion reaction: Any transfusion complication in the prehospital setting 
will be monitored. As the intervention is specific to the early phase of care 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 the 
time of administration and recorded. 
 
Platelet Function: We will assess platelet activation, aggregation, and adhesion to 
monitor the changes in platelet activity in recipients of whole blood of various ages of 
storage at sites with appropriate capabilities. Blood will be collected within 60 minutes of 
arrival to the TOWAR site when feasible and analyzed for aggregation via whole blood 
aggregometry using low dose collagen (2ug) as a stimulus. In addition, all patients will 
receive TEG (6s or 5000, depending on site availability) with platelet mapping utilizing 
ADP and arachidonic acid (AA) stimulation. Additionally, a rTEG will be run and the 
MA recorded. Collectively, the TEG with platelet mapping and the MA from rTEG will 
serve as quantitative assessment of clot strength, predominantly driven by platelet 
function. In a subset of patients presenting at centers with appropriate analytical 
capabilities, we will assess platelet activation via flow cytometry analysis for P-selectin 
expression (CD62p) as well as perform flow based microfluidic assays across collagen 
impregnated slides to assess for platelet adhesion under flow based conditions. Finally, 
due to the evolving importance of platelet extracellular vesicles in hemostasis and 
inflammation, when feasible we will perform size exclusion chromatography to isolate 
and characterize EVs from platelets collected from patients and utilize nanoparticle 
tracking analysis (Nanosight) to quantify the presence of EVs. 17,18 
 
Classification of Mortality: Classification of the underlying mechanisms responsible for 
mortality are essential to appropriately characterize regional variation and preventable morbidity 
and mortality. Classification of mortality outcomes will be assigned at the level of the enrolling 
institution by the respective Site Investigator. A predefined list of mortality classifications will 
be provided and adjudicated upon at the site level and will include  
1) Hemorrhage/Exsanguination, 2) TBI/herniation, 3) Multisystem Organ Failure, 4) Sepsis, 5) 
ARDS, 6) Coagulopathy, 7) Cardiac Arrest with 1-6, 8) Pulmonary Embolism, 9) Withdrawal of 
Care as well as other pertinent causes of injury related death. 
 
Predefined Subgroups: Predefined subset analyses for the trial will be performed looking at 1) 
Patients who ultimately did or did not required in-hospital blood transfusion; 2) Patients with and 
without significant traumatic brain injury (Head abbreviated injury scale- AIS >2 excluding 
cervical spine injury without TBI); 3) Patients arrived from the scene of injury versus those 
brought from a referral hospital; 4) Patients who ultimately did or did not require massive 
transfusion (≥ 10 units blood in first 24 hours); 5) Patients who received leukocyte reduced 

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whole blood versus those who did not; 6) Patients who had severe prehospital hypotension (SBP 
<70mmHg) versus those who did not; 7) Patients who required operative intervention in first 
24 hours versus those who did not; 8) age, 9) sex; 10) race; 11) trauma center; and 12) service. It 
is recognized that the study is not appropriately powered for these subgroup comparisons and the 
results and conclusions formulated from these subgroup analyses will be considered exploratory 
in nature and will not be used as a basis for treatment recommendations.  Please note that some 
of the planned subgroup analyses involve post-randomization factors.  In these instances, 
mediation analyses will be carried out.   
 
IV. 
Screening and Enrollment 
 
Inclusion and exclusion criteria will be assessed based on available information at the time of 
enrollment in the prehospital environment. Although all reasonable efforts will be made by the 
EMS crews to either directly witness or obtain documentation of eligibility criteria, due to the 
nature of the emergency pre-hospital setting, there may be occasions where the EMS 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 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 emergency 
medical record and will detail the information reported and by whom. 
 
Study participants will be randomly assigned to either LTWB or standard of care based on a 
cluster randomized design. Patients will be randomly assigned by EMS base to receive either 
standard of care (one-month time interval) or LTWB (two-month time interval).  
 
Subjects will undergo initial blood sampling for our secondary outcomes of interest during the 
first 60 minutes from arrival to the TOWAR trial site. A point of care rapid or conventional 
thromboelastography (TEG) will be performed for coagulation parameter measurements as close 
to arrival as possible and as close to 24 hours as possible (+/- 12 hours) when clinical care 
allows. 
V. 
Potential Risks and Benefits 
Potential Risks 
Risks Associated with LTWB: The whole blood product to be utilized starting in the prehospital 
environment is similar to the current whole blood product that has been transfused in 939 
patients over the last 45 months at the University of Pittsburgh without evidence of 
complications or transfusion reactions. There have been no hemolytic transfusion reactions in 
patients transfused LTWB at the University of Pittsburgh in the last 45 months. The primary 
risks with any blood transfusion can be found in the Circular of Information prepared jointly by 
AABB, the American Red Cross, America’s Blood Centers, and the Armed Services Blood 
Program. Those primary acute immunologic complications include hemolytic transfusion 

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reactions, immune mediated platelet destruction, febrile nonhemolytic reactions, allergic 
reactions, anaphylactoid reactions and transfusion-related acute lung injury (TRALI). Delayed 
immunologic complications include delayed hemolytic reaction, alloimmunization, 
posttransfusion purpura, and transfusion-associated graft-vs-host disease. Nonimmunologic 
complications include transmission of infectious agents, bacterial sepsis, transfusion-associated 
circulatory overload (TACO), hypothermia, and metabolic complications.  
 
The intervention product is group O  LTWB. A risk associated with transfusion of Rh+ blood in 
a woman of child-bearing age is hemolytic disease of the fetus during a future pregnancy. 
Complications of this disease include fetal anemia, fetal hydrops, and in the most severe cases, 
fetal death. However, the overall risk of poor fetal outcome in a future pregnancy for Rh- women 
that are administered Rh+ blood has been estimated to be less than 0.5%.19 Importantly, the 
incidence of a female being Rh- is 10-15%. The majority of women injured have no risk of Rh 
mismatch. For those that are at risk, the likelihood of poor fetal outcome in a future pregnancy is 
small. Importantly, an FDA approved EFIC pilot, prehospital thru in-hospital, LTWB 
randomized trial (PPOWER IND #17736) randomized group O RH+ LTWB and included 
women of childbearing age due to this low inherent risk.  Women of childbearing potential who 
receive O+ whole blood resuscitation and are determined to be Rh- will be notified and 
counseled following standard blood banking and trauma service guidelines. 
 
Potential Benefits/Safety 
The University of Pittsburgh has over the last 4 years initiated an urgent release whole blood 
transfusion program for trauma patients in hemorrhagic shock in our emergency department 
utilizing LTWB identical to the proposed intervention large multicenter trial. We published data 
on 172 patients demonstrating the feasibility and safety of such a program.20,21 We have 
continued this program and have currently utilized 2176 units of LTWB in over 939 patients 
with no safety concerns. We have simultaneously been monitoring LTWB patients for hemolytic 
side effects from ABO mismatched whole blood. In 102 non-group O patients, there were no 
significant differences in laboratory hemolysis markers.22 We have also demonstrated that 
LTWB is superior in its hemostatic potential, its ability to reverse shock and its association with 
reduced transfusion volumes when administered in children.23 These published data verify the 
feasibility, safety and potential benefits of this type of intervention in patients with hemorrhagic 
shock, providing the basis for the successful execution of the proposed multicenter trial. We have 
also executed a pilot prehospital thru in-hospital, LTWB randomized trial (PPOWER IND 
#17736) with one of the primary outcomes being feasibility. The experience from this NIH 
funded pilot trial have been leveraged for the current prehospital multi-center trial. 
  
VI. 
Statistical Analysis Plan 
 
Analysis for Trial Clinical Outcomes:  
 
AIM#1 Analysis: Determine whether prehospital low titer whole blood as compared to standard 
prehospital resuscitation results in lower 30-day mortality in patients at risk of hemorrhagic 
shock. 
 

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The analysis will begin by describing the baseline demographic and clinical characteristics of the 
overall population and then stratified by treatment arm to compare those who receive LTWB and 
those who receive standard care. For discrete variables, proportions will be generated, and a chi-
square test will be used to test for differences between the proportions. For continuous 
characteristics, means (medians) and standard deviations (interquartile ranges) will be calculated 
and t-tests (Wilcoxon) will be used to compare the means (distributions) between treatment arms.  
 
For the primary trial outcome, an indicator of death within 30 days will be generated for each 
participant. A two-sided z-test for proportions controlling for within cluster correlation utilizing 
the methods of Donner and Klar will serve as the primary approach to compare the proportions 
between the treatment arms.24 A mixed-effects logistics regression model will be used to assess 
the independent impact of LTWB on 30-day survival after controlling for potential confounding 
effects of baseline characteristics which reveal imbalance between treatment groups. Random 
effects will be included for intercept, slope, service.  Fixed effects will include treatment, 
baseline characteristics not balanced through random assignment, and month of study.   
  
Analyses to test for the homogeneity of the treatment effect will be carried out for the pre-
defined subgroups. Regression models appropriate for the outcome variable (e.g., mixed effect 
logistic regression for binary outcome variables) will be used to test for the homogeneity of the 
treatment effect. Main effects will be included in the model for treatment, the indicator of the 
subgroup and the two-way interaction between treatment and subgroup. If a statistically 
significant interaction is observed, we will reject the null hypothesis of a homogenous treatment 
effect.   
AIM#2 Analysis: Determine whether prehospital old whole blood (age > 14 days) as compared 
to young whole blood (age ≤ 14 days) is associated with similar clinical outcomes, hemostasis, 
prevention of coagulopathy, and platelet function in patients at risk of hemorrhagic shock. 
The analysis will begin by describing the baseline demographic and clinical characteristics of the 
overall population and then stratified by age of whole blood; whole blood age ≤ 14 days versus 
whole blood age > 14 days. For discrete variables, proportions will be generated, and a chi-
square test will be used to test for differences between the proportions. For continuous 
characteristics, means (medians) and standard deviations (interquartile ranges) will be calculated 
and t-tests (Wilcoxon) will be used to compare the means (distributions) between treatment arms.  
 
An unadjusted analysis comparing the 30-day mortality rate by blood age will be conducted 
using a chi-square test. Additionally, because of the observational nature of the study, a 
propensity adjusted analysis will be carried out to control for potential confounders (including 
biological sex, TBI, etc.). A generalized boosted regression model (GBM) will be used to 
generate a propensity score for each participant indicating the probability of receiving young 
whole blood. The GBM approach will be used to identify important characteristics that will be 
used to estimate the propensity scores. From this approach, a propensity score, 𝑝𝑝(𝑥𝑥), indicating 
the probability of receiving young whole blood given the observed characteristics will be 
obtained for each subject.  
 
We will use the Toolkit for Weighting and Analysis of Nonequivalent Groups (twang) software 
package and the SAS/Stata macros (http://www.rand.org/statistics/twang/downloads.html) to 
estimate and evaluate the propensity scores. We will estimate the propensity score for each 

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Version 8.0 dated 8/23/2022 
subject by running the macro or command ps (dichotomous) or mnps (multinomial). That is, 
GBM will fit separate GBMs to each dummy treatment indicator to estimate the propensity score 
for the given phenotype. We will consider all the subject characteristics when fitting GBM. The 
GBM approach will select which characteristics to include and the best functional form including 
interactions. If missing data is present for the subject characteristics, twang will attempt to 
construct weights that also balance rates of missingness by creating indicator variables.  
 
The maximum number of iterations for the GBM approach will be set to the default (i.e.10000). 
The optimal number of iterations will be selected as the one that minimizes the balance statistics 
of interest. We will use the balance statistics es.mean and ks.mean. The es.mean uses the 
absolute standardized bias (also referred as the effect size or absolute standardized mean 
difference) and summarizes across variables, and the ks.mean uses the KS statistic to assess 
balances and summarizes across variables. We will allow a maximum of three splits for each tree 
in the model, allowing for three-way interactions between all covariates to be considered. The 
shrinkage parameter will be set to 0.0005 to ensure a smooth fit. The tuning parameters involved 
in the GBM models will be adjusted if necessary, until covariate balance is achieved.  
 
To evaluate the model, we will plot the balance statistics as a function of the number of iterations 
(higher iterations correspond to more complicated fitted models). If more iterations are needed, 
we will increase the number of iterations. Balance tables and plots will be generated to assess 
balance. Multiple pairwise sets of balance metrics will be evaluated. We will use the ES and the 
KS as balance metrics to assess whether the groups are balanced with respect to the observed 
baseline and pre-treatment characteristics. For the ES metric, a value under 0.20 is indicative of 
good balance. For the KS metric, a value under 0.10 will be indicative of good balance, but p-
values will also be evaluated. The GBM fit (es.mean or ks.mean) that provides the best balance 
and yields the largest effective sample size will be preferred (McCaffrey et al., 2013). We will 
also plot the propensity score values using boxplots to compare the distributions and to evaluate 
the common support. Ideally, the propensity score distributions will overlap entirely; however, if 
there are areas of substantial non-overlap, we will discard subjects in those areas to increase 
generalizability. We will use a 1-dimensional function of the propensity score, referred to as the 
sensitivity function (SF), to quantify the hidden bias due to unmeasured confounders.  
 
Variables in the GBM will include demographic characteristics, clinical characteristics, and site. 
A mixed-effects log-binomial regression model will then be used to estimate the independent 
effect of receiving young whole blood on 30-day mortality. The mixed effects log-binomial 
regression model will include an indicator of 30-day mortality as the dependent variable and 
indicator of the age of whole blood as the independent variable, with the propensity scores used 
as an inverse probability weight.  
 
A similar approach will be taken for the secondary outcomes, though the analytic approach may 
vary based on the distribution of the outcome. For example, for a continuous secondary outcome 
(e.g., clotting time parameters); a mixed-effects linear regression model to estimate the 
independent effect of the age of whole blood on the outcome. For time to event outcomes (e.g., 
time to death), Kaplan-Meier curves will be generated for each treatment group and a log-rank 
test will be used to compare the distribution of the cumulative proportion. Observations will be 
censored at 30 days after arrival.  A multivariable analysis of survival with the use of a Cox 

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proportional-hazard with shared frailty model to evaluate the treatment effect with 
adjustment for possible confounding factors and site clustering on survival. 
 
AIM#3 Analysis: Determine whether prehospital low titer whole blood as compared to standard 
prehospital resuscitation results in lower early mortality endpoints, blood and blood component 
transfusion requirements, lower incidence of coagulopathy, and improved hemostatic and platelet 
function in patients at risk of hemorrhagic shock. 
 
The analysis of the secondary outcome will mirror the analytic approach for Aim 2. The analytic 
approach for other binary outcomes (e.g., 6-hour mortality) will be identical as those for the 
primary analysis. For continuous outcomes (e.g., 24-hour blood and component transfusion 
requirements), a mixed effect regression model will be used to determine if the average number 
of units transfused between the two treatment groups differ. For time to event outcomes (e.g., 
time to hemostasis), Kaplan-Meier curves will be generated for each treatment group and a log-
rank test will be used to compare the distribution of the cumulative proportion. A multivariable 
analysis of survival with the use of a Cox proportional-hazard with shared frailty model 
to evaluate the treatment effect with adjustment for possible confounding factors and site 
clustering on survival. 
 
Sample Size Justification and Power Analysis: The sample size calculations are based on the 
primary outcome, 30-day mortality, for Aim 1 of the study. With 40 service providers, a sample 
of 340 participants per treatment group is needed to detect a difference in the 30-day mortality 
rate of 26% vs. 16% (based on data from the PAMPer study), assuming 80% power, a type I 
error rate of 0.05, a two-sided alternative hypothesis, and an intraclass correlation coefficient of 
0.02, as was observed in the PAMPer study.12  The size of the ICC will have an impact on the 
size of the sample needed. If the ICC is smaller (e.g., 0.01 would require a sample size of 300 per 
arm), fewer people will be needed.  However, if it is larger, more will be needed (e.g., 0.05 
would require a sample size of 680 per arm).   
 
Using a 2:1 random allocation of study participants to LTWB:standard of care, and enduring that  
there are 340 participants in the standard care arm, will lead to a total sample size of 1020, with 
680 participants receiving LTWB. Assuming that 60% of these participants will receive whole 
blood ≤ 14 days in age and 40% will receive whole blood > 14 days in age, based on a chi-square 
test of proportions there will be 80% power to detect a higher mortality rate of 22.6% among 
those receiving whole blood over 14 days old, assuming a 30-day mortality rate of 14% among 
those receiving whole blood ≤ 14 days, a type 1 error of 0.05 and a two-sided alternative 
hypothesis (that whole blood > 14 days in age has a worse outcome than whole blood ≤ 14 days) 
vs. the null hypothesis that whole blood > 14 days is the same or better than whole blood ≤ 14 
days). 
 
Randomization of Ineligible Subjects: It is anticipated that there will be a small proportion of 
patients enrolled who receive whole blood or standard 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 

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limited inclusion and exclusion criteria it is anticipated that the frequency of this event will be 
low.   
 
Missing Data: Consistent with the intention-to-treat principle, the analysis methods used to 
analyze the primary outcome include all patients according to their assigned intervention.  
Baseline characteristics of patients with missing outcome data will be compared. Missing 
primary outcome data will be imputed.  Based on data from PAMPer, it is anticipated that the 
missing data rate will be less than 5%.12   
 
Non-adherence: In some circumstances, patients may receive standard care instead of the 
whole blood intervention when randomized to whole blood. Non-adherence is most likely to 
occur in the case of the patient who requires urgent care in the prehospital environment where 
logistics do not allow the intervention to be administered. 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. 
 
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, (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 two-interim looks before the final analysis. The groups 
sequential approach of Lan and DeMets using the O'Brien-Fleming spending function will be 
used to determine the type I error boundaries for each analysis. The selection of the Lan and 
DeMets approach permits flexibility with respect to the number of interim analyses. Two formal 
interim analyses of efficacy will be performed when 33% and 67% of the enrolled participants 
reach the assessment of the primary endpoint (30 days after injury). The level of significance will 
maintain an overall p value of 0.05 according to stopping boundaries leaving a p value of 0.038; 
 two sided, for the final analysis with a final z-value of 1.993. 
 
The DSMB may recommend termination of the trial if 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 small, then the DSMB may conclude that it would 
be futile to continue with the investigation. 
 
Data Sources: Data will be collected prospectively as patient care progresses. This will include 
a review of the prehospital and emergency medical patient care report(s), Emergency 
Department and electronic/paper hospital records.  
 
Data Entry: The DCC will create web-based HTML forms to collect necessary information from 
all participating sites. Web entry forms will have dynamic features such as edit and data type 
checks. Details and clarification about data items will be provided using pop-up windows. Data 

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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 platelet 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 TOWAR trial will be maintained by the DCC 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 on a regular schedule with full transaction 
log files in use and copies of the data will be stored offsite with a secure service. 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.   
 
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 on a 
regular schedule to a data repository that can be used by statistical software packages. This 
database will be kept as needed, e.g. for quarterly performance reports. 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. 
 
Surveillance for Outcomes and Data Elements: Data will be collected prospectively as patient  
care progresses. This will include a review of prehospital and emergency medical patient care 
report(s), Emergency Department and electronic/paper hospital records. 
  
Prehospital and In-Hospital Data: Demographics, shock severity (base deficit, lactate), 
injury characteristics, Prehospital and ED vitals, interventions (intubation, chest tubes), 
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, radiography reads, transfusion of 
blood and blood components, resuscitation requirements, all primary and secondary 
outcomes will be recorded. 
 
VII. Clinical Coordinating Center (CCC) 
 
Clinical Coordination specific for the TOWAR study will be performed by MACRO 
(Multidisciplinary Acute Care Research Organization) and the dedicated research teams at the 

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University of Pittsburgh, including all regulatory requirements, provider and coordinator training 
and monitoring. 
 
VIII. Data Coordinating Center (DCC) 
 
Data Coordination specific for the TOWAR study will be performed by the DCC and led by Dr. 
Wisniewski at the Graduate School of Public Health at the University of Pittsburgh. The DCC 
will coordinate all data collection and entry, management, security and confidentiality, data 
archiving, quality control and electronic medical record biomedical informatics as needed, as 
well as plan, coordinate and assist with all statistical analyses 
IX. 
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 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 central IRB will be undertaken prior to final IRB 
approval. We will utilize a central IRB at the University of Pittsburgh. 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 central IRB 
and may include such methods as 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. 
 
Institutional Review Board: A central IRB will be utilized at the University of Pittsburgh for 
the regulatory needs of studies. All current LITES Network sites have IRBs which have 
experience and engagement with central IRB procedures. 
 
Training and Participating Site Coordination: As the clinical coordinating center for the trial, 
the University of Pittsburgh (MACRO) at the University of Pittsburgh will be collaboratively 
responsible for all research coordinator training, provider training and sample collection and 
storage. Research coordinators, providers and associated staff will be trained during the months 
prior to the trial start date regarding the scientific basis for the study, specific inclusion and 
exclusion criteria, sample collection and processing, study procedures and SOPs, and rapid TEG 
performance. Training verification and retraining will occur if new staff is hired at individual 
participating sites. Trial enrollment and maintenance of data integrity will be assessed using the 

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web-based data platform. Trial screening, enrollment and data completeness and accuracy will be 
assessed at predefined time periods via site visit and random patient audit. 
 
X. 
Safety Monitoring 
 
Adverse Event and Non-compliance 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. Adverse reactions are a 
subset of all suspected adverse reactions where there is reason to conclude that the drug 
caused the event. 
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. Unexpected adverse event/reaction refers to an event/reaction that is not consistent with 
the risk information described in the general investigational plan or elsewhere in the IND 
application. 
f. 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. 
g. Reportable non-compliance refers to a failure on the part of the investigator or study team 
member to follow the terms of the IRB approved protocol or abide by applicable laws or 
regulations, that adversely affect the rights and welfare of subjects or significantly 
compromises the quality of the research data. Incidents of non-compliance on the part of the 
subject are not considered reportable. 
h. Unanticipated Problem Involving Risk to Subjects or Others (UPIRTSO) refers to any 
accident, experience, or outcome that meets the following criteria: unexpected in terms of 
nature, severity or frequency; related, or possibly related, to a subject’s participation in 
research; and places subjects or others at greater risk of harm (including physical, economic, 
or social) than was previously known or recognized. 
 
Assessing and Reporting Adverse Events (AEs) and Non-compliance: Adverse events will be 
reviewed by the study sites and assessed for relationship to the study intervention. Investigators 
and study team will determine if any related adverse events occur during the period from 

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enrollment through study participation termination. If reportable adverse events occur, they will 
be recorded on the adverse event case report form in the electronic data capture system, which 
will be submitted to the Coordinating Center. All reported adverse events will be classified by: a) 
Severity (fatal or life-threatening, serious, or non-serious); and b) Expected vs. Unexpected. 
Please refer to the table below for timelines for reporting. 
 
This study population is expected to have a large number of serious adverse events, including 
death from trauma related injuries. Expected adverse events that are related or possibly related to 
the intervention will be documented and reviewed for changes in nature, severity, or frequency 
across the study population.   
 
Organization 
Unexpected, 
fatal or life-
threatening, 
suspected 
adverse 
reactions 
Unexpected, 
serious, 
suspected 
adverse 
reactions 
Expected 
adverse 
reactions 
Reportable 
non-
compliance 
UPIRTSO 
IRB 
24 hours 
10 working 
days 
No reporting 
10 working 
days 
10 working days 
FDA 
7 calendar 
days 
15 calendar 
days 
No reporting 
No requirement No requirement 
Dept of Defense 
30 calendar 
days 
30 calendar 
days 
No reporting 
30 calendar 
days** 
30 calendar days* 
DSMB 
24 hours 
7 calendar 
days 
At next meeting 
(every 6 
months) 
At next meeting 
(every 6 
months) 
14 days* 
*reported based on IRB determination that event is UPIRTSO 
**reported based on IRB determination that non-compliance is serious or continuing 
 
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 

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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; 
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. 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.    
 
XI. 
Quality Control, Assurance and Confidentiality 
 
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 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 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 

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other investigators, the DOD and the FDA to see if the protocol needs to be amended or 
recruitment put on hold. 
 
Privacy and Confidentiality: The study site Investigators 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. 
 
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. 
 
Timetable 
 
 
 
XII. References 
1. 
Gonzalez EA, Moore FA, Holcomb JB, et al. Fresh frozen plasma should be given earlier to 
patients requiring massive transfusion. J Trauma. 2007;62(1):112-119. 
2. 
Holcomb JB, Jenkins D, Rhee P, et al. Damage control resuscitation: directly addressing the early 
coagulopathy of trauma. J Trauma. 2007;62(2):307-310. 
3. 
Holcomb JB, Tilley BC, Baraniuk S, et al. Transfusion of plasma, platelets, and red blood cells in a 
1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized 
clinical trial. JAMA. 2015;313(5):471-482. 
4. 
Cotton BA, Reddy N, Hatch QM, et al. Damage control resuscitation is associated with a 
reduction in resuscitation volumes and improvement in survival in 390 damage control 
laparotomy patients. Ann Surg. 2011;254(4):598-605. 

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5. 
Strandenes G, Berseus O, Cap AP, et al. Low titer group O whole blood in emergency situations. 
Shock. 2014;41 Suppl 1:70-75. 
6. 
Murdock AD, Berseus O, Hervig T, Strandenes G, Lunde TH. Whole blood: the future of traumatic 
hemorrhagic shock resuscitation. Shock. 2014;41 Suppl 1:62-69. 
7. 
Fox EE, Holcomb JB, Wade CE, Bulger EM, Tilley BC, Group PS. Earlier Endpoints are Required for 
Hemorrhagic Shock Trials Among Severely Injured Patients. Shock. 2017;47(5):567-573. 
8. 
Cardenas JC, Holcomb JB. Time to plasma transfusion: a patient centered approach and 
modifiable risk factor. Transfusion. 2017;57(4):869-873. 
9. 
Henriksen HH, Rahbar E, Baer LA, et al. Pre-hospital transfusion of plasma in hemorrhaging 
trauma patients independently improves hemostatic competence and acidosis. Scand J Trauma 
Resusc Emerg Med. 2016;24(1):145. 
10. 
Shackelford SA, Del Junco DJ, Powell-Dunford N, et al. Association of Prehospital Blood Product 
Transfusion During Medical Evacuation of Combat Casualties in Afghanistan With Acute and 30-
Day Survival. JAMA. 2017;318(16):1581-1591. 
11. 
Chang R, Eastridge BJ, Holcomb JB. Remote Damage Control Resuscitation in Austere 
Environments. Wilderness Environ Med. 2017;28(2S):S124-S134. 
12. 
Sperry JL, Guyette FX, Brown JB, et al. Prehospital Plasma during Air Medical Transport in 
Trauma Patients at Risk for Hemorrhagic Shock. N Engl J Med. 2018;379(4):315-326. 
13. 
Guyette FX, Sperry JL, Peitzman AB, et al. Prehospital Blood Product and Crystalloid 
Resuscitation in the Severely Injured Patient: A Secondary Analysis of the Prehospital Air 
Medical Plasma Trial. Ann Surg. 2019. 
14. 
Sauaia A, Moore EE, Johnson JL, Ciesla DJ, Biffl WL, Banerjee A. Validation of postinjury multiple 
organ failure scores. Shock. 2009;31(5):438-447. 
15. 
Minei JP, Cuschieri J, Sperry J, et al. The changing pattern and implications of multiple organ 
failure after blunt injury with hemorrhagic shock. Crit Care Med. 2012;40(4):1129-1135. 
16. 
Force ADT, Ranieri VM, Rubenfeld GD, et al. Acute respiratory distress syndrome: the Berlin 
Definition. JAMA. 2012;307(23):2526-2533. 
17. 
Vogel S, Bodenstein R, Chen Q, et al. Platelet-derived HMGB1 is a critical mediator of 
thrombosis. J Clin Invest. 2015;125(12):4638-4654. 
18. 
Ding N, Chen G, Hoffman R, et al. Toll-like receptor 4 regulates platelet function and contributes 
to coagulation abnormality and organ injury in hemorrhagic shock and resuscitation. Circ 
Cardiovasc Genet. 2014;7(5):615-624. 
19. 
Yazer MH, Brunker PA, Bakdash S, et al. Low incidence of D alloimmunization among patients 
with a serologic weak D phenotype after D+ transfusion. Transfusion. 2016;56(10):2502-2509. 
20. 
Seheult JN, Anto V, Alarcon LH, Sperry JL, Triulzi DJ, Yazer MH. Clinical outcomes among low-
titer group O whole blood recipients compared to recipients of conventional components in 
civilian trauma resuscitation. Transfusion. 2018;58(8):1838-1845. 
21. 
Seheult JN, Bahr M, Anto V, et al. Safety profile of uncrossmatched, cold-stored, low-titer, group 
O+ whole blood in civilian trauma patients. Transfusion. 2018;58(10):2280-2288. 
22. 
Harrold IM, Seheult JN, Alarcon LH, et al. Hemolytic markers following the transfusion of 
uncrossmatched, cold-stored, low-titer, group O+ whole blood in civilian trauma patients. 
Transfusion. 2020;60 Suppl 3:S24-S30. 
23. 
Leeper CM, Yazer MH, Triulzi DJ, Neal MD, Gaines BA. Whole Blood is Superior to Component 
Transfusion for Injured Children: A Propensity Matched Analysis. Ann Surg. 2020;272(4):590-
594. 
24. 
Donner A, Klar N. Design and analysis of cluster randomization trials in health research. London 
New York, NY: Arnold ;Co-published in the United States of America by Oxford University Press; 
2000. 

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25. 
Holcomb JB, Pati S. Optimal trauma resuscitation with plasma as the primary resuscitative fluid: 
the surgeon's perspective. Hematology Am Soc Hematol Educ Program. 2013;2013:656-659. 
26. 
Hernandez MC, Thiels CA, Aho JM, et al. Prehospital plasma resuscitation associated with 
improved neurologic outcomes after traumatic brain injury. J Trauma Acute Care Surg. 
2017;83(3):398-405. 
 
Appendix I 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 LTWB versus standard of care 
in patients in hemorrhagic shock following injury.  These patients are in a life-threatening situation with a 
mortality approaching 30-40% despite all efforts.12 The standard of care for management of these patients 
generally includes crystalloid resuscitation and in some instances red cell transfusion in the prehospital 
environment on air medical and rare ground EMS services with blood transfusion capabilities. 
Importantly, prior studies have demonstrated that injured patients who require large volume blood 
transfusion have improved survival if transfusion of high or equal ratios of plasma and platelets to blood 
occurs.3 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.1-
3,12,25 This is what whole blood resuscitation provides. 
 
(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 outside emergency department to provide the maximal survival benefit.12 (see discussion of 
therapeutic window below). In this uncontrolled setting, the hemorrhagic shock patient is unable to 
provide consent for study enrollment, as they are commonly unconscious or in extremis, and legal next-
of-kin are often not immediately available, nor is it practical for the prehospital provider to explain the 
study and receive consent while caring for the patient emergently. 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;  

26 
Version 8.0 dated 8/23/2022 
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 hemorrhagic shock and are facing a potentially life-
threatening situation that requires immediate intervention.  
(ii) Previous human studies suggest the potential for a direct benefit to individual patients who are in 
hemorrhagic shock.3,9,10,12,26 
(iii) Whole blood has been evaluated in the military and has been shown to offer a survival advantage. We 
have provided whole blood to over 939 patients without complication or incident. As discussed above, 
there are potential risks to subjects that may have not 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 initiate the 
intervention quickly in the prehospital setting en route, prior to trauma center arrival for hemorrhagic 
shock patients at significant risk of mortality.  
 
(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.2 There is no acceptable window of time to delay treatment in order to conduct an informed consent 
discussion with the subject. 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 as soon as feasible 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 Single Institutional Review Board (sIRB) of 
the study prior to the onset of the trial.  
 

27 
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(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 sIRB 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 do not want to participate. Public notification and community 
consultation will be performed as directed by the sIRB and may include such methods as 
using online surveys of the proposed study community, targeted small group meetings or 
consultation with community leaders if the pandemic allows it. 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 may 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 prehospital 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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Appendix II Donor -Patient LOOKBACK  
 
   
Donor-Patient “Lookback”  
Pg.  67 of 8  
Doc #:  ITxM-CS-00795  
Revision:  16  
Department:  ITxM Clinical Services  
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.  
 
Revised Principle:  Regulatory agencies require notification of consignees by donor centers 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).  Lookback will also be performed by CTS when 
notified by the blood center of donors confirmed positive for HBV, HTLV, WNV, Zika, and Ebola viruses 
and Babesia.  
 
Revised Section II title and step II.A:  RECIPIENTS PHYSICIAN NOTIFICATION OF 
POSSIBLE VIRAL/CJD/PARASITIC INFECTION (HIV, HCV, HBV, HTLV, WNV, Zika, Ebola, 
CJD, Babesia Ebola)   
A. General Requirements:  FDA has specific lookback requirements for some infectious 
agents, e.g., HIV, HCV, CJD, while others are performed by CTS as being important for 
patient safety (HVB, HTLV, WNV, Zika, Ebola, Babesia).  The CTS Pittsburgh and 
Chicago physician will identify a transfusion recipient according to records available 
described in Section IV of this policy.  Transfusion Service physician will send the 
patient’s physician a letter or secure e-mail notifying him/her of the lookback.  HIV and 
HCV notifications are sent by certified mail or secure e-mail.  The rest of the 
notification letters are sent by regular mail or secure e-mail.  
 
Revised step II.B.1;  step II.B.5 rewritten  
B.Lookback Notification Process  
1.HIV and HCV lookback process:  A notification letter is sent along with a notification form by 
certified mail or secure e-mail. The physician must promptly return the enclosed notification form 
…  
5.CJD lookback notification process and criteria:  The blood center will notify CTS of components from donors 
that were found to have CJD, vCJD, suspected vCJD, risk factors for CJD, or if withdrawal is recommended in cases 
under investigation for vCJD (CJD diagnosis and age less than 55). In those situations, consignee notification could 
enable the consignee to inform the physician, or other qualified personnel responsible for care of the recipients, so 
that recipient tracing and medically appropriate notification and counseling may be performed at the discretion of 
health care providers.  CTS will notify the patient’s physician in writing by letter or secure email and request that 
he/she provides follow up to the transfusion service of the patient outcome.  Follow up notification is not required if 
no response is received.  If the patient is deceased, physician notification is not required.  

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For transfusible components from a donor with one family member diagnosed with CJD, or with risk factors for 
vCJD, suspected vCJD (due to geographic risk deferral, transfusion in the U.K. or in France between 1980 and the 
present, or due to injection of bovine insulin), per FDA Guidance for Industry, it is not appropriate to conduct 
tracing and notification of recipients of prior donations.  
 
(Continued on next page) 
 
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 uncontrolled 
documents except when issued by Quality Assurance as an official hard copy for use in lieu of MASTERControl™.  
   
Donor-Patient “Lookback”  
Pg.  68 of 8  
Doc #:  ITxM-CS-00795  Revision:  16  
Department:  ITxM Clinical Services  
 
Revised step V.A.4    
V.RECORDS  
A.The following Documents are maintained in the lookback file.   
1. 4.Certified mail receipts or print out of secure e-mail communication.  
D. Lookback records are maintained for 10 years.   
E.HCV and HIV lookbacks are discussed at Transfusion Committee meetings and they are documented 
in Transfusion Committee records.   
 
• 
Deleted Procedure Notes 2-4  
 
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 uncontrolled 
documents except when issued by Quality Assurance as an official hard copy for use in lieu of MASTERControl™.  
 
   
Donor-Patient “Lookback”  
Pg.  69 of 8  
Doc #:  ITxM-CS-00795  Revision:  16  
Department:  ITxM Clinical Services  
 
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 consignees by donor centers of blood products from a donor 
who subsequently tests confirmed positive for HIV1, 2, HCV, or is at risk for transmitting Creutzfeldt-
Jakob disease (CJD).  Lookback will also be performed by CTS when notified by the blood center of 
donors confirmed positive for HBV, HTLV, WNV, Zika, and Ebola viruses and Babesia.  

30 
Version 8.0 dated 8/23/2022 
 
POLICY  
I.IDENTIFICATION OF INFECTED DONORS  
A. Units implicated in the lookback process are identified by the blood center according to their 
SOPs.  The transfusion service is notified in writing of the units and their shipping date.  Notification to 
external hospitals (non CTS facilities) is completed by the blood center, not the RCRL or CTS.  
 
II.RECIPIENTS PHYSICIAN NOTIFICATION OF POSSIBLE VIRAL/CJD/PARASITIC INFECTION 
(HIV, HCV, HBV, HTLV, WNV, Zika, Ebola, CJD,Babesia)  
A.General Requirements  
FDA has specific lookback requirements for some infectious agents, e.g., HIV, HCV, 
CJD, while others are performed by CTS as being important for patient safety (HVB, 
HTLV, WNV, Zika, Ebola, Babesia).  The CTS Pittsburgh and Chicago physician will 
identify a transfusion recipient according to records available described in Section IV of 
this policy.  Transfusion Service physician will send the patient’s physician a letter or 
secure e-mail notifying him/her of the lookback.  HIV and HCV notifications are sent by 
certified mail or secure e-mail.  The rest of the notification letters are sent by regular mail 
or secure e-mail.  
B.Lookback Notification Process  
1.HIV and HCV lookback process:  A notification letter is sent along with a 
notification form by certified mail or secure e-mail. The physician must promptly 
return the enclosed notification form 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 
notification form 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 12 weeks for 
HCV and HIV and reasonable attempts should be made.  In addition to the 
physician notification, the facility where the patient was transfused will be 
notified.  This notification will go to the transfusion committee or similar entity 
at the facility.  
 
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 uncontrolled 
documents except when issued by Quality Assurance as an official hard copy for use in lieu of MASTERControl™.  
  
Donor-Patient “Lookback”  
Pg.  70 of 8  
Doc #:  ITxM-CS-00795  Revision:  16  
Department:  ITxM Clinical Services  
2.HCV lookback notification criteria:  A reactive NAT result serves as one basis for 
initiating lookback.  Since confirmatory testing for HCV (RIBA) became 
unavailable in 2012, new FDA approved algorithms were developed for HCV 
notification.  Notification of transfusion recipients of prior collections from the 
same donor is not required when the donor is repeatedly reactive on the anti-
HCV screening assay but negative on a mini-pool or individual donation HCV 
NAT assay and non-reactive on a second anti-HCV screening assay.  Transfusion 
Services must make reasonable attempts to perform the notification within 12 
weeks when the donor is repeatedly reactive on the anti-HCV screening assay 

31 
Version 8.0 dated 8/23/2022 
and positive on a mini-pool or individual donation HCV NAT assay or 
negative on the HCV NAT assay and reactive on the second anti-HCV screening 
assay.  Notification for HCV is not required if the donor is deceased.  
3.HIV lookback notification criteria:  When testing for HIV is confirmed positive or 
NAT positive when the screening test is reactive and further testing is not 
available, or if under an IND or IDE is exempted for such use by FDA, you must 
notify transfusion recipients of previous collections of blood and blood 
components at increased risk of transmitting HIV infection, or the recipient's 
physician of record or a legal representative or relative if the recipient is a minor, 
deceased, adjudged incompetent by a State court, or if the recipient is competent 
but State law permits a legal representative or relative to receive information on 
behalf of the recipient of the need for recipient HIV testing and counseling (see 
above), you  must make reasonable attempts to perform the notification within 12 
weeks after receiving the results of further testing for evidence of HIV infection 
from the collecting establishment .  If the recipient received a transfusion in the 
hospital and died without ever being discharged from the hospital, you must 
notify the recipient’s physician of record but it is left up to the clinician’s medical 
judgement as to whether or not to inform a family member.  
4.HBV lookback notification process and criteria:  The blood center will notify CTS 
of components from donors that test confirmed positive for HBV on a current 
donation (surface antigen positive with positive neutralization and/or positive 
NAT).  CTS will notify the patient’s physician in writing by letter or secure 
email and request that he/she provides follow up to the transfusion service of the 
patient outcome and/or testing.  Follow up physician notification is not required 
if no response is received.  If the patient is deceased, physician notification is not 
required.  
5.CJD lookback notification process and criteria:  The blood center will notify 
CTS of components from donors that were found to have CJD, vCJD, suspected 
vCJD, risk factors for CJD, or if withdrawal is recommended in cases under 
investigation for vCJD (CJD diagnosis and age less than 55). In those situations, 
consignee notification could enable the consignee to inform the physician, or 
other qualified personnel responsible for care of the recipients, so that recipient 
tracing and medically appropriate notification and counseling may be performed 
at the discretion of health care providers.  CTS will notify the patient’s physician 
in writing by letter or secure email and request that he/she provides follow up to 
the transfusion service of the patient outcome.  Follow up notification is not 
required if no response is received.  If the patient is deceased, physician 
notification is not required.  
 
For transfusible components from a donor with one family member diagnosed 
with CJD, or with risk factors for vCJD, suspected vCJD (due to geographic risk 
deferral, transfusion in the U.K. or in France between 1980 and the present, or 
due to injection of bovine insulin), per FDA Guidance for Industry, it is not 
appropriate to conduct tracing and notification of recipients of prior donations.   
 
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 uncontrolled 
documents except when issued by Quality Assurance as an official hard copy for use in lieu of MASTERControl™.  
Donor-Patient “Lookback”  
Pg.  71 of 8  

32 
Version 8.0 dated 8/23/2022 
  
Doc #:  ITxM-CS-00795  Revision:  16  
Department:  ITxM Clinical Services  
 
6.HTLV I/II lookback notification process and criteria:  The blood center will notify 
CTS of components from donors that test confirmed positive for HTLV I/II.  CTS 
will notify the patient’s physician in writing by letter or secure email and request 
that he/she provides follow up to the transfusion service of the patient outcome 
and/or testing.  Follow up notification is not required if no response is 
received.  If the patient is deceased, physician notification is not required.  
7.Zika virus lookback notification process and criteria:  The blood center will notify 
CTS of components from donors that test NAT positive for Zika virus.  CTS will 
notify the patient’s physician in writing by letter or secure email and request that 
he/she provides follow up to the transfusion service of the patient outcome and/or 
testing.  Follow up notification is not required if no response is received. If the 
patient is deceased, physician notification is not required.  
8.WNV virus lookback notification process and criteria:  The blood center will notify 
CTS of components from donors that test NAT positive for WNV virus.  CTS 
will notify the patient’s physician in writing by letter or secure email and request 
that he/she provides follow up to the transfusion service of the patient outcome 
and/or testing.  Follow up notification is not required if no response is 
received.  If the patient is deceased, physician notification is not required.  
9.Ebola virus lookback notification process and criteria:  The blood center will notify 
CTS regarding blood and blood components collected from donors later 
determined to have Ebola virus infection or disease.  CTS will notify the patient’s 
physician in writing by letter or secure email and request that he/she provides 
follow up to the transfusion service of the patient outcome and/or testing.  Follow 
up notification is not required if no response is received.  If the patient is 
deceased, physician notification is not required.  
10.Babesia lookback notification process and criteria:  The blood center will notify 
CTS of components from donors that test positive by EIA only or EIA and 
NAT.  CTS will notify the patient’s physician in writing by letter or secure email 
and request that he/she provides follow up to the transfusion service of the 
patient outcome and/or testing.  Follow up notification is not required if no 
response is received.  If the patient is deceased, physician notification is not 
required.  
 
 
 
 
 
 
 
 
 
 
 
 

33 
Version 8.0 dated 8/23/2022 
Appendix III Abbreviations  
  
AABB – American Association of Blood Banks 
AE – Adverse Event  
AHTRs - Acute Hemolytic Transfusion Reactions  
AIS – Abbreviated Injury Scale  
ARDS – Acute Respiratory Distress Syndrome  
Cc – cubic centimeter  
CDC –Center for Disease control and prevention 
CPD – Citrate Phosphate Dextrose 
CPDA – Citrate Phosphate Dextrose Adenine 
CPR – cardiopulmonary resuscitation   
CRF – case report form  
DSMB – data safety monitoring board  
ED – emergency department  
ELISA - Enzyme-linked immunosorbent assay  
EMS – Emergency Medical Service 
FFP – Fresh Frozen Plasma  
GSW – Gun shot wound  
HR – heart rate  
ICF – informed consent form  
ICU – intensive care unit  
IND – investigational new drug  
INR – international normalized ratio 
IR – interventional radiology  
IRB – institutional review board  
IV - intravenous  
LAR – Legally Authorized Representative  
LTWB - Low Titer Whole Blood  
mmHg – millimeter of mercury  
MOF – Multiple Organ Failure  
NI – Nonsocomial Infections  
non-WB – non- Whole Blood  
OR – operating room 
PI – Principal Investigator   
PLT -Platelets  
PRBCs – Packed Red Blood Cells  
PT – Prothrombin Time  
PTT – Partial Thromboplastin Time  
SAE – Serious Adverse Event  
SBP – Systolic Blood Pressure   
SOP – Standard Operating Procedure   
TACO – Transfusion Associated Circulatory Overload  
TBD – to be determined 
TBI – traumatic brain injury 
TEG - Thromboelastograph  
TRALI – Transfusion Related Acute Lung Injury