Cold Stored Platelet Early Intervention in Traumatic Brain Injury Trial
Phase: PHASE2
Conditions: Traumatic Brain Injury
Sponsor: Jason Sperry

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Cold Stored Platelet Early Intervention –  
Traumatic Brain Injury (TBI)  
(CriSP-TBI) trial 
Task Order 0004 
 
Protocol number: STUDY20070044 
 
 
Version number and date: Version 12 - 02/08/2023 
 
 
Phase of clinical investigation 
Phase II Clinical Investigation 
 
 
IND number:  Investigational drug:  
IND application number #25180 
Cold Stored Platelets 
 
 
Sponsor-Investigator:  Jason L Sperry, MD, MPH 
 
 
Principal-Investigator: David Okonkwo, MD, PhD 
 
 
 
 
 
 
 
Linking Investigations in Trauma and Emergency Services 

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Contents 
Protocol Synopsis ........................................................................................................................................ 4 
Specific Aims ............................................................................................................................................... 5 
Hypothesis for clinical outcomes .......................................................................................................... 6 
Background and Significance .................................................................................................................... 6 
Study Design/Setting ................................................................................................................................... 6 
Study Population ....................................................................................................................................... 6 
Inclusion Criteria ...................................................................................................................................... 6 
Exclusion Criteria: .................................................................................................................................... 7 
Screening and enrollment: ........................................................................................................................ 7 
VerifyNow Measurements .................................................................................................................... 7 
Study Intervention ..................................................................................................................................... 7 
Study Intervention Arm ........................................................................................................................ 8 
Standard Care Arm ............................................................................................................................... 8 
Randomization and Masking .................................................................................................................... 8 
Follow-up procedures ............................................................................................................................... 9 
Study Drug/Intervention ......................................................................................................................... 10 
Study risks and benefits: ......................................................................................................................... 10 
Outcomes ................................................................................................................................................... 10 
Primary Outcome .................................................................................................................................... 10 
Secondary Outcomes .............................................................................................................................. 10 
Secondary Outcome Definitions ......................................................................................................... 10 
Severity Stratification ............................................................................................................................. 12 
Predefined Subgroups ............................................................................................................................. 12 
Statistical Analysis Plan ........................................................................................................................... 12 
Eligibility, Enrollment, and Participant Accrual: .................................................................................. 12 
Analysis for Clinical Outcomes .............................................................................................................. 12 
Sample Size Justification and Power Analysis ....................................................................................... 13 
Randomization of Ineligible Participants: ............................................................................................... 14 
Non-adherence ........................................................................................................................................ 14 
Interim Analyses ..................................................................................................................................... 14 
Clinical Coordinating Center (CCC) ...................................................................................................... 14 
Data Coordinating Center (DCC) ........................................................................................................... 14 

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Data Management ..................................................................................................................................... 15 
Data Sources ........................................................................................................................................... 15 
Surveillance for Outcomes and Data Elements ................................................................................... 15 
Data Entry ............................................................................................................................................... 15 
Database Management ............................................................................................................................ 15 
Human Participants .................................................................................................................................. 16 
Study Stopping Points: ............................................................................................................................ 16 
Institutional Review Board ..................................................................................................................... 16 
Training and Participating Site Coordination ......................................................................................... 17 
Safety Monitoring: .................................................................................................................................... 17 
Adverse Event definitions ....................................................................................................................... 17 
Assessing and Reporting Adverse Events (AEs): ................................................................................... 17 
Data Safety Monitoring Board (DSMB) ................................................................................................. 18 
Quality Control, Assurance and Confidentiality ..................................................................................... 19 
Protocol Compliance ............................................................................................................................... 19 
Protocol Deviations ................................................................................................................................. 19 
Privacy and Confidentiality .................................................................................................................... 20 
Investigator Responsibilities ................................................................................................................... 20 
Timetable ................................................................................................................................................ 20 
References .................................................................................................................................................. 20 
 
 
 
 
 
 
 
 
 
 

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Protocol Synopsis 
Protocol Title: 
Cold Stored Platelet Early Intervention - TBI (CriSP-TBI) Trial 
Protocol Number: 
STUDY20070044 
NCT Number: 
 NCT04726410 
Version # and Date: 
Version 12 dated 02/08/2023 
Investigational Drug: 
Cold Stored Platelets (CSP) 
Clinical Phase 
Phase II 
Funding Agency 
Department of Defense 
IND Sponsor: 
Jason L Sperry, MD, MPH 
Principal Investigator: 
David Okonkwo, MD, PhD 
Research Facility 
UPMC Presbyterian Hospital 
Study Aims: 
AIM#1: Determine the feasibility, most appropriate study 
population and primary outcome that will lead to a large multicenter 
clinical trial designed to evaluate the effectiveness of cold stored 
platelet early intervention in patients with TBI requiring platelet 
transfusion. 
AIM#2: Determine whether early cold stored platelet infusion 
compared to standard platelet transfusion results in improved clinical 
outcomes and hemostatic function in patients with traumatic brain 
injury requiring platelet transfusion. 
AIM#3: Determine if early cold stored platelet hemostatic function 
is similar at 1 through 7 days as compared to 8 through 14 days in 
patients with TBI on antiplatelet therapy.  
Study Design: 
Open label, single center, randomized trial designed to determine the 
feasibility, efficacy and safety of urgent release cold stored platelets 
in blunt injured patients with traumatic brain injury requiring platelet 
transfusion. 
Planned Sample Size:  
100 subjects with TBI 
Planned Study Time: 
3-year study with 2 years of enrollment 
Major Inclusion Criteria:  
Patients with traumatic brain injury, defined by presence of potential 
progressive intracranial injury on CT scan imaging, at significant 
risk for urgent neurosurgical procedure as determined by 
neurosurgical evaluation, who meet at least one of the following:  
a) History or indication of pre-injury oral antiplatelet agent use 
b) Need for platelet transfusion per standard practice 
Major Exclusion Criteria: 
1. Wearing NO CriSP opt out bracelet 
2. Hypotension in ED (SBP< 90 mmHg) 

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3. Age > 89 or < 18 years of age 
4. Penetrating injury 
5. Prisoner  
6. Pregnancy 
7. Going to operating room for non-neurosurgical intervention 
in first 60 minutes 
8. Platelet transfusion contraindicated per care team (for 
example, recent vascular stent, embolic stroke, intracranial 
and/or vascular lesions) 
9. Objection to study voiced by participant or family member 
in Emergency Department 
10. Currently on therapeutic anticoagulant in addition to aspirin 
and/or clopidogrel (e.g. warfarin, direct-acting oral 
anticoagulants) 
Primary Endpoint: 
Feasibility 
Secondary Endpoints:  
• 
24-hour mortality 
• 
GOSE at 6 months 
Specific Aims 
Platelet transfusion is commonly provided early after injury in patients with traumatic brain 
injury (TBI) to reverse antiplatelet medications (aspirin, Plavix). Taking antiplatelet medications 
potentially worsens intra-cranial hemorrhage and outcomes following TBI. Importantly, other 
antiplatelet medications such as NSAIDs have also been shown to inhibit platelet aggregation 
and compromise coagulation at doses commonly taken by warfighters.1 Whether current standard 
care room temperature (RT) platelet transfusion adequately reverses platelet inhibition and 
improves outcomes following traumatic brain injury remains poorly characterized. Cold stored 
platelets may provide better hemostatic correction and improve outcomes in patients with TBI 
requiring platelet transfusion.  
 
Platelet use in far forward environments are not available due to logistical storage and shelf-life 
requirements. Cold-stored platelets can be refrigerated like red blood cells and plasma units and 
may be less prone to bacterial contamination. Growing evidence suggests that cold-stored 
platelets have superior hemostatic capabilities.2-6 For patients with brain injury, cold stored 
platelets may be beneficial in an urgent release fashion soon after arrival to the trauma center as 
compared to current standard care. Currently there is no high-level clinical trial evidence 
demonstrating the safety and efficacy of urgent release cold stored platelet transfusion following 
injury. The aims of the Cold Stored Platelet early intervention TBI (CriSP-TBI) pilot trial are to 
determine the feasibility, efficacy and safety of urgent release cold stored platelets in patients 
with traumatic brain injury requiring platelet transfusion. 
      
AIM#1: Determine the feasibility, most appropriate study population and primary outcome that 
will lead to a large multicenter clinical trial designed to evaluate the effectiveness of cold stored 
platelet early intervention in patients with TBI requiring platelet transfusion. 
AIM#2: Determine whether early cold stored platelet transfusion compared to standard platelet 
transfusion results in improved hemostatic function and clinical outcomes in patients with 
traumatic brain injury requiring platelet transfusion. 

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AIM#3: Determine if early cold stored platelet hemostatic function is similar at 1 through 7 days 
as compared to 8 through 14 days in patients with TBI on antiplatelet therapy.  
 
Hypothesis for clinical outcomes: Early infusion of cold stored platelets as compared to standard 
platelet transfusion will result in improved 6 month Extended Glasgow Outcome Scale (GOS-E), 
lower 24 hour and in-hospital mortality, a lower need for craniotomy/craniectomy, lower need 
for ICP monitoring, a lower rate of TBI progression, improved hemostatic function, reversal of 
platelet inhibition and a similar rate of allergic/transfusion reactions and incidence of transfusion 
related acute lung injury in patients with TBI requiring platelet transfusion. 
Background and Significance 
Platelet transfusion is commonly provided to patients with moderate or severe TBI who are on 
antiplatelet medications. Evidence suggests that patients on antiplatelet medications may have 
worse outcomes following TBI.7-10 Current literature has not demonstrated major outcome 
improvements in those patients who receive platelet transfusion.11,12 This lack of significant 
benefit may be due to insufficient dosing or due to the poor hemostatic function of standard care 
room temperature platelets. Studying the potential benefits of Cold Stored Platelet transfusion in 
the TBI population will provide needed direct comparison of room temperature and cold stored 
platelet transfusion which is unable to occur in patients with hemorrhagic shock, who may 
require large volumes of red blood cells and plasma concomitantly with platelet transfusion.  
 
By providing Cold Stored Platelets in an urgent release fashion following injury, a potentially 
superior hemostatic agent is given early, closer to the time of injury. The current pilot trial was 
designed to determine the feasibility, efficacy and safety of urgent release cold stored platelets as 
compared to standard care in TBI patients requiring platelet transfusion. There are no high-level 
data which appropriately characterize the urgent release use of cold stored platelets out to 14 
days or their function over that time period as compared to standard room temperature platelets. 
These results will be able to inform future large randomized clinical trials allowing the most 
appropriate injured population, inclusion criteria, and primary outcome to be selected and 
utilized.  
Study Design/Setting 
The current proposed pilot study will be a 3-year, single center, open label, randomized trial 
utilizing a level-1 trauma center at the University of Pittsburgh and will randomize 
approximately 100 patients with TBI.  
 
Study Population: Traumatic brain injured patients with a non-penetrating injury requiring 
platelet transfusion. 
 
Inclusion Criteria: 
Patients with traumatic brain injury, defined by presence of potential progressive intracranial 
injury on CT scan imaging, at significant risk for urgent neurosurgical procedure as determined 
by neurosurgical evaluation, who meet at least one of the following: 
a) History or indication of pre-injury antiplatelet agent use 
b) Need for platelet transfusion per standard practice 
 

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Exclusion Criteria: 
1. Wearing NO CriSP opt out bracelet 
2. Hypotension in ED (SBP< 90 mmHg) 
3. Age > 89 or < 18 years of age 
4. Penetrating injury 
5. Prisoner  
6. Pregnancy 
7. Going to operating room for non-neurosurgical intervention in first 60 minutes 
8. Platelet transfusion contraindicated per care team (for example, recent vascular stent, 
embolic stroke, intracranial and/or vascular lesions) 
9. Objection to study voiced by participant or family member in Emergency Department 
10. Currently on therapeutic anticoagulant in addition to aspirin and/or clopidogrel (e.g. 
warfarin, direct-acting oral anticoagulants) 
 
Screening and enrollment:  Participants will be identified prospectively, within the 2-hour period 
after CT scan in the ED, by research personnel that are trained and familiar with the inclusion 
and exclusion criteria. An additional CT scan may be performed as standard care at UPMC 
Presbyterian for those participants being transferred to UPMC Presbyterian after the injury is 
identified at an outside facility. Those subjects who arrive more than 2 hours after initial scan at 
the outside hospital will still be considered for enrollment. Patients who meet all inclusion and 
no exclusion criteria will be randomized to CSPs or standard of care based upon the 
predetermined randomization assignment. Patients who meet all inclusion and no exclusion 
criteria will be randomized to CSPs or standard of care based upon the predetermined 
randomization assignment. 
 
Capacity to provide informed consent will be assessed prior to randomization and will primarily 
be determined by Glasgow Coma Scale (GCS).  Potential subjects with a GCS of less than 15 
will be considered unable to consent.  Potential subjects with a GCS of 15 will undergo a GOAT 
assessment, performed by a study investigator or neurosurgery CRC.  A score of 74 or below 
will be considered unable to consent.  For subjects that are determined to be unable to consent, 
assent will be obtained when applicable.  The study team will also attempt to identify an 
appropriate LAR to provide prospective informed consent.  If a LAR is identified within the 2-
hour period after initial CT scan in the ED, this individual will be approached for proxy consent. 
If not, the patient will be enrolled under EFIC. If a potential subject has a GCS of 15 and scores 
75 or above on the GOAT, we will presume s/he is capable of providing direct informed consent 
and will seek to obtain informed consent via a physician investigator.   
 
VerifyNow Measurements: When feasible, VerifyNow-Aspirin and VerifyNow-P2Y12 
measurements for patients with a history of aspirin and/or clopidogrel, respectively, may be 
performed prior to platelet transfusion and for response monitoring following initial platelet 
transfusion. However, need for platelet transfusion will be determined by neurosurgical and/or 
trauma surgery recommendations. VerifyNow measurements will only be obtained when 
feasible. Measurement cut points for determining platelet inhibition will follow manufacturer 
guidelines https://www.werfen.com/na/en/verifynow .  
 
Study Intervention:  

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Study Intervention Arm: Patients randomized to the intervention arm will receive an early 
infusion of urgent release cold stored platelets (CSP) once the patient is determined to meet all 
inclusion and no exclusion criteria. When clinically feasible, patients will undergo VerifyNow 
Aspirin or P2Y12 testing following initial platelet transfusion. Those patients who have not 
increased their respective ARU or PRU measurements to levels consistent with no drug effect 
(ARU > 550; PRU > 220), or who have another clinical indication for additional platelet 
transfusion, may undergo a second CSP infusion.  
 
CSP infusion will occur once IV access is obtained irrespective of location. CSP infusion should 
be initiated first when possible but can be infused concomitantly with other transfusion 
requirements including packed red blood cells, plasma, or whole blood per institutional standard 
care. The administration will be begun by clinical staff. 
 
Standard Care Arm: Patients randomized to the standard care arm will receive room temperature 
(RT) platelet transfusion per standard care at the University of Pittsburgh once the patient meets 
all inclusion and no exclusion criteria. When clinically feasible, patients will undergo VerifyNow 
Aspirin or P2Y12 testing following initial platelet transfusion. Those patients who have not 
increased their respective ARU or PRU measurements to levels consistent with no drug effect 
(ARU > 550; PRU > 220), or who have another clinical indication for additional platelet 
transfusion, may undergo a second RT platelet infusion.  
 
Randomization and Masking: Individual patients determined to meet all inclusion and no 
exclusion criteria in the emergency department will be randomized and assigned according to a 
1:1 ratio to CSP infusion or standard care using a permuted block design with variable block 
sizes of 4 and 6. The arm assignment will be provided in real time at the individual patient level 
by accessing an electronic randomization system.  Backup envelopes containing randomization 
assignments will be available by contacting the Data Coordinating Center should there be any 
issues or failure of the electronic randomization system. Trauma and Neurosurgical attending 
and ED physicians will not be masked to treatment assignment as the study intervention is a 
blood product and full traceability is required. Arm assignment will be concealed to all outcome 
assessors performing the GOSE during follow-up. 
 
In order to facilitate the early administration of platelets, randomization of eligible patients will 
occur within 2 hours of diagnosis of TBI via CT scan in the ED. 
 
The study team may call the participant to check on their status after 30 days and again after 6 
months. If the participant is discharged to another facility, they may be contacted at that facility 
for an update of their condition. 
 
If we are unable to get in touch with the participant or with the facility they were discharged to, 
we will check survival status on a public access database using personal identifiers such as name, 
date of birth, and social security number. 

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Follow-up procedures: Galveston Orientation and Amnesia Test (GOAT): We will obtain the 
GOAT score prior to discharge and the calculated score per standard methods.34 (Figure 1) 
GOAT is a 10-item questionnaire used to quickly assess post-traumatic amnesia following head 
injury. The GOAT is 
read orally to the 
patient and may be 
easily administered at 
the bedside. The total 
score accounts for 
orientation of person, 
place, and time, and 
recollection of events 
pre and post- injury. 
Cutoff scores are 
available to identify 
abnormal, borderline, 
and normal 
orientation and it will 
additionally 
determine if a 
participant is able to 
provide continuing 
participation consent 
after the process of 
EFIC. 
 
 
 
 
 
 
 
 
Extended Glasgow Outcome Scale (6 months-GOSE): The GOSE score will be obtained at 6 
months (+/- 1month) by home survey or direct patient contact, whichever is feasible. For those 
participants who were unable to consent at discharge, the GOAT will be administered to assess 
their ability to provide direct consent, prior to the administration of the GOSE. When the 
assessment is done by phone, the verbal consent of participants who have regained the ability to 
consent will be obtained to allow the GOSE to be completed. The score can characterize 6-month 
functional status into 8 well defined categories as shown in (Figure 2).  
 
Figure 1: 

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Figure 2: 
 
 
 
 
 
 
 
 
 
 
 
Study Drug/Intervention:  Up to 2 cold stored apheresis units issued at the University of 
Pittsburgh will represent the CSP intervention. The volume of each unit will be approximately 
200-300 mls and each will be stored in an FDA monitored approved refrigerator at 1-6 degrees 
Celsius for up to 14 days from preparation.   
 
Please refer to the Investigator Brochure for additional details regarding CSP preparation, 
labeling, storage, dosing, and administration.  
 
Study risks and benefits: Risks associated with blood component transfusion include infection, 
allergic reaction, fever, and respiratory distress.  Additional risks associated with platelet 
transfusion include bacterial contamination, platelet alloimmunization, and hemolysis.  Due to 
the higher activation in CSP as compared to RTP, there is a potential for increased risk of 
thrombotic complications.  A detailed list of risks associated with the transfusion of platelets is 
included in the Investigator Brochure. 
Outcomes 
 
Primary Outcome: The primary outcome for this pilot trial will be feasibility.  Secondary 
performance and feasibility outcomes will include the proportion of eligible patients that can be 
randomized, 2) the proportion of eligible patients who are enrolled in the trial, 3) proportion of 
enrolled patients which adherence to the study protocol, and 4) proportion of enrolled patients 
who complete study follow-up. 
 
Secondary Outcomes: Our principle secondary clinical outcome for the proposal will be 6-
month Extended Glasgow Outcome Scale (GOS-E). Additional secondary outcomes will include 
24-hour mortality, in-hospital mortality, need for craniectomy/craniotomy, need for ICP 
monitoring, TBI progression based upon serial CT imaging in initial 24 hours, Galveston 
Orientation and Amnesia Test (GOAT score) at discharge, incidence of allergic/transfusion 
reaction, incidence of transfusion related acute lung injury (TRALI), measurements of platelet 
hemostatic function, and incidence of thromboembolic events. 
 
Secondary Outcome Definitions: 
 

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Extended Glasgow Outcome Scale (6 months-GOSE): The GOSE score will be 
obtained at 6 months +/- 1month by phone survey or direct patient contact, whichever is 
feasible. Patients will be consented for this contact outcome. The score can characterize 
6-month functional status into 8 well defined categories. 
 
24-hour and In-Hospital Mortality: 24-hour and in hospital mortality will be recorded 
from the time of arrival. Over the first 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. 
 
TBI progression in 24 hours: Common Data Elements (CDE) for CT scan indicators of 
hemorrhage progression will be utilized.13  
https://www.commondataelements.ninds.nih.gov/Traumatic%20Brain%20Injury 
 
Galveston Orientation and Amnesia Test (GOAT): We will obtain the GOAT score 
prior to discharge and the calculated score per standard methods.14 GOAT is a 10-item 
questionnaire used to quickly assess post-traumatic amnesia following head injury. The 
GOAT is read orally to the patient and may be easily administered at the bedside. The 
total score accounts for orientation of person, place, and time, and recollection of events 
pre and post- injury. Cutoff scores are available to identify abnormal, borderline, and 
normal orientation and it will additionally determine if a participant is able to provide 
continuing participation consent. 
Allergic/Transfusion reaction: Any transfusion complication in the ED and OR/IR 
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 arrival 
and recorded. 
 
Transfusion Related Acute Lung Injury (TRALI): TRALI will be defined as the 
occurrence of ARDS (mild; PaO2/FIO2, ≤ 300 mm Hg) that occurs within 6 hours of 
transfusion of a blood product. There may be multiple blood products transfused to the 
patient including PRBCs, plasma in addition to platelets during the early resuscitation 
period. The causal factor that results in TRALI may be unable to be determined but will 
be recorded.15,16 
  
Platelet Hemostatic Function: Once randomized, blood sampling for platelet hemostatic 
function prior to platelet transfusion irrespective of arm assignment will be performed if 
clinically feasible. Following each platelet transfusion, further assessment of platelet 
hemostatic function may be performed (up to 2 times). Platelet hemostatic function will 
be assessed by TEG analysis and TEG with platelet mapping. Whole blood aggregometry 
and flow cytometry will be performed when feasible across both arms. 
 
Thromboembolic events:  Pulmonary embolism, venous thrombosis, or arterial 
thrombosis that occurs during the primary admission hospital stay will be documented for 
all enrolled patients. Radiographic confirmation via CT imaging, transthoracic or trans-

12 
 
esophageal echo, or ventilation/perfusion scanning will be required. Presumed or clinical 
suspicion for an embolic event that is unable to be verified radiographically will also be 
documented.     
 
Severity Stratification: TBI characteristics will be recorded and based upon CT imaging results 
(classification: subarachnoid, subdural, intracerebral hemorrhage, epidural, +/- shift, multifocal) 
and TBI severity will be characterized by presenting GCS, Abbreviated Injury Severity (AIS) 
coding and Rotterdam CT scores. 
 
Predefined Subgroups: Predefined subset analyses for the TBI cohort will be performed looking 
at 1) patients who did or did not receive a craniectomy/craniotomy, 2) patients who did or did not 
require ICP monitoring, 3) patients arrived from the scene of injury versus those brought from a 
referral hospital; 4) patients with a pre-injury history of aspirin use as compared to clopidogrel 
use; 5) CSPs with shelf time of 1 to 7 days as compared to 8 to 14 days. 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. 
 
Statistical Analysis Plan 
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 CSP 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.  
 
Eligibility, Enrollment, and Participant Accrual: The feasibility of enrollment will be 
evaluated by determining 1) the proportion of eligible patients that can be randomized, 2) the 
proportion of eligible patients who are enrolled in the trial, 3) proportion of enrolled patients 
which adherence to the study protocol, and 4) proportion of enrolled patients who complete 
study follow-up.  These proportions will be estimated directly as the observed ratio of numbers 
of patients, and 95% confidence intervals will be calculated to understand the likely range of 
values for a larger study with a comparable research protocol and population. The reasons why 
patients are not enrolled including frequencies of individual exclusions and the proportion of 
patients declining participation or not able to be randomized will be described. Rate of 
participants’ accrual per month with 95% C.I. will be calculated. 
 
Analysis for Clinical Outcomes: The principal secondary clinical outcome for the trial will 
be 6-month Extended Glasgow Outcome Scale (GOS-E). The null and alternative hypothesis of 
the study are 
 
H0:  There is no difference in the distribution of the GOS-E scores by treatment group  
H1:  There is a difference in the distribution of the GOS-E scores by treatment group  
 

13 
 
A two-sided Chi-square test will be used to compare the distribution of the GOS-E between the 
treatment arms. An ordinal polytomous regression model will then be used to assess the 
independent impact of CSP on GOS-E after controlling for potential confounding effects of 
baseline characteristics which reveal imbalance between treatment groups. The analytic approach 
for the secondary trial outcomes will vary based on the type of outcome. For binary outcomes, a 
two-sided Chi-square test for proportions will be used to compare the proportions between those 
receiving and not receiving CSP. A logistics regression model will then be used to assess the 
independent impact of CSP on the secondary trail outcomes while adjusting for baseline GCS. 
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. A Cox-proportional hazards regression model will be used to assess the independent 
impact of CSP on time to death after controlling for baseline GCS. For continuous outcomes a 
two-sided t-test for means will be used to compare the means between those receiving and not 
receiving CSP. An analysis of covariance model will be used to assess the independent effect of 
CSP. after controlling for baseline GCS . 
  
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., logistic 
regression for binary outcome variables) will stratified by the pre-defined subgroups.  Estimate 
of the treatment effect (odds ratio) and 95% confidence interval will be generated for each model 
and displayed on a forest plot.   
 
Secondary analyses will be conducted to assess the impact of age of the CSP on outcomes.  
These analyses will be carried out among those who are randomly assigned to the CSP group and 
the impact of the age of the CSP on outcomes will be evaluated.  Since the sample will not be 
randomly assigned, it will be important to adjust for potential confounding effects.  A propensity 
score will be generated as an indicator of the age of the CSP (<= 7 days vs. > 7 days).  
Multivariable regression models will be used to assess the independent relationship of age of the 
CSP on outcome.  The model type will vary based on the outcome (e.g., logistic regression for 
binary variables).  Each model will include a fixed main effect for the indicator of the age of the 
CSP as well as an inverse probability weight for the propensity of getting CSP <= 7 days of age. 
 
Sample Size Justification and Power Analysis (n=100): For the enrollment, adherence 
and event rates needed for planning and feasibility analyses, we calculated the two-sided 95% CI 
for proportions ranging from 0.70 to 0.90. For example, a sample size of 100 produces a two-
sided 95% CI of 0.82 to 0.95 when the sample proportion is 0.90. When the sample proportion is 
.70, the two-sided CI is 0.60 to 0.82.  These confidence intervals are then repeated within the 
treatment arm.  
 
 
Sample 
Size 
 
Width 
Proportion 
(P) 
Lower 
Limit 
Upper 
Limit 
Full Sample 
 
 
 
 
100 
0.19 
0.700 
0.60 
0.82 
100 
0.17 
0.800 
0.71 
0.87 
100 
0.13 
0.900 
0.82 
0.95 

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One Treatment Arm 
 
 
 
 
50 
0.27 
0.700 
0.55 
0.82 
50 
0.24 
0.800 
0.66 
0.90 
50 
0.19 
0.900 
0.78 
0.97 
 
For the principle secondary clinical outcome of the GOSE, based on a 2x8 (treatment x GOSE) 
there is 80% power to detect an effect size of 0.3788, assuming a type I error rate of 0.05, a two-
sided alternative hypothesis, 7 degrees of freedom, and a sample size of 50 participants per 
treatment group. 
 
Randomization of Ineligible Participants: It is anticipated that there will be a small 
proportion of patients enrolled who receive CSPs 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.  
 
Non-adherence: In some circumstances, patients may receive standard care instead of the 
CSPs intervention when randomized to CSPs. Non-adherence is most likely to occur in the case 
of the patient who requires urgent neurosurgical intervention and despite CSPs being available, 
are not used. In keeping with the intention-to-treat analytic design, these patients will be 
analyzed with the group to which they were randomized. 
 
Interim Analyses: The primary safety outcome will be 24-hour mortality. The analyses 
described earlier will be carried out twice, once when half of the sample has completed the 
assessment of the endpoint and once when the complete sample has completed the assessment of 
the endpoint.  To control for overall type I error a Bonferonni correction will be employed, 
allocating 0.025 of the type I error to each analysis. 
 
Clinical Coordinating Center (CCC) 
Clinical Coordination specific for the CriSP-TBI study will be performed by the LITES Network 
Clinical Coordinating Center at the University of Pittsburgh and Dr. Okonkwo’s Neurosurgery 
research staff and their dedicated research teams at the University of Pittsburgh, including all 
regulatory requirements, provider and coordinator training and monitoring. 
Data Coordinating Center (DCC) 
Data Coordination specific for the CriSP-TBI 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 design data collection forms, build and maintain an electronic data management 
system, provide training and technical assistance for site-based data entry personnel, develop and 
implement quality control mechanisms (including in-person and remote monitoring), and 
produce reports.  The DCC will also plan, coordinate, and carry out statistical analyses and make 
the datasets available for public use after the trial is completed. 

15 
 
Data Management 
Data Sources: Data will be collected prospectively as patient care progresses. This will include a 
review of the emergency medical patient care report(s), Emergency Department and electronic/ 
paper hospital records.  
 
Surveillance for Outcomes and Data Elements: Data will be collected prospectively as patient 
care progresses. This will include a review of the medical patient care report(s), Emergency 
Department and electronic/ paper hospital records. 
  
Prehospital elements: Mechanism of injury, prehospital vital signs including lowest GCS, 
lowest systolic blood pressure, highest heart rate, need for intubation/advanced airway, 
transported from scene, transported from referral hospital, ground transport, air medical 
transport. 
 
In-Hospital Data: Demographics, shock severity (base deficit, lactate), injury 
characteristics, GCS and pupil exam, ED vitals, ED interventions (chest tubes, 
intubation), injury severity, operative interventions and timing of interventions, injury 
severity score, ICU days, ventilator days, length of stay, multiple organ dysfunction 
scores (daily), nosocomial infectious outcomes, blood gas results, x-ray reads, transfusion 
of blood and blood components, resuscitation requirements, all primary and secondary 
outcomes will be recorded.  
 
Data Entry: The DCC will create an electronic data management system that will include a 
password-protected SSL website for data entry with built-in dynamic features such as data 
encryption, user authentication, range and data type checks, real time reports, data corrections 
tracking, and the capability to save and reload incomplete forms.  The DCC will also draft a 
comprehensive data management manual that includes detailed instructions and provide training 
and technical assistance.  Participants will be identified by a study ID only.  Site will be required 
to store hard-copy source documentation separately in a secured, locked cabinet.    
 
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. These datasets will 
be the basis for data queries, analyses, and monitoring reports. Various versions of this database 
will be kept as needed, e.g., for quarterly performance reports. Access to data will be limited to 
those who need access to perform their tasks. The database management system can 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.  Data will be backed up at regular intervals, with full 
transaction log files in use, and copies of the data will be stored offsite with a secure service.  
Servers will be migrated to a new host in the event of a hardware failure.  All servers are behind 
an enterprise firewall and access must be granted through the firewall even within the University 
network. 

16 
 
Human Participants 
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. 
 
Capacity to provide informed consent will be assessed prior to randomization and will primarily 
be determined by Glasgow Coma Scale (GCS).  Potential subjects with a GCS of less than 15 
will be considered unable to consent.  Potential subjects with a GCS of 15 will undergo a GOAT 
assessment, performed by a study investigator or neurosurgery CRC.  A score of 74 or below 
will be considered unable to consent.  For subjects that are determined to be unable to consent, 
assent will be obtained when applicable.  The study team will also attempt to identify an 
appropriate LAR to provide prospective informed consent.  If a LAR is identified within the 2-
hour period after initial CT scan in the ED, this individual will be approached for proxy consent. 
If not, the patient will be enrolled under EFIC. If a potential subject has a GCS of 15 and scores 
75 or above on the GOAT, we will presume s/he is capable of providing direct informed consent 
and will seek to obtain informed consent via a physician investigator.   
 
Community consultation as determined by the IRB will be undertaken prior to final IRB 
approval. We will utilize the 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 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 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. 
 
For additional details regarding the application of EFIC, procedures for notification and consent, 
and participant withdrawal, please refer to Appendix I – CriSP-TBI EFIC Plan. 
 
Study Stopping Points: 
The following describes the study stopping points regarding participant involvement: 
1) if the study procedures appear to be medically harmful 
2) if the participant no longer wishes to participate 
3) if the study is cancelled 
 
Institutional Review Board: An IRB will be utilized at the University of Pittsburgh for the 
regulatory needs of studies.  
 

17 
 
Training and Participating Site Coordination: As the clinical coordinating center for the 
trial, 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. Trial enrollment and maintenance of data integrity will 
be assessed monthly using the web-based data platform. Trial screening, enrollment and data 
completeness and accuracy will be accessed at 6 months by the CCC. 
Safety Monitoring: 
 
Adverse Event definitions:   
a. Adverse event means any untoward medical occurrence associated with the use of the drug 
in humans, whether or not considered drug related. 
      b. Adverse reaction means any adverse event caused by a drug. 
c. Suspected adverse reaction means any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event.  Suspected adverse reaction implies a 
lesser degree of certainty about causality than “adverse reaction” 
d. Reasonable possibility.  For the purpose of IND safety reporting, “reasonable possibility” 
means there is evidence to suggest a causal relationship between the drug and the adverse 
event. 
e. Life-threatening, suspected adverse reaction.  A suspected adverse reaction is considered 
“life-threatening” if, in the view of either the Investigator (i.e., the study site principal 
investigator) or Sponsor, its occurrence places the patient or research participant 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 participants or significantly 
compromises the quality of the research data.  Incidents of non-compliance on the part of the 
participant 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 participant’s participation in 
research; and places participants or others at greater risk of harm (including physical, 
economic, or social) than was previously known or recognized. 
 
 
Assessing and Reporting Adverse Events (AEs): Adverse events will be reviewed and 
assessed for relationship to the study intervention.  Investigators and study team will determine if 

18 
 
any related adverse events occur during the period from 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.  All reported adverse events will be classified 
by a) Severity (fatal or life-threatening, serious, or non-serious); and b) Expected vs. 
Unexpected.  An event will be determined to be unexpected if it is not consistent with the risks 
identified in the Investigator’s Brochure or with the information provided in the general 
investigational plan or elsewhere in the IND application.  Please refer to the table below for 
timelines for reporting. 
 
This study population is expected to have many 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 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 

19 
 
as scientific or therapeutic developments that may have an impact on the safety of the 
participants or the ethics of the study; 
d. Review clinical center performance, make recommendations and assist in the resolution 
of problems reported by the IND Sponsor or study site Investigators; 
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.   
 
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 participant. 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 participants 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 intervention, the relative focused inclusion criteria, and the short 
intervention period, we expect few protocol deviations as compared to other trials. If monitoring 
reports demonstrate evidence of continuing protocol deviations, we will analyze them and 
determine the best corrective action plan. 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 occur, retraining will be done. The problems will be 
discussed with Principal Investigator, the DOD and the FDA to see if the protocol needs 
amended or recruitment put on hold. 

20 
 
 
Privacy and Confidentiality: The study Principal investigator and members of the research team 
will make reasonable effort to ensure the research participants’ confidentiality. Participant name 
and other identifiable information will be kept in a secure, locked, limited access area. 
 
Investigator Responsibilities:  The study Principal investigator 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: 
 
 
 
 
 
 
 
 
 
 
 
 
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