A Pilot Randomized Clinical Trial of the XSTAT Hemostatic Device in the Prehospital Setting
Phase: NA
Conditions: Shock, Hemorrhagic, Injury Penetrating, Hemorrhage
Sponsor: University of Alabama at Birmingham

 
PhoXSTAT Protocol Version 1.3 
 
 
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Trial Protocol 
 
 
A PILOT RANDOMIZED CLINICAL TRIAL OF THE XSTAT® 
HEMOSTATIC DEVICE IN THE PREHOSPITAL SETTING  
 
 
 
 

 
 
 
 
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VERSION HISTORY 
Amendment no. 
Protocol no. 
Description of changes (incl. 
author(s) of changes) 
Date of 
protocol 
 
1  
New Document 
Dec 20, 2018 
1 
1.1 
Updated DSMB, Screening Cards, 
Stickers, other minor non-technical 
changes.  
Apr 19, 2019 
2 
1.2 
Updated Dr. Holcomb’s affiliation 
Oct 23, 2019 
3 
1.3 
Changes requested by FDA 
May 23, 2021 
 
 
 

 
 
 
 
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AWARD INFORMATION 
Sponsor: 
Department of Defense 
U.S. Army Medical Research Acquisition Activity 
820 Chandler Street 
Fort Detrick, MD 21702-50147 
Award Number / Project Title: 
W81XWH 18 2 0050 / Evaluation of a Novel Hemostatic Agent in Junctional Trauma 
 
PRINCIPAL INVESTIGATOR 
Dr. Jan Jansen, MBBS, PhD 
Associate Professor & Director of Research 
Center for Injury Science 
Division of Acute Care Surgery 
University of Alabama at Birmingham 
Kracke Building, Suite 120 
1922 7th Avenue South 
Birmingham, AL 35294-0016 
 
TRIAL OFFICE 
PHOXSTAT Trial Office 
Center for Injury Science 
University of Alabama at Birmingham 
Kracke Building, Suite 120 
1922 7th Avenue South 
Birmingham, AL 35294-0016 
 
TRIAL REGISTRATION 
Clinicaltrials.gov: [Pending] 
 
 

 
 
 
 
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ABBREVIATIONS 
AE 
 
Adverse Event 
APTT  
Activated Partial Thromboplastin Time 
CIRO   
Clinical Investigations Regulatory Office 
CIS 
 
Center for Injury Science 
CRF 
 
Case Report Form 
DOD  
Department of Defense 
DSMB  
Data Safety and Monitoring Board 
eCRF  
Electronic Case Report Form 
ED 
 
Emergency Department 
EFIC  
Exception From Informed Consent 
EMS 
 
Emergency Medical Services 
FDA 
 
Food and Drug Administration 
GCP 
 
Good Clinical Practice 
HRPO   
Human Research Protection Office 
INR 
 
International Normalized Ratio 
IRB 
 
Institutional Review Board 
NIH 
 
National Institute of Health 
LAR 
 
Legally Appointed Representative 
OR 
 
Operating Room 
ORP   
Office of Research Protections 
PT 
 
Prothrombin Time 
REDCap 
Research Electronic Data Capture 
ROC  
Resuscitation Outcomes Consortium 

 
 
 
 
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ROTEM 
Rotational Thromboelastometry 
RQ 
 
Research Question 
SAE 
 
Serious Adverse Event 
SOPM  
Standard Operating Procedures Manual 
TEG 
 
Thromboelastography 
UAB 
 
University of Alabama at Birmingham 
USAMRMC  
US Army Medical Research and Materiel Command 
 
 
 
 

 
 
 
 
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CONTENTS 
1. 
PROTOCOL SUMMARY .......................................................................................... 1 
1.1 Questions addressed ...................................................................................... 1 
1.2 Eligible population .......................................................................................... 1 
1.3 Interventions .................................................................................................... 1 
1.4 Outcome assessment ..................................................................................... 1 
1.5 Coordination .................................................................................................... 1 
2. 
TRIAL PERSONNEL ................................................................................................ 2 
2.1 Principal Investigator ...................................................................................... 2 
2.2 Program manager ............................................................................................ 2 
2.3 Statistical consultant and data manager ....................................................... 2 
2.4 Project management group ............................................................................ 3 
2.5 Medical Monitor ............................................................................................... 3 
2.6 Data and Safety Monitoring Board ................................................................. 3 
3. 
INTRODUCTION ...................................................................................................... 4 
3.1 Background ...................................................................................................... 4 
3.2 XSTAT® – A Novel Hemostatic Approach to Junctional Injuries ................ 5 
3.3 Rationale for this trial ...................................................................................... 6 
3.3.1 The need for further study .............................................................................. 6 
3.3.2 The need for a pilot trial .................................................................................. 7 
4. 
AIM AND OBJECTIVES .......................................................................................... 8 
4.1 Aim .................................................................................................................... 8 
4.2 Objectives and research questions (RQ) ...................................................... 8 
4.2.1 Trial feasibility ................................................................................................. 8 

 
 
 
 
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4.2.2 Device usability ............................................................................................... 8 
4.2.3 Device safety .................................................................................................. 9 
5. 
DESIGN AND INTERVENTION ............................................................................. 10 
5.1 Design ............................................................................................................. 10 
5.2 Intervention to be evaluated ......................................................................... 10 
5.3 Control treatment .......................................................................................... 11 
5.4 Other aspects of care .................................................................................... 12 
6. 
RECRUITMENT ..................................................................................................... 13 
6.1 Setting ............................................................................................................ 13 
6.2 Patients/Study Subjects ................................................................................ 13 
6.3 Randomization ............................................................................................... 13 
6.4 Consent (EFIC) ............................................................................................... 14 
7. 
OUTCOMES ........................................................................................................... 20 
7.1 Trial feasibility (Objectives 1-2) .................................................................... 20 
7.2 XSTAT usability (Objectives 3 and 4) .......................................................... 20 
7.3 XSTAT safety (Objective 5) ........................................................................... 21 
8. 
DATA COLLECTION ............................................................................................. 22 
8.1 Personnel ....................................................................................................... 22 
8.2 Case Report Form ......................................................................................... 22 
8.3 Patients entered into pilot trial: Prehospital data collection ..................... 22 
8.4 Patients entered into pilot trial: In-hospital data collection ...................... 23 
8.5 Data collection schedule .............................................................................. 25 
9. 
RECRUITMENT TARGETS ................................................................................... 27 
10. STATISTICAL ANALYSIS ..................................................................................... 28 
10.1 Feasibility ..................................................................................................... 28 

 
 
 
 
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10.2 Usability ........................................................................................................ 28 
10.3 Safety ............................................................................................................ 28 
10.4 Efficacy ......................................................................................................... 28 
11. TRIAL MANAGEMENT .......................................................................................... 29 
11.1 Trial office .................................................................................................... 29 
11.2 Project Management Group ........................................................................ 29 
11.3 Local organization in sites ......................................................................... 29 
12. RESEARCH GOVERNANCE ................................................................................. 30 
12.1 Lead site ....................................................................................................... 30 
12.2 Monitoring .................................................................................................... 30 
12.3 Relationship with the manufacturer of the XSTAT® device ..................... 30 
12.4 Data protection ............................................................................................ 30 
13. HUMAN SUBJECTS RESEARCH ......................................................................... 31 
13.1 FDA Requirements ...................................................................................... 31 
13.2 Potential risks .............................................................................................. 31 
13.3 Protection of human subjects .................................................................... 32 
14. ADVERSE EVENT/EFFECT REPORTING ............................................................ 33 
14.1 Definitions and classification ..................................................................... 33 
14.2 Reporting period .......................................................................................... 35 
14.3 Reporting procedure ................................................................................... 35 
14.4 Role and responsibility of the Independent Medical Monitor ................. 37 
14.5 Role and responsibility of the Data and Safety Monitoring Board ......... 38 
15. QUALITY ASSURANCE ........................................................................................ 39 
15.1 Training ........................................................................................................ 39 
15.2 Study Monitors ............................................................................................ 40 

 
 
 
 
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16. PROJECT TIMELINE ............................................................................................. 41 
16.1 Summary/Gantt Chart ................................................................................. 41 
16.2 Detailed description/Milestones ................................................................. 41 
17. REFERENCES ....................................................................................................... 44 
18. APPENDICES ........................................................................................................ 45 
Appendix  1: Sample tracking label ................................................................... 45 
Appendix  2: Data Dictionary Codebook ........................................................... 46 
 

 
 
 
 
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1. PROTOCOL SUMMARY 
1.1 Questions addressed 
How many patients might benefit from the XSTAT® device, in the civilian setting? How 
many patients could be enrolled into a trial? What are the baseline estimates of possible 
future primary and secondary outcomes for a full randomized clinical trial? Is the XSTAT® 
device easy to use, in the prehospital setting? How does the XSTAT impact operative 
management of penetrating junctional injuries and are the sponges easy to remove? Is 
the use of the XSTAT® device associated with adverse effects?  
1.2 Eligible population 
Patients aged 15 years and over, or with an estimated body weight of 50kg or more; who 
have suffered a penetrating junctional injury (femoral or axillary) with visible bleeding; who 
a suffering from class 3 or 4 hemorrhagic shock; and who will be taken directly to a level I 
trauma center participating in the PhoXSTAT trial. 
1.3 Interventions 
Standard prehospital care plus XSTAT®, compared with standard prehospital care. 
1.4 Outcome assessment 
We will assess feasibility of a future efficacy/effectiveness trial, and usability and safety of 
the XSTAT® device. 
1.5 Coordination 
Local: By investigators and research assistants in participating trial sites. Central: By Trial 
Office at UAB. 
 
 
 
 

 
 
 
 
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2. TRIAL PERSONNEL 
2.1 Principal Investigator 
Dr. Jan Jansen, MBBS, PhD 
Associate Professor & Director of Research 
Center for Injury Science 
Division of Acute Care Surgery 
University of Alabama at Birmingham 
Kracke Building, Suite 120 
1922 7th Avenue South 
Birmingham, AL 35294-0016 
2.2 Program manager 
Shannon W. Stephens, EMTP, CCEMTP 
Director, Alabama Resuscitation Center 
Department of Emergency Medicine 
University of Alabama at Birmingham 
619 19th Street South 
OHB 251 
Birmingham, AL 35249-7013  
2.3 Statistical consultant and data manager 
Dr. Russell Griffin, PhD 
Associate Professor 
Department of Epidemiology 
University of Alabama at Birmingham 
Old Hillman Building 
619 19th Street South 
Birmingham, AL 35294 
 

 
 
 
 
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2.4 Project management group 
Dr. Jan Jansen, University of Alabama at Birmingham 
Dr. Jeffrey Kerby, University of Alabama at Birmingham 
Shannon W. Stephens, University of Alabama at Birmingham 
2.5 Medical Monitor 
Patrick Bosarge, MD 
Division Chief, Trauma Department 
University of Arizona College of Medicine – Phoenix  
2.6 Data and Safety Monitoring Board 
Stacia M. DeSantis, Ph.D. 
Associate Professor 
Department of Biostatistics 
University of Texas Health Science Center at Houston 
 
Henry E. Wang, MD, MPH, MS 
Professor, Vice Chair for Research 
Department of Emergency Medicine 
University of Texas Health Science Center at Houston  
 
John B. Holcomb, MD, FACS 
Professor 
Division of Acute Care Surgery 
University of Alabama at Birmingham 
Kracke Building, Suite 120 
1922 7th Avenue South 
Birmingham, AL 35294-0016 
  
 
 

 
 
 
 
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3. INTRODUCTION  
3.1 Background 
3.1.1 Trauma is a major public health issue 
Trauma is the leading cause of death for people ≤45 years of age and is the third leading 
cause of death in the United States (US) overall. Trauma accounts for 41 million 
Emergency Department (ED) visits and 2 million hospital admissions in the US each 
year, with an economic burden of more than $585 billion.(1)  
Among the injured, hemorrhagic shock is a leading cause of early death, and is 
responsible for over 35% of prehospital deaths and 40% of deaths within the first 24 
hours after injury.(2) Hemorrhage control is of paramount importance in preventing 
battlefield mortality and is the top priority of the US military.(3) In a study of injuries from 
Operation Iraqi Freedom and Operation Enduring Freedom, hemorrhage accounted for 
82% of potentially survivable casualties.(4) 
3.1.2 Junctional bleeding is particularly challenging, and currently available treatments 
are unsatisfactory 
Junctional bleeding is hemorrhage occurring at the junction of two anatomically distinct 
regions. The PhoXSTAT trial will specifically investigate injuries to the axillary or femoral 
regions. These injuries are associated with high mortality. A National Trauma DataBank 
analysis of 120 isolated femoral arterial injuries revealed a mortality rate of 7.5%. (5)  
Bleeding from a junctional injury is difficult to control. Currently available treatments 
include tourniquets, direct and indirect pressure, and hemostatic dressings. These are 
unsatisfactory (21 CFR 50.24(a)(1)) because  
a) A tourniquet cannot be applied to these body regions: Junctional injuries are too 
proximal to permit the application of a tourniquet to temporarily occlude blood 
flow. It is not possible to occlude the iliac (for femoral arterial injuries) or 
subclavian (for axillary arterial injuries) arteries with a tourniquet. 
b) Indirect pressure on proximal vessels is ineffective. (6) For the same reasons, it 
is not possible to provide effective digital compression of the iliac or subclavian 
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c) Direct pressure is ineffective, particularly in deep wounds. (6) Penetrating injuries 
to the junctional vasculature are difficult to control with direct pressure. Inserting 
digits into these types of wounds can also exacerbate bleeding, by causing 
further injury to vascular structures. 
d) Existing hemostatic agents have important practical drawbacks that limit their 
effectiveness with junctional injuries. For example, junctional injuries often 
involve deep vascular structures that cannot be easily accessed from the skin 
surface. Hemostatic bandages inserted through small skin wounds cannot 
effectively compress deep vascular structures. Similarly, hemostatic powder 
applied through a small skin wound will not adequately coat deep vascular 
structures. Hemostatic powders are also difficult to remove during definitive 
vascular repair. 
There are few effective treatment options for junctional injuries other than operative 
control – which is rarely available in the prehospital setting. Current body armor also 
does not adequately protect junctional regions. In recent US military efforts, junctional 
injuries contributed to >70% of potentially survivable casualties.(4) 
3.2 XSTAT® – A Novel Hemostatic Approach to Junctional Injuries  
XSTAT® (RevMedxTM, Wilsonville, Oregon) is a novel hemostatic device with features 
potentially well suited to junctional hemorrhage control.(6)  
3.2.1 Mechanism of action 
The XSTAT® device injects small, rapidly-expanding cellulose sponges into the wound 
cavity using a syringe-like delivery system.  In the wound, XSTAT® sponges expand and 
swell to fill the wound cavity, within 20 seconds of contact with blood, facilitating 
compression of bleeding structures.  XSTAT® can be applied through skin wounds. The 
system can readily access deep vascular structures. While rapidly hemostatic, the 
hemostatic sponges are also relatively easy to remove. In the setting of junctional 
bleeding, XSTAT® may allow for hemostatic pressure generation from within the wound 
tract rather than from external compression (as with a tourniquet or manual 
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3.2.2 Why the XSTAT 12 device may be better than existing available therapies  
The XSTAT 12 device may be better than existing available therapies because of its mode 
of application: The device allows the delivery of the hemostatic component (the sponges) 
close to the site of bleeding, using the injector. This is particularly helpful for ballistic 
injuries, where the wound may be relatively small. The device is easily inserted into the 
wound tract, and directed towards the bleeding femoral or axillary artery – even if the 
arterial injury is out of reach of tourniquets, direct or indirect pressure, or hemostatic 
dressings. 
3.2.3 Operational philosophy 
Hemorrhage should be controlled as early as possible, ideally before reaching a trauma 
center or medical treatment facility. Given its small size, low weight, and ease of 
application, the XSTAT® device is well-suited for prehospital use, in both the civilian and 
military setting, and this is probably where the device’s applicability lies. 
There would appear to be less justification for the use of XSTAT® in the setting of a 
trauma center, where patients can be taken directly to an operating room, or have 
bleeding controlled by other means.  
3.2.4 Current evidence 
Although efficacious in animal studies, there have been few studies of the XSTAT device 
in humans. A recent ten-patient case series, eight of whom had arterial injuries, and two 
of whom had venous injuries or soft-tissue bleeding, showed that XSTAT appeared to 
control bleeding well. Overall, half were junctional injuries. XSTAT was able to stop 
bleeding in nine of ten patients on the first deployment, with the remaining patient 
requiring one repeat injection. There were no technical device failures or embolic 
complications.(7)  
3.3 Rationale for this trial  
3.3.1 The need for further study 
XSTAT® is approved by the US Federal Drug Administration (FDA) for application in 
battlefield and civilian trauma patients. However, other than the case series described 
above,(7) there have been no supporting human evaluations of XSTAT®. There is an 

 
 
 
 
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urgent need for data to demonstrate the safety and efficacy of the device, prior to 
recommending its widespread use in the prehospital setting. 
3.3.2 The need for a pilot trial 
Before a full-scale trial can be conducted, the feasibility of conducting such a study, and 
the planning assumptions underlying it, will need to be confirmed. The key issues which 
such a pilot trial needs to address are: 
a) The number of penetrating junctional zone injuries encountered in the prehospital 
civilian setting. 
b) The feasibility of randomizing patients in the prehospital setting. 
c) Usability. 
d) Safety. 
e) Validation of the proposed primary outcome of an efficacy trial. 
 
 

 
 
 
 
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4. AIM AND OBJECTIVES 
4.1 Aim 
The aim of the PhoXSTAT trial is to evaluate the feasibility of conducting a randomized 
clinical trial of the XSTAT® device, in the prehospital setting. 
4.2 Objectives and research questions (RQ) 
The objectives of the PhoXSTAT trial are: 
4.2.1 Trial feasibility 
Objective 1: 
To evaluate the number of patients with penetrating junctional (femoral 
and axillary) zone injuries that can be entered into a trial (RQ 1: “How 
many patients that might benefit from the XSTAT® device, in the civilian 
setting, can be entered into a trial?”) 
Objective 2: 
To evaluate possible future primary and secondary outcomes for a full 
randomized clinical trial, including admission lactate, admission base 
deficit, and mortality. (RQ 3: “What are the baseline estimates of possible 
future primary and secondary outcomes for a full randomized clinical 
trial?”) 
4.2.2 Device usability 
Objective 3:  To evaluate the usability of the XSTAT® device, in the prehospital setting, 
in patients with junctional injuries, in terms of the insertion of the device, 
and deployment of the sponges. (RQ 4: “Is the XSTAT® device easy to 
use, in the prehospital setting?”) 
Objective 4: 
To evaluate the usability of the XSTAT® device, in the operating room 
setting, in patients with junctional injuries, in terms of the removal of the 
sponges. (RQ 5: “Are the XSTAT® sponges easy to remove, in the 
operating room?”) 

 
 
 
 
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4.2.3 Device safety 
Objective 5:  To evaluate the safety of the XSTAT® device, in patients with junctional 
injuries. (RQ 6: “Is the use of the XSTAT® device associated with adverse 
effects?”) 
 
 

 
 
 
 
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5. DESIGN AND INTERVENTION  
5.1 Design  
Pragmatic, prehospital, randomized, multi-site, pilot/feasibility trial. 
Figure 1. Consort diagram 
 
5.2 Intervention to be evaluated 
Patients allocated to the intervention group are treated with standard prehospital care 
plus XSTAT®. The trial will only use the “XSTAT-12” device, which is more suited to the 
types of injuries seen in civilian practice. XSTAT® application will follow the 
manufacturer’s guidance, with injection into bleeding wounds. A sufficient number of 
sponges are used to fill the injury void. Repeat XSTAT® application is performed in the 
event of persistent bleeding. (The trial packs will contain two devices.)  
Randomization by 
EMS Unit
Patient enrolled
Allocated to XStat
Allocated to Standard Care
Follow-up to 30 days or 
discharge
Follow-up to 30 days or 
discharge
ENROLMENT
ALLOCATION
FOLLOW-UP
Outcomes: Feasibility, 
Usability, Safety
Standard Care
Treatment with XStat
PRE-HOSPITAL
IN-HOSPITAL
Outcomes: Feasibility, 
Usability, Safety

 
 
 
 
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Figure 2. Xstat device being used to treat right groin wound 
XSTAT® sponges must be removed surgically. However, all patients with junctional 
injuries typically undergo operative exploration and repair of vascular injuries. The 
radiopaque markers embedded in each sponge aid in identification of sponges retained 
within the body. Each XSTAT® device consists of 38 sponges. Because all sponges may 
not be deployed into the wound or there may be dislodgement from the wound during 
patient movement, a radiographic survey must be undertaken to identify any retained 
sponges. The recent cases series by Warriner et al identified retained sponges in two 
out of ten patients on initial post removal x-rays following wound exploration for definitive 
hemorrhage control and sponge removal.(7)  
It is possible that patients who are initially (in the prehospital setting) thought to have a 
serious injury, and who are treated with XSTAT, then turn out not to have an injury 
requiring operative treatment. These patients might have been managed non-
operatively, had they not been treated with XSTAT. Determining the number of “forced” 
or non-therapeutic explorations is a key outcome of this study. However, it is important 
to recognize that XSTAT is an FDA-approved device, and that this situation can 
therefore also arise in everyday practice, outwith the context of a trial. 
5.3 Control treatment  
Patients allocated to the control group receive standard prehospital care, consisting of 
direct pressure/dressings. 

 
 
 
 
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5.4 Other aspects of care 
All other aspects of trauma resuscitative care take place according to local protocol, 
including airway management, provision of supplemental oxygen, intravenous fluid 
resuscitation, administration of blood products, splinting of extremities, bandaging of 
wounds and surgical interventions. Upon arrival at the hospital, ED/trauma center 
personnel perform initial patient assessment according to standard Advanced Trauma Life 
Support protocols. Patients receive concurrent interventions, including provision of 
oxygen, insertion of intravenous lines, and infusion of intravenous fluids and blood 
products.  
 
 

 
 
 
 
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6. RECRUITMENT 
6.1 Setting  
The PhoXSTAT trial is conducted in the prehospital setting, by participating Emergency 
Medicine Service (EMS) providers, and associated level I trauma centers. 
6.2 Patients/Study Subjects 
The study’s entry criteria select patients with life-threatening injuries, as specified under 
21 CFR 40.24(a)(1): 
6.2.1 Inclusion criteria 
a) Age ≥15 years or estimated body weight ≥50 kg.  
b) Penetrating junctional injury (femoral or axillary), with  
i. 
visible bleeding 
ii. 
too proximal to be controlled with a tourniquet 
c) Class 3 or 4 hemorrhagic shock 
d) Patient will be taken to participating level I trauma center, directly from the scene 
6.2.2 Exclusion criteria 
a) Prisoners, children <15 years old, known pregnant patients.  
b) Patients receiving chest compressions (prior to XSTAT® use).  
c) Patients with an opt-out bracelet.  
Adolescents will be included because children aged 15 and over are typically 
transported to, and treated, in adult trauma centers. Only children below this age are 
taken to specialist pediatric trauma centers (when available). 
6.3 Randomization 
6.3.1 Randomization by vehicle 
Patients are individually randomized, albeit indirectly, by randomizing EMS vehicles. 
(Given the administrative and logistical difficulties of direct individual randomization in 
the prehospital setting, this approach is more practical.)  

 
 
 
 
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6.3.2 Trial intervention packs 
Each EMS vehicle randomly receives a pre-packaged, sealed, numbered trial 
intervention pack, consisting of a durable plastic case, which either contains either two 
XSTAT® devices, or is empty. The pack remains on the vehicle until used or expired. 
When a suitable patient meeting the inclusion criteria for the trial is identified by the EMS 
providers, the pack is opened. If it contains the device, it is used. Once a pack has been 
used, it is replaced (when the vehicle returns to its base location).  
6.3.3 Tracking labels 
The trial intervention packs also contain a tracking label, which must be attached to the 
patient, to ensure that the trauma center is a) made aware of the patient’s enrollment; 
and b) able to identify which treatment was administered. The tracking label is also used 
to collect a small amount of prehospital data. 
This mechanism avoids having to access a randomization mechanism in real-time and 
having to carry multiple packs. The disadvantage is that, should a crew encounter more 
than one suitable patient per shift, some patients may be missed. In addition, in a small 
study, there is a possibility that, purely by chance, eligible patients may be preferentially 
encountered by EMS units randomized to either the intervention, or the control 
treatment. This risk will be reduced with a larger sample size.    
6.4 Consent (EFIC) 
PhoXSTAT is an Exception from Informed Consent (EFIC) trial. We have extensive 
experience conducting major trauma trials under EFIC rules. Through our activities with 
the national Resuscitation Outcomes Consortium (ROC), we have executed eight trials 
on cardiac arrest or major trauma patients using EFIC. We are experienced with all 
aspects of EFIC, including communicating with the targeted communities, delivering 
information to patients and their families, and disseminating study information and 
results. Examples of studies that we have successfully carried out under EFIC include: 
ROC Hypertonic Saline Trial, ROC Hypotensive Resuscitation Trial, PROPPR, and the 
ROC TXA Trial. We have also conducted EFIC for numerous cardiac arrest trials.  
All patients participating in the trial, regardless of whether allocated to receiving the 
intervention, or control treatment, are likely to benefit. Those receiving treatment with 

 
 
 
 
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XSTAT® will benefit from its probable hemostatic action. Patients randomized to control 
treatment will also benefit, because they will be part of a carefully designed study to 
assess the safety of treatment and will thus receive more clinical attention than patients 
who are not participating in the trial. The severity of junctional injuries is often 
underestimated by clinicians, with serious consequences, and this benefit is therefore 
tangible. 
The procedures outlined below are based upon procedures that have been historically 
approved by the UAB Institutional Review Board and other related agencies such as the 
US Army Medical Research and Materiel Command (USAMRMC) Human Research 
Protection Office (HRPO). The nature and risk/benefit profile of XSTAT® is similar to 
these prior trials.  
Because of the time-critical nature of hemorrhage care, the trial will be carried out under 
“Exception from informed consent required for emergency research” (EFIC) rules 
outlined in the guidance document “Waiver of Informed Consent Requirements in 
Certain Emergency Research” (Federal Register, Vol. 61, pp. 51531-51533, November 
1, 1996 - http://www.gpo.gov/fdsys/pkg/FR-1996-10-02/html/96-24968.htm), OHRP 
“Basic HHS Policy for Protection of Human Research Subjects” (45 CFR 46.101(i) - 
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.101), and FDA 
regulations 21 CFR 50.24.23-25. 
6.4.1 Conditions present for conduct under 21 CFR 50.23 
The use of EFIC is justified, as per FDA regulations 21 CFR 50.24.23-25, because the 
victims of major trauma are: 
a) In a life-threatening situation that necessitates urgent intervention: Femoral and 
axillary arterial injuries are associated with high mortality 
b) Available treatments are unproven or unsatisfactory: Available treatments include 
tourniquets, direct and indirect pressure, and hemostatic dressings. Section 3.1.2 
contains details of why these treatments are unsatisfactory. 
c) Collection of valid scientific evidence is necessary to determine the safety and 
effectiveness of the intervention: Preclinical and clinical studies conducted to date 
confirm the safety of the XSTAT device. 

 
 
 
 
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d) Obtaining informed consent is not feasible because the subjects are not able to 
give their informed consent as a result of their medical condition: The patients who 
will be included in this trial will be suffering from life-threatening hemorrhagic chock 
(class 3, 30-40% of blood volume lost; class 4, 40% of more of blood volume lost). 
Class 3 hemorrhagic shock is associated with “changes in mental status”. In class 
4 
hemorrhagic 
shock, 
“mental 
status 
becomes 
increasingly 
altered” 
(https://www.ncbi.nlm.nih.gov/books/NBK470382/). 
Patients 
who 
meet 
the 
inclusion criteria for the trial are therefore unlikely to have capacity to provide 
informed consent to participate. 
e) The intervention must be administered before consent can be obtained from the 
subject’s legally authorized representative: The therapeutic window for controlling 
hemorrhage, before the patient exsanguinates, is small. The time required to 
contact a LAR could determine whether a patient who could have lived, dies. 
f) There is no reasonable way to identify prospectively individuals likely to become 
eligible for participation: Patients do not usually expect to suffer penetrating 
junctional injuries. 
g) Participation in the research holds out the prospect of direct benefit to the subjects: 
Preclinical and early clinical data suggest that there is a real possible and direct 
benefit to patients treated with the XSTAT device.   
h) The clinical investigation could not practicably be carried out without the waiver: 
There is no alternative means of carrying out this type of research. 
In conformance with EFIC rules, measures to protect the rights and welfare of subjects 
will include, at least: 
a) Community consultation 
b) Public disclosure 
c) Independent data monitoring 
d) Notification of LAR or family members of a subject’s enrollment in the trial, with 
opportunity to discontinue trial participation.  
Community consultation and public disclosure will be performed prior to study enrollment 
and at the completion of the study in the form of multimedia press releases organized by 
the study team. Examples of communication activities may include town hall meetings, 
press releases, website postings, random-digit-dialing surveys, and the use of social 

 
 
 
 
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media (Facebook and Instagram). These communications will describe plans for the 
study, including potential risks and benefits, equipoise and a summary of the results of 
the study upon completion. Information regarding the study will also be available on the 
UAB website.  
6.4.2 Informed consent by patient 
As described above, patients who meet the inclusion criteria for the trial, including the 
presence of class 3 or 4 shock (which is associated with mental status changes), are very 
unlikely to have the capacity to provide consent. Furthermore, a detailed discussion of the 
risks and benefits of participation could results in life-threatening delays to treatment. 
However, as per 21 CFR 50.24(a)(6), if patients are deemed to have capacity, informed 
consent will be sought and documented. 
6.4.3 Informed consent by LAR 
In the rare scenario where a LAR/family member is immediately available and the 
opportunity for consent is present, a short script (appendix 3) providing information 
regarding the study will be made available to the LAR/family member, affording the 
opportunity to withdraw consent for the patient’s participation. 
If an arterial injury is present, the therapeutic window for intervention is extremely short. 
Depending on the severity of the injury, exsanguination can occur within minutes. 
Importantly, this time is measured from the time of injury, rather than the time of arrival 
of emergency medical services. Once present, paramedics will be working to resuscitate 
(with intravenous fluid or blood transfusions, and sometimes also intubation) and 
transport the patient to a facilitate capable of definitive hemorrhage control, as quickly as 
possible. Contacting a family member of LAR who is not present at the scene is 
therefore unlikely to be feasible – both because contact details will not be available, and 
because of the time required. Nevertheless, should a situation arise where this is 
possible, efforts will be made to contact family members and ask whether he or she 
objects to the subject’s participation in the research, as required by 21 CFR 
50.24(a)(7)(v). This discussion will also be guided by the script in appendix 3.  

 
 
 
 
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6.4.4 Consent for ongoing participation 
Once a subject is enrolled in the study, the research team will make frequent attempts 
as soon as feasible to contact a LAR/family member to obtain permission for continued 
participation and provide an opportunity to withdraw. A verbal withdrawal will be 
considered binding. Attempts to contact a LAR/family member will include direct contact, 
telephone contact and written contact or any other contact options as approved by local 
IRB policy.  
6.4.5 Death before consent can be obtained 
In the event the subject does not survive following the traumatic injury, his/her 
information will be included in the data analysis. Written notification may be sent to the 
deceased’s family regarding participation in this study, per local IRB policy. Due to the 
severity of the injuries incurred, it is difficult to specify the timeframe involved with 
obtaining the consent, however multiple attempts will be made to obtain consent prior to 
completion of the study.  
6.4.6 Opt-out 
The ability and method of “opting out” of the study will be determined by the UAB 
Institutional Review Board, with updating by the other two sites (USC and VUMC). 
Because the population eligible for enrollment includes all citizens in the study regions, it 
will not be possible to target specific individuals, although the UAB IRB may suggest 
specific age groups and ethnic groups, determined by trauma registry data. Citizens 
wishing to opt-out of the trial will be provided with an “opt-out” bracelet. EMS personnel 
will be trained to check for opt-out identifiers prior to enrolling any patient. 
6.4.7 “Prospect of direct benefit” 
Information from animal and preclinical studies, and early clinical use support the 
potential for the investigational product to provide a direct benefit to the individual 
subjects.  Participation in this pilot trial holds out the prospect of direct benefit to the 
subjects because  
a) The subjects are in a life-threatening situation that necessitates intervention. 
Specifically, the condition in question (junctional hemorrhage) is not well-

 
 
 
 
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addressed with currently available treatments, and hemorrhage is frequently not 
controlled until the patient reaches hospital. 
b) Information from appropriate animal and other preclinical studies support the 
potential for the intervention to provide a direct benefit to the individual subjects. 
c) The 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.  
6.4.8 Choice of endpoints  
This protocol is for a pilot trial. The FDA recognizes that it is important to obtain 
preliminary information on the effect of new treatments on a variety of outcomes, 
including biomarkers (e.g., measurement of brain infarcted area, degree and extent of 
acidosis) before proceeding to a study that evaluates effectiveness. This pilot trial will 
evaluate several possible endpoints which could be used in a future effectiveness trial, 
including a biomarker (lactate). 
 
 

 
 
 
 
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7. OUTCOMES 
PhoXSTAT is a pilot trial, and consequently there is no “primary” outcome. As per the 
aims and objectives, the following will be evaluated: 
7.1 Trial feasibility (Objectives 1-2) 
We will evaluate the feasibility of a full efficacy/effectiveness trial, using the following 
parameters: 
a) Number of patients with penetrating junctional (femoral and axillary) zone injuries 
who are entered into the pilot trial, and randomized. (Objective 1) 
b) Ability to obtain baseline estimates of possible future primary and secondary 
outcomes for a full randomized clinical trial. (Objective 2) 
7.2 XSTAT usability (Objectives 3 and 4) 
In order to conduct a full trial, the device has to be usable. Usability will be evaluated in 
the prehospital and operating room setting. 
7.2.1 Prehospital setting (Objective 3) 
Many civilian penetrating injuries are caused by low energy transfer firearms (typically 
handguns). The resulting wounds can be small, which may make insertion of the 
XSTAT® device difficult. We will evaluate the usability of the device in the prehospital 
setting, by investigating the following: 
a) Ease of insertion  
b) Ease of deployment  
c) Overall satisfaction with the device 
7.2.2 Operating room (Objective 4) 
Use of the XSTAT device commits the patient and medical team to operative exploration 
of the wound, and retrieval of the sponges. We will evaluate surgeons’ views on the 
device, by collecting data on the following: 
a) The ease of sponge removal 
b) The time required to remove the sponges 

 
 
 
 
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c) The use of x-rays/image intensifiers to ensure complete removal of the sponges 
d) Overall satisfaction with the device  
7.3 XSTAT safety (Objective 5) 
Although XSTAT® is thought to be a low-risk device, we will nevertheless obtain formal 
data on its safety profile, which will include the following: 
a) Number of patients suffering allergic reactions or anaphylaxis  
b) Number of patients developing wound infections 
c) Number of patients developing tissue damage thought to be related to the 
insertion of the device or deployment of the sponges 
d) Number of patients suffering embolization of the sponges 
e) Number of patients who suffer inadvertent retention of sponges (beyond first 
operation) 
f) Number of patients in whom no vascular injury is identified 
 
 

 
 
 
 
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8. DATA COLLECTION 
8.1 Personnel 
All three participating PhoXSTAT sites have research assistants available in the 
emergency department. Research assistants initiate, and complete, the data collection 
for the trial. 
8.2 Case Report Form 
Data is initially collected using paper Case Report Forms (CRFs, appendix 2), and then 
transcribed into an electronic database. The electronic CRF uses the Research 
Electronic Data Capture (REDCap) system, a secure research database developed by 
NIH. Data logic checks are used to minimize data entry errors. Data audits are 
performed on a randomly selected 20% of enrolled subjects. When data are complete, 
and all suspect entries addressed, the database will be “locked” and exported to STATA 
or SAS for analysis.  
8.3 Patients entered into pilot trial: Prehospital data collection 
The PhoXSTAT trial requires the collection of a minimal amount of prehospital data – 
primarily relating to the usability and safety of the device. Each trial intervention pack 
contains a tracking label, which must be attached to the patient, using the cable tie 
supplied. The tracking label contains a mini-questionnaire. If the patient was allocated to 
treatment with Xstat, the following details must be completed: 
8.3.1 Usability 
Ease of insertion of device into wound 
a) Unable to insert (wound too small to accept device) 
b) Reasonably easy to use (wound accepted device with some manipulation) 
c) Easily inserted (wound accepted device without difficulty) 
Ease of deployment of sponges 
a) Unable to deploy sponges 
b) Reasonably easy to deploy sponges (several sponges successfully injected) 
c) Easily deployed (majority or all of sponges successfully injected) 

 
 
 
 
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Overall satisfaction with the device 
a) Dissatisfied 
b) Neither satisfied nor dissatisfied 
c) Satisfied 
8.3.2 Safety 
a) Anaphylaxis 
The tracking label is shown in appendix 1. The data on the patient’s tracking label must 
be transferred to the electronic case report form (eCRF) (see below) at the earliest 
opportunity, by research assistants in the emergency department, to mitigate against 
data loss.  
8.4 Patients entered into pilot trial: In-hospital data collection 
The following data are collected in-hospital. 
8.4.1 Physiological parameters 
The following measurements are collected on admission: 
a) Systolic, diastolic, and mean blood pressure 
b) Heart rate 
c) Shock index  
8.4.2 Usability 
The ease of sponge removal 
a) Unable to remove all sponges 
b) Reasonably easy to remove all sponges  
c) Sponges easily removed 
The time required to remove the sponges 
a) 1 hour or longer 
b) Between 5 and 59 minutes 
c) Less than 5 minutes 
The use of x-rays/image intensifiers to ensure complete removal of the sponges 

 
 
 
 
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a) Imaging not used due to patient’s clinical condition 
b) Imaging not used as not available 
c) Imaging deemed unnecessary 
d) Imaging used 
Outcome of imaging:  
a) Additional sponges seen on imaging  
 
b) No additional sponges seen on imaging 
 
 
 
 
 
Overall satisfaction with the device  
a) Dissatisfied 
b) Neither satisfied nor dissatisfied 
c) Satisfied 
8.4.3 Blood tests 
The following blood tests, which are all measured routinely as part of the clinical 
assessment of trauma patients, are collected, as soon as possible after admission: 
a) Blood lactate level (from arterial or venous blood gas measurement) 
b) Blood base deficit (from arterial or venous blood gas measurement) 
c) Hemoglobin/hematocrit, platelet count 
d) Prothrombin time (PT)/international normalized ratio (INR), activated partial 
thromboplastin time (APTT)/ratio 
e) Thromboelastograph (TEG) or thromboelastogram (ROTEM), if available 
8.4.4 Survival 
Time of death (if applicable) 
8.4.5 Blood product/adjunct use 
The amount of blood products used, over the first 24h since injury, are collected: 
a) Red cell concentrate (units) 
b) Plasma (units) 
c) Platelets (pools) 
d) Whole blood (units) 
e) Cryoprecipitate (units) 

 
 
 
 
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f) Tranexamic acid (grams) 
8.4.6 Length of stay 
a) Intensive care (days) 
b) Hospital (days) 
8.4.7 Safety 
PhoXSTAT collects data on a number of prespecified safety events, over the first 7 days  
following injury, unless discharged earlier, including: 
a) Allergic reactions or anaphylaxis  
b) Wound infections (clinical diagnosis) 
c) Tissue damage thought to be related to the insertion of the device or deployment 
of the sponges (clinical diagnosis) 
d) Embolization of the sponges 
e) Inadvertent retention of sponges (beyond first operation) 
f) Non-therapeutic exploration 
The above data are also to be entered into the eCRF as it becomes available. 
8.5 Data collection schedule 
The data collection schedule is summarized in table 1. 
Table 1: Data collection 
Data 
Pre-
hospital 
On 
admission 
OR 
6 hrs 
24 hrs 
7 days* 
30 days* 
Discharge 
Feasibility 
 
 
 
 
 
 
 
 
Lactate 
 
ü 
 
 
 
 
 
 
Blood pressure 
 
ü 
 
 
 
 
 
 
Heart rate 
 
ü 
 
 
 
 
 
 
Base deficit 
 
ü 
 
 
 
 
 
 
Hemoglobin 
 
ü 
 
 
 
 
 
 
Hematocrit 
 
ü 
 
 
 
 
 
 
Platelet count 
 
ü 
 
 
 
 
 
 
PT/INR 
 
ü 
 
 
 
 
 
 
APTT/ratio 
 
ü 
 
 
 
 
 
 
TEG / ROTEM 
 
ü 
 
 
 
 
 
 

 
 
 
 
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Blood products 
 
 
 
 
ü 
 
 
 
Survival 
 
ü 
 
ü 
ü 
 
ü 
ü 
Length of stay 
 
 
 
 
 
 
 
ü 
Safety 
ü 
ü 
 
 
 
ü 
 
 
Usability 
ü 
 
ü 
 
 
 
 
 
  *if still in hospital 
 
 
 

 
 
 
 
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9. RECRUITMENT TARGETS 
As PhoXSTAT is a feasibility trial, part of the rationale for which is to ascertain the 
number of eligible and recruitable subjects, there are no formal recruitment targets. An 
analysis of registry data from UAB suggests that there are around 10 patients per year 
who might benefit from XSTAT® application. On this basis, we anticipate enrolling a 
maximum of 50 patients, across the three PhoXSTAT sites, over two years.  
 
 

 
 
 
 
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10. STATISTICAL ANALYSIS  
10.1 Feasibility 
We will report the number of patients meeting the inclusion criteria, and the number of 
patients enrolled and randomized into the pilot trial. 
10.2 Usability 
This analysis will also be performed on intervention (XSTAT®) subjects only. We will 
report details for both categories. 
10.3 Safety  
We will identify and report the individual and composite incidence of each of the a priori 
defined adverse events. 
10.4 Efficacy  
We will compare the intervention (XSTAT®) and control groups, with regards to 
outcomes specified. As this is a pilot/feasibility study, no power or sample size 
calculation is required. 
 
 

 
 
 
 
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11. TRIAL MANAGEMENT  
11.1 Trial office  
The PhoXSTAT Trial Office is in the Center for Injury Science, University of Alabama at 
Birmingham, and provides support for the trial sites.   
11.2 Project Management Group 
The Program Manager takes responsibility for the day to day transaction of trial 
activities, such as site set-up and training, oversight of recruitment, etc. The PhoXSTAT 
Project Management Team meets at least weekly during the course of the trial to ensure 
smooth running and trouble-shooting.  
11.3 Local organization in sites 
Local PIs and research assistants are responsible for all aspects of local organization 
including identification of participants, data collection, and notification of any problems or 
unexpected developments for the duration of the trial. Specifically, participating sites will 
also be responsible for liaising with EMS agencies and providers, and for supplying and 
tracking trial intervention packs, including withdrawing packs which have expired.  
Research assistants are responsible for ensuring that study data is collected and logged 
onto the remote web-based data capture system in a timely manner. The site agreement 
documents the full list of responsibilities for sites. Appropriate members of the local team 
must be fully conversant with the trial protocol and have Good Clinical Practice training. 
A delegation log is prepared for each site, detailing the responsibilities of each member 
of staff working on the study. This delegation log is kept at each site and at the Clinical 
Trial Center. 
 
 

 
 
 
 
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12. RESEARCH GOVERNANCE  
12.1 Lead site  
The Center for Injury Science at the University of Alabama at Birmingham is a Clinical 
Trial Center with expertise in running multicenter EFIC clinical trials in the prehospital 
and emergency department setting.  The trial is run under the auspices of CIS aiding 
compliance with research governance and the principles of GCP and providing 
centralized trial administration. 
12.2 Monitoring 
The Principal Investigators ensure that adequate systems are in place for monitoring the 
quality of the trial and appropriate expedited and routine reports, to a level appropriate to 
the risk assessment of the trial. CIS’s Standard Operating Procedures will be followed.  
12.3 Relationship with the manufacturer of the XSTAT® device 
The manufacturers of the XSTAT® device (RevMedxTM) have no role in the design, 
conduct, analysis, or reporting of the trial. The relationship between XSTAT® and the trial 
staff is governed by a Clinical Supply Agreement. We have developed a close working 
relationship with RevMedxTM and will liaise with the company regarding any safety 
issues.  
12.4 Data protection 
Data collected during the course of the research will be kept strictly confidential and 
accessed only by members of the trial team. Participant’s details are stored on a secure 
database and regular checks and monitoring are in place to ensure compliance. The 
data manager (in collaboration with the Principal Investigators) manages access rights to 
the data set. Participants are allocated an individual specific trial number and their 
details are anonymized on the secure database.  

 
 
 
 
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13. HUMAN SUBJECTS RESEARCH 
13.1 FDA Requirements  
This study will enroll approximately 50 patients with Penetrating junctional injuries. The 
study intervention (XSTAT® 12) is approved by the Food and Drug Administration (FDA) 
as a Class II nonsignificant risk medical device under 21 CFR 878.4452 “Non-
absorbable expandable hemostatic sponge for temporary internal use.” Although it is a 
nonsignificant risk device being used in accordance with its defined indications, we are 
required to seek an FDA Investigational Device Exemption (IDE) because it is used in 
this setting in accordance with the regulations for exception from informed consent.  
13.2 Potential risks  
The patients in the feasibility trial will be randomized to one of two treatment arms – 
XSTAT or standard care. Eligible patients for this trial will have been identified as having 
non-compressible (and therefore life-threatening) junctional injuries. As the 
randomization will take place at EMS unit level (rather than patient level), the risk of 
delaying treatment is negligible.  
There is a possibility of some of the sponges, which form part of the device, being 
retained. This could occur because the sponges are not seen (at operation or on x-ray), 
or because they could not be located. Sponge retention could result in problems such as 
infection and pain. 
There is also a theoretical possibility that the wound which the sponges are injected into 
is in continuity with the pleural or peritoneal cavities. This may result in the patient 
requiring an additional procedure or operation, to remove these sponges. 
Lastly, it is possible that, despite the paramedics’ best belief, the bleeding originated 
from tissue, rather than a vascular injury, and might have stopped, or did stop, without 
surgical exploration and repair. In this case, patients might require an operation which 
they might otherwise not have needed. 
Overall, the risks of this study are deemed low.  

 
 
 
 
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13.3 Protection of human subjects 
The reasons for conducting an EFIC trial are outlined in section 6.4. A detailed 
explanation of each criterion stipulated in the regulations for this exception and how our 
trial design applies to these criteria is outlined in Appendix 3.  
 
 

 
 
 
 
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14. ADVERSE EVENT/EFFECT REPORTING 
The XSTAT device is FDA approved, has been in use for some time, and its safety 
profile is well established.(7) Nevertheless, it is possible that adverse events may occur, 
and the trial will collect data on adverse events that may be associated with the use of 
XSTAT. Adverse events will be reviewed by the sponsor, which is the Department of 
Defense. 
14.1 Definitions and classification 
All untoward medical occurrences will be classified by: 
a) Whether they involved a trial participant 
b) Were related to the use of the device  
c) Seriousness  
d) Whether anticipated/unanticipated. 
Note that adverse events are non-device-related medical occurrences, whereas adverse 
effects are caused by the investigational device or procedure.  
14.1.1 Untoward medical occurrence 
An untoward medical occurrence is an unintended disease or injury or untoward clinical 
sign in a trial participant caused by or related to the investigational device, device-related 
procedure, or comparator. Not all complaints about investigational devices have to do 
with untoward medical occurrences. If a complaint does not involve a trial participant or 
other person, it is not medical and is called a “non-medical complaint.” Non-medical 
complaints do not need to be logged. 
14.1.2 Adverse events 
If the untoward medical occurrence did involve a trial participant, but was not related to 
the device, it is an adverse event. These events are further classified as serious adverse 
events (SAE) or non-serious adverse events (AE).  

 
 
 
 
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14.1.3 Serious adverse events  
Serious adverse events are untoward medical occurrences in a subject that are not 
related to the investigational device, comparator, or trial procedures, but that meet the 
criteria of “serious.” A serious adverse event is one that:  
a) Led to a death 
b) Led to a serious deterioration in the health of the subject that:  
i. 
Resulted in a life-threatening illness or injury, or  
ii. 
Resulted in a permanent impairment of a body structure or a body 
function, or 
iii. 
Required in-patient hospitalization or prolongation of existing 
hospitalization, or  
iv. 
Resulted in medical or surgical intervention to prevent life threatening 
illness or injury or permanent impairment to a body structure or a body 
function 
v. 
Led to fetal distress, fetal death, or a congenital abnormality or birth 
defect.  
A planned hospitalization for a pre-existing condition or a condition required by the 
protocol, without serious deterioration in health, is not considered serious.  
14.1.4 Adverse device effects 
An untoward medical occurrence that happened in a subject and is related to the device 
or device procedure (but not the comparator) is an adverse device effect. If the 
occurrence does not meet the definition of serious, it is classified as an adverse device 
effect (ADE). Adverse device effects are a subset of adverse events.  
14.1.5 Serious adverse device effects  
An untoward medical occurrence that happens in a subject, is related to the 
investigational device, comparator, or procedure, and is serious, but is not unanticipated 
is a serious adverse device effect (SADE). Untoward medical occurrences that are not 
unanticipated, i.e. are unsurprising, are identified in the investigator’s brochure or 
protocol and informed consent form.  
As with serious adverse events, a serious adverse device effect is one which  

 
 
 
 
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a) Led to a death 
b) Led to a serious deterioration in the health of the subject that:  
i. 
Resulted in a life-threatening illness or injury, or  
ii. 
Resulted in a permanent impairment of a body structure or a body 
function, or 
iii. 
Required in-patient hospitalization or prolongation of existing 
hospitalization, or  
iv. 
Resulted in medical or surgical intervention to prevent life threatening 
illness or injury or permanent impairment to a body structure or a body 
function 
v. 
Led to fetal distress, fetal death, or a congenital abnormality or birth 
defect.  
A planned hospitalization for a pre-existing condition or a condition required by the 
protocol, without serious deterioration in health, is not considered serious.  
14.1.6 Unanticipated serious adverse device effect 
An untoward medical occurrence that happens in a subject; is related to the 
investigational device, device procedure, or comparator; is serious; and was 
unanticipated is classified as an unanticipated serious adverse device effect (USADE). 
Serious adverse device effect which are anticipated are listed below. 
14.2 Reporting period 
The reporting period includes any adverse events which occurred between 
randomization and discharge. 
14.3 Reporting procedure 
All members of the patient management teams will be instructed as to the possible 
adverse events prior to the start of the trial and will be given an emergency contact 
number to immediately report any suspected adverse event to the site investigators.   
Any possible untoward medical occurrence is identified will be evaluated and classified 
by the site PI, as follows: 
a) Relation to XSTAT device: “Effect” (device-related) vs “event” (device-unrelated) 

 
 
 
 
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b) Seriousness: Serious (meeting the criteria listed above) or not 
c) Anticipated: Anticipated (matching the conditions shown in the list below) or 
unanticipated 
14.3.1 Adverse events (AE)/adverse device effects (ADE) 
Adverse events and adverse device effects which are not deemed serious will be 
recorded using the “PHOXSTAT Adverse Event Recording Form”. 
14.3.2 Anticipated serious adverse events (SAE)/serious adverse device effects (SADE) 
Anticipated adverse device effects include: 
a) XSTAT sponges left in situ after the index operation (either because they cannot 
be located, or because they were overlooked) 
b) XSTAT sponges which entered the peritoneal or pleural cavities 
c) XSTAT sponge embolization 
Anticipated serious adverse events include: 
a) Need for surgical procedure to remove sponges, in the absence of a vascular 
injury requiring ligation or repair 
b) Death unrelated to XSTAT device 
c) Acute Kidney Injury 
d) Acute Lung Injury/Acute Respiratory Distress Syndrome 
e) Cardiac arrest 
f) Pulmonary embolus 
g) Extremity arterial thrombosis 
h) Multi-organ Failure 
i) Myocardial infarction 
j) Ventilator-Associated Pneumonia 
Anticipated serious adverse events and adverse device effects will also be recorded 
using the “PHOXSTAT Adverse Event Recording Form”. In addition, a “PHOXSTAT 
Serious Adverse Event/Serious Adverse Device Effect” form must be completed, and 
emailed to the PHOXSTAT Trial Office (swstephens@uabmc.edu) within 48 hours. All 
reports of anticipated SAE/SADE will be forwarded to the medical monitor. 

 
 
 
 
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14.3.3 Unanticipated serious adverse events/serious adverse device effects (USADE) 
Unanticipated serious adverse events and adverse device effects will also be recorded 
using the “PHOXSTAT Adverse Event Recording Form”. In addition, a “PHOXSTAT 
Unanticipated Serious Adverse Event/Serious Adverse Device Effect” form must be 
completed, and emailed to the PHOXSTAT Trial Office (swstephens@uabmc.edu) within 
48 hours. In addition, the Study PI must be notified, by telephone (205-757-9418) within 
48 hours. 
On notification of a USAE/USADE report, the PHOXSTAT Trial Office will, within 3 
business days: 
a) Forward the report to the medical monitor  
b) Notify the PHOXSTAT DSMB 
c) Notify the UAB IRB 
d) Notify the reporting site’s IRB 
e) Notify the DoD (ORP/HRPO, and USAMRMC) 
In addition, the PHOXSTAT Trial Office will, within 7 days, notify the FDA, using the 
MedWatch form. 
14.4 Role and responsibility of the Independent Medical Monitor 
An independent medical monitor will review all adverse events/effects and provide an 
unbiased written report of the events. At a minimum, the medical monitor must comment 
on the outcomes of the event or problem and in case of a serious adverse event/serious 
adverse device effect, comment on the relationship to participation in the trial. Because a 
moderate number of deaths are expected due to the nature of the injuries, individual 
reports to the PHOXSTAT DSMB will be aggregated and reported on a timely schedule 
acceptable to the DSMB.  
If the death is considered unexpected and is either suspected or probably due to 
treatment, this event will be promptly reported to the DSMB. The medical monitor must 
also indicate whether he/she concurs with the details of the report provided by the 
principal investigator.  
Dr. Patrick Bosarge is the independent medical monitor for this study. He has committed 
to comply with the following statements: 

 
 
 
 
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The monitor: 
a) Is independent of the research team. 
b) Possesses sufficient educational and professional experience to serve as a 
subject advocate. 
c) Will promptly report discrepancies or problems to the IRB. 
14.5 Role and responsibility of the Data and Safety Monitoring Board 
The PHOXSTAT DSMB is a distinct and separate entity and functions independently 
from the sponsor, and the Trial Office. It will be comprised of the following: 
a) Dr. Henry Wang (chairman) 
b) Dr. Stacia DeSantis (statistician) 
c) Dr. John Holcomb (methodologist) 
The DSMB has the authority to stop the research in progress, remove individual subjects 
from the research, and take whatever steps are necessary to protect the safety and well-
being of the subjects until the IRB can assess its reports. 
In addition to reviewing individual reports forwarded by the Independent Medical Monitor, 
the DSMB will, in conjunction with the trial’s biostatistician, conduct interim analyses of 
the data, at intervals of its choosing. The DSMB will meet at least annually, or more 
frequently if deemed necessary. 
 
 

 
 
 
 
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15. QUALITY ASSURANCE 
15.1 Training 
15.1.1 Clinical staff 
All clinical personnel (EMS and hospital-based) undergo initial and continuing training in 
XSTAT® application, which reviews indications, methods of deployment, and removal of 
the sponges. The training also covers the design and objectives of the trial, and data 
collection procedures.  
15.1.2 Research staff 
A Standard Operating Procedure Manual (SOPM) developed by the UAB research team 
provides standard definitions of all study variables (i.e., data elements) and describes all 
data collection and data entry procedures in detail. Copies of the SOPM will be 
distributed to all sites to be used in training each site‘s research team and will be 
available on the study website through UAB CIS.  
Initial training for research assistants and study coordinators is conducted on site. 
Training includes completing the case report forms, obtaining the laboratory data, and 
other procedures described in the SPOM. Training of other study staff is the 
responsibility of trial site coordinators. Training activities will be monitored by the clinical 
and/or data monitoring team through records of training sessions submitted.  
Awareness of the trial protocol in the ED and OR among all staff members is important. 
Sites will be responsible for orientation and education of all ED personnel on the study to 
ensure that those designated to collect data are notified of eligible patients upon arrival. 
Sites may wish to take advantage of staff meetings and in-services to inform and 
educate the ED staff. Also, the support and collaboration of hospital administrators and 
physicians can facilitate recruitment and data collection in the ED and OR. The 
additional tasks required of a research protocol may be taxing in a busy ED setting and, 
without a show of support from management, procedures outside patient treatment may 
be inconsistent. The trial sites are responsible for establishing and maintaining coalitions 
with physicians and hospital administrators to ensure they become stakeholders and 
receive recognition for their part in the trial.  

 
 
 
 
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15.2 Study Monitors 
The study monitors will report to UAB. Monitors will be trained in trial procedures, trained 
to identify source documentation, to assess regulatory compliance, to review source 
documents for agreement with study records, to identify possible unreported adverse 
events, and to look for protocol violations. Sites will be visited periodically to assess data 
quality, review training logs, and monitor study enrollment.   

 
 
 
 
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16. PROJECT TIMELINE  
16.1 Summary/Gantt Chart 
 
16.2 Detailed description/Milestones 
16.2.1 Year 1: Planning Phase 
Task & Timeline 
Notes 
Develop and document 
industry partnerships 
necessary for conduct of the 
clinical trial (Months 0-3) 
We will formalize a contractual agreement between 
UAB and RevMedxTM, Inc., to include at a minimum, 
intellectual property rights, and data ownership. 
YEAR 1
PLANNING AND PREPARATION PHASE
2018
2019
Oct
Nov
Dec
Jan
Feb
Mar
Apr
May
Jun
Jul
Aug
Sep
Finalize RevMedx Contract
Execute CTA with Sites
Develop Protocol
Develop Randomization Mechanism
Develop & test database
Conduct community consultation & public disclosure
Obtain HARPO approval
Obtain IRB approval
Investigator's Meeting  (kick-off meeting)
Train study personnel
Site 1 set-up (UAB)
Site 1 Enrollment Begins (UAB)
Site 2 set-up (USC)
Site 2 Enrollment Begins (USC)
Site 3 set-up (Vandy)
Site 3 Enrollment Begins (Vandy)
YEAR 2
EXECUTION PHASE
2020
Oct
Nov
Dec
Jan
Feb
Mar
Apr
May
Jun
Jul
Aug
Sep
Enrollment
YEAR 3
EXECUTION PHASE (cont'd)
2021
Oct
Nov
Dec
Jan
Feb
Mar
Apr
May
Jun
Jul
Aug
Sep
Enrollment
YEAR 4
EXECUTION PHASE (cont'd)
2022
Oct
Nov
Dec
Jan
Feb
Mar
Apr
May
Jun
Jul
Aug
Sep
Enrollment
Analysis
Report/Publication
ANALYSIS PHASE

 
 
 
 
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Liaison with additional sites 
(Months 3-6) 
Liaise with two additional trauma centers/EMS 
providers willing to participate in the trial.  
Develop protocol, case report 
forms, and study database 
(Months 0-6) 
We will develop and finalize the clinical trial protocol 
including a manual of procedures. We will test and 
finalize case report forms (CRF) for the study. 
(Sample data collection form in Appendix 2)  
Obtain HRPO approval 
(Months 0-12) 
 
All US Army Medical Research and Materiel 
Command (USAMRMC) supported research involving 
humans, human data, human specimens, or 
cadavers must be reviewed for compliance with 
Federal and Department of Defense (DoD) human 
subjects protection requirements and approved by 
the Office of Research Protections (ORP). The ORP 
has two human subjects protection review and 
compliance oversight offices, the Human Research 
Protections Office (HRPO) and the Clinical 
Investigations Regulatory Office (CIRO). Our 
research team has considerable experience obtaining 
HRPO approval.  
Obtain IRB approval (Months 
4-9) 
Once the protocol is finalized, we will obtain 
appropriate Institutional Review Board (IRB) 
approvals.  
Conduct Exception From 
Informed Consent Community 
Consultation and Public 
Disclosure Activities (Month 6-
12) 
The study will be carried out under federal Exception 
from Informed Consent (EFIC) regulations. We will 
conduct all required EFIC community consultation 
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Training (Months 11-12) 
Once the protocol is approved by HRPO and the 
UAB IRB, we will coordinate prehospital protocol 
training. The study team will provide training for all 
prehospital care providers, and additional training for 
trauma surgeons for the removal of XSTAT® devices.  
16.2.2  Year 2/3: Trial Execution Phase 
Task & Timeline 
Notes 
Enrollment (Months 13-36) 
Subject recruitment 
16.2.3 Year 3/4: Data Analysis Phase 
Task & Timeline 
Notes 
Data Analysis (Months 25-42) 
While data analysis will be ongoing throughout the 
trial, detailed final analyses will be commenced 
during the last year of trial enrollment. We will require 
6 months after trial completion to complete final data 
cleaning and analysis. 
 
 

 
 
 
 
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17. REFERENCES 
1. 
Institute NT. Trauma Statistics  [Available from: https://www.nattrauma.org/what-
is-trauma/trauma-statistics-facts/. 
2. 
Kauvar DS, Lefering R, Wade CE. Impact of hemorrhage on trauma outcome: an 
overview of epidemiology, clinical presentations, and therapeutic considerations. J 
Trauma. 2006;60(6 Suppl):S3-11. 
3. 
Eastridge BJ, Mabry RL, Seguin P, Cantrell J, Tops T, Uribe P, et al. Death on 
the battlefield (2001-2011): implications for the future of combat casualty care. J Trauma 
Acute Care Surg. 2012;73(6 Suppl 5):S431-7. 
4. 
Kelly JF, Ritenour AE, McLaughlin DF, Bagg KA, Apodaca AN, Mallak CT, et al. 
Injury severity and causes of death from Operation Iraqi Freedom and Operation 
Enduring Freedom: 2003-2004 versus 2006. J Trauma. 2008;64(2 Suppl):S21-6; 
discussion S6-7. 
5. 
Kauvar DS, Sarfati MR, Kraiss LW. National trauma databank analysis of 
mortality and limb loss in isolated lower extremity vascular trauma. J Vasc Surg 
2011;53:1598-603 
6.  
Bowley DM, Jansen JO, Nott D, Sapsford W, Streets CG, Tai NR. Difficult 
decisions in the surgical care of military casualties with major torso trauma. J R Army 
Med Corps. 2011;157(3 Suppl 1):S324-33. 
6. 
RevMedx. XStat  [Available from: https://www.revmedx.com/xstat. 
7. 
Warriner Z, Lam L, Matsushima K, Benjamin E, Strumwasser A, Demetriades D, 
et al. Initial Evaluation of the Efficacy and Safety of In-Hospital Expandable Hemostatic 
Minisponge Use In Penetrating Trauma. J Trauma Acute Care Surg. 2018. 
 
 
 

 
 
 
 
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18. APPENDICES 
Appendix  1: Sample tracking label 
The tracking labels are found inside the study packs. They are printed on stiff, waterproof 
card, are hole-punched, and be supplied with a tie. The label should be completed as 
directed, and then attached to the patient’s wrist or ankle. Labels are specific to trial sites. 
 
 
 
 

 
 
 
 
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Appendix  2: Data Dictionary Codebook 
 

 
 
 
 
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