A Prospective, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Large Simple Trial Evaluating the Use of BE1116 (4-Factor Prothrombin Complex Concentrate [Kcentra® / Beriplex®]) to Improve Survival in Patients With Traumatic Injury and Acute Major Bleeding
Phase: PHASE3
Conditions: Traumatic Injury
Sponsor: CSL Behring

 
Protocol version: Amendment 2 
 
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Effective Date: Week commencing 25-June-2018 
CLINICAL STUDY PROTOCOL 
 
A Prospective, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Large 
Simple Trial Evaluating the Use of BE1116 (4-Factor Prothrombin Complex 
Concentrate [Kcentra® / Beriplex®]) to Improve Survival in Patients with Traumatic 
Injury and Acute Major Bleeding 
Study Number: 
BE1116_3006 
Study Product: 
BE1116 (Kcentra® / Beriplex®; 4-Factor Prothrombin Complex 
Concentrate [Human]) 
Development Phase: 
Phase 3 
Short Title: 
Evaluation of BE1116 (4F-PCC) in patients with traumatic 
injury and acute major bleeding to improve survival 
Sponsor: 
CSL Behring LLC 
1020 First Avenue 
King of Prussia 
PA 19406, USA 
Protocol Version: 
Amendment 2  
EudraCT Number: 
2021-005060-21 
IND Number: 
27983 
Protocol Date: 
06 February 2024  
Compliance: 
This study will be conducted in accordance with standards of 
Good Clinical Practice (as defined by the International Council 
for Harmonisation) and all applicable national and local 
regulations 

CSL Behring 
Study Number: 
BE1116_3006 
 
Study Product: 
4F-PCC 
 
Protocol version: Amendment 2 
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Date: 06 February 2024 
 
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Effective Date: Week commencing 25-June-2018 
LIST OF PERSONNEL AND ORGANIZATIONS RESPONSIBLE FOR CONDUCT 
OF THE STUDY 
A list of personnel and organizations responsible for the conduct of the study will be supplied 
to study sites as part of the Investigator’s Study File. This list will be updated by 
CSL Behring (or delegate) and provided to the study sites as needed. 
Where the phrase site “investigator” is written in this protocol, the site “sub-investigator” 
who is on the delegation log and has appropriate training can also have the responsibility 
mentioned for the investigator, when in accordance with Applicable Law. 
REVISION HISTORY 
Date 
Version  
Summary of Changes 
22 October 2021 
Original 
Not applicable 
20 June 2022 
Amendment 1 
(Global) 
See Summary of Changes document for a description of all 
changes since the Original version of the protocol, together with 
the rationale for changes. 
See the redline version of Global Amendment 1 for viewing of all 
tracked changes since the Original version. 
06 February 2024 
Amendment 2 
(Global) 
See Summary of Changes document for a description of all 
changes since Global Amendment 1, together with the rationale for 
changes. 
See the redline version of Global Amendment 2 for viewing of all 
tracked changes since Global Amendment 1. 
 

CSL Behring 
Study Number: 
BE1116_3006 
 
Study Product: 
4F-PCC 
 
Protocol version: Amendment 2 
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Date: 06 February 2024 
 
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Clinical Study Protocol Synopsis 
Title 
A Prospective, Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Large Simple Trial Evaluating the Use of 
BE1116 (4-Factor Prothrombin Complex Concentrate 
[Kcentra® / Beriplex®]) to Improve Survival in Patients with 
Traumatic Injury and Acute Major Bleeding 
Study Number 
BE1116_3006 
Sponsor 
CSL Behring (CSL) 
Development Phase Phase 3 
Study Product 
BE1116 (Kcentra® / Beriplex®; 4-factor prothrombin complex 
concentrate [human]) 
Indication 
Treatment of acute major bleeding associated with traumatic injury 
Study Summary 
and Overview 
This is a prospective, multicenter, randomized, double-blind, 
placebo-controlled, parallel-group, large simple trial to investigate 
the efficacy and safety of a single intravenous (IV) infusion of 
BE1116 in subjects who have traumatic injury, with confirmed or 
suspected acute major bleeding and / or predicted to receive a large 
volume blood product transfusion. 
Randomization will be in a 1:1 ratio (BE1116:placebo) and 
stratified by study site. 
Subjects will receive a single IV infusion of either BE1116 or 
placebo, in addition to the study site’s standard resuscitation 
methods and protocol. 
The dose of BE1116 will be either 2000 IU or 3000 IU, based on 
the weight of the subject that is estimated or measured on arrival at 
the hospital: 
• Weight < 75 kg (< 165 lbs): 2000 IU 
• Weight ≥ 75 kg (≥ 165 lbs): 3000 IU 
The study consists of: (i) a Screening and Randomization 
(Enrollment) Period; (ii) a Treatment Period; and (iii) an In-hospital 
Follow-up Period. 
Screening and Randomization (Enrollment) Period 
Screening will begin once the subject has arrived at the hospital, and 
eligibility will be assessed. This study involves subjects who cannot 
be prospectively identified and who have life-threatening medical 
conditions necessitating emergent intervention. Because of the 

CSL Behring 
Study Number: 
BE1116_3006 
 
Study Product: 
4F-PCC 
 
Protocol version: Amendment 2 
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Date: 06 February 2024 
 
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Effective Date: Week commencing 25-June-2018 
subjects’ conditions, the emergent need for intervention, and the 
limited treatment window during which the investigational product 
(IP) must be administered for potential efficacy, it is anticipated that 
obtaining prospective Informed Consent from subjects or their 
Legally Acceptable Representatives may not be possible. For these 
reasons, the study will be conducted under emergency research 
Applicable Law which allows subjects to be enrolled into qualifying 
research without obtaining prospective Informed Consent. However, 
attempts to collect prospective Informed Consent must be made, if 
feasible, in accordance with Applicable Laws, and if prospective 
Informed Consent can be obtained from a subject or their Legally 
Acceptable Representative prior to enrollment, such Informed 
Consent must be obtained. Study sites must reference their 
country-specific Study Consent Manual (where available) for 
additional requirements. Study sites must follow Applicable Laws in 
the conduct of the study and should consult their legal counsel and 
Institutional Review Board (IRB) or Independent Ethics Committee 
(IEC) for any advice or guidance with respect to any Applicable 
Laws and IRB or IEC requirements. 
Once a subject meets all the eligibility criteria, the trauma team (or 
other applicable site staff) will select and open the IP study kit (for 
IP reconstitution and administration) with the next available 
sequential subject number, and the subject will be considered 
randomized (enrolled). The date and time of opening the IP study 
kit (randomization) will be recorded. 
Treatment Period 
The start of the IP infusion must be within 90 minutes after arrival 
at the hospital. 
Blinded, sealed IP study kits containing either BE1116 or placebo 
will be maintained in the trauma bay, or a location where they are 
readily accessible, at the study site at all times during the study. 
In-hospital Follow-up Period 
If Informed Consent is not obtained from a subject or their Legally 
Acceptable Representative prior to randomization, Informed 
Consent for continued participation will be sought after 
randomization in accordance with the country-specific Study 
Consent Manual (where available) and where required by 
Applicable Laws. Similarly, if during the study a subject regains 
capacity after they are enrolled, Informed Consent for continued 
participation from the subject shall be sought pursuant to the 
country-specific Study Consent Manual (where available) and 
where required by Applicable Laws. Study sites must reference 

CSL Behring 
Study Number: 
BE1116_3006 
 
Study Product: 
4F-PCC 
 
Protocol version: Amendment 2 
Page 5 of 108 
Date: 06 February 2024 
 
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Effective Date: Week commencing 25-June-2018 
their country-specific Study Consent Manual (where available) for 
additional requirements. Study sites must follow Applicable Laws 
in the conduct of the study. 
During the primary hospitalization, efficacy and safety data will be 
collected up to the time of death / hospital discharge / Day 30, 
whichever occurs first. If subject is discharged alive prior to 
6 hours, then the subject will be followed up to assess 6-hour 
survival status, serious adverse events (SAEs), and adverse events 
of special interest (AESIs). Primary hospitalization is defined as the 
initial hospitalization following the trauma. 
An Independent Data Monitoring Committee (IDMC) will review 
results periodically during the study. 
Primary Objective 
The primary objective is to assess the efficacy of a single IV 
infusion of BE1116 on all-cause mortality within 6 hours after 
randomization in subjects who have traumatic injury, with 
confirmed or suspected acute major bleeding and / or predicted to 
receive a large volume blood product transfusion. 
Primary Endpoint 
The primary endpoint is all-cause mortality within 6 hours after 
randomization. 
Secondary 
Objectives 
1. To assess all-cause in-hospital mortality up to 24 hours after 
randomization 
2. To assess all-cause in-hospital mortality up to 30 days after 
randomization 
3. To assess the requirement for surgical or interventional 
radiological procedures to stop bleeding related to the primary 
injury up to 24 hours after randomization 
4. To assess the safety of BE1116  

CSL Behring 
Study Number: 
BE1116_3006 
 
Study Product: 
4F-PCC 
 
Protocol version: Amendment 2 
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Date: 06 February 2024 
 
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Secondary 
Endpoints 
1. All-cause in-hospital* mortality up to 24 hours after 
randomization 
2. All-cause in-hospital* mortality up to 30 days after 
randomization 
3. Surgical or interventional radiological procedures to stop 
bleeding related to the primary injury up to 24 hours after 
randomization 
4. SAEs considered related to IP; and AESIs: 
• Thromboembolic events (TEEs), symptomatic or 
asymptomatic, and arterial or venous (eg, deep vein 
thrombosis, pulmonary embolism, ischemic stroke [including 
thromboembolic stroke], myocardial infarction) 
• Acute respiratory distress syndrome (ARDS) 
• Multiple organ failure 
• Acute kidney injury (AKI) requiring renal replacement 
therapy (dialysis, hemofiltration, or hemodiafiltration) 
Note: superficial thromboses will not be included as AESIs 
 
*In-hospital mortality will only be recorded and assessed for the 
primary hospitalization. 
Study Duration 
The study duration for an individual subject who dies while on the 
study is up to the time of death. For other subjects, the study 
duration is at least 6 hours and ends with hospital discharge, or 
30 days, whichever comes first. If the subject is discharged alive 
prior to 6 hours, then the subject will be followed up to assess 
6-hour survival status, SAEs, and AESIs. The overall study 
duration (ie, from screening of first subject through the end of the 
last subject’s In-hospital Follow-up Period) will be approximately 
3 years. 
Number of 
Subjects 
It is planned to enroll up to 8000 subjects (4000 per treatment arm). 
 
 

CSL Behring 
Study Number: 
BE1116_3006 
 
Study Product: 
4F-PCC 
 
Protocol version: Amendment 2 
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Date: 06 February 2024 
 
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Effective Date: Week commencing 25-June-2018 
Study Population 
and Criteria for 
Eligibility 
Inclusion criteria 
1.A2. (a) Estimated or actual age ≥ 15 years. Older minimum age is 
required in some locations. 
FOR United Kingdom: Estimated or actual age ≥ 16 years 
FOR Australia: Estimated or actual age ≥ 18 years 
AND 
(b) Estimated or actual weight ≥ 50 kg (110 lbs) 
2.A1. Traumatic injury with: (a) confirmed or suspected acute major 
bleeding; and / or (b) Revised Assessment of Bleeding and 
Transfusion (RABT) score ≥ 2 
3.A1. Not applicable. Criterion 3 was deleted at Global 
Amendment 1 
4. Activation of massive transfusion protocol 
5.A2. Initiation of blood product transfusion (Whole Blood or Red 
Blood Cells or Platelets or Plasma has started to enter the 
patient’s body) 
6.A1. Anticipated start of IP infusion within 90 minutes after arrival 
at the hospital 
Exclusion criteria 
1.A2. Healthcare professional cardiopulmonary resuscitation 
including chest compressions for ≥ 5 consecutive minutes at 
any time before randomization 
2. Isolated penetrating or blunt cranial injury, or exposed brain 
matter 
3. Known anticoagulation treatment or a history of a TEE, within 
the past 3 months 
4.A1. Isolated burns estimated to be > 20% total body surface area 
or suspected inhalational injury 
5. Ground level fall 
6. Drowning or hanging 
7. Subject transferred from another hospital 
8. Known heparin-induced thrombocytopenia 
9. Known hereditary disorders that significantly increase 
prothrombotic risk such as hereditary antithrombin III 
deficiency, Factor V Leiden, etc. 
10. Known or suspected pregnancy 
11. Known anaphylactic or severe systemic reactions to BE1116 or 
any components in BE1116 including heparin, Factors II, VII, 
IX, X, Proteins C and S, antithrombin III, and human albumin 

CSL Behring 
Study Number: 
BE1116_3006 
 
Study Product: 
4F-PCC 
 
Protocol version: Amendment 2 
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12.A2. Known prisoner at time of enrollment 
13. Known “Do Not Resuscitate” order 
14.A2. (a) FOR all study sites: Subject or Legally Acceptable 
Representative voiced an objection to participation in the 
trial 
 
OR 
 
(b) FOR United States: A family member voiced an 
objection to participation in the trial or subject was wearing 
an “opt-out” bracelet. 
15.A1. Known participation in another interventional clinical study 
except with prior documented agreement from the sponsors 
16.A1. Known treatment with any prohibited medications including 
3F-PCC, 4F-PCC, aPCC (FEIBA), and / or Factor VIIa after 
trauma and prior to randomization 
17.A2. Normal level of consciousness (Glasgow Coma Scale score 
of 15). 
18.A2. Moribund patient with devastating injuries expected to die 
within 1 hour of hospital arrival. 
Study Product 
Dose, Dosing 
Regimen and 
Administration  
BE1116 (4-factor prothrombin complex concentrate [4F-PCC] 
containing human coagulation Factors II, VII, IX, and X, Protein C, 
and Protein S), powder for reconstitution with sterile water for 
injection 
A single dose will be administered by IV infusion. The dose is 
dependent on body weight (estimated or measured): 
• Weight < 75 kg (< 165 lbs): 2000 IU 
• Weight ≥ 75 kg (≥ 165 lbs): 3000 IU 
Comparator 
Product, Dose, 
Dosing Regimen 
and Administration 
Placebo to match BE1116 

CSL Behring 
Study Number: 
BE1116_3006 
 
Study Product: 
4F-PCC 
 
Protocol version: Amendment 2 
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Date: 06 February 2024 
 
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Effective Date: Week commencing 25-June-2018 
Efficacy 
Assessments 
Efficacy data will be recorded from medical records. 
The survival status of the subject during primary hospitalization 
will be recorded from randomization up to the time of death, 
hospital discharge, or Day 30, whichever occurs first. The survival 
status check during primary hospitalization will be at 24 hours. 
If subject is discharged alive prior to 6 hours, then the subject will 
be followed up to assess 6-hour survival status, SAEs, and AESIs. 
Surgical or interventional radiological procedures performed to stop 
bleeding related to the primary injury, through the first 24 hours 
after randomization, will be recorded. 
Transfusion of blood products and IV fluids administered before 
arrival at the hospital through the first 24 hours after randomization 
will be recorded. 
Safety Assessments 
SAEs and AESIs will be recorded from the time of randomization 
through the end of the In-hospital Follow-up Period in each subject 
(ie, up to the time of death / hospital discharge / Day 30, whichever 
occurs first; if subject is discharged alive prior to 6 hours, then the 
subject will be followed up to assess 6-hour survival status, SAEs, 
and AESIs). 
Pregnancy status will be recorded from medical records (if 
available); pregnancies in female subjects will also be recorded. 
Daily assessments of ARDS, multiple organ failure, and AKI 
requiring renal replacement therapy will be recorded when a subject 
is in the intensive care unit (ICU). ICU assessments will be 
collected from the medical record of the subject using data 
collected as part of standard of care. 
Other Assessments 
To assess medical resource utilization, start and stop dates and 
times of ventilator use, time in the ICU, and primary hospitalization 
will be recorded. 
Statistical Analyses 
The Intent-to-treat (ITT) Population will include all randomized 
subjects. The Modified ITT (mITT) Population will include all 
subjects who receive a complete or partial dose of BE1116 or 
placebo. In these populations, analyses will be based on the 
treatment to which subjects were randomized, regardless of which 
treatment they actually received. The Per-protocol (PP) Population 
will include all subjects in the ITT Population with no major 
protocol deviations that would potentially affect the assessment of 
the primary endpoint. 

CSL Behring 
Study Number: 
BE1116_3006 
 
Study Product: 
4F-PCC 
 
Protocol version: Amendment 2 
Page 10 of 108 
Date: 06 February 2024 
 
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Effective Date: Week commencing 25-June-2018 
The Safety Population will include all subjects in the ITT 
Population who receive a complete or partial dose of BE1116 or 
placebo, based on the treatment actually received. 
Primary efficacy endpoint 
A Bayesian logistic regression will be used to compare all-cause 
mortality rate during the first 6 hours after randomization between 
the BE1116 and placebo arms, in the ITT Population. 
Null Hypothesis: The all-cause 6-hour mortality rate in BE1116 is 
no better than control. 
Alternative Hypothesis: The all-cause 6-hour mortality rate in 
BE1116 is lower than control. 
Interim analyses will occur when 1/4 (2000), 1/2 (4000), and 
3/4 (6000) of the targeted 8000 subjects have data for the primary 
outcome. A group sequential approach will be utilized. The study 
may be stopped if futility (nonbinding) criteria are met at any of the 
three planned interim analyses, or if efficacy criteria are met at 
Interim Analysis 2 or 3. The success threshold for each applicable 
interim analysis and final analysis will be calibrated to protect 
overall type I error at 2.5% depending on the actual number of 
subjects with data on the primary outcome. 
The study will continue to enroll 8000 subjects unless it is stopped 
for success or futility at one of the interim analyses. 
The following subgroups will be analyzed as subgroup analysis and 
sensitivity analysis for the primary endpoint: mechanism of trauma 
injury (any penetrating versus blunt), sex (male versus female), age 
(< 18 years versus 18 to 25 years versus 26 to 64 years versus 
> 64 years), weight-based dosing (2000 IU versus 3000 IU), and 
cause of death (hemorrhage versus non-hemorrhage). Additional 
subgroup and sensitivity analyses may be defined in the statistical 
analysis plan. 
Secondary efficacy endpoints 
After the primary endpoint is deemed successful, the 
efficacy-related secondary endpoints will be analyzed sequentially. 
A gated testing approach will be used to account for multiplicity, 
and testing will proceed in a stepwise manner conditioned on 
observing a statistically significant result at each endpoint. 
All secondary efficacy endpoints will be analyzed using the ITT, 
mITT, and PP Populations. All-cause in-hospital mortality up to 
hospital discharge or 24 hours after randomization (whichever 
occurs first), and all-cause in-hospital mortality up to hospital 
discharge or 30 days after randomization (whichever occurs first), 

CSL Behring 
Study Number: 
BE1116_3006 
 
Study Product: 
4F-PCC 
 
Protocol version: Amendment 2 
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Date: 06 February 2024 
 
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will be analyzed and summarized in the same manner as for the 
primary endpoint. The difference in proportion of subjects who 
undergo surgical or interventional radiological procedures to stop 
bleeding related to the primary injury up to 24 hours after 
randomization will be analyzed and summarized in a manner 
similar to the primary endpoint. Secondary efficacy endpoints will 
also be analyzed using the same subgroups listed above. 
Safety endpoints 
The safety endpoints will be assessed using the Safety Population, 
unless otherwise noted. The number and proportion of subjects with 
SAEs considered related to IP that occurred during primary 
hospitalization within the 30 days after randomization will be 
summarized by treatment arm. In-hospital TEEs and AESIs will 
also be summarized by treatment arm. 
 
 

CSL Behring 
Study Number: 
BE1116_3006 
 
Study Product: 
4F-PCC 
 
Protocol version: Amendment 2 
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Effective Date: Week commencing 25-June-2018 
Schedule of Assessments 
Study Period 
ScreeningA and Randomization 
(Enrollment) Period 
Treatment Period B 
In-hospital Follow-up Period 
Study Day 
1 
Up to Death / Hospital Discharge / Day 30 C 
Time Point 
0 to 90 minutes after hospital arrival 
0 to 24 hours 
post-randomization 
Up to 30 days 
post-randomization 
Informed Consent D 
X 
 
 
 
Informed Consent for 
Continued Participation D 
 
X 
X 
X 
Vital Signs, Body Weight, 
Height E 
X 
 
 
 
Glasgow Coma Scale F 
X 
 
 
 
RABT Score G 
X 
 
 
 
Inclusion and Exclusion 
Criteria H 
X 
 
 
 
IP Study Kit Opened 
(Randomized [Enrolled]) I 
X 
 
 
 
Hematology, Coagulation, 
and Arterial or Venous 
Blood Gas J 
X 
 
 
 
Start of IP Infusion K 
 
X 
 
 
IP Accountability L 
 
X 
X 
 
SAEs and AESIs M 
X 
X 
X 
X 
Recordings From Medical 
Records (as applicable): 
 
 
 
 
Demographics N 
X 
Medical History, Charlson 
Comorbidity Index O 
X 
Prior / Concomitant 
Medications P 
X 
X 
X 
X 
Concomitant Procedures Q 
X 
X 
X 
X 
Survival Status - Date and 
Time of Death R 
X 
X 
X 

CSL Behring 
Study Number: 
BE1116_3006 
 
Study Product: 
4F-PCC 
 
Protocol version: Amendment 2 
Page 13 of 108 
Date: 06 February 2024 
 
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Effective Date: Week commencing 25-June-2018 
Study Period 
ScreeningA and Randomization 
(Enrollment) Period 
Treatment Period B 
In-hospital Follow-up Period 
Study Day 
1 
Up to Death / Hospital Discharge / Day 30 C 
Time Point 
0 to 90 minutes after hospital arrival 
0 to 24 hours 
post-randomization 
Up to 30 days 
post-randomization 
Blood Product 
Transfusions, IV Fluids S 
X 
X 
X 
 
Surgical and Interventional 
Radiological Procedures 
Through First 24 Hours 
After Randomization T 
X 
X 
X 
 
Mode of Transport U 
X 
Life-saving Interventions V 
X 
X 
X 
 
Mechanism of Injury W 
X 
Date and Time of Call to 
Emergency Services and 
Arrival at Trauma Scene X 
X 
Hospital Arrival Time and 
Hospital Admission  
Time Y 
X 
Injury Severity Score Z 
X 
Pregnancy Status ZA 
X 
ICU Assessments ZB 
 
 
X 
X 
Medical Resource 
Utilization ZC 
X 
Discharge / Transfer 
Location ZD 
X 
AESI = adverse event of special interest; AKI = acute kidney injury; ARDS = acute respiratory distress syndrome; eCRF = electronic case report form; 
ICU = intensive care unit; IEC = Independent Ethics Committee; IP = investigational product; IRB = Institutional Review Board; IRT = interactive response 
technology; IV = intravenous; min = minute(s); RABT = Revised Assessment of Bleeding and Transfusion; SAE = serious adverse event. 
A 
Screening assessments must be performed prior to randomization but may be recorded in the eCRF after randomization. 
B 
Treatment period is defined as the start of IP infusion through the completion of IP infusion. 

CSL Behring 
Study Number: 
BE1116_3006 
 
Study Product: 
4F-PCC 
 
Protocol version: Amendment 2 
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Effective Date: Week commencing 25-June-2018 
C 
Subjects will be followed up until death, discharge from hospital, or Day 30, whichever occurs first. Transfer to another healthcare facility will be considered 
as discharge from hospital. If subject is discharged alive prior to 6 hours, then the subject will be followed up to assess 6-hour survival status, SAEs, and 
AESIs. 
D 
Informed Consent according to Applicable Laws. Study sites must reference their country-specific Study Consent Manual (where available). Study sites must 
follow Applicable Laws in the conduct of the study. For the avoidance of doubt, this definition of Informed Consent includes assent of a minor subject along 
with corresponding Informed Consent of their Legally Acceptable Representative, when allowed by Applicable Law. Informed Consent, Applicable Law, and 
Legally Acceptable Representative are as defined in Appendix 8. 
E 
Vital signs obtained as part of standard of care will be recorded at Screening prior to infusion, except as described. These include supine systolic and 
diastolic blood pressure (mmHg), pulse rate (bpm), respiratory rate (breaths per min), pulse oximetry (%), and body temperature (°C). Body weight (kg) will 
be estimated or measured on arrival at the hospital and used to define the dose of IP. If estimated, weight may also be subsequently measured. Height (cm) 
will be measured or taken from medical history. 
F 
Glasgow Coma Scale to be assessed at Screening and record individual components if available, otherwise total score; see Appendix 3. 
G 
If applicable. RABT score ≥ 2 may be used to fulfill inclusion criterion assessment. 
H 
All eligibility criteria should be met, including initiation of blood product transfusion (Whole Blood or Red Blood Cells or Platelets or Plasma has started to 
enter the patient’s body). 
I 
Time zero (0 hours) = IP study kit opened (randomization) after eligibility has been checked. 
J 
To be recorded from medical records (if available). The initial hematology, coagulation, and blood gas measurements only will be recorded in the eCRF from 
medical records. Initial = the first value obtained after arrival at the hospital prior to IP infusion. Hematology includes hemoglobin, hematocrit, and platelets; 
coagulation includes international normalized ratio and / or prothrombin time; and arterial or venous blood gas (if reported by clinical laboratory:  base 
excess; if base excess not reported by clinical laboratory, then the study site will collect the following parameters so that base excess can be calculated: pH, 
pCO2, pO2, and HCO3). 
K 
The start of the IP infusion needs to occur within 90 minutes after arrival at the hospital. 
L 
IP accountability will be performed in the IRT system when feasible within 24 hours after randomization. 
M All SAEs and AESIs will be recorded, reviewed, and assessed for relatedness. The observation period for the reporting of SAEs and AESIs for an individual 
subject will start at the time of randomization and finish with the end of the In-hospital Follow-up Period (ie, up to the time of death / hospital discharge / 
Day 30, whichever occurs first; if subject is discharged alive prior to 6 hours, then the subject will be followed up to assess 6-hour survival status, SAEs, and 
AESIs). 
N 
Demographics will be recorded when feasible. Demographic data include sex, race, ethnicity, and other factors according to the eCRF and regulatory and 
local requirements. Either actual age or estimated age will be collected during Screening. The actual age of subjects will be recorded, once confirmed. An 
enrolled subject whose confirmed age does not meet the inclusion criteria must be reported to Sponsor and the IRB / IEC as a prompt reporting event. 
O 
Medical history and the Charlson Comorbidity Index (see Appendix 6) will be recorded in the eCRF when feasible. Medical history should include all 
bleeding and coagulation history and surgical conditions, and any other pertinent findings. 
P 
Medications that impact bleeding and coagulation (including antiplatelets) for at least 1 week prior to randomization will be recorded when feasible. 
Tranexamic acid (if administered) should be recorded. Prohibited concomitant medications administered from trauma time through 6 hours after 
randomization should be recorded. Any anticoagulants, thrombolytic agents, and procoagulants used to treat AESIs at any time through the study will be 

CSL Behring 
Study Number: 
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Study Product: 
4F-PCC 
 
Protocol version: Amendment 2 
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Effective Date: Week commencing 25-June-2018 
recorded. In-hospital low-dose prophylactic anticoagulants are not considered concomitant medications. 
Q 
Any surgical or interventional radiological procedures, or other life-saving interventions, used to treat an SAE or AESI at any time through the study will be 
recorded as a concomitant procedure. 
R 
The survival status of the subject during primary hospitalization will be recorded from randomization up to the time of death, hospital discharge, or Day 30, 
whichever occurs first. The date and time of death / hospital discharge / Day 30 will be recorded, as applicable. The survival status check during primary 
hospitalization will be at 24 hours (the date and time of death / hospital discharge will be recorded, as applicable). If subject is discharged alive prior to 
6 hours, then the subject will be followed up to assess 6-hour survival status, SAEs, and AESIs. The primary cause of death, as determined by the 
investigator, will be recorded. 
S 
Transfusion of blood products before arrival at the hospital through the first 24 hours after randomization will be recorded according to the period in which 
the blood component transfusion started: before arrival at the hospital; from arrival at the hospital to the time of randomization; from randomization to 
6 hours after randomization; and from 6 to 24 hours after randomization. Administration of IV fluids will also be recorded for the same time periods. 
T 
All surgical or interventional radiological procedures performed to stop bleeding related to the primary injury, through the first 24 hours after randomization, 
will be recorded. 
U 
Mode of transport to the hospital will be recorded. 
V 
Prehospital life-saving interventions and any life-saving interventions performed on arrival at the hospital, will be recorded. 
W Mechanism of injury (blunt, penetrating, or both) will be recorded. 
X 
If applicable and available. 
Y 
Hospital arrival time and hospital admission time may be the same time, but should be recorded per study site processes. Hospital arrival time will determine 
timing of IP administration. 
Z 
The Injury Severity Score will be calculated and recorded (Appendix 4). The Injury Severity Score may be calculated after study completion. 
ZA To be recorded from medical records (if available). Pregnancies in female subjects will be recorded. 
ZB Daily assessments for ARDS, multiple organ failure, and AKI requiring renal replacement therapy will be recorded when a subject is in the ICU. ICU 
assessments will be collected from the medical record of the subject using data collected as part of standard of care. 
ZC Medical resource utilization: start and end dates and times of ventilator use, days in ICU, and days in hospital during primary hospitalization will be 
recorded. 
ZD Discharge / transfer information will be recorded (eg, transferred to another hospital, transferred to skilled nursing facility, transferred to in-patient 
rehabilitation, discharged to home, or transitioned to comfort care / palliative care). If subject is discharged within 2 days of enrollment, discharge time will 
also be recorded. Additionally, if the subject is designated “do not resuscitate”, the date and time (where applicable) will be recorded. 
 

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Table of Contents 
Clinical Study Protocol Synopsis .............................................................................................. 3 
Schedule of Assessments ......................................................................................................... 12 
Table of Contents ..................................................................................................................... 16 
List of Tables ............................................................................................................................ 21 
List of Figures .......................................................................................................................... 21 
List of Abbreviations ............................................................................................................... 22 
1 
Introduction .......................................................................................................... 24 
1.1 
Background ...................................................................................................... 24 
1.2 
Information on BE1116 .................................................................................... 25 
1.3 
Study Overview ................................................................................................ 27 
1.4 
Potential Risks and Benefits ............................................................................. 27 
2 
Study Objectives and Endpoints ........................................................................... 28 
2.1 
Primary Objective and Endpoint ...................................................................... 28 
2.1.1 
Primary Objective ......................................................................................... 28 
2.1.2 
Primary Endpoint ......................................................................................... 28 
2.1.3 
Primary Estimand ......................................................................................... 29 
2.2 
Secondary Objectives and Endpoints ............................................................... 30 
2.2.1 
Secondary Objectives ................................................................................... 30 
2.2.2 
Secondary Endpoints .................................................................................... 30 
2.3 
Exploratory Objectives and Endpoints ............................................................. 31 
2.3.1 
Exploratory Objectives ................................................................................. 31 
2.3.2 
Exploratory Endpoints .................................................................................. 32 
3 
Study Design and Oversight ................................................................................. 32 
3.1 
Overall Design .................................................................................................. 32 
3.2 
Dose and Dosing Regimen ............................................................................... 35 
3.3 
Scientific Rationale .......................................................................................... 35 
3.3.1 
Study Design Rationale ................................................................................ 35 
3.3.2 
Dose Rationale ............................................................................................. 41 
3.4 
Planned Study Duration ................................................................................... 41 
3.5 
Planned Number of Subjects ............................................................................ 42 

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3.6 
Definition of Start of the Clinical Study .......................................................... 42 
3.7 
Definition of End of the Clinical Study ........................................................... 42 
3.8 
Study Oversight ................................................................................................ 42 
3.8.1 
Independent Data Monitoring Committee .................................................... 42 
3.8.2 
Executive Committee ................................................................................... 44 
3.8.3 
Steering Committee ...................................................................................... 44 
3.8.4 
Publications Committee ............................................................................... 44 
3.8.5 
Stopping Criteria .......................................................................................... 44 
4 
Selection and Withdrawal of Subjects .................................................................. 45 
4.1 
Eligibility Criteria ............................................................................................ 45 
4.1.1 
Inclusion Criteria .......................................................................................... 45 
4.1.2 
Exclusion Criteria ......................................................................................... 47 
4.2 
Screen Failures ................................................................................................. 49 
4.3 
Discontinuation of Study Treatment and Subject Withdrawal ......................... 49 
4.3.1 
Discontinuation of Study Treatment ............................................................. 49 
4.3.2 
Subject Withdrawal ...................................................................................... 50 
4.3.3 
Procedures for Handling Withdrawals.......................................................... 50 
4.3.4 
Subjects Lost to Follow-up ........................................................................... 50 
4.3.5 
Replacement Policy ...................................................................................... 50 
5 
Study Interventions ............................................................................................... 50 
5.1 
Investigational Products ................................................................................... 51 
5.1.1 
Description of BE1116 ................................................................................. 51 
5.1.2 
Description of Placebo ................................................................................. 52 
5.1.3 
Dosing and Administration of Investigational Products ............................... 53 
5.1.4 
Description of Investigational Medical Device Constituent ........................ 54 
5.1.5 
Packaging, Labeling, Supply, and Storage ................................................... 54 
5.1.6 
Access to Investigational Product After the End of Study ........................... 55 
5.2 
Accountability and Destruction ........................................................................ 55 
5.3 
Other Interventions ........................................................................................... 55 
6 
Allocation to Treatment ........................................................................................ 55 
6.1 
Subject Assignment .......................................................................................... 55 
6.2 
Randomization Procedures ............................................................................... 56 
6.3 
Blinding Procedures ......................................................................................... 56 

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6.3.1 
Blinding Method ........................................................................................... 56 
6.3.2 
Breaking the Blind for an Emergency .......................................................... 57 
6.3.3 
Planned Unblinding Procedures ................................................................... 57 
6.3.4 
Ad-hoc Safety Unblinding ............................................................................ 57 
7 
Contraindications, Permitted Therapies, and Prohibited Therapies ..................... 58 
7.1 
Contraindications ............................................................................................. 58 
7.2 
Permitted Therapies .......................................................................................... 58 
7.3 
Prohibited Therapies......................................................................................... 58 
7.4 
Lifestyle Restrictions ........................................................................................ 59 
8 
Study Procedures and Visit Schedule ................................................................... 59 
8.1 
Clinical Procedures .......................................................................................... 59 
8.1.1 
Demographics and Clinical Conditions ........................................................ 59 
8.1.2 
Efficacy Assessments ................................................................................... 62 
8.1.3 
Safety Assessments ....................................................................................... 63 
8.1.4 
Other Assessments ........................................................................................ 63 
8.2 
Blood Samples .................................................................................................. 64 
8.3 
Retention of Samples ....................................................................................... 64 
8.4 
Prior and Concomitant Therapies ..................................................................... 64 
8.5 
Visit Schedule ................................................................................................... 65 
8.5.1 
Assessment Time Windows .......................................................................... 65 
8.5.2 
Screening and Randomization (Enrollment) Period ..................................... 65 
8.5.3 
Treatment Period .......................................................................................... 66 
8.5.4 
In-hospital Follow-up Period ........................................................................ 66 
8.5.5 
Withdrawal Assessments .............................................................................. 68 
9 
Adverse Events ..................................................................................................... 68 
9.1 
Definitions ........................................................................................................ 68 
9.1.1 
Adverse Event .............................................................................................. 68 
9.1.2 
Serious Adverse Event .................................................................................. 69 
9.1.3 
Adverse Events of Special Interest ............................................................... 69 
9.2 
Severity of Adverse Events .............................................................................. 71 
9.3 
Causality of Adverse Events ............................................................................ 71 
9.4 
Observation Period for Adverse Events ........................................................... 71 
9.5 
Follow-up of Adverse Events ........................................................................... 72 

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9.6 
Adverse Event Reporting ................................................................................. 72 
9.6.1 
Adverse Events ............................................................................................. 72 
9.6.2 
Adverse Events of Special Interest ............................................................... 72 
9.6.3 
Serious Adverse Events ................................................................................ 72 
9.6.4 
Other Significant Events .............................................................................. 74 
9.6.5 
Overdose ....................................................................................................... 74 
9.6.6 
Pregnancy ..................................................................................................... 74 
9.7 
IRB / IEC Reporting Requirements ................................................................. 74 
10 
Statistics ................................................................................................................ 74 
10.1 
Sample Size Estimation .................................................................................... 74 
10.2 
Description of Study Populations ..................................................................... 75 
10.2.1 
Intent-to-treat Population ............................................................................. 75 
10.2.2 
Modified Intent-to-treat Population .............................................................. 75 
10.2.3 
Per-protocol Population ................................................................................ 75 
10.2.4 
Safety Population ......................................................................................... 75 
10.3 
Statistical Analyses and Methods ..................................................................... 75 
10.3.1 
Subject Disposition and Characteristics ....................................................... 75 
10.3.2 
Efficacy Analyses ......................................................................................... 76 
10.3.3 
Safety Analyses ............................................................................................ 81 
10.3.4 
Interim Analyses ........................................................................................... 81 
11 
Quality Assurance ................................................................................................. 83 
12 
Regulatory and Ethics Considerations .................................................................. 84 
12.1 
Regulatory Considerations ............................................................................... 84 
12.2 
Institutional Review Board / Independent Ethics Committee .......................... 84 
12.3 
Subject Information and Informed Consent ..................................................... 84 
12.3.1 
Consent in the United States ........................................................................ 86 
12.4 
Subject Confidentiality ..................................................................................... 86 
12.5 
Indemnity and Compensation ........................................................................... 87 
13 
Administrative Considerations ............................................................................. 87 
13.1 
Clinical Trial Research Agreement .................................................................. 87 
13.2 
Clinical Study Registration and Results Disclosure ......................................... 87 
13.3 
Implementation of the Clinical Study Protocol and Amendment(s) ................ 88 
13.4 
Protocol Deviations .......................................................................................... 88 

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13.5 
Documentation and Record Keeping ............................................................... 89 
13.5.1 
Data Collection ............................................................................................. 89 
13.5.2 
Data Quality Assurance ................................................................................ 89 
13.5.3 
Record Retention .......................................................................................... 89 
13.6 
Study and Site Closure ..................................................................................... 90 
13.7 
Clinical Study Report ....................................................................................... 90 
13.8 
Use of Data and Publications ........................................................................... 91 
14 
References ............................................................................................................ 92 
15 
Appendices ........................................................................................................... 98 
Appendix 1 
Signature Pages ................................................................................................ 99 
Appendix 2 
Exception From Informed Consent for Emergency Research in the United 
States .............................................................................................................. 101 
Appendix 3 
Glasgow Coma Scale ..................................................................................... 103 
Appendix 4 
Injury Severity Score ...................................................................................... 104 
Appendix 5 
Multiple Organ Failure Assessment ............................................................... 105 
Appendix 6 
Charlson Comorbidity Index .......................................................................... 106 
Appendix 7 
Berlin Criteria for ARDS ................................................................................ 107 
Appendix 8 
Defined Terms ................................................................................................ 108 
 

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List of Tables 
Table 1 
RABT Variables and Scoring ........................................................................... 47 
Table 2 
Description of BE1116 ..................................................................................... 51 
Table 3 
Description of Placebo ..................................................................................... 52 
Table 4 
Summary of Prohibited Medications ............................................................... 59 
Table 5 
Demographics and Clinical Conditions ........................................................... 60 
Table 6 
Safety Assessments .......................................................................................... 63 
Table 7 
Time Windows for Assessments ...................................................................... 65 
Table 8 
Planned IDMC Reviews .................................................................................. 82 
 
List of Figures 
Figure 1 
Study Overview ............................................................................................... 34 
Figure 2 
All-cause 6-Hour Mortality Decreases With Time to Randomization (N = 677)
 ......................................................................................................................... 37 
Figure 3 
Hourly Mortality Rates From PROMMTT and PROPPR Studies .................. 38 
Figure 4 
Kaplan-Meier Plots of 24-hour and 30-day Mortality: Difference Between 
Groups Maintained From 3 Hours Onwards .................................................... 39 
 

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List of Abbreviations 
Abbreviation 
Term 
3F-PCC 
3-Factor prothrombin complex concentrate 
4F-PCC 
4-Factor prothrombin complex concentrate 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AIS 
Abbreviated Injury Scale 
AKI 
Acute kidney injury 
ARDS 
Acute respiratory distress syndrome 
CDC 
Centers for Disease Control and Prevention 
CI 
Confidence interval 
CSL 
CSL Behring 
EC 
Executive Committee 
eCRF 
Electronic case report form 
EFIC 
Exception From Informed Consent 
FDA 
Food and Drug Administration 
FEIBA 
Factor VIII inhibitor bypassing activity 
FII, FVII, FIX, FX 
Factor II, VII, IX, X 
FFP 
Fresh frozen plasma 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
IB 
Investigator’s brochure 
ICE 
Intercurrent event 
ICH 
International Council for Harmonisation 
ICU 
Intensive care unit 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IP 
Investigational product 
IRB 
Institutional Review Board 
IRT 
Interactive response technology 
ISS 
Injury Severity Score 
ITT 
Intent-to-treat 
IV 
Intravenous 

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Abbreviation 
Term 
KDIGO 
Kidney Disease Improving Global Outcomes 
LAR 
Legally authorized representative 
mITT 
Modified intent-to-treat 
OR 
Odds ratio 
PCC 
Prothrombin complex concentrate 
PP 
Per-protocol 
PROMMTT 
Prospective Observational Multicenter Major Trauma Transfusion 
PROPPR 
Pragmatic Randomized Optimal Platelet and Plasma Ratios 
RABT 
Revised Assessment of Bleeding and Transfusion 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Steering Committee 
TEE 
Thromboembolic event 
US 
United States 
VKA 
Vitamin K antagonist 

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1 
Introduction 
1.1 
Background 
In the United States (US), accidents (ie, unintentional injuries, including trauma) were the 
leading cause of mortality in children, adolescents, and young adults aged 1 to 44 years 
between 1981 and 2019 [CDC, 2021]. According to the US Centers for Disease Control and 
Prevention (CDC), more than 240,000 fatal injuries occurred in 2019 in the US [CDC, 2020]. 
Additionally, trauma is a significant economic burden in terms of medical expenses and 
work-loss costs. 
Hemorrhage is the most common, preventable cause of death following trauma. Mortality 
due to hemorrhage can reach as high as 40% in severely injured patients despite resuscitation 
efforts [Curry et al, 2011]. Hemorrhagic death occurs rapidly with a median time to death of 
2 to 3 hours after hospital arrival [Holcomb et al, 2013; Holcomb et al, 2015]. Trauma 
patients on the verge of exsanguination have a unique pattern of physiologic derangements, 
collectively referred to as the lethal triad: hypothermia, metabolic acidosis, and coagulopathy 
[Holcomb et al, 2007; Hess et al, 2008]. Hemorrhage control, in combination with treatment 
of shock and balanced resuscitation, greatly reduces mortality in trauma patients [Spahn et al, 
2019; Holcomb et al, 2015]. However, the optimal therapy is still not known. 
Trauma transfusion care has changed dramatically over the past 20 years. This change was 
precipitated by the discovery of acute traumatic coagulopathy and endotheliopathy, and by 
the need to prevent and treat devastating complications of acute blood loss. The easiest way 
to do this is to replace “like-with-like”: blood lost from injuries should be replaced with 
blood containing the correct amounts of red cells, platelets, coagulation factors, and other 
components essential to achieving hemostasis. 
The most common approach to trauma transfusion involves a formula or ratio-based 
approach, until the results of laboratory values become available, to guide the administration 
of specific products [Johannsen et al, 2021]. The spectrum of practice ranges from: (1) a ratio 
of one unit of plasma and / or platelets for every two units of red cells; (2) approximately 
equal ratios of units of plasma, platelets, and red cells; (3) some whole blood plus some 
components transfused at a ratio of 1:1:1 to 1:1:2; to (4) “whole blood only” (which only a 
handful of hospitals can provide). 
There is still a critical need for improved methods to control bleeding in these patients. Even 
with the transfusion of the higher blood component ratio, the “Pragmatic, Randomized 

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Optimal Platelet and Plasma Ratios” (PROPPR) study found that hemorrhagic deaths 
occurred in 9.2% of patients [Holcomb et al, 2015]. This result has accurately predicted 
real-world results, namely, that exsanguination continues to be a leading cause of traumatic 
mortality and even best practices have only reduced hemorrhagic deaths by 25 to 30% 
[Johannsen et al, 2021; Oyeniyi et al, 2017]. Hence, an improved approach to control 
hemorrhage is an important unmet need. 
A recently published systematic review and meta-analysis evaluated the effectiveness of 
prothrombin complex concentrate (PCC) administration in the treatment of bleeding in 
patients not taking anticoagulants in trauma, cardiac surgery, and liver surgery 
[Van den Brink et al, 2020]. From 4668 studies identified, 17 observational studies were 
included. In the trauma subgroup, mortality was significantly reduced in patients receiving 
PCC compared with patients not receiving PCC (odds ratio [OR] 0.64; confidence interval 
[CI] [0.46, 0.88]; P = 0.007; I2 = 0%; P for heterogeneity = 0.81). This benefit was observed 
when PCC was added to fresh frozen plasma (FFP) compared with FFP alone, but not when 
PCC as a stand-alone therapy was compared with FFP. Additionally, in trauma patients, PCC 
use resulted in a reduction of 3.0 red blood cell (RBC) units compared with patients not 
receiving PCC (95% CI [-4.1, -1.9]; P < 0.00001; I2 = 68%; P for heterogeneity = 0.02). 
While encouraging, the primary studies included in the systematic review and meta-analysis 
were all observational, and thus subject to confounding. 
Retrospective data show that 4-factor prothrombin complex concentrates (4F-PCCs) may be 
an effective therapy in trauma patients who are not on preinjury anticoagulants and 
irrespective of whether or not they have a coagulopathy [Zeeshan et al, 2019a; Zeeshan et al, 
2019b]. In a propensity score matched analysis, Zeeshan et al. showed that 4F-PCC as an 
adjunct to FFP was associated with improved survival and reduction in transfusion 
requirements compared with FFP alone in resuscitation of severely injured trauma patients 
[Zeeshan et al, 2019b]. It is possible that the effects of 4F-PCC extend beyond coagulopathy 
reversal, perhaps by decreasing endotheliopathy [Pati et al, 2016]. 
1.2 
Information on BE1116 
BE1116 is a human plasma-derived, highly purified, heat-treated, virus-filtered, lyophilized, 
4F-PCC product. It contains the vitamin K-dependent blood coagulation Factors II, VII, IX, 
and X (FII, FVII, FIX, and FX), as well as the anticoagulants Protein C and Protein S, and 
other proteins, and it represents a multimodal therapy that may be a safe and effective therapy 

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to achieve hemostasis in patients who have traumatic injury, with confirmed or suspected 
acute major bleeding and / or predicted to receive a large volume blood product transfusion. 
The preparation is obtained from pooled human plasma of healthy donors. Only plasma that 
passes virus screening is used for production. After dissolution in the appropriate amount of 
solvent, BE1116 is administered by intravenous (IV) infusion. 
BE1116 is registered under different trade names (eg, Kcentra®, Beriplex® P/N), and current 
marketing authorizations vary across regions. In the US, BE1116 is indicated for the urgent 
reversal of acquired coagulation factor deficiency induced by vitamin K antagonist (VKA) 
(eg, warfarin) therapy in adult patients with acute major bleeding or need for an urgent 
surgery / invasive procedure [CSL, 2018]. In the European Union, BE1116 is indicated for 
the treatment and perioperative prophylaxis of bleeding in acquired deficiency of the PCC 
factors, such as deficiency caused by treatment with VKAs, or in case of overdose of VKAs, 
when rapid correction of the deficiency is required, and the treatment and perioperative 
prophylaxis of bleeding in congenital deficiency of any of the vitamin K-dependent 
coagulation factors when purified specific coagulation factor products are not available 
[CSL, 2021]. 
An extensive nonclinical program supports the use of BE1116 in patients who are deficient of 
vitamin K-dependent factors experiencing major bleeding or requiring urgent surgery, with 
the main cause of acquired factor deficiency being anticoagulation with VKA. To support the 
use of BE1116 in the new proposed indication, additional pharmacological studies in 
clinically relevant animal models of hemodilutional coagulopathy and trauma were employed 
to demonstrate the efficacy and safety of BE1116 in situations associated with major blood 
loss. Overall, the nonclinical studies demonstrated efficacy to correct hemostasis at clinically 
relevant dose levels, adequate pharmacokinetic properties, and a favorable safety profile of 
BE1116. 
In all uncontrolled and controlled clinical studies of acute VKA reversal performed to date 
(333 total subjects treated with BE1116), BE1116 has been considered safe and well 
tolerated. Over 20 years of postmarketing experience also supports the favorable safety 
profile of BE1116 established during the clinical studies. The safety and efficacy of BE1116 
in children and adolescents has not yet been established in controlled clinical studies. 
Additionally, the safety of BE1116 for use in human pregnancy and during lactation has not 
been established. 

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A detailed description of BE1116 is provided in the investigator’s brochure (IB) for BE1116. 
This includes all relevant nonclinical and clinical data, including data from more than 
20 years of postmarketing experience, to provide comprehensive information to investigators 
and others involved in the proposed clinical study. 
1.3 
Study Overview 
There is good preliminary clinical evidence for a potential therapeutic role of 4F-PCC in 
trauma patients to improve survival (see Section 1.1). Therefore, this phase 3, randomized, 
double-blind, placebo-controlled study has been designed to evaluate the efficacy and safety 
of BE1116 when administered early in subjects who have traumatic injury, with confirmed or 
suspected acute major bleeding and / or predicted to receive a large volume blood product 
transfusion (ie, a massive transfusion protocol setting). 
In addition to the study site’s standard resuscitation methods and protocol, a single IV 
infusion of investigational product (IP) (BE1116 or placebo) will be administered, starting 
within 90 minutes of arrival at the hospital. Efficacy and safety data will be collected for the 
primary hospitalization period, up to the time of death / hospital discharge / Day 30, 
whichever occurs first. If subject is discharged alive prior to 6 hours, then the subject will be 
followed up to assess 6-hour survival status, SAEs, and AESIs. Primary hospitalization is 
defined as the initial hospitalization following the trauma. The primary endpoint is all-cause 
mortality within 6 hours after randomization. 
Details regarding the scientific rationale for the study design and selection of dose are 
provided in Section 3.3. 
1.4 
Potential Risks and Benefits 
The following benefits and risks are of consideration in this study: 
Benefits 
1. There is the potential for improved survival in patients who have traumatic injury, with 
confirmed or suspected acute major bleeding and / or predicted to receive a large volume 
blood product transfusion. 
2. There is the potential for decreased transfusion of blood products, including RBCs, 
FFP, whole blood, cryoprecipitate, intraoperative salvaged (cell-saver) blood, and 
platelets, with reduction of associated risks, eg, transfusion reactions including 

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transfusion-associated circulatory overload and transfusion-related acute lung injury or 
transmission of infectious agents [CSL, 2018]. 
3. There is the potential for decreased complications, including decreased length of stay 
in the intensive care unit (ICU) and hospital and decreased number of days on mechanical 
ventilation. 
Risks 
1. There is an increased risk of acute thromboembolic events (TEEs), including deep 
vein thrombosis, pulmonary embolism, ischemic stroke [including thromboembolic 
stroke], and myocardial infarction within 24 to 48 hours after BE1116 administration 
[CSL, 2018]. 
2. The concurrent use of off-label prothrombotic agents (eg, recombinant activated 
FVIIa, Factor VIII inhibitor bypassing activity [FEIBA]) may increase the risk of 
TEEs [Novo Nordisk, 2020; Baxalta, 2020]. 
3. Hypersensitivity reactions may occur [CSL, 2018]. 
4. There is a low risk of transmissible infectious agents (the PCC manufacturing process 
applies 2 dedicated virus reduction steps) [CSL, 2018]. 
Thus, the anticipated benefit-risk balance of BE1116 is considered acceptable for subjects 
enrolled in the study. 
Refer to the IB for BE1116 for detailed information on the product’s warnings, precautions, 
and full safety profile. 
2 
Study Objectives and Endpoints 
2.1 
Primary Objective and Endpoint 
2.1.1 
Primary Objective 
The primary objective is to assess the efficacy of a single IV infusion of BE1116 on all-cause 
mortality within 6 hours after randomization in subjects who have traumatic injury, with 
confirmed or suspected acute major bleeding and / or predicted to receive a large volume 
blood product transfusion. 
2.1.2 
Primary Endpoint 
The primary endpoint is all-cause mortality within 6 hours after randomization. 

C S L Be hri n g  
St u d y N u m ber:  B E 1 1 1 6 _ 3 0 0 6  
 
St u d y Pr o d uct:  4 F -P C C  
 
Pr ot oc ol versi o n: A me n d me nt 2  
 
Pa ge 2 9  of 1 0 8  
Date: 0 6 Fe br uar y 2 0 2 4  
 
C S -S O P -0 4 -T 0 2 Versi o n 2. 0  
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
2. 1. 3  
Pri m ar y Esti m a n d  
T he pri mar y esti ma n d  t o a d dress t he trial o bjecti ve is t he differe nce i n pr o p orti o n of all-ca use 
m ortalit y u p t o 6 h o urs after ra n d o mizati o n ( 6 - h o ur m ortalit y) i n s u bjects w h o ha ve tra u matic 
i nj ur y, wit h c o nfir me d or s us pecte d ac ute maj or blee di n g a n d / or pre dicte d t o recei ve a lar ge 
v ol u me bl o o d pr o d uct tra nsf usi o n (I nte nt -t o-treat [I T T] P o p ulati o n) bet wee n t he B E 1 1 1 6 a n d 
place b o ar ms, re gar dless of I P d osa ge recei ve d or ot her me dicati o ns use d. See Secti o n  1 0. 2. 1  
f or a defi niti o n of t he I T T P o p ulati o n. 
T he 4 attri b utes of t he pri mar y esti ma n d  ( p o p ulati o n, pri mar y e n d p oi nt, i nterc urre nt e ve nts 
[I C Es], a n d s u m mar y meas ure), as defi ne d i n t he I nter nati o nal C o u ncil f or Har m o nisati o n 
(I C H) E 9 ( R 1) g ui da nce, are descri be d bel o w. 
2. 1. 3. 1  P o p ul ati o n  
S u bjects w h o ha ve tra u matic i nj ur y, wit h c o nfir me d or s us pecte d ac ute maj or blee di n g 
a n d / or pre dicte d t o recei ve a lar ge v ol u me bl o o d pr o d uct tra nsf usi o n (I T T P o p ulati o n). 
2. 1. 3. 2  Pri m ar y E n d p oi nt  
As defi ne d i n Secti o n  2. 1. 2 . 
2. 1. 3. 3  I nterc urre nt E ve nts 
2. 1. 3. 4  S u m m ar y Me as ure  
T he s u m mar y meas ure of t he pri mar y e n d p oi nt is t he differe nce i n t he pr o p orti o n of s u bjects 
w h o die i n h os pital i n t he B E 1 1 1 6 ar m c o m pare d wit h t he place b o ar m d uri n g t he first 
6 h o urs after ra n d o mizati o n (see Secti o n  2. 1. 1 ), as esti mate d b y a Ba yesia n l o gistic 
re gressi o n m o del. 
C CI

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2.2 
Secondary Objectives and Endpoints 
2.2.1 
Secondary Objectives 
The secondary objectives of the study are as follows: 
1. To assess all-cause in-hospital mortality up to 24 hours after randomization 
2. To assess all-cause in-hospital mortality up to 30 days after randomization 
3. To assess the requirement for surgical or interventional radiological procedures to stop 
bleeding related to the primary injury up to 24 hours after randomization 
4. To assess the safety of BE1116 
  
2.2.2 
Secondary Endpoints 
The secondary endpoints (and corresponding summary measures) of the study are as follows: 
Secondary 
Objective 
Endpoint 
Summary Measure 
1 
All-cause in-hospital* mortality up 
to 24 hours after randomization 
Difference in proportion of subjects 
who die in hospital in the BE1116 
arm compared with the placebo arm 
up to the first 24 hours after 
randomization, as estimated by a 
Bayesian logistic regression model 
2 
All-cause in-hospital* mortality up 
to 30 days after randomization 
Difference in proportion of subjects 
who die in hospital in the BE1116 
arm compared with the placebo arm 
up to 30 days after randomization, as 
estimated by a Bayesian logistic 
regression model 
3 
Surgical or interventional 
radiological procedures to stop 
bleeding related to the primary 
injury up to 24 hours after 
randomization 
Difference in proportion of subjects 
who undergo surgical or 
interventional radiological 
procedures to stop bleeding related 
to the primary injury in the BE1116 
arm compared with the placebo arm 
up to 24 hours after randomization, 
as estimated by a Bayesian logistic 
regression model 

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Secondary 
Objective 
Endpoint 
Summary Measure 
4 
Serious adverse events (SAEs) 
considered related to IP 
During the primary hospital stay 
only, within the 30 days after 
randomization: 
• Number and proportion of 
subjects with SAEs considered 
related to IP by treatment 
(BE1116 or placebo) 
4 
Adverse events of special interest 
(AESIs): 
• TEEs, symptomatic or 
asymptomatic, and arterial or 
venous (eg, deep vein 
thrombosis, pulmonary 
embolism, ischemic stroke 
[including thromboembolic 
stroke], myocardial infarction) 
• Acute respiratory distress 
syndrome (ARDS) 
• Multiple organ failure 
• Acute kidney injury (AKI) 
requiring renal replacement 
therapy (dialysis, hemofiltration, 
or hemodiafiltration) 
Note: superficial thromboses will 
not be included as AESIs 
 
 
• TEEs: Number and proportion of 
in-hospital overall and related 
TEEs up to 30 days after 
randomization by treatment 
(BE1116 or placebo) 
• Number and proportion of 
subjects with the following: 
o 
ARDS 
o 
Multiple organ failure 
o 
AKI requiring renal 
replacement therapy 
*In-hospital mortality will only be recorded and assessed for the primary hospitalization. 
2.3 
Exploratory Objectives and Endpoints 
2.3.1 
Exploratory Objectives 
The exploratory objectives of the study are as follows: 
1. To assess transfusion of blood products 
2. To assess healthcare utilization during primary hospitalization 

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2.3.2 
Exploratory Endpoints 
The exploratory endpoints (and corresponding summary measures) of the study are as 
follows: 
Exploratory 
Objective 
Endpoint 
Summary Measure 
1 
Transfusion of blood 
products 
Number of units of blood products 
transfused before arrival at the hospital 
through the first 24 hours after 
randomization, overall and by type of 
product by treatment 
2 
Ventilator-free days 
Number of ventilator-free days during the 
primary hospital stay up to 30 days after 
randomization, by treatment  
2 
ICU-free days 
Number of ICU-free days during the 
primary hospital stay up to 30 days after 
randomization, by treatment  
2 
Hospital length of stay 
Number of days of primary hospitalization 
 
Details regarding how the exploratory endpoints will be calculated and adjusted for deaths 
will be provided in the statistical analysis plan (SAP). 
3 
Study Design and Oversight 
3.1 
Overall Design 
This is a phase 3, prospective, multicenter, randomized, double-blind, placebo-controlled, 
parallel-group, large simple trial to investigate the efficacy and safety of a single IV infusion 
of BE1116 in subjects who have traumatic injury, with confirmed or suspected acute major 
bleeding and / or predicted to receive a large volume blood product transfusion. 
The IP infusion will be given in addition to the study site’s standard resuscitation methods 
and protocol. All subjects will receive standard of care according to the study site’s normal 
clinical practice at all times during the study. Standard-of-care should not be interrupted or 
forgone to enable subject participation in the study. 

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Randomization will be in a 1:1 ratio (BE1116:placebo) and stratified by study site. The time 
of randomization is defined as the time at which the selected IP study kit is opened by the 
trauma team (or other applicable site staff) for IP reconstitution and administration. 
The study will be conducted at approximately 140 sites in the US and other countries with 
emergency medical services, trauma systems, in-hospital trauma teams, and resuscitation 
protocols. All participating study sites will be Level I or Level II trauma centers (or 
equivalent) that have a large number of patients and an existing, robust research 
infrastructure to support this trial. Level I trauma centers are defined as a comprehensive 
regional resource that is in a tertiary care facility, central to the trauma system, and capable of 
providing definitive care for every aspect of injury – from prevention through rehabilitation. 
Level II trauma centers are able to initiate definitive care for all injured patients [American 
Trauma Society, 2021]. Participating sites will deliver a contemporary balanced standard of 
transfusion care (“balanced resuscitation”) to ensure no confounding of results from 
differences in standard-of-care practices. 
The study consists of: (i) a Screening and Randomization (Enrollment) Period; 
(ii) a Treatment Period; and (iii) an In-hospital Follow-up Period, as summarized below. An 
overview of the study is shown in Figure 1. Further details regarding the assessments 
performed in each period are provided in Section 8.5. 
Screening and Randomization (Enrollment) Period 
Screening will begin once the subject has arrived at the hospital, and eligibility will be 
assessed. This study involves subjects who cannot be prospectively identified and who have 
life-threatening medical conditions necessitating emergent intervention. Because of the 
subjects’ conditions, the emergent need for intervention, and the limited treatment window 
during which the IP must be administered for potential efficacy, it is anticipated that 
obtaining prospective Informed Consent (as defined in Appendix 8) from study subjects or 
their Legally Acceptable Representatives (as defined in Appendix 8) may not be possible. For 
these reasons, the study will be conducted under emergency research Applicable Law (as 
defined in Appendix 8) which allows subjects to be enrolled into qualifying research without 
obtaining prospective Informed Consent. For details regarding Informed Consent, refer to 
Section 12.3 and Section 12.3.1. 
Once a subject meets all the eligibility criteria, the trauma team (or other applicable site staff) 
will select and open the IP study kit (for IP reconstitution and administration) with the next 

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available sequential subject number, and the subject will be considered randomized 
(enrolled). The date and time of opening the IP study kit (randomization) will be recorded. 
Treatment Period 
The start of the IP infusion must be within 90 minutes after arrival at the hospital. 
Blinded, sealed IP study kits containing either BE1116 or placebo will be maintained in the 
trauma bay, or a location where they are readily accessible, at the study site at all times 
during the study. 
In-hospital Follow-up Period 
During the primary hospitalization, efficacy and safety data will be collected up to the time of 
death / hospital discharge / Day 30, whichever occurs first. If subject is discharged alive prior 
to 6 hours, then the subject will be followed up to assess 6-hour survival status, SAEs, and 
AESIs. 
For details regarding Informed Consent, refer to Section 12.3 and Section 12.3.1. 
Figure 1 
Study Overview 
 
AESI = adverse event of special interest; IP = investigational product; SAE = serious adverse event; SOC = 
standard-of-care, T = time. 
Notes: Time = 0 hours is the time of opening the IP study kit (randomization). The start of the IP infusion must 
be within 90 minutes after arrival at the hospital. 
 

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3.2 
Dose and Dosing Regimen 
Subjects will receive a single IV infusion of either BE1116 or placebo, in addition to the 
study site’s standard resuscitation methods and protocol. 
The dose of BE1116 will be either 2000 IU or 3000 IU, based on the estimated or measured 
weight of the subject documented on arrival at the hospital: 
• Weight < 75 kg (< 165 lbs): 2000 IU 
• Weight ≥ 75 kg (≥ 165 lbs): 3000 IU 
Details regarding dose administration are provided in Section 5.1.3. 
3.3 
Scientific Rationale 
3.3.1 
Study Design Rationale 
This study has been designed to assess the efficacy and safety of BE1116 in subjects who 
have traumatic injury, with confirmed or suspected acute major bleeding and / or predicted to 
receive a large volume blood product transfusion. 
A randomized, double-blind, placebo-controlled design was considered appropriate to reduce 
bias. Placebo was chosen as the comparator because no licensed treatment is currently 
available for the indication under study. The study IP (BE1116 or placebo) will be 
administered in addition to the study site’s standard resuscitation methods and protocol (also 
referred to as “standard-of-care”). This will ensure that adequate treatment is given to 
subjects in both treatment arms, according to current treatment algorithms in this emergency 
setting. The study is pragmatic, there will not be a prescribed uniform resuscitation protocol 
employed by all study sites; thus, the study will reflect real-world practice. However, 
participating sites will deliver a contemporary balanced standard of transfusion care 
(“balanced resuscitation”) to ensure no confounding of results from differences in 
standard-of-care practices. 
This study involves subjects who cannot be prospectively identified and who have 
life-threatening medical conditions necessitating emergent intervention. Because of the 
subjects’ conditions, the emergent need for intervention, and the limited treatment window 
during which the IP must be administered for potential efficacy, it is anticipated that 
obtaining prospective Informed Consent from subjects or their Legally Acceptable 
Representatives may not be possible. For these reasons, the study will be conducted under 

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emergency research Applicable Law which allows subjects to be enrolled into qualifying 
research without obtaining prospective Informed Consent. This trial is designed to test 
whether early administration of BE1116 will reduce mortality in subjects with uncontrolled 
hemorrhage. The natural history of uncontrolled hemorrhage is of falling cardiac output and 
hypotension and ultimately failure of compensatory mechanisms with consequent cerebral 
and myocardial hypoperfusion leading to death [Peitzman et al, 1995]. The therapeutic 
window for exsanguinating trauma patients is short – often only minutes. It is imperative that 
BE1116 or placebo be administered rapidly and no later than 90 minutes from arrival in the 
trauma center [Abraham et al, 2022] for the following reasons: 
1. Deaths from hemorrhage occur early. An analysis of 42,135 patients with torso injury 
and hypotension showed that the majority of deaths occur within 30 minutes of injury 
[Alarhayem et al, 2016]. Harvin et al [2017] recently described the outcome of 
1706 patients requiring trauma laparotomy within 90 minutes of hospital arrival at 
12 Level I trauma centers. In patients who were hypotensive on admission, 41% of deaths 
occurred within 1 hour of arrival in the emergency department. 
2. Patients enrolled within 90 minutes of arrival have higher mortality than those enrolled 
later. A further analysis of the PROPPR study has shown that patients who were enrolled 
within 90 minutes of arrival at the trauma center had a high risk of early death (within 
24 hours), whereas none of the patients who were enrolled after 90 minutes died early 
[Abraham et al, 2022] (Figure 2). 

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Figure 2 
All-cause 6-Hour Mortality Decreases With Time to 
Randomization (N = 677) 
 
The primary study endpoint is all-cause mortality within 6 hours after randomization. This 
reflects the physiology and time course of hemorrhagic death, and the biology of the 
intervention. Trauma deaths from hemorrhage occur early, within hours of the injury, and if 
BE1116 has a beneficial effect, it is most likely to occur during this phase of treatment. Later 
deaths are usually due to other causes, such as traumatic brain injury, sepsis, or multiple 
organ failure and are therefore unlikely to be impacted by treatment with BE1116, targeted at 
aiding hemostasis [Holcomb et al, 2013; Tisherman et al, 2015; Fox et al, 2017; 
Herrera-Escobar et al, 2018; Holcomb et al, 2021; Spinella et al, 2021]. Hourly mortality 
rates from the PRospective Observational Multicenter Major Trauma Transfusion 
(PROMMTT) and PROPPR studies, which assessed hemorrhagic deaths following trauma, 
are provided in Figure 3. These show that the 6-hour time point for all-cause mortality aligns 
with the expected time of death due to hemorrhage and the time frame to detect an effect of 
the experimental intervention. 
n = 57
n = 16
n = 6
n = 0
0
10
20
30
40
50
60
0 to 30 minutes
31 to 60 minutes
61 to 90 minutes
91 to 120 minutes
Deaths within 6 hours of randomization
Time to Randomization

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Figure 3 
Hourly Mortality Rates From PROMMTT and PROPPR Studies 
 
PROMMTT = PRospective Observational Multicenter Major Trauma Transfusion (study); 
PROPPR = Pragmatic Randomized Optimal Platelet and Plasma Ratios (study) 
Source: Figure 1 in [Fox et al, 2017]. 
 
Importantly, prior similar studies have shown that mortality differences present in the first 
few hours persist over the next 30 days. The PROPPR study [Holcomb et al, 2015] was 
sponsored by the US National Institutes of Health (NCT01545232). The study compared a 
1:1:1 and a 1:1:2 transfusion ratio (of units of thawed plasma:platelets:red cells) and showed 
that mortality differences between the 2 treatment arms were already apparent at 3 hours 
post-randomization, and the absolute difference remained the same at the 30-day time point, 
as shown by the Kaplan-Meier curves in Figure 4. Likewise, the Prehospital Air Medical 
Plasma (PAMPer) study that found a benefit of prehospital administration of plasma at 
3 hours that persisted 30 days [Sperry et al, 2018]. 

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Figure 4 
Kaplan-Meier Plots of 24-hour and 30-day Mortality: Difference 
Between Groups Maintained From 3 Hours Onwards 
 
Source: [Holcomb et al, 2015] 
 
While the relative mortality trends in the first 6 hours will likely persist over time in the 
current study, secondary efficacy endpoints include all-cause in-hospital mortality up to 
24 hours after randomization, and all-cause in-hospital mortality up to 30 days after 
randomization. These will reflect the durability of survival benefit, provide valuable safety 
information about later mortality and relevant complications, and are in line with other 
trauma studies, such as the PROPPR study [Holcomb et al, 2015; Fox et al, 2017]. An earlier 
time to hemostasis was found to be independently associated with a decreased incidence of 
30-day mortality, AKI, ARDS, multiple organ failure, and sepsis in 408 bleeding trauma 
patients, indicating that the benefits of an earlier time to hemostasis are reflected in a number 
of outcomes, including mortality up to 30 days [Chang et al, 2019]. 
Safety data collected in the in-hospital period after randomization (up to the time of death, 
hospital discharge, or 30 days, whichever occurs first; if subject is discharged alive prior to 
6 hours, then the subject will be followed up to assess 6-hour survival status, SAEs, and 
AESIs) will allow the monitoring of AESIs and SAEs, which will be assessed for relatedness 
to the IP. TEEs are a defined AESI in this study because they are an identified important risk 
associated with use of BE1116. The other AESIs (ARDS, multiple organ failure, and AKI 
requiring renal replacement therapy) have been selected based on their importance in trauma 

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study populations. Nonserious adverse events (AEs) (other than AESIs) will not be collected 
in this study, because BE1116 has an established safety profile from more than 20 years of 
postmarketing experience in more than 45 countries, as well as from 10 clinical studies. In 
the current study, there will be a short duration of exposure (single dose), and the dosing 
range falls within that used in current clinical practice and in previous clinical studies. 
The design will be of a “large simple trial”. Large simple trials have been proposed by 
academia, industry, and regulatory authorities as an option to investigate interventions that 
are expected to show moderate, albeit clinically meaningful, improvements in the standard of 
care. The clinical meaningful outcome of interest of this trial is mortality. Even small 
improvements in mortality are highly relevant. The Clinical Trials Transformation Initiative, 
a public / private partnership founded by the US Food and Drug Administration (FDA) and 
Duke University (Durham, North Carolina, US) in 2013, convened a working group in 
May 2013. The group concluded that: large simple trials are helpful when moderate treatment 
effects are anticipated; they should have clinical, rather than surrogate, endpoints; they 
require streamlined data collection; and, for most therapies, they should be randomized 
[Eapen et al, 2014]. In line with these conclusions, this clinical trial: 1) has a large sample 
size with an objective, clinically meaningful primary endpoint of all-cause 6-hour mortality; 
2) limits data collection to that required to analyze the study endpoints; and, 3) is 
randomized. 
Analysis of the primary endpoint will be conducted with a Bayesian logistic regression model 
within a group sequential framework with three interim analyses planned. The study may be 
stopped early if futility (nonbinding) criteria are met at any of the three planned interim 
analyses, or if efficacy criteria are met at Interim Analysis 2 or 3. Trauma experts have 
recommended Bayesian models for analysis and to facilitate interpretation and easy 
translation of results into clinical practice of hemostasis research among clinicians 
[Jansen et al, 2017]. Furthermore, the Bayesian concept of posterior predictive probability 
presents a robust strategy to monitor futility while accounting for data remaining to be 
observed in the trial [Saville et al, 2014]. 
An Independent Data Monitoring Committee (IDMC) will also review results periodically 
during the study and will provide recommendations (see Section 3.8.1). An Executive 
Committee (EC) will provide oversight for the operation of the study (see Section 3.8.2). 
Rationale regarding the study population is provided with the inclusion and exclusion criteria 
in Section 4.1. 

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3.3.2 
Dose Rationale 
For the current study, a dose of BE1116 within the approved range for warfarin reversal of 
25 to 50 IU/kg will be tested. As a single dose range in trauma is unknown, and there is not a 
single dose that could be administered to all subjects, 2 weight-dependent doses will be 
administered in this study: 2000 IU and 3000 IU. Either estimated or actual (measured) 
weight may be used. This dichotomized approach is also pragmatic, which is helpful in the 
context of the pressured trauma clinical setting. Study staff will be able to reconstitute and 
administer the IP quickly without the need for weight-based calculations. 
Subjects with a body weight of < 75 kg (< 165 lbs) will receive a single dose of 2000 IU 
BE1116 (or matching placebo). It is expected that this dose will not exceed 50 IU/kg, because 
subjects would need to have a body weight of < 40 kg (< 88 lbs) to reach doses above 
50 IU/kg. The eligibility criteria will exclude subjects with a body weight of < 50 kg 
(< 110 lbs). 
Subjects with a body weight of ≥ 75 kg (≥ 165 lbs) will receive a single dose of 3000 IU 
BE1116 (or matching placebo). This is equivalent to a 40 IU/kg maximum dose for the 
lowest body weight (75 kg). To reach doses outside the currently approved 50 IU/kg, with a 
single dose of 3000 IU, the actual weight would need to be ≤ 60 kg (≤ 132 lbs). 
A pharmacokinetic analysis in 15 healthy volunteers who received an infusion of 50 IU/kg (at 
approximately 200 IU/min) resulted in an early peak of factor increase after 5 minutes. 
No increase in thrombogenicity marker (D-Dimer) was observed, and no clinical signs of 
thrombosis could be detected [Ostermann et al, 2007]. 
Details regarding dosing are provided in Section 5.1.3. 
3.4 
Planned Study Duration 
The study duration for an individual subject who dies while on the study is up to the time of 
death. For other subjects, the study duration is at least 6 hours and ends with hospital 
discharge, or 30 days, whichever comes first. If subject is discharged alive prior to 6 hours, 
then the subject will be followed up to assess 6-hour survival status, SAEs, and AESIs. 

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Time: 0 to 90 minutes after hospital arrival: 
• Screening 
• Randomization (enrollment) 
• Start of IP infusion 
Time: 0 to 30 days post-randomization: 
• Subjects will be followed up until death / hospital discharge / Day 30, whichever occurs 
first. If subject is discharged alive prior to 6 hours, then the subject will be followed up to 
assess 6-hour survival status, SAEs, and AESIs. 
The overall study duration (ie, from screening of first subject through the end of the last 
subject’s In-hospital Follow-up Period) will be approximately 3 years. 
3.5 
Planned Number of Subjects 
It is planned to enroll up to 8000 subjects (4000 per treatment arm). See Section 10.1 for 
further details on sample size. 
3.6 
Definition of Start of the Clinical Study 
The start of the clinical study is defined as the date of the first act of screening a potential 
subject at a study site. 
3.7 
Definition of End of the Clinical Study 
The end of the clinical trial (ie, completion of the study at all participating study sites) is 
defined as the date of the last subject’s death / hospital discharge / Day 30, whichever occurs 
first. If subject is discharged alive prior to 6 hours, then the subject will be followed up to 
assess 6-hour survival status, SAEs, and AESIs. 
3.8 
Study Oversight 
3.8.1 
Independent Data Monitoring Committee 
An IDMC will be established by CSL Behring (CSL), consisting of 1 chairperson, 
1 statistician, 2 clinical experts, and 1 bioethicist with a robust background in clinical studies. 
The IDMC will be established prior to enrollment of the first subject. Members of the IDMC 
will be external to CSL and should have the expertise in the field needed on the committee, 

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and independence from the direct ability to influence the clinical study. IDMC members may 
include a hematologist with experience in transfusion medicine, a trauma surgeon, an 
emergency medicine physician, a biostatistician, and a bioethicist. No members are to have 
financial or personal conflicts of interest, to ensure that the data are reviewed in an unbiased 
manner. The chairperson should confirm before each meeting that no member has any new 
conflict of interest related to the function of the IDMC. 
The IDMC will review relevant data, including safety data per treatment arm, periodically 
during the study and at least semi-annually, depending on the speed of recruitment. Ad-hoc 
meetings may be scheduled as required. 
The IDMC will monitor unblinded, death, AEs including SAEs and AESIs, as well as other 
safety data, with the objective of ensuring the safety of study subjects. 
The IDMC will provide recommendations on the continuation, modification, or termination 
of the study based on interim analysis and / or review of safety / efficacy data as described in 
Section 10.3.4. The IDMC may recommend temporarily or permanently stopping the study if 
BE1116 has a significantly higher safety risk compared with placebo. The IDMC 
recommendations will be relayed to CSL for final decision making. 
If a safety assessment concludes that a substantial protocol amendment (eg, additional risk 
mitigation measures) is required, the study will be paused until the protocol has been revised 
and accepted by the relevant regulatory authorities and Institutional Review Boards 
(IRBs) / Independent Ethics Committees (IECs). CSL will provide written communication of 
the decision from the safety assessment and instructions to the participating investigator sites 
in a timely manner. 
If the IDMC recommends and CSL decides that any additional dosing poses an unacceptable 
risk to subjects and no further risk mitigation steps can be applied, the study will be 
terminated. 
Relevant regulatory authorities and IRBs / IECs will be informed in accordance with local 
requirements, and all subjects that were dosed will be followed according to the scheduled 
study visits for safety. 
Further details on the composition, responsibilities, meeting schedule, data for review, 
recommendations of the IDMC, and stopping rules for the study are described in 
Section 10.3.4 and the IDMC Charter. 

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3.8.2 
Executive Committee 
An EC will be established to review and provide guidance and recommendations to CSL 
relating to the medical and scientific conduct of the study. 
The EC will be composed of members of the academic leadership of the clinical study and 
members of CSL. The EC will provide oversight for the operation of the study, including 
working with national leaders and local study site investigators to achieve goals for 
enrollment of subjects into the study, reviewing recommendations from the project team for 
study conduct, and reviewing recommendations from the IDMC for subject safety. 
Further details on the composition, responsibilities, meeting schedule, data for review, and 
recommendations of the EC will be described in an EC Charter. 
3.8.3 
Steering Committee 
A Steering Committee (SC) will be established to provide feedback to the Sponsor on 
ongoing study site activities and help facilitate communication with study sites regarding 
enrollment and conduct of the study. The SC will be composed of members of the academic 
leadership of the clinical study, study site principal investigators, and members of CSL. The 
SC will report to the EC. Further details on the composition, responsibilities, and meeting 
schedule of the SC will be described in an SC Charter. 
3.8.4 
Publications Committee 
A Publications Committee will be established to facilitate, encourage, and coordinate 
dissemination of results and analyses of Study BE1116_3006. Further details will be 
described in the Publications Committee Charter. 
3.8.5 
Stopping Criteria 
The study may be stopped early if futility (nonbinding) criteria are met at any of the 
three planned interim analyses, or if efficacy criteria are met at Interim Analysis 2 or 3, as 
described in Section 10.3.2.1 and Section 10.3.4. In addition, based on continuous safety 
monitoring, the study can be temporarily halted, modified via a protocol amendment, or 
terminated per the following. 
The IDMC will review and then decide if the assessment requires a cumulative review of the 
cases of in-hospital TEEs, in-hospital SAEs with a fatal outcome, and other safety data. In 

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addition, the IDMC will conduct periodic cumulative reviews of all in-hospital SAEs with a 
fatal outcome and all in-hospital TEEs and other in-hospital AESIs, as defined in the IDMC 
Charter. 
Specific stopping rules for the above-mentioned safety signals are elaborated in 
Section 10.3.4, the IDMC Charter, and the SAP. 
Discontinuation of study treatment and subject withdrawal is described in Section 4.3. Study 
and site closure is described in Section 13.6. 
4 
Selection and Withdrawal of Subjects 
4.1 
Eligibility Criteria 
The study population will be selected based on the inclusion and exclusion criteria described 
in the sections below. Subjects must meet all inclusion criteria and none of the exclusion 
criteria at the time of randomization (enrollment) to be eligible for this study. Prospective 
approval of protocol deviations from eligibility criteria, also known as protocol waivers or 
exemptions, is not permitted. Subject eligibility should be reviewed and documented by an 
appropriately medically qualified member of the investigator’s study team before subjects are 
included in the study. 
Criteria that were changed in Protocol Amendment 1 are identified by the addition of “A1” in 
the numbering. Criteria that were changed in Protocol Amendment 2 are identified by the 
addition of “A2” in the numbering. 
4.1.1 
Inclusion Criteria 
To be enrolled into the study, subjects must meet all of the following inclusion criteria: 
Inclusion Criterion 
Rationale 
1.A2. (a) Estimated or actual age 
≥ 15 years. Older minimum age 
is required in some locations. 
FOR United Kingdom: 
Estimated or actual age 
≥ 16 years 
FOR Australia: Estimated or 
actual age ≥ 18 years 
Subjects with an age ≥ 15 years globally are included 
in this study when in compliance with Applicable 
Laws, because trauma is the leading cause of 
mortality in the US among children, adolescents, and 
adults aged 1 to 44 years (see Section 1.1). Up to 
20% of trauma subjects may be < 18 years of age. In 
the US, older injured children are generally cared for 
in adult trauma centers, although the threshold varies. 
Also, older adolescents aged ≥ 15 years are 

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Inclusion Criterion 
Rationale 
 AND 
(b) Estimated or actual weight 
≥ 50 kg (110 lbs). 
physiologically comparable to young adults in the 
development of their coagulation system and 
response to trauma and shock [Liras et al, 2016]. 
In the setting of this study, it may not be possible to 
determine the subject’s age upon arrival at the 
hospital if no identification is available, especially if 
urgent treatment is required. A lower weight limit is 
included to limit enrollment of subjects aged 
< 15 years (for example, when age is estimated) and 
per the dose calculation considerations to 
demonstrate that that the dose would fall into the 
Sponsor’s known and studied dose range and to 
decrease the risk of overdose (Section 3.3.2). A 
higher minimum age is in effect for some 
jurisdictions, including United Kingdom and 
Australia, to be in compliance with Applicable Laws. 
No specific safety data exist for BE1116 use in the 
15- to 17-year-old age group, but no additional risks 
are expected compared with subjects aged ≥ 18 years. 
2.A1. Traumatic injury with: 
(a) confirmed or suspected 
acute major bleeding; and / or 
(b) Revised Assessment of 
Bleeding and Transfusion 
(RABT) score ≥ 2. 
Indication under investigation. A retrospective 
analysis found that a RABT score ≥ 2 had a 
sensitivity of 84% and specificity of 77% for 
predicting massive transfusion [Joseph et al, 2018]. 
3.A1. Not applicable.  
Deleted at Global Amendment 1. 
4. Activation of massive 
transfusion protocol. 
To ensure injury severity, corresponds to indication 
under study. 
5.A2. 
Initiation of blood product 
transfusion (Whole Blood or 
RBCs or Platelets or Plasma has 
started to enter patient’s body). 
To ensure injury severity, corresponds to indication 
under study. 
6.A1. Anticipated start of IP infusion 
within 90 minutes after arrival 
at the hospital. 
To ensure homogenous study population, known to 
be at high risk of early death. 
 

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Table 1 
RABT Variables and Scoring 
RABT Variables 
Score 
Notes 
Positive FAST 
1 = yes, 0 = no 
 
Shock index > 1 
1 = yes, 0 = no 
Shock index = ratio of heart rate to 
systolic blood pressure,  
ie, heart rate / systolic blood pressure 
Presence of a pelvic 
fracture 
1 = yes, 0 = no 
 
Penetrating mechanism 
of injury 
1 = yes, 0 = no 
 
FAST = Focused Assessment for the Sonography of Trauma examination; RABT = Revised Assessment of 
Bleeding and Transfusion. 
4.1.2 
Exclusion Criteria 
Subjects must not be enrolled into the study if they meet any of the following exclusion 
criteria: 
Exclusion Criteria 
Rationale 
1.A2. Healthcare professional 
cardiopulmonary resuscitation 
including chest compressions for 
≥ 5 consecutive minutes at any time 
before randomization. 
Very high probability of death and morbidity, 
unlikely to survive. 
2. 
Isolated penetrating or blunt cranial 
injury, or exposed brain matter. 
Very high probability of death and morbidity 
related to traumatic brain injury and not 
related to acute major bleeding. 
3. 
Known anticoagulation treatment or a 
history of a TEE, within the past 
3 months. 
Subject population could confound results 
and / or pose a safety risk. 
4.A1. Isolated burns estimated to be > 20% 
total body surface area or suspected 
inhalational injury. 
Significant total body surface area burns or 
smoke inhalation will influence 
coagulopathy and blood product 
administration.  
5. 
Ground level fall. 
Likely traumatic brain injury and not 
hemorrhagic shock due to trauma [Schreiber 
et al, 2015]. 
6. 
Drowning or hanging. 
Non-traumatic hypoxic / anoxic injury. 

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Exclusion Criteria 
Rationale 
7. 
Subject transferred from another 
hospital. 
Subject population likely to have received 
care before arrival at the hospital and / or 
spent time at another institution that could 
confound results. Subjects who were 
transported en route through, but did not 
enter, another institution are permitted if 
they did not receive care (eg, subject 
transferred from ambulance to helicopter). 
8. 
Known heparin-induced 
thrombocytopenia. 
Known heparin-induced thrombocytopenia. 
BE1116 contains heparin [CSL, 2018]. 
9. 
Known hereditary disorders that 
significantly increase prothrombotic 
risk such as hereditary 
antithrombin III deficiency, Factor V 
Leiden, etc. 
There is an increased risk of TEE associated 
with these underlying conditions that may 
confound safety data from BE1116 
administration. 
10. 
Known or suspected pregnancy. 
There are no data with BE1116 use in 
pregnancy to inform on drug-associated risk 
[CSL, 2018]. 
11. 
Known anaphylactic or severe 
systemic reactions to BE1116 or any 
components in BE1116 including 
heparin, Factors II, VII, IX, X, 
Proteins C and S, antithrombin III, 
and human albumin. 
Known anaphylactic or severe systemic 
reactions to BE1116 or any components in 
BE1116 including heparin, Factors II, VII, 
IX, X, Proteins C and S, antithrombin III and 
human albumin [CSL, 2018]. 
12.A2. Known prisoner at time of 
enrollment. 
Vulnerable population. 
13. 
Known “Do Not Resuscitate” order. 
Subject’s explicit wish must be respected. 
14.A2.(a) FOR all study sites: Subject or 
Legally Acceptable Representative 
voiced an objection to participation in 
the trial 
OR 
(b) FOR United States: A family 
member voiced an objection to 
participation in the trial or subject 
was 
wearing an “opt-out” bracelet. 
a. A patient with mental capacity should be 
granted full autonomy to object to study 
participation. If the subject lacks mental 
capacity, then an available Legally 
Acceptable Representative has the right to 
object on the potential subject’s behalf. 
b. In the United States, family members 
have the right to object to trial participation. 
Potential subjects wearing an “opt-out” 
bracelet will have previously opted out of the 
study during the community education 
procedure. 

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Exclusion Criteria 
Rationale 
15.A1. Known participation in another 
interventional clinical study except 
with prior documented agreement 
from the sponsors. 
Subjects receiving other investigational 
products may confound outcomes. However, 
participation in some studies may not 
prejudice subject safety or data integrity, so 
subjects enrolled in another study may 
participate in both if the site principal 
investigator obtains agreement from the 
sponsors of both studies in advance. 
16.A1. Known treatment with any 
prohibited medications including 
3F-PCC, 4F-PCC, aPCC (FEIBA), 
and / or Factor VIIa after trauma and 
prior to randomization. 
Administering 1 of these drugs and IP may 
confound primary endpoint and safety 
signals. 
17.A2. Normal level of consciousness 
(Glasgow Coma Scale score of 15).  
Level of consciousness is a subtle marker of 
cerebral perfusion. A normal level of 
consciousness indicates that the patient is 
unlikely to be in shock and thus unlikely to 
benefit from BE1116.  
18.A2. Moribund patient with devastating 
injuries expected to die within 
1 hour of hospital arrival.  
Patients that have virtually no chance of 
survival do not have potential to benefit 
from BE1116.  
 
4.2 
Screen Failures 
Screen failures are defined as individuals who are screened but do not meet the eligibility 
criteria for participation in the study. There is no requirement to collect data from screen 
failures in this study. 
4.3 
Discontinuation of Study Treatment and Subject Withdrawal 
4.3.1 
Discontinuation of Study Treatment 
This is a single-dose study. Discontinuation of the IP infusion is not expected. 
IP infusion may be stopped for medical reasons due to safety issues (eg, if pregnancy is 
confirmed for a subject). 
If a subject declines further study procedures, the subject will be withdrawn from the study. 
Refer to Sections 4.3.2 and 4.3.3 for details on handling subject withdrawals. 

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4.3.2 
Subject Withdrawal 
Subjects may withdraw from the study at any time at their own request (or that of their 
Legally Acceptable Representative, if applicable), or at the discretion of the investigator or 
CSL for safety, behavioral or administrative reasons (eg, because of an AE, protocol 
deviation, loss to follow-up, subject noncompliance, study termination). The investigator 
should record the reason and date of subject withdrawal in the electronic case report form 
(eCRF) and in the subject’s medical records. 
In accordance with the ICH principles of Good Clinical Practice (GCP), the investigator 
always has the option to advise a subject to withdraw from the study if the subject’s safety or 
wellbeing is compromised by his or her further participation in the study. Concern for the 
interests of the subject must always prevail over the interests of the study. 
4.3.3 
Procedures for Handling Withdrawals 
If a subject is withdrawn from the study, attempts will be made to complete and document the 
follow-up assessments. If the subject is withdrawn from the study after receiving IP, every 
effort will be made to ensure that the relevant safety assessments are completed. The subject 
may also be asked by the investigator to complete other study assessments. 
If the subject withdraws from the study and also withdraws consent for disclosure of future 
information, CSL may retain and continue to use any data collected before such withdrawal 
of consent. 
4.3.4 
Subjects Lost to Follow-up 
Not applicable. 
4.3.5 
Replacement Policy 
The decision to replace subjects will be at the discretion of CSL. 
5 
Study Interventions 
All subjects will receive standard of care according to the study site’s normal clinical practice 
at all times during the study. No standard of care practices will be interrupted or forgone as a 
result of enrollment evaluation, IP infusion, or other aspects of the study. 

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5.1 
Investigational Products 
The IPs in this study are BE1116 and placebo. 
5.1.1 
Description of BE1116 
Details of BE1116 are provided in Table 2. 
The lyophilized powder of BE1116 will be provided in labeled, single-use, glass vials. The 
product is provided in a study co-packaged kit (IP study kit) containing 3 vials of BE1116 (or 
placebo), 3 vials of sterile water for injection, and 3 Mix2Vial™ devices. The lyophilized 
concentrate of BE1116 must be reconstituted with sterile water for injection. 
The formulation of BE1116 to be used in this clinical study is unchanged from the 
commercial form and will be labeled as IP. 
Dose administration information is included in Section 5.1.3.1. 
Table 2 
Description of BE1116 
Substance name 
BE1116 
Trade name 
Kcentra® / Beriplex® 
Active substance 
Concentrate of human coagulation Factors II, VII, IX, and X (PCCs), 
Protein C, and Protein S 
Excipients 
Heparin, antithrombin III, human albumin, sodium chloride, sodium 
citrate, hydrogen chloride, sodium hydroxide 
Dosage form 
Powder for reconstitution (1000 IU/vial) 
Provided together with diluent (sterile water for injection) 
Dose 
• 
2000 IU for subjects with body weight < 75 kg (< 165 lbs) 
(2 vials) 
• 
3000 IU for subjects with body weight ≥ 75 kg (≥ 165 lbs) 
(3 vials) 
(Weight may be estimated and / or measured.) 
Dosing regimen 
Single dose 
Infusion volume 
Based upon dose: 
• 
80 mL for 2000 IU (2 vials) 
• 
120 mL for 3000 IU (3 vials) 
Mode of administration 
Intravenous infusion a 
IP = investigational product; PCC = prothrombin complex concentrate. 
a 
Further details regarding dose administration are provided in the Site IP Manual. 

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BE1116 will be manufactured by CSL in accordance with ICH Good Manufacturing Practice 
(GMP) guidelines and local regulatory requirements. 
5.1.2 
Description of Placebo 
Details of placebo are provided in Table 3. Placebo is a sterile filtered preparation comprising 
the BE1116 buffer and human albumin to support lyophilization cake formation. Placebo 
vials will match BE1116 vials in appearance. The lyophilized concentrate of placebo must be 
reconstituted with sterile water for injection. 
After reconstitution, each vial contains 2 to 4 mg/mL human albumin in sterile water for 
injection at a target pH of 6.5 to 7.5. The amount of albumin in the reconstituted placebo is 
the same as in the reconstituted drug product, BE1116. The placebo contains the same 
amounts of the excipients sodium chloride and sodium citrate as used for the drug product 
BE1116. 
Details of packaging and administration are the same as for BE1116. Dose administration 
information is included in Section 5.1.3.1. 
Table 3 
Description of Placebo 
Substance name 
Not applicable 
Substance 
Buffer solution with human albumin without active ingredient and 
without proteins and impurities related to the active ingredient or 
antithrombin III and heparin 
Trade name 
Not applicable 
Dosage form 
Powder for reconstitution (same vial as 1000 IU/vial for BE1116) 
Provided together with diluent (sterile water for injection) 
Dose 
• 
2 vials for subjects with body weight < 75 kg (< 165 lbs) 
• 
3 vials for subjects with body weight ≥ 75 kg (≥ 165 lbs) 
(Weight may be estimated and / or measured.) 
Dosing regimen 
Single dose 
Infusion volume 
Based upon dose: 
• 
80 mL for 2 vials 
• 
120 mL for 3 vials 
Mode of administration 
Intravenous infusion a 
IP = investigational product. 
a 
Further details regarding dose administration are provided in the Site IP Manual. Preparation and 
administration of placebo will be identical to BE1116. The placebo presentation looks the same as BE1116, 
and the kit contains the same vials and accessories as in the kit containing BE1116. 

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Placebo will be manufactured by CSL in accordance with ICH GMP guidelines and local 
regulatory requirements. 
5.1.3 
Dosing and Administration of Investigational Products 
5.1.3.1 Dose Administration 
Subjects who were enrolled but subsequently discovered to have an exclusion criterion prior 
to IP administration should not be administered IP. 
Each subject will receive a single dose of either BE1116 or placebo, according to their 
randomization (see Section 6). Enrolled subjects will receive IP from blinded study IP kits. 
A fixed dose (number of vials) will be administered according to the subject’s body weight 
(estimated or measured) (see Sections 5.1.1 and 5.1.2). 
The start of the IP infusion must be within 90 minutes after arrival at the hospital. 
Details of dose administration, including the start and stop times of the infusion and any 
infusion interruptions, will be recorded in the eCRF if available. 
The investigator (or other applicable site staff) will administer or dispense IP only to subjects 
included in this study following the procedures set out in this study protocol. 
Detailed information on the preparation and administration of IP is provided in the Site IP 
Manual. 
5.1.3.2 Dosing Modification 
A partial dose of IP may be administered (eg, if there is a product error or user error when 
reconstituting / administering the IP if the remainder of the IP is unaffected, when infusion 
needs to be stopped due to patient care issues, or if vial(s) are damaged). 
5.1.3.3 Treatment Compliance 
All doses of BE1116 (or matching placebo) will be administered by the investigator (or other 
applicable site staff) at the study site, and details will be recorded in the eCRF. 

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5.1.3.4 Overdose 
Overdose of BE1116 is defined as the infusion of more than the protocol-specified dose. The 
effects of any potential overdose with BE1116 have not been studied. In case of overdose, the 
subject should be closely monitored, and supportive treatment should be administered, as 
needed. 
See Section 9.6.5 for overdose reporting requirements. 
5.1.4 
Description of Investigational Medical Device Constituent 
Each IP study kit will include 3 Mix2Vial™ devices, as described in Section 5.1.1. 
5.1.5 
Packaging, Labeling, Supply, and Storage 
5.1.5.1 Packaging and Labeling 
The IP will be packaged and labeled according to current ICH GMP and GCP guidelines, and 
national legal requirements. Specific details regarding the packaging of IP are provided in the 
Site IP Manual. 
5.1.5.2 Supply and Storage 
Study kits containing IP will be supplied to the study sites by CSL or delegate. 
The kits must be stored under temperature-controlled and monitored conditions in a secure 
storage area, and must not be frozen, as specified in the Site IP Manual. 
Blinded, sealed IP study kits containing either BE1116 or placebo will be maintained in the 
trauma bay, or a location where they are readily accessible, at the study site at all times 
during the study. See also Section 6.1. 
Reconstitution of the vials should be performed at the time of dosing; therefore, there should 
be no storage of reconstituted vials. 
If an IP study kit is opened for a subject, it should not be used for any other subject, even if 
the kit is not subsequently used. 

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5.1.6 
Access to Investigational Product After the End of Study 
Subjects will not be provided with BE1116 by CSL after completion or discontinuation from 
the study. 
5.2 
Accountability and Destruction 
The IP must be used only as directed in the clinical study protocol. 
The investigator or delegate will confirm receipt of all shipments of IP in the interactive 
response technology (IRT) system. 
All supplies of IP must be accounted for throughout the study. IP accountability should be 
performed in the IRT system when feasible within 24 hours after randomization. 
Records for the delivery of IP to the study site, the inventory at the study site, the use by each 
subject, and the destruction or return of IP to CSL or designee must be maintained by the 
study site personnel delegated by the investigator using the appropriate form or IRT system. 
The study site personnel delegated by the investigator must provide reasons for any 
discrepancies in drug accountability in the IRT system. 
Further details regarding accountability and destruction of IP are provided in the Site IP 
Manual. 
5.3 
Other Interventions 
The IP will be administered in addition to the study site’s standard resuscitation methods and 
protocol. 
6 
Allocation to Treatment 
6.1 
Subject Assignment 
Eligible subjects will be assigned an IP study kit with the next available sequential subject 
number, as described in Section 6.2. The subject identification number will be used to 
identify the subject for the duration of the study. Subject identification numbers will not be 
reassigned or reused. 

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6.2 
Randomization Procedures 
The IRT external service provider will prepare the study randomization code according to the 
approved specifications. 
Subjects will be randomized in a 1:1 ratio to either the BE1116 or placebo treatment arm. 
Randomization will be stratified by study site. 
The blinded study staff will use the IRT system to randomize subject placeholders, resulting 
in a unique subject number assignment and pre-assignment of an IP study kit prior to subject 
arrival at the hospital. The research pharmacy staff (or equivalent) will record the 
IRT-assigned unique subject number on the label of the applicable kit and send the kit to be 
stored in the trauma bay, or a location where it is readily accessible. Once a subject meets all 
the eligibility criteria, the trauma team (or other applicable site staff) will select and open the 
IP study kit with the next available sequential subject number, and the subject will be 
considered randomized (enrolled). The date and time of opening the IP study kit 
(randomization) will be recorded. 
6.3 
Blinding Procedures 
Additional details on unblinding are provided in the study blinding plan. 
6.3.1 
Blinding Method 
CSL (or designee) will provide blinded IP study kits to the study sites. The IP will be 
packaged and labeled to ensure blinding is maintained. 
Investigational site staff, including the investigators, physicians, nurses, and pharmacists, will 
be blinded to treatment allocation. Subjects will also be blinded to treatment allocation 
(double-blind). 
CSL personnel (or delegates) will be blinded to treatment allocation, except for those 
personnel involved in the IRT system and clinical trial supply who will be unblinded. 
A separate statistician and programming team will provide unblinded data to the IDMC for 
adequate safety and efficacy reviews as planned. All individuals involved will be placed 
under strict confidentiality to protect the integrity of the study. If the IDMC makes a 
recommendation to stop the study, a few designated senior Sponsor stakeholders will access 

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the unblinded data before endorsing the recommendation. These senior stakeholders will not 
participate in any study conduct or analyses after unblinding. 
Review of unblinded data by treatment arms will occur during the scheduled interim 
analyses, the final analysis, and for IDMC reviews. In addition, individual subjects may be 
unblinded during the study in emergency situations for reasons of subject safety, if knowing 
treatment assignment will change medical management. 
6.3.2 
Breaking the Blind for an Emergency 
The randomization code for individual subjects may be unblinded to a study site during the 
study in emergency situations for reasons of subject safety, if knowing treatment assignment 
will change subject management. In case of an emergency situation for the reason of subject 
safety, the investigator should use the IRT system to identify the treatment allocation for a 
subject. Whenever possible, the investigator should consult with CSL before unblinding the 
randomization code. The reason for unblinding the randomization code must be fully 
recorded in the subject’s source documents, and the investigator must follow the defined 
procedures provided in the study reference manuals. The subject’s treatment allocation 
should not be recorded in the subject’s source document. 
6.3.3 
Planned Unblinding Procedures 
Periodic data reviews will be performed by the IDMC (see Section 3.8.1). With authorization 
by CSL, randomization codes will be provided to the unblinded statistician (external service 
provider) performing analyses for the interim analyses and / or IDMC, via the CSL Central 
Data Warehouse. 
At the end of the study, CSL will authorize that the study be unblinded after database lock. 
The randomization codes will be accessed via the CSL Central Data Warehouse. 
6.3.4 
Ad-hoc Safety Unblinding 
CSL’s Global Clinical Safety and Pharmacovigilance personnel may, on an ad-hoc basis, 
unblind the randomization code directly in the IRT at any time during the study, because of a 
safety concern. The purpose of the unblinded data review is to determine if there is a risk to 
subject safety that would require further action either for the individual management of a 
study subject or for the ongoing conduct of the study. The need to unblind a subject or group 
of subjects may not necessarily arise because of an SAE. The need to unblind on an ad-hoc 

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basis will be determined by CSL’s Global Clinical Safety and Pharmacovigilance senior 
leadership. 
7 
Contraindications, Permitted Therapies, and Prohibited Therapies 
7.1 
Contraindications 
BE1116 is contraindicated in the following: 
• Subjects with known anaphylactic or severe systemic reactions to BE1116 or any 
components in BE1116 including heparin, FII, FVII, FIX, FX, Proteins C and S, 
antithrombin III, and human albumin 
• Subjects with disseminated intravascular coagulation 
• Subjects with known heparin-induced thrombocytopenia; BE1116 contains heparin 
7.2 
Permitted Therapies 
Any medication or therapy determined by the treating trauma team to be required by the 
subject is allowed following IP administration, with the exception of PCCs, activated PCC, 
and FVIIa (see Section 7.3). 
7.3 
Prohibited Therapies 
Subjects will be excluded from the study if they have received a known anticoagulation 
treatment within the past 3 months. 
Prohibited medications during the study are summarized in Table 4. 

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Table 4 
Summary of Prohibited Medications 
Medication 
Dose 
Prohibited Period of Use 
3F-PCC 
Any 
From trauma time through 6 hours after 
randomization 
4F-PCC 
Any 
From trauma time through 6 hours after 
randomization 
aPCC (FEIBA) 
Any 
From trauma time through 6 hours after 
randomization 
Factor VIIa 
Any 
From trauma time through 6 hours after 
randomization 
3F-PCC = 3-factor prothrombin complex concentrate; 4F-PCC = 4-factor prothrombin complex concentrate; 
aPCC = activated prothrombin complex concentrate; FEIBA = Factor VIII inhibitor bypassing activity; 
IP = investigational product. 
 
7.4 
Lifestyle Restrictions 
Not applicable. 
8 
Study Procedures and Visit Schedule 
8.1 
Clinical Procedures 
The timing and frequency of the clinical procedures described in the following sections are 
detailed in the Schedule of Assessments. More frequent assessments may be performed, if 
clinically indicated, at the discretion of the investigator. 
The date and time of arrival at the hospital will be recorded in the eCRF. This will be 
considered the start of hospitalization. 
Where possible / applicable, the dates and times of study assessments will be recorded in the 
eCRF. 
8.1.1 
Demographics and Clinical Conditions 
Subject demographics and clinical conditions to be recorded in the eCRF are summarized in 
Table 5. 
The clinical laboratory tests (hematology, coagulation, and arterial or venous blood gases) 
will be performed at local laboratories per local standard of care. Results should be retained 

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at the study site as source data. The initial hematology, coagulation, and blood gas 
measurements only will be recorded in the eCRF from medical records. 
Table 5 
Demographics and Clinical Conditions 
Assessment 
Description 
Vital signs, body 
weight, and height a 
• Weight (kg) (estimated or measured on arrival at hospital; if estimated, 
weight may also be subsequently measured) 
• Height (cm) (measured or taken from medical history) 
• Supine systolic and diastolic blood pressure (mmHg) 
• Pulse rate (bpm) 
• Respiratory rate (breaths per minute) 
• Pulse oximetry (%) 
• Body temperature (°C) 
Glasgow Coma Scale b 
• Record individual components if available, otherwise total score. 
• See Appendix 3 
RABT score 
(if applicable) b 
• See Table 1 
Demographics c 
• Sex, race, ethnicity, and other factors according to the eCRF and regulatory 
and local requirements. Either actual age or estimated age will be collected 
during Screening. The actual age of subjects will be recorded, once 
confirmed. An enrolled subject whose confirmed age does not meet the 
inclusion criteria must be reported to Sponsor and the IRB / IEC as a 
prompt reporting event. 
Medical history and 
Charlson Comorbidity 
Index c 
• Medical history includes all bleeding and coagulation history and surgical 
conditions, and any other pertinent findings related to the Charlson 
Comorbidity Index, which will be recorded (see Appendix 6) 
Prior and concomitant 
medications c 
• Medications that impact bleeding and coagulation (including antiplatelets) 
for approximately 1 week prior to randomization will be recorded when 
feasible 
• Tranexamic acid (if administered) 
• Prohibited concomitant medications from trauma time through 6 hours after 
randomization 
• Anticoagulants, thrombolytic agents, and procoagulants used to treat AESIs 
• In-hospital low-dose prophylactic anticoagulants are not considered 
concomitant medications 
Concomitant procedures • Any surgical or interventional radiological procedures, or other life-saving 
interventions, used to treat an SAE or AESI at any time through the study 
will be recorded as a concomitant procedure. 
Hematology d 
• Hemoglobin 
• Hematocrit 
• Platelets 

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Assessment 
Description 
Coagulation d 
• International normalized ratio and / or prothrombin time 
Arterial or venous 
blood gases d 
• If reported by clinical laboratory: Base excess 
• If base excess not reported by clinical laboratory, then the study site will 
collect the following parameters so that base excess can be calculated: 
o pH 
o pCO2 
o pO2 
o HCO3 
Mode of transport e 
• Mode of transport to the hospital will be recorded, eg, ground (ambulance), 
air (medical flight), and / or self-presenter (walk-in or vehicle) 
Life-saving 
interventions e 
• Any prehospital life-saving interventions and any life-saving interventions 
performed on arrival at the hospital (eg, tracheal intubation, tourniquet, 
thoracotomy, etc.)  
Mechanism of injury e 
• Mechanism of injury (blunt, penetrating, or both) 
Date and time of call to 
emergency services and 
arrival at trauma scene e 
• Date and time of call to emergency services (if available) 
• Date and time of arrival of emergency medical services at trauma scene (if 
available) 
Hospital arrival time and 
hospital admission  
time e 
• Hospital arrival time (should be recorded per study site processes; 
hospital arrival time will determine timing of IP administration) 
• Hospital admission time (should be recorded per study site processes) 
Injury Severity Score f 
• Scoring relating to the injury(ies) sustained from the trauma (Appendix 4). 
The Injury Severity Score may be calculated after study completion. 
AESI = adverse event of special interest; eCRF = electronic case report form; IEC = Independent Ethics 
Committee; IRB = Institutional Review Board; RABT = Revised Assessment of Bleeding and Transfusion 
a 
Vital signs obtained as part of standard of care will be recorded at Screening prior to infusion, except as 
described. These include supine systolic and diastolic blood pressure (mmHg), pulse rate (bpm), respiratory 
rate (breaths per min), pulse oximetry (%), and body temperature (°C). Body weight (kg) will be estimated 
or measured on arrival at the hospital and used to define the dose of IP. If estimated, weight may also be 
subsequently measured. Height (cm) will be measured or taken from medical history. 
b 
To be performed at Screening prior to IP infusion, except as indicated. 
c 
To be recorded when feasible. 
d 
To be recorded from the subject’s medical records (if available). The initial hematology, coagulation, and 
blood gas measurements only will be recorded in the eCRF from medical records. Initial = the first value 
obtained after arrival at the hospital prior to IP infusion. 
e 
To be recorded at any time from Screening through the In-hospital Follow-up Period from the subject’s 
medical records. 
f 
To be recorded at any time during the In-hospital Follow-up Period from the subject’s medical records. 

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8.1.2 
Efficacy Assessments 
All efficacy data will be recorded in the eCRF from the subject’s medical records. 
8.1.2.1 Survival Status 
The survival status of the subject during primary hospitalization will be recorded from 
randomization up to the time of death, hospital discharge, or Day 30, whichever occurs first. 
The date and time of death / hospital discharge / Day 30 will be recorded, as applicable. The 
survival status check during primary hospitalization will be at 24 hours (the date and time of 
death / hospital discharge will be recorded, as applicable). If subject is discharged alive prior 
to 6 hours, then the subject will be followed up to assess 6-hour survival status, SAEs, and 
AESIs. 
The primary cause of death, as determined by the investigator, will be recorded. 
Discharge / transfer information will be recorded (eg, transferred to another hospital, 
transferred to skilled nursing facility, transferred to in-patient rehabilitation, discharged to 
home, or transitioned to comfort care / palliative care). If subject is discharged within 2 days 
of enrollment, discharge time will also be recorded. Additionally, if the subject is designated 
“do not resuscitate”, the date and time (where applicable) will be recorded. 
8.1.2.2 Surgical or Interventional Radiological Procedures Performed to 
Stop Bleeding Related to the Primary Injury, Through the First 
24 Hours After Randomization 
All surgical or interventional radiological procedures performed to stop bleeding related to 
the primary injury, through the first 24 hours after randomization, will be recorded. 
8.1.2.3 Blood Product Transfusion up to 24 Hours 
Transfusion of blood products (time and quantity) before arrival at the hospital through the 
first 24 hours after randomization (RBCs, FFP, whole blood, cryoprecipitate, intraoperative 
salvaged [cell-saver] blood, and platelets) will be recorded according to the period in which 
the blood component transfusion started: before arrival at the hospital; from arrival at the 
hospital to the time of randomization; from randomization to 6 hours after randomization; 
and from 6 to 24 hours after randomization (see Section 8.4). 

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Administration of IV fluids (crystalloids and / or colloids) will also be recorded for the same 
time periods. 
8.1.3 
Safety Assessments 
Safety assessments are summarized in Table 6. The investigator should make an evaluation of 
all available safety assessment results with respect to clinically relevant abnormalities. 
Table 6 
Safety Assessments 
Assessment 
Description 
SAEs a 
• SAEs will be recorded; see Section 9 for further details 
AESIs a 
• AESIs will be recorded; see Section 9 for further details (AESIs are 
defined in Section 9.1.3) 
Pregnancy status b 
• Pregnancy status (positive / negative) 
• Pregnancies in female subjects will also be recorded; see Section 9.6.6 
for further details 
ICU assessments c 
• ARDS, multiple organ failure, and AKI requiring renal replacement 
therapy (see Section 9.1.3) 
AESI = adverse event of special interest; AKI = acute kidney injury; ARDS = acute respiratory distress 
syndrome; eCRF = electronic case report form; ICU = intensive care unit; SAE = serious adverse event 
a 
To be recorded from the time of randomization through the In-hospital Follow-up Period until 
death / hospital discharge / or Day 30, whichever occurs first. If subject is discharged alive prior to 6 hours, 
then the subject will be followed up to assess 6-hour survival status, SAEs, and AESIs. 
b 
To be recorded from the subject’s medical records (if available). 
c 
To be recorded daily when a subject is in the ICU. ICU assessments will be collected from the medical 
record of the subject using data collected as part of standard of care. 
8.1.4 
Other Assessments 
8.1.4.1 Medical Resource Utilization 
Medical resource utilization during primary hospitalization, up to the time of death, hospital 
discharge, or Day 30, whichever occurs first, will be assessed through the following data 
recorded in the eCRF: 
• Start and stop dates and times of ventilator use (to calculate days with ventilator use) 
• Start and stop dates and times in ICU (to calculate ICU days) 
• Start and stop dates of primary hospitalization (to calculate hospital length of stay) 
The assessments above will be analyzed overall and separately as subgroups for those who 
die during primary hospitalization and those who remain alive during primary hospitalization. 

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8.2 
Blood Samples 
It is not planned to collect any blood samples as part of the study; clinical laboratory safety 
tests, as described in Section 8.1.1, will be recorded from the subject’s medical records. 
Components of the Denver postinjury multiple organ failure score, KDIGO AKI, and Berlin 
Criteria for ARDS will be collected from medical records, if available, even if all components 
are not collected per standard of care (Section 9.1.3). 
8.3 
Retention of Samples 
Not applicable. 
8.4 
Prior and Concomitant Therapies 
Medications that impact bleeding and coagulation (including antiplatelets) for at least 1 week 
prior to randomization will be recorded when feasible in the Concomitant and Prior 
Medications eCRF. In-hospital low-dose prophylactic anticoagulants are not considered 
concomitant medications. 
Other medications to be recorded on the eCRF are as follows: 
• Tranexamic acid (if administered) 
• Blood product transfusions and IV fluids administration before arrival at the hospital 
through the first 24 hours after randomization 
• Prohibited concomitant therapies taken from trauma time through 6 hours after 
randomization (see Section 7.3) 
• Anticoagulants, thrombolytic agents, and procoagulants used to treat AESIs at any time 
through the study 
Any surgical or interventional radiological procedures, or other life-saving interventions, that 
are used to treat an SAE or AESI at any time through the study will be recorded as a 
concomitant procedure. 
Surgical or interventional radiological procedures performed to stop bleeding related to the 
primary injury, through the first 24 hours after randomization, are described in 
Section 8.1.2.2. 

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8.5 
Visit Schedule 
8.5.1 
Assessment Time Windows 
The timing and frequency of the study assessments are described in the Schedule of 
Assessments. Time windows are summarized in Table 7. 
Table 7 
Time Windows for Assessments 
Study Period 
Time Window 
Screening and Randomization 
(Enrollment) 
Subjects must be screened and randomized within 
90 minutes after hospital arrival and before the start of IP 
infusion 
Treatment Period (Start of IP infusion 
through completion of IP infusion) 
IP infusion must be started post-randomization and 
within 90 minutes after hospital arrival 
In-hospital Follow-up Period 
Subjects will be followed up until death, discharge from 
hospital, or Day 30, whichever occurs first. If subject is 
discharged alive prior to 6 hours, then the subject will be 
followed up to assess 6-hour survival status, SAEs, and 
AESIs.  
IP = investigational product. 
 
8.5.2 
Screening and Randomization (Enrollment) Period 
Screening will begin once the subject has arrived at the hospital (eg, emergency department, 
trauma bay, or operating room). Upon arrival, subjects will be assessed for eligibility. For 
details regarding Informed Consent, refer to Section 12.3 and Section 12.3.1. 
The following Screening assessments will be performed and recorded: 
• Vital signs (supine systolic and diastolic blood pressure, pulse rate, respiratory rate, pulse 
oximetry, and body temperature) 
• Body weight (estimated or measured; if estimated, weight may also be subsequently 
measured) 
• Height (measured or taken from medical history) 
• Glasgow Coma Scale (record individual components if available, otherwise total score) 
• RABT score (if applicable) 

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• Hematology, coagulation, and arterial or venous blood gases (initial measurements only 
to be recorded; initial = first value obtained after arrival at the hospital prior to IP 
infusion) 
• Inclusion / exclusion criteria check 
Once a subject meets all the eligibility criteria, the trauma team (or other applicable site staff) 
will select and open the IP study kit with the next available sequential subject number, and 
the subject will be considered randomized (enrolled). 
If study sites have sufficient safeguards and processes in place, more than 1 subject who 
meets the eligibility criteria may be randomized (enrolled) in the study at the same time, 
assigned IP, and treated. 
8.5.3 
Treatment Period 
The start time of the IP infusion will be within 90 minutes after arrival at the hospital. The 
blinded, sealed IP study kits will be available to the trauma team (see Section 6.2). At the 
time of subject randomization (enrollment), the selected kit will be provided to the trauma 
team (or other applicable site staff) for IP reconstitution and administration. 
• IP administration: must start within 90 minutes after arrival at the hospital (eg, emergency 
department, trauma bay, or operating room) (see Section 5.1.3.1) 
IP administration is in addition to the site’s standard resuscitation methods and protocol. 
8.5.4 
In-hospital Follow-up Period 
Subjects will be followed up until death, discharge from hospital, or Day 30, whichever 
occurs first. If subject is discharged alive prior to 6 hours, then the subject will be followed 
up to assess 6-hour survival status, SAEs, and AESIs. Transfer to another healthcare facility 
will be considered as discharge from hospital. For details regarding Informed Consent, refer 
to Section 12.3 and Section 12.3.1. 
The following assessments will be performed: 
• IP accountability (to be performed in the IRT system when feasible within 24 hours after 
randomization) 
• Demographics (to be recorded when feasible)* 
• Medical history and Charlson Comorbidity Index (to be recorded when feasible)* 

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• Prior and concomitant medications (medications that impact bleeding and coagulation 
[including antiplatelets] for at least 1 week prior to randomization; tranexamic acid [if 
administered]; prohibited concomitant medications administered from trauma time 
through 6 hours after randomization; and anticoagulants, thrombolytic agents, and 
procoagulants used to treat AESIs; to be recorded when feasible)* 
• Concomitant procedures (any surgical or interventional radiological procedures, or other 
life-saving interventions, used to treat an SAE or AESI at any time through the study will 
be recorded)* 
• SAEs and AESIs 
• Survival status (survival status of the subject during primary hospitalization will be 
recorded from randomization up to the time of death, hospital discharge, or Day 30, 
whichever occurs first. The date and time of death / hospital discharge / Day 30 will be 
recorded, as applicable. For expired subjects, details of their death may be recorded on 
the Subject Death Record. The survival status check during primary hospitalization will 
be at 24 hours [the date and time of death / hospital discharge will be recorded, as 
applicable]. If subject is discharged alive prior to 6 hours, then the subject will be 
followed up to assess 6-hour survival status, SAEs, and AESIs)* 
• Blood product transfusions (eg, RBCs, FFP, whole blood, cryoprecipitate, intraoperative 
salvaged [cell-saver] blood, and platelets) and IV fluid administrations (crystalloids 
and / or colloids) before arrival at the hospital through the 24 hours after randomization* 
• All surgical or interventional radiological procedures performed to stop bleeding related 
to the primary injury, through the first 24 hours after randomization* 
• Mode of transport to the hospital* 
• Life-saving interventions (prehospital and on arrival at hospital)* 
• Mechanism of injury (blunt, penetrating, or both)* 
• Date and time of call to emergency services (if available)* 
• Date and time of arrival of emergency medical services at trauma scene (if available)* 
• Hospital arrival time (should be recorded per study site processes; hospital arrival time 
will determine timing of IP administration)* 
• Hospital admission time (should be recorded per study site processes)* 
• Injury Severity Score (may be calculated after study completion)* 
• Pregnancy status (pregnancies will also be reported as described in Section 9.6.6)* 

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• Daily assessments for ARDS, multiple organ failure, and AKI requiring renal 
replacement therapy recorded when a subject is in the ICU. ICU assessments will be 
collected from the medical record of the subject using data collected as part of standard of 
care* 
• Medical resource utilization (see Section 8.1.4.1)* 
• Discharge / transfer location* 
• Date and time if subject is designated “do not resuscitate”* 
*Recorded from medical records (as applicable). 
If subject is discharged within 2 days of enrollment, discharge time will also be recorded. 
8.5.5 
Withdrawal Assessments 
If a subject is withdrawn from the study, the investigator should make every effort to 
complete and document the follow-up assessments, as described in Section 8.5.4. 
9 
Adverse Events 
Nonserious AEs (except AESIs) will not be recorded in this study. However, information 
regarding AEs is provided below, to be used in the context of assessing AESIs and SAEs, 
which will be recorded in this study. 
9.1 
Definitions 
9.1.1 
Adverse Event 
As per the ICH Topic E2A (Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting), an AE is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have a causal relationship with this treatment. An AE can, therefore, be any unfavorable and 
unintended sign (including an abnormal, clinically significant laboratory finding), symptom, 
or disease temporally associated with the use of a medicinal (investigational) product, 
whether or not considered related to the medicinal (investigational) product. 
The primary safety risk factors identified for this study population are: 
• In-hospital SAEs with a fatal outcome up to 30 days after the start of IP infusion 
• In-hospital TEEs up to 30 days after the start of IP infusion 

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9.1.2 
Serious Adverse Event 
In this study, a SAE is defined as any untoward medical occurrence that at any dose meets at 
least one of the following criteria: 
• Results in death – The event must be the cause of death for the SAE to meet this serious 
criterion. Refer to Section 9.6.3 for details regarding reportability. 
• Is life-threatening – The term “life-threatening” refers to an event in which the subject 
was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it had been more severe. 
• Requires in-patient hospitalization or prolongation of existing hospitalization – CSL 
considers “hospitalization or prolongation of existing hospitalization” for at least 
24 hours as the defining criterion for an SAE. Hospital admissions for planned surgery or 
for normal disease management procedures (eg, chemotherapy) are not considered as 
defining criteria for SAEs. 
• Results in persistent or significant disability or incapacity. 
• Is a congenital anomaly or birth defect. 
• Is medically significant – A medically significant event is defined as an event that does 
not necessarily meet any of the SAE criteria, but which is judged by a physician to 
potentially jeopardize the subject or require medical or surgical intervention to prevent 
one of the above outcomes listed as an SAE criterion. 
Adverse events that do not fall into the above categories are defined as nonserious AEs. 
A preexisting medical condition should be recorded as an SAE only if the frequency, severity, 
or character of the condition worsens during the study. A preexisting medical condition is one 
that is present at the time of randomization. 
9.1.3 
Adverse Events of Special Interest 
The AESIs in this study are: 
• TEEs, symptomatic or asymptomatic, and arterial or venous (eg, deep vein thrombosis, 
pulmonary embolism, ischemic stroke [including thromboembolic stroke], and 
myocardial infarction) 
• ARDS 

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• Multiple organ failure 
• AKI requiring renal replacement therapy (dialysis, hemofiltration, or hemodiafiltration) 
Note: superficial thromboses will not be included as AESIs 
Multiple Organ Failure 
Multiple organ failure will be assessed using the Denver score [Sauaia et al, 2009] (see 
Appendix 5). Components of the Denver postinjury multiple organ failure score will be 
collected from medical records, if available, even if all components are not collected per 
standard of care. The Denver score will be recorded in the eCRF in addition to the severity 
assessment described in Section 9.2. 
Acute Kidney Injury 
The definition of AKI follows the Kidney Disease Improving Global Outcomes (KDIGO) 
guidelines [Kidney International, 2012]. 
AKI is defined as any of the following: 
• Increase in serum creatinine by ≥ 0.3 mg/dL (≥ 26.5 µmol/L) within 48 hours; or 
• Increase in serum creatinine to ≥ 1.5 × baseline, which is known or presumed to have 
occurred within the prior 7 days; or 
• Urine volume < 0.5 mL/kg/h for 6 hours. 
Components of the KDIGO AKI will be collected from medical records, if available, even if 
all components are not collected per standard of care. The reporting requirements for AESIs 
are described in Section 9.6.2. 
Acute Respiratory Distress Syndrome 
ARDS will be assessed using the Berlin criteria [ARDS Definition Task Force, 2012; 
Fan et al, 2018; Matthay et al, 2021] (Appendix 7). Components of the Berlin Criteria for 
ARDS will be collected from medical records, if available, even if all components are not 
collected per standard of care. 

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9.2 
Severity of Adverse Events 
The severity of each AESI and SAE is to be assessed by the investigator as follows: 
Severity 
Definition 
Mild 
A type of AE that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere 
with usual activities of daily living. 
Moderate 
A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm to the 
subject. 
Severe 
A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. 
CDISC SDTM Severity Intensity Scale for Adverse Event Terminology. 
9.3 
Causality of Adverse Events 
The causal relationship of an AESI or SAE to IP must always be assessed by the 
investigator. All AESIs and SAEs will be classified as either related or not related to IP. If a 
causality assessment is not provided for an AESI or SAE, that event will be considered as 
related to the IP. 
The degree of certainty with which an AESI or SAE is attributed to IP or an alternative cause 
(eg, natural history of the underlying disease, concomitant therapy) will be determined by 
how well the event can be understood in terms of: 
• Known pharmacology of IP. 
• Clinically and / or pathophysiologically plausible context. 
• Reaction of a similar nature previously observed with similar products, or reported in the 
literature for similar products as being product related (eg, headache, facial flushing, 
pallor). 
• Plausibility supported by the temporal relationship (eg, the event being related by time to 
administration or termination of treatment with IP, or drug withdrawal). 
9.4 
Observation Period for Adverse Events 
The observation period for the reporting of AESIs and SAEs for an individual subject will 
start at the time of randomization and finish with the end of the In-hospital Follow-up Period 
(ie, up to the time of death / hospital discharge / Day 30, whichever occurs first; if subject is 

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discharged alive prior to 6 hours, then the subject will be followed up to assess 6-hour 
survival status, SAEs, and AESIs). 
If the investigator becomes aware of an SAE that has started after the observation period has 
finished, and there is at least a possible causal relationship with the IP, the event must be 
reported to CSL (see Section 9.6.3). 
9.5 
Follow-up of Adverse Events 
Every effort should be made to follow AESIs and SAEs until resolution or stabilization. 
Ongoing AESIs and SAEs that have not resolved or stabilized will be followed until the 
subject completes the study. 
9.6 
Adverse Event Reporting 
9.6.1 
Adverse Events 
Nonserious AEs (except AESIs) will not be recorded in this study. 
9.6.2 
Adverse Events of Special Interest 
AESIs are defined in Section 9.1.3. Any AESI should be reported following expedited 
reporting procedures, as described for SAEs (Section 9.6.3). Any surgical or interventional 
radiological procedures, or other life-saving interventions used to treat SAEs or AESIs and 
the use of therapeutic anticoagulants, thrombolytic agents, or procoagulants to treat AESIs 
will be reported. 
AESIs, even those with a fatal outcome, should still be reported as AESIs. If an AESI meets 
the definition of an SAE (Section 9.1.2), then the AESI should be marked as meeting serious 
criteria on the electronic data capture system. 
9.6.3 
Serious Adverse Events 
This study will comply with all applicable regulatory requirements and adhere to the full 
requirements of ICH Topic E2A (Clinical Safety Data Management: Definitions and 
Standards for Expedited Reporting). 
For SAEs occurring during the study, the investigator or delegate will enter all relevant 
information in the eCRF. 

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SAEs that occur during the course of the study, whether or not causally related to the 
IP, must be entered into the eCRF immediately (within 24 hours of the investigator 
becoming aware of the event). 
Any SAE that occurs after the observation period has finished and is considered to be 
causally related to the IP must be reported immediately (ie, within 24 hours of the 
investigator becoming aware of the event) to CSL. Such events are not entered into the 
eCRF and should be reported on the Serious Adverse Event Data Collection Form (paper) 
and sent to CSL Global Clinical Safety and Pharmacovigilance and will be documented in the 
CSL safety database only. 
The minimum reporting requirements for reporting of SAEs include: 
• Subject identification number 
• Suspected medicinal product and / or procedure 
• Event term 
• Reporting source identification 
If the minimum requirements for reporting are fulfilled, the investigator should not wait to 
receive additional information to fully document the event. 
In addition, the investigator must: 
• Report relevant SAEs as required to the relevant IRB / IEC within the timeframe 
specified by the IRB / IEC. Refer to Section 9.7. 
• If the subject is an active participant in the study: 
o Enter follow-up information in the eCRF until the SAE has resolved, or, in the case of 
permanent impairment, until stabilized 
o Ensure that the causality assessment for all SAEs is entered in the eCRF 
• If the subject is no longer participating in the study, report the follow-up information to 
CSL when available 
• A SAE resulting in death up to the timeline for initial reporting (ie, within 24 hours of the 
investigator becoming aware of the event) does not require reporting as an SAE unless 
considered causally related to IP by the investigator. 
• If a SAE / AESI is previously reported and subsequently results in death, the SAE / AESI 
outcome must be updated and reported. 

C S L Be hri n g  
St u d y N u m ber:  B E 1 1 1 6 _ 3 0 0 6  
 
St u d y Pr o d uct:  4 F -P C C  
 
Pr ot oc ol versi o n: A me n d me nt 2  
 
Pa ge 7 4  of 1 0 8  
Date: 0 6 Fe br uar y 2 0 2 4  
 
C S -S O P -0 4 -T 0 2 Versi o n 2. 0  
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
9. 6. 4  
Ot her Si g nific a nt E ve nts  
N ot a p plica ble. 
9. 6. 5  
O ver d ose  
A n y o ver d ose t hat is ass ociate d wit h a n A E SI or S A E will be rec or de d o n a n A E / S A E e C R F 
f or m (see als o Secti o n  9. 6. 3 ). 
Details of o ver d ose of I P ( defi ne d i n Secti o n  5. 1. 3. 4 ) m ust be rec or de d i n t he st u d y treat me nt 
a d mi nistrati o n e C R F.  
9. 6. 6  
Pre g n a nc y  
If a pre g na nt fe male s u bject is e x p ose d t o I P, C S L m ust be n otifie d wit hi n 5 da ys of t he 
i n vesti gat or bec o mi n g a ware a nd t here s h o ul d be e ntr y of a p pr o priate data i nt o t he e C R F. 
Pre g na nc y s h o ul d be f oll o we d u p as feasi ble t o o btai n t he o utc o me of t he pre g na nc y. 
9. 7  
I R B / I E C Re p orti n g Re q uire me nts 
T he ti me fra me wit hi n w hic h a n I R B / I E C m ust be n otifie d of deat hs a n d I P -relate d 
u ne x pecte d S A Es is sti p ulate d b y eac h I R B / I E C. It is t he i n vesti gat or’s res p o nsi bilit y t o 
c o m pl y wit h t he re q uire me nts f or I R B  / I E C n otificati o n. C S L will pr o vi de i n vesti gat ors wit h 
all details of all S A Es re p orte d t o healt h a ut h orities.  
1 0  
St atistics  
1 0. 1  
S a m ple Size Esti m ati o n  
A sa m ple size of 8 0 0 0 s u bjects ( 4 0 0 0 per treat me nt ar m) is re q uire d t o ac hie ve 8 0 % p o wer 
w hile c o ntr olli n g f or a o ne -si de d t y pe I err or of 0. 0 2 5 testi n g f or s u peri orit y. 
C CI

C S L Be hri n g  
St u d y N u m ber:  B E 1 1 1 6 _ 3 0 0 6  
 
St u d y Pr o d uct:  4 F -P C C  
 
Pr ot oc ol versi o n: A me n d me nt 2  
 
Pa ge 7 5  of 1 0 8  
Date: 0 6 Fe br uar y 2 0 2 4  
 
C S -S O P -0 4 -T 0 2 Versi o n 2. 0  
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
1 0. 2  
Descri pti o n of St u d y P o p ul ati o ns  
1 0. 2. 1  I nte nt-t o-tre at P o p ul ati o n 
T he I T T P o p ulati o n will i ncl u de all ra n d o mize d s u bjects. I n t his p o p ulati o n, a nal y ses will be 
base d o n t he treat me nt t o w hic h s u bjects were ra n d o mize d, re gar dless of w hic h treat me nt 
t he y act uall y recei ve d. 
1 0. 2. 2  M o difie d I nte nt -t o-tre at P o p ul ati o n 
T he M o difie d I T T ( mI T T) P o p ulati o n will i ncl u de all s u bjects w h o recei ve a c o m plete or 
partial d ose of B E 1 1 1 6 or place b o. I n t his p o p ulati o n, a nal yses will be base d o n t he treat me nt 
t o w hic h s u bjects were ra n d o mize d, re gar dless of w hic h treat me nt t he y act uall y recei ve d. 
1 0. 2. 3  Per -pr ot oc ol P o p ul ati o n  
T he Per - pr ot oc ol ( P P) P o p ulati o n will i ncl u de all s u bjects i n t he I T T P o p ulati o n wit h n o 
maj or pr ot oc ol de viati o ns t hat w o ul d p ote ntiall y affect t he assess me nt of t he pri mar y 
e n d p oi nt. Pr ot oc ol de viati o ns will be d oc u me nte d i n t he data re vie w meeti n g hel d bef ore t he 
st u d y data are u n bli n de d. 
1 0. 2. 4  S afet y P o p ul a ti o n 
T he Safet y P o p ulati o n will i ncl u de all s u bjects i n t he I T T P o p ulati o n w h o recei ve a c o m plete 
or partial d ose of B E 1 1 1 6 or place b o, base d o n t he treat me nt act uall y recei ve d. 
1 0. 3  
St atistic al A n al yses a n d Met h o ds  
A c o m plete descri pti o n of t he statistical a na l yses a n d met h o ds will be a vaila ble i n t he S A P. 
1 0. 3. 1  S u bject Dis p ositi o n a n d C h ar acteristics  
1 0. 3. 1. 1  S u bject Dis p ositi o n  
T he n u m bers of s u bjects w h o were ra n d o mize d (e nr olle d), d ose d, a n d w h o c o m plete d or 
wit h dre w fr o m t he treat me nt a n d  / or st u d y, were disc har ge d or t ra nsferre d, a n d die d, will be 
prese nte d i n s u m mar y ta bles b y treat me nt ar m a n d t otal s u bjects. T he reas o ns f or 
disc o nti n ui n g I P or wit h dra wi n g fr o m t he st u d y will be liste d b y s u bject.  
C CI

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10.3.1.2 Subject Characteristics 
Subject characteristics will be presented in summary tables. Continuous data will be 
summarized by descriptive statistics and categorical data will be summarized by frequency 
distributions. Age will be described as both a continuous and a discrete variable. Supportive 
data will be listed by subject. Clinical condition, including mechanism and type of injury, 
Injury Severity Score, Abbreviated Injury Scale (AIS) scores by region, Glasgow Coma Scale 
score, and RABT score will be summarized. Glasgow Coma Scale score will be summarized 
as a continuous variable and by categories ≤ 8, 9 to 12, and ≥ 13. RABT score will be 
summarized as a categorical variable. Charlson comorbidity index will be summarized as a 
continuous variable. Medical history (coded using the Medical Dictionary for Regulatory 
Activities) will be presented by system organ class and preferred term. 
10.3.2 Efficacy Analyses 
10.3.2.1 Primary Efficacy Endpoint Analyses 
A Bayesian logistic regression will be used to compare all-cause mortality rate during the 
first 6 hours after randomization between the BE1116 and placebo arms, in the 
ITT Population. 
Hypotheses: 
Null Hypothesis (𝐻𝐻0):  
The all-cause 6-hour mortality rate in BE1116 is no better than 
control. 
𝑝𝑝𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘−𝑝𝑝𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐≥0 
Alternative Hypothesis (𝐻𝐻1):  The all-cause 6-hour mortality rate in BE1116 is lower than 
control. 
𝑝𝑝𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘−𝑝𝑝𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐< 0 
Let 𝑦𝑦𝑖𝑖 be the outcome of all-cause 6-hour death (1 = yes, 0 = no), the model is: 
𝑦𝑦𝑖𝑖∼𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵(𝑝𝑝𝑖𝑖) 
𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙(𝑝𝑝𝑖𝑖) = 𝛽𝛽0 + 𝛽𝛽1𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑖𝑖 
where 𝑝𝑝𝑖𝑖 is the probability of all-cause 6-hour mortality for subject 𝑖𝑖 treatment intervention. 
The coefficient 𝛽𝛽0 is the effect of placebo on the primary outcome in the logit scale. The 

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coefficient 𝛽𝛽1 is the treatment effect of BE1116 over placebo on the primary outcome in the 
log OR scale. While this model gives direct estimates of ORs, the absolute risk differences 
(primary outcome of interest) will be derived using posterior draws from the coefficients. We 
assume independent normal prior distributions for the regression coefficients: 
𝛽𝛽0 ∼𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁(𝜇𝜇0, 𝜏𝜏0
2) 
𝛽𝛽1 ∼𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁(𝜇𝜇1, 𝜏𝜏1
2) 
where, 𝜇𝜇s and 𝜏𝜏s are respectively the means and standard deviations of distributions. 
For all interim and final analysis, the following noninformative priors are used:  
𝛽𝛽0 ∼𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁(0, 102), 𝛽𝛽1 ∼𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁(0, 12). These priors are centered at zero, which for 𝛽𝛽1 
corresponds to a piori no intervention effect. This noninformative prior allows considerable 
uncertainty; the 95% interval for 𝛽𝛽1on the OR scale ranges from 0.14 to 7.1 while avoiding 
unreasonable values. 
The study will be considered a success and primary objective considered met if the posterior 
probability 𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃(𝑝𝑝𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘−𝑝𝑝𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐< 0|data) of lower all-cause 6-hour mortality in the 
BE1116 arm compared with the placebo arm is greater than the success threshold. 
Interim analyses will occur when 1/4 (2000), 1/2 (4000), and 3/4 (6000) of the targeted 
8000 subjects have data for the primary outcome. A group sequential approach will be 
utilized (see Section 10.3.4). 
The success threshold for each applicable interim analysis and final analysis will be 
calibrated to protect overall type I error at 2.5% depending on the actual number of subjects 
with data on the primary outcome. 
A nonbinding futility assessment at interim will also be considered. The study may stop for 
lack of benefit (futility) at interim if the posterior predictive probability of a lower all-cause 
6-hour mortality for BE1116 compared with placebo upon trial completion is unlikely (< 8%) 
given the observed interim results. The futility boundary may be subject to change to reflect 
subsequent program-related decisions by CSL. 
The posterior probability of lower all-cause 6-hour mortality in the BE1116 arm compared 
with the placebo arm will be reported. Posterior means and medians along with the relevant 
credible intervals will also be reported. 

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The study will continue to enroll 8000 subjects unless it is stopped for success or futility at 
one of the interim analyses. 
Further details will be provided in the SAP. 
10.3.2.2 Subgroup Analyses for Primary Endpoint 
Subgroup analyses will be used to help determine whether the treatment effect for the 
primary endpoint is homogeneous across the study population. Each subgroup will be 
analyzed as for the primary analysis described in Section 10.3.2.1. Additional subgroup 
analyses may be detailed in the SAP. 
The subgroups of interest for this study are as follows: 
• Mechanism of trauma injury: any penetrating versus blunt 
• Sex: male versus female 
• Age: < 18 years versus 18 to 25 years versus 26 to 64 years versus > 64 years 
• Weight-based dosing (2000 IU versus 3000 IU) 
• Cause of death (hemorrhage versus non-hemorrhage). 
Subgroup analysis of penetrating versus blunt trauma injury will provide evidence of BE1116 
efficacy and safety in these populations with different mechanisms of traumatic injury. Blunt 
trauma, also called nonpenetrating trauma or blunt force trauma, is an injury to the body 
caused by forceful impact, injury, or physical attack with a dull object or surface. It is in 
contrast to penetrating trauma, in which an object pierces the body surface, causing an open 
wound [NIGMC, 2018]. 
Well documented subpopulation analysis of sex differences has shown that males experience 
an increased risk of mortality and hospital length of stay, and a higher incidence of 
complications, when compared with females [Liu et al, 2015]. 
Subgroup analysis of subjects aged < 18 years is important to confirm there are no important 
differences between older teenagers and young adults [Liras et al, 2016]. 
Subjects weighing between 50 and < 75 kg will receive 2000 IU and subjects weighing 
≥ 75 kg will receive 3000 IU. This dosing regimen was designed to ensure equivalent doses 
of IP per kg body weight, so that all subjects receive equivalent blood concentrations of the 
coagulation factors present in the IP. This is the standard dosing used for non-trauma 

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subjects. However, it is possible that the total dose of IP, rather than the blood concentration 
of IP, will be most important in trauma patients with acute hemorrhage who are at risk of the 
lethal triad. This analysis will aim to determine whether total dose impacts outcomes. 
10.3.2.3 
Sensitivity Analyses for Primary Endpoint 
A Bayesian logistic regression model, akin to the primary analysis model, but with site as a 
covariate together with an interaction term with treatment group will be used for other 
analyses of the primary endpoint. Further details will be provided in the SAP. 
The primary analysis will be conducted as stated but adjusted for covariates together with an 
interaction term with treatment group in 4 separate analyses. Results for the primary endpoint 
in each analysis will be reported. The covariates will be as follows: 
• Mechanism of injury: any penetrating versus blunt 
• Sex: male versus female 
• Age: < 18 years versus 18 to 25 years versus 26 to 64 years versus > 64 years 
• Weight-based dosing (2000 IU versus 3000 IU) 
• Cause of death (hemorrhage versus non-hemorrhage). 
Additional sensitivity analyses might be defined in the SAP. 
10.3.2.4 Supplementary Analyses for Primary Endpoint 
Primary analysis based on the mITT and PP Population will also be conducted. 
Other analyses may be specified in the SAP. 
10.3.2.5 Secondary Efficacy Endpoint Analyses 
All-cause in-hospital mortality up to hospital discharge or 24 hours after randomization 
(whichever occurs first) and all-cause in-hospital mortality up to hospital discharge or 
30 days after randomization (whichever comes first), will be analyzed and summarized in the 
same manner as for the primary endpoint, ie, estimated by a Bayesian logistic regression 
model. The same noninformative priors as specified for the primary analysis will be used. 
In-hospital mortality will only be recorded and assessed for the primary hospitalization. 

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The difference in proportion of subjects who undergo surgical or interventional radiological 
procedures to stop bleeding related to the primary injury, up to 24 hours after randomization, 
will also be analyzed and summarized in a manner similar to the primary endpoint. 
After the primary endpoint is deemed successful, the efficacy-related secondary endpoints 
will be analyzed sequentially in the order mentioned in Section 2.2.2. A gated testing 
approach will be used to account for multiplicity, and testing will proceed in a stepwise 
manner conditioned on observing a statistically significant result at each endpoint. 
All secondary efficacy endpoints will be analyzed using the ITT, mITT, and PP Populations. 
Subgroup analysis will also be conducted similarly as for the primary endpoint. 
Missing efficacy data handling is described in Section 10.3.2.7. 
Further details will be specified in the SAP. 
10.3.2.6 Exploratory Efficacy Endpoint Analyses 
Summaries and analyses of exploratory endpoints described in Section 2.3 will be detailed in 
the SAP. 
10.3.2.7 Missing Data 
For efficacy endpoints, missing data will be handled according to the following rules. 
• All-cause mortality up to 6 hours after randomization: if a subject withdrew from the 
study prior to 6 hours after randomization, the survival status at the time of study 
withdrawal will be carried forward to the 6-hour time point. 
• All-cause in-hospital mortality up to 24 hours after randomization: if a subject withdrew 
or discharged from the study prior to 24 hours after randomization, the survival status at 
the time of study withdrawal or discharged will be carried forward to the 24-hour time 
point. 
• All-cause in-hospital mortality up to 30 days after randomization: if a subject withdrew or 
discharged from the study prior to 30 days after randomization, the survival status at the 
time of study withdrawal or discharged will be carried forward to the 30-day time point. 
• Use of surgical or interventional radiological procedures to stop bleeding: if a subject 
withdrew early or died, the usage of any surgical or interventional radiological procedures 
to stop bleeding up to the time of study withdrawal or death will be carried forward to the 
24-hour time point. 

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Additional missing data will be handled as described in the SAP. 
10.3.3 Safety Analyses 
All endpoints related to safety analyses are secondary. The safety endpoints will be assessed 
using the Safety Population, unless otherwise noted. 
The number and proportion of subjects with SAEs considered related to IP that occurred 
during primary hospitalization within the 30 days after randomization will be summarized by 
treatment arm. 
All-cause in-hospital mortality will also be summarized.  
The number and proportion of in-hospital overall and related TEEs up to 30 days after 
randomization will be summarized by treatment arm. 
The incidence of the following AESIs will be summarized by treatment arm: ARDS; multiple 
organ failure; and AKI requiring renal replacement therapy. 
Further details will be specified in the SAP. 
10.3.4 Interim Analyses 
The IDMC will meet to review unblinded data for both safety and efficacy according to the 
planned interim analysis schedule shown in Table 8. 
The IDMC will have the flexibility to coordinate data reviews with the protocol-specified 
reviews as detailed below and ad-hoc reviews at the discretion of the IDMC Chair. 

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Table 8 
Planned IDMC Reviews 
IDMC Meeting Type 
Number of Subjects Enrolled 
Safety review 
500 
Safety review 
1000 
Scheduled Interim Analysis 1 – Safety and 
futility review 
2000 
Safety review 
3000 
Scheduled Interim Analysis 2 – Safety, 
efficacy, and futility review 
4000 
Safety review 
5000 
Scheduled Interim Analysis 3 – Safety, 
efficacy, and futility review 
6000 
IDMC = Independent Data Monitoring Committee 
 
Commensurate with its mandate to review ongoing safety data, the IDMC will monitor 
unblinded deaths, AEs including SAEs and AESIs, as well as other safety data, with the 
objective of ensuring the safety of study participants. 
Prior to a decision whether to recommend study termination for any reason, the IDMC will 
conduct a further data review of subgroups and other safety endpoints. The totality of the 
data, including the findings from all best available data at the time of the review, should be 
considered in deciding whether the overall benefit / risk is unfavorable enough to warrant a 
recommendation to terminate the study for safety concerns. 
Interim Efficacy and Futility Analyses: Interim futility analyses will be conducted by the 
IDMC when approximately 25%, 50%, and 75% of subjects have been enrolled. 
Stopping criteria for each interim analysis with 2000 (Interim Analysis 1), 4000 (Interim 
Analysis 2), and 6000 subjects (Interim Analysis 3) having data on the primary outcome 
respectively are displayed below. 
The following success thresholds were considered: 
The study will not stop for efficacy at Interim Analysis 1. 
At Interim Analysis 2, the study will be assessed for overwhelming efficacy. 

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Pbenefit : 𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃(𝑝𝑝𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘−𝑝𝑝𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐< 0|𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖) > 99.8% 
If the study does not stop at Interim Analysis 2, the study would continue and Interim 
Analysis 3 would be performed. 
At Interim Analysis 3, the study will be assessed for overwhelming efficacy. 
Pbenefit : 𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃(𝑝𝑝𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘−𝑝𝑝𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐< 0|𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖) > 99.3% 
If the study does not stop at Interim Analysis 3, the study would continue and final analysis 
will be performed, and the primary objective is considered met if: 
Pbenefit : 𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃൫𝑝𝑝𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘−𝑝𝑝𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐< 0|𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓൯> 98.0% 
The study will be considered to stop for futility (nonbinding) at each interim analysis if the 
posterior predictive probability of a lower all-cause 6-hour mortality for BE1116 compared 
with placebo upon trial completion is unlikely (< 8%) given results observed at interim. 
Pfutile : Prob(𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃൫𝑝𝑝𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘−𝑝𝑝𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐< 0|𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓> 98.0%൯|𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖) <
 8%. 
An IDMC will be responsible for reviewing the interim results, and CSL will remain blinded 
unless the study is stopped. Further details on the safety and efficacy interim analyses and 
study conduct will be provided in the SAP and IDMC Charter. See also Section 3.8.1. 
11 
Quality Assurance 
The study may be subject to an audit by CSL, an authorized representative(s) of CSL and / or 
inspections by an authorized health authority (eg, US FDA). Health authorities may request 
access to all study documentation, including source documents for inspection and copying, in 
keeping with local regulations. CSL will notify the investigator of any upcoming 
audit / inspection. 
In the event of an audit, all pertinent study-related documentation must be made available to 
the auditor(s). If an audit or inspection occurs, the investigator at each study site will permit 
the auditor / inspector direct access to all relevant documents and allocate their time as well 
as the time of relevant staff to discuss the findings and any relevant issues. 

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12 
Regulatory and Ethics Considerations 
12.1 
Regulatory Considerations 
CSL or its agents will submit the appropriate documents to the local regulatory agencies and, 
if required by the regulatory agency, wait for approval before proceeding with the clinical 
investigation. 
This study will be conducted under an Investigational New Drug Application, Therapeutic 
Goods Administration Clinical Trial Notification, or other, as appropriate, and documented in 
accordance with the applicable regulatory guidelines and requirements. 
The procedures set out in this clinical study protocol are designed to ensure that CSL and the 
investigator abide by the principles of the current ICH GCP guideline on the conduct, 
evaluation, and documentation of this study, as described in ICH Topic E6 (Guideline for 
GCP). The study will also be carried out according to all applicable international and national 
regulatory requirements. 
12.2 
Institutional Review Board / Independent Ethics Committee 
The investigator must submit the clinical study protocol and Informed Consent forms for 
review by an authorized and properly constituted (according to local guidelines) IRB / IEC. 
Written approval must be received from the IRB / IEC before commencement of the study. 
12.3 
Subject Information and Informed Consent 
This study involves subjects who cannot be prospectively identified and have life-threatening 
medical conditions necessitating emergent intervention. Because of the subjects’ conditions, 
the emergent need for intervention, and the limited treatment window during which the IP 
must be administered for potential efficacy, it is anticipated that obtaining prospective 
Informed Consent from the subject or their Legally Acceptable Representative may not be 
possible. For these reasons, the study will be conducted under emergency research Applicable 
Law which allows subjects to be enrolled into qualifying research without obtaining 
prospective Informed Consent. However, attempts to collect prospective Informed Consent 
must be made, if feasible, in accordance with Applicable Laws, and if prospective Informed 
Consent can be obtained from a subject or their Legally Acceptable Representative prior to 
enrollment, such Informed Consent must be obtained. Study sites must reference their 
country-specific Study Consent Manual (where available) for additional requirements. Study 
sites must follow Applicable Laws in the conduct of the study and should consult their legal 

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counsel and IRB or IEC for any advice or guidance with respect to any Applicable Laws and 
IRB or IEC requirements. 
If Informed Consent is not obtained from a subject or their Legally Acceptable 
Representative prior to randomization, Informed Consent for continued participation will be 
sought after randomization in accordance with the country-specific Study Consent Manual 
(where available) and where required by Applicable Laws. Similarly, if during the study a 
subject regains capacity after they are enrolled, Informed Consent for continued participation 
from the subject shall be sought pursuant to the country-specific Study Consent Manual 
(where available) and where required by Applicable Laws. Study sites must reference their 
country-specific Study Consent Manual (where available) for additional requirements. Study 
sites must follow Applicable Laws in the conduct of the study. 
The rationale for emergency research without prospective consent of subjects includes the 
following general principles: 
1. Subjects are in a life-threatening situation, and collection of valid scientific evidence is 
necessary to determine the safety and effectiveness of the particular intervention. 
2. Obtaining Informed Consent is not feasible, because the subject cannot give reasonable 
consent due to the medical condition and subjects cannot be prospectively selected. 
3. There is the prospect of direct benefit to subjects because they are in a life-threatening 
situation requiring intervention, and risks associated with this study are reasonable 
compared with standard-of-care therapy alone. 
4. The research could not be practically carried out if prospective consent is required. 
5. An IRB / IEC has reviewed and approved the Informed Consent procedures and 
documents to be used with the subjects or their Legally Acceptable Representative for 
this study. 
6. Additional protection of rights will be provided including monitoring of the study by an 
established IDMC. 
Informed Consent may be completed on site or remotely, using paper or electronic means 
where permitted, in accordance with Applicable Laws. In all cases, the Informed Consent 
process utilized must follow Applicable Laws and regulatory expectations, including 

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documentation of the form and process utilized, classification of the signatories, and retention 
of the signed consent(s). Any reference to “written Informed Consent” in this protocol refers 
to signatures obtained either on paper or electronically. 
If there are any amendments to the clinical study protocol that would directly affect the 
subject’s decision to continue participation in the study (eg, a change in any procedure), the 
applicable Informed Consent forms must be amended to incorporate the amendment. Subjects 
or their Legally Acceptable Representative must be informed of the changes promptly in an 
amended Informed Consent form, prepared for their review and signature. 
12.3.1 Consent in the United States 
The US FDA and the Department of Health and Human Services outline regulations allowing 
Exception From Informed Consent (EFIC) for research conducted in an emergency setting. In 
the US, due to the emergent nature of this study, the study will be conducted with an EFIC. 
This study qualifies for the EFIC required for emergency research outlined in the US FDA 
regulation 21 CFR §50.24. 
The rationale for EFIC emergency research includes those previously listed in Section 12.3. 
Additional protection of rights will be provided, which includes: 
1. Community consultation and public disclosure. 
2. A subject will only be enrolled without prospective consent if the intervention must be 
given before consent can be obtained from a Legally Acceptable Representative 
(hereafter, in the US, Legally Authorized Representative [LAR]). 
3. Efforts will be made to inform and honor objections of family members if the LAR is not 
available (if permitted, according to Applicable Law). 
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 2. 
12.4 
Subject Confidentiality 
All subject names and contact details will be kept 
 Subjects will be identified 
throughout documentation and evaluation by the number allotted to them during the study. 
Each subject (and / or their Legally Acceptable Representative, as applicable) will be told 
that all study findings will be handled in the strictest confidence. 

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The investigator at the study site will be responsible for retaining sufficient information about 
each subject (eg, name, address, telephone number and identity in the study) so that 
regulatory agencies or CSL may access this information should the need arise. These records 
should be retained in a 
 manner as long as legally mandated according to 
Applicable Law. 
Subject medical records pertaining to the study may be inspected / audited at any time by 
CSL employees or their duly authorized representatives, a health authority, or the IRB / IEC. 
All records accessed will be strictly 
 Consent to participate in the study includes 
consent to these inspections / audits. 
12.5 
Indemnity and Compensation 
CSL has taken out insurance to cover its obligations under both the Indemnity and the 
Compensation guidelines for injury to subjects involved in the study. 
Other details regarding compensation and the obligations of the investigator / CSL are 
provided in the Clinical Trial Research Agreement for the study (see Section 13.1). 
13 
Administrative Considerations 
13.1 
Clinical Trial Research Agreement 
This study will be conducted under a Clinical Trial Research Agreement between CSL 
(“Sponsor”) and the institution(s) representing the investigational study site(s) (“Authority”). 
Financial support to the investigational site(s) will be detailed in the Clinical Trial Research 
Agreement. The Clinical Trial Research Agreement must be signed before the 
commencement of the study and will clearly delineate the responsibilities and obligations of 
the investigator and CSL and will form the contractual basis under which the clinical study 
will be conducted. Clinical Trial Research Agreements may be executed by electronic 
signature (current provider DocuSign) in compliance with 21 CFR Part 11 and simple or 
advanced electronic signature according to European Union Regulation 
No. 910/2014-eIDAS. 
13.2 
Clinical Study Registration and Results Disclosure 
CSL will provide the relevant clinical study protocol information in public database(s) before 
or at commencement of the study. CSL may also provide study information for inclusion in 
national registries according to local regulatory requirements. 

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Results of this study will be disclosed according to the relevant regulatory requirements. All 
publications in peer-reviewed medical journals resulting from this study will be listed in the 
original clinical study protocol registration record. 
13.3 
Implementation of the Clinical Study Protocol and Amendment(s) 
With the exception of medical emergencies, no changes, or deviations in the conduct of the 
signed clinical study protocol will be permitted without documented approval of CSL’s 
medical monitor or designee and the IRB / IEC. In the event of a medical emergency, the 
investigator at the study site will institute any medical procedures deemed appropriate. 
However, all such procedures must be promptly reported to CSL’s medical monitor and the 
IRB / IEC. 
Modifications to the clinical study protocol that may affect subject safety or the way the 
study is to be conducted will be documented in a protocol amendment, which must be 
approved by the IRB / IEC. 
Administrative changes to the clinical study protocol, defined as minor corrections and / or 
clarifications that have no effect on the way the study is to be conducted, will not require 
IRB / IEC approval, but will be submitted to the IRB / IEC for their information. 
13.4 
Protocol Deviations 
All instances where the requirements of the clinical study protocol were not complied with 
will be tracked. Corresponding subjects may be withdrawn from the study at the discretion of 
the investigator and / or CSL. Clinical study protocol deviations arise when either subjects 
who have been entered in the study and / or the study sites deviate from the 
IEC / IRB-approved study protocol. 
If a major protocol deviation (ie, a deviation that could have a significant effect on the 
subject’s safety, rights, or welfare and / or on the integrity of the study data) occurs, the 
investigator must notify CSL and the appropriate IRB / IEC as soon as possible or as per 
local requirements. 

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13.5 
Documentation and Record Keeping 
13.5.1 Data Collection 
The investigator (or delegate) will maintain individual records for each subject. These records 
should include dates when a subject visited the study site, records of vital signs, medical 
history, administration of IP, any SAEs or AESIs experienced, and other notes as appropriate. 
These records (electronic or paper) constitute source data. 
eCRF entries will be considered source data if the eCRF is the site of the original recordings 
(ie, there is no other written or electronic record of the data). In this study, the eCRF will not 
be used as the source document for any data. 
An eCRF will be provided by CSL (or delegate) for each randomized (enrolled) subject. The 
investigator is responsible for ensuring accurate and proper completion of the eCRF in a 
timely manner so that it always reflects the latest observations on the randomized subjects. 
All entries on the eCRF must be backed up by source data. All source data will be kept 
according to all applicable regulatory requirements. Source data must be completed legibly 
for each randomized subject. 
Data from the clinical trial management system and data from the IRT system may be either 
integrated or later reconciled with the eCRF. 
13.5.2 Data Quality Assurance 
Data generated throughout the study will be monitored and the eCRFs checked against the 
subject records for completeness and accuracy. The investigator must provide direct access to 
source data documents. CSL’s study monitor will perform this function. 
Following completion of eCRF pages and entry of the data into a database, the data will be 
checked electronically for consistency and plausibility. Queries will be generated for 
questionable data and clarification sought from the investigator. These data queries must be 
resolved in a timely manner by the investigator (or delegate). 
13.5.3 Record Retention 
The investigator must follow the principles for record retention outlined in the Clinical Trial 
Research Agreement. An investigator study file prepared by CSL (or delegate), containing all 
applicable documents for use at the study site, will be made available to the investigator 

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before the start of the study. All study documentation and materials maintained in the 
investigator study file must be kept in conformance with applicable national laws and 
regulations. 
All study documentation and materials maintained in the investigator study file at the study 
site must be available for inspection by CSL’s study monitor (or delegate) to determine that 
all required documentation is present and correct. 
The study may be audited or inspected by qualified delegates from CSL or a competent 
health authority. 
Following completion of the study, the investigator is responsible for archiving the 
investigator’s study file, the subject’s records and the source data according to applicable 
regulatory requirements. 
13.6 
Study and Site Closure 
CSL reserves the right to prematurely discontinue or suspend the study either at a particular 
site or at all study sites at any time and for any reason. If such action is taken, CSL’s study 
monitor (or delegate) will discuss this with the investigator at each study site at that time and 
notify the investigators in writing. If the study is suspended or terminated for safety reasons, 
all investigators and the relevant regulatory agencies will be immediately notified of the 
action as well as the reason for the suspension / termination. The investigator at each study 
site will advise their IRB / IEC overseeing the study of the suspension / termination. 
13.7 
Clinical Study Report 
A clinical study report will be written after the completion of the study. CSL or its agent will 
write the report in consultation with the investigator or, if applicable, a nominated 
coordinating investigator (or delegate). CSL requires that the coordinating investigator will 
sign the clinical study report. 
Progress reports may be provided to the relevant regulatory bodies in accordance with their 
requirements. 

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13.8 
Use of Data and Publications 
The rights and obligations of investigators and CSL concerning any formal presentation or 
publication of data collected as a direct or indirect result of this study will be addressed 
specifically in the Clinical Trial Research Agreement for the study. 
In addition to maintaining the study websites for the duration and months following study 
completion (as outlined in the community consultation/public disclosure plan), CSL will also 
provide study results and links to any scientific manuscripts produced from this study. 
Advertisements of the study results will also be made, including updates to ClinicalTrials.gov 
website. 

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14 
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Novo Nordisk. NovoSeven® RT coagulation factor VIIa (recombinant). Highlights of 
prescribing information. July 2020. Available at: https://www.novo-pi.com/novosevenrt.pdf. 
Ostermann H, Haertel S, Knaub S, Kalina U, Jung K, Pabinger I. Pharmacokinetics of 
Beriplex P/N prothrombin complex concentrate in healthy volunteers. Thromb Haemost. 
2007;98(4):790-7. 
Oyeniyi BT, Fox EE, Scerbo M, Tomasek JS, Wade CE, Holcomb JB. Trends in 1029 trauma 
deaths at a level 1 trauma center: Impact of a bleeding control bundle of care. Injury. 
2017;48(1):5-12. 
Pati S, Potter DR, Baimukanova G, Farrel DH, Holcomb JB, Schreiber MA. Modulating the 
endotheliopathy of trauma: factor concentrate versus fresh frozen plasma. J Trauma Acute 
Care Surg. 2016;80(4):576-84; discussion 584-5. 
Peitzman AB, Billiar TR, Harbrecht BG, Kelly E, Udekwu AO, Simmons RL. Hemorrhagic 
shock. Curr Probl Surg. 1995;32(11):925-1002. 

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Study Product: 
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Protocol version: Amendment 2 
 
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Quan H, Li B, Couris CM, Fushimi K, Graham P, Hider P, et al. Updating and validating the 
Charlson comorbidity index and score for risk adjustment in hospital discharge abstracts 
using data from 6 countries. Am J Epidemiol. 2011;173(6):676-82. 
Sauaia A, Moore EE, Johnson JL, Ciesla DJ, Biffl WL, Banerjee A. Validation of postinjury 
multiple organ failure scores. Shock. 2009;31(5):438-47. 
Saville BR, Connor JT, Ayers GD, Alvarez J. The utility of Bayesian predictive probabilities 
for interim monitoring of clinical trials. Clin Trials. 2014;11(4):485-93. 
Schreiber MA, Meier EN, Tisherman SA, Kerby JD, Newgard CD, Brasel K, et al. A 
controlled resuscitation strategy is feasible and safe in hypotensive trauma patients: results of 
a prospective randomized pilot trial. J Trauma Acute Care Surg. 2015;78(4):687-95. 
Spahn DR, Bouillon B, Cerny V, Duranteau J, Filipescu D, Hung BJ, et al. The European 
guideline on management of major bleeding and coagulopathy following trauma: fifth 
edition. Crit Care. 2019;23(1):98. 
Sperry JL, Guyette FX, Brown JB, Yazer MH, Triulzi DJ, Early-Young BJ, et al. Prehospital 
plasma during air medical transport in trauma patients at risk for hemorrhagic shock. N Engl 
J Med. 2018;379(4):315-26. 
Spinella PC, El Kassar N, Cap AP, Kindzelski AL, Almond CS, Barkun A, et al. 
Recommended primary outcomes for clinical trials evaluating hemostatic blood products and 
agents in patients with bleeding: proceedings of a National Heart Lung and Blood Institute 
and United States Department of Defense Consensus Conference. J Trauma Acute Care Surg. 
2021;May 26. Doi: 10.1097/TA.0000000000003300. Online ahead of print. 
Stephens SW, Williams C, Gray R, Kerby JD, Wang HE. Preliminary experience with social 
media for community consultation and public disclosure in exception from informed consent 
trials. Circulation. 2013;128(3):267-70. 
Tisherman SA, Schmicker RH, Brasel KJ, Bulger EM, Kerby JD, Minei JP, et al. Detailed 
description of all deaths in both the shock and traumatic brain injury hypertonic saline trials 
of the Resuscitation Outcomes Consortium. Ann Surg. 2015;261(3):586-90. 

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Study Product: 
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Protocol version: Amendment 2 
 
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Effective Date: Week commencing 25-June-2018 
US Department of Health and Human Services. Food and Drug Administration. Guidance for 
Institutional Review Boards, Clinical Investigators, and Sponsors. Exception from Informed 
Consent Requirements for Emergency Research. March 2011. Updated April 2013. Available 
at: https://www.fda.gov/media/80554/download. 
Van den Brink DP, Wirtz MR, Neto AS, Schöchl H, Viersen V, Binnekade J, et al. 
Effectiveness of prothrombin complex concentrate for the treatment of bleeding: a systematic 
review and meta-analysis. J Thromb Haemost. 2020;18(10):2457-67. 
[Zeeshan et al, 2019a] Zeeshan M, Hamidi M, Kulvatunyou N, Jehan F, O’Keeffe T, Khan M, 
et al. 3-Factor versus 4-factor PCC in coagulopathy of trauma: four is better than three. 
Shock. 2019;52(1):23-8. 
[Zeeshan et al, 2019b] Zeeshan M, Hamidi M, Feinstein AJ, Gries L, Jehan F, Sakran J, et al. 
Four-factor prothrombin complex concentrate is associated with improved survival in 
trauma-related hemorrhage: a nationwide propensity-matched analysis. J Trauma Acute Care 
Surg. 2019;87(2):274-81. 

CSL Behring 
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Study Product: 
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Protocol version: Amendment 2 
 
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15 
Appendices 

C S L Be hri n g 
A p pe n di x 1 
Si g n at ure P a ges 
St u d y N u m ber: 
B El 1 1 6 _ 3 0 0 6 
St u d y Pr o d uct: 
4 F- P C C 
Si g n at ure o n Be h alf of S p o ns or 
St u d y Title: 
A Pr os pecti ve , M ultice nter , Ra n d o mize d , D o u ble- Bli n d , 
Place b o- C o ntr olle d Lar ge Si m ple Trial E val uati n g t he Use of 
B El 1 1 6 ( 4- Fact or Pr ot hr o m bi n C o m ple x C o nce ntrate [ Kce ntra® / 
Beri ple x ® ]) t o I m pr o ve S ur vi val i n Patie nts wit h Tra u matic I nj ur y 
a n d Ac ute Maj or Blee di n g 
Pr ot oc ol N u m ber: 
B El 1 1 6 3 0 0 6 
I ha ve rea d t he Cli nical St u d y Pr ot oc ol A me n d me nt 2 title d " A Pr os pecti ve , M ultice nter , 
Ra n d o mize d, D o u ble- Bli n d , Place b o- C o ntr olle d Lar ge Si m ple Trial E val uati n g t he Use of 
B E 1 1 1 6 ( 4- F act or Pr ot hr o m bi n C o m ple x C o nce ntrate [ Kce ntra® / Beri ple x ® ]) t o I m pr o ve 
S ur vi val i n Patie nts wit h Tra u matic I nj ur y a n d Ac ute Maj or Blee di n g " a n d c o nfir m t hat, t o 
t he best of m y k n o wle d ge , t he pr ot oc ol acc uratel y descri bes t he desi g n a n d c o n d uct of t he 
st u d y. 
Date ( D D M M M Y Y Y 
Pr ot oc ol versi o n : A me n d me nt 2 
Date: 0 6 Fe br uar y 2 0 2 4 
Pa ge 9 9 of 1 0 8 
 
C S- S O P- 0 4- T 0 2 Versi o n 2.0 
Effecti ve Date : Wee k c o m me nci n g 2 S-J u ne- 2 0 1 8 
P P D
P P D
P P D
P P D

CSL Behring 
Study Number: 
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Study Product: 
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Protocol version: Amendment 2 
 
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Date: 06 February 2024 
 
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Effective Date: Week commencing 25-June-2018 
Signature of the Principal Investigator 
 
Study Title: 
A Prospective, Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Large Simple Trial Evaluating the Use of 
BE1116 (4-Factor Prothrombin Complex Concentrate [Kcentra® 
/ Beriplex®]) to Improve Survival in Patients with Traumatic 
Injury and Acute Major Bleeding 
Protocol Number: 
BE1116_3006 
Site Number: 
 
 
I have read the Clinical Study Protocol Amendment 2 titled “A Prospective, Multicenter, 
Randomized, Double-Blind, Placebo-Controlled Large Simple Trial Evaluating the Use of 
BE1116 (4-Factor Prothrombin Complex Concentrate [Kcentra® / Beriplex®]) to Improve 
Survival in Patients with Traumatic Injury and Acute Major Bleeding”. 
By signing this Clinical Study Protocol, I agree to conduct the clinical study, after approval 
by an Institutional Review Board or Independent Ethics Committee (as appropriate), in 
accordance with the Clinical Study Protocol, the standards of Good Clinical Practice (as 
defined by the International Council on Harmonisation) and applicable regulatory 
requirements. 
Changes to the Clinical Study Protocol will only be implemented after written approval is 
received from CSL Behring (CSL) and the Institutional Review Board or Independent Ethics 
Committee (as appropriate) with the exception of medical emergencies. 
I will ensure that study staff fully understand and follow the Clinical Study Protocol. 
 
 
 
(Signature) 
 
Date (DD MMM YYYY) 
(Printed name) 
 
 
(Title) 
 
 
 

CSL Behring 
Study Number: 
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Study Product: 
4F-PCC 
 
Protocol version: Amendment 2 
 
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Effective Date: Week commencing 25-June-2018 
Appendix 2 
Exception From Informed Consent for Emergency Research 
in the United States 
This study qualifies under the Exception From Informed Consent (EFIC) requirements for 
emergency research outlined in 21 CFR §50.24 and all applicable conforming amendments, 
and shall be conducted in accordance with the provisions contained therein and all other 
Applicable Laws. Please also refer to the corresponding US Department of Health and 
Human Services Food and Drug Administration (FDA) Guidance for Institutional Review 
Boards, Clinical Investigators, and Sponsors – Exception from Informed Consent 
Requirements for Emergency Research [US Department of Health and Human Services, 
2013], hereafter EFIC Guidance. 
This study qualifies for EFIC because it involves subjects who cannot be prospectively 
identified and have life-threatening medical conditions necessitating emergent intervention. 
Because of the subjects’ conditions, the emergent need for intervention, and the limited 
treatment window during which the investigational product must be administered for 
potential efficacy, it is anticipated that obtaining prospective Informed Consent from subjects 
or their Legally Acceptable Representatives (hereafter Legally Authorized Representative 
[LAR]) may not be possible. 
In order to provide additional protections for the rights and welfare of subjects, prior to study 
initiation at a clinical site, community consultation must be performed with representatives of 
the communities in which the study will be conducted and from which subjects will be 
drawn, and public disclosure to these communities must occur, each of which must be 
Institutional Review Board (IRB) reviewed and approved. If a member of the community 
does not want to participate in the study, there is an option for the subject to receive an “opt-
out” bracelet, which, if worn at the time of hospital administration, would exclude the subject 
from participation in the study. Further details are provided in the Trauma and PCC (TAP) 
Trial Community Consultation and Public Disclosure Plan. In addition, after the study has 
concluded or terminated, public disclosure of study results must be provided to the 
communities and researchers in sufficient detail according to the EFIC Guidance and IRB 
requirements. 
Based on previous data, BE1116 is anticipated to be most effective if administered 
immediately following injury. In this setting, the patient often has an altered mental status 
secondary hemorrhagic shock, which can cause confusion and loss of consciousness. As a 

CSL Behring 
Study Number: 
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Study Product: 
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Protocol version: Amendment 2 
 
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Effective Date: Week commencing 25-June-2018 
result, the patient is often unable to provide consent for study enrollment. LARs are often not 
immediately available, nor is it typically feasible for the emergency department providers to 
explain the study and receive consent while caring for the critically injured patient. Taken 
together, these issues provide sufficient support for EFIC in order to evaluate an intervention 
that may have significant outcome benefits to this patient population. 
In the event that the subject does not survive following the traumatic injury, their information 
will be included in the data analysis.  The deceased’s family or LAR will be notified 
regarding their participation in the study. Due to the severity of the injuries sustained, it is 
difficult to specify the time frame involved with obtaining the consent, however multiple 
attempts will be made to obtain consent prior to completion of the study. Each site’s consent 
will be available in English and other appropriate languages based upon the local population. 
All consenting procedures will be compliant with Health Insurance Portability and 
Accountability Act and GCP regulations. 
One of the key steps for EFIC research is community consultation and public disclosure, a 
process that connotes consultation between the investigative team, the IRB / IEC, 
representatives of the communities where the research will be conducted, and communities 
likely to have the condition. Although traditional methods for community consultation and 
public disclosure include public meetings and telephone-based surveys, the ability of these 
modalities to access the target populations, to effectively deliver information, and to elicit 
useful feedback remains unclear. Investigators within this study team have extensive 
experience using internet-based social media, as a popular and powerful new modality for 
communications about EFIC research internationally [Holcomb et al, 2015; 
Stephens et al, 2013]. 
Public disclosures will be performed both prior to study enrollment and at the completion of 
the study in the form of multimedia press releases organized by CSL. Local sites may decide 
to target notification to specific community groups. These will include plans for the study, 
including potential risks and benefits, equipoise and a summary of the results of the study 
upon completion. In the event that the press releases are not widely circulated, 
advertisements will also be placed on the study website used in the social media campaigns. 

CSL Behring 
Study Number: 
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Study Product: 
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Protocol version: Amendment 2 
 
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Appendix 3 
Glasgow Coma Scale 
The Glasgow Coma Scale will be used according to the Glasgow structured approach to 
assessment of the Glasgow Coma Scale. Details are provided at the following location: 
https://www.glasgowcomascale.org/. A summary of the scoring system is provided below. 
Eye Opening 
• Spontaneous--open before stimulus: 4 points 
• To sound--after spoken or shouted request: 3 points 
• To pressure—after fingertip stimulus: 2 points 
• None—no opening at any time, no interfering factor: 1 point 
•  Non testable (NT)—closed by local factor: NT 
Verbal Response 
• Orientated—correctly gives name, place and date: 5 points 
• Confused—not orientated but communication coherently: 4 points 
• Words—intelligible single words: 3 points 
• Sounds—only moans / groans: 2 points 
• None—no audible response, no interfering factor: 1 point 
•  Non testable (NT)—factor interfering with communication: NT 
Best Motor Response 
• Obeys commands—obey 2-part request: 6 points 
• Localising—brings hand above clavicle to stimulus on head neck: 5 points 
• Normal flexion—bends arm at elbow rapidly but features not predominantly abnormal: 
4 points 
• Abnormal flexion—bends arm at elbow, features clearly predominantly abnormal: 
3 points 
• Extension—extends arm at elbow: 2 points 
• None—no movement in arms / legs, no interfering factor: 1 point 
•  Non testable (NT)—paralysed or other limiting factor: NT 

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Study Number: 
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Study Product: 
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Protocol version: Amendment 2 
 
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Appendix 4 
Injury Severity Score 
The Injury Severity Score (ISS) [Baker et al, 1974; Baker and O’Neill, 1976] will be 
calculated as follows: 
ISS = A2 + B2 + C2 where A, B, and C are the Abbreviated Injury Scale (AIS) scores of the 
3 most injured body regions. The AIS scores of all 6 assessed body regions will also be 
recorded. 
The AIS incorporates current medical terminology providing an internationally accepted tool 
for ranking injury severity. The AIS is an anatomically based, consensus-derived, global 
severity scoring system that classifies an individual injury by body region according to its 
relative severity on a 6-point scale (1 = minor and 6 = maximal) [AAAM, 2021]. 
The ISS has a maximum score of 75. Additionally, if any single body system has a score of 6, 
the ISS score is automatically 75. 
The ISS may be calculated after study completion. 

CSL Behring 
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Protocol version: Amendment 2 
 
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Appendix 5 
Multiple Organ Failure Assessment 
Multiple organ failure will be assessed using the Denver postinjury multiple organ failure 
score [Sauaia et al, 2009]. The Denver score rates the dysfunction of 4 organ systems 
(pulmonary, renal, hepatic, and cardiac), which are each graded on a scale from 0 to 3 (see 
below), with a total score ranging from 0 to 12. Multiple organ failure is defined as a 
score > 3. 
Dysfunction 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Pulmonary: 
 
PaO2 / FiO2 ratio 
> 208 
208 to 165 
164 to 83 
< 83 
Renal: 
 
Creatinine 
(µmol/L) 
< 159 
160 to 210 
211 to 420 
> 420 
Hepatic: 
 
Total bilirubin 
(µmol/L) 
< 34 
34 to 68 
69 to 137 
> 137 
Cardiac: 
 
Inotropes 
No inotropes 
Only one 
inotrope at a 
small dose a 
Any inotrope at a 
moderate dose or 
> 1 agent, all at 
small doses a 
Any inotrope at a 
large dose or 
> 2 agents at 
moderate doses a 
FiO2 = fraction of inspired oxygen; PaO2 = partial pressure of arterial oxygen 
a 
Inotrope doses (in µg/kg/min) are provided in the following summary: 
 
 
Small 
Moderate 
Large 
Vasopressin 
< 0.03 
0.03 to 0.07 
> 0.07 
Dopamine 
< 6 
6 to 10 
> 10 
Dobutamine 
< 6 
6 to 10 
> 10 
Epinephrine 
< 0.06 
0.06 to 0.15 
> 0.15 
Norepinephrine 
< 0.11 
0.11 to 0.5 
> 0.5 
Phenylephrine 
< 0.6 
0.6 to 3 
> 3 
 
Components of the Denver postinjury multiple organ failure score will be collected from 
medical records, if available, even if all components are not collected per standard of care. 

CSL Behring 
Study Number: 
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Study Product: 
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Protocol version: Amendment 2 
 
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Appendix 6 
Charlson Comorbidity Index 
Comorbidity will be assessed using the Charlson Comorbidity Index [Quan et al, 2011]. 
Risk-adjusted hazard ratio for mortality within 1 year after hospital discharge among 
55,929 patients aged ≥ 18 years, Calgary, Alberta, Canada, 2004 
Variable 
Hazard  
Ratio 
Updated 
Weight 
Charlson 
Weight 
Male sex 
1.28 
 
 
Age ≥ 65 years 
4.40 
 
 
Charlson comorbidity a 
 
 
 
Myocardial infarction 
0.99* 
0 
1 
Congestive heart failure 
1.91 
2 
1 
Peripheral vascular disease 
1.10* 
0 
1 
Cerebrovascular disease 
1.10* 
0 
1 
Dementia 
2.39 
2 
1 
Chronic pulmonary disease 
1.28 
1 
1 
Rheumatologic disease 
1.30 
1 
1 
Peptic ulcer disease 
1.08* 
0 
1 
Mild liver disease 
1.94 
2 
1 
Diabetes without chronic complications 
1.12* 
0 
1 
Diabetes with chronic complications 
1.22 
1 
2 
Hemiplegia or paraplegia 
2.26 
2 
2 
Renal disease 
1.43 
1 
2 
Any malignancy, including leukemia 
and lymphoma 
2.28 
2 
2 
Moderate or severe liver disease 
3.83 
4 
3 
Metastatic solid tumor 
6.01 
6 
6 
AIDS/HIV 
3.69 
4 
6 
Maximum comorbidity score 
 
24 
29 
AIDS = acquired immunodeficiency syndrome; HIV = human immunodeficiency virus 
*  P > 0.05. 
a 
The following comorbid conditions were mutually exclusive: diabetes with chronic complications and 
diabetes without chronic complications; mild liver disease and moderate or severe liver disease; and any 
malignancy and metastatic solid tumor. 
Source: Table 2 in [Quan et al, 2011]. 

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Study Number: 
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Study Product: 
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Protocol version: Amendment 2 
 
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Appendix 7 
Berlin Criteria for ARDS 
Acute respiratory distress syndrome (ARDS) will be assessed using the Berlin criteria 
[ARDS Definition Task Force, 2012; Fan et al, 2018; Matthay et al, 2021]. 
The expanded Berlin definition of acute respiratory distress syndrome 
 
Acute Respiratory Distress Syndrome 
Timing 
Within 1 week of a known clinical insult or new or worsening respiratory 
symptoms 
Chest imaging a 
Bilateral opacities—not fully explained by effusions, lobar/lung collapse, 
or nodules 
Origin of edema 
Respiratory failure not fully explained by cardiac failure or fluid overload 
Need objective assessment (eg, echocardiography) to exclude hydrostatic 
edema if no risk factor present 
Oxygenation b 
 
Mild 
200 mm Hg < PaO2/FiO2 ≤ 300 mm Hg with PEEP or CPAP ≥ 5 cm H2O c 
Moderate 
100 mm Hg < PaO2/FiO2 ≤ 200 mm Hg with PEEP ≥ 5 cm H2O 
Severe 
PaO2/FiO2 ≤ 100 mm Hg with PEEP ≥ 5 cm H2O 
High-flow nasal 
oxygen 
Use of high-flow nasal oxygen ≥ 30 L/min 
CPAP = continuous positive airway pressure; FiO2 = fraction of inspired oxygen; PaO2 = partial pressure of 
arterial oxygen; PEEP = positive end-expiratory pressure. 
a 
Chest radiograph or computed tomography scan. 
b 
If altitude is higher than 1000 m, the correction factor should be calculated as follows: 
[PaO2/FiO2 × (barometric pressure/760)]. 
c 
This may be delivered noninvasively in the mild acute respiratory distress syndrome group. 
Source: Table 3 in [ARDS Definition Task Force, 2012]; [Matthay et al, 2021]. 
 
Components of the Berlin Criteria for ARDS will be collected from medical records, if 
available, even if all components are not collected per standard of care. 

CSL Behring 
Study Number: 
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Study Product: 
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Protocol version: Amendment 2 
 
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Appendix 8 
Defined Terms 
Informed Consent means the process by which a subject or their Legally Acceptable 
Representative voluntarily confirms his or her willingness to participate in a particular trial 
after having been informed about all aspects relevant to the subject’s decision to participate. 
Informed Consent is documented by means of a written (whether electronic or paper copy), 
signed and dated Informed Consent form. For the avoidance of doubt, this definition of 
Informed Consent includes assent of a minor subject along with corresponding Informed 
Consent of their Legally Acceptable Representative, when allowed by Applicable Law. 
Informed Consent nuances, processes, and requirements are further discussed in the 
applicable country-specific Study Consent Manual (where available). 
Legally Acceptable Representative means an individual or judicial or other body authorized 
under Applicable Law to provide Informed Consent on behalf of a prospective subject, to the 
subject’s participation in the clinical trial. The term Legally Acceptable Representative may 
be referred to by an alternative defined term (eg, Legally Authorized Representative in the 
US) in the applicable country-specific Study Consent Manual (where available) according to 
the nomenclature used in the applicable country. 
Applicable Law(s) means all applicable laws, rules, regulations, guidance, regulatory and 
IRB / IEC requirements related to the conduct of the study and emergency research. 

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