Clinical trial NCT05523297
Conditions: Bleeding Cardiac Surgery Patients
Sponsor: Octapharma
Start date: 2022-11-30; Completion date: 2024-06-27
Enrollment: 420 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multicenter, active-control randomized, prospective, Phase 3 study in adult cardiac surgery patients. 420 patients were randomized at 12 hospitals.

Detailed description:
Patients were randomized to receive either 4-factor PCC (Octaplex) or frozen plasma (FP). The study compared the hemostatic treatment response to Octaplex versus FP, defined as effective if no additional systemic or surgical hemostatic intervention is required from 60 minutes to 24 hours after initiation of the first treatment dose. The study includes adult (≥18 years old) patients who underwent cardiac surgery with cardiopulmonary bypass (CPB) and required coagulation factor replacement due to bleeding post-CPB and after adequate reversal of heparin with protamine (as assessed by the surgical staff based on clinical and laboratory criteria) during surgery, and who have a known (e.g., as indicated by INR) or suspected coagulation factor deficiency.

Arms: arm 1: Participants were administered Octaplex according to a recommended initial dose of 1,500 IU for patients weighing ≤60 kg and 2,000 IU for patients weighing \>60 kg. A second dose of IMP could be administered if the patient continued to have at least moderate bleeding and suspected coagulation deficiency (e.g., INR ≥1.5) after completion of the first dose, up to the maximum allowable dose (3,000 IU if ≤60 kg or 4,000 IU if \>60 kg).

Octaplex: Prothrombin complex concentrate arm 2: Participants were administered FP according to a recommended initial dose of 3 U for patients weighing ≤60 kg and 4 U for patients weighing \>60 kg. A second dose of IMP could be administered if the patient continued to have at least moderate bleeding and suspected coagulation deficiency (e.g., INR ≥1.5) after completion of the first dose, up to the maximum allowable dose (6 U if ≤60 kg or 8 U if \>60 kg).

Frozen Plasma Product, Human
Interventions: intervention 1: Octaplex intervention 2: Frozen Plasma Product, Human
Intervention descriptions: intervention 1: Prothrombin complex concentrate intervention 2: If additional treatment is required after the maximum dose of IMP is administered or the treatment period has elapsed, patients in both groups will receive frozen plasma

Protocol documents:
Prot_002.pdf: 
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This document contains confidential and proprietary information of Octapharma AG.
Do not copy or distribute without written permission.
090-CSP-LEX-211-v9_ Aug 2023_final_clean /DOC ID 3649
CLINICAL STUDY PROTOCOL 
LEX-211
FActor REplacement in Surgery
Four-Factor Prothrombin Complex Concentrate versus 
Frozen Plasma in Bleeding Adult Cardiac Surgical
Patients (“FARES-II” Study)
Investigational Product:
Octaplex
Indication:
Bleeding cardiac
surgery patients
requiring
coagulation factor replacement
Study Design:
Multicentre, randomised, active-control, Phase 3
study
Sponsor:
Octapharma AG
Seidenstrasse 2, CH-8853 Lachen, Switzerland
Study Number:
LEX-211
IND Number:
IND 28027
Development Phase:
Phase 3
Planned Clinical Start:
Quarter 4 2022
Planned Clinical End:
Quarter 4 2024
Date of Protocol:
25-Aug-2023
Version:
9.0
Previous Protocol Versions:
08 – 17 Apr 2023 (Canada only)
07 – 17 Apr 2023 (United States only)
06 – 12 Apr 2022 (Canada only)
05 – 12 Apr 2022 (United States only)
04 – 28 Jan 2022 (Canada only)
03 – 28 Jan 2022 (United States only)
02 – 28 Oct 2021
01 – 07 Sep 2021
Co-ordinating Investigator:
Department 
of 
Anaesthesia 
and 
Pain 
Management
This document contains confidential and proprietary information of Octapharma. 
Copying or distribution of this document is only permitted with the written permission of Octapharma. 
Any commercial use of the information is subject to the permission of Octapharma and a license fee.


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Study Protocol No. LEX-211, Version 9.0 CONFIDENTIAL 
25 Aug 2023 
Toronto General Hospital
200 Elizabeth Street, 3EN-460
Toronto, ON  
M5G 2C4
Canada


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Study Protocol No. LEX-211, Version 9.0 CONFIDENTIAL 
25 Aug 2023 
Page 1 of 86
STUDY OUTLINE 
Name of Sponsor/Company:
Octapharma AG
Name of Investigational Product:
Octaplex
Protocol Identification Code:
LEX-211
Name of Active Ingredient:
Prothrombin complex concentrate, human
Date of Final Protocol:
25-Aug-2023
Title of Study:
Prospective, multicentre, active-control randomised trial comparing 4-factor prothrombin 
complex concentrate with frozen plasma in bleeding adult cardiac surgical patients
Indication:
Bleeding cardiac surgery patients requiring coagulation factor replacement
Number of Study Centre(s):
Approximately 10 hospitals in Canada and 2 in the United States
Objectives:
Primary Objective:
1. To demonstrate that the 4-factor prothrombin complex concentrate (PCC)
Octaplex is clinically non-inferior to frozen plasma (FP) with respect to
haemostatic
effectiveness,
as measured by the
need for
post-therapy
haemostatic interventions.
Secondary Objectives:
1. To compare global haemostatic response between the Octaplex and FP groups,
as measured by a composite of the need for post-therapy haemostatic
interventions and drop in haemoglobin.
2. To compare the amount of bleeding as measured by the amount of chest tube
drainage between the Octaplex and FP groups.
3. To compare the incidence of severe to massive bleeding between the Octaplex
and FP groups.
4. To compare efficacy in terms of the total number of allogeneic blood components
transfused between the Octaplex and FP groups.
5. To compare efficacy in terms of the incidence and number of individual allogeneic
blood components transfused between the Octaplex and FP groups.
6. To compare the incidence of use of other coagulation factor products between
the Octaplex and FP groups.


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Page 2 of 86
Name of Sponsor/Company:
Octapharma AG
Name of Investigational Product:
Octaplex
Protocol Identification Code:
LEX-211
Name of Active Ingredient:
Prothrombin complex concentrate, human
Date of Final Protocol:
25-Aug-2023
7. To compare the incidence of other bleeding-related clinical endpoints, i.e.,
intracerebral haemorrhage,
gastrointestinal haemorrhage
and
surgical re-
exploration, between the Octaplex and FP groups.
8. To compare the effect of Octaplex versus FP administration on the international
normalised ratio (INR) between the Octaplex and FP groups.
9. To compare the effect of Octaplex versus FP administration on other coagulation
parameters.
10. To compare time from IMP initiation to arrival at ICU between the Octaplex and
FP groups.
11. To compare safety as measured by serious treatment-emergent adverse events
(TEAEs) between the Octaplex and FP groups.
12. To compare other secondary safety endpoints including duration of mechanical
ventilation, duration of intensive care unit (ICU) stay, duration of hospitalisation,
incidence of death and days alive and out of hospital between the Octaplex and
FP groups.
Study Design:
This is a multicentre, randomised, active-control, prospective, Phase 3 study in adult
cardiac surgery patients.
Approximately 500
patients will be randomised
at
approximately 12 hospitals and the study will require approximately two years to
complete.
The study will include adult ( 18 years old) patients who undergo cardiac surgery with
cardiopulmonary bypass (CPB) and require coagulation factor replacement due to
bleeding post-CPB and after adequate reversal of heparin with protamine (as assessed 
by the surgical staff based on clinical and laboratory criteria) during surgery, and who
have a known (e.g., as indicated by INR) or suspected coagulation factor deficiency.
Patients will be randomised to receive either 4-factor PCC (Octaplex) or FP when the 
blood bank/pharmacy receives the first order for coagulation factor replacement and 
determines patient eligibility with the study team based on the study inclusion and 
exclusion criteria. IMP will be administered once treatment indications are met. Patients
will be treated according to their assigned group until the maximum dose of IMP is
administered during the treatment period, which represents 24 hours after IMP initiation
(defined as the start of IMP administration). If additional treatment is required after the
maximum dose of IMP is administered or the treatment period has elapsed, patients in
both groups will receive FP.
Other aspects of coagulation management will be according to a standardised
transfusion algorithm. Measurements of INR and haemoglobin will be performed at 


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Study Protocol No. LEX-211, Version 9.0 CONFIDENTIAL 
25 Aug 2023 
Page 3 of 86
Name of Sponsor/Company:
Octapharma AG
Name of Investigational Product:
Octaplex
Protocol Identification Code:
LEX-211
Name of Active Ingredient:
Prothrombin complex concentrate, human
Date of Final Protocol:
25-Aug-2023
preestablished time points, if not available already. No other aspects of care will be 
modified.


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Study Protocol No. LEX-211, Version 9.0 CONFIDENTIAL 
25 Aug 2023 
Page 4 of 86
Name of Sponsor/Company:
Octapharma AG
Name of Investigational Product:
Octaplex
Protocol Identification Code:
LEX-211
Name of Active Ingredient:
Prothrombin complex concentrate, human
Date of Final Protocol:
25-Aug-2023
Number of Patients: 
The study is split in two stages. In the first stage, randomisation (1:1) will continue until 
200 evaluable patients are obtained. Then, an administrative unblinded interim analysis
will be carried out to re-estimate the sample size or stop for futility (non-binding) if
necessary. The sample size in the second stage is limited to 210–800 evaluable patients.
Accounting for 20% dropouts, the total sample size of the study will range between 513–
1250 if the study is not stopped for futility at the interim.
Subject/Patient Selection Criteria:
Inclusion Criteria:
1. Adult ( 18 years old) patients undergoing any index cardiac surgery employing
CPB
2. Coagulation factor replacement with PCC or FP ordered in the operating room
for:
a. Management of bleeding, or
b. Anticipated bleeding in a patient who has been on-pump for >2 hours or has
undergone a complex procedure (e.g., aortocoronary bypass [ACB] plus aortic
valve replacement)
3. Coagulation factor deficiency, either known to exist (e.g., as indicated by elevated
EXTEM clotting time [CT] or INR) or suspected based on the clinical situation
4. Patients who have given written informed consent1
Exclusion Criteria:
1. Undergoing heart transplantation, insertion or removal of ventricular assist
devices (not including intra-aortic balloon pump [IABP]) or repair of
thoracoabdominal aneurysm
2. Critical state immediately before surgery with high probability of death within 24
hours of surgery (e.g., acute aortic dissection, cardiac arrest within 24 hours
before surgery)
1 In Canada, informed consent will be obtained after randomisation, in accordance with Article 3.7A of 
the 2018 Tri-Council Policy Statement on the Ethical Conduct for Research Involving Humans.


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Study Protocol No. LEX-211, Version 9.0 CONFIDENTIAL 
25 Aug 2023 
Page 5 of 86
Name of Sponsor/Company:
Octapharma AG
Name of Investigational Product:
Octaplex
Protocol Identification Code:
LEX-211
Name of Active Ingredient:
Prothrombin complex concentrate, human
Date of Final Protocol:
25-Aug-2023
3. Severe right heart failure (clinical diagnosis ± echocardiography)
4. Known contraindications to heparin
5. PCC required for reversal of warfarin or direct oral anticoagulant (DOAC;
dabigatran, rivaroxaban, apixaban or edoxaban) within 3 days prior to or during
surgery
6. Known thromboembolic event (TEE) within 3 months prior to surgery
7. History of severe allergic reactions to PCC or FP
8. Individuals who have immunoglobulin A (IgA) deficiency with known antibodies
against IgA
9. Refusal of allogeneic blood products
10. Known pregnancy
11. Currently enrolled in other interventional clinical trials
Test Product, Dose and Mode of Administration:
Octaplex and FP will be administered intravenously. For the first ordered dose, the blood 
bank/pharmacy will prepare and release either Octaplex or FP, as per the randomised
group allocation. The dose for Octaplex will be 1500 IU for patients weighing 
and
2000 IU for patients weighing >60 kg. The dose for FP will be 3 U for patients weighing
and 4 U for patients weighing >60 kg).
If a second order of coagulation factors is received during the treatment period of 24 
hours after IMP initiation, the blood bank/pharmacy will release a second dose of
Octaplex or FP as above. The maximum allowable dose of IMP will be: Octaplex 3000
If further doses of
coagulation factors are required, non-IMP FP will be administered. That is, once the
maximum dose of IMP (i.e., two doses) has been administered, if additional amounts of
coagulation factors are ordered during the treatment period, and for any requests after 
the treatment period, the blood bank/pharmacy technologist will release FP (in 1–4 U
increments at the discretion of the ordering physician) for both groups; these additional
FP units will not be counted as part of the IMP.
Duration of Treatment:
Twenty-four hours from IMP initiation or until the maximum dose of the IMP has been 
administered, whichever occurs first. 


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Study Protocol No. LEX-211, Version 9.0 CONFIDENTIAL 
25 Aug 2023 
Page 6 of 86
Name of Sponsor/Company:
Octapharma AG
Name of Investigational Product:
Octaplex
Protocol Identification Code:
LEX-211
Name of Active Ingredient:
Prothrombin complex concentrate, human
Date of Final Protocol:
25-Aug-2023
Reference Therapy, Dose and Mode of Administration: 
Two methods of coagulation factor replacement will be compared in the study, with 
patients randomly assigned (1:1 ratio) to receive IV infusion of 1500 to 2000 of Octaplex 
or 3 to 4 units of FP. If a second order is received during the treatment period of 24 hours 
after IMP initiation, the blood bank/pharmacy will release a second dose of Octaplex or 
FP as above. If further doses of coagulation factors are required, all patients will receive 
non-IMP FP. 
Study Outcome Parameters (Primary and Secondary Endpoints):
Efficacy Parameters:
Primary Endpoint:
1. Comparison of haemostatic treatment response to Octaplex versus FP, defined
as ‘effective’ if no additional haemostatic intervention, such as administration of
any systemic haemostatic agents (including platelets, cryoprecipitate, fibrinogen
concentrate, activated recombinant factor VII, other coagulation factor products
or a second dose of IMP) or any haemostatic interventions (including surgical re-
opening for bleeding) is required from 60 minutes to 24 hours after initiation of the
first dose of IMP.
Secondary Endpoints:
1. Comparison of global haemostatic response to Octaplex versus FP, defined as
‘positive’ if no additional haemostatic intervention (as per the primary endpoint) is
required and haemoglobin levels decrease by <30% (after accounting for red cell
transfusions) from 60 minutes to 24 hours after initiation of the first dose of IMP.
2. Comparison of the total amount of chest tube drainage at 12 and 24 hours after
chest closure between the Octaplex and FP groups.
3. Comparison of the incidence of severe to massive bleeding, using a modification
of the universal definition of perioperative bleeding (UDPB) in cardiac surgery and
its individual components during the first 24 hours after start of surgery, after the
end of CPB and after IMP initiation, between the Octaplex and FP groups.
4. Comparison of the mean number of total allogeneic blood components – including
red cells, platelets and all (IMP and non-IMP) FP – administered during the first
24 hours after the end of CPB, between the Octaplex and FP groups.


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Study Protocol No. LEX-211, Version 9.0 CONFIDENTIAL 
25 Aug 2023 
Page 7 of 86
Name of Sponsor/Company:
Octapharma AG
Name of Investigational Product:
Octaplex
Protocol Identification Code:
LEX-211
Name of Active Ingredient:
Prothrombin complex concentrate, human
Date of Final Protocol:
25-Aug-2023
5. Comparison of the mean number of total non-IMP allogeneic blood components
– including red cells, platelets and non-IMP FP – administered during the first 24
hours after the end of CPB, between the Octaplex and FP groups.
6. Comparison of the mean number of total non-IMP allogeneic blood components
– including red cells, platelets, cryoprecipitate and non-IMP FP – administered
during the first 24 hours and 7 days after IMP initiation, between the Octaplex and
FP groups.
7. Comparison of the mean number of individual allogeneic blood components –
including red cells, platelets, cryoprecipitate and non-IMP FP – administered
during the first 24 hours and 7 days after the start of surgery, after the end of CPB
and after IMP initiation, between the Octaplex and FP groups.
8. Comparison of the incidence of transfusion of individual allogeneic blood
components – including red cells, platelets, cryoprecipitate and non-IMP FP –
during the first 24 hours and 7 days after the start of surgery, after the end of CPB
and after IMP initiation, between the Octaplex and FP groups.
9. Comparison of the incidence of administration of non-IMP coagulation factor
products – including fibrinogen concentrate and activated recombinant factor VII
– during the first 24 hours and 7 days after the start of surgery, after the end of
CPB and after IMP initiation, between the Octaplex and FP groups.
10. Comparison of the incidence of intracerebral haemorrhage during the first 24
hours after start of surgery, after the end of CPB and after IMP initiation between
the Octaplex and FP groups.
11. Comparison of the incidence of gastrointestinal haemorrhage during the first 24
hours after start of surgery, after the end of CPB and after IMP initiation between
the Octaplex and FP groups.
12. Comparison of the incidence of surgical re-exploration during the first 24 hours
after start of surgery, after the end of CPB and after IMP initiation between the
Octaplex and FP groups.
13. Comparison of the change in INR, from within 30 minutes before to within 60
minutes after the initiation of IMP administration, between the Octaplex and FP
groups; INR reduction will be considered successful if the magnitude of the
reduction is >1.0 or the post-treatment level drops below 1.5.
14. Comparison of the changes in other coagulation parameters, including PT, aPTT,
fibrinogen activity, ROTEM EXTEM CT and MCF, ROTEM FIBTEM MCF and
platelets, from within 75 minutes before to within 75 minutes after the initiation of
IMP administration, between the Octaplex and FP groups.


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Study Protocol No. LEX-211, Version 9.0 CONFIDENTIAL 
25 Aug 2023 
Page 8 of 86
Name of Sponsor/Company:
Octapharma AG
Name of Investigational Product:
Octaplex
Protocol Identification Code:
LEX-211
Name of Active Ingredient:
Prothrombin complex concentrate, human
Date of Final Protocol:
25-Aug-2023
15. Comparison of time elapsed from initiation of the first dose of IMP to arrival at the
ICU room between the Octaplex and FP groups.
Safety Endpoints:
All adverse events (AEs) and serious AEs (SAEs) will be collected from beginning of
surgery (defined as entry into OR) to POD-30.
1. Comparison of the incidence of serious treatment-emergent adverse events
(TEAEs), individually and as composite where appropriate (e.g., TEEs, major
adverse cardiac events), between the Octaplex and FP groups.
2. Comparison of the duration of mechanical ventilation (measured as duration of
ventilation and ventilator-free days) up to POD-30 between the Octaplex and FP
groups.
3. Comparison of the duration of ICU stay up to POD-30 between the Octaplex and
FP groups.
4. Comparison of the duration of hospitalisation up to POD-30 between the Octaplex
and FP groups.
5. Comparison of the incidence of death up to POD-30 between the Octaplex and
FP groups.
6. Comparison of the number of days alive and out of hospital at POD-30 between
the Octaplex and FP groups.
Study Procedures:
At the screening assessment, voluntarily given, written, informed consent will be obtained
from the patient. Once consent has been obtained and the patient enrolled into the study,
eligibility according to inclusion criteria 1 and 4
, undergoing
any index cardiac surgery employing CPB, who have provided informed consent) and 
the exclusion criteria will be confirmed.
Only patients who bleed and require coagulation factor replacement therapy during 
surgery will be randomised to receive study drug, and undergo the following visits and
assessments. 
When the first order for PCC or FP is received by the blood bank/pharmacy while the 
patient is in the operating room, the blood bank/pharmacy technologist will confirm 
patient eligibility with the clinical team. Following confirmation of eligibility, the 
technologist will randomise the patient to PCC or FP according to the randomisation and 


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Study Protocol No. LEX-211, Version 9.0 CONFIDENTIAL 
25 Aug 2023 
Page 9 of 86
Name of Sponsor/Company:
Octapharma AG
Name of Investigational Product:
Octaplex
Protocol Identification Code:
LEX-211
Name of Active Ingredient:
Prothrombin complex concentrate, human
Date of Final Protocol:
25-Aug-2023
dosing schedule and prepare and release the IMP in a tamper sealed container (with 
weight device in PCC containing boxes to ensure adequate concealment). Operating 
room personnel will remain blinded until the decision to administer the IMP is made.
IMP can be administered if bleeding is severe enough to necessitate treatment (meaning
at least a grade 2 level [moderate] bleeding according to the validated Bleeding Severity
Scale - see Appendix 1), heparin is adequately reversed (confirmed by the return of post-
protamine activated clotting time [ACT] to within 10% of pre-
IMP can also be administered if bleeding is severe enough to require urgent therapy, in
which case treatment can be initiated irrespective of the INR value. Once the decision is
made to administer the IMP, the administering clinician will break the seal on the
container, carry out routine safety checks, and initiate IMP administration according to 
the weight-based dosing recommendations.
A second dose of IMP can be administered if the patient continues to have at least
moderate bleeding and a suspected coagulation deficiency (e.g.
) after 
completion of the first dose. If an order for a second dose of coagulation factors is 
received within 24 hours after IMP initiation (either from the operating room or in the ICU
after surgery), the blood bank/pharmacy technologist will release the IMP as determined 
by the randomisation schedule up to the maximum allowable dose, as per usual practice 
(a tamper-sealed container will not be used for these orders as clinicians will by now be
unblinded).
If further doses of coagulation factors are required after the second dose of IMP, all 
patients will receive non-IMP FP. That is, for subsequent orders once the maximum dose
of IMP has been administered (i.e., two doses), or after the 24-hour treatment period has 
elapsed, the technologist will release non-IMP FP for both groups.
The type of IMP administered will be recorded in a manner that will not unblind the
outcome assessor. Patients will also be blinded to treatment allocation.
If any of the IMP doses is returned from the operating room without any part of the IMP
being administered for any reason, the reason for return of the IMP and status of the seal
on the tamper-sealed container will be recorded by the blood bank/pharmacy
technologist. Octaplex will be accounted for and FP will be handled according to the local 
practice.
Study Visits:
Screening visit (maximum 28 days before surgery)
Voluntarily given, written (signed and dated) informed consent obtained from
patients


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Study Protocol No. LEX-211, Version 9.0 CONFIDENTIAL 
25 Aug 2023 
Page 10 of 86
Name of Sponsor/Company:
Octapharma AG
Name of Investigational Product:
Octaplex
Protocol Identification Code:
LEX-211
Name of Active Ingredient:
Prothrombin complex concentrate, human
Date of Final Protocol:
25-Aug-2023
Determine eligibility according to inclusion criteria 1 and 4
old, undergoing any index cardiac surgery employing CPB, who have provided
informed consent) and the exclusion criteria
If screening is performed before the day of surgery, exclusion criterion 3 (i.e.,
severe right heart failure [clinical diagnosis ± echocardiography]) will be
rechecked on the day of surgery
The following visits will only be performed for patients who bleed and require coagulation 
factor replacement therapy during surgery
Visit 1: (POD 0 pre-randomization): Pre-randomisation visit (blood bank/pharmacy)
Surgical staff records the patient’s body weight
Visit 2: (POD 0 post-randomization and POD 1): First visit after IMP initiation (0 to
24 hours after IMP initiation)
Collect baseline data
Administer first dose of IMP
Collect surgical data
Collect laboratory, transfusion and haemostatic therapy, and bleeding data
Administer second dose of IMP, if needed
Collect extubation time
Collect concomitant medications
Collect AEs and SAEs
Visit 3: (POD 2-7): Days 2–7 after IMP initiation (or at discharge, if earlier)
Collect laboratory, transfusion and haemostatic therapy, and bleeding data
Record intracerebral haemorrhage, gastrointestinal haemorrhage and surgical re-
exploration. Collect extubation time, length of stay in the ICU and hospital (if
applicable)
Collect concomitant medications
Collect AEs and SAEs
Visit 4: (POD 30): Day 30 after IMP initiation (in person if in hospital or by phone)
Collect concomitant medications
Collect AEs and SAEs
Collect extubation time, length of stay in the ICU, length of stay in the hospital (if
extended), readmissions and 30-day mortality
Concomitant Therapies and Management:


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Study Protocol No. LEX-211, Version 9.0 CONFIDENTIAL 
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Page 11 of 86
Name of Sponsor/Company:
Octapharma AG
Name of Investigational Product:
Octaplex
Protocol Identification Code:
LEX-211
Name of Active Ingredient:
Prothrombin complex concentrate, human
Date of Final Protocol:
25-Aug-2023
Transfusion of non-IMP blood components and all haemostatic agents will be
administered according to a standardised transfusion management algorithm that will 
employ point-of-care and standard coagulation assays. Hospitals will also be provided
with point-of-care INR assays to measure and document INR before and after IMP
administration. Other than the treatment algorithm, and the haemoglobin and INR
measurements at preestablished time points (if not available already), no other aspects 
of routine clinical care will be modified.
Ethics:
This is a prospective trial that compares two coagulation factor replacement therapies
that are routinely used in the treatment of bleeding related to coagulation factor 
deficiency in multiple regions globally and in various settings. Informed consent will be
obtained from the patient before the patient is exposed to any study-related procedure.
Statistical Analysis Plan:
The analysis of the primary efficacy endpoint will involve comparison of haemostatic
treatment response to IMP, defined as ‘effective’ if no additional
haemostatic
intervention, such as administration of any systemic haemostatic agents (including
platelets, cryoprecipitate, fibrinogen concentrate, activated recombinant factor VII, other 
coagulation factor products or a second dose of IMP) or any haemostatic interventions
(including surgical re-opening for bleeding) is required from 60 minutes to 24 hours after
initiation of the first dose of IMP.
Patients categorised as having an ‘ineffective’ haemostatic treatment response to IMP,
due to requiring administration of any haemostatic intervention, including a second dose
of IMP, in the time window from 60 minutes to 24 hours after initiation of the first IMP
dose, will be considered as treatment failures.
Of the more than 100 patients studied in the FARES pilot study, approximately 75% of
patients in the PCC group and 65% in the FP group demonstrated haemostatic treatment
response from 60 minutes to 24 hours after initiation of the first IMP dose. Using a more
conservative estimate of 70% versus 65%, it is estimated that 410 patients will be
required to demonstrate non-inferiority with a one-
2
non-inferiority margin of 0.10 when using a Farrington-Manning score test.
It is anticipated that up to 20% of randomised patients may not meet administration 
criteria (based on objective Bleeding Severity Scale and INR) due to cessation of 
haemorrhage between randomisation and delivery of IMP to the operating room and 
therefore will not receive the therapy.  


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Study Protocol No. LEX-211, Version 9.0 CONFIDENTIAL 
25 Aug 2023 
Page 12 of 86
Name of Sponsor/Company:
Octapharma AG
Name of Investigational Product:
Octaplex
Protocol Identification Code:
LEX-211
Name of Active Ingredient:
Prothrombin complex concentrate, human
Date of Final Protocol:
25-Aug-2023
An administrative unblinded interim analysis will be carried out after approximately 200 
patients have been randomised and treated and will be used to re-estimate the sample
size or stop for futility (non-binding). Patient recruitment will continue during the conduct
of the interim analysis. The study can only be stopped for futility and not for efficacy at
the time of the interim analysis. The sample size re-estimation will be based on the 
evaluation of the conditional power making use of the observed response rates and
inverse normal combination test statistic with equal weights given by (
-1(1 – p1) +
-1(1
– p2))/ 2, where p1 and p2 denote the p-values for testing the non-inferiority null
hypothesis for the first and the second stage of the trial, respectively. The aspired
conditional power used for the new intended sample size will be 90%. The sample size
in the second stage is limited to 210–800 evaluable patients. Accounting for dropouts as
described above, the total sample size will range between 513–1250 if the study is not
stopped for futility at the interim.
The non-inferiority of the primary endpoint ‘haemostatic response’ will be tested between 
the treatment groups by means of a Farrington-Manning score test with a non-inferiority
margin of 0.10. At the end of the trial, the inverse normal test statistic with equal weights
given by (
-1(1 – p1) +
-1(1 – p2))/ 2 is calculated, where p1 and p2 denote the p-values
for testing the non-inferiority null hypothesis for the first and the second stage of the trial,
respectively. If the test statistic exceeds the value 1.96, non-inferiority is demonstrated.
Only in case that non-inferiority is demonstrated, i.e., the null hypothesis is rejected at
the one-sided 2.5% level of significance, superiority of PCC with regard to the primary
endpoint will be investigated.
Descriptive statistics or frequency tables will be presented for all efficacy and safety data 
in addition to the inferences performed. The summary tables and exploratory inferences
will be chosen according to the scaling level of the measurements, e.g., frequency tables
for categorical responses, sampling statistics for continuous data. Safety endpoints will
be analysed analogously to the primary endpoint, presenting point estimates and two-
sided 95% CIs in addition to descriptive statistics. The Statistical Analysis Plan (SAP)
will detail all analyses to be undertaken prior to study initiation.
The full analysis set (FAS) will consist of all consented and randomised patients who 
receive any amount of the intervention, which will serve as the primary analysis set. A 
secondary efficacy analysis will be performed for the per-protocol set (PPS), which will 
exclude all patients with major deviations. Consented, randomised but untreated patients 
will not be included in the efficacy or safety analyses, but will be followed for 30 days to 
determine between-group comparability in baseline characteristics and outcomes. 


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TABLE OF CONTENTS
STUDY OUTLINE ..................................................................................................................................1 
FLOW CHART OF ASSESSMENTS ...............................................................................................13 
PROTOCOL SIGNATURES ..............................................................................................................15 
TABLE OF CONTENTS .....................................................................................................................20 
LIST OF ABBREVIATIONS ..............................................................................................................23 
1 
INTRODUCTION ........................................................................................................................25 
1.1 RATIONALE FOR CONDUCTING THE STUDY ........................................................... 25 
1.2 DOSE RATIONALE ................................................................................................... 30 
1.3 BENEFIT-RISK STATEMENT ................................................................................... 31 
1.4 COVID-19 BENEFIT-RISK STATEMENT ................................................................ 31 
2 
STUDY OBJECTIVES ...............................................................................................................33 
2.1 PRIMARY OBJECTIVE ............................................................................................. 33 
2.2 SECONDARY OBJECTIVES ..................................................................................... 33 
3 
INVESTIGATIONAL PLAN .......................................................................................................34 
3.1 PRIMARY AND SECONDARY ENDPOINTS ............................................................... 34 
3.1.1 Primary Endpoint ................................................................................................34 
3.1.2 Secondary Endpoints ........................................................................................34 
3.1.3 Safety Endpoints ................................................................................................35 
3.2 OVERALL STUDY DESIGN AND PLAN ..................................................................... 35 
3.3 DISCUSSION OF STUDY DESIGN AND CHOICE OF CONTROL GROUP ................... 37 
3.3.1 Study Design .......................................................................................................37 
3.3.2 Control Group .....................................................................................................40 
3.3.3 Study Parameters ..............................................................................................40 
4 
STUDY POPULATION ..............................................................................................................41 
4.1 POPULATION BASE ................................................................................................ 41 
4.1.1 Inclusion Criteria .................................................................................................41 
4.1.2 Exclusion Criteria ...............................................................................................41 
4.2 PRIOR AND CONCOMITANT THERAPY .................................................................... 42 
4.2.1 Permitted Concomitant Therapy ......................................................................42 
4.2.2 Forbidden Concomitant Therapy .....................................................................42 
4.3 WITHDRAWAL AND REPLACEMENT OF PATIENTS .................................................. 42 
4.3.1 Premature Subject/Patient Withdrawal ...........................................................42 
4.3.2 Subject/Patient Replacement Policy ...............................................................42 
4.4 ASSIGNMENT OF PATIENTS TO TREATMENT GROUPS .......................................... 42 
4.5 RELEVANT PROTOCOL DEVIATIONS ...................................................................... 43 
4.6 SUBSEQUENT THERAPY ......................................................................................... 43 
5 
INVESTIGATIONAL MEDICINAL PRODUCT(S) .................................................................44 
5.1 CHARACTERISATION OF INVESTIGATIONAL PRODUCT(S) ...................................... 44 
5.1.1 Octaplex ...............................................................................................................44 
5.1.2 Frozen plasma ....................................................................................................44 
5.2 PACKAGING AND LABELLING .................................................................................. 44 


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5.3 CONDITIONS FOR STORAGE AND USE ................................................................... 45 
5.4 DOSE AND DOSING SCHEDULE ............................................................................. 45 
5.5 PREPARATION AND METHOD OF ADMINISTRATION ............................................... 45 
5.6 BLINDING, EMERGENCY ENVELOPES AND BREAKING THE STUDY BLIND ............. 45 
5.7 TREATMENT COMPLIANCE ..................................................................................... 46 
5.7.1 Drug Dispensing and Accountability ...............................................................46 
5.7.2 Assessment of Treatment Compliance ...........................................................46 
6 
STUDY CONDUCT ....................................................................................................................47 
6.1 OBSERVATIONS BY VISIT ....................................................................................... 49 
6.1.1 Screening visit (maximum 28 days before surgery) .....................................49 
6.1.2 Visit 1 (POD 0 pre-randomization): Pre-randomisation visit (blood 
bank/pharmacy) ..................................................................................................49 
6.1.3 Visit 2 (POD 0 post-randomization and POD 1): First visit after IMP 
initiation (0 to 24 hours after IMP initiation) ....................................................49 
6.1.4 Visit 3 (POD 2-7): Days 2–7 after IMP initiation (or at discharge, if earlier)
 ..............................................................................................................................50 
6.1.5 Visit 4 (POD 30): Day 30 after IMP initiation (in person if in hospital, or by 
phone) ..................................................................................................................51 
6.1.6 Time Windows Used in this Study, including Tolerances ............................51 
6.2 DURATION OF STUDY ............................................................................................. 52 
6.2.1 Planned Duration for an Individual Subject/Patient ......................................52 
6.2.2 Planned Duration for the Study as a Whole ...................................................52 
6.2.3 Premature Termination of the Study ...............................................................52 
7 
ASSESSMENTS AND METHODS ..........................................................................................53 
7.1 DEMOGRAPHIC AND BASELINE INFORMATION ....................................................... 53 
7.1.1 Demographic and baseline characteristics ....................................................53 
7.1.2 Medical history and prior/concomitant medications ......................................53 
7.2 EFFICACY ASSESSMENTS ...................................................................................... 53 
7.2.1 Assessments for Primary Efficacy Endpoint ..................................................53 
7.2.2 Assessments for Secondary Efficacy Endpoints ...........................................54 
7.3 SAFETY ASSESSMENTS ......................................................................................... 56 
7.3.1 Assessments for Safety Endpoints ..................................................................56 
7.3.2 Adverse Events (AEs) .......................................................................................56 
7.3.3 Serious Adverse Events (SAEs) ......................................................................59 
7.3.4 SAE Reporting Timelines ..................................................................................60 
7.3.5 Occurrence of TEEs ..........................................................................................60 
7.3.6 Laboratory Tests ................................................................................................61 
7.3.7 Other Relevant Safety Information ..................................................................62 
7.4 APPROPRIATENESS OF MEASUREMENTS .............................................................. 63 
8 
DATA HANDLING AND RECORD KEEPING .......................................................................64 
8.1 DOCUMENTATION OF DATA.................................................................................... 64 
8.1.1 Source Data and Records ................................................................................64 
8.1.2 Case Report Forms............................................................................................64 
8.1.3 Changes to Case Report Form (CRF) Data ...................................................64 
8.2 INFORMATION TO INVESTIGATORS ......................................................................... 65 
8.3 RESPONSIBILITIES .................................................................................................. 65 


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8.4 INVESTIGATOR’S SITE FILE .................................................................................... 66 
8.5 PROVISION OF ADDITIONAL INFORMATION ............................................................ 67 
8.6 INDEPENDENT DATA AND SAFETY MONITORING COMMITTEE .............................. 67 
9 
STATISTICAL METHODS AND SAMPLE SIZE ...................................................................68 
9.1 DETERMINATION OF SAMPLE SIZE ........................................................................ 68 
9.2 STATISTICAL ANALYSIS .......................................................................................... 69 
9.2.1 Populations for Analysis ....................................................................................69 
9.2.2 Efficacy Analysis Plan .......................................................................................70 
9.2.3 Safety Analysis Plan ..........................................................................................70 
9.2.4 Handling of Missing Data ..................................................................................71 
9.3 RANDOMISATION, STRATIFICATION AND CODE RELEASE ..................................... 71 
9.4 INTERIM ANALYSIS ................................................................................................. 72 
10 
ETHICAL/REGULATORY, LEGAL AND ADMINISTRATIVE ASPECTS ........................73 
10.1 ETHICAL/REGULATORY FRAMEWORK ................................................................... 73 
10.2 APPROVAL OF STUDY DOCUMENTS ...................................................................... 73 
10.3 SUBJECT/PATIENT INFORMATION AND INFORMED CONSENT ............................... 73 
10.3.1 Evidence for the prospect of direct benefit to patients because of 
participation in the study ...................................................................................74 
10.4 PROTOCOL AMENDMENTS ..................................................................................... 74 
10.5 CONFIDENTIALITY OF SUBJECT/PATIENT DATA .................................................... 75 
11 
QUALITY CONTROL AND QUALITY ASSURANCE ..........................................................76 
11.1 PERIODIC MONITORING ......................................................................................... 76 
11.2 AUDIT AND INSPECTION ......................................................................................... 76 
12 
REPORTING AND PUBLICATION .........................................................................................77 
12.1 CLINICAL STUDY REPORT ...................................................................................... 77 
12.2 PUBLICATION POLICY ............................................................................................. 77 
13 
LIABILITIES AND INSURANCE ..............................................................................................78 
14 
REFERENCES ............................................................................................................................79 
15 
APPENDICES .............................................................................................................................86 
15.1 APPENDIX 1: BLEEDING SCORE ............................................................................ 86 


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LIST OF ABBREVIATIONS
Abbreviation
Description
ACB
Aortocoronary Bypass
ACT
Activated Clotting Time
ADR
Adverse Drug Reaction
AE
Adverse Event
AKI
Acute Kidney Injury
ALT
Alanine Aminotransferase
aPTT
Activated Partial Thromboplastin Time
AST
Aspartate Aminotransferase
BMI
Body Mass Index
CABG
Coronary Artery Bypass Grafting
CC
Community Consultation
CCA
Complete Case Analysis
CI
Confidence Interval
CPB
Cardiopulmonary Bypass
CRF
Case Report Form
CRO
Contract Research Organisation
CT
Clotting Time
DOAC
Direct Oral Anticoagulant
E-CABG
European Coronary Artery Bypass Grafting
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EXTEM
ROTEM Test Assessing the Extrinsic Coagulation Pathway
FIBTEM
Fibrin-Based ROTEM Test Extrinsically Activated with Tissue Factor 
and Containing the Platelet Inhibitor Cytochalasin D
GCP
Good Clinical Practice
HIV
Human Immunodeficiency Virus
IABP
Intra-Aortic Balloon Pump
IB
Investigator’s Brochure
ICU
Intensive Care Unit
IDSMC
Independent Data and Safety Monitoring Committee
IgA
Immunoglobulin A
IMP
Investigational Medicinal Product
INR
International Normalised Ratio
IRB
Institutional Review Board
IV
Intravenous
KDIGO
Kidney Disease: Improving Global Outcomes
MACE
Major Adverse Cardiac Events
MCF
Maximum Clot Firmness


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Abbreviation
Description
MedDRA
Medical Dictionary for Regulatory Activities
OR
Operating Room
PCC
Prothrombin Complex Concentrate
PD
Public Disclosure
PI
Package Insert
POD
Postoperative Day
PP
Per-Protocol
PRV
Pseudorabies Virus
PT
Prothrombin Time
RBC
Red Blood Cell
rFVIIa
Activated Recombinant Factor VII
ROTEM
Rotational Thromboelastometry
SAE
Serious Adverse Event
SAF
Safety Analysis Population
SBV
Schmallenberg Virus
SDV
Source Data Verification
SmPC
Summary of Product Characteristics
TACS
Transfusion Avoidance in Cardiac Surgery
TEAE
Treatment-Emergent Adverse Event
TEE
Thromboembolic Event
UDPB
Universal Definition of Perioperative Bleeding
WFI
Water for Injections


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1 
INTRODUCTION 
1.1
Rationale for Conducting the Study
Bleeding in Cardiac Surgery
Cardiac surgery is frequently complicated by coagulopathic bleeding that often leads to 
excessive blood loss, blood product transfusion and bleeding-related complications [1-4].
Bleeding and transfusions are associated with increased morbidity and mortality, including 
up to an 8-fold increase in the odds of death [2], and patients with major bleeding are at 
particularly high risk of adverse outcomes (e.g., infection, heart failure and mortality) [5-
17]. 
Coagulopathy during cardiac surgery is caused by several factors, including the contact of 
blood with the cardiopulmonary bypass (CBP) circuit, which activates the intrinsic and 
extrinsic coagulation pathways (despite the use of heparin and heparin-coated circuits), 
causing excessive clot formation and breakdown. Other contributory factors include 
haemodilution, hypothermia, blood loss, surgical trauma and use of foreign substances 
such as aortic grafts causing the consumption of coagulation factors [18-22]. These in turn 
can lead to excessive fibrinolysis, fibrinogen deficiency, platelet dysfunction and 
thrombocytopenia [20, 21]. Deficiency of enzymatic coagulation factors (e.g., vitamin K-
dependent factors II, VII, IX, X and XI) is also an important cause of coagulopathy, leading 
to impaired generation of thrombin, which is a central component of the coagulation 
cascade [23, 24]. Activated thrombin converts soluble fibrinogen into insoluble strands of 
fibrin, which forms the basis of the clot, and it also catalyses numerous other coagulation-
related reactions [25]. Consequently, replacement of coagulation factors is an important 
aspect of a multimodal approach to coagulopathy to reduce bleeding and transfusion [4,
26].
To replenish depleted coagulation factors and improve thrombin generation, two 
therapeutics, frozen plasma (FP) and prothrombin complex concentrate (PCC), are 
available. FP is currently the mainstay of therapy for patients with acquired coagulopathies 
in North America whereas PCC is the mainstay of therapy in much of Europe [27]. 
Frozen Plasma
FP is obtained from donated whole blood and contains all enzymatic coagulation factors, 
although some coagulation factor activity is lost during storage and processing (including 
freezing for storage and thawing prior to transfusion) [28]. FP utilised in North America is 
not commonly pathogen-reduced. FP is the mainstay of therapy for bleeding cardiac 
surgery patients requiring coagulation factor replacement in many countries and is 
administered in around 15% of all cardiac surgeries in the United States [29]. Despite being 
a mainstay of therapy, there is limited clinical trial evidence on the use of FP in bleeding 
cardiac surgery patients requiring coagulation factor replacement [30]. Nevertheless, it is 
recommended by current guidelines and is considered standard practice to transfuse FP 
in bleeding patients who have coagulation factor deficiency, as indicated by an elevated 
international normalised ratio (INR) >1.5, which indicates that one or more coagulation 
factor levels are below the 30% critical threshold [31-37]. 
The widespread use of FP needs to be considered in the context of the risks associated 
with its use [38, 39]. FP can cause serious adverse events (SAEs) including allergic 
reactions (which occur in 1–3% of transfusions, ranging from mild to life-threatening 


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anaphylaxis) [30]; transfusion-related acute lung injury (TRALI), which is a leading cause 
of transfusion-related death [30, 40]; and transfusion-associated circulatory overload 
(TACO), which occurs in approximately 5% of transfusions as a result of the large volume 
of transfusion (10–15 mL/kg) that is required to achieve therapeutic effect with FP [41]. FP 
transfusion can also lead to transmission of infectious diseases, as FP is not usually filtered 
or treated with solvent/detergent [42]. These adverse effects are often dose-dependent 
[43-46]. Another important consideration with FP use is that it requires ABO blood group 
compatibility matching and thawing, which can delay therapy. The large volumes of FP 
needed to achieve therapeutic effect can further delay time to haemostatic control and lead 
to substantial haemodilution, resulting in additional RBC transfusions [47]. Therefore, 
although FP is currently a mainstay of therapy in North America, due to the disadvantages 
and risks associated with its use, it could be considered to be an unsatisfactory treatment.
Prothrombin Complex Concentrate (PCC)
PCC offers a potential alternative to FP for treating bleeding cardiac surgery patients 
requiring coagulation factor replacement; however, no PCC product is currently approved 
for this indication in the United States. PCCs contain prothrombin and other enzymatic 
coagulation factors, the anticoagulant proteins C and S, and small amounts of heparin; 
thus, they are contraindicated in patients who are allergic to heparin or have a prior history 
of heparin-induced thrombocytopenia. PCCs are routinely defined as 3-factor (containing 
factors II, IX and X) or 4-factor (containing factors II, VII, IX and X) formulations [48]. PCCs 
are purified from human pooled plasma, which is fractionated into cryoprecipitate and 
cryoprecipitate-free plasma fractions through a process of slow thawing, then eluted from 
cryoprecipitate-free plasma [48]. The production of PCCs includes numerous pathogen 
inactivation steps using solvents, detergents, pasteurisation, nanofiltration and vapor-
heated treatment [1, 48].
PCCs have several potential advantages over FP. Solvent/detergent treatment and 
filtering to remove pathogens substantially reduces the risk of transmission of infectious 
agents with PCCs. Indeed, a Consensus Conference recommended in 2007 that pathogen 
reduction technologies should be implemented to improve the safety of transfusion when 
they became available [49]. Unlike FP, PCCs do not require ABO compatibility matching 
or thawing, and can therefore be prepared and administered more quickly. PCCs are 
associated with a substantially lower risk of TRALI (due to pooling of the source donor 
plasma), and also a lower risk of TACO [38] as substantially lower volumes of PCC are 
required than with FP to achieve dose-equivalence for increasing thrombin generation (for 
example, in a 70-kg patient, a standard dose of 25 IU/kg PCC would be administered in a 
volume of 80 mL, whereas a standard dose of 15 mL/kg FP would be administered in a 
volume of 1000 mL) [47]. Finally, PCCs contain standardised levels of coagulation factors 
and thus have a more predictable therapeutic effect than FP, whose coagulation factor 
concentrations vary depending on the characteristics of the donor [50, 51].
On the other hand, PCCs do not contain the full balanced complement of procoagulants 
and anticoagulants present in FP [52] and it is therefore conceivable that they might be 
less effective, although in vitro studies suggest that PCCs may be more effective than FP 
in enhancing thrombin generation after cardiac surgery [47]. Also, because PCCs contain 
more procoagulants than anticoagulants, they may carry a higher risk of thrombotic events, 
disseminated intravascular coagulation and acute kidney injury (AKI) when administered 
in high doses [48, 53-57]. However, the FARES pilot study in adult patients who required 
coagulation factor replacement for bleeding during cardiac surgery showed that the rates 


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of adverse events (AEs; 77.8% in PCC group versus 87.2% in FP group) and 
thromboembolic events (TEEs; 7.4% in PCC group versus 8.2% in FP group) were similar 
between patients receiving PCC or FP [58]. Other prospective studies, as well as 
retrospective studies and meta-analyses, have also reported comparable rates of AEs and 
TEEs between cardiac surgery patients treated with PCC or FP [59-66]. Furthermore, 
some of these studies in cardiac surgery patients, including a recent meta-analysis [64],
the PROPHESY pilot study (organ failure, including renal) [62] and the FARES pilot study 
[58], reported the risk of AKI with PCC to be similar to that with FP [61]. Outside of cardiac 
surgery, meta-analyses and Phase 3 studies have shown that PCC also has a favourable
safety profile and is well tolerated in patients requiring anticoagulant reversal, with rates of 
AEs and TEEs comparable with FP [38, 67-69]. 
Review of the Literature
Few guidelines exist on the use of PCC in acquired coagulopathies. The European Society 
of Anaesthesiology recommends goal-directed therapy with coagulation factor 
concentrates, including PCC, suggesting that their use may reduce transfusions during 
cardiac surgery [70], and the American Society of Anaesthesiologists suggests PCCs for 
excessive bleeding in the presence of elevated INR [71]. Joint guidelines from the 
European Association for Cardio-Thoracic Surgery and the European Association of 
Cardiothoracic Anaesthesiology recommend PCC or FP in patients with bleeding related 
to coagulation factor deficiency and suggest that PCC may be preferred over FP in 
situations where rapid normalisation of coagulation factors is needed [72]. However, there 
is little high-quality clinical evidence to support these recommendations: there are few 
direct comparisons of PCC versus FP for managing coagulopathy resulting from 
coagulation factor deficiency during cardiac surgery (or other types of surgery) and 
randomised controlled trials are limited to small, pilot studies [58, 62].
An observational study that compared outcomes for patients at Toronto General Hospital 
who received FP (n=1151), PCC (n=79) or both (n=125) for management of coagulopathy 
after cardiac surgery was carried out between 2012 and 2016 [61]. Using propensity score 
matching, 117 patients who received FP were matched with 117 patients with similar risk 
and surgery profiles who received PCC (with or without FP). The odds ratio (OR) for red 
cell transfusion avoidance was 2.4-fold (95% confidence interval [CI] 1.2–4.8) higher for 
patients receiving PCC. In addition, incidences of massive transfusion (OR 0.58; 95% CI 
0.33–1.0) and refractory bleeding (OR 0.49; 95% CI 0.24–1.03) tended to be lower in 
patients who received PCC. Results from this exploratory study suggest that PCC is 
potentially more efficacious than FP in avoiding transfusion, and AE profiles were similar 
between groups, suggesting a comparable safety profile. 
These results are similar to those from other observational studies. A recent systematic 
review identified 4 observational studies – including our study noted above [61] – 
comparing perioperative PCCs to FP in cardiac surgery [64]. The meta-analysis showed 
that PCCs were associated with reduced risk of RBC transfusion (OR 2.22; 95% CI 1.45–
3.40) and fewer units of RBCs transfused (OR 1.34; 95% CI 0.78–1.90). PCCs were not 
associated with increased hospital mortality (OR 0.94; 95% CI 0.59–1.49), stroke (OR 
0.80; 95% CI 0.41–1.56) or AKI occurrence (OR 0.80; 95% CI 0.58–1.12). In one of the 
studies in the systematic review, Arnekian and colleagues [59] compared three groups of 
cardiac surgical patients: 24 who received only PCC, 26 who received only FP and 27 who 
received both products. In an unadjusted analysis, they found that RBC transfusions 
occurred least frequently in the PCC group and most frequently in patients who received 
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both products. However, given the small sample size and lack of risk-adjusted analysis, 
few conclusions can be drawn from this study. In another study that included only patients 
who underwent pulmonary endarterectomy with cardiopulmonary bypass (CPB), Ortmann 
and colleagues [63] compared transfusion requirements and outcomes between 55 
patients who received only FP and 45 patients who received only PCC for management of 
post-CPB coagulopathic bleeding. In an unadjusted analysis, they found that the PCC 
group had lower blood loss than the FP group, but transfusion rates were similar. They 
conducted multivariable regression analysis for AEs and found no differences between the 
two groups. However, given its small sample size, limited generalisability and lack of risk-
adjustment for efficacy outcomes, this study should be interpreted with caution. In a larger 
study involving 3,454 consecutive cardiac surgery patients, Cappabianca and colleagues 
[73] used propensity scores to match 225 patients who received PCC (with or without FP)
to 225 patients who received only FP for management of post-CPB coagulopathy. Among
the propensity-score matched pairs, RBC transfusion requirements were lower in the PCC
group (84% versus 93%), as were multiple (more than two units) RBC transfusions (51%
versus 70%) and number of units of RBCs transfused (3.4 versus 5.2 units). While there
were no major between-group differences in adverse outcomes, in a regression analysis
that incorporated the propensity score in a larger patient series, the authors noted an
association between PCC use and AKI that led them to caution about this potential risk,
though the difference was not statistically significant among the 225 matched pairs.
Similarly, in a recent multicentre observational study not included in the above systematic
review, Biancari and colleagues compared 101 patients who received FP following
coronary artery bypass grafting (CABG) to 101 propensity-score-matched patients who
received PCC with or without FP [74]. PCC was associated with a significant decrease in
the rate of RBC transfusions (67.3% versus 83.2%) but was also associated with an
increased risk of AKI as measured by the Kidney Disease: Improving Global Outcomes
(KDIGO) score, though not with KDIGO AKI stage 3. The authors suggested that this could
be related to a relative hypovolemia in patients treated with PCC compared with those
receiving FP. However, there were many limitations to this study, including unknown
differences in PCC dosage, bleeding severity and coagulopathy. Furthermore, in the group
of patients that received both FP and PCC, it was not known what the order of
administration was and so PCC could have been given as salvage therapy [74]. Together,
these studies suggest that PCC may be more efficacious than FP in cardiac surgery;
however, data from adequately powered, prospective, randomised trials are lacking.
Pilot Randomised Studies
There are now two completed pilot randomised trials that have compared 4-factor PCC 
with FP [58, 62]. The study by Green et al. included 50 patients who underwent cardiac 
surgery and required coagulation factor replacement, with 25 randomised to 4-factor PCC 
and 25 randomised to FP [62]. IMP dose was limited to 1000 IU (approximately 15 IU/kg) 
for PCC and 4 units (approximately 15 mL/kg) for FP. The study aimed to assess 
recruitment rate for a large trial and hypothesis testing was not carried out, but safety and 
efficacy event rates were similar between the groups.
A randomised pilot trial (the FARES study) [58] was carried out at two hospitals for the 
purpose of exploring feasibility. The study randomised 101 adult patients who required
coagulation factor replacement for management of bleeding during cardiac surgery to 
Octaplex (N=54) or FP (N=47). IMP dosing was weight based: PCC dose was 1500 IU for 
and 4 U, respectively. Dosing could be repeated only once as needed within 24 hours; FP 
was used for any subsequent doses in both groups. Patients and outcome assessors were 


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blinded to treatment allocation, but no other aspects of care were modified. Both hospitals 
employed a validated point-of-care based coagulation management algorithm for bleeding 
patients. 
Overall, the PCC group received a median (IQR) of 24.9 (21.8–27.0) IU/kg of PCC [two 
patients (3.7%; 95% CI 0.4–12.7%) required FP after PCC], and the FP group received a 
median (IQR) of 12.5 (10.0–15.0) mL/kg of FP [four patients (8.5%; 95% CI 2.4–20.4%) 
required >2 doses of FP]. Median (IQR) 12-hour chest tube drainage was 310 (250–455) 
mL and 500 (310–750) mL in the PCC and FP groups, respectively (P<0.001). One of the 
primary measures of haemostatic effects was treatment response, based on receipt of any 
haemostatic therapies from 60 minutes to 4 and 24 hours after initiation of study treatment. 
Haemostatic therapy was not required at the 4-hour time point for 43 patients (79.6%) in 
the PCC group and 32 patients (68.1%) in the FP group (P=0.25), nor at the 24-hour time 
point for 41 patients (75.9%) in the PCC group and 31 patients (66.0%) in the FP group 
(P=0.28). Another primary outcome measure was cumulative and individual allogeneic 
blood component units administered within 24 hours after the start of surgery. Median 
(IQR) 24-hour post-bypass cumulative allogeneic transfusions, including red cells, 
platelets and all (IMP + non-IMP) FP were 5.0 (4.0–9.0) units in the PCC group and 12.0 
(7.0–19.0) in the FP group; ratio 0.56, 95% CI 0.43–0.73; P<0.001. Excluding IMP FP, the 
median (IQR) cumulative allogeneic transfusions were 5.0 (4.0–9.0) and 8.0 (4.0-15.0) 
units, respectively; ratio 0.78, 95% CI 0.58–1.06; P=0.11. For red cells alone, the median 
(IQR) was 1.0 (0.0–2.0) and 2.0 (1.0–3.0) units, respectively; ratio 0.53, 95% CI 0.36–0.78; 
P<0.001. Adverse event profiles were similar.
This pilot study showed that 4-factor PCC may be a suitable substitute for FP for mitigation 
of bleeding in cardiac surgery and validated the study methodology and dosing that will be 
used for the proposed trial. It also clearly illustrated that a large, multicentre, confirmatory 
trial is warranted to determine the relative risk-benefit profiles of these two therapeutics. 
Purpose of the Study
The purpose of the LEX-211 study is to determine whether the PCC, Octaplex, is clinically 
non-inferior to FP with respect to haemostatic effectiveness when used to treat bleeding 
in cardiac surgical patients requiring coagulation factor replacement. Haemostatic
management in bleeding surgical patients is evolving from empirical therapy with non-
purified allogeneic blood products to targeted therapy with purified products that have 
undergone treatment with pathogen reduction technologies [75]. The proposed study, by 
comparing two currently available but distinctly different therapies for treating bleeding 
surgical patients requiring coagulation factor replacement, is well aligned with this change. 
Given the potential advantages of PCC over FP detailed above (viral inactivation, ease of 
administration, standardised dosing/predictable effect and substantially lower risk of 
TRALI and TACO due to smaller volume), as well as the haemostatic superiority signals 
detected in observational studies and the recently completed FARES pilot randomised trial 
[58], a large multicentre trial adequately powered to establish haemostatic superiority or 
non-inferiority is warranted. The need for such a trial was highlighted in a recent editorial 
[76], as it will have a profound impact on clinical practice, potentially altering the long-
established practice of administering FP for coagulation factor replacement in bleeding 
patients. If the study is positive, it will lead to the adoption of PCC over FP as first-line 
therapy for the management of bleeding surgical patients requiring coagulation factor 
replacement. If it is negative, on the other hand, it will prevent the inappropriate adoption 


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of PCC over FP for this indication. Thus, the study will inform clinical practice and promote 
the rational use of healthcare resources.
Study Population
To ensure that the results of the study are clinically relevant and generalisable, the LEX-
211 study aims to include a wide spectrum of cardiac surgery patients (including simple or 
complex procedures and elective or non-elective procedures). In particular, two important,
interrelated risk factors for haemorrhage due to coagulation factor deficiency are complex
surgery and prolonged CPB duration. Complex surgeries include combined procedures
(e.g., CABG + valve or multiple valves) and surgery on the aorta, and these are the
procedures that also require prolonged CPB duration. Another equally important risk factor 
is non-elective surgery, as the risk of haemorrhage is substantially higher in patients who
require emergency cardiac surgery. Thus, it is important to include patients undergoing
complex or non-elective cardiac surgery in clinical
studies on
management
of
haemorrhage during cardiac surgery to ensure that the findings are clinically relevant and 
generalisable to this important population.
Therefore, the study will include adult patients undergoing any type of cardiac surgery
(excluding those undergoing highly specialised procedures where there is wide variability 
in clinical practice, such as heart transplantation) who require coagulation factor
replacement due to haemorrhage in the operating room, post-CPB. Given that patients 
undergoing isolated CABG are at low risk for haemorrhage, with approximately 2.5–7.5%
receiving coagulation factor replacement with FP [77], it is anticipated that the study will 
primarily include patients who develop haemorrhage after complex surgeries, non-elective 
surgery or both. Overall, cardiac surgery patients who require coagulation factor
replacement due to haemorrhage represent a small proportion of those undergoing cardiac
surgery. In the FARES pilot study, patients for whom coagulation factor replacement was
ordered during surgery for management of bleeding represented approximately 12% (169 
of 1360) of all adults who underwent cardiac surgery at the two study centres in Canada
during the study period [58].
Importantly, the study will not involve treating patients prophylactically before surgery as a
Cochrane review found no evidence to support the prophylactic administration of FP to
patients without coagulopathy undergoing elective cardiac surgery [30].
In the study, IMP will be administered if bleeding is severe enough to necessitate treatment
or require urgent therapy. The severity of bleeding will be graded according to the Bleeding
Severity Scale [78], which fulfils US Food and Drug Administration requirements for a
validated,
clinician-reported scale to standardise bleeding in clinical
studies of
intraoperative bleeding. The scale was developed to assess the performance of
haemostatic agents in clinical studies, in order to generate clinically relevant labelling 
claims and identify appropriate haemostatic agents for clinical use.
The study will be conducted in compliance with the protocol, International Conference on 
Harmonization Good Clinical Practice (ICH-GCP), and other regulatory requirements. 
1.2
Dose rationale
The doses of PCC and FP selected for the study are the same doses used for the pilot 
FARES study. There is an absence of a consensus regarding PCC dosing in acquired 
coagulation factor deficiency; however, the study dose of PCC represents current 
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recommended dosing for bleeding indications in various settings and is consistent with 
doses used in other studies in cardiac settings [27, 61, 79, 80]. Moreover, the maximum 
dose is equal to or lower than doses of PCC that have demonstrated a good safety and 
tolerability profile in other clinical settings (e.g., factor Xa inhibitor reversal in major 
bleeding [81-83] and trauma [84]. Of note, neither PCC nor FP will be administered to 
patients unless they are deemed to be clinically indicated by the ordering physician based 
on objective clinical criteria that will ensure adherence to best blood management 
practices. 
1.3
Benefit-Risk Statement
Substituting either PCC or FP for the other is not expected to pose any material risks to 
the participants. Patients will only be included in the trial when their clinicians have ordered 
coagulation factor replacement for treatment of bleeding according to clinical and 
laboratory criteria; thus, patients would have received one or the other therapy as part of 
their routine clinical care. The two coagulation factor replacement therapies, Octaplex (the 
PCC to be used in this study) and FP, are both commonly used therapies for this procedure 
in many regions, with an expected comparable clinical safety profile. Octaplex is currently 
approved for use in Canada (but not in the United States) for the “treatment of bleeding 
and perioperative prophylaxis of bleeding in acquired deficiency of prothrombin complex 
coagulation factors, such as deficiency caused by treatment with vitamin K antagonists, or 
in case of overdose of vitamin K antagonists, when rapid correction of the deficiency is 
required” [85]. This approved indication falls within the proposed use in this study. In 
contrast, in the United States, Octaplex is approved under the tradename Balfaxar for the 
urgent reversal of acquired coagulation factor deficiency induced by Vitamin K antagonist 
(VKA, e.g., warfarin) therapy in adult patients with need for an urgent surgery/invasive 
procedure.
The experience to date with this PCC has shown a favourable safety profile [81, 82, 86-
88]. As discussed, PCC is pathogen-reduced, can be administered quickly and in 
predictable doses, and has a substantially lower risk of TRALI and TACO compared with 
FP, making its administration likely to be both safer than, and at least as efficacious as, 
FP. It is possible that treatment with PCC may not be as effective as FP given that it does 
not contain the full complement of clotting factors that plasma contains, but the study 
protocol will allow patients in the PCC group to receive FP if haemostatic control is not 
achieved after two doses of PCC. By limiting maximal PCC dosing to well within acceptable 
limits that have been proven safe in other settings [81, 82, 86-88], theoretical risks for 
thrombotic complications have been mitigated.
1.4
COVID-19 Benefit-Risk Statement
Patients in the LEX-211 study will attend hospital for either emergency or scheduled 
elective cardiac surgery. The patients will not receive any additional contact with study 
staff beyond those required for undergoing the surgical procedure. The final postoperative 
visit will be carried out by phone unless the patient is currently in hospital, in order to reduce 
contact between the patient and healthcare staff. All surgeries will be carried out using 
standard safety measures in place at the treatment centres in line with local requirements 
for COVID-19 risk management. The study therefore does not place patients at any 
additional risk, since emergency surgical procedures must take place immediately, and 
elective cardiac surgery likewise cannot be postponed for long periods of time and 
therefore would go ahead even during the COVID-19 pandemic. 


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Potential COVID-19 related risks for site and project management will be evaluated in 
advance and options such as alternative monitoring approaches will be implemented. In 
addition, for the support of the study processes (e.g., provision of the study medication), 
only well-established service providers are selected which have strong regional expertise 
and strict risk and quality guidelines in place, including with regards to potential COVID-
19-related risks. The current regulations regarding transport and logistics will be
continuously monitored for the countries participating in the study, and flexible solutions
and longer lead times will be implemented wherever appropriate.


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2 
STUDY OBJECTIVES 
2.1
Primary Objective
1. To demonstrate that the 4-factor prothrombin complex concentrate (PCC) Octaplex
is clinically non-inferior to frozen plasma (FP) with respect to haemostatic
effectiveness, as measured by the need for post-therapy haemostatic interventions.
2.2
Secondary Objectives
1. To compare global haemostatic response between the Octaplex and FP groups, as
measured by a composite of the need for post-therapy haemostatic interventions
and drop in haemoglobin.
2. To compare the amount of bleeding as measured by the amount of chest tube
drainage between the Octaplex and FP groups.
3. To compare the incidence of severe to massive bleeding between the Octaplex and
FP groups.
4. To compare efficacy in terms of the total number of allogeneic blood components
transfused between the Octaplex and FP groups.
5. To compare efficacy in terms of the incidence and number of individual allogeneic
blood components transfused between the Octaplex and FP groups.
6. To compare the incidence of use of other coagulation factor products between the
Octaplex and FP groups.
7. To compare the incidence of other bleeding-related clinical endpoints, i.e.,
intracerebral haemorrhage, gastrointestinal haemorrhage
and surgical re-
exploration, between the Octaplex and FP groups.
8. To compare the effect of Octaplex versus FP administration on the international
normalised ratio (INR) between the Octaplex and FP groups.
9. To compare the effect of Octaplex versus FP administration on other coagulation
parameters.
10. To compare time from IMP initiation to arrival in the ICU between the Octaplex and
FP groups.
11. To compare safety as measured by serious treatment-emergent adverse events
(TEAEs) between the Octaplex and FP groups.
12. To compare other secondary safety endpoints including duration of mechanical
ventilation, duration of intensive care unit (ICU) stay, duration of hospitalisation,
incidence of death and days alive and out of hospital between the Octaplex and FP
groups.


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3
INVESTIGATIONAL PLAN
3.1
Primary and Secondary Endpoints
3.1.1
Primary Endpoint 
1. Comparison of haemostatic treatment response to Octaplex versus FP, defined as
‘effective’ if no additional haemostatic intervention, such as administration of any
systemic haemostatic agents (including platelets, cryoprecipitate, fibrinogen
concentrate, activated recombinant factor VII, other coagulation factor products or
a second dose of IMP) or any haemostatic interventions (including surgical re-
opening for bleeding) is required from 60 minutes to 24 hours after initiation of the
first dose of IMP.
3.1.2
Secondary Endpoints
1. Comparison of global haemostatic response to Octaplex versus FP, defined as
‘positive’ if no additional haemostatic intervention (as per the primary endpoint) is
required and haemoglobin levels decrease by <30% (after accounting for red cell
transfusions) from 60 minutes to 24 hours after initiation of the first dose of IMP.
2. Comparison of the total amount of chest tube drainage at 12 and 24 hours after
chest closure between the Octaplex and FP groups.
3. Comparison of the incidence of severe to massive bleeding, using a modification of
the universal definition of perioperative bleeding (UDPB) in cardiac surgery [89] and
its individual components during the first 24 hours after start of surgery, after the
end of CPB and after IMP initiation, between the Octaplex and FP groups.
4. Comparison of the mean number of total allogeneic blood components – including
red cells, platelets and all (IMP and non-IMP) FP – administered during the first 24
hours after the end of CPB, between the Octaplex and FP groups.
5. Comparison of the mean number of total non-IMP allogeneic blood components –
including red cells, platelets and non-IMP FP – administered during the first 24
hours after the end of CPB, between the Octaplex and FP groups.
6. Comparison of the mean number of total non-IMP allogeneic blood components –
including red cells, platelets, cryoprecipitate and non-IMP FP – administered during
the first 24 hours and 7 days after IMP initiation, between the Octaplex and FP
groups.
7. Comparison of the mean number of individual allogeneic blood components –
including red cells, platelets, cryoprecipitate and non-IMP FP – administered during
the first 24 hours and 7 days after the start of surgery, after the end of CPB and
after IMP initiation, between the Octaplex and FP groups.
8. Comparison of the incidence of transfusion of individual allogeneic blood
components – including red cells, platelets, cryoprecipitate and non-IMP FP –
during the first 24 hours and 7 days after the start of surgery, after the end of CPB
and after IMP initiation, between the Octaplex and FP group.
9. Comparison of the incidence of administration of non-IMP coagulation factor
products – including fibrinogen concentrate and activated recombinant factor VII –


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during the first 24 hours and 7 days after the start of surgery, after the end of CPB 
and after IMP initiation, between the Octaplex and FP groups.
10. Comparison of the incidence of intracerebral haemorrhage during the first 24 hours
after start of surgery, after the end of CPB and after IMP initiation between the
Octaplex and FP groups.
11. Comparison of the incidence of gastrointestinal haemorrhage during the first 24
hours after start of surgery, after the end of CPB and after IMP initiation between
the Octaplex and FP groups.
12. Comparison of the incidence of surgical re-exploration during the first 24 hours after
start of surgery, after the end of CPB and after IMP initiation between the Octaplex
and FP groups.
13. Comparison of the change in INR, from within 30 minutes before to within 60
minutes after the initiation of IMP administration, between the Octaplex and FP
groups; INR reduction will be considered successful if the magnitude of the
reduction is >1.0 or the post-treatment level drops below 1.5.
14. Comparison of the changes in other coagulation parameters, including PT, aPTT,
fibrinogen activity, ROTEM EXTEM CT and MCF, ROTEM FIBTEM MCF and
platelets, from within 75 minutes before to within 75 minutes after the initiation of
IMP administration, between the Octaplex and FP groups.
15. Comparison of time elapsed from initiation of the first dose of IMP to arrival into the
ICU between the Octaplex and FP groups.
3.1.3
Safety Endpoints
All AEs and serious AEs (SAEs) will be collected from beginning of surgery (defined as 
entry into OR) to POD-30.
1. Comparison of the incidence of serious treatment-emergent adverse events
(TEAEs), individually and as composite where appropriate (e.g., TEEs, major
adverse cardiac events), between the Octaplex and FP groups.
2. Comparison of the duration of mechanical ventilation (measured as duration of
ventilation and ventilator-free days) up to POD-30 between the Octaplex and FP
groups.
3. Comparison of the duration of ICU stay up to POD-30 between the Octaplex and
FP groups.
4. Comparison of the duration of hospitalisation up to POD-30 between the Octaplex
and FP groups.
5. Comparison of the incidence of death up to POD-30 between the Octaplex and FP
groups.
6. Comparison of the number of days alive and out of hospital at POD-30 between the
Octaplex and FP groups.
3.2 Overall Study Design and Plan 
This is a multicentre, randomised, active-control, prospective, Phase 3 study in adult 
cardiac surgery patients. Approximately 500 patients will be randomised at approximately 
12 hospitals (10 in Canada and two in the United States), and the study will require 


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approximately two years to complete. The study is planned to start in quarter 4, 2022 and 
to be completed in quarter 4, 2024.
The study will include adult ( 18 years old) patients who undergo cardiac surgery on CPB 
and require coagulation factor replacement due to bleeding post-CPB and after adequate 
reversal of heparin with protamine (as assessed by the surgical staff based on clinical and 
laboratory criteria) during surgery, and who have a known (e.g., as indicated by INR) or 
suspected coagulation factor deficiency. Patients will be randomised to receive either 
4-factor PCC (Octaplex) or FP when the blood bank/pharmacy receives the first order for
coagulation factor replacement and determines patient eligibility with the study team based
on the study inclusion and exclusion criteria.
Following confirmation of eligibility, the technologist will randomise the patient to PCC or 
FP according to the randomisation and dosing schedule and prepare and release the IMP 
in a tamper sealed container. Operating room personnel will remain blinded until the 
decision to administer the IMP is made.
IMP can be administered if bleeding is severe enough to necessitate IMP (meaning at least 
a grade 2 level [moderate] bleeding according to the validated Bleeding Severity Scale 
[78]), heparin is adequately reversed (confirmed by the return of post-protamine activated 
clotting time [ACT] to within 10% of pre-pump ACT)
administered if bleeding is severe enough to require urgent therapy, in which case 
treatment can be initiated irrespective of the INR value. Once the decision is made to 
administer the IMP, the administering clinician will break the seal on the container, carry 
out routine safety checks and initiate IMP administration according to the weight-based 
dosing recommendations.
The recommended initial dose for Octaplex will be 1500 IU for patients weighing 
and 2000 IU for patients weighing >60 kg. The recommended initial dose for FP will be 3
U for patients weighing 
 kg and 4 U for patients weighing >60 kg. 
A second dose of IMP can be administered if the patient continues to have at least
moderate bleeding and suspected coagulation deficiency (e.g., INR 
) after completion 
of the first dose. If an order for a second dose of coagulation factors is received within 24 
hours after IMP initiation (either from the operating room or in the ICU after surgery), the 
blood bank/pharmacy
technologist will release the IMP as determined by the 
randomisation schedule up to the maximum allowable dose (Octaplex
-sealed container will not be 
used for these orders as clinicians will by now be unblinded).
If further doses of coagulation factors are required after the second dose of IMP, all 
patients will receive non-IMP FP. That is, for subsequent orders once the maximum dose 
of IMP has been administered (i.e., 2 doses), or after the 24-hour treatment period has 
elapsed, the technologist will release FP for both groups (in 1–4 U increments as per the 
ordering physician); these additional FP units will not be counted as part of the IMP (Figure 
1). 
Transfusion of non-IMP blood components and all haemostatic agents will be according to 
a standardised transfusion management algorithm (Figure 2). Measurements of INR and 
haemoglobin will be performed at preestablished time points, if not available already. No 
other aspects of routine clinical care will be modified.


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Figure 1: Study Flow
1 FP in 1U increments as per the ordering physician
PCC, prothrombin complex concentrate; FP, frozen plasma; BW, body weight; IU, international units;
3.3
Discussion of Study Design and Choice of Control Group
3.3.1
Study Design
3.3.1.1 Criteria for Administration of IMP
The decision to administer the IMP will be based on objective clinical and laboratory criteria 
(Section 6). Incorporating these criteria in the study will standardise administration of IMP 
such that it is administered when clinically indicated. 
3.3.1.2 Transfusion Protocol Standardisation
All participating hospitals will be required to follow an established transfusion management 
protocol for administration of non-IMP blood components and all haemostatic agents. 
Recognising that the intervention will occur during a very dynamic period (i.e., bleeding 
during surgery); however, the study employs a pragmatic design that will allow clinicians 


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to use best judgment within the context of the transfusion protocol. This will allow the 
surgical team flexibility while maintaining clinical practice standardisation that conforms to
best clinical practices. This is important since other multicentre studies that have included 
a very strict design so far have failed when studied in later phase trials because of the 
inability of the sites to accurately follow the specified design, which itself has been criticised 
for not being consistent with usual clinical practice. 
3.3.1.3 External Validity
This Phase 3 study will be performed in multiple hospitals with different characteristics. 
Moreover, patients will be randomised after the clinical team orders coagulation factor 
replacement and the only change to routine practice is dictating the choice of coagulation 
factor replacement amongst the two therapies that are currently available and used 
interchangeably. For these reasons, external validity should not be an issue. 
3.3.1.4 Randomisation and Baseline Differences
Given the size of the study and random patient assignment stratified by centre, study 
groups should be reasonably balanced with respect to important clinical variables. The 
random allocation schedule will be prepared by a biostatistician not involved in the conduct 
of the trial, and neither the individual randomising nor any of the health care providers will 
know which treatment will be assigned to the patient when coagulation factor replacement 
is ordered.
3.3.1.5 Recruitment and Informed Consent
This is a pragmatic trial that compares two coagulation factor replacement therapies that 
are currently routinely used for the study indication in multiple regions globally and in 
various settings. It is not expected that participating in the trial will pose any risks to 
patients. 
All patients 
undergoing cardiac surgery with CPB at the study centres will
be offered the chance to participate in the study prior to their surgery. Voluntarily given, 
written, informed consent will be obtained from the patient before the study procedures 
start. Once consent has been obtained and the patient enrolled into the study, eligibility 
according to inclusion criteria 1 and 4 
years old, undergoing any index 
cardiac surgery employing CPB, who have provided informed consent) and the exclusion 
criteria will be confirmed. If screening is performed before the day of surgery, exclusion 
criterion 3 (i.e., severe right heart failure [clinical diagnosis ± echocardiography]) will be 
rechecked on the day of surgery2. 
Only patients who require coagulation factor replacement therapy during surgery will be 
randomised, receive study drug, and undergo the proceeding visits and assessments.
When the first order for PCC or FP is received by the blood bank/pharmacy while the 
patient is in the operating room, the blood bank/pharmacy technologist will confirm patient 
eligibility with the clinical team. Following confirmation of eligibility, the technologist will 
randomise the patient to PCC or FP according to the randomisation and dosing schedule.
2In Canada, informed consent will be obtained after randomisation, in accordance with Article 3.7A of 
the 2018 Tri-Council Policy Statement on the Ethical Conduct for Research Involving Humans.


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Randomisation (1:1) will continue until at least 410 evaluable patients are obtained (205 
patients per group).
3.3.1.6 Blinding
Given that the products have quite different physical properties, it is not possible to blind 
treating clinicians to group assignment. To minimise bias, treating clinicians will be blinded 
to group assignment until immediately prior to IMP infusion. The blood bank/pharmacy
technologist will randomise the patient to PCC or FP, according to the randomisation
schedule, and prepare and release the product in a tamper sealed container (with weight 
device in PCC boxes to ensure adequate concealment). The operating room personnel 
will be blinded to group allocation until the tamper lock seal is broken in the operating room 
immediately prior to infusion. For subsequent orders, a tamper-sealed container will not 
be necessary, and the blood bank/pharmacy technologist will release IMP as determined 
by the randomisation schedule, as per usual practice. The type of IMP administered will 
be recorded in manner that will not unblind the outcome assessor.
Patients will also be 
unaware of treatment allocation. These same processes were successful in the pilot study 
noted above.
3.3.1.7 Drop-outs and Crossovers
Drop-outs: Based on the results of the FARES pilot study, it is anticipated that 
approximately 20% of randomised patients will not receive the IMP due to cessation of 
bleeding or identification of other causes of bleeding by the time the IMP is received in the 
operating room. (Significant dropouts are not anticipated for any other reasons, including 
not having undergone an index cardiac procedure.) Since clinicians will be blinded to group 
assignment until the decision is made to administer the IMP, and the decision to administer 
the IMP will be based on objective criteria, exclusion of these randomised but untreated 
patients from the primary analysis set will not bias the results. Study sample size has been 
calculated to compensate for dropouts. To ensure between-group comparability in 
baseline characteristics and outcomes, data will be collected for these patients for 30 days
after surgery.
Product switching: Other than the coagulation factor replacement order being cancelled, 
all patients will be treated according to the randomisation schedule up to the maximum 
allowable dose during the treatment period (24 hours after IMP initiation). Thereafter, all 
patients will receive non-IMP FP when coagulation factor replacement is required. To 
ensure minimal product switching, instructions will be entered into the blood 
bank/pharmacy information system to dictate the randomisation product for the 24 hours 
after IMP initiation and will flag the laboratory technologists if attempts are made to override 
the instruction. In the FARES pilot trial, all treated patients received the appropriate IMP; 
thus, product switching is not anticipated to be a significant problem.
3.3.1.8  Independent Data and Safety Monitoring Committee (IDSMC)
An IDSMC will review accumulating safety, endpoint and other study data (recruitment, 
retention and compliance, data quality and timeliness, risk versus benefit).
The function of the IDSMC will be to protect and serve the recruited patients particularly 
pertaining to patient safety as well as to assist and advise the Sponsor on medical 
questions and issues of study conduct and continuation. The IDSMC will be independent 
of the investigating team and the Sponsor in operating and formulating recommendations. 


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The responsibilities of the IDSMC are listed in Section 8.6.The full role of the IDSMC will 
be detailed in the IDSMC Charter.
3.3.2
Control Group
The trial will not include a placebo arm because delaying coagulation factor replacement 
in bleeding patients may expose them to the negative consequences of excessive blood 
loss, is not consistent with standard practice [90] and would withhold an effective treatment 
from patients and thus be unethical. Moreover, the question being addressed does not 
meet any of Freedman’s five conditions that would justify the use of a placebo control, 
which are: 1) no standard treatment exists; 2) standard treatment is not better than 
placebo; 3) standard treatment is a placebo or no treatment; 4) new evidence has shown 
uncertainty of the risk-benefit profile of the standard treatment; and 5) effective treatment 
is not readily available due to cost or supply issues [91]. 
3.3.3 Study Parameters
A dichotomous classification of haemostatic effectiveness will be used to assess treatment 
response to PCC or FP in bleeding adult cardiac surgical patients. Treatment will be 
considered ‘effective’ if no additional haemostatic intervention is required in the time 
window from 60 minutes to 24 hours after initiation of the first IMP dose. The 60-minute 
time period will allow for the administration of the IMP and establishment of treatment 
effect. Patients will be assigned a haemostatic treatment response classification of 
‘ineffective’ if their management required haemostatic interventions during the time window 
from 60 minutes to 24 hours after initiation of the first IMP dose. 
Haemostatic intervention includes the administration of any systemic haemostatic agents 
(including platelets, cryoprecipitate, fibrinogen concentrate, activated factor VII, other 
coagulation factor products, or a second dose of IMP) or any haemostatic interventions 
(including surgical re-opening for bleeding). Because of the complexity and dynamic nature 
of cardiac surgery, as well as the multifactorial nature of haemorrhage during cardiac 
surgery, it is inherently not feasible to assess the specific haemostatic response to 
individual therapeutic agents.
The following secondary endpoints will be included to provide supportive evidence of 
haemostatic efficacy: global haemostatic response, INR reduction, the incidence and 
amount of individual allogeneic blood components transfused and the incidence of other 
bleeding-related clinical endpoints.
Global haemostatic response will be based on the haemostatic efficacy scale used 
successfully in a Phase 3b RCT by Sarode and colleagues [69] (in discussion with the 
Food and Drug Administration), modified to reflect the special considerations of 
haemorrhage during cardiac surgery.


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4 
STUDY POPULATION 
4.1
Population Base
The study will include approximately 500 randomised bleeding adult ( 18 years old) 
cardiac surgical patients who require coagulation factor replacement after CPB. The study 
will continue until there are at least 410 evaluable patients, accounting for dropouts in both 
arms, with a minimum of 205 patients assigned to each of the two treatment groups.
4.1.1
Inclusion Criteria
Patients undergoing the following criteria will be eligible for inclusion in the study:
1. Adult ( 18 years old) patients undergoing any index cardiac surgery employing
CPB
2. Coagulation factor replacement with PCC or FP ordered in the operating room for:
a. Management of bleeding, or
b. Anticipated bleeding in a patient who has been on-pump for >2 hours or
undergone a complex procedure (e.g., aortocoronary bypass [ACB] plus
aortic valve replacement)
3. Coagulation factor deficiency, either known to exist (e.g., as indicated by elevated
EXTEM clotting time [CT] or INR) or suspected based on the clinical situation
4. Patients who have given written informed consent3
4.1.2
Exclusion Criteria  
Patients who meet any of the following criteria are not eligible for the study:
1. Undergoing heart transplantation, insertion or removal of ventricular assist devices
(not including intra-aortic balloon pump [IABP]) or repair of thoracoabdominal
aneurysm
2. Critical state immediately before surgery with high probability of death within 24
hours of surgery (e.g., acute aortic dissection, cardiac arrest 24 hours before
surgery)
3. Severe right heart failure (clinical diagnosis ± echocardiography)
4. Known contraindications to heparin
5. PCC required for reversal of warfarin or direct oral anticoagulant (DOAC;
dabigatran, rivaroxaban, apixaban or edoxaban) within 3 days prior to or during
surgery
6. Known TEE within 3 months prior to surgery
7. History of severe allergic reactions to PCC or FP
8. Individuals who have IgA deficiency with known antibodies against IgA
9. Refusal of allogeneic blood products
3 In Canada, informed consent will be obtained after randomisation, in accordance with Article 3.7A of 
the 2018 Tri-Council Policy Statement on the Ethical Conduct for Research Involving Humans.


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10.Known pregnancy
11.Currently enrolled in any other interventional clinical trials
4.2
Prior and Concomitant Therapy
Details on medications taken within 1 week before enrolment and concomitant medications 
taken during the study (excluding drugs given for routine anaesthesia) will be recorded in 
the case report form (CRF).
4.2.1
Permitted Concomitant Therapy
Participating hospitals will use a standardised point-of-care based transfusion algorithm 
that will employ a targeted approach to correct coagulopathy (as per the validated TACS 
algorithm) [79], but with selection of PCC or FP determined according to the patient’s 
assigned grouping and using the doses described in Section 5.4.
Concomitant administration of any therapies required as part of standard patient care is 
permitted but must be recorded in the CRFs. All haemostatic drugs or products 
administered (e.g., heparin and protamine dose, antifibrinolytic drugs, desmopressin, 
rFVIIa, idarucizumab, andexanet alpha or topical haemostatic agents) will be recorded, as 
well as all procedures that may influence amount of bleeding (e.g., retrograde autologous 
priming of CPB circuit, cell salvage). In addition, concomitant medications used to treat 
SAEs will be reported throughout the duration of follow-up (up to POD-30).
4.2.2
Forbidden Concomitant Therapy
No concomitant therapies are forbidden. 
4.3
Withdrawal and Replacement of Patients
4.3.1
Premature Subject/Patient Withdrawal
Patients have the right to withdraw from the study at any time for any reason, without the 
need to justify their decision. The Investigator also has the right to withdraw patients for 
reasons such as intervention no longer indicated due to cessation of bleeding, 
randomisation of ineligible patients and adverse events attributed to previous doses of 
IMP. For any withdrawals after study entry, the Investigator will obtain all the required 
details and document the reason(s) for discontinuation, and report to the IDSMC and 
institutional review board (IRB) where indicated. If the reason for withdrawal of a patient is 
an AE, the main specific event or laboratory test will be recorded, and the Investigator will 
make thorough efforts to clearly document outcomes up to the time of withdrawal of 
participation.
4.3.2
Subject/Patient Replacement Policy
Patients withdrawn from the study for safety reasons will not be replaced.
4.4
Assignment of Patients to Treatment Groups
Patients will be assigned to treatment with either PCC or FP using a permuted-block, 
stratified (by centre) random allocation scheme prepared by a biostatistician not involved 
in the conduct of the trial. Group allocation will apply to the first two doses of IMP during 
the treatment period (up to 24 hours from IMP initiation). For any additional doses (i.e., the 


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third dose and thereafter), patients in both groups will receive FP. Patients are not 
permitted to re-enrol in the study.
4.5
Relevant Protocol Deviations
Classification of protocol deviations as minor and major will be defined a priori. Patients 
with major protocol deviations will be excluded from the per-protocol analyses. The 
Sponsor and IDSMC will review the number and nature of major protocol deviations and 
take appropriate measures to minimise the impact on the study.
4.6
Subsequent Therapy
Any subsequent haemostatic therapy will be according to institutional standard of care. 


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5 
INVESTIGATIONAL MEDICINAL PRODUCT(S) 
5.1
Characterisation of Investigational Product(s)
5.1.1
Octaplex
Octaplex is a product derived from human plasma containing the coagulation factors II, 
VII, IX and X and proteins C and S. It is manufactured by chromatographic purification of 
cryoprecipitate-poor plasma.
The Octaplex manufacturing process includes two dedicated virus inactivation/removal 
steps, by way of a solvent/detergent viral inactivation process and a virus removal 
nanofiltration step. The solvent/detergent treatment causes enveloped viruses such as 
pseudorabies virus (PRV), Schmallenberg virus (SBV) and human immunodeficiency virus 
(HIV) type 1 to be irreversibly destroyed. Nanofiltration removal of infectious agents from 
protein solutions on the basis of their size may be the only method to date permitting 
efficient removal of enveloped (e.g., HIV-1, SBV, PRV, bovine viral diarrhoea virus) and 
non-enveloped viruses (e.g., hepatitis A virus) under conditions where 90–95% of protein 
activity is recovered [92]. Other precautions against viral transmission include: selection of 
plasma donors, screening of donations and plasma pool, as well as quality control 
measurements of the final product.
5.1.1.1 Composition of Octaplex
Octaplex is a human PCC for intravenous (IV) use. The composition of Octaplex is 
described in the current edition of the IB. Differences in composition may exist between 
countries; please refer to the country-specific Summary of Product Characteristics (SmPC) 
and Package Insert (PI). 
5.1.2
Frozen plasma
For patients randomised to FP, the blood bank/pharmacy will assign to the study, prepare
and release FP for the first and second orders received during the treatment period (24 
hours after IMP initiation). The recommended dose for FP will be 3 U for patients weighing 
and 4 U for patients weighing >60 kg.  While there is no maximum dose for FP, 
up to 8 U for patients weighing >60 kg will be counted as part of the IMP.
FP will be provided by local supplier of blood components and will be stored, thawed and 
pooled by the blood bank/pharmacy according to current standards. FP will be infused as 
per standard hospital protocols at the participating institutions (i.e., infused using timing 
recommended in the current monograph through standard 140 µm blood infusing set).
5.2
Packaging and Labelling
Octaplex 500 IU and 1000 IU will be used in this study. Octaplex is supplied as a powder 
for solution for injection together with a solvent (20 mL or 40 mL Water for Injection, 
respectively), which should be used for the reconstitution. The batch number(s) used will 
be recorded in the Clinical Study Report. Octaplex will be labelled and packed as IMP 
according to the local regulations.


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Final labelling will comply with the national requirements of the respective countries, 
Canada and the United States, where the study is to be conducted.
5.3
Conditions for Storage and Use
Octaplex must be stored at room temperature (not more than 25°C) and protected from 
light. The product must not be frozen. The Investigator/authorised personnel at the site will 
ensure that Octaplex is stored in appropriate conditions with restricted access and in 
compliance with national regulations.
FP is to be stored at the blood bank/pharmacy in line with the local standard practice.
5.4
Dose and Dosing Schedule
For patients randomised to Octaplex, the blood bank/pharmacy will prepare and release
either 1500 or 2000 IU of Octaplex for the first and second orders received during the 
treatment period (24 hours after IMP initiation). The recommended dose for Octaplex will 
be 1500 IU for patients weighing 
and 2000 IU for patients weighing >60 kg. The 
maximum dose of Octaplex will be 4000 IU. If requests for additional doses are received 
during the treatment period or at any time thereafter, FP will be used, which will not be 
counted as part of the IMP.
5.5
Preparation and Method of Administration
Each vial of Octaplex will be reconstituted with 20 mL or 40 mL WFI (as per the 
manufacturer’s instructions) at room temperature (not more than 25°C). Octaplex
dissolves at room temperature to an almost colourless and slightly opalescent solution 
within 10 minutes. It will not be used if it remains cloudy or contains particulates. 
Octaplex
will be administered intravenously, immediately after reconstitution as 
recommended, via free-flowing IV syringe injection. Octaplex should not be mixed with 
other medicinal products or crystalloid intravenous solutions.
FP will be thawed and administered according to the local standard.
5.6
Blinding, Emergency Envelopes and Breaking the Study Blind
This is a partially blinded randomised study, with patients and outcome assessors blinded 
to treatment allocation. Given the physical differences in the products and the emergency 
nature of the intervention, attending clinicians will not be blinded to the treatment. Thus, 
breaking the study blind is not an issue in this study.
The random allocation schedule will be prepared by a biostatistician not involved in the 
conduct of the trial (see Section 9.3). To minimise bias, neither the individual randomising 
nor any of the health care providers will know which treatment will be assigned to a given 
patient when coagulation factor replacement is ordered. Blood products will be transported 
to the OR in weighted temper-proof boxes to maintain the blind until IMP infusion.
The type of IMP administered will be recorded in a manner that will not unblind the outcome 
assessor. Patients will also be blinded to treatment allocation.


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5.7
Treatment Compliance
5.7.1
Drug Dispensing and Accountability
A drug dispensing log and the inventory will be kept current by the Investigator, detailing 
the dates and quantities of Octaplex administered to each patient. The inventory and the 
drug dispensing log will be available to the monitor to verify drug accountability during the 
study. Used or partially used vials are to be destroyed at the site. Any unused Octaplex
either not dispensed or returned from the operating room or the ICU will be accounted for.
After the Sponsor has granted written approval of destruction, these can be destroyed 
either at the study site or returned to the depot for destruction. Destruction can be initiated 
only after accountability has been verified and fully reconciled by the monitor.
FP assigned to the study and dispensed accordingly will be tracked in an IMP FP 
dispensing log which will be available to the monitor to verify drug accountability during the 
study. FP returned unused from the operating room or the ICU will be handled according 
to the local practice.
5.7.2
Assessment of Treatment Compliance
Coagulation factor replacement will be ordered and administered by the clinical team in 
the hospital and will not be dependent on patient compliance. Treatment compliance for 
each patient will be based on calculating the ratio of total IMP administered to scheduled 
amount of IMP, expressed as a percentage.  


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6 
STUDY CONDUCT 
All patients 
undergoing cardiac surgery with CPB at the study centres will
be the potential patients in the study. Voluntarily given, written, informed consent will be 
obtained from the patient. Once consent has been obtained and the patients enrolled into 
the study, eligibility according to inclusion criteria 1 and 4 
undergoing any index cardiac surgery employing CPB, who have provided informed 
consent) and the exclusion criteria will be determined. If screening is performed before the 
day of surgery, exclusion criterion 3 (i.e., severe right heart failure [clinical diagnosis ± 
echocardiography]) will be rechecked on the day of surgery.
Only patients who require coagulation factor replacement therapy during surgery will be 
randomised, receive study drug, and undergo the proceeding visits and assessments.
When the first order for PCC or FP is received by the blood bank/pharmacy while the 
patient is in the operating room, the blood bank/pharmacy technologist will confirm patient 
eligibility with the clinical team. Following confirmation of eligibility, the technologist will 
randomise the patient to PCC or FP according to the randomisation and dosing schedule 
and prepare and release the IMP in a tamper sealed container (with weight device in PCC 
containing boxes to ensure adequate concealment). Operating room personnel will remain 
blinded until the decision to administer the IMP is made.
IMP can be administered if bleeding is severe enough to necessitate IMP (meaning at least 
a grade 2 level [moderate] bleeding according to the validated Bleeding Severity Scale 
[78] – see Appendix 1), heparin is adequately reversed (confirmed by the return of post-
protamine ACT to within 10% of pre-pump ACT)
Signature Elite; Instrumentation Laboratory). IMP can also be administered if bleeding is
severe enough to require urgent therapy, in which case treatment can be initiated
irrespective of the INR value. Once the decision is made to administer the IMP, the
administering clinician will break the seal on the container, carry out routine safety checks,
and initiate IMP administration according to the weight-based dosing recommendations:
For Octaplex
Octaplex and FP will be administered intravenously. For the first ordered dose, the blood 
bank/pharmacy will prepare and release either Octaplex or FP, as per the randomised
group allocation. The recommended dose for Octaplex will be 1500 IU for patients 
weighing 
and 2000 IU for patients weighing >60 kg. The recommended dose for 
FP will be 3 U for patients weighing 
and 4 U for patients weighing >60 kg.   
A second dose of IMP can be administered if the patient continues to have at least 
moderate bleeding and a suspected coagulation deficiency (e.g.
) after 
completion of the first dose. If this second order of coagulation factors is received within 
24 hours after IMP initiation (either from the operating room or in the ICU after surgery), 
the blood bank/pharmacy technologist will release the IMP as determined by the 
randomisation schedule up to the maximum allowable dose, as per usual practice (a 
tamper-sealed container will not be used for these orders as clinicians will by now be 
unblinded). The maximum allowable dose of IMP will be: Octaplex 3000 IU 
If further doses of coagulation factors are required after two doses of IMP, all patients will 
receive non-IMP FP. That is, for subsequent orders once the maximum dose of IMP has 
been administered (i.e., two doses), or after the 24-hour treatment period has elapsed, the 
technologist will release FP (in 1–4 U increments as per the ordering physician) for both 
groups, but these will not be counted as part of the IMP (Figure 1). To maintain blinding 


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6.1
Observations by Visit
6.1.1
Screening visit (maximum 28 days before surgery)
At the screening assessment, voluntarily given, written (signed and dated) informed 
consent will be obtained from the patient. 
Eligibility according to inclusion criteria 1 and 4 
any index cardiac surgery employing CPB, who have provided informed consent) and the 
exclusion criteria will be confirmed. If screening is performed before the day of surgery, 
exclusion criterion 3 (i.e., severe right heart failure [clinical diagnosis ± echocardiography]) 
will be rechecked on the day of surgery.
The following visits will only be performed for patients who bleed and require coagulation 
factor replacement therapy during surgery
6.1.2
Visit 1 (POD 0 pre-randomization): Pre-randomisation visit (blood 
bank/pharmacy) 
First coagulation factor replacement order from the surgical team received at the 
blood bank/pharmacy
Surgical staff will confirm protocol criteria before the blood bank/pharmacy order is made.
Surgical staff will record the patient’s body weight.
The blood bank/pharmacy technologist will confirm and document the following:
All eligibility criteria are met
The blood bank/pharmacy technologist will then randomise patients to Octaplex or FP 
according to the randomisation schedule and prepare and release the product.
Note; if subsequent coagulation factor replacement orders are made within 24 hours from 
IMP initiation, the blood bank/pharmacy technologist will confirm and document that all 
contents of the order have been administered.
6.1.3
Visit 2 (POD 0 post-randomization and POD 1): First visit after IMP initiation 
(0 to 24 hours after IMP initiation)
For any specified activity that cannot be completed during the first visit after IMP initiation, 
additional visits will be made on postoperative day 1 until all study data are obtained.
Collect baseline data
o
Demographics (sex, age, height and Body Mass Index [BMI])
o
Medical history
o
Preoperative concomitant medications
o
Laboratory assessments where available as part of routine care
Clinical chemistry (sodium, potassium, chloride, bicarbonate, pH)
Haematology (complete blood count)


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Safety laboratory analyses if available (creatinine, liver function tests
[ALT, ALP], bilirubin, troponin)
Administer first dose of IMP
Collect surgical data
o
Intraoperative concomitant medications
o
CPB start and end times
o
Cross-clamp time
o
Circulatory arrest start and end times
o
Fluid intake and output monitoring
o
Inotropes and vasopressors
o
Start and end time of IMP administration
o
Length of stay in the OR
Collect laboratory assessments where available as part of routine care
o
Clinical chemistry (sodium, potassium, chloride, bicarbonate, pH)
o
Haematology (complete blood count)
o
Any coagulation measures (e.g. PT, aPTT, INR, plasma fibrinogen level,
ROTEM EXTEM CT and MCF, ROTEM FIBTEM MCF, platelet count,
platelet function) measured from within 75 minutes before to within 75
minutes after IMP initiation.
o
Safety laboratory analyses if available (creatinine, liver function tests [ALT,
ALP], bilirubin, troponin)
Measure haemoglobin within 30±15 minutes before and at 60±15 minutes after
IMP initiation
Measure INR within 30±15 minutes before and at 60±15 minutes after IMP
initiation and document results
Administer second dose of IMP, if needed
Collect all transfusions and haemostatic therapies
Collect chest tube drainage at 1, 6,12 and 24hours after chest closure
Measure haemoglobin at 24 hours ±1 hour after IMP initiation and document results
Collect extubation time
Collect concomitant medications
Collect AEs and SAEs
6.1.4
Visit 3 (POD 2-7): Days 2–7 after IMP initiation (or at discharge, if earlier)
Collect daily laboratory assessments where available as part of routine care
o
Chemistry (sodium, potassium, chloride, bicarbonate, pH)


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o
Haematology (complete blood count)
o
Coagulation profile (e.g. PT, aPTT, INR, plasma fibrinogen level, ROTEM
EXTEM CT and MCF, ROTEM FIBTEM MCF platelet count, platelet
function)
o
Safety labs (creatinine, liver function tests [ALT, ALP], bilirubin, troponin)
Collect all transfusions and haemostatic therapies
Record incidence of intracerebral haemorrhage, gastrointestinal haemorrhage and
surgical re-exploration.
Collect extubation time (if applicable)
Collect length of stay in the ICU and hospital (if applicable)
Collect concomitant medications
Collect AEs and SAEs
6.1.5
Visit 4 (POD 30): Day 30 after IMP initiation (in person if in hospital, or by 
phone)
Collect concomitant medications
Collect AEs and SAEs
Collect extubation time (if applicable)
Collect length of stay in the ICU (if applicable)
Collect length of stay in the hospital (if hospital stay is extended) and hospital
readmissions
Document patient outcome and survival at 30 days (still in hospital; dead or alive)
After Visit 4 or on POD-30, the clinical study is considered completed for the patient. No 
further study-related assessments will be performed, unless safety concerns (e.g., ongoing 
AEs) require follow-up.
6.1.6 Time Windows Used in this Study, including Tolerances
In this study, the following time windows and tolerances apply (Table 2): 


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Table 2: 
Time Windows Used in this Study
Time point
Time stated
Tolerance
Blood sampling for 
haemoglobin
Within 30 minutes of IMP initiation
At 60 minutes after IMP initiation
At 24 hours after IMP initiation
N/A
±15 minutes
±1 hour
Blood sampling for INR
Within 30 minutes of IMP initiation
At 60 minutes after IMP initiation
N/A
±15 minutes
POD-30 follow-up
±2 days
IMP, investigational medicinal product; INR, international normalised ratio; N/A, not applicable; POD, postoperative 
day
6.2 Duration of Study 
6.2.1
Planned Duration for an Individual Subject/Patient
The duration of the treatment period is 24 hours from initiation of IMP. 
The duration of the study for an individual patient is 30 days from patient randomisation. 
6.2.2
Planned Duration for the Study as a Whole
The study will be considered completed when at least 410 patients are consented, 
randomised, treated, and have finalised day 30 data. It is estimated that the study will take 
approximately two years for recruitment. The estimated start of the study (enrolment of 
first patient) is quarter 4 2022, and the estimated end of the study (last visit of last patient) 
is quarter 4 2024.
6.2.3
Premature Termination of the Study
The Sponsor, in consultation with the IDSMC, reserves the right to terminate the study at 
any time. In this event, any necessary procedures will be arranged on an individual study 
basis after review and consultation by both parties. In terminating the study, the 
Investigators will ensure that adequate consideration is given to the protection of the 
patients’ interests.
Regulatory authorities and IRBs will be informed in accordance with national regulations.
Early termination of the study as a whole or by centre may apply for the following reasons:
6.2.3.1 Early Termination of the Entire Clinical Study
At any time, the study will be terminated prematurely if:
New toxicological or pharmacological findings or safety reports invalidate the earlier
positive benefit-risk-assessment.
6.2.3.2 Early Termination at an Individual Study Centre
At any time, the study can be terminated at an individual centre if:
The centre cannot comply with the requirements of the protocol.
The centre cannot comply with GCP standards.
The a priori determined required recruitment rate is not met.


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7 
ASSESSMENTS AND METHODS 
7.1
Demographic and Baseline Information
The baseline information and medical history will be recorded during Visit 1, i.e., as soon 
as possible after randomisation. 
7.1.1
Demographic and baseline characteristics
The demographic and baseline characteristics are sex, age, height and BMI.
7.1.2
Medical history and prior/concomitant medications
The medical history will be obtained by interviewing the patient or from the medical records.
Prior and concomitant medications from within 1 week prior to surgery will be obtained.
7.2
Efficacy Assessments
7.2.1
Assessments for Primary Efficacy Endpoint
7.2.1.1 Haemostatic Treatment Response to IMP
A dichotomous classification of haemostatic effectiveness will be used to assess the 
primary endpoint of haemostatic treatment response to PCC or FP in bleeding cardiac 
surgical patients. Treatment will be considered ‘effective’ if no additional haemostatic
intervention is required in the time window from 60 minutes to 24 hours after initiation of 
the first IMP dose (Table 3). The 60-minute time period will allow for the administration of 
the IMP and establishment of treatment effect. Patients will be assigned a haemostatic
treatment response classification of ‘ineffective’ if their management required haemostatic
interventions during the time window from 60 minutes to 24 hours after initiation of the first 
IMP dose.
Table 3: 
Objective Criteria for Determination of Haemostatic Treatment 
Response to IMP
Haemostatic
Response
Haemostatic Intervention
Effective
No additional haemostatic interventions1 administered between 60 minutes and 24 hours 
after initiation of infusion2
Ineffective
Additional haemostatic interventions1 administered between 60 minutes and 24 hours after 
initiation of infusion2
1 Administration of any systemic haemostatic agents (including platelets, cryoprecipitate, fibrinogen concentrate, 
activated recombinant factor VII, other coagulation factor products or a second dose of IMP) or any haemostatic 
interventions (including surgical re-opening for bleeding). 
 
2 The 60-minute period allows for the administration of the IMP and establishment of treatment effect.


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Patients categorised as having an ‘ineffective’ haemostatic treatment response to IMP, 
due to requiring administration of any haemostatic intervention, including a second dose 
of IMP, in the time window from 60 minutes to 24 hours after initiation of the first IMP dose, 
will be considered as treatment failures.
7.2.2
Assessments for Secondary Efficacy Endpoints
7.2.2.1 Global Haemostatic Response
A secondary endpoint of global haemostatic response is included to provide supportive 
evidence of haemostatic effectiveness. This will be based on the haemostatic efficacy 
scale developed by Sarode and colleagues [69] (in discussion with the Food and Drug 
Administration), modified to reflect the special considerations of haemorrhage during 
cardiac surgery. Global haemostatic response will be considered as ‘positive’ if no 
additional haemostatic intervention (as per Table 4) is required and haemoglobin levels 
decrease by <30% (after accounting for red cell transfusions) in the time window from 60 
minutes to 24 hours after initiation of the first IMP dose. Global haemostatic response will 
be considered as ‘negative’ if additional haemostatic intervention is required or
haemoglobin
30% (after accounting for red cell transfusions) from 60 
minutes to 24 hours after initiation of the first IMP dose.
Table 4: 
Objective Criteria for Determination of Global Haemostatic 
Response, Adapted from Sarode et al. 2013
Global 
Haemostatic Response
Haemostatic Intervention
Drop in Haemoglobin
Excellent (positive)
No 
additional 
coagulation 
interventions1
administered 
between 1 and 24 hours after 
initiation of infusion2
AND
<15% 
decrease 
in 
haemoglobin
between 1 and 24 hours after 
initiation of infusion2,3
Good (positive)
No 
additional 
coagulation 
interventions1
administered 
between 1 and 24 hours after 
initiation of infusion2
AND
15% 
to 
<30% 
decrease 
in 
haemoglobin between 1 and 24 hours 
after initiation of infusion2,3
Poor (negative)
Additional 
coagulation 
interventions1
administered 
between 1 and 24 hours after 
initiation of infusion2
OR
haemoglobin
between 1 and 24 hours after 
initiation of infusion2,3
1 Administration of any systemic haemostatic agents (including platelets, cryoprecipitate, fibrinogen concentrate, activated 
recombinant factor VII, other coagulation factor products or a second dose of IMP) or any haemostatic interventions (including
surgical re-opening for bleeding).
2 The 60-minute period allows for the administration of the IMP and establishment of treatment effect.
3 Each unit of RBC transfused during this time period will be counted as a drop of 1.0 g/dL in haemoglobin.


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7.2.2.2 Surgical and Surgery-Related Data
The following surgical data will be collected: details of procedure, CPB duration, CPB start 
and end times, cross-clamp duration, circulatory arrest duration, fluid intake and output, 
any medications administered, haemodynamic support (e.g., IABP), as well as any blood 
conservation methods used (e.g., haemoconcentration, retrograde prime, cell salvage), 
length of stay in the OR and need for surgical re-exploration.
In addition, extubation time, ICU length of stay and hospital length of stay will be 
documented. Data collected will be used for a pharmacoeconomic analysis to be 
conducted at a later date.
7.2.2.3 Transfusion Data
Details of all blood products and haemostatic agents released from the blood 
bank/pharmacy and transfused will be collected from the blood bank/pharmacy databases. 
These include allogeneic blood components (RBCs, pooled or apheresis platelets and 
plasma) and albumin. Other haemostatic agents include: desmopressin, fibrinogen 
concentrates, cryoprecipitate, rFVIIa, antithrombin, idarucizumab and andexanet alpha.
Data collected will be used for a pharmacoeconomic analysis to be conducted at a later 
date.
7.2.2.4 Bleeding Data
Severity of bleeding before IMP administration according to the Bleeding Severity Scale 
by Lewis et al [78] will be collected during surgery. 
The comparison of ‘major’ bleeding based on the universal definition of perioperative 
bleeding (UDPB) in cardiac surgery [89, 93] (Table 5Error! Reference source not found.)
will be assessed. The UDPB is a multistage definition for perioperative bleeding based on 
easily measured clinical endpoints, including total blood loss from chest tubes at 12 hours 
and 24 hours after chest closure, allogeneic blood components transfused, surgical re-
exploration including cardiac tamponade, delayed sternal closure and the need for salvage 
treatment. Modifications to the UDPB will include addition of fibrinogen concentrate to 
cryoprecipitate and exclusion of the category of delayed sternal closure.
Depending on these components, bleeding is graded as insignificant, mild, moderate, 
severe or massive (Table 5Error! Reference source not found.) [89]. 
Intracerebral and gastrointestinal haemorrhages will be documented.


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Table 5:
Bleeding categories according to the UDPB in adult cardiac surgery 
(if different categories indicate mixed definitions of bleeding, the worst definition 
applies) [89] 
Bleeding 
definition
Postoperative 
chest tube 
blood loss 
within 12 h 
(mL)
RBC
(units)
FP 
(units)
PLT 
(units)
Fibrinogen 
concentrate 
or 
Cryoprecipitate
PCC
rFVIIa
Re-
exploration/
tamponade
Class 0 
(insignificant)
<600
0 
0 
0 
No
No
No
No
Class 1 
(mild)
601–800
1 
0 
0 
No
No
No
No
Class 2 
(moderate)
801–1000
2–4 
2–4
Yes
Yes
Yes
No
No
Class 3 
(severe)
1001–2000
5–10
5–10
N/A
N/A
N/A
No
Yes
Class 4 
(massive)
>2000
>10
>10
N/A
N/A
N/A
Yes
N/A
FP, frozen plasma; N/A, not applicable; PCC, prothrombin complex concentrate; PLT, platelets; rFVIIa, activated recombinant 
factor VII; UDPB, universal definition of perioperative bleeding.
To remove any potential bias from PCC and/or FP dosing, as their use is dictated by the 
randomisation schedule, a modified version of the UDPB will also be applied, with the 
following components of the score omitted: administration of PCC and transfusion of FP.
7.3
Safety Assessments
7.3.1
Assessments for Safety Endpoints
Any of the following drug safety information shall be collected:
AEs and SAEs temporally associated with the administration of IMP (for definitions
and reporting requirements, see Sections 7.3.2, 7.3.3 and 7.3.4.
Pregnancies, drug overdose, interaction, medication error, lack of efficacy and post-
study SAEs (see Section 7.3.6).
7.3.2
Adverse Events (AEs)
7.3.2.1 Definitions
Adverse event (AE): An AE is any untoward medical occurrence in a study patient
receiving an IMP and which does not necessarily have a causal relationship with
this treatment. An AE can therefore be any unfavourable and unintended sign
(including an abnormal laboratory finding), symptom or disease temporally
associated with the use of an IMP, whether or not related to the IMP. An AE is
defined as a treatment-emergent AE (TEAE) if first onset or worsening is after the
first treatment with study drug.
Adverse drug reaction (ADR): An ADR is any noxious and unintended response
to an IMP related to any dose. The phrase ‘response to an IMP’ means that a causal
relationship between the IMP and an AE carries at least a reasonable possibility,
i.e., the relationship cannot be ruled out.


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Other significant AEs: Any marked laboratory abnormalities or any AEs that lead
to an intervention, including withdrawal of drug treatment, dose reduction or
significant additional concomitant therapy.
Withdrawal due to AE/ADR: AE/ADR leading to discontinuation of treatment with
IMP. Any such events will be followed up by the Investigator until the event is
resolved or until the medical condition of the patient is stable. All follow-up
information collected will be made available to the Sponsor.
7.3.2.2 Collection of AEs
The condition of the patient will be monitored throughout the study. At each visit, whether 
scheduled or unscheduled, AEs will be elicited using a standard non-leading question such 
as “How have you been since the last visit/during the previous study period?” In addition, 
the Investigator/blinded outcome assessor will check the patient records for any 
documented event.
Any AE or ADR which occurs during the study will be noted in detail on the appropriate 
pages of the CRF. If the patient reports several signs or symptoms representing a single 
syndrome or diagnosis, the diagnosis should be recorded in the CRF. The Investigator will 
grade the severity of all AEs or ADRs (mild, moderate or severe), the seriousness (non-
serious or serious) and the causality as defined below. The Sponsor is responsible for 
assessing the expectedness of each ADR (expected or unexpected) as defined below. 
In the event of clinically significant abnormal laboratory findings, the tests will be confirmed 
and the patient followed up until the laboratory values have returned to normal and/or an 
adequate explanation for the abnormality has become available. 
Diseases, signs and symptoms and/or laboratory abnormalities already present before the 
first administration of IMP will not be considered AEs unless an exacerbation in intensity 
or frequency (worsening) occurs.  
The Investigator will provide detailed information about any abnormalities and about the 
nature of and reasons for any action taken, as well as any other observations or comments 
that may be useful for the interpretation and understanding of an AE or ADR.
7.3.2.3 Severity of AEs
The intensity/severity of AEs will be graded as follows:
Mild: an AE, usually transient, which causes discomfort but does not interfere with
the patient’s routine activities
Moderate: an AE which is sufficiently discomforting to interfere with the patient’s
routine activities
Severe: an AE which is incapacitating and prevents the pursuit of the patient’s
routine activities
The grading of an AE is up to the medical judgement of the Investigator and will be decided 
on a case-by-case basis.
7.3.2.4 Causality of AEs
The relationship of AEs to the administered IMP will be assessed by the Investigator: 


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Probable: reports including good reasons and sufficient documentation to assume
a causal relationship, in the sense of plausible, conceivable, likely, but not
necessarily highly probable. A reaction that follows a reasonable temporal
sequence from administration of the IMP; or that follows a known or expected
response pattern to the suspected medicine; or that is confirmed by stopping or
reducing the dosage of the medicine and that could not reasonably be explained by
known characteristics of the patient’s clinical state.
Possible: reports containing sufficient information to accept the possibility of a
causal relationship, in the sense of not impossible and not unlikely, although the
connection is uncertain or doubtful, for example because of missing data or
insufficient evidence. A reaction that follows a reasonable temporal sequence from
administration of the IMP; that follows a known or expected response pattern to the
suspected medicine; but that could readily have been produced by a number of
other factors.
Unlikely: reports not following a reasonable temporal sequence from IMP
administration. An event which may have been produced by the patient’s clinical
state or by environmental factors or other therapies administered.
Not related (unrelated): events for which sufficient information exists to conclude
that the aetiology is unrelated to the IMP.
Unclassified: reports which for one reason or another are not yet assessable, e.g.,
because of outstanding information (can only be a temporary assessment).
7.3.2.5 Classification of ADRs by Expectedness
ADRs will be classified by the Sponsor as either expected or unexpected: 
Expected: an ADR that is listed in the current edition of the Investigator’s Brochure
(IB) or other reference safety information.
Unexpected: an ADR that is not listed in the current edition of the IB or other
reference safety information, or that differs because of greater severity or greater
specificity.
7.3.2.6 Outcome of AEs
The outcome of all reported AEs has to be documented as follows: 
1. Recovered, resolved
2. Recovering, resolving
3. Not recovered, not resolved
4. Recovered, resolved with sequelae
5. Fatal
6. Unknown
NOTE: A patient’s death per se is not an event, but an outcome. The event which resulted 
in the patient’s death must be fully documented and reported, even in cases where the 


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death occurs within 4 weeks after IMP treatment end and regardless of whether or not it is 
considered treatment related.
7.3.2.7 Action(s) taken
AEs requiring action or therapy must be treated with recognised standards of medical care 
to protect the health and well-being of the patient. Appropriate resuscitation equipment 
and medicines must be available to ensure the best possible treatment in an emergency 
situation.
The action taken by the Investigator must be documented:
a) General actions taken in the event of an AE
–
None
–
Medication (other than IMP) or other (e.g., physical) therapy started
–
Test performed
–
Other (to be specified)
b) IMP-related actions taken in the event of an AE
–
None
–
Product withdrawn
–
Dose reduced
–
Dose increased
The Investigator will follow up on each AE until it has resolved or until the medical condition 
of the patient has stabilised. Any relevant follow-up information will be reported to the 
Sponsor.
7.3.3
Serious Adverse Events (SAEs)
Standard statement:
A serious AE (SAE) is any untoward medical occurrence that at any dose: 
results in death,
is life-threatening (see below),
requires hospitalisation or prolongation of existing hospitalisation,
results in persistent or significant disability/incapacity,
is a congenital anomaly/birth defect,
is another important medical event.
NOTE: The term ‘life-threatening’ refers to an event in which the patient was, in the view 
of the reporting Investigator, at immediate risk of death at the time of the event; it does not 
refer to an event which may hypothetically have caused death had it been more severe.
In deciding whether an AE/ADR is serious, medical judgment should be exercised. Thus, 
important AEs/ADRs that are not immediately life-threatening or do not result in death or 
hospitalisation but may jeopardise the patient or may require intervention to prevent one 
of the other outcomes listed in the definitions above should also be considered serious. 


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In addition, although not classified under the seriousness criteria, all suspected 
transmissions of an infectious agent should be reported as SAEs. A suspected virus 
transmission means that virus antigen has been detected in the patient. A passive 
transmission of antibodies alone does not constitute a suspected virus transmission. 
7.3.4
SAE Reporting Timelines
All SAEs, whether or not they are suspected to be related to study treatment, are to be 
reported within 24 hours of recognition of the event by email to Ozmosis and to 
Octapharma Clinical by submitting the Serious Adverse Event Reporting Form:  
The contact details will also be communicated at the study initiation visit.
Ozmosis Research will inform Octapharma’s Safety Medical Expert and Octapharma’s
Central Drug Safety Unit (treatment emergent SAEs only) within 24 hours of receiving the
event:
Octapharma Safety Medical Expert:
Email: 
Octapharma's Central Drug Safety Unit:
OCTAPHARMA Pharmazeutika Produktionsges.m.b.H.
Oberlaaer Straße 235, 1100 Vienna, Austria
Fax:
Email:
24 hours emergency telephone number: 
24 hours emergency telephone number: 
Waivers from SAE Reporting Requirement
Waivers from the SAE reporting requirement are surgical procedures that are elective or
were planned before study entry, and prolongation of the existing hospitalisation that is 
performed for economic or social reasons and not for medical reasons. Such events should 
not be considered as SAEs.
7.3.5
Occurrence of TEEs
All TEEs (thrombotic, embolic, or thromboembolic events) must be recorded in the source 
data and reported as SAEs within 24 hours. If TEEs are suspected, appropriate 
examinations according to local standards (e.g. Doppler scan using color duplex, X-ray, 
CT scan) should be obtained and documented. Therapeutic measures for managing TEEs 
shall be initiated according to local clinical practice (e.g., anticoagulation).


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As a component of the assessment of AEs, the Investigator will also be questioned 
regarding the occurrence of TEEs. These are defined according to the Standardized 
Medical Dictionary for Regulatory Activities (MedDRA) query “Embolic and thrombotic 
events”.
7.3.6
Laboratory Tests
The following laboratory parameters will be investigated during the study at the time points 
specified in Section 6. 
7.3.6.1 Central Laboratory
No laboratory tests will be done at a central laboratory:
7.3.6.2 Local Laboratory
Table 6 summarises all test parameters performed as part of standard of care, the results 
of which will be collected as available.
Table 6 
Test Parameters and Laboratories
Test
Material
needed
Responsible
Laboratory
Coagulation profile
Point-of-care INR
Fresh blood
Local
(PT, aPTT, INR, fibrinogen activity via Clauss assay)
Citrated blood
Local
*ROTEM EXTEM CT
Citrated blood
Local
*ROTEM EXTEM MCF
Citrated blood
Local
*ROTEM FIBTEM MCF
Citrated blood
Local
PlateletWorks
Fresh blood
Local
Haematology – standard panel as per local lab
Citrated blood
Local
Clinical chemistry – standard panel as per local lab
Serum
Local
Safety laboratory analyses
Troponin
Serum
Local
ALT/ALP
Serum
Local
Bilirubin
Serum
Local
Creatinine
Serum
Local
ALT, alanine aminotransferase; ALP, alkaline phosphatase; CT, clotting time; MCF, maximum clot firmness; PT, 
prothrombin time; aPTT, activated partial thromboplastin time; ROTEM, thromboelastometry
*ROTEM or TEG can be measured


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The haemoglobin and INR measurements will be performed at preestablished time points 
(Table 7). 
Table 7 
Mandatory Test Parameters and Laboratories
Test
Material
needed
Responsible
laboratory
Coagulation profile
     Point-of-care INR 
Fresh blood
Local
Citrated blood
Local
Haematology
Haemoglobin
Citrated blood
Local
Blood Sampling
All blood sampling will be performed as per standard practice at the local institution.
The actual time of blood sampling will be recorded. If the draw time is not recorded for 
samples processed in the laboratory, the draw time will be estimated based on the received 
time in the laboratory minus 10 minutes. For ROTEM and PlateletWorks, if the exact draw
time is not recorded, the time for start of testing will be used for draw time. 
Citrated and Fresh Blood
Citrated and fresh blood as required by the local laboratory will be collected and processed 
in accordance with local requirements.
Serum
Serum will be obtained for the determination of clinical chemistry, haematology, and safety 
labs (ALT, ALP, creatinine, bilirubin, troponin), where a serum blood sample has been 
collected.
Recording of Clinically Significant Abnormal Laboratory Values as AEs/ADRs
Other than abnormal laboratory values due to the underlying condition, the Investigator 
must assess the clinical significance of abnormal laboratory values outside the specified 
normal range. Any clinically significant abnormalities will be documented. All specified 
clinically significant abnormalities will be documented as AEs/SAEs and investigated.
Additional tests and other evaluations required to establish the significance or aetiology of 
specified abnormalities or to monitor the course of an AE will be obtained if clinically 
indicated. Follow-up will persist until resolution or up to the Study Completion Visit, 
whichever occurs first. 
7.3.7
Other Relevant Safety Information
a) Post-study related safety reports
Proactive monitoring for post-study SAEs is not required.
In case a post-study SAE is identified, the Investigator should complete an SAE form and 
also state the relation to the clinical study in the report.


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b) Pregnancies
Patients who are known to be pregnant will not be included in the study. In patients of 
reproductive age, pregnancy is ruled out prior to the cardiac surgery as part of standard of 
care.
Overdose, interaction, medication error and lack of efficacy
The following safety relevant information should be reported as AE or, if the reaction fulfils 
one of the criteria for seriousness, as SAE.
c) Drug overdose
An overdose is a deliberate or inadvertent administration of a treatment at a dose higher 
than specified in the protocol and higher than the known therapeutic dose that is of clinical 
relevance. The reaction must be clearly identified as an overdose.
d) Drug interaction
A drug interaction is a situation in which a substance or medicinal product affects the 
activity of an IMP, i.e., increases or decreases its effects, or produces an effect that none 
of the products would exhibit on its own. The reaction must be clearly identified as a drug 
interaction.
e) Medication error
A medication error involves the inadvertent administration or unintended use of a medicinal 
product which may be caused by the naming, presentation of pharmaceutical 
form/packaging or instructions for use/labelling. The reaction must be clearly identified as 
a medication error.
7.4
Appropriateness of Measurements
Since the ultimate goal of the study is the measure the need for post-therapy haemostatic 
interventions following cardiac surgery in adults, the clinical assessment of haemostatic 
effectiveness provides the key clinical information on treatment efficacy. Haemostatic 
effectiveness will be based on the haemostatic efficacy scale developed by Sarode and 
colleagues [69] (in discussion with the Food and Drug Administration), modified to reflect 
the special considerations of haemorrhage during cardiac surgery. The secondary and 
exploratory endpoints will provide further information on the clinical efficacy and safety of 
Octaplex in this clinical setting. 


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8 
DATA HANDLING AND RECORD KEEPING 
8.1
Documentation of Data
8.1.1
Source Data and Records
Source data are defined as all information related to clinical findings, observations or other 
activities in the study, written down in original records or certified copies of original records, 
allowing reconstruction and evaluation of the clinical study.
The Investigator will maintain adequate source records (e.g., case histories or patient files 
for each patient enrolled). Source records should be preserved as required by local 
regulations.
For each patient enrolled, the Investigator will indicate in the source record(s) that the 
patient participates in this study.
For data capture, a validated Electronic Data Capture (EDC) system providing an 
electronic CRF (eCRF) application will be used.
All data entered in the eCRF must be supported by source data in the patient records.
The Investigator will permit study-related monitoring, audit(s), IRB review(s) and regulatory 
inspection(s), by providing direct access to the source data/records.
The Investigator may authorise site staff (e.g., sub-investigators, clinical research 
coordinators/assistants, nurses) to enter study data into the eCRF. This must be 
documented in the Delegation of Authority Log signed by the Investigator.
8.1.2
Case Report Forms
Authorised study site staff (e.g., blood bank/pharmacy
technologist, research 
coordinator/assistant) will be responsible for completing an eCRF record for each patient 
enrolled. All site personnel will be trained on completion of a patient’s eCRF. The site is 
also provided with the approved eCRF Completion Guidelines which will assist in data 
entry and data issues/questions. Additional site training may be provided as refreshers 
throughout the study, if needed. All persons allowed to enter or to change eCRF data must 
be listed in the Delegation of Authority Log.
For each patient enrolled, an eCRF record will be completed within the EDC system and 
finally approved by the Investigator or an authorised sub-investigator. 
Prior to operational use, the eCRF application will be validated. All site personnel will be 
trained on the EDC system and study specific eCRFs prior to receiving access to the live 
system for data entry.
8.1.3
Changes to Case Report Form (CRF) Data
Monitors will perform source data verification (SDV) as defined for the study and described 
in the study Monitoring Plan.
If any errors or discrepancies in the eCRFs are found during data entry or review, 
discrepancies will be generated programmatically within the EDC system, and ‘manual’ 
queries will be generated by either a monitor or Data Management.


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The Investigator is responsible for maintaining a confidential patient identification code list, 
which provides the unique link between named source records and CRF data. The 
Investigator must arrange for the retention of this confidential list for the maximum period 
of time required by local regulations.
No study document should be destroyed without prior written agreement between the 
Investigator and the Sponsor. Should the Investigator elect to assign the study documents 
to another party, or move them to another location, the Sponsor must be notified in writing.
8.5
Provision of Additional Information
If errors in data transcription are encountered, a query should be raised which needs to be 
answered by appropriately delegated site staff. Provision of additional patient data should 
be avoided (except if needed for SAE reporting). In case of particular issues or 
governmental queries, it is also necessary to have access to the complete study records, 
provided that the patient’s confidentiality is protected in accordance with applicable 
regulations.
8.6
Independent Data and Safety Monitoring Committee
An IDSMC will be established by the Sponsor. The IDSMC will be composed of recognised
experts in the field of statistics, perioperative medicine and haematology who are not 
actively recruiting patients.
The IDSMC will review accumulating safety, endpoint and other study data (recruitment, 
retention and compliance, data quality and timeliness, risk versus benefit, summary 
statistics of outcomes) every time 100 patients have completed the study.  
The IDSMC will provide recommendations about continuing, modifying and/or stopping the 
study based on considerations of treatment efficacy, patient safety and trial futility as 
appropriate. In addition, the IDSMC may make observations or recommendations to the 
sponsor about, but not limited to, the following:
Efficacy of the study intervention;
Definitions of and responses to AEs and patterns in AEs;
Benefit/risk ratio of procedures and participant burden;
Selection, recruitment and retention of participants;
Adherence to protocol requirements;
Completeness, quality and analysis of measurements;
Amendments to the study protocol and consent forms;
Performance of individual centres and core labs; and
Patient safety.
A written study-specific charter will define in detail the composition, responsibilities and 
procedures of the IDSMC.  


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9 
STATISTICAL METHODS AND SAMPLE SIZE 
The statistical analysis will be delegated under an agreement of transfer of responsibilities 
to an external statistician. Details on planned descriptive and exploratory analyses will be 
provided in a separate Statistical Analysis Plan (SAP).
9.1
Determination of Sample Size
The analysis of the primary efficacy endpoint will involve comparison of haemostatic
treatment response to IMP, defined as ‘effective’ if no additional haemostatic intervention, 
such as administration of any systemic haemostatic agents (including platelets, 
cryoprecipitate, fibrinogen concentrate, activated recombinant factor VII, other coagulation 
factor products or a second dose of IMP) or any haemostatic interventions (including 
surgical re-opening for bleeding) is required from 60 minutes to 24 hours after initiation of 
the first dose of IMP. 
Patients categorised as having an ‘ineffective’ haemostatic treatment response to IMP, 
due to requiring administration of any haemostatic intervention, including a second dose 
of IMP, in the time window from 60 minutes to 24 hours after initiation of the first IMP dose, 
will be considered as treatment failures.
Of the more than 100 patients studied in the FARES pilot study, approximately 75% of 
patients in the PCC group and 65% in the FP group demonstrated haemostatic treatment 
response from 60 minutes to 24 hours after initiation of the first IMP dose [58]. Using a 
more conservative estimate of 70% versus 65%, it is estimated that 410 patients will be 
required to demonstrate non-inferiority with a one-
2
non-inferiority margin of 0.10 when using a Farrington-Manning score test.
It is anticipated that up to 20% of randomised patients may not meet administration criteria 
(based on objective Bleeding Severity Scale and INR) due to cessation of haemorrhage
between randomisation and delivery of IMP to the operating room and therefore will not 
receive the therapy.
An administrative unblinded interim analysis will be carried out after 200 evaluable patients
have been randomised and treated and will be used to re-estimate the sample size or stop 
for futility (non-binding) (Section 9.4). Patient recruitment will continue during the conduct 
of the interim analysis. The sample size in the second stage is limited to 210–800 evaluable 
patients. Accounting for drop-outs as described above, the total sample size will range 
between 513–1250 if the study is not stopped for futility at the interim (see table below). 
Stage 1 
Stage 2 – 
Minimum
Stage 2 – 
Maximum
Total -
Maximum
Evaluable 
patients
200
210
800
1000
Sample size 
including 20% 
dropouts  
250 
263
1000
1250 


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9.2
Statistical Analysis
A formal SAP describing all details of the analyses to be performed will be prepared by the 
study statistician and approved by the Sponsor prior to study initiation. 
The non-inferiority of the primary endpoint ‘haemostatic response’ will be tested between 
the treatment groups by means of a Farrington-Manning score test with a non-inferiority 
margin of 0.10 at a one-sided significance level alpha of 2.5%, testing the null hypothesis 
as follows:
H0
p(FP) – 0.10 
will be tested against the alternative 
H1: p(PCC) > p(FP) – 0.10
where p(PCC) and p(FP) denote the haemostatic response proportions in the PCC and 
FP treatment groups, respectively.
At the end of the trial, the inverse normal test statistic with equal weights given by 
(
-1(1 – p1) + 
-1(1 – p2))/ 2 
is calculated, where p1 and p2 denote the p-values for testing the non-inferiority null 
hypothesis for the first and the second stage of the trial, respectively. If the test statistic 
exceeds the value 1.96, non-inferiority is demonstrated (see [94]). 
Only in case that non-inferiority is demonstrated at the second stage of the study, i.e., the 
null hypothesis is rejected at the one-sided 2.5% level of significance, superiority of PCC 
with regard to the primary endpoint will be investigated:
H0
p(FP)  
will be tested against the alternative 
H1: p(PCC) > p(FP) 
The Farrington-Manning score test will be used to calculate a two-sided 95% confidence 
interval based on the inverse normal test statistic as given above. This confidence interval 
corresponds with the test decision for showing non-inferiority and/or superiority [95]. This
hierarchical test procedure allows to perform the superiority test at the full alpha of 2.5%. 
9.2.1
Populations for Analysis
The full analysis set (FAS) will consist of all consented and randomised patients who 
receive any amount of the intervention, which will serve as the primary analysis set. A 
supporting efficacy analysis will be performed for the per-protocol set (PPS), which will 
exclude all patients with major deviations (e.g., patients who receive an IMP different to 
the IMP assigned by randomisation; patients who receive <50% of the planned dose; and 
patients who significantly violate inclusion/exclusion criteria). Randomised but untreated 
patients will not be included in the efficacy or safety analyses, but will be followed for 30 
days to determine between-group comparability in baseline characteristics and outcomes. 
A final decision about the classification of protocol deviations and their consequences 
regarding assignment of patients to analysis populations will be made during the data 
review meeting prior to the final analyses. All protocol deviations documented during the 
conduct of the study or identified at the data review process prior to database lock will be 
reviewed and classified as minor or major and with respect to their significance for the 


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planned analyses. This classification of protocol deviations is the joint responsibility of the 
clinical project manager, the study statistician, and Octapharma’s responsible medical 
expert, and will be agreed and documented before the database is locked and the 
statistical analyses are performed.
The safety analysis population (SAF) will be identical to the FAS. In addition, to ensure 
that the safety reporting is complete, all haemostatic therapy and SAE data will be collected
in cases where consent for remaining in the study cannot be obtained from Canadian sites
due to logistical issues (e.g., patient died and a legally authorised representative could not 
be reached) and REB approval is obtained to collect the information. For Canadian 
patients who refuse consent, only treatment allocation data will be collected, and patients 
will not be included in any analyses.
The following subgroups will be analysed: sex (male/female); urgency (elective/non-
elective surgery); and complexity (simple/complex surgery [procedures other than isolated 
ACB, single valve or repair of atrial septal defect]). Moreover, the impact of CPB duration 
on effectiveness will be evaluated by assessing treatment effect based on CPB duration 
increments.
Details on the subgroup analyses will be given in a Statistical Analysis Plan. 
9.2.2
Efficacy Analysis Plan
Descriptive statistics or frequency tables will be presented for all efficacy data in addition 
to the inferences performed. Simple tests of comparison will be used to compare endpoints
between the two groups. The summary tables and exploratory inferences will be chosen 
according to the scaling level of the measurements. Frequency tables will be provided for 
categorical responses and summary statistics for continuous data. The SAP will detail all 
analyses, including exploratory analyses (e.g., p-values and confidence intervals) to be 
undertaken.
9.2.3
Safety Analysis Plan
Secondary safety endpoints will be analysed analogously to the primary endpoint, 
presenting point estimates and two-sided 95% CIs in addition to descriptive statistics. Prior 
to study initiation, the SAP will detail all analyses to be undertaken.
9.2.3.1 Adverse events, including thromboembolic and other events of special 
interest
AEs will be coded according to the latest Medical Dictionary for Regulatory Activities 
(MedDRA) version as specified in the Data Management Plan. The analysis will focus on 
treatment-emergent adverse events (TEAEs), i.e., AEs that started or worsened after start 
of infusion with IMP.
All TEAEs, related TEAEs (i.e., AEs unlikely, probably or possibly related to the IMP) and 
serious TEAEs will be summarised and tabulated according to primary system organ class 
and preferred term. TEAEs leading to death and TEAEs resulting in withdrawal from the 
study will be tabulated using frequency tables if a reasonable number of events of this type 
are observed.
Analogous frequency tables for TEEs (identified using MedDRA SMQs) and composite 
events will be provided separately.
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Patient listings will be provided for patients with SAEs, TEEs, AEs leading to withdrawal 
from the study and AEs leading to death. Listings for non-treatment-emergent AEs, e.g., 
for patients enrolled but not randomised will be provided separately.
9.2.3.2 Mortality 
The number of patients who died will be summarised. A possible difference between 
treatment groups will be estimated by a risk ratio with 95% CI. Kaplan-Meier estimates for 
the time to death distribution will be calculated and graphically presented if a sufficient 
number of cases have been registered. 
Routine laboratory data
All laboratory values will be classified as normal or abnormal according to the laboratories’ 
normal ranges and indicated as clinically significant or not clinically significant by the 
Investigator. The following approaches will be taken for each laboratory parameter for the 
statistical analysis:
Quantitative data will be examined for trends using descriptive analysis (number of
patients, number of missing values, mean, SD, median, quartiles, minimum,
maximum) of actual values at each scheduled time point and changes from
baseline to each scheduled time point. Mean concentration versus time profiles will
be plotted for quantitative data
Qualitative data based on reference ranges will be described according to the
categories (i.e., low, normal, high)
Shift tables illustrating changes with respect to the laboratories’ normal ranges
between baseline and a defined scheduled time point. Scatterplots between
scheduled time points of lab values with normal ranges will be used for visual
illustration.
Number and frequency of patients with clinically significant laboratory values. A
separate patient listing will be provided
9.2.4
Handling of Missing Data
In general, missing data will not be imputed. Due to the nature of the study, important 
variables are expected to have few missing data. In addition to presentation of the primary 
and secondary endpoints for different analysis sets, further multiple imputation methods
may be used to impute missing values. Technical details will be described in the Statistical 
Analysis Plan.
9.3
Randomisation, Stratification and Code Release
Eligible patients will be randomly assigned to receive either Octaplex
or FP. 
Randomisation lists using a permuted-block, randomisation scheme (stratified by site) will 
be prepared by the biostatistician. Sealed randomisation envelopes based on the 
randomisation lists will then be provided to the blood banks/pharmacies of the participating 
centres who will be responsible for providing the IMP.
Patients will be identified using a sequential numbering system within the centre.
Randomisation will then be performed in sequential order of the patient IDs.


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9.4
Interim Analysis
An administrative unblinded interim analysis will be carried out by an independent 
statistician when approximately 200 patients have been randomised and treated.
Unblinded information will be communicated only to the IDSMC. Possible outcomes of this 
analysis and recommendations to the sponsor are: 
The study will be stopped for futility. The decision to stop for futility is non-binding.
The sample size will be re-estimated by the independent statistician.
Patient recruitment will continue during the conduct of the interim analysis. The study 
cannot be stopped for efficacy at the interim analysis.
The sample size re-estimation will be based on the evaluation of the conditional power, 
calculated as described in section 7.3 of [94] making use of the observed response rates
at the time of the interim analysis and inverse normal combination test statistic with equal 
weights given by 
(
-1(1 – p1) + 
-1(1 – p2))/ 2,
where p1 and p2 denote the p-values for testing the non-inferiority null hypothesis for the 
first and the second stage of the trial, respectively. The aspired conditional power used for 
the new intended sample size will be 90%.  
A 20% drop-out rate will be added to the re-estimated sample size of evaluable patients to 
receive the number of patients to be enrolled in the second stage.
The minimum number of patients for the second stage is 210 evaluable subjects (even if 
the re-estimated sample size is below this number) or 263 including the possible dropouts
(+20%). The sample size for the second stage cannot exceed 1250 patients (dropouts
included). If the drop-out adjusted re-estimated sample size exceeds this threshold, the 
IDSMC may recommend to either stop the trial for futility or to enrol the maximum number 
of 1250 patients. 
In addition, the IDSMC will review selected unblinded summary statistics every time 100 
patients have completed the study (Section 8.6).  


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10 ETHICAL/REGULATORY, LEGAL AND ADMINISTRATIVE ASPECTS 
10.1 Ethical/Regulatory Framework
This study will be conducted under 21 CFR Part 312, the FDA’s investigational new drug 
application (IND) requirements and the FDA’s human subject protection requirements at 
21 CFR Parts 50 and 56. In addition, we are seeking a waiver to allow informed consent 
to be obtained after randomisation at the Canadian sites, in accordance with Article 3.7A 
of the 2018 Tri-Council Policy Statement on the Ethical Conduct for Research Involving 
Humans. The study will also be conducted in accordance with the ethical principles laid 
down in the Declaration of Helsinki. The study protocol and any subsequent amendment(s) 
will be submitted to the applicable IRBs and relevant regulatory authorities. The study will 
be conducted in compliance with the protocol, GCP guidelines and applicable regulatory 
requirements.
The regulatory application or submission for regulatory approval will be made by the 
Sponsor or designated third party (e.g., CRO). 
10.2 Approval of Study Documents
The study protocol, informed consent form, and any other materials provided to the 
patients and further requested information will be submitted by the Sponsor or the Site 
Investigator to the appropriate IRB. The study must be approved by the IRB before the 
patient is exposed to a study-related procedure.
The Sponsor, the Site Investigator and any third party (e.g., CRO) involved in obtaining 
approval must inform each other in writing that all ethical and legal requirements have 
been met before the first patient is enrolled in the study.
10.3 Subject/Patient Information and Informed Consent
This is a pragmatic trial that compares two coagulation factor replacement therapies that 
are currently routinely used for the study indication in multiple regions globally and in 
various settings.   
The Investigator will obtain freely given written consent from each patient after an 
appropriate explanation of the aims, methods, anticipated benefits, potential hazards, and 
any other aspect of the study which is relevant to the patient’s decision to participate. The 
informed consent form must be signed, with name and date and time noted by the patient
before they are exposed to any study-related procedure, including screening tests for 
eligibility.4 Should consent be later withdrawn by the patient, no additional data will be 
collected. 
The study coordinator or assistant will explain that the patients are completely free to 
refuse to enter or withdraw from the study at any time, without any consequences to their 
future care and without the need to justify. Each patient will be informed that his/her 
medical (source) records may be reviewed by the study monitor, a quality assurance 
auditor or a health authority inspector, in accordance with applicable regulations, and that 
4 In Canada, informed consent will be obtained after randomisation, in accordance with Article 3.7A of 
the 2018 Tri-Council Policy Statement on the Ethical Conduct for Research Involving Humans.


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these persons are bound by confidentiality obligations. In addition to the study protocol, 
study hospitals will also follow their institutional guidelines and approvals when consenting 
and collecting data. Their process will be documented in their SOPs. 
10.3.1 Evidence for the prospect of direct benefit to patients because of 
participation in the study
Cardiac surgery can be complicated by coagulopathic bleeding that often leads to 
excessive blood loss, blood product transfusion and bleeding-related complications [1-4].
Bleeding and transfusions are associated with increased morbidity, mortality and risk of 
adverse outcomes (e.g., infection, heart failure) [2, 5-17]. 
The current standard of care for this complication in North America is FP, which is 
administered in around 15% of all cardiac surgeries in the United States [29]. However, 
FP can cause SAEs including allergic reactions [30]; TRALI, which is a leading cause of 
transfusion-related death [30, 40]; and TACO, which occurs in approximately 5% of 
transfusions [41]. FP transfusion can also lead to transmission of infectious diseases, as 
FP is not usually filtered or treated with solvent/detergent [42]. FP use also requires ABO 
blood group compatibility matching and thawing, which can delay therapy. The large 
volumes of FP needed to achieve therapeutic effect can further delay time to haemostatic 
control and lead to substantial haemodilution, resulting in additional RBC transfusions [47]. 
PCCs, such as Octaplex, have several potential advantages over FP. PCCs are 
associated with a substantially lower risk of TRALI (due to pooling of the source donor 
plasma), and also a lower risk of TACO [38] as substantially lower volumes of PCC are 
required than with FP to achieve dose-equivalence for increasing thrombin generation [47]. 
The production of PCCs includes numerous pathogen-inactivation steps using solvents, 
detergents, pasteurisation, nanofiltration and vapor-heated treatment [1, 48], which is 
beneficial to patients because of the reduction in the risk of transmission of infectious 
agents. Unlike FP, PCCs do not require ABO compatibility matching or thawing, and can 
therefore be prepared and administered more quickly.
The potential benefits of Octaplex, compared with FP, were investigated in FARES, a
multicentre, randomised, active-control, pragmatic, Phase 2 pilot study [58]. Efficacy data 
obtained from the FARES study showed significantly lower chest tube drainage in the PCC 
group (P<0.001); a numerically higher percentage of treatment response in the PCC group; 
and a significantly lower number of transfused units of ABP in the PCC group versus the 
FP group (P<0.001) [58]. The significantly lower blood loss and, consequently, reduced 
exposure to ABP transfusions and their associated risks demonstrates how PCC use can 
directly benefit patients in this context, as both bleeding and transfusions during cardiac 
surgery have been associated with increased morbidity and mortality [2, 11, 14, 15, 17]. 
LEX-211 will expand the supporting scientific evidence for use of PCCs to treat bleeding 
in cardiac surgical patients requiring coagulation factor replacement.
10.4 Protocol Amendments
Any amendments will be submitted to the institutional IRB and any authority as required 
by applicable regulations.
IRB approval will, at a minimum, be requested for any change to this protocol which could 
affect the safety of the patients, the objective or design of the study, any increase in dosage 
or duration of exposure to the IMP, an increase in the number of patients treated, the 
addition of a new test or procedure or the dropping of a test intended to monitor safety.


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10.5 Confidentiality of Subject/Patient Data
The Investigator will ensure that the patient’s confidentiality is preserved. On CRFs or any 
other documents submitted to the Sponsor, the patients will not be identified by their 
names, but by a unique patient identifier. Documents not intended for submission to the 
Sponsor, i.e., the confidential patient identification code list, original consent forms and 
source records, will be maintained by the Investigator in strict confidence.


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11 QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 Periodic Monitoring
The monitor will contact and visit the Investigator periodically to review all study-related 
source data/records, verify the adherence to the protocol and the completeness, 
correctness and accuracy of all CRF entries compared to source data. The Investigator 
will co-operate with the monitor to ensure that any discrepancies identified are resolved.
For this study, the first monitoring visit shall take place shortly after the inclusion of the first 
patient. Thereafter, monitoring frequency will depend on study progress. All enrolled 
patients will be monitored, with 100% source data verification for the data relevant for the 
primary and safety endpoints. 
The monitor must be given direct access to source documents (original documents, data 
and records). Direct access includes permission to examine, analyse, verify and reproduce 
any records and reports that are important to the evaluation of the clinical study. Source 
data will be available for all data in the CRFs, including all laboratory results.
Monitoring will take place as per the study Monitoring Plan.
11.2 Audit and Inspection
The Investigator will make all study-related source data and records available to a qualified 
quality assurance auditor, IRB or regulatory inspectors, after reasonable notice. The main 
purposes of an audit or inspection are to confirm that the rights and welfare of the patients 
have been adequately protected, and that all data relevant for the assessment of safety 
and efficacy of the IMP have been captured.


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12 REPORTING AND PUBLICATION 
12.1 Clinical Study Report
A clinical study report (in accordance with relevant guidelines) will be prepared by the 
Sponsor after completion of the study. 
12.2 Publication Policy
The results of this study will be published and may be presented at scientific meetings.
In accordance with standard editorial and ethical practice, the Sponsor will publish the 
multicentre data only in their entirety and not as individual centre data. Authorship will be 
determined by mutual agreement. Any subsequent publications based on subsets of the 
data will require approval from the Sponsor.


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13 LIABILITIES AND INSURANCE 
In order to cover any potential damage or injury occurring to a patient in association with 
the IMP or participation in the study, the Investigators and/or their institutions will contract 
insurance in accordance with local regulations.
The Investigator is responsible for dispensing the IMP according to this protocol and for its 
secure storage and safe handling throughout the study.


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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.
66.
Zweng I, Galvin S, Robbins R, Bellomo R, Hart GK, Seevanayagam S, et al. Initial
Experience of the Use of 3-Factor Prothrombin Complex Concentrate and
Thromboembolic Complications After Cardiac Surgery. Heart Lung Circ.
2019;28(11):1706-13.
67.
Faulkner H, Chakankar S, Mammi M, Lo JYT, Doucette J, Al-Otaibi N, et al. Safety
and efficacy of prothrombin complex concentrate (PCC) for anticoagulation reversal
in patients undergoing urgent neurosurgical procedures: a systematic review and
metaanalysis. Neurosurg Rev. 2020.
68.
Goldstein JN, Refaai MA, Milling TJ, Jr., Lewis B, Goldberg-Alberts R, Hug BA, et
al. Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K
antagonist reversal in patients needing urgent surgical or invasive interventions: a
phase 
3b, 
open-label, 
non-inferiority, 
randomised 
trial. 
Lancet.
2015;385(9982):2077-87.
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Sarode R, Milling TJ, Jr., Refaai MA, Mangione A, Schneider A, Durn BL, et al.
Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on
vitamin K antagonists presenting with major bleeding: a randomized, plasma-
controlled, phase IIIb study. Circulation. 2013;128(11):1234-43.
70.
Kozek-Langenecker SA, Ahmed AB, Afshari A, Albaladejo P, Aldecoa C,
Barauskas G, et al. Management of severe perioperative bleeding: guidelines from
the European Society of Anaesthesiology: First update 2016. Eur J Anaesthesiol.
2017;34(6):332-95.
71.
American Society of Anesthesiologists Task Force on Perioperative Blood M.
Practice guidelines for perioperative blood management: an updated report by the
American Society of Anesthesiologists Task Force on Perioperative Blood
Management*. Anesthesiology. 2015;122(2):241-75.
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Pagano D, Milojevic M, Meesters MI, Benedetto U, Bolliger D, von Heymann C, et
al. 2017 EACTS/EACTA Guidelines on patient blood management for adult cardiac
surgery. Eur J Cardiothorac Surg. 2018;53(1):79-111.
73.
Cappabianca G, Mariscalco G, Biancari F, Maselli D, Papesso F, Cottini M, et al.
Safety and efficacy of prothrombin complex concentrate as first-line treatment in
bleeding after cardiac surgery. Crit Care. 2016;20:5.
74.
Biancari F, Ruggieri VG, Perrotti A, Gherli R, Demal T, Franzese I, et al.
Comparative Analysis of Prothrombin Complex Concentrate and Fresh Frozen
Plasma in Coronary Surgery. Heart Lung Circ. 2019;28(12):1881-7.
75.
Fries D. The early use of fibrinogen, prothrombin complex concentrate, and
recombinant-activated factor VIIa in massive bleeding. Transfusion. 2013;53 (Suppl
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Study Protocol No. LEX-211, Version 9.0 CONFIDENTIAL 
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76.
Thalji NK, Patel PA. Out of Control: Why Randomized Trials of Factor Concentrates
are So Elusive. J Cardiothorac Vasc Anesth. 2021;[Online ahead of
print.]:doi.org/10.1053/j.jvca.2021.06.011.
77.
Werner RS, Lipps C, Waldhans S, Kunzli A. Blood consumption in total arterial
coronary artery bypass grafting. J Cardiothorac Surg. 2020;15(1):23.
78.
Lewis KM, Li Q, Jones DS, Corrales JD, Du H, Spiess PE, et al. Development and
validation of an intraoperative bleeding severity scale for use in clinical studies of
hemostatic agents. Surgery. 2017;161(3):771-81.
79.
Karkouti K, Callum J, Wijeysundera DN, Rao V, Crowther M, Grocott HP, et al.
Point-of-Care Hemostatic Testing in Cardiac Surgery: A Stepped-Wedge Clustered
Randomized Controlled Trial. Circulation. 2016;134(16):1152-62.
80.
Weber CF, Gorlinger K, Meininger D, Herrmann E, Bingold T, Moritz A, et al. Point-
of-care testing: a prospective, randomized clinical trial of efficacy in coagulopathic
cardiac surgery patients. Anesthesiology. 2012;117(3):531-47.
81.
Majeed A, Agren A, Holmstrom M, Bruzelius M, Chaireti R, Odeberg J, et al.
Management
of
rivaroxaban-
or apixaban-associated major
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with
prothrombin complex concentrates: a cohort study. Blood. 2017;130(15):1706-12.
82.
Schulman S, Gross PL, Ritchie B, Nahirniak S, Lin Y, Lieberman L, et al.
Prothrombin Complex Concentrate for Major Bleeding on Factor Xa Inhibitors: A
Prospective Cohort Study. Thromb Haemost. 2018;118(5):842-51.
83.
Tao J, Bukanova EN, Akhtar S. Safety of 4-factor prothrombin complex concentrate
(4F-PCC) for emergent reversal of factor Xa inhibitors. J Intensive Care. 2018;6:34.
84.
Grassetto A, De Nardin M, Ganzerla B, Geremia M, Saggioro D, Serafini E, et al.
ROTEM(R)-guided coagulation factor concentrate therapy in trauma: 2-year
experience in Venice, Italy. Crit Care. 2012;16(3):428.
85.
Octapharma. Octaplex Product Monograph. 2017.
86.
Lubetsky A, Hoffman R, Zimlichman R, Eldor A, Zvi J, Kostenko V, et al. Efficacy
and safety of a prothrombin complex concentrate (Octaplex) for rapid reversal of
oral anticoagulation. Thromb Res. 2004;113(6):371-8.
87.
Kerebel D, Joly LM, Honnart D, Schmidt J, Galanaud D, Negrier C, et al. A French
multicenter randomised trial comparing two dose-regimens of prothrombin complex
concentrates in urgent anticoagulation reversal. Crit Care. 2013;17(1):R4.
88.
Riess HB, Meier-Hellmann A, Motsch J, Elias M, Kursten FW, Dempfle CE.
Prothrombin complex concentrate (Octaplex) in patients requiring immediate
reversal of oral anticoagulation. Thromb Res. 2007;121(1):9-16.
89.
Dyke C, Aronson S, Dietrich W, Hofmann A, Karkouti K, Levi M, et al. Universal
definition of perioperative bleeding in adult cardiac surgery. J Thorac Cardiovasc
Surg. 2014;147(5):1458-63.
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Ellenberg SS, Temple R. Placebo-controlled trials and active-control trials in the
evaluation of new treatments. Part 2: practical issues and specific cases. Ann Intern
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Freedman B. Placebo-controlled trials and the logic of clinical purpose. IRB.
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Burnouf T, Radosevich M. Nanofiltration of plasma-derived biopharmaceutical
products. Haemophilia. 2003;9(1):24-37.


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93.
Mariscalco G, Gherli R, Ahmed AB, Zanobini M, Maselli D, Dalen M, et al. Validation
of the European Multicenter Study on Coronary Artery Bypass Grafting (E-CABG)
Bleeding Severity Definition. Ann Thorac Surg. 2016;101(5):1782-8.
94.
Wassmer G, Brannath W. Group Sequential and Confirmatory Adaptive Designs in
Clinical Trials. Switzerland: Springer, Cham; 2016.
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Bauer P, Kieser M. A Unifying Approach for Confidence Intervals and Testing of
Equivalence and Difference. Biometrika. 1996;83(4):934-7.


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15 APPENDICES  
15.1 Appendix 1: Bleeding Score 

SAP_003.pdf: 
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LEX-211-SAP-v5.0/DOC ID 3810 
Confidential 
FActor REplacement in Surgery 
Four-Factor Prothrombin Complex Concentrate versus Frozen
Plasma in Bleeding Adult Cardiac Surgical Patients 
(“FARES-II” Study)
Study number: LEX-211 
Version 5.0 
Dated 28-Oct-2024
Previous versions: V4.0 (25-Apr-2023), V3.0 (29-Mar-2022), V2.0 (02-Feb-2022), V1.0 
(07-Sep-2021)
(According to Protocol Version 7.0, 17-Apr-2023 [US only]) and Version 8.0, 17-Apr-2023
[Canada only])
The contents of this document were approved by the following (approval date of document 
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STATISTICAL ANALYSIS PLAN 
LEX-211 
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Document history 
Version 
Date 
Author 
Description 
5.0 
28-Oct-2024
-
Updated definition of PP population
to clarify not all major protocol
deviations result in exclusion from
PP population
-
Added age group and race as
subgroups of interest
-
Added clarifications to endpoints in
section 10.3
-
Added AE summaries
-
Updated transformation of 1
apheresis unit of frozen plasma to 
allogeneic units 
4.0 
25-Apr-2023
-
Per protocol update, updated 
secondary endpoint time from IMP
initiation to leaving the operating 
room to time from IMP initiation to
arrival at ICU room
3.0 
29-Mar-2022
-
Addition of inclusion criterion to
specify that informed consent will be 
obtained prior to study enrolment in
patients at the US study sites 
-
Detailed description of interim
analysis and sample size
re-estimation procedures
-
Description of intercurrent events
and estimands
2.0 
02-Feb-2022
-
Change of test statistics for primary
endpoint to ensure maintenance of
overall type I error in case that
sample size re-estimation results in
substantial imbalance between
study stages,
-
Inclusion of details on estimands,
-
Explicitly adding a section on
sensitivity analyses.
1.0
07-Sep-2021
New document 


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Table of Contents 
1.
List of Abbreviations .......................................................................................................... 4 
2.
Introduction ........................................................................................................................ 5 
3.
Study Objectives ................................................................................................................ 6 
3.1. 
Primary Objective ................................................................................................................ 6 
3.2. 
Secondary Objectives.......................................................................................................... 6 
4.
Study Design ...................................................................................................................... 7 
4.1. 
Inclusion/Exclusion .............................................................................................................. 8 
4.1.1. 
Inclusion Criteria .......................................................................................................... 8 
4.1.2. 
Exclusion Criteria ......................................................................................................... 9 
4.2. 
Sample Size ........................................................................................................................ 9
4.3. 
Randomisation .................................................................................................................. 10
4.4. 
Study Assessments........................................................................................................... 10
5.
Endpoints.......................................................................................................................... 10
5.1. 
Primary Endpoint............................................................................................................... 10
5.2. 
Secondary Endpoints ........................................................................................................ 10
6.
Analysis Populations ....................................................................................................... 12
6.1. 
All Patients Population (APP) ............................................................................................ 13
6.2. 
Failed Consent Patients (FCP) Population ........................................................................ 13
6.3. 
Full Analysis Set (FAS) Population .................................................................................... 13
6.4. 
Safety (SAF) Population.................................................................................................... 14
6.5. 
Per-Protocol Set (PPS) ...................................................................................................... 14
6.6. 
Subgroup Analysis ............................................................................................................ 14
6.7. 
Protocol Deviations ........................................................................................................... 14
7.
Statistical Methods........................................................................................................... 14
7.1. 
Conventions ...................................................................................................................... 15
7.1.1. 
Baseline definition...................................................................................................... 15
7.1.2. 
Missing data .............................................................................................................. 15
7.2. 
IMP exposure, compliance ................................................................................................ 15
7.2.1. 
Medical history........................................................................................................... 15
7.3. 
Prior and concomitant medication ..................................................................................... 15
7.4. 
Interim Analysis................................................................................................................. 15
7.5. 
Software and analyses ...................................................................................................... 16
8.
Demographics and Baseline Characteristics ................................................................. 16
9.
Evaluation of Treatment Compliance and Exposure ..................................................... 16
10.
Evaluation of Efficacy ...................................................................................................... 16
10.1.
Estimand ................................................................................................................... 16 
10.2.
Primary Endpoint ....................................................................................................... 17 
10.3.
Secondary Endpoints ................................................................................................. 18 
10.4.
Sensitivity Analyses ................................................................................................... 20 
11.
Safety Analysis ................................................................................................................. 20 
11.1. 
Adverse events .......................................................................................................... 20 
11.2. 
Laboratory variables .................................................................................................. 21 
12.
Data Derivations and Data Transfer ................................................................................ 22 
13.
Tables, Figures and Lists ................................................................................................ 22 
14.
Changes from Analyses Specified in the Protocol ........................................................ 23 
15.
Quality Control ................................................................................................................. 23 
16.
References ........................................................................................................................ 23 
Appendix 1. Transformations/Derivations ................................................................................ 25 


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1. List of Abbreviations
Term 
Description
AE 
Adverse Event
ABC 
Allogenic Blood Component
ACB 
Aortocoronary Bypass
ALT 
Alanine Aminotransferase
ALP 
Alkaline Phosphatase 
ANOVA 
Analysis of Variance 
APE 
All Patients Enrolled
aPTT 
Activated Partial Thromboplastin Time
ASD 
Atrial Septal Defect
BMI 
Body Mass Index
BW 
Body Weight
CCA 
Complete Case Analysis 
CPB 
Cardiopulmonary Bypass 
CRF 
Case Report Form
CRO 
Contract Research Organisation
CT 
Clotting Time
DMP 
Data Management Plan
DOAC 
Direct Oral Anticoagulant
EXTEM 
ROTEM Test Assessing the Extrinsic Coagulation Pathway 
FAS 
Full Analysis Set
FCP 
Failed Consent Patients
FIBTEM 
Fibrin-Based ROTEM Test Extrinsically Activated with Tissue Factor and
Containing the Platelet Inhibitor Cytochalasin D 
FP 
Frozen Plasma
GLIM 
Generalised Linear Interactive Modelling 
IABP 
Intra-Aortic Balloon Pump
ICU
Intensive Care Unit
ID 
Identification 
IDSMC 
Independent Data and Safety Monitoring Committee
IgA 
Immunoglobulin A
IMP 
Investigational Medicinal Product
INR 
International Normalised Ratio
ITT 
Intention-To-Treat
IU 
International Units
MACE 
Major Adverse Cardiovascular Event


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Term 
Description
MCF 
Maximum Clot Firmness
MedDRA 
Medical Dictionary for Regulatory Activities
N 
Number of patients/events in a set
n 
Number of patients/events contributing to a particular output
PCC 
Prothrombin Complex Concentrate
POD 
Postoperative Day
PPS 
Per-Protocol Set
PT 
Prothrombin Time
RBC 
Red Blood Cell Concentrate
ROTEM 
Rotational Thromboelastometry 
SAE 
Serious Adverse Event
SAF 
Safety Analysis Population 
SAP 
Statistical Analysis Plan
SD 
Standard Deviation 
SOC 
System Organ Class 
TACO 
Transfusion-Associated Circulatory Overload 
TRALI 
Transfusion-Related Acute Lung Injury 
TEAE 
Treatment-Emergent Adverse Event
TEE 
Thromboembolic Event
TLF 
Tables, Listings, Figures 
UDPB 
Universal Definition of Perioperative Bleeding
2. Introduction
Cardiac surgery is frequently complicated by coagulopathic bleeding that often leads to excessive
blood loss, blood product transfusion and bleeding-related complications [1-4]. Coagulopathy during
cardiac surgery is caused by several factors, including the contact of blood with the cardiopulmonary
bypass (CBP) circuit, which activates the intrinsic and extrinsic coagulation pathways (despite the
use of heparin and heparin-coated circuits), causing excessive clot formation and breakdown. Other
contributory factors include haemodilution, hypothermia, blood loss, surgical trauma and use of
foreign substances such as aortic grafts causing the consumption of coagulation factors [5-9].
Replacement of coagulation factors is an important aspect of a multimodal approach to coagulopathy 
to reduce bleeding and transfusion [4, 10]. To replenish depleted coagulation factors and improve 
thrombin generation, two therapeutics, frozen plasma (FP) and prothrombin complex concentrate 
(PCC), are available. FP is currently the mainstay of therapy for patients with acquired 
coagulopathies in North America whereas PCC is the mainstay of therapy in much of Europe [11]. 
The purpose of the LEX-211 study is to determine whether the PCC, Octaplex, is clinically non-
inferior to FP with respect to haemostatic effectiveness when used to treat bleeding in cardiac 
surgical patients requiring coagulation factor replacement. Haemostatic management in bleeding 
surgical patients is evolving from empirical therapy with non-purified allogeneic blood products to 
targeted therapy with purified products that have undergone treatment with pathogen reduction 


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Page 6 of 25 
technologies [12]. The proposed study, by comparing two currently available but distinctly different 
therapies for treating bleeding surgical patients requiring coagulation factor replacement, is well 
aligned with this change. 
Given the potential advantages of PCC over FP, including viral inactivation, ease of administration,
standardised dosing/predictable effect and substantially lower risk of transfusion-related acute lung 
injury (TRALI) and transfusion-associated circulatory overload (TACO) due to smaller volume, as
well as the haemostatic superiority signals detected in observational studies and the recently 
completed FARES pilot randomised trial [13], a large multicentre trial adequately powered to
establish haemostatic superiority or non-inferiority is warranted. The need for such a trial was 
highlighted in a recent editorial [14], as it will have a profound impact on clinical practice, potentially
altering the long-established practice of administering FP for coagulation factor replacement in 
bleeding patients. If the study is positive, it will lead to the adoption of PCC over FP as first-line 
therapy for the management of bleeding surgical patients requiring coagulation factor replacement.
If it is negative, on the other hand, it will prevent the inappropriate adoption of PCC over FP for this
indication. Thus, the study will inform clinical practice and promote the rationale use of healthcare
resources.
3. Study Objectives
3.1. Primary Objective
1.
To demonstrate that the 4-factor prothrombin complex concentrate (PCC) Octaplex is
clinically non-inferior to frozen plasma (FP) with respect to haemostatic effectiveness, as 
measured by the need for post-therapy haemostatic interventions.
3.2.Secondary Objectives
1.
To compare global haemostatic response between the Octaplex and FP groups, as
measured by a composite of the need for post-therapy haemostatic interventions and drop 
in haemoglobin.
2.
To compare the amount of bleeding as measured by the amount of chest tube drainage
between the Octaplex and FP groups.
3.
To compare the incidence of severe to massive bleeding between the Octaplex and FP
groups.
4.
To compare efficacy in terms of the total number of allogeneic blood components transfused
between the Octaplex and FP groups.
5.
To compare efficacy in terms of the incidence and number of individual allogeneic blood
components transfused between the Octaplex and FP groups.
6.
To compare the incidence of use of other coagulation factor products between the Octaplex
and FP groups.
7.
To compare the incidence of other bleeding-related clinical endpoints, i.e., intracerebral
haemorrhage, gastrointestinal haemorrhage and surgical re-exploration, between the
Octaplex and FP groups.
8.
To compare the effect of Octaplex versus FP administration on the international normalised
ratio (INR) between the Octaplex and FP groups.
9.
To compare the effect of Octaplex versus FP administration on other coagulation parameters.
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10. To compare time from Investigational Medicinal Product (IMP) initiation to arrival in the ICU
between the Octaplex and FP groups.
11. To compare safety as measured by serious treatment-emergent adverse events (TEAEs)
between the Octaplex and FP groups.
12. To compare other secondary safety endpoints including duration of mechanical ventilation,
duration of intensive care unit (ICU) stay, duration of hospitalisation, incidence of death and
days alive and out of hospital between the Octaplex and FP groups.
4. Study Design
This is a multicentre, randomised, active-control, prospective, Phase 3 study in adult cardiac surgery 
patients. Approximately 12 hospitals will participate, and the study will require approximately two
years to complete. The study is planned to start in quarter 4, 2022 and to be completed in quarter 4,
2024.
The study will include adult (≥18 years old) patients who undergo cardiac surgery on CPB and require
coagulation factor replacement due to bleeding post-CPB and after adequate reversal of heparin
with protamine during surgery, and who have a known or suspected coagulation factor deficiency.
Patients will be randomised to receive either 4-factor PCC (Octaplex) or FP when the blood
bank/pharmacy receives the first order for coagulation factor replacement from the operating room
and patient eligibility is confirmed. IMP will be administered once treatment indications are met.
Patients will be treated according to their assigned group until the maximum dose of IMP is 
administered during the treatment period, which represents 24 hours after IMP initiation. If additional 
treatment is required after the maximum dose of IMP is administered or the treatment period has 
elapsed, patients in both groups will receive FP (Figure 1).
Other aspects of coagulation management will be according to a standardised transfusion algorithm.
Measurements of INR and haemoglobin will be performed at preestablished time points, if not
available already. No other aspects of care will be modified.


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1 FP in 1U increments as per the ordering physician
PCC, prothrombin complex concentrate; FP, frozen plasma; BW, body weight; IU, international units
4.1.Inclusion/Exclusion
4.1.1. Inclusion Criteria
Patients meeting the following criteria will be eligible for inclusion in the study:
1.
Adult (≥18 years old) patients undergoing any index cardiac surgery employing CPB
2.
Coagulation factor replacement with PCC or FP ordered in the operating room for:
a.
Management of bleeding, or
b.
Anticipated bleeding in a patient who has been on-pump for >2 hours or has
undergone a complex procedure (e.g., aortocoronary bypass [ACB] plus aortic valve
replacement)
3.
Coagulation factor deficiency, either known to exist (e.g., as indicated by elevated EXTEM
clotting time [CT] or INR) or suspected based on the clinical situation
4. Patients who have given written informed consent1
1 US sites only; in Canada informed consent will be obtained in accordance with Article 3.7A of the 2018 Tri-
Council Policy Statement on the Ethical Conduct for Research Involving Humans. 
Figure 1. Study flow 


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4.1.2. Exclusion Criteria 
Patients who meet any of the following criteria are not eligible for the study: 
1.
Undergoing heart transplantation, insertion or removal of ventricular assist devices (not
including intra-aortic balloon pump [IABP]) or repair of thoracoabdominal aneurysm
2.
Critical state immediately before surgery with high probability of death within 24 hours of
surgery (e.g., acute aortic dissection, cardiac arrest within 24 hours before surgery)
3.
Severe right heart failure (clinical diagnosis ± echocardiography)
4.
Known contraindications to heparin
5.
PCC required for reversal of warfarin or direct oral anticoagulant (DOAC; dabigatran,
rivaroxaban, apixaban or edoxaban) within 3 days prior to or during surgery
6.
Known thromboembolic event (TEE) within 3 months prior to surgery
7.
History of severe allergic reactions to PCC or FP
8.
Individuals who have immunoglobulin A (IgA) deficiency with known antibodies against IgA
9.
Refusal of allogeneic blood products
10. Known pregnancy
11. Currently enrolled in any other interventional clinical trials 
4.2. Sample Size 
The analysis of the primary efficacy endpoint will involve comparison of haemostatic treatment
response to IMP, defined as ‘effective’ if no additional haemostatic intervention, such as
administration of any systemic haemostatic agents (including platelets, cryoprecipitate, fibrinogen 
concentrate, activated recombinant factor VII, other coagulation factor products or a second dose
of IMP) or any haemostatic interventions (including surgical re-opening for bleeding) is required
from 60 minutes to 24 hours after initiation of the first dose of IMP.
Patients categorised as having an ‘ineffective’ haemostatic treatment response to IMP, due to
requiring administration of any haemostatic intervention in the time window from 60 minutes to 24
hours after initiation of the first IMP dose, will be considered as treatment failures.
Of the more than 100 patients studied in the FARES pilot study, approximately 75% of patients in
the PCC group and 65% in the FP group demonstrated haemostatic treatment response from 60
minutes to 24 hours after initiation of the first IMP dose [13]. Using a more conservative estimate of
70% versus 65%, it is estimated that 410 patients will be required to demonstrate non-inferiority with
a one-sided ɑ of 0.025, power of ≥90% and non-inferiority margin of 0.10 when using a Farrington-
Manning score test.
It is anticipated that up to 20% of randomised patients may not meet administration criteria (based 
on objective Bleeding Severity Scale and INR) due to cessation of haemorrhage between 
randomisation and delivery of IMP to the operating room and therefore will not receive the therapy 
or will withdraw consent.  
An administrative interim analysis will be carried out after approximately 50% of the target 
number of evaluable patients have been randomised and treated (100 patients enrolled in each 
group) and will be used to re-estimate the sample size or stop for futility (non-binding) (Section 


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7.4). The sample size in the second stage is limited to 210–800 evaluable patients. Accounting 
for dropouts as described above, the total sample size will range between 513–1250 if the study 
is not stopped for futility at the interim (see table below).  
Stage 1 
Stage 2 – Min-
imum 
Stage 2 – 
Maximum 
Total - Maxi-
mum 
Evaluable pa-
tients 
200 
210 
800 
1000 
Sample size 
including 20% 
dropouts  
250 
263 
1000 
1250 
4.3. Randomisation 
Eligible patients will be randomly assigned to receive either Octaplex or FP. Randomisation lists 
using a permuted-block, randomisation scheme (stratified by site) will be prepared by the
biostatistician. Sealed randomisation envelopes based on the randomisation lists will then be
provided to the blood banks/pharmacies of the participating centres who will be responsible for 
providing the IMP.
Patients will be identified using a sequential numbering system within the centre. Randomisation will 
then be performed in sequential order of the patient IDs.
4.4. Study Assessments 
An overview of all assessments during the study is contained in Table 1 of the study protocol. For
further details, observations and procedures per visit are described in section 6.1 and study
assessments are described in sections 7.1 to 7.3 of the study protocol.
5. Endpoints
5.1.Primary Endpoint 
1.
Comparison of haemostatic treatment response to Octaplex versus FP, defined as ‘effective’ 
if no additional haemostatic intervention, such as administration of any systemic haemostatic 
agents (including platelets, cryoprecipitate, fibrinogen concentrate, activated recombinant
factor VII, other coagulation factor products or a second dose of IMP) or any haemostatic 
interventions (including surgical re-opening for bleeding) is required from 60 minutes to 24
hours after initiation of the first dose of IMP.
5.2. Secondary Endpoints 
Efficacy endpoints 
1.
Comparison of global haemostatic response to Octaplex versus FP, defined as ‘positive’ if
no additional haemostatic intervention (as per the primary endpoint) is required and 
haemoglobin levels decrease by <30% (after accounting for red cell transfusions) from 60 
minutes to 24 hours after initiation of the first dose of IMP. 
2.
Comparison of the total amount of chest tube drainage at 12 and 24 hours after chest closure
between the Octaplex and FP groups. 


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3.
Comparison of the incidence of severe to massive bleeding, using a modification of the
universal definition of perioperative bleeding (UDPB) in cardiac surgery and its individual 
components during the first 24 hours after start of surgery, after the end of CPB and after 
IMP initiation, between the Octaplex and FP groups. 
4.
Comparison of the mean number of total allogeneic blood components – including red cells,
platelets and all (IMP and non-IMP) FP – administered during the first 24 hours after the end 
of CPB, between the Octaplex and FP groups. 
5.
Comparison of the mean number of total non-IMP allogeneic blood components – including
red cells, platelets and non-IMP FP – administered during the first 24 hours after the end of 
CPB, between the Octaplex and FP groups. 
6.
Comparison of the mean number of total non-IMP allogeneic blood components – including
red cells, platelets, cryoprecipitate and non-IMP FP – administered during the first 24 hours 
and 7 days after IMP initiation, between the Octaplex and FP groups. 
7.
Comparison of the mean number of individual allogeneic blood components – including red
cells, platelets, cryoprecipitate and non-IMP FP – administered during the first 24 hours and
7 days after the start of surgery, after the end of CPB and after IMP initiation, between the
Octaplex and FP groups. 
8.
Comparison of the incidence of transfusion of individual allogeneic blood components –
including red cells, platelets, cryoprecipitate and non-IMP FP – during the first 24 hours and
7 days after the start of surgery, after the end of CPB and after IMP initiation, between the
Octaplex and FP groups. 
9.
Comparison of the incidence of administration of non-IMP coagulation factor products –
including fibrinogen concentrate and activated recombinant factor VII – during the first 24
hours and 7 days after the start of surgery, after the end of CPB and after IMP initiation,
between the Octaplex and FP groups.
10. Comparison of the incidence of intracerebral haemorrhage during the first 24 hours after start
of surgery, after the end of CPB and after IMP initiation between the Octaplex and FP groups.
11. Comparison of the incidence of gastrointestinal haemorrhage during the first 24 hours after
start of surgery, after the end of CPB and after IMP initiation between the Octaplex and FP
groups.
12. Comparison of the incidence of surgical re-exploration during the first 24 hours after start of
surgery, after the end of CPB and after IMP initiation between the Octaplex and FP groups.
13. Comparison of the change in INR, from within 30 minutes before to within 60 minutes after
the initiation of IMP administration, between the Octaplex and FP groups; INR reduction will 
be considered successful if the magnitude of the reduction is >1.0 or the post-treatment level 
drops below 1.5. 
14. Comparison of the changes in other coagulation parameters, including prothrombin time
(PT), activated partial thromboplastin time (aPTT), fibrinogen activity, ROTEM EXTEM CT 
and maximum clot firmness (MCF) and platelets, from within 75 minutes before to within 75 
minutes after the initiation of IMP administration, between the Octaplex and FP groups. 
15. Comparison of time elapsed from initiation of the first dose of IMP to arrival at the ICU room
between the Octaplex and FP groups. 
Safety endpoints 
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All adverse events (AEs) and serious AEs (SAEs) will be collected from beginning of surgery (defined 
as entry into operating room) to postoperative day (POD)-30. 
1.
Comparison of the incidence of serious treatment-emergent adverse events (TEAEs),
individually and as composite where appropriate (e.g., TEEs and major adverse cardiac
events [MACE]), between the Octaplex and FP groups.
2.
Comparison of the duration of mechanical ventilation (measured as duration of ventilation
and ventilator-free days) up to POD-30 between the Octaplex and FP groups.
3.
Comparison of the duration of ICU stay up to POD-30 between the Octaplex and FP groups.
4.
Comparison of the duration of hospitalisation up to POD-30 between the Octaplex and FP
groups.
5.
Comparison of the incidence of death up to POD-30 between the Octaplex and FP groups.
6.
Comparison of the number of days alive and out of hospital at POD-30 between the Octaplex
and FP groups.
6. Analysis Populations
US Study Sites: 
At the US study sites, voluntarily given, written informed consent will be obtained from the patient
before any study-related procedures are conducted.
Canadian Study Sites: 
At the Canadian study sites, informed consent will be obtained from the patient or the patient’s legally 
authorised representative (LAR) as soon as possible after surgery. If neither the patient nor the LAR
is reachable for consent during the follow-up period, a family member who is not a LAR is to be
provided with an opportunity to object to the patient’s participation in the study.
Due to the emergency nature of the condition being studied (i.e., bleeding during surgery) the trial 
will include only patients who are incapable of providing informed consent at the time the therapy is
needed and in whom delays in obtaining surrogate consent can be severely detrimental to their well-
being. Thus, this study qualifies for alteration to consent requirement before randomisation, in
accordance with Article 3.7A of the 2018 Tri-Council Policy Statement on the Ethical Conduct for 
Research Involving Humans. Patient or LAR consent from all patients, including those untreated,
will be obtained at the earliest possible opportunity after surgery.
It is not possible to predict which patients will bleed due to coagulation factor deficiency, and 
once identified, any delays in therapy will lead to patient harm. The entire process from
termination of CPB to administration of the blood products is around 50 minutes. However, the 
time frame for therapy decision, and consequently for seeking consent from a LAR for the patient
to participate in the trial (meaning consent to randomisation and all study procedures thereafter),
is even shorter, as it consists of the 5–10 minutes in which coagulation assays are reviewed and 
a call is placed to the blood bank to order coagulation factors. Even if it were possible to contact
a LAR to seek consent during this time, the acuity of the situation would likely be highly stressful
to the LAR, which could preclude them from effectively making an informed decision regarding
consent. These factors make it essentially impossible to obtain prospective informed consent
from a LAR during the surgery.


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As a rule, only data from randomised and treated patients with informed consent will be analysed. 
Consented and randomised but untreated patients will not be included in the efficacy or safety 
analyses but will be followed for 30 days to determine between-group comparability in baseline 
characteristics and outcomes. 
To ensure that the safety reporting is complete, all haemostatic therapy and SAE data will be 
collected in cases where consent for remaining in the study cannot be obtained from Canadian sites 
due to logistical issues (e.g., patient died and a legally authorised representative could not be 
reached) and REB approval is obtained to collect the information. For Canadian patients who refuse 
consent, only treatment allocation data will be collected, and patients will not be included in any 
analyses. 
Hence, the disposition of patients will be displayed according to the following analysis populations:

All Patients population (APP)
•
Patients consented at the US study sites (US APP)
•
Patients randomised at the Canadian study sites (Canadian APP)

Failed Consent Patients (FCP) population

Full Analysis Set (FAS) population

Safety (SAF) population

Per-Protocol Set (PPS)
A final decision about the classification of protocol deviations and their consequences regarding
assignment of patients to analysis populations will be made during the data review meeting prior to 
the final analyses. All protocol deviations documented during the conduct of the study or identified
at the data review process prior to database lock will be reviewed and classified as minor or major
and with respect to their significance for the planned analyses. This classification of protocol
deviations is the joint responsibility of the clinical project manager, the study statistician, and
Octapharma’s responsible medical expert, and will be agreed and documented before the database
is locked and the statistical analyses are performed.
6.1.All Patients Population (APP) 
The AP population will include all patients regardless of the consent status. This population will only 
be used for displays of patient disposition. This population will also be separated by the country
where patients are enrolled, i.e., into the US APP, containing all patients screened and consented
at US sites, and the Canadian APP, containing all patients randomised to treatment at the Canadian 
sites.
6.2. Failed Consent Patients (FCP) Population 
The FCP population will consist of all randomised Canadian patients who receive at least one 
treatment with either PCC or FP for whom consent cannot be obtained (due to logistical reasons and 
if approved by the REBs). This population will only be used for displays of haemostatic therapy and 
serious adverse events. 
6.3. Full Analysis Set (FAS) Population 
The full analysis set (FAS) will be defined according to the intention-to-treat (ITT) principle and will 
consist of all randomised patients who provide consent and receive any amount of the intervention. 


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The FAS will serve as the primary analysis set. For patients who withdraw consent, data will be used 
up until the time consent is withdrawn. 
6.4. Safety (SAF) Population 
The safety analysis population (SAF) will be identical to the FAS. 
For patients who refuse consent only treatment allocation data will be collected and they will not be 
included in any of the analyses. 
6.5. Per-Protocol Set (PPS) 
The per-protocol set (PPS) will exclude all patients in the FAS with major deviations that may have
an impact on the primary endpoint (e.g., patients who receive an IMP different to the IMP assigned
by randomisation; patients who receive <50% of the planned dose; and patients who significantly
violate inclusion/exclusion criteria).
6.6. Subgroup Analysis 
The following subgroups will be analysed: sex (male/female); age group (<65 years/ ≥65 years),
race, urgency (elective/non-elective surgery); and complexity (simple/complex surgery [procedures
other than isolated ACB, single valve or repair of Atrial Septal Defect (ASD)]). Moreover, the impact
of CPB duration on effectiveness will be evaluated by assessing treatment effect based on CPB
duration increments (≤120 minutes, 121-180 minutes, >180 minutes).
6.7. Protocol Deviations 
No specific protocol deviations will be considered as this is a randomised, active-control, Phase 3
study.
Classification of protocol deviations as minor and major will be defined a priori. Patients with major
protocol deviations that may have an impact on the primary endpoint will be excluded from the per-
protocol analyses. The Sponsor and Independent Data and Safety Monitoring Committee (IDSMC) 
will review the number and nature of major protocol deviations and take appropriate measures to
minimise the impact on the study.
A complete listing of protocol deviations (documented as well as derived ones) and the judgement
for assessment of patient disposition will be signed before clinical database lock. A description of
protocol violations that led to exclusion from any analysis sets will be included in the table part of the
Clinical Study Report.
7. Statistical Methods 
All statistical analyses will be performed using the SAS® software (Version 9.4 or later).
The analysis of safety will be based on the FAS population.
The primary evaluation of overall efficacy will be performed on the FAS population. In addition, 
selected efficacy analyses will also be presented for the PPS population. 
If not stated otherwise, the following standard descriptive statistics will be presented: 
-
Descriptive statistics for continuous data
Number (N), mean, standard deviation (SD), min, lower quartile, median, upper quartile and max will 
be presented. These descriptive statistics will be determined for measured values and optionally for 
differences to baseline. 


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-
Descriptive statistics for categorical data
Absolute frequencies and percentages will be presented. Percentage bases (denominators) will be 
identified in the table title or footnote (i.e., all patients at risk, all non-missing cases, all cases). For 
changes from baseline, shift tables may be generated.  
-
Exploratory statistics
Although statistical methods are primarily descriptive, two-sided 95% confidence intervals may be 
presented for selected parameters (e.g., incidences of adverse events) in an exploratory manner.  
-
Listings
All recorded data will be listed by patient. Identification variable will be the patient ID. 
Derived data will be stored in special analysis data sets and will be calculated as outlined in
Appendix 1.
7.1.  
Conventions 
7.1.1. Baseline definition
Baseline will be defined as the last value on or prior to the first IMP administration.
7.1.2. Missing data 
In general, missing data will not be imputed. Due to the nature of the study, important variables are
expected to have few missing data. Only for the primary efficacy endpoint in addition to presentation 
of the primary and secondary endpoints for different analysis sets, multiple imputation methods, may
be used to impute missing values.
7.2. IMP exposure, compliance 
Dose and frequency of IMP administrations of PCC or FP will be summarised in appropriate tables
(summary statistics or frequency tables) for the FAS and PPS populations.
7.2.1. Medical history
Medical history findings will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) thesaurus in the version current at the time of study start. Coding will be performed by 
the CRO and agreed upon with the Sponsor before database lock (cf. Data Management Plan
[DMP]). The summary tables will display the medical history findings for pre-specified conditions by 
MedDRA System Organ class (SOC) and Preferred term. Displays will be presented for the FAS and
PP populations. Other medical history texts will only be listed.
7.3.Prior and concomitant medication
Medications will be coded using the WHO Drug Global thesaurus in the version current at the time
of study start. Coding will be performed by the CRO and agreed upon with the Sponsor before
database lock (cf. DMP). For concomitant medications, tables will show the frequencies of patients
by WHO preferred term. Prior medication will only be listed.
7.4. Interim Analysis 
An administrative unblinded interim analysis will be carried out when approximately 50% of the target 
number of evaluable patients have been randomised and treated (100 evaluable patients in each 
treatment group) by an independent statistician. Unblinded information will be communicated only to 
the IDSMC. Possible outcomes of this analysis are:  

The study may be stopped for futility after an evaluation of the sample size calculation at
the interim analysis.


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
The sample size will be re-estimated by the independent statistician.
The study cannot be stopped for efficacy at the interim analysis. 
The sample size re-estimation will be based on the evaluation of the conditional power, calcu-
lated as described in section 7.3 of [15] making use of the observed response rates and inverse 
normal combination test statistic with equal weights given by  
(-1(1 – p1) + -1(1 – p2))/2, 
where p1 and p2 denote the p-values for testing the non-inferiority null hypothesis for the first 
and the second stage of the trial, respectively. The aspired conditional power used for the new 
intended sample size will be 90%.  
A 20% dropout rate will be added to the re-estimated sample size of evaluable patients to receive
the number of patients to be enrolled in the second stage.
The minimum number of patients for the second stage is 210 evaluable subjects (even if the re-
estimated sample size is below this number) or 263 including dropouts. The sample size for the 
second stage cannot exceed 1250 patients (dropouts included). If the dropout adjusted re-esti-
mated sample size exceeds this threshold, the IDSMC may recommend to either stop the trial 
for futility or to enrol the maximum number of additional 1250 patients.
7.5.  Software and analyses 
All study data will be transferred to a SAS database (version 9.4 or later) for statistical analysis 
purposes. Data will be imported from an Electronic Data Capture System via validated SAS
programs. If applicable, external data will also be transferred to SAS for presentation of these data
in the statistical analyses.
The SAP will be finalised before any unblinded analysis, after agreement with the Sponsor.
8. Demographics and Baseline Characteristics
All available demographic data (sex, age, height and body mass index [BMI]) will be summarised in
appropriate tables (summary statistics or frequency tables) for the SAF, FAS and PPS populations.
9. Evaluation of Treatment Compliance and Exposure
All study treatment will be administered on-site by study-site staff, and all doses are to be
documented in the electronic CRF. Administered doses of Octaplex or FP will be recorded for every 
infusion, including dates, times and batch numbers; the batch numbers will be reported in the final
study report. Individual compliance will be derived from these entries and presented as a percentage
relative to the recommended dose. Summary statistics for treatment compliance will be displayed.
10.Evaluation of Efficacy 
10.1.
Estimand 
The components of the estimand are presented in 
Table 1 below.  
Table 1. 
Description of the primary estimand 
Population 
Bleeding cardiac surgery patients with valid informed consent requiring 
coagulation factor replacement randomized and treated with PCC or FP 
as defined by in- and exclusion criteria for this study 
Endpoint 
Haemostatic effectiveness, defined as the absence of any additional 
haemostatic interventions during the period from 60 minutes to 24 hours 
after administration of the first treatment
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Yes/No response 
Intercurrent 
events (ICE) 
Event 
Strategy 
Discontinuation from study or 
death 
Composite variable strategy: 
Haemostatic efficacy will be set to 
‘No’, if the patient discontinues for any 
reason or dies before end of 24-hour 
period. If discontinuation occurs after 
the 24-hour period, the response will 
be considered a valid response.
Receipt of study medication 
different from randomisation 
schedule 
Treatment policy strategy: 
Patients with this ICE will be followed 
until the end of the 24-hour period 
and their response will contribute to 
the analysis as collected and 
assigned to the randomised treatment 
group (ITT principle). 
Partial administration of study 
treatment 
Treatment policy strategy: 
Patients with this ICE will be followed 
until the end of the 24-hour period 
and their response will contribute to 
the analysis as collected. 
Population level 
summary 
Difference in proportions of patients with haemostatic effectiveness 
between the PCC and FP treatment group
 
   
10.2. 
Primary Endpoint 
The primary population for the analysis of the efficacy of the IMPs will be the FAS.  
The analysis of efficacy will focus on the following primary endpoint: 
P1. Comparison of haemostatic treatment response to Octaplex versus FP, defined as 
‘effective’ if no additional haemostatic intervention, such as administration of any 
systemic haemostatic agents (including platelets, cryoprecipitate, fibrinogen 
concentrate, activated recombinant factor VII, other coagulation factor products or a 
second dose of IMP) or any haemostatic interventions (including surgical re-opening 
for bleeding) is required from 60 minutes to 24 hours after initiation of the first dose of 
IMP. 
The non-inferiority of the primary endpoint ‘haemostatic response’ will be tested between the 
treatment groups by means of a one-sided Farrington-Manning score test with non-inferiority margin 
0.10 at a significance level of 2.5%, testing the null hypothesis as follows: 
H0: p(PCC) ≤ p(FP) – 0.10 will be tested against the alternative H1: p(PCC) > p(FP) – 0.10 
where p(PCC) and p(FP) denote the haemostatic response proportions in the PCC and FP treatment 
groups, respectively. 
At the end of the trial, the inverse normal test statistic with equal weights given by  
 
(-1(1 – p1) + -1(1 – p2))/2 


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is calculated, where p1 and p2 denote the p-values for testing the non-inferiority null hypothesis 
for the first and the second stage of the trial, respectively. If the test statistic exceeds the value 
1.96, non-inferiority is demonstrated (see [15]). 
Only in case that non-inferiority is demonstrated, i.e., the null hypothesis is rejected at the one-sided 
2.5% level of significance, superiority of PCC with regard to the primary endpoint will be investigated: 
H0: p(PCC) ≤ p(FP) will be tested against the alternative H1: p(PCC) > p(FP) 
The Farrington-Manning score test will be used to calculate a two-sided 95% confidence interval 
based on the inverse normal test statistic as given above. This confidence interval corresponds 
with the test decision for showing non-inferiority and/or superiority [16]. This hierarchical test 
procedure allows to perform the superiority test at the full alpha of 2.5%. 
10.3. 
Secondary Endpoints 
The following secondary efficacy endpoints will be explored: 
S1. Comparison of global haemostatic response to Octaplex versus FP, defined as 
‘positive’ if no additional haemostatic intervention (as per the primary endpoint) is 
required and haemoglobin levels decrease by <30% (after accounting for red cell 
transfusions) from 60 minutes to 24 hours after initiation of the first dose of IMP. The 
24-hour haemoglobin result will be reduced by 1 g/dL for each unit of RBC transfused 
from 60 minutes to 24 hours. 
S2. Comparison of the total amount of chest tube drainage at 12 and 24 hours after chest 
closure between the Octaplex and FP groups. 
S3. Comparison of the incidence of severe to massive bleeding, using a modification of 
the universal definition of perioperative bleeding (UDPB) in cardiac surgery and its 
individual components during the first 24 hours after start of surgery, after the end of 
CPB and after IMP initiation, between the Octaplex and FP groups. 
S4. Comparison of the mean number of total allogeneic blood components – including red 
cells, platelets and all (IMP and non-IMP) FP – administered during the first 24 hours 
after the end of CPB, between the Octaplex and FP groups. 
S5. Comparison of the mean number of total non-IMP allogeneic blood components – 
including red cells, platelets and non-IMP FP – administered during the first 24 hours 
after the end of CPB, between the Octaplex and FP groups. 
S6. Comparison of the mean number of total non-IMP allogeneic blood components – 
including red cells, platelets, cryoprecipitate and non-IMP FP – administered during 
the first 24 hours and 7 days after IMP initiation, between the Octaplex and FP groups. 
S7. Comparison of the mean number of individual allogeneic blood components – 
including red cells, platelets, cryoprecipitate and non-IMP FP – administered during 
the first 24 hours and 7 days after the start of surgery, after the end of CPB and after 
IMP initiation, between the Octaplex and FP groups. 
S8. Comparison of the incidence of transfusion of individual allogeneic blood components 
– including red cells, platelets, cryoprecipitate and non-IMP FP – during the first 24 
hours and 7 days after the start of surgery, after the end of CPB and after IMP initiation, 
between the Octaplex and FP groups. 


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S9. Comparison of the incidence of administration of non-IMP coagulation factor products 
– including fibrinogen concentrate and activated recombinant factor VII – during the 
first 24 hours and 7 days after the start of surgery, after the end of CPB and after IMP 
initiation, between the Octaplex and FP groups. 
S10. Comparison of the incidence of intracerebral haemorrhage during the first 24 hours 
after start of surgery, after the end of CPB and after IMP initiation between the 
Octaplex and FP groups. 
S11. Comparison of the incidence of gastrointestinal haemorrhage during the first 24 hours 
after start of surgery, after the end of CPB and after IMP initiation between the 
Octaplex and FP groups. 
S12. Comparison of the incidence of surgical re-exploration for bleeding during the first 24 
hours after start of surgery, after the end of CPB and after IMP initiation between the 
Octaplex and FP groups. 
S13. Comparison of the change in INR, from within 30 minutes before to within 60 minutes 
after the initiation of IMP administration, between the Octaplex and FP groups; INR 
reduction will be considered successful if the magnitude of the reduction is >1.0 or the 
post-treatment level drops below 1.5. 
S14. Comparison of the changes in other coagulation parameters, including PT, aPTT, 
fibrinogen activity, ROTEM EXTEM CT and MCF and platelets, from within 75 minutes 
before to within 75 minutes after the initiation of IMP administration, between the 
Octaplex and FP groups. For a given parameter, if there are multiple results in the 
window within 75 minutes before to initiation of IMP administration, the most recent 
result before IMP initiation will be used. If there are multiple results in the window within 
75 minutes after the initiation of IMP administration, the earliest result after IMP 
administration will be used.  
S15. Comparison of time elapsed from initiation of the first dose of IMP to arrival at the ICU 
room between the Octaplex and FP groups. Patients in the ICU at the time of first dose 
of IMP will be excluded from this analysis. 
The following analysis methods will be applied to the different endpoints, according to their data type: 
The analysis of categorical variables (S1, S3, S8, S9, S10, S11, S12) will present relative frequency 
tables and estimates of the proportions with 95% confidence intervals separately in the treatment 
groups. The proportions will be compared between the treatment groups in the context of a logistic 
regression model. 
The analysis of continuous variables (S2, S13, S14, S15) will present descriptive statistics of the 
sampling distribution and the differences between treatment groups. Also, 95% confidence intervals 
and results of F-test of the treatment group differences will be reported in the context of an ANOVA 
model. 
The analysis of integer count variables (S4, S5, S6, S7) will present descriptive statistics of the 
sampling distribution and the differences between treatment groups. Treatment group comparisons 
for variables (S4, S5, S6, S7) will be performed in the context of a counting regression model for the 
ABCs and their components (SAS PROC GENMOD with Negative-Binomial distribution). Tests and 
95% confidence intervals for the treatment group differences will be derived from this statistical 
model and reported.  


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10.4. 
Sensitivity Analyses 
The analysis results for the primary endpoint will be presented in different contexts. This will include 
those involving the different multiple imputation procedures for missing data, if needed. The analysis 
of the primary endpoint will be presented for the PPS. Haemostatic treatment response will also be 
summarized descriptively by study site.  
11. Safety Analysis 
All safety analyses will be based on the FAS population. If the SAF population differs from the FAS 
population, then only AE information will additionally be displayed for the SAF.  
All AEs and SAEs will be collected from beginning of surgery (defined as entry into OR) to POD-30. 
The analysis of safety will study the following endpoints: 
1. 
Comparison of the incidence of serious treatment-emergent adverse events (TEAEs), 
individually and as composite where appropriate (e.g., TEEs and MACE), between the 
Octaplex and FP groups. 
2. 
Comparison of the duration of mechanical ventilation (measured as duration of 
ventilation and ventilator-free days) up to POD-30 between the Octaplex and FP 
groups. 
3. 
Comparison of the duration of initial ICU stay up to POD-30 between the Octaplex and 
FP groups. 
4. 
Comparison of the duration of hospitalisation up to POD-30 between the Octaplex and 
FP groups. 
5. 
Comparison of the incidence of death up to POD-30 between the Octaplex and FP 
groups. 
6. 
Comparison of the number of days alive and out of hospital at POD-30 between the 
Octaplex and FP groups. 
 
11.1. 
Adverse events 
AEs will be coded according to the MedDRA. Coding will be agreed upon with the Sponsor before 
database lock (cf. DMP). 
All AEs recorded for patients in the SAF will be listed in the appendix of the study report, differentiated 
by treatment-emergent and non-treatment-emergent AEs.  
Only treatment-emergent AEs (TEAE) will be analysed, i.e., all new and worsening pre-existing AEs 
occurring after first IMP administration up to POD-30. It is assumed that for each increase in intensity 
of an AE a new entry of the AE will be recorded by the investigator; hence, such cases will be 
analysed like different phases of the same AE. 
A descriptive analysis will be performed. This analysis will comprise the following set of tables, 
separated by treatment group and time of first occurrence (within 48 hours, 7 days and 30 days post-
surgery): 
 
Global incidence  
 
Incidences by primary system organ classes (SOC) and incidences of preferred 
term within primary SOC sorted according to the Internationally Agreed Order 


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Global incidences of primary SOC and preferred terms will be calculated for 
 
All TEAE irrespective of the causality assessment 
 
TEAE by relationship (probable, possible, unlikely, not related and unclassified) 
 
TEAEs by worst severity 
 
Serious TEAEs 
 
TEAEs possibly or probably related per PI assessment 
 
TEAEs possibly or probably related per sponsor assessment 
 
TEAEs possibly or probably related per PI and/or sponsor assessment 
 
TEEs per PI assessment 
 
TEEs per MedDRA SMQ 
 
TEEs per sponsor assessment 
 
Treatment-emergent major adverse cardiac events (MACE) 
Multiple counts within a preferred term or SOC (repeated or different included terms or changes in 
descriptors) will be counted only once for the calculation of incidences. 
A listing of 'special cases' containing patient ID, age, sex, AE descriptors and start and end of 
treatment will be prepared for the following types of TEAEs: 
 
Fatal SAEs 
 
AEs which led to discontinuation 
 
Myocardial infarction 
 
Stroke 
 
Acute liver injury 
 
Acute kidney injury 
 
TEEs  
 
MACE 
 
TRALI 
 
TACO 
The number of patients who died will be summarised. A possible difference between treatment 
groups will be estimated by the risk ratio with 95% confidence interval. Kaplan-Meier estimates for 
the time to death distribution will be calculated and graphically presented. The incidence of death up 
to POD-30 will be calculated, as well as the incidence of death within 48 hours or 7 days, and special 
cause mortality. 
11.2. 
Laboratory variables 
In case of derived items in the database (e.g., after transformation to standard units, see DMP), only 
the derived items will be analysed. Results of all individual laboratory tests will be listed in original 
and standard units in appendix 16.2 to the clinical trial report. 
The following laboratory parameters will be analysed (as available from local laboratories): 


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Coagulation profile   
Point-of-care INR, PT, aPTT, INR, fibrinogen activity via Clauss assay,  
ROTEM EXTEM CT, ROTEM EXTEM MCF, ROTEM FIBTEM MCF, 
PlateletWorks platelet count and function 
Haematology  
 
Standard panel as per local laboratory 
Clinical chemistry 
 
Standard panel as per local laboratory 
Safety laboratory analyses 
Troponin, ALT/ALP, bilirubin, creatinine 
 
All laboratory values will be classified as normal or abnormal according to the laboratories’ reference 
ranges and indicated as clinically significant or not clinically significant by the investigator on 
specified ranges. The following approaches will be taken for each laboratory parameter for the 
statistical analysis: 
Quantitative data will be examined for trends using descriptive analysis (number of patients, number 
of missing values, mean, SD, median, quartiles, minimum, maximum) of actual values at each 
scheduled time point and changes from baseline to each scheduled time point. In addition, mean 
concentration vs. time profiles (including standard deviations) will be plotted by treatment to illustrate 
any time trends.  
Qualitative data based on reference ranges will be described according to the categories (i.e., low, 
normal, high).  
Shift tables will be generated illustrating changes with respect to the laboratories’ reference ranges 
between baseline and a defined scheduled time point.  
Patient listings will be provided showing individual laboratory abnormalities. 
12. Data Derivations and Data Transfer 
The results of all data transformations and derivations will be stored in analysis data sets. 
Laboratory data received electronically will be integrated into the database. 
13. Tables, Figures and Lists 
A complete List of Tables, Listings, Figures (TLFs) will be given in a separate document which can 
be updated without updating the SAP. The List will serve as a reference for the Sponsor, the Trial 
Statistician and the statistical programmer and describes the entire set of statistical output to be 
produced. Therefore, this List will be versioned and approved by both Ergomed and the Sponsor 
before commencing the statistical programming. 
Each output page will have an appropriate heading specifying the study ID and abbreviated study 
title. 
Each output page will show a common date and page numbers in the form 'Page [x / y]' where x 
denotes the current page within an output and y the total number of pages of that output. The output 
pages will not contain any other sequential page numbering. 
All statistical output will identify the underlying analysis set(s) and indicate the number of 
patients/events in this set (N) and the number of patients/events actually contributing to the particular 
output (n). 
All patient listings will contain, in addition to the patient ID, the treatment arm and the analysis set. 


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14. Changes from Analyses Specified in the Protocol 
The described statistical analyses match those pre-specified in the study protocol. 
15. Quality Control 
The SAP was reviewed by the Trial Statistician before signature. In particular, the Trial Statistician 
has checked the consistency of the described methods and outputs with the actual version of the 
study protocol. In addition, a Sponsor representative has reviewed the SAP before final approval. 
Log files of all SAS® programs used in the analysis will be checked for errors, warnings and 
suspicious notes by the statistical programmer. All findings will be either eliminated or commented 
upon. The final version of each program will be stored along with its log file in the electronic archive.  
All programs will be validated by the program author or an independent statistical programmer, 
depending on the requested validation level selected in the List of TLFs.  
The agreement of the program outputs with the SAP and their consistency and plausibility will be 
checked by the Trial Statistician. Moreover, the Trial Statistician will review the outputs regarding 
completeness, readability and comprehensibility. 
The described process is associated with the 'normal' level of program validation. Additional levels 
of quality control can be specified in the List of TLFs (Section 14) for individual outputs. 
 
16. References 
1. 
Stokes ME, Ye X, Shah M, Mercaldi K, Reynolds MW, Rupnow MF, et al. Impact of 
bleeding-related complications and/or blood product transfusions on hospital costs in 
inpatient surgical patients. BMC Health Serv Res. 2011;11:135. 
2. 
Karkouti K, Wijeysundera DN, Yau TM, Beattie WS, Abdelnaem E, McCluskey SA, et al. 
The independent association of massive blood loss with mortality in cardiac surgery. 
Transfusion. 2004;44(10):1453-62. 
3. 
Karkouti K, Arellano R, Aye T, Dupuis JY, Kent B, Lee TW, et al. Off-label use of 
recombinant activated factor VII in surgical and non-surgical patients at 16 Canadian 
hospitals from 2007 to 2010 (Canadian Registry Report). Can J Anaesth. 2014;61(8):727-
35. 
4. 
Society of Thoracic Surgeons Blood Conservation Guideline Task F, Ferraris VA, Brown 
JR, Despotis GJ, Hammon JW, Reece TB, et al. 2011 update to the Society of Thoracic 
Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical 
practice guidelines. Ann Thorac Surg. 2011;91(3):944-82. 
5. 
Hartmann M, Sucker C, Boehm O, Koch A, Loer S, Zacharowski K. Effects of cardiac 
surgery on hemostasis. Transfus Med Rev. 2006;20(3):230-41. 
6. 
Parr KG, Patel MA, Dekker R, Levin R, Glynn R, Avorn J, et al. Multivariate predictors of 
blood product use in cardiac surgery. J Cardiothorac Vasc Anesth. 2003;17(2):176-81. 
7. 
Johansson PI, Solbeck S, Genet G, Stensballe J, Ostrowski SR. Coagulopathy and 
hemostatic monitoring in cardiac surgery: an update. Scand Cardiovasc J. 2012;46(4):194-
202. 
8. 
Despotis G, Eby C, Lublin DM. A review of transfusion risks and optimal management of 
perioperative bleeding with cardiac surgery. Transfusion. 2008;48(1 Suppl):2S-30S. 
9. 
Bevan DH. Cardiac bypass haemostasis: putting blood through the mill. Br J Haematol. 
1999;104(2):208-19. 
10. 
Ghadimi K, Levy JH, Welsby IJ. Perioperative management of the bleeding patient. Br J 
Anaesth. 2016;117(suppl 3):iii18-30. 
11. 
Chowdary P, Tang A, Watson D, Besser M, Collins P, Creagh MD, et al. Retrospective 
Review of a Prothrombin Complex Concentrate (Beriplex P/N) for the Management of 


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Perioperative Bleeding Unrelated to Oral Anticoagulation. Clin Appl Thromb Hemost. 
2018;24(7):1159-69. 
12. 
Fries D. The early use of fibrinogen, prothrombin complex concentrate, and recombinant-
activated factor VIIa in massive bleeding. Transfusion. 2013;53 (Suppl 1):91S-5S. 
13. 
Karkouti K, Bartoszko J, Grewal D, Bingley C, Armali C, Carroll J, et al. Comparison of 4-
Factor Prothrombin Complex Concentrate With Frozen Plasma for Management of 
Hemorrhage During and After Cardiac Surgery: A Randomized Pilot Trial. JAMA Netw 
Open. 2021;4(4):e213936. 
14. 
Thalji NK, Patel PA. Out of Control: Why Randomized Trials of Factor Concentrates are So 
Elusive. J Cardiothorac Vasc Anesth. 2021;[Online ahead of print.]: 
doi.org/10.1053/j.jvca.2021.06.011. 
15. 
Wassmer G, Brannath W. Group Sequential and Confirmatory Adaptive Designs in Clinical 
Trials. Switzerland: Springer, Cham; 2016. 
16. 
Bauer P, Kieser M. A Unifying Approach for Confidence Intervals and Testing of 
Equivalence and Difference. Biometrika. 1996;83(4):934-7. 
 
 
 


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Appendix 1. Transformations/Derivations 
 
Formulas for derived variables: 
 
Variable
Definition / Derivation 
Response (24h) 
(Treatment response) 
= ‘Effective’ (‘Yes’) if no additional haemostatic intervention, such as 
administration of any systemic haemostatic agents (including platelets, 
cryoprecipitate, fibrinogen concentrate, activated recombinant factor VII, 
other coagulation factor products or a second dose of IMP) or any 
haemostatic interventions (including surgical re-opening for bleeding) is 
required from 60 minutes to 24 hours after initiation of the first dose of 
IMP. 
= ‘Ineffective’ (‘No’) otherwise.
Response (24h) 
(Global response) 
= ‘Positive’ (‘Yes’) if no additional haemostatic intervention (as per the 
primary endpoint) is required and haemoglobin levels decrease by <30% 
(after accounting for red cell transfusions) from 60 minutes to 24 hours 
after initiation of the first dose of IMP. 
= ‘Negative’ (‘No’) otherwise.
ABC(time frame) 
= Mean number of total Allogenic Blood Components (RBCs, Platelets 
and all [IMP and non-IMP] FP) transfused in specified time frame.
Non-IMP ABC(time 
frame) 
= Mean number of total non-IMP Allogenic Blood Components (RBCs, 
Platelets, Cryoprecipitate and non-IMP FP) transfused in specified time 
frame. 
Individual ABC(time 
frame) 
= Mean number of individual Allogenic Blood Components (RBCs, 
Platelets, Cryoprecipitate and non-IMP FP) transfused in specified time 
frame.
Incidence of 
ABC(time frame) 
= Incidence of transfusion of individual Allogenic Blood Components 
(RBCs, Platelets, Cryoprecipitate and non-IMP FP) in specified time 
frame. 
 
Transformations to be applied 
In order that the sim of Allogenic Blood Products and its constituents adequately represent the 
exposure to donors, the following transformations will be applied before any derivations:  
 
Platelets
1 apheresis unit
= 4 allogeneic units, 
1 non-apheresis unit 
= 4 allogeneic units 
Frozen plasma (used in transfusions):
 
1 apheresis unit
= 1 allogeneic unit, 
1 non-apheresis unit
= 1 allogeneic unit 
 
Transfusion units without any information about apheresis are handled as apheresis units.