Clinical trial NCT02740335
Conditions: Significant Bleeding Risk
Keywords: anticoagulant reversal urgent surgery invasive procedures vitamin K prothrombin complex concentrate four-factor prothrombin complex concentrate (4F-PCC)
Sponsor: Octapharma
Start date: 2017-06-08; Completion date: 2022-02-23
Enrollment: 208 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
To demonstrate that the efficacy of OCTAPLEX as a reversal agent in patients under Vitamin K Antagonist (VKA) therapy with the need for urgent surgery with significant bleeding risk is clinically non-inferior to that Beriplex® P/N (Kcentra).

Detailed description:
The primary objective of the study is to demonstrate that the efficacy of OCTAPLEX as a reversal agent in patients under Vitami n K Antagonist (VKA)therapy with the need for urgent surgery with significant bleeding risk is clinically non-inferior to that Beriplex® P/N (Kcentra).

The secondary objective of the study is to investigate the safety and tolerability of OCTAPLEX compared to Beriplex® P/N (Kcentra) in patients under Vitamin K Antagonist (VKA) therapy with the need for urgent surgery with significant bleeding risk.

Arms: arm 1: Participants to receive1 Octaplex infusion intravenously arm 2: Participants to receive1 Kcentra infusions intravenously
Interventions: intervention 1: Octaplex intervention 2: Beriplex P/N (Kcentra)
Intervention descriptions: intervention 1: OCTAPLEX will be administered by intravenous infusion at a rate of 0.12 mL/kg/min (\~3 units/kg/min), up to a maximum rate of 8.4 mL/min (\~210 units/min). intervention 2: Beriplex® P/N (Kcentra) will be administered by intravenous infusion at a rate of 0.12 mL/kg/min (\~3 units/kg/min), up to a maximum rate of 8.4 mL/min (\~210 units/min).

Protocol documents:
Prot_000.pdf: 
Property of Octapharma. Do not copy or distribute without written permission.
NOTE: This document contains confidential and proprietary information of Octapharma AG. Do not copy or distribute without 
written permission. 
File Name 090-CSP-LEX-209-V04/DOC ID 2715 
CLINICAL STUDY PROTOCOL 
STUDY TITLE
A Phase III, randomized, double-blind, multicenter study to assess the
efficacy and safety of OCTAPLEX, a four-factor prothrombin complex 
concentrate (4F-PCC), compared to the 4F-PCC Beriplex® P/N (Kcentra),
for the reversal of vitamin K antagonist induced anticoagulation in patients 
needing urgent surgery with significant bleeding risk.
Investigational Product: 
OCTAPLEX 
Indication: 
Reversal of anticoagulation due to vitamin K antagonists in 
patients needing urgent surgery associated with significant
bleeding risk.
Study Design: 
Prospective, multi-center, randomized, double-blind, active-
control, group-sequential, non-inferiority study.
Sponsor: 
Octapharma Pharmazeutika Produktionsges.m.b.H
Oberlaaer Strasse 235
A-1100 Vienna, Austria
Study Number: 
LEX-209
EudraCT and/or IND Number:
2016-002649-41/BB IND: 13323 
Development Phase:
Phase III 
Planned Clinical Start:
Quarter 4 2016 
Planned Clinical End:
Quarter 2 2021 
Date of Protocol:
19 Jan 2018 
Version:
 04 
Coordinating Investigator: 
UT Southwestern Medical Center, 
5323 Harry Hines Blvd 
Dallas, TX 75390, USA 
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 
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Version 04
No. LEX-209 
19-Jan-2018
ii 
STUDY OUTLINE 
Name of Sponsor/Company: 
Octapharma Pharmazeutika Produktionsges.m.b.H 
Oberlaaer Strasse 235 
A-1100 Vienna, Austria
Name of Investigational Product: OCTAPLEX 
Name of Comparator: Beriplex® P/N (Kcentra) 
Protocol Identification Code: LEX-209 
Name of Active Ingredient: Four-factor 
prothrombin complex concentrate  
Date of Final Protocol: 19-Jan-2018 
Title of Study: 
A Phase III, randomized, double-blind, multicenter study to assess the efficacy and safety of 
OCTAPLEX, a four-factor prothrombin complex concentrate (4F-PCC), compared to the 4F-
PCC Beriplex® P/N (Kcentra), for the reversal of vitamin K antagonist  induced 
anticoagulation in patients needing urgent surgery with significant bleeding risk. 
Indication: 
Reversal of vitamin K antagonist (VKA) induced anticoagulation in patients needing urgent 
surgery associated with significant bleeding risk. 
Number of Study Centre(s): 
Approximately 70 centers will participate in the study worldwide. 
Objectives: 
Primary 
The primary objective of the study is to demonstrate that the efficacy of OCTAPLEX as a 
reversal agent in patients under VKA therapy with the need for urgent surgery with significant 
bleeding risk is clinically non-inferior to Beriplex® P/N (Kcentra). 
Secondary 
The secondary objective of the study is to investigate the safety and tolerability of 
OCTAPLEX compared to Beriplex® P/N (Kcentra) in patients under VKA therapy with the 
need for urgent surgery with significant bleeding risk. 
Study Design: 
This study is a prospective, multi-center, randomized, double-blind, active-control, group-
sequential, non-inferiority study.  
Number of Patients: 
Enrollment of a total of 370 patients is planned (185 patients per treatment group). 
Patient Selection Criteria: 
Inclusion Criteria 
1. Male or female patients at least 18 years of age.
2. Patients currently on oral anticoagulation treatment with VKA of coumadin or
warfarin type.
3. Patients being admitted to the hospital or currently hospitalized where:
•
an urgent surgery carrying significant bleeding risk (≥50 mL expected blood loss
in normal coagulation state) is required as part of routine clinical care within 24
hours of the start of investigational medicinal product;
•
VKA withdrawal and use of oral or parenteral vitamin K alone to reverse
anticoagulation is deemed too slow or inappropriate for reversal;


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Study Protocol 
CONFIDENTIAL 
Version 04
No. LEX-209 
19-Jan-2018
iii 
Name of Sponsor/Company: 
Octapharma Pharmazeutika Produktionsges.m.b.H 
Oberlaaer Strasse 235 
A-1100 Vienna, Austria
Name of Investigational Product: OCTAPLEX 
Name of Comparator: Beriplex® P/N (Kcentra) 
Protocol Identification Code: LEX-209 
Name of Active Ingredient: Four-factor 
prothrombin complex concentrate  
Date of Final Protocol: 19-Jan-2018 
4. Patients with an international normalized ratio (INR) of 2.0 or above at the time of
decision to reverse the anticoagulation status.
5. Patients who have given written informed consent and who are able and willing to
comply with the procedures described in the study protocol.
Exclusion Criteria 
1. Patients with a life expectancy of less than 48 hours per physician’s judgment (e.g.
patients with a Glasgow Coma Scale equal to 3 or a Head Abbreviated Injury Score of
6, patients requiring continuous inotropic or pressor support, and patients whose status
is post cardiac arrest).
2. Patients for whom the planned surgery or procedure is commonly associated with a
very low bleeding risk (e.g. catheter placement, gastroscopy).
3. Patients with a history of thromboembolic events (TEEs), myocardial infarction,
unstable angina pectoris, critical aortic stenosis, cerebrovascular accident, transient
ischemic attack, severe peripheral vascular disease (e.g. Fontaine IV), or disseminated
intravascular coagulation within 3 months of enrollment. (Note: ongoing thrombosis
in-situ or severe unilateral peripheral arterial disease (PAD) undergoing surgical
intervention is not an exclusion criterion).
4. Patients with a known congenital bleeding disorder.
5. Patients with a known antiphospholipid antibody syndrome.
6. Patients with present or past specific factor inhibitor activity.
7. Patients with thrombocytopenia of <80,000/μL or history of heparin-induced
thrombocytopenia.
8. Patients who have received more than 5000 units of systemic unfractionated heparin
(UFH), any dose of low-molecular-weight heparin (LMWH) or any dose of non-VKA
anticoagulant (i.e. direct oral anticoagulant) within 24 hours prior to enrollment into
the study or with potential need to receive these medications in mentioned doses before
completion of hemostasis evaluation at the end of surgery.
9. Patients who have received prothrombin complex concentrates (PCCs), fresh frozen
plasma or vitamin K within 72 hours prior to enrollment into the study.
10. Patients receiving P2Y12 platelet inhibitors (e.g. Clopidogrel, Prasugrel, Ticagrelor)
11. Patients with a known history of hypersensitivity to plasma-derived products.
12. Patients requiring urgent surgical procedures where according to the surgeon's clinical
judgment an accurate estimate of expected blood loss and transfusion requirements is
not possible, e.g.:
a.
Surgeries requiring massive transfusion protocols (e.g., major polytrauma,
major injuries, organ transplant surgeries),
b. Patients with acute major bleeding (e.g., gastrointestinal bleeds, obstetric
haemorrhage),


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Study Protocol 
CONFIDENTIAL 
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No. LEX-209 
19-Jan-2018
iv 
Name of Sponsor/Company: 
Octapharma Pharmazeutika Produktionsges.m.b.H 
Oberlaaer Strasse 235 
A-1100 Vienna, Austria
Name of Investigational Product: OCTAPLEX 
Name of Comparator: Beriplex® P/N (Kcentra) 
Protocol Identification Code: LEX-209 
Name of Active Ingredient: Four-factor 
prothrombin complex concentrate  
Date of Final Protocol: 19-Jan-2018 
c.
Surgeries with unpredictable intraoperative blood loss (e.g., ruptured
aneurysm, primary surgery for intracranial hemorrhage (ICH)).
13. Pregnant or nursing women.
14. Patients participating in another interventional clinical study currently or during the
past 30 days prior to enrollment into this study.
15. Patients previously enrolled in this study.
Test Product, Dose, Mode of Administration, and Batch Number(s): 
OCTAPLEX (500 IU) is to be reconstituted with 20 mL Water for Injection. 
The OCTAPLEX dose will depend on the body weight (BW) and baseline INR (INR0) of the 
patient and will be calculated by the responsible treating investigator according to the 
following dosing table. BW should be rounded to the nearest whole kilogram number for IMP 
dose calculation. Baseline INR value should be rounded to the 1st decimal place. 
Baseline INR 
2 to <4 
4-6
>6
Dose (IU of Factor IX/kg BW) 
25 
35 
50 
Maximum dose (IU of Factor IX) 
2500 
3500 
5000 
OCTAPLEX will be administered by intravenous (IV) infusion at a rate of 0.12 mL/kg/min 
(~3 units/kg/min), up to a maximum rate of 8.4 mL/min (~210 units/min). The total 
OCTAPLEX volume used and time of infusion will be recorded. Batch numbers for 
OCTAPLEX will be reported in the final clinical study report. 
Reference Therapy, Dose, Mode of Administration, and Batch Number(s): 
Beriplex® P/N (Kcentra) (500 IU) is to be reconstituted with 20 mL Water for Injection. The 
Beriplex® P/N (Kcentra) dose will depend on the BW and INR0 of the patient and will be 
calculated by the responsible treating investigator according to the following dosing table. 
BW should be rounded to the nearest whole kilogram number for IMP dose calculation. 
Baseline INR value should be rounded to the 1st decimal place. 
Baseline INR 
2 to <4 
4-6
>6
Dose (IU of Factor IX/kg BW) 
25 
35 
50 
Maximum dose (IU of Factor IX) 
2500 
3500 
5000 
Beriplex® P/N (Kcentra) will be administered by IV infusion at a rate of 0.12 mL/kg/min (~3 
units/kg/min), up to a maximum rate of 8.4 mL/min (~210 units/min). The total Beriplex® P/N 
(Kcentra) volume used and time of infusion will be recorded. Batch numbers for 
Beriplex® P/N (Kcentra) will be reported in the final clinical study report. 
Duration of Treatment: 
Only a single administration of study drug is planned per patient. The dose of study drug will 
depend on the baseline INR and patient BW, and will conform to the dosing table. Both 


Property of Octapharma. Do not copy or distribute without written permission.
Study Protocol 
CONFIDENTIAL 
Version 04
No. LEX-209 
19-Jan-2018
v 
Name of Sponsor/Company: 
Octapharma Pharmazeutika Produktionsges.m.b.H 
Oberlaaer Strasse 235 
A-1100 Vienna, Austria
Name of Investigational Product: OCTAPLEX 
Name of Comparator: Beriplex® P/N (Kcentra) 
Protocol Identification Code: LEX-209 
Name of Active Ingredient: Four-factor 
prothrombin complex concentrate  
Date of Final Protocol: 19-Jan-2018 
treatments will be administered in a blinded fashion. A concomitant administration of vitamin 
K is to be administered, unless the patient requires resumption of VKA anticoagulation within 
24 hours after surgery. Vitamin K should be administered within 1 hour before or within 1 
hour after investigational medicinal product (IMP) infusion at a dose of 2, 5, or 10 mg 
according to local clinical practice. The preferred route for vitamin K administration is by 
slow IV infusion. If vitamin K is not administered, the reason must be documented.  
Study Outcome Parameters (Efficacy and Safety  Endpoints): 
Efficacy: 
The primary efficacy endpoint is the hemostatic efficacy rating at the end of the surgery. 
Efficacy will be rated by the investigator at the end of the surgery in a blinded manner based 
on a 4-point hemostatic efficacy scale taking into account blood loss and transfusion 
requirements in the context of the surgery. 
The hemostatic efficacy rating will also be assessed by an independent endpoint adjudication 
board (IEAB) consisting of clinical experts. All adjudications will be conducted in a blinded 
manner and the IEAB will be provided with all relevant details (e.g., duration of surgery, co-
medication, medical history, predicted and actual blood loss, and transfusion information) of 
the patient and the actual procedure performed1 covering the time period up to the end of the 
surgery, as documented in the anesthesia record. To ensure the effectiveness of blinding and 
avoid potential bias, the INR and prothrombin time values will not be provided to the IEAB. 
The dichotomized final adjudicated hemostatic efficacy rating from the IEAB will serve as 
the primary efficacy variable for the statistical analysis. The concordance or discordance of 
the investigator and the IEAB ratings will also be determined as part of the final analysis; the 
IEAB will be kept blinded to the investigator’s rating.  
Secondary efficacy endpoints are: 
•
Proportion of patients with an INR value of less than or equal to 1.5 at 30 (± 15)
minutes after the end of infusion.
•
Change in coagulation factor levels from baseline to 30 (± 15) minutes after the end
of infusion:
o
Factor FII
o
Factor FVII
o
Factor FIX
o
Factor FX
•
Proportion of patients receiving red blood cells (RBC) during the surgery
1 A detailed description of the information to be provided to the IEAB will be developed with the clinical experts 
and will be included in an IEAB charter. 


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Study Protocol 
CONFIDENTIAL 
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No. LEX-209 
19-Jan-2018
vi 
Name of Sponsor/Company: 
Octapharma Pharmazeutika Produktionsges.m.b.H 
Oberlaaer Strasse 235 
A-1100 Vienna, Austria
Name of Investigational Product: OCTAPLEX 
Name of Comparator: Beriplex® P/N (Kcentra) 
Protocol Identification Code: LEX-209 
Name of Active Ingredient: Four-factor 
prothrombin complex concentrate  
Date of Final Protocol: 19-Jan-2018 
Exploratory endpoints are: 
•
Change in INR from baseline.
•
Change in Protein C (PC), and Protein S (PS) from baseline to 30 (± 15) minutes after
the end of infusion.
•
Change in coagulation factor levels (FII, FVII, FIX, FX, PC, and PS) from baseline to
2, 4, 12, and 24 hours after end of infusion.
•
Assessment of blood loss after end of surgery.
•
Proportion of patients receiving plasma and platelets transfusions initiated during the
surgery.
•
Total volume of RBC and other blood product transfusions initiated during the surgery
normalized by patient's BW.
•
Change in hematological parameters (hemoglobin (Hgb), hematocrit, RBC, white
blood cells [WBC], platelets) from the beginning to the end of the surgery.
•
RBC transfusion corrected change from baseline in Hgb at 12 and 24 hours after start
of surgery.
•
Proportion of patients experiencing surgical wound hematoma requiring surgical
evacuation.
•
Ratio of actual estimated blood loss as documented after surgery to the pre-operative
predicted blood loss.
Safety: 
Clinical safety will be assessed using the following endpoints: 
•
Occurrence of adverse events (AEs).
•
Occurrence of TEEs (overall, within 3, 21, and 45 days after end of surgery).
•
Mortality (overall, within 3, 21, and 45 days after end of surgery).
•
Monitoring vital signs, laboratory parameters.
•
Viral safety (at baseline, and Day 9 (-2/+5 days) after administration of IMP for
patients with negative baseline virology test).
Summary of Study Procedures and Statistical Analysis Plan: 
Study Procedures: 
A maximum of 370 patients will be enrolled (185 patients per treatment group). One group 
will receive OCTAPLEX and the other group will receive Beriplex® P/N (Kcentra). 
Patients will be on oral anticoagulant therapy with VKA and will need to undergo an urgent 
surgery that bears a significant risk of bleeding (≥50 mL expected blood loss). 


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Study Protocol 
CONFIDENTIAL 
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No. LEX-209 
19-Jan-2018
vii 
Name of Sponsor/Company: 
Octapharma Pharmazeutika Produktionsges.m.b.H 
Oberlaaer Strasse 235 
A-1100 Vienna, Austria
Name of Investigational Product: OCTAPLEX 
Name of Comparator: Beriplex® P/N (Kcentra) 
Protocol Identification Code: LEX-209 
Name of Active Ingredient: Four-factor 
prothrombin complex concentrate  
Date of Final Protocol: 19-Jan-2018 
The intent of the physician performing the procedure is to start the surgery within 3 hours 
after the end of 4F-PCC administration. 
At least 40% of all patients enrolled will be scheduled for an urgent surgery with expected 
blood loss of ≥200 mL. At least 20% of all patients enrolled will be scheduled for an urgent 
surgery with expected blood loss of ≥100 mL but <200 mL. At most 40% of all patients 
enrolled will be scheduled for an urgent surgery with expected blood loss ≥50 mL but 
<100 mL. 
After determination of the acceptability for the study, patients have to give their written 
informed consent and must meet the inclusion criteria of the study. Written informed consent 
must be obtained from the patient. 
The qualifying INR (INR available at the time of decision to reverse the anticoagulation 
status) should be used for the decision to enroll a patient into the study. Treatment allocation 
will then be performed by an Interactive Response Technology (IRT) where the patient will 
be assigned to one of the 2 treatment groups with equal probability (i.e., 1:1). In order to 
achieve a balance between the 2 treatment groups with respect to the planned type of surgery 
and history of TEE, the treatment allocation by the IRT will be stratified according to the 
parameters ‘Expected blood loss (“≥200 mL”, “≥100 mL but <200 mL” or “≥50 mL but 
<100 mL”)’,  ‘History of TEE (“yes” or “no”)’ and ‘Type of planned surgery (“orthopaedic 
surgery”, “cardiothoracic surgery” or “other surgery”).  To ensure that the intended 
proportions of patients enrolled are kept for subgroups of expected blood loss,  the IRT will 
preclude enrollment into the subgroup once its targeted number of enrolled patients is reached. 
The same applies to the population considered in the interim analysis. 
Details on the patient's medical history (especially occurrence of previous TEEs), the current 
clinical status, the expected amount of blood loss (mL) due to the surgery, the reason for, 
duration and time of last administration of anticoagulant therapy and details about 
concomitant medication should be recorded. Baseline measurements will be performed for all 
relevant parameters within 3 hours before administration of study drug. 
The dose of study drug to be administered will be calculated by the responsible treating 
investigator based on the patient's BW and baseline INR according to the recommended 
dosing table. Based on the calculated dose and the assigned treatment code, the IMP will be 
prepared in a manner that will blind the investigator to the study treatment. 
After baseline measurements, blood samples and the administration of IMP, blood samples 
will be taken for safety assessments, coagulation tests and for factor level measurements at 
pre-defined time points. All relevant details of the surgery will be recorded. The time and 


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Study Protocol 
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19-Jan-2018
viii 
Name of Sponsor/Company: 
Octapharma Pharmazeutika Produktionsges.m.b.H 
Oberlaaer Strasse 235 
A-1100 Vienna, Austria
Name of Investigational Product: OCTAPLEX 
Name of Comparator: Beriplex® P/N (Kcentra) 
Protocol Identification Code: LEX-209 
Name of Active Ingredient: Four-factor 
prothrombin complex concentrate  
Date of Final Protocol: 19-Jan-2018 
amount of all blood and plasma products given during and after the surgery will be recorded 
in the Case Report Form, as well as the reason and timing for their administration. An 
assessment of the hemostatic efficacy of the study treatments based on the provided guidance 
document (see Section 7.2.1), including the 4-point hemostatic efficacy scale, will be recorded 
by the investigator after the surgery. 
Clinical safety will be assessed by monitoring vital signs, laboratory parameters, and by 
documenting AEs and vital status. 
Statistical Analysis: 
The primary efficacy variable is the hemostatic efficacy as assessed by the IEAB. The 
hemostatic efficacy is to be assessed based on objective criteria in the categories 'excellent', 
'good', 'moderate' or 'none'. Ratings of 'excellent' and 'good' will be considered as 'effective' 
hemostasis, while a rating of 'moderate' and 'none' will be considered as 'ineffective' 
hemostasis. 
The dichotomous 'hemostatic success' variable will be used in the analyses. 
To demonstrate that treatment with OCTAPLEX is clinically not inferior to treatment with 
Beriplex® P/N (Kcentra) with respect to hemostatic success, a two-sample, one-sided test of 
the pair of hypotheses: 
H0: 
pK – pO ≥ δ (inferiority) 
vs.  
H1: 
pK – pO < δ (non-inferiority) 
will be carried out with a type I error probability of α = 0.025 and clinical non-inferiority 
margin of δ = 0.15. Whereby pO and pK present the probabilities of hemostatic success of 
OCTAPLEX and Beriplex® P/N (Kcentra), respectively. 
The study employs a sequential design that allows one pre-planned interim analysis using the 
data from the first 50% of randomized patients. The interim analysis will be performed on the 
cohort of the first 185 randomized patients after documentation of the primary endpoint has 
been performed. See Section 9.4 for details. 
Farrington’s and Manning’s test for difference in proportions will be used to assess the 
primary hypothesis in the interim and final analyses. One-sided p-values and the 
corresponding nominal and repeated confidence intervals (CIs) for the difference in 
hemostatic success probabilities will be presented. 
The primary analysis will be performed on the intent-to-treat (ITT) population. Additional 
analyses will be performed for the modified intent-to-treat (mITT) and per-protocol (PP) 
population. 


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Study Protocol 
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ix 
Name of Sponsor/Company: 
Octapharma Pharmazeutika Produktionsges.m.b.H 
Oberlaaer Strasse 235 
A-1100 Vienna, Austria
Name of Investigational Product: OCTAPLEX 
Name of Comparator: Beriplex® P/N (Kcentra) 
Protocol Identification Code: LEX-209 
Name of Active Ingredient: Four-factor 
prothrombin complex concentrate  
Date of Final Protocol: 19-Jan-2018 
In case of non-inferiority in the ITT, mITT and the PP population a “tipping point” analysis 
will be done to determine the robustness of the results. Iteratively patients excluded from the 
mITT analysis assigned to the control arm will be considered as treatment successes, and 
patients excluded from the mITT analysis and assigned to the OCTAPLEX arm will be 
considered as treatment failures, to determine the number of such imputed outcomes required 
to “tip” the study result from positive to negative in the randomized population. 
Farrington’s and Manning’s test for difference in proportions will be used to test the secondary 
variables on proportions. Point estimates and two-sided 95% CIs will be presented in addition 
to descriptive statistics for these endpoints. 
Analysis of the secondary and further exploratory endpoints will be done on the ITT and 
mITT, and PP populations unless indicated otherwise. These analyses will be exploratory, by 
presenting descriptive statistics. 
Safety analyses will be performed for the Safety Analysis Set. Analyses will generally be 
descriptive. For TEEs and mortality, a possible difference between treatment groups will be 
estimated by a risk ratio with 95% CI and Kaplan-Meier estimates for time to event will be 
calculated and graphically presented. 
The Statistical Analysis Plan details the full analysis to be performed. This analysis plan is 
available as a separate document. 
The study assessments and scheduled time points are summarized in the Flow Chart: 


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Study Protocol 
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FLOW CHART 
Table 1: Overview of Study Assessments and Time Points 
Before Infusion 
Infusion 
After END of Infusion 
OP 1 
POST OPERATIVE 2 
FOLLOW-UP 
Screening / 
Randomisation 
Baseline 
30 min  
after END 
2h after 
END 
4h after 
END 
12h after 
END 
24h after 
END 
Prior OP 
Post OP 
12h after 
START 
24h after  
START 
Day 2  Day  4 
Discharge 
Day  9 Day 21 
Day 45 
within 3h 
prior infusion 
± 15 min  ± 30 min 
± 30 min 
± 1 h 
± 2 h 
- 1h 
+1h
± 3h  
± 3h  
-2/+5 
days
± 1 
week 
± 1 week 
Informed Consent 
X 
Collect Baseline Information 
X 3 
Inclusion/Exclusion Criteria 
X 
Hemostatic Assessment 
X 
X 
Screening Registration 
X 
Physical Examination 
X 
X 
X 
IMP dose calculation,  Randomization 
 X 4 
IMP assignment, preparation 
X 
Vital Signs 
X 
X 
X 
X 
X 
Local 
Lab 
Coagulation Factors 5 
PT, INR, aPTT 
X 4 
X 
X 
X 
X 
X 
X 6 
X 6 
Hematology 5
Hct, Hgb, RBC, WBC, Platelets 
X 
X 
X 
X 
X 
X 
X 
X 7 
X 
Liver Function & Electrolytes 
LDH, Sodium, Potassium 
X 
X 
X 7 
X 
Kidney Function 
BUN or Urea, Creatinine 
X 
X 
X 7 
X 
Pregnancy Test 
X 8 
C. 
Lab 
Coagulation Factors 
X 
X 
X 
X  
X  
X  
Virology tests 
X 
X 9 
Vitamin K Administration 
X 10 
IMP Infusion 
X 11 
Wound Drainage Evaluation 
X 
X 
X 
Hematoma Assessment 
X 
X 
X 
X 
Concomitant  Medications  and 
Transfusions 12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X13 
X13 
X13 
AEs, Vital Status  
-----------------------------------------------------------------------------X 14 ------------------------------------------------------------------------------- 


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1  Time of surgery start is time of anesthesia initiation. Time of surgery end is surgical end time of principal procedure. 
2
Assessments at Days 1, 2, or 4 are done if patient remains hospitalized. Discharge assessments should be done at the day of discharge. If discharge falls on Days 1, 2, or 4, schedule 
of discharge assessments should be followed. 
3
Baseline information includes collection of demographics, medical history, prior and concomitant medication use, determination of vitamin K administration details (see Section 7.1).
4
If baseline INR value is not available when patient must be randomized to initiate preparation of IMP, qualifying INR (used for inclusion of the patient) can be used. Baseline INR
test can be skipped if qualifying INR is taken within 3 hours before IMP infusion start and was analyzed by local laboratory participating in the study. If initial IMP dose calculation
was based on qualifying INR and later Baseline INR was performed it must be checked whether IMP dose requires adjustment due to INR change. If required, IMP dose must be 
adjusted to Baseline INR and revised INR and IMP dose registered using IRT.
5
Results of hematology and coagulation factors blood tests performed as part of standard patient care should be documented in eCRF.
6  Prior OP/Post OP coagulation samples can be skipped if one of the After the END of Infusion samples is scheduled within its time window.
7
Samples will not be done if patient has been discharged earlier. Discharge visit samples should be taken at the day of discharge.
8
Urine or blood pregnancy test should be done only in women of childbearing potential (WOCBP). See Section 7.3.9 for definition of WOCBP status.
9
Day 9 Virology tests should only be done in patients who had at least one negative result of Baseline Virology tests (See Section 7.3.7)
10 Vitamin K can be administered within timeframe ±1h of IMP infusion. For patients with mechanical heart valve, LVAD or any other hypercoagulable/prothrombotic condition
administration of vitamin K is not mandatory. 
11 If reconstituted IMP not used within 4 hours following reconstitution it should be discarded and new IMP assigned via IRT.
12 Transfusions should be collected during hospitalization for the original admission.
13 Only concomitant medications related to ongoing AE should be recorded.
14 AEs are to be followed-up until Day 4. Serious adverse events (SAEs) are to be followed-up until Day 45. Note: If TEEs are suspected at any time during the study, appropriate 
examinations according to local standards should be performed (e.g. Doppler scan using color duplex, X-ray) and the results documented.


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PROTOCOL SIGNATURES 
Signature of the Sponsor's Representative 
Version 04 
l 9-Jan-2018
This study is intended to be conducted in compliance with the protocol, 
Good Clinical Practice and the applicable regulatory requirements. 
on behalf of the Sponsor 
Octapharma Pharmazeutika Produktionsges.m.b.H 
Oberlaaerstr. 235, A-1100 Vienna, Austria 
Signature of the Principal Coordinating Investigator 
This study is intended to be conducted in compliance with the protocol, 
Good Clinical Practice and the ai:1 
Coordinating Investigator 
University of Texas - Southwestern Medical Center 
5323 Harry Hines Blvd, Dallas, TX 75390, United States 


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This study is intended to be conducted in compliance with the protocol, Good Clinical 
Practice and the applicable regulatory requirements. 
Octapharma Pharmazeutika Produktionsges.m.b.H 
Oberlaaerstr. 235, A-1100 Vienna, Austria 
Signature 
Date 
Signature of the Biostatistician 
This study is intended to be conducted in compliance with the protocol, 
Good Clinical Practice and the applicable regulatory requirements. 
Octapharma Pharmazeutika Produktionsges.m.b.H 
Oberlaaerstr. 235, A-1100 Vienna, Austria 
2 
19- ::)1-W -2o,þ
Date 


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TABLE OF CONTENTS 
STUDY OUTLINE .................................................................................................................. II 
FLOW CHART ....................................................................................................................... X 
PROTOCOL SIGNATURES .................................................................................................. 1 
TABLE OF CONTENTS ......................................................................................................... 3 
LIST OF ABBREVIATIONS.................................................................................................. 7
1
INTRODUCTION .......................................................................................................... 10
1.1 BACKGROUND ............................................................................................................... 10
1.1.1
OCTAPLEX .......................................................................................................... 11
1.1.1.1 
Efficacy of OCTAPLEX..........................................................................................11
1.1.1.2 
Safety of OCTAPLEX.............................................................................................12
1.1.2
Beriplex® P/N (Kcentra)....................................................................................... 12
1.1.2.1 
Efficacy of Beriplex® P/N (Kcentra) .......................................................................12
1.1.2.2 
Safety of Beriplex® P/N (Kcentra)...........................................................................13
1.2 RATIONALE FOR CONDUCTING THE STUDY ................................................................... 14
1.3 DOSE RATIONALE.......................................................................................................... 15
1.4 BENEFIT-RISK STATEMENT ........................................................................................... 15
2
STUDY OBJECTIVES .................................................................................................. 17
2.1 PRIMARY OBJECTIVE..................................................................................................... 17
2.2 SECONDARY OBJECTIVE................................................................................................ 17
3
INVESTIGATIONAL PLAN........................................................................................ 18
3.1 PRIMARY AND SECONDARY ENDPOINTS ........................................................................ 18
3.1.1 Primary Endpoint ................................................................................................. 18
3.1.2 Secondary Endpoints............................................................................................ 18
3.1.3 Further Exploratory Endpoints ............................................................................ 18
3.1.4 Clinical safety....................................................................................................... 19
3.2 OVERALL STUDY DESIGN AND PLAN............................................................................. 19
3.3 DISCUSSION OF STUDY DESIGN AND CHOICE OF CONTROL GROUP ............................... 21
3.3.1 Study Design ......................................................................................................... 21 
3.3.2
Control Group ...................................................................................................... 21 
3.3.3 Patient Population ................................................................................................ 21 
3.3.4 Primary Endpoint ................................................................................................. 21 
3.3.5 Rationale for Choice of Non-Inferiority Margin .................................................. 21 
3.3.6 Study Procedures .................................................................................................. 22 
3.3.7 Dose Justification ................................................................................................. 22 
3.3.8 Sample Size Justification ...................................................................................... 22 
3.3.9 Use of an Interim Analysis ................................................................................... 22 
3.3.10 Stratification of Randomization ............................................................................ 22 
3.3.11 Independent Committees....................................................................................... 23 
4 
STUDY POPULATION ................................................................................................. 24 
4.1 POPULATION BASE ........................................................................................................ 24 


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4.1.1 Inclusion Criteria ................................................................................................. 24 
4.1.2 Exclusion Criteria ................................................................................................ 24 
4.2 PRIOR AND CONCOMITANT THERAPY ............................................................................ 25 
4.2.1 Prior Treatment .................................................................................................... 25 
4.2.2 Permitted Concomitant Therapy .......................................................................... 25 
4.2.3 Forbidden Concomitant Therapy ......................................................................... 25 
4.3 WITHDRAWAL AND REPLACEMENT OF PATIENTS .......................................................... 26 
4.3.1 Premature Patient Withdrawal ............................................................................. 26 
4.3.2 Patient Replacement Policy .................................................................................. 26 
4.4 ASSIGNMENT OF PATIENTS TO TREATMENT GROUPS ..................................................... 26 
4.5 RELEVANT PROTOCOL DEVIATIONS .............................................................................. 27 
4.6 SUBSEQUENT THERAPY ................................................................................................. 27 
5 
INVESTIGATIONAL MEDICINAL PRODUCTS .................................................... 28 
5.1 CHARACTERIZATION OF INVESTIGATIONAL PRODUCTS ................................................. 28 
5.1.1 OCTAPLEX 500 IU .............................................................................................. 28 
5.1.2 Kcentra 500 IU ..................................................................................................... 28 
5.1.3 Beriplex® P/N 500 IU ........................................................................................... 29 
5.2 PACKAGING AND LABELING .......................................................................................... 29 
5.3 CONDITIONS FOR STORAGE AND USE ............................................................................ 30 
5.4 DOSE AND DOSING SCHEDULE ...................................................................................... 30 
5.5 PREPARATION AND METHOD OF ADMINISTRATION ....................................................... 30 
5.6 BLINDING AND BREAKING THE STUDY BLIND ............................................................... 31 
5.7 TREATMENT COMPLIANCE ............................................................................................. 31 
5.7.1 Drug Dispensing and Accountability ................................................................... 31 
5.7.2 Assessment of Treatment Compliance .................................................................. 31 
6 
STUDY CONDUCT ....................................................................................................... 32 
6.1 OBSERVATIONS BY VISIT ............................................................................................... 32 
6.1.1 Screening and Randomization .............................................................................. 32 
6.1.2 Baseline ................................................................................................................ 32 
6.1.3 Infusion of IMP ..................................................................................................... 33 
6.1.4 Procedures After End of Infusion ......................................................................... 33 
6.1.5 Procedures Prior to Surgery ................................................................................ 33 
6.1.6 Procedures After Surgery ..................................................................................... 33 
6.1.7 Procedures 12 and 24 hours After Start of Surgery ............................................. 34 
6.1.8 Procedures in Post-Operative Period .................................................................. 34 
6.1.9 Follow-up Assessments ......................................................................................... 34 
6.1.10 Interpretation of time windows in this study ........................................................ 34 
6.2 DURATION OF STUDY .................................................................................................... 35 
6.2.1 Planned Duration for an Individual Patient ........................................................ 35 
6.2.2 Planned Duration for the Study as a Whole ......................................................... 35 
6.2.3 Premature Termination of the Study .................................................................... 35 
7 
ASSESSMENTS AND METHODS .............................................................................. 36 
7.1 BACKGROUND / BASELINE INFORMATION ..................................................................... 36 
7.2 EFFICACY ASSESSMENTS ............................................................................................... 36 
7.2.1 Assessments for Primary Efficacy Endpoints ....................................................... 36 
7.2.2 Assessments for Secondary and Further Exploratory Efficacy Endpoints ........... 37 


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7.2.2.1 
Measurement of INR ...............................................................................................37 
7.2.2.2 
Measurement of Coagulation Factor Levels (FII:C, FVII:C, FIX:C, FX:C, PC, and 
PS) 
38 
7.2.2.3 
Red Blood Cell, Plasma and Platelets Transfusions Initiated During the Surgery ..38 
7.2.2.4 
Change in hematological parameters .......................................................................39 
7.2.2.5 
Incidence of Hematoma and Proportion of Patients with Surgical Wound 
Hematomas That Need Evacuation ...........................................................................................39 
7.3 SAFETY ASSESSMENTS .................................................................................................. 39 
7.3.1 Adverse Events ...................................................................................................... 39 
7.3.1.1 
Definitions ...............................................................................................................39 
7.3.1.2 
Collection .................................................................................................................40 
7.3.1.3 
Severity ....................................................................................................................40 
7.3.1.4 
Causality ..................................................................................................................40 
7.3.1.5 
Outcome ...................................................................................................................41 
7.3.1.6 
Action(s) taken .........................................................................................................41 
7.3.2 Serious Adverse Events ......................................................................................... 42 
7.3.3 Occurrence of TEEs ............................................................................................. 43 
7.3.4 Vital Status ............................................................................................................ 43 
7.3.5 Physical Exam ...................................................................................................... 43 
7.3.6 Laboratory Tests ................................................................................................... 43 
7.3.7 Viral Safety Tests .................................................................................................. 44 
7.3.8 Vital Signs ............................................................................................................. 45 
7.3.9 Other Relevant Safety Information ....................................................................... 45 
7.4 APPROPRIATENESS OF MEASUREMENTS ........................................................................ 46 
8 
DATA HANDLING AND RECORD KEEPING ........................................................ 47 
8.1 DOCUMENTATION OF DATA ........................................................................................... 47 
8.1.1 Source Data and Records ..................................................................................... 47 
8.1.2 Case Report Forms ............................................................................................... 47 
8.1.3 Changes to Case Report Form Data .................................................................... 48 
8.2 INFORMATION OF INVESTIGATORS ................................................................................. 48 
8.3 RESPONSIBILITIES .......................................................................................................... 48 
8.4 INVESTIGATOR’S SITE FILE ............................................................................................ 49 
8.5 PROVISION OF ADDITIONAL INFORMATION .................................................................... 49 
8.6 INDEPENDENT DATA MONITORING COMMITTEE ............................................................ 49 
9 
STATISTICAL METHODS AND SAMPLE SIZE .................................................... 50 
9.1 DETERMINATION OF SAMPLE SIZE ................................................................................. 50 
9.2 STATISTICAL ANALYSIS ................................................................................................. 51 
9.2.1 Population for Analysis ........................................................................................ 51 
9.2.2 In addition the primary endpoint will also be analysed using the mITT and the PP 
population. Efficacy Analysis Plan ................................................................................... 52 
9.2.2.1 
Primary Endpoint: Hemostatic Efficacy ..................................................................52 
9.2.2.2 
Secondary Endpoints ...............................................................................................53 
9.2.2.3 
Further Exploratory Endpoints ................................................................................53 
9.2.2.4 
Subgroup Analyses for Efficacy ..............................................................................54 
9.2.3 Safety Analysis Plan ............................................................................................. 54 
9.2.3.1 
Adverse Events ........................................................................................................54 
9.2.3.2 
Thromboembolic Events ..........................................................................................54 
9.2.3.3 
Mortality ..................................................................................................................54 


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9.2.3.4 
Routine Laboratory Data .........................................................................................55 
9.2.3.5 
Vital Signs ...............................................................................................................55 
9.2.3.6 
Viral Safety ..............................................................................................................55 
9.2.3.7 
Subgroup Analyses for Safety .................................................................................55 
9.2.4 Handling of Missing Data .................................................................................... 56 
9.3 RANDOMIZATION / STRATIFICATION / CODE RELEASE .................................................. 56 
9.4 INTERIM ANALYSIS ........................................................................................................ 56 
10 ETHICAL / REGULATORY, LEGAL AND ADMINISTRATIVE ASPECTS ...... 57 
10.1 ETHICAL / REGULATORY FRAMEWORK .......................................................................... 57 
10.2 APPROVAL OF STUDY DOCUMENTS ............................................................................... 57 
10.3 PATIENT INFORMATION AND INFORMED CONSENT ........................................................ 57 
10.4 PROTOCOL AMENDMENTS ............................................................................................. 57 
10.5 CONFIDENTIALITY OF PATIENTS´ DATA......................................................................... 58 
11 QUALITY CONTROL AND QUALITY ASSURANCE ........................................... 59 
11.1 PERIODIC MONITORING ................................................................................................. 59 
11.2 AUDIT AND INSPECTION................................................................................................. 59 
12 REPORTING AND PUBLICATION ........................................................................... 60 
12.1 CLINICAL STUDY REPORT.............................................................................................. 60 
12.2 PUBLICATION POLICY .................................................................................................... 60 
13 LIABILITIES AND INSURANCE ............................................................................... 61 
14 REFERENCES ............................................................................................................... 62 
15 APPENDICES ................................................................................................................. 63 


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LIST OF ABBREVIATIONS 
Abbreviation 
Description 
:C 
Concentration 
4F-PCC 
Four-Factor Prothrombin Complex Concentrate 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ASA 
American Society of Anesthesiologists 
aPTT 
Activated Partial Thromboplastin Time 
BUN 
Blood Urea Nitrogen 
BW 
Body Weight 
CI 
Confidence Interval 
CRF/eCRF 
Case Report Form/electronic Case Report Form 
DVT 
Deep Vein Thrombosis 
EDC 
Electronic Data Capture 
FII 
Coagulation factor II 
FVII 
Coagulation factor VII 
FIX 
Coagulation factor IX 
FX 
Coagulation factor X 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FFP 
Fresh Frozen Plasma 
GCP 
Good Clinical Practice 
Hct 
Hematocrit 
Hgb 
Hemoglobin 
HIT 
Heparin-induced Thrombocytopenia 
IB 
Investigator’s Brochure 
ICH 
Intracranial Hemorrhage 
IDMC 
Independent Data Monitoring Committee 
IEAB 
Independent Endpoint Adjudication Board 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
INR0 
Baseline International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 


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ITT 
Intention-To-Treat 
IU 
International Units 
IV 
Intravenous 
LDH 
Lactic Acid Dehydrogenase 
LMWH 
Low-Molecular-Weight Heparin 
LVAD 
Left Ventricular Assist Device 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified Intent-To-Treat 
OP 
Operation 
PAD 
Peripheral Arterial Disease 
PC 
Protein C 
PCC 
Prothrombin Complex Concentrate 
PE 
Pulmonary Embolism 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PS 
Protein S 
PT 
Prothrombin time 
RAND 
Randomized population 
RBC 
Red Blood Cells 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Population 
SAP 
Statistical Analysis Plan 
SDV 
Source Data Verification 
SOP 
Standard Operating Procedure 
SMQ 
Standardized MedDRA query 
TEAE 
Treatment Emergent Adverse Event 
TEE 
Thromboembolic Events 
UFH 
Unfractionated Heparin 
US 
United States 
TIA 
Transient Ischemic Attack 
VKA 
Vitamin K Antagonist 
WBC 
White Blood Cell (count) 
WOCBP 
Women Of Childbearing Potential 
GLOSSARY OF TERMS AND TRADEMARKS 


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Beriplex® P/N (Kcentra) 
CSL Behring 


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1 
INTRODUCTION 
1.1 
Background 
Freeze-dried human prothrombin complex concentrate (PCC) is a plasma protein fraction 
containing coagulation factor IX (FIX) and comparable quantities of coagulation factor II (FII), 
factor VII (FVII), and factor X (FX). It is prepared from human plasma by fractionation. 
PCC can be used for the substitutive therapy of patients with either inherited or acquired single 
or multiple deficiency in coagulation factors II, VII, IX, or X. Acquired deficiency of 
coagulation factors is seen in conjunction with a prophylactic, oral anticoagulant therapy using 
the coumadin or warfarin type drugs to prevent thrombosis/embolism in patients at high risk 
(e.g. previous venous or arterial thrombosis, heart valvular lesions or atrial fibrillation). 
Patients treated with oral anticoagulants who need to undergo surgical interventions represent 
a special risk population. If anticoagulant therapy is not interrupted before the surgical 
intervention, the risk of bleeding is high. The desirable therapeutic range of the international 
normalized ratio (INR) for patients needing anticoagulation, appears to be 2-3 for most clinical 
situations except perhaps for prosthetic heart valves, which appear to benefit from a slightly 
higher target range of 2.5-3.5. Nevertheless, the incidence of adverse bleeding on warfarin rises 
4 fold with INRs over 4.5 (1) and each 0.5 increase in the INR increases the risk of intracranial 
bleeding by 1.43 (2). Almost half of all warfarin-related bleeds occur with INRs less than 4 (3). 
In a recent study, mortality from all causes of death was strongly related to the INR level. 
Minimum risk of death was attained at 2.2 INR for all patients and 2.3 INR for patients with 
mechanical heart valve prostheses. A high INR was associated with an excess mortality: with 
an increase of 1 unit of INR above 2.5, the risk of death from cerebral bleeding (149 deaths) 
and from any cause was about doubled (4). 
Special attention should be paid to emergency patients who are treated with anticoagulants. 
These patients need additional interventions for a rapid reversal of oral anticoagulant therapy 
to avoid major bleeding. 
Three approaches have been recommended in cases where bleeding occurring peri-operatively 
needs to be treated. One strategy involves injection of vitamin K. However, vitamin K injection 
attains full effect after 12 to 24 hours, which might be too long for effective substitution. A 
second approach involves the administration of fresh frozen plasma (FFP). A third approach 
involves the use of PCC. In the latter two cases, between 20-50 International Units (IU) of each 
factor/kg body weight (BW) should be administered but this is dependent on the initial INR of 
the patient. It has been shown that individualized dosing dependent on the INR of the patient is 
a more effective way of dosing PCCs (5). FFP attains full effect shortly after the appropriate 
volume of infusion has been completed; however, the thawing of FFP could add a significant 
time delay, especially in emergency situations. Another major disadvantage with plasma is the 
large volume required to reduce a high INR to below 2.0, with the consequence that patients 
treated with this alternative may have a residual anticoagulant effect and the hemorrhage may 
progress (6). 
PCC administration is an effective treatment modality for the correction of warfarin 
anticoagulation in the urgent setting (5, 7, 8). Advantages over FFP include more timely 
correction, absence of volume overload and potentially more complete correction (9). The use 
of PCC provides a simple and convenient tool for a quick and predictive correction of the 
depleted coagulation factors. 


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These products contain all factors needed for quick reversal of VKA anticoagulant related 
bleeding in predefined activities. It is, therefore, possible to attain a full effect with an optimal 
reduced time to the correction of the coagulation deficit. 
OCTAPLEX is a four-factor prothrombin complex concentrate (4F-PCC) being developed by 
Octapharma. In the current study, the control will consist of Beriplex® P/N (Kcentra), a 4F-PCC 
developed and marketed by CSL Behring. 
1.1.1 OCTAPLEX 
1.1.1.1 Efficacy of OCTAPLEX 
Octapharma has carried out 6 clinical trials with OCTAPLEX in patients. 
Study LEX-201 included patients with single or multiple congenital deficiencies in coagulation 
factors II, VII, IX and X. The results of the clinical study have shown that OCTAPLEX is an 
efficient preparation for the chronic substitutive treatment of patients with congenital 
deficiencies of these coagulation factors. With respect to safety, OCTAPLEX was well 
tolerated. No viral seroconversion was observed. The very sensitive markers of 
thrombogenicity, which were tested, did not indicate any thrombogenicity of the product. No 
inhibitor development was observed, and recovery and terminal half-life measured in 10 
patients after 6 months of treatment did not suggest immunogenicity of the product. 
Study LEX-202 included patients either undergoing major surgery or having major bleeding 
during treatment with anticoagulants of coumadin or warfarin type. The results indicate that 
OCTAPLEX, given as single dose, is a valuable, new alternative to achieve a profound rise in 
prothrombin time (PT) associated with a profound decrease of the INR and having a good 
overall clinical efficacy. In this study, two patients seroconverted for Parvovirus B19, however, 
without any clinical symptoms. Otherwise no safety concerns have been raised during the 
clinical testing. 
Study LEX-203 concluded that the clinical efficacy of OCTAPLEX administered in appropriate 
doses could be demonstrated conclusively: 51 of the 56 patients in the per protocol population 
(91.1%) showed an efficacy response, i.e., reached the efficacy endpoint of a post infusion PT 
value equal to or larger than the desired and corrected PT value pre-defined by the investigator. 
In all responders these post infusion PT values could be measured within 10 minutes after 
administration of the calculated dosage. Even in five remaining patients the clinical response 
was adequate. The individual coagulation factor levels showed a sufficient rise from baseline 
into the therapeutic range. All patients showed an excellent clinical response, in particular, no 
complications caused by uncontrollable bleeding were observed after OCTAPLEX treatment. 
The clinical tolerability of the product was excellent. In this study OCTAPLEX appears to be 
an efficacious treatment for the prophylaxis and treatment of bleeding in acquired deficiency of 
the prothrombin complex coagulation factors. 
Study LEX-204 was an observational study in patients with prothrombin complex factor 
deficiency in Germany and Study LEX-206 was conducted in in patients with intracranial 
hemorrhage related to oral anticoagulant therapy in France. Results for these studies are 
summarized in the Investigator’s Brochure (IB). 
Study LEX-205 was a randomized, open-label, efficacy and safety study of OCTAPLEX and 
fresh frozen plasma (FFP) in patients under vitamin K antagonist (VKA) therapy with the need 
for urgent surgery or invasive procedures. Correction of INR to a value below 1.5 within 


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15 minutes of the end of study infusion was achieved for 76% of the OCTAPLEX-treated 
patients and 30% of the FFP-treated patients.   
This new clinical study (LEX-209) will be conducted to facilitate marketing authorization in 
the US; the rationale for conducting this study is provided in Section 1.2.  
1.1.1.2 Safety of OCTAPLEX 
OCTAPLEX has received marketing authorization in 76 countries worldwide. Between 
March 2003 andSeptember 2017, more than 
 of OCTAPLEX have been sold. 
Assuming a mean single dose of about 30 IU/kg BW and a mean patient weight of 70 kg, this 
figure represents about 
 of OCTAPLEX.  
OCTAPLEX is not to be administered to patients with: 
•
Hypersensitivity to the active substance or to any of the excipients.
•
Known allergy to heparin or history of heparin induced thrombocytopenia.
Patients receiving a VKA may have an underlying hyper-coagulation state and infusion of PCC 
may exacerbate this. 
If allergic or anaphylactic-type reactions occur, the infusion should be stopped immediately. In 
case of shock, standard medical treatment for shock should be implemented. 
There is a risk of thrombosis or disseminated intravascular coagulation when patients, with 
either congenital or acquired deficiency are treated with human prothrombin complex, 
particularly with repeated dosing. Patients given human prothrombin complex should be 
observed closely for signs or symptoms of intravascular coagulation or thrombosis. Because of 
the risk of thromboembolic complications, close monitoring should be exercised when 
administering human prothrombin complex to patients with a history of coronary heart disease, 
to patients with liver disease, to peri- or postoperative patients, to neonates, or to patients at risk 
of thromboembolic events (TEE) or disseminated intravascular coagulation. In each of these 
situations, the potential benefit of treatment should be weighed against the risk of these 
complications. 
The known risks of treatment with OCTAPLEX are consistent with the inclusion and exclusion 
criteria in this study, which minimize the risk to patients enrolled in this study. 
1.1.2 Beriplex® P/N (Kcentra) 
Beriplex® P/N (Kcentra) (CSL Behring), Prothrombin Complex Concentrate (Human), is a 
blood coagulation factor replacement product indicated for the urgent reversal of acquired 
coagulation factor deficiency induced by VKA (e.g., warfarin) therapy in adult patients with: 
•
acute major bleeding (approved April 2013 in the US) or
•
need for an urgent surgery/invasive procedure (approved April 2013 in the United States
[US]).
Full details on Beriplex® P/N (Kcentra) are available in the respective US Prescribing 
Information and local labeling. 
1.1.2.1 Efficacy of Beriplex® P/N (Kcentra) 
Of particular relevance to the current OCTAPLEX study, the efficacy of Beriplex® P/N 
(Kcentra) was evaluated in a prospective, open-label, active-controlled, non-inferiority, 


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multicenter randomized controlled trial in subjects who had been treated with VKA therapy and 
who required urgent replacement of their Vitamin K-dependent clotting factors because of their 
need for an urgent surgery/invasive procedure.  
A total of 181 subjects with acquired coagulation factor deficiency due to oral VKA therapy 
were randomized to a single dose of Beriplex® P/N (Kcentra) or plasma. One hundred seventy-
six (176) subjects received Beriplex® P/N (Kcentra) or plasma because of their need for an 
urgent surgery/invasive procedure in the setting of a baseline INR ≥2.0 and recent use of a VKA 
anticoagulant. The doses of Beriplex® P/N (Kcentra) (25 IU/kg, 35 IU/kg, or 50 IU/kg) based 
on nominal Factor IX content and plasma (10 mL/kg, 12 mL/kg, or 15 mL/kg) were calculated 
according to the subject’s baseline INR (2‒< 4, 4‒6, >6, respectively). The observation period 
lasted for 90 days after the infusion of Beriplex® P/N (Kcentra) or plasma. The modified 
efficacy (ITT-E) population for Beriplex® P/N (Kcentra) included 87 subjects and for plasma 
included 81 subjects. Additionally, oral or intravenous (IV) Vitamin K was administered. 
The efficacy endpoint was hemostatic efficacy for the time period from the start of infusion of 
Beriplex® P/N (Kcentra) or plasma until the end of the urgent surgery/invasive procedure. 
Criteria for effective hemostasis were based upon the difference between predicted and actual 
blood losses, subjective hemostasis rating, and the need for additional blood products 
containing coagulation factors. The proportion of subjects with effective hemostasis was 89.7% 
in the Beriplex® P/N (Kcentra) group and 75.3% in the plasma group. The lower limit of the 
95% confidence interval (CI) for the difference in proportions of Beriplex® P/N (Kcentra) 
minus plasma was 2.8%, which exceeded -10% and thereby demonstrated the non-inferiority 
of Beriplex® P/N (Kcentra) versus plasma (the study’s primary objective). Because the lower 
limit of the CI was greater than 0, the prospectively defined criterion for superiority of 
Beriplex® P/N (Kcentra) for hemostatic efficacy (a secondary objective) was also met. 
An additional endpoint was the reduction of INR to ≤1.3 at 30 minutes after the end of infusion 
of Beriplex® P/N (Kcentra) or plasma for all subjects that received study product. The 
proportion of subjects with this decrease in INR was 55.2% in the Beriplex® P/N (Kcentra) 
group and 9.9% in the plasma group. The 95% CI for the difference in proportions of 
Beriplex® P/N (Kcentra) minus plasma was 31.9% to 56.4%. The lower limit of the 95% CI of 
31.9% demonstrated superiority of Beriplex® P/N (Kcentra) versus plasma for this endpoint. 
The relationship between a decrease in INR to less than or equal to 1.3 and clinical hemostatic 
efficacy was not established. 
A summary of this study, including key safety findings, is provided in the Beriplex® P/N 
(Kcentra) US Prescribing Information and local labeling, and the results have also been 
published (10). 
1.1.2.2 Safety of Beriplex® P/N (Kcentra) 
The following “black box warning” is included in the Kcentra US Prescribing Information: 
WARNING: ARTERIAL AND VENOUS THROMBOEMBOLIC COMPLICATIONS 
Patients being treated with VKA therapy have underlying disease states that predispose 
them to thromboembolic events. Potential benefits of reversing VKA should be weighed 
against the potential risks of thromboembolic events, especially in patients with the history 
of a thromboembolic event. Resumption of anticoagulation should be carefully considered 
as soon as the risk of TEE outweighs the risk of acute bleeding. 


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•
Both fatal and non-fatal arterial and venous thromboembolic complications have been
reported with Kcentra in clinical trials and post marketing surveillance. Monitor patients
receiving Kcentra for signs and symptoms of thromboembolic events.
•
Kcentra was not studied in subjects who had a thromboembolic event, myocardial
infarction, disseminated intravascular coagulation, cerebral vascular accident, transient
ischemic attack (TIA), unstable angina pectoris, or severe peripheral vascular disease
within the prior 3 months. Kcentra may not be suitable in patients with TEE in the prior
3 months.
Kcentra is contraindicated in patients with: 
•
Known anaphylactic or severe systemic reactions to Kcentra or any components in
Kcentra including heparin, Factors II, VII, IX, X, Proteins C and S, Antithrombin III
and human albumin.
•
Disseminated intravascular coagulation.
•
Known heparin-induced thrombocytopenia (HIT). Kcentra contains heparin.
These warnings and contraindications are consistent with the exclusion criteria in this study, 
which exclude such patients from enrollment in this study. 
Warnings and Precautions for Kcentra: 
•
Hypersensitivity reactions may occur. If necessary, discontinue administration and
institute appropriate treatment.
•
Arterial and venous thromboembolic complications have been reported in patients
receiving Kcentra. Monitor patients receiving Kcentra for signs and symptoms of
thromboembolic events. Kcentra was not studied in subjects who had a thrombotic or
TEE within the prior 3 months. Kcentra may not be suitable in patients with TEE in the
prior 3 months.
•
Kcentra is made from human blood and may carry a risk of transmitting infectious
agents, e.g., viruses, the variant Creutzfeldt-Jakob disease agent, and theoretically, the
Creutzfeldt-Jakob disease agent.
Adverse Reactions with Kcentra 
•
The most common adverse reactions (frequency ≥2.8%) observed in subjects receiving
Kcentra were headache, nausea/vomiting, hypotension, and anemia.
•
The most serious adverse reactions were TEE including stroke, pulmonary embolism,
and deep vein thrombosis.
1.2 
Rationale for Conducting the Study 
To evaluate the efficacy and safety of OCTAPLEX, the Food and Drug Administration (FDA) 
proposed a prospective, parallel, randomized, controlled trial in patients needing urgent surgery 
and judged to carry significant risk of intraoperative/procedural hemorrhage. FDA advised that 
the control group should receive a product licensed for this indication. The trial should achieve 
greater statistical power than LEX-205.  
This adequately powered study is intended to meet these requests by demonstrating that the 
efficacy of OCTAPLEX is not clinically inferior to that of Beriplex® P/N (Kcentra). The 
efficacy and safety results will be compared with those of Beriplex® P/N (Kcentra), the only 


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currently FDA-approved PCC therapy indicated for the urgent reversal of acquired coagulation 
factor deficiency induced by VKA. 
This study will be conducted in compliance with the protocol, International Council on 
Harmonisation-Good Clinical Practice (ICH-GCP), and other regulatory requirements.  
1.3 
Dose Rationale 
The dosage recommended in the current US Prescribing Information of Beriplex® P/N 
(Kcentra) will be used for both OCTAPLEX and Beriplex® P/N (Kcentra) in this study. This 
dose allows blinding for both groups as the same amount of product would be injected.  
The dose of investigational medicinal product (IMP) will depend on the BW and baseline INR 
(INR0) of the patient and will be calculated by the responsible treating investigator according 
to the following dosing table. BW should be rounded to the nearest whole kilogram number for 
IMP dose calculation. Baseline INR value should be rounded to the 1st decimal place. 
Baseline INR 
2 to <4 
4-6
>6
Dose (IU of Factor IX/kg BW) 
25 
35 
50 
Maximum dose (IU of Factor IX) 
2500 
3500 
5000 
IMP will be administered by IV infusion at a rate of 0.12 mL/kg/min (~3 units/kg/min), up to a 
maximum rate of 8.4 mL/min (~210 units/min). The total volume of IMP used and time of 
infusion will be recorded. Batch numbers will be reported in the final clinical study report. 
1.4 
Benefit-Risk Statement 
To date, 6 clinical trials with OCTAPLEX have been performed resulting in marketing 
authorization in Europe and other non-US countries. The tolerability and efficacy of the product 
was good. The active control in this study, Beriplex® P/N (Kcentra), is approved in the US for 
the indication under investigation. Demonstration of the efficacy of OCTAPLEX in the targeted 
indication would add another independent 4F-PCC treatment option, which is of particular 
importance for such medicinal products that are prepared from human blood or plasma.  
Currently available efficacy data indicate that treatment with OCTAPLEX should be non-
inferior to Beriplex® P/N (Kcentra) in the targeted indication. To minimize the risk of treating 
patients with a non-efficacious treatment, the study will be conducted in 2 stages, with one un-
blinded interim analysis after enrollment of 50% of the planned sample size, allowing for an 
early stopping of the study for demonstrated non-inferiority of OCTAPLEX or futility to 
achieve this. Any decision to prematurely terminate the study will be made in consultation with 
the relevant regulatory authorities. 
For both 4F-PCC preparations, the following adverse reactions may occur: 
1. Allergic or anaphylactic reactions in rare cases. Symptoms of an increased sensitivity can
vary from fever, chills, nausea, urticaria, chest tightness, shortness of breath, and
hypotension up to anaphylactic shock.
2. There is a risk of thrombosis or disseminated intravascular coagulation when patients are
treated with PCC. Close monitoring should be exercised when administering
OCTAPLEXPCC to patients with a history of coronary heart disease, to patients with liver
disease, or to patients at risk of TEE or disseminated intravascular coagulation.


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3. Very rarely, a sudden, allergy induced reduction of the blood platelet count below
100,000/µL or 50% of the starting count may be observed (HIT; thrombocytopenia type II).
In patients not previously hypersensitive to heparin, this decrease in platelets may occur 6
to 14 days after the start of treatment. In patients with previous heparin hypersensitivity this
reduction may happen within a few hours. This severe form of blood platelet reduction may
be accompanied by, or result in, arterial thrombosis, thromboembolism, severe clotting
disorder (consumptive coagulopathy), skin necrosis at injection site, petechia, purpura or
melaena. Also, a reduction of the anticoagulant effect of heparin may occur (heparin-
tolerance). Patients with the specified allergic reactions must immediately stop
administration with the IMP and should not use medication containing heparin in the future.
4. Development of antibodies to one or more of the prothrombin complex factors.
5. As for all medicinal products prepared from human blood or plasma, infectious diseases
due to transmission of infective agents cannot be totally excluded. This applies also to
pathogens of hitherto unknown origin. However, in the current manufacturing process for
both OCTAPLEX and Beriplex® P/N (Kcentra), various steps are included that contribute
towards the reduction/inactivation of viruses.
The inclusion and exclusion criteria in this study have been selected to minimize the risk to 
patients enrolled in this study. Safety will be continuously monitored throughout the study as it 
accrues, including monitoring of unblinded safety data by an Independent Data Monitoring 
Committee (IDMC). 
In conclusion, the benefit/risk analysis for this study is acceptable for the patient population to 
be enrolled. 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of the study is to demonstrate that the efficacy of OCTAPLEX as a 
reversal agent in patients under VKA therapy with the need for urgent surgery with significant 
bleeding risk is clinically non-inferior to Beriplex® P/N (Kcentra). 
2.2 
Secondary Objective 
The secondary objective of the study is to investigate the safety and tolerability of OCTAPLEX 
compared to Beriplex® P/N (Kcentra) in patients under VKA therapy with the need for urgent 
surgery with significant bleeding risk. 


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3 
INVESTIGATIONAL PLAN 
3.1 
Primary and Secondary Endpoints 
3.1.1 Primary Endpoint 
The primary efficacy endpoint is the hemostatic efficacy rating at the end of the surgery. 
Efficacy will be rated by the investigator at the end of the surgery in a blinded manner based 
on a 4-point hemostatic efficacy scale taking into account blood loss and transfusion 
requirements in the context of the surgery. 
The hemostatic efficacy rating will also be assessed by an independent endpoint adjudication 
board (IEAB) consisting of clinical experts. See Section 7.2.1 for details. All adjudications will 
be conducted in a blinded manner and the IEAB will be provided with all relevant details (e.g., 
duration of surgery, co-medication, medical history, predicted and actual blood loss, and 
transfusion information) of the patient and the actual procedure performed1 covering the time 
period up to the end of the surgery, as documented in the anesthesia record. To ensure the 
effectiveness of blinding and avoid potential bias, the INR and PT values will not be provided 
to the IEAB. The dichotomized final adjudicated hemostatic efficacy rating from the IEAB will 
serve as the primary efficacy variable for the statistical analysis. The concordance or 
discordance of the investigator and the IEAB ratings will also be determined as part of the final 
analysis; the IEAB will be kept blinded to the investigator’s rating.  
3.1.2 Secondary Endpoints 
•
Proportion of patients with an INR value of less than or equal to 1.5 at 30  (± 15 )
minutes after the end of infusion.
•
Change in coagulation factor levels from baseline to 30 (± 15 ) minutes after the end of
infusion:
o
Factor FII
o
Factor FVII
o
Factor FIX
o
Factor FX
•
Proportion of patients receiving red blood cells (RBC) during the surgery
3.1.3 Further Exploratory Endpoints 
•
Change in INR from baseline.
•
Change in Protein C (PC), and Protein S (PS) from baseline to 30 (± 15 min) after the
end of infusion.
•
Change in coagulation factor levels (FII, FVII, FIX, FX, PCC, and PS) from baseline to
2 h, 4 h, 12 h, and 24 h after end of infusion.
•
Assessment of blood loss after end of surgery.
•
Proportion of patients receiving plasma and platelets transfusions initiated during the
surgery.
1 A detailed description of the information to be provided to the IEAB will be developed with the clinical experts 
and be included in an IEAB charter. 


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•
Total volume of RBC and other blood product transfusions initiated during the surgery
normalized by patient's BW.
•
Change in hematological parameters (hemoglobin (Hgb), hematocrit (Hct), RBC, white
blood cell (WBC), platelets) from the beginning to the end of the surgery.
•
RBC transfusion corrected change from baseline in Hgb at 12 and 24 hours after start
of surgery.
•
Proportion of patients experiencing surgical wound hematoma requiring surgical
evacuation.
•
Ratio of actual estimated blood loss as documented after surgery to the pre-operative
predicted blood loss for the type of planned surgery.
3.1.4 Clinical safety 
•
Occurrence of AEs.
•
Occurrence of TEEs (overall, within 3, 21, and 45 days after end of surgery).
•
Mortality (overall, within 3, 21, and 45 days after end of surgery).
•
Monitoring vital signs, laboratory parameters.
•
Viral safety (at baseline and day 9 (-2/+5  days) after administration of IMP).
3.2 
Overall Study Design and Plan 
This study is a prospective, multi-center, randomized, double-blind, active-control, group-
sequential, non-inferiority Phase III study. The study is planned to start in Q4 2016 and be 
completed by Q2 2021, and will be performed at sites in the US and Europe. 
A maximum of 370 patients (male and female patients at least 18 years of age) will be enrolled 
(185 patients per treatment group). One group will receive OCTAPLEX and the other group 
will receive Beriplex® P/N (Kcentra). Patients will be on oral anticoagulant therapy with VKAs 
and will need to undergo an urgent surgery that bears a significant risk of bleeding (≥50 mL 
expected blood loss). The intent of the physician performing the procedure is to start the surgery 
within 3 hours after the end of 4F-PCC administration. 
At least 40% of all patients enrolled will be scheduled for an urgent surgery with expected blood 
loss of ≥200 mL. At least 20% of all patients enrolled will be scheduled for an urgent surgery 
with expected blood loss of ≥100 mL but <200 mL. At most 40% of all patients enrolled will 
be scheduled for an urgent surgery with expected blood loss ≥50 mL but <100 mL. 
After determination of the acceptability for the study, patients have to give their written 
informed consent (see Section 10.3) and must meet the inclusion criteria of the study. Written 
informed consent must be obtained from the patient. The INR value available at the time of 
decision to reverse the anticoagulation status (qualifying INR) should be used for the decision 
to enroll a patient into the study. Treatment allocation will then be performed by an Interactive 
Response Technology (IRT), where the patient will be assigned to one of the 2 treatment groups 
with equal probability (i.e., 1:1). In order to achieve a balance between the 2 treatment groups 
with respect to the planned type of surgery and history of TEE, the treatment allocation by the 
IRT will be stratified according to the parameters ‘Expected blood loss (“≥200 mL”, “≥100 mL 
but <200 mL” or “≥50 mL but <100 mL”)’,  ‘History of TEE (“yes” or “no”)’ and ‘Type of 
planned surgery (“orthopaedic surgery”, “cardiothoracic surgery” or “other surgery”).  To 
ensure that the intended proportions of patients enrolled are kept for subgroups of expected 
blood loss,  the IRT will preclude enrollment into the subgroup once its targeted number of 


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enrolled patients is reached. The same applies to the population considered in the interim 
analysis. 
Details on the patient's medical history (especially occurrence of previous TEEs), the current 
clinical status, the expected amount of blood loss (mL) due to the surgery (average and 
maximum blood loss and expected average and maximum transfusion requirements for non-
anticoagulated patients undergoing the same type of surgical procedure), the reason for, 
duration and time of last administration of anticoagulant therapy and details about concomitant 
medication should be recorded. Baseline measurements will be performed for all relevant 
parameters within 3 hours before administration of study drug. 
The dose of study drug to be administered will be calculated by the responsible treating 
investigator based on the patient's BW and baseline INR according to the recommended dosing 
table. Based on the calculated dose and the assigned treatment code, the IMP will be prepared 
and infused in a manner that will blind the investigator to the study treatment. 
A concomitant administration of vitamin K is to be administered, unless the patient requires 
resumption of VKA anticoagulation within 24 hours after surgery. Patients not requiring 
concomitant vitamin K administration are those with: 
•
Presence of a mechanical heart valve
•
Presence of a Left Ventricular Assist Device (LVAD)
•
Presence of a hypercoagulable/prothrombotic condition identified by the treating
physician and documented with audit trail prior to surgery as an indication for the
resumption of VKA treatment within 24 hours.
Vitamin K should be administered within 1 hour before IMP infusion or within 1 hour after 
IMP infusion, at a dose of 2, 5, or 10 mg according to local clinical practice. The preferred route 
for vitamin K administration is by slow IV infusion. If vitamin K is not administered, the reason 
must be documented.  
After baseline measurements, blood samples and the administration of IMP, blood samples will 
be taken for safety assessments, coagulation tests and for factor level measurements at pre-
defined time points. All relevant details of the surgery will be recorded. The time, reason, and 
amount of all blood and plasma products given during the hospital stay for the primary 
procedure will be recorded. An assessment of the hemostatic efficacy of the study treatments 
based on the provided guidance (see Section 7.2.1), including the 4-point hemostatic efficacy 
scale, will be recorded by the investigator after the surgery. 
Clinical safety will be assessed by monitoring vital signs, laboratory parameters, and by 
documenting AEs. 
An IDMC will continually monitor safety during the study (see Section 8.6). 
An IEAB will be established to determine the primary efficacy outcome for the study (see 
Section 3.3.11). 
One un-blinded interim analysis will be conducted after enrollment of 50% of the planned 
sample size. The critical values of the chosen group sequential method (11) will protect the 
overall type I error but allow an early stopping of the study for demonstrated non-inferiority of 
OCTAPLEX or futility to achieve this. 


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3.3 
Discussion of Study Design and Choice of Control Group 
3.3.1 Study Design 
Octapharma designed the study to use a randomized double-blind non-inferiority design 
comparing OCTAPLEX with Beriplex® P/N (Kcentra). A further consideration was to have a 
study design and patient population that would allow comparison with the Beriplex® P/N 
(Kcentra) confirmatory trial, which demonstrated that Beriplex® P/N (Kcentra) is non-inferior 
and superior to plasma for rapid INR reversal and effective hemostasis (10); this is the only 
published confirmatory trial comparing 4F-PCC with plasma (the standard agent for rapid 
reversal of VKA-induced anticoagulation). There are no published confirmatory trials 
comparing 4F-PCC with placebo. 
3.3.2 Control Group 
The FDA advised that the control group in this study should receive a product licensed for this 
indication in the US. Beriplex® P/N (Kcentra) is the only currently FDA-approved 4F-PCC 
therapy indicated for the urgent reversal of acquired coagulation factor deficiency induced by 
VKA and is therefore used as the control in this study. 
3.3.3 Patient Population 
Patients requiring rapid reversal of VKA-induced anticoagulation needing urgent surgery 
associated with significant bleeding risk are to be enrolled in this study. At least 40% of all 
patients enrolled will be scheduled for an urgent surgery with expected blood loss of ≥200 mL. 
At least 20% of all patients enrolled will be scheduled for an urgent surgery with expected blood 
loss of ≥100 mL but <200 mL. At most 40% of all patients enrolled will be scheduled for an 
urgent surgery with expected blood loss ≥50 mL but <100 mL. This patient population should 
also be comparable to that described for the Beriplex® P/N (Kcentra) confirmatory study (10). 
In the selected clinical setting, patients may require resumption of VKA anticoagulation within 
24 hours after surgery. To facilitate inclusion of such patients into this study, criteria to waive 
concomitant vitamin K administration were included in the study, with the stipulation that the 
reason(s) must be documented in the Case Report Form (CRF).  
3.3.4 Primary Endpoint 
The chosen hemostatic efficacy endpoint with blinded, perioperative hemostatic efficacy rating 
by an independent adjudication board captures all clinical aspects of the restoration of 
hemostasis. See Section 7.2.1 for details. 
3.3.5 Rationale for Choice of Non-Inferiority Margin 
In the publication of Goldstein et al. (10), an absolute difference in hemostatic efficacy of 15% 
of the planned control drug (Beriplex® P/N [Kcentra]) over FFP was reported (90% versus 
75%). Therefore, demonstrating non-inferiority to Beriplex® P/N (Kcentra) based on a 15% 
non-inferiority margin would necessarily imply a hemostatic efficacy that is not less than that 
of FFP, which is another FDA approved agent for this indication. The positive demonstration 
of non-inferiority to the control drug (Beriplex® P/N [Kcentra]) will, of course, require that the 
point estimate for the difference in success rates between Beriplex® P/N (Kcentra) and 
OCTAPLEX be substantially below the non-inferiority margin. When assuming a success rate 
for Beriplex® P/N (Kcentra) comparable to the one cited in the publication of Goldstein et al. 


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(10), the point estimate for the success rate with OCTAPLEX will be substantially higher than 
the point estimate for FFP. Finally, the current clinical use of both the control drug 
(Beriplex® P/N [Kcentra]) and FFP for the reversal of VKA anticoagulation in the US, given 
the observed 15% higher efficacy with Beriplex® P/N (Kcentra), demonstrates that a 15% 
difference in clinical success rates lies within a range that is clinically similar. 
3.3.6 Study Procedures 
The study procedures were selected based on standards for the clinical setting, the procedures 
used in the OCTAPLEX LEX-205 study and Beriplex® P/N (Kcentra) confirmatory study (10), 
and to provide the data required to allow assessment of the selected efficacy and safety 
endpoints. 
A follow-up sample will be taken for Parvovirus B19 PCR and anti-Parvovirus B19 IgM Ab 
assessments at 9 days (-2/+5 days) following administration of IMP for patients seronegative at 
baseline. This time point was chosen as it has been shown that at this time post-infection, 
significant concentrations of both virus and IgM antibodies directed against the virus can be 
detected in blood. Patients seropositive at baseline do not need to have repeat Parvovirus B19 
serology performed. 
3.3.7 Dose Justification  
The dose justification is provided in Section 5.4. 
The maximum infusion rate (8.4 mL per minute) is consistent with that recommended in the 
Kcentra US Prescribing Information. 
3.3.8 Sample Size Justification 
See Section 9.1. 
3.3.9 Use of an Interim Analysis 
One un-blinded interim analysis will be conducted after enrollment of 50% of the planned 
sample size, to allow for an early stopping of the study for demonstrated non-inferiority of 
OCTAPLEX or for an early stopping for futility. Any decision to prematurely terminate the 
study will be made in consultation with the relevant regulatory authorities. The interim analysis 
is detailed in Section 9.4. 
3.3.10 
Stratification of Randomization 
Patients receiving a VKA generally have an underlying higher risk of TEEs, the reason for 
administration of the antagonist. Withdrawal of the antagonist and restoration of coagulation 
via administration of PCC can therefore raise the risk of TEEs, with the risk being more 
pronounced in those patients who have experienced TEEs in the past. To balance this factor 
that may impact on safety comparisons between the treatment groups, randomization will be 
stratified by ‘History of TEE (yes/no)’. 
As the type of surgery and expected blood loss volume may impact on efficacy comparisons  
‘Expected blood loss (“≥200 mL”, “≥100 mL but <200 mL” or “≥50 mL but <100 mL”)’ and 
‘Type of planned surgery (“orthopaedic surgery”, “cardiothoracic surgery” or “other surgery”)’ 
will be a further stratification factors.  


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3.3.11 
Independent Committees 
The primary efficacy endpoint will be the assessment of clinical hemostasis as assessed by the 
blinded IEAB. In order to adjudicate the primary efficacy endpoint, the IEAB will receive the 
pre-operative documented expected average and maximum blood loss (both recorded 
irreversibly prior to randomization), the estimated actual blood loss, and all information on any 
transfusions and administration of “rescue” clotting factor-containing products. Additionally 
the IEAB will be provided with all available Hgb and Hct values and information on volume of 
hemorrhagic would drainage. INR and PT values will not be provided to help ensure the 
effectiveness of blinding and avoid potential bias. IEAB will be blinded to Investigator’s 
clinical hemostasis rating. A detailed description of the information to be provided to the IEAB 
will be developed with the clinical experts and will be included in an IEAB charter. 
An IDMC will be established by the Sponsor and will routinely monitor safety in the study. The 
IDMC will also advise on the further conduct/stopping of the study once the interim analysis 
has been performed. Details are provided in Section 8.6 and Section 9.4. 


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4 
STUDY POPULATION 
4.1 
Population Base 
Patients under VKA therapy who need urgent surgery associated with significant bleeding risk 
will be eligible for study inclusion. 
The studied patient population is appropriate since these patients have an acquired prothrombin 
complex factor deficiency caused by anticoagulant therapy. This puts them at risk of excessive 
bleeding either spontaneously, due to trauma, or during surgery. The population to be studied 
would be most vulnerable since they would not have time to have their anticoagulation therapy 
reversed by administration of vitamin K in order to prevent the possibility of excessive bleeding 
during surgery. Patients needing urgent surgery can be defined as those that cannot be 
postponed until reversal of anticoagulation can be safely performed by vitamin K 
administration. 
Sites will identify patients for enrollment in this active-controlled prospective study. 
Independent Ethics Committee (IEC) / Institutional Review Board (IRB) approval will be 
obtained at all participating sites before start of enrollment. 
4.1.1 Inclusion Criteria 
Patients who meet all of the following criteria are eligible for the study: 
1. Male or female patients at least 18 years of age.
2. Patients currently on oral anticoagulation treatment with VKA of coumadin or warfarin
type.
3. Patients being admitted to the hospital or currently hospitalized where:
•
an urgent surgery carrying significant bleeding risk (≥50 mL expected blood loss in
normal coagulation state) is required as part of routine clinical care within 24 hours
of the start of investigational medicinal product;
•
VKA withdrawal and  use of oral or parenteral vitamin K alone to reverse
anticoagulation is deemed too slow or inappropriate for reversal;
4. Patients with an INR of 2.0 or above at the time of decision to reverse the
anticoagulation status.
5. Patients who have given written informed consent and who are able and willing to
comply with the procedures laid out in the study protocol.
4.1.2 Exclusion Criteria 
Patients who do meet any of the following criteria are not eligible for the study: 
1. Patients with a life expectancy of less than 48 hours per physician’s judgment (e.g.,
patients with a Glasgow Coma Scale  equal to 3 or a head Abbreviated Injury Score of
6, patients requiring continuous inotropic or pressor support, and patients whose status
is post cardiac arrest).
2. Patients for whom the planned surgery or procedure is commonly associated with a very
low bleeding risk (e.g., catheter placement, gastroscopy).
3. Patients with a history of TEEs, myocardial infarction  (MI), unstable angina pectoris,
critical aortic stenosis, cerebrovascular accident, TIA, severe peripheral vascular
disease (e.g. Fontaine IV) or disseminated intravascular coagulation within 3 months of


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enrollment. (Note: ongoing thrombosis in-situ or severe unilateral peripheral arterial 
disease (PAD) undergoing surgical intervention is not an exclusion criterion). 
4. Patients with a known congenital bleeding disorder.
5. Patients with a known antiphospholipid antibody syndrome.
6. Patients with present or past specific factor inhibitor activity.
7. Patients with thrombocytopenia of <80,000/μL or history of heparin-induced
thrombocytopenia.
8. Patients who have received more than 5000 units of systemic unfractionated heparin
(UFH), any dose of low-molecular-weight heparin (LMWH) or  any dose of non-VKA
anticoagulant (i.e. direct oral anticoagulant) within 24 hours prior to enrollment into the
study or have potential need to receive these medications in mentioned doses before
completion of hemostasis evaluation at the end of surgery.
9. Patients who have received PCCs, FFP or vitamin K within 72 hours prior to enrollment
into the study.
10. Patients receiving P2Y12 platelet inhibitors (e.g. Clopidogrel, Prasugrel, Ticagrelor)
11. Patients with a known history of hypersensitivity to plasma-derived products.
12. Patients requiring urgent surgical procedures where according to the surgeon's clinical
judgment an accurate estimate of expected blood loss and transfusion requirements is
not possible, e.g.:
a.
Surgeries requiring massive transfusion protocols (e.g., major polytrauma,
major injuries, organ transplant surgeries),
b. Patients with acute major bleeding (e.g., gastrointestinal bleeds, obstetric
haemorrhage),
c.
Surgeries with unpredictable intraoperative blood loss (e.g., ruptured aneurysm,
primary surgery for intracranial hemorrhage (ICH)).
13. Pregnant or nursing women.
14. Patients participating in another interventional clinical study currently or during the past
30 day prior to enrollment into this study.
15. Patients previously enrolled in this study.
4.2 
Prior and Concomitant Therapy 
4.2.1 Prior Treatment 
Details on medications taken within 30 days prior to enrollment and any concomitant 
medications taken during the study, including any over the counter medications, herbal 
supplements, vitamins, IV fluids, blood products, must be recorded in the CRF. 
4.2.2 Permitted Concomitant Therapy 
Concomitant administrationsof therapies not interfering with the primary objectives of the study 
are permitted. 
Patients taking acetylsalicylic acid concomitantly with Warfarin are eligible. 
Administration of vitamin K is permitted within 1 hour before IMP infusion or within 1 hour 
after IMP infusion, at a dose of 2, 5, or 10 mg according to local clinical practice.  
4.2.3 Forbidden Concomitant Therapy 


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Patient taking P2Y12 platelet inhibitors (e.g. Clopidogrel, Prasugrel, Ticagrelor) concomitantly 
with VKA are not eligible for the study. P2Y12 platelet inhibitors must not be used until 
completion of hemostasis evaluation at the end of surgery. 
UFH in dose above 5000 units, LMWH and/or non-VKA anticoagulant (i.e. direct oral 
anticoagulant) in any dose, must not be used from the time 24 hours before enrollment into the 
study and until completion of hemostasis evaluation at the end of surgery.The reconstituted 
IMP should not be mixed with other drugs. This could lead to an activation or inactivation of 
coagulation factor(s). 
Generally, administration of blood products should be avoided if possible. However, it is up to 
the treating physician to decide whether a surgical procedure can start or if additional pre-
operative administration of coagulation treatment is required per standard of care (eg, PCC, 
single coagulation factors, plasma). If used, all details must be documented (eg, product name, 
reason for administration, dose etc.). 
4.3 
Withdrawal and Replacement of Patients 
4.3.1 Premature 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 in case of AEs, 
poor compliance, or other reasons. Since an excessive rate of withdrawal can render the study 
non-interpretable, the unnecessary withdrawal of patients must be avoided. 
For any discontinuation after study entry, the investigator will obtain all the required details 
and document the reason(s) for discontinuation. 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 the outcome. 
4.3.2 Patient Replacement Policy 
Patients withdrawn from the study because of safety or efficacy reasons will not be replaced. 
4.4 
Assignment of Patients to Treatment Groups 
Each patient will receive a patient number (in numeric order per center) after having signed a 
written informed consent form. The site will enter the patient number and the initials of each 
patient in the CRF and in the confidential patient identification list. 
Each patient will be randomized to receive IMP (either OCTAPLEX or Beriplex® P/N 
[Kcentra]). In order to achieve a balance between the 2 treatment groups with respect to the 
planned type of surgery and history of TEE, the treatment allocation by the IRT will be stratified 
according to the parameters ‘Expected blood loss (“≥200 mL”, “≥100 mL but <200 mL” or 
“≥50 mL but <100 mL”)’,  ‘History of TEE (“yes” or “no”)’ and ‘Type of planned surgery 
(“orthopaedic surgery”, “cardiothoracic surgery” or “other surgery”).  To ensure that the 
intended proportions of patients enrolled are kept for subgroups of expected blood loss, the IRT 
will preclude enrollment into the subgroup once its targeted number of enrolled patients is 
reached. 


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4.5 
Relevant Protocol Deviations 
In the case of any major protocol deviation the investigator and Octapharma will decide on the 
further participation of the patient in this study, after having discussed all relevant aspects. All 
major protocol deviations should be notified to IEC/IRBs or regulatory authorities if required 
by local regulation. 
Each patient who has received IMP will be included in the safety population. With respect to 
the Per-Protocol efficacy analysis, protocol deviations will be handled on an individual basis. 
After each study part the decision on membership of the patients in a particular analysis 
population will be made at a blinded data review meeting, prior to database lock. 
4.6 
Subsequent Therapy 
Any patient who discontinues from the study should continue medical treatment according to 
local standards. 


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5 
INVESTIGATIONAL MEDICINAL PRODUCTS 
5.1 
Characterization of Investigational Products 
Commercially available investigational products will be used in this study: OCTAPLEX 500IU 
(in all participating countries), Kcentra 500 IU (in the US), Beriplex® P/N 500 IU (in all 
participating countries except the US). All products are supplied as a powder for solution for 
injection together with a solvent (20 mL Water for Injection), which should be used for the 
reconstitution of the investigational products. The batch number(s) used will be recorded in the 
clinical study report. 
5.1.1 OCTAPLEX 500 IU 
The reconstituted solution contains the following ingredients as shown in Table 2: 
Table 2: Ingredients in the Reconstituted OCTAPLEX 500IU Solution 
Ingredients 
Quantity per vial 
(20 mL)  
Quantity per mL 
reconstituted solution 
Total protein 
260-820 mg
13 – 41 mg/mL 
Active substances 
1. Coagulation factors
Human coagulation factor II (FII) 
220 – 760 IU 
11 – 38 IU/mL 
Human coagulation factor VII (FVII) 
180 – 480 IU 
9 – 24 IU/mL 
Human coagulation factor IX (FIX) 
400 – 620 IU 
20 – 31 IU/mL 
Human coagulation factor X (FX) 
360 – 600 IU 
18 – 30 IU/mL 
2. Further active ingredients
Protein C 
140 – 620 IU 
7 – 31 IU/mL 
Protein S 
140 – 640 IU 
7 – 32 IU/mL 
Excipients 
Heparin 
100 – 250 IU 
5 – 12.5 IU/mL 
Sodium citrate 
0.34 – 0.54 mmol 
0.017 – 0.027 mmol/mL 
5.1.2 Kcentra 500 IU 
The reconstituted solution contains the following ingredients as shown in Table 3: 


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Table 3: Ingredients in the Reconstituted Kcentra 500 IU Solution 
Ingredients 
Quantity per vial 
(20 mL)  
Quantity per mL 
reconstituted solution 
Total protein 
120 – 280 mg 
6 – 14 mg/mL 
Active substances 
1. Coagulation factors
Human coagulation factor II (FII) 
380 – 800 IU 
19 – 40 IU/mL 
Human coagulation factor VII (FVII) 
200 – 500 IU 
10 – 25 IU/mL 
Human coagulation factor IX (FIX) 
400 – 620 IU 
20 – 31 IU/mL 
Human coagulation factor X (FX) 
500 – 1020 IU 
25 – 51 IU/mL 
2. Further active ingredients
Protein C 
420 – 820 IU 
21 – 41 IU/mL 
Protein S 
240 – 680 IU 
12 – 34 IU/mL 
Excipients 
Heparin 
8 – 40 IU 
0.4 – 2 IU/mL 
Antithrombin III 
4 – 30 IU 
0.2 – 1.5 IU/mL 
Human albumin 
40 – 80 mg 
2 – 4 mg/mL 
Sodium chloride 
60 – 120 mg 
3 – 6 mg/mL 
Sodium citrate 
40 – 80 mg 
2 – 4 mg/mL 
HCL 
Small amounts 
Small amounts 
NaOH 
Small amounts 
Small amounts 
5.1.3 Beriplex® P/N 500 IU 
The reconstituted solution contains the following ingredients as shown in Table 4: 
Table 4: Ingredients in the Reconstituted Beriplex ® P/N 500 IU Solution 
Ingredients 
Quantity per vial 
(20 mL)  
Quantity per mL 
reconstituted solution 
Total protein 
120 – 280 mg 
6 – 14 mg/mL 
Active substances 
1. Coagulation factors
Human coagulation factor II (FII) 
400 – 960 IU 
20 – 48 IU/mL 
Human coagulation factor VII (FVII) 
200 – 500 IU 
10 – 25 IU/mL 
Human coagulation factor IX (FIX) 
400 – 620 IU 
20 – 31 IU/mL 
Human coagulation factor X (FX) 
440 – 1020 IU 
22 – 60 IU/mL 
2. Further active ingredients
Protein C 
300 – 900 IU 
15 – 45 IU/mL 
Protein S 
240 – 760 IU 
12 – 38 IU/mL 
Excipients 
Heparin 
8 – 40 IU 
0.4 – 2 IU/mL 
Antithrombin III 
4 – 30 IU 
0.2 – 1.5 IU/mL 
Human albumin 
40 – 80 mg 
2 – 4 mg/mL 
Sodium chloride 
60 – 120 mg 
3 – 6 mg/mL 
Sodium citrate 
40 – 80 mg 
2 – 4 mg/mL 
HCL 
Small amounts 
Small amounts 
NaOH 
Small amounts 
Small amounts 
5.2 
Packaging and Labeling 
Commercially available IMPs will be re-packed and additionally labeled according to local 
regulations. 


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5.3 
Conditions for Storage and Use 
IMP should be stored at ≥ 2°C (35°F) and ≤25°C (77°F) protected from light and must not be 
frozen. The investigator must ensure that the IMP is stored under appropriate temperature 
conditions and in a reasonably secure area of restricted access.  
Reconstituted product must be used within 4 hours following reconstitution. Reconstituted 
product can be stored at 2-25°C (35°F -77°F). If cooled, the solution should be warmed to 20-
25°C prior to administration. Do not freeze the reconstituted product. Discard partially used 
vials.  
5.4 
Dose and Dosing Schedule 
The dose of IMP to be administered should be determined based on BW and baseline INR. BW 
should be rounded to the nearest whole kilogram number for IMP dose calculation.  Baseline 
INR value should be rounded to the 1st decimal place. If the baseline INR value is not available 
at the time when patient must be randomized to initiate preparation of IMP, qualifying INR 
(used for inclusion of the patient) can be used. If the qualifying INR is within 3 hours of IMP 
infusion start and was analyzed by the laboratory participating in the study it can serve as the 
baseline INR and additional baseline INR testing is not mandatory. Otherwise baseline INR 
must be obtained. If the baseline INR value compared to qualifying INR value used for initial 
IMP dose calculation falls within different IMP dosing ranges, the dose of IMP should be 
adjusted to baseline INR using IRT. 
The dose of IMP will depend on the BW and baseline INR  of the patient and will be calculated 
by the responsible treating investigator according to the following dosing table. 
Baseline INR 
2 to <4 
4-6
>6
Dose (IU of Factor IX/kg BW) 
25 
35 
50 
Maximum dose (IU of Factor IX) 
2500 
3500 
5000 
The nominal IMP potency of 25 IU/mL of factor IX will be used for volume calculation (each 
vial has ~500 IU of OCTAPLEX or Beriplex® P/N (Kcentra) and is reconstituted in 20 mL of 
Water for Injection).  
IMP will be administered by IV infusion at a rate of 0.12 mL/kg/min (~3 units/kg/min), up to a 
maximum rate of 8.4 mL/min (~210 units/min). The total volume of IMP used and time of 
infusion will be recorded.  
One infusion of IMP will be given according to the table above. 
5.5 
Preparation and Method of Administration 
The preparation is dissolved with water for injection, by transferring it into the vial containing 
the concentrate using the Mix2Vial™ transfer set. 
Before the IMP is infused, the solution must be warmed up to room temperature. The 
preparation must be used immediately after dissolution, and any unused solution must be 
discarded. If reconstituted IMP is not used within 4 hours following reconstitution, it should be 
discarded and new IMP assigned via IRT. Usually, the solution is clear or slightly opalescent. 
Do not use solutions that are cloudy or have deposits. The reconstitution time is less than 10 


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minutes at room temperature. During the procedure described, aseptic technique must be 
maintained. 
The total volume used and time of start and end of infusion will be recorded. 
Infusion line should be flushed with 0.9% sodium chloride.  
5.6 
Blinding and Breaking the Study Blind 
Following randomization, IMP will be assigned using IRT and will be prepared for infusion by 
unblinded site personnel. IMP will be prepared and infused in a manner that will blind the 
investigator and other blinded site personnel to the study treatment. Unblinded site personnel 
must not communicate to the investigator or other blinded site personnel which product was 
assigned to the patient.  
Breaking of blinding in individual patients is only permitted in case of a SAE or unexpected 
adverse drug reaction (ADR), when knowledge of the type of the administered IMP is required 
for therapeutic decisions regarding this event. 
Emergency patient unblinding will be managed in a dedicated IRT system. In the event an 
investigator needs to unblind a study patient, authorized study personnel at the site will log into 
IRT to request access to the unblinded randomization code for the patient in question. In order 
to do so, the investigator will have to acknowledge the serious nature of unblinding. Upon 
taking these steps, the dedicated web-based system will then provide the investigator the 
specific treatment arm for that patient. Upon exiting the dedicated web-based system, an email 
notification of this action will automatically be sent to appropriate management and safety 
officials acknowledging the patient unblinding without providing the specific treatment arm. 
This information will also be captured in the study audit trail. 
5.7 
Treatment Compliance 
5.7.1 Drug Dispensing and Accountability 
IMP will be delivered to all sites by a central distribution facility or local depot. A drug 
dispensing log will be kept up-to-date by each investigator, detailing the dates and quantities of 
the IMP administered to each patient. The inventory will be available to the monitor to verify 
drug accountability during the study. Any unused IMP and empty bottles will be disposed 
locally if allowed by local regulation or returned to Sponsor’s designee for disposal. 
5.7.2 Assessment of Treatment Compliance 
IMP will be infused at the study site under the guidance of the investigator. The number of vials 
used will be documented together with IMP batch numbers.  


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6 
STUDY CONDUCT  
6.1 
Observations by Visit 
6.1.1 Screening and Randomization 
The following assessments will be performed during screening: 
•
Obtain voluntarily given, written (signed and dated) informed consent
•
Screening registration
•
Collection of baseline information:
o
demographics (including weight and height measurements) (see Section  7.1)
o
medical history (see Section  7.1)
o
prior and concomitant medication use (see Section 7.1 and 4.2.1)
•
planned vitamin K administration (see Section  7.1)Check and document compliance
with inclusion and exclusion criteria
•
Urine or blood pregnancy test for women of childbearing potential (WOCBP) (see
Section 7.3.9)
•
Initial hemostatic assessment (see Section 7.2.1)
•
Calculate IMP dose (see Section 5.4) and randomize patient via IRT
•
Assign IMP following randomization using IRT, prepare product for infusion,
document time of reconstitution. IMP reconstitution should start within 4 hours prior to
infusion.
The expected average and maximum blood loss and expected average and maximum 
transfusion requirements for non-anticoagulated patients undergoing the same type of 
surgical procedure need to be documented with audit trail prior to randomization.  
Patients with ongoing thrombosis in-situ or severe unilateral peripheral arterial disease 
(PAD) undergoing intervention must be consulted with the Sponsor/Sponsor’s designee 
medical monitor before randomization. Contact details will be provided in the Investigator 
File. 
6.1.2 Baseline 
The following baseline assessments will be performed within 3 hours before the administration 
of IMP: 
•
Vital signs
•
Physical examination (see Section 7.3.5)
•
Blood sampling for local lab (see Section 7.2.2.1 and Section 7.3.6)
•
Blood sampling for central lab (see Section 7.3.6) including viral markers
•
Vitamin K administration 1 hour before IMP infusion and at the latest within 1 hour
after IMP infusion. Document dose and administration time. For patients with the
following clinical conditions, vitamin K administration is not mandatory:
o
mechanical heart valve


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o
Left Ventricular Assist Device (LVAD)
o
any other hypercoagulable/prothrombotic condition identified by the treating
physician
If vitamin K is not administered, the clinical reason for non-administration must be 
documented in the CRF. 
•
Document vital status, AEs
6.1.3 Infusion of IMP 
•
Check time of IMP reconstitution. If IMP was reconstituted more than 4 hours before
infusion it should be discarded and new IMP assigned using IRT.
•
Infuse IMP by IV infusion at a rate of 0.12 mL/kg/min (~3 units/kg/min), up to a
maximum rate of 8.4 mL/min (~210 units/min). The total volume of IMP used, time,
and speed of infusion will be recorded.
•
Document AEs, vital status
•
Document concomitant medications and transfusions.
6.1.4 Procedures After End of Infusion 
The following assessments will be performed after the End of Infusion of IMP: 
•
Vital signs (30 min and 2 hours after the end of infusion)
•
Blood sampling for local lab (see Section 7.3.6) (30 min, 2 hours, 4 hours, 12 hours, and
24 hours after end of infusion).
•
Blood sampling for central lab (see Section 7.3.6) (30 min, 2 hours, 4 hours, 12 hours,
and 24 hours after end of infusion).
•
Document AEs, vital status, concomitant medications, and transfusions
If TEEs are suspected at any time during the study, appropriate examinations according to 
local standards should be performed (e.g. Doppler scan using color duplex, X-ray) and the 
results documented in CRF. 
6.1.5 Procedures Prior to Surgery  
The following assessments will be performed within 1 hour prior to surgery start: 
•
Blood sampling for local lab (see Section 7.3.6)
•
Document AEs, vital status, concomitant medications, and transfusions (see
Section 7.2.2.3).
•
Hematoma assessment (see Section 7.2.2.5)
The time of start of surgery is defined as the time of initiation of anesthesia, as documented in 
the anesthesia protocol. 
6.1.6 Procedures After Surgery  
The following assessments will be performed within 1 hour post-surgery end: 
•
Blood sampling for local lab (see Section 7.3.6)
•
Document AEs, vital status (see Section 7.3), concomitant medications (see Section 4.2)
and transfusions (see Section 7.2.2.3).


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•
Hemostatic assessment (see Section 7.2.1)
•
Hematoma assessment (see Section 7.2.2.5)
•
Wound drainage evaluation
The time of surgery end is defined as the surgery end time of the principal procedure. 
6.1.7 Procedures 12 and 24 hours After Start of Surgery  
The following assessments will be performed 12 and 24 hours after the start of surgery: 
•
Hematoma assessment including documentation of cases that require surgical
evacuation (see Section 7.2.2.5).
•
Document AEs, vital status (see Section 7.3), concomitant medications (see Section 4.2)
and transfusions (see Section 7.2.2.3).
•
Blood sampling for local lab (see Section 7.3.6)
•
Wound drainage evaluation
6.1.8 Procedures in Post-Operative Period 
The following assessments will be performed in the days after surgery: 
•
Vital signs (Day 2, discharge)
•
Physical examination (Day 2, discharge)
•
Blood sampling for local lab (see Section 7.3.6) (Day 2, discharge)
•
Document AEs, vital status, concomitant medications and transfusions (see
Section 7.2.2.3) (Day 2, 4, discharge)
Assessments at Days 2 or 4 are done if the patient remains hospitalized. Discharge assessments 
should be done on the day of discharge. If discharge falls on Days 2 or 4, the schedule of 
discharge assessments should be followed. 
6.1.9 Follow-up Assessments 
The following follow-up assessments will be performed: 
•
Blood sampling for central lab to test for Parvovirus B19 (Day 9) in patients with
negative results for one or both Parvovirus B19 Baseline tests (see Section 7.3.7)
•
Document vital status (Day 9, 21, and 45)
•
Follow-up for serious AEs (Day 9, 21, and 45) and concomitant medication
(documentation of concomitant medication at Days 9, 21, and 45 is only required if AEs
are ongoing)
If no blood collection is required and it is otherwise deemed appropriate by the investigator 
(e.g. there is no need for any onsite follow up) these assessments can be done via phone. 
6.1.10 
Interpretation of time windows in this study 
The allowed time windows in this study are outlined in the Flow Chart. 


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6.2 
Duration of Study 
6.2.1 Planned Duration for an Individual Patient 
The duration of the entire study for each patient will be approximately 45 days. Patients 
randomized, but given no IMP, will be withdrawn from the study. All patients who received 
IMP, but whose surgery was cancelled due to any reason, should complete all protocol 
procedures with the exception of OP procedures (prior OP, post OP, 12h after START and 24h 
after START), which will be skipped. Post operative time points (Day 2, Day 4, and Discharge) 
will be calculated from the day of IMP infusion. 
6.2.2 Planned Duration for the Study as a Whole 
The study will be considered completed, when all patients have completed the final examination 
(Day 45 follow-up). 
The estimated start of the study (enrollment of first patient) is Q4 2016, and the estimated end 
of the study (last visit of last patient) is Q2 2021. As one un-blinded interim analysis will be 
performed after enrollment of 50% of the planned sample size, early stopping of the study for 
demonstrated non-inferiority of OCTAPLEX or futility to achieve this could occur. 
6.2.3 Premature Termination of the Study 
Both the investigator and the Sponsor reserve the right to terminate the study at any time. Should 
this be necessary, the procedures will be arranged on an individual study basis after review and 
consultation by both parties. In terminating the study, the Sponsor and the investigator will 
ensure that adequate consideration is given to the protection of the patients' interests. 
Regulatory authorities and IECs/IRBs will be informed according to national regulations. 
Should the study be prematurely terminated, all study materials (IMPs, laboratory kits etc.) 
must be returned to the Sponsor or disposed at the study site if approved by the Sponsor. 


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7 
ASSESSMENTS AND METHODS 
7.1 
Background / Baseline Information 
The following information will be captured at Screening and upon enrollment: 
Demographics: including sex, age, weight and height (calculated Body Mass Index), and ethnic 
origin. Weight must be measured using weighing scales, estimating or asking the patients for 
their weight is not acceptable. 
Medical history: obtained by interviewing the patient. Records of past diseases and treatments 
(e.g., hospital discharge letters) will be obtained for the study files if available. As history of 
TEEs, estimated blood loss, and type of surgery are stratification factors for randomization in 
this study, this information must be carefully checked and entered in the CRF. 
Previous and concomitant medication: obtained by interviewing the patient 
Vitamin K administration: documentation of time and dose. If vitamin K is not administered, 
the clinical reason for non-administration must be documented in the CRF. 
7.2 
Efficacy Assessments 
7.2.1 Assessments for Primary Efficacy Endpoints 
During screening, an initial hemostatic assessment will be conducted and documented with an 
audit trail before randomization. This evaluation will include determination of the nature of the 
operation and the predicted estimated blood loss and anticipated transfusion requirements. 
Details to be documented include the expected average and maximum blood loss and expected 
average and maximum transfusion requirements for non-anticoagulated patients undergoing the 
same type of surgical procedure. Cell saver blood is to be accounted for when assessing the 
predicted volume of transfusions. The surgeon will also note any extenuating circumstances 
that may affect the estimated blood loss or transfusion requirements (e.g., prior surgery with 
resulting adhesions, limited or extensive surgery). Any planned adjunct therapy should also be 
recorded prior to surgery.  
At the conclusion of the surgical procedure the actual estimated blood loss (by local practice) 
and transfusion requirements will be documented. Efficacy will be rated by the investigator at 
the end of the surgery in a blinded manner based on a 4-point hemostatic efficacy scale. 
The hemostatic efficacy rating will also be assessed by an IEAB consisting of clinical experts. 
All adjudications will be conducted in a blinded manner and the IEAB will be provided with 
all relevant details (e.g. duration of surgery, co-medication, medical history, predicted and 
actual blood loss, transfusion information, details of hemorrhagic wound drainage) of the 
patient and the actual procedure performed covering the time period up to the end of the surgery, 
as documented in the anesthesia record. To ensure the effectiveness of blinding and avoid 
potential bias, the INR and PT values will not be provided to the IEAB. The IEAB will also be 
blinded to Investigator’s clinical hemostasis rating. 
The hemostatic efficacy of the study treatments is to be assessed in the categories 'excellent', 
'good', 'moderate' or 'none'. Ratings of 'excellent' and 'good' will be considered as 'effective' 
hemostasis, while a rating of 'moderate' and 'none' will be considered as 'ineffective' hemostasis. 


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Assessment should be guided by clinical experience, the specifics of the surgery actually 
performed, additional transfusion requirements and blood loss occurred during the surgery. The 
criteria below involve aspects of intraoperative blood loss and transfusions. 
Hemostatic Efficacy Scale (assessment at the end of the surgery – as documented in the 
anesthesia record)*: 
•
Excellent: Intra-operative blood loss and transfusion requirements were lower than or
equal to the average expected ones for the type of procedure performed in a patient with
normal hemostasis and of the same sex, age, and stature.
•
Good: Intra-operative blood loss and transfusion requirements were higher than the
average expected ones but lower or equal to the maximal expected blood loss and
transfusion requirements for the type of procedure in a patient with normal hemostasis.
•
Moderate: Intra-operative blood loss and transfusion requirements were higher than the
maximal expected ones for the type of procedure performed in a patient with normal
hemostasis, but hemostasis was controlled.
•
None: Hemostasis was uncontrolled necessitating a change in clotting factor
replacement regimen.
* For all ratings (excellent, good, moderate and none), unexpected blood loss due to surgical
complications will not be taken into consideration when assessing intra-operative efficacy.
These include:
1. Direct injury to a vessel (artery or vein).
2. Vessel injury not adequately responding to routine surgical procedures achieving
hemostasis.
3. Accidental injury of parenchymatous tissue (e.g. liver, lung).
When quantifying the deviation between average and actual intra-operative blood loss and 
transfusions, unexpected transfusions of plasma, red cells, platelets and coagulation factor 
products due to surgical complications should be excluded. For example: 
1. Direct injury to a vessel (artery or vein),
2. Vessel injury not adequately responding to routine surgical procedures achieving
hemostasis,
3. Accidental injury of parenchymatous tissue (e.g. liver, lung),
4. Treatment of pre-existing conditions like anemia.
Transfusions for pre-existing anemia will be excluded only if the number of units of red cells 
to be transfused for this purpose is clearly documented prior to administration of the IMP and 
before the start of surgery. 
7.2.2 Assessments for Secondary and Further Exploratory Efficacy Endpoints 
7.2.2.1 Measurement of INR 
INR will be calculated from the PT results. The INR system is used to standardize variability 
of response of different thromboplastin reagents to warfarin. The INR is calculated from the PT 
ratio of test plasma to the geometric mean normal PT, to the power of the international 


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sensitivity index of the thromboplastin, using the following formula: INR = (patient 
PT/GMNPT)ISI. 
Baseline INR will be determined within 3 hours prior to the start of the first infusion of IMP. 
Samples will also be drawn for INR determination at 30 minutes (±15 minutes), 2 hours (±30 
minutes), 4 hours (±30 minutes), 12 hours (±1 hour), and 24 hours (±2 hours) after the end of 
IMP infusion, prior OP (within 1 hour prior surgery start) and post OP (within 1 hour after 
surgery end) and at any point considered necessary by the investigator. All tests performed per 
standard of care should be documented in CRF. 
Certified portable INR monitoring devices may only be used for qualifying INR measurements. 
All study specific INR measurements must be tested in local laboratory. 
7.2.2.2 Measurement of Coagulation Factor Levels (FII:C, FVII:C, FIX:C, FX:C, PC, 
and PS) 
Baseline will be determined within 3 hours prior to the start of the first infusion of IMP. Samples 
will also be drawn for these determinations at 30 minutes (±15 minutes), 2 hours (± 30 minutes), 
4 hours (± 30 minutes), 12 hours (± 1 hour), and 24 hours (± 2 hours) after the end of infusion 
or at any point considered necessary by the investigator.  
7.2.2.3 Red Blood Cell, Plasma and Platelets Transfusions Initiated During the Surgery 
The time, amount (units and mL) and reason of all intra-operative RBC, plasma, and platelet 
transfusions during surgery will be recorded and analyzed. All blood and plasma products given 
throughout the hospitalization for the original admission and the reason for their administration 
will be captured on a CRF page designed specifically for this purpose. This will include any 
blood product and/or volume expanders. Blood products will be defined as autologous blood, 
allogenic whole blood, whole blood, RBC, FFP, platelets, and cryoprecipitate (14)  (American 
Society of Anesthesiologists 2006).  
Cell saver blood is to be accounted for when assessing the volume of transfusions. 
The ASA (American Society of Anesthesiologists) recommendations for triggering a RBC 
transfusion will be used to assess the need for RBC transfusions. These guidelines recommend 
RBC transfusion when Hg levels fall acutely below 6 g/dL and no transfusion when Hg levels 
are above 10 g/dL (14) (ASA 2006). The determination of whether intermediate Hgb 
concentrations (i.e., 6–10 g/dL) justify or require red blood cell transfusion should be based on 
any ongoing indication of organ ischemia, potential or actual ongoing bleeding (rate and 
magnitude), the patient’s intravascular volume status, and the patient’s risk factors for 
complications of inadequate oxygenation. These risk factors include a low cardiopulmonary 
reserve and high oxygen consumption indicated by decreased urine output, unstable vital signs, 
evidence of myocardial ischemia, increased lactate or base deficit, change in level of 
consciousness, orthostatic signs (dizziness or decreased blood pressure with standing), or with 
impending blood loss (expected for the scheduled surgery). If there is a deviation from this 
guideline the physician/surgeon will be asked to document the justification for any transfusion 
outside of these guidelines. 


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7.2.2.4 Change in hematological parameters 
Hematological parameters (Hgb, Hct, RBC, WBC, platelets) will be determined at the local 
laboratory within 3 hours prior to the start of the first infusion of IMP. Samples will also be 
drawn for determination of these parameters at 30 minutes (±15 minutes) and 24 hours (±2 
hours) after the end of IMP infusion, prior OP (within 1 hours prior surgery start) and post OP 
(within 1 hours after surgery end), at 12 and 24 hours after start of operation and at Day 2, 
Discharge, or at any point considered necessary by the investigator.  
7.2.2.5 Incidence of Hematoma and Proportion of Patients with Surgical Wound 
Hematomas That Need Evacuation 
The patient will be initially assessed for the presence of hematoma. The extent of hematomas 
after surgery will be evaluated. The need for evacuation of any hematoma post-surgery will be 
evaluated and recorded. 
7.3 
Safety Assessments 
The following drug safety information shall be collected: 
•
AEs and SAEs temporally associated with administration of IMP, or comparator
(definitions and reporting requirements see Section 7.3.1)
•
Pregnancies, drug overdose, interaction, medication error, lack of efficacy, post study
SAEs (see Section 7.3.9).
•
Occurrence of TEEs
•
Vital status (alive vs dead)
•
Physical examination
•
Vital signs
•
Clinical laboratory tests
•
Viral markers
7.3.1 Adverse Events 
7.3.1.1 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 unfavorable 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. 
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. 
7.3.1.2 Collection 
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?”. 
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 one 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 
causality, as defined below (Sections 7.3.1.3, 7.3.1.4 and 7.3.2). The Sponsor is responsible to 
assess the expectedness of each ADR (expected or unexpected), as defined below 
(Section 7.3.1.4). 
In the event of clinically significant abnormal laboratory findings, the tests will be confirmed 
and followed-up until they have returned to normal and/or an adequate explanation is available. 
Diseases, signs and symptoms and/or laboratory abnormalities already existing before the first 
administration of IMP are not considered as AEs when observed at a later stage unless they 
represent an exacerbation in intensity or frequency (worsening). 
The investigator should always provide detailed information concerning any abnormalities and 
the nature of, and reasons for any necessary action(s), as well as any other observations or 
comments, which are useful for the interpretation and understanding of the patients’ AEs or 
ADRs. 
7.3.1.3 Severity 
The intensity/severity of all 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.
Grading of an AE is up to the medical judgment of the investigator and will be decided on a 
case by case basis. 
7.3.1.4 Causality 
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 etiology 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).
Classification of ADRs: 
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.
•
unexpected: an ADR that is not listed in the current edition of the Investigator's
Brochure, or that differs because of greater severity or greater specificity.
7.3.1.5 Outcome 
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 that resulted in a 
patient’s death must be fully documented and reported, even in case the death occurs within 45 
days after IMP treatment end, and without respect of being considered treatment-related or not. 
7.3.1.6 Action(s) taken 
AEs requiring action or therapy must be treated with recognized 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. 


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The action taken by the investigator must be documented: 
a)
in general
-
none
-
medication (other than IMP) or other (e.g., physical) therapy started
-
test performed
-
other (to be specified)
b)
on IMP
-
none
-
product withdrawn
-
dose reduced
-
dose increased
The investigator will follow-up each AE until it is resolved or until the medical condition of the 
patient is stable, and all relevant follow-up information will be reported to the Sponsor. 
7.3.2 Serious Adverse Events 
An SAE is any untoward medical occurrence that at any dose: 
•
results in death,
•
is life-threatening,
•
requires hospitalization (with the exception of hospitalizations for surgeries that were
planned prior to study enrollment) or prolongation of existing hospitalization,
•
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 hypothetically might have caused death if it were more severe. 
Medical judgment should be exercised in deciding whether an AE/reaction is serious in other 
situations: Important AEs/ADRs that are not immediately life-threatening or do not result in 
death or hospitalization but may jeopardize the patient or may require intervention to prevent 
one of the other outcomes listed in the definitions above, should also be considered serious.  
In addition, although not classified under the seriousness criteria, all suspected transmissions 
of an infectious agent should be reported as SAE. 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. 
SAE reporting timelines 
All SAEs, whether suspected to be related to study treatment or not, are to be reported by 
telephone, fax or e-mail immediately to the Sponsor and the Sponsor’s designee. An SAE form 
must be completed and submitted to the Sponsor and the Sponsor’s designee within 24 hours 
after recognition of the event. 


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Sponsor contact details for SAE reporting: 
Octapharma’s Corporate Drug Safety Unit: 
OCTAPHARMA Pharmazeutika Produktionsges.m.b.H. 
Oberlaaer Strasse 235, 1100 Vienna, Austria 
Sponsor’s designee contact details for SAE reporting: 
Waiver from SAE reporting requirement: 
These exceptions/waivers include surgeries that are elective or planned before study entry, and 
prolongation of the existing hospitalizations due to economic or social reasons, but not medical 
reasons. These should not be considered as SAEs. 
7.3.3 Occurrence of TEEs 
As a component of the assessment of AE, the investigator will be questioned regarding the 
occurrence of TEEs. These are defined according to the Standardized Medical Dictionary for 
Regulatory Activities (MedDRA) query (SMQ) “Embolic and thrombotic events”. TEEs will 
be captured on a specific page of the CRF. All TEEs must also be recorded on the AE page of 
the CRF. If TEEs is suspected at any time during the study, appropriate examinations according 
to local standards should be performed (e.g. Doppler scan using color duplex, X-ray) and the 
results documented. 
7.3.4 Vital Status 
Vital status (alive or dead) will be documented from consent through the 45-day follow-up or 
discontinuation of the patient to allow determination of all-cause mortality. 
7.3.5 Physical Exam 
A standard physical exam will be performed at baseline, and at post-operative day 2 or 
discharge (whichever comes first). 
7.3.6 Laboratory Tests 
The actual time of blood sampling must be documented and recorded in the CRF. 
Details of test parameters to be collected are listed in Table 5. 
Coagulation, hematology, electrolytes, liver enzymes, Blood Urea Nitrogen (BUN) (or Urea), 
and creatinine tests will be performed at the respective local laboratories.   
Tests for coagulation parameters and virology will be performed at a central laboratory. 


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Samples for the central laboratory will be taken, processed, stored, and shipped in accordance 
with the laboratory manual provided by the central laboratory. 
Lab samples will be drawn at the time frames noted in the Flow Chart, until patient discharge, 
with the exception of parvovirus B19 virology samples in patients with negative results for 
either PCR or IgM test at Baseline. These patients will need to be called back at Day 9 for the 
completion of virology tests. 
Table 5: 
Details of Laboratory Tests 
Parameter 
Investigational Site 
Coagulation parameters 
INR, PT 
Locally 
aPTT 
Locally 
FII:C, FVII:C, FIX:C, FX:C 
Central lab 
PC, PS 
Central lab 
Hematology 
Hematocrit 
Locally 
Hemoglobin 
Locally 
Blood cell count (WBC, RBC, 
platelets) 
Locally 
Liver Function & Electrolytes Others 
LDH 
Locally 
Sodium, potassium 
Locally 
Kidney Function 
BUN (or Urea) and Creatinine 
Locally 
Virology 
Anti-Parvovirus B19 IgM Ab 
Central lab 
Parvovirus B19 PCR 
Central lab 
Pregnancy test 
        Urine or blood pregnancy test 
Locally 
The methods used for each parameter and the normal ranges of each determination at each 
laboratory involved will be provided in the Clinical Study Report.  
7.3.7 Viral Safety Tests 
Viral marker samples are taken at the baseline visit and at Day 9 (-2/+5 days) after the last 
administration of IMP. 
At the baseline visit, all patients will undergo serologic testing for Parvovirus B19 (anti-
Parvovirus B19 IgM Ab), as well as PCR for Parvovirus B19.   
At Day 9 (-2/+5 days) following the study infusion of IMP, a follow-up sample will be taken 
for Parvovirus B19 PCR and anti-Parvovirus B19 IgM Ab assessments in patients who had 
negative results of one or both Parvovirus B19 tests at baseline. Patients with positive results 
of both baseline tests do not need to have Parvovirus B19 testing repeated on Day 9. 


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The virus safety samples will be analyzed in the central laboratory. In case there is a change 
from baseline of the viral status of a patient and a suspected seroconversion, the viral tests will 
be repeated by the laboratory on back up aliquots of the Baseline and Day 9 samples.  
7.3.8 Vital Signs 
Safety evaluation will include monitoring of vital signs, i.e., body temperature, heart rate, blood 
pressure, and respiratory rate. Measurements will be carried out at baseline (just prior to 
infusion), and at the time points specified in the Flow Chart. Hemodynamic changes are 
frequently observed during surgery. For this reason, only alterations in heart rate or blood 
pressure not coinciding with periods of rapid blood loss and/or deemed significant by the 
physician will be recorded as AEs. In case fever occurs, temperature will be measured every 
morning until normalized. Fever will be defined as a body temperature >37.8°C orally (or 
>38.2°C rectally or >38.0°C axillary) and will be documented as an AE.
7.3.9 Other Relevant Safety Information 
Post-study related safety reports: 
Any SAE that occurs up to 4 weeks after the completion of the study should be reported by the 
investigator to the Sponsor if the investigator becomes aware of it. Proactive monitoring for 
post study SAEs is not required. 
If a post study SAE is identified, the investigator should complete an SAE form. Relation to the 
clinical study should be stated on the report. 
If a patient dies within up to 45 days after the last IMP administration, this should be reported 
as well, regardless of being considered treatment-related or not. 
Pregnancies 
Every effort will be made to avoid a pregnancy during the use of an IMP. A pregnancy test will 
be done for all WOCBP to exclude pregnant patients.  
WOCBP is defined as fertile woman, following menarche and until becoming post-menopausal 
unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy. A postmenopausal state is defined as no menses 
for 12 months without an alternative medical cause.  
Pregnancies occurring during the study (fetal exposure to the IMP) need to be reported by the 
investigator using  a pregnancy notification form. The form must be submitted to Sponsor and 
Sponsor’s designee following SAE reporting instructions provided in Section 7.3.2. 
Follow-up information on the outcome of both mother and fetus will be requested by a Sponsor 
representative. 
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. 
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 and of clinical relevance. 
The reaction must be clearly identified as an overdose. 


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Interaction: 
A drug interaction is a situation in which a substance/medicinal product affects the activity of 
an IMP, i.e., the effects are increased or decreased, or they produce an effect that none of the 
products exhibits on its own. The reaction must be clearly identified as drug interaction. 
Medication error: 
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, 
instructions for use/labeling. The reaction must be clearly identified as a medication error. 
7.4 
Appropriateness of Measurements 
Since the ultimate goal of the administered treatments is to restore a clinically satisfactory 
hemostasis for the duration of the surgery/invasive procedure, the clinical assessment of 
hemostatic efficacy provides the key clinical information on treatment efficacy. Blinded 
assessment of hemostatic efficacy has therefore been chosen as the primary endpoint. The 
secondary and further exploratory endpoints will provide further information on the clinical 
comparability of OCTAPLEX and Beriplex® P/N (Kcentra). 


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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 the information related to clinical findings, observations, or other 
activities in the study, provided 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 for the maximum period of time 
required by local regulations. 
For each patient enrolled, the investigator will indicate in the source records that the patient 
participates in this study. 
All data entered in the CRF must be supported by source data in the patient records. 
The investigator will permit study-related monitoring, audit(s), IEC/IRB review(s) and 
regulatory inspection(s), by providing direct access to source data/records. 
The investigator may authorize site staff (e.g. sub-investigators, nurses) to enter study data into 
the CRF. This must be documented in the “Delegation of Authority Log”, signed by the 
investigator. 
8.1.2 Case Report Forms 
For each patient enrolled, an electronic CRF (eCRF) will be completed within the Electronic 
Data Capture (EDC) system and approved by the investigator or an authorized sub-investigator. 
Study site staff (e.g. research nurse) will be responsible for entering patient data into the 
validated EDC system. All site personnel will be trained on the EDC system and study specific 
eCRFs prior to receiving access to the live database for data entry. The site is also provided 
with the approved eCRF Completion Guidelines which will assist in data entry and data 
issues/questions. The site will be notified once the database is active to begin data entry. 
Additional site training may be provided as refreshers throughout the study, if needed. All 
persons allowed to enter or change eCRF data must appear on the delegation of authority log. 
If any errors in the eCRFs are found during the data review process discrepancies will be 
generated programmatically within the EDC system, and ‘manual’ queries will be generated by 
either a monitor or Data Management. The programmed checks fire automatically once an 
eCRF page is saved within the system. The outputs of the programmed checks are referred to 
as ‘discrepancies’. Discrepancies are generated by the input of illogical eCRF data with the 
purpose to clarify the context or insertion of illogical or missing data with the site or designee. 
All discrepancies (programmed and manual) will be submitted to the site personnel or monitor 
for the site within the EDC system. Once the site responds to a discrepancy, Data Management 
or the monitor will review the new or changed data to ensure an appropriate response and close 
the discrepancy within the system. 


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8.1.3 Changes to Case Report Form Data 
Monitors will perform source data verification (SDV) as defined for the study. 
Errors occurring on the EDC system can only be corrected by the investigator(s) or other 
authorized site personnel. An audit trail documents all changes to the data over the entire study 
period. If data is changed as a result of a query, a comment must be supplied within the query’s 
text, stating the reason for the change, prior to closing. The study monitor should provide 
guidance to investigators and the investigators' designated representatives on making such 
corrections. In addition, any changes to a previously saved eCRF page that has not had a query 
generated will need to have a reason specified for the data change. This is handled within the 
EDC system and relevant prompts appear once any changes are made. 
Once queries have been resolved by the site staff, the resolutions are assessed by Data 
Management. If the query response provided confirms the data as correct, the discrepancy will 
be closed. If the response does not adequately address the question raised, a new query will be 
issued for further clarification. 
Manual checks are performed and programs are run throughout the study until the data is clean 
and the database is ready for lock. All discrepancies will be resolved prior to database lock. 
There will be a final run of the programmed checks to ensure all discrepancies are closed out, 
SDV will be confirmed as complete by the monitor, and all eCRFs will be approved by the 
investigator prior to database lock. 
8.2 
Information of Investigators 
An IB will be handed out to the investigator before the start of the study. This Brochure contains 
all information in the Sponsor’s possession necessary for the investigator to be fully and 
accurately informed about the safety of the IMP under evaluation and the respective benefit-
risk ratio. 
The IB will be updated by the Sponsor at regular intervals and in case new information 
concerning the IMP becomes available. 
The investigators will be informed about the methods for rating relevant study outcomes and 
for completing CRFs in order to reduce discrepancies between participating investigators and 
study sites. 
The investigator will be kept informed of important data that relate to the safe use of the IMP 
as the study proceeds. 
8.3 
Responsibilities 
The principal investigator is accountable for the conduct of the clinical study. Responsibilities 
may be delegated to appropriately qualified persons.   
A “Delegation of Authority Log” will be filled in and signed by the investigator. In accordance 
with this authority log, study site staff (e.g. sub-investigators, nurses) are authorized to perform 
tasks relating to the study. 


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8.4 
Investigator’s Site File 
At each study site, the investigator is responsible for maintaining all records to enable the 
conduct of the study to be fully documented. Essential documents as required by GCP 
guidelines and regulations (e.g., copies of the protocol, study approval letters, all original 
informed consent forms, site copies of all CRFs, drug dispensing and accountability logs, 
correspondence pertaining to the study, etc.) should be filed accurately and kept by the 
investigator for the maximum period of time required by local regulations. 
The investigator is responsible for maintaining a confidential patient identification code list, 
which provides the unique link between named source records and CRF data for the Sponsor. 
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 
On request, the investigator will supply the Sponsor with additional data relating to the study, 
or copies of relevant source records, ensuring that the patient’s confidentiality is maintained. 
This is particularly important when CRFs are illegible or when errors in data transcription are 
encountered. 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 Monitoring Committee 
An IDMC will be established by the Sponsor. The IDMC will be composed of recognized 
experts in the field of clinical care who are not actively recruiting patients and an independent 
statistician. 
A study specific IDMC charter will define in detail the composition, responsibilities and 
procedures of the IDMC. 
This Committee will have the following tasks: 
•
To review all serious AEs in a timely manner;
•
To review all non-serious AEs on a regular basis;
•
Review interim analysis results and give recommendations whether to continue the study
or not;
•
To give advice on the continuation, modification or termination of the study.
The IDMC will have access to the Investigator's Brochure for Octaplex and the current package 
insert for Beriplex® P/N (Kcentra), which includes all the ADRs that have been observed with 
the investigational product. 
The IDMC will review individual unblinded safety data in order to monitor the accruing data 
for safety. IDMC review determinations will be communicated to investigators by the 
Sponsor/the Sponsor’s designee. 


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9 
STATISTICAL METHODS AND SAMPLE SIZE 
9.1 
Determination of Sample Size 
The statistical analysis of the primary variable hemostatic success will be based on the 
probabilities of hemostatic success (derived from the blinded rating by the IEAB of 
OCTAPLEX and Beriplex® P/N (Kcentra) (pO and pK). 
To demonstrate that the treatment with OCTAPLEX is clinically not inferior to the treatment 
with Beriplex® P/N (Kcentra) with respect to hemostatic success, a two-sample, one-sided test 
of the pair of hypotheses: 
H0: 
pK – pO ≥ δ 
vs.  
H1: 
pK – pO < δ 
will be carried out with a type I error probability of α = 0.025 and clinical non-inferiority margin 
of δ = 0.15.  
Farrington’s and Manning’s test for difference in proportions will be used to assess the primary 
hypothesis in an interim and in the final analysis.  
Based on this method and a one-sided overall type I error probability α = 0.025, 
power 1 - β = 0.8, and a non-inferiority margin of δ = 0.15, the table below presents the 
estimated sample sizes per treatment group for the one-sided testing problem taking into 
account one planned interim analysis after half of the planned patients are enrolled for different 
constellations of OCTAPLEX and Beriplex® P/N (Kcentra) hemostatic success probabilities. 
The calculations are based on the following additional assumptions: 
•
A multiple one-sided significance level (family-wise error rate) of 0.025 for the
interim and final analysis
•
An α-spending function according to Hwang, Shi and Cani (11)  with parameter γ=-
0.8 which allows an early efficacy stop if p <0.01.
•
A β-spending function according to Hwang, Shi and Cani (11) with parameter γ=-
4.584 which allows a non-binding futility stop if p> 0.5.
Beriplex® P/N 
(Kcentra) 
hemostatic 
success probability 
89% 
85% 
90% 
95% 
OCTAPLEX 
hemostatic 
success probability 
85% 85% 90% 95% 85% 90% 95% 85% 90% 95% 
sample 
size 
per 
group 
166 
100 
51 
28 
193 
75 
37 
615 
135 
50 
actual power 
80.3 
80.5 
81.5 
82.2 
80.7 
80.8 
80.6 
80.1 
80.6 
82.0 
Conservatively assuming an OCTAPLEX hemostatic success probability of at least 85% and a 
Beriplex® P/N (Kcentra) hemostatic success probability of at most 89%, it is planned to enrol 
185 patients in each treatment arm, i.e. 370 patients in total. 
Assuming a proportion of about 10% randomized patients who were not treated or did not 
undergo the surgical procedure for administrative reasons; this would ensure that data on at 


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least 166 patients per treatment group in the modified ITT (mITT) population will be available 
for the final statistical analysis as derived from the sample size calculation. 
9.2 
Statistical Analysis 
A formal statistical analysis plan (SAP) describing all details of the analyses to be performed 
will be prepared by the study statistician and approved by the Sponsor prior to the start of the 
statistical analysis. 
9.2.1 Population for Analysis 
The randomized population (RAND) will include all randomized patients irrespective of 
whether they received treatment. This is the intent-to-treat (ITT) population according to the 
most rigid definition of ITT.  
The safety analysis population (SAF) will include all randomized patients who received at least 
one dose of IMP. Patients receiving different study treatments than originally randomized will 
be considered according to the treatment actually received (rather than that of the original 
randomization). 
For further statistical analysis of the efficacy parameters, a modified Intention-to-Treat 
population (mITT) is defined: All randomized patients who received at least one infusion of 
IMP, and who had the surgery initiated or for whom the surgery was not initiated for medical 
reasons related to insufficient coagulation. Patients in whom the surgery was not initiated due 
to technical reasons/aesthesia/etc (i.e., not related to insufficient coagulation) will be excluded 
from the mITT, whereas patients in whom the surgery was not initiated for coagulation-related 
reasons will be considered as treatment failures. 
The Per-protocol (PP) population: This analysis population will consist of all patients in the 
mITT population, excluding patients with major protocol deviations potentially affecting the 
primary endpoint. The following patients will be excluded: 
•
Patients who receive an IMP different to the IMP assigned by randomization
•
Patients who receive less than 70% of the planned dose
•
Patients who significantly violate inclusion/exclusion criteria
•
Patients with missing primary efficacy assessment
•
Start of surgery more than 5 hours after end of infusion of IMP
A final decision about the classification of protocol deviations as major and minor and their 
consequences regarding assignment of patients to analysis populations will be made during the 
blinded data review meetings prior to unblinding of patient cohorts for the interim and final 
analyses. Decisions and outcome will be approved by the Sponsor.  
The analysis of safety will be based on the SAF. 
The primary efficacy analysis will be based on all randomized subjects (RAND=ITT). 


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9.2.2 In addition the primary endpoint will also be analysed using the mITT and the PP 
population. Efficacy Analysis Plan 
9.2.2.1 
Primary Endpoint: Hemostatic Efficacy 
The primary efficacy variable is the hemostatic efficacy as assessed by the IEAB. The 
hemostatic efficacy is to be assessed based on objective criteria in the categories 'excellent', 
'good', 'moderate' or 'none'. Ratings of 'excellent' and 'good' will be considered as 'effective' 
hemostasis, while a rating of 'moderate' and 'none' will be considered as 'ineffective' hemostasis. 
The dichotomous 'hemostatic success' variable will be used in the analyses.  This variable will 
be imputed as ‘ineffective’ under the following two circumstances: 
•
If hemostatic efficacy value is missing, then hemostatic efficacy will be considered
‘none’ for the analysis.  This can occur in the RAND population if the patient is
randomized and not treated (or does not undergo surgery), also in the mITT population
if the patient is treated but does not undergo surgery due to insufficient coagulation.
•
If patient receives additional coagulation treatment (e.g. PCC, single coagulation
factors, plasma) after initial IMP infusion, then hemostatic efficacy will be considered
‘none’ for the analysis.
To demonstrate that treatment with OCTAPLEX is clinically not inferior to treatment with 
Beriplex® P/N (Kcentra) with respect to hemostatic success, a two-sample, one-sided test of the 
pair of hypotheses: 
H0: 
pK – pO ≥ δ (inferiority) 
vs.  
H1: 
pK – pO < δ (non-inferiority) 
will be carried out with a type I error probability of α = 0.025 and clinical non-inferiority margin 
of δ = 0.15. Whereby pO and pK present the probabilities of hemostatic success of OCTAPLEX 
and Beriplex® P/N (Kcentra) respectively. 
Farrington’s and Manning’s test for difference in proportions will be used to assess the primary 
hypothesis in an interim and in the final analysis. One-sided p-values and the corresponding 
nominal and repeated CIs for the difference in hemostatic success probabilities will be 
presented. 
The primary analysis will be performed on the RAND population. Additional analyses will be 
performed for the mITT and the PP population. 
In case of non-inferiority in the RAND, mITT and the PP population a “tipping point” analysis 
will be done to determine the robustness of the results. Iteratively patients excluded from the 
RAND/mITT/PP analysis assigned to the control arm will be considered as treatment successes, 
and patients excluded from the RAND/mITT/PP analysis and assigned to the OCTAPLEX arm 
will be considered as treatment failures, to determine the number of such imputed outcomes 
required to “tip” the study result from positive to negative in the randomized population. 
A sensitivity analysis will be conducted in the RAND, mITT, and PP populations based on the 
hemostatic efficacy rating by  the investigators at the end of surgery. 
A concordance analysis will be done to assess the agreement between the assessment by the 
IEAB and the investigator assessment. 


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9.2.2.2 
Secondary Endpoints 
The following measurements will be considered as exploratory secondary endpoints in the 
analysis of the efficacy of the study treatments: 
•
Proportion of patients with an INR value of less or equal to 1.5 to 30 minutes
(± 15 minutes) after the end of infusion.
•
Change in coagulation factor levels from baseline to 30 minutes (± 15 minutes) after the
end of infusion:
o
Factor FII
o
Factor FVII
o
Factor FIX
o
Factor FX
•
Proportion of patients receiving RBC during the surgery
The primary analysis of secondary endpoints will be based on the ITT population, except for 
the proportion of patients receiving RBC during surgery, this will be based on subset of patients 
undergoing surgery. Additionally the same analyses will be done on the mITT and PP 
populations. 
Farrington’s and Manning’s test for difference in proportions will be used to test the secondary 
variables on proportions. Point estimates and two-sided 95% CIs will be presented in addition 
to descriptive statistics for these endpoints. 
The change in the individual coagulation factors from baseline to end of infusion will be tested 
with the Wilcoxon rank-sum test between OCTAPLEX and Beriplex® P/N (Kcentra). The 
Hodges-Lehmann estimator of the median difference of the intra-individual change in the 
individual coagulation factors from baseline to end of infusion between OCTAPLEX and 
Beriplex® P/N (Kcentra) and the corresponding 95% CI will be calculated. 
9.2.2.3 
Further Exploratory Endpoints 
Analysis of the further exploratory endpoints will be done on the ITT, mITT, and PP population 
unless indicated otherwise. All analyses will be exploratory, by presenting descriptive statistics. 
•
Change in INR from baseline.
•
Change in PC, and PS from baseline to the end of infusion.
•
Change in coagulation factor levels (FII, FVII, FIX, FX, PC, and PS) from baseline to
2 h, 4 h, 12 h and 24 h after end of infusion
•
Assessment of blood loss after end of surgery.
•
Proportion of patients receiving plasma and platelets transfusions initiated during the
surgery.
•
Total volume of RBC and other blood product transfusions initiated during the surgery
normalized by patient's BW.
•
Change in hematological parameters (Hgb, Hct, RBC, WBC, platelets) from the
beginning to the end of the surgery.
•
RBC transfusion corrected change from baseline in Hgb at 12 and 24 hours after start
of surgery
•
Proportion of patients experiencing surgical wound hematoma requiring surgical
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•
Ratio of actual estimated blood loss as documented after surgery to the pre-operative
predicted blood loss for the type of planned surgery
9.2.2.4 
Subgroup Analyses for Efficacy 
To study the sensitivity of the efficacy results subgroup analysis will be performed for the 
primary and the secondary efficacy endpoints based on the following characteristics: 
•
expected blood loss (“≥200 mL”, “≥100 mL but <200 mL” or “≥50 mL but
<100 mL”) according to information provided at randomisation
•
type of planned surgery (“orthopaedic surgery”, “cardiothoracic surgery” or “other
surgery”)gender (male/female)
•
age in years (<=60, 60+)
•
race
•
history of TEE (yes/no)
•
baseline INR (2 to <4 / 4 to <6 / ≥6)
•
concomitant treatment with Vitamin K (yes/no)
These subgroup analyses are considered to be exploratory and will involve no type I error 
adjustment. The subgroup analyses will be based on the primary analysis population for 
efficacy. 
9.2.3 Safety Analysis Plan 
Safety analyses will be performed for the SAF. 
9.2.3.1 Adverse Events 
AEs will be coded according to the latest 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 probably or possibly related to the IMP), and serious TEAEs will be summarized and 
tabulated according to primary system organ class and preferred term. TEAEs leading to death 
and TEAEs resulting in withdrawal from the study, respectively, will be tabulated using 
frequency tables if a reasonable number of events of this type are observed. 
Patient listings will be provided for patients with SAEs, AEs leading to withdrawal from study, 
and AEs leading to death. The listings will also include patients enrolled but not randomized. 
9.2.3.2 Thromboembolic Events 
The number of patients with TEEs overall and within 3, 21 and 45 days after end of surgery 
will be summarized. A possible difference between treatment groups will be estimated by a risk 
ratio with 95% CI. Kaplan-Meier estimates for time to first occurrence of a TEE event will be 
calculated and graphically presented. 
9.2.3.3 Mortality 
The number of patients who died overall and within 3, 21 and 45 days after end of surgery will 
be summarized. A possible difference between treatment groups will be estimated by a risk 


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ratio with 95% CI. Kaplan-Meier estimates for time to death will be calculated and graphically 
presented. 
9.2.3.4 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 visit and changes from baseline to each visit over time
•
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 visit
•
Number and frequency of patients with clinically significant laboratory values. A separate
patient listing will be provided
9.2.3.5 Vital Signs 
Blood pressure (systolic/diastolic), pulse rate, and body temperature will be presented by time 
point. 
9.2.3.6 Viral Safety 
The incidence of Parvovirus B19 seroconversion will be calculated. Parvovirus B19 
seroconversion is defined as the percentage of patients who have a positive post-baseline value 
but were negative at baseline. Seroconversion rates will be by treatment group both for serology 
and nucleic acid tests. 
9.2.3.7 
Subgroup Analyses for Safety 
Subgroup analysis will be performed for overall number of TEAEs, related TEAEs and serious 
TEAEs, overall TEE and mortality rates based on the following characteristics: 
•
any TEE in medical history
•
occurrence of any TEE within 1 year prior to surgery (yes/no),
•
gender (male/female),
•
baseline INR (2 to <4 / 4 to <6 / ≥6),
•
concomitant treatment with vitamin K (yes/no)
These subgroup analyses are considered to be exploratory and will involve no type I error 
adjustment. 


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9.2.4 Handling of Missing Data 
In general, missing data will not be imputed. 
Patients for whom the primary efficacy endpoint ‘hemostatic success’ can’t be assessed will be 
considered as having clinical hemostasis rated as “none”.  This efficacy analysis is performed 
with the RAND population (as primary), and additionally with the mITT and PP. 
9.3 
Randomization / Stratification / Code Release 
The IMPs will be administered only to patients for whom a signed written IC form is available. 
Eligible patients will be randomly assigned to receive either OCTAPLEX or Beriplex® P/N 
(Kcentra). To ensure balance between the two treatment groups with respect to type of surgery, 
estimated blood loss and history of TEE, randomization will be stratified by type of surgery, 
estimated blood loss and presence or absence of TEE in the medical history. 
Randomization will be implemented by site staff using an IRT system. Randomization allocation 
will be 1:1 to OCTAPLEX or Beriplex® P/N (Kcentra), respectively.  
Patients will be identified using a sequential numbering system. 
9.4 
Interim Analysis 
The study employs a sequential design that allows one pre-planned interim analysis using the 
data from the first 50% of randomized patients. The interim analysis will be performed on the 
cohort of the first 185 randomized patients after documentation of the primary endpoint has 
been performed.  
The interim analysis will focus on the analysis of hemostatic success probabilities based on the 
independent adjudication in the ITT population. The allocation of patients in the ITT population 
will be done in a blinded data review meeting prior to unblinding. 
After the interim analysis, a positive outcome for non-inferiority test may be claimed and 
enrollment may be stopped if the primary test statistic in the ITT population is greater than the 
adjusted critical value z1 = 2.33 corresponding to an adjusted significance level of α1 = 0.01 
(efficacy stop). If a p-value > 0.5 is observed, the study may be stopped for futility (non-binding 
futility stop). The worst effect of a possible overrunning on the final result will be assessed if 
the result suggests a termination of the study. Individual patient data relevant to the 
interpretation of interim results will be listed. 
The interim analysis will be performed by a statistical team which is independent from the study 
team. An IDMC will be established to review the interim analysis results and give 
recommendations whether to continue the study or not. 
Details on the composition and charter of the IDMC will be provided before study start. A final 
analysis including all study data will be performed and reported if enrollment is stopped after 
the interim analysis. Otherwise, the study will continue until the maximum sample size is 
reached, and the final analysis will be performed as described above. 
Further details of the interim analysis will be described in the respective sections of the SAP. 


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10 ETHICAL / REGULATORY, LEGAL AND ADMINISTRATIVE ASPECTS 
10.1 Ethical / Regulatory Framework 
This study will 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 an Independent Ethics Committee (IEC) / IRB and to the Regulatory Authority. 
The study will be conducted in compliance with the protocol, GCP regulations and applicable 
regulatory requirements. 
The regulatory application or submission for regulatory approval will be made by the Sponsor 
or designated third party (e.g. Contract Research Organization) as required by national law. 
10.2 Approval of Study Documents 
The study protocol, a sample of the patient information and informed consent form, any other 
materials provided to the patients, and further requested information will be submitted by the 
Sponsor or the investigator to the appropriate IEC/IRB and the Regulatory Authority. The study 
approval letter must be available before any patient is exposed to a study-related procedure. 
The Sponsor, the investigator and any third party (e.g., Contract Research Organization) 
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 Patient Information and Informed Consent 
The investigators will obtain a freely given written consent from each patient. Children are not 
to be included in this study. 
The investigators will explain that the subjects are completely free to refuse to enter the study 
or to withdraw from it at any time, without any consequences for the subject’s further care and 
without the need to justify. The investigator will complete the informed consent section of the 
CRF for each subject enrolled. 
Each patient will be informed that their source records may be reviewed by the study monitor, 
a quality assurance auditor or a health authority inspector, in accordance with applicable 
regulations, that the investigator will protect any personal information not related to the study, 
and that these persons are bound by confidentiality obligations. 
10.4 Protocol Amendments 
Any prospective change to the protocol will be agreed between the investigator (co-ordinating 
investigator in multi-centre studies) and the Sponsor prior to its implementation. Any such 
amendments will be submitted to the IEC(s/IRB) and/or competent authority responsible as 
required by applicable regulations. IEC(s)/IRB approval will at a minimum be requested for 
any change to this protocol which could affect the safety of the patients, the objective/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 Patients´ 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 number. Documents not 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 cooperate 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. 
The monitor must be given direct access to source documents (original documents, data and 
records). Direct access includes permission to examine, analyze, 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. 
11.2 Audit and Inspection 
The investigator will make all study-related source data and records available to a qualified 
quality assurance auditor mandated by the Sponsor, or to IEC/IRB/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 effectiveness of the IMP have been reported to the Sponsor. 


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12 REPORTING AND PUBLICATION 
12.1 Clinical Study Report 
A clinical study report (in accordance with relevant guidelines and Sponsor’s Standard 
Operating Procedure) will be prepared by the Sponsor after the completion of the study. The 
coordinating investigator will approve the final study report after review. 
12.2 Publication Policy 
The results of this study may be published or presented at scientific meetings. If this is 
envisaged by an investigator, the investigator agrees to inform the Sponsor and to submit all 
manuscripts or abstracts to the Sponsor prior to submission to an editorial board or scientific 
review committee. This will allow the Sponsor to protect proprietary information and to provide 
comments based on information that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will support publication 
of multi-centre studies only in their entirety and not as individual centre data. Authorship will 
be determined by mutual agreement. 


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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 the participation in the study, the Sponsor 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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14 REFERENCES 
1.
C GB. Anticoagulation in surgery, after hemorrhagic complications and in pregnancy.
. ZKardiol 1998;87:56-62.
2.
Palareti G, Leali N, Coccheri S, Poggi M, Manotti C, D'Angelo A, et al. Bleeding
complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative
study (ISCOAT). Italian Study on Complications of Oral Anticoagulant Therapy. Lancet.
1996;348(9025):423-8.
3.
A randomized trial of anticoagulants versus aspirin after cerebral ischemia of presumed
arterial origin. The Stroke Prevention in Reversible Ischemia Trial (SPIRIT) Study Group. Ann
Neurol. 1997;42(6):857-65.
4.
Campbell P RG, Eaton V.  . Managing warfarin therapy in the community. . Aust
Prescriber 2001; 24:86-89.
5.
Oden A, Fahlen M. Oral anticoagulation and risk of death: a medical record linkage
study. BMJ. 2002;325(7372):1073-5.
6.
van Aart L, Eijkhout HW, Kamphuis JS, Dam M, Schattenkerk ME, Schouten TJ, et al.
Individualized dosing regimen for prothrombin complex concentrate more effective than
standard treatment in the reversal of oral anticoagulant therapy: an open, prospective
randomized controlled trial. Thromb Res. 2006;118(3):313-20.
7.
Makris M, Greaves M, Phillips WS, Kitchen S, Rosendaal FR, Preston EF. Emergency
oral anticoagulant reversal: the relative efficacy of infusions of fresh frozen plasma and clotting
factor concentrate on correction of the coagulopathy. Thromb Haemost. 1997;77(3):477-80.
8.
Yasaka M, Sakata T, Minematsu K, Naritomi H. Correction of INR by prothrombin
complex concentrate and vitamin K in patients with warfarin related hemorrhagic complication.
Thromb Res. 2002;108(1):25-30.
9.
Lankiewicz MW, Hays J, Friedman KD, Tinkoff G, Blatt PM. Urgent reversal of
warfarin with prothrombin complex concentrate. J Thromb Haemost. 2006;4(5):967-70.
10.
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.
11.
Hwang IK, Shih WJ, De Cani JS. Group sequential designs using a family of type I error
probability spending functions. Stat Med. 1990;9(12):1439-45.
12.
al. CMe. Clinical Practice Guide on Antithrombotic Drug Dosing and Management of
Antithrombotic Drug-Associated Bleeding Complications in Adults. American Society of
Hematology. 2014.
13.
Keeling D, Baglin T, Tait C, Watson H, Perry D, Baglin C, et al. Guidelines on oral
anticoagulation with warfarin - fourth edition. Br J Haematol. 2011;154(3):311-24.
14.
American Society of Anesthesiologists Task Force on Perioperative Blood T, Adjuvant
T. Practice guidelines for perioperative blood transfusion and adjuvant therapies: an updated
report by the American Society of Anesthesiologists Task Force on Perioperative Blood
Transfusion and Adjuvant Therapies. Anesthesiology. 2006;105(1):198-208.


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15 APPENDICES 
Not applicable. 

SAP_001.pdf: 
Property of Octapharma. Do not copy or distribute without written permission.
This document is the confidential information of 
Octapharma and inVentiv Health.  It may not be 
disclosed to parties not associated with this 
project or used for any purpose without the prior 
written consent of Octapharma. 
CONFIDENTIAL 
Octapharma 
A Phase III, randomized, double-blind, multicenter study to assess
the efficacy and safety of OCTAPLEX, a four-factor prothrombin
complex concentrate (4F-PCC), compared to the 4F-PCC
Beriplex® P/N (Kcentra), for the reversal of vitamin K antagonist
induced anticoagulation in patients needing urgent surgery with
significant bleeding risk.
Statistical Analysis Plan
Version: 03 
Date: January 06, 2021 
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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Table of Contents 
1 
Introduction .................................................................................................................... 5 
1.1 
Preface .................................................................................................................. 5 
1.2 
Timing of statistical analyses ................................................................................. 5 
2 
Modification History ........................................................................................................ 6 
2.1 
Changes to the study protocol...............................................................................6
2.2 
Changes to previous SAP versions ....................................................................... 6
3 
Study Design .................................................................................................................7
3.1 
Sample size estimation..........................................................................................7
3.2 
Randomization, blinding and unblinding procedures.............................................. 8
4 
Analysis Populations.................................................................................................... 10
5 
General Statistical Methods and Definitions................................................................. 12
5.1 
General statistical methods ................................................................................. 12
5.2 
Strata ..................................................................................................................12
5.3 
Subgroups.............................................................................................................13
5.4 
Missing data........................................................................................................ 13
5.5 
Observation and analysis times........................................................................... 14
6
Patient Accounting and Disposition.............................................................................. 15
6.1 
Patient accounting............................................................................................... 15
6.2 
Disposition and withdrawals ................................................................................ 15
6.3 
Major protocol deviations..................................................................................... 15
7
Demographics and Background Characteristics........................................................... 16
7.1 
Demographics ..................................................................................................... 16
7.2 
Disease characteristics........................................................................................ 16
7.3 
Medical history .................................................................................................... 16
8
Exposure and Compliance ........................................................................................... 17
8.1
Treatment groups................................................................................................ 17
8.2
Dosage ................................................................................................................ 17 
8.3
Infusion duration .................................................................................................. 17 
8.4 
Discontinuations from study therapy .................................................................... 17 
8.5 
Compliance ......................................................................................................... 17 
9 
Previous and Concomitant Therapies .......................................................................... 18 
10 Efficacy ........................................................................................................................ 19 
10.1 Primary efficacy analysis ..................................................................................... 19 
10.2 Secondary efficacy analyses ............................................................................... 20 
10.3 Further exploratory efficacy analyses .................................................................. 21 
11 Safety .......................................................................................................................... 22 
11.1 Adverse events.................................................................................................... 22 


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11.2 Clinical safety laboratory ..................................................................................... 23 
11.3 Viral Safety .......................................................................................................... 24 
11.4 Vital signs ............................................................................................................ 24 
11.5 Physical examination ........................................................................................... 24 
12 Interim Analyses .......................................................................................................... 25 
12.1 Objective(s) of the interim analyses ..................................................................... 25 
12.2 Timing of interim analyses ................................................................................... 25 
12.3 Interim analysis populations ................................................................................ 25 
12.4 Stopping rules and adaptations ........................................................................... 25 
12.5 Documentation of the interim analysis and disclosure of results.......................... 26
13
Statistical Analyses for Safety Monitoring..................................................................... 27
14
Software ......................................................................................................................28
15
Abbreviations...............................................................................................................29
16
References ..................................................................................................................31


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1 
Introduction 
1.1 Preface 
The objective of this document is to detail the statistical methodology to be used for the 
interim and the final statistical analysis of Octaplex study LEX-209. 
  
The statistical analysis plan is based on the following information and documents: 
Current Study Protocol 
19 January 2018 – Version 04 
Amendments to Study 
Protocol / Observational 
Plan 
Original protocol dated: 1 April 2016 
Version 02  dated: 1 Oct 2016 
Version 03 dated: 21 October 2016 
1.2 Timing of statistical analyses 
The following statistical analyses are planned for this study: 
 Interim analysis: one interim analysis after half of the patients are randomized and 
adjudication of the primary endpoint is available 
 Safety analyses: quarterly safety analyses to be provided to Independent Data 
Monitoring Committee (IDMC) 
 Final analysis: after all patients completed the study and the database is locked 


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2 
Modification History 
2.1 Changes to the study protocol 
The statistical analysis as specified in this SAP is consistent with the statistical analysis as 
specified in the study protocol dated 21-Oct-2016, version 03.  
 
2.2 Changes to previous SAP versions 
 
Version (Date) 
Revision 
01 (01-Apr-2016) 
Initial version 
02 (27-Oct-2016) 
Updated for consistency with protocol dated 21-Oct-2016, version 03 
03 (06-Jan-2021) 
Updates following review of SAP before execution of the interim 
analysis 
 
 


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3 
Study Design 
 
Indication 
Reversal of vitamin K antagonist (VKA) induced anticoagulation in 
patients needing urgent surgery associated with significant bleeding 
risk. 
Design 
Prospective, multi-center, randomized, parallel group, double-blind, 
active-controlled, group-sequential non-inferiority  
Phase 
III 
Primary Objective(s) 
The primary objective of the study is to demonstrate that the 
efficacy of OCTAPLEX as a reversal agent in patients under VKA 
therapy with the need for urgent surgery with significant bleeding 
risk is clinically non-inferior to Beriplex® P/N (Kcentra). 
Secondary Objective(s) 
The secondary objective of the study is to investigate the safety and 
tolerability of OCTAPLEX compared to Beriplex® P/N (Kcentra) in 
patients under VKA therapy with the need for urgent surgery with 
significant bleeding risk. 
Treatments 
OCTAPLEX, Beriplex® P/N (Kcentra) 
Number of patients 
370 (185 per treatment group) 
Interim analysis 
One interim analysis after half of the patients are randomized and  
adjudication of the primary endpoint is available 
 
 
3.1 Sample size estimation 
The statistical analysis of the primary variable hemostatic success will be based on the 
probabilities of hemostatic success (derived from the blinded rating by the independent 
endpoint adjudication board (IEAB) of OCTAPLEX and Beriplex® P/N (Kcentra) (pO and 
pK). 
To demonstrate that the treatment with OCTAPLEX is clinically not inferior to the treatment 
with Beriplex® P/N (Kcentra) with respect to hemostatic success, a two-sample, one-sided 
test of the pair of hypotheses: 
 
 
H0: 
pK – pO ≥ δ 
vs.  
H1: 
pK – pO < δ 


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will be carried out with a type I error probability of α = 0.025 and clinical non-inferiority 
margin of δ = 0.15.  
Farrington’s and Manning’s test for difference in proportions will be used to assess the 
primary hypothesis in an interim and in the final analysis.  
Based on this method and a one-sided overall type I error probability α = 0.025, 
power 1 - β = 0.8 and a non-inferiority margin of δ = 0.15 the table below presents the 
estimated sample sizes per treatment group for the one-sided testing problem taking into 
account one planned interim analysis after half of the planned patients are enrolled for 
different constellations of OCTAPLEX and Beriplex® P/N (Kcentra) hemostatic success 
probabilities. The calculations are based on the following additional assumptions: 
• A multiple one-sided significance level (family-wise error rate) of 0.025 for the 
interim and final analysis 
• An α-spending function according to Hwang, Shi and Cani [1] with parameter γ=-0.8 
which allows an early efficacy stop if p <0.01. 
• A β-spending function according to Hwang, Shi and Cani [1] with parameter γ=-4.584 
which allows a non-binding futility stop if p> 0.5. 
 
Beriplex® P/N 
(Kcentra) 
hemostatic 
success probability 
89% 
85 % 
90 % 
95 % 
OCTAPLEX 
hemostatic 
success probability 
85% 
85 % 90 % 95 % 85 % 90 % 95 % 85 % 90 % 95 % 
sample size per 
group 
166 
100 
51 
28 
193 
75 
37 
615 
135 
50 
actual power 
80.3 
80.5 
81.5 
82.2 
80.7 
80.8 
80.6 
80.1 
80.6 
82.0 
 
Conservatively assuming an OCTAPLEX hemostatic success probability of at least 85 % and 
a Beriplex® P/N (Kcentra) hemostatic success probability of at most 89%, it is planned to 
enroll 185 patients in each treatment arm, i.e. 370 patients in total. 
Assuming a proportion of about 10% randomized patients who were not treated or did not 
undergo the surgical procedure for administrative reasons this would ensure that data on at 
least 166 patients per treatment group in the modified ITT (mITT) population will be 
available for the final statistical analysis as derived from the sample size calculation. 
 
3.2 Randomization, blinding and unblinding procedures 
Randomization will be implemented by site staff using an IRT system. Randomization 
allocation will be 1:1 to OCTAPLEX or Beriplex® P/N (Kcentra), respectively.  


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Patients receiving a VKA generally have an underlying higher risk of thromboembolic events 
(TEEs), the reason for administration of the antagonist. Withdrawal of the antagonist and 
restoration of coagulation via administration of prothrombin complex concentrates (PCC) can 
therefore raise the risk of TEEs, with the risk being more pronounced in those patients who 
have experienced TEEs in the past. To balance this factor that may impact on safety 
comparisons between the treatment groups, randomization will be stratified by ‘History of 
TEE (yes/no)’. 
As the type of surgery and expected blood loss volume may impact on efficacy comparisons 
Expected blood loss (“≥200 mL”, “≥100 mL but <200 mL” or “≥50 mL but <100 mL”)’ and 
‘Type of planned surgery (“orthopaedic surgery”, “cardiothoracic surgery” or “other 
surgery”)’ will be a further stratification factor.  
 
Regarding expected blood loss: 
• At least 40% of all patients enrolled will be scheduled for an urgent surgery with 
expected blood loss of ≥200 mL.  
• At least 20% of all patients enrolled will be scheduled for an urgent surgery with 
expected blood loss of ≥100 mL but <200 mL.  
• At most 40% of all patients enrolled will be scheduled for an urgent surgery with 
expected blood loss ≥50 mL but <100 mL. 
 


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4 
Analysis Populations 
Enrolled Analysis Population 
The enrolled analysis population includes all patients who provided informed consent.  
Randomized Population (RAND) 
The randomized population will include all randomized patients irrespective of whether they 
received treatment. Following the intent-to-treat principle all patients will be analysed 
according to the treatment group to which they were randomized.  This is the intent-to-treat 
(ITT) population according to the most rigid definition of ITT.   
Safety Analysis Population (SAF)  
The safety analysis population (SAF) will include all randomized patients who received 
investigational medicinal product (IMP). Patients receiving different study treatments than 
originally randomized will be considered according to the treatment actually received (rather 
than that of the original randomization). 
Modified Intention-to-Treat Population (mITT) 
The mITT population will consist of all randomized patients who received IMP, and who had 
the surgery initiated or for whom the surgery was not initiated for medical reasons related to 
insufficient coagulation.  
Per Protocol Population (PP) 
The PP population will consist of all those patients in the mITT population, excluding 
patients with major protocol deviations potentially affecting the primary endpoint. The 
following patients will be excluded: 
• Patients who receive an IMP different to the IMP assigned by randomization 
• Patients who receive less than 70% of the planned dose 
• Patients who significantly violate inclusion/exclusion criteria 
• Patients with missing primary efficacy assessment 
• Start of surgery more than 5 hours after end of infusion of IMP 
A final decision about the classification of protocol deviations as major and minor and their 
consequences regarding assignment of patients to analysis populations will be made during 
the blinded data review meetings prior to unblinding of patient cohorts for the interim and 
final analyses. Decisions and outcome will be approved by the Sponsor.  
All patients excluded from the different analysis populations will be listed together with the 
reason for exclusion. The listing will also be presented by study site. 
All safety analyses will be based on the SAF population.  The primary efficacy analysis will 
be based on the RAND population. 
Furthermore, additional efficacy analyses will be performed using the mITT and the PP 
populations, as specified in section 10 Efficacy. Demographic and background characteristics 
will be presented on the SAF, RAND and mITT. In case of only minor differences between 


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any analysis set, it will be discussed during the blind data review meeting to omit the creation 
of individual sets and use the next available set for the given analyses. 
If not otherwise stated in the respective section, the statistical analyses will be performed for 
the following analysis populations: 
 
Analyses 
RAND (ITT) 
 
mITT 
PP 
SAF 
Demographics and background 
characteristics 
 
 
 
 
 
Exposure and compliance 
 
 
 
 
 
Previous and concomitant 
therapies 
 
 
 
 
 
Surgery information 
 
 
 
 
 
Efficacy: Primary  
 
 
 
 
 
Efficacy: Secondary  
 
 
 
 
 
Efficacy: Exploratory 
 
 
 
 
 
Efficacy: Subgroup analysis 
 
 
 
 
 
Safety 
 
 
 
 
 


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5 
General Statistical Methods and Definitions 
5.1 General statistical methods 
The statistical analyses will be presented by treatment group for the different analysis 
populations as defined in section 4 Analysis Populations. 
Summary tables will usually be structured with a column for each treatment in the order 
Beriplex® P/N (Kcentra) and OCTAPLEX. For demographic and background characteristics 
a "Total" column will be additionally provided.   
In general, continuous variables will be summarized using descriptive statistics, i.e. generally 
displaying number of patients in the respective analysis population, number of patients with 
data, number of patients with missing values, mean, standard deviation, minimum, lower 
quartile, median, upper quartile, and maximum.  
Categorical variables will be summarized by using frequency counts and percentages. In 
addition, the number of patients with missing values will be displayed. Percentages usually 
relate to the number of patients with data. This includes data obtained by the respective 
missing data replacement strategy (see section 5.4 Missing data). 
Means, medians, and standard deviations will be presented by 1 additional decimal place than 
the standard presentation level of the respective patient data. Minimum and maximum values 
will be presented using the same number of decimal places as the patient data. Percentages 
will be presented to 1 decimal place if not otherwise stated. 
In listings, data will be sorted by treatment, site, and patient, and when appropriate by visit or 
other identifiers for sequence or type of observation.  
If not otherwise specified, all statistical tests will be two-sided. The significance level of one 
sided tests will be divided by two to ensure comparability with two-sided tests.  
The confidence level for calculation of confidence intervals will be chosen as (1-significance 
level) of the respective statistical test.  
 
5.2 Strata 
Treatment allocation by the IRT will be stratified according to the following three 
parameters, documented as baseline prior to randomization. 
History of TEE 
Presence or absence of any embolic or thrombotic event, defined according to the 
Standardized MedDRA query (SMQ) “Embolic and thrombotic event”, in the medical history 
of the patient. 
Type of surgery 
The type of surgery will be categorized into one of the following: “orthopaedic surgery”, 
“cardiothoracic surgery” or “other surgery”. 
 


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Expected Blood Loss 
Expected blood loss will be categorized into one of the following: “≥200 mL”, “≥100 mL but 
<200 mL” or “≥50 mL but <100 mL”. 
5.3 
Subgroups 
The following subgroups will be defined: 
1. expected blood loss (“≥200 mL”, “≥100 mL but <200 mL” or “≥50 mL but 
<100 mL”) according to information provided at randomisation  
2. gender (male/female) 
3. baseline INR (2 to <4 / 4 to <6 / ≥6) 
4. concomitant treatment with vitamin K (yes/no) 
5. any TEE in medical history (yes/no) 
6. occurrence of any TEE within 1 year prior to surgery (yes/no) 
7. type of planned surgery (“orthopaedic surgery”, “cardiothoracic surgery” or “other 
surgery”) 
8. age in years (<=60, 60+) 
9. race 
 
To study the sensitivity of the efficacy results subgroup analysis will be performed for the 
primary and the secondary efficacy endpoints for the first four subgroups. Results for the 
different subgroups will be presented descriptively by presenting the results separately for 
each subgroup and its complement.  
These subgroup analyses are considered to be exploratory and will involve no type I error 
adjustment. The subgroup analyses will be based on the primary analysis population for 
efficacy. 
Regarding safety, subgroup analysis will be performed for overall number of treatment 
emergent adverse events (TEAEs), related TEAEs and serious TEAEs, overall TEE and 
mortality rates for the subgroups 2-6. 
5.4 Missing data 
Missing data will not be imputed except for analyses of the primary efficacy endpoint (see 
section 10.1 Primary efficacy analysis and 10.2 Secondary efficacy analyses for details) and 
partial and missing dates as specified below. 
 
Partial or missing dates and times 
Where the start date of an event or medical condition is missing or partially missing, the 
event will be assumed to be started after the start of IMP, unless there is clear evidence 
(through comparison of partial dates/times) to suggest otherwise. 
In case of a partial or missing end date the medical condition will be assumed to be ongoing 
after start of IMP except if the partial date indicates that the condition stopped prior to start of 
IMP.  


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5.5 Observation and analysis times 
Study days  
Study day is defined as the number of days since start of infusion of IMP and, for a particular 
date, and is calculated as: 
 
Study day = Assessment date – Date of start of infusion of IMP + 1. 
Therefore, the date of infusion of IMP will be Day 1.  
Study periods  
Start and End of infusion and start and end of surgery define important timepoints during the 
course of the study. The following study periods are defined using these timepoints: 
- 
Before start of infusion, comprises screening and baseline period: all observations 
until start of infusion of IMP 
- 
Before start of surgery: from start of infusion till start of surgery 
- 
During surgery: all observation during surgery 
- 
After end of surgery to Day 4/discharge 
- 
Follow-up: all observations after Day 4/discharge to end of study (day 45) 
Definition of baseline values 
The baseline value is in general defined to be the last value which was assessed before the 
start of infusion.  
For INR the baseline value is defined as the INR value used for dose calculation.  
Definition of analysis timepoints or time windows 
The definition of analysis timepoints / time windows is specified in the following table. 
Measurement 
Analysis Timepoint 
Time window 
Coagulation Factors 
30 min after end of infusion 
30 min ± 15 min 
2h after end of infusion 
2 h ± 15 min 
4h after end of infusion 
4 h ± 30 min 
12h after end of infusion 
12 h ± 1h 
24h after end of infusion 
24 h ± 2 h 
Virology 
Day 9 
Day 9 - 2 days/+ 5 days 
Rate of TEE/Mortality 
Day 4 
Day 4 
Day 21 
Day 21 ± 1 week 
Day 45 
Day 45 ± 1 week 
 


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6 
Patient Accounting and Disposition 
6.1 Patient accounting 
The number and relative frequencies of patients in each analysis population as defined in 
section 4 Analysis Populations will be presented overall and by randomized treatment, 
country and site. The enrolled population will only be presented overall. 
Furthermore the number and percentage of patients in each analysis population will be 
presented overall and by treatment group including individual reasons of exclusion from the 
respective analysis population. 
A list of patients with all randomization assignment information will be generated in order to 
confirm that the randomization was performed according to the randomization plan. 
6.2 Disposition and withdrawals 
The number and relative frequency will be presented for 
 Patients not undergoing surgery and reasons thereof 
 Patients who prematurely discontinued the study, 
 Reasons for discontinuation.  
Patients who discontinued the study will be listed. 
6.3 Major protocol deviations 
Major protocol deviations leading to exclusion from the per-protocol population are specified 
in section 4 Analysis Populations. 
The number and relative frequency of patients with major protocol deviations leading to 
exclusion from the per-protocol population will be presented by treatment group, country, 
and study site for RAND.  
In addition, all deviations of the in-/exclusion criteria will be summarized by treatment group 
and study site for the RAND. 
All patients with protocol deviations as specified above will be listed. 


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7 
Demographics and Background Characteristics 
Demographic and baseline characteristics as specified in detail below will be presented 
descriptively by treatment group.  
A statistical testing for baseline differences is not considered appropriate in a randomized 
study. In randomized controlled studies, randomization ensures that, on average, the 
distribution of baseline covariates will be similar between the different treatment groups.  
7.1 Demographics 
The following demographic characteristics will be presented 
• Sex (male/female) 
• Age (years), as entered in the eCRF  
• Race (Caucasian, African (black), Asian, Other) 
• Weight (kg) at baseline 
• Height (cm) at baseline 
• BMI (kg/m2) at baseline = weight in kg / (height in cm)2× 10000 
The demographic data will be listed. 
7.2 Disease characteristics 
The following disease characteristics will be presented 
• Pre-infusion anti-coagulation therapy 
• History of TEE 
• Type of planned surgery 
• Estimated blood loss 
7.3 Medical history 
The diseases are coded according to Medical Dictionary for Regulatory Activities 
(MedDRA®) Version 18.1 or higher and will be classified as follows: 
 Previous medical conditions, i.e. medical conditions that stopped prior to start of 
treatment 
 Ongoing (concomitant) medical conditions, i.e. medical conditions still present after 
start of treatment 
The frequency of diseases recorded from medical history will be presented after classification 
into previous and concomitant conditions by system organ class (SOCs) as well as the 
frequencies of preferred terms (PT) within each SOC. If patients have more than one disease 
within a SOC or PT they will be counted only once for the respective SOC or PT. 
Additionally, all PTs occurring in the MedDRA SMQ “Embolic and thrombotic events” will 
be presented. For patients with a history of TEE, time (in months) since occurrence of last 
TEE event before enrollment will be presented with descriptive statistics. 


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8 
Exposure and Compliance 
8.1 Treatment groups 
Treatments will be labelled as follows: 
 KCentra 
 Octaplex 
For the RAND and mITT, patients will be assigned to the treatment groups they were 
randomized to and for the SAF to the treatment they actually received.  
The number and percentage of patients will be presented by treatment group, study site and 
analysis population. 
Deviations from the randomized treatment will be presented in the protocol deviation listing, 
see section 6.3 Major protocol deviations. 
8.2 Dosage 
Descriptive statistics for the total dose of IMP per patient will be presented by treatment 
group for the RAND, mITT and SAF. Both dose (IU) and weight adjusted dose (IU/kg) will 
be analyzed. 
8.3 Infusion duration 
The infusion duration will be calculated in minutes as:  
Duration of exposure (minutes) = (time of stop of infusion – time of start of infusion)  
Descriptive statistics for the infusion duration will be presented.  
8.4 Discontinuations from study therapy 
The number and percentage of patients who discontinued the infusion prematurely will be 
presented by treatment group.  
Patients who discontinued study prematurely will be listed by study site and treatment group 
(Annex V to the CSR according to ICH E3 [2]). The listing will include age, sex, last visit, 
day of discontinuation, duration of treatment, and reason of discontinuation. 
8.5 Compliance 
IMP will be infused at the study site under the guidance of the investigator. However, 
compliance will be analysed and number of subjects who have received a miscalculated dose 
will be evaluated.  


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9 
Previous and Concomitant Therapies 
Previous and concomitant medications are coded according to WHO drug dictionary (Version 
SEP 16) and stored with ATC codes and generic names.  
Therapies will be classified as previous if they stopped before start of infusion and as 
concomitant if taken after start of first infusion. 
The number and frequency of previous and concomitant medications will be given per ATC 
level 2. Additionally, previous anti-coagulant therapy will be presented per ATC level 3. If a 
patient has received more than 1 drug within an ATC class, he/she will be counted only once 
for this ATC class. 
The number of patients with Vitamin K administration will be presented, including 
descriptive statistics on the dose level administered. The number of patients who did not 
receive Vitamin K will be presented, with the reason of non-administration. Patients for 
whom a Vitamin K administration was planned and did not receive it will also be presented. 


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10 Efficacy 
10.1 Primary efficacy analysis 
The primary efficacy variable is the hemostatic efficacy as assessed by the IEAB. The 
hemostatic efficacy is to be assessed based on objective criteria in the categories 'excellent', 
'good', 'moderate' or 'none'. Ratings of 'excellent' and 'good' will be considered as 'effective' 
hemostasis, while a rating of 'moderate' and 'none' will be considered as 'ineffective' 
hemostasis. For details on the derivation see CSP Section 7.2.1 (Assessments for Primary 
Efficacy Endpoints). 
The dichotomous 'hemostatic success' variable will be used in the analyses. This variable will 
be imputed as ‘ineffective’ under the following two circumstances: 
• If hemostatic efficacy value is missing, then hemostatic efficacy will be considered 
‘none’ for the analysis.  This can occur in the RAND population if the patient is 
randomized and not treated (or does not undergo surgery), also in the mITT 
population if the patient is treated but does not undergo surgery due to insufficient 
coagulation.  
• If patient receives additional coagulation treatment (e.g. PCC, single coagulation 
factors, plasma) after initial IMP infusion, then hemostatic efficacy will be considered 
‘none’ for the analysis. 
 
To demonstrate that treatment with OCTAPLEX is clinically not inferior to treatment with 
Beriplex® P/N (Kcentra) with respect to hemostatic success, a two-sample, one-sided test of 
the pair of hypotheses: 
 
 
H0: 
pK – pO ≥ δ (inferiority) 
 
vs.  
H1: 
pK – pO < δ (non-inferiority) 
will be carried out with a type I error probability of α = 0.025 and clinical non-inferiority 
margin of δ = 0.15. Whereby pO and pK present the probabilities of hemostatic success of 
OCTAPLEX and Beriplex® P/N (Kcentra) respectively. 
Farrington’s and Manning’s test for difference in proportions will be used to assess the 
primary hypothesis in an interim and in the final analysis. One-sided p-values and the 
corresponding nominal and repeated confidence intervals for the difference in hemostatic 
success probabilities will be presented. 
The primary analysis will be performed on the RAND population. Additional analyses will be 
performed using the mITT and PP populations. 
All patient data related to the primary efficacy analysis will be listed. 
Handling of Missing Data 
Patients with missing information on the primary efficacy endpoint (for example, patient for 
whom the surgery was not initiated due to an insufficient coagulation), will be assessed as 
having no hemostasis (i.e., hemostatic efficacy will be considered ‘none’ for the analysis). 


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Sensitivity and Robustness Analyses 
In order to assess the treatment effect using different assumptions from those in the RAND 
analysis, the primary efficacy analysis will also be performed using the mITT and PP 
populations. 
In case of non-inferiority in the mITT and the PP populations a “tipping point” analysis will 
be done to determine the robustness of the results  
Iteratively patients excluded from the mITT/PP analysis assigned to the control arm will be
considered as treatment successes, and patients excluded from the mITT/PP analysis and
assigned to the OCTAPLEX arm will be considered as treatment failures, to determine the
number of such imputed outcomes required to “tip” the study result from positive to negative
in the RAND population. 
A sensitivity analysis will be conducted in the RAND, mITT, and PP populations based on
the hemostatic efficacy rating by the investigators at the end of surgery.  This analysis will be
conducted with the same methods as described above for the primary efficacy endpoint.
A concordance analysis (hemostasis agreement) will be done to assess the agreement between
the assessment by the IEAB and the investigator assessment. 
10.2 Secondary efficacy analyses 
The secondary efficacy endpoints will be tested for differences between OCTAPLEX and 
Beriplex® P/N (Kcentra). No confirmatory hypotheses testing will be done. Treatment will be
compared exploratorily, point estimates and corresponding 95% confidence intervals will be
presented in addition to descriptive statistics.
The following measurements will be considered as exploratory secondary endpoints:
•
Proportion of patients with an INR value of less or equal to 1.5 at 30 (± 15) minutes
after the end of infusion.
•
Change in coagulation factor levels from baseline to 30 (± 15) minutes after the end
of infusion:
o
Factor FII
o
Factor FVII
o
Factor FIX
o
Factor FX
•
Proportion of patients receiving red blood cells (RBC) during the surgery
The primary analysis of secondary endpoints will be based on the RAND population, except
for the proportion of patients receiving RBC during surgery, this will be based on subset of
patients undergoing surgery. Additionally, the same analyses will be done on the mITT and
PP populations.
Farrington’s and Manning’s test for difference in proportions will be used to test the 
secondary variables on proportions. Point estimates and two-sided 95% confidence intervals 
will be presented in addition to descriptive statistics for these endpoints. 
The change in the individual coagulation factors from baseline to 30 minutes after the end of 
infusion will be tested with the Wilcoxon rank-sum test between OCTAPLEX and 
Beriplex® P/N (Kcentra). The Hodges-Lehmann estimator of the median difference of the 
intra-individual change in the individual coagulation factors from baseline to 30 minutes after 


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the end of infusion between OCTAPLEX and Beriplex® P/N (Kcentra) and the corresponding 
95% CI will be calculated. 
Missing data will not be imputed. 
All patient data related to the secondary efficacy analyses will be listed. 
10.3 Further exploratory efficacy analyses 
Analysis of the further exploratory endpoints will be done on the RAND, mITT and PP 
populations unless indicated otherwise. All analyses will be exploratory, by presenting 
descriptive statistics. 
• Change in INR from baseline. 
• Change in Protein C, and Protein S from baseline to 30 (± 15) minutes after the end of 
infusion. 
• Change in coagulation factor levels (FII, FVII, FIX, FX, Protein C, and Protein S) 
from baseline to 2, 4, 12 and 24 hours after end of infusion 
• Assessment of blood loss after end of surgery. 
• Proportion of patients receiving plasma and platelets transfusions initiated during the 
surgery. 
• Total volume of RBC and other blood product transfusions initiated during the 
surgery normalized by patient's body weight. 
• Change in hematological parameters (hemoglobin, hematocrit, RBC, WBC, platelets) 
from the beginning to the end of the surgery. 
• RBC transfusion corrected change from baseline in hemoglobin at 12 and 24 hours 
after start of surgery 
Correction of change will be calculated as follows: 
 
𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑐𝑐ℎ𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎  ( 𝑔𝑔
𝑑𝑑𝑑𝑑) = 𝑐𝑐ℎ𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑖𝑖𝑖𝑖 𝐻𝐻𝐻𝐻 ( 𝑔𝑔
𝑑𝑑𝑑𝑑) −𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡
200𝑚𝑚𝑚𝑚
∗1𝑔𝑔
𝑑𝑑𝑑𝑑 
 
• Proportion of patients experiencing surgical wound hematoma requiring surgical 
evacuation 
• Ratio of actual estimated blood loss as documented after surgery to the pre-operative 
predicted blood loss  


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11 Safety 
11.1 Adverse events 
Adverse events (AE) will be coded using MedDRA®) Version 18.1 or higher and presented 
by primary System Organ Class (SOC) and Preferred Term (PT).  
Treatment-emergent adverse events 
The analysis will focus on treatment emergent adverse events (TEAEs), i.e., AEs that started 
or worsened after start of infusion with IMP.  
Number and frequencies of patients with TEAEs and number of events will be given by SOC 
and by PT within each SOC for the following: 
• All TEAEs by treatment group 
• All TEAEs considered at least possibly related (i.e. considered as possibly or probably 
related) by treatment group 
• Serious TEAEs by treatment group 
• Serious TEAEs considered at least possibly related (i.e. considered as possibly or 
probably related) by treatment group 
• TEAEs with fatal outcome by treatment group  
• TEAEs leading to study discontinuation by treatment group  
Number and frequencies of patients with TEAEs will be given by SOC and by PT within 
each SOC for the following: 
• All TEAE by maximum intensity by treatment group 
Number and frequencies of patients with TEAEs will be given by PTs by decreasing 
frequency for the following: 
• All TEAEs by treatment group 
• All TEAEs considered at least possibly related (i.e. considered as possible, probable 
or definite related) by treatment group 
• Serious TEAEs by treatment group 
• Serious TEAEs considered at least possibly related (i.e. considered as possible, 
probable or definite related) by treatment group 
• All TEAEs by maximum intensity and by treatment group 
• TEAEs with fatal outcome by treatment group 
• TEAEs leading to study discontinuation by treatment group 
If severity is missing, the event will not be included in the frequency tables presenting events 
by intensity. If relationship to study drug is missing, the event will be assessed as unrelated if 
it started before start of infusion; in all other cases it will be assumed to be related. 


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Patient listings will be provided for patients with adverse events, serious adverse events, for 
all patients with adverse events leading to discontinuation of IMP, and for all adverse events 
with fatal outcome. The listings will also include patients enrolled but not randomized. 
Thromboembolic events (TEE) 
The number of patients with TEE overall and within 3, 21 and 45 days after end of surgery 
will be summarized. A possible difference between treatment groups will be estimated by a 
risk ratio with 95% confidence interval. Kaplan-Meier estimates for time to first occurrence 
of a TEE event will be calculated and graphically presented. If the patient did not experience 
a TEE, the time to first occurrence will be censored at the last visit for the patient. 
Mortality 
The number of patients who died overall and within 3, 21 and 45 days after end of surgery 
will be summarized. A possible difference between treatment groups will be estimated by a 
risk ratio with 95% confidence interval. Kaplan-Meier estimates for time to death will be 
calculated and graphically presented. The last information date on vital status will be taken as 
censoring date for patients who did not die. 
Additionally, deaths will be summarized by MedDRA primary system organ class and 
preferred term of the principal cause of death. All deaths will be listed. 
11.2 Clinical safety laboratory  
Hematology and clinical chemistry 
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 visit and changes from baseline to each visit over time 
• 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 visit 
• Number and frequency of patients with clinically significant laboratory values. A separate 
patient listing will be provided 
Data from unplanned determinations, i.e. usually determinations where the investigator felt 
follow-up was necessary, will be included in the number and frequency counts of clinically 
significant values. They will also be included in the data listings. 
Laboratory values that are outside the normal range will also be flagged in the data listings, 
along with corresponding normal ranges. Any out-of-range values that are identified by the 
investigator as being clinically significant will also be shown in a data listing. 
 


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11.3 Viral Safety 
The incidence of Parvovirus B19 seroconversion will be calculated. Parvovirus B19 
seroconversion is defined as the percentage of patients who have a positive post-baseline 
value but were negative at baseline. Seroconversion rates will be by treatment group both for 
serology and nucleic acid tests. 
11.4 Vital signs 
The values measured at each timepoint as well as the change from baseline in vital signs will 
be summarized over time with n, mean, standard deviation, and median, quartiles, minimum, 
and maximum.  
11.5 Physical examination 
All available data will be listed. 


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12 Interim Analyses 
12.1 Objective(s) of the interim analyses 
The study will be conducted in 2 stages, with one un-blinded interim analysis after 
enrollment of 50% of the planned sample size, to allow for an early stopping of the study for 
demonstrated non-inferiority of OCTAPLEX or to allow for an early stopping due to futility 
to achieve this. Any decision to prematurely terminate the study will be made in consultation 
with the relevant authorities.  
12.2 Timing of interim analyses 
The study employs a sequential design that allows one pre-planned interim analysis using the 
data from the first 50% of randomized patients. The interim analysis will be performed on the 
cohort of the first 185 randomized patients after documentation of the primary endpoint has 
been performed.  
12.3 Interim analysis populations  
Cut-off date:  The cut-off date for the interim analysis is defined as the date when the 
primary endpoint of the first 185 randomized patients is available. 
The assignment of patients to analysis population will follow the rules provided in Section 4 
Analysis Populations. 
12.4 Stopping rules and adaptations  
A sequential design with α- and β-spending function according to Hwang, Shi and Cani will 
be used.  
After the interim analysis, a positive outcome for non-inferiority test may be claimed and 
enrollment may be stopped (after consultation between the IDMC and relevant parties, see 
section 9.4 of the CSP) if the primary test statistic in the RAND population is greater than the 
adjusted critical value z1 = 2.33 corresponding to an adjusted significance level of α1 = 0.01 
(efficacy stop), as reported in the table below. If a p-value > 0.5 is observed, the study may be 
stopped for futility (non-binding futility stop). The worst effect of a possible overrunning on 
the final result will be assessed if the result suggests a termination of the study. Individual 
patient data relevant to the interpretation of interim results will be listed. 
Operational Characteristics of Study Design 
 
 
Significant Boundaries 
 
n per arm 
Z-value 
p-Value 
Interim 
83 
2.33216 
0.00985 
Final 
166 
2.07753 
0.01888 
 
 


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If study success can be claimed on the interim results, enrollment of additional patients may 
be discontinued prematurely. In this case, all patients enrolled until a decision to stop the 
study has been made will be observed until the end of follow-up period. A final analysis and 
study report including all data collected during the study will be prepared. 
12.5 Documentation of the interim analysis and disclosure of results 
The interim analysis will be performed by a statistical team which is independent from the 
study team.  
The results of the interim analysis will be presented to the IDMC. The following statistical 
summaries and listings will be presented: 
• Analysis of patient populations and withdrawal status  
(Number and percentage of patients in the enrolled population, RAND, SAF, and 
withdrawals)  
• A statistical summary of important demographic and baseline data for the RAND. 
• Descriptive statistics and statistical test results including the p-value, point estimates and 
confidence intervals for the RAND of the primary efficacy variable.  
• Descriptive statistics of the secondary efficacy variables 
• An analysis of AEs for the SAF. This will include frequency tables of TEAEs and TEAEs 
assessed by the investigator as related (i.e. any possibly, probably, or definitely related 
TEAEs) according to primary SOC and preferred term. Serious TEAEs, TEAEs with fatal 
outcome, and TEAEs resulting in withdrawal from the study will be tabulated using 
frequency tables if a reasonable number of AEs of this type are observed.  
• Frequency tables of TEEs 
• Patient listings will be provided for all AEs reported, for patients with SAEs, for all 
patients with AEs leading to study discontinuation and for all AEs with fatal outcome. 
The listings will include all patients in the SAF and will show the investigator verbatim 
term and the MedDRA coded term simultaneously. 
 


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13 Statistical Analyses for Safety Monitoring  
The statistical analysis for safety monitoring is specified in a separate IDMC charter. 
 
 
 


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14 Software  
If not stated otherwise, the data will be analysed using SAS Version 9.3 or higher.  
 
 


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15 Abbreviations 
 
4F-PCC 
Four-Factor Prothrombin Complex Concentrate 
AE 
Adverse Event 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
 
 
 
 
eCRF 
Electronic Case Report Form 
FII 
Coagulation Factor II 
FVII 
Coagulation Factor VII 
FIX 
Coagulation Factor IX 
FX 
Coagulation Factor X 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee 
IEAB 
Independent Endpoint Adjudication Board 
IMP 
Investigational Medicinal Product 
INR 
International Normalized Ratio 
IRT 
Interactive Response Technology 
ITT 
Intention-to-Treat Population 
IU 
International Unit 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intention-to-Treat Population 
PCC 
Prothrombin Complex Concentrate 
PP 
Per Protocol Population 
PT 
Preferred Term 
RAND 
Randomized Population 
RBC 
Red Blood Cell Count 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAF 
Safety Analysis Population 
SD 
Standard Deviation 


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SMQ 
Standardized MedDRA query 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
TEE 
Thromboembolic events 
VKA 
Vitamin K antagonist 
WBC 
White Blood Cell Count 
 


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16 References 
1. Hwang IK, Shih WJ, De Cani JS. Group sequential designs using a family of type I error 
probability spending functions. Stat Med. 1990 Dec; 9(12):1439-45. 
2. ICH Harmonised Tripartite Guideline E3, Structure and Content of Clinical Study 
Reports. 1995.