A Randomized, Active-controlled, Multicenter, Phase III Study Investigating Efficacy and Safety of Intra-operative Use of BT524 (Human Fibrinogen Concentrate) in Subjects Undergoing Major Spinal or Abdominal Surgery (AdFIrst)
Phase: PHASE3
Conditions: Bleeding Disorder, Hypofibrinogenemia; Acquired
Sponsor: Biotest

 
 
CONFIDENTIAL 
 Page 1 of 102 
 
 
Clinical Study Protocol 
 
Title: A randomized, active-controlled, multicenter, phase III study 
investigating efficacy and safety of intra-operative use of BT524 
(human fibrinogen concentrate) in subjects undergoing major 
spinal or abdominal surgery (AdFIrst) 
 
Short 
Title: 
AdFIrst 
- 
Adjusted 
Fibrinogen 
replacement 
strategy  
 
 
Clinical Phase: 
III 
 
Version incl. date: 
Final 4.3 of 06-SEP-2021 
Country specific amendment for United Kingdom 
 
EudraCT Number: 
2017‐001163‐20 
 
Study No.: 
995 
 
 
Sponsor 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coordinating Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
This protocol is property of 
, and may not be circulated, reproduced or 
published - either in whole or in part - without the company’s written permission. 
 
 
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Study No.: 995 
Final 4.3_UK 
Clinical Study Protocol 
EudraCT No.: 2017‐001163‐20 
 
06-SEP-2021 
 
 
CONFIDENTIAL 
 Page 2 of 102 
Overview of Amendments integrated in the protocol text of Version 4.1 of 04-MAR-2020 
 
Amendment No / 
CSP Version 
Date 
Sections concerned 
Rationale 
1 / CSP V2.0 
26-Apr-2018 
Signature Page, 
Synopsis, 
2, 3, 4, 6, 7, 8, 9, 10  
Introduction of a new Biostatistician.  
Update with clarification of wording, 
corrections and formatting.  
Revision of the protocol to eliminate 
inconsistencies between different protocol 
sections. 
1 / CSP V2.0 
26-Apr-2018 
Flowchart,  
3, 7, 9 
Clarification regarding the time-period 
between screening and baseline and the 
need of repeated assessments and 
diagnostic tests at these visits.  
1 / CSP V2.0 
26-Apr-2018 
Synopsis, 4 
Incomplete exclusion criterion 4 was 
complemented. 
1 / CSP V2.0 
26-Apr-2018 
3 
Clarification of treatment algorithm. 
1 / CSP V2.0 
26-Apr-2018 
6  
Clarification of treatment algorithm resulted 
in a revised definition for prohibited 
medication (section 6.10). 
Restructuring of section 6.11 'Warnings and 
Precautions'. 
1 / CSP V2.0 
26-Apr-2018 
9, 11 
Update and clarification regarding the 
handling of laboratory samples and the 
assessment of results. 
2 / CSP V3.0 
07-Jun-2019 
Signature page, 
Introduction, 4 
Introduction of a new Biostatistician 
.  
Update with clarification of wording, 
corrections and formatting. 
2 / CSP V3.0 
07-Jun-2019 
Synopsis, Flowchart,  
3, 4, 7, 9, 10 
Intra-operative inclusion criterion was 
adapted. Based on patients’ bodyweight and 
clinical condition, the clinical need of FFP 
transfusion during surgery can already 
occur after a clinically relevant bleeding of 
approximately 1 liter. 
Instead of measurement and calculation of 
blood loss prior to the ‘decision to treat’, in 
case of a clinically relevant bleeding an 
estimation of blood loss will take place. 
2 / CSP V3.0 
07-Jun-2019 
4.2 
Inclusion criterion 4 aims to ensure that only 
patients without hereditary bleeding 
disorders are to be included in this study. 
Therefore, a footnote for clarification of 
wording was included. 
2 / CSP V3.0 
07-Jun-2019 
Synopsis, Flowchart,  
3, 6, 7, 9 
The dosage was adapted in order to avoid 
under-dosing of subjects. The first BT524 
treatment was changed to a minimum dose 
of 2 g. The option for repeated dosing with 
IMP was included. The wording of the 
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Study No.: 995 
Final 4.3_UK 
Clinical Study Protocol 
EudraCT No.: 2017‐001163‐20 
 
06-SEP-2021 
 
 
CONFIDENTIAL 
 Page 3 of 102 
Amendment No / 
CSP Version 
Date 
Sections concerned 
Rationale 
secondary endpoints was adapted 
accordingly.  
The dose justification was updated. 
2 / CSP V3.0 
07-Jun-2019 
Flowchart, 7 
The time points ‘90 minutes after treatment 
start’ and ‘end of the surgery’ can be close 
together. In this case, blood samples do not 
have to be taken at both times. Update with 
clarification of wording. The option for 
repeated dosing with IMP was included. 
2 / CSP V3.0 
07-Jun-2019 
7 
Clarification of wording regarding the re-
screening of subjects. 
2 / CSP V3.0 
07-Jun-2019 
9.3, Appendix 2 
Update and clarification regarding the 
definition of Adverse Events of Special 
Interest (AESI) and the respective reporting 
procedures. 
3 / CSP V4.0 
04-Dec-2019 
Cover Page, 
Signature page, 
1, 9 
Introduction of a new Biostatistician 
. 
General update with clarification of wording, 
corrections and formatting. 
3 / CSP V4.0 
04-Dec-2019 
Synopsis, Flowchart 
2, 3, 5, 7.2, 8.1 
Study synopsis, study objectives and study 
design have been modified to extend the 
target population of the study to allow 
inclusion of subjects undergoing 
pseudomyxoma peritonei surgery  
(only applicable in the United Kingdom)  
and to introduce the active comparator 
cryoprecipitate in this treatment group. 
3 / CSP V4.0 
04-Dec-2019 
4.1 and 4.2, 6.6 
Update in order to take particular account of 
subjects with pseudomyxoma peritonei. 
3 / CSP V4.0 
04-Dec-2019 
Synopsis, 3, 
4.2, 6.1, 6.6, 7 
Clarification of wording of the intra-operative 
inclusion criterion. 
3 / CSP V4.0 
04-Dec-2019 
Synopsis, 10 
Update with clarification of wording and 
revision to include interim analyses.  
Following the Data Monitoring, the assumed 
standard deviation has been adjusted and 
the power has been reduced. 
3 / CSP V4.0 
04-Dec-2019 
19 
Update of scientific literature mainly 
regarding the inclusion of subjects with 
pseudomyxoma peritonei. 
4 / CSP V4.1 
04-Mar-2020 
Cover Page, 
Signature page 
Introduction of a new Biostatistician 
. 
 
4 / CSP V4.1 
04-Mar-2020 
Synopsis, 
Flowchart, 
3, 4, 5, 6, 7.1, 9, 10.9 
Study synopsis, study design and study 
treatment have been modified to describe in 
detail the treatment of subjects undergoing 
pseudomyxoma peritonei surgery in the 
United Kingdom. 
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Study No.: 995 
Final 4.3_UK 
Clinical Study Protocol 
EudraCT No.: 2017‐001163‐20 
 
06-SEP-2021 
 
 
CONFIDENTIAL 
 Page 4 of 102 
Amendment No / 
CSP Version 
Date 
Sections concerned 
Rationale 
General update with clarification of wording, 
corrections and formatting. 
4 / CSP V4.1 
04-Mar-2020 
Study Population 
4.1 
Update in order to take particular account of 
subjects with pseudomyxoma peritonei. 
4 / CSP V4.1 
04-Mar-2020 
IMP 
5.3 
Detailed description of the active 
comparator cryoprecipitate. 
4 / CSP V4.1 
04-Mar-2020 
Methods for Assessing 
Primary Efficacy 
Parameter, 9.1.2 
Adaption of process for quantification of 
blood loss due to cytoreductive PMP 
surgery. 
4 / CSP V4.1 
04-Mar-2020 
Laboratory Parameters, 
9.2.1, Table 1 
Introduction of two additional laboratory 
parameters to be analysed in PMP subjects, 
update of Table 1. 
4 / CSP V4.1 
04-Mar-2020 
Assessment of Adverse 
Events, 9.3.4 
Update of section “Responsibilities of 
Sponsor” to clearly specify where to find the 
Reference Safety Information of both, 
BT524 and cryoprecipitate. 
5 / CSP V4.2 
04-Aug-2020 
Synopsis, 
2, 3, 4.1, 4.2, 5.2, 6.6,  
7.2, 9.2.1.4, 10.3 
General update to clarify that in the United 
Kingdom (UK) only one site will be involved 
and only subjects undergoing cytoreductive 
surgery for PMP can be included. 
Removal of information regarding the 
treatment of subjects undergoing spinal 
surgery. 
5 / CSP V4.2 
04-Aug-2020 
Procedures for Emergency 
Unblinding, 6.7 
Clarification of wording to emphasize that 
the investigator has the final decision and 
unilateral right for unblinding. 
5 / CSP V4.2 
04-Aug-2020 
Assessment of Adverse 
Events, 9.3.4 
Update of section “Responsibilities of 
Sponsor” to change the Reference Safety 
Information (RSI) for cryoprecipitate. 
Reference to the new Reference Safety 
Information for cryoprecipitate (section 4.8 
of the SmPC of 
 solution for 
infusion). 
5 / CSP V4.2 
04-Aug-2020 
Pregnancy, 9.3.8.1 
(Gender Distribution 4.1.1) 
Adding of a list of reliable birth control 
methods. 
6 / CSP V4.3 
06-Sep-2021 
III Flowchart 
Reintroduction of urinalysis on follow-up 
day 5 in the flowchart as this item was 
deleted in the CSP V3.0 by mistake. 
Adaption of footnotes: 
• Option for rescheduling tests and 
procedures that require an in-person 
visit from Day 36 (closing visit) to the 
day of discharge from hospital. 
• Inclusion of missing footnote for 
coagulation factors on day 1, end of 
surgery. 
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Study No.: 995 
Final 4.3_UK 
Clinical Study Protocol 
EudraCT No.: 2017‐001163‐20 
 
06-SEP-2021 
 
 
CONFIDENTIAL 
 Page 5 of 102 
Amendment No / 
CSP Version 
Date 
Sections concerned 
Rationale 
6 / CSP V4.3 
06-Sep-2021 
7.1 Visit Schedule for PMP 
subjects 
7.2 Duration of the Clinical 
Study 
Option for using a phone call instead of an 
in-person closing visit is depicted. 
Option for rescheduling tests and 
procedures that require an in-person visit 
from Day 36 (closing visit) to the day of 
discharge from hospital is depicted. 
6 / CSP V4.3 
06-Sep-2021 
9.2.1.4 Laboratory 
Parameters 
Clarification regarding increased laboratory 
parameter values (liver function tests) and 
the documentation as adverse events. 
6 / CSP V4.3 
06-Sep-2021 
3, 5.2.1, 7.1, 9.1.2, 10.1 
Editorial changes. 
 
 
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Study No.: 995 
Final 4.3_UK 
Clinical Study Protocol 
EudraCT No.: 2017‐001163‐20 
 
06-SEP-2021 
 
 
CONFIDENTIAL 
 Page 7 of 102 
 
I.I 
Signature Page for Investigators 
 
Declaration of the Principal Investigator 
 
I have read and understood this Clinical Study Protocol and agree to the following: 
• To adhere to the ethical and scientific principles of Good Clinical Practice, and the 
principles of the Declaration of Helsinki, the local laws and regulations, and the 
applicable regulatory requirements. 
• To conduct the clinical study as set out in the protocol.  
This includes: 
• 
To wait until I have received approval from the appropriate Independent Ethics 
Committee / Institutional Review Board (IEC/IRB) before enrolling any subject in 
this study. 
• 
To obtain informed consent for all subjects prior to any study-related measure 
performed. 
• 
To permit study-related monitoring, audits, IEC/IRB review, and regulatory 
authority inspections. 
• 
To provide direct access to all study-related records, source documents, and 
subject files for the monitor, auditor, IEC/IRB, or regulatory authority upon 
request. 
• 
To use the IMP and all study materials only within the framework of this Clinical 
Study Protocol. 
• 
To understand that changes to the Clinical Study Protocol must be made in the 
form of an amendment that has the prior written approval of Biotest and, as 
applicable, of the appropriate IEC/IRB and regulatory authority. 
• 
To comply with the reporting obligations for all Adverse Events  
 
I understand that all documentation that has not been previously published will be kept 
in the strictest confidence. This documentation includes the Clinical Study Protocol, 
Investigator’s Brochure, Case Report Forms, and other scientific data. 
 
Principal Investigator 
Name 
 
 
____________________________________________ 
Date, signature 
 
 
Investigator stamp: 
 
 
 
 
 
 
 
Please insert stamp of investigational site 
 
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Study No.: 995 
Final 4.3_UK 
Clinical Study Protocol 
EudraCT No.: 2017‐001163‐20 
 
06-SEP-2021 
 
 
CONFIDENTIAL 
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II. 
STUDY SYNOPSIS 
Title  
A randomized, active-controlled, multicenter, phase III study 
investigating efficacy and safety of intra-operative use of 
BT524 (human fibrinogen concentrate) in subjects 
undergoing major spinal or abdominal surgery (AdFIrst) 
Clinical Phase 
III 
Coordinating Investigator 
 
Study Objectives 
The main purpose of this phase III study is to demonstrate 
the efficacy of BT524 as a complementary therapy to 
management of uncontrolled severe hemorrhage in subjects 
undergoing elective major spinal or abdominal surgery. 
The primary objective of this study is to demonstrate that 
BT524 is non-inferior that means not worse than fresh 
frozen plasma (FFP)/cryoprecipitate with a non-inferiority 
margin of 150 mL in reducing intra-operative blood loss by 
intravenous (IV) administration in subjects with acquired 
hypofibrinogenaemia undergoing elective major spinal or 
abdominal surgery.  
If therapeutic equivalence (non-inferiority) has been 
demonstrated, therapeutic superiority of BT524 compared 
with FFP/cryoprecipitate will also be assessed. 
Secondary objectives are to demonstrate the efficacy of 
BT524 by assessing the correction of the fibrinogen level 
intra-operatively, the transfusion requirements, post-
operative blood loss in the first 24 hours, the number of 
subjects with rebleeds, the hospital length of stay and the in-
hospital mortality. Secondary objectives also comprise the 
safety of BT524 by documenting the number of adverse 
events (AE) including changes in laboratory parameters, the 
viral status, and the frequency and severity of thrombosis 
and of thromboembolic events (TEEs). 
Study Design 
Prospective, randomized, active-controlled, multicenter, non-
inferiority study 
Study Population 
In the United Kingdom: 
Adult subjects (≥ 18 years) of both gender undergoing 
elective abdominal surgery with expected major blood loss 
Inclusion Criteria 
At screening: 
1. Written informed consent 
2. Subjects scheduled for elective cytoreductive 
pseudomyxoma peritonei (PMP) surgery with expected 
major blood loss 
3. Male or female, aged ≥ 18 years  
4. No increased bleeding risk as assessed by standard 
coagulation tests and medical history 
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Study No.: 995 
Final 4.3_UK 
Clinical Study Protocol 
EudraCT No.: 2017‐001163‐20 
 
06-SEP-2021 
 
 
CONFIDENTIAL 
 Page 9 of 102 
5. Intra-operative trigger for treatment:1 
Intra-operative prediction of clinically relevant bleeding 
of > 2 L, requiring hemostatic treatment during surgery. 
Exclusion Criteria 
1. Pregnancy or unreliable contraceptive measures or 
breast feeding (women only) 
2. Hypersensitivity to proteins of human origin or known 
hypersensitivity reactions to components of the 
Investigational Medicinal Products (IMP) 
3. Participation in another clinical study within 30 days 
before entering the study or during the study and/or 
previous participation in this study 
4. Treatment with any fibrinogen concentrate and/or 
fibrinogen-containing product within 30 days prior to 
infusion of IMP 
5. Employee or direct relative of an employee of the 
Contract Research Organization (CRO), the study site, 
or Biotest 
6. Inability or lacking motivation to participate in the study 
7. Medical condition, laboratory finding (e.g. clinically 
relevant biochemical or hematological findings outside 
the normal range), or physical exam finding that in the 
opinion of the investigator precludes participation  
8. Presence or history of venous/arterial thrombosis or TEE 
in the preceding 6 months 
Number of Subjects 
100 evaluable subjects per treatment arm 
Countries / Number of 
Study Sites 
Multicenter, multinational, Europe / 15-20 sites 
EU and Switzerland: Spine surgery, FFP as comparator 
United Kingdom (one site): PMP surgery, cryoprecipitate 
as comparator 
Investigational Medicinal 
Products (IMP) 
BT524 (human fibrinogen concentrate) and cryoprecipitate 
BT524 is a heat-treated, lyophilized fibrinogen concentrate 
manufactured from human plasma. 
BT524 is presented as a single-use vial containing 1 g of 
lyophilized fibrinogen. The lyophilisate is to be reconstituted 
with 50 mL of water for injections, resulting in a final 
concentration of 20 mg/mL for IV infusion. 
FFP refers to the liquid portion of human blood that has 
been frozen and preserved after a blood donation and will 
be used for blood transfusion. 
Cryoprecipitate is made from FFP which is frozen and 
repeatedly thawed in a laboratory to produce a source of 
concentrated clotting factors including fibrinogen, factor VIII, 
factor XIII, von Willebrand factor (vWF) and fibronectin and 
platelet microparticles. 
                                            
1 Approximately 60 minutes after the start of cytoreductive PMP surgery. 
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Study No.: 995 
Final 4.3_UK 
Clinical Study Protocol 
EudraCT No.: 2017‐001163‐20 
 
06-SEP-2021 
 
 
CONFIDENTIAL 
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Dosage and Mode of 
Administration 
Subjects undergoing cytoreductive PMP surgery: 
BT524, administered intravenously:  
Fixed first dose of 4 g, subsequent intra-operative 
infusions (4 g) as required.  
Cryoprecipitate, administered intravenously: 
Therapeutic dose is 2 pools, each pool consisting of 
5 units (10 units, dose-equivalent to 4 g fibrinogen 
concentrate), subsequent intra-operative infusions of 
2 pools as required. 
Duration of Treatment 
Single or repeated intra-operative administration of IMP. 
Follow-up per subject: 
Each subject will be followed for at least 5 weeks, with 
clinical and laboratory data collected on visits scheduled on 
Days 2, 3, 5 and 8, and the closing visit, scheduled on 
Day 36* after the day of surgery (*+35, up to Day 71 if 
required). 
Criteria for Evaluation 
 
- Efficacy 
Primary Endpoint:  
• Intra-operative blood loss after decision to treat the 
subject with IMP until the end of surgery as measured by 
amount of blood from the blood suction unit and amount 
of blood from swabs, surgical cloths and compresses. 
 
Secondary Endpoints:  
• Proportion (%) of subjects with successful correction of 
fibrinogen level 15 minutes after start of first IMP 
administration 
• Time to first successful correction of fibrinogen level 
• Total amount of transfusion products (allogenic blood 
products) or autologous blood transfusion infused after 
start of first IMP administration until end of surgery 
• Amount of red blood cells (allogenic and autologous 
RBCs) infused after start of first IMP administration until 
end of surgery 
• Post-operative blood loss in the first 24 hours 
• Proportion (%) of subjects with rebleeds after the end of 
surgery until Day 8 
• Hospital length of stay after surgery 
• In-hospital mortality 
 
- Safety 
Secondary Endpoints: 
• AEs  
• Changes in vital signs 
• Changes in clinical laboratory assessments of 
hematology, clinical chemistry, and urinalysis 
• Changes in clinical laboratory assessments of markers 
of coagulation 
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Study No.: 995 
Final 4.3_UK 
Clinical Study Protocol 
EudraCT No.: 2017‐001163‐20 
 
06-SEP-2021 
 
 
CONFIDENTIAL 
 Page 11 of 102 
• Changes in clinical laboratory assessments of 
coagulation factors 
• Frequency and severity of thrombosis and of TEEs 
• Viral status 
Biostatistical Concept 
Assuming a blood loss of about 500 mL in the FFP2-/ 
cryoprecipitate-treatment arm after the decision to treat the 
subject with IMP until the end of surgery, a standard 
deviation of 375 mL, a non-inferiority margin of 150 mL, and 
an alpha-level of 2.5% (1-sided) 100 evaluable subjects per 
treatment arm are needed to demonstrate the non-inferiority 
of BT524 by using a t-test with 80% power. The sample size 
was calculated with nQuery Advisor Version 4.0 or higher. 
Primary Endpoint: 
The primary endpoint is intra-operative blood loss after the 
decision to treat the subject with IMP until the end of 
surgery. The primary analysis of this endpoint will test for 
non-inferiority. The final analysis will be performed using 
analysis of covariance (ANCOVA) with the predictive blood 
loss (> 1,000 mL to ≤ 2,000 mL and > 2,000 mL) as a 
covariate. Non-inferiority will be demonstrated if the upper 
confidence limit of the 2-sided 95% confidence interval for 
the difference in the least square means is less than the 
non-inferiority margin (150 mL). If non-inferiority is 
demonstrated, then superiority will be assessed. 
Interim analyses: 
In this study, 3 interim analyses with an alpha-adjustment 
according to Haybittle/Peto (Haybittle, 1971; Peto et al., 
1976; Schulz and Grimes, 2005) are planned. This leads to 
local alpha levels of 0.001 for each interim analysis, a 
significance level of 0.05 for the final analysis, and to an 
overall global alpha level of 0.05. 
All interim analyses will be based on the per-prototocl set. 
The first interim analysis is planned with approximately 50 
spine subjects, the second one with at least 40 PMP 
subjects and all other evaluable spine subjects at that time-
point. The third interim analysis is planned with 
approximately 80% of subjects of the total sample size. 
Aim of all interim analyses is to adapt the sample size 
according to the observed blood losses and the standard 
deviations: 
a.) Early termination due to non-inferiority of BT524 in 
comparison with the used standard therapies. 
b.) Continuation with the sample size as initially planned. 
c.) Adjustment of sample size to take into account changes 
from the previous assumptions on the additional blood 
loss. 
                                            
2 FFP treatment is not applicable for subjects in the UK. 
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Study No.: 995 
Final 4.3_UK 
Clinical Study Protocol 
EudraCT No.: 2017‐001163‐20 
 
06-SEP-2021 
 
 
CONFIDENTIAL 
 Page 12 of 102 
d.) Stopping the study early due to futility if the sample size 
re-estimation indicates a much higher number than 
planned before. 
Secondary Endpoints: 
All secondary efficacy endpoints will be summarized 
descriptively by treatment arm. 
The secondary endpoints of proportion of subjects with a 
successful correction of fibrinogen level and proportion of 
subjects with rebleeds will be compared between the 
treatment arms using a Cochran-Mantel-Haenszel (CMH) 
approach stratified by predictive blood loss. 
The secondary endpoint ‘time to first successful correction of 
fibrinogen level’ will be compared between the treatment 
arms using a Chi-Square test. 
The secondary endpoints of consumption of transfusion 
products, amount of RBCs and post-operative blood loss in 
the first 24 hours will be analysed using ANCOVA with the 
predictive blood loss as a covariate. 
Safety will be assessed based on AEs, laboratory data, vital 
signs data, frequency and severity of thrombosis and of TEE 
and viral status which will be summarized descriptively. 
Data Safety Monitoring Board: 
An independent Data Safety Monitoring Board (DSMB) will 
review unblinded safety data at regular intervals during the 
study.  
Data Monitoring: 
After 40 subjects have completed, the overall mean and 
standard deviation of the primary endpoint will be derived 
using blinded data of all 40 subjects without separating 
according to treatment to assess if the sample size needs to 
be adjusted. 
First Subject In  
Q1 2018 
Last Subject Last Visit 
(planned) 
Tbd 
 
Confidentiality Statement 
This protocol is the property of Biotest AG, and may not be circulated, reproduced or published - either in 
whole or in part - without the company’s written permission.  
PPD

 
Study No.: 995 
Final 4.3_UK 
Clinical Study Protocol 
EudraCT No.: 2017‐001163‐20 
 
06-SEP-2021 
 
 
CONFIDENTIAL 
Page 13 of 102 
 
 
 
 
III. 
FLOWCHART OF STUDY 
Study Schedule 
Day 
D-42 to D-1 D-2 to D1 
D1 
D1 
D1 
D1 
D2 
D3 
D5 
D8 
D36 (+35) 
Assessments 
Visit 
Screening 
Prior 
surgery 
(Baseline) 
Surgery 
Follow-
up 
Follow-
up 
Follow-
up 
Follow-
up 
Closing 
prior  
1st dose 
pre-
dose 
post-
dose 
end of 
surgery 
Informed consent 
• 
 
 
 
 
 
 
 
 
 
 
Check/re-check of inclusion / exclusion criteria 
• 
•1 
 
 
 
 
 
 
 
 
 
Demographic data  
• 
 
 
 
 
 
 
 
 
 
 
Classification of type of surgery 
• 
 
 
 
 
 
 
 
 
 
 
Recording expected blood loss 
 
• 
 
 
 
 
 
 
 
 
 
Body weight 
• 
•2 
 
 
 
 
 
 
 
 
 
Physical examination 
• 
•2 
 
 
 
 
• 
• 
• 
• 
•3 
Pregnancy test, only in females of childbearing potential 
• 
•2 
 
 
 
 
 
 
 
 
 
Medical and surgical history 
• 
•4 
 
 
 
 
 
 
 
 
 
Viral safety: Collection of retention sample 
• 
 
 
 
 
 
 
 
 
 
•³ 
Virus serology (hepatitis B, hepatitis C, HIV) 
• 
 
 
 
 
 
 
 
 
 
•³ 
Vital signs  
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
•³ 
Hematology and clinical chemistry 
• 
•2 
• 
 
 
• 
• 
• 
• 
• 
•³ 
Urinalysis 
• 
•2 
 
 
 
 
• 
• 
• 
• 
•³ 
Markers of coagulation (coagulation activation tests) 
• 
•2 
• 
 
•5 
•6 
• 
• 
• 
• 
•³ 
Plasma concentration of fibrinogen activity (Clauss assay)  
• 
•2 
• 
 
•5 
•6 
• 
 
 
 
 
FIBTEM A10 (ROTEM) 
• 
•2 
• 
• 
•5 
•6 
• 
 
 
 
 
Maximum clot firmness (MCF) (ROTEM) 
• 
•2 
• 
• 
•5 
•6 
• 
 
 
 
 
                                            
1 Diagnostic tests will be repeated at the investigator’s discretion. 
2 Diagnostic tests have to be done prior to surgery. In case of short time-period between screening and baseline (≤ 2 days) these tests have only to be repeated based on medical 
judgment of the investigator. If not repeated, screening results will serve as baseline. 
3 Diagnostic tests are required as part of the closing visit. In case the closing visit is scheduled as a phone call, these tests can be performed on the day of hospital discharge. 
4 Previous medication: change from screening. 
5 Tests have to be done only 15 and 90 minutes after start of 1st IMP administration. 
6 Tests (Markers of coagulation, Clauss assay, FIBTEM A10, MCF, coagulation factors) have to be done ’90 min after start of 1st IMP administration’ and at the ‘end of surgery’. In 
case of a short time-period between these two time points (<30 min) these tests have only to be repeated based on medical judgment of the investigator. 
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Study No.: 995 
Final 4.3_UK 
Clinical Study Protocol 
EudraCT No.: 2017‐001163‐20 
 
06-SEP-2021 
 
 
CONFIDENTIAL 
Page 14 of 102 
 
 
 
 
Study Schedule 
Day 
D-42 to D-1 D-2 to D1 
D1 
D1 
D1 
D1 
D2 
D3 
D5 
D8 
D36 (+35) 
Assessments 
Visit 
Screening 
Prior 
surgery 
(Baseline) 
Surgery 
Follow-
up 
Follow-
up 
Follow-
up 
Follow-
up 
Closing 
prior  
1st dose 
pre-
dose 
post-
dose 
end of 
surgery 
Coagulation factors (including vWF) 
 
• 
• 
 
•7 
•6 
 
 
 
 
 
Intra-operative inclusion criteria 
 
 
• 
 
 
 
 
 
 
 
 
Intravenous infusion(s) of IMP (BT524 or 
cryoprecipitate) 
 
 
•8 
 
 
 
 
 
 
Recording start/end of surgery 
 
 
• 
 
 
• 
 
 
 
 
 
Continuous measurement of blood loss from start of surgery 
 
 
• 
• 
• 
 
 
 
 
Calculation and recording of blood loss 
 
 
 
 
 
•9 
•10 
 
 
 
 
Recording time of decision to treat the subject with IMP 
 
 
• 
 
 
 
 
 
 
 
 
Order of IMP 
 
 
• 
• 
 
 
 
 
 
 
 
Randomization 
 
 
• 
 
 
 
 
 
 
 
 
Rebleeding episodes 
 
 
 
 
 
• 
• 
• 
• 
• 
 
Concomitant medication or treatment  
 
 
• 
• 
• 
• 
• 
• 
• 
Transfusion products 
 
 
• 
• 
• 
• 
• 
• 
• 
Adverse events 
• 
• 
• 
• 
• 
• 
• 
• 
• 
                                            
7 Test has to be done only 90 minutes after start of 1st IMP administration. 
8 Total volume and total infusion time (start and end of each infusion) to be recorded. 
9 Intra-operative blood loss from time point of decision to treat the patient with IMP until end of surgery. 
10 Recording of blood loss (drainage volume) until 24 hours after end of surgery. 
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Study No.:  995 
Final 4.3_UK 
Clinical Study Protocol 
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IV. 
TABLE OF CONTENTS 
I. 
SIGNATURE PAGE .................................................................................. 6 
I.I 
Signature Page for Investigators ........................................................... 7 
II. 
STUDY SYNOPSIS .................................................................................. 8 
III. 
FLOWCHART OF STUDY ...................................................................... 13 
IV. 
TABLE OF CONTENTS ......................................................................... 15 
V. 
LIST OF ABBREVIATIONS ................................................................... 19 
1 
INTRODUCTION .................................................................................... 21 
2 
STUDY OBJECTIVES ............................................................................ 24 
3 
STUDY DESIGN ..................................................................................... 25 
4 
STUDY POPULATION ........................................................................... 30 
 
Study Population, Diagnosis and Number of Subject ....................... 30 
4.1.1 
Gender Distribution ........................................................................................ 30 
 
Inclusion Criteria ................................................................................... 31 
 
Exclusion Criteria ................................................................................. 31 
 
Subjects Withdrawal Criteria and Replacements ............................... 32 
 
Subjects Information ............................................................................ 33 
 
Declaration of Informed Consent ........................................................ 33 
5 
INVESTIGATIONAL MEDICINAL PRODUCTS ..................................... 34 
 
Investigational Medicinal Product BT524 ........................................... 34 
5.1.1 
Description of Investigational Medicinal Product BT524 ............................. 34 
5.1.2 
Formulation, Packaging and Labelling ......................................................... 34 
5.1.3 
Storage Conditions and Stability ................................................................... 35 
5.1.4 
Preparation for Use ........................................................................................ 35 
 
Investigational Medicinal Product Cryoprecipitate ............................ 35 
5.2.1 
Description of Investigational Medicinal Product Cryoprecipitate .............. 35 
5.2.2 
Formulation, Packaging and Labelling ......................................................... 35 
5.2.3 
Storage Conditions and Stability ................................................................... 36 
5.2.4 
Preparation for Use ........................................................................................ 36 
6 
STUDY TREATMENT ............................................................................. 36 
 
Dosage Regimen ................................................................................... 36 
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Dosage and Administration ................................................................. 36 
 
Compliance with Dosage Regimens ................................................... 38 
 
Dose Justification ................................................................................. 38 
 
Treatment of Overdose ......................................................................... 39 
 
Randomization Code ............................................................................ 39 
 
Procedures for Emergency Unblinding .............................................. 40 
 
Drug Accountability .............................................................................. 40 
 
Previous and Concomitant Medication or Treatment ........................ 40 
 
Prohibited Medication or Treatment .................................................... 41 
 
Warnings and Precautions ................................................................... 41 
7 
COURSE OF THE CLINICAL STUDY .................................................... 43 
 
Visit Schedule for PMP subjects ......................................................... 43 
 
Duration of the Clinical Study .............................................................. 51 
7.2.1 
End of Study ................................................................................................... 51 
 
Criteria for Premature Termination ..................................................... 51 
7.3.1 
Premature Termination of the Entire Clinical Study ..................................... 51 
7.3.2 
Premature Termination of an Individual Study Site ..................................... 52 
 
Treatment and Care after the End of the Study .................................. 52 
8 
BENEFIT-RISK EVALUATION............................................................... 53 
 
Benefit of BT524 .................................................................................... 53 
 
Foreseeable Risk and Discomfort Related to BT524 ......................... 53 
 
Other Sources of Possible Risk and Discomfort ............................... 53 
 
Summary of Possible Risk and Discomfort ........................................ 53 
9 
ASSESSMENT OF OBJECTIVES / CRITERIA FOR EVALUATION ..... 54 
 
Efficacy .................................................................................................. 54 
9.1.1 
Specification of Efficacy Parameters ............................................................ 54 
9.1.1.1 Primary Efficacy Parameter .............................................................................. 54 
9.1.1.2 Secondary Efficacy Parameter.......................................................................... 54 
9.1.2 
Methods for Assessing and Recording Efficacy Parameters ...................... 55 
9.1.2.1 Methods for Assessing Primary Efficacy Parameter .......................................... 55 
9.1.2.2 Methods for Assessing Secondary Efficacy Parameter ..................................... 56 
9.1.3 
Specification of Efficacy Endpoints .............................................................. 58 
9.1.3.1 Specification of Primary Efficacy Endpoint ........................................................ 58 
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9.1.3.2 Specification of Secondary Efficacy Endpoints ................................................. 58 
 
Safety ..................................................................................................... 59 
9.2.1 
Specification of Safety Parameters ............................................................... 59 
9.2.1.1 Adverse Events ................................................................................................ 59 
9.2.1.2 Physical Examination ........................................................................................ 60 
9.2.1.3 Vital Signs ........................................................................................................ 60 
9.2.1.4 Laboratory Parameters ..................................................................................... 61 
9.2.1.5 Retention Samples ........................................................................................... 66 
9.2.2 
Methods for Assessing and Recording Safety Parameter(s) ....................... 67 
9.2.3 
Safety Endpoints ............................................................................................ 67 
 
Adverse Events ..................................................................................... 67 
9.3.1 
Definitions ....................................................................................................... 67 
9.3.2 
Recording Adverse Events ............................................................................ 69 
9.3.3 
Period of Observation .................................................................................... 70 
9.3.4 
Assessment of Adverse Events ..................................................................... 71 
9.3.5 
Immediate Reporting by Investigator to Sponsor ........................................ 72 
9.3.6 
Use of IMP outside the Specifications of the Clinical Study Protocol ........ 72 
9.3.7 
Investigational Medicinal Product Complaints ............................................. 73 
9.3.8 
Special Situations Requiring Immediate Reporting ..................................... 73 
9.3.8.1 Pregnancy ........................................................................................................ 73 
 
Data Safety Monitoring Board.............................................................. 74 
10 
STATISTICS ........................................................................................... 75 
 
Analysis Sets......................................................................................... 75 
 
Protocol Deviations .............................................................................. 75 
 
General Considerations ....................................................................... 76 
 
Efficacy Analyses ................................................................................. 76 
 
Primary Efficacy Analysis .................................................................... 77 
 
Secondary Efficacy Analyses .............................................................. 77 
10.6.1 
Correction of Fibrinogen Level ...................................................................... 78 
10.6.2 
Consumption of Transfusion Products ......................................................... 78 
10.6.3 
Amount of Red Blood Cells............................................................................ 78 
10.6.4 
Post-operative Blood Loss ............................................................................ 78 
10.6.5 
Proportion of Subjects with Rebleeds .......................................................... 79 
10.6.6 
Hospital Length of Stay after Surgery ........................................................... 79 
10.6.7 
In-hospital Mortality ........................................................................................ 79 
 
Safety Analysis ..................................................................................... 79 
 
Interim Analyses ................................................................................... 79 
 
Determination of Sample Size.............................................................. 80 
10.9.1 
Data Monitoring .............................................................................................. 81 
11 
DATA MANAGEMENT ........................................................................... 81 
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Data Collection ...................................................................................... 81 
 
Correction of Data ................................................................................. 82 
 
Data Handling ........................................................................................ 82 
12 
QUALITY CONTROL AND QUALITY ASSURANCE ............................ 82 
 
Study Initiation Activities ..................................................................... 82 
 
Training of site staff .............................................................................. 82 
 
Documentation and Filing .................................................................... 83 
 
Monitoring ............................................................................................. 83 
 
Audits and Inspections ........................................................................ 84 
 
Archiving ............................................................................................... 84 
13 
GENERAL REGULATIONS, AGREEMENTS AND ORGANISATIONAL 
PROCEDURES....................................................................................... 84 
 
Study Administrative Structure ........................................................... 84 
 
Ethical and Regulatory Considerations .............................................. 84 
 
Committees / Monitoring Boards ......................................................... 85 
 
Written Agreements .............................................................................. 85 
 
Insurance/Liability ................................................................................ 85 
 
Investigator’s Brochure (IB) ................................................................. 85 
 
Amendments to the Protocol ............................................................... 85 
 
Confidentiality ....................................................................................... 85 
 
Final Report and Publication ............................................................... 86 
14 
LIST OF REFERENCES ......................................................................... 87 
15 
APPENDICES......................................................................................... 94 
 
Figure 1: Overview of Study Design ........................................................................................................ 26 
Figure 2: Quantification of Blood Loss Intra-operatively ......................................................................... 27 
Figure 3: Repeated IMP Administration .................................................................................................. 29 
Figure 4: ROTEM Readout of Citrated Normal Blood ............................................................................. 57 
 
Table 1: 
Clinical Laboratory Parameters ................................................................................................ 62 
 
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V. 
LIST OF ABBREVIATIONS 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALAT 
Alanine aminotransferase 
ANCOVA 
Analysis of Covariance 
AP 
Alkaline phosphatase 
aPTT 
Activated partial thromboplastin time 
ASAT 
Aspartate aminotransferase 
AT III 
Antithrombin III 
BDRM 
Blind Data Review Meeting 
BUN 
Blood Urea Nitrogen 
BW 
Body Weight 
CDS 
Corporate Drug Safety 
CHMP 
Committee for Medicinal Products for Human Use 
CMH 
Cochran-Mantel-Haenszel 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
CRO 
Contract Research Organization 
DEVP 
Drug Exposure Via Parent 
DIC 
Disseminated Intravascular Coagulation 
DOAC 
Direct Oral Anti-Coagulants 
DSMB 
Data Safety Monitoring Board 
eCRF 
electronic Case Report Form 
EDC 
Electronic Data Capture 
EMA 
European Medicines Agency 
IEC 
Ethics Committee 
IRB 
Institutional Review Board 
FAS 
Full Analysis Set 
FII 
Factor II 
FV 
Factor V 
FVII 
Factor VII 
FVIII 
Factor VIII 
FIX 
Factor IX 
FX 
Factor X 
FXI 
Factor XI 
FXIII 
Factor XIII 
F1+2 
Prothrombin Fragments 1+2 
FAS 
Full Analysis Set 
FFP 
Fresh Frozen Plasma 
GCP 
Good Clinical Practice 
ɣ-GT 
Gamma glutamyltransferase 
IB 
Investigator’s Brochure 
HAV 
Hepatitis A Virus 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HEV 
Hepatitis E Virus 
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HIV 
Human Immunodeficiency Virus 
ICF 
Informed Consent Form 
IMP 
Investigational Medicinal Product 
ICH 
International Conference on Harmonization 
i.e. 
id est 
INR 
International normalized ratio 
IRAE(s) 
Immediately Reportable Adverse Event(s) 
IV 
Intravenous 
IWRS/IVRS 
Interactive Web/Voice Response System 
MCF 
Maximum Clot Firmness 
MedDRA® 
Medical Dictionary for Regulatory Activities 
NTEAE 
Non-Treatment Emergent Adverse Event 
NIMP 
Non-Investigational Medicinal Product 
PC 
Protein C 
PEI 
Paul-Ehrlich-Institut, Germany 
PHI 
Protected Health Information 
PPS 
Per-Protocol Set 
PS 
Protein S 
PMP 
Pseudomyxoma peritonei 
PT(INR) 
Prothrombin Time (International Normalized Ratio) 
QBL 
Quantification of Blood Loss 
RBC 
Red Blood Cells 
ROTEM 
Rotational Thromboelastometry 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SmPC 
Summary of Product Characteristics 
SOC 
System Organ Class 
TAT 
Thrombin-antithrombin III complex 
TEAE 
Treatment-Emergent Adverse Event 
TEE 
Thromboembolic Event 
TGT 
Thrombin Generation Test 
TMF 
Trial Master File 
TT 
Thrombin Time 
TXA 
Tranexamic Acid 
vWF 
von Willebrand factor 
WBC 
White Blood Cells 
 
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1 INTRODUCTION 
BT524 is a lyophilized, heat-treated fibrinogen concentrate manufactured from human 
plasma. BT524 is currently developed for the treatment and prophylaxis of bleeding in 
patients with congenital afibrinogenaemia or severe congenital hypofibrinogenaemia with 
bleeding tendency. Moreover, BT524 will be developed as complementary therapy to 
management of uncontrolled severe hemorrhage in acquired hypofibrinogenaemia. 
To date, no clinical studies have previously been conducted with BT524 in subjects with 
acquired hypofibrinogenaemia. The pharmacokinetic properties of BT524 were 
investigated in the treatment and prophylaxis of bleeding in patients with congenital 
fibrinogen deficiency (afibrinogenaemia or severe hypofibrinogenaemia) in the ongoing 
prospective, open-label, phase I/III study 
. Details on the clinical pharmacology of 
BT524 and further information on non-clinical studies with BT524 are provided in the 
Investigator’s Brochure. 
In addition to the ongoing clinical development in congenital fibrinogen deficiency, the 
present prospective, multi-center, randomized, active-controlled, pivotal phase III study 
aims to demonstrate the efficacy and safety of BT524 in subjects with acquired 
hypofibrinogenaemia caused by major surgery associated with major blood loss. 
Fibrinogen (coagulation factor I) is a soluble plasma glycoprotein synthesized by hepatic 
parenchymal cells. The normal blood fibrinogen concentration is between 2.0 and 4.5 g/L 
although this range can vary (Levy and Goodnough, 2015). Fibrinogen plays a central 
role by clot forming in wound healing and furthermore, is important in primary hemostasis 
as it contributes to blood platelet aggregation. In case of a fibrinogen deficiency the blood 
coagulation is disordered, which leads to (severe) hemorrhagic events. 
Acquired fibrinogen deficiency is the most common type of fibrinogen deficiency. It is 
characterized by an impaired hemostatic function caused by fibrinogen concentrations 
below the normal ranges, classified as hypofibrinogenaemia. Hypofibrinogenaemia 
results from either reduced fibrinogen synthesis due to hepatic disorders, increased 
intravascular consumption due to a breakdown of fibrinogen, disseminated intravascular 
coagulation (DIC) or increased fibrinogen loss caused by certain medical conditions such 
as surgical procedures or uncontrolled life-threatening bleeding. Acquired fibrinogen 
deficiency can cause severe intra-operative bleeding. Depending on the severity and the 
extent of the event (i.e. trauma, surgery) and the patient’s clinical condition fibrinogen 
plasma concentrations are highly variable in acquired fibrinogen deficiency.  
Acquired fibrinogen deficiency is associated with increased morbidity and mortality. Thus, 
effective management of this hemostatic disorder is necessary to prevent potentially life-
threatening bleeding, to reduce increased blood loss, transfusion requirements and the 
risk of surgery (Fenger-Eriksen et al., 2009).  
Fibrinogen is an important contributor to clot strength and is the first coagulation factor to 
become critically reduced during intra-operative hemorrhage (Haas et al., 2012). 
Therefore, a rapid and accurate determination of fibrinogen level is important during 
hemorrhage to establish a timely hemostatic intervention. The rapid fibrinogen 
supplementation to restore plasma levels is an important component for normalizing clot 
formation in bleeding patients and maintaining fibrinogen levels is an important 
therapeutic target in bleeding, particular in intra-operative settings (Levy and Goodnough, 
2015).  
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There is growing evidence that fibrinogen levels > 1.5 to 2 g/L are necessary to control 
major bleeding in the intra-operative settings (Haas et al., 2012; Levy and Goodnough, 
2015). Accordingly, European trauma guidelines from 2013 (Spahn et al., 2013) and the 
guidelines from the European Society of Anaesthesiology (Kozek-Langenecker et al., 
2013) recommend target levels of at least 1.5 to 2.0 g/L in intra-operative settings. 
Because of the large variability in fibrinogen concentrations among bleeding patients, 
individualized dosing of fibrinogen concentrate based upon both the level of bleeding and 
the plasma fibrinogen concentration are recommended (Levy et al., 2012). Fibrinogen 
concentrate infusion guided by point-of-care tests is recommended by the European 
Society of Anaesthesiology (Kozek-Langenecker et al., 2013) and the FIBTEM test has 
been used extensively in clinical studies to determine fibrinogen levels and calculate 
dosing (Levy and Goodnough, 2015).  
Nevertheless, the optimal treatment level, the use of pre-emptive treatment and the 
preferred source of fibrinogen for acquired fibrinogen deficiency remain disputed. 
Fibrinogen concentrate is increasingly used and recommended for bleeding with acquired 
hemostatic deficiencies in several countries, but evidence is inconsistent regarding 
surgery settings, dosing and efficacy. Fresh frozen plasma (FFP) also contains fibrinogen 
and is available in all hospital settings and is comparatively cheap but requires the 
administration of large quantities of FFP to achieve a reasonable fibrinogen dose. 
Therefore, further clinical studies investigating fibrinogen replacement in acquired 
fibrinogen deficiency are needed. 
Currently, conventional replacement therapy in fibrinogen deficiency consists of 
transfusion of allogenic blood products such as FFP and cryoprecipitate.  
FFP is a blood product that has been available since 1941. Initially used as a volume 
expander, it is currently indicated for the management and prevention of bleeding in 
coagulopathic patients (Nascimento et al., 2010).  
FFP is the liquid portion of blood that contains all the clotting factors, as well as other 
blood proteins and that is stored by freezing (WHO 2007). FFP is usually authorized 
nationally. Examples of FFP authorized in Germany are available from the website of the 
German authority Paul-Ehrlich-Institut (PEI). A solvent/detergent treated frozen plasma 
(
 by 
 is nationally approved in several EU countries (
 
). 
Compared to fibrinogen concentrate FFP is stored frozen and must be thawed before use 
which is a limitation in time critical and potentially life-threatening situations such as 
severe bleeding. FFP contains 2.0 to 4.5 g/L of fibrinogen which is much lower than in 
fibrinogen concentrates (i.e. up to 10-fold lower than in BT524 with 20 g/L). Since FFP 
contains relatively low amounts of fibrinogen, it requires the administration of large 
volumes to provide meaningful increases in the fibrinogen plasma level. The large 
volumes carry the risk of hypervolemia, cardiac stress, circulatory overload, transfusion-
related acute lung injury, hypothermia and metabolic complications once bleeding 
resolves (Bornikova et al., 2011; Elliott and Aledort, 2013; Mumford et al., 2014; Ofosu et 
al., 2008). Furthermore, the use of allogenic blood confers an additional risk for blood 
borne pathogens. Also noteworthy is the risk for transfusion related reactions, immune 
suppression, and a decrease in coagulation factors. There is also evidence that 
transfusion of allogenic blood is increasingly harmful as more blood is transfused (Verma 
et al., 2015). 
 
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As the concentration of fibrinogen in fibrinogen concentrates is markedly higher than in 
plasma the required dose to reach the fibrinogen target concentration can be 
administered in a minor volume. Furthermore, the amount of fibrinogen in FFP varies 
making it difficult to predict the increase in plasma fibrinogen concentration. The precisely 
defined fibrinogen content in fibrinogen concentrates allows accurate calculation of the 
amount of reconstituted concentrate needed for a targeted fibrinogen supplementation. 
Cryoprecipitate is made from FFP and contains various proteins including fibrinogen. It 
contains higher concentrations of fibrinogen than FFP and some (but not all) coagulation 
factors, so less volume is needed. The minimum amount of fibrinogen required by 
standards of the American Association of Blood Banks is 150 mg per bag of 
cryoprecipitate; current preparations yield a median of 388 mg per bag, but the amount 
of fibrinogen is variable and cannot be determined accurately. A single unit of 
cryoprecipitate also contains variable amounts of FVIII, FXIII, von Willebrand factor 
(vWF), fibronectin and platelet microparticles (Callum et al., 2009). Therefore, the use of 
cryoprecipitate for fibrinogen replacement alone exposes the patient to potentially 
unneeded coagulation proteins which could increase the risk of thrombosis (Elliott and 
Aledort, 2013; Franchini and Lippi, 2012). Cryoprecipitate was withdrawn from most 
European countries some years ago because of safety concerns (Karkouti et al., 2018; 
Schochl et al., 2013) but remains available in Scandinavia, the UK and the USA, 
essentially for the purpose of fibrinogen replacement. 
In summary fibrinogen concentrate seems to have certain advantages over other 
replacement therapies like FFP and cryoprecipitate, such as precisely determined high 
amounts of purified fibrinogen dissolved in a small volume, low risk of pathogen 
transmission and instant administration without need for thawing or testing AB0 blood 
group compatibility (Warmuth et al., 2012). 
A number of clinical studies have been published in subjects with acquired 
hypofibrinogenaemia, such as following trauma, cardiothoracic surgery and obstetric 
hemorrhage, documenting that fibrinogen concentrate is able to improve clotting function 
and reduce blood loss. The results of these studies have shown that fibrinogen 
concentrate raises the levels of fibrinogen and improves clot firmness. Additionally, 
fibrinogen substitution has been reported to reduce bleeding and post-operative 
transfusion requirements. Published data from completed clinical studies in subjects 
undergoing major surgeries not only suggest that fibrinogen plays a critical role in 
achieving and maintaining hemostasis; in particular, they appear to show benefit of 
individualized dosing of fibrinogen concentrate using a target ROTEM/FIBTEM value 
integrating rapid diagnostic testing with appropriate therapeutic dosing of fibrinogen 
concentrate in line with patients' needs (Haas et al., 2015; Rahe-Meyer et al., 2013a; 
Rahe-Meyer et al., 2009a; Rahe-Meyer et al., 2013b; Rahe-Meyer et al., 2009b; Ranucci 
et al., 2015). In a prospective, randomized, single-center, controlled phase 2 study, 
published in 2019 
, 45 adult subjects undergoing cytoreductive surgery for 
pseudomyxoma peritonei (PMP) were treated pre-emptively with fibrinogen concentrate 
or cryoprecipitate. Subjects were randomized to one of the two treatment groups (4 g 
fibrinogen concentrate or 2 pools cryoprecipitate), when assessment after the start of 
surgery predicted intra-operative blood loss ≥ 2 L without targeted fibrinogen 
replacement. Further intra-operative doses were based on thromboelastometry (FIBTEM 
A20 < 12 mm). Hemostatic efficacy was successful in 100% of subjects in both groups, 
with similar blood loss. No thromboembolic events (TEEs) occurred in subjects who 
received fibrinogen concentrate.  
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The published data indicate that fibrinogen concentrate is at least comparable with 
cryoprecipitate in terms of benefits for hemostatic therapy in the treatment of clinically 
relevant bleeding associated with acquired fibrinogen deficiency in subjects undergoing 
cytoreductive surgery for PMP (Roy et al., 2020). 
As there is no guideline on the clinical investigation of fibrinogen in patients with 
uncontrolled severe hemorrhage in acquired hypofibrinogenaemia available, the EMA 
guideline on core SmPC for human fibrinogen products (EMA (Committee for Medicinal 
Products for Human Use), 2015) has been taken into account when planning this phase 
III study in acquired fibrinogen deficiency. Furthermore, currently ongoing clinical studies 
with fibrinogen concentrate as well as recently finalized clinical studies in this clinical 
setting (Roy et al., 2020) have been considered. 
BT524 will be developed as complementary therapy to management of uncontrolled 
severe hemorrhage in acquired hypofibrinogenaemia caused by major surgeries 
associated with major blood loss. As it is expected that BT524 will show a safety 
advantage over the standard treatment with FFP/cryoprecipitate, an efficacy comparison 
to the standard is required to allow a risk-benefit assessment to be made for BT524. 
Therefore, the present prospective, multi-center, randomized, active-controlled, pivotal 
phase III non-inferiority study aims to investigate efficacy and safety of BT524 in subjects 
with acquired hypofibrinogenaemia. 
 
2 STUDY OBJECTIVES 
The main purpose of this phase III study is to demonstrate the efficacy of BT524 as a 
complementary therapy to management of uncontrolled severe hemorrhage in acquired 
hypofibrinogenaemia in subjects undergoing elective major spinal or abdominal surgery.  
The primary objective of this study is to demonstrate that BT524 is non-inferior that 
means not worse than FFP/cryoprecipitate with a non-inferiority margin of 150 mL in 
reducing intra-operative blood loss by IV administration in subjects with acquired 
hypofibrinogenaemia undergoing elective major spinal or abdominal surgery. 
If therapeutic equivalence (non-inferiority) has been demonstrated, therapeutic 
superiority of BT524 compared with FFP/cryoprecipitate will also be assessed. 
Secondary objectives are to demonstrate the efficacy of BT524 by assessing the 
correction of the fibrinogen level intra-operatively, the transfusion requirements, post-
operative blood loss in the first 24 hours, the number of subjects with rebleeds, hospital 
length of stay and in-hospital mortality. Secondary objectives also comprise the safety of 
BT524 by documenting the number of AEs including changes in laboratory parameters, 
the viral status, and the frequency and severity of thrombosis and of TEEs.  
Since this is a country specific clinical study protocol (CSP) version for subjects 
undergoing cytoreductive PMP surgery at one site in the UK only, the treatment of 
subjects undergoing spinal surgery (with BT524 or FFP) is not described in this protocol 
version. 
 
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3 STUDY DESIGN 
This is a phase III, prospective, randomized, active-controlled, multicenter, non-inferiority 
clinical study in subjects undergoing major spinal (not applicable for subjects in the UK) 
or abdominal surgery to demonstrate the efficacy and the safety of intra-operative use of 
BT524 as a complementary therapy to management of uncontrolled severe hemorrhage 
in acquired hypofibrinogenaemia. 
This non-inferiority study is focused on the primary objective, to demonstrate that BT524 
is non-inferior that means not worse than FFP/cryoprecipitate with a non-inferiority margin 
of 150 mL in reducing intra-operative blood loss by IV administration in subjects with 
acquired hypofibrinogenaemia undergoing elective major spinal or abdominal surgery. If 
therapeutic equivalence has been demonstrated, therapeutic superiority of BT524 
compared with FFP/cryoprecipitate will also be assessed.  
Secondary objectives are to demonstrate the efficacy of BT524 by assessing the 
correction of fibrinogen level during surgery, the transfusion requirements, post-operative 
blood loss in the first 24 hours, the number of subjects with rebleeds, the hospital length 
of stay and the in-hospital mortality. Secondary objectives also comprise the safety of 
BT524 by documenting the number of AEs including changes in laboratory parameters, 
the viral status, and the frequency and severity of thrombosis and of TEEs. 
The study comprises a screening visit within 42 days prior to surgery to assess subjects 
eligibility, a baseline visit on the day of the surgery prior anaesthesia (Day 1, but if 
required this could be Day -2 or Day -1 due to local hospital procedures), the surgery 
phase (including randomization, Day 1) and the follow-up phase of at least 5 weeks with 
4 follow-up visits on Days 2, 3, 5 and 8 and the closing visit, including the final safety 
examination, and a safety follow-up scheduled on Day 36* after the day of surgery (*+35, 
up to Day 71 if required). The duration of individual study participation for eligible 
screened subjects is at least 5 weeks.  
 
Since this is a country specific clinical study protocol (CSP) version for subjects 
undergoing cytoreductive PMP surgery only, the study design for subjects undergoing 
spinal surgery is not outlined here.  
The study design for subjects undergoing cytoreductive PMP surgery is shown in 
the following figure (Figure 1): 
 
 
 
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Figure 1: 
Overview of Study Design 
 
 
Further details on the assessment schedule (including the follow-up period) that will be used for the 
assessment of the efficacy and safety parameters in this study are presented in the flowchart in section III 
and in the visit schedule section 7.1. 
At least 200 subjects will be enrolled to ensure data are available for 100 evaluable 
subjects per treatment arm (BT524 or FFP1/cryoprecipitate). The multicenter, 
multinational study will be conducted at approximately 15-20 sites in the EU and 
Switzerland with subjects undergoing major spinal surgery, and at one site in the United 
Kingdom with subjects undergoing cytoreductive PMP surgery and treated with 
BT524 and cryoprecipitate. 
 
Detailed Description of the PMP Surgery Phase 
The continuous determination/measurement of blood loss during the entire surgery will 
be separated into two parts: 
• First part: blood loss will be determined from start of surgery until decision to treat 
by estimating the bleeding mass in the blood suction unit, taking the blood loss in 
swabs, surgical cloths and compresses into account. This is the prerequisite for 
the intra-operative inclusion criterion (intra-operative prediction of clinically 
relevant bleeding of > 2 L, requiring hemostatic treatment during surgery) and the 
decision to treat the subject with IMP. 
• Second part: blood loss will be measured after decision to treat until end of 
surgery and represents the blood loss considered for the primary objective. During 
                                            
1 FFP treatment is not applicable for subjects in the UK. 
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this part of the surgery the blood loss will be quantified by measuring the 
continuous bleeding mass removed from the surgical field by a blood suction unit 
and by calculation of the amount of blood absorbed by swabs, surgical cloths and 
compresses. In a final step, the total blood loss will be calculated. 
Prior to the start of surgery the weight of dry swabs, surgical cloths and compresses 
will be recorded (weighing of swabs is required if weight is not specified on the 
packaging). 
The first part of blood measurement starts at the start of surgery with the collection of 
blood in the blood suction unit: The blood is salvaged by a suction catheter from the 
operating field. In case a manual compression is necessary, dry swabs, surgical cloths 
and compresses will be applied to the surgical field, and - at the latest - prior to the 
decision to treat the subject with IMP removed. 
The anaesthesiologist will estimate the blood volume collected in the suction container 
continuously, taking the blood loss in swabs, surgical cloths and compresses into 
account. Allowance must also be made for the presence of mucinous ascites and 
washout. During the surgery, the anaesthesiologist must calculate these volumes 
suctioned into the container. The anaesthesiologist subtracts these amounts to estimate 
the volume of blood in the container.  
The quantification of blood loss (QBL) intra-operatively is shown in Figure 2: 
 
Figure 2: Quantification of Blood Loss Intra-operatively 
 
 
After opening and inspection of the abdomen the inside of the abdominal cavity will be 
washed out with a certain amount of irrigation solution (physiological saline solution) to 
remove mucinous ascites. Afterwards, approximately 60 minutes after the start of 
cytoreductive PMP surgery, the subject’s intra-operative bleeding risk has to be assessed 
by the surgeon and the anaesthesiologist. In case of a predicted clinically relevant blood 
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loss of more than 2 L, and the assessment that hemostatic treatment will be required 
during surgery (high risk for the need of fibrinogen supplementation, either with 
cryoprecipitate or BT524), the decision to treat the subject with IMP can be made.  
At this point the time has to be documented. 
Immediately after the prediction of clinically relevant bleeding of > 2 L, requiring 
hemostatic treatment during surgery, the person responsible for randomization will be 
informed about the decision to treat the subject with IMP. The subject will be randomized 
to one of the treatment arms. 
At the same time, the suction container will be emptied and all remaining swabs, 
surgical cloths and compresses will be removed from the surgical field. 
The second part of blood measurement is initiated with collection of blood in the empty 
blood suction unit. In addition, in case a manual compression is necessary after decision 
to treat the subject with IMP, new swabs, surgical cloths and compresses will be applied 
to the surgical field. 
The first dose of BT524 (4 g) or cryoprecipitate (2 pools, each pool consisting of 5 
units/donations, dose-equivalent to 4 g fibrinogen concentrate) will be administered pre-
emptively, based on clinical judgement (prediction of clinically relevant bleeding of more 
than 2 L intra-operatively).  
IMP will be delivered to the operating room by the blood bank (cryoprecipitate) or by the 
pharmacy (BT524) according to local standards, and administered by the unblinded 
anaesthesiologist. 
The content of each syringe with BT524 (1 g fibrinogen concentrate dissolved in 50 mL 
water for injection) can be administered in less than 20 seconds. Cryoprecipitate can be 
infused as rapidly as possible by the anaesthesiologist. 
In the further course of the surgery, qualitative assessment of bleeding will be used by 
the surgeon to estimate if further bleeding intervention is required. Surgeon and surgical 
staff are blinded to therapy and will inform the anaesthesiologist regarding the bleeding 
assessment. In addition, FIBTEM A10 should be determined in order to guide further IMP 
doses. In case of a further intra-operative clinically relevant bleeding, a FIBTEM A10 < 12 
mm (known or presumed hypofibrinogenaemia) may trigger the administration of IMP. If 
no further relevant bleeding occurs, the surgery will proceed to completion. 
If the bleeding remained unchanged and an ongoing relevant blood loss will be confirmed 
or the hemostatic control is not considered sufficient and requires further intervention or 
a new major blood loss occurred in the course of the surgery, subjects can be treated 
with repeated IMP administration according to their randomized treatment group. If further 
IMP treatment is not advisable a transfusion protocol according to local standards 
(standard of care) should be followed (at the discretion of the surgeon and 
anesthesiologist). 
At the end of the surgery, all swabs, surgical cloths and compresses will be removed from 
the surgical field, wrung out (blood will be collected in the suction container) until almost 
dry and weighed (weight will be recorded). The end of surgery is defined as time of last 
suture. 
The fluid volume collected in the blood suction container will be measured and recorded, 
the proportion of blood, and irrigation solution will be calculated and also recorded. 
 
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Standardized Transfusion Algorithm 
Tranexamic Acid (TXA) can be administered prophylactically in all subjects according to 
local standards, e.g. TXA 1.5 g at the start of surgery as a single IV infusion, followed by 
a further dose of 1 g TXA 4 hours after first dose, if required (in case the surgery is still 
ongoing). 
Repeated IMP Administration 
According to the study design and the described treatment algorithm BT524 or 
cryoprecipitate will be administered pre-emptively as the primary hemostatic therapy if 
clinical judgement approximately 60 minutes after the start of cytoreductive PMP surgery 
predicts a clinically relevant bleeding of > 2 L intra-operatively, requiring hemostatic 
treatment during surgery.  
Repeated intra-operative administration of IMP is possible depending on the subjects’ 
clinical condition and their individual FIBTEM A10 results (Figure 3). 
If bleeding continued after completion of IMP administration, and further IMP treatment 
is not advisable a transfusion protocol according to local standards (standard of 
care) should be followed. 
 
Figure 3: Repeated IMP Administration 
 
 
The decision to transfuse allogeneic blood products in the intra-operative period depends 
on the concentration of hemoglobin, the amount and speed of the blood loss and the 
clinical condition of the subject at the discretion of the surgeon and/or the 
anaesthesiologist.  
The allogeneic blood components that can be used are RBCs, platelet concentrates, 
cryoprecipitate and FFP. 
Furthermore, plasma-derived drugs (e.g. albumin) can be used according to local 
standards. The total volume (number of units and volume per unit) of all blood 
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components (e.g. RBCs, platelets, cryoprecipitate, FFP) or plasma derivatives (such as 
albumin and coagulation factors) given intra-operatively will be recorded. 
4 STUDY POPULATION 
 Study Population, Diagnosis and Number of Subject 
A total of at least 200 adult subjects (≥ 18 years) of both gender undergoing elective 
spinal (not applicable for subjects in the UK) or abdominal surgery with expected major 
blood loss are planned to be treated within this study. Eligibility is defined by the inclusion 
and exclusion criteria as described below. 
In the UK the type of surgery is restricted by the eligibility criteria to cytoreductive 
surgery for PMP with an expected major blood loss. 
Pseudomyxoma peritonei (PMP) is a rare clinically entity that usually results from a 
perforated primary appendiceal tumor. The sequence of events culminating in PMP is 
thought to involve growth of an appendiceal adenoma with distension of the appendix by 
mucus and mucinous tumor cells. The appendix eventually ruptures and mucinous 
deposits develop throughout the abdomen. The established intervention for PMP is 
cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (Sugarbaker 
procedure) (Mohamed and Moran, 2011). Clinically relevant bleeding and acquired 
fibrinogen deficiency are common complications of this surgery. Patients undergoing the 
PMP surgery may develop a coagulopathy, predominantly characterised by reduced 
levels of fibrinogen, resulting in reduced whole blood clot firmness (Sargant et al., 2016). 
4.1.1 Gender Distribution 
There are no gender-based enrolment restrictions applicable for the study i.e., male and 
female subjects are intended to be included. 
Since men and women undergoing elective surgery might suffer from acquired 
hypofibrinogenaemia, subjects of both genders should be included into the study. 
Equitable inclusion of both genders in research is important to ensure that both receive 
a proportionate share of benefits of research and that neither bears a disproportionate 
burden. 
Women of childbearing potential are allowed to participate when using reliable/ effective 
contraceptive method(s) during the study and at least one month after the last 
administration of study drug (see section 9.3.8.1). However, pregnant women are to be 
excluded (see general exclusion criterion 1). 
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 Inclusion Criteria 
Only subjects meeting all of the following inclusion criteria will be considered for study 
inclusion: 
Inclusion Criteria 
Rationale 
Screening Intra-
operatively  
1. Written informed consent obtained from subjects indicating 
that they understand the purpose of and procedures 
required for the study and are willing to participate in it 
Ethical 
aspects 
X 
 
2. Subjects scheduled for elective cyto-reductive PMP 
surgery with expected major blood loss 
Disease 
requirement 
X 
 
3. Male or female, aged ≥ 18 
Study 
population 
requirement 
X 
 
4. No increased bleeding risk as assessed by standard 
coagulation tests and medical history * 
Pre-treatment 
requirement 
X 
 
5. Intra-operative trigger for treatment: ** 
Intra-operative prediction of clinically relevant bleeding of 
> 2 L, requiring hemostatic treatment during surgery 
Pre-treatment 
requirement 
 
X 
* Inclusion criterion no. 4 aims to ensure that only subjects without hereditary bleeding disorders are to 
be included in this study. 
Subjects with continuous ‘aspirin intake’, subjects under Direct Oral Anti-Coagulants (DOACs), or with 
a hepatic disease are at higher bleeding risk. Nevertheless, these subjects can be included at the 
discretion of the investigator. 
** Approximately 60 minutes after the start of cytoreductive PMP surgery. 
 
 Exclusion Criteria 
Subjects having any of the following criteria, either at screening and/or at baseline will 
not be included in the study: 
Exclusion Criteria 
Rationale 
Screening 
Baseline 
(prior start of 
surgery) 
1. Pregnancy or unreliable contraceptive measures 
or breast feeding (women only) 
Lack of suitability due to 
not yet established 
safety in a clinical study 
X 
 
2. Hypersensitivity to proteins of human origin or 
known hypersensitivity reactions to components 
of the IMP 
Lack of suitability for 
study due to safety 
reasons 
X 
 
3. Participation in another clinical study within 30 
days before entering the study or during the 
study and/or previous participation in this study * 
Lack of suitability for 
study 
X 
 
4. Treatment with any fibrinogen concentrate 
and/or fibrinogen-containing product within 30 
days prior to infusion of IMP 
Lack of suitability for 
study 
X 
 
5. Employee or direct relative of an employee of 
the CRO, the study site, or Biotest 
Ethical aspects 
X 
 
6. Inability or lacking motivation to participate in the 
study 
Subject compliance 
X 
 
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Exclusion Criteria 
Rationale 
Screening 
Baseline 
(prior start of 
surgery) 
7. Medical condition, laboratory finding (e.g. 
clinically relevant biochemical or hematological 
findings outside the normal range), or physical 
exam finding that in the opinion of the 
investigator precludes participation 
Lack of suitability for 
study due to safety 
reasons 
X 
 
8. Presence or history of venous/arterial 
thrombosis or TEE in the preceding 6 months 
Lack of suitability for 
study due to safety 
reasons 
X 
 
* Exclusion criterion no. 3 aims to ensure that only subjects without participation in another interventional 
clinical study are to be included in this study. 
 
 Subjects Withdrawal Criteria and Replacements 
The participation of an individual subject may be terminated prematurely for reasons 
such as: 
a. Withdrawal of written informed consent 
b. Study discontinuation due to subject's own request (e.g. personal reasons) 
c. Required treatment with any medication known or suspected to interfere with the 
IMP 
d. Life threatening thrombosis or TEE or life threatening hypersensitivity or any AE, 
laboratory abnormality, or other medical condition or situation occurs suggesting 
that continued participation in the study would not be in the best interest of the 
subject. 
e. Protocol deviation requiring discontinuation of study treatment 
f.  Evidence of exclusion criteria or inclusion criteria not met 
g.  Lack of study compliance 
h. Recommendation of the Data Safety Monitoring Board (DSMB) 
A subject is entitled to discontinue participation in the clinical study at their own request 
at any time without stating a reason.  
The investigator can terminate a subject's participation in the study at any time if 
continuation could lead to disadvantages for the subject which cannot be justified by the 
investigator. 
The reason for withdrawal of the subject must be documented by the investigator together 
with all data collected until the day of premature study termination including laboratory 
results and assessment of AE. All examinations foreseen for the subject's last study visit 
(closing visit) should be performed. Afterwards, the subject will be treated according to 
local standards at the discretion of the investigator.  
In case a subject withdraws due to an AE or SAE please follow the instructions given in 
section 15 Appendix 2: Reporting Procedures of this protocol.  
Withdrawn subjects will not be replaced. 
 
For screening failures occurring during the screening period the following data need to 
be documented in eCRF only: 
• Informed consent 
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• Demographic data 
• In-/Exclusion criteria 
• End of Study (day and reason) 
• AE information 
For intra-operative screening failures (not randomized subjects) the following data need 
to be documented in eCRF only: 
• Informed consent 
• Demographic data 
• In-/Exclusion criteria 
• Classification of type of planned PMP surgery (due to underlying cause of the 
condition, that is the location and extent of the original tumor, including the inability 
to achieve complete cytoreduction) 
• Estimated blood loss 
• FIBTEM A10 at Baseline 
• Duration of surgery 
• End of Study (day and reason) 
• AE information 
 Subjects Information 
The subject will be informed about the clinical study according to the requirements of 
GCP and the legal requirements of the country in which the subject is recruited. 
The clinical study, its objectives, possible benefits and risks, and its consequences will 
be verbally explained to the subject. Moreover, the subject is provided with written 
information about the clinical study. Sufficient time will be allowed for the information to 
be read and for questions to be asked. Attention should be paid to signs of undue distress 
in subjects who are unable to clearly articulate their distress. The subject must be told 
that refusal to participate in the clinical study does not cause any disadvantages to their 
treatment; similarly, withdrawal of written informed consent is possible at any time, 
without stating a reason and without prejudice to further medical management. 
Subjects should be informed and should agree that medical data may be reviewed by 
authorized persons during monitoring and during an audit or an inspection by the 
appointed regulatory authority or ethics committee, but that personal data will be treated 
with absolute confidentiality. 
Upon request, the subject must be granted access to the insurance terms and conditions.  
Any new and relevant information that evolves during the course of the clinical study 
concerning the IMP, alternative treatments, or the benefit/risk ratio will be communicated 
to the subject. 
 Declaration of Informed Consent 
The subject must have given written consent to participate in the clinical study by signing 
and personally dating the Informed Consent Form (ICF). Informed consent to the 
proposed data handling and to data inspection must also be documented in written form. 
Written informed consent must be obtained from each subject before any study-related 
procedures are performed. The subject’s written informed consent will be filed at the 
investigator’s site. 
A duplicate of the signed and dated written ICF must be handed over to the subject. 
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5 INVESTIGATIONAL MEDICINAL PRODUCTS 
 Investigational Medicinal Product BT524 
BT524 is a lyophilized, heat-treated, virus and prion safe human fibrinogen concentrate 
manufactured from human plasma. Fibrinogen conversion to fibrin strands during blood 
clot formation is one of the major steps in the coagulation cascade to stop bleeding. In 
subjects with fibrinogen deficiencies, therapeutic substitution with human fibrinogen 
concentrate will help correct the hemostatic defect and arrest or prevent bleeding. 
The manufacturing process of BT524 contains 
steps that were shown to be effective 
for removal/inactivation of enveloped viruses such as HIV, HBV and HCV, and for the 
non-enveloped viruses such as Reo, HAV and parvovirus B19. Moreover, 
 
 
 
 are effectively removed during the production process.  
Thus, BT524 is a virus and prion safe plasma-derived product fulfilling the requirements 
of the national German and European (CHMP) guidelines on a virus and prion safe 
pharmaceutical product. 
BT524 is presented as a single-use vial with a nominal content of 1 g fibrinogen 
(lyophilized powder for solution for injection/infusion) to be reconstituted under aseptic 
conditions with 50 mL of water for injections, resulting in a final concentration of 20 mg/mL 
for infusion. 
5.1.1 Description of Investigational Medicinal Product BT524 
Substance code: 
BT524 
Active ingredients: 
Fibrinogen concentrate from human plasma 
Composition: 
Lyophilized powder for solution for injection/infusion 
Dosage form: 
1 g 
Concentration: 
20 mg/mL after reconstitution with 50 mL water for injections 
Container: 
100 mL glass vial with rubber stopper 
Manufacturer: 
Biotest AG, D-63303 Dreieich, Germany 
 
Batch number and expiry date are given in the applicable certificates of analysis. 
5.1.2 Formulation, Packaging and Labelling 
BT524 is a lyophilized, heat-treated fibrinogen concentrate manufactured from human 
plasma according to the description of Ph. Eur. monograph 0024 on Human Fibrinogen. 
BT524 drug product is presented as a single-use 100 mL Type I glass vial with a nominal 
content of 1 g fibrinogen (lyophilized powder for solution for injection/infusion). 
The labelling of BT524 will be performed according to local requirements. A sample label 
will be filed in the Trial Master File (TMF). 
Batch number and vial number must be documented in the eCRF and the drug 
accountability log. 
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5.1.3 Storage Conditions and Stability 
BT524 is to be stored in a cabinet or other enclosure which is security locked. Generally 
access should be restricted to the investigator and authorized personnel.  
BT524 is to be stored at a temperature 
. Continuous 
temperature recording should be documented on a temperature log. 
5.1.4 Preparation for Use  
BT524 is presented as a single-use glass vial of 100 mL with a nominal content of 1 g of 
lyophilisate (powder for solution for injection/ infusion). The lyophilisate is to be 
reconstituted under aseptic conditions with 50 mL of water for injections using an 
appropriate transfer device or syringe.  
The vial is to be swirled gently until the product is fully dissolved. After reconstitution, the 
solution should be almost colorless and clear to slightly opalescent. Reconstituted 
products should be inspected visually for particulates and discoloration prior to 
administration. Do not use solutions that are cloudy or contain deposits.  
BT524 will be delivered to the operating room by the pharmacy according to local practice 
and immediately after reconstitution administered by the unblinded anaesthesiologist. 
 Investigational Medicinal Product Cryoprecipitate 
Cryoprecipitate will be used as active comparator to BT524 in subjects undergoing 
cytoreductive PMP surgery at one site in the UK. 
Cryoprecipitate is produced in the UK, USA, Canada, Australia, and New Zealand, where 
it is mainly used as a concentrated source of fibrinogen for treatment of acquired 
hypofibrinogenaemia. 
Cryoprecipitate consists of the cryoglobulin fraction of plasma containing the major 
portion of Factor VIII and fibrinogen. It is obtained by thawing a single donation of FFP at 
4°C ± 2°C resulting in the formation of the cryoprecipitate. Following centrifugation, the 
supernatant plasma is removed. The cryoprecipitate is then rapidly frozen to ≤ -25°C. It 
is available as single units or as pools of five. A single unit contains a mean of 
approximately 400 to 460 mg fibrinogen. The adult therapeutic dose is two pools of five 
units (NHS Blood and Transplant, May 2018. Access Date: 05-Feb-2020.; NHSBT, 2016; 
Walters, 2016). 
5.2.1 Description of Investigational Medicinal Product Cryoprecipitate 
Substance code: 
Cryoprecipitate 
Active ingredients: 
Human plasma proteins (fibrinogen, vWF, factor VIII, 
factor XIII, fibronectin and platelet microparticles 
Dosage form: 
AB0-blood group specific solution for infusion, which 
appears (slightly) yellow 
Concentration: 
400-460 mg (per unit) 
Container 
Bags with pooled cryoprecipitate containing 
approximately 100 - 300 mL frozen solution (mean 
236 mL) 
5.2.2 Formulation, Packaging and Labelling 
The labelling of cryoprecipitate will be performed according to local requirements.  
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Bag number must be documented in the eCRF and the drug accountability log. 
5.2.3 Storage Conditions and Stability 
In general, cryoprecipitate will be stored protected from light, at a temperature at ≤ -25°C. 
Continuous temperature recording should be documented on a temperature log. 
5.2.4 Preparation for Use  
Cryoprecipitate is to be thawed and prepared for administration by the blood bank 
according to local standards, delivered to the operating room, and administered upon 
arrival.  
Cryoprecipitate should be inspected visually for particulate matter and discoloration prior 
to administration, whenever solution and container permit. Do not use if turbid. Avoid 
shaking. 
Once thawed, cryoprecipitate should be used immediately. If delay is unavoidable, 
cryoprecipitate should be stored at ambient temperature and used within four hours. 
Thawed plasma components must not be re-frozen. The infusion must be completed as 
soon as possible and within 4 hours of thawing (Walters, 2016). ABO group identical 
cryoprecipitate should be given whenever possible; if not possible cryoprecipitate of a 
different ABO group may be acceptable according to local transfusion standards. 
6 STUDY TREATMENT 
 Dosage Regimen 
After a bleeding risk assessment, which takes place approximately 60 minutes after the 
start of cytoreductive PMP surgery, only subjects with the prediction of an intra-operative 
clinically relevant bleeding of more than 2 L, requiring hemostatic treatment (high risk for 
the need of fibrinogen supplementation with BT524 or cryoprecipitate) during surgery, will 
be treated with BT524 or cryoprecipitate according to the predefined treatment algorithm. 
 Dosage and Administration 
The first IMP (BT524 or cryoprecipitate) dose will be administered pre-emptively, based 
on clinical judgement (prediction of clinically relevant bleeding of more than 2 L, requiring 
hemostatic treatment during surgery).  
Further IMP administration depends on the extent of bleeding and the subject's clinical 
condition, and will be guided by FIBTEM A10 results. Therefore, the functional fibrinogen 
level should be determined intra-operatively on an individual subject basis by FIBTEM 
thromboelastometry prior to IMP administration.  
A FIBTEM A10 < 12 mm may trigger the administration of IMP in case a further clinically 
relevant bleeding occurs. Nevertheless, IMP may be administered prior to the 
determination of FIBTEM A10 in a subject who is bleeding if deemed appropriate as per 
current clinical standards (that is suspected acquired hypofibrinogenaemia with rapid 
bleeding precluding waiting for laboratory results). 
 
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Blinding  
Study 995 will be partially blinded; surgeon, surgical staff and subjects will be blinded to 
treatment allocation throughout the entire surgery. The anaesthesiologist who will 
administer the IMP could not be blinded to treatment allocation because of the inherent 
characteristics of the IMPs BT524 and cryoprecipitate. Whereas BT524 is administered 
by syringe with a small volume and fast infusion to rapidly supplement missing fibrinogen 
to restore hemostasis, cryoprecipitate is administered as infusion bag with larger volume 
and longer infusion time. Due to the different methods of application, the different volume, 
resulting in different infusion times of the two IMPs a blinding technique at the level of the 
anaesthesiologist is considered not feasible (either impossible or heavily impractical) to 
allow the study to be conducted successfully. 
The basis for the partial blinding in the operating room is the spatial separation between 
the anaesthetic field and the surgical, sterile field (operating field). As a basic principle, 
the anaesthesiologist remains outside of the operating field. By using a sterile drape with 
non-transparent material between these two fields, the surgeon will not be able to see 
which IMP is being administered by the anaesthesiologist. The sterile drape will 
especially cover up the infusion stands and therefore the administration of 
cryoprecipitate. The anaesthesiologist has a professional and organizational 
responsibility regarding the maintenance of blinding of the surgeon and the surgical staff 
during the entire surgery. In general, the anaesthesiologist is responsible for 
administering all medications including IMP, and for monitoring and maintenance of vital 
functions (including e.g. heart rate, oxygen saturation) and laboratory values of the 
subject. 
 
BT524 
The dose of BT524 to be infused will be a fixed dose of 4 g with the aim of restoring the 
fibrinogen plasma levels according to guidelines. The first BT524 dose will be 
administered pre-emptively. In case of repeated dosing, regular monitoring of the plasma 
level of fibrinogen (FIBTEM A10) during therapy is indicated. Subjects randomized to the 
BT524 group will receive 4 g BT524 each time fibrinogen supplementation is ordered. 
BT524 will be administered as IV infusion with a maximum infusion rate of 
/min 
(1 g fibrinogen concentrate 
). BT524 is to be administered preferably in the 
forearm vein. Alternatively, BT524 can be administered through a central venous line or 
a peripherally inserted central catheter (PICC). Other administration routes are only 
allowed after approval from the sponsor. 
 
Cryoprecipitate 
Cryoprecipitate will be administered by IV infusion following hospital transfusion policies 
at the participating study site. A single unit of cryoprecipitate contains approximately 400 
to 460 mg fibrinogen. The adult therapeutic cryoprecipitate dose is 2 pools, each pool 
consisting of 5 units/donations (10 units, dose-equivalent to 4 g fibrinogen concentrate), 
which should increase plasma fibrinogen levels by 1 g/L depending on the clinical setting.  
The first cryoprecipitate dose will be given pre-emptively. Further cryoprecipitate 
administration intra-operatively will be guided by the FIBTEM A10 test. Subjects 
randomized to the cryoprecipitate group will receive 2 pools of cryoprecipitate each time 
IMP (fibrinogen supplementation) is ordered. If cryoprecipitate will be administered with 
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a common infusion rate of 10 - 20 mL/kg/hr, 2 pools can be infused in approximately 30 
minutes. 
 Compliance with Dosage Regimens 
As the IMP (BT524 or cryoprecipitate) will be administered IV to each subject under the 
supervision of the unblinded anaesthesiologist, the compliance is expected to be 100%. 
In addition, the assessment of plasma fibrinogen concentrations may also serve as an 
adherence measure. 
If a subject’s treatment deviates from the dosage regimen (e.g., a dosing interruption 
occurs due to the occurrence of an AE), this will be recorded in the eCRF. 
 Dose Justification 
In general, the dosage of IMP (BT524 or cryoprecipitate) depends on the clinical situation 
and the extent of bleeding during surgery. 
Subjects undergoing cytoreductive surgery for PMP will be randomized to one of the two 
treatment arms, when clinical judgement approximately 60 minutes after the start of 
cytoreductive PMP surgery predicts an intra-operative bleeding of > 2 L (without targeted 
fibrinogen replacement), requiring hemostatic treatment during surgery. Subjects will be 
treated pre-emptively with BT524 or cryoprecipitate as the primary hemostatic therapy. 
Cryoprecipitate is available as a single unit, or as a pooled product made up of five single 
units. A commonly used adult dose is 2 pools, each pool consisting of 5 units/donations 
(10 single units), and containing approximately 4 g fibrinogen. Therefore, the 
corresponding BT524 dose is 4 g. The repeated further IMP administration (4 g BT524 
or 2 pools cryoprecipitate) will be dependent on the clinical condition (i.e. clinically 
relevant bleeding) and may be triggered by FIBTEM A10 results of <12 mm. 
Fibrinogen is the first coagulation factor to become critically reduced during major surgical 
blood loss and the observation that patients with higher fibrinogen levels experience 
fewer bleeding complications than those with low levels highlights the importance of 
fibrinogen in the maintenance of hemostasis (Charbit et al., 2007; Ucar et al., 2007). 
Consequently, fibrinogen replacement therapy targeting a high-normal level of plasma 
fibrinogen and fibrin-based clot formation may be an important first step in restoring 
hemostasis during major bleeding (Rahe-Meyer et al., 2013a).  
The normal blood fibrinogen concentration is between 2.0 and 4.5 g/L although this range 
can vary (Levy and Goodnough, 2015). Restoring the individual physiological fibrinogen 
level seems reasonable to ensure sufficient fibrinogen supplementation without risk of 
overdosing.  
Therefore, the repeated IMP dosing in this study will be guided by determination of the 
functional fibrinogen level via ROTEM/FIBTEM thromboelastometry intra-operatively with 
the aim to restore patient’s fibrinogen level. A FIBTEM A10 < 12 mm and evidence of 
clinically relevant bleeding may trigger the administration of IMP (4 g BT524 or 2 pools 
cryoprecipitate). In line with current clinical standards, subjects with relevant bleeding 
may also be treated if acquired hypofibrinogenaemia is suspected but plasma FIBTEM 
A10 results are still pending at the time of required treatment. 
Rotational thromboelastometry (ROTEM) is an established viscoelastic method for 
hemostasis testing in whole blood, and ROTEM/FIBTEM that measures the fibrin or 
fibrinogen contribution to clot strength can be used to determine the most appropriate 
therapeutic dose of fibrinogen concentrate (Levy et al., 2014).  
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The ROTEM/FIBTEM test will be used in the intra-operative setting to quickly identify 
deficits in fibrin quality, and to guide hemostatic therapy. In contrast to conventional 
laboratory tests (measurement of fibrinogen concentration via Clauss assay), 
ROTEM/FIBTEM can measure early variables describing the clot firmness, such as clot 
amplitude obtained after 10 minutes (A10), and provide a forecast on the expected 
Maximum Clot Firmness (MCF) value at an earlier stage already. This early variable 
allows for a more rapid decision about therapeutic interventions. Owing to its rapid 
assessment of fibrinogen, ROTEM is frequently used to guide transfusion therapy 
(Schochl et al., 2011), and the data from Schochl and colleagues revealed the effective 
use of ROTEM-guided coagulation management in trauma patients by reducing the 
amount of allogeneic blood product transfusion (Schochl et al., 2010).  
Accordingly, the IMP treatment in this clinical study will be guided by ROTEM/FIBTEM to 
obtain results more quickly and to initiate repeated dosing if FIBTEM A10 is less than 12 
mm in case a clinically relevant bleeding occurs.. 
 Treatment of Overdose 
In order to avoid overdosage in subjects with acquired hypofibrinogenaemia undergoing 
major surgery, point-of-care FIBTEM guided dosing according to fibrinogen plasma levels 
will be used. Monitoring of the plasma level of fibrinogen intra-operatively will be 
performed as defined in section III. 
In case of overdosage, the risk of development of thromboembolic complications is 
enhanced (EMA (Committee for Medicinal Products for Human Use), 2015). 
 Randomization Code  
There will be a stratified randomization per surgery type. Subjects undergoing 
cytoreductive PMP surgery are to be randomized on a 1:1 basis to receive either BT524 
or cryoprecipitate. 
Randomization of PMP subjects to treatment will occur intra-operatively (pre-dose) when 
eligibility for the clinical study has been confirmed. Immediately after the prediction of 
clinically relevant bleeding > 2 L, requiring hemostatic treatment (high risk for the need of 
fibrinogen supplementation with BT524 or cryoprecipitate) during surgery, the person 
responsible for randomization will be informed and the randomization request will be sent. 
The person responsible for randomization retrieves the randomization code via 
Interactive Web Response System (IWRS) and informs the blood bank/pharmacy.  
BT524 will be delivered to the operating room by the pharmacy. After randomization 
BT524 will be prepared in the operating room in accordance with the manufacturer’s 
instructions and administered immediately after reconstitution by the unblinded 
anaesthesiologist. 
After randomization, cryoprecipitate will be thawed and prepared for administration by the 
local blood bank, delivered to the operating room, and administered upon arrival. 
In case the anaesthesiologist retrieves the randomization code via IWRS, the blood bank/ 
pharmacy will be informed accordingly and can provide the IMP. 
Subject Identification 
For the coherent assignment of the study documents all subjects having signed the 
informed consent and having entered the screening period will receive a subject number. 
The subject number comprises a five digit number of which the first two digits define the 
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investigational site and the last three digits the subject enrolled at the corresponding site. 
Subject numbers are assigned consecutively per site. Subject numbers are assigned 
unique and will not be replaced i.e., in case of a screening failure. 
An interactive web/voice response system (IWRS/IVRS) will be implemented and used 
for randomization and re-supply. Detailed instructions for the use of IWRS systems are 
provided in a separate document that will be filed in the Investigator Site File. 
The random allocation of treatments to subjects will be done using a computerized 
randomization program. Subjects will receive a randomization number, which will be 
recorded along with the date of randomization in the eCRF. 
 Procedures for Emergency Unblinding 
In the event of an emergency, each study site will be able to unblind subject treatment 
allocation via IWRS (either the principal investigator or a designated medic sub-
investigator at the study site) without undue delay. 
However, unblinding shall only be carried out if a medical emergency requires the 
identification of the IMP for that particular participant. If the code is broken for a subject 
(via the IWRS), Biotest must be informed immediately. The reason for opening the code 
break must be documented on the appropriate eCRF page along with the date and the 
initials of the person who broke the code. 
Any subject for whom the blind is broken will be discontinued from the clinical study, 
however will be followed-up. 
 Drug Accountability 
The IMP BT524 will be supplied to the investigator at the time of site initiation under the 
assumption that all required regulatory documents are in place. The investigator or 
his/her designee should maintain records that document adequately that the subjects 
were provided the doses specified in the protocol and reconcile all IMPs received for the 
clinical study. The investigator has to ensure that consignments of IMP are received 
correctly by a dedicated person (e.g. blood bank, pharmacy) and that the IMP is safely 
and appropriately handled and stored. 
The investigator or designee is obliged to keep sufficient documentation of the delivery, 
use, and destruction or return of unused, used or partially used packages of IMP. The 
investigator must allow the monitor to perform drug reconciliation before any IMP is 
returned or destroyed. The documentation must include dates, quantities, subject 
numbers, batch numbers (if applicable), bag numbers (if applicable) and expiry dates. 
The entries in the eCRF as well as the documentation kept in the Investigator Site File 
will be compared with the returned and residual IMPs, with clarification of any 
discrepancies or inconsistencies. 
 Previous and Concomitant Medication or Treatment 
All previous medication and treatment in the previous 4 weeks prior to the elective surgery 
and the administration of IMP are to be recorded in the eCRF. 
Concomitant medication therapeutically required is allowed during the study. If a change 
in concomitant medication is necessary during the study, it is the responsibility of the 
investigator to ensure that details regarding the medication are recorded in full in the 
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eCRF (i.e. identity of all medications, dosage and route of administration, frequency, 
duration of administration, and indication for use at each visit). 
 Prohibited Medication or Treatment 
The administration of allogeneic or autologous blood products interacting relevantly with 
the coagulation system (e.g. platelet concentrates, cryoprecipitate, FFP) and of 
hemostatic agents (including coagulation factor concentrates) is not allowed prior to start 
of or during the first IMP administration within this study. In such instances, the subject 
can not be randomized or will be withdrawn from the study. 
RBCs can be infused according to institutional practice. 
 Warnings and Precautions 
Brief Summary 
A Guideline for Core SmPC for Human Fibrinogen Products (EU Core SmPC) is in place 
which also describes the well established benefit-risk profile of the authorized fibrinogen 
concentrates [Guideline on Core SmPC for Human Fibrinogen Products (EMA 
(Committee for Medicinal Products for Human Use), 2015)]. 
It provides the following AEs as undesirable effects considered established for all 
authorized and marketed human fibrinogen concentrate formulations:  
In the MedDRA System Organ Class (SOC) "Immune system disorders": Allergic or 
anaphylactic-type reactions; in the MedDRA SOC "Vascular disorders": Thromboembolic 
episodes (including myocardial infarction and pulmonary embolism), and in the MedDRA 
SOC "General disorders and administration site conditions": Increase in body 
temperature. 
Description of Potential Risks  
There is a risk of thrombosis when subjects, with either congenital or acquired deficiency, 
are treated with human fibrinogen particularly with high dose or repeated dosing. Subjects 
given human fibrinogen should be observed closely for signs or symptoms of thrombosis. 
In subjects with a history of coronary heart disease or myocardial infarction, in subjects 
with liver disease, in peri- or post-operative subjects, in neonates, or in subjects at risk of 
TEEs or DIC, the potential benefit of treatment with human plasma fibrinogen should be 
weighed against the risk of thromboembolic complications. Caution and close monitoring 
should also be performed. 
Acquired hypofibrinogenaemia is associated with low plasma concentrations of all 
coagulation factors (not only fibrinogen) and inhibitors and so treatment with blood 
products containing coagulation factors should be considered. Careful monitoring of the 
coagulation system is necessary. 
If allergic or anaphylactic-type reactions occur, the injection/infusion should be stopped 
immediately. In case of anaphylactic shock, standard medical treatment for shock should 
be implemented.  
There is currently no data on fibrinogen inhibitors available with human fibrinogen.  
Standard measures to prevent infections resulting from the use of medicinal products 
prepared from human blood or plasma include selection of donors, screening of individual 
donations and plasma pools for specific markers of infection and the inclusion of effective 
manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal 
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products prepared from human blood or plasma are administered, the possibility of 
transmitting infective agents cannot be totally excluded. This also applies to unknown or 
emerging viruses and other pathogens. 
The measures taken are considered effective for enveloped viruses such as human 
immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) and 
for the non-enveloped hepatitis A and parvovirus B19 viruses. Every time that fibrinogen 
is administered to a patient, the name and batch number of the product are to be recorded 
in order to maintain a link between the patient and the batch of the product. 
Special precautions for BT524 administration 
All plasma-derived human products may lead to allergic or anaphylactic reactions. Thus, 
the administration of BT524 will be performed under medical supervision where proper 
medical care for allergic or anaphylactic reactions can be provided. If allergic or 
anaphylactic-type reactions occur, the infusion must be stopped immediately. In case of 
anaphylactic shock, standard medical treatment for shock must be applied. 
Prothrombin time PT(INR), activated partial thromboplastin time (aPTT), prothrombin 
fragments F1+2, thrombin-antithrombin III complex (TAT), D-dimer, PS, PC, antithrombin 
III (AT III) activity, thrombin time (TT), thrombin generation test (TGT)2 and further 
coagulation parameters are monitored regularly to detect a hypercoagulable state.  
Changes in vital signs (including pulse [heart rate], blood pressure, respiratory rate, body 
temperature) are monitored during the surgery and according to the flow chart (see 
section III). 
Incompatibilities 
Fibrinogen must not be mixed with other medicinal products and should be administered 
by a separate injection/infusion line. 
 
 
 
                                            
2 Only applicable for subjects undergoing cytoreductive surgery for PMP 
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7 COURSE OF THE CLINICAL STUDY  
 Visit Schedule for PMP subjects 
 
Screening Visit Day -42 through Day -1: 
All subjects will attend a screening visit (if required more than one visit) between  
Day -42 and Day -1 prior to elective major cytoreductive PMP surgery, where the 
following procedures will be performed:  
• Written informed consent will be obtained. 
• In general, eligibility to take part in the study will be assessed against the 
inclusion and exclusion criteria. 
• Demographic data (including sex, year of birth, race) will be recorded. 
• Classification of type of the planned PMP surgery will be recorded. 
• Physical examination (including body weight and body height) will be 
performed. 
• Body weight will be recorded. 
• A serum pregnancy test (human chorionic gonadotropin) will be performed for 
all females of child-bearing potential (a woman of child bearing potential is one 
that has NOT had a hysterectomy and/or a bilateral oophorectomy, or has NOT 
been naturally postmenopausal for at least 24 consecutive months). 
• Medical and surgical history with regard to the subjects’ drug history, 
previous medication and treatment, disease history, and other medical and 
surgical history will be recorded. Previous medication taken up to 4 weeks 
before enrollment will be recorded. The type of previous medication, dose 
schedule, duration, and the indication the previous medication was given for 
will be documented. 
• Vital signs (including pulse [heart rate], blood pressure, respiratory rate, body 
temperature) will be recorded. 
• Samples for clinical laboratory parameters (hematology, clinical chemistry, 
urinalysis) will be taken: 
o Hematology (RBC, WBC, platelet count, hemoglobin, hematocrit) 
o Clinical chemistry (ALAT, ASAT, γ-GT, AP, total bilirubin, creatinine, 
creatinine clearance, BUN/Urea, potassium, sodium, calcium, chloride) 
o Urinalysis (pH, blood, WBC, protein, glucose, ketone bodies, nitrite, 
bilirubin, urobilinogen) 
Some of these tests for clinical laboratory parameters may have been 
performed by the investigator as standard of care prior to the subject signing 
the ICF. If test(s) were done within 42 days before the first scheduled treatment 
with IMP (BT524 or cryoprecipitate), the investigator may use the results 
obtained from standard of care for the purpose of this study. 
• Sample for coagulation activation tests (PT(INR), aPTT, TAT, F1+2, D-dimer, 
PS, PC, AT III, TT, TGT) will be taken. 
• Sample for plasma activity of fibrinogen (Clauss assay) will be taken.  
• FIBTEM A10 and Maximum clot firmness (MCF) (ROTEM) will be performed. 
• Retention samples for viral safety laboratory parameters will be taken. 
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• Samples for virus serology laboratory parameters (hepatitis B, hepatitis C, 
HIV) will be taken. 
• AEs will be documented. 
 
If a subject does not fulfill the eligibility criteria, re-assessment is allowed within the 42 
days screening period. 
 
Baseline Visit Day 1 (or Day -2 or Day -1, prior to surgery): 
All subjects will attend a baseline visit on Day 1, the day of PMP surgery. The baseline 
visit can be scheduled one or two days prior to surgery (Day -2 or Day -1) if required due 
to local hospital procedures. 
The following assessments will be performed prior to start of surgery, before the 
potential IMP administration (BT524 or cryoprecipitate): 
• Re-check of inclusion and exclusion criteria: Eligibility to take part in the 
study will be confirmed against the inclusion and exclusion criteria, as 
appropriate (i.e., diagnostic tests will be repeated at the investigator’s 
discretion). 
• Any changes in medical and surgical history since the screening visit will 
be recorded. The type of previous medication, dose schedule, duration, and 
the indication the previous medication was given for, will be documented. 
• Expected blood loss will be recorded. 
• Physical examination will be performed.  
• Pregnancy test (urine or serum) will be performed for all females of child-
bearing potential (a woman of child bearing potential is one that has NOT had 
a hysterectomy and/or a bilateral oophorectomy, or has NOT been naturally 
postmenopausal for at least 24 consecutive months). 
• Body weight will be recorded to calculate subject dose. 
• Vital signs (including pulse [heart rate], blood pressure, respiratory rate, body 
temperature) will be recorded. 
• Samples for clinical laboratory parameters (hematology, clinical chemistry, 
urinalysis) will be taken: 
o Hematology (RBC, WBC, platelet count, hemoglobin, hematocrit) 
o Clinical chemistry (ALAT, ASAT, γ-GT, AP, total bilirubin, creatinine, 
creatinine clearance, BUN/Urea, potassium, sodium, calcium, chloride) 
o Urinalysis (pH, blood, WBC, protein, glucose, ketone bodies, nitrite, 
bilirubin, urobilinogen) 
• Sample for coagulation activation tests (PT(INR), aPTT, TAT, F1+2, D-dimer, 
PS, PC, AT III, TT, TGT) will be taken. 
• Sample for coagulation factors (FII, FV, FVII, FVIII, FIX, FX, FXI, FXIII, and 
vWF) will be taken. 
• Sample for plasma activity of fibrinogen (Clauss assay) will be taken and 
• FIBTEM A10 and MCF (ROTEM) will be performed. 
• AEs will be documented. 
 
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Please note: The following tests and assessments have to be done prior to surgery. In 
case of a short time-period between screening and baseline (≤ 2 days) these tests have 
only to be repeated based on medical judgment of the investigator. If not repeated, 
screening results will serve as baseline. 
• Physical examination 
• Pregnancy test 
• Body weight 
• Hematology 
• Clinical chemistry 
• Urinalysis 
• Coagulation activation tests 
• Plasma activity of fibrinogen (Clauss assay) 
• FIBTEM A10 and MCF (ROTEM) 
 
Surgery Day 1 (pre-dose): 
• Time of start of surgery will be recorded. 
• Continuous collection and measurement of blood loss from start of surgery. 
• Amount of blood in blood suction unit and swabs, surgical cloths and 
compresses will be estimated. 
• Approximately 60 minutes after the start of cytoreductive PMP surgery, 
eligibility to take part in the study will be assessed against the intra-operative 
inclusion criteria: 
an intra-operative prediction of clinically relevant bleeding of > 2 L, requiring 
hemostatic treatment (high risk for the need of fibrinogen supplementation with 
BT524 or cryoprecipitate) during surgery. 
 
In subjects who do not meet the intra-operative inclusion criteria no IMP administration 
will take place and no further assessments intra-operatively will be performed. These 
subjects will be considered as screening failures and will be treated with standard of care. 
 
Only for subjects considered to be eligible for IMP administration with BT524 or 
cryoprecipitate the following assessments will be performed:  
 
• Time of decision to treat the subject with IMP will be recorded. 
• Amount of blood from blood suction unit and from swabs, surgical cloths and 
compresses after decision to treat the subject with IMP until end of surgery will 
be measured. 
• Sample for plasma activity of fibrinogen (Clauss assay) will be taken. 
• FIBTEM A10 and MCF (ROTEM) will be performed. 
• Randomization will be initiated with order of IMP. 
• Sample for coagulation activation tests (PT(INR), aPTT, TAT, F1+2, D-dimer, 
PS, PC, AT III, TT, TGT) will be taken prior start of first IMP administration. 
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• Sample for coagulation factors (FII, FV, FVII, FVIII, FIX, FX, FXI, FXIII, and 
vWF) will be taken prior start of first IMP administration. 
• Samples for clinical laboratory parameters (hematology, clinical chemistry) 
will be taken prior start of first IMP administration:  
o Hematology (RBC, WBC, platelet count, hemoglobin, hematocrit) 
o Clinical chemistry (ASAT, ALAT, creatinine, creatinine clearance, 
BUN/Urea, γ-GT, AP, total bilirubin, potassium, sodium, calcium, 
chloride) 
• Vital signs (pulse [heart rate], blood pressure, respiratory rate, body 
temperature) will be recorded prior start of IMP administration. 
• Transfusion products (allogenic blood products) given intra-operatively will 
be documented.  
• Concomitant medication or treatment will be recorded. The type of 
concomitant medication/treatment, dose/schedule, duration, and the indication 
the concomitant medication was given for will be documented. 
• AEs will be documented. 
• IMP (4 g BT524 or 2 pools cryoprecipitate) will be infused IV.  
The total volume and the total infusion time of each IMP administration 
(start and end of infusion) will be recorded. 
 
Surgery Day 1 (post-dose): 
• Continuous collection and measurement of blood loss 
• Vital signs (pulse [heart rate], blood pressure, respiratory rate, body 
temperature) will be recorded 15 minutes and 90 minutes after start of IMP 
administration.  
• Sample for coagulation activation tests (PT(INR), aPTT, TAT, F1+2, D-dimer, 
PS, PC, AT III, TT, TGT) will be taken only 15 minutes and 90 minutes after 
start of first IMP administration. 
• Sample for coagulation factors (FII, FV, FVII, FVIII, FIX, FX, FXI, FXIII, and 
vWF) will be taken only 90 minutes after start of first IMP administration. 
• Sample for plasma activity of fibrinogen (Clauss assay) will be taken only 
15 minutes and 90 minutes after start of first IMP administration. 
• FIBTEM A10 and MCF (ROTEM) will be performed only 15 minutes and 90 
minutes after start of first IMP administration. 
• Transfusion products (allogenic blood products) given intra-operatively will 
be documented.  
• Concomitant medication or treatment will be recorded. The type of 
concomitant medication/treatment, dose/schedule, duration, and the indication 
the concomitant medication/treatment was given for will be documented. 
• AEs will be documented. 
 
 
 
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Please note: The following tests have to be done 90 minutes after start of first IMP 
treatment. In case this time point is within a short timeframe (< 30 min) after the ‘end of 
surgery’, these tests have only to be repeated based on medical judgment of the 
investigator. 
• Markers of coagulation (Coagulation activation tests) 
• Plasma activity of fibrinogen (Clauss assay) 
• FIBTEM A10 and MCF (ROTEM) 
• Coagulation factors 
 
Surgery Day 1 (prior to repeated IMP administration): 
• Vital signs (pulse [heart rate], blood pressure, respiratory rate, body 
temperature) will be recorded prior start of each IMP administration. 
• FIBTEM A10 and MCF (ROTEM) will be performed. 
• IMP will be ordered: 4 g BT524 or 2 pools cryoprecipitate, according to the 
previously assigned treatment arm. 
• IMP will be administered. The total volume and the total infusion time of each 
IMP administration (start and end of infusion) will be recorded. 
• Amount of blood from blood suction unit and from swabs, surgical cloths and 
compresses will be collected and measured. 
• Transfusion products (allogenic blood products) given intra-operatively will 
be documented.  
• Concomitant medication or treatment will be recorded. 
• AEs will be documented. 
 
Surgery Day 1 (end of surgery): 
• Vital signs (including pulse [heart rate], blood pressure, respiratory rate, body 
temperature) will be recorded at the end of the surgery. 
• Samples for clinical laboratory parameters (hematology, clinical chemistry) 
will be taken at the end of the surgery:  
o Hematology (RBC, WBC, platelet count, hemoglobin, hematocrit) 
o Clinical chemistry (ASAT, ALAT, creatinine, creatinine clearance, 
BUN/Urea, γ-GT, AP, total bilirubin, potassium, sodium, calcium, 
chloride) 
• Sample for coagulation activation tests (PT(INR), aPTT, TAT, F1+2, D-dimer, 
PS, PC, AT III, TT, TGT) will be taken at the end of the surgery. 
• Sample for coagulation factors (FII, FV, FVII, FVIII, FIX, FX, FXI, FXIII, and 
vWF) will be taken at the end of the surgery. 
• Sample for plasma activity of fibrinogen (Clauss assay) will be taken at the 
end of the surgery. 
• FIBTEM A10 and MCF (ROTEM) will be performed at the end of the surgery. 
• Start continuous measurement of blood loss until 24 hours post-operative. 
• Amount of blood from blood suction unit and from swabs, surgical cloths and 
compresses will be calculated and recorded (blood loss after the decision to 
treat the subject with IMP until end of surgery). 
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• Transfusion products (allogenic blood products) given intra-operatively will 
be documented. 
• Concomitant medication or treatment will be recorded. The type of 
concomitant medication/treatment, dose/schedule, duration, and the indication 
the concomitant medication//treatment was given for will be documented. 
• AEs will be documented. 
• Time of end of surgery (time of last suture) will be recorded. 
• Rebleeding episodes will be recorded. 
 
Please note: The following tests have to be done at the ‘end of surgery’. In case the end 
of surgery is within a short timeframe (< 30 min) after the blood draw ‘90 minutes after 
start of first IMP treatment‘, these tests have only to be repeated based on medical 
judgment of the investigator. 
• Markers of coagulation (Coagulation activation tests) 
• Plasma activity of fibrinogen (Clauss assay) 
• FIBTEM A10 and MCF (ROTEM) 
• Coagulation factors 
 
Follow-up Visit Day 2: 
All subjects treated with IMP will attend the follow-up visit one day after surgery (Day 2). 
The following procedures will be performed: 
• Continuous measurement of post-operative blood loss (drainage volume) and 
recording until 24 hours after end of surgery. 
• Physical examination will be performed. 
• Vital signs (including pulse [heart rate], blood pressure, respiratory rate, body 
temperature) will be recorded. 
• Sample for coagulation activation tests (PT(INR), aPTT, TAT, F1+2, D-dimer, 
PS, PC, AT III, TT, TGT) will be taken. 
• Samples for clinical laboratory parameters (hematology, clinical chemistry, 
urinalysis) will be taken:  
o Hematology (RBC, WBC, platelet count, hemoglobin, hematocrit) 
o Clinical chemistry (ASAT, ALAT, creatinine, creatinine clearance, 
BUN/Urea, γ-GT, AP, total bilirubin, potassium, sodium, calcium, chloride) 
o Urinalysis (pH, blood, WBC, protein, glucose, ketone bodies, nitrite, 
bilirubin, urobilinogen) 
• Sample for plasma activity of fibrinogen (Clauss assay) will be taken and 
• FIBTEM A10 and MCF (ROTEM) will be performed. 
• Transfusion products (allogenic blood products) will be documented.  
• Concomitant medication or treatment will be documented. The type of 
concomitant medication/treatment, dose/schedule, duration, and the indication the 
concomitant medication/treatment was given for will be documented. 
• AEs will be documented. 
• Rebleeding episodes will be recorded. 
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Follow-up Visits Day 3, Day 5 and Day 8: 
All subjects treated with IMP will attend the follow-up visits 2, 4 and 7 days after surgery 
(Day 3, 5 and 8): 
The following procedures will be performed: 
• Physical examination will be performed. 
• Vital signs (including pulse [heart rate], blood pressure, respiratory rate, body 
temperature) will be recorded. 
• Sample for coagulation activation tests (PT(INR), aPTT, TAT, F1+2, D-dimer, 
PS, PC, AT III, TT, TGT) will be taken. 
• Samples for clinical laboratory parameters (hematology, clinical chemistry, 
urinalysis) will be taken:  
o Hematology (RBC, WBC, platelet count, hemoglobin, hematocrit) 
o Clinical chemistry (ASAT, ALAT, creatinine, creatinine clearance, 
BUN/Urea, γ-GT, AP, total bilirubin, potassium, sodium, calcium, chloride) 
o Urinalysis (pH, blood, WBC, protein, glucose, ketone bodies, nitrite, 
bilirubin, urobilinogen) 
• Transfusion products (allogenic blood products) will be documented.  
• Concomitant medication or treatment will be documented. The type of 
concomitant medication/treatment, dose/schedule, duration, and the indication the 
concomitant medication/treatment was given for will be documented. 
• AEs will be documented. 
• Rebleeding episodes will be recorded. 
 
Discharge from Hospital: 
• The day of the discharge from hospital will be recorded at the closing visit 
Day 36. 
• If the closing visit Day 36 (+35, up to Day 71 if required) is scheduled as a phone 
call, all tests and procedures requiring an in-person visit (physical examination, 
vital signs, samples for laboratory tests) must be performed on the day of hospital 
discharge: 
o Physical examination 
o Vital signs (including pulse [heart rate], blood pressure, respiratory rate, 
body temperature) 
o Sample for coagulation activation tests (PT(INR), aPTT, TAT, F1+2, D-
dimer, PS, PC, AT III, TT, TGT) 
o Samples for clinical laboratory parameters: 
 Hematology (RBC, WBC, platelet count, hemoglobin, hematocrit) 
 Clinical chemistry (ASAT, ALAT, creatinine, creatinine clearance, 
BUN/Urea, γ-GT, AP, total bilirubin, potassium, sodium, calcium, 
chloride) 
 Urinalysis (pH, blood, WBC, protein, glucose, ketone bodies, nitrite, 
bilirubin, urobilinogen) 
o Retention samples for viral safety laboratory parameters 
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o Samples for virus serology laboratory parameters (hepatitis B, 
hepatitis C, HIV) 
 
Closing Visit Day 36 (+35, up to Day 71 if required): 
All subjects treated with IMP will attend a closing visit including the final safety 
examination, and a safety follow-up at least 5 weeks after the surgery, scheduled on 
Day 36 (+35, up to Day 71 if required). 
Using a phone call instead of a protocol-directed in-person study visit is acceptable if all 
tests and procedures scheduled for Day 36 (+35) requiring an in-person visit (physical 
examination, vital signs, samples for laboratory tests), were performed on the day of 
hospital discharge. These results are to be entered in the eCRF in the fields provided for 
the closing visit. 
The documentation of transfusion products, concomitant medication or treatment, and 
the recording of AEs can be performed by using a phone call. In addition, the follow-up 
of AEs can be completed with the subject by telephone (for the follow-up of AEs please 
refer to section 9.3.4). 
An appropriate documentation of the phone call is kept. 
 
The following procedures will be performed: 
• A physical examination will be performed. 
• Vital signs (including pulse [heart rate], blood pressure, respiratory rate, body 
temperature) will be recorded. 
• Sample for coagulation activation tests (PT(INR), aPTT, TAT, F1+2, D-dimer, 
PS, PC, AT III, TT, TGT) will be taken. 
• Samples for clinical laboratory parameters (hematology, clinical chemistry, 
urinalysis) will be taken: 
o Hematology (RBC, WBC, platelet count, hemoglobin, hematocrit) 
o Clinical chemistry (ASAT, ALAT, creatinine, creatinine clearance, 
BUN/Urea, γ-GT, AP, total bilirubin, potassium, sodium, calcium, chloride) 
o Urinalysis (pH, blood, WBC, protein, glucose, ketone bodies, nitrite, 
bilirubin, urobilinogen) 
• Retention samples for viral safety laboratory parameters will be taken. 
• Samples for virus serology laboratory parameters (hepatitis B, hepatitis C, 
HIV) will be taken. 
 
• Transfusion products (allogenic blood products) will be documented.  
• Concomitant 
medication 
or 
treatment: 
type 
of 
concomitant 
medication/treatment, dose/schedule, duration, and the indication the concomitant 
medication/treatment was given for will be documented continuously up to Day 36 
(+35). 
• AEs will be recorded continuously up to Day 36 (+35). 
 
Further details on the visit schedule that will be used for the assessment of the efficacy 
and safety parameters in this study are presented in section III, Flowchart of Study.  
 
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 Duration of the Clinical Study 
 
First Subject in (planned) 
Q1 2018 
Last Subject Last Visit (planned) 
tbd 
 
Individual Subject 
Regular duration of individual study participation for eligible screened subjects is at least 
5 weeks plus time between screening (signed ICF) and surgery. 
Each subject fulfilling the intra-operative inclusion criteria will be administered BT524 or 
cryoprecipitate during surgery. The usual stay in hospital after elective surgery varies 
depending on the type of surgery and subjects overall conditions. Each subject will have 
follow-up visits 1, 2, 4 and 7 days after surgery (Day 2, 3, 5 and 8) and the day of 
discharge from hospital will be recorded.  
Subsequent, each subject has to attend a closing visit including the final safety 
examination, and a safety follow-up at least 5 weeks after surgery, scheduled on Day 36. 
Using a phone call for the closing visit Day 36 is acceptable if all tests and procedures 
scheduled for Day 36 requiring an in-person visit, were performed on the day of hospital 
discharge. 
The closing visit can be postponed up to Day 71 (Day 36 +35) if required due to subject's 
availability (e.g., stay in rehabilitation center). 
Subjects not meeting inclusion criteria or meeting exclusion criteria are screen failures 
and will end study participation at the day of screen failure. Subjects that do not meet the 
intra-operatively inclusion criterion are also considered as screen failure and will end 
study participation on the day of the surgery. 
A subject is considered to have completed the study when he/she is presumed to have 
followed the protocol (i.e., completed visits approximately 5 weeks after surgery). If for 
any reason, a subject discontinues involvement in the study early, every effort should be 
made to ensure the subject attends a closing visit (section 4.4). 
For each subject date and reason for the end of the study participation will be recorded. 
7.2.1 End of Study 
The end of clinical study will be defined as the Last Visit of the Last Subject.  
 Criteria for Premature Termination 
7.3.1 Premature Termination of the Entire Clinical Study 
The clinical study as a whole may be stopped by Biotest after consultation with the 
Coordinating Investigator if there are reasons for which continuation of clinical study is 
no longer justified, such as: 
a) Unacceptable delay of study completion 
b) Low recruitment rate 
c) A large number of subjects with premature termination 
d) Changed benefit-risk ratio according to the efficacy and/or safety results from this or 
parallel studies 
e) Lack of efficacy 
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f) Recently emerged information suggest that the study population can be offered a 
more advantageous study design 
In case of premature termination of the entire clinical study, the sponsor has to notify the 
appropriate Ethics Committees and Regulatory Authorities as soon as possible but at the 
latest within 15 days. 
7.3.2 Premature Termination of an Individual Study Site 
The clinical study may be stopped at an individual study site for reasons such as: 
a) Determination of unexpected, significant, or unacceptable risk to subjects. 
b) Low recruitment rate, 
c) Lack of co-operation, 
d) Severe deviations from study protocol, 
e) Manipulation of study data, 
f) Violation of other ethical or legal principles. 
 
 Treatment and Care after the End of the Study 
For subjects who have finished the clinical study and for all subjects who drop out 
prematurely it is the responsibility of the investigator to choose adequate therapeutic 
measurements. 
After termination of the clinical study, any unexpected safety issue that changes the 
benefit-risk evaluation and is likely to have an impact on the subjects who have 
participated in it, should be reported as soon as possible to the sponsor. Sponsor 
expeditiously reports the event to the competent authority(ies) concerned (see also 
section 9.3.4). 
 
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8 BENEFIT-RISK EVALUATION 
 Benefit of BT524 
Fibrinogen plays a critical role in achieving and maintaining hemostasis in patients 
undergoing major surgeries and the observation that patients with higher fibrinogen levels 
experience fewer bleeding complications than those with low levels highlights the 
importance of fibrinogen in the maintenance of hemostasis. Consequently, fibrinogen 
replacement therapy targeting a high-normal level of plasma fibrinogen and fibrin-based 
clot formation may be an important first step in restoring hemostasis during major 
bleeding.  
Major spinal and abdominal surgeries represent elective surgeries often associated with 
significant intra- and post-operative blood loss resulting in decreased fibrinogen levels. 
An accurate and rapid determination of (functional) fibrinogen level is important during 
hemorrhage to establish a timely hemostatic intervention. Individualized dosing of 
fibrinogen concentrate using a target ROTEM/FIBTEM value integrates rapid diagnostic 
testing with appropriate therapeutic dosing of fibrinogen concentrate according to 
patients' needs.  
The principal benefit for the participating subjects randomized to the BT524 treatment 
arm will be to receive the required individualized fibrinogen replacement therapy in a goal-
directed treatment algorithm as a timely hemostatic intervention if significant bleeding is 
accompanied by acquired hypofibrinogenaemia. Moreover, fibrinogen concentrate 
seems to have certain advantages over the standard replacement therapy with 
FFP/cryoprecipitate, such as precisely determined, high amount of purified fibrinogen 
dissolved in a small volume, low risk of pathogen transmission and instant administration 
without need for thawing or testing AB0 blood group compatibility. 
 Foreseeable Risk and Discomfort Related to BT524 
At that point of time the pre-clinical and clinical study data are still considered too scarce 
to finally define risks as "identified" in the context of BT524. Therefore at present all 
signals as derived from class-labelling, currently remain to be regarded as potential risks. 
Please also refer to section 6.11 Warnings and Precautions. 
 Other Sources of Possible Risk and Discomfort 
Please refer to section 6.11 Warnings and Precautions. 
 Summary of Possible Risk and Discomfort 
Human fibrinogen concentrate is a well-known substance, established for decades in the 
treatment of congenital fibrinogen deficiency as well as of various indications of acquired 
fibrinogen deficiency. Fibrinogen concentrates have shown to be safe and well-tolerated 
(Fenger-Eriksen et al., 2009; Henselmans et al., 1999). 
A Guideline for Core SmPC for Human Fibrinogen Products (EU Core SmPC) is in place 
which also describes the well established benefit-risk profile of the authorized fibrinogen 
concentrates (EMA (Committee for Medicinal Products for Human Use), 2015). 
It provides the following AEs as undesirable effects considered established for all 
authorized and marketed human fibrinogen concentrate formulations: In the MedDRA 
SOC "Immune system disorders": Allergic or anaphylactic-type reactions; in the MedDRA 
SOC "Vascular disorders": Thromboembolic episodes (including myocardial infarction 
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and pulmonary embolism); and in the MedDRA SOC "General disorders and 
administration site conditions": Increase in body temperature. 
Currently, there is no data with human fibrinogen products in regard to inhibitor formation. 
With regard to transmissible agents refer to section 6.11 Warnings and Precautions. 
The safety profile of BT524 is anticipated to be in line with the marketed fibrinogen 
concentrates and the content of the EU Core SmPC [Guideline on Core SmPC for Human 
Fibrinogen Products (EMA/CHMP/BPWP/691754/2013 Rev 1)]. 
The safety and tolerability and the benefit-risk profile of BT524 (fibrinogen concentrate 
from human plasma) is considered favorable. 
 
9 ASSESSMENT OF OBJECTIVES / CRITERIA FOR EVALUATION 
 Efficacy  
9.1.1 Specification of Efficacy Parameters 
9.1.1.1 Primary Efficacy Parameter 
The primary efficacy parameter is determined from the intra-operative blood loss after the 
decision to treat the subject with IMP until the end of the surgery as measured by the 
amount of blood from the blood suction unit and the amount of blood from swabs, surgical 
cloths and compresses.  
 
9.1.1.2 Secondary Efficacy Parameter 
Secondary efficacy will be determined using the following parameters: 
• 
Proportion (%) of subjects with successful correction of fibrinogen level (FIBTEM 
A10) 15 minutes after start of first IMP administration 
• 
Time to first successful correction of fibrinogen level (15 minutes or 90 minutes after 
start of first IMP administration, end of surgery, not within surgery) 
• 
Total amount (volume in mL and number of units) of transfusion products (allogenic 
blood products) or autologous blood transfusion infused after start of first IMP 
administration until end of surgery 
• 
Amount (volume in mL and number of units) of RBCs (allogenic and autologous) 
infused after start of first IMP administration until end of surgery 
• 
Post-operative blood loss in the first 24 hours 
• 
Proportion (%) of subjects with rebleeds after the end of surgery until Day 8 
• 
Hospital length of stay after surgery 
• 
In-hospital mortality 
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9.1.2 Methods for Assessing and Recording Efficacy Parameters 
9.1.2.1 Methods for Assessing Primary Efficacy Parameter 
Amount of Blood Loss 
The blood loss will be quantified by measuring the continuous bleeding mass with a blood 
suction unit and by calculation of the amount of blood from swabs, surgical cloths and 
compresses (see section 3). 
The blood suction unit will be used to remove fluid and blood from the area being 
operated. Allowance must be made also for the presence of mucinous ascites. After 
opening and inspection of the abdomen the inside of the abdominal cavity will be washed 
out with a certain amount of irrigation solution (physiological saline solution) to remove 
mucinous ascites. 
Prior to the start of surgery the weight of dry swabs, surgical cloths and compresses 
will be recorded (weighing of swabs is required if weight is not specified on the 
packaging). In case a manual compression is necessary during surgery, dry swabs, 
surgical cloths and compresses will be applied to the surgical field, afterwards removed 
and wrung out until almost dry. By wringing out surgical cloths, the blood can be caught 
in a kidney dish and finally collected in the suction container. Subsequently, all cloths and 
compresses will be weighed (before they dry out) and the weight will be recorded.  
 
For the primary endpoint the amount of blood loss will be measured from the time 
of decision to treat the subject with IMP until the end of the surgery: 
Immediately after the prediction of an intra-operative clinically relevant bleeding of more 
than 2 L, and the assessment that hemostatic treatment will be required during surgery 
(high risk for the need of fibrinogen supplementation, either with cryoprecipitate or BT524 
during surgery), the person responsible for randomization will be informed about the 
decision to treat the subject with IMP. At the same time, the suction container will be 
emptied and the blood measurement for the primary endpoint is initiated with 
collection of blood in the empty blood suction unit.  
In addition, in case a manual compression is necessary after decision to treat the subject 
with IMP, new swabs, surgical cloths and compresses will be applied to the surgical field. 
At the end of the surgery, all swabs, surgical cloths and compresses will be removed 
from the surgical field, wrung out (blood will be collected in the suction container) until 
almost dry and weighed. The weight will be recorded. The end of surgery is defined as 
time of last suture. 
The fluid volume collected in the blood suction container will be measured and 
documented.  
The amount of irrigation solution suctioned into the container through irrigation of the 
wound must be calculated. This can be done by knowing the capacity of the irrigation 
syringe in use and keeping track of the number of times it is used. The calculated amount 
of irrigation solution must also be recorded. 
The amount of irrigation solution will be subtracted from the entire fluid volume in the 
suction container to determine the actual amount of blood collected in the suction 
container. 
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In a final step the total blood loss will be calculated. The calculation of blood loss 
based on the volume of blood removed from the surgical field by the blood suction unit 
and that absorbed by swabs, surgical cloths and compresses. 
 
9.1.2.2 Methods for Assessing Secondary Efficacy Parameter 
Correction of Fibrinogen Level via FIBTEM A10 (mm)  
The correction of the fibrinogen level will be measured via thromboelastometry 
(ROTEM/FIBTEM A10). ROTEM is an established viscoelastic method for hemostasis 
testing in whole blood and ROTEM/FIBTEM that measures the fibrin or fibrinogen 
contribution to clot strength, can be used to determine the most appropriate therapeutic 
dose of fibrinogen concentrate (Levy et al., 2014). 
Whole blood viscoelastic tests such as the fibrin-based thromboelastometry (ROTEM) 
test FIBTEM will be used in the intra-operative setting to quickly identify deficits in fibrin 
quality, and to guide hemostatic therapy. In contrast to conventional laboratory tests 
(measurement of fibrinogen concentration via Clauss assay), ROTEM/FIBTEM can 
measure early variables describing the clot firmness, such as clot amplitude obtained 
after 5 minutes (A5) or 10 minutes (A10), and provide a forecast on the expected MCF 
value at an earlier stage already. These early variables allow for a more rapid decision 
about therapeutic interventions. 
The fibrinogen activity will be measured by FIBTEM A10, MCF and Clauss assay at 
screening, prior surgery (baseline), pre-dose, 15 and 90 minutes after the start of first 
IMP administration, at the end of the surgery and one day after surgery. 
For the evaluation of the secondary efficacy endpoint successful correction of the 
fibrinogen level is defined as restoring fibrinogen FIBTEM A10 baseline levels measured 
by ROTEM 15 minutes after start of first IMP administration.  
Accordingly, the time to first successful correction of fibrinogen level is defined as the 
time point (15 minutes or 90 minutes after start of first IMP administration, end of surgery, 
not within surgery) the fibrinogen FIBTEM A10 baseline levels measured by rotational 
thromboelastometry are restored the first time. 
However, correction of fibrinogen will also be analysed based on results obtained from 
MCF and Clauss assay to perform sensitivity analyses.  
Clauss Assay 
The most widely used technique for determination of fibrinogen concentration is the 
Clauss (FIBClauss) assay (Clauss, 1957). In this method, dilutions of a plasma standard 
of known fibrinogen concentration are clotted by addition of a high concentration of 
thrombin, and a standard curve is prepared. Because the clotting time is inversely 
proportional to the fibrinogen concentration, the clotting time of diluted patient plasma is 
used to read the fibrinogen concentration from the standard curve. This method is 
reliable, accurate, and precise, and easily adapted to automated coagulation analyzers. 
 
 
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Maximum Clot Firmness (MCF, mm)  
MCF addresses the clot integrity and will be measured by ROTEM® (ROTEM delta or 
ROTEM sigma).  
MCF will be determined locally from whole blood or at the central laboratory by means of 
the Fib-tem S assay (tissue factor activation and platelet inhibition), a ready-to-use 
ROTEM system reagent (
, Mar 2011) for the ROTEM delta/sigma 
which allows the assessment of the fibrinogen level and the quality of the fibrin 
polymerization in citrated blood by inhibiting the platelets. For ROTEM sigma the 
FIBTEM C system reagent will be used accordingly. 
Fibtem measures the viscoelastic properties of the clot and provides information on the 
speed of coagulation initiation, kinetics of clot growth (MCF, mm), clot strength, and 
breakdown(Lang et al., 2009). Figure 4 shows an example of the ROTEM readout of 
citrated normal blood.  
 
Figure 4: ROTEM Readout of Citrated Normal Blood 
 
The ROTEM® analyses: FibTEM® test (fibrin clot obtained by platelet inhibition with cytochalasin D). The clotting time (CT (seconds)) 
represents the time from the start of the test until a clot firmness of 2 mm is detected; maximum clot firmness (MCF (mm)) represents 
the total amplitude of the clot (Schöchl et al., 2010).  
In the ROTEM read out of Fib-tem S test expected reference (normal range) values for 
the amplitude of MCF are 9-25 mm for fibrinogen levels (Fib-tem S 2011).  
Consumption of Transfusion Products  
The amount of transfusion products (allogenic blood products or autologous blood 
transfusion) given after start of first IMP administration until end of surgery to counteract 
hemodynamic instability will be documented (volume in mL and number of units if 
applicable) and evaluated. 
The amount of RBCs (allogenic and autologous) required intra-operatively after start of 
first IMP administration until end of surgery will be documented (volume in mL and 
number of units if applicable) and evaluated. 
 
 
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Postoperative Blood Loss (Drainage Volume) 
The plasma drainage tube and disposable drainage bag will be emptied 24 hours after 
the end of the surgery. The end of surgery is defined as time of last suture. The drainage 
volume will be measured and postoperative blood loss will be recorded. 
Rebleeds 
Any bleed judged by the surgeon and/or the anaesthesiologist as requiring hemostatic 
treatment (including reoperation) after the end of the surgery until follow-up Day 8 will be 
recorded. The end of surgery is defined as time of last suture. 
Hospital Length of Stay after Surgery 
The day of the surgery and the day of the discharge from hospital will be recorded. 
The hospital length of stay after surgery is used to compare the number of days patients 
stayed in the hospital after surgery. The hospital length of stay after surgery is calculated 
by the following formula: 
Length of stay after surgery = date of discharge - date of surgery 
In-hospital Mortality 
In-hospital mortality is defined as death occurring during the hospital stay. A death during 
hospitalization will be recorded as an SAE. 
 
9.1.3 Specification of Efficacy Endpoints 
9.1.3.1 Specification of Primary Efficacy Endpoint 
Intra-operative blood loss as measured by amount of blood from the blood suction unit 
and amount of blood from swabs, surgical cloths and compresses after the decision to 
treat the subject with IMP until end of surgery. The end of surgery is defined as time of 
last suture. 
 
9.1.3.2 Specification of Secondary Efficacy Endpoints 
• Proportion (%) of subjects with successful correction of fibrinogen level 15 minutes 
after start of first IMP administration.  
Successful correction of fibrinogen level in a subject is defined as restoring fibrinogen 
FIBTEM A10 baseline level to at least 95% measured by ROTEM 15 minutes after 
start of first IMP administration. A correction of at least 95% is considered successful, 
as measurement methods has a coefficient of variation of about 5% (Solomon et al., 
2015). 
• Time to first successful correction of fibrinogen level (15 minutes or 90 minutes after 
start of first IMP administration, end of surgery, not within surgery). 
• Total amount of transfusion products (allogenic blood products) or autologous blood 
transfusion infused after start of first IMP administration until end of surgery. The 
end of surgery is defined as time of last suture. 
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• Amount of RBCs (allogenic and autologous) infused after start of first IMP 
administration until end of surgery. The end of surgery is defined as time of last 
suture. 
• Post-operative blood loss in the first 24 hours. 
• Proportion (%) of subjects with rebleeds. 
Rebleeds are defined as any bleed requiring hemostatic treatment (including 
reoperation) after the end of surgery until Day 8.  
• Hospital length of stay after surgery, defined as the date of discharge minus the 
date of surgery. 
• In-hospital mortality. 
 
 Safety 
9.2.1 Specification of Safety Parameters 
Safety and tolerability in this clinical study will be addressed by the following safety 
parameters:  
• 
AEs 
• 
Changes in vital signs (including pulse [heart rate], blood pressure, respiratory 
rate, body temperature) 
• 
Change in clinical laboratory assessments of hematology, clinical chemistry and 
urinalysis.  
• 
Change in clinical laboratory assessments of markers of coagulation: 
PT(INR), aPTT, TAT, F1+2,D-dimer, PS, PC, AT III, TT, TGT3 
• 
Change in clinical laboratory assessments of coagulation factors: 
FII, FV, FVII, FVIII, FIX, FX, FXI, FXIII, and vWF2 
• 
Frequency and severity of thrombosis and of TEEs 
• 
Viral status. 
 
For the timing of individual safety parameters refer to section 7.1 Visit Schedule and 
section III FLOWCHART OF STUDY. Any abnormal observation or finding detected 
during the screening procedures after subject's informed consent that is considered 
clinically relevant must be documented as concomitant disease (ongoing medical history) 
or as past medical history. All medications other than the study medications should also 
be documented. 
 
9.2.1.1 Adverse Events  
After informed consent has been signed, AE data are obtained by the investigator through 
observation of the subject (including examinations and investigations) before, during and 
after surgery, from any information volunteered by the subject, and through active 
questioning. At each visit, subjects will be asked about AE that occurred since the last 
visit, by questioning them with regard to their well-being by ‘non-leading’ questions. All 
AEs should be recorded and reported to safety department (see section 9.3.2). This 
includes AEs occurring after informed consent has been signed (before, during or after 
surgery), as well as changes in concomitant diseases (i.e., ongoing medical history).  
                                            
3 Only applicable for subjects undergoing cytoreductive surgery for PMP 
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Occurrence, frequency, nature and severity of AEs will be recorded. This includes 
observations or abnormalities in physical examination, vital signs, laboratory or other 
investigations reported as AEs. Any treatments for AEs will also be recorded. 
For further details regarding AEs including definitions and reporting procedures refer to 
Appendix 1: Safety Definitions. 
 
9.2.1.2 Physical Examination 
For each subject, a complete physical examination will be performed at the time points 
specified in III Flowchart of Study (before and after surgery). Physical examination 
includes inspection of general appearance, skin, neck (including thyroid) eyes, ears, 
nose, throat, heart, lungs, abdomen, lymph nodes, vascular system, extremities, 
musculoskeletal system and nervous system. Clinical findings and existing diseases at 
screening are to be documented as medical and surgical history. A new appearance of 
an abnormal finding or worsening of a concomitant disease that occurs after signature of 
informed consent must be documented as AE. 
• BW is measured in kilograms (kg) only at screening visit and at baseline. 
• Body height is measured in cm once at screening visit for the purpose of 
calculation of BMI. 
 
9.2.1.3 Vital Signs 
Before and after surgery (Screening, baseline, follow-up Day 2 to Day 36) vital signs are 
measured with the following methods/units: 
• Blood pressure is measured in mmHg according to the Riva Rocci method while 
the subject has been resting in supine position for at least 15 minutes. The same 
arm should be used for blood pressure measurements throughout the study. The 
size of the cuff has to be chosen appropriately in relation to the subject’s arm 
circumference. 
• Heart rate and pulse is measured in beats per minute (either electronically and/or 
by palpation for 1 minute) while the subject is supine and has been resting for at 
least 15 minutes. When heart rate is of concern, cardiac monitors are used to 
determine not only rate, but also rhythm. 
• Respiratory rate per minute. 
• Body temperature is measured in °C. 
 
During surgery (Day 1): Surgery/anaesthesia standard methods should be used for 
monitoring of vital parameters including standard measurement methods for blood 
pressure, pulse, heart rate and rhythm, respiratory rate and temperature. These 
monitoring results are to be reviewed by the investigator, under consultation with a 
specialist if necessary.  
Results must be summarized in writing and classified as ‘normal’ or ‘abnormal’. Abnormal 
monitoring results must in addition be classified as ‘abnormal, clinically not relevant’ or 
‘abnormal, clinically relevant’. Abnormal, clinically relevant findings have to be reported 
as AE (unless already pre-existing at baseline with the same severity). 
In addition, vital signs will be assessed and recorded in the eCRF at the following time-
points: prior IMP treatment, 15 and 90 min after start of first IMP administration and end 
of surgery. 
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Measurements outside the normal range (according to the age and gender of the subject) 
or even changed values within the normal range showing a trend have to be assessed 
for clinical relevance by the investigator, and reported as AE if considered to represent a 
clinically significant change as compared to pre-treatment values. 
 
9.2.1.4 Laboratory Parameters 
All laboratory results have to be evaluated either in the eCRF or in the web-base tool of 
the central laboratory by the investigator/subinvestigator (anaesthesiologist) according to 
the following pattern: 
a) Within reference range (normal range) 
b) Outside reference range but not clinically relevant (e.g. marginal deviation only, 
due to underlying medical history diseases in the study population) 
c) Outside reference range and clinically relevant  
Laboratory values occurring (by date of blood sampling) after signature of informed 
consent, which are outside the reference range and assessed as clinically relevant (as 
determined by investigator), have to be documented as AE. 
Postoperative elevation of liver function tests (LFTs) in patients undergoing cytoreductive 
PMP surgery are expected due to the specific surgical intervention and are therefore not 
assessed as clinically relevant and not documented as an AE. The exception to this is if 
a therapy is required, in which case an AE should be recorded. LFTs include the liver 
enzymes alanine aminotransferase [ALT], aspartate aminotransferase [AST], gamma-
glutamyltransferase [γ-GT], alkaline phosphatase [AP], and Bilirubin. 
 
An abnormal laboratory value that is a sign of an AE (e.g. increased leukocytes due to 
bacterial infection) that has already been reported during the present clinical study, has 
to be documented as a symptom together with the diagnosis (bacterial infection) and 
does not constitute a separate AE.  
For the routine laboratory parameters, the total volume of blood that will be drawn from a 
subject who completes the study is defined in the Laboratory Manual. 
The laboratory parameters to be assessed in subjects undergoing cytoreductive PMP 
surgery are summarized in Table 1: 
 
 
 
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Table 1: Clinical Laboratory Parameters 
Clinical Laboratory Parameters 
Assessment to be done 
locally or centrally 
Clinical Chemistry 
 
• 
Alanine aminotransferase (ALAT)  
• 
Aspartate aminotransferase (ASAT)  
• 
Gamma-glutamyltransferase (ɣ-GT) 
• 
Alkaline phosphatase (AP) 
• 
Bilirubin (direct and indirect if total bilirubin is elevated) 
• 
Creatinine / creatinine clearance 
• 
Blood Urea Nitrogen (BUN) or Urea (UREA) 
• 
Sodium 
• 
Chloride 
• 
Potassium 
• 
Calcium 
• 
locally 
• 
locally 
• 
locally 
• 
locally 
• 
locally 
• 
locally 
• 
locally 
• 
locally 
• 
locally 
• 
locally 
• 
locally 
Hematology 
 
• 
Hematocrit 
• 
Hemoglobin 
• 
Red blood cells (RBCs) 
• 
White blood cells (WBC) 
• 
Differential white blood cells 
• 
Platelets 
• 
locally 
• 
locally 
• 
locally 
• 
locally 
• 
locally 
• 
locally 
Coagulation 
 
Markers of Coagulation 
• 
Prothrombin time (PT) / international normalized ratio (INR) 
• 
Activated partial thromboplastin time (aPTT) 
• 
Thrombin-antithrombin III complex (TAT) 
• 
Prothrombin fragments (F1+2) 
• 
D-Dimer 
• 
Protein S (PS) 
• 
Protein C (PC) 
• 
Antithrombin III (AT III) activity 
• 
Thrombin Time (TT) 
• 
Thrombin Generation Test (TGT) 
Coagulation Factors (including vWF) 
• 
von Willebrand factor (vWF)3 
• 
Factor I (activity of fibrinogen, Clauss assay) 
• 
Factor I (ROTEM: FIBTEM A10, Maximum clot firmness) 
• 
Factor II (FII) 
• 
Factor V (FV) 
• 
Factor VII (FVII) 
• 
Factor VIII (FVIII) 
• 
Factor IX (FIX) 
• 
Factor X (FX) 
• 
Factor XI 
• 
Factor XIII (FXIII) 
 
• 
locally 
• 
locally 
• 
centrally 
• 
centrally 
• 
centrally 
• 
centrally 
• 
centrally 
• 
centrally 
• 
centrally 
• 
locally 
 
• 
centrally 
• 
centrally 
• 
locally 
• 
centrally 
• 
centrally 
• 
centrally 
• 
centrally 
• 
centrally 
• 
centrally 
• 
centrally 
• 
centrally 
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Clinical Laboratory Parameters 
Assessment to be done 
locally or centrally 
Urinalysis 
 
• 
pH 
• 
Qualitative for blood 
• 
White blood cells (WBC) 
• 
Protein 
• 
Glucose 
• 
Ketone bodies 
• 
Bilirubin 
• 
Urobilinogen 
• 
Nitrites 
• 
locally 
• 
locally 
• 
locally 
• 
locally 
• 
locally 
• 
locally 
• 
locally 
• 
locally 
• 
locally 
Pregnancy Test 
 
• 
Human chorionic gonadotropin (hCG) 
• 
locally 
Virus Serology 
 
• 
HIV 
• 
Hepatitis B 
• 
Hepatitis C 
• 
locally 
• 
locally 
• 
locally 
Viral Safety 
 
• 
Retention sample for viral safety laboratory parameters 
• 
centrally 
 
The following markers of coagulation will be assessed at the time points specified in 
section III, Flowchart of clinical study: 
• 
Prothrombin Time (PT) / International Normalized Ratio (INR) 
 
PT is a measure of the integrity of the extrinsic and final common pathways of the 
procoagulant cascade. PT presents the time for patient plasma to clot after the 
addition of calcium and thromboplastin as an activator of the extrinsic pathway. 
Therefore, deficiencies or inhibitors of clotting factors within the extrinsic (factor 
VII) and final common pathways (factors V, X, II, I [fibrinogen]) result in 
prolongation of the PT. 
 
The INR is a mathematical conversion of a patient’s PT that accounts for the 
sensitivity of thromboplastin used by factoring in the international sensitivity index 
(ISI) value supplied by its manufacturer (Kamal et al., 2007). 
• 
Activated Partial Thromboplastin Time (aPTT) 
 
aPTT measures the integrity of the intrinsic and final common pathways of the 
coagulation cascade and represents the time for patient plasma to clot after the 
addition of phospholipid (intrinsic pathway activator) and calcium (Kamal et al., 
2007). 
• 
Thrombin-Antithrombin III Complex (TAT) 
 
TATs develop during the inactivation of thrombin – the central enzyme of the 
coagulation system – via complexion with anti-thrombin. TATs are also an indirect 
measure of thrombin generation. In combination with F1+2 a hypercoagulable state 
can be detected (Wagner C, 2008). 
• 
Prothrombin Fragments 1 and 2 (F1+2) 
 
During the activation process of prothrombin to thrombin F1+2 are split off and 
represent an indirect measure of thrombin generation. They are useful to detect 
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and follow-up a hypocoagulable state (Wagner C, 2008).  
• 
D-dimer 
 
D-dimer is a fibrin degradation product, a small protein fragment present in the 
blood after a blood clot is degraded by fibrinolysis. D-dimer contains two 
crosslinked D fragments of the fibrinogen protein. D-dimers are produced when 
fibrin is cleaved by plasmin. The presence of D-dimer may be used to assist with 
the diagnosis of DIC, Deep Venous Thrombosis (DVT) or Pulmonary Embolism 
(PE).  
• 
Antithrombin III (AT III) Activity (functional ATIII level) 
Antithrombin is a glycoprotein and is a natural anticoagulant that inhibits the 
activated coagulation factors thrombin (factor IIa), factor Xa, and, to a lesser 
extent, factor XIa and factor IXa. Heparin significantly increases the inhibition rate. 
The antithrombin level does not influence the results of screening coagulation tests 
such as partial thromboplastin time (PTT), PT, and TT (Teruya and Kostousov, 
Updated: Jan 30, 2014. Access Date: 15-Jun-2016.).  
• 
Thrombin Time (TT) 
TT is a screening coagulation test designed to assess fibrin formation from 
fibrinogen in plasma. TT is performed as the next step in the evaluation of 
abnormally prolonged aPTT or PT (Rodgers and Lehman, 2007). 
• 
Protein C (PC) 
PC is an inactive protein. When activated, it plays a significant part in blood clot, 
inflammation, and cell death regulation, as well as in maintenance of blood vessel 
cell wall permeability. The inactive form of PC circulates in blood plasma and is a 
vitamin K–dependent glycoprotein. When inactive PC binds to thrombin, it 
becomes activated (Beckmann et al., 1985; Foster et al., 1985; Mather et al., 
1996).  
PC has a crucial role as an anticoagulant, and individuals with a PC deficiency or 
with some type of P activation dysfunction are at much greater risk of thrombosis 
(Beckmann et al., 1985).  
• 
Protein S (PS) 
PS is a vitamin K-dependent plasma glycoprotein. The two forms of PS are a free 
form that is active and a complex form (65%) that is inactive (Lundwall et al., 1986).  
PS plays a significant role in the anticoagulation cascade, where it functions as a 
cofactor to the serine protease activated PC in the inactivation of factors Va and 
VIIIa. Through direct binding to factors Va, Xa, and VIII, PS exerts activated PC–
independent anticoagulant activity (Francis, 1988). If the amount of PC or PS is 
inadequate or if either one is not functioning properly, thrombin generation 
essentially remains undeterred, which may promote inappropriate or excessive 
clotting, with resultant blockage of blood flow in the veins and, rarely, the arteries 
(thrombosis) (Esmon, 2003; Mosnier et al., 2007). (Bonhomme and Fontana, 
2015; Castoldi and Rosing, 2011) 
• 
Thrombin Generation Test (TGT) 
The thrombin generation test is a global assay that measures the overall tendency 
of a plasma sample to form thrombin after initiation of coagulation. TGT measures 
the quantity of thrombin produced in response to a calibrated stimulus. It is 
performed on plasma, with or without platelets. The amount of thrombin reflects 
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the overall functioning of the hemostatic system (activators and inhibitors), without 
assessing fibrinolysis (Bonhomme and Fontana, 2015). Although several studies 
have shown a correlation between thrombin generation and the risk of bleeding or 
venous thrombosis, the application of thrombin generation assays to clinical 
decision-making is still hampered by standardisation problems (Castoldi and 
Rosing, 2011). 
 
The following coagulation factors (including von vWF) will be assessed at the time 
points specified in section III, Flowchart of clinical study: 
• 
Factor II (FII) 
Clotting factor II, or prothrombin, is a vitamin K–dependent proenzyme that 
functions in the blood coagulation cascade (Harel et al., 2016).  
• 
Factor V (FV) 
Factor V is an essential component in the blood coagulation cascade. The factor V 
protein is a catalyst, accelerating the process by which prothrombin is converted 
to thrombin, the initial step in clot formation. 
• 
Factor VII (FVII) 
Factor VII is a vitamin K-dependent serine protease glycoprotein. The 
physiological activator of factor VII is thought to be factor Xa. The factor Vlla/tissue 
factor complex activates both factors IX and X (Roberts et al., 2001). 
• 
Factor VIII (FVIII) 
Factor VIII (antihemophilic factor) is a key factor of the intrinsic clotting cascade. 
Normal hemostasis requires at least a quarter (25%) of factor VIII activity (Bishnu 
Prasad Devkota, Updated: Jan 17, 2014. Access Date: Jun 15, 2016.).  
• 
Factor IX (FIX) 
Factor IX, or Christmas factor, is one of the serine proteases of the coagulation 
system. Factor IX can be activated either by factor Xla or by the factor Vlla/tissue 
factor complex. In complex with its cofactor, factor VllIa, factor IXa activates factor 
X (Roberts et al., 2001). 
• 
Factor X (FX) 
Clotting factor X, or Stuart-Prower factor, is a vitamin K–dependent serine 
protease that serves as the first enzyme in the common pathway of thrombus 
formation (Schwartz, Updated: Mar 01, 2017. Access Date: 15-Mar-2017.). 
• 
Factor XI (FXI) 
Factor XI or plasma thromboplastin antecedent is the zymogen form of factor XIa, 
one of the enzymes of the coagulation cascade. It is a serine protease. 
Deficiencies of factor XI may lead to a bleeding tendency reflecting the significant 
role of factor XI in hemostasis (Roberts et al., 2001).  
• 
Factor XIII (FXIII) 
Factor XIII (FXIII), which was initially termed fibrin stabilizing factor, is involved in 
clot preservation (Shanbhag et al., 2016). Thrombin, generated by reactions 
initiated by activated tissue factor VII/factor IX pathways, leads to clot formation. 
Fibrin monomers polymerize spontaneously; this is followed by development of a 
complex branching clot as a result of the actions of activated FXIII (FXIIIa) 
(Andersen et al., 2009; Casadio et al., 1999; Fox et al., 1999). Several controls in 
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the complex activation process focus the actions of FXIIIa on fibrin rather than on 
fibrinogen. Cross-linking of polymerized soluble fibrin by FXIIIa is the final step in 
hemostasis (Lorand, 2000; 2001). (Sadler, 1998; Shahidi, 2017; Taylor, 2015). 
• 
Von Willebrand factor (vWF) 
von Willebrand factor is a blood glycoprotein involved in hemostasis. vWF 
performs two essential functions in hemostasis: it mediates the adhesion of 
platelets to subendothelial connective tissue, and it binds blood clotting factor VIII 
(the protein missing in hemophilia A). In the absence of vWF, factor VIII is rapidly 
removed from the circulation. Consequently, patients who lack vWF have a severe 
bleeding disorder (von Willebrand disease) because they have profound defects 
both in blood clotting and in the formation of platelet plugs at sites of vascular 
injury. von Willebrand factor (vWF) is also involved in fibrin clot formation through 
its role as a carrier protein for factor VIII (Sadler, 1998; Taylor, 2015). 
Increased plasma levels in many cardiovascular, neoplastic, and connective tissue 
diseases are presumed to arise from adverse changes to the endothelium, and 
may predict an increased risk of thrombosis (Shahidi, 2017). 
 
In addition, the following specific safety laboratory parameters will be assessed at the 
time points specified in section III, Flowchart of clinical study: 
• 
Pregnancy Test 
In females of childbearing potential, a pregnancy human chorionic gonadotropin test 
in serum will be performed at screening as specified in section III, Flowchart of clinical 
study. In addition, a second pregnancy test in urine (or serum) will be performed at 
baseline as specified in section III, Flowchart of clinical study. Pregnancy tests will be 
performed in the local laboratory. 
• 
Virus Serology 
The immunological status of viral infections will be assessed at screening and closing 
visits for HIV, HBV and HCV, section III, Flowchart of clinical study. The following tests 
will be performed in the local laboratory: 
o HIV (anti HIV1 and anti HIV2) 
o hepatitis B (total hepatitis B core antibody [anti HBc], hepatitis B surface 
antibody [anti HBs], hepatitis B surface antigen [HBsAg]) 
o hepatitis C (anti HCV) 
 
9.2.1.5 Retention Samples 
In order to respond rapidly to any reports on additional viral infections, a pre-treatment 
serum sample (5 mL) from each subject included in the study must be taken pre-dose 
and stored at -70 °C for possible future testing (screening visit).  
At closing visit (Day 36) an additional serum sample (5 mL) must be taken and stored up 
to 6 months after study end.  
Viral safety retention samples will be analysed in the central laboratory (if applicable). 
 
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9.2.2 Methods for Assessing and Recording Safety Parameter(s) 
The following safety parameters are recorded in the eCRF: AEs, vital signs (including 
pulse [heart rate], blood pressure, respiratory rate, body temperature), clinical laboratory 
values of hematology, clinical chemistry and urinalysis. Clinical laboratory assessments 
of markers of coagulation and coagulation factors: PT(INR), aPTT, TAT, F1+2, D-dimer, 
PS, PC, AT III, TT, TGT, FII, FV, FVII, FVIII, FIX, FX, FXI, FXIII, vWF. Virus status.  
For documentation of abnormal, clinically relevant findings refer to the respective sections 
above: section 9.2.1.4. 
The results of all analyses performed by the central laboratory 
, 
, will be transferred to the investigational site, CRO’s Data 
Management, and 
 Medical Advisor in a timely manner. All laboratory 
analyses performed by the local laboratory using standard assay methods will be 
transcribed to the eCRF by the investigator also in a timely manner. 
For alert processes in the situation of abnormal results refer to Laboratory Manual. 
 
9.2.3 Safety Endpoints 
 
The following variables are defined as secondary safety endpoints: 
• 
AEs  
• 
Changes in vital signs 
• 
Changes in clinical laboratory assessments of hematology, clinical chemistry, and 
urinalysis 
• 
Changes in clinical laboratory assessments of markers of coagulation 
• 
Changes in clinical laboratory assessments of coagulation factors 
• 
Frequency and severity of thrombosis and of TEEs 
• 
Virus status 
 
 Adverse Events 
9.3.1 Definitions  
(also refer to Appendix 1: Safety Definitions) 
• Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical study subject 
administered an IMP and which does not necessarily have a causal relationship 
with this treatment. An AE may be any aggravation or new unfavorable and 
unintended sign, symptom, or disease temporally associated with the use of an 
IMP, whether or not considered related to the IMP (ICH Guideline for Good Clinical 
Practice E6(R2)).  
• Adverse drug reaction of an investigational medicinal product (ADR):  
All untoward and unintended responses to an IMP related to any dose 
administered. All AEs judged by either the reporting investigator or the sponsor as 
having a reasonable causal relationship to a medicinal product qualify as adverse 
reactions. The expression reasonable causal relationship means to convey in 
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general that there is evidence or argument to suggest a causal relationship. All 
non-serious AE (related and not related) should also be entered in eCRF as soon 
as possible but not later than one month after occurrence. 
• Serious Adverse Event (SAE) 
An SAE is any untoward medical occurrence or effect that at any dose*: 
• results in death 
• is life-threatening 
• requires hospitalization or prolongation of existing hospitalization  
• results in persistent or significant disability / incapacity 
• is a congenital anomaly / birth defect 
• is another important medical event 
* “At any dose” does not necessarily imply that the subject is receiving the study drug at the time 
of the event. 
Reporting requirements are detailed in Appendix 2. 
• Adverse Event of Special Interest (AESI) 
An AE of special interest (serious or non-serious) is one of scientific and medical 
concern specific to the sponsor’s IMP or development program, for which ongoing 
monitoring and immediate communication by the investigator to the sponsor may 
be appropriate. Such events may require further investigation in order to 
characterize and understand them. Reporting requirements are detailed in 
Appendix 2. 
The following AEs have been defined as AESI for this study: 
• Thrombosis or TEE  
• Relevant bleeding complication: 
Relevant changes of a vital sign or laboratory value (e.g. severe 
tachycardia, severe hypotension, hypovolemic shock, severe anemia) 
occurring after IMP administration, during and/or after surgery that require 
immediate corrective action/treatment and are caused by bleeding. 
Note: Corrective treatment includes e.g. the administration of unplanned 
blood products or other drugs. 
• Suspicion of transmission of infective agents (viral safety). 
• Immediately Reportable Adverse Event (IRAE) 
An AE that must be reported to the sponsor within 24 hours of the study site being 
aware of the AE. Reporting requirements are detailed in Appendix 2. 
For this clinical study, IRAEs include  
• all SAEs 
• all AESIs (serious and non-serious) 
• all AEs that result in a subject’s withdrawal from the study (including 
suspected allergic reaction) 
• Medication error (incl. overdose) 
• Pregnancy 
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• Adverse Events Leading to Subject’s Withdrawal from the Clinical Study 
An AE, serious or non-serious, resulting in subject’s withdrawal from the clinical 
study, i.e., permanent treatment discontinuation (see section 4.4). Reporting 
requirements by the investigator are detailed in section Appendix 2. 
• Medication Error 
A medication error is an unintended failure in the drug treatment process that leads 
to, or has the potential to harm the patient (EMA Good Practice Guide definition). 
• A ‘failure in the drug treatment process’ does not refer to lack of efficacy 
of the drug, rather to human or process mediated failures.  
• The error is unintended. The concepts of intentional overdose, off-label 
use, misuse and abuse as defined in GVP (good pharmacovigilance 
practices) Module VI.A.2.1.2 are outside scope and should be clearly 
distinguished from medication errors.  
• ‘Drug treatment process’ includes prescribing, storing, dispensing, 
preparation for administration and administration of a medicine in clinical 
practice. 
The dose and administration of the study medication is described in section 6 
Study Treatment. Any deviation from the study medication (wrong medication, 
wrong dose, wrong route of administration, wrong patient) is a medication error. 
Any higher administered dose of the study medication, than described in section 6 
Study Treatment, is an overdose.  
9.3.2 Recording Adverse Events 
All AEs, serious and non-serious, that occur during the period of observation defined for 
the clinical study (section III, Flowchart of Study) have to be fully documented in the eCRF 
according to the provisions given in this section of the study protocol and eCRF 
completion guidelines, as well as in the subject’s source data. This applies also to AEs in 
subjects who signed the informed consent but never received the study drug. AEs 
considered not related to study medication observed after Day 36 (defined closing visit) 
will not be recorded in the eCRF. 
In addition, for a subset of AEs (SAE, AESI, AE leading to withdrawal) immediate 
reporting from investigator to sponsor is required (Immediately Reportable Adverse 
Events, IRAE). This is further detailed in Appendix 2. The following information is 
necessary:  
• Diagnosis vs. Signs/Symptoms 
The investigator should provide a diagnosis rather than individual signs and 
symptoms, wherever possible and appropriate. However, if there is not enough 
information to provide a diagnosis, individual signs and symptoms are to be 
recorded. If a diagnosis is accompanied by unusual symptoms, the diagnosis itself 
and the unusual symptoms have to be reported separately. For serious and other 
IRAEs the investigator shall provide any other supporting information that may be 
required for the assessment of the events. 
A complication of an AE constitutes another AE. For example in diarrhea leading 
to dehydration, diarrhea and dehydration would be captured as separate AEs. 
The eCRF provides for a number of items to be completed for each AE. This 
includes the onset date, end date, intensity/severity, seriousness, action taken with 
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study medication, treatment for the AE, outcome, and causal relationship of the 
AE with the study medication, other drugs, or study procedures (Appendix 2: 
Reporting Procedures). 
Severe vs. Serious: The severity is used to describe the intensity of an event. 
This is not the same as seriousness, which is based on subject/event outcome or 
action criteria usually associated with events that pose a threat to subject’s life or 
functioning. Seriousness, not severity, serves as the guide for defining regulatory 
reporting obligations.  
• Causal Relationship of AE 
The causal relationship with the study medication has to be reported for each AE. 
It refers to the presence or absence of a reasonable possibility of a causal 
relationship between the study medication and the AE.  
The investigator is asked to use medical judgment and take into account the nature 
of the AE, subject’s medical and surgical history, temporal relation, response to 
withdrawal or interruption of study drug (dechallenge), response to re-introduction 
of study drug (rechallenge), any alternative explanations such as underlying or 
concomitant diseases, concomitant drugs, study procedures.  
The investigator should also provide the causality assessment with the NIMP (e.g. 
background medication, concomitant medication - see Appendix 1 for definition). 
The following categories are used:  
• Related: There is a reasonable possibility of a causal relationship between 
the study medication and the AE. 
• Not related: There is no reasonable possibility of a causal relationship 
between the study medication and the AE. 
For serious and other immediately reportable AEs the investigator is asked to 
specify if there are alternative and/or additional explanations for the occurrence of 
the event, e.g. concomitant drugs, study procedures, or concomitant/underlying 
disease and should provide this information already with the initial case report. 
9.3.3 Period of Observation 
The period of observation for collection of AEs extends from the time the subject signs 
the ICF until the last study visit (Day 36), which is scheduled 5 weeks after the day of the 
surgery (day of IMP administration). 
Abnormal, clinically relevant findings or observations made prior to signature of informed 
consent are to be recorded as medical history/concomitant disease but not as AEs.  
AEs (including any change in severity or trait of the concomitant disease/ medical history) 
occurring in the pre-treatment period between signature of informed consent until first 
administration of study medication are non-treatment emergent AEs (NTEAEs). 
AEs (including any change in severity or trait of the concomitant disease/ medical history) 
occurring from the administration of study medication until the subject’s last study visit 
are treatment-emergent AEs (TEAEs). 
If an SAE occurs in a subject after the period of observation, i.e., after the last study visit, 
which is considered by the investigator to be related to the study medication, this should 
be recorded as SAE and follow the immediate reporting process for SAEs as described 
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in Appendix 2. If the eCRF has been closed for the subject, the investigator should contact 
the sponsor to determine how to report the SAE (see also section 7.4). 
 
9.3.4 Assessment of Adverse Events 
• Responsibilities of Investigator 
AEs are assessed by the investigator in a standardized manner including, but not 
limited to the seriousness, severity, outcome, and causality. This has to be 
performed in line with the definitions and provisions given in Appendix 1.  
Laboratory values outside the reference range have to be assessed for clinical 
relevance taking into account the pre-treatment values. For reporting of abnormal 
laboratory values as AEs refer to section 9.2.1.4. 
If an AE meets the definition of any of the mandatory AE related stopping rules 
(section 9.3.1), the investigator must withdraw the subject and report the AE as 
IRAE according to section Appendix 2. If no mandatory AE related stopping rules 
defined for the study, delete this sentence. 
For all AEs the causality assessment has to be provided in the eCRF, even if based 
on preliminary data. Once more information is available, the investigator may 
change a preliminary causality assessment. 
During and after participation of a subject in a clinical study the 
investigator/institution has to ensure that adequate medical care is provided to the 
subject for any ongoing AEs including clinically significant abnormal laboratory 
values. The investigator has to inform the subject when medical care is needed for 
any intercurrent disease of which the investigator becomes aware. 
• Responsibilities of Sponsor 
AEs are reviewed and assessed by the sponsor during ongoing safety monitoring 
activities throughout the study, as well as medical evaluation and regulatory 
assessment for reportability of SAEs and IRAEs. For the purpose of regulatory 
reporting, the causality assessment given by the investigator will not been 
downgraded by the sponsor. If the sponsor disagrees with the investigator’s 
causality assessment, both the opinion of the investigator and the sponsor will be 
recorded. 
Regulatory assessment of an AE by the sponsor comprises further the assessment 
of expectedness. For BT524, Fibrinogen Concentrate from Human Plasma, it is 
based on section 7.9 of the Investigator’s Brochure (IB). For cryoprecipitate it is 
based on the Summary of Product Characteristics of a reference product: 
Reference Safety Information (RSI) for the cryoprecipitate is the section 4.8 of the 
SmPC of 
 solution for infusion (
 
• Follow-up of Adverse Events 
AEs should be followed up to determine the outcome.  
AEs that are serious or severe or considered related to the study medication or 
study procedures must be followed up by the investigator until the AE is resolved 
or resolved with sequelae, and until all queries related to the AE have been 
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clarified. If the subject had an AE with fatal outcome, an autopsy report should be 
provided if possible.  
If AEs that are serious or severe or considered related to study medication or study 
procedures are ongoing at the time of the subject’s last study visit, or if the subject 
has clinically relevant laboratory parameter abnormalities at the last study visit, 
one or more safety follow-up visit should be scheduled for those subjects. The 
investigator should set the interval to the additional safety follow-up visit according 
to his/her medical judgment. Follow-up activities should be continued until the 
investigator considers it medically justifiable to stop further follow-up. 
All other AEs must be followed up by the investigator until the AE is resolved or 
resolved with sequelae or the end of the period of observation (= last study visit), 
whichever comes first.  
The investigator should respond to any queries raised by the sponsor in relation 
to AEs, including provision of supporting documentation for SAEs or other IRAEs 
(e.g. ECG data, laboratory results, hospital summary, autopsy report) within the 
requested timeline. In case of fatal or life-threatening SAEs the sponsor may 
request urgent clarification within one calendar day. In general, if for AEs requiring 
immediate reporting from investigator to sponsor (IRAE/SAE) follow-up 
information becomes available, this must be reported to the sponsor within 24 h 
of becoming aware of this information (i.e., the same timeframe as for initial 
IRAE/SAE reports). Any supporting documents have to be identified by the subject 
ID, and personal data (e.g. subject name, address or phone number) obliterated 
prior to sending to the sponsor. For details on reporting IRAE/SAE see Appendix 
2. 
AE data in the eCRF must be updated accordingly when follow-up information is 
received.  
All efforts to collect follow-up information must be documented in the subject’s 
source data. 
Subjects who were treated with the study medication but did not complete the 
study as per protocol, should receive all the examinations and investigations 
scheduled for the last study visit. The investigator should make all efforts to contact 
subjects lost to follow-up and document the attempts in the subject’s source data. 
9.3.5 Immediate Reporting by Investigator to Sponsor 
(also refer to Appendix 2: Reporting Procedures) 
9.3.6 Use of IMP outside the Specifications of the Clinical Study Protocol  
Situations may occur where the IMP is used outside the specifications of the protocol, 
which may or may not be associated with an AE. These special situations comprise 
• Medication errors (including overdose) 
• Abuse/ misuse of the IMP. 
Such situations, whether or not associated with an AE, are documented in the eCRF on 
dedicated pages. Any AE that occurred in association with such a special situation has 
to be cross-referenced on the dedicated eCRF page. An IRAE/SAE occurring in 
conjunction with a medication error or abuse/ misuse of the IMP has to follow the 
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immediate reporting process for IRAE/SAE as described in Appendix 2 in addition to its 
documentation in the eCRF (also refer to sections 9.3.8 and 10.2). 
9.3.7 Investigational Medicinal Product Complaints 
IMP complaints must be recorded in the eCRF and in addition reported to the sponsor on 
the “Investigational Medicinal Product Complaint Report Form” within 24 hours of the 
investigator becoming aware of the IMP complaint. If the IMP complaint is associated 
with an AE, the AE must be entered in the eCRF also. 
Any complaint samples should be provided to the sponsor upon request. 
9.3.8 Special Situations Requiring Immediate Reporting 
Special situations may occur that may or may not be associated with AEs. For these 
situations special reporting provisions apply. 
Special situations comprise: 
• Pregnancy in a female study subject or the partner of a male study subject 
• Investigational Medicinal Product Complaint. 
• Use of IMP outside the specifications of the CSP (e.g. Medication errors, 
overdose, misuse and abuse (also refer to sections 9.3.6 and 10.2). 
• Protocol deviations (refer to section 10.2) 
If such a situation occurs, the investigator should contact the sponsor immediately. A 
special paper report form has to be completed always in these situations and sent to the 
sponsor immediately, but not later than 24 hours after the investigator becoming aware 
of the situation. 
 
9.3.8.1 Pregnancy 
Pregnant women are excluded from the study, and female study subjects of child-bearing 
potential undergo pregnancy testing at screening and regularly during the study (section 
III, Flowchart of study). If pregnancy is suspected in a study subject during treatment with 
the IMP, the IMP must be immediately withheld until the result of a confirmatory test is 
available. If confirmed, the subject must be withdrawn from the study. Furthermore, the 
reason and the contraception methods may need to be reviewed and documented as a 
preventative measure for other participants. 
Reliable methods of contraception are 
• 
combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation, 
• 
progestogen-only hormonal contraception associated with inhibition of ovulation, 
• 
intrauterine device (IUD), 
• 
intrauterine hormone-releasing system (IUS), 
• 
bilateral tubal occlusion, 
• 
vasectomised partner, 
• 
sexual abstinence - only when abstinence is the usual and preferred lifestyle of 
the subject. 
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Although not an AE per se, pregnancy in a female study subject or the partner of a male 
study subject must be recorded if it occurs during the period of observation of the study 
(see definition in section 9.3.3). The investigator must contact the sponsor immediately 
in such a situation. 
The pregnancy must be documented on a “Drug Exposure Via Parent" (DEVP) Report 
Form and reported to the sponsor within 24 hours of the investigator becoming aware 
of the pregnancy. If an AE occurs in relation to the pregnancy, it has to be noted on the 
DEVP form and recorded in the eCRF. If an IRAE/SAE occurs in relation to the 
pregnancy, it has to be noted on the DEVP form and recorded in the eCRF and follow 
the immediate reporting process for IRAE including SAE as described in Appendix 2.  
The investigator must make all reasonable efforts to follow up the pregnancy until its end 
and will report all outcomes associated with the pregnancy to the sponsor. In the situation 
of pregnancy of the female partner of a male study subject, consent for the release of 
medical data should be obtained from the female partner to allow collection of information 
on the outcome of the pregnancy.  
 
 Data Safety Monitoring Board 
A DSMB will independently monitor the study. 
The DSMB will independently review and assess the unblinded safety data throughout 
the entire study at regular intervals. The DSMB consists of three voting members: an 
expert in pharmacovigilance, an expert in the field of hematology/hemostaseology and 
an expert in anaesthesiology. Two members of the DSMB constitute a quorum.  
In addition, a statistician without a vote will be responsible for adequate data supply. Prior 
to the data safety monitoring phase, a meeting will be held to familiarize the DSMB with 
all relevant procedures. The DSMB members are unblinded during both evaluation 
periods and will be provided with the following information: reports of SAEs and AEs, data 
on markers of coagulation and coagulation factors, clinical laboratory assessments of 
hematology, clinical chemistry and urinalysis, and vital signs.  
DSMB meetings will take place at regular intervals. The DSMB will be provided with data 
covering the screening visit, the day of surgery plus 4 additional follow-up visits (Day 2, 
3, 5 and 8) and will evaluate the subjects’ risks at a formal DSMB meeting with regards 
to the relevant parameters and outcome criteria. In addition, subject's data from the 
closing visit will also be evaluated if data already available at the time of the DSMB 
meeting. After each meeting treatment of the following subjects can continue unless the 
DSMB has not actively disapproved it.  
Minutes of the DSMB will describe the proceedings from all sessions of the DSMB 
meeting, and will summarize all recommendations, which will also be reported to Biotest 
and the principal investigator. 
The DSMB members can propose to stop the study at any time after a scheduled or 
unscheduled meeting in case of major safety concerns related to study treatment. 
Further details will be provided in the DSMB Charter. 
 
 
 
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10 STATISTICS 
The statistical planning and evaluation of the clinical study will be carried out by a qualified 
biostatistician in accordance with the ICH-guidelines and adequate biostatistical SOPs in 
SAS version 9.4 or later. A detailed Statistical Analysis Plan (SAP), providing details 
about the statistical methods for the analyses, will be finalized before unblinding. This 
ensures that the integrity of the analyses is maintained. 
Any deviations from the planned analyses will be described and justified in the Clinical 
Study Report (CSR). 
 Analysis Sets 
The following analysis sets will be defined: 
All Subjects Enrolled Set:  
The All Subjects Enrolled Set includes all subjects who have given informed consent to 
this study. 
Safety Analysis Set (SAF):  
The SAF comprises all subjects who have received at least one dose of IMP. Subjects 
will be analyzed according to the treatment received. 
Full Analysis Set (FAS):  
The FAS comprises all subjects who received at least one dose of IMP prior to the ‘end 
of surgery’ and have at least one post dose efficacy assessment.  
Subjects will be analyzed as randomized. 
Per-protocol Set (PPS):  
The PPS includes all subjects who are compliant with the study protocol without any 
major protocol deviations thought to have the potential to impact the results of the efficacy 
analysis, e.g. no treatment with IMP, treatment with IMP after the ‘end of surgery’, no post 
dose efficacy assessment. Classification of protocol deviations as major or minor will be 
agreed upon at the Blind Data Review Meeting (BDRM) prior to database lock. 
Subjects will be analyzed according to the treatment received. 
 Protocol Deviations 
Deviations from the protocol will be documented on an on-going basis during conduct of 
the clinical study based on monitoring reports (e.g. failure of eligibility criteria), data 
management checks and statistical programming (e.g. prohibited medications based on 
drug codes). Protocol deviations will be discussed and agreed in the BDRM to find 
protocol deviations with major impact on subject safety or the validity of the study data. 
Subjects with major protocol deviations will be excluded from the PPS under the 
assumption that the deviation may have an impact on the efficacy analysis. 
The investigator should not implement any deviation from, or changes of the protocol 
without agreement by the sponsor and prior review and documented approval/ favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an 
immediate hazard(s) to study subjects. The investigator, or person designated by the 
investigator, should document and explain any deviation from the approved protocol.  
 
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 General Considerations 
BT524 will be compared with standard treatment (FFP in the EU and Switzerland / 
cryoprecipitate in the UK) whereas FFP and cryoprecipitate will be considered as one 
treatment group. 
The global significance level will be 2.5% (one-sided), confidence intervals will be 95% 
(two-sided). All statistical tests will be two-sided, unless otherwise stated. 
Quantitative (continuous) data - absolute values and differences from baseline, where 
appropriate - will be summarized with number of observations (n), arithmetic mean, 
standard deviation, median, minimum, and maximum.  
Qualitative (categorical) data will be summarized using number of observations (n), 
frequency and percentages of subjects. Unless stated otherwise the calculation of 
percentages will be based on the total number of subjects in the population of interest. 
Thus counts of missing observations will be included in the denominator and presented 
as a separate category. 
Definition of Baseline 
If not stated otherwise, the last non-missing valid observation prior to surgery will serve 
as the baseline measurement. 
Missing Data Conventions 
In this short study, not many missing values are expected. Therefore, data will not be 
imputed for safety analyses or continuous efficacy endpoints. 
For binary endpoints, an observed case analysis (excluding missing data) will be 
considered to be the primary analysis method and a non-responder analysis (treating 
missing values as non-responders or the worst case) may be performed as a sensitivity 
analysis if deemed necessary. Details will be given in the SAP. 
Pooling of Centers 
In case of low number of subjects per center, summaries of data by center would be 
unlikely to be informative. Therefore, data from all centers per country/region (if 
applicable) and in total will be pooled prior to analysis. 
Subgroups 
A subgroup analysis according to the predictive blood loss is planned at least for the 
primary efficacy variable blood loss. 
Disposition 
The number of subjects screened and who failed screening prior to surgery or during 
surgery will be summarized. The number of subjects randomized; number and 
percentage of subjects treated with IMP; and number and percentage of subjects who 
prematurely withdrew from the study with the reason for withdrawal will be summarized 
by treatment arm. The number and percentage of subjects in each of the analysis sets 
will also be summarized by treatment arm.  
Demographic and Baseline Data 
Demographic and baseline data will be summarized descriptively. 
 Efficacy Analyses 
Analyses of the efficacy parameters will be based on the PPS and FAS as appropriate 
and defined in the SAP. 
 
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 Primary Efficacy Analysis 
The primary endpoint / efficacy variable is the intra-operative blood loss after decision to 
treat the subject with IMP until the end of surgery as measured and calculated by amount 
of blood from the blood suction unit and amount of blood from surgical cloths and 
compresses. 
The primary analysis of this endpoint will test for non-inferiority in the PPS. 
The null hypothesis for the primary analysis is that the degree of inferiority of BT524 
compared to standard treatment (FFP/cryoprecipitate) is greater than or equal to the non-
inferiority margin. The alternative hypothesis is that the degree of inferiority of BT524 
compared to FFP/cryoprecipitate is less than the non-inferiority margin.   
H0: µ1 - µ2 ≥ δ 
H1: µ1 - µ2 < δ 
where 
µ1 = mean intra-operative blood loss after the decision to treat the subject with IMP 
in the BT524 treatment arm 
µ2 = mean intra-operative blood loss after the decision to treat the subject with IMP 
in the FFP-/cryoprecipitate-treatment arm 
δ = non-inferiority margin = 150 mL 
 
The final analysis will be performed using ANCOVA with the intra-operative blood loss 
after the decision to treat the subject with IMP until the end of surgery as the dependent 
variable and the predictive blood loss (>1,000 mL to ≤ 2,000 mL and > 2,000 mL) as a 
covariate. The least square means and treatment difference (BT524 versus standard 
treatment) in least square means will be presented with the corresponding 95% 
confidence intervals and 2-sided p-value. Non-inferiority will be demonstrated if the upper 
confidence limit of the 2-sided 95% confidence interval for the difference in the least 
square means is less than the non-inferiority margin (150 mL). 
This analysis will also be performed in the FAS as a sensitivity analysis. 
If non-inferiority is demonstrated, then superiority will be assessed in the FAS with 
superiority demonstrated if the 2-sided p-value is less than 0.05 (i.e., the upper 
confidence interval is less than 0 mL) using the analysis performed to assess Non-
Inferiority. 
No imputation for missing values will be applied. 
 
 Secondary Efficacy Analyses 
All secondary efficacy analyses will be conducted with the FAS. The secondary 
endpoints / efficacy variables are:  
• Proportion (%) of subjects with successful correction of fibrinogen level 15 minutes 
after start of first IMP administration. Successful correction of fibrinogen level in a 
subject is defined as restoring fibrinogen FIBTEM A10 baseline levels measured 
by ROTEM 15 minutes after start of first IMP administration. A correction of at least 
95% is considered successful. 
• Time to first successful correction of fibrinogen level (15 minutes or 90 minutes 
after start of first IMP administration, end of surgery, not within surgery). 
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• Total amount of transfusion products (allogenic blood products) or autologous 
blood transfusion infused after start of first IMP administration until end of surgery. 
• Amount of RBCs (allogenic and autologous) infused after start of first IMP 
administration until end of surgery. 
• Post-operative blood loss in the first 24 hours. 
• Proportion (%) of subjects with rebleeds after the end of the surgery until Day 8. 
• Hospital length of stay after surgery. 
• In-hospital mortality. 
10.6.1 Correction of Fibrinogen Level 
The proportion of subjects with a successful correction of fibrinogen level will be 
compared between the treatment arms using a CMH approach stratified by predictive 
blood loss (> 1,000 mL to ≤ 2,000 mL and > 2,000 mL). The number and percentage of 
subjects with a successful correction of fibrinogen level will be presented with 
corresponding 95% confidence intervals. The estimated treatment effect (i.e., the 
difference in correction rate between the treatment arms), corresponding 95% confidence 
interval, and 2-sided p-value for the difference will be presented. 
The time to first successful correction of fibrinogen level will be compared between the 
treatment arms using a Chi-Square test. The number and percentage of subjects 
reaching a successful correction at each time point (15 minutes or 90 minutes after start 
of first IMP administration, end of surgery, not within surgery) will be presented together 
with the p-value for differences between treatment arms. 
Absolute values and change from baseline in fibrinogen levels will be presented 
descriptively over time by treatment arm. 
10.6.2 Consumption of Transfusion Products 
The total amount of transfusion products (allogenic blood products or autologous blood 
transfusion or cell salvage) infused until end of surgery will be descriptively summarized 
by type of transfusion product and treatment arm.  
10.6.3 Amount of Red Blood Cells 
The amount of RBCs required intra-operatively will be descriptively summarized by 
treatment arm.  
An ANCOVA analysis will be performed with the amount of RBCs required as the 
dependent variable and the predictive blood loss (> 1,000 mL to ≤ 2,000 mL and > 2,000 
mL) as a covariate. The least square means and difference in least square means will be 
presented with the corresponding 95% confidence intervals and 2-sided p-value.  
10.6.4 Post-operative Blood Loss 
The post-operative blood loss in the first 24 hours will be descriptively summarized by 
treatment arm. 
An ANCOVA analysis will be performed with the post-operative blood loss in the first 24 
hours as the dependent variable and the predictive blood loss (> 1,000 mL to ≤ 2,000 mL 
and > 2,000 mL) as a covariate. The least square means and difference in least square 
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means will be presented with the corresponding 95% confidence intervals and 2-sided p-
value.  
10.6.5 Proportion of Subjects with Rebleeds 
The proportion of subjects with rebleeds after the end of surgery (until Day 8) will be 
compared between the treatment arms using a CMH approach stratified by predictive 
blood loss (> 1,000 mL to ≤ 2,000 mL and > 2,000 mL). The number and percentage of 
patients with a rebleed will be presented with corresponding 95% confidence intervals. 
The estimated treatment effect (i.e., the difference in rebleed rate between the treatment 
arms), corresponding 95% confidence interval, and 2-sided p-value for the difference will 
be presented.  
10.6.6 Hospital Length of Stay after Surgery 
The hospital length of stay after surgery will be descriptively summarized by treatment 
arm. 
10.6.7 In-hospital Mortality 
The number and percentage of subjects died during hospital stay will be presented by 
treatment arm. 
 Safety Analysis 
AEs will be coded using the most current version of Medical Dictionary for Regulatory 
Activities (MedDRA®). The version used will be defined in the SAP. Incidence rates (i.e., 
number and percentage of affected subjects) will be calculated for the coding levels SOC 
and preferred term and will be presented by treatment arm. Further analyses of AEs will 
focus on seriousness, intensity, causal relationship to IMP, and outcome. IRAE including 
SAEs etc. will be displayed in detail. 
Safety laboratory assessments (hematology, clinical chemistry, urinalysis and 
coagulation parameters) will be categorized with respect to the laboratory specific 
reference ranges as normal/abnormal. Abnormal values will be further classified with 
respect to clinical relevance. Changes over time will be described by means of “shift-
tables” by treatment arm as well as summarized with descriptive statistics by time point 
and treatment arm. 
Vital signs data will be summarized descriptively before and after surgery by treatment 
arm. 
The frequency of thrombosis and of TEEs, virus status, exposure data and concomitant 
medication will be summarized by treatment arm. 
All safety analyses will be based on the SAF. 
 Interim Analyses 
In this study, 3 interim analyses of the observed blood losses are planned to have the 
option of adjusting the sample size needed (primary: PPS, secondary: FAS). 
For this purpose, an alpha-adjustment according to Haybittle/Peto (Haybittle, 1971; Peto 
et al., 1976; Schulz and Grimes, 2005) is planned. This leads to local alpha levels of 
0.001 for each interim analysis and a significance level of 0.05 for the final analysis to 
reach a global significance level of 5%. 
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All interim analyses will be based on the PPS. 
The first interim analysis is planned with approximately 50 spine subjects, the second 
one with at least 40 PMP subjects and all other evaluable spine subjects at that time-
point. The third interim analysis is planned after approximately 80% of subjects of the 
total sample size. 
Aim of all interim analyses is to adapt the sample size according to the observed blood 
losses and the standard deviations: 
a.) Early termination due to non-inferiority of BT524 in comparison with the used 
standard therapies. 
b.) Continuation with the sample size as initially planned. 
c.) Adjustment of sample size to take into account changes from the previous 
assumptions on the additional blood loss. 
d.) Stopping the study early due to futility if the sample size re-estimation indicates a 
much higher number than planned before. 
 Determination of Sample Size 
The non-inferiority margin is defined as 150 mL blood loss, as such difference in blood 
loss after the decision to treat the subjects with IMP is considered as clinically not 
relevant.  
The intra-operative trigger for treatment, “a clinically relevant bleeding or the prediction 
of a clinically relevant bleeding, requiring hemostatic treatment during surgery”, is defined 
as the time of decision to treat the subjects with IMP. Based on the assumption of an 
additional blood loss of about 500 mL in the FFP-/cryoprecipitate-treatment arm after the 
decision to treat, a further intra-operative blood loss of approximately 150 mL would not 
lead to a further transfusion of ≥ 1 unit of packed RBCs, ≥ 1 unit of FFP/cryoprecipitate, 
or ≥ 1 unit of whole blood.  
Whole blood contains RBCs and plasma components of circulating blood. A single whole 
blood donation contains approximately 500 mL of blood with a minimum hematocrit of 
38%. When the plasma is removed, RBCs remain and have a hematocrit of > 80% and 
a volume of 225-350 mL. Additive solutions mixed with the red cells result in a hematocrit 
of 55-65% and a volume of 300-400 mL. One unit of whole blood or one unit of RBCs can 
be expected to result in a hemoglobin increase of 1 g/dL or a hematocrit increase of 3% 
in a typical adult. Therefore, one unit of RBCs can replace a blood loss of 500 mL (Avery 
and Avery, Spring 2010; Liumbruno et al., 2009). Accordingly, a volume of 150 mL (after 
an assumed blood loss of 500 mL) is still below a clinically relevant blood loss and would 
not trigger an additional administration of transfusion products. 
It is assumed that BT524 is non-inferior that means not worse than FFP/cryoprecipitate 
with a non-inferiority margin of 150 mL in reducing intra-operative blood loss. Assuming 
a blood loss of about 500 mL in the FFP-/cryoprecipitate-treatment arm after the decision 
to treat the subject with IMP until end of surgery, a standard deviation of 375 mL, a non-
inferiority margin of 150 mL, an alpha-level of 2.5% (1-sided) 100 evaluable subjects per 
treatment arm are needed to demonstrate the non-Inferiority of BT524 by using a t-test 
(equivalence) with 80% power. 
The sample size will be recalculated at the interim analyses as defined in section 10.8. 
Sample size estimations will be performed by using nQuery Advisor Version 4.0 or higher. 
With 100 subjects per treatment arm superiority of BT524 can also be tested with a power 
of >80% (t-test, alpha=0.05 2-sided, effect size ∆=0.5). 
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10.9.1 Data Monitoring 
After 40 subjects have completed the study, the overall mean and standard deviation for 
the primary efficacy variable intra-surgery blood loss after decision to treat the subject 
with IMP will be derived using blinded aggregate data of all 40 subjects without separating 
according to treatment.  
If the assumed mean and standard deviation blood loss are not reflected in these 
subjects, then a sample size adjustment will be considered to ensure that a sufficient 
number of subjects has been randomized to maintain a power of 90%.  
If an adaption of the sample size is intended, this will be documented in a protocol 
amendment.  
This data monitoring is not an interim analysis because the analysis is performed with all 
subjects without separating the subjects according to treatment. Therefore, no alpha-
adjustment is necessary. 
 
11 DATA MANAGEMENT 
 Data Collection 
Electronic Case report form (eCRF)  
The eCRF is the primary data collection instrument for the clinical study. All data to be 
recorded according to this CSP must be documented. Entries in the eCRF must only be 
made by the investigator or persons authorized by the investigator. A list of all persons 
who are allowed to make entries in the eCRF must be available in each study site. 
eCRF completion guidelines will be provided as electronic version with the eCRF as a 
link on the dashboard.  
Clinical study data will be directly entered via eCRF into the study database on a central 
server by authorized investigator and/or study personnel.  
It is ensured that the electronic data capture (EDC) system (including the eCRF) is built 
up with following requirements: validated system, functionality of different user roles and 
access administration, password protection, given traceability, record keeping, and 
availability of audit trail functionality as well appropriate standard operation procedures 
are maintained. 
 
The investigator and/or assigned study personnel at each site will enter data from source 
documents corresponding to a subject’s visit into the protocol-specific eCRF. Subjects 
will be identified by a unique study specific number and/or code in any database. The 
subject's name and any other identifying detail will not be included in any study data-
electronic file. 
Laboratory samples (e.g. safety lab, clinical immunology, pharmacokinetic, other study 
specific laboratory data) will be collected and analyzed in local laboratories at each site 
or shipped to central laboratory for analysis (section 9.2.1.4). The results of local 
laboratory samples will be sent back to the investigator to be entered into the eCRF. The 
central laboratory data will be available for evaluation by the investigator via the web-
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based tool provided by the vendor. Data will be sent to the CRO on a regular basis to join 
with the clinical data entered via eCRF.  
The complete data management activities (data entry, data validation, query handling, 
data editing after entry, coding, data base closure, etc.) will be defined in advance within 
a data management plan together with a description of the personnel responsible for data 
correction, performance, and controlling as well as specific data handling procedures. 
MedDRA® dictionary will be used for coding of AE, concomitant diseases and medical 
history. Concomitant medication will be coded using the Word Health Drug Dictionary 
(WHO-DD). Details are provided in the data management plan and the study specific 
safety manual. 
 Correction of Data 
After data have been entered into the clinical study database, a system of computerized 
data validation checks will be implemented and applied to the database on a regular 
basis.  
Definition and details are provided in the data validation specifications. 
Queries are entered, tracked, and resolved through the eCRF system directly. If a 
correction is required for an eCRF, the time and date stamps tracking function creates an 
electronic audit trail for the person entering/updating the eCRF data. 
 Data Handling 
The data will be entered into a validated database. The Data Management personnel will 
be responsible for data processing, in accordance with procedural documentation. 
Database lock will occur once all data entered are clean and quality assurance 
procedures have been completed. 
All procedures for the handling and analysis of data will be conducted according to 
available ICH-GCP guidelines for the handling and analysis of data for clinical studies. 
 
12 QUALITY CONTROL AND QUALITY ASSURANCE 
 Study Initiation Activities 
The investigator(s) is/are informed about objectives and methods of the study, the 
inclusion and exclusion criteria, the time-schedule, and the applied procedures by means 
of a Pre-Study Visit by the monitor (if necessary), an investigators’ meeting prior to start 
of the study, and during the Site Initiation Visit by the monitor. 
 Training of site staff 
The Principal Investigator needs to ensure that all persons assisting with the clinical study 
are adequately informed about the protocol, the investigational product(s) and their study 
related duties and functions. Furthermore the Principal Investigator is requested to 
maintain a list of appropriately qualified persons to whom the investigator has delegated 
significant study-related duties. 
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 Documentation and Filing 
List of Subjects (subject identification log) 
The investigator is asked to keep a confidential list of names of all subjects participating 
in the study, giving reference to the subjects' records.  
With the help of this list it must be possible to identify the subjects and their medical 
records. In addition, the investigator is asked to keep a list of all subjects screened on a 
screening log to document identification of subjects who entered pre-study screening. In 
case of non-eligibility a reason is to be provided. 
Source Data 
Source data is all information in original records and certified copies of original records 
of clinical findings, observations, or other activities in a clinical study necessary for the 
reconstruction and evaluation of the study. Source data are contained in source 
documents which comprise clinical documentation, data, and records (e.g. hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects' diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate copies, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, 
and records kept at the pharmacy or blood bank, at the laboratories and at medico-
technical departments involved in the clinical study). Any data recorded directly in the 
eCRFs (i.e., no prior written or electronic record of data) will also be considered to be 
source data. 
 
Investigator Site File / Regulatory Binder 
Before site initiation the CRO will provide an Investigator Site File / Regulatory Binder to 
each study site. The Investigator Site File will include essential documents as defined by 
the ICH GCP guideline and applicable local requirements. 
The investigator will be responsible for the continual update and maintenance of the 
investigator site file, which will be periodically reviewed by the monitor(s). In case of an 
audit by the sponsor or an inspection by the Regulatory Authorities these documents will 
be reviewed. 
All study related documents are to be archived and stored according to legal 
requirements, but at least for 25 years after completion of the study. 
Prior to destruction the investigator will contact Biotest AG for approval and conformation 
of such. 
 Monitoring 
The monitor is responsible for checking the quality of data and adherence to the study 
protocol and to legal and ethical requirements according to local laws and GCP. 
The interval between monitoring visits will be dependent on the recruitment rate and the 
complexity of the study. 
Source data verification is an essential part of the monitoring process and the investigator 
must grant direct access to the subjects' source data. 
The extent and nature of monitoring will be described in detail within the monitoring plan. 
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 Audits and Inspections 
Audits will be performed according to the corresponding audit program, including the 
possibility that a member of the sponsor’s quality assurance function may arrange to visit 
the investigator in order to audit the performance of the study at the study site, as well as 
all study documents originating there. Audits may also be performed by contract auditors. 
In this case, the sponsor’s quality assurance function will agree with the contract auditor 
regarding the timing and extent of the audit(s). In case of audits at the investigational site, 
the monitor, PM-CRO (Project Manager CRO) or CCR (Clinical Manager (cM) Biotest) 
will usually accompany the auditor(s).  
Inspections by regulatory authority representatives and IECs/IRBs are possible at any 
time, even after the end of study. The investigator has to notify the sponsor immediately 
of any such inspection. The investigator and institution will permit and support study-
related monitoring, audits, reviews by the IEC/IRB and/or Regulatory Authorities, and will 
allow direct access to source data and source documents for monitoring, audits, and 
inspections. The principal investigator shall personally participate in all audits and 
inspections. 
 
 Archiving 
After evaluation and reporting of the study data, all documents relating to the clinical study 
will be kept in the archives of the sponsor or of a contracted service provider and the 
study site(s) according to applicable regulatory requirements. 
 
13 GENERAL REGULATIONS, AGREEMENTS AND 
ORGANISATIONAL PROCEDURES 
 Study Administrative Structure 
Details for the study administrative structure are kept as a separate list filed in the Trial 
Master File. 
 Ethical and Regulatory Considerations 
This CSP and any amendments will be submitted to a properly constituted Independent 
Ethics Committee (IEC) / Institutional Review Board (IRB) and/or Regulatory Authorities 
(RA), in agreement with applicable regulatory requirements, for formal approval of the 
study conduct. A copy of these approvals must be submitted to Biotest before initiation 
of the clinical study and each site needs to keep a copy of these documents. 
Changes to the CSP must be made in the form of an amendment that has the prior written 
approval of Biotest. Substantial CSP amendments need to be notified to/approved by 
IEC/IRB and/or Competent Authorities (CA) / Regulatory Authorities (RA) prior to 
implementation as required by applicable regulations. 
The clinical study will be performed according to the applicable regulatory requirements 
taking into account the principles of GCP and the latest version of the Declaration of 
Helsinki. 
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 Committees / Monitoring Boards  
Safety data from the clinical study will be evaluated by a DSMB at regular intervals during 
the study, to ensure that the continuation of the study is appropriate and to make 
recommendations to the sponsor. The DSMB will consist of permanent members who 
are not associated with the sponsor or with the operative conduct of the study. A 
description of the scope of work and operating procedures for the DSMB is provided in 
the DSMB Charter. The composition of the DSMB will also be outlined in the DSMB 
Charter. 
 
 Written Agreements 
A written agreement will be set up between Biotest and each investigator setting out any 
arrangements on delegation and distribution of tasks and obligations and, if appropriate, 
on financial matters. 
 Insurance/Liability 
In accordance with the relevant national regulations, the sponsor has taken out a subject 
liability insurance for all subjects who have given their consent to the clinical study. The 
subjects are insured against injury caused by study medication or participation. The 
subjects will be informed about the insurance and their own responsibilities and duties. 
The insurance company issuing the policy is defined by the Insurance Certificate for 
Clinical Trials for the respective county. This certificate will comply with the country-
specific legal requirements. 
 Investigator’s Brochure (IB) 
The investigator will be informed about current knowledge concerning the study 
medication BT524 through an Investigator´s Brochure (IB). All investigators will be 
informed immediately about relevant new information available. 
 Amendments to the Protocol 
Changes to the CSP must be made in the form of a CSP Amendment that has the prior 
written approval of Biotest. Substantial changes to the protocol need to be notified 
to/approved by IEC/IRB and/or Regulatory Authorities prior to implementation, as 
required by applicable regulations. 
Amendments in order to eliminate immediate hazard to subjects may be implemented 
before the approval of the IEC/IRB and/or Regulatory Authorities after consultation with 
Biotest. 
In the event that a significant deviation from the protocol is anticipated based on the 
subjects status, or occurs due to an accident or mistake, the investigator or his/her 
designee must contact Biotest or 
 (CRO) at the earliest possible 
time. This will allow an early joint decision to be made as to whether or not the subject 
should continue in the study. This decision will be documented by both the investigator 
and Biotest or 
 (CRO). 
 Confidentiality 
The objectives and contents of this clinical study as well as its results are to be treated 
as confidential and may not be made accessible to third parties. 
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Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996.  Those 
regulations require a signed subject authorization informing the subject of the following: 
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, 
by regulation, retains the ability to use all information collected prior to the revocation of 
subject authorization.  For subjects that have revoked authorization to collect or use PHI, 
attempts should be made to obtain permission to collect at least vital status (i.e. that the 
subject is alive) at the end of their scheduled study period. 
 Final Report and Publication 
For each study an integrated final report according to ICH-requirements will be produced. 
At the end of the study the sponsor will provide the competent authority and IEC/IRB with 
a summary of the CSR within < 1 year after the end of the study, where required. 
It is generally recommended that the results of clinical studies be presented at 
congresses and symposia and/or published in scientific journals. Prior to their publication, 
all results of medical tests with the sponsor’s products, and/or publications or lecture 
manuscripts concerning such results, are to be reviewed and discussed by the 
coordinating investigator and the sponsor by mutual agreement. 
Each investigator is obligated to keep data pertaining to the study secret. He/she must 
consult with the sponsor before any study data are published.  
The legitimate interests of the sponsor, such as acquiring optimum patent protection, 
coordinating submissions to the health authorities or coordination with other studies in 
the same field that are underway, protection of confidential data and information, etc. will 
be given due consideration by all partners involved. 
 
 
 
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14 LIST OF REFERENCES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Diagnose - Indikation und Bewertung von Laborbefunden für die medizinische 
 
 
 
 
 
 
 
 
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15 APPENDICES 
Appendix 1: Safety Definitions 
Appendix 2: Reporting Procedures 
 
 
 
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Appendix 1: Safety Definitions 
• Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical study subject 
administered an IMP and which does not necessarily have a causal relationship 
with this treatment. An AE may be any aggravation or new unfavorable and 
unintended sign, symptom, or disease temporally associated with the use of an 
IMP, whether or not considered related to the IMP.  
This includes abnormal laboratory and other investigation results which are 
considered clinically relevant by the investigator (unless already pre-existing at 
baseline). However, if an abnormal laboratory value is a sign of an already 
reported AE (e.g. infection), the respective abnormal laboratory value does not 
constitute a separate AE.  
A surgical or invasive procedure is not an AE in itself. Instead, the condition for 
which the surgical or invasive procedure is performed may be an AE. Planned or 
elective surgery or procedures (i.e. planned prior to signature of informed consent) 
for a pre-existing condition and the pre-existing condition leading to surgery or 
procedure are not AEs. However, if the pre-existing condition worsened after 
signature of informed consent, the worsening of the condition constitutes an AE.  
Worsening of the disease under study (underlying disease): This will be captured 
by efficacy parameters and should not usually be recorded as AE, unless one or 
more of the following criteria are met: 
 The worsening of the disease under study constitutes a serious AE 
 A deterioration exceeding the usual fluctuations of the disease under study 
has occurred in the opinion of the investigator 
 The worsening leads to discontinuation of the study medication 
 Additional treatment is required for the worsening, e.g. concomitant 
medication is added or changed. 
No causal relationship with the investigational drug, or comparator drug, or study 
procedures is implied by the use of the term “Adverse Event”. 
• Adverse reaction of an investigational medicinal product:  
All untoward and unintended responses to an IMP related to any dose 
administered. All AEs judged by either the reporting investigator or the sponsor as 
having a reasonable causal relationship to a medicinal product qualify as adverse 
reactions. The expression reasonable causal relationship means to convey in 
general that there are facts, evidence or arguments to suggest a causal 
association with the drug. 
• Serious Adverse Event (SAE) 
An SAE is any untoward medical occurrence or effect that at any dose*: 
 results in death 
- 
Death is an outcome of an AE and not an AE in itself. All 
deaths, regardless of cause or relationship must be reported 
for study subjects. 
 is life-threatening 
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- 
“Life-threatening” refers to an event in which the subject was 
at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it were 
more severe. 
 requires hospitalization or prolongation of existing hospitalization  
- 
In-subject hospitalization means that the subject has been 
formally admitted to a hospital for medical reasons, for any 
length of time, which may or may not be overnight. It does not 
include presentation and care within an emergency 
department.  
- 
A complication that occurs during hospitalization and 
prolongs the existing hospitalization is an SAE. Complications 
that occur during hospitalization but do not prolong the 
existing hospitalization and do not meet any other 
seriousness criteria are non-serious AEs. 
- 
Elective or pre-planned (prior to signature of informed 
consent) hospitalization for investigations, medical or surgical 
treatment does not meet this seriousness criterion. However, 
if the underlying condition for which hospital treatment or 
surgery had been planned worsened during the study, the 
worsening of the condition is to be reported as SAE. 
 results in persistent or significant disability / incapacity 
 is a congenital anomaly / birth defect 
 is another important medical event 
- 
Adverse events that may not be immediately life-threatening 
or result in death or hospitalization but my jeopardize the 
subject or may require medical or surgical intervention to 
prevent one of the other outcomes listed above, should be 
reported as serious. Medical and scientific judgment must be 
exercised in deciding whether an event is serious. 
* “At any dose” does not necessarily imply that the subject is receiving the study 
drug at the time of the event. 
• Diagnosis vs. Signs/Symptoms 
The investigator should provide a diagnosis rather than individual signs and 
symptoms, wherever possible and appropriate. However, if there is not enough 
information to provide a diagnosis, individual signs and symptoms are to be 
recorded. If a diagnosis is accompanied by unusual symptoms, the diagnosis itself 
and the unusual symptoms have to be reported separately. For serious and other 
IRAEs the investigator shall provide any other supporting information that may be 
required for the assessment of the events, specifically in the free text narrative 
description of the case. This is of particular importance in situations where a 
diagnosis cannot (yet) be made. Any subject identifying data on supporting 
documents (e.g. name, address, phone number) have to be obliterated prior to 
sending them to the sponsor. 
 
 
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A complication of an AE constitutes another AE. For example in diarrhea leading 
to dehydration, diarrhea and dehydration would be captured as separate AEs. 
The eCRF provides for a number of items to be completed for each AE. This 
includes the onset date, end date, intensity/severity, seriousness, action taken with 
study medication, treatment for the AE, outcome, and causal relationship of the 
AE with the study medication, other drugs, or study procedures.  
• Onset date, end date 
If an AE started during the study but did not end before the final follow-up visit, the 
investigator must make a reasonable effort to establish the outcome and the end 
date. If this is not possible, e.g. because the AE is still ongoing, or the subject is 
lost to follow-up, there will be no end date for the AE. 
For all AEs that resolve, resolve with sequelae, or have a fatal outcome, an end 
date must be provided.  
If an AE stops and restarts later, all occurrences have to be recorded separately.  
If an AE starts as non-serious AE and becomes serious at a later point in time, the 
following applies in regard to onset and end dates:  
• Intensity/Severity 
Refers to the extent to which an AE affects the subject’s daily activities. Severity 
will be categorized according to the following criteria: 
Table: Adverse Event Severity 
Mild 
The AE does not interfere with the subject’s routine 
activities. 
Moderate 
The AE interferes with the subject’s daily routine, but 
usual routine activities can still be carried out. 
Severe 
The AE results in inability to perform routine activities. 
Severe vs. Serious: The severity is used to describe the intensity of an event. 
This is not the same as seriousness, which is based on subject/event outcome or 
action criteria usually associated with events that pose a threat to subject’s life or 
functioning. Seriousness, not severity, serves as the guide for defining regulatory 
reporting obligations.  
Example: While an event may be of “severe” intensity, it may be of relatively minor 
medical significance, such as severe headache. On the other hand, a myocardial 
infarction would be usually regarded as serious, even if its intensity is “mild”.  
If formal severity classifications are used, such as the NCI CTC classification used 
in oncology studies, provisions should be made regarding the reporting of events 
of defined grading (e.g. ≥ 3) as serious.  
AEs with changes in severity: If an AE changes in severity, this will be captured 
as one AE with the highest severity grade recorded. 
 
 
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• Seriousness 
For definition of seriousness criteria refer to section 9.3.1. For a serious AE all 
seriousness criteria that apply have to be reported. Reporting requirements by the 
investigator are detailed in Appendix 2.  
If a list of always serious terms is to be used in the study, this should be mentioned 
here, as well as its use by the investigator. For example a PT-based auto-
seriousness in the eCRF, or an urgent query process once a verbatim is coded to 
a PT on the list.  
 
• Action Taken with Study Medication 
The action taken with study medication as a result of the AE has to be documented. 
In the situation that the AE leads to permanent discontinuation of the study 
medication, this meets the definition of an AE leading to subject’s withdrawal from 
the study, which is an immediately reportable AE (IRAE). Reporting requirements 
by the investigator are detailed in section Appendix 2. 
 
• Treatment for the AE 
It has to be specified in the eCRF if counteractive treatment was given for the AE. 
Any treatment for an AE, whether pharmacological or other (e.g. surgical) 
treatment, has to be recorded in the eCRF.  
 
• Outcome 
The following categories are used:  
 Resolved 
- 
Indicates that the event has fully resolved. 
 Resolving 
- 
Indicates that the event is in the process of recovery but has not yet 
fully resolved. 
 Not resolved 
- 
Indicates that the event is ongoing and there has been no recovery.  
 Resolved with sequelae 
- 
Indicates that there is a residual, possibly permanent consequence 
of the event (e.g. residual hemiparesis subsequent to stroke). 
 Fatal 
- 
Indicates that the subject died due to the event. The outcome “fatal” 
applies only to the event(s) that were the cause(s) of death. For other 
AEs that were ongoing at the time of death, the outcome must not 
be “fatal” but “not resolved”.  
• Causal Relationship of AE 
The causal relationship with the study medication has to be reported for each AE. 
It refers to the presence or absence of a reasonable possibility of a causal 
relationship between the study medication and the AE. The investigator is asked 
to use medical judgment and take into account the nature of the AE, subject’s 
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medical history, temporal relation, response to withdrawal or interruption of study 
drug (dechallenge), response to re-introduction of study drug (rechallenge), any 
alternative explanations such as underlying or concomitant diseases, concomitant 
drugs, study procedures.  
The following categories are used:  
 Related: There is a reasonable possibility of a causal relationship between 
the study medication and the AE. 
 Not related: There is no reasonable possibility of a causal relationship 
between the study medication and the AE. 
For serious and other immediately reportable AEs the investigator is asked to 
specify if there are alternative and/or additional explanations for the occurrence of 
the event, e.g. concomitant drugs, study procedures, or concomitant/underlying 
disease and should provide this information already with the initial case report. 
 
• Concomitant medication 
Concomitant medication will be documented according to categories of medicinal 
products which are normally used in clinical studies as NIMPs (European 
Commission, 18/03/2011):  
(1) Rescue medication 
(2) Challenge agents 
(3) Concomitant medicinal products systematically prescribed to the study patients 
(4) Background treatment 
 
Definitions adapted from the Guidance on IMPs and NIMPs (European Commission, 
18/03/2011): 
• Rescue medication 
Rescue medications are medicines identified as those that may be administered to 
the patients when the efficacy of the IMP is not satisfactory, or the effect of the IMP is 
too great and is likely to cause a hazard to the patient, or to manage an emergency 
situation. Rescue medication allows patients to receive effective treatment, e.g. where 
a standard treatment is available.  
• Challenge agents 
Challenge agents are usually given to study subjects to produce a physiological 
response that is necessary before the pharmacological action of the IMP can be 
assessed.  
• Concomitant medicinal products systematically prescribed to the study 
patients 
This type of NIMP is given to clinical study participants as required in the protocol as 
part of their standard care for a condition which is not the indication for which the IMP 
is being tested, and is therefore not the object of the study. 
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• Background treatment 
This type of medicinal product is administered to each of the clinical study subjects, 
regardless of randomization arm, to treat the indication which is the object of the study. 
Background treatment is generally considered to be the current standard care for the 
particular indication. In these studies, the IMP is given in addition to the background 
treatment and safety and efficacy are assessed. The protocol may require that the 
IMP plus the background treatment is compared to an active comparator or to placebo 
plus background treatment. 
 
 
 
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Appendix 2: Reporting Procedures 
Reporting procedure:  
All IRAE information has to be recorded in the IRAE/SAE form and reported to 
 Corporate Drug Safety (CDS) immediately (i. e. within 24 hours) by e-mail 
or fax (see addresses below in the box) after the investigational site becoming aware of 
the IRAE. 
In addition, this IRAE has to be recorded on the AE page of the eCRF and the following 
eCRF pages have to be updated or completed at the same time as necessary: Study 
drug documentation, subject demographics, medical history, concomitant medication, 
and study completion/termination (in case of an AE leading to withdrawal). 
Entry of an IRAE/SAE into the eCRF will trigger an alert message to 
 and 
 
CDS. 
  
 
  
 
 
 
 
 
 
For questions regarding IRAEs including SAEs or to notify the sponsor of an IRAE 
including SAE in the event of technical failure of the e-mail or fax system, the investigator 
should contact
 
. 
Whenever follow-up information becomes available to a previously recorded IRAE/SAE, 
this has to be captured in the IRAE/SAE form and should be send by e-mail or fax 
together with any supporting documents (e.g. medical records, autopsy report, ECG or 
laboratory reports) as part of the follow-up information accompanied by a cover page 
within max. 24 hours of the investigator becoming aware of the follow-up information to 
the reporting contact above.  
In addition, the new information should be captured in the eCRF on the AE page within 
max. 24 hours after becoming aware of the follow-up information. 
The investigator has to undertake active follow-up for subjects with IRAE/SAEs. The 
investigator shall respond to queries raised by the sponsor with regard to IRAE/SAEs 
within the timelines stipulated in the query, and provide all necessary information as 
requested. In case of a fatal or life-threatening SAE, the sponsor will contact the 
investigator urgently to obtain required additional information within one business day. If 
supporting documents are requested by the sponsor (e.g. copies of medical records, 
laboratory reports, ECG tracings, autopsy report), the investigator must ensure that 
subject identifying data are obliterated prior to sending to the sponsor. The supporting 
documents should carry the subject ID for identification. 
If required the investigator is responsible to inform local IECs/IRBs of safety reports in 
compliance with applicable regulatory requirements. Copies of all correspondence 
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relating to reporting of safety reports to IEC/IRB should be maintained in the Investigator 
Site File/ Regulatory Binder. 
The sponsor is responsible for fulfilling all obligations regarding notification of regulatory 
authorities, ethics committees according to applicable regulatory requirements, in regard 
to expedited reporting (e.g. serious unexpected suspected adverse reactions) and 
periodic reporting (e.g. development Safety Update Report). In addition, the sponsor is 
responsible for information of investigators according to the current legislation. 
 
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