Conditions: Congenital Afibrinogenemia Congenital Hypofibrinogenemia
Keywords: fibrinogen, bleeding,
Allocation: NA | Intervention model: SEQUENTIAL
Enrollment: 67
Healthy volunteers: no

Brief summary:
This was a prospective, open-label, multicenter, phase I/III study investigating the 14-day single-dose pharmacokinetic and pharmacodynamic properties, efficacy and safety of BT524 following intravenous administration in the treatment or prophylaxis of bleeding in patients with congenital afibrinogenemia or severe congenital hypofibrinogenemia.

Detailed description:
The study was divided into two parts (Part I and Part II). Part I focused on the primary endpoint of the study, 14-day single-dose pharmacokinetics (PK) and 14-day single-dose pharmacodynamics (PD), as well as the assessment of maximum clot firmness (MCF) as a surrogate parameter for efficacy. Part I of the study was followed by Part II, which evaluated the efficacy and safety of single and repetitive administration of BT524 in patients undergoing on-demand prophylaxis (ODP) and/or on-demand treatment (ODT) for various bleeding events \[e.g., elective surgery, spontaneous or post-traumatic major bleeding\]. All patients who participated in the PK assessment (Part I) without severe post-administration complications ideally continued treatment with BT524 for ODP and/or ODT in Part II.

Arms:
arm 1: Part I: A single intravenous infusion of BT524 for assessment of PK/PD of BT524.

Part II: A single or repetitive intravenous infusion(s) of BT524 for on-demand prophylaxis/on-demand treatment of bleeding events.

Interventions: intervention 1: BT524 (Part I) intervention 2: BT524 (Part II)
Intervention descriptions: intervention 1: Single intravenous infusion of 70 mg BT524 per kg body weight. intervention 2: Single or repetitive intravenous infusion(s) of BT524, depending on the severity of the disorder, location and extent of the bleeding and patient's clinical condition. Dosage based on individual body weight and fibrinogen level.

Protocol document:
ICF_002.pdf: 
Adult Informed Consent Document for Enrolment 
Pharmacokinetics, efficacy and safety of BT524 
EudraCT number (EU only): 2011-004154-25 
 
02Aug2018, Version 6.0_PK Part I & Part II(Master) 
<Insert Investigator Name, City and State>    
Page 1 of 19 
INFORMATION FOR ADULT PATIENT 
AND 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
 
 
Protocol Title: A prospective, open-label, phase I/III study investigating 
pharmacokinetic properties of BT524 and efficacy and 
safety of BT524 in the treatment and prophylaxis of 
bleeding 
in 
patients 
with 
congenital 
fibrinogen 
deficiency 
 
Protocol Number: 984 
  
  
  
Sponsor: Biotest AG 
Investigator:        
Address:       
       
       
       
       
Phone:       
Email:       
  
A.  Patient Information 
 
We are asking you to be a subject in a research study. If you agree to participate in this study, we 
would like to ask you to sign this informed consent document. Informed consent is a written 
agreement that you sign indicating your willingness to participate in this research.  
 
Before you agree (consent) to participate in this study, it is important that you read (or have read 
to you) and understand the information contained in this informed consent document. This 
document describes your rights as a research patient and the study’s purpose, procedures, risks, 
discomforts, precautions, alternate procedures and possible benefits. It is important for you to 
understand that no guarantees or assurances can be made regarding the study results. You should 
consent only after you have received all the necessary information and have had enough time to 
decide whether you wish to participate. Your signature on this form is voluntary and does not waive 
any of your legal rights or make any institutions or persons involved in this research any less 


Adult Informed Consent Document for Enrolment 
Pharmacokinetics, efficacy and safety of BT524 
EudraCT number (EU only): 2011-004154-25 
 
02Aug2018, Version 6.0_PK Part I & Part II(Master) 
<Insert Investigator Name, City and State>    
Page 2 of 19 
responsible for your well being. Also after having signed you can decide to withdraw your 
agreement at any time. 
 
In this consent form, ‘you’ always refers to the study patient. If you are a legal representative, please 
remember that ‘you’ refers to the study patient. 
 
Review of the Study 
 
This clinical study will be conducted in accordance with the principles of the World Health 
Organization, as stipulated in the Declaration of Helsinki, and in accordance with the requirements 
of the drug approval agencies in Middle East and North Africa (MENA) region, and the European 
Union. Prior to study start an Independent Ethics Committee <country specific designation> 
favourably evaluated the conduct of the clinical study. This organization is an independent body of 
experts whose responsibility is to ensure the protection of the rights, safety, and well-being of 
patients involved in a study. In particular, the Ethics Committee reviewed whether the participants 
are adequately protected and their rights are safeguarded.  
 
Why am I being asked to be a part of this study?  
 
This research study is being done by the pharmaceutical company Biotest AG (Biotest). This study 
is evaluating how BT524, a Fibrinogen Concentrate (a medicine containing human fibrinogen) is 
handled by your body and how well it controls bleeding. Fibrinogen is normally made by our body 
and plays an important part in stopping bleeding. 
 
You are being asked to take part in this study because you have a congenital fibrinogen deficiency 
that may result in severe bleeding events. 
 
Do I have to participate in this study?  
 
No, you do not have to participate in this study. Your participation is voluntary. Even if you decide 
today that you will participate, you can drop out of the study at any time. You do not have to give 
any reasons, and there will be no penalty. You will not lose any benefits or medical care to which 
you are otherwise entitled. If you decide to withdraw from the study before it ends, you will be asked 
to visit your study doctor for a final study visit/examination in order to make some final assessments 
and have an orderly end to your participation. 
 
If new information becomes available about this study product during the study, we will tell you 
about it. If this happens, you can also leave the study at any time. 
 
In certain circumstances, it may also happen that the study doctor decides to stop the study. 
 
Your participation in the study could also be terminated by the study doctor without your consent, 
if the study doctor decides that this is in your best medical interest. Your participation may also be 
terminated without your consent by Biotest if you fail to comply with the requirements of the study 
or if Biotest decides to discontinue the study. 
 
Who is responsible for the data collected in this study?  
 
<Insert Name and Address of Principal Investigator.> 
 


Adult Informed Consent Document for Enrolment 
Pharmacokinetics, efficacy and safety of BT524 
EudraCT number (EU only): 2011-004154-25 
 
02Aug2018, Version 6.0_PK Part I & Part II(Master) 
<Insert Investigator Name, City and State>    
Page 3 of 19 
Where will this study be done? 
 
This study is being conducted at approximately 5-7 centres in Middle East and North Africa (MENA) 
region  and in the European Union. You will be one of approximately 40 subjects who will receive 
this study treatment. 
 
Introduction and Study Rationale 
 
Fibrinogen is made by our body and plays an important part in stopping bleeding. It does this by 
helping to thicken the blood (blood clotting) at the site of the bleed. Enough quantity of fibrinogen 
needs to be available in our body in order to achieve this, otherwise bleeding may continue. Some 
people are born with too little fibrinogen (congenital deficiency).  
 
Congenital fibrinogen deficiency is a rare inherited bleeding disorder that is passed from parents to 
their children. It induces moderate to severe bleeding after injuries or surgical procedures. In the 
most severe form of this disease, fibrinogen levels are undetectable or extremely low.  
 
Today, Fibrinogen Concentrate preparations are available in some countries. These preparations 
are derived from human donor blood and are used as a replacement therapy, providing fibrinogen 
to people with fibrinogen deficiency for the treatment and prevention of their bleeding. These 
Fibrinogen Concentrates are licensed (doctors can prescribe them to their patients) in several 
European countries and in the United States.  
 
Biotest has also developed a Fibrinogen Concentrate, BT524, derived from human donor blood, 
which will be used in this study. BT524 is manufactured in Germany under very strict guidelines 
according to international regulations, to ensure that it is safe for patients. BT524 is not licensed 
and only available in clinical studies.  
 
Patients with severe fibrinogen deficiency will be included in this clinical study, which is designed 
to follow the outcome of BT524 in their body and to demonstrate its efficacy and safety in their 
bleeding situations. 
 
Study Overview and Procedures 
 
The study will be conducted in two parts. In Part 1 you will receive a single infusion of BT524. Blood 
samples will be taken before and after the infusion to analyse what happens to BT524 and how 
long it stays in your body. In Part 2 you may receive BT524 as treatment in case of a bleeding event 
or as treatment prior to surgery to prevent a bleeding event. Only those who meet the study entry 
requirements can participate.  
 
Part 1 of the study will last approximately up to 66 days. You will have a Screening Visit which will 
allow the study doctor to make sure you are eligible to take part in the study. Various examinations 
will be done and blood samples will be collected during the Screening Visit. Then within the next 
17 days you will be admitted to the hospital and will receive one treatment with BT524. Each 
infusion of BT524 lasts an average of 45 minutes to one hour. You will have blood samples 
collected and undergo various examinations. You will stay in the hospital for 48 hours. During the 
time you are in the hospital, you will be encouraged to be active (spend time walking) to reduce the 
risk of clots that can sometimes form when patients are immobile. Each day additional blood 
samples will be taken and examinations will be done. Then you will need to come to the study 
centre about once every three days for the next two weeks for additional blood sampling and 
examinations. There will be a final check up on Day 49.  
 
Part 2 of the study will begin after Part 1 and will last for at least 13.5 months, dependent on the 
timepoint when you will be included into the study. During Part 2, you may be treated with BT524 


Adult Informed Consent Document for Enrolment 
Pharmacokinetics, efficacy and safety of BT524 
EudraCT number (EU only): 2011-004154-25 
 
02Aug2018, Version 6.0_PK Part I & Part II(Master) 
<Insert Investigator Name, City and State>    
Page 4 of 19 
if you have a bleeding event or prior to any surgery you may need. After every BT524 treatment 
you will have one or two follow-up visits. You will be hospitalised during Part 2 if you are undergoing 
surgery or if the bleeding event requires it. The total duration of the study, for Part 1 and Part 2, will 
be at least 15.5 months. 
 
It is very important that throughout the study period, you note and remember any illness and any 
medication you will be taking (please note their dates and their dosage also), because your study 
doctor will ask you about them at each of your visits to the hospital. 
 
Study Part 1: Measuring the fibrinogen and how long it stays in your body 
 
Before anything is done in the study you must give your written informed consent to participate. 
Then you will have a screening examination. First your study doctor will need to check that you 
have a severe fibrinogen deficiency (plasma fibrinogen level less than or equal to 50 mg/dL). He or 
she will consult your medical records to do this. If the study doctor treating you today is not your 
regular doctor, he or she may need to contact your regular doctor to check that you can participate 
in the study. 
 
The study doctor will also perform a physical examination, take a detailed medical history (including 
what medications you are currently taking), ask about any allergies you may have and check that 
you will not be having any vaccinations within the 3 weeks before you have your BT524 infusion. 
You will also have the following procedures done as Screening assessments: 
 
 
measurement vital signs (temperature, blood pressure, pulse rate) and weight 
 
a urine pregnancy test, to ensure you are not pregnant (if applicable)  
 
an electrocardiogram (ECG) which makes a “picture” of the electrical activity of the heart, 
to check for heart problems 
 
an ultrasound of your lower limbs to ensure there are no blood clots 
 
a urine laboratory test 
 
blood samples taken from your arm for testing of routine laboratory parameters, specific 
clotting parameters, confirmation of fibrinogen levels, and to see if you have any antibodies 
to fibrinogen.  
 
Then within the next 17 days you will be admitted to the hospital to begin the study; this will be 
Day 0. You are asked not to perform excessive physical exercise (extreme sports activities, sauna) 
during the 72 hours before you go to the hospital. You should not drink any alcohol and should limit 
your caffeine intake (for example, coffee, tea, chocolate, etc.) during the 24 hours before you go to 
the hospital.  
 
On Day 0, the doctor will again confirm that you meet the criteria for entry into the study. If so, you 
will receive one infusion of BT524 through a needle into a blood vessel (vein) in your arm. Before 
you receive the infusion the study doctor will perform most of the examinations that were done at 
the Screening Visit, and collect blood samples for measurement of your fibrinogen levels and for 
routine and specific clotting laboratory parameters. Some samples will also be stored for further 
analysis, in case it becomes necessary to check for any viral infection. 
 
Additional blood samples will be taken from the opposite arm. A sample will be collected as soon 
as the infusion is complete, and at the following time points after the infusion: 
 
30 minutes 
 
one hour 
 
two hours 


Adult Informed Consent Document for Enrolment 
Pharmacokinetics, efficacy and safety of BT524 
EudraCT number (EU only): 2011-004154-25 
 
02Aug2018, Version 6.0_PK Part I & Part II(Master) 
<Insert Investigator Name, City and State>    
Page 5 of 19 
 
four hours 
 
eight hours.  
 
These blood samples will be analysed to measure your fibrinogen levels. The study doctor will also 
check your vital signs during and after the infusion and evaluate if you have had any unpleasant 
reactions (side effects) from the BT524 infusion. You will have a physical examination done by your 
study doctor 2 hours after the end of the infusion, and an ECG six hours after the end of the infusion. 
 
On Day 1 and Day 2 you will remain in the hospital. Each day you will have blood samples collected 
to check routine and specific clotting parameters and to measure your fibrinogen levels. You will 
also have a physical examination, your vital signs will be measured and a urine laboratory test 
(Day2 only) will be done. The doctor will continue to check if you have had any side effects from 
the BT524 infusion. An ECG will be done on Day 1. The doctor will decide if an ultrasound is needed 
to check for any blood clots.  
 
You will be discharged from the hospital on Day 2 after all the tests have been completed. 
 
You will return to the hospital on Day 4, Day 7, Day 10 and Day 14 for a check up. At each visit the 
following procedures will be done: 
 
 
blood samples will be taken to measure your fibrinogen levels and for routine and specific 
clotting laboratory parameters 
 
a urine laboratory test (D14 only) 
 
a physical examination 
 
measurement of your vital signs and  
 
a check to see if you have had any side effects from the BT524 infusion.  
 
A urine pregnancy test will be done on Day 14, if applicable. 
 
If you have no bleeding events after the Day 14 Visit, or if you do not need any surgery, you will 
return to the facility on Day 49 (49 days after the infusion of BT524) for the last visit in Part 1. At 
this time the study doctor will do the following procedures: 
 
 
collect blood samples for specific clotting laboratory parameters and to see if you have 
developed any antibodies to fibrinogen. Some of the blood will be stored in case analysis 
is needed for viral infection. 
 
perform a physical examination 
 
measure vital signs 
 
check to see if you have had any side effects from the BT524 infusion. 
 
IT IS VERY IMPORTANT THAT YOU COMPLY WITH THE EXACT DATES AND TIMES WHERE 
YOU SHOULD BE PRESENT IN THE HOSPITAL IN THIS PART 1 OF THE STUDY. 
 
Study Part 2: Treating or preventing a bleeding event 
 
Part 2 of the study will begin with the first bleeding event for which you receive treatment after your 
Day 14 follow up visit in Part 1. This may be a bleeding event that happens because of an injury, 
or it may be to prevent a bleeding event if you are going to have surgery (including dental surgery), 
If this occurs before your Day 49 Visit, the Day 49 Visit will be postponed.  
 


Adult Informed Consent Document for Enrolment 
Pharmacokinetics, efficacy and safety of BT524 
EudraCT number (EU only): 2011-004154-25 
 
02Aug2018, Version 6.0_PK Part I & Part II(Master) 
<Insert Investigator Name, City and State>    
Page 6 of 19 
The BT524 treatment you receive (dosage, number of infusions and length of infusions) will be 
based on how severe the bleeding is, the location and extent of the surgical procedure or bleeding, 
and your condition at the time of the event. If the study doctor decides it is necessary, you may 
have more than one infusion for a single bleeding event. 
 
In Part 2, the BT524 infusion, and the blood sampling that will be done 1 hour after the infusion is 
done, will always be done in the hospital. However, you will only be hospitalised if the study doctor 
decides it is necessary. Otherwise, you will be discharged from the hospital or the dentist’s office 
on the same day you came in.  
 
Prior to the infusion of BT524, the study doctor will confirm that you meet all the requirements to 
participate in Part 2 of the study, and will carry out the following procedures: 
 
a physical examination 
 
measurement of your vital signs  
 
collection of blood samples to measure routine and specific clotting laboratory parameters, 
fibrinogen levels, and for storage, in case it become necessary to check for any viral 
infections 
 
a urine pregnancy test, to ensure you are not pregnant (if applicable) 
 
an ultrasound of your lower limbs.  
 
1 hour after the end of the infusion, you will have blood sampling for determination of your fibrinogen 
level and of specific clotting laboratory parameters. Your vital signs will be measured regularly. 
 
You may receive more than one infusion of BT524 for each bleeding event, if the study doctor 
decides it is necessary, and/or if after each infusion your blood samples show that your fibrinogen 
levels are too low. The study doctor may also decide that you need to stay overnight in the hospital, 
or that you need to come back to the hospital for your follow-up visits. 
 
Follow up assessments performed in the hospital will include a physical examination, measurement 
of vital signs and blood sampling for the measure of routine and specific clotting laboratory 
parameters. If you have been hospitalised, these assessments will be performed at the following 
times: 
 
 
24 hours after the last infusion of BT524 
 
at the day of your hospital discharge (if you stayed overnight) 
 
and anytime during your hospitalisation period when your study doctor decides it is needed. 
 
At any time, the doctor may decide to do an ultrasound of your lower limbs. 
 
If the doctor has decided it is not necessary for you to stay in the hospital, or return to the hospital, 
he or she will call you on further days to check your condition.  
 
If the doctor decides it isn’t necessary for you to return to the study facility, he or she will call you 
to check on your condition. After every infusion and at every visit or phone call, the doctor will ask 
you about any possible side effects from the BT524 infusion. 
 
You will have a visit at Day 49 after the last infusion you receive for each bleeding event. The only 
exception is if you have another bleeding event prior to the Day 49 Visit. If this happens the Day 49 
Visit will be postponed. At the Day 49 Visit you will undergo the following procedures: 


Adult Informed Consent Document for Enrolment 
Pharmacokinetics, efficacy and safety of BT524 
EudraCT number (EU only): 2011-004154-25 
 
02Aug2018, Version 6.0_PK Part I & Part II(Master) 
<Insert Investigator Name, City and State>    
Page 7 of 19 
 
physical examination 
 
measurement of vital signs 
 
an ultrasound of your lower limbs (in case of thromboembolic event) 
 
collection of blood samples to for specific clotting laboratory parameters, for storage, in 
case it become necessary to check for any viral infections, and to see if you have 
developed any antibodies to fibrinogen 
 
and the doctor will ask you about any possible side effects you may have experienced 
since the last visit. 
 
Alternative Treatments 
 
Your study doctor will explain to you the standard treatments available for people who have 
congenital fibrinogen deficiency. Alternative treatment options are the use of cryoprecipitate, fresh 
frozen plasma or fibrinogen concentrates that might be available in your country to treat bleeding. 
 
If the treatment with BT524 ever seems to be insufficient in controlling your bleeding events, the 
study doctor can use another available alternative treatment. 
 
Possible Benefits For You 
 
By participation in this study you will be treated with the Fibrinogen Concentrate BT524 when 
needed, and this may provide a direct benefit to you in terms of treating your bleeding. Your 
participation could also help advance medical research. Information learned may benefit future 
subjects who have congenital fibrinogen deficiency. 
 
Possible General Risks 
 
The risks and side effects of BT524 are expected to be in line with the safety profile of authorised 
fibrinogen concentrates. These are described in the next section. But as with any other treatment 
BT524 and study procedures in this investigation may cause unknown risks. All drugs, in theory, 
can have both temporary and permanent side effects or discomfort and can cause unforeseen 
adverse reactions, including death. A lot of measurements are done in this study to closely monitor 
your safety, and at every visit your study doctor and study staff will ask you about any side effects 
you may have experienced. If you have any problems, or any side effects you think might be related 
to this study or the study treatment, you should let the study doctor know at once. 
 
Known Possible Risks Associated with Fibrinogen Concentrate (Human) 
 
The safety of authorised fibrinogen concentrate (human) has been evaluated in clinical studies and 
by collecting reports of possible side effects since it was originally approved for use in Europe in 
1986. The following side effects have been reported after market authorisation or in the scientific 
literature: 
 
 
Allergic or anaphylactic type reactions such as generalised urticaria (hives over the whole 
body), rash, fall in blood pressure, dyspnoea (shortness of breath) 
 
Increase in body temperature 
 
Thromboembolic episodes, including myocardial infarction and pulmonary embolism 
(episodes of formation or presence of a blood clot  inside a blood vessel that may break off 
and damage some body organs such as the heart (heart attack) or the lungs (possible 
failure to breathe))  
 


Adult Informed Consent Document for Enrolment 
Pharmacokinetics, efficacy and safety of BT524 
EudraCT number (EU only): 2011-004154-25 
 
02Aug2018, Version 6.0_PK Part I & Part II(Master) 
<Insert Investigator Name, City and State>    
Page 8 of 19 
If allergic or anaphylactic-type reactions occur, the injection/ infusion has to be stopped 
immediately. In case of anaphylactic shock (life-threatening allergic reaction, such as difficulty 
breathing, low blood pressure, and/ or organ failure), your doctor will start with standard medical 
treatment for shock to treat this reaction. 
 
There is a risk of thrombosis when patients with congenital fibrinogen deficiency are treated with 
human fibrinogen, particularly with high dose or repeated dosing. If you are given human 
fibrinogen, you should be observed closely for signs or symptoms of thrombosis. 
 
If you have e.g. a history of coronary heart disease or myocardial infarction (heart attack), a liver 
disease, if you are having or just had a surgery, or if you are otherwise at risk of thromboembolic 
events or disseminated intravascular coagulation (blood clots form throughout the body's small 
blood vessels, which can reduce or block blood flow through the blood vessels, and can damage 
the body's organs), 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 by your doctor.  
 
BT524 is a Fibrinogen Concentrate made from human plasma (collected from blood). Products 
made from human plasma may contain infectious agents, such as viruses like hepatitis or HIV (the 
AIDS virus), that can cause disease. The risk that BT524 will transmit an infectious (viral) agent 
has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for 
the presence of current viral infections, and by inactivating and/or removing certain viruses during 
the manufacturing process. Despite these measures, such products may still potentially contain 
infectious agents, including those not yet known or identified. Thus, the risk of transmission of 
infectious agents cannot be totally eliminated. 
 
Collection of blood samples 
 
Blood samples will be collected during this study. A needle is put into a vein in the arm and a blood 
sample is taken. Although one blood draw is usually sufficient, a second one may be necessary if 
the first is not successful. Blood drawing does not usually have any risks, but in rare cases it can 
cause pain, bleeding, burning, dizziness, fainting, or a bruise or an infection at the site where the 
needle was inserted to take the blood. 
 
In each part of the study, blood samples will be drawn to study the effects of treatment with BT524 
on blood fibrinogen and other measures of blood clotting, and for other laboratory tests related to 
general health (safety measures). Estimates of the amount of blood that will be taken are shown in 
the table below: 
 
 
Part 1 
 
Screening  
 35.2 mL 
        Day 0 
167,3 mL 
 
Days 1-to-14 
160,3 mL 
 
Day 49 (Final visit) 
 51,2 mL 
 
 
Part 2 :On-demand prophylaxis / treatment without hospitalisation 
 
 
Days 0 
85.9 mL 
 
Optional visit 
14,7 mL 
 
Day 49 (Final visit) 
45.2 mL 
 
 


Adult Informed Consent Document for Enrolment 
Pharmacokinetics, efficacy and safety of BT524 
EudraCT number (EU only): 2011-004154-25 
 
02Aug2018, Version 6.0_PK Part I & Part II(Master) 
<Insert Investigator Name, City and State>    
Page 9 of 19 
Part 2 : On-demand prophylaxis / treatment with hospitalisation 
 
Days 0 
85.9 mL 
 
24h after end of last infusion  and Discharge Day 
17.4 mL 
 
Optional visit 
8,7 ml 
 
Day 49 (Final visit) 
45.2 mL 
 
 
Total for  
 
Screening; Part 1; one bleeding event in Part 2; and 
two Day 49 visits (one in Part 1 and one in Part 2) 
559.8 mL or 
571.2 mL in 
case of 
hospitalization  
 
 
For each additional bleeding event in Part 2, approximately 145.8 mL or 157.2 mL of blood will be 
collected over the 49 day treatment period. This is approximately 29 or 31 teaspoons. 
 
The total amount of blood drawn during the study will vary according to how many bleeding events 
or surgeries take place during Part 2 and how many times you are examined for a “Day 49” follow-
up. If you experience symptoms that seem like they might be an allergic reaction, the study plan 
calls for several additional samples. Many of the blood tests planned during Part 2 are blood tests 
that would likely be drawn as part of regular clinical care. If a bleeding or surgery event in Part 2 
requires hospitalisation, other blood samples may be drawn by your doctors, including additional 
samples that measure the blood clotting at timepoints other than those named in the study plan. If 
this happens, the results will be recorded as part of the study. 
 
The estimated blood requirement for the whole study as shown above is 559.8 mL or 571.2 mL in 
case of hospitalization. This is based on participation in Parts 1 and 2 with a Day 49 follow-up visit 
after each part. For purposes of comparison, when volunteer donors give blood to a blood bank for 
use in transfusion of patients, the blood volume taken is approximately 500 mL at one day. 
 
A portion of the blood from the blood samples will be kept frozen to test for any viral infections in 
the future, if needed. 
 
Electrocardiogram (ECG) 
 
The ECG test that will be used to monitor your heart rhythm at different times during the study is a 
non-invasive, standard medical procedure performed routinely at medical centres. There are no 
direct risks from a diagnostic ECG but please ask your doctor if you have any questions. 
 
Ultrasound 
 
Ultrasound is another standard imaging method that is performed routinely at medical centres. 
Ultrasound uses low power sound waves to produce relatively precise images of structures within 
your body. The ultrasound examinations done during this study are also a non-invasive procedure, 
and will use a sonar device outside of your body. There are no direct risks from a diagnostic 
ultrasound exam but please ask your doctor if you have any questions. 
 
Pregnancy 
 
There is no information about the risks of Fibrinogen Concentrate on pregnancy or breast feeding. 
Therefore, if you are a woman, you will not be allowed to participate in the study if you are pregnant 
or breast feeding, and you are not allowed to get pregnant while participating in this study (until the 
final study visit has been done). During the study and at least one month after the last administration 
of BT524, women will have to use an approved contraceptive method: oral/ injectable/ 


Adult Informed Consent Document for Enrolment 
Pharmacokinetics, efficacy and safety of BT524 
EudraCT number (EU only): 2011-004154-25 
 
02Aug2018, Version 6.0_PK Part I & Part II(Master) 
<Insert Investigator Name, City and State>    
Page 10 of 19 
implantable/insertable/topical hormonal contraceptives, intrauterine devices, female sterilization, 
partner's vasectomy or condoms. If you become pregnant during your participation in this study, 
you will be withdrawn from the study but representatives from Biotest will follow the progress and 
outcome of your pregnancy, to monitor your safety and the safety of your baby. In order to achieve 
this, Biotest will need to collect information from the physician following up your pregnancy.  
 
New Findings 
 
If new information becomes available during your participation in this study that may influence your 
willingness to participate, your study doctor will communicate this to you and/or your legal 
representative promptly. 
 
Costs to You 
 
The study treatment BT524, hospital stays, and any tests or procedures associated with the study 
(for example, blood tests) will be provided to you free of charge by Biotest. You will be responsible 
for paying all other charges associated with your treatment and follow up not related to this study. 
<to be adapted to country specific requirements and needs> 
 
Compensation 
 
<to be adapted to country specific requirements and needs.>  
<As per Biotest, patients in Lebanon to receive the equivalent of US$80.00 per day. To be 
paid after Screening for patients who are Screening failures and after completion of Day 49 
assessments for patients who are enrolled.> 
You will not receive payment for your participation in this study. You will receive full reimbursement 
for study-related expenses e.g. necessary travel and overnight stays, or they will be pre-arranged 
by Biotest. Your doctor and the institution will receive payment for the testing and data collection 
associated with this study. 
 
If you have a planned or elective surgery during the course of the study, you or your insurance 
company will be responsible for the costs of the surgery, and all costs associated with your hospital 
stay. Biotest will only be responsible for the costs of the study treatment BT524 and any procedures 
required for this study. 
 
Research Related Injury – Information about Insurance 
 
For any costs directly resulting from health problems caused by the study treatment you are 
covered by Biotest’s insurance during the clinical study. 
 
Under the insurance <to be adapted as needed for each country: Name of Insurance 
Company>, participants are obliged to report to the study doctor immediately any change 
(especially worsening) of the state of health, which might be connected to study participation. The 
study doctor also has to be informed about additional treatment (whether medical or non-medical) 
which is initiated while the patient is taking part in the study. After informing the study doctor you 
should also inform the insurance company. Otherwise insurance coverage cannot be guaranteed. 
In cases where you are not able to inform the insurance company by yourself, a relative should do 
this. The details of the insurance conditions will be provided to you by your doctor. 
 
If you are injured as a direct result of receiving BT524 while following your study doctor’s 
instructions, you should immediately contact 
_____________________________________ <insert study doctor and study coordinator 
names> at _____________________________________ <insert primary and back up 
telephone numbers for emergency contacts> and emergency medical treatment will be 


Adult Informed Consent Document for Enrolment 
Pharmacokinetics, efficacy and safety of BT524 
EudraCT number (EU only): 2011-004154-25 
 
02Aug2018, Version 6.0_PK Part I & Part II(Master) 
<Insert Investigator Name, City and State>    
Page 11 of 19 
provided. You will be reimbursed for the reasonable cost of your treatment not covered by your 
health or other insurance. By signing this form, you will not give up any of your legal rights that you 
may have under federal or state laws and regulations (as a research patient). 
 
The insurance company for this study is: 
 
<to be added> 
 
Insurance No.: <to be added> 
In case of a claim to the insurance please contact: 
 
 
 
<to be added> 
 
Phone: 
<to be added> 
 
Fax: 
<to be added> 
 
Please note that any damages occurring during your travels to or from your study doctor/study 
hospital (e.g. accident, theft) are not covered by the above mentioned insurance and you are 
responsible for any consequences. 
 
Treatment after the End of the Study 
 
After study is completed, you can either return to your prior treatment or ask your doctor to continue 
on another Fibrinogen containing product that may be available in your country for the treatment of 
future acute bleeding.  
 
Source of Funding 
 
Biotest will provide funding for this study. 
 
Confidentiality and Data Protection 
In connection with the conduct of the research study, certain personal data will be collected and 
processed. This section aims at informing you on how the collection and processing of your 
personal data is handled in connection with the research study.  
Please read this data protection information carefully. To confirm that you have read and 
understood its content and that you agree with the processing of your personal data as described 
herein, please provide your signature at the end of the document. 
Who is responsible for the data processing? 
As the sponsor, Biotest AG (“Sponsor”) determines the purposes and means of the processing of 
your personal data in the context of the research study together with study center and/or the study 
doctor. Therefore, both the Sponsor and the study center/study doctor are considered data 
controller under applicable data protection laws. 
 
Contact details of the Sponsor: 
Biotest AG  
Landsteinerstraße 5 
63303 Dreieich 
Germany 
Tel.: 0049 6013  801 0 


Adult Informed Consent Document for Enrolment 
Pharmacokinetics, efficacy and safety of BT524 
EudraCT number (EU only): 2011-004154-25 
 
02Aug2018, Version 6.0_PK Part I & Part II(Master) 
<Insert Investigator Name, City and State>    
Page 12 of 19 
E-Mail: datenschutz@biotest.com 
 
You can also contact our data protection officer at the e-mail address provided if you have any 
questions about data processing concerning you or if you wish to exercise any rights to which you 
are entitled. 
Contact details of [study center and study doctor]: 
[Insert name and contact details, including telephone number and e-mail address as necessary] 
What types of personal data are processed? 
In connection with your participation in the research study, the following personal data, including 
sensitive personal data, will be processed: your name/initials, sex, month, year of birth, contact 
details, information needed for reimbursement purposes, body weight and height, racial and ethnic 
origin, health data, including medical records and information on how you respond to the treatment, 
as necessary for the purpose of the research study, including blood and urine samples. 
How and for what purpose will my personal data be used? 
Your personal data will be collected by [the study doctor and the study center staff] and will be 
recorded on paper and/or on electronic data storage devices in/at [insert Clinical Site Name & 
Address] to run the research study and to monitor your safety as a study participant. In addition, 
some of your health data may be obtained from other treating physicians, provided you have 
released them from their obligation to maintain medical confidentiality.  
The personal data collected will be processed in a manner that ensures appropriate security and 
confidentiality of your data. The Sponsor and its representatives (e.g. Clinical Research 
Organisation - CRO), as well as the study center and the study doctor will take all reasonable steps 
to protect your privacy as is required by applicable laws and regulations. These include, e.g., 
measures to prevent unauthorized access to or use of your personal data and the equipment used 
for the processing, e.g. by limiting access to the rooms and equipment where your personal data 
is stored and by pseudonymizing your personal data. Specifically, for the purpose of this research 
study, your name will be replaced by a code (study patient number) at the beginning of the trial, in 
order to rule out that you can be directly identified or to make your identification significantly harder. 
The list with patient names and their respective codes will be kept in a secure place, separate from 
the research study documentation. Only your study doctor and the study center staff/persons 
explicitly authorized by the study doctor have access to the list and can link your study patient 
number to your name in case of emergency in/at [insert Clinical Site Name & Address]. The analysis 
and usage of the data obtained during the research study by the study doctor and the study center 
staff takes place exclusively in pseudonymized form.  
Your pseudonymized personal data may be disclosed to and processed under supervision of [insert 
CRO Name & Address], in accordance with applicable laws and the terms of this consent form. 
[insert CRO Name] and its authorized personnel have signed a non-disclosure agreement or are 
legally obliged to maintain secrecy. In addition, your personal data, including your ethnicity and 
health data can be: 
a) kept available in/at [insert Clinical Site Name & Address] and disclosed to competent 
supervisory authorities for inspection or monitors appointed by the Sponsor to verify 
the proper conduct of the research study; 


Adult Informed Consent Document for Enrolment 
Pharmacokinetics, efficacy and safety of BT524 
EudraCT number (EU only): 2011-004154-25 
 
02Aug2018, Version 6.0_PK Part I & Part II(Master) 
<Insert Investigator Name, City and State>    
Page 13 of 19 
b) transferred, in pseudonymized form, to the Sponsor or to a service provider (Clinical 
Research Organization) commissioned by the latter for scientific evaluation, 
c) transferred, in pseudonymized form, to the Sponsor and the competent authority for 
the marketing authorization if an application for a marketing authorization is filed; 
d) transferred, in pseudonymized form, to the Sponsor and the competent authority and 
subsequently by the latter to the European database in the event of adverse events 
in connection with the investigational medicinal product, 
e) transferred to the responsible health authority in case of a positive test result for 
hepatitis B and/or C, as far as the test result indicates an acute infection and to the 
Robert-Koch-Institut Berlin in case of a positive test result for HIV. 
The blood and urine samples collected from you during the research study will be pseudonymized 
and shipped to, temporarily stored and tested by SYNLAB, SYNLAB Analytics & Services 
Germany GmbH, Bayerstr. 53, 80335 Munich / Germany.  
The blood samples for Fibrinogen activity and antigen analyses will be shipped to, temporarily 
stored and tested by Institute for clinical Chemie and Lab Diagnostics at University Hospital 
Duesseldorf Moorenstraße 5, 40225 Duesseldorf, Germany.  
The samples will only be used for research purposes and no analyses except those specified in 
the Patient Information for the research study will be performed without your prior consent and the 
approval of the competent Ethics Committee. Your identity is kept confidential as the laboratory will 
only receive your study patient number. All data gained through the analysis of the samples will be 
transferred in pseudonymized form to the Sponsor or to a site commissioned by the Sponsor for 
the purposes of further analysis within scope of the research study. Following the completion of the 
research study all samples will be destroyed except for those blood samples that will be frozen and 
stored in case you develop a viral reaction after you have been treated with BT524, or for further 
analysis in case of future suspicion of a new virus not yet identified. The frozen blood samples will 
be kept up to six months following the completion of the research study, or longer if required by 
applicable laws. The Sponsor will be responsible for storage and record keeping after completion 
of the research study. Subsequent to the six months period, the samples will be destroyed.  
Neither the Sponsor, nor its CRO or any other company supporting the Sponsor in conducting the 
research study will be able to identify you directly, as these parties will receive pseudonymized 
personal data (e.g. month, year of birth, gender, race and health data relevant to the research 
study). This, however, does not apply to monitors, who are appointed by the Sponsor to ensure the 
appropriate implementation of the research study and that your rights and well-being is protected. 
They will verify that you have provided informed consent prior to participating in the research study 
and that the source documents and other trial records are accurate, complete, kept up-to-date, and 
maintained. For that purpose, these monitors require direct access to your personal data, including 
your health data. Further, your personal data may be disclosed in response to lawful requests by 
public authorities, including those to meet national security or law enforcement requirements. For 
this purpose, you have to release the study doctor from the obligation to maintain medical 
confidentiality. All other individuals or companies acting on behalf of the Sponsor for the purpose 
of conducting the research study have been sworn to confidentiality. 
Your personal data will be processed for the purposes of analyzing and reporting the results of this 
research study; to develop future study protocols; for product performance monitoring and scientific 
research investigating new treatments, interventions and management procedures so that patient 


Adult Informed Consent Document for Enrolment 
Pharmacokinetics, efficacy and safety of BT524 
EudraCT number (EU only): 2011-004154-25 
 
02Aug2018, Version 6.0_PK Part I & Part II(Master) 
<Insert Investigator Name, City and State>    
Page 14 of 19 
outcomes are continually improved; and for ensuring compliance with medical, ethical and medical 
device laws and regulations.  
If the Sponsor or the study doctor makes public any study results your identity will remain 
confidential, as the study results will be published in a form that does not allow your re-identification. 
With your permission, the study doctor will tell your family doctor about your participation in this 
study. 
Will my personal data be transferred to a third party? 
Qualified representatives of the Study Sponsor and its Clinical Research Organization, [insert CRO 
Name], and/or national and foreign regulatory authorities (including the Paul-Ehrlich-Institute (PEI) 
and /or the Food and Drug Administration (FDA); and/or independent auditors may look at your 
medical notes (including un-coded personal data), to check the information collected in this study, 
to check how the study was conducted and to monitor participant's safety. Further, [insert CRO 
Name] may be required to disclose your personal data in response to lawful requests by public 
authorities, including those to meet national security or law enforcement requirements. 
Will my personal data be transferred abroad? 
The disclosure of your personal data to the above-mentioned recipients, may include transferring 
your (pseudonymized) personal data to countries other than where you are based and outside the 
European Economic Area (“EEA”), such as the USA. The laws protecting personal data in third 
countries may not be not as strict as those applicable in Germany. However, the Sponsor will 
ensure that your personal data is transferred in compliance the provisions of the General Data 
Protection Regulation (GDPR). You may contact Biotest's data protection officer to get more 
information about the safeguards used to protect your personal data transferred to third country. 
Some ways in which your personal data is kept safe includes having study sites put the appropriate 
arrangements for the security of your personal data, removing some direct identifiers of your 
personal data or key-coding it so that it is not identifiable and collecting only the personal data 
needed. You may also ask the study doctor for a copy of those safeguards. 
On which legal basis is the personal data processed? 
The processing of your personal data, including your health data, is based on Article 6(1)(a) and 
Article 9(2)(a) of the GDPR in connection with [insert applicable national law]. 
For how long will my personal data be stored? 
Your personal data will be kept as long as necessary for the purpose of conducting the research 
study, unless longer periods are provided by applicable laws. The code to link your study patient 
number to your name will be deleted by the study doctor as soon as the purpose of the research 
study allows for it. However, applicable laws may provide for a longer retention period of the 
personal data. In that regard, your personal data may be stored for at least 
 
10 years following the completion or discontinuation of the research study, or 
 
2 years following the investigational medicinal product has received its last approval for a 
marketing authorization, or 
 
2 years after the development of the present investigational medicinal product has been 
stopped, 


Adult Informed Consent Document for Enrolment 
Pharmacokinetics, efficacy and safety of BT524 
EudraCT number (EU only): 2011-004154-25 
 
02Aug2018, Version 6.0_PK Part I & Part II(Master) 
<Insert Investigator Name, City and State>    
Page 15 of 19 
depending on whichever period is longer. 
Absent other statutory or contractual retention periods, your personal data will be deleted 
afterwards. 
Do I have to agree to the processing of my personal data? 
No, your consent to the processing of your personal data is voluntary. However, you will not be 
able to participate in the research study without giving the consent for the processing of the above-
mentioned personal data. 
Do I have the right to withdraw my consent to the processing of personal data? 
No, your consent to the processing of your personal data is irrevocable pursuant [insert applicable 
national law]. However, you are free to revoke your consent to participate in the research study at 
any time pursuant to [insert applicable national law] 
What happens with my personal data if I revoke my declaration of consent to participate in 
the research study? 
If you withdraw your consent to participate in the research study, the Sponsor and its 
representatives (e.g., CRO), as well as the study center and the study doctor will determine without 
undue delay whether the stored data is still required to: 
a) determine effects of the investigational medicinal product,  
b) ensure that those of your interests which are worthy of special protection are not 
prejudiced, 
c) satisfy the obligation to provide complete marketing authorization documents. 
Personal data that is no longer necessary for the above-mentioned purposes will be deleted 
immediately or anonymized (e.g., by destroying the key code linking your name with your study 
patient number). Only the study doctor is able to restore the personal reference. 
Which rights do I have in connection with my personal data? 
You have the right to gain access to your personal data stored by the Sponsor, the study center or 
the study doctor (Article 15 of the GDPR). You also have the right to request the rectification of 
inaccurate personal data without undue delay according to Article 16 of the GDPR. Under certain 
conditions, you can also request deletion of your personal data without undue delay (Article 17 
GDPR) or restricted processing of your personal data (Article 18 GDPR). You may also have the 
right to receive the personal data concerning your person, in a structured, commonly used and 
machine-readable format and to transmit those data to another controller without hindrance (Article 
20 GDPR). 
If you believe that the processing of your personal data violates the provisions of the GDPR, you 
have the right to lodge a complaint with the competent data protection supervisory authority. Further 
information regarding competent supervisory authorities can be found on the website of the Federal 
Commissioner for Data Protection and Freedom of Information: www.bfdi.bund.de. 
Who can I contact if I have any questions? 
If you have any questions regarding the handling of your data, you can contact Biotest’s data 
protection officer using the following contact details: 
SPIE GmbH 


Adult Informed Consent Document for Enrolment 
Pharmacokinetics, efficacy and safety of BT524 
EudraCT number (EU only): 2011-004154-25 
 
02Aug2018, Version 6.0_PK Part I & Part II(Master) 
<Insert Investigator Name, City and State>    
Page 16 of 19 
Lyoner Straße 9 
60528 Frankfurt, Germany 
Phone : 0049 (0)69 6649-6921 
E-Mail: datenschutz@biotest.com 
As the Sponsor usually only receives pseudonymous information and, therefore, cannot always 
respond to all requests, please contact the study center’s data protection officer with your 
questions. Please use the following contact details: 
[insert contact details (address, telephone number and email address) of the study center’s data 
protection officer] 
Finally, a description of this research study will be available on http://www.ClinicalTrials.gov as 
required 
by 
U.S. 
Law 
and 
on 
the 
European 
Clinical 
Trials 
database 
at 
https://www.clinicaltrialsregister.eu as required by European Law. This website will not include 
information that can identify you. At most, this website will include a summary of the results. You 
can search this website at any time. 
 
 
 
 
 
 
Opportunity to Ask Questions 
 
At any time you are permitted and are encouraged to ask the study doctor <name & phone 
number> any questions about the treatment, the study, your rights as a patient, etc. In addition, to 
gain more information about this study and/or your rights as a patient, or if you feel that your 
questions have not been sufficiently addressed, contact ___________________________ <name, 
address and telephone number of IEC contact person, human research office and/or 
hospital patient advocacy group> at this facility. 
 


Adult Informed Consent Document for Enrolment 
Pharmacokinetics, efficacy and safety of BT524 
EudraCT number (EU only): 2011-004154-25 
 
02Aug2018, Version 6.0_PK Part I & Part II(Master) 
<Insert Investigator Name, City and State>    
Page 17 of 19 
B.  Consent to Participate in the Study titled 
 
Protocol Title: 
A 
prospective, 
open-label, 
phase 
I/III 
study 
investigating 
pharmacokinetic properties of BT524 and efficacy and safety of 
BT524 in the treatment and prophylaxis of bleeding in patients with 
congenital fibrinogen deficiency 
 
 
Please initial the box if you agree with the following: 
  
I confirm that I have read and understand the information sheet dated 02Aug2018 (Version 
6.0) for the above study. I have had the opportunity and enough time to consider the 
information, ask questions and have had these answered satisfactorily.  
 
 
 
I have read the above explanations and I agree to participate in Part 1 and Part 2 of this 
study, if I am eligible. I understand that I should comply with the exact dates and time of my 
scheduled visits to the hospital in Part 1 and I will do so. 
 
  
If I have any question about this study, I realise that I am encouraged to ask them now or 
at any time during the study by contacting: 
 
<Principal Investigator's name, address, office number phone, fax, and email. 
Include possible alternate contacts too.> 
 
 
 
I understand that my participation is voluntary and that I am free to withdraw at any time 
without giving any reason, without my medical care or legal rights being affected. 
 
 
 
I agree to use or have my partner use an acceptable method of birth control (as defined in 
the consent form) from the beginning of the screening period until the final study visit.  
 
(Write a cross in the box if you are a male.) 
 
 
 
I understand the pharmaceutical company carrying out this study, Biotest, has contracted 
an insurance policy to cover my participation in this study. 
 
 
 
I understand that I must not participate in the study if I am pregnant or breastfeeding or if I 
intend to become pregnant between the time that I have signed this consent form and until 
30 days after my last dose of BT524.  
 
(Write a cross in the box if you are a male.) 
 
 
 
I understand that relevant sections of my medical notes and data collected during the study 
may be looked at by individuals or representatives of Biotest, auditors, Independent Ethics 
Committee/Independent Review Board or from Regulatory Authorities in order to verify the 
conduct of the study and the protection of my rights and welfare. I give permission for these 
individuals to have access to my records. 
 
 
 
 
 
 
 
 
 
 


Adult Informed Consent Document for Enrolment 
Pharmacokinetics, efficacy and safety of BT524 
EudraCT number (EU only): 2011-004154-25 
 
02Aug2018, Version 6.0_PK Part I & Part II(Master) 
<Insert Investigator Name, City and State>    
Page 18 of 19 
 
I am willing for my anonymous research data, and the results arising from the study, to be 
used as appropriate. 
 
 
 
I am willing for my anonymous research data to be sent to a country where the same level 
of data protection may not apply. 
 
 
 
I am willing for my general practitioner to be informed about my participation and progress 
in this study. 
 
  
I realise that I may report any objections to this study, either orally or in writing, to: 
 
< Insert country specific contact information, including address, email and phone>  
  
I understand that, in signing this consent form, I give Biotest and <Principal Investigator> 
permission to present the results of this study, with my personal data being anonymised. 
The results may be presented in written and oral form, without further permission from me. 
  
I understand that I will receive a signed and dated copy this informed consent form for my 
records.  
 
 
 
 
 
 
 
Patient’s first name and 
family name (printed) 
 
 
 
 
 
Signature of Patient  
(18 years and older)  
 
Date  
Legally Authorised 
Representative’s first name 
and family name (printed) 
(if applicable) 
 
 
 
Signature of Legally Authorised 
Representative  
(if applicable) 
 
Date  
Investigator’s first name 
and last name (printed)  
 
 
Signature of Investigator who conducted 
the Informed Consent Discussion 
 
Date  
1 copy for the patient; 1 (original) to be kept in the Investigator File 
 
N.B The patient/patient authorized representative must date his/her own signature (or affix his/her 
thumb print if illiterate) 
 
 
 
 
 
 
 
Statement of an impartial witness in case of an illiterate patient/patient legally authorized 
representative: 
 
 
 
 
 
 


Adult Informed Consent Document for Enrolment 
Pharmacokinetics, efficacy and safety of BT524 
EudraCT number (EU only): 2011-004154-25 
 
02Aug2018, Version 6.0_PK Part I & Part II(Master) 
<Insert Investigator Name, City and State>    
Page 19 of 19 
I certify that the patient/patient legally authorized representative was given full information about 
the study as described herein, and agrees to participate to the study 
 
 
 
 
Impartial Witness first 
name and last name 
(printed)  
 
 
Signature of Impartial Witness 
 
Date  
 

Prot_000.pdf: 


Clinical Study Protocol 
Study No.: 984 
Final Version 6.0 
08-May-2018
EudraCT No.: 2011-004154-25 
 
 
 
CONFIDENTIAL 
Page 2 of 119 
Overview of Amendments integrated in the protocol text of version 6.0 of 08-May-2018 
 
 
Amendment No 
Date 
Sections concerned
Rationale 
1 
16 Jan 2013 
Cover page 
Title page amended to change the 
telephone number of the Director Clinical 
Operations Corporate Clinical Research. 
1 
16 Jan 2013 
 
Introduction of overview table on protocol 
amendments added according to SOP. 
1 
16 Jan 2013 
2 
Modification of the involved countries and 
sites. 
Date of First Patient In. 
1 
16 Jan 2013 
3 
Minor corrections in the Study Flow Chart 
for adults. 
Introduction of two additional Flow-charts for 
the newly defined subgroups of children with 
different bodyweight: Children Group I (6 to 
18 years, bodyweight > 43 kg) and Children 
Group II (6 to 18 years, bodyweight between  
22 and 43 kg). 
1 
16 Jan 2013 
13, 14 
Reduction of time points of blood draw in 
children Group I (>43kg body weight) for the 
assessment of Coagulation, Hematology 
and Biochemistry. 
Reduction of time points of blood draw in 
children Group II (22-43 kg body weight) for 
the assessment of Coagulation, Hematology 
and Biochemistry as well as of 
pharmacokinetics and pharmacodynamics. 
1 
16 Jan 2013 
14 
Addition of a new chapter concerning 
Pregnancy Reporting. 
2 
15-Jun-2014 
Cover page, 1, 2, 3, 5, 6, 9, 
10, 12, 13, 14, 15 
Update with clarification of wording, 
additions, corrections and formatting. 
2 
15-Jun-2014 
2, 
7, 
11.1.5, 
12.1.2, 
13.3, 
14.3 
Implementation of a Data Monitoring 
Committee (DMC) to approve the inclusion 
of children and adolescents after the 10th 
adult patient treated and to survey the study 
as a whole. 
The DMC is to ensure the safety of the 
study participants in particular with regard to 
the inclusion of children and adolescents. 
Implementation of an appropriate procedure 
and a related stopping rule. 
2 
15-Jun-2014 
2, 
12.2, 
12.3, 
Inclusion criterion 1 (now 1 and 2) and 
exclusion criterion 12 were modified to 
clarify the target population. 
2 
15-Jun-2014 
2, 
13.2 
The study duration has been extended due 
to slow patient recruitment. Furthermore, 
study subjects already on trial will be offered 
to extend their study participation (in part II) 
until the last subject enrolled has finished 
study part II. 
2 
15-Jun-2014 
3 
Tables 3.1, 3.2, 3.3 ‘Flowcharts of Study’ 
were changed according to the above 
mentioned changes. 


Clinical Study Protocol 
Study No.: 984 
Final Version 6.0 
08-May-2018
EudraCT No.: 2011-004154-25 
 
 
 
CONFIDENTIAL 
Page 3 of 119 
Amendment No 
Date 
Sections concerned
Rationale 
2 
15-Jun-2014 
3 
13.1.1.2, 
13.1.2.2 
14.1.1 
Modified method for determination of 
Fibrinogen Antigen (Assay); ELISA changed 
to nephelometry. 
2 
15-Jun-2014 
3, 
13.1.1.2, 
13.1.2.2 
13.1.2.4 
13.5.6, 
14.5.1.12 
Assessments of risk and burden in children 
and adolescents and a justification 
regarding the risks and burden these age 
groups are exposed by the clinical trial. 
2 
15-Jun-2014 
13.5.3, 
13.5.4, 
13.5.5 
Implementation of risk minimization 
measures for all study participants as well 
as for the enrolment and treatment of 
children and adolescents. 
2 
15-Jun-2014 
14.5.1.4 
The determination of Fibrinogen inhibitory 
antibodies was stated more precisely. The 
development of Fibrinogen inhibitory 
antibodies has to be reported as serious 
adverse events (SAEs). 
3 
15-Jul-2015 
Cover page, 1, 2, 3, 6, 9, 
11, 12, 13, 14, 15 
Update with clarification of wording, 
additions, corrections and formatting. 
3 
15-Jul-2015 
1, 2, 3, 7, 9,  
11, 12, 13, 14, 15 
Extension of the ongoing phase I/II study 
into a phase I/III study. 
Treatment of at least 10 additional patients 
into part II (without part I PK/PD). 
3 
15-Jul-2015 
3 
Tables 3.4.1, 3.4.2, 3.4.3 ‘Flowcharts of 
Study’ were introduced according to the 
above mentioned changes. 
3 
15-Jul-2015 
11.1.1 
The calculation of the BT524 dose to be 
administered to the patients was revised in 
regard to the specifications in the certificate 
of analysis. 
4 
15-Mar-2017 
Cover Page, 
1, 5, 6, 9 
Update with clarification of wording, 
additions, corrections and formatting. 
Introduction of the new statistician. 
4 
15-Mar-2017 
2, 8, 9, 11, 
12, 13, 14, 15 
Update and revision of study protocol 
covering the Paediatric Investigational Plan 
(Inclusion of children below 6 years). 


Clinical Study Protocol 
Study No.: 984 
Final Version 6.0 
08-May-2018
EudraCT No.: 2011-004154-25 
 
 
 
CONFIDENTIAL 
Page 4 of 119 
Amendment No 
Date 
Sections concerned
Rationale 
4 
15-Mar-2017 
3 
Update and formatting of flowcharts. 
Deletion of redundant abbreviations in order 
to streamline the flowcharts. Deletion of 
redundant flowcharts in section 3.6.2 and 
3.6.3 and cross reference to the 
corresponding sections 3.1 to 3.5. 
Correction of Fibrinogen antigen and activity 
assessments in flowchart 3.6.1 (Screening 
visit for the additional patients) in order to 
reflect the actual assessments. 
Introduction of 6 additional flowcharts for the 
newly defined subgroups of children below 6 
years (Pre-school Children Group III and 
Newborns/ Infants and Toddlers Group IV) 
4 
15-Mar-2017 
19 
Update of scientific literature. 
4 
15-Mar-2017 
20 
Deletion of Appendix 20.1 'Overview of 
Protocol Changes' and transfer of this 
section to a separate document (SOP-K-
00044_A02) in order to adhere to the 
updated SOP template K-00044_A01 
(previous SOP-CCR-007-T001). 
Introduction of a new Appendix 20.1 
'Dosage for Newborns, infants and children. 
5 
08-May-2018 
Cover Page 
 
2, 3, 5, 8, 11, 12, 13, 14, 
15, 20 
Introduction of a new project manager 
CCR&D. 
Update with clarification of wording, 
additions, corrections and formatting. 
5 
08-May-2018 
2, 0 
20.2 
Adaption of exclusion criterion 12 in order to 
clarify that this criterion is only applicable for 
patients in PK part I. 
Adaption of exclusion criterion 13 in order to 
harmonize the 'lower body weight limit' (the 
5th percentile of the normal range) between 
all children age groups. 
Information regarding the WHO Child 
Growth Standards was included in appendix 
20.2. 
5 
08-May-2018 
14.6 
Introduction of new sections 'Adverse Event 
of Special Interest (AESI)' and 'Follow-up of 
Adverse Events'  
5 
08-May-2018 
15.1 
Correction of Sample Size Calculation as 
this section was adapted within 
amendment 3 (CSP V4.0) to the new patient 
numbers in error. 
5 
08-May-2018 
14.4, 20.3 
The investigator is asked to classify any 
bleeding event post-dose as minor or major. 
A recommendation for the assessment of 
bleeding events was introduced in the 
appendix. 
 
 




Clinical Study Protocol 
Study No.: 984 
Final Version 6.0 
08-May-2018
EudraCT No.: 2011-004154-25 
 
 
 
CONFIDENTIAL 
Page 6 of 119 
1.1 
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 patient 
in this study. 
• 
To obtain informed consent of each patient 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 
patient 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 Adverse Events / Serious Adverse 
Events (AE/SAEs). 
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 (IB), Case Report Forms (CRF), and other scientific 
data. 
Principal Investigator 
<Name> 
 
 
__________________________________________ 
Date, signature 
Investigator stamp: 


Clinical Study Protocol 
Study No.: 984 
Final Version 6.0 
08-May-2018
EudraCT No.: 2011-004154-25 
 
 
 
CONFIDENTIAL 
Page 7 of 119 
2 STUDY SYNOPSIS 
Title 
A 
prospective, 
open-label, 
phase 
I/III 
study 
investigating 
pharmacokinetic properties of BT524, and efficacy and safety of 
BT524 in the treatment and prophylaxis of bleeding of patients with 
congenital fibrinogen deficiency 
Clinical Phase 
I/III 
Coordinating 
Investigator 
 
Study 
Objectives 
Primary objective: 
To investigate the 14 day single-dose pharmacokinetics (PK) of 
BT524 following intravenous infusion in patients with congenital 
fibrinogen deficiency (afibrinogenemia or severe hypofibrinogenemia). 
Secondary objectives: 
To investigate the 14 day single-dose pharmacodynamics (PD), the 
surrogate efficacy and safety of the single intravenous infusion of 
BT524. 
To investigate efficacy, surrogate efficacy and safety, of single and/or 
repetitive intravenous infusions of BT524 for on-demand prophylaxis 
(ODP) and/or on-demand treatment (ODT) of bleeding events. 
Study Design 
Prospective, open-label, multicentre 
Study 
Population 
Patients with congenital afibrinogenemia or severe congenital 
hypofibrinogenemia. 
Enrolment Procedures: 
Part I 
The first 5 patients are to be enrolled consecutively with a dosing-free 
safety interval of 7 days between each patient. Subsequently, patients 
6 to 20 are allowed to be treated simultaneously, if applicable. 
A Data Monitoring Committee (DMC) will review and assess the 
safety and PK data from the first 10 adult patients prior to enrolment 
of any children or adolescents into the study. Children ≥ 6 years and 
adolescents are only allowed to be enrolled after completion of the 7-
day dosing-free safety interval of the 10th adult patient and 
assessment of these data by the DMC. 
Subsequently, after the first 20 patients of ≥ 6 to ≤ 75 years finished 
part I, at least 3 additional paediatric patients < 6 years of age are 
planned to be enrolled in the study part I.  
 
 
PPD


Clinical Study Protocol 
Study No.: 984 
Final Version 6.0 
08-May-2018
EudraCT No.: 2011-004154-25 
 
 
 
CONFIDENTIAL 
Page 8 of 119 
Study 
Population 
(continued) 
Part II 
All patients included in part I will be eligible for participation in part II. 
At least 10 additional patients ≥ 6 to ≤ 75 years and at least 3 
additional patients < 6 years will be enrolled in part II (ODT/ODP) 
without PK/PD assessments (part I).  
Prior to enrolment of any children < 6 years of age a DMC will review 
and assess all available safety and PK/PD data from adults and 
children ≥ 6 years enrolled in the study so far (including data of least 3 
children ≥ 6 to < 12 years and of at least 3 adolescents ≥ 12 to < 18 
years). 
All patients will be offered to extend their study participation (in part II) 
until the last enrolled subject (of these additional patients) has 
finished study part II (12 months). 
Inclusion 
Criteria 
Only patients meeting all of the following inclusion criteria will be 
considered for study inclusion: 
1. Known congenital afibrinogenemia or severe congenital 
hypofibrinogenemia  
2. Plasma fibrinogen activity ≤ 0.5 g/l and antigen ≤ 0.5 g/l 
3. Male or female 
4. Age 0 to 75 years, with the first ten patients will be 18 years or 
older 
5. Presumed to be compliant with the study procedures and to 
terminate the study as scheduled 
6. Willing and able to be hospitalized for 3 days for the pharmaco-
kinetic assessment (if applicable) 
7. Willing and able to be hospitalized - if required - in case of 
interventions (e.g., surgical procedures, major bleeds)  
8. Written informed consent by the patient, his/her parents or by the 
patient's legal / authorized representative as applicable 
Exclusion 
Criteria 
Patients having any of the following general exclusion criteria, 
either at screening (pre-visit) or at enrolment (visit 1) are to be 
excluded from the study: 
1. Known congenital dysfibrinogenemia 
2. Known bleeding disorder other than congenital fibrinogen 
deficiency 
3. History of esophageal variceal bleeding  
4. Known presence or history of venous/arterial thrombosis or 
thromboembolic event (TEE) in the preceding 6 months 
5. Known presence or history of fibrinogen inhibitory antibodies  
6. Known presence or history of hypersensitivity to human 
fibrinogen or human plasma proteins e.g., immunoglobulins, 
vaccines or hypersensitivity to any of the excipients 
7. Known positive serology for HIV-1 and HIV-2 
8. Clinically relevant biochemical or hematological findings (except 
due to underlying disease or emergency bleeding) outside the 
normal range (at the investigator's discretion) 
9. Clinically relevant pathological findings in physical examination 
including electrocardiogram (ECG)  


Clinical Study Protocol 
Study No.: 984 
Final Version 6.0 
08-May-2018
EudraCT No.: 2011-004154-25 
 
 
 
CONFIDENTIAL 
Page 9 of 119 
10. Treatment with any fibrinogen concentrate and/or fibrinogen-
containing product within 2 weeks prior to infusion of BT524 
11. Concomitant medication interacting relevantly with the 
coagulation system (e.g., low molecular weight heparin, 
unfractioned heparin, factor Xa inhibitors, factor IIa inhibitors or 
PY12 inhibitors) within 2 weeks prior to infusion of BT524 
12. Recent vaccination within 3 weeks prior to infusion* 
13. Body weight (BW) below 22 kg for patients ≥ 6 years*; BW below 
the 5th percentile of the normal range for children ** 
14. End stage disease  
15. Abuse of drugs 
16. Unable to understand and follow the study requirements (refers to 
the patient, his/her parents or to the patient's legal / authorized 
representative as applicable) 
17. Participation in another interventional clinical study within 30 days 
before entering the study or during the study 
18. Pregnant/ nursing woman, or woman of childbearing potential not 
using reliable/ effective contraceptive method(s) during the study 
and at least one month after the last administration of study drug 
(e.g., oral/ injectable/ implantable/ insertable/ topical hormonal 
contraceptives, intrauterine devices, female sterilization, partner's 
vasectomy or condoms) 
19. Any other condition that, to the investigator's judgment, could 
have an impact on patient's safety or the study results 
* only applicable for patients in PK part I 
** refers to local standards (Appendix 20.12) 
Exclusion 
Criteria 
(continued) 
Pharmacokinetics (PK) 
In addition to the general exclusion criteria mentioned above, patients 
meeting any of the following PK-specific exclusion criteria at 
enrolment are to be excluded from the pharmacokinetic assessment. 
Patient enrolment is to be postponed until no PK exclusion criterion 
applies. 
20. Elective surgery during the 14 day PK blood sampling period  
21. Acute infection 
22. Clinically relevant increase or decrease in body temperature 
23. Actively bleeding or anticipated bleeding (including female 
menorrhea) at the time point of or within 7 days prior to infusion of 
BT524 
24. Surgery within 7 days prior to infusion of BT524 
25. Immobilization within 7 days prior to infusion of BT524 
26. Intake of alcohol or significantly increased intake of caffeine 
containing products within 24 hours prior to infusion of BT524 
27. Blood donation or comparable blood loss within 60 days prior to 
infusion of BT524 
28. Excessive physical exercise (extreme sports activities, sauna) 
within 72 hours prior to infusion of BT524 
 
 


Clinical Study Protocol 
Study No.: 984 
Final Version 6.0 
08-May-2018
EudraCT No.: 2011-004154-25 
 
 
 
CONFIDENTIAL 
Page 10 of 119 
Number of 
Study Patients  
Part I 
Approximately 20 patients ≥ 6 to ≤ 75 years will be included to have 
about 15 evaluable patients for the analyses of the PK/PD of BT524 
and the surrogate efficacy parameter. 
At least 3 additional patients 0 to < 6 years of age are to be included 
to have 3 evaluable datasets for PK/PD assessment.  
Part II 
At best, all patients who have completed part I will continue with the 
extended on-demand prophylaxis (ODP)/ on-demand treatment 
(ODT).  
Subsequent to completion of part I by the first 20 subjects ≥ 6 to ≤ 75 
years, at least 10 additional patients and at least 3 additional patients 
< 6 years will be treated in part II without PK/PD assessments in 
part I.  
In total, approximately 36 patients 0 to ≤ 75 years should be treated in 
part II. Thereof, at least 6 patients should be < 6 years, 6 patients 
should be ≥ 6 to < 12 years and 6 patients should be ≥ 12 to < 18 
years of age. 
With respect to the evaluation of efficacy, surrogate efficacy and 
safety of the single or repetitive intravenous infusions of BT524, each 
bleeding event (part II) will be considered as an individual case in the 
primary analysis. 
Countries/ 
Number of 
Study Sites 
5-7 sites in the European Union and in non-EU countries 
Investigational 
Medicinal 
Product (IMP) 
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 
infusion. 
Dosage and 
Mode of 
Administration 
The dosage and duration of the substitution therapy depend on the 
severity of the disorder, location and extent of bleeding and the 
patient’s clinical condition. In addition, dosage is always based on 
individual BW and fibrinogen baseline level. Similar dosage strategy 
will be applied to planned subjects < 6 years, as for subjects ≥ 6 to 
≤ 75 years. 
Unless valid information on the recovery rate of BT524 is available, 
the dosage regimen for surgical interventions and spontaneous 
bleedings will target (functional) fibrinogen levels recommended by 
the Core SmPC for Human Fibrinogen Products.  
 
 


Clinical Study Protocol 
Study No.: 984 
Final Version 6.0 
08-May-2018
EudraCT No.: 2011-004154-25 
 
 
 
CONFIDENTIAL 
Page 11 of 119 
Dosage and 
Mode of 
Administration 
(continued) 
Dosage for the PK dose (part I) and Guidance for On-demand 
Prophylaxis and/ or On-demand Treatment 
 
Dose 
Target Level 
No. of 
Doses  MOA 
Infusion Rate 
Pharmacokinetics 
 
70 mg/kg 
BW 
— 
single 
IV 
5 ml/min* 
< 5 ml/min** 
(< 100 mg/min) 
* for Adults and Children/Adolescents Group I and Group II (≥ 6 years) 
** for Pre-school Children Group III and Newborns/Infants + Toddlers Group IV (< 6 years) 
Surgical intervention 
On-demand 
prophylaxis 
(ODP) 
variable*
1 g/l** 
as 
required 
IV 
max 100 mg/min 
On-demand 
treatment 
(ODT) 
variable*
1 g/l** 
maintained until 
hemostasis is secure
as 
required 
IV 
max 100 mg/min 
> 0.5 g/l** 
until wound healing is 
complete 
Spontaneous bleeding 
On-demand 
treatment 
variable*
— 
as 
required 
IV 
max 100 mg/min 
Target levels recommended by the Core SmPC for Human Fibrinogen Products 
BW: body weight; IV: intravenous; max: maximum; min: minute; MOA: mode of administration; 
Values given are guidance only, and higher or lower levels and increased frequency of 
administration may be necessary 
* adapted on severity, location and extent of bleeding, and patient’s clinical condition 
** depending on the severity of the event fibrinogen levels may be raised in individual cases to 
a maximum of 1.5 g/l at the discretion of the investigator. 
In children < 6 years the reconstituted solution of BT524 will be 
administered intravenously (IV) via an infusion pump with an adapted 
infusion rate below 5 ml/min (100 mg/minute) according to age, BW, 
and medical condition at the discretion of the treating physician of the 
patient. 
Once valid information on the recovery rate of BT524 is available, the 
dose to be administered is to be calculated according to the formula 
given by the Core SmPC: 
Dose (g) = [desired levels (g/l) – baseline level (g/l)] x 1/recovery (g/l / 
g/kg) x BW (kg). 
Duration of 
Treatment  
Part I: A single intravenous infusion for the assessment of PK/PD.  
Part II: On-demand prophylaxis (ODP):  
 
Single or repetitive intravenous infusion(s) 
 
On-demand treatment (ODT):  
 
Single or repetitive intravenous infusion(s) 
For each patient the individual treatment period in part II will last at 
least 12 month upon enrollment. 


Clinical Study Protocol 
Study No.: 984 
Final Version 6.0 
08-May-2018
EudraCT No.: 2011-004154-25 
 
 
 
CONFIDENTIAL 
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Duration of 
Follow-up 
Part I 
Individual follow-up (virus safety) is 49±4 days after the administration 
of BT524 for PK/PD assessment. 
Part II 
For each bleeding event, individual follow-up (virus safety) is 
49±4 days after the last administration of BT524 for the respective 
event. 
Criteria for 
Evaluation 
 
Primary 
Criterion 
Pharmacokinetics (PK) 
PK parameters will be derived from time concentration profiles using 
adapted methodology (non-compartmental analysis, compartment 
analysis, or population modeling, as appropriate/ required).  
Single-dose PK of fibrinogen antigen will be assessed by the following 
variables: 
• Terminal Elimination Half-life (t1/2) for fibrinogen antigen 
• Time to reach Maximum Concentration (tmax) 
• Maximum Concentration (Cmax) 
• Area Under the Concentration-Time Curve (AUC) calculated to the 
last measured concentration (AUC(0-t)) and extrapolated to infinity 
(AUC(0-inf) 
• Clearance (CL) 
• Mean Residence Time (MRT) 
• Volume of Distribution (Vss) 
• Incremental Recovery (IR) 
• Classical in vivo Recovery (IVR) 
Secondary 
Criteria 
Pharmacodynamics (PD) 
Single-dose PD of fibrinogen activity will be assessed by the following 
variables: 
• Terminal Elimination Half-life (t1/2) for fibrinogen activity 
• Time to reach Maximum Concentration (tmax) 
• Maximum Concentration (Cmax) 
• Area Under the Concentration-Time Curve (AUC) calculated to the 
last measured concentration (AUC(0-t)) and extrapolated to infinity 
(AUC(0-inf) 
• Clearance (CL) 
• Mean Residence Time (MRT) 
• Volume of Distribution (Vss) 
• Incremental Recovery (IR) 
• Classical in vivo Recovery (IVR) 
 
 


Clinical Study Protocol 
Study No.: 984 
Final Version 6.0 
08-May-2018
EudraCT No.: 2011-004154-25 
 
 
 
CONFIDENTIAL 
Page 13 of 119 
Secondary 
Criteria 
(continued) 
Surrogate Efficacy 
Maximum clot firmness (MCF, mm) 
measured by rotational thromboelastometry  
Part I 
• Comparison of MCF pre-dose and at 1 and 8 hours post-end of 
IV infusion 
• Correlation between MCF and fibrinogen activity pre-dose and at 
1 and 8 hours post-end of IV infusion 
Part II 
• Comparison of MCF pre-dose and at 1 hour post-end of each 
IV infusion 
• Correlation between MCF and fibrinogen activity pre-dose and at 
1 hour post-end of each IV infusion 
 
Clinical Efficacy 
The following efficacy parameters will be assessed after each 
bleeding event: 
• Overall hemostatic response to treatment with BT524 for each 
surgical procedure and each treated bleed as assessed by the 
investigator according to a 4 point scale:  
"none", "moderate", "good" or "excellent" 
• Total loss of blood (e.g., intra- and postoperatively, re-bleedings),  
if applicable 
• Units of other fibrinogen-containing products infused besides 
BT524 e.g., fresh frozen plasma or cryoprecipitate 
• Units of transfusion products infused e.g., allogenic or autologous 
blood (packed red blood cells, fresh whole blood), platelets  
• Consumption of BT524 (dose per kilogram BW required pre-, intra- 
or post-operatively for effective treatment) 
The following efficacy parameter will be assessed after wound healing 
is expected to be resolved 
• Quality of wound healing, if applicable 
 
Safety 
• Electrocardiogram  
• Adverse events 
• Development of fibrinogen antibodies   
• Changes in vital signs e.g., blood pressure, heart rate, body 
temperature 
• Change in physical examination 
• Change in clinical laboratory assessments of hematology, 
biochemistry, and urine analysis 
• Change in markers of coagulation activation: 
 
PT(INR), aPTT, TAT, F1+2, D-dimer 
 
 


Clinical Study Protocol 
Study No.: 984 
Final Version 6.0 
08-May-2018
EudraCT No.: 2011-004154-25 
 
 
 
CONFIDENTIAL 
Page 14 of 119 
Biostatistical 
Concept  
All data collected will be listed and tabulated. Categorical variables 
will be presented with absolute and relative frequencies. For 
continuous variables descriptive statistics will be given including 
mean, 
standard 
deviation, 
median, 
quartiles, 
minimum, 
and 
maximum. Additionally, for PK data, efficacy and safety parameters, 
95 % confidence intervals will be calculated where appropriate. PK 
parameters will be summarized by descriptive statistics for each age 
group, and compared descriptively between age groups. No formal 
statistical test will be used. 
All analyses of this open-label study will be performed on intention-to-
treat (ITT) as well as per protocol population (PP). ITT population will 
include all patients who received at least any portion of BT524. 
 
The PP population will include all patients who received at least 
90% of the planned total dose of BT524, met all inclusion and no 
exclusion criteria, complied with the protocol procedures and had no 
major deviations impacting on study analysis. 
 
Response to therapy with BT524 will be evaluated per bleeding event 
using a 4-point scale (‘none’, ‘moderate’, ’good’, ’excellent’) by the 
investigator. The clinical response, summarizing the excellent and 
good rating, will be analysed descriptively (providing estimate and 
95% confidence interval). These estimations will be compared with a 
historical control from a retrospective physician survey, where the 
outcome excellent/good was reported with 90%. 
 
All analyses will be described in detail within a statistical analysis plan 
(SAP). 
The PK of BT524 will be analyzed and reported in a separate report 
after completion of study part I.  
First Patient In 
(planned) 
Adults: 20-Mar-2013 
Children/Adolescents (≥ 6 to < 18 years): 09-Nov-2014 
Children < 6 years: Q2/2018 (planned) 
Last Patient 
Last Visit (planned) Q1/2020 
Confidentiality Statement 
This protocol is the property of Biotest AG, D-63303 Dreieich, and may not be circulated, reproduced 
or published - either in whole or in part - without the company’s written permission. 


































Clinical Study Protocol 
08-May-2018 
 
Study No.: 984 
Final Version 6.0 
EudraCT No.: 2011-004154-25 
 
 
 
CONFIDENTIAL 
Page 31 of 119 
3.6.2 On-Demand Prophylaxis/Treatment without Hospitalisation 
Please refer to the corresponding Flowcharts: 
Flowchart 3.1 
Part II 
for Adults (18 to 75 years) 
Flowchart 3.2 
Part II 
for Children/Adolescents Group I (≥ 6 years, BW > 43 kg) 
Flowchart 3.3 
Part II 
for Children/Adolescents Group II (≥ 6 years, BW ≤ 43 kg) 
Flowchart 3.4 
Part II 
for Pre-school Children Group III (2 to < 6 years) 
Flowchart 3.5 
Part II 
for Newborns/ Infants and Toddlers Group IV (0 days to < 2 years) 
 
 
3.6.3 On-Demand Prophylaxis/Treatment with Hospitalisation 
Please refer to the corresponding Flowcharts: 
Flowchart 3.1 
Part II 
for Adults (18 to 75 years) 
Flowchart 3.2 
Part II 
for Children/Adolescents Group I (≥ 6 years, BW > 43 kg) 
Flowchart 3.3 
Part II 
for Children/Adolescents Group II (≥ 6 years, BW ≤ 43 kg) 
Flowchart 3.4 
Part II 
for Pre-school Children Group III (2 to < 6 years) 
Flowchart 3.5 
Part II 
for Newborns/ Infants and Toddlers Group IV (0 days to < 2 years) 
 


Clinical Study Protocol 
Study No.: 984 
Final Version 6.0 
08-May-2018
EudraCT No.: 2011-004154-25 
 
 
 
CONFIDENTIAL 
Page 32 of 119 
 
 
4 TABLE OF CONTENTS 
1 
SIGNATURE PAGE ............................................................................................ 5 
1.1 
Signature Page for Investigators ..................................................................... 6 
2 
STUDY SYNOPSIS ............................................................................................ 7 
3 
FLOWCHARTS OF STUDY ............................................................................. 15 
3.1 
Flowchart of Study - Adults (18 to 75 years) ................................................ 15 
3.2 
Flowchart of Study - Children/Adolescents Group I 
(≥ 6 years, BW > 43 kg) ................................................................................... 18 
3.3 
Flowchart of Study - Children/Adolescents Group II 
(≥ 6 years, BW ≤ 43 kg) ................................................................................... 21 
3.4 
Flowchart of Study - Pre-school Children Group III (2 to < 6 years) ........... 24 
3.5 
Flowchart of Study - Newborns/Infants and Toddlers Group IV 
(0 days to < 2 years)........................................................................................ 27 
3.6 
Flowchart of Study - For additional patients without participation in 
PK/PD part I ..................................................................................................... 30 
3.6.1 
Screening Visit ............................................................................................................ 30 
3.6.2 
On-Demand Prophylaxis/Treatment without Hospitalisation .................................. 31 
3.6.3 
On-Demand Prophylaxis/Treatment with Hospitalisation ....................................... 31 
4 
TABLE OF CONTENTS ................................................................................... 32 
5 
LIST OF ABBREVIATIONS ............................................................................. 37 
6 
INTRODUCTION .............................................................................................. 39 
7 
STUDY OBJECTIVES ...................................................................................... 41 
8 
ETHICAL AND REGULATORY CONSIDERATIONS ...................................... 42 
9 
STUDY DESIGN ............................................................................................... 42 
10 
INVESTIGATIONAL MEDICINAL PRODUCT .................................................. 44 
10.1 
Investigational Medicinal Product BT524 ..................................................... 44 
10.1.1 
Description of Investigational Medicinal Product BT524 ........................................ 44 
10.1.2 
Packaging and Labeling ............................................................................................. 45 
10.1.3 
Storage Conditions ..................................................................................................... 45 
11 
STUDY TREATMENT ....................................................................................... 45 
11.1 
Dosage Regimen ............................................................................................. 45 
11.1.1 
Dosage and Administration ........................................................................................ 45 
11.1.2 
Compliance with Dosage Regimens .......................................................................... 48 
11.1.3 
Dose Justification ....................................................................................................... 48 


Clinical Study Protocol 
Study No.: 984 
Final Version 6.0 
08-May-2018
EudraCT No.: 2011-004154-25 
 
 
 
CONFIDENTIAL 
Page 33 of 119 
 
 
11.1.4 
Treatment of Overdosage ........................................................................................... 48 
11.1.5 
Enrolment Procedures ................................................................................................ 49 
11.2 
Randomization Code ...................................................................................... 50 
11.3 
Assignment of Patient Identification ............................................................. 50 
11.4 
Drug Accountability ........................................................................................ 50 
11.5 
Previous and Concomitant Medication or Treatment .................................. 50 
11.6 
Prohibited Medication or Treatment .............................................................. 51 
11.7 
Risks and Precautions ................................................................................... 51 
12 
STUDY POPULATION ..................................................................................... 52 
12.1 
Study Population, Diagnosis and Number of Study Participants ............... 52 
12.1.1 
Gender Distribution ..................................................................................................... 52 
12.1.2 
Children and adolescents ........................................................................................... 53 
12.2 
Inclusion Criteria ............................................................................................. 53 
12.3 
Exclusion Criteria ........................................................................................... 54 
12.4 
Study Participants Withdrawal Criteria and Procedures ............................. 55 
12.5 
Postponement of Enrolment for PK Assessment (Part I) and During 
ODP/ODT (PART II) ......................................................................................... 56 
12.6 
Study Participants' Information ..................................................................... 56 
12.7 
Declaration of Informed Consent .................................................................. 57 
13 
COURSE OF THE STUDY ............................................................................... 57 
13.1 
Visit Schedule ................................................................................................. 57 
13.1.1 
Visit Types and Detailed Visit Schedules for the Assessment of the 
Pharmacokinetics/Pharmacodynamics of BT524 (PART I) ..................................... 57 
13.1.2 
Bleeding Events, Visit Types and Detailed Visit Schedules for On-demand 
Prophylaxis/On-demand Treatment with BT524 (PART II) ....................................... 66 
13.2 
Duration of the Study ..................................................................................... 76 
13.2.1 
End of Study ................................................................................................................ 77 
13.3 
Criteria for Premature Termination ............................................................... 77 
13.3.1 
Premature Termination of the Entire Clinical Study ................................................ 77 
13.3.2 
Premature Termination of an Individual Study Site ................................................. 78 
13.4 
Treatment and Care after the End of the Study ............................................ 78 
13.5 
Benefit-Risk Evaluation .................................................................................. 78 
13.5.1 
Benefit .......................................................................................................................... 78 
13.5.2 
Foreseeable Risk and Discomfort Related to BT524 ............................................... 79 


Clinical Study Protocol 
Study No.: 984 
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08-May-2018
EudraCT No.: 2011-004154-25 
 
 
 
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13.5.3 
Risk minimization measures for all study participants ........................................... 81 
13.5.4 
Risk minimization measures regarding the enrolment and treatment of 
children and adolescents ........................................................................................... 82 
13.5.5 
Reduction of Pharmacokinetics blood sampling volume and time points in 
Paediatric Patients ...................................................................................................... 82 
13.5.6 
Justification of Risk and Burden in Paediatric Patients .......................................... 83 
13.5.7 
Other Sources of Possible Risk and Discomfort ...................................................... 83 
13.5.8 
Summary of Possible Risk and Discomfort .............................................................. 83 
14 
ASSESSMENT OF PRIMARY AND SECONDARY OBJECTIVES AND 
CRITERIA FOR EVALUATION ........................................................................ 84 
14.1 
Pharmacokinetics ........................................................................................... 84 
14.1.1 
Specification of Pharmacokinetic Parameters ......................................................... 84 
14.2 
Pharmacodynamics ........................................................................................ 84 
14.2.1 
Specification of Pharmacodynamic Parameters ...................................................... 84 
14.3 
Data Monitoring Committee (DMC) ................................................................ 85 
14.4 
Efficacy ............................................................................................................ 86 
14.4.1 
Specification of Surrogate Efficacy Parameter ........................................................ 86 
14.4.2 
Specifications of Clinical Efficacy Parameters......................................................... 86 
14.4.3 
Methods for Assessing, Recording and Analyzing Pharmacokinetic 
Parameters ................................................................................................................... 87 
14.4.4 
Methods for Assessing, Recording and Analyzing Pharmacodynamic 
Parameters ................................................................................................................... 87 
14.4.5 
Methods for Assessing, Recording and Analyzing Efficacy Parameters .............. 88 
14.5 
Safety ............................................................................................................... 91 
14.5.1 
Specification of Safety Parameter(s) and Timing ..................................................... 91 
14.5.2 
Methods for Assessing, Recording and Analyzing Safety Parameter(s) ............... 99 
14.6 
Adverse Events ............................................................................................... 99 
14.6.1 
Definitions .................................................................................................................... 99 
14.6.2 
Recording Adverse Events ....................................................................................... 101 
14.6.3 
Evaluation of Adverse Events .................................................................................. 104 
14.6.4 
Notifying of Adverse Events .................................................................................... 104 
15 
STATISTICS ................................................................................................... 105 
15.1 
Calculation of Sample Size .......................................................................... 106 
15.2 
Statistical Methods ....................................................................................... 106 
15.2.1 
Populations for Analysis .......................................................................................... 106 
15.2.2 
General Methodology ................................................................................................ 107 
15.2.3 
Demographic Data and Other Baseline Characteristics ........................................ 107 
15.2.4 
Primary Objective ...................................................................................................... 108 
15.2.5 
Efficacy Analysis ....................................................................................................... 108 
15.2.6 
Safety Analysis .......................................................................................................... 109 
15.2.7 
Further Statistical Issues .......................................................................................... 109 
16 
DATA MANAGEMENT ................................................................................... 109 
16.1 
Data Collection .............................................................................................. 109 


Clinical Study Protocol 
Study No.: 984 
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16.2 
Correction of Data ......................................................................................... 110 
16.3 
Data Handling ................................................................................................ 110 
16.3.1 
Deviations from the Study Protocol ........................................................................ 110 
17 
QUALITY CONTROL AND QUALITY ASSURANCE .................................... 110 
17.1 
Study Initiation Activities ............................................................................. 110 
17.2 
Training of Site Staff ..................................................................................... 110 
17.3 
Documentation and Filing ............................................................................ 110 
17.4 
Monitoring ..................................................................................................... 112 
17.5 
Audits and Inspections ................................................................................ 112 
17.6 
Archiving ....................................................................................................... 112 
18 
GENERAL REGULATIONS, AGREEMENTS AND ORGANISATIONAL 
PROCEDURES ............................................................................................... 112 
18.1 
Study Administrative Structure ................................................................... 112 
18.2 
Written Agreements ...................................................................................... 112 
18.3 
Insurance/Liability ........................................................................................ 113 
18.4 
Investigator’s Brochure (IB) ......................................................................... 113 
18.5 
Amendments to the Protocol ....................................................................... 113 
18.6 
Confidentiality ............................................................................................... 113 
18.7 
Final Report and Publication ....................................................................... 113 
19 
LIST OF REFERENCES ................................................................................. 115 
20 
APPENDICES ................................................................................................. 117 
 


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LIST OF TABLES 
Table 1: 
Types of Congenital Fibrinogen Deficiency .................................................. 40 
Table 2: 
Overview of Study Design and Endpoints ..................................................... 43 
Table 3: 
Pharmacokinetics: Dose, Target Level, Mode of Administration and 
Infusion Rate of BT524 ................................................................................. 46 
Table 4: 
Guidance for On-demand Prophylaxis and/ or On-demand Treatment ......... 47 
Table 5: 
Known Adverse Drug Reactions with Human Fibrinogen ............................. 81 
 
LIST OF FIGURES 
Figure 1:  ROTEM Readout of Citrated Normal Blood .................................................. 89 
Figure 2:  Fib-tem S Readout in Afibrinogenemia ......................................................... 90 


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5 LIST OF ABBREVIATIONS 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALAT 
alanine aminotransferase (syn. ALT or GPT) 
AP 
alkaline phosphatase 
aPTT 
activated partial thromboplastin time 
AR 
Adverse Reaction 
ASAT 
aspartate aminotransferase (syn. AST or GOT) 
AUC 
area under the concentration-time curve 
BW 
body weight 
°C 
degrees centigrade 
CHMP 
Committee for Medicinal Products for Human Use 
CL 
clearance 
Cmax 
maximum concentration 
COA 
certificate of analysis 
CRO 
Contract Research Organization 
CTA 
Clinical Trial Application 
DIC 
Disseminated Intravascular Coagulation 
DMC 
Data Monitoring Committee 
dL 
Deciliter 
DVT 
Deep Vein Thrombosis 
ECG 
electrocardiogram  
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
e.g. 
for example 
ELISA 
enzyme-linked immunosorbant assay 
EMA 
European Medicines Agency 
EMEA 
European Medicines Evaluation Agency (previous name for EMA) 
FAS 
Full Analysis Set 
FDP 
Fibrin/Fibrinogen degradation product 
FFP 
fresh frozen plasma 
F1+2 
prothrombin fragment 1 and 2 
FU 
Follow-up 
g 
Gram 
GCP 
Good Clinical Practice 
γ-GT 
h 
gamma glutamyl transferase 
hour 
HAV 
hepatitis A virus 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
i.e. 
that is 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin 
IMP 
Investigational Medicinal Product 
INR 
International normalized ratio 
IR 
Incremental Recovery 


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IRAE(s) 
Immediately Reportable Adverse Event(s) 
IRB 
Institutional Review Board 
ISI 
international sensitivity index  
ITT 
intent-to-treat population 
IV 
Intravenous(lV) 
IVR 
In Vivo Recovery 
kg 
Kilogram 
l or L 
Liter 
LOCF 
last-observation-carried-forward 
LPLV 
Last Patient Last Visit 
max 
maximum 
MCF 
maximum clot firmness 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
min 
minute 
Ml 
MOA 
Milliliter 
mode of administration 
MRT 
mean residence time 
ODP 
on-demand prophylaxis (with BT524) 
ODT 
on-demand treatment (with BT524) 
PCR 
polymerase chain reaction 
PD 
pharmacodynamic(s) 
PDCO 
Paediatric Committee 
PICC 
peripherally inserted central catheter 
PK 
pharmacokinetic(s) 
PP 
per protocol population 
PT 
RBC 
prothrombin time 
red blood cell 
RICD 
Rare inherited coagulation disorder 
ROTEM 
rotational thromboelastometry 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SAP 
Statistical Analysis Plan 
SAS 
statistical analysis software 
SD 
standard deviation 
SDV 
Source data verification 
SmPC 
Summary of Product Characteristics  
SUSAR 
Serious Unexpected Suspected Adverse Reactions 
SOC 
System Organ Class 
TAT 
thrombin antithrombin III complex 
TEAE 
treatment emergent adverse event 
TEE 
thromboembolic event 
TMF 
Trial Master File 
TNBP 
tri-n-butyl phosphate 
t1/2 
terminal elimination half-life 
tmax 
time to reach maximum concentration 
Vss 
WBC 
volume of distribution 
white blood cell 


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6 INTRODUCTION 
BT524 is a fibrinogen concentrate manufactured from human plasma. 
Fibrinogen (coagulation factor I) is a soluble plasma glycoprotein synthesized by 
hepatic parenchymal cells. 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 the case of low fibrinogen levels or impaired function, blood 
coagulation is disordered, which leads to often severe hemorrhagic events. Normal 
blood fibrinogen concentration is between 1.5 - 4.5 g/l although this range can vary. 
The critical plasma fibrinogen level below which hemorrhages may occur is considered 
to be approximately 0.5 - 1.0 g/l. 
Congenital fibrinogen deficiency is a rare inherited coagulation disorder (RICD) 
characterized by an impaired hemostatic function. Congenital fibrinogen deficiencies 
are categorized on the basis of plasma concentration as follows: quantitative 
deficiencies (including afibrinogenemia and hypofibrinogenemia) with reduced levels of 
antigen 
and 
functional 
activity 
and 
qualitative 
deficiencies 
(including 
dysfibrinogenemias and hypodysfibrinogenemias) with normal or reduced antigen 
levels associated with abnormal functional activity. Functional activity assay measures 
clottable protein e.g. on the basis of coagulation time (Clauss 1957). The antigen level 
is measured by most labs using a radioimmunodiffusion assay. Qualitative disorders 
are due to genetic mutations in any of the 3 genes that encode the α, ß, and γ chains 
of fibrinogen, which are located on chromosome 4 and thus have autosomal 
inheritance.  
Afibrinogenemia is associated with a bleeding tendency, which is highly variable 
including life-threatening and spontaneous/trauma-related bleeds. Afibrinogenemia is 
often diagnosed in the newborn period because of umbilical cord bleeding. 
Afibrinogenemia is characterized by the complete absence or reduced amounts of 
immunoreactive fibrinogen as measured by antigenic and functional assays (< 0.1 g/l) 
(Acharya and Dimichele 2008). 
Patients with Hypofibrinogenemia have similar bleeding patterns but have a milder 
course. Hypofibrinogenemia is associated with fewer bleeding episodes and may not 
be diagnosed until a traumatic or surgical challenge occurs. Hypofibrinogenemia is 
defined by a decreased level of normal fibrinogen (activity and antigen below lower 
limit of normal range for local laboratory) (Acharya and Dimichele 2008).  
Dysfibrinogenemias 
are 
commonly 
diagnosed 
in 
adulthood. 
Patients 
with 
Dysfibrinogenemia have an unpredictable clinical phenotype which varies from 
asymptomatic (around 55%) to bleeding (25%) and/or thrombosis (20%) (Cheah et al. 
2012). Dysfibrinogenemia is characterized by a structural abnormality of the fibrinogen 
molecule resulting in altered functional properties. Classically, the functional assay of 
fibrinogen yields low levels compared with immunological assays but levels may be 
concordant and functional levels may be normal. Therefore, a discrepancy between 
clottable protein and immunologically measured fibrinogen is characteristic of 
dysfibrinogenemia (Acharya and Dimichele 2008).  
Hypodysfibrinogenemia is a subcategory of this disorder. Even in specialized 
laboratories, the precise diagnosis of some fibrinogen disorders may be difficult. 
Hypodysfibrinogenemia which is defined by both quantitative and qualitative defects in 
fibrinogen result in levels ranging from 0.5 to 1.2 g/l (Acharya and Dimichele 2008). 


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Compared with dysfibrinogenemia, patients are more often symptomatic. The 
prevalence of bleeding and cardiovascular events is high. Bleeding is frequently 
spontaneous and involves all tissues, including the central nervous system. 
Thrombosis develops in both arterial and venous territories and can be recurrent 
despite an adequate anticoagulant therapy (Casini et al. 2016). 
 
Table 1 provides an overview of the prevalence, fibrinogen levels, and symptoms of 
congenital fibrinogen deficiency.  
The present study is exclusively concerned with congenital afibrinogenemia and 
congenital severe hypofibrinogenemia. 
Table 1: 
Types of Congenital Fibrinogen Deficiency 
 
Afibrinogenemia 
Hypofibrinogenemia 
Dysfibrinogenemia 
Transmission 
Autosomal recessive 
Autosomal dominant and 
recessive 
Autosomal dominant and 
recessive 
Prevalence 
~ 1 in 1 million 
< 1 in 1 million 
~ 1 in 1 million 
Fibrinogen 
level 
< 0.1 g/l plasma 
Between 0.1 g/l and lower 
limit of normal 
< 1.5 and 3.5 g/l plasma, 
but dysfunctional 
Symptoms 
Umbilical cord bleeding, 
cutaneous bleeding, 
gastrointestinal 
hemorrhage, intracranial 
bleeding, articular 
bleeding 
Umbilical cord bleeding, 
cutaneous bleeding, 
gastrointestinal 
hemorrhage, intracranial 
bleeding, articular 
bleeding 
No symptoms, or 
hemorrhage, thrombosis 
   Source: Adapted from Acharya 2008 
There are wide discrepancies in reported incidences of congenital deficiencies and the 
true incidence is largely unknown as some patients are asymptomatic. In countries/ 
populations where consanguineous marriages are frequent, the prevalence of 
recessive coagulation disorders is higher (Fried and Kaufman 1980, Lak et al. 1999, 
Khalid et al. 2008).  
Effective management of congenital fibrinogen deficiency is necessary to prevent 
potentially life-threatening bleeding, to reduce increased loss of blood, transfusion 
requirements and the risk of surgery, and to improve pregnancy outcomes. Currently, 
conventional replacement therapy in fibrinogen deficiency given to counteract 
hemodynamic instability consists of transfusion of allogenic blood products such as 
fresh frozen plasma (FFP) and cryoprecipitate. The therapeutic target of these options 
is to achieve a fibrinogen activity concentration of at least 1 - 1.5 g/l (Peyvandi et al. 
2006).  
However, treatments with these preparations have certain limitations and moreover, 
expose the patients to multiple risks. As compared with fibrinogen concentrates, 
infusion of FFP or cryoprecipitate is limited by the lack of a virus inactivation/ removal 
process, leaving a potential risk of pathogen transmission (e.g., HBV, HCV, HIV). 
Moreover, both contain large amounts of proteins (fibronectin, von Willebrand factor, 
factor VIII, factor XIII, alpha macroglobulins, and anaphylatoxins), increasing the risk of 
allergic reactions (Silberstein et al. 1989, Sonntag et al. 1997). In addition, FFP and 
cryoprecipitate are insufficiently standardized in composition and must be thawed 


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before use, which is a limitation in time-critical and potentially life-threatening situations 
of severe bleeding. Moreover, cryoprecipitate and FFP, for which precise 
concentrations of fibrinogen are not standardized, can be associated with transfusion 
reactions or volume overload (Bevan 2009, Casini et al. 2015). Risks of transfusion of 
plasma products and limitations in handling led to the development of fibrinogen 
concentrate as a further important therapeutic option. Fibrinogen concentrates have 
shown to be safe, well-tolerated (Henselmans et al. 1999, Fenger-Eriksen et al. 2009) 
and to rapidly restore and maintain hemostasis in patients with congenital as well as 
acquired fibrinogen deficiencies in different indications (e.g., obstetrics, cardiovascular 
surgery). Different fibrinogen concentrates are commercially available in certain 
countries. As the concentration of fibrinogen in fibrinogen concentrates is notably 
higher (20 mg/ml) than in plasma, the required dose to reach the desired fibrinogen 
target level can be administered in a small volume. As with FFP and cryoprecipitate, 
potential risks associated with the administration of fibrinogen concentrate are 
hypersensitivity and thrombosis. 
In the present study, the 14 day single-dose pharmacokinetics/ pharmacodynamics 
following intravenous (IV) infusion of BT524 in patients with congenital afibrinogenemia 
or severe congenital hypo-fibrinogenemia will be evaluated (part I). Moreover, 
hemostatic efficacy of BT524 on single and/or repetitive administrations of BT524 in 
surgical procedures and/or spontaneous or post-traumatic severe bleeds will be 
assessed by means of clinical endpoints (part II) and a surrogate efficacy parameter. 
Furthermore, safety of BT524 will be evaluated. No final clinical data with BT524 are 
available so far. Based on all safety information from the ongoing Study 984 currently 
available, it can be considered that BT524 continues to have an adequate safety and 
tolerability. 
7 STUDY OBJECTIVES 
The primary objective of this study is to investigate the 14 day single-dose 
pharmacokinetics of BT524 following IV infusion in patients with congenital 
afibrinogenemia or severe congenital hypofibrinogenemia (part I).  
Secondary objectives are to investigate the 14 day single-dose PD of BT524, and the 
surrogate efficacy and safety of BT524 in part I of the study. In addition, the hemostatic 
efficacy, surrogate efficacy, and safety of single and/or repetitive administrations for 
on-demand prophylaxis (ODP) and/or on-demand treatment (ODT) of bleeding events 
(i.e., surgical procedure, spontaneous or post-traumatic severe bleeding) will be 
investigated in part II of the study. Surrogate efficacy of single (part I) and/or repetitive 
administrations of BT524 (part II) will be evaluated by the determination of the 
maximum clot firmness (MCF).  
In spite of the extension of the ongoing phase I/II study 984 to a phase I/III pivotal 
study and the expansion of the patient number of part II by 10 additional patients the 
parameter 'clinical response' will stay as a secondary endpoint. In a Scientific Advice 
meeting the 
) confirmed 'clinical response' being an 
appropriate efficacy endpoint and recommended to keep the efficacy evaluation as 
secondary endpoint having PK/PD as primary endpoint for the whole study (part I and 
part II).  
PPD


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8 ETHICAL AND REGULATORY CONSIDERATIONS 
This clinical study protocol and any amendments will be submitted to a properly 
constituted Independent Ethics Committee (IEC) / Institutional Review Board (IRB) 
and/or Regulatory Authorities, 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 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. 
The clinical study will be performed according to the legal requirements of the national 
law/s of the participating country/ies taking into account the principles of Good Clinical 
Practice (GCP) and the ethical principles that guided development of the Declaration of 
Helsinki. 
A Paediatric Investigational Plan application for agreement on data needed on 
paediatric age groups in congenital fibrinogen deficiency, as well as on the planned 
study design and the investigation procedure in this age group was submitted to EMA 
in June 2016. The planned inclusion and treatment of children 0 to < 6 years into the 
ongoing study 984 was described in detail. The positive opinion of the Paediatric 
Committee on the agreement of the Paediatric Investigation Plan (EMA-001931-PIP01-
16) was obtained in March 2017 and the extension of the ongoing study 984 was 
introduced within protocol amendment No 4.  
9 STUDY DESIGN 
The present study is designed as a prospective, open-label, multicentre, phase I/III 
study investigating the 14 day single-dose pharmacokinetic and pharmacodynamic 
properties, efficacy and safety of BT524 following intravenous administration in the 
treatment or prophylaxis of bleeding in patients with congenital afibrinogenemia or 
severe congenital hypofibrinogenemia.  
As shown in Table 2 the study is divided into two study parts (part I and part II), briefly 
described in the following:  


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Table 2: 
Overview of Study Design and Endpoints 
 
PART I
PART II
(Individual follow‐up 49 ± 4 days after the last administration of BT524)
BT524 
Single IV Infusion 
(70 mg/kg BW)
On‐Demand Treatment (ODT) 
On‐Demand Prophylaxis (ODP)
BT524 
Single or repetitive IV Infusion (s) 
as individually required
Pharmacokinetics (PK)
Pharmacodynamics (PD)
Clinical Efficacy
20 patients (≥ 6 years)
3 patients (< 6 years)
In total: 
n = 23 patients (part I)
 3 patients (< 6 years)
Ö additional patients without PK/PD :
 at least 3 patients < 6 years
In total:
all patients who have completed part I :
20 patients (≥ 6 years) and
at least 10 patients (≥ 6 years) and
n ≈36 patients (part II)
1‐2 months
min. 12 months
Surrogate Efficacy
Safety
Part I  
Part I is focused on the primary endpoint of the study, the 14 day single-dose 
pharmacokinetics, and the 14 day single-dose PD, and the evaluation of the maximum 
clot firmness (MCF) as a surrogate efficacy parameter. Moreover, initial safety will be 
investigated.  
With respect to safety, study-specific enrolment procedures comprising consecutive 
enrolment of the first five patients with a treatment-free safety interval of 7 days 
between each patient and restriction in age are implemented (see section 11.1.5). 
Safety will be assessed by physical examination (including ECG), vital signs, routine 
lab parameters, adverse events, development of fibrinogen antibodies and coagulation 
activation monitoring. 
Maximum duration of individual study participation in part I is up to 66±4 days for 
eligible screened patients (in case the patient does not experience a bleeding event 
within this safety interval).  
Part II 
Part I will subsequently be extended to a part II in which individual patients will be 
investigated for the efficacy and safety of single and/or repetitive administrations of 
BT524 in on-demand prophylaxis (ODP) and/or on-demand treatment (ODT) of 
different bleeding events [e.g., (elective) surgical procedure, spontaneous or post-
traumatic severe bleeding], if required. Thus, part II is expected to comprise a variety 
of singular events of different types, severity, and BT524-dosing requirements. All 
patients who have taken part in the pharmacokinetic assessment (part I) without 
severe post-dosing complications ideally continue treatment for ODP and/or ODT with 
BT524 in part II.  
At least 10 additional patients ≥ 6 to ≤ 75 years and at least 3 additional patients < 6 
years will be enrolled in part II (ODP/ODT) without PK/PD assessment (part I). 




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10.1.2 Packaging and Labeling 
A single container (100 ml glass bottle with rubber stopper) of BT524 contains 1 g 
fibrinogen, lyophilisate. The labeling of BT524 will be performed according to local 
requirements. A sample label will be contained in the Trial Master File (TMF).  
10.1.3 Storage Conditions 
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.  
  
The temperature has to be documented on a temperature log.  
11 STUDY TREATMENT 
11.1 
Dosage Regimen 
BT524 is available as lyophilized powder to be reconstituted in water for injections.  
The content of each vial of BT524 is to be reconstituted with 50 ml water for injections 
resulting in a nominal final concentration of 20 mg/ml. After reconstitution, the solution 
is recommended to be used immediately. Any unused solution must be discarded 
because of risk of bacterial contamination. 
The total dose, the infusion rate, and the batch and vial numbers of each infusion of 
BT524 must be recorded in the eCRF (electronic Case Report Form) and the drug 
accountability log. The dose per kilogram BW will be calculated. 
11.1.1 Dosage and Administration 
The study is divided into two study parts with a fixed dose of BT524 to be administered 
for the pharmacokinetic assessment (part I) and variable, individually tailored dose 
regimens in the extended ODP/ ODT part of the study (part II). 
Part I 
Dosage for the Assessment of the Pharmacokinetics/ Pharmacodynamics of BT524 
Each patient fulfilling the inclusion/ exclusion criteria is to receive a fixed dose of 70 mg 
BT524 per kilogram BW via a single intravenous infusion for the assessment of the 
pharmacokinetics/ pharmacodynamics of BT524 (see Table 3).  
Adults (18 to 75 years), Children/Adolescents Group I and Group II (≥ 6 years): 
BT524 is to be administered intravenously (IV) via an infusion pump with an infusion 
rate of 5 ml/min (part I) corresponding to a maximum infusion rate of 100 mg/min. 
BT524 is to be administered preferably in the forearm vein. Other administration routes 
are only allowed after approval from the sponsor.  
Pre-school Children Group III (2 to < 6 years), Newborns/Infants and Toddlers 
Group IV (0 days to < 2 years): 
BT524 is to be administered intravenously (IV) via an infusion pump with an adapted 
infusion rate below 5 ml/min (100 mg/minute) according to age, BW, and medical 
condition at the discretion of the treating physician of the patient (for further details 
please refer to Appendix 20.1). 
CCI


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Table 3: 
Pharmacokinetics: Dose, Target Level, Mode of Administration and 
Infusion Rate of BT524 
 
Dose of 
BT524 
Target Level 
No. of 
Doses 
MOA 
Infusion Rate 
Pharmacokinetics 
 
70 mg/kg 
BW 
— 
single 
IV 
5 ml/min* 
< 5 ml/min** 
(< 100 mg/ml) 
BW: body weight; IV: intravenous; min: minute; MOA: mode of administration 
* for Adults and Children/Adolescents Group I and Group II (≥ 6 years). 
** for Pre-school Children Group III and Newborns/Infants and Toddlers Group IV (< 6 years)  
For the assessment of the pharmacokinetics/ pharmacodynamics the total dose will be 
individually calculated on each patient’s BW taking into account the actual activity of 
BT524 of the batch used as specified in the COA as Fibrinogen activity (Precipitation). 
The corresponding volume to the calculated total dose of BT524 is to be administered 
according to the following example.  
 
For example: A patient with a BW of 60 kg is to receive a total dose of 4,200 mg BT524 
(m). The actual Fibrinogen activity (Precipitation) for the batch used is ~19 g/l according to 
COA. The volume to be administered is 221.05 ml. Duration of infusion is 44.21 minutes.  
Vinf. = 
m (mg) 
= 
4,200 mg 
= 
221.05 ml 
c (mg/ml) 
19 mg/ml 
Detailed information regarding the prevention of potential risks associated with the 
administration of BT524 is given in section 11.7. 
Part II 
On-demand Prophylaxis and On-demand Treatment 
In part II, patients will receive BT524 for on-demand prophylaxis (ODP) and/or on-
demand treatment (ODT) in case of bleeding events (i.e., surgical procedure, 
spontaneous or post-traumatic severe bleeding). With respect to ODP and/or ODT, the 
dosage, frequency of administration and duration of the substitution therapy with 
BT524 is individually tailored, to be adapted on the severity of the hemostatic disorder, 
the location and extent of the surgical procedure/ spontaneous bleed and the patient’s 
clinical condition.  
Adults (18 to 75 years), Children/Adolescents Group I and Group II (≥ 6 years): 
BT524 is to be administered intravenously (IV) with a maximum infusion rate of 
100 mg/min.  
Pre-school Children Group III (2 to < 6 years), Newborns/Infants and Toddlers 
Group IV (0 days to < 2 years): 
BT524 is to be administered intravenously (IV) via an infusion pump with an adapted 
infusion rate below 5 ml/min (100 mg/minute) according to age, BW, and medical 
condition at the discretion of the treating physician of the patient (for further details 
please refer to Appendix 20.1). 


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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) in case of elective surgeries. Other administration routes are only 
allowed after approval from the sponsor.  
Guidance for On-demand Prophylaxis (ODP) and On-demand Treatment (ODT) 
Unless valid information on the recovery rate for BT524 is available, the dosage 
regimen for surgical interventions and spontaneous bleedings will target (functional) 
fibrinogen levels recommended by the Core SmPC for Human Fibrinogen Products. 
Hence, the dosage, the amount and frequency of BT524 administration should be 
calculated on an individual patient basis by regular measurement of plasma fibrinogen 
activity levels and continuous monitoring of the clinical condition of the patient and - if 
applicable – on other replacement therapies used. Guidance for on-demand 
prophylaxis and/or on-demand treatment with BT524 in case of surgical interventions 
or spontaneous bleeding is given in Table 4. 
Table 4: 
Guidance for On-demand Prophylaxis and/ or On-demand Treatment 
Target levels recommended by the Core SmPC for Human Fibrinogen Products 
 
Dose of 
BT524 
Target Level 
No. of 
Doses 
MOA 
Infusion Rate 
Surgical intervention 
On-demand 
prophylaxis 
(ODP) 
variable* 
1 g/l** 
as 
required 
IV 
max 100 mg/min 
On-demand 
treatment 
(ODT) 
variable* 
1 g/l** 
maintained until 
hemostasis is secure 
as 
required 
IV 
max 100 mg/min 
> 0.5 g/l** 
until wound healing is 
complete 
Spontaneous bleeding 
On-demand 
treatment  
(ODT) 
variable* 
— 
as 
required 
IV 
max 100 mg/min 
IV: intravenous; max: maximum; min: minute; MOA: mode of administration 
Values given are guidance only, and higher or lower levels and increased frequency of administration may be 
necessary. 
* 
adapted on the severity, location and extent of bleeding, and the patient’s clinical condition 
** depending on the severity of the event fibrinogen levels may be raised in individual cases to a maximum of 
1.5 g/l at the discretion of the investigator. 
Calculation of Doses for On-demand Prophylaxis (ODP) and On-demand Treatment 
(ODT) by recovery rate of BT524 
Once valid information on the recovery rate of BT524 is available, the doses of BT524 
to be administered for surgical procedure or treatment of a bleeding episode should be 
calculated according to the following formula given by the Core SmPC for Human 
Fibrinogen Products: 


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Dose (g) =[desired levels (g/l) – baseline level (g/l)] x 1/recovery (g/l / g/kg) x BW (kg). 
11.1.2 Compliance with Dosage Regimens 
As the IMP will be administered intravenously to each patient under the supervision of 
the study investigator or designated qualified study personnel, the compliance is 
expected to be 100%. In addition, the assessment of plasma concentrations of BT524 
may also serve as an adherence measure. 
11.1.3 Dose Justification 
Therapeutic target levels of fibrinogen of at least 1 - 1.5 g/l are recommended for the 
prevention and treatment of congenital fibrinogen deficiency (Peyvandi et al. 2006, 
Manco-Johnson et al. 2009); however, others recommend target levels > 1 g/l for 
spontaneous bleeding and > 0.5 g/l until the bleeding surface is completely healed 
(Core SmPC for Human Fibrinogen Products, 2009/2015); (EMA 2009, Tziomalos et 
al. 2009, EMA (Committee for Medicinal Products for Human Use) 2015).  
The dose to be administered for the assessment of the pharmacokinetics of BT524 is 
70 mg per kg BW. The doses as well as the mode of administration and the infusion 
rates planned for BT524 in the present study are based on the results of preclinical 
studies with BT524 in comparison to Haemocomplettan. This applies in particular to 
the safety pharmacology (influence on core battery, Harbauer rabbit model, see 
Investigator's Brochure, section 5.3) and toxicology (thrombogenicity, Wessler model, 
see Investigator's Brochure, section 5.4.1) as well as primary (clottable protein, 
Clauss assay) and secondary pharmacodynamics (fib-tem, maximum clot firmness) 
(see Investigator's Brochure, section 5.1).  
 
All preclinical testing resulted in comparability between BT524 and Haemocomplettan. 
Therefore, published PK data (Manco-Johnson et al. 2009) and product information 
from a commercially available human fibrinogen concentrate (RiaSTAP Full Prescribing 
Information, March 2010 (CSL Behring 2010), which is identical to Haemocomplettan 
(Manco-Johnson et al. 2009, CSL Behring 2015) have been taken into consideration. 
For the first patients to be treated in part II, product-specific information on recovery 
might not be available. For these patients guidance on on-demand prophylaxis and/or 
on-demand treatment with BT524 in case of surgical intervention or spontaneous 
bleeding is provided. This guidance complies with the dosage recommendations of the 
Core SmPC for Human Fibrinogen Products. Once valid information on the recovery 
rate of BT524 is available the recommended formula of the Core SmPC is to be used 
to calculate the dosage for the target level desired.  
11.1.4 Treatment of Overdosage 
In order to avoid overdosage in patients with congenital afibrinogenemia or severe 
congenital hypofibrinogenemia, regular monitoring of the plasma level of fibrinogen 
during therapy is indicated. 
In case of overdosage, the risk of development of thromboembolic complications is 
enhanced (Core SmPC for Human Fibrinogen Products, 2009/2015). Please refer to 
Section 11.7. 


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11.1.5 Enrolment Procedures 
With respect to safety, the following study-specific enrolment procedures are 
implemented in study part I: 
The first five of the approximately 20 patients planned are to be recruited consecutively 
taken into account a dosing-free safety interval of 7 days between each patient.  
The dosing-free safety interval of two expected biological half-lives of BT524 
(according to the Core SmPC of Human Fibrinogen: t1/2 = 3-4 days) is considered to be 
sufficient for the detection of immediate (i.e., hypersensitivity) and later adverse effects 
(i.e., thrombosis).  
Subsequently, patients 6 to 20 are allowed to be treated simultaneously, if applicable. 
The first 10 of the approximately 20 patients planned are to be adults (aged 18 to 75 
years). Patients 11 to 20 are allowed to be 6 to 75 years of age. A Data Monitoring 
Committee (DMC) has been established to assess the available adult safety- and PK- 
data prior to the enrolment of any children (≥ 6 years) and adolescents into the study. 
Each patient is to be hospitalized until PK follow-up day 2 to ensure a close monitoring 
of the safety parameters and potential adverse effects. 
 
Planned enrolment of children and adolescents: 
Patients 6 to 10 may then be treated simultaneously; again there will be a 7-day 
dosing-free safety interval after the 10th adult patient. After completion of patient 10, a 
DMC will review the available safety data prior to the enrolment of any children and 
adolescents into the study. Patients 11 to 20 are also allowed to be treated 
simultaneously, if applicable.  
Subsequently, after the first 20 patients of ≥ 6 to ≤ 75 years finished part I, at least 3 
additional paediatric patients < 6 years of age are planned to be enrolled in the study 
part I. Prior to enrolment of any children < 6 years of age a DMC will review and 
assess all available safety and PK/PD data from adults and children ≥ 6 years 
including data of at least 3 children ≥ 6 to < 12 years and of at least 3 adolescents ≥ 12 
to < 18 years. 
 
With respect to safety, the following study-specific enrolment procedures are 
implemented in study part II: 
All patients included in part I will be eligible for participation in part II.  
At least 10 additional patients ≥ 6 to ≤ 75 years and at least 3 additional patients < 6 
years will be enrolled in part II (ODP/ODT) of the study without PK/PD assessments of 
part I.  
Subsequently, after the first 20 patients of ≥ 6 to ≤ 75 years finished part I, at least 3 
additional paediatric patients < 6 years of age are planned to be enrolled in the study 
part II without PK/PD assessment in study part I. Prior to enrolment of any children < 6 
years of age a DMC will review and assess all available safety and PK/PD data from 
adults and children ≥ 6 years including data of at least 3 children ≥ 6 to < 12 years and 
of at least 3 adolescents ≥ 12 to < 18 years. In total, approximately 36 patients are 
planned to be treated in this study: approximately 23 patients in part I and II, at least 
10 additional patients ≥ 6 years and at least 3 paediatric patients < 6 years in part II 
without PK/PD assessment of part I. 


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11.2 
Randomization Code  
Not applicable. As this is an open-label study design patients will not be randomized. 
11.3 
Assignment of Patient Identification 
Screening identification 
For the coherent assignment of the study documents all patients having signed the 
informed consent and having entered the screening period will receive a screening 
number prior to the first dosing of BT524. The screening number is composed of an ‘S’ 
followed by a four digit number (e.g., S0101 or S1204) of which the first two digits 
define the investigational site and the last two digits the patient screened at the 
corresponding site. Screening numbers are assigned consecutively per site. Screening 
numbers are assigned once only and will not be replaced i.e., in case of a screening 
failure. 
Patient identification 
In addition to the screening number, a patient number will be assigned if the patient 
fulfils the eligibility criteria (inclusion/ exclusion criteria) and is to receive BT524. 
The patient number comprises a four digit number of which the first two digits define 
the investigational site and the last two digits the patient enrolled at the corresponding 
site. Patient numbers are assigned consecutively per site. Patient numbers are 
assigned unique and will not be replaced e.g., in case of a patient prematurely 
withdrawn. 
11.4 
Drug Accountability 
The IMP will be supplied to the investigator or a local pharmacy 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 study participants were provided the doses specified in the protocol and 
reconcile all IMPs received for the study. The investigator has to ensure that 
consignments of IMPs are received correctly by a competent person and that the IMP 
is safely and appropriately handled and stored. 
Before the IMP is returned or destroyed, 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 documentation must include dates, quantities, 
patient numbers, batch numbers or other identification numbers, and expiry dates. 
The investigator must allow the monitor to perform drug reconciliation. 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. 
11.5 
Previous and Concomitant Medication or Treatment 
All previous medication and treatment in the previous 3 months prior to the 
administration of BT524 are to be recorded in the 'Previous and Concomitant 
medications' section of the eCRF.  


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Concomitant medication therapeutically required and not interacting relevantly with the 
coagulation system is allowed, as long as it is kept stable 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 
eCRF (i.e., identity of all medications, dosage and route of administration, frequency, 
duration of administration, and indication for use) at each visit.  
11.6 
Prohibited Medication or Treatment 
Blood donation or comparable blood loss within 60 days prior to infusion of BT524 for 
the pharmacokinetic assessment is not allowed.  
Any concomitant medication interacting relevantly with the coagulation system such as  
• fibrinogen concentrates other than BT524 (for prophylaxis or on-demand 
treatment) 
• fresh frozen plasma 
• cryoprecipitate 
• low molecular weight heparin or unfractioned heparin 
• factor Xa inhibitors (e.g., rivaroxaban, apixaban)  
• factor IIa inhibitors (e.g., dabigatran) 
• PY12 inhibitors (e.g., clopidogrel, prasugrel, ticagrelor) etc.  
• and other blood or plasma derivatives 
is prohibited 2 weeks prior to infusion of BT524 and within the study unless required by 
an emergency situation (major surgeries or major bleeding events that requires 
respective medication). 
In case prohibited medication had to be administered for emergency situations details 
of the event, reason for intake, product administered, and the dosage must be 
recorded accurately in the eCRF at the corresponding visit. Moreover, in case fresh 
frozen plasma, cryoprecipitate or other blood or plasma derivatives had to be 
administered the virus safety measures on the product must be recorded.  
11.7 
Risks and Precautions 
Transmissible agents 
Despite standard measures (i.e., selection of donors, screening of individual donations 
and plasma pools for specific markers of infection, and effective manufacturing steps 
for inactivation/ removal of viruses) to prevent infections resulting from the use of 
medicinal products prepared from human blood or plasma, the possibility of 
transmitting infective agents cannot be totally excluded. This also applies to unknown 
or emerging viruses and other pathogens.  
The manufacturing measures taken are considered effective for enveloped viruses 
such as HIV, HBV and HCV, for the non-enveloped viruses HAV and parvovirus B19, 
and prions.  
Hypersensitivity reactions 
All plasma or plasma-derived human products may lead to allergic or anaphylactic 
reactions. These might also be induced by BT524, by the active substance or any of 
the excipients of the medicinal product. With an authorized fibrinogen concentrate 


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allergic like/ anaphylactic like reactions such as generalized urticaria, erythema, drop 
in blood pressure, dyspnoea, and/or body temperature increase were observed in rare 
cases. 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 (Core SmPC for Human Fibrinogen Products, 2009/2015). 
Thus, due to the risk of potential allergic or anaphylactic reactions, the initial 
administration of BT524 should, according to the treating physician's judgment, be 
performed under medical supervision where proper medical care for allergic or 
anaphylactic reactions can be provided. 
Thromboembolic episodes  
There is a risk of thrombosis when patients with congenital fibrinogen deficiency are 
treated with human fibrinogen particularly with high dose or repeated dosing (Core 
SmPC for Human Fibrinogen Products, 2009/2015]; (de Moerloose et al. 2010, EMA 
(Committee for Medicinal Products for Human Use) 2015). Thus, patients given human 
fibrinogen should be observed closely for signs or symptoms of thrombosis.  
Prothrombin fragments F1+2, TAT, and D-dimer are monitored regularly to detect a 
hypercoagulable status.  
An (transient) increase in body temperature may occur (Core SmPC for Human 
Fibrinogen Products, 2009/2015). 
Overdosage 
Regular monitoring of the plasma level of fibrinogen during treatment is indicated to 
avoid overdosage. In case of overdosage, the risk of development of thromboembolic 
complications is enhanced. 
12 STUDY POPULATION 
12.1 
Study Population, Diagnosis and Number of Study Participants 
In view of the limited number of patients, a total of approximately 36 patients with 
congenital afibrinogenemia or severe congenital hypofibrinogenemia are planned to be 
treated within this study: approximately 20 patients ≥ 6 to ≤ 75 years and at least 3 
additional patients 0 to < 6 years in part I and II, at least 10 additional patients ≥ 6 
years and at least 3 patients < 6 years in part II without PK/PD assessment of part I. 
Eligibility is defined by the inclusion and exclusion criteria as described below. 
12.1.1 Gender Distribution  
There are no gender-based enrolment restrictions applicable for the study i.e., male 
and female patients are intended to be included. 
Since men and women might suffer from congenital afibrinogenemia or severe 
congenital hypofibrinogenemia, patients 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 


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administration of study drug. However, pregnant women are to be excluded (see 
general exclusion criterion 18). 
12.1.2 Children and adolescents 
Children and adolescents (≥ 6 years) will be enrolled only after completion of dosing 
and the associated 7-day dosing-free safety interval of the first 10 adult patients 
enrolled into the study and after the DMC has reviewed the data from these 10 adult 
patients. The measures taken to minimize risk for children and adolescents enrolled in 
the study are described in section 13.5.4.  
Subsequently, after the first 20 patients of ≥ 6 to ≤ 75 years finished part I, three 
additional paediatric patients < 6 years of age are planned to be enrolled in the study 
part I and subsequently in the part II. 
Prior to enrolment of any children < 6 years into the study a DMC will review and 
assess all available safety and PK/PD data from adults and children ≥ 6 years enrolled 
in the study so far (including data of least 3 children ≥ 6 to < 12 years and 3 
adolescents ≥ 12 to < 18 years).  
At least 3 additional patients < 6 years will be enrolled in part II (ODT/ODP) without 
PK/PD assessments (part I). 
12.2 
Inclusion Criteria 
Only patients meeting all of the following inclusion criteria will be considered for study 
inclusion: 
Inclusion Criteria 
Rationale 
Screening 
1. Known congenital afibrinogenemia or severe 
congenital hypofibrinogenemia 
medical 
X 
2. Plasma fibrinogen activity ≤ 0.5 g/l and antigen 
≤ 0.5 g/l 
medical 
X 
3. Male or female 
administrative 
X 
4. Age 0 to 75 years, with the first ten patients will 
be 18 years or older 
administrative 
X 
5. Presumed to be compliant with the study 
procedures and to terminate the study as 
scheduled 
Administrative / 
medical 
X 
6. Willing and able to be hospitalized for 3 days for 
the pharmacokinetic assessment (if applicable) 
administrative / 
medical 
X 
7. Willing and able to be hospitalized - if required - in 
case of interventions (e.g., surgical procedures, 
major bleeds) 
administrative / 
medical 
X 
8. Written informed consent by the patient, his/her 
parents or by the patient's legal / authorized 
representative as applicable 
administrative 
X 
 
 


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12.3 
Exclusion Criteria 
Patients having any of the following general exclusion criteria, either at screening (pre-
visit) or at enrolment (visit 1) are to be excluded from the study:  
Exclusion Criteria 
Rationale 
Screening 
1. 
Known congenital dysfibrinogenemia 
medical 
X 
2. 
Known bleeding disorder other than 
congenital fibrinogen deficiency 
medical 
X 
3. 
History of esophageal variceal bleeding 
medical 
X 
4. 
Known presence or history of venous/arterial 
thrombosis or thromboembolic event (TEE) in 
the preceding 6 months 
Medical 
X 
5. 
Known presence or history of fibrinogen 
inhibitory antibodies 
medical 
X 
6. 
Known presence or history of hypersensitivity 
to human fibrinogen or human plasma 
proteins e.g., immunoglobulins, vaccines or 
hypersensitivity to any of the excipients.  
medical 
X 
7. 
Known positive serology for HIV-1 and HIV-2 
medical 
X 
8. 
Clinically relevant biochemical or 
hematological findings (except due to 
underlying disease or emergency bleeding) 
outside the normal range (at the investigator's 
discretion) 
medical 
X 
9. 
Clinically relevant pathological findings in 
physical examination including ECG 
medical 
X 
10. Treatment with any fibrinogen concentrate 
and/or fibrinogen-containing product within 
2 weeks prior to infusion of BT524 
medical 
X 
11. Concomitant medication interacting relevantly 
with the coagulation system (e.g., low 
molecular weight heparin, unfractioned 
heparin, factor Xa inhibitors, factor IIa 
inhibitors or PY12 inhibitors) within 2 weeks 
prior to infusion of BT524 
medical 
X 
12. Recent vaccination within 3 weeks prior to 
infusion (only applicable for patients in PK part I) 
medical 
X 
13. BW below 22 kg for patients ≥ 6 years (only 
applicable for patients in PK part I);  
BW below the 5
th percentile of the normal range for 
children (refers to local standards*) 
medical 
X 
14. End stage disease  
medical 
X 
15. Abuse of drugs 
medical 
X 
16. Unable to understand and follow the study 
requirements (refers to the patient, his/her 
parents or to the patient's legal / authorized 
representative as applicable) 
administrative 
X 
17. Participation in another interventional clinical 
study within 30 days before entering the study 
or during the study 
administrative 
X 


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Exclusion Criteria 
Rationale 
Screening 
18. Pregnant/ nursing woman, or woman of 
childbearing potential not using reliable/ 
effective contraceptive method(s) during the 
study and at least one month after the last 
administration of study drug (e.g., oral/ 
injectable/ implantable/ insertable/ topical 
hormonal contraceptives, intrauterine devices, 
female sterilization, partner's vasectomy or 
condoms) 
medical 
X 
19. Any other condition that, in the investigator's 
judgment, could have an impact on patient's 
safety or study results 
administrative 
/medical 
X 
(*Please refer to Appendix 20.1) 
 
Pharmacokinetics (PK) 
In addition to the general exclusion criteria mentioned above, patients meeting any of 
the following PK-specific exclusion criteria at enrolment are to be excluded from the 
pharmacokinetic assessment. Patient enrolment is to be postponed until no PK 
exclusion criterion applies. 
PK-Specific Exclusion Criteria 
Rationale 
Screening 
20. Elective surgery during the 14 day PK blood 
sampling period  
medical 
X 
21. Acute infection 
medical 
X 
22. Clinically relevant increase or decrease in body 
temperature  
medical 
X 
23. Actively 
bleeding 
or 
anticipated 
bleeding 
(including female menorrhea) at the time point 
of or within 7 days prior to infusion of BT524 
medical 
X 
24. Surgery within 7 days prior to infusion of BT524 
medical 
X 
25. Immobilization within 7 days prior to infusion of 
BT524 
medical 
X 
26. Intake of alcohol or significantly increased 
intake of caffeine containing products within 
24 hours prior to infusion of BT524 
Medical 
X 
27. Blood donation or comparable blood loss within 
60 days prior to infusion of BT524 
medical 
X 
28. Excessive physical exercise (extreme sports 
activities, sauna) within 72 hours prior to 
infusion of BT524 
medical 
X 
 
12.4 
Study Participants Withdrawal Criteria and Procedures 
The participation of an individual study participant may be terminated prematurely for 
reasons such as: 
a) 
Withdrawal of written informed consent 
b) 
Withdrawal due to study participant's own request (e.g. personal reasons) 


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c) 
Adverse reactions during or upon administration of the investigational medicinal 
product 
d) 
Occurrence of pregnancy  
e) 
Lack of study compliance 
f) 
Any other condition which in the opinion of the investigator no longer permits a 
safe participation in the study 
A study participant and/or his parents or legally acceptable representative is/are 
entitled to discontinue participation in the clinical study at their own request at any time 
without stating a reason.  
The investigator can terminate a patient's participation in the study at any time if 
continuation could lead to disadvantages for the study participant which cannot be 
justified by the investigator. 
The reason for withdrawal of the study participant must be documented by the 
investigator together with all data collected until the day of premature study termination 
including laboratory results and assessment of adverse events. All examinations 
foreseen for the patient's last study visit (e.g., safety visit) should be performed.  
In case a patient withdraws due to an adverse event or serious adverse event please 
follow the instructions given in section 14.6 of this protocol. 
12.5 
Postponement of Enrolment for PK Assessment (Part I) and During 
ODP/ODT (PART II) 
The administration of BT524 for any event (PK assessment, ODP, ODT) of an 
individual study participant must be postponed for reasons such as: 
a) Required treatment with any medication known or suspected to interfere with the 
investigational medicinal product within the PK assessment period of 14 days 
b) Treatment with any fibrinogen concentrate and/or fibrinogen-containing product 
within two weeks prior to infusion of BT524 
c) Treatment with medication interacting relevantly with the coagulation system (e.g., 
low molecular weight heparin, unfractioned heparin, factor Xa inhibitors, factor IIa 
inhibitors or PY12 inhibitors) within two weeks of the respective product prior to 
infusion of BT524 
12.6 
Study Participants' Information 
The study participant and/or - if applicable - legally acceptable representative will be 
informed about the study according to the requirements of GCP and the legal 
requirements of the country in which the patient is recruited. 
The study, its objectives, possible benefits and risks, and its consequences will be 
verbally explained to the study participant and/or his/her legally acceptable 
representative. 
Moreover, 
the 
study 
participant 
and/or 
legally 
acceptable 
representative is/are provided with written information about the study. Sufficient time 
will be allowed for the information to be read and for questions to be asked. Attention 
should be paid to any signs of undue distress in paediatric subjects who are unable to 
clearly indicate their distress (ICH Harmonised Tripartite Guideline; E11 Step 4, 2000). 
The study participant and/or legally acceptable representative must be told that refusal 
to participate in the study does not cause any disadvantages to their treatment; 


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similarly, withdrawal of written informed consent is possible at any time, without stating 
a reason and without prejudice to further medical management. 
Study participants and/or legally acceptable representative 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 study participant and/or legally acceptable representative must be 
granted access to the insurance terms and conditions.  
Any new and relevant information that evolves during the course of the study 
concerning the investigational medicinal product, alternative treatments, or the 
benefit/risk ratio will be communicated to the study participant and/or legally 
acceptable representative. 
The study participant’s and/or legally acceptable representative's written informed 
consent will be filed at the investigator’s site. 
12.7 
Declaration of Informed Consent 
The study participant and/or - if applicable - legally acceptable representative must 
give written consent to participate in the study by signing and personally dating the 
informed consent form. 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 study participant or legally acceptable representative before any 
study-related procedures are performed. A duplicate of the signed and dated written 
informed consent form must be handed over to the study participant and/or – if 
applicable - legally acceptable representative. 
13 COURSE OF THE STUDY 
13.1 
Visit Schedule 
The study flowcharts (see section 3 Flowcharts of Study) provide tabular overviews 
on the visit dates and the assessments to be performed at each visit in the respective 
patient subgroup. Patients are assigned to the subgroups according to their age and 
BW: Adults (18 to 75 years), Children/Adolescents Group I (6 years or older) with BW 
above 43 kg, Children/Adolescents Group II (6 years or older) with BW ≤ 43 kg, Pre-
school Children Group III (2 to < 6 years), and Newborns/Infants and Toddlers Group 
IV (0 days to < 2 years). Detailed description on the measures and methods to be used 
for the assessments are given in section 14. 
13.1.1 Visit Types and Detailed Visit Schedules for the Assessment of the 
Pharmacokinetics/Pharmacodynamics of BT524 (PART I) 
13.1.1.1 
Visit Types 
The following visit types are planned for study part I. 
• Screening visit: 
The patient known to suffer from congenital afibrinogenemia or severe congenital 
hypofibrinogenemia and having signed informed consent to participate in the study 


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will have a screening visit (day -17 to day -1) to confirm eligibility for the study. The 
assessments as depicted in the flowchart for screening visit have to be performed. 
• PK Dosing day 0: 
The patient considered to be eligible will enter study part I. After inclusion and 
exclusion criteria have been re-checked, and blood samples for predose 
measurements collected, the patient will receive a fixed single intravenous infusion 
of BT524 (at 70 mg per kg BW) for the assessment of the PK/PD of BT524. The 
subgroup specific assessments as depicted in the flowchart for PK dosing day 0 
have to be performed (see section 3.1 Flowchart of Study - Adults, section 3.2 
Flowchart of Study - Children/Adolescents Group I, section 3.3 Flowchart of Study - 
Children/Adolescents Group II, section 3.4 Flowchart of Study - Pre-school Children 
Group III and section 3.5 Flowchart of Study - Newborns/Infants and Toddlers 
Group IV). 
• PK Follow-up day 1 and Follow-up day 2: 
Patient will be hospitalized until day 2 and will be closely monitored. The subgroup 
specific assessments as depicted in the respective flowchart for PK follow-up day 1 
and PK follow-up day 2 have to be performed.  
• PK Follow-up days 4, 7, 10, and 14: 
Patient will have regular site visits on the PK follow-up days 4, 7, 10, and 14. The 
subgroup specific assessments as depicted in the respective flowchart for PK 
follow-up days 4, 7, 10, and 14 have to be performed.  
• PK Safety visit: 
In part I a safety visit is to be conducted on day 49±4 after the administration of 
BT524. The subgroup specific assessments as depicted in the respective flowchart 
for PK Safety visit have to be performed. 
Exception: In case a patient experiences a bleeding event and is to receive at least 
one administration of BT524 within this time interval of 49±4 days, the safety visit of 
the PK/PD assessment on that Day 49 can be omitted. In this case, the respective 
dosing day 0 and the safety visit on day 49±4 after the (last) administration of 
BT524 for the bleeding event will serve as the safety visit related to part I. The 
safety visit is also to be performed for each patient prematurely withdrawn from 
study participation due to any reason. 
 
13.1.1.2 
Detailed Visit Schedules 
The following procedures are planned for study part I. 
Screening Visit (day -17 to day -1): 
After having obtained Informed consent (patient and/or legal representative) the 
following assessments are to be performed for all subjects unless otherwise specified: 
• Inclusion / exclusion criteria 
• Medical history 
• Plasma concentration of Fibrinogen antigen is to be done by enzyme-linked 
immunosorbant assay (ELISA) locally  
o only in Adults and Children/Adolescents Group I and II (≥ 6 years) 
• Plasma concentration of Fibrinogen antigen is to be done by nephelometry 
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• Plasma activity of Fibrinogen (Clauss assay) is to be done locally 
o only in Adults and Children/Adolescents Group I and II (≥ 6 years)  
• Plasma activity of Fibrinogen (Clauss assay) is to be done centrally 
• Fibrinogen inhibitory antibodies: to be done locally (by available method e.g., 
correction test of thrombin time) 
• Coagulation activation: PT(INR), aPTT, TAT, F1+2, D-dimer, to be done locally or 
centrally (depending on local availability of validated test systems)  
o only in Adults and Children/Adolescents Group I and II (≥ 6 years) 
• Safety laboratory to be done locally  
o in Adults and Children/Adolescents Group I and II (≥ 6 years) 
B Hematology (RBC, WBC, platelet count, hemoglobin, hematocrit) 
B Biochemistry (ASAT, ALAT, creatinine, and urea)  
• Safety laboratory to be done locally  
o in Pre-school Children Group III and in Newborns/Infants and Toddlers 
Group IV 
B Biochemistry (ASAT, ALAT, creatinine, urea, γ-GT, AP, total bilirubin, 
potassium, sodium, calcium, chloride) 
• Urine analysis (pH, blood, WBC, protein, glucose, ketone bodies, nitrite, 
bilirubin, urobilinogen) 
• Vital signs (pulse, blood pressure, body temperature) 
• Physical examination 
• Electrocardiogram (ECG)  
• Ultrasonography of lower limbs (according to study specific ultrasonography 
manual) 
• Pregnancy test (urine) - only in females of childbearing potential 
• Concomitant disease / concomitant medication 
• Assessment of risk and burden (paediatric patients) 
 
PK Dosing Day 0: 
The patient will be hospitalized 
• Check/re-check of inclusion / exclusion criteria 
• Single IV infusion of BT524 (at 70 mg/kg BW) 
• PK assessment:  
B Plasma concentration of fibrinogen antigen (nephelometry), 
 
to be done centrally  
B Plasma concentration of fibrinogen activity (Clauss assay), 
 
to be done centrally 
Time points for both fibrinogen antigen and fibrinogen activity as following: 
o Adults (18 - 75 years) and Children/Adolescents Group I (≥ 6 years, BW 
> 43 kg): pre-dose, immediately at the end of infusion, and 0.5, 1, 2, 4, 
and 8 hours post-end of infusion 


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o Children/Adolescents Group II (≥ 6 years, BW ≤ 43 kg): pre-dose, 
immediately at the end of infusion, and 1 and 4 hours post-end of 
infusion 
o Pre-school Children Group III (2 to < 6 years): pre-dose, immediately at 
the end of infusion, and 1 and 12 hours post-end of infusion 
o Newborns/Infants and Toddlers Group IV (0 days to < 2 years): pre-dose, 
immediately at the end of infusion, and 4 h* post-end of infusion (*only in 
infants and toddlers, at the discretion of the investigator considering the 
exact clinical situation of the patient) 
• Maximum clot firmness (MCF) by Fib-tem S of ROTEM:  
o Adults (18 - 75 years) and Children/Adolescents Group I and Group II 
(≥ 6 years): pre-dose, 1 and 8 hours post-end of infusion, to be done 
centrally and locally (if possible) 
o Pre-school Children Group III (2 to < 6 years): pre-dose, and 1 hour post-
end of infusion, to be done centrally 
o Newborns/Infants and Toddlers Group IV (0 days to < 2 years): pre-dose, 
and immediately at the of infusion, to be done centrally 
• Fibrinogen inhibitory antibodies: pre-dose, to be done centrally  
o only in Adults and Children/Adolescents Group I and II (≥ 6 years) 
• Coagulation activation: PT(INR), aPTT, TAT, F1+2, D-dimer, to be done locally or 
centrally (depending on local availability of validated test systems):  
o Adults (18 - 75 years): pre-dose and 1, 4, and 8 hours post-end of 
infusion 
o Children/Adolescents Group I and Group II (≥ 6 years): pre-dose, 4 and 
8 hours post-end of infusion 
o Pre-school Children Group III (2 to < 6 years): pre-dose, and 1 hour post-
end of infusion 
o Newborns/Infants and Toddlers Group IV (0 days to < 2 years): pre-dose 
and immediately at the of infusion 
• Safety laboratory: pre-dose, to be done locally 
B Hematology (RBC, WBC, platelet count, hemoglobin, hematocrit) 
• Safety laboratory: pre-dose, to be done locally  
o only in Adults and Children/Adolescents Group I and II (≥ 6 years) 
B Biochemistry (ASAT, ALAT, γ-GT, AP, total bilirubin, creatinine, urea, 
potassium, sodium, calcium, and chloride) 
B Urine analysis (pH, blood, WBC, protein, glucose, ketone bodies, nitrite, 
bilirubin, urobilinogen) 
• Immunoglobulin E (IgE):  
o Adults and Children/Adolescents Group I and Group II (≥ 6 years): pre-
dose, to be done centrally 
o Pre-school Children Group III (2 to < 6 years) and Newborns/Infants and 
Toddlers Group IV (0 days to < 2 years): only in case of any suspected 
hypersensitivity/ allergy/ anaphylaxis, to be done centrally 
• Viral safety: analysis pre-dose, collection of retention sample  


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• Vital signs (pulse, blood pressure, body temperature): pre-dose, 0.5 hours after 
start of infusion, and 0.5, 1, 2, 4, and 8 hours post-end of infusion 
• Physical examination: pre-dose and 2 hours post-end of infusion 
• ECG 6 hours post-end of infusion 
• Ultrasonography of lower limbs (according to study specific ultrasonography 
manual): whenever a thrombosis or TEE is suspected 
• Pregnancy test (urine): pre-dose - only in females of childbearing potential 
• Adverse events 
• Concomitant disease / concomitant medication 
• Assessment of risk and burden (paediatric patients) 
 
PK Follow-up Day 1: 
The patient will be hospitalized. 
• PK assessment: 
B Plasma concentration of fibrinogen antigen (nephelometry), 
 
to be done centrally 
B Plasma concentration of fibrinogen activity (Clauss assay), 
 
to be done centrally  
o Adults (18 - 75 years) and Children/Adolescents Group I and Group II 
(≥ 6 years): 24 hours post-end of infusion 
o Pre-school Children Group III (2 to < 6 years): no assessment 
o Infants and Toddlers Group IV (28 days to < 2 years): 24 hours post-end 
of infusion 
o Newborns Group IV (0 days to 27 days): no assessment 
• Coagulation activation: PT(INR), aPTT, TAT, F1+2, D-dimer, to be done locally or 
centrally (depending on local availability of validated test systems) 
o Adults (18 - 75 years) and Children/Adolescents Group I and Group II 
(≥ 6 years): follow-up Day 1 
o Pre-school Children Group III (2 to < 6 years): no assessment 
o Infants and Toddlers Group IV (28 days to < 2 years): follow-up Day 1 
(24 hours post-end of infusion) 
o Newborns Group IV (0 days to 27 days): no assessment 
• Safety laboratory: to be done locally 
B Hematology (RBC, WBC, platelet count, hemoglobin, hematocrit) and 
B Biochemistry (ASAT, ALAT, creatinine, and urea)  
o Adults (18 - 75 years) and Children/Adolescents Group I and Group II 
(≥ 6 years): follow-up Day 1 
o Pre-school Children Group III (2 to < 6 years): no assessment 
o Infants and Toddlers Group IV (28 days to < 2 years): follow-up Day 1 
(24 hours post-end of infusion) 
o Newborns Group IV (0 days to 27 days): no assessment 
• IgE: only in case of any suspected hypersensitivity/ allergy/ anaphylaxis, to be 
done centrally  


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• Vital signs (pulse, blood pressure, body temperature) 
• Physical examination 
• ECG  
• Ultrasonography of lower limbs (according to study specific ultrasonography 
manual): whenever a thrombosis or TEE is suspected 
• Adverse events 
• Concomitant disease / concomitant medication 
• Assessment of risk and burden (paediatric patients) 
 
PK Follow-up Day 2: 
Last day of hospitalization. 
• PK assessment: 
B Plasma concentration of fibrinogen antigen (nephelometry), 
 
to be done centrally 
B Plasma concentration of fibrinogen activity (Clauss assay), 
 
to be done centrally  
o Adults (18 - 75 years) and Children/Adolescents Group I (≥ 6 years): 
48 hours post-end of infusion 
o Children/Adolescents Group II (≥ 6 years): no assessment 
o Pre-school Children Group III (2 to < 6 years): 48 hours post-end of 
infusion 
o Newborns/Infants and Toddlers Group IV (0 days to < 2 years): no 
assessment 
• Coagulation activation: PT(INR), aPTT, TAT, F1+2, D-dimer, to be done locally or 
centrally (depending on local availability of validated test systems): 
o Adults (18 - 75 years): follow-up Day 2 
o Children/Adolescents Group I and Group II (≥ 6 years): no assessment 
o Pre-school Children Group III (2 to < 6 years): follow-up Day 2 
o Newborns/Infants and Toddlers Group IV (0 days to < 2 years): no 
assessment 
• Safety laboratory: to be done locally: 
B Hematology (RBC, WBC, platelet count, hemoglobin, hematocrit) 
B Biochemistry (ASAT, ALAT, γ-GT, AP, total bilirubin, creatinine, urea, 
potassium, sodium, calcium, and chloride) 
B Urine analysis (pH, blood, WBC, protein, glucose, ketone bodies, nitrite, 
bilirubin, urobilinogen) 
o Adults (18 - 75 years) and Children/Adolescents Group I and Group II 
(≥ 6 years): follow-up Day 2 
o Pre-school Children Group III (2 to < 6 years): follow-up Day 2 
o Newborns/Infants and Toddlers Group IV (0 days to < 2 years): no 
assessment 
• IgE: only in case of any suspected hypersensitivity/ allergy/ anaphylaxis, to be 
done centrally 


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• Vital signs (pulse, blood pressure, body temperature) 
• Physical examination 
• Ultrasonography of lower limbs (according to study specific ultrasonography 
manual): whenever a thrombosis or TEE is suspected 
• Adverse events 
• Concomitant disease / concomitant medication 
• Assessment of risk and burden (paediatric patients) 
END OF REGULAR HOSPITALIZATION 
 
PK Follow-up Day 4: 
Visit at the site. 
• PK assessment: 96 hours post-end of infusion  
o only in Adults and Children/Adolescents Group I and II (≥ 6 years) 
B Plasma concentration of fibrinogen antigen (nephelometry), 
 
to be done centrally 
B Plasma concentration of fibrinogen activity (Clauss assay), 
 
to be done centrally 
• Coagulation activation: PT(INR), aPTT, TAT, F1+2, D-dimer, to be done locally or 
centrally (depending on local availability of validated test systems)  
o only in Adults 
• Safety laboratory: to be done locally  
o only in Adults 
B Hematology (RBC, WBC, platelet count, hemoglobin, hematocrit) 
B Biochemistry (ASAT, ALAT, creatinine, and urea)  
• IgE: only in case of any suspected hypersensitivity/ allergy/ anaphylaxis, to be 
done centrally 
• Vital signs (pulse, blood pressure, body temperature) 
• Physical examination 
• Ultrasonography of lower limbs (according to study specific ultrasonography 
manual): whenever a thrombosis or TEE is suspected 
• Adverse events 
• Concomitant disease / concomitant medication 
• Assessment of risk and burden (paediatric patients) 
 
PK Follow-up Day 7: 
Visit at the site. 
• PK assessment: 168 hours post-end of infusion  
o only in Adults and Children/Adolescents Group I and II (≥ 6 years) 
B Plasma concentration of fibrinogen antigen (nephelometry), 
 
to be done centrally 
B Plasma concentration of fibrinogen activity (Clauss assay), 
 
to be done centrally 


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• Coagulation activation: PT(INR), aPTT, TAT, F1+2, D-dimer, to be done locally or 
centrally (depending on local availability of validated test systems)  
o only in Adults and Children/Adolescents Group I and II (≥ 6 years) 
• Safety laboratory: to be done locally  
o only in Adults and Children/Adolescents Group I and Group II (≥ 6 years) 
B Hematology (RBC, WBC, platelet count, hemoglobin, hematocrit) 
B Biochemistry (ASAT, ALAT, creatinine, and urea)  
• IgE: only in case of any suspected hypersensitivity/ allergy/ anaphylaxis, to be 
done centrally  
• Vital signs (pulse, blood pressure, body temperature) 
• Physical examination 
• Ultrasonography of lower limbs (according to study specific ultrasonography 
manual): whenever a thrombosis or TEE is suspected 
• Adverse events 
• Concomitant disease / concomitant medication 
• Assessment of risk and burden (paediatric patients) 
 
PK Follow-up Day 10: 
Visit at the site. 
• PK assessment: 240 hours post-end of infusion  
o only in Adults and Children/Adolescents Group I and II (≥ 6 years) 
B Plasma concentration of fibrinogen antigen (nephelometry), 
 
to be done centrally 
B Plasma concentration of fibrinogen activity (Clauss assay), 
 
to be done centrally 
• Coagulation activation: PT(INR), aPTT, TAT, F1+2, D-dimer, to be done locally or 
centrally (depending on local availability of validated test systems)  
o only in Adults 
• Safety laboratory: to be done locally  
o only in Adults 
B Hematology (RBC, WBC, platelet count, hemoglobin, hematocrit) 
B Biochemistry (ASAT, ALAT, creatinine, and urea)  
• IgE: only in case of any suspected hypersensitivity/ allergy/ anaphylaxis, to be 
done centrally 
• Vital signs (pulse, blood pressure, body temperature) 
• Physical examination 
• Ultrasonography of lower limbs (according to study specific ultrasonography 
manual): whenever a thrombosis or TEE is suspected 
• Adverse events 
• Concomitant disease / concomitant medication 
• Assessment of risk and burden (paediatric patients) 
 


Clinical Study Protocol 
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PK Follow-up Day 14: 
Visit at the site. 
• PK assessment: 336 hours post-end of infusion  
o only in Adults and Children/Adolescents Group I (≥ 6 years, BW > 43 kg) 
B Plasma 
concentration 
of 
fibrinogen 
antigen 
(nephelometry)  
to be done centrally 
B Plasma concentration of fibrinogen activity (Clauss assay), 
 
to be done centrally 
• Coagulation activation: PT(INR), aPTT, TAT, F1+2, D-dimer, to be done locally or 
centrally (depending on local availability of validated test systems)  
o only in Adults and Children/Adolescents Group I and Group II (≥ 6 years) 
• Safety laboratory: to be done locally  
o only in Adults and Children/Adolescents Group I and Group II (≥ 6 years) 
B Hematology (RBC, WBC, platelet count, hemoglobin, hematocrit) 
B Biochemistry (ASAT, ALAT, γ-GT, AP, total bilirubin, creatinine, urea, 
potassium, sodium, calcium, and chloride) 
B Urine analysis (pH, blood, WBC, protein, glucose, ketone bodies, nitrite, 
bilirubin, urobilinogen) 
• IgE: only in case of any suspected hypersensitivity/ allergy/ anaphylaxis, to be 
done centrally 
• Vital signs (pulse, blood pressure, body temperature) 
• Physical examination 
• Ultrasonography of lower limbs (according to study specific ultrasonography 
manual) 
• Pregnancy test (urine) - only in females of childbearing potential 
• Adverse events 
• Concomitant disease / concomitant medication 
• Assessment of risk and burden (paediatric patients) 
END OF PK/PD ASSESSMENT/SAMPLING PERIOD 
 
Safety Visit (Day 49±4): 
Visit at the site; also to be performed for each patient prematurely withdrawn from 
study participation due to any reason. 
• Fibrinogen inhibitory antibodies: to be done locally (by available method e.g., 
correction test of thrombin time) 
• Coagulation activation: PT(INR), aPTT, TAT, F1+2, D-dimer, to be done locally or 
centrally (depending on local availability of validated test systems) Ö only in 
Adults 
• Viral safety: collection of retention sample 
• IgE: only in case of any suspected hypersensitivity/ allergy/anaphylaxis, to be 
done centrally 
• Vital signs (pulse, blood pressure, body temperature) 
• Physical examination 


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• Adverse events 
• Concomitant disease / concomitant medication 
• Assessment of risk and burden (paediatric patients) 
 
13.1.2 Bleeding Events, Visit Types and Detailed Visit Schedules for On-demand 
Prophylaxis/On-demand Treatment with BT524 (PART II) 
PART II 
At discretion of the investigator, patients with no major safety complications in part I 
will continue in study part II. At least 10 additional patients ≥ 6 to ≤ 75 years and at 
least 3 additional patients < 6 years without PK/PD assessment of part I will be treated 
in part II. 
In part II, a variety of singular events of different types, severity, and BT524-dosing 
regimens for ON-DEMAND PROPHYLAXIS/ ON-DEMAND TREATMENT is expected. 
The following types of events and procedures in various combinations are possible: 
- 
Minor non-surgical bleeding event 
- 
Major non-surgical bleeding event 
- 
Spontaneous bleeding event 
- 
Elective bleeding event: an event that is planned e.g., surgery  
- 
Hospitalization: patient needs to stay overnight at hospital 
- 
No Hospitalization: patient will be treated with BT524 at site and will leave without 
overnight stay 
 
13.1.2.1 
Visit Types for Bleeding Events (Without Hospitalization) 
In study part II, the following visit types are planned for bleeding events for which a 
hospitalization of the patient is not required. 
• Screening visit (only for additional patients not treated within PK/PD part I): 
The patient known to suffer from congenital afibrinogenemia or severe 
congenital hypofibrinogenemia and having signed informed consent to 
participate in the study will have a screening visit to confirm eligibility for the study. 
The assessments as depicted in the flowchart for screening visit (see 3.6.1) have to 
be performed.  
• Dosing Day 0 – Pre-dose: 
The patient experiencing any bleeding and considered to be eligible for on-demand 
prophylaxis/on-demand treatment with BT524 for this bleeding event will enter 
study part II. After having re-checked the inclusion and exclusion criteria, the 
assessments regarding safety as depicted in the flowchart for dosing day 0 - pre-
dose have to be performed.  
• Dosing Day 0 – Post-End of Infusion: 
The patient will receive a single dose or repetitive doses of BT524 which is/are 
individually tailored depending on the type and severity of this particular event. The 
assessments regarding efficacy and safety as depicted in the flowchart for dosing 
day 0 - post-end of infusion have to be performed. 


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• Follow-up Days 1, 2, 5, and 10: 
Since the patient will not be hospitalized, follow-up telephone contacts to the 
patient by the investigator regarding potential adverse events and concomitant 
disease/ concomitant medication are to be performed for each case on the follow-
up days 1, 2, 5, and 10.  
• Optional Visit: 
An optional visit might be conducted at any time within 3 weeks after discharge at 
the discretion of the investigator. The assessments regarding safety as depicted in 
the flowchart for the optional visit have to be performed. 
• Safety Visit: 
A safety visit is to be conducted on day 49±4 after the (last) administration of 
BT524 for this bleeding event.  
Exception: In case a patient experiences a further bleeding and is to receive at 
least one administration of BT524 within this time interval of 49±4 days, the safety 
visit related to the preceding bleeding event can be omitted. In this case, the 
respective dosing day 0 and the safety visit on day 49±4 after the (last) 
administration of BT524 related to the current bleeding event will also serve as the 
safety visit related to the preceding event.  
The safety visit is also to be performed for each patient prematurely withdrawn for 
any reason. 
 
13.1.2.2 
Detailed Visit Schedules or Bleeding Events (Without Hospitalization) 
The following visit types with respective procedures are planned in study part II for 
each bleeding event for which hospitalization of the patient is not required. 
• Screening Visit (only for additional patients not treated within PK/PD part I): 
After having obtained Informed consent (patient and/or legal representative) the 
following assessments are to be performed: 
• Inclusion / exclusion criteria 
• Medical history 
• Plasma concentration of Fibrinogen antigen is to be done by nephelometry 
centrally 
• Plasma activity of Fibrinogen (Clauss assay) is to be done centrally 
• Fibrinogen inhibitory antibodies: to be done locally (by available method e.g., 
correction test of thrombin time) 
• Coagulation activation: PT(INR), aPTT, TAT, F1+2, D-dimer, to be done locally or 
centrally (depending on local availability of validated test systems)  
o only in Adults and Children/Adolescents Group I and Group II (≥ 6 years) 
• Safety laboratory: to be done locally  
o only in Adults and Children/Adolescents Group I and Group II (≥ 6 years) 
B Hematology (RBC, WBC, platelet count, hemoglobin, hematocrit)  
• Safety laboratory: to be done locally  
B Biochemistry (ASAT, ALAT, creatinine, urea, γ-GT, AP, total bilirubin, 
potassium, sodium, calcium, chloride)  


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B Urine analysis (pH, blood, WBC, protein, glucose, ketone bodies, nitrite, 
bilirubin, urobilinogen) 
• Vital signs (pulse, blood pressure, body temperature) 
• Physical examination 
• Electrocardiogram (ECG)  
• Ultrasonography of lower limbs (according to study specific ultrasonography 
manual) 
• Pregnancy test (urine) - only in females of childbearing potential 
• Concomitant disease / concomitant medication 
• Assessment of risk and burden (paediatric patients)  
 
Dosing Day 0 – Pre-dose: 
The patient will not be hospitalized. 
• Re-check of inclusion / exclusion criteria 
• Documentation of the type of the event (e.g., spontaneous bleeding, surgery) 
• Fibrinogen inhibitory antibodies: only if the patient received fibrinogen since last 
test.  
If applicable, to be done locally (by available method e.g., correction test of 
thrombin time). 
• Single or repetitive IV infusion(s) of BT524 for ODP/ ODT (according to 
Table 4 or according to the formula given by the Core SmPC for Human 
Fibrinogen Products once valid information on the recovery rate of BT524 is 
available) 
• Plasma concentration of fibrinogen activity (Clauss assay): to be done locally 
and centrally 
• Maximum clot firmness (MCF) by Fib-tem S of ROTEM): to be done centrally, 
and locally (if possible) 
• Coagulation activation: PT(INR), aPTT, TAT, F1+2, D-dimer, to be done locally or 
centrally (depending on local availability of validated test systems) 
• Safety Laboratory: to be done locally 
B Hematology (RBC, WBC, platelet count, hemoglobin, hematocrit) 
• Safety Laboratory: to be done locally  
o only in Adults and Children/Adolescents Group I and Group II (≥ 6 years): 
B Biochemistry (ASAT, ALAT, γ-GT, AP, total bilirubin, creatinine, urea, 
potassium, sodium, calcium, and chloride)  
B Urine analysis (pH, blood, WBC, protein, glucose, ketone bodies, nitrite, 
bilirubin, urobilinogen) 
• Viral safety: collection of retention sample 
• Ultrasonography of lower limbs (according to study specific ultrasonography 
manual) 
• Vital signs (pulse, blood pressure, body temperature) 
• Physical examination 
• Pregnancy test (urine) - only in females of childbearing potential 


Clinical Study Protocol 
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EudraCT No.: 2011-004154-25 
 
 
 
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• Adverse events 
• Concomitant disease / concomitant medication 
• Assessment of risk and burden (paediatric patients) 
 
Dosing Day 0 – Post-End of Infusion: 
The patient will not be hospitalized. 
• Plasma concentration of fibrinogen activity (Clauss assay): 1 hour post-end of 
infusion and as required, to be done locally and centrally 
• Maximum clot firmness (MCF) by Fib-tem S of ROTEM: 1 hour post-end of 
infusion and as required, to be done centrally, and locally (if possible) 
• Coagulation activation: PT(INR), aPTT, TAT, F1+2, D-dimer: before discharge, to 
be done locally or centrally (depending on local availability of validated test 
systems) 
•  Safety laboratory: before discharge, to be done locally 
B Hematology (RBC, WBC, platelet count, hemoglobin, hematocrit) 
B Biochemistry (ASAT, ALAT, γ-GT, AP, total bilirubin, creatinine, urea, 
potassium, sodium, calcium, and chloride) 
B Urine analysis (pH, blood, WBC, protein, glucose, ketone bodies, nitrite, 
bilirubin, urobilinogen) 
• Ultrasonography of lower limbs (according to study specific ultrasonography 
manual) and of any other suspected site: whenever a thrombosis or TEE is 
suspected  
• Vital signs (pulse, blood pressure, body temperature): 0.5 hours after start of 
infusion, 0.5 hours post-end of infusion, and before discharge 
• Physical examination: before discharge 
• Adverse events 
• Concomitant disease / concomitant medication 
• Assessment of risk and burden (paediatric patients) 
 
Follow-up Days 1, 2, 5, and 10: 
Phone contacts by the investigator to the patient regarding 
• Adverse events 
• Concomitant disease / concomitant medication 
• Assessment of risk and burden (paediatric patients) 
 
Optional Visit: 
At the discretion of the investigator the patient may have an optional visit at any time 
within three weeks after discharge. 
• Coagulation activation: PT(INR), aPTT, TAT, F1+2, D-dimer, to be done locally or 
centrally (depending on local availability of validated test systems) 
• Safety laboratory: to be done locally  
o in Children Group III and IV only if required 
B Hematology (RBC, WBC, platelet count, hemoglobin, hematocrit) 


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B Biochemistry (ASAT, ALAT, γ-GT, AP, total bilirubin, creatinine, urea, 
potassium, sodium, calcium, and chloride) 
B Urine analysis (pH, blood, WBC, protein, glucose, ketone bodies, nitrite, 
bilirubin, urobilinogen) 
• Ultrasonography examination of lower limbs (according to study specific 
ultrasonography manual) and of any other suspected site: whenever a 
thrombosis or TEE is suspected 
• Vital signs (pulse, blood pressure, body temperature) 
• Physical examination 
• Pregnancy test (urine) - only in females of childbearing potential 
• Adverse events 
• Concomitant disease / concomitant medication 
• Assessment of risk and burden (paediatric patients) 
 
Safety Visit (Day 49±4): 
Visit at the site; also to be performed for each patient prematurely withdrawn from 
study participation due to any reason. 
• Fibrinogen inhibitory antibodies: to be done locally (by available method e.g., 
correction test of thrombin time) 
• Coagulation activation: PT(INR), aPTT, TAT, F1+2, D-dimer, to be done locally or 
centrally (depending on local availability of validated test systems)  
o only in Adults and Children/Adolescents Group I and Group II (≥ 6 years) 
• Virus safety: collection of retention sample 
• Ultrasonography of lower limbs (according to study specific ultrasonography 
manual) and of any other suspected site: whenever a thrombosis or TEE is 
suspected 
• Vital signs (pulse, blood pressure, body temperature) 
• Physical examination 
• Pregnancy test (urine) - only in females of childbearing potential 
• Adverse events 
• Concomitant disease / concomitant medication 
• Assessment of risk and burden (paediatric patients) 
 
13.1.2.3 
Visit Types for Surgery or Bleeding Events (With Hospitalization) 
In study part II, the following visit types are planned for bleeding events for which a 
hospitalization of the patient is required. 
• Screening visit (for additional patients not treated within PK/PD part I): 
The patient known to suffer from congenital afibrinogenemia or severe 
congenital hypofibrinogenemia and having signed informed consent to 
participate in the study will have a screening visit to confirm eligibility for the study. 
The assessments as depicted in the flowchart for screening visit have to be 
performed. 


Clinical Study Protocol 
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EudraCT No.: 2011-004154-25 
 
 
 
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• Dosing Day 0 – Pre-dose: 
The patient experiencing any bleeding and considered to be eligible for on-demand 
prophylaxis/on-demand treatment with BT524 for this bleeding event requiring 
hospitalization will enter study part II. After having re-checked inclusion and 
exclusion criteria the patient will receive a single dose or repetitive doses of BT524 
which is/are individually tailored depending on the type and severity of this 
particular event. The assessments regarding safety as depicted in the flowchart for 
dosing day 0 - pre-dose have to be performed. 
• Dosing Day 0 – Post-End of Infusion: 
The assessments regarding efficacy and safety of BT524 as depicted in the 
flowchart for dosing day 0 - post-end of infusion have to be performed. 
• Follow-up Day 1 (24 h Post-End of Infusion): 
The patient will be closely monitored regarding efficacy and safety of BT524. The 
assessments regarding efficacy and safety as depicted in the flowchart for 24 hours 
after the end of last infusion have to be performed.  
• Follow-up Day 2 until Day Before Hospital Discharge: 
The patient will be monitored regarding safety of BT524 on the follow-up day 2 until 
the day before hospital discharge. The assessments regarding safety as depicted 
in the flowchart for from day 2 until the day before discharge (if applicable) have to 
be performed. 
• Day of Hospital Discharge (if Different than 24 h Post-End of Infusion): 
On the day of hospital discharge the patient will have final assessments regarding 
safety of BT524. The assessments regarding safety as depicted in the flowchart for 
the discharge day have to be performed.  
• Optional Visit: 
After hospital discharge, an optional visit might be conducted at any time before 
day 49 at discretion of the investigator. The assessments regarding safety as 
depicted in the flowchart for the optional visit have to be performed. 
• Safety Visit: 
A safety visit is to be conducted on day 49±4 after the (last) administration of 
BT524 for this bleeding event.  
Exception: In case a patient experiences a further bleeding and is to receive at 
least one administration of BT524 within this time interval of 49±4 days, the safety 
visit related to the preceding bleeding event can be omitted. In this case, the 
respective dosing day 0 and the safety visit on day 49±4 after the (last) 
administration of BT524 related to the current bleeding event will also serve as the 
safety visit related to the preceding event.  
The safety visit is also to be performed for each patient prematurely withdrawn from 
study participation for any reason. 
 
13.1.2.4 
Detailed Visit Schedules for Bleeding Events (With Hospitalization) 
The following visit types with respective procedures are planned in study part II for 
each bleeding event for which hospitalization of the patient is required. 


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• Screening Visit (only for additional patients not treated within PK/PD part I): 
After having obtained Informed consent (patient and/or legal representative) the 
following assessments are to be performed: 
• Inclusion / exclusion criteria 
• Medical history 
• Plasma concentration of Fibrinogen antigen is to be done by nephelometry 
centrally 
• Plasma activity of Fibrinogen (Clauss assay) is to be done locally and centrally 
• Fibrinogen inhibitory antibodies: to be done locally (by available method e.g., 
correction test of thrombin time) 
• Coagulation activation: PT(INR), aPTT, TAT, F1+2, D-dimer, to be done locally or 
centrally (depending on local availability of validated test systems)  
o only in Adults and Children/Adolescents Group I and Group II (≥ 6 years) 
• Safety laboratory: to be done locally  
o only in Adults and Children/Adolescents Group I and Group II (≥ 6 years) 
B Hematology (RBC, WBC, platelet count, hemoglobin, hematocrit)  
• Safety laboratory: to be done locally  
B Biochemistry (ASAT, ALAT, creatinine, urea, γ-GT, AP, total bilirubin, 
potassium, sodium, calcium, chloride)  
B Urine analysis (pH, blood, WBC, protein, glucose, ketone bodies, nitrite, 
bilirubin, urobilinogen) 
• Vital signs (pulse, blood pressure, body temperature) 
• Physical examination 
• Electrocardiogram (ECG)  
• Ultrasonography of lower limbs (according to study specific ultrasonography 
manual) 
• Pregnancy test (urine) - only in females of childbearing potential 
• Concomitant disease / concomitant medication 
• Assessment of risk and burden (paediatric patients)  
 
Dosing Day 0 – Pre-dose 
The patient will be hospitalized. 
• Re-check of inclusion / exclusion criteria 
• Documentation of the type of the event (e.g., spontaneous bleeding, surgery) 
• Single or repetitive IV infusion(s) of BT524 for ODP/ ODT (according to 
Table 4 or according to the formula given by the Core SmPC for Human 
Fibrinogen Products once valid information on the recovery rate of BT524 is 
available) 
• Plasma concentration of fibrinogen activity (Clauss assay), to be done locally 
and centrally 
• Maximum clot firmness (MCF) by Fib-tem S of ROTEM: to be done centrally, 
and locally (if possible) 


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• Fibrinogen inhibitory antibodies: only if the patient received fibrinogen since last 
test.  
If applicable, to be done locally (by available method e.g., correction test of 
thrombin time)  
• Coagulation activation: PT(INR), aPTT, TAT, F1+2, D-dimer, to be done locally or 
centrally (depending on local availability of validated test systems) 
• Safety laboratory: to be done locally 
B Hematology (RBC, WBC, platelet count, hemoglobin, hematocrit) 
• Safety Laboratory: to be done locally  
o only in Adults and Children/Adolescents Group I and Group II (≥ 6 years) 
B Biochemistry (ASAT, ALAT, γ-GT, AP, total bilirubin, creatinine, urea, 
potassium, sodium, calcium, and chloride) 
B Urine analysis (pH, blood, WBC, protein, glucose, ketone bodies, nitrite, 
bilirubin, urobilinogen) 
• Viral safety: collection of retention sample 
• Vital signs (pulse, blood pressure, body temperature) 
• Ultrasonography of lower limbs (according to study specific ultrasonography 
manual) 
• Physical examination 
• Pregnancy test (urine) - only in females of childbearing potential 
• Adverse events 
• Concomitant disease / concomitant medication 
• Assessment of risk and burden (paediatric patients) 
 
Dosing Day 0 – Post-End of Infusion 
The patient will be hospitalized. 
• Plasma concentration of fibrinogen activity (Clauss assay): 1 hour post-end of 
infusion and as required, to be done locally and centrally 
• Maximum clot firmness (MCF) by Fib-tem S of ROTEM: 1 hour post-end of 
infusion and as required, to be done centrally, and locally (if possible) 
• Coagulation activation: PT(INR), aPTT, TAT, F1+2, D-dimer: to be done locally or 
centrally (depending on local availability of validated test systems)  
o Adults (18 - 75 years) and Children/Adolescents Group I and Group II 
(≥ 6 years): 1 hour post-end of infusion and as required  
o Pre-school Children Group III (2 to < 6 years): as required 
o Newborns/Infants and Toddlers Group IV (0 days to < 2 years): as 
required 
• Safety laboratory: to be done locally, as required, 
B Hematology (RBC, WBC, platelet count, hemoglobin, hematocrit) 
B Biochemistry (ASAT, ALAT, γ-GT, AP, total bilirubin, creatinine, urea, 
potassium, sodium, calcium, and chloride) 
B Urine analysis (pH, blood, WBC, protein, glucose, ketone bodies, nitrite, 
bilirubin, urobilinogen) 


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• Ultrasonography of lower limbs (according to study specific ultrasonography 
manual) and of any other suspected site: whenever a thrombosis or TEE is 
suspected 
• Vital signs (pulse, blood pressure, body temperature): 0.5 hours after start of 
infusion, 0.5 hours post-end of infusion, and 4 hours post-end of infusion or as 
appropriate 
• Adverse events 
• Concomitant disease / concomitant medication 
• Assessment of risk and burden (paediatric patients) 
 
Follow-up Day 1 (24 h Post-End of Infusion) 
The patient will be hospitalized. 
• Coagulation activation: PT(INR), aPTT, TAT, F1+2, D-dimer, to be done locally or 
centrally (depending on local availability of validated test systems) 
• Safety laboratory: to be done locally 
B Hematology (RBC, WBC, platelet count, hemoglobin, hematocrit) 
B Biochemistry (ASAT, ALAT, γ-GT, AP, total bilirubin, creatinine, urea, 
potassium, sodium, calcium, and chloride) 
B Urine analysis (pH, blood, WBC, protein, glucose, ketone bodies, nitrite, 
bilirubin, urobilinogen) 
o in Adults (18 - 75 years) and Children/Adolescents Group I and Group II 
(≥ 6 years): as required, but at least to be done once after last infusion of 
BT524 and before discharge 
o Pre-school Children Group III (2 to < 6 years): 24 h post end of last 
infusion 
o Newborns/Infants and Toddlers Group IV (0 days to < 2 years): 24 h post 
end of last infusion 
• Ultrasonography of lower limbs (according to study specific ultrasonography 
manual) and of any other suspected site: whenever a thrombosis or TEE is 
suspected 
• Vital signs (pulse, blood pressure, body temperature) 
• Physical examination 
• Adverse events 
• Concomitant disease / concomitant medication 
• Assessment of risk and burden (paediatric patients) 
 
Follow-up Day 2 until Day before Hospital Discharge (if applicable): 
The patient will be hospitalized.  
• Coagulation activation: PT(INR), aPTT, TAT, F1+2, D-dimer: as required, to be 
done locally or centrally (depending on local availability of validated test 
systems) 
• Safety laboratory: as required, to be done locally 
B Hematology (RBC, WBC, platelet count, hemoglobin, hematocrit) 


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B Biochemistry (ASAT, ALAT, γ-GT, AP, total bilirubin, creatinine, urea, 
potassium, sodium, calcium, and chloride) 
B Urine analysis (pH, blood, WBC, protein, glucose, ketone bodies, nitrite, 
bilirubin, urobilinogen) 
• Ultrasonography of lower limbs (according to study specific ultrasonography 
manual) and of any other suspected site: whenever a thrombosis or TEE is 
suspected 
• Vital signs: as required 
• Adverse events 
• Concomitant disease / concomitant medication 
• Assessment of risk and burden (paediatric patients) 
 
Day of Hospital Discharge (if Different than 24 h Post-End of Infusion): 
The patient will be discharged from hospital. 
• Coagulation activation: PT(INR), aPTT, TAT, F1+2, D-dimer, to be done locally or 
centrally 
• Safety laboratory: as required, to be done locally 
B Hematology (RBC, WBC, platelet count, hemoglobin, hematocrit) 
B Biochemistry (ASAT, ALAT, γ-GT, AP, total bilirubin, creatinine, urea, 
potassium, sodium, calcium, and chloride) 
B Urine analysis (pH, blood, WBC, protein, glucose, ketone bodies, nitrite, 
bilirubin, urobilinogen) 
• Ultrasonography of lower limbs (according to study specific ultrasonography 
manual) and of any other suspected site: whenever a thrombosis or TEE is 
suspected 
• Vital signs 
• Physical examination 
• Adverse events 
• Concomitant disease / concomitant medication 
• Assessment of risk and burden (paediatric patients) 
 
Optional Visit 
After hospital discharge, an optional visit might be conducted at any time before day 49 
at discretion of the investigator. 
• Coagulation activation: PT(INR), aPTT, TAT, F1+2, D-dimer, to be done locally or 
centrally 
• Safety laboratory: as required, to be done locally 
B Hematology (RBC, WBC, platelet count, hemoglobin, hematocrit) 
B Biochemistry (ASAT, ALAT, γ-GT, AP, total bilirubin, creatinine, urea, 
potassium, sodium, calcium, and chloride) 
B Urine analysis (pH, blood, WBC, protein, glucose, ketone bodies, nitrite, 
bilirubin, urobilinogen) 


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• Ultrasonography examination of lower limbs (according to study specific 
ultrasonography manual) and of any other suspected site: whenever a 
thrombosis or TEE is suspected 
• Vital signs (pulse, blood pressure, body temperature) 
• Physical examination 
• Pregnancy test (urine) - only in females of childbearing potential 
• Adverse events 
• Concomitant disease / concomitant medication 
• Assessment of risk and burden (paediatric patients) 
 
Safety Visit (Day 49±4) 
Visit at the site; also to be performed for each patient prematurely withdrawn from 
study participation due to any reason. 
• Fibrinogen inhibitory antibody: to be done locally (by available method e.g., 
correction test of thrombin time) 
• Coagulation activation: PT(INR), aPTT, TAT, F1+2, D-dimer, to be done locally or 
centrally  
o only in Adults and Children/Adolescents Group I and Group II (≥ 6 years) 
• Ultrasonography examination of lower limbs (according to study specific 
ultrasonography manual) and of any other suspected site: whenever a 
thrombosis or TEE is suspected 
• Viral safety: collection of retention sample 
• Vital signs (pulse, blood pressure, body temperature) 
• Physical examination 
• Pregnancy test (urine) - only in females of childbearing potential 
• Adverse events 
• Concomitant disease / concomitant medication 
• Assessment of risk and burden (paediatric patients) 
 
 
13.2 
Duration of the Study 
First Patient in  
Adults: 20-Mar-2013 
Children/Adolescents (≥ 6 to < 18 years): 09-
Nov-2014 
Children < 6 years: Q2/2018 (planned) 
Last Patient Last Visit (planned) 
Q1/2020 
Individual Study Participant 
Study part I comprises of 14 days (including hospitalization until day 2) for the 
assessment of the pharmacokinetics/ pharmacodynamics of BT524 and the conduct of 
the safety visit (i.e., day 49±4 after the administration of BT524). Regular duration of 
individual study participation for eligible screened patients in part I is approximately 
1.5 months. Maximum duration of individual study participation in part I is up to 
66±4 days. 


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Duration of study part II is variable for the individual patient. For the last patient 
included it comprises of a minimum of 12 months period for optional on-demand 
prophylaxis and/or on-demand treatment including the conduct of the safety visit (i.e., 
day 49±4 after the last administration of BT524).  
All study subjects will be offered to extend their study participation (in part II) until the 
last enrolled subject (of the additional patients without PK/PD assessment) has 
finished study part II. This implicates that probably the total duration of individual study 
participation in both study parts will be more than 15.5 months. 
In case the patient experiences a bleeding event at the very end of his/her individual 
study participation even including the last day of month 12, regular individual study 
duration in part II is extended at maximum until day 49±4 after the administration of 
BT524 for the conduct of the safety visit for this very last event.  
13.2.1 End of Study 
The end of study will be defined as the Last Visit of the Last Study Participant (= LPLV 
(Last Patient Last Visit).  
13.3 
Criteria for Premature Termination 
13.3.1 Premature Termination of the Entire Clinical Study 
The study as a whole may be stopped by Biotest after consultation with the 
Coordinating Investigator if there are reasons for which continuation of study is no 
longer justified, such as: 
a) 
Unacceptable delay of study completion 
b) 
Low recruitment rate 
c) 
A large number of study participants with premature termination 
d) 
Changed benefit-risk ratio according to the efficacy and/or safety results from this 
or parallel studies 
e) 
Recommendation by the DMC (please refer to section 14.3) 
 
Stopping rule 
The DMC is expected to review all safety relevant information for each participating 
subject individually with the purpose to identify safety issues that are pertinent to the 
decision whether a) the study can be continued as intended and/or b) whether the 
safety relevant methods and procedures need to be adjusted.  
These decisions will be based on the in-depth review of all individual safety pertinent 
information by qualified experts; their resulting recommendations will be guided by 
following considerations: 
a. Occurrence of any fatal serious adverse event for which a causal relationship to 
the investigational medication is reasonably possible (i.e. SAR whether 
unexpected or not) 
b. Occurrence of any non-fatal serious adverse event for which a causal relationship 
to the investigational medication is reasonably possible (i.e. SAR whether 
unexpected or not) that is life-threatening or results in persistent or significant 
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c. Occurrence of any non-fatal adverse event for which a causal relationship to the 
investigational medication is reasonably possible (i.e. SAR whether unexpected or 
not) and that is medically significant since it put the trial participant at risk for an 
outcome as specified under a) or b) above if no intervention had been undertaken 
d. Occurrence of non-serious adverse reactions (AR whether unexpected or not) of 
severe intensity in more than 1/3 of the trial exposed patients 
e. Occurrence of non-serious non-severe adverse reactions (AR whether unexpected 
or not) that cause severe bother and inconvenience (in terms of duration and 
intensity) in more than 1/3 of the trial exposed patients. 
In the event of any of the above, the DMC will also review possibly contributing factors 
unrelated to the trial medication in order to identify ways to reduce the risk of such 
complications significantly by adapting the trial's methods (eligibility criteria, trial test 
procedures, schedule, etc.).  
In the event of any of the above, the DMC will recommend to stop the study if the risk 
for the reoccurrence of such event(s) cannot be reduced to a significant extent by 
adapting the trial's methods. 
In case of premature termination of the entire study, the sponsor has to notify the 
appropriate regulatory authorities within 15 days. 
13.3.2 Premature Termination of an Individual Study Site 
The study may be stopped at an individual study site for reasons such as: 
a) 
Low recruitment rate 
b) 
Lack of co-operation 
c) 
Severe deviations from study protocol 
d) 
Manipulation of study data 
e) 
Violation of other ethical or legal principles. 
13.4 
Treatment and Care after the End of the Study 
For patients having finished the study and for all patients who drop out prematurely, it 
is the responsibility of the investigator to choose adequate therapeutic measures. 
13.5 
Benefit-Risk Evaluation 
13.5.1 Benefit 
It is to be expected that patients with congenital fibrinogen deficiency e.g. a- and 
hypofibrinogenemia have a benefit from the single BT524 PK infusion due to the 
reduction of their bleeding risk (e.g. induced by [minor] trauma) for a period of 
approximately 1 to 2 weeks. In addition in part II the on-demand prophylaxis is 
expected to prevent bleeding during e.g. tooth extractions, surgical procedures etc. 
The on-demand treatment will be applied to stop any bleeding that may occur during 
the course of the study. 
In part I, the main character of this study is non-therapeutic (evaluation of PK, safety 
and tolerability data). Part II adds the benefits of treatment and prophylaxis for the 
participating patients. Moreover, the study patients contribute to the evaluation of a 
clinically needed, important therapy option to the benefit of future patients to be treated 
with BT524. 


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13.5.2 Foreseeable Risk and Discomfort Related to BT524 
Adverse drug reactions (ADRs) to be expected with BT524 
In study 984, BT524 is applied to humans for the first time. BT524 is a highly purified 
fibrinogen concentrate manufactured by Biotest from human plasma. 
Data on experience in humans is not yet available specifically for BT524. An EMA 
"Guideline on Core SmPC for Human Fibrinogen Products (EMEA/CHMP/BPWP/ 
691754/2013 Rev 1)" is in place dated 23-July-2015. This guideline is applicable to 
BT524 and comprises the following data on foreseeable risks with human fibrinogen.  
• Section 4.3 Contraindications 
Section 4.3 Contraindications names "Hypersensitivity to the active substance or to 
any of the excipients" and "[Product specific for products containing heparin:] 
<Known allergy to heparin or history of heparin induced thrombocytopenia type II.>".  
As BT524 does not contain heparin, the second point does not apply to BT524. With 
regard to the contraindication hypersensitivity, this point is addressed in the exclusion 
criteria (see general exclusion criterion 6). 
• Section 4.4 Special warnings and precautions for use 
Section 4.4 Special warnings and precautions for use states:  
 
(1) 
"There is a risk of thrombosis when patients, with either congenital or acquired 
deficiency, are treated with human fibrinogen particularly with high dose or repeated 
dosing. Patients given human fibrinogen should be observed closely for signs or 
symptoms of thrombosis. 
In patients with a history of coronary heart disease or myocardial infarction, in patients 
with liver disease, in peri- or post-operative patients, in neonates, or in patients at risk 
of thromboembolic events or disseminated intravascular coagulation, 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. 
(2) 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. 
(3) 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. 
(4) [Product specific for products containing heparin:] 
<Interference with clotting tests> 
When performing clotting tests which are sensitive to heparin in patients receiving high 
doses of human fibrinogen, the heparin as a constituent of the administered product 
must be taken into account. 
 
(5) [The text to be inserted here for transmissible agents should be in accordance with 
the current version of the guideline on the Warning on Transmissible Agents in SmPCs 
and Package Leaflets for plasma-derived medicinal products (EMA/CHMP/BWP/ 
360642/2010 rev. 1) (EMA 2011).] 


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When medicines are made from human blood or plasma, certain measures are put in 
place to prevent infections being passed on to patients. These include: 
• careful selection of blood and plasma donors to make sure those at risk of carrying 
infections are excluded, 
• the testing of each donation and pools of plasma for signs of virus/infections, 
• the inclusion of steps in the processing of the blood or plasma that can inactivate or 
remove viruses. 
Despite these measures, when medicines prepared from human blood or plasma are 
administered, the possibility of passing on infection cannot be totally excluded. This 
also applies to any unknown or emerging viruses or other types of infections. 
The measures taken are considered effective for enveloped viruses such as HIV, HBV 
and HCV and for the non-enveloped viruses HAV and parvovirus B19. 
 
It is strongly recommended that every time you receive a dose of BT524 the name and 
batch number of the product are recorded in order to maintain a record of the batches 
used. 
 
In the case of replacement therapy with coagulation factors in other congenital 
deficiencies, antibody reactions have been observed, but there is currently no data 
with fibrinogen". 
 
With regard to the special warnings and precautions for use, the first paragraph on 
thromboembolic events is addressed in several exclusion criteria (e.g. see exclusion 
criteria 4). 
The risk of thromboembolic events is addressed in several exclusion criteria (e.g. 
Known bleeding disorders other than congenital fibrinogen deficiency, history of 
esophageal variceal bleeding, known presence or history of venous/arterial thrombosis 
or thromboembolic events in the preceding 6 months). It is also closely followed up 
throughout the study, by ultrasonography of lower limbs as well as determination of 
coagulation activation parameters, and by more routinely follow-up of the patient (vital 
signs, physical exams, adverse events, etc.) 
The second paragraph of section 4.4 applies to acquired hypofibrinogenemia only and 
does therefore not apply to the study population of study 984.  
The study population of study 984 is limited to patients with congenital a- or severe 
hypofibrinogenemia as a homologous model population for patients with fibrinogen 
deficiency. This model population was chosen because it allows the generation of a 
representative PK profile in fibrinogen deficient plasma with a minimization of any 
interferences and heterogenicity as opposed to PK sampling in patients with acquired 
fibrinogen deficiency. 
The third paragraph on allergic or anaphylactic type reactions is addressed in the 
exclusion criterion 6. 
The fourth paragraph is only applicable to heparin containing products. BT524 does 
not contain heparin. 
The fifth paragraph addresses the risk of transmissible agents in plasma derived 
medicinal products. This risk is minimized in the production process (see also section 
10.1). Additionally, virology sample are taken pre-treatment and a virus safety follow-
up visit is planned on day 49±4 to confirm that no seroconversion has occurred within 
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The last, sixth paragraph on antibody reactions is again addressed in the exclusion 
criteria (Known presence or history of fibrinogen inhibitory antibodies). The risk of 
development of antibodies exists in theory and this will be monitored during the 
present study. 
 
• 4.8 Undesirable effects 
The following table of known adverse drug reactions with human fibrinogen is provided 
by the EMA guideline: 
 
Table 5: 
Known Adverse Drug Reactions with Human Fibrinogen 
MedDRA Standard 
System Organ Class 
Undesirable effects 
Frequency 
Immune system disorders: 
Allergic or anaphylactic-type reactions  
 
Vascular disorders: 
Thromboembolic episodes (including 
myocardial infarction and pulmonary 
embolism (see section 4.4) 
 
General disorders and 
administration site conditions: 
Increase in body temperature 
 
According to EMA Guideline 
In addition, the risk of transmissible agents in plasma-derived medicinal products is 
addressed [see section 4.4 of "Guideline on Core SmPC for Human Fibrinogen 
Products (EMEA/CHMP/BPWP/ 691754/2013 Rev 1)"].  
As described above, these potential risks are addressed in the respective exclusion 
criteria, e.g. "Known presence or history of hypersensitivity to human fibrinogen or 
human plasma proteins e.g., immunoglobulins, vaccines" as this predisposition may 
imply an increased risk for allergic or anaphylactic-type reactions as well as for 
hypersensitivity reactions (with in body temperature as one potential symptom) and 
"Known presence or history of venous/arterial thrombosis/thromboembolic events in 
the preceding 6 months". 
13.5.3 Risk minimization measures for all study participants 
Although risks cannot entirely be excluded, they are to be minimized by the following 
established measures: 
• By the careful selection of the patients as reflected in the inclusion and 
exclusion criteria. 
• By the close surveillance of patients throughout the study (ultra-sonography 
examination of lower limbs and of any other suspected site, as well as close 
follow-up of coagulation activation parameters, and regular evaluation of viral 
safety and of development of antibodies). 
• By routine and frequent patients follow-up procedures (including physical 
examination, assessment of vital signs, and adverse event reporting). 
• By the implementation of the stopping rule procedures as outlined in 
Section 13.3.1. 
• By the implementation of a DMC. A DMC has been established in order to 
review the first ten adult patients’ data before inclusion of children and 


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adolescents. The DMC is to ensure the safety of all study participants but in 
particular with regard to the inclusion of children and adolescents. 
13.5.4 Risk minimization measures regarding the enrolment and treatment of children 
and adolescents  
The anticipated risks to paediatric patients in Study 984 are considered comparable 
with those that adult patients may encounter from administration of BT524 and which 
are listed in Table 5: allergic or anaphylactic-type reactions, thromboembolic events, 
increase in body temperature, and a theoretical risk of transmissible agents from 
plasma-derived medicinal products. No additional risks for children and adolescents 
have been identified so far. 
Although risks for children and adolescents cannot entirely be excluded, they can be 
minimized by the following additionally implemented measures:  
• By assessment of individual risk and burden in paediatric patients by the 
investigator at every visit. 
• By the adaptation of the treatment to medical requirements and dosing 
according to the subject’s BW. 
• By the timing of the inclusion of children and adolescents: Children and 
adolescents will not be enrolled until after completion of dosing and the 
associated 7-day dosing-free safety interval of the first 10 adult patients enrolled 
into the study and after the DMC has reviewed the data from these 10 patients. 
13.5.5 Reduction of Pharmacokinetics blood sampling volume and time points in 
Paediatric Patients 
Blood sampling time points in paediatric patients were selected to ensure a reliable 
estimate of the product’s pharmacokinetics as a valid basis for comparison with other 
fibrinogen products and as a valid basis for dose selection in paediatric patients other 
than a simple adjustment to BW.  
A total of 13 blood samplings pre- and post-infusion are performed in adult patients 
and in children and adolescents with BW > 43 kg, requiring a total of 252 ml of blood in 
adults.  
In children and adolescents with a BW of ≤ 43 kg, the number of blood samplings pre- 
and post-infusion is reduced to 8 over a period of 10 days, with longer time intervals 
between each sampling and the next.  
In addition, the amount of blood was reduced to lower the burden on children and 
adolescents and avoid additional risks. The total volume needed in the PK part I of the 
study does not exceed 173.3 ml in children and adolescents with a BW ≤ 43 kg and 
203.3 ml in children and adolescents with a BW above 43 kg. 
In very young paediatric patients a further reduced sampling scheme will be applied. 
This includes sparse sampling with 5 PK sampling time points for children between 2 
to < 6 years, a minimal sampling with 3 PK samples for the infants and toddlers and 
only two PK sampling time points for newborns. Time points have been selected 
trough an optimal design to support best the derived PK information. The volume of 
blood to be drawn is reduced as much as possible by procedures adopted for the 
paediatric age group, using for example paediatric tubes and plasma micro-sampling.  


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The number of sampling time points for paediatric patients and the reduced amount of 
blood drawn are the minimal necessary number needed to meet the study’s PK 
objectives. 
13.5.6 Justification of Risk and Burden in Paediatric Patients 
The participation of children and adolescents in the preliminary pharmacokinetic and 
safety part of Study 984 will allow an understanding of each included child and 
adolescent profile in terms of fibrinogen deficiency characteristics (antigen level is 
rarely assessed), and in terms of response to administration of fibrinogen concentrate. 
Only in this way the study can yield a tangible benefit while ensuring a reliable 
estimate of the product’s pharmacokinetics. 
Furthermore, children and adolescents with fibrinogen deficiency are a target 
population that may benefit from BT542 administration, especially for treatment of 
trauma-related bleedings (frequently expected in childhood) and for prevention of 
surgery-related bleedings. Dental care is also frequently needed before 18 years of 
age, and in Egypt, Lebanon and Tunisia (where Study 984 is also conducted), a 
number of male children undergo circumcision before the age of 10. 
Risks and the burden in paediatric patients have been reduced as far as possible by 
the described measures, and the assessed risks and burden appear to be justified by 
the expected benefits. The risk and burden for each paediatric patient in the study will 
be assessed by the investigator at each visit. 
13.5.7 Other Sources of Possible Risk and Discomfort 
Puncture of a vein and/or placement of indwelling catheters for blood withdrawal may 
cause pain and occasionally results in hematoma, thrombosis or thrombophlebitis. 
Discomfort may be caused by any study procedure such as pre- and post-study 
examinations (including drug and virological HIV tests) and sampling (blood, urine). 
13.5.8 Summary of Possible Risk and Discomfort 
The anticipated risks all study participants (adults and paediatric patients) may 
encounter from administration of single/ multiple dose(s) of BT524 are allergic or 
anaphylactic-type reactions, thromboembolic events, an increase in body temperature, 
and the theoretical risk of transmissible agents from plasma-derived medicinal 
products.  
During this hospitalization period possible allergic or anaphylactic-type reactions as 
well as thromboembolic events are likely to be detected early and can be treated 
adequately and timely to minimize any medium- or long-term risks.  
Moreover, patients will be advised to walk and not to immobilize themselves to 
minimize the risk for thrombosis. 
Overall the risk benefit profile of this study is regarded as favorable. This conclusion is 
based on the fact that Fibrinogen concentrates have shown to be safe, well-tolerated 
(Henselmans et al. 1999, Fenger-Eriksen et al. 2009) and to rapidly restore and 
maintain hemostasis in patients with congenital as well as acquired fibrinogen 
deficiencies in different indications (e.g., obstetrics, cardiovascular surgery). All 
available investigations for BT524 indicate an expected benefit risk profile comparable 


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to the long available marketed fibrinogen concentrates and a safety profile that is in 
line with the available EMA Core SmPC.  
14 ASSESSMENT OF PRIMARY AND SECONDARY OBJECTIVES 
AND CRITERIA FOR EVALUATION 
14.1 
Pharmacokinetics 
The primary objective of this study is the assessment of 14 day single-dose 
pharmacokinetics of BT524 following IV infusion of 70 mg/kg BW (PART I). 
14.1.1 Specification of Pharmacokinetic Parameters 
For evaluation of the pharmacokinetics (PK) of BT524 the plasma concentration of 
fibrinogen antigen (nephelometry) will be determined at several time points during the 
14 day sampling period (see section 14.4.3.1). 
The exact time (actual time) post-end of infusion at which the actual samples were 
collected and their corresponding precise values are to be considered for PK analyses. 
Pharmacokinetics of BT524 will be evaluated by means of standard formulae using a 
statistical software package. The pharmacokinetic parameters to be evaluated 
comprise: 
• Terminal Elimination Half-life (t1/2) for fibrinogen antigen  
• Time to reach Maximum Concentration (tmax) 
• Maximum Concentration (Cmax) 
• Area Under the Concentration-Time Curve (AUC) calculated to the last measured 
concentration (AUC(0-t)) and extrapolated to infinity (AUC(0-inf) 
• Clearance (CL) 
• Mean Residence Time (MRT) 
• Volume of Distribution (Vss) 
• Incremental Recovery (IR) 
• Classical in vivo recovery (IVR) 
 
PK parameters will be derived from time-concentration profiles using adapted 
methodology (non-compartmental analysis, compartment analysis, or population 
modeling, as appropriate/ required). 
14.2 
Pharmacodynamics 
The 14 day single-dose pharmacodynamics of BT524 following IV infusion of 70 mg/kg 
BW is a secondary objective of this study (PART I). 
14.2.1 Specification of Pharmacodynamic Parameters 
For evaluation of the pharmacodynamics (PD) of BT524 the plasma concentration of 
fibrinogen activity (Clauss assay) will be determined at several time points during the 
14 day sampling period (see section 14.4.3.1). 


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The exact time post-end of infusion at which the actual samples were collected and 
their corresponding precise values are to be considered for PD analyses. 
Pharmacodynamics of BT524 will be evaluated by means of standard formulae using 
a statistical software package. The pharmaco-dynamic parameters to be evaluated 
comprise:  
- Terminal Elimination Half-life (t1/2) for fibrinogen activity  
- Time to reach Maximum Concentration (tmax) 
- Maximum Concentration (Cmax) 
- Area Under the Concentration-Time Curve (AUC) calculated to the last measured 
concentration (AUC(0-t)) and extrapolated to infinity (AUC(0-inf) 
- Clearance (CL) 
- Mean Residence Time (MRT) 
- Volume of Distribution (Vss). 
- Incremental Recovery (IR) 
- Classical in vivo recovery (IVR) 
Those parameters will be derived using adapted methodology, non-compartmental 
analysis, compartment analysis, or population modeling, as appropriate/ required. 
14.3 
Data Monitoring Committee (DMC)  
The DMC has been constituted by members who have expertise in the field of 
hematology/hemostaseology and/or investigation and/or experience in the proper 
conduct of clinical studies, and/or statistical knowledge, and who do not have any 
limiting conflicts of interest (i.e., financial, intellectual, professional or regulatory). 
The main aim of the DMC is to ensure the safety of the study participants in particular 
with regard to the inclusion of children and adolescents (< 18 years). Children and 
adolescents (≥ 6 to < 18 years) will not be enrolled until after completion of dosing and 
the associated 7-day dosing-free safety interval of the first 10 adult patients enrolled 
into the study and after the DMC has duly reviewed these data sets. 
In addition, the DMC will perform a second mandatory data review after the last patient 
has finished the PK safety visit and respective data are available.  
Subsequently, after the first 20 patients of ≥ 6 to ≤ 75 years finished part I, at least 3 
additional paediatric patients < 6 years of age are planned to be enrolled in the study 
part I and at least 3 additional patients < 6 years of age are planned to be enrolled 
directly in the study part II without PK/PD assessment in part I. Prior to enrolment of 
any children < 6 years of age the DMC will review and assess all available safety and 
PK/PD data from adults and children ≥ 6 years enrolled in the study so far (including 
data of least 3 children ≥ 6 to < 12 years and of at least 3 adolescents ≥ 12 to < 18 
years). 
The DMC will be fully established before enrolment of any children and adolescents 
into the study so that it can respond to any safety signal identified in adult patients. 
The DMC can also make other recommendations to the Sponsor concerning 
termination of the trial based on the assessment of the likelihood to reach a tangible 
benefit without exposing trial participants to undue risk and inconvenience.  
For details on stopping rule please refer to section 13.3.1. 


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In addition, the extent and timing of the pharmacokinetic profiling will be observed, 
including the between-subject variability of the data, the smoothness of the disposition 
curves, and the likelihood to capture the disposition profile with the smallest possible 
blood sampling load. 
The DMC will remain in office until completion of the end-of-trial visit in the last patient. 
The proceedings of the DMC will be governed by a separate charter.  
14.4 
Efficacy 
Within the study surrogate efficacy will be assessed in both parts whereas clinical 
endpoints will be assessed in part II only.  
14.4.1 Specification of Surrogate Efficacy Parameter 
Maximum clot firmness (MCF, mm) addresses the clot integrity and will be measured 
by rotational thromboelastometry. MCF serves as a surrogate endpoint. 
In Part I MCF pre-dose and at 1 and 8 hours post-end of each IV infusion will be 
compared and correlation between MCF and fibrinogen activity pre-dose and at 1 and 
8 hours 
post-end 
of 
each 
IV infusion 
will 
be 
assessed 
(in 
Adults 
and 
Children/Adolescents Group I and Group II (≥ 6 years). 
In Pre-school Children Group III (2 to < 6 years) MCF will be compared pre-dose and 
at 1 hour post-end of each IV infusion and correlation between MCF and fibrinogen 
activity pre-dose and at 1 hour post-end of each IV infusion will be assessed. 
In Newborns (0 days to 27 days) and in Infants and Toddlers (28 days to < 2 years), 
Group IV, MCF will be compared pre-dose and at the end of each IV infusion and 
correlation between MCF and fibrinogen activity pre-dose and at the end of each 
IV infusion will be assessed. 
In Part II MCF will be compared pre-dose and at 1 hour post-end of each IV infusion 
and correlation between MCF and fibrinogen activity pre-dose and at 1 hour post-end 
of each IV infusion will be assessed. 
14.4.2 Specifications of Clinical Efficacy Parameters 
PART II 
Efficacy of BT524 will be assessed as secondary objectives.  
The following efficacy parameters will be assessed after each bleeding event: 
• Overall hemostatic response to treatment with BT524 for each surgical procedure 
and each treated bleed as assessed by the investigator according to a 4 point scale:  
"none", "moderate", "good" or "excellent" 
• Total loss of blood (e.g., intra- and postoperatively, re-bleedings), if applicable 
• Units of other fibrinogen-containing products infused besides BT524 e.g., fresh 
frozen plasma or cryoprecipitate 
• Units of transfusion products infused, e.g., allogenic or autologous blood (packed 
red blood cells, fresh whole blood), platelets 
• Consumption of BT524 (doses per kilogram BW required pre-, intra- or post-
operatively for effective treatment) 


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The following efficacy parameter will be assessed after wound healing is expected to 
be completed: 
• Quality of wound healing, if applicable 
With respect to the evaluation of efficacy, patients with multiple events are to be 
considered as individual cases in a primary analysis. 
14.4.3 Methods for Assessing, Recording and Analyzing Pharmacokinetic Parameters 
14.4.3.1 
Determination of Fibrinogen Antigen 
PART I 
For evaluation of the primary endpoint, the 14 day pharmacokinetics of BT524, the 
plasma concentration of fibrinogen antigen will be determined at several time points 
during the 14 day sampling period. 
Fibrinogen antigen will be determined quantitatively by means of nephelometry 
(detection limit of 0.03 mg/l).  
Plasma samples are to be collected: 
In Adults and Children/Adolescents Group I (≥ 6 years and BW > 43 kg): on PK dosing 
day 0 pre-dose, immediately at the end of BT524 IV infusion, at 0.5, 1, 2, 4, 8, 24, 48, 
96, 168, 240, and at 336 hours post-end of infusion; 
In Children/Adolescents Group II (≥ 6 years and BW ≤ 43 kg): on PK dosing day 0 pre-
dose, immediately at the end of BT524 IV infusion, at 1, 4, 24, 96, 168, and at 
240 hours post-end of infusion; 
In Pre-school Children Group III (2 to < 6 years): on PK dosing day 0 pre-dose, 
immediately at the end of BT524 IV infusion, at 1, 12, and 48 hours post-end of 
infusion; 
In Infants and Toddlers (28 days to < 2 years): on PK dosing day 0 pre-dose, 
immediately at the end of BT524 IV infusion, and 24 hours post-end of infusion;  
In Newborns (0 days to 27 days): on PK dosing day 0 pre-dose, immediately at the end 
of BT524 IV infusion; (see sections 3.1 to 3.5). 
It is very important to record the exact time post-end of infusion at which the 
actual samples were collected and to consider their corresponding precise 
values for the PK analyses.  
Plasma concentration of fibrinogen antigen will be determined locally (by ELISA) and 
centrally (by nephelometry) at screening, at all other timepoints only at the central 
laboratory. Sample collection and processing are described in the laboratory manual. 
14.4.4 Methods for Assessing, Recording and Analyzing Pharmacodynamic 
Parameters 
14.4.4.1 
Determination of Fibrinogen Activity 
PART I 
For evaluation of the pharmacodynamics (PD) of BT524 the plasma concentration of 
fibrinogen activity will be determined at several time points during the 14 day sampling 
period. 


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Fibrinogen activity (functional) will be determined by means of the Clauss assay 
(detection limit of 0.2 g/l) (Clauss 1957, Palareti and Maccaferri 1990).  
Plasma samples are to be collected: 
In Adults and in Children/Adolescents Group I (≥ 6 years and BW > 43 kg): on PK 
dosing day 0 pre-dose, immediately at the end of BT524 IV infusion, at 0.5, 1, 2, 4, 8, 
24, 48, 96, 168, 240, and at 336 hours post-end of infusion; 
In Children/Adolescents Group II (≥ 6 years and BW ≤ 43 kg): on PK dosing day 0 pre-
dose, immediately at the end of BT524 IV infusion, at 1, 4, 24, 96, 168, and at 
240 hours post-end of infusion; 
In Pre-school Children Group III (2 to < 6 years): on PK dosing day 0 pre-dose, 
immediately at the end of BT524 IV infusion, at 1, 12, and 48 hours post-end of 
infusion; 
In Infants and Toddlers (28 days to < 2 years): on PK dosing day 0 pre-dose, 
immediately at the end of BT524 IV infusion, 4* and 24 hours post-end of infusion 
(*only at the discretion of investigator considering the exact clinical situation of the 
patient); 
In Newborns (0 days to 27 days): on PK dosing day 0 pre-dose, immediately at the end 
of BT524 IV infusion; (see sections 3.1 to 3.5). 
The exact time post-end of infusion at which the actual samples were collected and 
their corresponding precise values are to be considered for PD analyses. 
Plasma concentration of fibrinogen activity will be determined locally and centrally at 
screening, all other timepoints only at the central laboratory. Sample collection and 
processing are described in the laboratory manual. 
14.4.5 Methods for Assessing, Recording and Analyzing Efficacy Parameters 
14.4.5.1 
Method for Assessing, Recording and Analyzing Surrogate Efficacy 
Parameter 
14.4.5.2.1 Maximum Clot Firmness (MCF) by Fib-tem S of ROTEM Device 
Hemostatic efficacy of BT524 serves as a surrogate efficacy (secondary endpoint) and 
will be investigated by the determination of the Maximum Clot Firmness (MCF, mm) 
measured by rotational thromboelastometry. MCF as a surrogate efficacy parameter 
likely to predict clinical benefit was accepted by the FDA for the conditional approval of 
the fibrinogen concentrate RiaSTAP in 2009.  
PART I 
In part I, MCF is to be determined in Adults and Children/Adolescents Group I and 
Group II (≥ 6 years) on PK dosing day 0 pre-dose, at 1 and 8 hours post-end of 
BT524 IV infusion. 
In Pre-school Children Group III (2 to < 6 years) MCF is to be determined on PK 
dosing day 0 pre-dose and at 1 hour post-end of BT524 IV infusion. 
In Newborns and in Infants and Toddlers Group IV (0 days to < 2 years) MCF is to be 
determined on PK dosing day 0 pre-dose and immediately at the end of BT524 
IV infusion (see study flowchart for pharmacokinetics, sections 3.1 to 3.5). MCF pre-
dose value will be compared to the post-dose MCF values. 


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PART II 
In part II, MCF is to be determined for each administration of BT524 (if applicable) pre-
dose, at 1 hour and as required post-end of BT524 IV infusion (see sections 3.1 to 
3.6). MCF pre-dose value will be compared to the post-dose MCF values. 
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® (rotational thromboelastometry) system reagent (
 
) which allows the assessment of the fibrinogen level and the quality 
of the fibrin polymerization in citrated blood by inhibiting the platelets.  
Fib-tem S 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 1 shows an example of the ROTEM readout 
of citrated normal blood.  
Figure 1: 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 (Schochl 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 (
 
 
In 
patients 
with 
congenital 
afibrinogenemia 
or 
severe 
congenital 
hypofibrinogenemia the MCF would not be measurable (refer to Figure 2): 
PPD
PPD


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Figure 2: Fib-tem S Readout in Afibrinogenemia 
 
Sample collection and processing are described in the laboratory manual. 
14.4.5.2 
Methods for Assessing, Recording and Analyzing Clinical Efficacy 
Parameters 
14.4.5.2.1 Investigator Assessment on Overall Hemostatic Response to Treatment 
with BT524 
PART I 
No clinical parameters will be evaluated. 
PART II 
The investigator is asked to classify any bleeding event (spontaneous bleeding, 
surgery, post traumatic bleeding) post-dose as minor or major (please refer to 
Appendix 20.3 Recommendation for the 'Assessment of Bleeding Events'). For each 
surgical procedure as well as for each treated bleed, the investigator will classify the 
overall hemostatic response to treatment with BT524 according to a 4 point scale as 
"none", "moderate", "good" or "excellent". The overall assessment is to be performed 
at the day of hospital discharge (if applicable) or at the end of the treated bleeding 
event.  
14.4.5.2.2 Loss of Blood 
PART I 
No clinical parameters will be evaluated. 
PART II 
For each surgical procedure total loss of blood (e.g., intra- and postoperatively, re-
bleedings) will be evaluated - if applicable - or at least estimated as far as possible. In 
addition, loss of blood is to be rated by the investigator according to the following 
classifications 
- 
loss of blood is lower than expected for the procedure performed 
- 
loss of blood is within the expected range for the procedure performed 
- 
loss of blood is higher than expected for the procedure performed 


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14.4.5.2.3 Consumption of Alternative Fibrinogen-containing Products 
PART I 
No clinical parameters will be evaluated. 
PART II 
Units of other fibrinogen-containing products such as fresh frozen plasma, 
cryoprecipitate or alternative commercially available fibrinogen concentrates given to 
counteract hemodynamic instability will be documented and evaluated for each 
bleeding event (e.g., surgical intervention). 
14.4.5.2.4 Consumption of Transfusion Products 
PART I 
No clinical parameters will be evaluated. 
PART II 
Units of transfusion products (allogenic or autologous blood [packed red blood cells, 
fresh whole blood], platelets) given to counteract hemodynamic instability will be 
documented and evaluated for each bleeding event (e.g., surgical intervention). 
14.4.5.2.5 Consumption of BT524 
PART I 
Consumption of BT524 (dose per kilogram BW and total dose) will be calculated. 
PART II 
Consumption of BT524 (dose per kilogram BW, dose per infusion and total dose) 
required pre-, intra- or post-operatively for effective treatment will be calculated. 
14.4.5.2.6 Wound Healing 
PART I 
No clinical parameters will be evaluated. 
PART II 
Quality of wound healing will be assessed in part II only if applicable. 
14.5 
Safety 
14.5.1 Specification of Safety Parameter(s) and Timing 
The following safety parameters are described in the following sections: 
• 
ECG  
• 
Adverse events 
• 
Development of fibrinogen antibodies 
• 
Vital signs e.g., blood pressure, heart rate, body temperature 
• 
Physical examination 
• 
Clinical laboratory parameters of 


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Hematology: 
 
RBC, WBC, platelet count, hemoglobin, and hematocrit 
 
Biochemistry: 
 
Aspartate aminotransferase, alanine aminotransferase, γ-glutamintransferase, 
 
alkaline phosphatase, total bilirubin, creatinine, urea, potassium, sodium, 
 
calcium, chloride 
• 
 Markers of coagulation activation: 
 
PT(INR), aPTT, TAT, F1+2, D-dimer 
 
Urine Analysis: 
 
pH, blood, WBC, protein, glucose, ketone bodies, nitrite, bilirubin, urobilinogen 
• 
Virus safety 
14.5.1.1 
Adverse Events 
Safety issues will be addressed by occurrence, frequency, nature, and severity of 
adverse events (AEs). 
The number of AEs will be documented including safety laboratory parameters 
reported as adverse events. 
The patients are asked about AEs during the infusion and since the last visit. The 
patients will furthermore be explicitly inquired with regard to their well-being by 'non-
leading' questions at each visit.  
14.5.1.2 
Physical Examination and Vital Signs 
Physical examination will include the inspection of general appearance, skin, neck 
(including thyroid), eyes, ears, nose, throat, heart, lungs, abdomen, lymph nodes, 
extremities, musculoskeletal and nervous system.  
Time points for the assessment of physical examinations are given in the study flow 
charts (see section 3.1 to 3.6).  
PART I 
Physical examinations are to be performed at screening visit, on dosing day 0 pre-
dose and at 2 hours post-end of BT524 IV infusion, and on the follow-up days 1, 2, 4, 
7, 10, and 14 post-infusion, and at the safety visit.  
PART II 
On-demand prophylaxis/ on-demand treatment  
• Without hospitalization: physical examinations are to be performed at screening 
visit (only for additional patients without participation in PK/PD part I) and at 
dosing day pre-dose of BT524 IV infusion and before discharge, at the optional 
visit and the safety visit.  
• With hospitalization: physical examinations are to be performed at screening 
visit (only for additional patients without participation in PK/PD part I) and at 
each dosing day pre-dose of BT524 IV infusion, at 24 hours after the end of last 
infusion, on the day of hospital discharge, at the optional visit and the safety 
visit.  
In addition to the scheduled physical examinations symptom directed physical 
examination will be conducted whenever necessary. 
For all changes assessed to be clinically relevant an AE form must be completed.  


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Vital signs are measured with the following method/unit. 
• blood pressure [mmHg] 
• heart rate in beats/min measured by pulse rate 
• body temperature in grade Celsius [°C] (tympanic measurements) 
Time points for the assessment of vital signs are given in the study flow charts (see 
section 3).  
PART I 
Vital signs are to be performed at screening visit, on PK dosing day 0 pre-dose of 
BT524 IV infusion and at 0.5 hours after start of infusion, and at 0.5, 1, 2, 4, 8 hours 
post-end of infusion, and on the follow-up days 1, 2, 4, 7, 10, and 14 post-infusion, and 
at the safety visit (see study flowchart for pharmacokinetics, sections 3.1 - 3.5). 
PART II 
On-demand prophylaxis/ on-demand treatment  
• Without hospitalization: vital signs are to be performed at screening visit (only 
for additional patients without participation in PK/PD part I) and on the dosing 
day pre-dose of BT524 IV infusion, 0.5 hours after start of infusion, at 0.5 hours 
post-end of infusion, before discharge, and at the optional visit and the safety 
visit.  
• With hospitalization: vital signs are to be performed at screening visit (only for 
additional patients without participation in PK/PD part I) and at each dosing day 
pre-dose of BT524 IV infusion, 0.5 hours after start of infusion, at 0.5 and 
4 hours post-end of infusion, at 24 hours after the end of last infusion, from day 
2 until the day before hospital discharge whenever required, on the day of 
hospital discharge, at the optional visit, and the safety visit. 
14.5.1.3 
Coagulation Parameters 
The following safety coagulation parameters will be investigated: 
• 
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) values supplied by its manufacturer PT (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 


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hypercoagulable status can be detected (Wagner and Dati 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 
and follow-up hypocoagulable status (Wagner and Dati 2008).  
• 
D-dimer 
 
D-dimer is a fibrin degradation product (or FDP), 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).  
Time points for the assessment of coagulation parameters are given in the study flow 
charts (see section 3). Coagulation parameters are to be determined locally or 
centrally. 
PART I 
Coagulation parameters are to be determined: 
• In Adults (18 to 75 years): at screening visit, on PK dosing day 0 pre-dose of 
BT524 IV infusion and at 1, 4, and 8 hours post-end of infusion. Additional 
determinations are to be performed on the follow-up days 1, 2, 4, 7, 10, and 14 
post-infusion and at the safety visit.  
• In Children/Adolescents Group I and Group II (6 to < 18 years): at screening 
visit, on PK dosing day 0 pre-dose of BT524 IV infusion and at 4 and 8 hours 
post-end of infusion. Additional determinations are to be performed on the 
follow-up days 1, 7, and 14 post-infusion.  
• In Pre-school Children Group III (2 to < 6 years): on PK dosing day 0 pre-dose 
of BT524 IV infusion and at 1 hour post-end of infusion. Additional 
determinations are to be performed on the follow-up day 2 post-infusion.  
• In Infants and Toddlers (28 days to < 2 years): on PK dosing day 0 pre-dose of 
BT524 IV infusion, immediately at the end of infusion, and 24 hours post-end of 
infusion;  
• In Newborns Group IV (0 days to 27 days): on PK dosing day 0 pre-dose of 
BT524 IV infusion and immediately at the end of infusion. 
PART II 
On-demand prophylaxis/ on-demand treatment  
• Without hospitalization: coagulation parameters are to be assessed at screening 
visit (only for additional patients without participation in PK/PD part I) and on the 
dosing day pre-dose of BT524 IV infusion, before discharge, and at each 
optional and safety visit.  
• With hospitalization: coagulation parameters are to be assessed at screening 
visit (only for additional patients without participation in PK/PD part I) and on the 
dosing day pre-dose of BT524 IV infusion, at 1 hour post-end of infusion and as 
required, at 24 hours after the end of infusion, from day 2 until the day before 


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hospital discharge as required, on the day of hospital discharge, and at each 
optional and safety visit. 
14.5.1.4 
Determination of Fibrinogen inhibitory antibodies 
The routine determination of antibodies directed against fibrinogen epitopes leading to 
inhibition of fibrinogen activity will be done locally at the screening visit and at the PK 
safety visit (day 49 +/- 4).  
PART I 
• In Adults: at screening visit, on PK dosing day 0 pre-dose of BT524 IV infusion 
and at the safety visit (day 49 +/- 4). 
• In Children/Adolescents Group I and Group II: at screening visit, on PK dosing 
day 0 pre-dose of BT524 IV infusion and at the safety visit (day 49 +/- 4). 
• In Pre-school Children Group III: at screening visit (locally and centrally) and at 
the safety visit (day 49 +/- 4). 
• In Newborns/Infants and Toddlers Group IV: at screening visit (locally and 
centrally) and at the safety visit (day 49 +/- 4).  
PART II 
• Fibrinogen inhibitory antibodies are to be assessed at screening visit (only for 
additional patients without participation in PK/PD part I) and at the safety visit 
(day 49 +/- 4).  
• Furthermore the investigators can decide to undertake further determinations 
during the clinical trial pre-dose of BT524 IV infusion depending on the clinical 
course of the patient and suspicion of Fibrinogen inhibitor development of the 
individual patient. 
The development of Fibrinogen inhibitory antibodies has to be reported as serious 
adverse event (SAE). 
Patients who have developed Fibrinogen inhibitor antibodies have to be withdrawn 
from the study and standard treatment or prophylaxis of bleeding has to be initiated by 
the investigator / treating physician. 
14.5.1.5 
Safety Laboratory 
The following safety laboratory parameters will be determined: 
Hematology 
- 
RBC 
- 
WBC 
- 
Platelet count 
- 
Hemoglobin 
- 
Hematocrit 
Clinical chemistry 
- 
aspartate aminotransferase 
- 
alanine aminotransferase 
- 
γ-glutamyltransferase 


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- 
alkaline phosphatase 
- 
total bilirubin 
- 
creatinine 
- 
urea 
- 
potassium 
- 
sodium 
- 
calcium 
- 
chloride 
Urinalysis 
• pH 
• Qualitative investigation for 
- 
pH 
- 
blood 
- 
white blood cells 
- 
protein 
- 
glucose 
- 
ketone bodies 
- 
nitrite 
- 
bilirubin 
- 
urobilinogen 
Time points for the assessment of safety laboratory parameters are given in the study 
flow charts (see section 3). 
PART I 
In part I, safety laboratory parameters are to be determined: 
• In Adults: at screening visit, on PK dosing day 0 pre-dose of BT524 IV infusion, 
and on the follow-up days 1, 2, 4, 7, 10, and 14 post-infusion (see study 
flowchart for pharmacokinetics, section 3.1). 
• In Children/Adolescents Group I and Group II: at screening visit, on PK dosing 
day 0 pre-dose of BT524 IV infusion, and on the follow-up days 1, 2, 7, and 14 
post-infusion (see study flowchart for pharmacokinetics, section 3.2 and 3.3). 
• In Pre-school Children Group III: at screening visit, on PK dosing day 0 pre-
dose of BT524 IV infusion, and on the follow-up day 2 post-infusion (see study 
flowchart for pharmacokinetics, section 3.4). 
• In Newborns/Infants and Toddlers Group IV: at screening visit (biochemistry 
and urine analysis), and on PK dosing day 0 pre-dose of BT524 IV infusion 
(hematology). Additional determinations (hematology and biochemistry) on the 
follow-up day 1 (24 hours post-infusion) are to be performed only in infants and 
toddlers (see study flowchart for pharmacokinetics, section 3.5).  
PART II 
On-demand prophylaxis/ on-demand treatment  
• Without hospitalization: safety laboratory parameters are to be determined at 
screening visit (only for additional patients without participation in PK/PD part I) 
and on the dosing day 0 pre-dose of BT524 IV infusion, before discharge, and 
at each optional visit as required.  


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• With hospitalization: safety laboratory parameters are to be determined at 
screening visit (only for additional patients without participation in PK/PD part I) 
and on the dosing day 0 pre-dose of BT524 IV infusion and as required post-
end of infusion, at 24 hours post-end of infusion as required, from day 2 until the 
day before hospital discharge as required, on the day of hospital discharge as 
required, and at each optional visit as required. In all cases, they are to be 
determined at least once after the last infusion of BT542 and before discharge. 
Safety laboratory parameters will be determined at the local laboratory. Details on 
collection, processing and handling of blood samples are described in the laboratory 
manual. 
All safety laboratory blood and urine samples will be tested on an ongoing basis and 
will be destroyed after successful analysis. 
14.5.1.6 
Determination of Immunoglobulin Classes in Case of Anaphylaxis and/or 
Inhibitor Development 
Immunglobulin E is to be determined in Adults and Children/Adolescents Group I and 
Group II (≥ 6 years) on PK dosing day 0 pre-dose of BT524 IV infusion. In any patient 
developing anaphylaxis and/or inhibitors to fibrinogen, data on IgE against fibrinogen 
will be determined and recorded.  
14.5.1.7 
Ultrasonography Imaging  
The ultrasonography is an imaging technique used in the study to visualize 
thromboembolic events (e.g., deep vein thrombosis). Detailed instruction on the 
performance of the ultrasonography will be provided in the ultrasonography guidance 
manual.  
PART I 
In part I, ultrasonography imaging will be performed at screening visit, during the 14 
day pharmacokinetic sampling period assessment whenever a thrombosis or TEE is 
suspected, and on follow-up day 14 (see study flowcharts for pharmacokinetics, 
section 3). 
 
PART II 
On-demand prophylaxis/ on-demand treatment  
• Without hospitalization: ultrasonography imaging are to be performed at 
screening visit (only for additional patients without participation in PK/PD part I) 
and on the dosing day pre-dose, post-end of infusion whenever a 
thromboembolic event is suspected, and at the safety visit if a thrombosis or 
TEE is suspected.  
• With hospitalization: ultrasonography imaging are to be performed at screening 
visit (only for additional patients without participation in PK/PD part I) and on the 
dosing day pre-dose and from post-end of infusion until day of hospital 
discharge whenever a thrombosis or TEE is suspected. 


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14.5.1.8 
Electrocardiogram (ECG) 
PART I 
Standard ECG assessments are to be performed at screening visit, on PK dosing 
day 0, 6 hours post-end of BT524 IV infusion, and on follow-up day 1 (see study 
flowcharts for pharmacokinetics, section 3). The ECG print outs are signed by the 
investigator (= source document) and placed in the patient’s chart. 
PART II 
Standard ECG assessments are to be performed at screening visit only for additional 
patients without participation in PK/PD part I.  
14.5.1.9 
Pregnancy Test 
PART I 
In all women of childbearing potential a negative pregnancy test (test sample either 
from urine) must be available at screening visit, on PK dosing day 0 pre-dose of BT524 
IV infusion and on the follow-up day 14 (see study flowchart for pharmacokinetics, 
section 3). 
PART II 
In part II, a pregnancy test (urine) must be confirmed negative before each elective 
surgery and/or bleeding event on screening visit (only for additional patients without 
participation in PK/PD part I) and on dosing day 0 pre-dose. At each optional visit and 
at the safety visit (in case of a prematurely withdrawn from study participation) a further 
pregnancy test (urine) will be performed. 
14.5.1.10 Viral Safety 
Several pre- and post-dose serum samples (5 ml each) are to be taken from each 
patient participating in the study. The samples are to be collected and stored at -70 °C 
for possible future testing. Sample collection and processing are described in the 
laboratory manual.  
PART I 
A serum sample is to be drawn on PK dosing day 0 pre-dose of the BT524 IV infusion 
for analysis, and as retention sample. At the safety visit, a serum sample is to be 
drawn as retention sample (day 49±4 after the administration of BT524). 
PART II 
On-demand prophylaxis/ on-demand treatment  
• Without hospitalization: a serum sample is to be drawn on dosing day pre-dose 
and at each safety visit (day 49±4 after the last administration of BT524).  
• With hospitalization: a serum sample is to be drawn on dosing day pre-dose and 
at each safety visit (day 49±4 after the last administration of BT524). 
14.5.1.11 Retention Samples 
All retention samples collected for local or central determination or for possible future 
testing (e.g., suspected transmission of an infective agent) will be destroyed after 
successful analysis, if applicable and finalization of the study report. This applies also 
for laboratory samples described in the efficacy chapter (refer to sections 14.4.3.1 and 
14.4.5). 


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14.5.1.12 Assessment of Risk and Burden in Newborns, Infants and Toddlers, 
Children and Adolescents 
At each study visit the investigator will assess and document whether the risk and 
burden imposed on each paediatric patient (0 to < 18 years) by participation in the 
study are acceptable. This has to be documented on a separate form. 
14.5.2 Methods for Assessing, Recording and Analyzing Safety Parameter(s) 
All laboratory results have to be evaluated in the eCRF according to the following 
pattern: 
a) 
outside reference range but not clinically relevant (e.g. due to already known 
conditions, due to sampling conditions, only marginal deviation, due to underlying 
diseases in the study population) 
b) 
outside reference range and clinically relevant. 
Laboratory values which are outside the reference range and assessed as clinically 
relevant have to be controlled and documented as adverse events if they occur for the 
first time after administration of investigational medicinal product BT524.  
If abnormal laboratory values are signs of an adverse event (e.g. an infection) that has 
already been reported during the present study, this has to be stated but the respective 
abnormal laboratory value does not constitute a separate adverse event. 
14.6 
Adverse Events 
14.6.1 Definitions 
Adverse Event (AE) 
Any unfavorable or unintended sign, symptom, or disease that appears or worsens in a 
patient or clinical investigation subject during the period of observation in a clinical 
study. The AE may be any of the following: 
• A new illness 
• An exacerbation of a sign or symptom or the underlying condition under 
treatment or of a concomitant illness 
• Unrelated to participation in the clinical study or an effect of the study 
medication or comparator drug 
• A combination of one or more of the above factors 
No causal relationship with the study medication is implied by the use of the term 
"adverse event".  
Planned or elective surgical or invasive procedures for pre-existing conditions that 
have not worsened are not AEs.  
However, any complication that occurs during a planned or elective surgery is an AE. 
Conditions leading to unplanned surgical procedures may be AEs.  
When an AE occurs after written consent has been obtained but before the first dose 
of study drug, the AE will be considered a non-treatment emergent AE. An AE that 
occurs from the time the subject/patient receives his/her first dose of study drug until 
his/her last study visit will be considered a treatment emergent AE (TEAE).  


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Immediately Reportable Adverse Event (IRAE) 
Immediately reportable AEs (IRAEs) are AEs that must be reported to the Sponsor 
within 24 hours of the study site being informed of the IRAE.  
Immediately reportable AEs include  
− All Serious Adverse Events (SAEs)  
− All AESIs  
− AEs that result in a patient's withdrawal from the study (including TEE, 
fibrinogen inhibitory antibody, suspected allergic reaction)  
− Pregnancy 
 
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 itself. All deaths, 
regardless of cause or relationship must be reported for patients 
on study. 
• 
Is life-threatening, 
- 
life-threatening means that the patient was at immediate risk of 
death from the event as it occurred. This does not include an event 
that might have led to death if it were more severe. 
• 
Requires hospitalization or prolongation of existing hospitalization, 
- 
complications that occur during hospitalizations are AEs. However, 
if a complication prolongs hospitalization or requires new 
hospitalization, it is an SAE. In-patient hospitalization means the 
patient 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. If a patient experiences an AE during 
dosing and remains in hospital until the AE resolves, this is not 
considered an SAE unless the investigator considers that the 
event would have required hospitalization 
• 
Results in persistent or significant disability or incapacity, 
• 
Is a congenital anomaly or birth defect, or  
• 
Is another medically important condition  
An important medical event that is not immediately life threatening or will result in 
death or hospitalization, but which may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above, should be reported as 
“serious” as well. 
Medical and scientific judgment should be exercised in deciding whether a case is 
serious. 
“Occurring at any dose” does not imply that the patient is receiving study drug at the 
time of the event.  


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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 / Notifying requirements are detailed in section 14.6.4. 
The following AEs have been defined as AESI for this study: Thrombosis or TEE, and 
suspicion of transmission of infective agents (viral safety). 
Severity of Adverse Event: 
Refers to the extent to which an AE affects the patient's daily activities. Severity will be 
categorized according to the criteria shown in Table 6.  
Table 6: Severity of Adverse Event 
Mild: 
The AE does not interfere with the patient’s routine activities. 
Moderate: The AE interferes with the patient’s daily routine, but usual routine 
activities can still be carried out. 
Severe: 
The AE results in the inability to perform routine activities. 
 
The term "severity" is used to describe the intensity of an event. This is not the same 
as "serious". Seriousness, not severity, serves as the guide for defining regulatory 
reporting obligations. The highest severity grade attained should be reported, for AEs 
with divergent severities. 
Causality of Adverse Event:  
Refers to the relationship of the AE to study drug. Causality will be categorized 
according to the following criteria: 
Not related: 
AEs for which a reasonable explanation for an alternative cause is considered 
plausible e.g., no study drug taken, plausible clinical alternative like accidental injury, 
expected progression of underlying or concomitant disease, pharmacologically 
incompatible temporal relationship, intercurrent illness.  
Related: 
AEs for which a reasonably possible clinical and/or pharmacological relationship to 
study drug cannot be excluded e.g., lacking plausible alternatives. 
14.6.2 Recording Adverse Events 
In this study adverse events will be recorded electronically in the eCRF. 
Period: 
• Patient Enrolment to the First Administration of Study Drug: Non-treatment 
emergent AEs will be recorded from the time when the patient is enrolled into 
the study (date of signature of the informed consent) until first administration of 
study drug.  


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• After Administration of Study Drug until respective 49 day visit (Part I and 
Part II): All TEAEs will be recorded.   
• In-between individual 49 day periods or after last 49 day visit: Any serious 
treatment emergent AE considered to be related to the study medication by the 
investigator will be recorded. 
If an AE (serious or not) started after administration of study drug but did not end 
before the 49 day visit, the investigator should make a reasonable effort to establish 
the outcome and the end date. If this is not possible, the outcome recorded at the 
49 day visit will be assumed to be the final outcome. 
If an event stops and later restarts, all the occurrences must be reported. AEs 
assessed as related to study medication by the investigator and all SAEs must be 
followed up until resolution. 
The investigator should attempt to establish a diagnosis of the event based on signs, 
symptoms and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE and/or SAE and not the individual signs/symptoms. Signs/ 
symptoms should be documented only if a diagnosis cannot be established. If a 
diagnosis is accompanied by unusual symptoms, the diagnosis itself and the 
symptoms have to be reported separately.  
In addition to the definition as given, the following special types of events should be 
recorded: 
• Laboratory values that are outside the normal range and if, in the opinion of the 
investigator, these values represent a clinically relevant change versus pre-
treatment values are also defined as AEs. 
If abnormal laboratory values are signs of an AE (e.g. an infection) that has 
already been recorded, the respective abnormal laboratory value does not 
constitute a separate AE. Wherever reasonable the reporting investigator will 
use the clinical term rather than the laboratory term (e.g., anemia versus low 
hemoglobin value). 
14.6.2.1 
Responsibilities of Investigator 
AE data should be obtained through observation of the patient, from any information 
volunteered by the patient, or through patient questioning. The general type of 
question asked could be similar to: “Do you have any health problems?” or “Have you 
had any health problems since your last clinic visit?” 
AEs are to be documented/ recorded accurately and completely on the AE pages of 
the respective eCRF and in the patient's source data.  
All non-treatment emergent AEs will be recorded. During an individual 49 day period all 
TEAEs are to be recorded. In between individual 49 day periods or after last 49 day 
visit all serious TEAE considered to be related to the study medication by the 
investigator will be recorded. 
This is true even if the study drug was not administered according to the study 
protocol. 
For conditions leading to unplanned surgical procedures the underlying condition, 
should be documented as an AE, but not the procedure.  


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All known information regarding IRAEs must be recorded on the AE log of the eCRF 
within 24 hours of the study center being informed of the IRAE. For IRAEs, all other 
eCRF pages must be updated or completed as necessary. Electronic CRFs that must 
be completed for all IRAEs are: patient identification, study drug accountability, 
demographics, medical history, and concomitant medication. This information must be 
completed within 24 hours of the study center being informed of the IRAE.  
For all IRAEs where important or relevant information is missing, active follow-up 
should be undertaken. 
If for the further evaluation of an AE additional information is required by Biotest's 
Corporate Drug Safety department, then a representative of the sponsor must be 
granted access to the medical records. A respective statement has to be integrated in 
the written informed consent form to ensure adequate assessment of all AEs. 
Investigators also have the duty to assist in the elucidation of cases and if requested to 
provide a final written opinion.  
• Follow-up of Adverse Events 
Adverse events 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 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 adverse events, 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 patient number, 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 section 14.6.4. 
Adverse event data in the CRF must be updated accordingly when follow-up 
information is received.  


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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. 
 
14.6.2.2 
Responsibilities of Sponsor 
For purposes of safety analyses all AEs will be recorded in the clinical database. To 
ensure the basis for expedited and periodic notification of authorities, IRAEs will be 
additionally recorded in the drug safety database of the sponsor.  
14.6.3 Evaluation of Adverse Events 
14.6.3.1 
Responsibilities of Investigator 
To permit standardized assessment of AEs, the investigator will evaluate amongst 
others the seriousness, severity and causality of each AE using the AE pages of the 
eCRF. 
The seriousness, severity and causality of each AE will be evaluated by the 
investigator in accordance with the definitions in section 14.6.1. 
Causality of AE: 
For all AEs a causality assessment must be provided, even if based on preliminary 
data, and documented on AE page of the eCRF. 
14.6.3.2 
Responsibilities of Sponsor 
The causality assessment given by the investigator will not be 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.  
14.6.4 Notifying of Adverse Events 
14.6.4.1 
Responsibilities of Investigator 
In this study AEs will be reported electronically from the site to the sponsor using the 
eCRF. 
All known information regarding IRAEs (SAEs, AESIs, pregnancy, and AEs leading to 
withdrawal) must be recorded on the AE log of the eCRF within 24 hours of the site 
learning of the event (see also section 14.6.2.1).  
In case the electronic system is not function 24 hours, SAE paper forms will be 
provided to be used in the case of an IRAE. The paper forms will also need to be faxed 
or e-mailed to the sponsor within 24 hours of the site learning of the AE. 
Adverse Event Reporting Contact: 
For questions regarding IRAEs, or to provide information that cannot be provided 
electronically via the eCRF, or to notify the sponsor of an IRAE in the event of 
technical failure, the investigator should contact: 


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Biotest AG – Department Corporate Drug Safety 
Fax: +49 6103 / 801 - 854 
E-mail: Error! Hyperlink reference not valid.drugsafety@biotest.com 
Any requested supporting documentation (e.g., discharge summary, ECG, laboratory 
results, autopsy report) should be sent to the sponsor's Corporate Drug Safety 
department using the contact details provided above.  
Prior to forwarding any personal data for safety reporting reasons, it needs to be 
ensured that the documents are coded in a way that keeps patient's identity 
confidential (e.g., by using the patient's identification code, randomization number). 
If required, the investigator is responsible for informing local IECs/IRBs of safety 
reports in compliance with applicable regulatory requirements. Copies of all 
correspondence relating to reporting of any safety reports to the EC/IRB should be 
maintained in the Investigator Site File / Regulatory Binder.  
 
14.6.4.2 
Responsibilities of Sponsor 
Biotest's Corporate Drug Safety department is responsible for fulfilling all obligations 
regarding notification of Regulatory Authorities and IECs/ IRBs according to applicable 
regulatory requirements (expedited and periodic reporting, e.g. serious unexpected 
suspected adverse reactions, Development Safety Update Report). In addition, the 
sponsor will be responsible for information of investigators according to the current 
legislation. 
 
14.6.4.3 
Pregnancy Reporting 
In the unlikely event that a woman becomes pregnant during the study this is reported 
within 24 hours of the site learning of the situation using the "Drug Exposure via Parent 
Report Form" paper form and the contact details as above. The investigator should 
make any reasonable effort to follow-up the pregnancy until birth of the child; and will 
report all outcomes associated with the pregnancy to the sponsor. 
 
14.6.4.4 
Investigational Product Complaints  
Complaints associated with the investigational medicinal product must be recorded in 
the eCRF and reported to the sponsor within 24 hours of the investigator becoming 
aware of the IMP complaint, using the “Investigational Medicinal Product Complaint” 
report form. In case of corresponding AEs related to suspected quality defects, the 
AEs have to be entered in the respective eCRF pages (AE page/ IRAE page). 
Any complaint samples should be provided to the sponsor upon request. 
 
15 STATISTICS 
The statistical planning and evaluation of the study will be carried out by a qualified 
statistician in accordance with the ICH-guidelines and adequate biostatistical SOPs.  
A detailed Statistical Analysis Plan (SAP) will be prepared at the latest before data 
base lock. 


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15.1 
Calculation of Sample Size 
The primary objectives of this study are key PK parameters. For the PK parameters no 
formal sample size calculation is carried out. As a general rule approximately 
20 patients in this single cohort should suffice to calculate PK parameters with the 
corresponding range of distribution. 
For the surrogate (secondary) efficacy variable MCF (maximal clot firmness), a formal 
sample size calculation was performed. 
On the basis of a t-test assessing the difference between dependent means (post- 
minus pre-treatment MCF difference; one sample) the sample size can be calculated. 
The mean MCF in the study population consisting of patients with congenital fibrinogen 
deficiency (i.e., a- or severe hypofibrinogenemia) prior to BT524 treatment and 1 hour 
after treatment will be measured by Fib-tem S of ROTEM.  
With 15 patients, a pre-treatment mean of 4 mm (SD 7 mm) and a post-treatment 
mean of 10 mm (SD 8 mm) an effect size of 0.8 mm can be detected with a power of 
80% at α = 0.05 (2-sided) significance level. 
15.2 
Statistical Methods 
The statistical planning and evaluation of the study will be carried out by a qualified 
statistician in accordance with the ICH-guidelines and adequate biostatistical SOPs.  
A more detailed description of the statistical analysis will be provided in the SAP. The 
SAP is to be finalized and approved prior to database lock. 
All analyses of this open-label study will be performed on the intent-to-treat (ITT) as 
well as the per protocol (PP) population. ITT population will include all patients who 
received at least any portion of BT524. The PP population will include all patients who 
received at least 90 % of the planned total dose of BT524, met all inclusion and no 
exclusion criteria, complied with the protocol procedures and had no major deviations 
impacting on study analysis. 
Statistical tests will be performed descriptively. Only the one test of a secondary 
efficacy endpoint of Part I (1-hour post-end to pre-value of MCF) is considered 
confirmatory. A p-value less than 0.05 will be considered statistically significant.  
Only descriptive analyses will be performed to compare the efficacy results of study 
984 with the results from published clinical trials (Manco-Johnson 2009 and Peyvandi 
2006). 
15.2.1 Populations for Analysis 
Four study populations will be defined for analysis: 
Part I PK/PD 
Intent-to-treat population (ITT) / Full Analysis Set (FAS) 
All patients, who received any portion of BT524, are part of the ITT population. 
Per protocol population (PP) 
The PP population consists of all patients of the ITT population, who will have received 
at least 90 % of the planned total dose of BT524, met all inclusion criteria and none of 
the exclusion criteria and won’t have received any alternative fibrinogen-containing 
blood product during the specimen collection phase (until day 14).  


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The PP population will exclude all patients of the ITT population who finish the study 
with major protocol deviations (e.g. patients who have received any fibrinogen 
concentrate and/or fibrinogen-containing product within two weeks prior to infusion of 
BT524) or who terminate the study prematurely due to an event which could be 
possibly related to the study medication. Classification of protocol deviations as major 
or minor will be agreed upon between sponsor and study statistician prior to the 
database lock. 
Pharmacokinetic per protocol population (PK PP) 
The PK PP population consists of all patients of the PP population of the part I, who 
will have provided PK data.  
Safety population  
The safety population comprises of all patients who were exposed to BT524 (equal to 
ITT). 
Part II ODP/ODT 
With respect to the evaluation of efficacy, surrogate efficacy and safety of the single or 
repetitive intravenous infusions of BT524, each bleeding event will be considered as 
an individual case in the primary analysis; in addition efficacy analysis for bleeding 
events and surgical interventions will be analyzed as repeated measurements per 
subject in the ITT and PP populations. 
15.2.2 General Methodology 
All data collected will be analyzed using appropriate descriptive statistical methods 
using SAS® version 9.2 or higher for the production of all tables, listings and figures 
and for the statistical analysis. For continuous variables descriptive statistics will be 
given including mean, SD, median, quartiles, minimum, and maximum. Additionally, for 
PK data, efficacy and safety parameters 95 % confidence intervals will be calculated 
where appropriate. Categorical data will be presented in frequency tables using counts 
and percentages.  
Data will be summarized with respect to demographic and baseline characteristics, 
efficacy and safety observations and measurements. 
Tabulations will be presented for each parameter and will be sorted by age group and 
gender, if applicable. Generally, for presentation overall totals of the cohort will be 
provided. 
15.2.3 Demographic Data and Other Baseline Characteristics 
Assessments made at screening visit and at PK Dosing Day 0 (pre-dose) will be 
summarized for the total of the sample (all patients enrolled) and by the sample of 
patients treated with BT524 using descriptive statistical methods only. These 
assessments will include demographic and other relevant baseline characteristics 
(medical history, physical examination, previous or concomitant medication, vital signs, 
etc.). Summary tables with summary statistics and frequency tables will be presented 
as appropriate. Graphical presentations will be used if they increase transparency and 
understanding of the data. 


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15.2.4 Primary Objective 
The following standard PK parameters of BT524/fibrinogen will be derived from plasma 
antigen concentration data measured at each documented time point using adequate 
PK analysis software: 
- Terminal Elimination Half-life (t1/2) for fibrinogen antigen  
• Time to reach Maximum Concentration (tmax) 
• Maximum Concentration (Cmax) 
• Area Under the Concentration-Time Curve (AUC) calculated to the last measured 
concentration (AUC(0-t)) and extrapolated to infinity (AUC(0-inf) 
• Clearance (CL) 
• Mean Residence Time (MRT) 
• Volume of Distribution (Vss) 
• Incremental Recovery (IR) 
• Classical in vivo recovery (IVR) 
A more detailed algorithm/software used for the calculation of the PK parameters will 
be provided in the statistical analysis plan.  
Descriptive statistical methods will be employed to show the distribution of each 
parameter in the whole population and within each subgroup. Further population PK 
modelling analysis will be investigated to allow analysis of the sparse sampling data 
obtained in the children < 6 years and the research of influence of covariate on the PK 
behavior.  
Similar approach will be used for the analysis of the fibrinogen activity. 
15.2.5 Efficacy Analysis 
Secondary Objectives  
Descriptive statistical methods will be employed for all secondary variables of efficacy. 
Details will be given in the statistical analysis plan. 
Part I 
For analysis of PD, the same software will be used to determine the respective 
parameters with fibrinogen activity data.  
Surrogate efficacy parameter MCF, assessed by fib-tem S, will be evaluated by a one 
sample t-test (pre-/post-comparison) and presented in a tabular format and/or 
graphical format. This analysis will be confirmatory for the 1 hour post-end of infusion 
assessment. 
Part II 
Efficacy will be evaluated based on ODP and/or ODT of bleeding events (i.e. surgical 
procedures, spontaneous or post- traumatic severe bleeding). Response will be 
assessed by the investigator by means of a 4 point scale (‘none’, ‘moderate’, ’good’, 
and ’excellent’). Response rates will be presented with 95 % confidence intervals both 
considering each event as an individual case and considering events as repeated 
measurements within the same patient, if applicable (e.g. by General estimation 
equations with intra-subject correlation structure). Additionally, type of surgery, loss of 
blood intra- and postoperatively, quality of wound healing, units of other fibrinogen-
containing products, and units of transfusion products will be considered. Moreover, 


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the consumption of BT524 required for effective treatment (bleeding events; pre-, intra-
, post-operatively) will be calculated. Furthermore, MCF as a surrogate efficacy 
parameter will be evaluated also in part II of the study (non-confirmatory). 
Details will be described in the statistical analysis plan. 
15.2.6 Safety Analysis 
Adverse events (AEs) will be coded by means of the MedDRA® dictionary. Incidence 
rates (i.e. number and percentage of affected patients) will be calculated for the coding 
levels system organ class and preferred term. Further analyses of AEs will focus on 
seriousness, intensity, causal relationship to study medication, and outcome. Serious 
adverse events (SAEs) will be displayed in detail. 
Safety laboratory assessments 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”. 
Safety analysis will be based on the safety population. 
Descriptive methods will be applied for all variables of safety. Details will be provided 
in the statistical analysis plan. 
15.2.7 Further Statistical Issues 
A detailed description of statistical analyses will be provided in the SAP which will be 
finalized prior to data base closure. 
In case of missing efficacy data (e.g. due to premature discontinuation) the last-
observation-carried-forward (LOCF) principle will be applied, if appropriate. 
16 DATA MANAGEMENT 
16.1 
Data Collection 
Study data will be directly entered via eCRF into the study database on a central 
server by authorized investigator and/or study personnel. Automatic and manual 
queries according to the data validation plan will be generated by the data 
management department and sent through the EDC (electronic data capture) system 
for clarification to the investigator. Corrections will be entered directly into the system. 
This procedure will be repeated until all queries are solved. All query forms are linked 
to the eCRF in the EDC system. 
The complete data management (data capture, data entry, data validation, checks on 
plausibility, query handling, data editing after entry, coding, data base closure, etc.) will 
be defined in advance within a data handling plan/ data management plan together 
with a description of the personnel responsible for data entry performance and 
controlling and specific data handling procedures. 
The final data will be transported to the SAS-system for subsequent data analyses in 
accordance with the statistical analysis plan. 
MedDRA will be used for coding of Adverse Events. Concomitant medication will be 
coded of the A(natomical) T(herapeutical C(hemical)-code, levels 2-5. For coding of 
concomitant diseases, MedDRA will be used, too. 


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16.2 
Correction of Data 
All corrections and changes of original data are recorded in an audit trail including all 
former and present values. The audit trail records all changes made, the reason for 
change, at what time they were done and by whom. The audit trail cannot be changed. 
The Investigator is obliged to keep the database up-to-date at all times, i.e., data are to 
be entered by the Investigator preferably on the same day as the respective patient 
contact. Only the authorized investigator and/or study personnel can change data. 
16.3 
Data Handling 
Data cleaning and coding will be carried out by data managers and qualified persons 
for medical coding, respectively. After data entry by authorized investigator and/or 
study personnel and source data verification, logical and numerical plausibility checks 
will be performed. All study specific data management procedures will be described in 
the data management plan and data validation checks specification. 
16.3.1 Deviations from the Study Protocol 
Deviations from the protocol will be judged during the study and/or when an individual 
patient's eCRF is completed and monitored. 
Before closure of the data base, responsible persons will decide which patients have to 
be considered as major/minor protocol violators (as defined in the statistical analysis 
plan) in the statistical analysis.  
17 QUALITY CONTROL AND QUALITY ASSURANCE 
17.1 
Study Initiation Activities 
The investigator(s) will be 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. 
17.2 
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 IMP 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. 
17.3 
Documentation and Filing 
eCRF-System 
For present clinical study the EDC system AptivAdvantage will be used for online data 
entry, data validation and data management. 
All data to be recorded according to this study protocol must be documented in the 
eCRF. The investigator will be instructed how to complete the eCRF. For each patient 
a separate eCRF record will be created and completed. For the selected patient record 


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the study number, the screening number and patient number will be displayed in the 
eCRF. The Investigator must ensure that the patient’s pseudonymity will be 
maintained. 
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 at each study site. 
Corrections to case report forms may only be carried out by persons listed on the site 
signature and delegation log. 
The investigator must verify that all data entries in the eCRF are accurate and correct. 
Entries are to be checked against appropriate source documentation by the monitor. 
An archiving CD or DVD with the PDFs containing all study data or study data of the 
specific site will be sent to Biotest and the Investigator respectively. 
List of study participants (patient identification log) 
The investigator is asked to keep a confidential list of names of all patients 
participating in the study, giving reference to the patients' records. With the help of this 
list it must be possible to identify the patients and their medical records. In addition, the 
investigator is asked to keep a list of all patients screened on a screening log to 
document identification of patients 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, patients' 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, 
patient files, and records kept at the pharmacy, at the laboratories and at medico-
technical departments involved in the clinical study). 
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. 
Prior to destruction the investigator will contact Biotest AG for approval and 
conformation of such. 


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17.4 
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 study 
participants' source data. The extent and nature of monitoring will be described in 
detail within the monitoring plan. 
17.5 
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 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 is to notify the sponsor immediately 
of any such inspection. The investigator and institution will permit 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. 
17.6 
Archiving 
After evaluation and reporting of the study data, all documents relating to the study will 
be kept in the archives of the sponsor and the study site(s) according to applicable 
regulatory requirements. 
18 GENERAL REGULATIONS, AGREEMENTS AND 
ORGANISATIONAL PROCEDURES 
18.1 
Study Administrative Structure 
Details for the study administrative structure are kept as a separate list filed in the 
TMF. 
18.2 
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. 


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18.3 
Insurance/Liability 
In accordance with the relevant national regulations, the sponsor has taken out patient 
liability insurance for all patients who have given their consent to the clinical study. The 
study participants are insured against injury caused by study medication or 
participation. The study participants 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. 
18.4 
Investigator’s Brochure (IB) 
The investigator will be informed about current knowledge concerning the study 
medication through an IB for this study. All investigators will be informed immediately 
about relevant new information available. 
18.5 
Amendments to the Protocol 
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.  
Amendments, submission(s) and approvals(s) will be distributed to the concerned 
study site(s). 
Amendments in order to eliminate immediate hazard to patients may be implemented 
before the approval of the ethics committee and/or Regulatory Authorities after 
consultation with Biotest. 
In the event that a significant deviation from the protocol is anticipated based on the 
patients status, or occurs during the protocol due to an accident or mistake, the 
investigator or his/her designee must contact the sponsor at the earliest possible time. 
This will allow an early joint decision to be made as to whether or not the patient 
should continue in the study. This decision will be documented by both the investigator 
and sponsor. 
18.6 
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.  
18.7 
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 clinical study report within 6 months 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 


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or lecture manuscripts concerning such results, should 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. 
For the present study, the pharmacokinetics of BT524 will be analyzed and reported in 
a separate report before the finalization of the study. 


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19 LIST OF REFERENCES 
Acharya, SS and Dimichele, DM (2008). "Rare inherited disorders of fibrinogen." 
Haemophilia 14(6): 1151-1158. 
Bevan, DH (2009). "Cryoprecipitate: no longer the best therapeutic choice in congenital 
fibrinogen disorders?" Thromb Res 124 Suppl 2: S12-16. 
Casini, A, de Moerloose, P and Neerman-Arbez, M (2016). "Clinical Features and 
Management of Congenital Fibrinogen Deficiencies." Semin Thromb Hemost 42(4): 
366-374. 
Casini, A, Neerman-Arbez, M, Ariens, RA and de Moerloose, P (2015). 
"Dysfibrinogenemia: from molecular anomalies to clinical manifestations and 
management." J Thromb Haemost 13(6): 909-919. 
Cheah, CY, Brennan, SO, Kennedy, H, Januszewicz, EH, Maxwell, E and Burbury, K 
(2012). "Fibrinogen Melbourne: a novel congenital hypodysfibrinogenemia caused by 
gamma326Cys-Phe in the fibrinogen gamma chain, presenting as massive splanchnic 
venous thrombosis." Blood Coagul Fibrinolysis 23(6): 563-565. 
Clauss, A (1957). "[Rapid physiological coagulation method in determination of 
fibrinogen]." Acta Haematol 17(4): 237-246. 
CSL Behring, G (2010). RiaSTAP®, Fibrinogen Concentrate (Human), Full Prescribing 
Information. 
CSL Behring, G (2015). Haemocomplettan®, Fibrinogen Concentrate (Human), . 
de Moerloose, P, Boehlen, F and Neerman-Arbez, M (2010). "Fibrinogen and the risk 
of thrombosis." Semin Thromb Hemost 36(1): 7-17. 
EMA (2009). Guideline on Core SmPC for Human Fibrinogen Products (Committee for 
Medicinal Products for Human Use) EMEA/CHMP/BPWP/122007/2005. C. f. M. P. f. 
H. U. (CHMP). 
EMA (2011). Guideline on the warning on transmissible agents in summary of product 
characteristics (SmPCs) and package leaflets for plasma-derived medicinal products 
(Committee for Medicinal Products for Human Use) EMA/CHMP/BWP/360642/2010 
rev. 1. C. f. M. P. f. H. U. (CHMP). 
EMA (Committee for Medicinal Products for Human Use) (2015). "Guideline on Core 
SmPC for Human Fibrinogen Products." EMA/CHMP/BPWP/691754/2013 Rev 1. 
Fenger-Eriksen, C, Ingerslev, J and Sorensen, B (2009). "Fibrinogen concentrate--a 
potential universal hemostatic agent." Expert Opin Biol Ther 9(10): 1325-1333. 
Fried, K and Kaufman, S (1980). "Congenital afibrinogenemia in 10 offspring of uncle-
niece marriages." Clin Genet 17(3): 223-227. 
Henselmans, JM, Meijer, K, Haaxma, R, Hew, J and van der Meer, J (1999). 
"Recurrent spontaneous intracerebral hemorrhage in a congenitally afibrinogenemic 
patient: diagnostic pitfalls and therapeutic options." Stroke 30(11): 2479-2482. 


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Kamal, AH, Tefferi, A and Pruthi, RK (2007). "How to interpret and pursue an abnormal 
prothrombin time, activated partial thromboplastin time, and bleeding time in adults." 
Mayo Clin Proc 82(7): 864-873. 
Khalid, S, Bilwani, F, Adil, SN and Khurshid, M (2008). "Frequency and clinical 
spectrum of rare inherited coagulopathies--a tricenter study." J Pak Med Assoc 58(8): 
441-444. 
Lak, M, Keihani, M, Elahi, F, Peyvandi, F and Mannucci, PM (1999). "Bleeding and 
thrombosis in 55 patients with inherited afibrinogenaemia." Br J Haematol 107(1): 204-
206. 
Lang, T, Johanning, K, Metzler, H, Piepenbrock, S, Solomon, C, Rahe-Meyer, N and 
Tanaka, KA (2009). "The effects of fibrinogen levels on thromboelastometric variables 
in the presence of thrombocytopenia." Anesth Analg 108(3): 751-758. 
Manco-Johnson, MJ, Dimichele, D, Castaman, G, Fremann, S, Knaub, S, Kalina, U, 
Peyvandi, F, Piseddu, G, Mannucci, P and Fibrinogen Concentrate Study, G (2009). 
"Pharmacokinetics and safety of fibrinogen concentrate." J Thromb Haemost 7(12): 
2064-2069. 
Palareti, G and Maccaferri, M (1990). "Specific assays of hemostasis proteins: 
fibrinogen." Ric Clin Lab 20(2): 167-176. 
Peyvandi, F, Haertel, S, Knaub, S and Mannucci, PM (2006). "Incidence of bleeding 
symptoms in 100 patients with inherited afibrinogenemia or hypofibrinogenemia." J 
Thromb Haemost 4(7): 1634-1637. 
Schochl, H, Nienaber, U, Hofer, G, Voelckel, W, Jambor, C, Scharbert, G, Kozek-
Langenecker, S and Solomon, C (2010). "Goal-directed coagulation management of 
major trauma patients using thromboelastometry (ROTEM)-guided administration of 
fibrinogen concentrate and prothrombin complex concentrate." Crit Care 14(2): R55. 
Silberstein, LE, Kruskall, MS, Stehling, LC, Johnston, MF, Rutman, RC, Samia, CT, 
Ramsey, G and Eisenstaedt, RS (1989). "Strategies for the review of transfusion 
practices." JAMA 262(14): 1993-1997. 
Sonntag, J, Stiller, B, Walka, MM and Maier, RF (1997). "Anaphylatoxins in fresh-
frozen plasma." Transfusion 37(8): 798-803. 
Tem Innovations GmbH (Mar 2011). fib-tem - Instructions for use. V 20 0001, 
manufactured by Tem Innovations GmbH, D-81829 Munich, Germany. 
Tziomalos, K, Vakalopoulou, S, Perifanis, V and Garipidou, V (2009). "Treatment of 
congenital fibrinogen deficiency: overview and recent findings." Vasc Health Risk 
Manag 5: 843-848. 
World Health Organization. (2018). "Growth reference data for 5-19 years." WHO 
Growth reference 5-19 years  Retrieved 13.04.2018, 2018. 
World Health Organization. (2018). "The WHO Child Growth Standards." Child growth 
standards  Retrieved 13.04.2018, 2018. 
 


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20 APPENDICES 
Appendix 20.1 
Dosage for Newborns, infants and children 
The dose should be determined according to the BW and the clinical need. 
The reconstituted solution of BT524 should be administered intravenously (IV) via an 
infusion pump with an adapted infusion rate below 5 ml/min based on the age of the 
paediatric patient.  
A recommendation for infusion rates of BT524 in the paediatric population is presented 
in the table below. Nevertheless, selection of the infusion rate remains principally at 
the discretion of the treating paediatrician (investigator) considering the exact clinical 
situation of the patient. 
 
Table: Recommended infusion rates of BT524 in the paediatric population 
Age Group 
Infusion rate 
ml/min§ 
Infusion rate 
ml/h§ 
Adults 
5.0 
300.0 
12 to <18 years 
5.0 
300.0 
6 to <12 years 
5.0 
300.0 
4 to <6 years 
1.0 
60.0 
2 to <4 years 
0.75 
45.0 
3 months to <2 years 
0.30 
18.0 
28 days to <3 months 
0.30 
18.0 
Newborns (0 to 27 days) 
0.10 
6.0 
 
§ Fibrinogen solution at 20mg/ml. 
 
 
 


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Appendix 20.2 
Growth charts for children and adolescents 
Pediatric growth charts consist of a series of percentile curves that illustrate the 
distribution of selected body measurements in children and adolescents. Pediatric 
growth charts are tools that contribute to forming an overall clinical impression for the 
child being measured. Growth charts are not intended to be used as a sole diagnostic 
instrument.  
Growth is not only a result of nutrition but also a result of inherited factors. Ethnicity 
can influence a child's growth patterns, and so some countries have their own growth 
charts. However, the World Health Organization's (WHO) growth charts are used most 
often and considered the standard around the world. 
The WHO Child Growth Standards (World Health Organization 2018, World Health 
Organization 2018) 
 
The following web sites present growth reference data for children and adolescents: 
 
WHO Weight-for-age GIRLS Birth to 13 weeks (percentiles) 
WHO Weight-for-age GIRLS Birth to 5 years (percentiles) 
WHO Weight-for-age GIRLS 5 to 10 years (percentiles) 
 
WHO Weight-for-age BOYS Birth to 13 weeks (percentiles) 
WHO Weight-for-age BOYS Birth to 5 years (percentiles) 
WHO Weight-for-age BOYS 5 to 10 years (percentiles) 
 



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Study 984 
 
A prospective, open-label, phase I/III study investigating 
pharmacokinetic properties of BT524 and efficacy and safety of 
BT524 in the treatment and prophylaxis of bleeding in patients with 
congenital fibrinogen deficiency 
Biotest AG 
Statistical Analysis Plan 
 
Version: 3.0 final 
Date: July 02, 2020 
 
 
 
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Table of Contents 
 
1 
Introduction .................................................................................................................... 5 
1.1 
Preface ............................................................................................................. 5 
1.2 
Timing of statistical analyses ............................................................................ 5 
2 
Modification History ........................................................................................................ 6 
2.1 
Changes to the study protocol .......................................................................... 6 
2.2 
Changes to previous SAP versions .................................................................. 6 
3 
Study Design ................................................................................................................. 7 
3.1 
Sample size estimation ..................................................................................... 8 
3.2 
Randomisation, blinding and unblinding procedures ......................................... 9 
4 
Analysis Sets ............................................................................................................... 10 
4.1 
Study populations ........................................................................................... 10 
4.1.1 
Study populations (part I) ........................................................................... 10 
4.1.2 
Study populations (part II) .......................................................................... 11 
4.1.2.1 
Study populations (part II –patient based) .................................................. 11 
4.1.2.2 
Study populations (part II – event based) ................................................... 11 
5 
General Statistical Methods and Definitions ................................................................. 13 
5.1 
General statistical methods ............................................................................ 13 
5.2 
Subgroups ...................................................................................................... 13 
5.3 
Missing data ................................................................................................... 14 
5.3.1 
Missing severity assessment for adverse events ........................................ 14 
5.3.2 
Missing relationship to investigational product for adverse events ............. 14 
5.3.3 
Missing seriousness assessment for adverse events ................................. 14 
5.4 
Handling of partial dates and missing/incomplete times .................................. 14 
5.4.1 
Incomplete start date and time ................................................................... 14 
5.4.2 
Incomplete stop date and time ................................................................... 15 
5.5 
Observation and analysis times ...................................................................... 16 
5.6 
Handling of MCF, Fibrinogen Activity and Fibrinogen Antigen values 
below detection limit ................................................................................... 18 
6 
Patient Accounting and Disposition .............................................................................. 19 
6.1 
Patient accounting .......................................................................................... 19 
6.2 
Disposition and withdrawals ........................................................................... 19 
6.3 
Protocol deviations ......................................................................................... 20 
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7 
Demographics and Background Characteristics ........................................................... 21 
7.1 
Demographics ................................................................................................ 21 
7.2 
Medical history/ concomitant diseases ............................................................ 22 
7.3 
Bleeding history .............................................................................................. 22 
8 
Exposure and Compliance ........................................................................................... 23 
8.1 
Treatment groups ........................................................................................... 23 
8.2 
Dosage ........................................................................................................... 23 
8.3 
Treatment/infusion duration ............................................................................ 24 
8.4 
Compliance .................................................................................................... 24 
9 
Previous and Concomitant Medication or Treatment .................................................... 25 
10 Pharmacokinetics, Pharmacodynamics and Efficacy ................................................... 26 
10.1 
Primary endpoint analysis of part I .................................................................. 26 
10.2 
Secondary endpoint analyses of part I ............................................................ 26 
10.3 
Secondary endpoint analyses of part II ........................................................... 27 
11 Safety .......................................................................................................................... 29 
11.1 
Adverse events ............................................................................................... 29 
11.2 
Deaths ............................................................................................................ 31 
11.3 
Adverse events leading to discontinuation from study .................................... 31 
11.4 
Pregnancies ................................................................................................... 31 
11.5 
Vital signs ....................................................................................................... 31 
11.6 
Fibrinogen inhibitory antibodies ...................................................................... 31 
11.7 
Viral safety ...................................................................................................... 32 
11.8 
Clinical safety laboratory ................................................................................. 32 
11.9 
ECG ............................................................................................................... 33 
11.10 
Physical examination ...................................................................................... 33 
12 Software ...................................................................................................................... 34 
13 Abbreviations ............................................................................................................... 35 
14 References .................................................................................................................. 37 
15 Appendices .................................................................................................................. 38 
15.1 
Table of Content of TLF numbers, titles, and analysis populations ................. 38 
 
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1 Introduction 
1.1 Preface 
This statistical analysis plan (SAP) is exclusively based on the following information and 
documents: 
Study Protocol  
08-MAY-2018 – Version 6.0 
 
The objective of this document is to detail the statistical methodology to be used for the final 
statistical analysis of Biotest Study-№ 984 ("A prospective, open-label, phase l/llI study 
investigating pharmacokinetic properties of BT524 and efficacy and safety of BT524 in the 
treatment and prophylaxis of bleeding in patients with congenital fibrinogen deficiency").  
This SAP covers the part of the statistical analysis to be conducted 
 .  
For the evaluation of pharmacokinetics (PK; fibrinogen antigen) and pharmacodynamics (PD; 
fibrinogen activity), PK/PD parameters will be derived from time-concentration profiles using 
adapted methodology, non-compartmental analysis, compartment analysis, or population 
modelling, as appropriate/ required. This part of the statistical analysis, including the analysis 
for the primary objective of PK-part, will be conducted by Pharmetheus and is described in a 
separate analysis plan.  
 
1.2 Timing of statistical analyses 
The statistical analysis, for which this SAP applies, is the final analysis after all data of this 
study is collected, cleaned and locked. 
 
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2 Modification History 
2.1 Changes to the study protocol 
The statistical analysis as specified in this SAP is consistent with the statistical analysis as 
specified in the study protocol (version 6.0).  
In the study protocol age groups were defined to describe/define differences in time points of 
study assessments to be perfomed for different age groups (see flowchart of study in study 
protocol section 3). In the SAP age groups were defined differently for data analyses.  
Shift tables specified in the study protocol for safety laboratory assessment will be not used. 
No changes in the clinical study protocol were considered necessary by the Sponsor to 
handle clinical protocol deviations possibly related to the COVID-19 pandemic at the end of 
the study. It was therefore decided in the Blinded Data Review Meeting (BDRM) of June 25, 
2020, that any non-conformancies in the study conduct caused by the COVID-19 pandemic 
will be described in a note to file, and any COVID-19 related protocol deviation per patient 
will be listed in BDRM minutes and presented in study listings where appropriate. 
 
2.2 Changes to previous SAP versions 
The first version of the SAP was based on study protocol version 4.0 and signed on 17-Sep-
2015.  
The amended SAP version 2.0 was intended to reflect the inclusion and treatment of 
children 0 to <6 years into the ongoing study 984. This extension of the ongoing study 984 
was introduced within the study protocol version 5.0 after the positive opinion of the 
Paediatric Committee on the agreement of the Paediatric Investigation Plan (EMA-001931-
PIP01-16) obtained in March 2017. 
The amended SAP version 3.0 is intended to precisely describe the responsibilities of the 
different CROs to the analysis of the study. Definition of analysis sets was refined and PK 
population added for the descriptive analysis of PK within this SAP. For the age subgroups it 
was clarified how age of patients and bleeding events is calculated/defined for the respective 
analysis sets and study parts. Additional clarification for presentation of data was added 
where needed and the list of table shells in Appendix 15.1 was updated due to changes 
made. 
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3 Study Design 
The present study is designed as a prospective, uncontrolled, open-label, multicentre, phase 
I/III study investigating the 14 day single-dose pharmacokinetic and pharmacodynamic 
properties, efficacy and safety of BT524 following intravenous administration in the treatment 
or prophylaxis of bleeding in patients with congenital afibrinogenemia or severe congenital 
hypofibrinogenemia. 
The study is divided into two study parts (part I and part II), briefly described in the following: 
Table 1: Overview of Study Design and Endpoints 
PART I 
PART II 
 
(Individual follow-up 49 ± 4 days 
after the last administration of BT524) 
BT524 
Single IV Infusion 
(70 mg/kg BW) 
On-Demand Treatment (ODT) 
On-Demand Prophylaxis (ODP) 
 
BT524 
Single or repetitive IV Infusion(s) 
as individually required 
Pharmacokinetics (PK) 
Pharmacodynamics (PD) 
Clinical Efficacy 
n = 20 patients ≥ 6 to ≤ 75 years 
and at least 3 patients 0 to < 6 years 
In total: 
n = 23 patients (part I) 
All patients who have completed part I  
(n = 23) 
and additional patients without PK/PD: 
at least 10 patients ≥ 6 to ≤ 75 years and  
at least 3 patients 0 to < 6 years 
In total (planned): n ≥ 36 patients (part II) 
1-2 months 
min. 12 months 
Surrogate Efficacy 
Safety 
 
Part I 
Part I is focused on the primary endpoint of the study, the 14 day single-dose 
pharmacokinetics, and on the 14 day single-dose pharmacodynamics and the evaluation of 
the maximum clot firmness (MCF) as a surrogate efficacy parameter. Moreover, safety will 
be investigated (by physical examination, vital signs, routine lab parameters, adverse 
events, development of fibrinogen antibodies and coagulation activation monitoring). 
20 patients ≥ 6 to ≤ 75 years and at least 3 patients < 6 years are to be enrolled in part I. 
With respect to safety, study-specific enrolment procedures comprising consecutive 
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enrolment of the first five patients with a treatment-free safety interval of 7 days between 
each patient and restriction in age are implemented (see protocol). 
Maximum duration of individual study participation in part I is up to 66±4 days for eligible 
screened patients (in case the patient does not experience a bleeding event within this 
safety interval). 
Part II 
Part I will subsequently be extended to a part II in which individual patients will be 
investigated for the efficacy and safety of single and/or repetitive administrations of BT524 in 
on-demand prophylaxis (ODP) and/or on-demand treatment (ODT) of different bleeding 
events [e.g., (elective) surgical procedure, spontaneous or posttraumatic severe bleeding], if 
required. Thus, part II is expected to comprise a variety of singular events of different types, 
severity, and BT524-dosing requirements. All patients who have taken part in the 
pharmacokinetic assessment (part I) without severe post-dosing complications ideally 
remain enrolled and will continue treatment for ODP and/or ODT with BT524 in part II. 
At least 10 additional patients ≥ 6 to ≤ 75 years and at least 3 additional patients < 6 years 
will be treated in part II (ODP/ODT) without PK/PD assessments (part I). 
Duration of individual study participation is variable and depends on the time point of the last 
bleeding episode necessitating application of study medication. For the last patient included 
the minimum duration is 12 months (12 months plus 49±4 days in case the patient 
experiences a bleeding event at the very end of his/her individual study participation on the 
last day of month 12). 
Efficacy of BT524 will be assessed by clinical endpoints such as the overall hemostatic 
response to treatment (as assessed by the investigator according to a 4 point scale: "none", 
"moderate", "good" or "excellent"), total loss of blood (e.g., intra- and postoperatively, re-
bleedings), need of other fibrinogen-containing products (fresh frozen plasma, 
cryoprecipitate), need of transfusion products (allogenic or autologous blood), and quality of 
wound healing, whenever applicable. Moreover, the consumption of BT524 required for 
effective treatment (pre-, intra-, post-operatively) will be calculated. Furthermore, MCF as a 
surrogate efficacy parameter will be evaluated. 
For details regarding the study flowcharts see section 3 of the study protocol. 
3.1 Sample size estimation 
The primary objectives of this study are key PK parameters. For the PK parameters no 
formal sample size calculation was carried out. As a general rule approximately 20 patients 
in this single cohort should suffice to calculate PK parameters with the corresponding range 
of distribution. 
For the surrogate (secondary) efficacy variable MCF, a formal sample size calculation was 
performed. On the basis of a t-test assessing the difference between dependent means 
(post minus pre-treatment MCF difference; one sample) the sample size can be calculated. 
The mean MCF (measured by Fib-tem S of ROTEM) in the study population consisting of 
patients with congenital fibrinogen deficiency (i.e., a- or severe hypofibrinogenemia) will be 
determined prior to BT524 treatment and 1 hour after treatment. 
With 15 patients, a pre-treatment mean of 4 mm (SD 7 mm) and a post-treatment mean of 
10 mm (SD 8 mm) an effect size of 0.8 mm can be detected with a power of 80% at α = 5% 
(2-sided) significance level. 
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3.2 Randomisation, blinding and unblinding procedures 
This is an uncontrolled, open-label study design and patients will not be randomized. No 
special procedures regarding blinding or unblinding are applied. 
 
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4 Analysis Sets 
4.1 Study populations  
4.1.1 Study populations (part I) 
Please note, for all part I analysis populations the relevant framework in which to check the 
criteria (such as informed consent, exposure to BT524, protocol deviation, premature 
termination etc.) per patient is restricted to the period of its part I participation, i.e. from 
enrolment in part I up to PK safety visit (Day 49 +/- 4). 
 
PK Set (PK) 
The PK population consists of all patients of part I with PK data. 
For the PK-specific study population of part I (PK/PD), please see also the PK-Analyses 
Plan (cf. section 1.1 above).  
All Patients Enrolled Set (APE I) 
The APE includes all patients who have given informed consent to part I of the study. 
Intent to Treat Set (ITT I)  
All patients, who received any portion of BT524 in part I of the study.  
Full Analysis Set (FAS I)  
All patients, who received any portion of BT524 in part I of the study, and have at least one 
part I efficacy assessment.  
Per Protocol Set (PP I) 
The PP is a subset of FAS and includes all patients in part I of the study who are compliant 
with the study protocol without any major protocol deviations in part I thought to have the 
potential to impact the results of the efficacy analysis (PK/PD). 
In the BDRM, dated 25-Jun-2020, all minor and major protocol deviations on patient level 
were reviewed and agreed upon. Following from the decisions taken, assignments to per-
protocol (PP I) analysis population were done. A complete list of all protocol deviations is 
attached to the meeting minutes of the BDRM, dated 25-Jun-2020, and included in the 
listings of the final analysis. 
Safety Set (SAF I) / Treated Set 
The safety population comprises of all patients who were exposed to BT524 in part I of the 
study. 
 
 
 
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4.1.2 Study populations (part II) 
4.1.2.1 
Study populations (part II –patient based) 
Please note, for all part II analysis populations the relevant framework in which to check the 
criteria (such as informed consent, exposure to BT524, protocol deviation, premature 
termination etc.) per patient is restricted to the period of its part II participation, i.e. from 
enrolment into solely part II (or for patients who completed Part I from entry in part II defined 
as 1st day after part I PK safety visit) up to the safety visit (Day 49 +/- 4) of the last treated 
bleeding event.  
 
All Patients Enrolled Set (APE II) 
The APE includes all patients who have given informed consent to exclusive part II of the 
study and patients consented for Part I/II who completed Part I. 
Intent to Treat Set (ITT II)  
All patients, who received any portion of BT524 in part II of the study.  
Full Analysis Set (FAS II)  
All patients, who received any portion of BT524 in part II of the study, and have at least one 
part II efficacy assessment.  
Per Protocol Set (PP II) 
The PP is a subset of FAS and includes all patients in part II of the study who are compliant 
with the study protocol without any major protocol deviations in part II thought to have the 
potential to impact the results of the efficacy analysis.  
In the BDRM, dated 25-Jun-2020, all minor and major protocol deviations on patient level 
were reviewed and agreed upon. Following from the decisions taken, assignments to per-
protocol (PP II) analysis population were done. A complete list of all protocol deviations is 
attached to the meeting minutes of the BDRM, dated 25-Jun-2020, and included in the 
listings of the final analysis. 
Safety Set (SAF II) / Treated Set 
The safety population comprises of all patients who were exposed to BT524 in part II of the 
study. 
 
4.1.2.2 
Study populations (part II – event based) 
For part II (ODP/ODT), the following specifications as to analysis sets apply: 
With respect to the evaluation of efficacy, surrogate efficacy and safety of the single or 
repetitive intravenous infusions of BT524, each bleeding event will be considered as an 
individual case in the primary analysis. 
There are 2 event-based analysis sets: 
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Full Bleeding Event Set (FBE)  
All events treated with any portion BT524, and with at least one efficacy assessment. 
Per Protocol Bleeding Event Set (PPBE)  
Subset of FBE of patients who are compliant with the study protocol (i.e. without any major 
protocol deviations in part II) and includes all bleeding events without any major protocol 
deviation with potential to impact the results of the efficacy analysis.  
In the BDRM, dated 25-Jun-2020, all minor and major protocol deviations on bleeding event 
level were reviewed and agreed upon. Following from the decisions taken, assignments to 
PPBE analysis population were done. A complete list of all protocol deviations is attached to 
the BDRM minutes and included in the listings of the final analysis. 
As agreed in the BDRM (25-Jun-2020), all bleeding events documented for a patient with at 
least one major protocol deviation (i.e. patients excluded from PP II set) will be excluded from 
the PPBE. 
In addition, selected efficacy analyses for bleeding events and surgical interventions will be 
analyzed per patient in the FBE and PPBE populations as defined above. 
With respect to the evaluation of adverse events, the patient is the relevant unit for analyzing 
these endpoints. Therefore, their evaluation across all parts is based on the safety 
population as defined in section 4.1 above. 
 
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5 General Statistical Methods and Definitions 
5.1 General statistical methods 
All data collected will be analyzed using appropriate statistical methods for the production of 
all tables, listings and figures and for the statistical analysis. 
Data will be summarized with respect to demographic and baseline characteristics, efficacy 
and safety observations and measurements (cf. section 4). Tabulations will be presented for 
each parameter. Generally, age subgroups will be presented in columns and overall totals 
will be provided, too. Data will be presented for the overall population, and for ODP and 
ODT, each for minor events, major events and overall in rows, as specified in the section for 
the respective parameter. 
For continuous variables descriptive statistics will be given including mean, SD, median, 
quartiles, minimum, and maximum. Additionally, for PK data, efficacy and safety parameters 
95 % confidence intervals will be calculated where appropriate. Categorical data will be 
presented in frequency tables using counts and percentages. In addition, the number of 
patients with missing values will be displayed. Percentages relate to the number of patients 
(or events, for part II) with data. This includes data obtained by the respective missing data 
replacement strategy (see section 5.3 Missing data). 
Means and medians will be presented by 1 additional decimal place and standard deviation 
will be presented by 2 additional decimal places than the standard presentation level of the 
respective patient data. Minimum and maximum values will be presented using the same 
number of decimal places as the patient data. Percentages will be presented to 1 decimal 
place if not otherwise stated. Statistical tests will be performed descriptively, two-sided if not 
specified otherwise. Only the one test of a secondary efficacy endpoint of part I (1-hour post-
end to pre-value of MCF) is considered confirmatory. A (two-sided) p-value less than 0.05 
will then be considered statistically significant. The confidence level for calculation of 
confidence intervals will be chosen as (1-significance level) of the respective statistical test. 
All collected data will also be presented in listings (cf. separate tables shells document). 
Only additional special listings such as for protocol deviations (cf. section 6.3), bleeding 
history (cf. section 7.3), AEs leading to death (cf. section 11.2), AEs leading to 
discontinuation (cf. section 11.3), or normal ranges (cf. section 11.8) are explicitly referred to 
within the applicable section. In listings, data will be sorted by site, and patient, and when 
appropriate by visit or other identifiers for sequence or type of observation.  
5.2 Subgroups 
For analyses, patients are assigned to the following age subgroups: Adults (18 to 75 years), 
adolescents (12 to < 18 years), children (6 to < 12 years), and children < 6 years. The group 
< 6 years will in addition be subdivided into pre-school children (2 to < 6 years), infants and 
toddlers (28 days to < 2 years), and newborns (0 days to 27 days). 
For patient-based analyses using the APE set, patients will be assigned to age subgroups 
according to their age (years) as derived from date of birth (year) as age at date of ICF 
signature for each of the study parts. 
For patient-based analyses using the SAF, FAS, PP, or PK set in both study parts, patients 
will be assigned to age subgroups according to the age group assessment provided for their 
first BT524 treatment in the respective study part.  
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For the event-based analysis (FBE, PPBE) in part II, each bleeding event will be assigned to 
the age subgroup according to the age group assessment provided for the specific bleeding 
event. 
Another subgroup for event based analysis is ODP/ODT with major/minor classification. 
Results for the different subgroups will be presented descriptively by presenting the results 
for selected analyses (as defined in the respective section) separately for each subgroup 
and the overall population.  
5.3 Missing data 
5.3.1 Missing severity assessment for adverse events 
If severity is missing for an AE starting prior to the administration of IMP, then a severity of 
“Mild” will be assigned. If the severity is missing for an AE starting on or after administration 
of IMP, then a severity of “Severe” will be assigned. The imputed values for severity 
assessment will be used for incidence summaries, while the actual values will be used in data 
listings. 
5.3.2 Missing relationship to investigational product for adverse events 
If the relationship to investigational product is missing for an AE starting on or after the 
administration of IMP, a causality of “Related” will be assigned. The imputed values for 
relationship to investigational product will be used for incidence summaries, while the actual 
values will be presented in data listings.  
5.3.3 Missing seriousness assessment for adverse events 
If no information about seriousness is available, the AE will be considered serious. The 
imputed values for seriousness assessment will be used for incidence summaries, while the 
actual values will be used in data listings. 
5.4 Handling of partial dates and missing/incomplete times 
For prior or concomitant medications, incomplete (i.e., partially missing) start date and/or stop 
date will be imputed. When the start date and the stop date are both incomplete for a patient, 
impute the start date first.  
For AEs, incomplete (i.e., partially missing) start dates and times and/or incomplete stop dates 
and times will be imputed.   
Imputation rules for incomplete dates for prior or concomitant medications, incomplete dates 
and times for AEs are described in sections 5.4.1 and 5.4.2.   
5.4.1 Incomplete start date and time 
The following rules will be applied to impute the missing numerical fields. If the stop date is 
complete and the imputed start date is after the stop date, then the start date will be imputed 
using the stop date. 
Missing day and month 
• 
If the year of the incomplete start date is the same as the year of the date of the first 
dose of investigational product, then the day and month of the date of the first dose of 
investigational product will be assigned to the missing fields. 
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• 
If the year of the incomplete start date is before the year of the date of the first dose of 
investigational product, then December 31 will be assigned to the missing fields. 
• 
If the year of the incomplete start date is after the year of the date of the first dose of 
investigational product, then 01 January will be assigned to the missing fields. 
Missing month only 
• 
The day will be treated as missing and both month and day will be replaced according 
to the above procedure. 
Missing day only 
• 
If the month and year of the incomplete start date are the same as the month and year 
of the date of the first dose of investigational product, then the day of the date of the first 
dose of investigational product will be assigned to the missing day. 
• 
If either the year is before the year of the date of the first dose of investigational product 
or if both years are the same but the month is before the month of the date of the first 
dose of investigational product, then the last day of the month will be assigned to the 
missing day. 
• 
If either the year is after the year of the date of the first dose of investigational product 
or if both years are the same but the month is after the month of the date of the first 
dose of investigational product, then the first day of the month will be assigned to the 
missing day.  
Missing/Incomplete Time 
• 
If the time is missing and the date is complete and is the same as the date of the first 
dose of investigational product, or the date is imputed to be this date, then the time will 
be set to the time of the first dose of investigational product. Otherwise, missing times 
will be imputed as 00:00. 
• 
If the minutes are given but the hour is not, then the time will be regarded as completely 
missing and handled as above. If the hour is given but the minutes are not, then if the 
hour is the same as the hour of the first dose of investigational product, then the minutes 
of that dose of investigational product will be assigned to the missing fields. Otherwise 
00 will be assigned to the missing minutes. 
5.4.2 Incomplete stop date and time 
The following rules will be applied to impute the missing numerical fields.  If the imputed stop 
date is before the start date (imputed or non-imputed start date), then the imputed stop date 
will be equal to the start date.  
Missing day and month 
• 
The stop day and month will be set to the maximum of the date of study 
discontinuation/completion, as appropriate, or the date of the Day 49 FU visit of the last 
dose of IMP.  
• 
If the year of the incomplete stop date is before the year of the date of study 
discontinuation/ completion, as appropriate, or the date of the Day 49 FU visit of the last 
dose of IMP, the day and month will be set to 31 December; 
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• 
If the year of the incomplete stop date is after the year of the date of study 
discontinuation/ completion, as appropriate, or the date of the Day 49 FU visit of the last 
dose of IMP, the day and month will be set to 01 January. 
Missing month only 
• 
The stop day will be treated as missing and both month and day will be replaced 
according to the above procedure. 
Missing day only 
• 
The stop day will be set to the last day of the month. 
Totally missing stop date 
• 
The concomitant medication will be considered ongoing. 
Missing Time 
• 
If the time is missing it will be imputed as 23:59. 
5.5 Observation and analysis times 
Study periods or stages 
The study primarily differentiates between the two parts, part I (PK/PD) and part II 
(ODP/ODT). Within each part different periods are defined: 
Part I: 
o Screening period: Day -17 to Day -1 
o PK/PD assessment/sampling period: 
 
Hospitalization from Day 0 (IV infusion) through Day 2 
 
Subsequent PK FU from Day 4 through Day 14 
o PK safety FU period ending with the PK safety visit at Day 49 (+/- 4) 
Accordingly, the participation time for part I is defined as time from screening visit (ICF date) 
until PK safety visit and defines the analysis time for part I.  
Part II periods differ depending on conduct (with or without hospitalization) but are usually 
ending with the follow up safety visit at Day 49 (+/- 4). Please see the protocol (e.g. 
section 3) for more details. 
Accordingly, the participation time of patients for part II starts 
 at screening visit (ICF date) for patients solely enrolled in part II or  
 at 1st day after part I PK safety visit for patients enrolled into part I/II 
and lasts until the date of patients study completion/termination.  
For the patient based analysis in part II the analysis time is defined by the participation start 
time until the safety visit (Day 49 +/- 4) of the patients last treated bleeding event. 
For the bleeding event based analysis in part II the analysis time of a bleeding event starts 
with its Treatment Day 0 and ends with its safety visit. Accordingly, data from in-between 
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individual 49 day periods or after last Day 49 visit will only be listed and not included in the 
analysis. 
 
For adverse events reporting related periods are defined: 
• 
Patient Enrolment to the First Administration of Study Drug (NTEAE) 
• 
After first Administration of Study Drug until respective Day 49 visit (part I and part II) 
(TEAE) 
• 
In-between individual 49 day periods or after last Day 49 visit (only related SAEs will 
be listed and included in the analysis), all other AEs will be counted and listed. 
 
For concomitant medication please refer to section 9. 
Study days and bleeding event number 
Primarily, study days are counted since first dose of study medication (i.e. in part I) up until 
the end of study participation. 
Because the study is divided into parts with the possibility of multiple bleeding events in 
part II, study days are additionally considered for each part II bleeding event separately. 
More precisely, study day is also defined as the number of days since first dose of study 
medication of the applicable part II bleeding event and, for a particular date, is calculated as: 
 
Study day = Assessment date – Date of first dose of study medication 
 
 
 for this bleeding event 
 
Due to consideration of several bleeding events as individual cases and the repeated 
observation periods in part II, related events will be numbered per patient, sorted by start 
date and time of the events associated with part II participation.  
 
Definition of baseline values 
Part I: The baseline value is defined to be the last value, which was assessed during 
screening before and up to PK dosing Day 0 (all pre-dose). In other words, if for example 
pre-dose value of fibrinogen antigen at Day 0 of PK is missing, baseline will use the value 
measured at the screening visit. 
Part II: For event-based analysis in part II, baseline value is defined to be Day 0 (pre-dose) 
per event. In case this is not available, for fibrinogen antigen and fibrinogen activity the 
baseline values from last event will be used. For all other values Day 0 (pre-dose) will not be 
replaced, if missing.  
 
Definition of analysis time points or time windows 
The following definition of analysis time points, time windows and measurement 
assignments applies unless specified differently in the respective sections. In particular, for 
PK parameter specific decisions, the definitions in the PK analyses plans prevail. 
Time points for the different endpoints to be measured are specified in the protocol, e.g. in 
the flowcharts. For each endpoint measurements are taken at an (individual) selection from 
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time points during Screening, on Day 0 (pre- as well as post-dose) and/or on Days 1, 2, 4, 7, 
10, 14 or 49. 
Time windows for measuring times are not provided except for the Day 49 measurements, 
where the window is +/- 4 days. Therefore, no exclusions due to window deviations will be 
applied. For the PK analysis, actual times will be used. Should time windows be set-up (at a 
later stage) and result in exclusions of data from analyses, this will be documented in an 
amendment to this SAP or - at the latest - by means of the applicable data review meeting 
minutes prior to data base lock. 
5.6 Handling of MCF, Fibrinogen Activity and Fibrinogen Antigen 
values below detection limit 
MCF (Maximum Clot Firmness) samples are analysed by central lab. Given that MCF values 
below the detection limit of “< 2mm” are indicated in the output of the testing as “not 
measurable”, it was discussed and decided in the BDRM (dated 25-Jun-2020) that for the 
purpose of the planned descriptive statistical analyses these values will be set to half of the 
range below the detection limit (range is “0 to 2”, i.e. value used is “1 mm”). In the listings of 
individual patient data, the MCF output “non measurable” will be presented as “< 2mm” 
(2 mm is the lower detection limit). 
Fibrinogen Activity samples are analysed by local and central lab. Given that Fibrinogen 
Activity values below the detection limit are indicated by “<” sign before the lower detection 
limit in the output of the testing, it was discussed and decided that for the purpose of the 
planned descriptive statistical analyses these values will be set to half of the range below the 
detection limit. 
Fibrinogen Antibody samples are analysed by central lab. Given that Fibrinogen Antibody 
values below the detection limit are indicated by “<” sign before the lower detection limit in 
the output of the testing, it was discussed and decided that for the purpose of the planned 
descriptive statistical analyses these values will be set to half of the range below the 
detection limit. For values indicated in the output of the testing as “<0.0” the value “0” will be 
used in the planned descriptive statistical analyses. 
 
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6 Patient Accounting and Disposition 
6.1 Patient accounting 
Based on all enrolled patients, the number and relative frequencies (i.e. percentages) of 
patients in each study population as defined in section 4 Analysis Sets will be presented by 
age subgroup and overall for part I. For part II the number and relative frequencies (i.e. 
percentages) of all enrolled patients will be presented by age subgroup and overall based on 
the APE set; number and relative frequencies of patients in the SAF, ITT, FAS, and PP sets 
will be presented based on the SAF set. A listing with patient accounting data will be also 
presented.  
An analogue presentation, including age groups, will be generated showing frequencies and 
percentages of the event based analysis sets (FBE and PPBE) from part II (ODP or ODT, 
each for minor events, major events and overall). Note, however, that these reflect events 
rather than patients. A listing with bleeding event based data will also be presented. 
 
6.2 Disposition and withdrawals 
The number and relative frequency (i.e. percentages) based on all enrolled patients (APE) 
will be presented by study part and overall for 
• 
Patients by site and country (worldwide) 
• 
Patients by site and country (European Economic Area (EEA) 
• 
Patients by age group according to EudraCT 
(in utero subjects, preterm newborn infants (gestational age <37 weeks), 
newborns (0-27 days), infants and toddlers (28 days-23 months),  
children (2-11 years), adolescents (12-17 years), adults (18-64 years), 
from 65 years on, from 65-84 years, 85 years and over) 
The number and relative frequency (i.e. percentages) based on all enrolled patients (APE) 
will be presented by age group and overall for 
Part I: 
• 
Patients participating in part I (Patients enrolled) 
• 
Patients not eligible (Screen failures) 
• 
Patients eligible 
• 
Patients who prematurely discontinued the study part I before treatment (with 
reasons for discontinuation) 
Part II: 
• 
Patients participating in part II (Patients enrolled) 
• 
Patients not eligible (Screen failures) 
• 
Patients eligible 
• 
Patients who prematurely discontinued the study part II before treatment (with 
reasons for discontinuation) 
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• 
Patients who completed the study without bleeding event (study completion defined 
as regular study completion/no early termination) 
 
The number and relative frequency (i.e. percentages) based on all treated patients (SAF) will 
be presented by age group and overall for 
Part I: 
• 
Patients treated in part I 
• 
Patients who prematurely discontinued the study part I after treatment (with reasons 
for discontinuation) 
• 
Patients who completed the study part I (Patient was treated in part I and 
completed/terminated the study after part I PK safety visit; in case PK safety visit was 
not done/has no date, date is calculated as 49 days after “PK Dosing Day 0”.) 
Part II: 
• 
Patients treated in part II 
• 
Patients treated in part I and II 
• 
Patients who prematurely discontinued the study part II after treatment (with reasons 
for discontinuation) 
• 
Patients who completed the study part II (study completion defined as regular study 
completion/no early termination) 
A listing with all the patient disposition data will be also presented. 
For the event based analysis the frequencies of part II bleeding events by patient (total) and 
additional descriptive statistics for frequencies of events by age group and overall will be 
presented (mean, SD, min, max, median) for FBE and PPBE. A listing with bleeding event 
data will be also presented.  
  
6.3 Protocol deviations 
The number and relative frequency of patients (and/or events) with protocol deviations 
(major/minor) will be presented overall for SAF and FAS (part I and part II) and FBE in part II 
for total and categories. All patients/events with their protocol deviations will be listed. 
In the BDRM, dated 25-Jun-2020, all minor and major protocol deviations on patient and on 
bleeding event level were reviewed and agreed upon. Following from the decisions taken, 
assignments to analysis populations were done. A complete list of all protocol deviations is 
attached to the BDRM minutes and included in the listings of the final analysis. 
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7 Demographics and Background Characteristics 
All assessments will be done for part I and II separately. 
Assessments made at screening visit and at PK Dosing Day 0 (pre-dose) will be 
summarized for patients treated with BT524 (SAF) using descriptive statistical methods only. 
These assessments will include demographic data and medical history as specified below as 
well as previous or concomitant medications (see section 9 below). Other relevant baseline 
characteristics from screening visit (such as physical examination, vital signs, etc.) will be 
presented as part of the applicable safety evaluations or only be listed (such as history of 
alcohol consumption or smoking).  
Summary tables with summary statistics and frequency tables will be presented as 
appropriate. Graphical presentations will be used if they increase transparency and 
understanding of the data. Details on what outputs will be produced along with their layout 
and technical specifications will be provided in the separate tables shell document. 
 
7.1 Demographics 
The following demographic characteristics will be presented on patient level for both part I 
and part II 
• 
Gender (male/female) 
• 
Age (years) at date of first BT524 treatment in the respective study part.  
• 
Race (White, Black, Asian, Other) 
• 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino)  
• 
Weight (kg) at baseline (if documented in lb it will be transformed into kg via:  
weight (kg) = weight(lb) x 0.4536, rounded to 2 digits) 
• 
Height (cm) at baseline (if documented in inch it will be transformed into cm via:  
height (cm) = height (inch) x 2.54, rounded to 2 digits) 
• 
BMI (kg/m2) at baseline = weight in kg / (height in cm)2× 10000  
• 
Disease characteristics (Afibrinogenemia, severe hypofibrinogenemia) 
The following information will be presented on event level for the FBE set 
• 
Age (years) as age at date of each event treatment (Day 0 of part II). 
Presentations for event level will be done overall as well as by ODP or ODT. 
Presentations will be done overall as well as by age group (0 to 27 days, 28 days to 
< 2 years, 2 to < 6 years, < 6 years, 6 to < 12 years, 12 to < 18 years, >=18 years). 
An additional table will be generated presenting the age classification according to EudraCT 
(in utero subjects, preterm newborn infants (gestational age < 37 weeks), newborns (0-27 
days), infants and toddlers (28 days-23 months), children (2-11 years), adolescents (12-17 
years), adults (18-64 years), from 65 years on, from 65-84 years, 85 years and over), but the 
classification is only presented in the patient disposition part of the analysis. 
All patients/events with their demographics data will be listed. 
 
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7.2 Medical history/ concomitant diseases 
The diseases and conditions are coded on a regular base during study conduct and at time 
of database lock the 2012Q3 version of the WHO Drug Dictionary will be used for the final 
coding. The medical conditions will be classified as follows: 
 
Previous medical conditions, i.e. medical conditions that stopped prior to start of first 
treatment 
 
Concomitant medical conditions, i.e. medical conditions still present or occurring after 
start of first treatment  
The frequency of diseases recorded from medical history will be presented (SAF) after 
classification into previous and concomitant conditions by system organ class (SOCs) as 
well as the frequencies of preferred terms  within each SOC. If patients have more than one 
disease within an SOC or   Preferred Term they will be counted only once for the respective 
SOC or Preferred Term. A listing with all patient medical history/concomitant medical 
condition data will be also presented. 
7.3 Bleeding history 
On patient level the following analyses will be done: 
 
Frequencies of bleeding events for Epistaxis, Oral cavity bleeding, Gastrointestinal 
bleeding, Post-partum bleeding, Umbilical cord bleeding, Menorrhagia, Muscle 
Haematoma, Haemarthrosis, Intraperitoneal bleeding, Intracranial bleeding, Others, 
and total. 
 
Annual bleeding rate = Number of bleedings within the last 12 months before ICF 
signature (spontaneous, total). Not applicable for patients < 1 year. 
 
Frequencies of bleedings due to surgical procedure 
Descriptive statistics for total number of bleedings and Number of bleedings due to surgical 
procedure, as well as for annual bleeding rate (based on patients ≥ 1 year at ICF signature) 
will be presented for each age group and overall. 
For patients below 1 year of age total number of bleeds will be given and described in a 
footnote. 
A listing with all patient bleeding history data will be also presented. 
 
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8 Exposure and Compliance 
All assessments will be done for part I and II separately. 
8.1 Treatment groups 
Not applicable. 
8.2 Dosage 
For part I descriptive statistics for the following dose data will be presented for SAF, FAS, 
PP, PK sets for the overall population and each age group. 
• 
Calculated dose (of fibrinogen) (mg) 
• 
Calculated dose (of fibrinogen) per kg (mg/kg) = Calculated dose (of fibrinogen) (mg)/ 
body weight (kg) 
• 
Calculated volume (mL) 
• 
Volume administered (mL),  
• 
Total dose administered (mg), 
• 
Nominal dose (of fibrinogen) administered (mg) = calculated dose x (volume 
administered / calculated volume) 
• 
Nominal dose (of fibrinogen) per kg administered (mg/kg) = calculated dose per kg x 
(volume administered / calculated volume)  
For part II (ODP or ODT) descriptive statistics for the following dose data will be presented 
for FBE and PPBE on event level (ODP or ODT, each for minor events, major events and 
overall) for the overall population and each age group: 
• 
Target Fibrinogen level (g/L) 
• 
Baseline Fibrinogen level (g/L) 
• 
Total volume administered (mL) 
• 
Total dose administered (mg) 
• 
Total dose administered per kg BW (mg/kg) (will be calculated) 
• 
Number of infusions per bleeding event 
In case of repetitive infusions for treatment of one bleeding event (only applicable for part II), 
all parameters per single infusion will be listed. In addition the mean values of the repeated 
infusions will be listed for Target Fibrinogen level and Baseline Fibrinogen level  and the sum 
of the repeated infusions will be listed for Total volume administered, Total dose 
administered, and Total dose administered per kg BW. For the descriptive statistics, the 
mean of the Target Fibrinogen level and the Baseline Fibrinogen level will be calculated for 
each patient per bleeding event. These mean values will then be used for the descriptive 
analysis. For all other parameters in the list above, the sum of single infusions for treatment 
of one bleeding event will be used for the descriptive statistics. 
Descriptive statistics (frequencies and percentages) for treated surgery events will be 
provided for the FBE set, separated into pre-operative administration, intra-operative 
administration and post-operative administration. 
Descriptive statistics for the FBE set (frequencies and percentages) of number of infusions 
per bleeding event will also be produced according to no repeated infusion (only one 
infusion), at least one repeated infusion (at least 2 infusions), and numbers of infusions per 
bleeding event: 1, 2, 3, >3. 
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A listing with all patient study medication dosage data will also be presented. 
 
8.3 Treatment/infusion duration 
Descriptive statistics for the following treatment duration data will be presented for part I 
(SAF, FAS, PP, PK) and on event level from part II (for FBE and PPBE) for the overall 
population and each age group. 
• 
Treatment duration will be calculated in minutes as end of administration (time/date) 
– start of administration (time/date) 
• 
Infusion rate (mL/min.) 
Also descriptive statistics (frequencies and percentages) of changes in infusion rates will be 
produced according to no change in infusion rates, at least one change in infusion rate, and 
numbers of changes in infusion rates (per treatment/event): 1, 2, 3, >3. Same evaluation will 
be done for infusion interruption. 
A listing with all patient treatment/infusion duration data will also be presented. 
8.4 Compliance 
For part I compliance can be assessed by the statistics on calculated dose of fibrinogen per 
kg (mg/kg) presented within the dosage evaluation (cf. section 8.2 above). For part I, 
analyses will use actual time, actual dose and infusion rate to derive the different 
characteristics. 
Due to the individually tailored dose for treatment of part II bleeding events no compliance 
rules based on calculated dose as for part I treatments apply. As the IMP will be 
administered intravenously to each patient under the supervision of the study investigator or 
designated qualified study personnel, the compliance is expected to be 100%. In addition, 
compliance can be assessed based on infusion interruptions (cf. section 8.3 above). 
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9 Previous and Concomitant Medication or Treatment 
All assessments will be done for part I and part II separately for the SAF set. 
Previous and concomitant medications are coded according to WHO drug dictionary. version 
2012Q3 which will be used at time of database lock and stored with A(natomical) 
T(herapeutical) C(hemical) codes and generic names.  
Treatment will be classified as previous if stopped prior first infusion and as concomitant if 
overlapping with study participation after first infusion. 
The numbers and frequencies of previous and concomitant medications will be given per 
ATC level 2. If a patient has received more than 1 drug within an ATC class he/she will be 
counted only once for this ATC class. A listing with all patient previous and concomitant 
medication or treatment will be also presented. 
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10 Pharmacokinetics, Pharmacodynamics and Efficacy 
All assessments will be done for part I and part II separately. 
Unless explicitly specified otherwise efficacy analyses will consist of descriptive methods 
and not test hypotheses but rather aim at parameter estimation and determination of 
confidence intervals. Should tests be conducted and/or p-values be given (beyond the one in 
section 10.2), note that these are not adjusted for multiplicity (which would be needed for 
fully confirmatory conclusions across all tests given the number of endpoints to investigate). 
Also, only descriptive analyses will be performed to compare the efficacy results of study 
984 with the results from published clinical trials (cf. protocol section 15.2). 
10.1 Primary endpoint analysis of part I  
The primary objective being the description of the PK characteristics of BT524 is not covered 
in great detail by this SAP. In the scope of this SAP, descriptive summary statistics, including 
changes from baseline for the fibrinogen antigen (from part I), will be provided for each age 
group (based on SAF, FAS, PP, and PK population). Values from each age group will be 
evaluated by a one-sample t-test (pre-/post-comparison) and presented in a tabular format.  
A listing with all patient fibrinogen antigen (from part I) data will be also presented. 
PK parameters defined for the primary objective will be derived from concentration-time 
profiles using adapted methodology, non-compartmental analysis, compartment analysis, or 
population modelling, as required. Details related to the analysis of these PK parameters will 
be specified in separate PK analyses plans. 
10.2 Secondary endpoint analyses of part I 
PD parameters defined for the secondary objective will be derived from concentration-time 
profiles using adapted methodology, non-compartmental analysis, compartment analysis, or 
population modelling, as required. Details related to the analysis of these PD parameters will 
be specified in separate PK analyses plans. 
In the scope of this SAP, descriptive summary statistics, including changes from baseline for 
the fibrinogen activity (from part I), will be provided for each age group (based on SAF, FAS, 
PP, and PK population). Values from each age group will be evaluated by a one-sample t-
test (pre-/post-comparison) and presented in a tabular format. Surrogate efficacy parameter 
MCF, assessed by fib-tem S, will be measured in part I pre-dose and at 1 and 8 hours post-
end of each IV infusion in patients ≥ 6 years. MCF will be measured pre-dose and at 1 hour 
post-end of infusion in children between 2 and < 6 years and pre-dose and at the end of 
each infusion in children < 2 years. 
Descriptive statistics including change from baseline will be presented for each age group, 
i.e. < 2 years, 2 to < 6 years, ≥ 6 to < 12 years, 12 to < 18 years, ≥ 18 years (based on FAS, 
PP, and SAF population). 
Values for the patients ≥ 18 years will be evaluated by a one-sample t-test (pre-/post-
comparison) and presented in a tabular format.  
This analysis, done for both post-dosing time points, will be considered confirmatory for the 1 
hour post-end of infusion assessment in patients ≥ 18 years. Additionally, 95%-confidence 
levels will be calculated.  
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More precisely, the t-test will assess the mean difference µ1,0 between dependent 
measurements (1h post minus pre-treatment MCF difference; one sample) and test the null 
hypothesis H0: µ1,0 < 0 versus the alternative H1: µ1,0 > 0 at a two-tailed α-level of 0.05. 
Correlation between MCF and fibrinogen activity pre-dose and at 1 and 8 hours post-end of 
each IV infusion will also be assessed in patients ≥ 6 years. 
Note that (according to protocol section 14.4.5.2.5) consumption of BT524 (dose per 
kilogram body weight and total dose) during part I, calculated and presented in the 
framework of exposure and compliance (cf. section above), can also be assessed and 
interpreted as efficacy endpoint in respect to MCF. 
Also the efficacy parameter MCF will be presented as a whisker box plot for FAS. 
10.3 Secondary endpoint analyses of part II 
Each of the below secondary efficacy parameters will be evaluated and descriptive statistics 
presented on event level from part II (ODP or ODT, each for minor events, major events and 
overall) for the overall population and each age group. More precisely, the following efficacy 
parameters after each event will be assessed: 
Overall haemostatic response to treatment with BT524 for each surgical procedure and each 
treated bleed as assessed by the investigator according to a 4 point scale ("none", 
"moderate", "good" or "excellent") will be evaluated presenting response rates with 95 % 
confidence intervals for each scale and for the sum of excellent and good, classified as 
success. These event-based evaluations will be conducted according to two concepts:  
1) descriptively (showing frequencies and percentages based on the event level FBE 
and PPBE analysis set) considering each event as an individual case and  
2) by modelling considering events as repeated measurements within the same patient 
(based on FBE and PPBE), if applicable (e.g. by general estimation equations with 
intra-patient correlation structure). Provided sufficient numbers of ODT and ODP, 
minor /major events should be considered (e.g. analysis by type according to concept 
1 above). 
Overall haemostatic response will also be presented in pie chart and listed. 
For each surgical procedure loss of blood (intra- and postoperatively, re-bleedings) will be 
listed considering each event as an individual case (based on the event level FBE and PPBE 
analyses sets).  
In addition, loss of blood is to be rated by the investigator according to classifications (loss of 
blood is below/within/above the expected range for the procedure performed) for surgical 
bleeding events. These ratings will be evaluated presenting numbers and percentages of 
events considering each bleeding event as an individual case (cf. concept 1 above). 
Descriptive analysis on event level (based on event based FBE and PPBE analyses sets) 
will be conducted for and also listed 
• 
Units of other fibrinogen-containing products infused besides BT524 (e.g., fresh 
frozen plasma or cryoprecipitate) given to counteract hemodynamic instability at the 
day of BT524 administration or 1 day after. 
• 
Units of transfusion products infused, e.g., allogenic or autologous blood (packed red 
blood cells, fresh whole blood), platelets, given to counteract hemodynamic instability 
at the day of BT524 administration or 1 day after. 
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• 
Consumption of BT524 (dose per kilogram body weight, dose per infusion and total 
dose) required pre-, intra- or post-operatively for effective treatment of surgical 
bleeding events. 
• 
Quality of wound healing assessed after wound healing is expected to be completed. 
Furthermore, MCF as a surrogate efficacy parameter will be evaluated pre-dose and at 1 
hour post-end of each IV infusion (including repetitive infusion for one bleeding event) by 
means of non-confirmatory t-test(s) pre/post comparison plus correlation between MCF and 
fibrinogen activity. Also MCF will be presented as a whisker box plot and also listed.  
Descriptive summary statistics including changes from baseline for the fibrinogen activity will 
be provided for each age group. MCF and fibrinogen activity values from additional 
samplings (beside pre-dose and 1 hour post-dose) taken as required per investigator will be 
listed and not used in the analyses described above.  These analyses will be conducted on 
event level, i.e. based on the event based FBE and PPBE analysis set. Otherwise, details 
correspond to those of part I analysis, except that the testing is considered as non-
confirmatory. 
With respect to the two evaluation concepts of efficacy, the concept when multiple events 
per patient are to be handled as individual cases is considered primary analysis within the 
framework of secondary analyses of part II. 
Descriptive summary statistics and a listing for the fibrinogen antigen at screening will be 
provided for each age group on patient level (SAF, FAS, and PP analysis sets). 
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11 Safety 
All assessments will be done for part I and part II separately. 
APE-Set will be used to present overall numbers of AEs incl. NTEAEs. All safety analyses 
will be based on the SAF. 
11.1 Adverse events 
All assessments will be done for all patients, part I and part II separately. 
Adverse events (AE) will be coded using the MedDRA® dictionary. The current version will 
be used at time of database lock and presented by primary System Organ Class (SOC) and 
Preferred Term.  
The analysis will focus on the treatment-emergent AEs (TEAEs). When an AE occurs after 
written consent has been obtained but before the first dose of study drug, the AE will be 
considered a non-treatment emergent AE. An AE that occurs (or worsened) on or after the 
time the patient receives his/her first dose of study drug (until his/her last study visit) will be 
considered a treatment emergent AE (TEAE). See also CSP section 14.6.2 for definition of 
non-treatment adverse events. 
Please note the definition of study periods and adverse event reporting periods in section 5.5 
above. Please also note that analyses for TEAE will be based on the safety population 
(SAF). Overview tables including non-TEAEs will be based on the APE to also include 
patients not treated in the study.  
For the analysis of TEAEs only those TEAEs are taken into consideration which are reported 
from first treatment to the safety visit after treatment (independent of the planned duration 
between treatment start and Day 49 safety visit). For part I this is the duration between PK 
treatment and the Day 49 PK safety visit or ealier (if a bleeding event happened before Day 
49 PK safety visit), and for part II this is for each bleeding event the duration between 
treatment of the bleeding event and  Day 49 safety visit or ealier (if another bleeding event 
happened before Day 49 safety visit).  
All other TEAEs reported out of these time frames will be counted and listed. Exception is 
the analysis of related serios adverse events (related SAEs)  which are inlcuded in the 
analysis irrespective of the onset time after first administration of IMP:  
If Day 49 safety visit’ is not done,  the period for inclusion of TEAEs in the analysis is from 
baseline (treatment start) to 49 days post-baseline . 
The total number and percentage of patients reporting at least one AE and the absolute 
count of AEs will be tabulated for each age group and overall. This initial summary will be 
based on the APE set and provide a breakdown of the following: 
• Any AE 
• Any non-severe AE 
• Any TEAE 
• Any non-serious TEAE 
• Any non-severe TEAE 
• Any treatment-related TEAE 
• Any severe AE 
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• Any severe TEAE 
• Any severe treatment-related TEAE 
• Any SAE 
• Any serious TEAE 
• Any serious treatment-related TEAE 
• Any AE leading to discontinuation from study 
• Any TEAE leading to discontinuation from study 
• Any treatment-related TEAE leading to discontinuation from study 
• Any AE with outcome of death 
• Any death 
• Any pregnancy 
 
In the SAF number and frequencies (i.e. percentages) of patients with TEAEs will be given 
by System Organ Class (SOC) and by Preferred term  within each SOC (total, for each age 
group) together with the number of events for the following: 
1. All TEAEs 
2. Serious TEAEs 
3. All TEAEs considered related (see details below) 
4. Serious TEAEs considered related (see details below) 
5. All TEAEs by maximum severity (‘mild’, ‘moderate’, ‘severe’) 
6. TEAEs leading to death 
7. TEAEs leading to study discontinuation  
8. The TEAEs occurring under infusion and within 24 hours after the start of IMP 
infusion (Infusion related reaction (IRR))  
9. Related TEAEs occurring within 24 hours after start of infusion 
10. Adverse events of special interest (AESI): 
- 
Hypersensitivity/ Anaphylactic reactions/anaphylactic shock: Hypersensitivity 
(SMQ, restricted to narrow search), Anaphylactic reaction (SMQ, restricted to 
narrow search), "Anaphylactic shock conditions" (SMQ, restricted to narrow 
search) 
- 
Thrombogenicity: SMQ Embolic and thrombotic events (restricted to narrow 
search) 
- 
Transmission of infective agents: Preferred Term "Transmission of infectious 
agent via product" and "Suspected transmission of an infectious agent via 
product (Preferred Term) 
- 
Fibrinogen inhibitory antibodies: SOC"Investigations" 
11. Related AESI: 
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- 
Hypersensitivity/ Anaphylactic reactions/anaphylactic shock: Hypersensitivity 
(SMQ, restricted to narrow search), Anaphylactic reaction (SMQ, restricted to 
narrow search), "Anaphylactic shock conditions" (SMQ, restricted to narrow 
search) 
- 
Thrombogenicity: SMQ Embolic and thrombotic events (restricted to narrow 
search) 
- 
Transmission of infective agents: Preferred Term "Transmission of infectious 
agent via product" and "Suspected transmission of an infectious agent via 
product (Preferred Term) 
- 
Fibrinogen inhibitory antibodies: SOC"Investigations" 
 
Additionally, number and frequencies of patients with TEAEs will be presented by 
decreasing frequency for all TEAEs, serious TEAEs and TEAEs considered related. 
11.2 Deaths 
Patient listings will be provided for patients with AEs leading to death. 
11.3 Adverse events leading to discontinuation from study 
Patient listings will be provided for patients with AEs leading to discontinuation. 
11.4 Pregnancies 
Pregnancy test results will be listed for all enrolled female patients (APE). 
11.5 Vital signs 
Vital signs are measured with the following method/unit: 
• 
Blood pressure [mmHg] 
• 
Heart rate in beats/min measured by pulse rate 
• 
Body temperature in grade Celsius [°C] (tympanic measurements) 
Measured values of vital signs will be summarized descriptively across the measurement 
time points (per observation period, cf. study protocol flowchart section 3) for part I (SAF) 
and on event level from part II (separated by ODP/ODT, hospitalization, age group) for FBE. 
Note that ‘baseline’ refers to the pre-dose measurement within each observation period of 
the indication/event. A listing with all patients vital signs data will be presented. 
11.6 Fibrinogen inhibitory antibodies 
Fibrinogen inhibitory antibodies are locally measured from sampling at screening, pre-dose 
(if applicable) and at the safety visit and will be categorized as positive, negative, or 
missing/not done.  
Number of patients and percentages in each category will be summarized for part I (PK) and 
part II for SAF and on event level from part II for FBE. A listing with all patients fibrinogen 
inhibitory antibodies data will also be presented.  
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11.7 Viral safety 
For part I viral safety is assessed based on pre-dose sample. 
The following statistical analyses will be presented for part I pre-dose samples: 
1. Qualitative data based on laboratory specific normal ranges will be categorized 
according to the categories “negative/positive”. 
2. Quantitative results will be categorized qualitatively based on specific normal ranges 
and presented as qualitative result ”normal”/”above normal”. The quantitative data for 
these parameters will be listed. 
3. Number and percentages of patients with values considered as clinically significant 
by the investigator will be tabulated. 
Retention samples from safety visit of part I and II and pre-dose samples from part II are 
only listed. No summaries will be produced. 
11.8 Clinical safety laboratory  
All safety lab values will be re-calculated to SI units before further processing.  
The following statistical analyses will be presented for part I (SAF) and on event level from 
part II for FBE (separated by ODP/ODT, hospitalization, age group as appropriate) per lab 
test (as listed subsequently). Note that ‘baseline’ refers to the pre-dose measurement within 
each observation period of the indication/event: 
1. Quantitative data will be examined for trends using descriptive statistics (number of 
patients/events with data, number of patients/events with missing values, mean, SD, 
median, minimum, and maximum) of measured values at baseline and each planned 
post-baseline visit over time. 
2. Qualitative data based on laboratory specific normal ranges will be categorized 
according to the categories (e.g. below normal/normal/above normal) and presented 
as number and relative frequency of patients (and/or events).  
3. Number and percentages of patients/events with on treatment values considered as 
clinically significant (CS) by the investigator will be tabulated (across planned visits). 
Out of range values not assessed for clinical significance are not included in the 
analysis and are provided in Listing. 
Note that in the listings, laboratory values that are outside the normal range will additionally 
be flagged. Any out-of-range values that are identified by the investigator as being clinically 
significant will also be shown in an extra data listing. Additionally, a separate listing showing 
the normal ranges will be generated. 
Hematology and clinical chemistry 
Hematology tests include RBC, WBC, platelet count, hemoglobin, and hematocrit (all 
quantitatively). 
Biochemistry tests measure aspartate aminotransferase, alanine aminotransferase, γ-
glutamintransferase, alkaline phosphatase, total bilirubin, creatinine, urea, potassium, 
sodium, calcium, chloride (all quantitatively). 
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Urinalysis 
Blood, leukocytes, protein, glucose, ketones, nitrite, bilirubin, urobilinogen were measured 
only qualitative, pH was measured quantitatve. For the analysis only qualitative results will 
be used (for pH the normal ranges are used for classification of results into “normal”, 
“abnormal”). Frequencies and percentages of normal and abnormal values will be presented. 
The quantitative results will only included in the listings.  
Markers of coagulation activation 
Coagulation activation parameters include PT, PT(INR), aPTT, TAT, F1+2, D-dimer. 
Measurements of coagulation activation parameters from additional samplings (beside pre-
defined timepoints) taken as required per investigator will be listed and not used in the 
analyses. 
11.9 ECG 
Overall ECG evaluations for part I will be analyzed for SAF. ECG measurements - according 
to the qualitative data categories “normal”, “abnormal – not clinically significant”, and 
“abnormal – clinically significant” - will be described by means of “shift-tables” between 
baseline and each of the planned post-baseline visits. ‘Baseline’ visit is the time point of pre-
dose measurement at screening within the PK period. ECG at screening for part II and 
unscheduled measurements will only be provided in the listings. 
 
11.10 Physical examination 
Physical examination will include the inspection of general appearance, skin, neck (including 
thyroid), eyes, ears, nose, throat, heart, lungs, abdomen, lymph nodes, extremities, 
musculoskeletal and nervous system. 
Number and percentages of patients for each category (“normal”, “abnormal – not clinically 
significant”, and “abnormal – clinically significant”) for part I and on event level from part II, 
will be generated per inspected organ (plus ‘other’) for pre-dose and overall.  
The overall assessment per inspected organ number and percentage of patients/events will 
be presented for the categories  
• 
NORMAL, defined as patients/events without any abnormal post baseline evaluation,  
• 
ABNORMAL NOT CS, defined as patients/events with at least one abnormal not 
clinically significant post baseline evaluation, and  
• 
ABNORMAL CS, defined as patients/events with at least one abnormal clinically 
significant post baseline evaluation.  
‘Baseline’ visit is the time point of pre-dose measurement within each observation period of 
the indication/event. 
Shift tables comparing baseline visit and Day 49 visit will also be produced for part I and on 
event level from part II. Values that are identified by the investigator as being clinically 
significant will also be shown in an additional data listing. 
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12 Software  
If not stated otherwise, the data will be analyzed using SAS Version 9.4 or higher. 
 
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13 Abbreviations 
 
AE 
Adverse Event 
APE 
All Patients Enrolled Set 
aPTT 
Activated partial Thromboplastin Time 
ATC 
Anatomical Therapeutical Chemical 
BW 
Body Weight 
°C 
Degrees Centigrade 
cf. 
confer  
CHMP 
Committee for Medicinal Products for Human Use 
cm 
Centimetre 
COA 
Certificate Of Analysis 
CRO 
Contract Research Organization 
CS 
Clinically Significant 
BDRM 
Blind Data Review Meeting 
ECG 
Electrocardiogram 
e.g. 
For example 
EMA 
European Medicines Agency 
FAS 
Full analysis set 
F1+2 
Prothrombin Fragment 1 and 2 
FiAc 
Fibrinogen  activity 
FiAg 
Fibrinogen antigen 
FU 
Follow-up 
g 
Gram 
h 
Hour 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization 
i.e. 
That is 
IMP 
International Medicinal Product 
INR 
International Normalized Ratio 
IRR 
Infusion Related Reaction 
IV 
Intravenous 
kg 
Kilogram 
L 
Liter 
lb 
Pound 
max 
Maximum 
MCF 
Maximum Clot Firmness 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Miligram 
min 
Minimum 
min. 
Minute 
mL 
Mililiter 
mm 
Millimetre 
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mmHg 
millimeters of mercury 
NTEAE 
Not Treatment Emergent Adverse Event 
ODP 
On-Demand Prophylaxis 
ODT 
On-Demand Treatment 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PP 
Per Protocol 
PT 
Prothrombin Time 
RBC 
Red Blood Cell 
ROTEM 
Rotational Thromboelastometry 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAF 
Safety analysis set 
SAS 
Statistical Analysis Software 
SD 
Standard Deviation 
SMQ 
Standardised MedDRA Queries 
SOC 
System Organ Class 
TAT 
Thrombin Antithrombin III Complex 
TEAE 
Treatment Emergent Adverse Event 
WBC 
White Blood Cell 
 
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14 References 
1. ICH Harmonised Tripartite Guideline E9, Statistical Principles for Clinical Trials, 1998 
2. ICH Harmonised Tripartite Guideline E3, Structure and Content of Clinical Study 
Reports. 1995 
3. ICH Harmonised Tripartite Guideline E6(R1), Guideline for Good Clinical Practice, 1996 
4. ICH guideline E2F, Note for guidance on development safety update reports, 
EMA/CHMP/ICH/309348/2008, September 2010 
5. SAS / STAT® 9.22 User’s Guide (2010). The Power Procedure, Cary, NC: SAS Institute 
Inc. 
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Clinipace Worldwide, ACC 1870 
15 Appendices 
 
15.1 Table of Content of TLF numbers, titles, and analysis populations 
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Figure 
14.2.2.1.17 
Overall Haemostatic Response on Event Level – Mean response by event number – FBE 
Figure 
14.2.2.1.18 
Overall Haemostatic Response on Event Level – Mean response by event number – PPBE 
Figure 
14.2.2.1.19 
Overall Haemostatic Response on Event Level - Line plot of haemostatic response by patient and event number – FBE 
Figure 
14.2.2.1.20 
Overall Haemostatic Response on Event Level - Line plot of haemostatic response by patient and event number – PPBE 
Listing 
16.8.1 
Secondary Endpoint Analysis  – Overall Haemostatic Response, Total of Loss of Blood, and Wound Healing –  FBE 
Table 
14.2.2.2.1 
Administration of Other FCPs on Event Level – Overall Summary Statistics for all Events – FBE 
Table 
14.2.2.2.2 
Administration of Other FCPs on Event Level – Overall Summary Statistics for all Events – PPBE 
Table 
14.2.2.2.3 
Administration of Other FCPs on Event Level – Administration Frequency Statistics for all Events – FBE 
Table 
14.2.2.2.4 
Administration of Other FCPs on Event Level – Administration Frequency Statistics for all Events – PPBE 
Table 
14.2.2.3.1 
Administration of Other TPs on Event Level – Overall Summary Statistics for all Events – FBE 
Table 
14.2.2.3.2 
Administration of Other TPs on Event Level – Overall Summary Statistics for all Events – PPBE 
Table 
14.2.2.3.3 
Administration of Other TPs on Event Level – Administration Frequency Statistics for all Events – FBE 
Table 
14.2.2.3.4 
Administration of Other TPs on Event Level – Administration Frequency Statistics for all Events – PPBE 
Listing 
16.8.2 
Secondary Endpoint Analyses  – Administration of Other FCPs and TPs – SAF II 
Table 
14.2.2.4.1 
BT524 Consumption/Dosing on Event Level: Descriptive Statistics Overall and per Infusion for Treated Surgeries – FBE 
Table 
14.2.2.4.2 
BT524 Consumption/Dosing on Event Level: Descriptive Statistics Overall and per Infusion for Treated Surgeries – PPBE 
Table 
14.2.2.5.1 
Wound Healing on Event Level: Frequency Statistics for all Events by Degree of Event – FBE 
Table 
14.2.2.5.2 
Wound Healing on Event Level: Frequency Statistics for all Events by Degree of Event – PPBE 
Table 
14.2.2.5.3 
Wound Healing on Event Level: Frequency Statistics for ODP by Degree of Event and Overall – FBE 
Table 
14.2.2.5.4 
Wound Healing on Event Level: Frequency Statistics for ODP by Degree of Event and Overall – PPBE 
Table 
14.2.2.5.5 
Wound Healing on Event Level: Frequency Statistics for ODT by Degree of Event and Overall – FBE 
Table 
14.2.2.5.6 
Wound Healing on Event Level: Frequency Statistics for ODT by Degree of Event and Overall – PPBE 
Table 
14.2.2.6.1 
Maximum Clot Firmness on Event Level by Age Group: Statistics of Changes from Predosing – FBE 
Table 
14.2.2.6.2 
Maximum Clot Firmness on Event Level by Age Group: Statistics of Changes from Predosing – PPBE 
Table 
14.2.2.6.3 
Maximum Clot Firmness on Event Level by Age Group: Statistics of Changes from Predosing for ODP by Degree of Event and Overall 
– FBE 
Table 
14.2.2.6.4 
Maximum Clot Firmness on Event Level by Age Group: Statistics of Changes from Predosing for ODP by Degree of Event and Overall 
– PPBE 
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Table 
14.2.2.6.5 
Maximum Clot Firmness on Event Level by Age Group: Statistics of Changes from Predosing for ODT by Degree of Event and Overall 
– FBE 
Table 
14.2.2.6.6 
Maximum Clot Firmness on Event Level by Age Group: Statistics of Changes from Predosing for ODT by Degree of Event and Overall 
– PPBE 
Table 
14.2.2.6.7 
Maximum Clot Firmness on Event Level by Age Group: Correlation Statistics with Fibrinogen Activity by Time Point – FBE 
Table 
14.2.2.6.8 
Maximum Clot Firmness on Event Level by Age Group: Correlation Statistics with Fibrinogen Activity by Time Point – PPBE 
Figure 
14.2.2.6.9 
Maximum Clot Firmness on Event Level by Age Group: Whisker Box Plot for all Events – FBE 
Figure 
14.2.2.6.10 
Maximum Clot Firmness on Event Level by Age Group: Whisker Box Plot for all Events – PPBE 
Figure 
14.2.2.6.11 
Maximum Clot Firmness on Event Level by Age Group: Whisker Box Plot for ODP by Degree of Event and Overall – FBE 
Figure 
14.2.2.6.12 
Maximum Clot Firmness on Event Level by Age Group: Whisker Box Plot for ODP by Degree of Event and Overall – PPBE 
Figure 
14.2.2.6.13 
Maximum Clot Firmness on Event Level by Age Group: Whisker Box Plot for ODT by Degree of Event and Overall – FBE 
Figure 
14.2.2.6.14 
Maximum Clot Firmness on Event Level by Age Group: Whisker Box Plot for ODT by Degree of Event and Overall – PPBE 
Listing 
16.8.3 
Secondary Endpoint Analysis Maximum Clot Firmness  – SAF I and FBE 
Table 
14.2.2.7.1 
Fibrinogen Activity (g/L) on Event Level by Age Group: Descriptive Statistics of Changes from Predosing for all Events – FBE 
Table 
14.2.2.7.2 
Fibrinogen Activity (g/L) on Event Level by Age Group: Descriptive Statistics of Changes from Predosing for all Events – PPBE 
Table 
14.2.2.7.3 
Fibrinogen Activity (g/L) on Event Level by Age Group: Descriptive Statistics of Changes from Predosing for ODP by Degree of Event 
and Overall – FBE 
Table 
14.2.2.7.4 
Fibrinogen Activity (g/L) on Event Level by Age Group: Descriptive Statistics of Changes from Predosing for ODP by Degree of Event 
and Overall – PPBE 
Table 
14.2.2.7.5 
Fibrinogen Activity (g/L) on Event Level by Age Group: Descriptive Statistics of Changes from Predosing for ODT by Degree of Event 
and Overall – FBE 
Table 
14.2.2.7.6 
Fibrinogen Activity (g/L) on Event Level by Age Group: Descriptive Statistics of Changes from Predosing for ODT by Degree of Event 
and Overall – PPBE 
Listing 
16.8.4 
Secondary Endpoint Analysis: Fibrinogen Activity  – SAF I and FBE 
Table 
14.2.2.8.1 
Fibrinogen Antigen (g/L): Descriptive Statistics of Screening Values by Age Group – SAF II 
Table 
14.2.2.8.2 
Fibrinogen Antigen (g/L): Descriptive Statistics of Screening Values by Age Group – FAS II 
Table 
14.2.2.8.3 
Fibrinogen Antigen (g/L): Descriptive Statistics of Screening Values by Age Group – PP II 
Listing 
16.8.5 
Fibrinogen Antigen – SAF II 
Table 
14.2.2.9.1 
Total Loss of Blood Classifications on Event Level: Frequency Statistics for Treated Surgeries – FBE 
Table 
14.2.2.9.2 
Total Loss of Blood Classifications on Event Level: Frequency Statistics for Treated Surgeries – PPBE 
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Table 
14.3.2.3.4 
Treatment-Emergent Adverse Events Considered Related by Age Group: Frequencies and Percentages of Patients by SOC and 
Preferred Term – SAF II 
Table 
14.3.2.4.1 
Treatment-Emergent Serious Adverse Events Considered Related: Frequencies and Percentages of Patients by SOC and Preferred 
Term – SAF I and II 
Table 
14.3.2.4.2 
Treatment-Emergent Serious Adverse Events Considered Related: Overall by Age Group: Frequencies and Percentages of Patients by 
SOC and Preferred Term – SAF I and II 
Table 
14.3.2.4.3 
Treatment-Emergent Serious Adverse Events Considered Related by Age Group: Frequencies and Percentages of Patients by SOC 
and Preferred Term – SAF I 
Table 
14.3.2.4.4 
Treatment-Emergent Serious Adverse Events Considered Related by Age Group: Frequencies and Percentages of Patients by SOC 
and Preferred Term – SAF II 
Table 
14.3.2.5.1 
Treatment-Emergent Adverse Events by Severity: Frequencies and Percentages of Patients by SOC and Preferred Term – SAF I and II 
Table 
14.3.2.5.2 
Treatment-Emergent Adverse Events by Severity : Overall by Age Group: Frequencies and Percentages of Patients by SOC and 
Preferred Term – SAF I and II 
Table 
14.3.2.5.3 
Treatment-Emergent Adverse Events by Severity by Age Group: Frequencies and Percentages of Patients by SOC and Preferred Term 
– SAF I 
Table 
14.3.2.5.4 
Treatment-Emergent Adverse Events by Severity by Age Group: Frequencies and Percentages of Patients by SOC and Preferred Term 
– SAF II 
Table 
14.3.2.6.1 
Treatment-Emergent Adverse Events by Maximal Severity: Frequencies and Percentages of Patients by SOC and Preferred Term – 
SAF I and II 
Table 
14.3.2.6.2 
Treatment-Emergent Adverse Events by Maximal Severity : Overall by Age Group: Frequencies and Percentages of Patients by SOC 
and Preferred Term – SAF I and II 
Table 
14.3.2.6.3 
Treatment-Emergent Adverse Events by Maximal Severity by Age Group: Frequencies and Percentages of Patients by SOC and 
Preferred Term – SAF I 
Table 
14.3.2.6.4 
Treatment-Emergent Adverse Events by Maximal Severity by Age Group: Frequencies and Percentages of Patients by SOC and 
Preferred Term – SAF II 
Table 
14.3.2.7.1 
Treatment-Emergent Adverse Events Leading to Death: Frequencies and Percentages of Patients by SOC and Preferred Term – SAF I 
and II 
Table 
14.3.2.7.2 
Treatment-Emergent Adverse Events Leading to Death: Overall by Age Group: Frequencies and Percentages of Patients by SOC and 
Preferred Term – SAF I and II 
Table 
14.3.2.7.3 
Treatment-Emergent Adverse Events Leading to Death:  part I by Age Group: Frequencies and Percentages of Patients by SOC and 
Preferred Term – SAF I 
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Table 
14.3.2.7.4 
Treatment-Emergent Adverse Events Leading to Death:  part II by Age Group: Frequencies and Percentages of Patients by SOC and 
Preferred Term – SAF II 
Table 
14.3.2.8.1 
Treatment-Emergent Adverse Events Leading to Study Discontinuation: Frequencies and Percentages of Patients by SOC and 
Preferred Term – SAF I and II 
Table 
14.3.2.8.2 
Treatment-Emergent Adverse Events Leading to Study Discontinuation:  Overall by Age Group: Frequencies and Percentages of 
Patients by SOC and Preferred Term – SAF I and II 
Table 
14.3.2.8.3 
Treatment-Emergent Adverse Events Leading to Study Discontinuation:  part I by Age Group: Frequencies and Percentages of 
Patients by SOC and Preferred Term – SAF I 
Table 
14.3.2.8.4 
Treatment-Emergent Adverse Events Leading to Study Discontinuation:  part II by Age Group: Frequencies and Percentages of 
Patients by SOC and Preferred Term – SAF II 
Table 
14.3.2.9.1 
Treatment-Emergent Adverse Events Occurring under Infusion and within 24 Hours after the Start of IMP Infusion (Infusion Related 
Reaction (IRR)):  Frequencies and Percentages of Patients by SOC and Preferred Term – SAF I and II 
Table 
14.3.2.9.2 
Treatment-Emergent Adverse Events Occurring under Infusion and within 24 Hours after the Start of IMP Infusion (Infusion Related 
Reaction (IRR)):  Overall by Age Group: Frequencies and Percentages of Patients by SOC and Preferred Term – SAF I and II 
Table 
14.3.2.9.3 
Treatment-Emergent Adverse Events Occurring under Infusion and within 24 Hours after the Start of IMP Infusion (Infusion Related 
Reaction (IRR)) by Age Group: Frequencies and Percentages of Patients by SOC and Preferred Term – SAF I 
Table 
14.3.2.9.4 
Treatment-Emergent Adverse Events Occurring under Infusion and within 24 Hours after the Start of IMP Infusion (Infusion Related 
Reaction (IRR)) by Age Group: Frequencies and Percentages of Patients by SOC and Preferred Term – SAF II 
Table 
14.3.2.10.1 
Treatment-Emergent Related Adverse Events Occurring under Infusion and within 24 Hours after the Start of IMP Infusion (Infusion 
Related Reaction (IRR)): Frequencies and Percentages of Patients by SOC and Preferred Term – SAF I and II 
Table 
14.3.2.10.2 
Treatment-Emergent Related Adverse Events Occurring under Infusion and within 24 Hours after the Start of IMP Infusion (Infusion 
Related Reaction (IRR)): Overall by Age Group: Frequencies and Percentages of Patients by SOC and Preferred Term – SAF I and II 
Table 
14.3.2.10.3 
Treatment-Emergent Related Adverse Events Occurring under Infusion and within 24 Hours after the Start of IMP Infusion (Infusion 
Related Reaction (IRR)) by Age Group: Frequencies and Percentages of Patients by SOC and Preferred Term – SAF I 
Table 
14.3.2.10.4 
Treatment-Emergent Related Adverse Events Occurring under Infusion and within 24 Hours after the Start of IMP Infusion (Infusion 
Related Reaction (IRR)) by Age Group: Frequencies and Percentages of Patients by SOC and Preferred Term – SAF II 
Table 
14.3.2.11.1 
Treatment-Emergent Adverse Events with Hypersensitivity/Anaphylactic reaction/Anaphylactic Shock: Frequencies and Percentages 
of Patients by SOC and Preferred Term – SAF I and II 
Table 
14.3.2.11.2 
Treatment-Emergent Adverse Events with Hypersensitivity/Anaphylactic reaction/Anaphylactic Shock: Overall by Age Group: 
Frequencies and Percentages of Patients by SOC and Preferred Term – SAF I and II 
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Table 
14.3.2.11.3 
Treatment-Emergent Adverse Events with Hypersensitivity/Anaphylactic reaction/Anaphylactic Shock by Age Group: Frequencies 
and Percentages of Patients by SOC and Preferred Term – SAF I  
Table 
14.3.2.11.4 
Treatment-Emergent Adverse Events with Hypersensitivity/Anaphylactic reaction/Anaphylactic Shock by Age Group: Frequencies 
and Percentages of Patients by SOC and Preferred Term – SAF II 
Table 
14.3.2.12.1 
Treatment-Emergent Adverse Events with Thrombogenicity: Frequencies and Percentages of Patients by SOC and Preferred Term – 
SAF I and II 
Table 
14.3.2.12.2 
Treatment-Emergent Adverse Events with Thrombogenicity: Overall by Age Group: Frequencies and Percentages of Patients by SOC 
and Preferred Term – SAF I and II 
Table 
14.3.2.12.3 
Treatment-Emergent Adverse Events with Thrombogenicity by Age Group: Frequencies and Percentages of Patients by SOC and 
Preferred Term – SAF I  
Table 
14.3.2.12.4 
Treatment-Emergent Adverse Events with Thrombogenicity by Age Group: Frequencies and Percentages of Patients by SOC and 
Preferred Term – SAF II 
Table 
14.3.2.13.1 
Treatment-Emergent Adverse Events with Transmission of Infectious Agents: Frequencies and Percentages of Patients by SOC and 
Preferred Term – SAF I and II 
Table 
14.3.2.13.2 
Treatment-Emergent Adverse Events with Transmission of Infectious Agents: Overall by Age Group: Frequencies and Percentages of 
Patients by SOC and Preferred Term – SAF I and II 
Table 
14.3.2.13.3 
Treatment-Emergent Adverse Events with Transmission of Infectious Agents by Age Group: Frequencies and Percentages of Patients 
by SOC and Preferred Term – SAF I 
Table 
14.3.2.13.4 
Treatment-Emergent Adverse Events with Transmission of Infectious Agents by Age Group: Frequencies and Percentages of Patients 
by SOC and Preferred Term – SAF II 
Table 
14.3.2.14.1 
Treatment-Emergent Adverse Events with Fibrinogen Inhibitory Antibodies: Frequencies and Percentages of Patients by SOC and 
Preferred Term – SAF I and II 
Table 
14.3.2.14.2 
Treatment-Emergent Adverse Events with Fibrinogen Inhibitory Antibodies: Overall by Age Group: Frequencies and Percentages of 
Patients by SOC and Preferred Term – SAF I and II 
Table 
14.3.2.14.3 
Treatment-Emergent Adverse Events with Fibrinogen Inhibitory Antibodies by Age Group: Frequencies and Percentages of Patients 
by SOC and Preferred Term – SAF I 
Table 
14.3.2.14.4 
Treatment-Emergent Adverse Events with Fibrinogen Inhibitory Antibodies by Age Group: Frequencies and Percentages of Patients 
by SOC and Preferred Term – SAF II 
Table 
14.3.2.15.1 
Treatment-Emergent Related Adverse Events with Hypersensitivity/Anaphylactic reaction/Anaphylactic Shock: Frequencies and 
Percentages of Patients by SOC and Preferred Term – SAF I and II 
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Table 
14.3.2.15.2 
Treatment-Emergent Related Adverse Events with Hypersensitivity/Anaphylactic reaction/Anaphylactic Shock: Overall by Age 
Group: Frequencies and Percentages of Patients by SOC and Preferred Term – SAF I and II 
Table 
14.3.2.15.3 
Treatment-Emergent Related Adverse Events with Hypersensitivity/Anaphylactic reaction/Anaphylactic Shock by Age Group: 
Frequencies and Percentages of Patients by SOC and Preferred Term – SAF I 
Table 
14.3.2.15.4 
Treatment-Emergent Related Adverse Events with Hypersensitivity/Anaphylactic reaction/Anaphylactic Shock by Age Group: 
Frequencies and Percentages of Patients by SOC and Preferred Term – SAF II 
Table 
14.3.2.16.1 
Treatment-Emergent Related Adverse Events with Thrombogenicity: Frequencies and Percentages of Patients by SOC and Preferred 
Term – SAF I and II 
Table 
14.3.2.16.2 
Treatment-Emergent Related Adverse Events with Thrombogenicity: Overall by Age Group: Frequencies and Percentages of Patients 
by SOC and Preferred Term – SAF I and II 
Table 
14.3.2.16.3 
Treatment-Emergent Related Adverse Events with Thrombogenicity by Age Group: Frequencies and Percentages of Patients by SOC 
and Preferred Term – SAF I 
Table 
14.3.2.16.4 
Treatment-Emergent Related Adverse Events with Thrombogenicity by Age Group: Frequencies and Percentages of Patients by SOC 
and Preferred Term – SAF II 
Table 
14.3.2.17.1 
Treatment-Emergent Related Adverse Events with Transmission of Infectious Agents: Frequencies and Percentages of Patients by 
SOC and Preferred Term – SAF I and II 
Table 
14.3.2.17.2 
Treatment-Emergent Related Adverse Events with Transmission of Infectious Agents: Overall by Age Group: Frequencies and 
Percentages of Patients by SOC and Preferred Term – SAF I and II 
Table 
14.3.2.17.3 
Treatment-Emergent Related Adverse Events with Transmission of Infectious Agents by Age Group: Frequencies and Percentages of 
Patients by SOC and Preferred Term – SAF I 
Table 
14.3.2.17.4 
Treatment-Emergent Related Adverse Events with Transmission of Infectious Agents by Age Group: Frequencies and Percentages of 
Patients by SOC and Preferred Term – SAF II 
Table 
14.3.2.18.1 
Treatment-Emergent Related Adverse Events with Fibrinogen Inhibitory Antibodies: Frequencies and Percentages of Patients by SOC 
and Preferred Term – SAF I and II 
Table 
14.3.2.18.2 
Treatment-Emergent Related Adverse Events with Fibrinogen Inhibitory Antibodies: Overall by Age Group: Frequencies and 
Percentages of Patients by SOC and Preferred Term – SAF I and II 
Table 
14.3.2.18.3 
Treatment-Emergent Related Adverse Events with Fibrinogen Inhibitory Antibodies by Age Group: Frequencies and Percentages of 
Patients by SOC and Preferred Term – SAF I 
Table 
14.3.2.18.4 
Treatment-Emergent Related Adverse Events with Fibrinogen Inhibitory Antibodies by Age Group: Frequencies and Percentages of 
Patients by SOC and Preferred Term – SAF II 
Listing 
16.9.1 
All Adverse Events –  APE I and II 
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Table 
14.3.3.2.4 
Chemistry Laboratory Data on Event Level by Age Group: Descriptive Statistics of ASAT, ALAT, GGT, Alkaline Phosphatase, Bilirubin, 
Creatinine, Urea, Potassium, Sodium, Calcium, Chloride by Time Point – FBE 
Table 
14.3.3.2.5 
Chemistry Laboratory Data on Event Level by Hospitalization: Descriptive Statistics of ASAT, ALAT, GGT, Alkaline Phosphatase, 
Bilirubin, Creatinine, Urea, Potassium, Sodium, Calcium, Chloride by Time Point – FBE 
Table 
14.3.3.2.6 
Chemistry Laboratory Data on Event Level: Frequencies and Percentages of  Clinically Significant ASAT, ALAT, GGT, Alkaline 
Phosphatase, Bilirubin, Creatinine, Urea, Potassium, Sodium, Calcium, Chloride by Indication and Time Point – FBE 
Table 
14.3.3.2.7 
Chemistry Laboratory Data on Event Level by Age Group: Frequencies and Percentages of Clinically Significant ASAT, ALAT, GGT, 
Alkaline Phosphatase, Bilirubin, Creatinine, Urea, Potassium, Sodium, Calcium, Chloride by Time Point – FBE 
Table 
14.3.3.2.8 
Chemistry Laboratory Data on Event Level by Hospitalization: Frequencies and Percentages of Clinically Significant ASAT, ALAT, GGT, 
Alkaline Phosphatase, Bilirubin, Creatinine, Urea, Potassium, Sodium, Calcium, Chloride by Time Point – FBE 
Listing 
16.11.1 
Chemistry Laboratory Data – SAF I 
Listing 
16.11.2 
Chemistry Laboratory Data assess as clinically significant by the investigator – SAF I 
Listing 
16.11.3 
Chemistry Laboratory Data – FBE 
Listing 
16.11.4 
Chemistry Laboratory Data assess as clinically significant by the investigator – FBE 
Listing 
16.11.5 
Chemistry Laboratory Data normal range values 
Table 
14.3.3.3.1 
Urinalysis Laboratory Data: Descriptive Statistics of pH, Blood, WBC, Protein, Glucose, Ketone Bodies, Nitrite, Bilirubin, Urobilinogen 
by Time Point – SAF I 
Table 
14.3.3.3.2 
Urinalysis Laboratory Data: Frequencies and Percentages of Clinically Significant pH, Blood, WBC, Protein, Glucose, Ketone Bodies, 
Nitrite, Bilirubin, Urobilinogen by Time Point – SAF I 
Table 
14.3.3.3.3 
Urinalysis Laboratory Data on Event Level: Descriptive Statistics of pH, Blood, WBC, Protein, Glucose, Ketone Bodies, Nitrite, 
Bilirubin, Urobilinogen by Indication and Time Point – FBE 
Table 
14.3.3.3.4 
Urinalysis Laboratory Data on Event Level by Age Group: Descriptive Statistics of pH, Blood, WBC, Protein, Glucose, Ketone Bodies, 
Nitrite, Bilirubin, Urobilinogen by Time Point – FBE 
Table 
14.3.3.3.5 
Urinalysis Laboratory Data on Event Level by Hospitalization: Descriptive Statistics of pH, Blood, WBC, Protein, Glucose, Ketone 
Bodies, Nitrite, Bilirubin, Urobilinogen by Time Point – FBE 
Table 
14.3.3.3.6 
Urinalysis Laboratory Data on Event Level: Frequencies and Percentages of Clinically Significant pH, Blood, WBC, Protein, Glucose, 
Ketone Bodies, Nitrite, Bilirubin, Urobilinogen by Indication and Time Point – FBE 
Table 
14.3.3.3.7 
Urinalysis Laboratory Data on Event Level by Age Group: Frequencies and Percentages of Clinically Significant pH, Blood, WBC, 
Protein, Glucose, Ketone Bodies, Nitrite, Bilirubin, Urobilinogen by Time Point – FBE 
PPD
PPD