Prospective, Open-label, Uncontrolled, Phase III Study to Assess the Efficacy, Safety and Pharmacokinetic of Octafibrin for On-demand Treatment of Acute Bleeding and to Prevent Bleeding During and After Surgery in Paediatric Subjects With Congenital Fibrinogen Deficiency
Phase: PHASE3
Conditions: Congenital Fibrinogen Deficiency
Sponsor: Octapharma

CLINICAL STUDY PROTOCOL 
FORMA-04 
NOTE: This document contains confidential and proprietary information of Octapharma AG. 
Do not copy or distribute without written permission. 
 
 
 
Prospective, open-label, uncontrolled, phase III study to assess the 
efficacy, safety, and pharmacokinetics of Octafibrin for 
on-demand treatment of acute bleeding and to 
prevent bleeding during and after surgery 
in paediatric subjects with congenital fibrinogen deficiency 
 
Investigational Product: 
Octafibrin 
Indication: 
Congenital fibrinogen deficiency 
Study Design: 
Multinational, multi-centre, prospective, open-label, 
uncontrolled 
Sponsor: 
Octapharma AG 
Study Number: 
FORMA-04 
EudraCT Number: 
2014-005115-16 
Development Phase: 
Phase III 
Planned Clinical Start: 
3rd quarter 2015 
Planned Clinical End: 
3rd quarter 2020 
Date of Protocol: 
30-May-2017 
Version: 
4.0, includes 
Protocol Amendment #3, 30-May-2017 
Protocol Amendment #2, 08-Jul-2016 (CSP V3.0) 
Protocol Amendment #1, 15-Sep-2015 (CSP V2.0) 
Co-ordinating Investigator: 
Flora Peyvandi MD, PhD, 
Associate Professor of Internal Medicine, 
A. Bianchi Bonomi Hemophilia and Thrombosis Center, 
University of Milan, 
Department of Medicine and Medical Specialties, 
IRCCS Maggiore Hospital, 
Mangiagalli and Regina Elena Foundation, 
Via Pace 9 
20122 Milan, Italy 
 
090-CSP-FORMA-04-04/DOC ID 2614 

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STUDY OUTLINE 
 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Octafibrin 
Protocol Identification Code: 
FORMA-04 
Name of Active Ingredient: 
Fibrinogen 
Date of Final Protocol: 
30-May-2017 
 
Title of Study: 
Prospective, open-label, uncontrolled, Phase III study to assess the efficacy, safety, and 
pharmacokinetics of Octafibrin for on-demand treatment of acute bleeding and to prevent 
bleeding during and after surgery in paediatric subjects with congenital fibrinogen de-fi- 
ciency 
Indication: Congenital fibrinogen deficiency 
Number of Study Centres: Approximately 5 study centres worldwide. 
Study Duration: 3rd quarter 2015 to 3rd quarter 2020 
Development Phase: III 
Objectives: 
Primary: 
• To demonstrate the efficacy of Octafibrin for on-demand treatment of acute bleeding 
episodes (spontaneous or after trauma) 
Secondary: 
• To determine the single-dose pharmacokinetics of Octafibrin in paediatric subjects 
with congenital fibrinogen deficiency 
• To investigate an association between the overall clinical assessment of haemostatic 
efficacy and the surrogate endpoint ‘clot strength’ or ‘clot firmness’ (referred to as 
‘maximum clot firmness’ [MCF] in this protocol) via thromboelastometry (ROTEM). 
Therefore, MCF as surrogate efficacy parameter will be determined before and after 
the first infusion of IMP for treatment of a bleeding episode 
• To achieve a peak target plasma fibrinogen level of 100 mg/dL in minor bleeds and 
150 mg/dL for major bleeds 1 hour post-infusion 
• To determine the response to Octafibrin based on incremental in vivo recovery (IVR) 
• To demonstrate the efficacy of Octafibrin in preventing bleeding during and after sur- 
gery 
• To assess the safety of Octafibrin in subjects with congenital fibrinogen deficiency, 
including immunogenicity, thromboembolic complications, and early signs of allergic 
or hypersensitivity reactions 

Study Protocol 
No. FORMA-04 
CONFIDENTIAL 
Version 4.0 
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ii 
 
 
 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Octafibrin 
Protocol Identification Code: 
FORMA-04 
Name of Active Ingredient: 
Fibrinogen 
Date of Final Protocol: 
30-May-2017 
 
Study Design: 
Multinational, multi-centre, prospective, open-label, uncontrolled, Phase III study. 
Number of Subjects: 
At least 12 male or female paediatric subjects with congenital fibrinogen deficiency will be 
enrolled into the study and undergo PK assessment. Of these 12 subjects, at least 6 subjects 
will undergo on-demand treatment of 6 first bleeding episodes. Of these 6 subjects, at least 
3 should be aged between 0 and <6 years and 3 should be aged between 6 and <12 years. 
In addition, at least 2 surgical procedures will be assessed. 
Subject Selection Criteria: 
Inclusion criteria: 
1. Aged <12 years (at the start of treatment) 
2. Documented diagnosis of congenital fibrinogen deficiency, expected to require 
on-demand treatment for bleeding or surgical prophylaxis: 
– Fibrinogen deficiency manifested as afibrinogenaemia or severe hypofibrino- 
genaemia 
– Historical plasma fibrinogen activity of <50 mg/dL or levels below the limit 
of detection of the local assay method. 
3. Expected to have an acute bleeding episode (spontaneous or after trauma) or plan- 
ning to undergo elective surgery 
4. Informed consent signed by the subject’s legal guardian 
Exclusion criteria: 
1. Life expectancy <6 months 
2. Bleeding disorder other than congenital fibrinogen deficiency, including 
dysfibrinogenaemia 
3. Prophylactic treatment with a fibrinogen concentrate 
4. Treatment with: 
– Any fibrinogen concentrate or other fibrinogen-containing blood product 
within 2 weeks prior to start of treatment for the PK phase, a bleeding epi- 
sode, or surgery 
– Any coagulation-active drug (i.e., non-steroidal anti-inflammatory drugs, war- 
farin, coumarin derivatives, platelet aggregation inhibitors) within 1 week 
prior to start of the PK phase or treatment for the bleeding episode or surgery, 
or as a planned or expected medication during the time period from Day 1 un- 
til 24 hours (i.e., 1 day) after the last Octafibrin infusion 

Study Protocol 
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Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Octafibrin 
Protocol Identification Code: 
FORMA-04 
Name of Active Ingredient: 
Fibrinogen 
Date of Final Protocol: 
30-May-2017 
 
5. Presence or history of: 
– Hypersensitivity to study medication 
– Deep vein thrombosis or pulmonary embolism within 1 year prior to start of 
treatment for the bleeding episode or surgery 
– Arterial thrombosis within 1 year prior to start of treatment for the bleeding 
episode or surgery 
– Hypersensitivity to human plasma proteins 
– Oesophageal varicose bleeding 
– End-stage liver disease (i.e., Child-Pugh score B or C) 
6. Known positive HIV infection with a viral load >200 particles/μL or >400,000 cop- 
ies/mL 
7. Polytrauma 1 year prior to start of treatment for the bleeding episode or surgery 
8. Diagnosis or suspicion of a neutralizing anti-fibrinogen inhibitor currently or at any 
time in the past 
9. Acute or chronic medical condition which may, in the opinion of investigator, 
affect the conduct of the study, including subjects receiving immune-modulating 
drugs (other than anti-retroviral chemotherapy), such as alpha-interferon, predni- 
sone (equivalent to >10 mg/day), or similar drugs, at study start 
10. Treatment with IMP in another interventional clinical study currently or during the 
past 4 weeks 
 
Test Product, Dose, Mode of Administration, and Batch Number(s): 
In this study, Octafibrin will be administered as intravenous (i.v.) bolus injection. Contin- 
uous infusion is not allowed. 
 
PK Dose Schedule and Mode of Administration 
For PK assessments, subjects will receive a single intravenous infusion of 70 mg/kg body 
weight of Octafibrin. 
 
Octafibrin Treatment Dose Calculation 
Octafibrin will be individually dosed to achieve a recommended target fibrinogen plasma 
level dependent on the type of bleeding or surgery (minor or major). The dose will be cal- 
culated individually as follows: 
 
Fibrinogen dose 
= 
(mg/kg body weight) 
[Target peak plasma level (mg/dL) − measured level (mg/dL)**] 
Median response* (mg/dL per mg/kg body weight) 
* The median response in this dose calculation formula is the median incremental in vivo recovery reported for 
the PK of Octafibrin in the final analysis of study FORMA-01 which was calculated as 1.77. 
**The measured level for the first infusion will be the historical level for that patient after a washout or, if below 
the limit of detection of the local assay, zero (0) will be used. 

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Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Octafibrin 
Protocol Identification Code: 
FORMA-04 
Name of Active Ingredient: 
Fibrinogen 
Date of Final Protocol: 
30-May-2017 
 
Dosing for On-Demand Treatment of Bleeding 
For each bleeding episode that is treated as part of the study, each subject will receive at 
least 1 infusion of Octafibrin for the treatment of a major or minor acute bleeding episode 
on Day 1. 
Octafibrin will be individually dosed to achieve a recommended target fibrinogen plasma 
level dependent on the bleeding type (minor or major). 
• Minor bleeding will be treated to achieve a recommended target fibrinogen plasma 
level of 100 mg/dL and an accepted lower limit of 80 mg/dL. 
• Major bleeding will be treated to achieve a recommended target fibrinogen plasma 
level of 150 mg/dL and an accepted lower limit of 130 mg/dL. 
On subsequent study days, fibrinogen plasma levels will be measured daily to determine 
whether additional infusions of Octafibrin are needed: 
• Minor bleeding will be observed for at least 3 days. 
• Major bleeding will be observed for at least 7 days. 
Additional Octafibrin infusions, as required 
• Additional infusions of Octafibrin should be administered if the actual fibrinogen 
plasma level measured on subsequent study days is below the accepted lower limit of 
the target level (80 mg/dL for minor bleeding, 130 mg/dL for major bleeding). 
• If the actual fibrinogen plasma level is above the accepted lower limit of the target 
level, Octafibrin should not be administered. 
Definition of minor and major bleeding 
• Minor bleeding events are defined as mild haemarthrosis or superficial muscle, soft 
tissue, and oral bleeding. 
• Major bleeding events are defined as symptomatic bleeding in a critical area or or- 
gan, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular, or per- 
icardial bleeding, or intramuscular bleeding with compartment syndrome, or bleeding 
causing a decrease in haemoglobin level by 20 g/L (1.24 mmol/L) or more. 
Characterisation of any other bleeding events not within these categories will be discussed 
individually with the investigator. 
Dosing for Surgery 
For each surgery that is treated as part of the study, within 3 hours prior to surgery, each 
subject will receive a loading infusion of Octafibrin. 

Study Protocol 
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Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Octafibrin 
Protocol Identification Code: 
FORMA-04 
Name of Active Ingredient: 
Fibrinogen 
Date of Final Protocol: 
30-May-2017 
 
Octafibrin will be individually dosed to achieve a recommended target fibrinogen plasma 
level dependent on the surgery type (minor or major). 
• Patients undergoing minor surgery will be treated to achieve a recommended target 
fibrinogen plasma level of 100 mg/dL and an accepted lower limit of 80 mg/dL. 
• Patients undergoing major surgery will be treated to achieve a recommended target 
fibrinogen plasma level of 150 mg/dL and an accepted lower limit of 130 mg/dL. 
On each post-operative day, fibrinogen plasma levels will be measured daily to determine 
whether maintenance infusions of Octafibrin are needed: 
• Minor surgery will be observed for at least 3 post-operative days. 
• Major surgery will be observed for at least 7 post-operative days. 
Maintenance infusions, as required: 
• Additional infusions of Octafibrin should be administered if the actual fibrinogen 
plasma level measured on subsequent study days is below the accepted lower limit of 
the target level (80 mg/dL for minor surgery, 130 mg/dL for major surgery). 
• If the actual fibrinogen plasma level is above the accepted lower limit of the target 
level, Octafibrin should not be administered. 
Definition of minor and major surgery 
Surgeries are defined as major, if any of the following criteria are met: 
• Requiring general or spinal anaesthesia. 
• Requiring opening into the great body cavities. 
• In the course of which hazards of severe haemorrhage is possible. 
• Requiring haemostatic therapy for at least 6 days. 
• Orthopaedic interventions involving joints (ankle, knee, hip, wrist, elbow, shoulder). 
• Surgeries/conditions in which the subject's life is at stake. 
Characterisation of any other surgery not within these categories and considered major by 
the investigator will be discussed individually with the investigator. 
All other surgeries are classified as minor. The classification is made prospectively. 
Duration of Treatment: 
Planned duration over the entire study: The planned study duration is up to 5 years. The 
study will be considered completed when a minimum of 12 subjects have undergone PK 
assessments, 6 subjects (i.e., at least 3 subjects aged between 0 and <6 years and 3 subjects 
aged between 6 and <12 years) have at least one documented bleeding episode, and a min- 
imum of 2 surgical procedures have been performed. 

Study Protocol 
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Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Octafibrin 
Protocol Identification Code: 
FORMA-04 
Name of Active Ingredient: 
Fibrinogen 
Date of Final Protocol: 
30-May-2017 
 
Planned duration for an individual subject: 
All patients (at least 12) will undergo a PK study after screening. This will have a duration 
of 14 days, after which a patient can be treated for a bleeding episode or planned surgical 
procedure when they occur. 
For subjects receiving on-demand treatment, 
• The individual subject observation and follow-up period for each documented epi- 
sode starts with the first dose of Octafibrin administered for on-demand treatment of 
an acute bleeding episode (Day 1) and will be followed up to at least Day 30. 
• Each subject’s treatment observation period is defined according to the severity of 
the event and will last at least 3 days for minor and 7 days for major bleeding epi- 
sodes. 
For subjects undergoing surgical prophylaxis, 
• the surgical observation period starts with the first dose of Octafibrin administered 
prior to elective surgery (Day 1) and, depending on the severity of the event, will last 
at least 3 post-operative days for minor and 7 post-operative days for major surgeries 
or until the day of the last post-operative infusion, whichever comes last. 
During the study observation period, enrolled patients will be treated for any bleeding epi- 
sodes or planned surgeries that can be managed under the protocol. Patients may remain in 
the study until the 6th patient (at least 3 patients each in the specified age groups) has at 
least one documented bleeding episode and there are at least 2 surgical procedures docu- 
mented. 
As many bleeding episodes or surgeries as possible occurring throughout the study obser- 
vation period will be documented. Only the first bleeding episodes will be used for the 
analysis of the primary endpoint. All bleeding episodes documented in the study will be 
assessed as a secondary endpoint. 
Patients who were screened for the study but did not receive any IMP will be considered 
‘no treatment’ patients and reported separately. 
All patients completing the PK phase will also be analyzed separately, regardless of 
whether they received any IMP for the treatment of a bleeding episode or surgery. 
Reference Therapy, Dose, Mode of Administration, and Batch Number(s): 
Not applicable. 

Study Protocol 
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Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Octafibrin 
Protocol Identification Code: 
FORMA-04 
Name of Active Ingredient: 
Fibrinogen 
Date of Final Protocol: 
30-May-2017 
 
Study Outcome Parameters (Primary and Secondary Endpoints): 
Primary endpoint 
The primary endpoint is the overall clinical assessment of the haemostatic efficacy of 
Octafibrin in treating the first documented bleeding episode of each patient. The first bleed- 
ing episode covers the time period from the first Octafibrin infusion for the treatment of a 
bleeding episode until 24 hours (i.e., 1 day) after the last infusion or the end of the treatment 
observation period, whichever comes last. 
The investigator’s overall clinical assessment of haemostatic efficacy for bleeding will be 
based on a 4-point haemostatic efficacy scale (see table below). The final efficacy assess- 
ment of each patient will be adjudicated by the Independent Data Monitoring & Endpoint 
Adjudication Committee (IDMEAC). The number of subjects per outcome category will 
be assessed in the final analysis. 
4-point haemostatic efficacy scale 
 
Category 
Definition 
 
Excellent 
Immediate and complete cessation of bleeding in the absence of other haemo- 
static intervention as clinically assessed by the treating physician; and/or 
<10% drop in haemoglobin compared to pre-infusion. 
Good 
Eventual complete cessation of bleeding in the absence of other haemostatic 
intervention as clinically assessed by the treating physician; and/or <20% drop 
in haemoglobin compared to pre-infusion. 
Moderate 
Incomplete cessation of bleeding and additional haemostatic intervention re- 
quired, as clinically assessed by the treating physician; and/or between 20 and 
25% drop in haemoglobin compared to pre- infusion. 
None 
No cessation of bleeding and alternative haemostatic intervention required, as 
clinically assessed by the treating physician; and/or >25% drop in haemoglo- 
  
bin compared to pre-infusion. 
 
Secondary endpoints 
PK endpoints: 
• Area under the concentration-time curve (AUC) 
• Response: Incremental In Vivo Recovery (IVR) 
• Classical IVR 
• Terminal elimination half-life (t1/2) 
• Maximum plasma concentration (Cmax) 
• Time to reach maximum plasma concentration (Tmax) 
• Mean residence time (MRT) 

Study Protocol 
No. FORMA-04 
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Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Octafibrin 
Protocol Identification Code: 
FORMA-04 
Name of Active Ingredient: 
Fibrinogen 
Date of Final Protocol: 
30-May-2017 
 
• Volume of distribution (Vss) 
• Clearance (Cl) 
Secondary efficacy endpoints: 
• MCF assessment before first infusion and 1 hour after end of first infusion of each 
documented bleeding episode. 
• Fibrinogen plasma level before and 1 hour after the end of each infusion as well as at 
the time of the overall clinical assessment of haemostatic efficacy (i.e., 24 hours after 
the last infusion or end of the observation period of each documented bleeding epi- 
sode). 
• Response after the first infusion of each bleeding episode as indicated by incremental 
IVR, calculated as the maximum increase in plasma fibrinogen (Clauss data) between 
the pre-infusion and the 3-hour post-infusion measurement, divided by the exact dose 
of Octafibrin (expressed as mg/kg dosed). 
• Efficacy of Octafibrin in all bleeding episodes collected in the study using the investi- 
gator’s overall clinical assessment of haemostatic efficacy for bleeding based on a 
4-point haemostatic efficacy scale. 
• Efficacy of Octafibrin in surgical prophylaxis will be assessed at the end of surgery by 
the surgeon and post-operatively by the haematologist using the following scales: 
 
Category Definition 
Intra-operative efficacy as assessed by surgeon (at the end of the surgery=after last suture) 
Excellent Intra-operative blood loss* was lower than or equal to the average expected  
blood loss for the type of procedure performed in a subject with normal haemo- 
stasis and of the same sex, age, and stature. 
Good 
Intra-operative blood loss* was higher than average expected blood loss but 
lower or equal to the maximal expected blood loss for the type of procedure in 
a subject with normal haemostasis. 
Moderate Intra-operative blood loss* was higher than maximal expected blood loss for the 
type of procedure performed in a subject with normal haemostasis, but haemo- 
stasis was controlled. 
None 
Haemostasis was uncontrolled necessitating a change in clotting factor replace- 
ment regimen. 
 
*Excludes unexpected blood loss due to surgical complications, i.e., 
–Direct injury of a vessel (artery or vein) 
–Vessel injury not adequately responding to routine surgical procedures achieving haemostasis 
–Accidental injury of parenchymatous tissue (e.g., liver, lung) 
Post-operative efficacy as assessed by haematologist 

Study Protocol 
No. FORMA-04 
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ix 
 
 
 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Octafibrin 
Protocol Identification Code: 
FORMA-04 
Name of Active Ingredient: 
Fibrinogen 
Date of Final Protocol: 
30-May-2017 
 
 
Excellent No post-operative bleeding or oozing that was not due to complications of sur- 
gery. All post-operative bleeding (due to complications of surgery) was con- 
trolled with Octafibrin as anticipated for the type of procedure. 
Good 
No post-operative bleeding or oozing that was not due to complications of sur- 
gery. Control of post-operative bleeding due to complications of surgery re- 
quired increased dosing with Octafibrin or additional infusions, not originally 
anticipated for the type of procedure. 
Moderate Some post-operative bleeding and oozing that was not due to complications of 
surgery; control of post-operative bleeding required increased dosing with Oc- 
tafibrin or additional infusions, not originally anticipated for the type of proce- 
dure. 
None 
Extensive uncontrolled post-operative bleeding and oozing. Control of post-op- 
  
erative bleeding required use of an alternate fibrinogen concentrate. 
 
An overall efficacy assessment taking both the intra- and post-operative assessment into 
account will be adjudicated by the IDMEAC. The final endpoint determination will be 
based on the adjudicated assessments using an agreed algorithm. 
The surgical observation period starts with the first dose of Octafibrin administered 
prior to elective surgery (Day 1) and, depending on the severity of the event, will last 
at least 3 post-operative days for minor and 7 post-operative days for major surgeries 
or until the day of the last post-operative infusion, whichever comes last. 
In addition, the location, severity and type of surgery will be documented. Expected 
and actual duration of surgical procedure and details of administered dose(s) of Oc- 
tafibrin (pre-, intra- and/or post-operatively) will be recorded. Fibrinogen plasma levels 
(pre-, intra-, and post-operatively) will be measured. Details of concomitantly adminis- 
tered products (except standard anaesthesia) along with a brief narrative describing the 
outcome of the intervention will be recorded. 
Safety endpoints: 
• Vital signs 
• Physical examination 
• Thromboembolic event (TEE) questionnaire 
• Routine clinical laboratory assessment, including coagulation parameters 
• Adverse events (AEs), including thromboembolic complications and early signs of al- 
lergic or hypersensitivity reactions 
• Thrombogenicity testing before and after each IMP infusion for the treatment of 
bleeding, except on the Day of Last Infusion 
• Immunogenicity testing before the first infusion of IMP and on Day 30 after the treat- 
ment of each bleeding episode 

Study Protocol 
No. FORMA-04 
CONFIDENTIAL 
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Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Octafibrin 
Protocol Identification Code: 
FORMA-04 
Name of Active Ingredient: 
Fibrinogen 
Date of Final Protocol: 
30-May-2017 
 
Summary of Study Procedures: 
SCREENING ASSESSMENTS 
Patients identified by the study sites as potential study participants will undergo the follow- 
ing screening assessments: 
• Inclusion and exclusion criteria, including written informed consent by the subject’s 
legal guardian for participation in the study 
• Demography, medical history (including details concerning allergic tendencies), re- 
view of previous therapy, and prior/concomitant medication 
PHARMACOKINETICS ASSESSMENTS 
Within 2 weeks after the screening process,  subjects  will  receive a single infusion  of  
70 mg/kg Octafibrin on Day 1 of PK testing (PK-Day 1). Before the start of the PK phase, 
there must be an at least 2-week wash-out period of any fibrinogen containing product. 
Before first injection vital signs and blood draws for baseline fibrinogen levels will be as- 
sessed. Retention serum samples for potential retesting will be collected within 30 minutes 
before the PK infusion. At 1 and 3 hours post-infusion, vital signs and fibrinogen for PK 
will be assessed, and AEs will be recorded. Subjects will be further followed on: 
• PK-Days 2, 4, 7, and 10 
− 
Fibrinogen for PK 
− 
Recording of AEs, including potential thromboembolic events 
• PK-Day 14 
− 
Fibrinogen for PK 
− 
Vital signs 
− 
Physical examination including any signs or symptoms of potential thromboem- 
bolic events 
− 
Recording of AEs, including potential thromboembolic events 
ASSESSMENTS IN SUBJECTS UNDERGOING ON-DEMAND TREATMENT OF 
BLEEDING 
Subjects presenting to the study site for an acute bleeding episode will undergo a 30-day 
observation and follow-up period as outlined below. Throughout the study, subjects may 
undergo more than one 30-day observation and follow-up period for additional bleeding 
episodes as required until the close of the study. At the end of their study participation, 
patients will be asked to return for a final Study Completion Visit. 

Study Protocol 
No. FORMA-04 
CONFIDENTIAL 
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Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Octafibrin 
Protocol Identification Code: 
FORMA-04 
Name of Active Ingredient: 
Fibrinogen 
Date of Final Protocol: 
30-May-2017 
 
NOTE: All adverse events (AEs), including thromboembolic events and early signs of al- 
lergic or hypersensitivity reactions, occurring between the start of the first Octafibrin infu- 
sion and the end of each 30-day observation and follow-up period will be recorded. The 
detection of thromboembolic events will be supported by completing a TEE questionnaire 
at each study visit for the treatment of bleeding episodes and for surgeries. Concomitant 
medications will also be recorded throughout each 30-day observation and follow-up pe- 
riod. Administered doses of Octafibrin will be recorded for every infusion, including dates, 
times, and batch numbers. 
All SAEs occurring after the first IMP infusion will be documented and reported for a pa- 
tient throughout the duration of the patient’s participation in the study or as required to 
meet local regulations. Also, any concomitant medications used to treat an SAE will be 
recorded. 
Day 1 (first day of treatment) 
On Day 1, subjects will visit their site for treatment of an acute bleeding episode. 
Pre-infusion assessments 
The following assessments will be performed before the first infusion of Octafibrin for each 
bleeding episode: 
• Medical history (including details of any non-study bleeding episodes and therapy), 
and prior/concomitant medication 
• Characterisation of bleeding episode 
• Vital signs 
• Physical examination 
• TEE questionnaire 
• Height and weight 
• Blood draw for: 
− 
fibrinogen plasma level (local lab–activity; central lab–antigen and activity; within 
30 minutes before infusion) 
− 
MCF (within 30 minutes before infusion) 
− 
safety lab (local–haematology and clinical chemistry) 
− 
thrombogenicity 
− 
immunogenicity 
NOTE: If the period between screening and treatment is more than 3 months, informed 
consent will be re-reviewed and confirmed prior to treatment, and details of the review 
process will be recorded in the patient chart and indicated in the CRF by the investigator. 
Also, inclusion/exclusion criteria will be confirmed prior to treatment. 

Study Protocol 
No. FORMA-04 
CONFIDENTIAL 
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xii 
 
 
 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Octafibrin 
Protocol Identification Code: 
FORMA-04 
Name of Active Ingredient: 
Fibrinogen 
Date of Final Protocol: 
30-May-2017 
 
First infusion of Octafibrin 
After the pre-infusion assessments, subjects will receive the first infusion of Octafibrin for 
treatment of bleeding. 
Post-infusion assessments 
On Day 1, the following post-infusion assessments will be performed: 
1 hour (±15 minutes) after the end of infusion: 
• Vital signs 
• TEE questionnaire 
• Blood draw for: 
− 
fibrinogen plasma level (local lab–activity; central lab–antigen and activity) 
− 
MCF 
3 hours (±15 minutes) after the end of infusion: 
• Vital signs 
• TEE questionnaire 
• Blood draw for: 
− 
fibrinogen plasma level (central lab–antigen and activity) 
− 
thrombogenicity 
• AEs and concomitant medications 
NOTE: If, in the investigator’s judgement, the infusion of Octafibrin administered on 
Day 1 is deemed the only infusion needed for treatment of the subject’s bleeding event, the 
subject will need to reach the end of the treatment observation period, where the “24 hours 
(i.e., 1 day) after the last infusion” assessments should be performed. 
All study days after Day 1 (treatment observation period) 
Each subject’s treatment observation period is defined according to the severity of the 
event and will last at least 3 days for minor and 7 days for major bleeding episodes. 
If the patient requires multiple infusions, the actual treatment duration will be determined 
by the investigator based on his/her judgement of the subject’s condition. 
On subsequent study days (at least 3 days for minor bleeding or 7 days for major bleeding), 
fibrinogen plasma levels will be measured daily to determine whether additional infusions 
of Octafibrin are needed. 

Study Protocol 
No. FORMA-04 
CONFIDENTIAL 
Version 4.0 
30-May-2017 
xiii 
 
 
 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Octafibrin 
Protocol Identification Code: 
FORMA-04 
Name of Active Ingredient: 
Fibrinogen 
Date of Final Protocol: 
30-May-2017 
 
Daily assessments (for at least 3 days for minor bleeding or 7 days for major bleeding) 
• TEE questionnaire 
• Blood draw for: 
− 
fibrinogen plasma level (local lab–activity; central lab–antigen and activity): Based 
on local lab results, the investigator will determine whether additional infusions of 
Octafibrin are needed. 
− 
safety lab (local–haematology) 
• AEs and concomitant medications 
Octafibrin infusion, as required 
After these daily assessments, additional IMP dosing should occur as required depending 
on the actual and target plasma level and based on the following criteria: 
• If the actual fibrinogen plasma level is below the accepted lower limit of the target fi- 
brinogen plasma level (80 mg/dL for minor bleeding, 130 mg/dL for major bleeding), 
the subject should receive another infusion of Octafibrin. 
• If the fibrinogen plasma level is greater than or equal to the accepted lower limit of 
the target fibrinogen plasma level, Octafibrin should not be administered on that day. 
Pre- and post-infusion assessments 
If the subject receives an additional infusion of Octafibrin, the following pre- and post- 
infusion assessments will be done. 
Pre-infusion assessments: 
• TEE questionnaire 
• Blood draw for (within 30 minutes before infusion): 
− 
fibrinogen plasma level (local lab–activity; central lab–antigen and activity) 
− 
thrombogenicity 
1 hour (±15 minutes) after the end of each infusion: 
• Vital signs 
• TEE questionnaire 
• Blood draw for: 
− 
fibrinogen plasma level (local lab–activity; central lab–antigen and activity) 
− 
thrombogenicity 

Study Protocol 
No. FORMA-04 
CONFIDENTIAL 
Version 4.0 
30-May-2017 
xiv 
 
 
 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Octafibrin 
Protocol Identification Code: 
FORMA-04 
Name of Active Ingredient: 
Fibrinogen 
Date of Final Protocol: 
30-May-2017 
 
NOTE: If, in the investigator’s judgement, there are no additional infusions of Octafibrin 
needed to treat the bleeding event, the subject will need to reach the end of the treatment 
observation period, where the “24 hours (i.e., 1 day) after the last infusion” assessments 
should be performed. 
Last Infusion or End of the Treatment Observation Period (whichever comes last) 
On the Day of Last Infusion for a patient requiring multiple infusions for a bleeding event 
as defined by the investigator based on his/her judgement of the subject’s condition or if 
the subject comes to the end of the treatment observation period (whichever comes last), 
the following assessments will be performed: 
Pre-infusion assessments 
The following assessments will be performed prior to the last infusion of Octafibrin if mul- 
tiple infusions are needed: 
• TEE questionnaire 
• Blood draw for (within 30 minutes before infusion): 
− 
fibrinogen plasma level (local lab–activity; central lab–antigen and activity) 
Last infusion of Octafibrin 
Following the pre-infusion assessments, subjects will receive their last infusion of Oc- 
tafibrin depending on the actual and target plasma levels. 
Post-infusion assessments 
On the Day of Last Infusion, post-infusion assessments will be as follows: 
1 hour (±15 minutes) after the end of last infusion: 
• Vital signs 
• TEE questionnaire 
• Blood draw for: 
− 
fibrinogen plasma level (local lab–activity; central lab–antigen and activity) 
24 hours (i.e., 1 day) after the last infusion or at the end of the treatment observation period 
(whichever comes last): 
• Vital signs 
• Physical examination 
• TEE questionnaire 

Study Protocol 
No. FORMA-04 
CONFIDENTIAL 
Version 4.0 
30-May-2017 
xv 
 
 
 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Octafibrin 
Protocol Identification Code: 
FORMA-04 
Name of Active Ingredient: 
Fibrinogen 
Date of Final Protocol: 
30-May-2017 
 
• Blood draw for: 
− 
fibrinogen plasma level (central lab–antigen and activity) 
• Final assessment of haemostatic efficacy by the investigator with respect to the ade- 
quacy of stopping an acute bleed. The assessment is to include the entire period from 
the start of the first infusion until 24 hours (i.e., 1 day) after the last infusion and in- 
cludes the clinical condition of the subject, laboratory values such as haematocrit and 
haemoglobin, and any additional haemostatic treatments. 
Day 30 (29 days after the first infusion)—Final Examination 
On Day 30 (± 1 week), the following assessments will be performed: 
• Physical examination 
• TEE questionnaire 
• Blood draw for: 
− 
immunogenicity 
− 
retention serum sample for potential retesting 
• AEs and concomitant medications 
The Day 30 assessment concludes the series of observations for a bleeding episode. No 
further study-related assessments for this episode will be performed, unless safety concerns 
(e.g., ongoing AEs) require follow-up. Subjects returning to the study site for another acute 
bleeding episode within the study observation period will again undergo the same series of 
Day 1 to Day 30 assessments as outlined above. At the end of the study duration, all subjects 
having received any IMP will be asked to return for a Study Completion Visit. 
If the patient experiences another bleeding event before Day 30, this will be treated as a 
new bleeding event, provided that it is not directly related to the prior event. In this case, 
Day 30 evaluations will be postponed until 30 days after the start of the new bleeding epi- 
sode. 
ASSESSMENTS IN SUBJECTS UNDERGOING SURGICAL PROPHYLAXIS 
In the case of a surgical procedure, Octafibrin will be given prior to surgery as well as 
during and after surgery based on the physician’s judgement, the patient’s history, and the 
severity of the procedure. Subjects enrolled for elective surgery will be treated (as required) 
and assessed throughout the surgical observation period. 
The surgical observation period starts with the first dose of Octafibrin administered prior 
to elective surgery (Day 1) and, depending on the severity of the event, will last at least  
3 post-operative days for minor and 7 post-operative days for major surgeries or until the 
day of the last post-operative infusion, whichever comes last. 

Study Protocol 
No. FORMA-04 
CONFIDENTIAL 
Version 4.0 
30-May-2017 
xvi 
 
 
 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Octafibrin 
Protocol Identification Code: 
FORMA-04 
Name of Active Ingredient: 
Fibrinogen 
Date of Final Protocol: 
30-May-2017 
 
NOTE: All adverse events (AEs), including thromboembolic events and early signs of al- 
lergic or hypersensitivity reactions, occurring between first infusion of IMP before the start 
of surgery and the Last Post-operative Day will be recorded. 
All SAEs occurring after the first IMP infusion will be documented and reported for a pa- 
tient throughout the duration of the patient’s participation in the study or as required to 
meet local regulations. Also, any concomitant medications used to treat an SAE will be 
recorded. 
Day 1 
For subjects enrolled for surgical prevention, Day 1 is the day they undergo surgery and 
receive their first dose of Octafibrin in this study. The following surgery-related data will 
be recorded: 
Pre-operative assessments 
The following data will be recorded before surgery: 
• Medical history 
• Vital signs 
• Physical examination 
• TEE questionnaire 
• Body weight (kg) 
• Blood draw for: 
− 
fibrinogen plasma levels (local lab–activity; central lab–antigen and activity) 
− 
safety lab (local–haematology and clinical chemistry). 
• Location and type of surgery 
• Severity of surgery (minor/major) 
• Expected duration of surgical procedure (start and end times, i.e., skin to skin) 
• Expected blood loss for the procedure 
• Estimate of any blood/blood product transfusions needed during the surgery 
• Any planned ancillary therapy to be used during the surgery (e.g., antifibrinolytics, 
pre-panned blood transfusions, etc.) 
First infusion of Octafibrin 
Following the pre-operative assessments and within 3 hours before the start of surgery, the 
subject may receive the first infusion of Octafibrin. 
NOTE: If, in the investigator’s judgement, there are no additional infusions of Octafibrin 
needed to prevent bleedings post surgery, the post-infusion assessments as detailed in the 
schedule for the Last Post-Operative Day should be performed instead. 

Study Protocol 
No. FORMA-04 
CONFIDENTIAL 
Version 4.0 
30-May-2017 
xvii 
 
 
 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Octafibrin 
Protocol Identification Code: 
FORMA-04 
Name of Active Ingredient: 
Fibrinogen 
Date of Final Protocol: 
30-May-2017 
 
Intra-operative assessments 
The following data will be recorded during and at the end of surgery: 
• Blood draw for: 
− 
intra-operative fibrinogen plasma levels (local lab–activity; central lab–antigen and 
activity) 
• AEs and concomitant medications 
Assessments at the end of surgery 
• TEE questionnaire 
• Blood draw for: 
− 
fibrinogen plasma levels (local lab–activity; central lab–antigen and activity) 
• Actual duration of surgical procedure (start and end times, i.e., skin to skin) 
• Details of surgery 
• Actual blood loss 
• Details on concomitantly administered products including any blood/blood product 
transfusions but excluding drugs given for routine anaesthesia 
• Intra-operative efficacy assessment at the end of surgical procedure by the surgeon. 
• AEs and concomitant medications 
Any post-operative day before the Last Post-Operative Day 
On any post-operative day before the Last Post-Operative Day, the following assessments 
will be performed: 
Daily post-operative assessments 
• Vital signs 
• TEE questionnaire 
• Blood draw for: 
− 
fibrinogen plasma levels (local lab–activity; central lab–antigen and activity) 
− 
safety lab (local–haematology and clinical chemistry) 
• Wound haematomas and oozing (noting whether surgical evacuation is required and 
severity and volume of oozing) 
• AEs and concomitant medications 

Study Protocol 
No. FORMA-04 
CONFIDENTIAL 
Version 4.0 
30-May-2017 
xviii 
 
 
 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Octafibrin 
Protocol Identification Code: 
FORMA-04 
Name of Active Ingredient: 
Fibrinogen 
Date of Final Protocol: 
30-May-2017 
 
Octafibrin infusion, as required 
Additional dosing should occur as required depending on the actual and target plasma level 
and based on the following criteria: 
• If the actual fibrinogen plasma level is below the accepted lower limit of the target fi- 
brinogen plasma level (80 mg/dL for minor surgery, 130 mg/dL for major surgery), 
the subject should receive another infusion of Octafibrin. 
• If the fibrinogen plasma level is greater than or equal to the accepted lower limit of 
the target fibrinogen plasma level, Octafibrin should not be administered on that day. 
Pre- and post-infusion assessments 
If the subject receives an infusion of Octafibrin, the following pre- and post-infusion as- 
sessments will be performed: 
Pre-infusion assessments: 
• TEE questionnaire 
• Blood draw for (within 30 minutes before infusion): 
− 
fibrinogen plasma level (local lab–activity; central lab–antigen and activity) 
• AEs and concomitant medications 
1 hour (±15 minutes) after the end of each infusion: 
• Vital signs 
• TEE questionnaire 
• Blood draw for: 
− 
fibrinogen plasma level (local lab–activity; central lab–antigen and activity) 
− 
safety lab (local–haematology and clinical chemistry) 
• AEs and concomitant medications 
Last Post-Operative Day 
The Last Post-Operative Day is either at least post-operative day 3 for minor and post- 
operative day 7 for major surgery or the day of the last post-operative infusion, whichever 
comes last. 
The assessments performed on the Last Post-Operative Day are identical to those per- 
formed on any other post-operative day (see ‘Any post-operative day before the Last Post- 
Operative Day’ as described on page xvii). 

Study Protocol 
No. FORMA-04 
CONFIDENTIAL 
Version 4.0 
30-May-2017 
xix 
 
 
 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Octafibrin 
Protocol Identification Code: 
FORMA-04 
Name of Active Ingredient: 
Fibrinogen 
Date of Final Protocol: 
30-May-2017 
 
In addition, the following assessments will be performed on the Last Post-Operative Day: 
• post-operative efficacy assessment by the haematologist 
• brief narrative describing the details of hospitalisation (start and end date, details of 
the procedure), follow-up, outcome, and efficacy of the intervention 
The assessments performed on the Last Post-Operative Day conclude the surgical observa- 
tion period. No further study-related assessments will be performed, unless safety concerns 
(e.g., ongoing AEs) require follow-up. 
Patients may remain in the study until at least 12 patients have undergone PK assessment, 
the 6th patient (at least 3 patients each in the specified age groups) has at least one docu- 
mented bleeding episode, and at least 2 surgical procedures have been documented. When 
the study is closed, all subjects having received any IMP will be asked to return for a Study 
Completion Visit. 
Study Completion Visit 
At the end of the study duration, all subjects having received any IMP will be asked to 
return for a Study Completion Visit, during which the following assessments will be per- 
formed: 
• Medical history since the last study visit 
• Physical examination 
• TEE questionnaire 
After the Study Completion Visit, the clinical study is considered completed for the subject. 
Patients who were screened for the study but did not receive any IMP throughout the study 
duration will be notified of the end of the study. No further assessments will need to be 
performed. These patients will be considered ‘no treatment’ patients and reported sepa- 
rately. 
Statistical analysis: 
Continuous variables will be summarised using descriptive statistics (including arithmetic 
mean, standard deviation (SD), median, minimum and maximum, and number of observa- 
tions and missing observations). Categorical variables will be summarised with counts and 
percentages. Additionally, for PK data and efficacy parameters, two-sided 95% confidence 
intervals will be calculated where appropriate. 

Study Protocol 
No. FORMA-04 
CONFIDENTIAL 
Version 4.0 
30-May-2017 
xx 
 
 
 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Octafibrin 
Protocol Identification Code: 
FORMA-04 
Name of Active Ingredient: 
Fibrinogen 
Date of Final Protocol: 
30-May-2017 
 
Primary endpoint 
The primary endpoint is the overall clinical assessment of the haemostatic efficacy of Oc- 
tafibrin in treating the first documented bleeding episode of each patient. The first bleeding 
episode covers the time period from the first Octafibrin infusion for the treatment of a 
bleeding episode until 24 hours (i.e., 1 day) after the last infusion or the end of the treatment 
observation period, whichever comes last. 
For the analysis, the assessment made by the investigator on the 4-point rating scale will 
be transformed to a dichotomous endpoint with success defined as a rating of excellent or 
good. The final efficacy assessment of each patient will be adjudicated by an Independent 
Data Monitoring & Endpoint Adjudication Committee (IDMEAC). Bleeding efficacy data 
will be summarised using descriptive statistics and displayed graphically, differentiating 
between the first bleeding episode per patient (primary endpoint) and all bleeding episodes 
(secondary endpoint). 
Secondary endpoints 
PK endpoints: 
The PK endpoints (i.e., area under the concentration-time curve (AUC), incremental IVR, 
classical IVR, terminal elimination half-life (t1/2), maximum plasma concentration (Cmax), 
time to reach maximum plasma concentration (Tmax), mean residence time (MRT), volume 
of distribution (Vss), and clearance (Cl)) will be assessed after a single intravenous infusion 
of 70 mg/kg body weight of Octafibrin. 
PK analysis on fibrinogen activity and antigen levels will be performed per patient with a 
non-compartmental model using standard PK software (Phoenix); this includes graphical 
displays of individual elimination curves. The resulting PK parameters will be summarized 
and presented as described for continuous variables. 
Secondary efficacy endpoints: 
Clot strength (MCF) 
Fibrinogen levels 1 hour after infusion of the investigational medicinal product (IMP), 
MCF at pre-infusion and at 1 hour after the first infusion as well as changes of MCF from 
pre-infusion will be summarised using descriptive statistics and displayed graphically. 
Octafibrin use 
The dose of the IMP used per day and in total will be summarised using descriptive statis- 
tics for minor and major bleeding events. Frequency of infusions and duration of treatment 
will also be summarised. 

Study Protocol 
No. FORMA-04 
CONFIDENTIAL 
Version 4.0 
30-May-2017 
xxi 
 
 
 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Octafibrin 
Protocol Identification Code: 
FORMA-04 
Name of Active Ingredient: 
Fibrinogen 
Date of Final Protocol: 
30-May-2017 
 
In-vivo recovery (IVR) 
IVR will be calculated for the first infusion of each bleeding episode. Descriptive tables 
will show the distributions of the IVR, separated by minor and major bleeding events. 
Haemostatic efficacy in the treatment of all bleeding episodes 
In addition to the ‘first BE per patient approach’ (primary endpoint), success rates will be 
presented with two-sided 95% confidence intervals for all documented bleeding episodes, 
both considering each bleeding episode as an independent case within each subject and 
considering outcomes of assessments as repeated measurements within the same patient, if 
applicable (e.g., by general estimation equations with intra-subject correlation structure). 
Surgical prophylaxis 
Efficacy of Octafibrin in surgical prophylaxis will be assessed intra-operatively (at the end 
of surgery = after last suture) by the surgeon and post-operatively by the haematologist 
using two 4-point efficacy scales. The overall surgical efficacy will be adjudicated by the 
IDMEAC and summarised using descriptive statistics. 
Safety analysis: 
Safety parameters will be descriptively summarised. 
Interim analysis 
An administrative interim analysis will be performed after at least 12 patients have under- 
gone PK assessment within the study. The interim analysis will focus on the PK data only. 

Study Protocol 
No. FORMA-04 
CONFIDENTIAL 
Version 4.0 
30-May-2017 
xxii 
 
 
 
FLOW CHART OF ASSESSMENTS FOR ON-DEMAND TREATMENT OF ACUTE BLEEDING 
Screening 
14-day PK Phase within 14 days after screening [j] 
On Demand Bleeding - OBSERVATION AND FOLLOW-UP PERIOD 
Study 
Completion 
Visit 
Day 1 
All study days after Day 1 
TREATMENT OBSERVATION 
PERIOD 
(at least 3 days for minor bleeding, 
7 days for major bleeding) 
Day of 
Last Infusion 
24 hours 
(i.e., 1 day) 
after last 
infusion 
Day 30 
(± 1 week) 
Pre- 
infusion 
Post-infusion 
Daily 
Pre- 
infusion [a] 
1 h post- 
infusion [a] 
(± 15 min) 
Pre- 
infusion 
1 h post- 
infusion 
(± 15 min) 
or end of the 
observation 
period 
1 h 
(± 15 min) 
3 h 
(± 15 min) 
Eligibility and informed consent 
x 
# 
Demography 
x 
Medical history, review of previous therapy 
x 
x 
Physical examination 
x 
x 
x 
x 
Vital signs 
x 
x 
x 
x 
x 
x 
TEE questionnaire 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Height and weight 
x 
Characterisation of bleeding episode 
x 
Blood draw for: 
Fibrinogen activity 
x [b,c,d] 
x [c,d] 
x [d] 
x [c,d] 
x [b,c,d] 
x [c,d] 
x [b,c,d] 
x [c,d] 
x [d] 
Fibrinogen antigen 
x [b,d] 
x [d] 
x [d] 
x [d] 
x [b,d] 
x [d] 
x [b,d] 
x [d] 
x [d] 
MCF [d] 
x [b] 
x 
Thrombogenicity [d] 
x 
x 
x 
x 
Immunogenicity [d] 
x 
x 
Safety lab (haematology and clinical chemistry) [c] 
x 
x [i] 
Retention serum samples [e] 
x 
Infusion of Octafibrin 
x [f] 
x [f,g] 
x 
Final haemostatic efficacy assessment 
x 
AEs [h] 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
Concomitant medications 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
Medical history since last study visit 
x 
TEE = thromboembolic event; AE = adverse event; MCF = Maximum clot firmness (clot strength). 
# To be re-reviewed if period between screening and treatment is more than 3 months. 
[a] If, based on the daily assessment, the investigator considers an additional infusion of Octafibrin necessary (see footnote f). 
[b] Within 30 minutes before infusion. 
[c] Measured in local laboratories. 
[d] Measured in the central laboratory. 
[e] Serum retention sample for potential viral testing. 
[f] If the Octafibrin infusion administered on this day is deemed the only infusion needed for treatment of the subject's bleeding event, 
the post-infusion assessments as detailed in the more comprehensive schedule for the Day of Last Infusion must be performed. 
[g] If the actual fibrinogen plasma level is below the accepted lower limit of the target fibrinogen plasma level, the subject should receive another infusion of Octafibrin. 
If the fibrinogen plasma level is greater than or equal to the accepted lower limit of the target fibrinogen plasma level, Octafibrin should not be administered. 
[h] Including thromboembolic events or hypersensitivity reactions. 
[i] Haematology only. 
[j] Retention serum sample taken before PK infusion; PK infusion of 70 mg/kg of Octafibrin; subsequent blood sampling (see separate PK flow chart) (if not previously performed prior to a surgical procedure). 

Study Protocol 
No. FORMA-04 
CONFIDENTIAL 
Version 4.0 
30-May-2017 
xxiii 
 
 
 
FLOW CHART OF ASSESSMENTS FOR SURGICAL PROPHYLAXIS 
Screening 
14-day PK Phase within 14 days after screening [j] 
SURGICAL OBSERVATION PERIOD 
Study 
Completion 
Visit 
Before surgery 
Day 1 
Surgery 
Any POP day 
(i.e., up to and excluding either 
Day 4 for minor 
and Day 8 for major surgery 
or the day of the last 
post-operative infusion, 
whichever comes later) 
Last POP Day 
(i.e., either Day 4 for minor 
and Day 8 for major surgery 
or the day of the last 
post-operative infusion, 
whichever comes later) 
Within 12 h 
before start 
Within 3 h 
before start 
Start 
Intra- 
operative 
End 
Daily [i] 
Pre- 
infusion 
1 h post- 
infusion 
(± 15 min) 
Daily [i] 
Pre- 
infusion 
1 h post- 
infusion 
(± 15 min) 
Eligibility and informed consent 
x 
# 
Demography 
x 
Medical history, review of previous therapy 
x 
x 
Details of surgery (location, type, severity) 
x 
Estimated blood loss, duration of surgery, transfusion requirements 
x 
Any planned ancillary therapy during the surgery (e.g., antifibrinolytics) 
x 
Actual duration of surgery 
x 
Details of hospitalisation and follow-up (narrative) 
x 
Actual blood loss and transfusion requirements 
x 
Physical examination 
x 
x 
Vital signs 
x 
x 
x 
x 
x 
TEE questionnaire 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Body weight 
x 
Blood draw for: 
Fibrinogen activity 
x [a,b,c] 
x [a,b,c] 
x [b,c] 
x [b,c] 
x* [b,c] 
x [b,c] 
x [b,c] 
x* [b,c] 
x [b,c] 
Fibrinogen antigen 
x [a,c] 
x [a,c] 
x [c] 
x [c] 
x [c] 
x [c] 
x [c] 
x [c] 
x [c] 
Safety lab (haematology and clinical chemistry) [b] 
x 
x 
x 
Infusion of Octafibrin 
x 
x** 
x [e] 
x [e] 
Haemostatic efficacy assessments (intra- and postoperative) 
x [f] 
x [g] 
Wound haematomas and oozing 
x 
x 
Narrative of outcome 
x 
AEs [h] 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
Concomitant medications 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
Medical history since last study visit 
x 
TEE = thromboembolic event; AE = adverse event; POP = postoperative. 
* ≤ 30 minutes before each infusion of Octafibrin. 
** If considered necessary. 
# To be re-reviewed if period between screening and treatment is more than 3 months. 
[a] ≤30 minutes before and after each infusion of Octafibrin . 
[b] Measured in local laboratories. 
[c] Measured in central laboratory. 
[d] Plasma retain sample for potential retesting; serum retain sample for potential viral testing. 
[e] If the actual fibrinogen plasma level is below the accepted lower limit of the target fibrinogen plasma level, the subject should receive another infusion of Octafibrin. 
If the fibrinogen level is greater than or equal to the accepted lower limit of the the target fibrinogen level, Octafibrin should not be administered. 
[f] Intraoperative efficacy assessment by surgeon. 
[g] Postoperative efficacy assessment by haematologist. 
[h] Including thromboembolic events and hypersensitivity reactions. 
[i] Only if no infusions given. 
[j] Retention serum sample taken before PK infusion; PK infusion of 70 mg/kg of Octafibrin; subsequent blood sampling (see separate PK flow chart) (if not previously performed prior to a bleeding episode). 

Study Protocol 
No. FORMA-04 
CONFIDENTIAL 
Version 4.0 
30-May-2017 
xxiv 
 
 
 
 
FLOW CHART OF ASSESSMENTS FOR PK PHASE 
 

 
 
 
 
 
 
 
 
 
 
Study Protocol 
No. FORMA-04 
CONFIDENTIAL 
Version4.0 
30-May-2017 
 
PROTOCOL SIGNATURES 
 
 
This study is intended to be conducted in compliance with the protocol, 
Good Clinical Practice, and the applicable regulatory requirements. 
 
Signature of the Sponsor's Representative 
 
 
 
 
 
Dr. Cristina Solomon, MBA 
Senior Director, CR&D Haematology 
Octapharma AG 
Seidenstrasse 2 
8853 Lachen 
Switzerland 
 
 
 
 
 
 
 
 
Signatures of the 
 
 
Signature 
Date 
Clinical Project Manager and Biostatistician 
// /1 
/>/ 
 
 
 
Bruce A. Schwartz, PhD 
Director, CR&D Haematology 
Octapharma USA 
121 River Street, Suite 1201 
.i ,Vy 
Signature 
Date 
 
 
Biostatistician 
Accovion GmbH 
Softwarecenter 3 
D-35037 Marburg, 
Germany 
// 
./ Signature 
Date 
 
 
 
 
 
 
 
Page 1 
Hoboken, NJ 07030 
USA 
Heinz-Otto Keinecke, MSc 

Study Protocol 
No. FORMA-04 
CONFIDENTIAL 
Version 4.0 
30-May-2017 
Page 2 
 
 
 
TABLE OF CONTENTS 
1 
INTRODUCTION ............................................................................................................ 8 
1.1 
BACKGROUND ........................................................................................................................................... 8 
1.2 
OCTAFIBRIN ............................................................................................................................................... 8 
1.3 
RATIONALE FOR CONDUCTING THE STUDY .................................................................................... 9 
1.4 
DOSE RATIONALE .................................................................................................................................... 9 
1.5 
BENEFIT-RISK STATEMENT ................................................................................................................ 10 
2 
STUDY OBJECTIVES .................................................................................................. 11 
2.1 
PRIMARY OBJECTIVE ............................................................................................................................ 11 
2.2 
SECONDARY OBJECTIVES .................................................................................................................... 11 
3 
INVESTIGATIONAL PLAN ........................................................................................ 12 
3.1 
PRIMARY AND SECONDARY ENDPOINTS ........................................................................................ 12 
3.1.1 
Primary Endpoint ...................................................................................................... 12 
3.1.2 
Secondary Endpoints ................................................................................................ 12 
3.1.2.1 
Secondary PK Endpoints ............................................................................ 12 
3.1.2.2 
Secondary Efficacy Endpoints .................................................................... 12 
3.1.2.3 
Safety Endpoints ......................................................................................... 13 
3.2 
OVERALL STUDY DESIGN AND PLAN .............................................................................................. 13 
3.2.1 
Pharmacokinetics Assessment ................................................................................... 14 
3.2.2 
On-demand Treatment of Acute Bleeding ................................................................. 15 
3.2.3 
Surgical Prophylaxis ................................................................................................. 16 
3.3 
DISCUSSION OF STUDY DESIGN AND CHOICE OF CONTROL GROUP(S) ......................... 17 
4 
STUDY POPULATION ................................................................................................. 18 
4.1 
POPULATION BASE ................................................................................................................................ 18 
4.2 
INCLUSION CRITERIA ............................................................................................................................ 18 
4.3 
EXCLUSION CRITERIA .......................................................................................................................... 18 
4.4 
PRIOR AND CONCOMITANT THERAPY ............................................................................................. 19 
4.4.1 
Permitted Concomitant Therapy ............................................................................... 19 
4.4.2 
Forbidden Concomitant Therapy .............................................................................. 20 
4.5 
WITHDRAWAL AND REPLACEMENT OF SUBJECTS ...................................................................... 20 
4.5.1 
Premature Subject Withdrawal ................................................................................. 20 
4.5.2 
Subject Replacement Policy ...................................................................................... 20 
4.6 
ASSIGNMENT OF SUBJECTS TO TREATMENT GROUPS ................................................................ 20 
4.7 
RELEVANT PROTOCOL DEVIATIONS ................................................................................................ 21 
4.8 
SUBSEQUENT THERAPY ....................................................................................................................... 21 
5 
INVESTIGATIONAL MEDICINAL PRODUCT....................................................... 22 
5.1 
CHARACTERISATION OF INVESTIGATIONAL PRODUCT .............................................................. 22 
5.2 
PACKAGING AND LABELLING ............................................................................................................ 22 
5.3 
CONDITIONS FOR STORAGE AND USE ............................................................................................. 22 
5.4 
DOSE AND DOSING SCHEDULE .......................................................................................................... 22 
5.4.1 
PK Dose Schedule and Mode of Administration ....................................................... 23 
5.4.2 
Octafibrin Treatment Dose Calculation.................................................................... 23 
5.4.3 
Dosing for On-demand Treatment of Bleeding ......................................................... 23 
5.4.4 
Dosing for Surgery .................................................................................................... 24 

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5.5 
PREPARATION AND METHOD OF ADMINISTRATION ................................................................... 25 
5.5.1 
Preparation ................................................................................................................25 
5.5.2 
Method of Administration ..........................................................................................25 
5.6 
BLINDING, EMERGENCY ENVELOPES, AND BREAKING THE STUDY BLIND ........................ 25 
5.7 
DRUG DISPENSING AND ACCOUNTABILITY .................................................................................. 25 
5.8 
ASSESSMENT OF TREATMENT COMPLIANCE ................................................................................ 25 
6 
STUDY CONDUCT ....................................................................................................... 26 
6.1 
OBSERVATIONS PERFORMED THROUGHOUT THE STUDY ......................................................... 26 
6.1.1 
Screening Assessments ...............................................................................................26 
6.1.2 
Assessments During the PK Phase .............................................................................26 
6.1.3 
Assessments in Subjects Undergoing On-demand Treatment of Bleeding .................27 
6.1.3.1 
Day 1 (first day of treatment) ..................................................................... 27 
6.1.3.2 
All Study Days after Day 1 (Treatment Observation Period) ..................... 29 
6.1.3.3 
Last Infusion or End of the Observation Period (whichever 
comes last) .................................................................................................. 30 
6.1.3.4 
Day 30 (29 Days after the First Infusion)—Final Examination ................. 31 
6.1.4 
Assessments in Subjects Undergoing Surgical Prophylaxis ......................................31 
6.1.4.1 
Day 1 .......................................................................................................... 33 
6.1.4.2 
Any Post-Operative Day before the Last Post-Operative Day ................... 34 
6.1.4.3 
Last Post-Operative Day ............................................................................. 35 
6.1.5 
Study Completion Visit ...............................................................................................35 
6.2 
DURATION OF STUDY ........................................................................................................................... 36 
6.2.1 
Planned Duration for the Study as a Whole ...............................................................36 
6.2.2 
Planned Duration for an Individual Subject ..............................................................36 
6.2.3 
Premature Termination of the Study ..........................................................................36 
7 
ASSESSMENTS AND METHODS .............................................................................. 38 
7.1 
BACKGROUND AND SCREENING INFORMATION .......................................................................... 38 
7.2 
EFFICACY ASSESSMENTS .................................................................................................................... 38 
7.2.1 
Assessments for Primary Efficacy Endpoint ..............................................................38 
7.2.2 
Assessments for Secondary Endpoints .......................................................................39 
7.2.2.1 
Pharmacokinetics ........................................................................................ 39 
7.2.2.2 
Clot Strength ............................................................................................... 39 
7.2.2.3 
Recovery ..................................................................................................... 40 
7.2.2.4 
Surgical Prophylaxis ................................................................................... 40 
7.3 
LABORATORY ASSESSMENTS ............................................................................................................ 42 
7.3.1 
Blood Sampling ..........................................................................................................42 
7.3.2 
Citrated Plasma .........................................................................................................43 
7.3.3 
EDTA Blood ...............................................................................................................43 
7.3.4 
Serum .........................................................................................................................43 
7.3.5 
Recording of Clinically Significant Abnormal Laboratory Values as AEs/ADRs ......43 
7.4 
SAFETY ASSESSMENTS ......................................................................................................................... 44 
7.4.1 
Adverse Events (AEs) .................................................................................................44 
7.4.1.1 
Definitions .................................................................................................. 44 
7.4.1.2 
Collection of AEs ....................................................................................... 45 
7.4.1.3 
Severity of AEs ........................................................................................... 45 
7.4.1.4 
Causality of AEs ......................................................................................... 46 
7.4.1.5 
Classification of ADRs ............................................................................... 46 
7.4.1.6 
Outcome of AEs ......................................................................................... 46 
7.4.1.7 
Action(s) Taken .......................................................................................... 47 
7.4.2 
Serious Adverse Events ..............................................................................................47 

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7.4.3 
SAE Reporting Timelines .......................................................................................... 48 
7.5 
VITAL SIGNS AND PHYSICAL EXAMINATION, INCLUDING THROMBOEMBOLIC EVENT 
(TEE) QUESTIONNAIRE ....................................................................................................................... 49 
7.6 
OTHER RELEVANT SAFETY INFORMATION ................................................................................... 49 
7.6.1 
Post-study Related Safety Reports .............................................................................49 
7.6.2 
Overdose, Interaction, Misuse, Medication Error .....................................................49 
7.7 
OTHER ASSESSMENTS .......................................................................................................................... 50 
7.8 
APPROPRIATENESS OF MEASUREMENTS ........................................................................................ 50 
8 
DATA HANDLING AND RECORD KEEPING ......................................................... 51 
8.1 
SOURCE DATA AND RECORDS ........................................................................................................... 51 
8.2 
CASE REPORT FORMS ........................................................................................................................... 51 
8.3 
CHANGES TO CASE REPORT FORM DATA ...................................................................................... 51 
8.4 
INFORMATION OF INVESTIGATORS ................................................................................................... 52 
8.5 
RESPONSIBILITIES .................................................................................................................................. 52 
8.5.1 
Co-ordinating Investigator ........................................................................................53 
8.5.2 
External Parties ........................................................................................................ 53 
8.6 
INVESTIGATOR’S SITE FILE ................................................................................................................ 53 
8.7 
PROVISION OF ADDITIONAL INFORMATION .................................................................................. 54 
8.8 
INDEPENDENT DATA MONITORING & ENDPOINT ADJUDICATION COMMITTEE ............... 54 
9 
STATISTICAL METHODS AND SAMPLE SIZE ..................................................... 55 
9.1 
SAMPLE SIZE ........................................................................................................................................... 55 
9.2 
POPULATIONS FOR ANALYSIS ............................................................................................................ 55 
9.2.1 
Safety Population .......................................................................................................55 
9.2.2 
Full Analysis Set ....................................................................................................... 55 
9.2.3 
PK Analysis Population ............................................................................................ 56 
9.2.4 
PK-PP Population .................................................................................................... 56 
9.2.5 
FirstBLEED Population ............................................................................................ 56 
9.2.6 
FirstBLEED-PP Population ..................................................................................... 56 
9.2.7 
BLEED Population ................................................................................................... 57 
9.2.8 
BLEED-PP Population ............................................................................................. 57 
9.2.9 
SURG population ...................................................................................................... 57 
9.2.10 Subpopulations .......................................................................................................... 57 
9.3 
EFFICACY ANALYSIS PLAN ................................................................................................................ 58 
9.3.1 
Primary Endpoint ...................................................................................................... 58 
9.3.2 
Secondary Endpoints ................................................................................................ 58 
9.3.2.1 
Pharmacokinetics (PK) ............................................................................... 58 
9.3.2.2 
Clot strength (MCF) ................................................................................... 59 
9.3.2.3 
In-vivo recovery ......................................................................................... 59 
9.3.2.4 
Efficacy of Octafibrin in All Bleeding Episodes ........................................ 60 
9.3.2.5 
Surgical Prophylaxis ................................................................................... 60 
9.4 
SAFETY ANALYSIS PLAN ..................................................................................................................... 61 
9.5 
ADDITIONAL ANALYSES ...................................................................................................................... 62 
9.6 
HANDLING OF MISSING DATA ........................................................................................................... 62 
9.7 
RANDOMISATION ................................................................................................................................... 62 
9.8 
INTERIM ANALYSIS ............................................................................................................................... 62 
10 ETHICAL, REGULATORY, LEGAL AND ADMINISTRATIVE ASPECTS ........ 63 
10.1 ETHICAL AND REGULATORY FRAMEWORK ................................................................................... 63 
10.2 APPROVAL OF STUDY DOCUMENTS ................................................................................................. 63 

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10.3 SUBJECT INFORMATION AND INFORMED CONSENT ................................................................... 63 
10.4 PROTOCOL AMENDMENTS .................................................................................................................. 64 
10.5 CONFIDENTIALITY OF SUBJECTS DATA .......................................................................................... 64 
11 QUALITY CONTROL AND QUALITY ASSURANCE ............................................ 65 
11.1 PERIODIC MONITORING ....................................................................................................................... 65 
11.2 AUDIT AND INSPECTION ...................................................................................................................... 65 
12 REPORTING AND PUBLICATION ........................................................................... 66 
12.1 CLINICAL STUDY REPORT ................................................................................................................... 66 
12.2 PUBLICATION POLICY........................................................................................................................... 66 
13 LIABILITIES AND INSURANCE ............................................................................... 67 
14 REFERENCES ............................................................................................................... 68 
15 APPENDICES ................................................................................................................. 70 

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LIST OF ABBREVIATIONS 
 
AE 
Adverse event 
ADR 
Adverse drug reaction 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
BLEED 
Analysis population of all treated bleeding episodes 
b.w. 
Body weight 
CI 
Confidence interval 
Cl 
Clearance 
Cmax 
Maximum concentration 
CRF 
Case report form 
CRO 
Contract research organisation 
EMA 
European Medicines Agency 
EU 
European Union 
FAS 
Full analysis set 
FirstBLEED 
Analysis population of subjects with at least one treated bleeding episode 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GLP 
Good Laboratory Practice 
HAV 
Hepatitis A virus 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
IDMEAC 
Independent Data Monitoring & Endpoint Adjudication Committee 
IEC 
Independent Ethics Committee 
IMP 
Investigational medicinal product 
IRB 
Institutional Review Board 
ITT 
Intention-to-treat 
IVR 
In vivo recovery 
MCF 
Maximum clot firmness (‘clot strength’) 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRT 
Mean residence time 
PCR 
Polymerase chain reaction 
PK 
Pharmacokinetic(s) 
PP 
Per protocol 
SAE 
Serious adverse events 
SD 
Standard deviation 
SOC 
System organ class 
SOP 
Standard Operating Procedure 
SURG 
Analysis population of all surgeries with IMP prophylaxis/treatment 
t1/2 
Half-life 

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TEE 
Thromboembolic event 
TEM 
Thromboelastometry 
Tmax 
Time of maximum concentration 
US 
United States 
Vss 
Volume of distribution at steady state 
WFI 
Water for injection 
WNV 
West Nile virus 

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1 INTRODUCTION 
 
1.1 Background 
Human fibrinogen is a plasma glycoprotein synthesised in the liver, and it circulates in the 
plasma at a concentration of 2.9–4.5 g/L. In healthy human adults, about 2–5 g of fibrinogen is 
synthesised daily, and the same amount is catabolised [1, 2]. Fibrinogen is essential for haemo- 
stasis, wound healing, fibrinolysis, inflammation, angiogenesis, cellular and matrix interac- 
tions, and neoplasia. These processes involve the conversion of fibrinogen into fibrin, and often 
the interaction of fibrinogen with various proteins and cells. The plasma half-life of fibrinogen, 
under normal physiological conditions, has been estimated to be 3–5 days [3, 4]. 
The plasma level of clottable fibrinogen may be markedly decreased or even undetectable in 
various congenital or acquired conditions [5, 6]. Conditions of congenital fibrinogen deficiency 
include: 
• Afibrinogenaemia: Complete absence or extremely low levels of plasma fibrinogen 
• Hypofibrinogenaemia: Reduced concentration of plasma fibrinogen 
• Dysfibrinogenaemia: Presence of abnormal or dysfunctional fibrinogen molecules 
Congenital afibrinogenaemia is a rare inherited autosomal recessive disorder occurring in ho- 
mozygotic patients with an estimated incidence of 1 in 106 in the European population [7]. The 
disease is characterised by a complete lack of coagulable and/or immunologically determinable 
fibrinogen in the plasma. Patients present with frequent severe bleeding episodes since birth or 
early childhood [8, 9]. Bleeding may occur after a minor trauma or a small surgical intervention, 
into the skin, mucosa, muscles, gastrointestinal tract, or the brain. 
Congenital hypofibrinogenaemia is more common than afibrinogenaemia and is characterised 
by low but measurable fibrinogen plasma levels. Clinical symptoms of hypofibrinogenaemia 
are usually milder compared to afibrinogenaemia, and the condition is frequently combined 
with a dysfibrinogenaemia that is characterised by an abnormal fibrinogen variant. Several mis- 
sense mutations in the 3 fibrinogen genes have been identified as the cause of dysfibrinogenae- 
mia and hypofibrinogenaemia that lead to abnormal gene expression resulting in the decreased 
fibrinogen concentration or dysfunctional fibrinogen molecules. 
Therapeutic substitution with human fibrinogen concentrate can correct the haemostatic defect 
and arrest bleeding in patients with these fibrinogen deficiencies [5, 7, 9, 10, 11]. 
 
1.2 Octafibrin 
Octafibrin is a highly purified, lyophilised, human plasma fibrinogen concentrate, without 
added albumins. Octafibrin is double virus inactivated using 2 dedicated virus inactivation/re- 
moval steps, i.e., solvent/detergent treatment and nanofiltration. 
Solvent/detergent treatment mode of action causes enveloped viruses to be irreversibly de- 
stroyed. These include the most transfusion-relevant viruses, such as human immunodeficiency 
virus types l and 2 (human immunodeficiency virus [HIV]-1, HIV-2), hepatitis B virus (HBV) 
and hepatitis C virus (HCV), but also many other adventitious agents, e.g., newly emerging 
viruses that are enveloped, such as West Nile virus (WNV).The Planova 20N filter was specif- 

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ically developed by Asahi Kasei Pharma Corp. to remove infectious agents from protein solu- 
tions on the basis of their size. Thus, this nanofiltration step is in principle effective for remov- 
ing even very small enveloped and non-enveloped viruses. Nanofiltration may be the only 
method to date permitting efficient removal of enveloped and non-enveloped viruses under 
conditions where 90-95% of protein activity is recovered [12]. 
 
1.3 Rationale for Conducting the Study 
It is estimated that there are 500 to 1000 patients with congenital fibrinogen deficiency in the 
European Union (EU). Historically, the principal source for the treatment of congenital fibrin- 
ogen deficiency has been cryoprecipitate [7]. Plasma-derived and viral-inactivated fibrinogen 
concentrates are proven to be safer and more specific in the treatment of congenital fibrinogen 
deficiency compared to cryoprecipitate [13]. 
The introduction of Octafibrin will present an additional and safe option, providing more 
choices of supply for the benefit of the medical community and patients affected by congenital 
fibrinogen deficiency. 
This phase III study is designed as a multinational, multi-centre, prospective, open-label, un- 
controlled study to assess the efficacy, safety, and pharmacokinetics of Octafibrin for on-de- 
mand treatment of acute bleeding in paediatric subjects with congenital fibrinogen de-ficiency. 
As there are currently no guidelines concerning fibrinogen concentrates in either the United 
States (US) or the EU, this pivotal study was designed following the European Medicines 
Agency (EMA) Guideline on the Clinical Investigation of Recombinant and Human Plasma- 
Derived Factor IX Products (CHMP/BPWP/144552/2009) [14] and discussions with the Paul 
Ehrlich Institute and the Paediatric Committee (PDCO) of the EMA. 
 
1.4 Dose Rationale 
The dose rationale is based on published data from an assessment survey based upon the data 
obtained in 100 a- or hypofibrinogenaemic patients [15]. Based on this representative sample 
(53 males and 47 females with median fibrinogen plasma level of 6 mg dL-1), the peak fibrino- 
gen plasma level most often recommended for on-demand treatment of minor bleeding was 
approximately 100 mg/dL, but the target level for major episodes, such as central nervous sys- 
tem bleeding, was higher (150 mg/dL). Minor episodes, like epistaxis, gum bleeding, menor- 
rhagia, were usually treated with target peaks of 50 to 70 mg/dL. Duration of treatment ranged 
from 1 to 2 weeks for major events, from 1 to 7 days for minor events. Minor surgeries were 
treated for up to 7 days with a target fibrinogen plasma level of 100 mg/dL. Major surgeries 
were treated for 4 to 14 days with a target fibrinogen plasma level of 150 mg/dL. 

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1.5 Benefit-Risk Statement 
Effective management of congenital fibrinogen deficiencies in bleeding situations is necessary 
for the prevention of potentially life-threatening bleeding episodes. 
Studies consistently showed that fibrinogen substitution was able to successfully control bleed- 
ing, increase fibrinogen plasma levels, and reduce the amount of transfusions needed with al- 
logeneic blood products. In addition, it was shown to be well tolerated and to have a very good 
overall safety profile. 
Provided that the pharmacokinetic (PK) values are in the same range as for the already licensed 
fibrinogen concentrate, Octafibrin is expected to be efficacious in the treatment of congenital 
fibrinogen deficiency. 
As known for other fibrinogen plasma-derived concentrates, the following adverse reactions 
may occur with the use of Octafibrin: 
1. Hypersensitivity or allergic reactions 
Observed symptoms may include hives, generalised urticaria, tightness of the chest, wheez- 
ing, and hypotension. These reactions may progress to severe anaphylaxis, including shock. 
2. Thromboembolic events 
Such events have been reported in patients treated with plasma-derived fibrinogen concen- 
trates. Thus, patients receiving Octafibrin should be monitored for signs and symptoms of 
thrombosis. 
3. Infections caused by medicinal products prepared from human blood or plasma Stand- 
ard measures to prevent these infections include the selection of donors, screening of indi- 
vidual donations and plasma pools for specific markers of infection, and the inclusion of 
effective manufacturing steps for the inactivation/removal of viruses. Despite this, when 
medicinal products prepared from human blood or plasma are administered, the possibility 
of transmitting infective agents cannot be totally excluded. This also applies to unknown or 
emerging viruses and other pathogens. The measures taken are considered effective for en- 
veloped viruses, such as HIV, HBV, and HCV, and for the non-enveloped hepatitis A virus 
(HAV). The measures taken may be of limited value against non-enveloped viruses, such 
as parvovirus B19. 
In conclusion, there is no reason to believe that participation in this study presents the subjects 
with any greater risk of viral transmission or thrombosis than treatment with currently marketed 
products. The manufacturing process of Octafibrin, which includes 2 viral inactivation steps 
with different chemical/physical action principles, represents a high standard for plasma-de- 
rived concentrates in terms of viral safety. 

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2 STUDY OBJECTIVES 
 
2.1 Primary Objective 
The primary objective is to demonstrate the efficacy of Octafibrin for on-demand treatment of 
acute bleeding episodes (spontaneous or after trauma). 
 
2.2 Secondary Objectives 
The secondary objectives are: 
• To determine the single-dose pharmacokinetics of Octafibrin in paediatric subjects with 
congenital fibrinogen deficiency 
• To investigate an association between the overall clinical assessment of haemostatic effi- 
cacy and the surrogate endpoint ‘clot strength’ or ‘clot firmness’ (referred to as ‘maximum 
clot firmness’ [MCF] in this protocol) that was used as a surrogate endpoint for haemostatic 
efficacy and determined via thromboelastometry (ROTEM) in the pivotal PK study 
FORMA-01. Therefore, MCF as surrogate efficacy parameter will be determined before 
and after the first infusion of IMP for treatment of a bleeding episode. 
• To achieve  a peak target plasma fibrinogen level of 100 mg/dL in minor bleeds and     
150 mg/dL for major bleeds 1 hour post-infusion 
• To determine the response to Octafibrin based on incremental in vivo recovery (IVR) 
• To demonstrate the efficacy of Octafibrin in preventing bleeding during and after surgery 
• To assess the safety of Octafibrin in subjects with congenital fibrinogen deficiency, includ- 
ing immunogenicity, thromboembolic complications, and early signs of allergic or hyper- 
sensitivity reactions 

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3 INVESTIGATIONAL PLAN 
 
3.1 Primary and Secondary Endpoints 
 
3.1.1 Primary Endpoint 
The primary endpoint is the overall clinical assessment of the haemostatic efficacy of Oc- 
tafibrin in treating the first documented bleeding episode of each patient. 
The first bleeding episode covers the time period from the first Octafibrin infusion for the treat- 
ment of a bleeding episode until 24 hours (i.e., 1 day) after the last infusion or the end of the 
treatment observation period, whichever comes last. 
The investigator’s overall clinical assessment of haemostatic efficacy for bleeding will be based 
on a 4-point haemostatic efficacy scale as described in Section 7.2.1. The final efficacy assess- 
ment of each patient will be adjudicated by the Independent Data Monitoring & Endpoint Ad- 
judication Committee (IDMEAC). 
In the final analysis, the number of subjects per outcome category will be assessed. 
 
3.1.2 Secondary Endpoints 
 
3.1.2.1 Secondary PK Endpoints 
The following PK parameters will be assessed as secondary endpoints: 
• Area under the concentration-time curve (AUC) 
• Response: Incremental In Vivo Recovery (IVR) 
• Classical IVR 
• Terminal elimination half-life (t1/2) 
• Maximum plasma concentration (Cmax) 
• Time to reach maximum plasma concentration (Tmax) 
• Mean residence time (MRT) 
• Volume of distribution (Vss) 
• Clearance (Cl) 
 
3.1.2.2 Secondary Efficacy Endpoints 
The following efficacy parameters will be calculated as secondary endpoints: 
• MCF assessment before first infusion and 1 hour after end of first infusion of each docu- 
mented bleeding episode (see Section 7.2.2.2) 
• Fibrinogen plasma level before and 1 hour after the end of each subsequent infusion as well 
as at the time of the overall clinical assessment of haemostatic efficacy (i.e., 24 hours after 
the last infusion or end of the observation period of each documented bleeding episode) 

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• Response after the first infusion of each bleeding episode as indicated by incremental IVR, 
calculated as the maximum increase in plasma fibrinogen (Clauss data) between the pre- 
infusion and the 3-hour post-infusion measurement, divided by the exact dose of Octafibrin 
(expressed as mg/kg dosed) (see Section 7.2.2.3) 
• Efficacy of Octafibrin in all bleeding episodes collected in the study using the investigator’s 
overall clinical assessment of haemostatic efficacy for bleeding based on a 4-point haemo- 
static efficacy scale 
• Efficacy of Octafibrin in preventing bleeding during and after surgery as assessed at the end 
of surgery by the surgeon and post-operatively by the haematologist using two 4-point hae- 
mostatic efficacy scales (see Section 7.2.2.4). An overall efficacy assessment taking both 
the intra- and post-operative assessment into account will be adjudicated by the IDMEAC. 
The surgical observation period starts with the first dose of Octafibrin administered prior to 
elective surgery (Day 1) and, depending on the severity of the event, will last at least 3 post- 
operative days for minor and 7 post-operative days for major surgeries or until the day of 
the last post-operative infusion, whichever comes last. The number of subjects per outcome 
category will be assessed and will include at least 4 surgeries. 
 
3.1.2.3 Safety Endpoints 
The following safety parameters will be calculated as secondary safety endpoints: 
• Vital signs 
• Physical examination 
• Thromboembolic event (TEE) questionnaire 
• Routine clinical laboratory assessment, including coagulation parameters 
• Adverse events (AEs), including thromboembolic complications and early signs of allergic 
or hypersensitivity reactions 
• Thrombogenicity testing before and after each IMP infusion for the treatment of bleeding, 
except on the Day of Last Infusion 
• Immunogenicity testing before the first infusion of IMP and on Day 30 after the treatment 
of each bleeding episode 
 
3.2 Overall Study Design and Plan 
This is a multinational, multi-centre, prospective, open-label, uncontrolled, Phase III study to 
assess the efficacy, safety, and pharmacokinetics of Octafibrin for on-demand treatment of 
acute bleeding and surgical prophylaxis in paediatric subjects with congenital fibrinogen defi- 
ciency. 
At least 12 male or female paediatric subjects with congenital fibrinogen deficiency will be 
enrolled into the study and undergo PK assessment. Of these 12 subjects, at least 6 subjects will 
undergo on-demand treatment of 6 first bleeding episodes. Of these 6 subjects, at least 3 should 
be aged between 0 and <6 years and 3 should be aged between 6 and <12 years. In addition, at 
least 2 surgical procedures will be assessed. The study will be conducted in approximately     
5 study centres worldwide. 

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During the study observation period, enrolled patients will participate in a 14-day PK phase 
with administration of a single dose of Octafibrin and will subsequently be treated for any 
bleeding episodes or planned surgeries that can be managed under the protocol. Patients may 
remain in the study until at least 12 patients have undergone PK assessment, the 6th patient (at 
least 3 patients each in the specified age groups) has at least one documented bleeding episode, 
and a minimum of 2 surgical procedures have been performed. 
The study will be considered completed when a minimum of 12 subjects have undergone PK 
assessment, 6 subjects (at least 3 subjects aged between 0 and <6 years and 3 subjects aged 
between 6 and <12 years) have at least one documented bleeding episode, and at least 2 surgical 
procedures have been documented. The study as a whole should be completed within 5 years. 
As many bleeding episodes or surgeries as possible occurring throughout the study observation 
period will be documented. Only the first bleeding episodes will be used for the analysis of the 
primary endpoint. All bleeding episodes documented in the study will be assessed as a second- 
ary endpoint. 
The investigator will inform the monitor of any recruitment difficulty or delay of the anticipated 
completion date. 
Patients should be treated with the investigational medicinal product (IMP) whenever possible. 
If, in the opinion of the investigator, a bleeding episode is not effectively stopped or surgical 
prophylaxis is not adequate after the recommended dose of Octafibrin has been administered, 
the subject may receive a different licensed fibrinogen concentrate (e.g., Haemocomplettan 
P®/RiaSTAP™) or whatever the investigator considers standard of care. The use of another 
licensed fibrinogen concentrate is also permitted in emergency situations, e.g., if the IMP is not 
available for the patient in time. 
 
3.2.1 Pharmacokinetics Assessment 
Within 2 weeks after screening, subjects will receive a single infusion of 70 mg/kg Octafibrin. 
Before the start of the PK phase, there must be an at least 2-week wash-out period of any fi- 
brinogen containing product. 
Before first injection vital signs and blood draws for baseline fibrinogen levels will be assessed. 
Retention serum samples for potential retesting will be collected within 30 minutes before the 
PK infusion. At 1 and 3 hours post-infusion, vital signs and fibrinogen for PK will be assessed. 
Subjects will be further followed on days 2, 4, 7, 10, and 14 and undergo study assessments as 
specified. 
All adverse events (AEs), including thromboembolic events and early signs of allergic or hy- 
persensitivity reactions, occurring between the start of the first Octafibrin infusion and the end 
of the PK phase will be recorded. 
All SAEs occurring after the first IMP infusion will be documented and reported for a patient 
throughout the duration of the patient’s participation in the study or as required to meet local 
regulations. 
At the end of the study (i.e., when at least 12 patients have completed the PK assessment, 3 pa- 
tients in each of the specified age groups have had at least one treated bleeding episode, and a 
minimum of 2 surgical procedures have been performed), all patients having received any IMP 
will be asked to return for a Study Completion Visit. 

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3.2.2 On-demand Treatment of Acute Bleeding 
Subjects presenting to the study site for on-demand treatment of an acute bleeding episode who 
are eligible for enrolment and whose legal guardians have provided written informed consent 
will be included into the study. 
Each subject will receive at least 1 infusion of Octafibrin for the treatment of acute bleeding on 
Day 1. The individual subject observation and follow-up period for each documented episode 
starts with the first dose of Octafibrin administered for on-demand treatment of an acute bleed- 
ing episode (Day 1) and will be followed up to at least Day 30. 
Each subject’s treatment observation period is defined according to the severity of the event 
and will last at least 3 days for minor and 7 days for major bleeding episodes. 
On each day of the treatment observation period (i.e., 3 days for minor and 7 days for major 
bleeding), fibrinogen plasma levels will be measured daily to determine whether additional in- 
fusions of Octafibrin are needed: 
• Additional infusions of Octafibrin should be administered if the actual fibrinogen plasma 
level measured on these days is below the accepted lower limit of the target level (80 mg/dL 
for minor bleeding, 130 mg/dL for major bleeding). 
• If the actual fibrinogen plasma level is above the accepted lower limit of the target level, 
Octafibrin should not be administered. 
 
The actual treatment duration will be determined by the investigator based on his/her judgement 
of the subject’s condition. 
All adverse events (AEs), including thromboembolic events and early signs of allergic or hy- 
persensitivity reactions, occurring between the start of the first Octafibrin infusion and the end 
of each 30-day observation and follow-up period will be recorded. The detection of thrombo- 
embolic events (TEEs) will be supported by completing a TEE questionnaire at each study visit 
for the treatment of bleeding episodes and for surgeries. Concomitant medications will also be 
recorded throughout each 30-day observation and follow-up period. 
All SAEs occurring after the first IMP infusion will be documented and reported for a patient 
throughout the duration of the patient’s participation in the study or as required to meet local 
regulations. Also, any concomitant medications used to treat an SAE will be recorded. 
At the end of the study (i.e., when at least 3 patients in each of the specified age groups have 
had at least one treated bleeding episode and when a minimum of 2 surgical procedures have 
been performed) all patients having received any IMP will be asked to return for a Study Com- 
pletion Visit. 

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3.2.3 Surgical Prophylaxis 
Subjects planning to undergo elective surgery may also be enrolled in the study. 
Within 3 hours prior to surgery, each patient will receive a loading infusion of Octafibrin to 
achieve a recommended fibrinogen plasma level of  100  mg/dL  for  minor  surgeries  and 
150 mg/dL for major surgeries. 
Each subject’s surgical observation period starts with the first dose of Octafibrin administered 
prior to elective surgery (Day 1) and, depending on the severity of the event, will last at least 
3 post-operative days for minor and 7 post-operative days for major surgeries or until the day 
of the last post-operative infusion, whichever comes last. 
On each post-operative day, fibrinogen plasma levels will be measured daily (i.e., at least 3 
post-operative days for minor and 7 post-operative days for major surgeries) to determine 
whether additional infusions of Octafibrin are needed. 
• Additional infusions of Octafibrin should be administered if the actual fibrinogen plasma 
level measured on subsequent days is below the accepted lower limit of the target level 
(80 mg/dL for minor surgeries, 130 mg/dL for major surgery). 
• If the fibrinogen plasma level is greater than or equal to the accepted lower limit of the 
target fibrinogen plasma level, Octafibrin should not be administered. 
The actual treatment duration will be determined by the investigator based on his/her judgement 
of the subject’s condition. 
All AEs, including thromboembolic events and early signs of allergic or hypersensitivity reac- 
tions, occurring between first infusion of IMP before the start of surgery and the Last Post- 
Operative Day will be recorded. The detection of thromboembolic events (TEEs) will be sup- 
ported by completing a TEE questionnaire at each study visit for the treatment of bleeding 
episodes and for surgeries. 
All SAEs occurring after the first IMP infusion will be documented and reported for a patient 
throughout the duration of the patient’s participation in the study or as required to meet local 
regulations. Also, any concomitant medications used to treat an SAE will be recorded. 
At the end of the study (i.e., when at least 3 patients in each of the specified age groups have 
had at least one treated bleeding episode and when a minimum of 2 surgical procedures have 
been performed. All patients having received any IMP will be asked to return for a Study Com- 
pletion Visit. 

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3.3 Discussion of Study Design and Choice of Control Group(s) 
As there are currently no guidelines concerning fibrinogen concentrates in either the US or the 
EU, the study was designed following established programs for Factor IX concentrates. 
Typically, the clinical evaluation of a new concentrate initially examines the IVR and the PK 
properties of the principal active factor. Prior to initiating the present study, comparative PK 
data in adults were obtained in study FORMA-01. A study similar to the one described in this 
protocol, i.e., FORMA-04, is currently ongoing in adults patients (FORMA-02), the main dif- 
ference being the additional examination of PK properties in paediatric patients in FORMA-04. 
The open-label uncontrolled design and choice of study objectives are motivated by regulatory 
requirements for Factor IX [14] and discussions with the regulatory bodies. 
The median response value used in the fibrinogen dosage calculation is the median incremental 
in vivo recovery reported in the final analysis of study FORMA-01. 
Although all bleeding episodes occurring throughout the study observation period will be doc- 
umented, only the first bleeding episode per patient will be used for the analysis of the primary 
endpoint (see Section 3.1.1). This is because the study will end once at least 12 patients have 
undergone PK assessment and the 6th patient (i.e., at least 3 patients in each of the specified 
age groups) has at least one documented bleeding episode, potentially resulting in a large di- 
versity in the number of bleeding episodes between patients; also, the haemostatic outcomes in 
different bleeding episodes within one patient cannot be regarded as independent/uncorrelated. 
The entirety of bleeding episodes documented in the study will be assessed as a secondary 
endpoint (see Section 3.1.2). 

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4 STUDY POPULATION 
 
4.1 Population Base 
At least 12 paediatric subjects with clinically diagnosed congenital fibrinogen deficiency (i.e., 
afibrinogenaemia or severe hypofibrinogenaemia) will be enrolled into the study and undergo 
PK assessment. Of these 12 subjects, at least 6 subjects will undergo on-demand treatment of 6 
first bleeding episodes. Of these 6 subjects, at least 3 should be aged between 0 and <6 years 
and 3 should be aged between 6 and <12 years. 
 
4.2 Inclusion Criteria 
Subjects who meet all of the following criteria are eligible for the study: 
1. 
Aged <12 years (at the start of treatment) 
2. 
Documented diagnosis of congenital fibrinogen deficiency, expected to require on- 
demand treatment for bleeding or surgical prophylaxis: 
– Fibrinogen deficiency manifested as afibrinogenaemia or severe hypofibrinoge- 
naemia 
– Historical plasma fibrinogen activity of<50 mg/dL or levels below the limit of de- 
tection of the local assay method 
3. 
Expected to have an acute bleeding episode (spontaneous or after trauma) or planning 
to undergo elective surgery. 
4. 
Informed consent signed by the subject’s legal guardian 
 
4.3 Exclusion Criteria 
Subjects who meet any of the following criteria are not eligible for the study: 
1. 
Life expectancy <6 months 
2. 
Bleeding disorder other than congenital fibrinogen deficiency, including dysfibrino- 
genaemia 
3. 
Prophylactic treatment with a fibrinogen concentrate 
4. 
Treatment with: 
– Any fibrinogen concentrate or other fibrinogen-containing blood product within 
2 weeks prior to start of treatment for the PK phase, a bleeding episode, or surgery 
– Any coagulation-active drug (i.e., non-steroidal anti-inflammatory drugs, warfa- 
rin, coumarin derivatives, platelet aggregation inhibitors) within 1 week prior to 
start of the PK phase or treatment for the bleeding episode or surgery, or as a 
planned or expected medication during the time period from Day 1 until 24 hours 
(i.e., 1 day) after the last Octafibrin infusion 

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5. 
Presence or history of: 
– Hypersensitivity to study medication 
– Deep vein thrombosis or pulmonary embolism within 1 year prior to start of treat- 
ment for the bleeding episode or surgery 
– Arterial thrombosis within 1 year prior to start of treatment for the bleeding epi- 
sode or surgery 
– Hypersensitivity to human plasma proteins 
– Oesophageal varicose bleeding 
– End-stage liver disease (i.e., Child-Pugh score B or C) 
6. 
Known positive HIV infection with a viral load >200 particles/μL or >400,000 cop- 
ies/mL 
7. 
Polytrauma 1 year prior to start of treatment for the bleeding episode or surgery 
8. 
Diagnosis or suspicion of a neutralising anti-fibrinogen inhibitor currently or at any 
time in the past 
9. 
Acute or chronic medical condition which may, in the opinion of investigator, affect 
the conduct of the study, including subjects receiving immune-modulating drugs (other 
than anti-retroviral chemotherapy), such as alpha-interferon, prednisone (equivalent to 
>10 mg/day), or similar drugs, at study start 
10. Treatment with IMP in another interventional clinical study currently or during the 
past 4 weeks 
 
NOTE: If the period between screening and treatment or between treatments is more than 3 
months, informed consent will be re-reviewed and confirmed prior to treatment, and details of 
the review process will be recorded in the patient chart and indicated in the CRF by the inves- 
tigator. Also, inclusion/exclusion criteria will be confirmed prior to treatment. 
 
4.4 Prior and Concomitant Therapy 
 
4.4.1 Permitted Concomitant Therapy 
Concomitant administration of therapies not interfering with the primary objective of the study 
is permitted. Details of any concomitant therapies, including other fibrinogen concentrates, 
must be recorded in the case report forms (CRFs). 
Concomitant medications will be recorded only for each patient’s 30-day observation and fol- 
low-up period (for on-demand treatments) and during their surgical observation period (for 
treatment during surgeries). 
In addition, concomitant medications used to treat SAEs will be reported throughout the dura- 
tion of the patient’s participation in the study or as required to meet local regulations for SAE 
reporting. 

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Patients should be treated with IMP whenever possible. If, in the opinion of the investigator, a 
bleeding episode is not effectively stopped or surgical prophylaxis is not adequate after the 
recommended dose of Octafibrin has been administered, the subject may receive a different 
licensed fibrinogen concentrate (e.g., Haemocomplettan P®/RiaSTAP™) or whatever the in- 
vestigator considers standard of care. The use of another licensed fibrinogen concentrate is also 
permitted in emergency situations, e.g., if the IMP is not available for the patient in time. 
 
4.4.2 Forbidden Concomitant Therapy 
Subjects may not receive any coagulation-active drug (i.e., non-steroidal anti-inflammatory 
drugs, warfarin, coumarin derivatives, platelet aggregation inhibitors) within 1 week prior to 
start of treatment for the bleeding episode or surgery, or as a planned or expected medication 
during the time period from Day 1 until 24 hours after the last Octafibrin infusion. 
 
4.5 Withdrawal and Replacement of Subjects 
4.5.1 Premature Subject Withdrawal 
The subjects’ legal guardians have the right to withdraw the subject from the study at any time 
for any reason, without the need to justify their decision. The investigator also has the right to 
withdraw subjects in case of AEs, protocol violations, or other reasons. Since an excessive rate 
of withdrawal can render the study non-interpretable, the unnecessary withdrawal of subjects 
must be avoided. 
For any discontinuation after study entry, the investigator will obtain all the required details 
and document the reason(s) for discontinuation in the CRF. If the reason for withdrawal of a 
subject is an AE, the main specific event or laboratory test will be recorded in the CRF, and the 
investigator will make thorough efforts to clearly document the outcome. 
 
If possible, the Study Completion Visit should be performed. 
 
4.5.2 Subject Replacement Policy 
The study will recruit patients until a minimum of 12 subjects have undergone PK assessment, 
6 subjects (at least 3 subjects aged between 0 and <6 years and 3 subjects aged between 6 and 
<12 years) have at least one documented bleeding episode, and a minimum of 2 surgical pro- 
cedures have been documented. Patients with no documented bleeding episode, e.g., those only 
receiving PK treatment or those withdrawn for safety reasons before the first bleeding, will be 
replaced. 
 
4.6 Assignment of Subjects to Treatment Groups 
Not applicable. 

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4.7 Relevant Protocol Deviations 
In the case of any major protocol deviation or violation, the investigator and Octapharma will 
decide on the further participation of the subject in this study, after having discussed all relevant 
aspects. 
 
4.8 Subsequent Therapy 
In case the bleeding is not effectively stopped or surgical prophylaxis is deemed not to be ade- 
quate after the recommended Octafibrin dosing as judged by the investigator (see 
Section 5.4), the subject may receive a different licensed fibrinogen concentrate (e.g., Haemo- 
complettan P®/RiaSTAP™) or whatever the investigator considers standard of care. 

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5 INVESTIGATIONAL MEDICINAL PRODUCT 
 
5.1 Characterisation of Investigational Product 
Octafibrin is a human plasma-derived fibrinogen concentrate for intravenous use. Its ingredi- 
ents are listed in Table 1. 
 
Table 1: Composition of Octafibrin 
Ingredients 
Quantity per mL reconstituted so- 
lution, mean values 
Standard 
 
Active ingredient 
Fibrinogen as clottable protein 
20 mg 
Ph. Eur. 
Excipients 
Sodium chloride 
6 mg 
Ph. Eur. 
Sodium citrate dehydrate 
1.5 mg 
Ph. Eur. 
Glycine 
10 mg 
Ph. Eur. 
L-arginine hydrochloride 
10 mg 
Ph. Eur. 
Ph. Eur. = Pharmacopoea Europaea. 
 
Octafibrin is a powder for solution for injection supplied in labelled 100 mL vials to be recon- 
stituted with 50 mL sterile Water for Injection (WFI). 
Several batches of the product will be used in the study. The batch numbers will be reported in 
the final study report. 
The final product will be released by the responsible Octapharma Quality Control Department, 
according to a defined final product specification. 
 
5.2 Packaging and Labelling 
The open-label study design does not necessitate the blinding of study participants or study site 
personnel to treatment information. 
The IMP will be labelled according to GMP Annex 13. Final labelling and packaging will com- 
ply with the national requirements of each country where the study is to be conducted. 
 
5.3 Conditions for Storage and Use 
The IMP has to be stored at 2°C to 8°C and protected from light. The product must not be 
frozen. The investigator/authorised personnel at the site will ensure that the IMP is stored in 
appropriate conditions with restricted access and in compliance with national regulations. 
 
5.4 Dose and Dosing Schedule 
In this study, Octafibrin will be administered as intravenous (i.v.) bolus injection. Continuous 
infusion is not allowed. 

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5.4.1 PK Dose Schedule and Mode of Administration 
For PK assessments, subjects will receive a single intravenous infusion of 70 mg/kg body 
weight of Octafibrin. 
 
5.4.2 Octafibrin Treatment Dose Calculation 
Octafibrin will be individually dosed to achieve a recommended target fibrinogen plasma level 
dependent on the type of bleeding or surgery (minor or major). The dose will be calculated 
individually as follows: 
 
Fibrinogen dose 
= 
(mg/kg body weight) 
[Target peak plasma level (mg/dL) − measured level (mg/dL)**] 
Median response* (mg/dL per mg/kg body weight) 
*The median response in this dose calculation formula is the median incremental in vivo recovery reported for the PK 
of Octafibrin in the final analysis of study FORMA-01 which was calculated as 1.77 (g/L / mg/kg). 
**The measured level for the first infusion will be the historical level for that patient after a washout or, if below the 
limit of detection of the local assay, zero (0) will be used. 
 
5.4.3 Dosing for On-demand Treatment of Bleeding 
For each bleeding episode that is treated as part of the study, each subject will receive at least 
1 infusion of Octafibrin for the treatment of a major or minor acute bleeding episode on Day 1. 
Octafibrin will be individually dosed to achieve a recommended target fibrinogen plasma level 
dependent on the bleeding type (minor or major). 
• Minor bleeding will be treated to achieve a recommended target fibrinogen plasma level 
of 100 mg/dL and an accepted lower limit of 80 mg/dL. 
• Major bleeding will be treated to achieve a recommended target fibrinogen plasma level 
of 150 mg/dL and an accepted lower limit of 130 mg/dL. 
 
On subsequent study days, fibrinogen plasma levels will be measured daily to determine 
whether additional infusions of Octafibrin are needed: 
• Minor bleeding will be observed for at least 3 days. 
• Major bleeding will be observed for at least 7 days. 
Additional Octafibrin infusions, as required 
• Additional infusions of Octafibrin should be administered if the actual fibrinogen plasma 
level measured on subsequent study days is below the accepted lower limit of the target 
level (80 mg/dL for minor bleeding, 130 mg/dL for major bleeding). 
• If the actual fibrinogen plasma level is above the accepted lower limit of the target level, 
Octafibrin should not be administered. 

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Definition of minor and major bleeding 
• Minor bleeding events are defined as mild haemarthrosis or superficial muscle, soft tissue, 
and oral bleeding. 
• Major bleeding events are defined as symptomatic bleeding in a critical area or organ, such 
as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular, or pericardial bleed- 
ing, or intramuscular bleeding with compartment syndrome, or bleeding causing a decrease 
in haemoglobin level by 20 g/L (1.24 mmol/L) or more. 
Characterisation of any other bleeding events not within these categories will be discussed in- 
dividually with the investigator. 
 
5.4.4 Dosing for Surgery 
For each surgery that is treated as part of the study, within 3 hours prior to surgery, subjects 
will receive a loading infusion of Octafibrin. 
Octafibrin will be individually dosed to achieve a recommended target fibrinogen plasma level 
dependent on the surgery type (minor or major). 
• Patients undergoing minor surgery will be treated to achieve a recommended target fibrin- 
ogen plasma level of 100 mg/dL and an accepted lower limit of 80 mg/dL. 
• Patients undergoing major surgery will be treated to achieve a recommended target fibrin- 
ogen plasma level of 150 mg/dL and an accepted lower limit of 130 mg/dL. 
On each post-operative day, fibrinogen plasma levels will be measured daily to determine 
whether maintenance infusions of Octafibrin are needed. 
• Minor surgery will be observed for at least 3 post-operative days. 
• Major surgery will be observed for at least 7 post-operative days. 
Maintenance infusions, as required: 
• Additional infusions of Octafibrin should be administered if the actual fibrinogen plasma 
level measured on subsequent study days is below the accepted lower limit of the target 
level (80 mg/dL for minor surgery, 130 mg/dL for major bleeding). 
• If the actual fibrinogen plasma level is above the accepted lower limit of the target level, 
Octafibrin should not be administered. 
 
Definition of minor and major surgery 
Surgeries are defined as major, if any of the following criteria are met: 
• Requiring general or spinal anaesthesia 
• Requiring opening into the great body cavities 
• In the course of which hazards of severe haemorrhage is possible 
• Requiring haemostatic therapy for at least 6 days 
• Orthopaedic interventions involving joints (ankle, knee, hip, wrist, elbow, shoulder) 
• Surgeries/conditions in which the subject’s life is at stake 
Characterisation of any other surgery not within these categories and considered major by the 
investigator will be discussed individually with the investigator. 
All other surgeries are classified as minor. 

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The classification is made prospectively. 
 
5.5 Preparation and Method of Administration 
 
5.5.1 Preparation 
Each vial of Octafibrin will be reconstituted with 50 mL WFI. The solvent (i.e., WFI) and the 
concentrate in the closed vials must be warmed up to room temperature. Room temperature 
must be maintained during reconstitution. Octafibrin dissolves at room temperature to an almost 
colourless and slightly opalescent solution within 30 minutes. If the solution is cloudy or con- 
tains particulates, it should not be used. The solution should not be frozen. 
Octafibrin should be administered immediately after reconstitution at a rate not exceeding 5 mL 
per minute. Octafibrin should not be mixed with other medicinal products or intravenous solu- 
tions. 
 
5.5.2 Method of Administration 
Octafibrin will be administered as intravenous (i.v.) bolus injection not exceeding an injection 
rate of 5 mL per minute. 
NOTE: In this study, only bolus injections of Octafibrin are permitted. Continuous infusion 
is not allowed. 
 
5.6 Blinding, Emergency Envelopes, and Breaking the Study Blind 
Not applicable. 
 
5.7 Drug Dispensing and Accountability 
A drug dispensing log and the inventory will be kept current by the investigator, detailing the 
dates and quantities of IMP received at the site/pharmacy, and dispensed to each subject. The 
inventory will be available to the monitor to verify drug accountability during the study. Any 
unused or partially used IMP, including empty containers (if possible), will be accounted for. 
Unused IMP may be destroyed at the study site, however, only after drug accountability has 
been verified and fully re-conciliated and written approval from the Sponsor has been obtained. 
Unused IMP can be returned to the Sponsor for destruction when drug accountability has been 
verified and fully re-conciliated and written approval from the Sponsor has been received. 
 
5.8 Assessment of Treatment Compliance 
Treatment compliance will be measured in terms of the subject receiving an infusion of Oc- 
tafibrin from the study personnel. Administered doses of Octafibrin will be recorded for every 
infusion, including dates, times, and batch numbers; the batch numbers will be reported in the 
final study report. 

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6 STUDY CONDUCT 
 
6.1 Observations Performed Throughout the Study 
Patients identified by the study sites as potential study participants will be screened for inclu- 
sion into the study. The screening assessments will be performed as summarised in Section 
6.1.1. 
The PK assessments are summarised in Section 6.1.2. The assessments for patients enrolled and 
then having on-demand treatment of an active bleeding episode are summarised in 
Section 6.1.3. The assessments for patients planning to undergo elective surgery are summa- 
rised see Section 6.1.4. 
All treated patients will undergo a Study Completion Visit as summarised in Section 6.1.5. 
 
6.1.1 Screening Assessments 
Patients identified by the study sites as potential study participants will undergo the following 
screening assessments: 
• Inclusion and exclusion criteria, including written informed consent for participation in 
the study by the subject’s legal guardian 
• Demography, medical history (including details concerning allergic tendencies), review of 
previous therapy 
NOTE: If the period between screening and first treatment of acute bleeding or surgical prophy- 
laxis is more than 3 months, informed consent will be re-reviewed and confirmed prior to treat- 
ment, and details of the review process will be recorded in the patient chart and indicated in the 
CRF by the investigator. Also, inclusion/exclusion criteria will be confirmed prior to treatment. 
 
6.1.2 Assessments During the PK Phase 
Within 2 weeks after the screening process, subjects will receive a single infusion of 70 mg/kg 
Octafibrin on Day 1 of PK testing (PK-Day 1). Before the start of the PK phase, there must be 
an at least 2-week wash-out period of any fibrinogen containing product. 
Before first injection vital signs and blood draws for baseline fibrinogen levels will be assessed. 
Retention serum samples for potential retesting will be collected within 30 minutes before in- 
fusion. At 1 and 3 hours post-infusion, vital signs and fibrinogen for PK will be assessed, and 
AEs will be recorded. Subjects will be further followed on: 
 
PK-Days 2 (24 hrs), 4 (72 hrs), 7 (144 hrs), and 10 (216 hrs) 
− 
Fibrinogen for PK 
− 
Recording of AEs, including potential thromboembolic events 

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PK-Day 14 (312 hrs) 
− 
Fibrinogen for PK 
− 
Vital signs 
− 
Physical examination, including any signs or symptoms of potential thromboembolic 
events 
− 
Recording of AEs, including potential thromboembolic events 
The flow chart of assessments for the PK phase is provided on page xxiv. 
NOTE: All adverse events (AEs, see Section 7.4), including thromboembolic events and early 
signs of allergic or hypersensitivity reactions, occurring between the start of the first Octafibrin 
infusion and the end of the PK phase will be recorded. 
All SAEs occurring after the first IMP infusion will be documented and reported for a patient 
throughout the duration of the patient’s participation in the study or as required to meet local 
regulations. 
 
6.1.3 Assessments in Subjects Undergoing On-demand Treatment of Bleeding 
Subjects presenting to the study site for an acute bleeding episode will undergo a 30-day obser- 
vation and follow-up period as outlined below. Throughout the study, subjects may undergo 
more than one 30-day observation and follow-up periods for treatment of additional bleeding 
episodes as required until the close of the study. At the end of their study participation, patients 
will be asked to return for a final Study Completion Visit. 
For information on the dose calculation and a definition of minor and major bleeding, see Sec- 
tion 5.4.3. The flow chart of assessments for on-demand treatment is provided on page xxii. 
NOTE: All adverse events (AEs, see Section 7.4), including thromboembolic events and early 
signs of allergic or hypersensitivity reactions, occurring between the start of the first Octafibrin 
infusion and the end of each 30-day observation and follow-up period will be recorded. The 
detection of thromboembolic events will be supported by completing a TEE questionnaire at 
each study visit for the treatment of bleeding episodes and for surgeries. Concomitant medica- 
tions will also be recorded throughout each 30-day observation and follow-up period. Admin- 
istered doses of Octafibrin will be recorded for every infusion, including dates, times, and batch 
numbers. 
All SAEs occurring after the first IMP infusion will be documented and reported for a patient 
throughout the duration of the patient’s participation in the study or as required to meet local 
regulations. Also, any concomitant medications used to treat an SAE will be recorded. 
 
6.1.3.1 Day 1 (first day of treatment) 
For subjects requiring on-demand treatment, Day 1 is the day they present for treatment of an 
acute bleeding episode. 

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Pre-infusion assessments 
The following assessments will be performed before the first infusion of Octafibrin for each 
bleeding episode: 
• Medical history (including details of any non-study bleeding episodes and therapy), and 
prior/concomitant medication 
• Characterisation of bleeding episode 
• Vital signs 
• Physical examination 
• TEE questionnaire 
• Height and weight 
• Blood draw for: 
– fibrinogen plasma level (local lab–activity; central lab–antigen and activity; within 
30 minutes before infusion) 
– MCF (within 30 minutes before infusion) 
– safety lab (local–haematology and clinical chemistry) 
– thrombogenicity 
– immunogenicity 
NOTE: If the period between screening and first treatment of acute bleeding is more than 3 
months, informed consent will be re-reviewed and confirmed prior to treatment, and details of 
the review process will be recorded in the patient chart and indicated in the CRF by the inves- 
tigator. Also, inclusion/exclusion criteria will be confirmed prior to treatment. 
 
First infusion of Octafibrin 
After the pre-infusion assessments, subjects will receive the first infusion of Octafibrin for 
treatment of bleeding (see Section 5.4). 
 
Post-infusion assessments 
On Day 1, the following post-infusion assessments will be performed: 
 
1 hour (±15 minutes) after the end of infusion: 
• Vital signs 
• TEE questionnaire 
• Blood draw for: 
– fibrinogen plasma level (local lab–activity; central lab–antigen and activity) 
– MCF 
• AEs and concomitant medications 

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3 hours (±15 minutes) after the end of infusion: 
• Vital signs 
• TEE questionnaire 
• Blood draw for: 
– fibrinogen plasma level (central lab–antigen and activity) 
– thrombogenicity 
• AEs and concomitant medications 
NOTE: If, in the investigator’s judgement, the infusion of Octafibrin administered on Day 1 is 
deemed the only infusion needed for treatment of the subject’s bleeding event, the subject will 
need to reach the end of the treatment observation period, where the “24 hours (i.e., 1 day) after 
the last infusion” assessments should be performed. 
 
6.1.3.2 All Study Days after Day 1 (Treatment Observation Period) 
Each subject’s treatment observation period is defined according to the severity of the event 
and will last at least 3 days for minor and 7 days for major bleeding episodes. If the patient 
requires multiple infusions, the actual treatment duration will be determined by the investigator 
based on his/her judgement of the subject’s condition, and the treatment observation period will 
last until 24 hours after the last infusion. 
 
Daily assessments (for at least 3 days for minor bleeding or 7 days for major bleeding) 
• TEE questionnaire 
• Blood draw for: 
– fibrinogen plasma level (local lab–activity; central lab–antigen and activity): Based 
on local lab results, the investigator will determine whether additional infusions of 
Octafibrin are needed. 
– safety lab (local–haematology) 
• AEs and concomitant medications 
Octafibrin infusion, as required 
After these daily assessments, additional IMP dosing should occur as required depending on 
the actual and target plasma levels based on the following criteria: 
• If the actual fibrinogen plasma level is below the accepted lower limit of the target fibrino- 
gen plasma level (80 mg/dL for minor bleeding, 130 mg/dL for major bleeding; see Sec- 
tion 5.4), the subject should receive another infusion of Octafibrin. 
• If the fibrinogen plasma level is greater than or equal to the accepted lower limit of the 
target fibrinogen plasma level, Octafibrin should not be administered on that day. 

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Pre- and post-infusion assessments 
If the subject receives an additional infusion of Octafibrin, the following pre- and post-infusion 
assessments will be performed: 
 
Pre-infusion assessments: 
• TEE questionnaire 
• Blood draw for (within 30 minutes before infusion): 
– fibrinogen plasma level (local lab–activity; central lab–antigen and activity) 
– thrombogenicity 
1 hour (±15 minutes) after the end of each infusion: 
• Vital signs 
• TEE questionnaire 
• Blood draw for: 
– fibrinogen plasma level (local lab–activity; central lab–antigen and activity) 
– thrombogenicity 
 
NOTE: If, in the investigator’s judgement, there are no additional infusions of Octafibrin 
needed to treat the bleeding event, the subject will need to reach the end of the treatment obser- 
vation period, where the “24 hours (i.e., 1 day) after the last infusion” assessments should be 
performed. 
 
6.1.3.3 Last Infusion or End of the Observation Period (whichever comes last) 
If a patient requires multiple infusions for a bleeding event as defined by the investigator based 
on his/her judgement of the subject’s condition, or the subject comes to the end of the observa- 
tion period (whichever comes last), the following assessments will be performed: 
 
Pre-infusion assessments 
The following assessments will be performed prior to the last infusion of Octafibrin if multiple 
infusions are needed: 
• TEE questionnaire 
• Blood draw for (within 30 minutes before infusion): 
– fibrinogen plasma level (local lab–activity; central lab–antigen and activity) 
 
Last infusion of Octafibrin 
Following the pre-infusion assessments, subjects will receive their last infusion of Octafibrin 
depending on the actual and target plasma levels (see Section 5.4). 

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Post-infusion assessments 
On the Day of Last Infusion, post-infusion assessments will be as follows: 
1 hour (±15 minutes) after the end of last infusion: 
• Vital signs 
• TEE questionnaire 
• Blood draw for: 
– fibrinogen plasma level (local lab–activity; central lab–antigen and activity) 
 
24 hours (i.e., 1 day) after the last infusion or at the end of the treatment observation period 
(whichever comes last) 
• Vital signs 
• Physical examination 
• TEE questionnaire 
• Blood draw for: 
– fibrinogen plasma levels (central lab–antigen and activity) 
• Final assessment of haemostatic efficacy by the investigator with respect to the adequacy 
of stopping an acute bleed. The assessment is to include the entire period from the start of 
the first infusion until 24 hours (i.e., 1 day) after the last infusion and includes the clinical 
condition of the subject, laboratory values such as haematocrit and haemoglobin, and any 
additional haemostatic treatments (see Section 7.2.1). 
• AEs and concomitant medications 
 
6.1.3.4 Day 30 (29 Days after the First Infusion)—Final Examination 
On Day 30 (± 1 week), the following assessments will be performed: 
• Physical examination 
• TEE questionnaire 
• Blood draw for: 
– immunogenicity 
– retention serum sample for potential retesting 
• AEs and concomitant medications 
The Day 30 assessment concludes the series of observations by bleeding episode. No further 
study-related assessments will be performed, unless safety concerns (e.g., ongoing AEs) require 
follow-up. 
If the patient experiences another bleeding event before Day 30, this will be treated as a new 
bleeding event, provided that it is not directly related to the prior event. In this case, Day 30 
evaluations will be postponed until 30 days after the start of the new bleeding episode. 
Subjects returning to the study site for another acute bleeding episode within the study will 
again undergo the same Day 1 to Day 30 assessments as outlined in Section 6.1.3.1 through 
Section 6.1.3.4. At the end of the study duration, all subjects having received any IMP will be 
asked to return for a Study Completion Visit as summarised in Section 6.1.5. 
 
6.1.4 Assessments in Subjects Undergoing Surgical Prophylaxis 

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Subjects enrolled for elective surgery will undergo a treatment and assessment cycle as outlined 
in Section 6.1.4.1 through Section 6.1.4.3. Octafibrin will be given prior to surgery as well as 
during and after surgery based on the physician’s judgement, the patient’s history, and the se- 
verity of the procedure. Subjects enrolled for elective surgery will be treated (as required) and 
assessed from Day 1 (i.e., the day of surgery) to the Last Post-Operative Day. The Last Post- 
Operative Day is either at least post-operative day 3 for minor and post-operative day 7 for 
major surgery or the day of the last post-operative infusion, whichever comes last. 
For information on the dose calculation and a definition of minor and major surgery, see 
Section 5.4. 
The flow chart of assessments for surgical prophylaxis is provided on page xxiii. 
 
Definitions of Pre-, Intra-, and Post-operative 
• Pre-operative refers to the time period covering the last 12 hours before the start of surgery. 
• Intra-operative is defined as the time from the start of surgery to the end of surgery, i.e., 
the time of completion of the last suture. 
• Post-operative refers to the time from the end of surgery to the Last Post-Operative Day. 
Determination of Fibrinogen Plasma Levels in Surgical Prophylaxis 
Fibrinogen plasma levels will be documented immediately (≤30 minutes) before and after each 
pre-, intra-, or post-operative injection of Octafibrin. 
 
Estimation of Blood Loss 
Prior to surgery, the surgeon will provide written estimates of the following: 
• Volume (mL) of average expected blood loss for the planned surgical procedure, as it 
would be expected for the same procedure in a subject with normal haemostasis, of the same 
sex, age, and stature. 
• Volume (mL) of maximal expected blood loss for the planned surgical procedure as it 
would be expected for the same procedure in a subject with normal haemostasis, of the same 
sex, age, and stature. 
Following surgery, the actual blood loss will be estimated by the surgeon. 
NOTE: All adverse events (AEs), including thromboembolic events and early signs of allergic 
or hypersensitivity reactions, occurring between first infusion of IMP before the start of surgery 
and the Last Post-operative Day will be recorded. The detection of thromboembolic events will 
be supported by completing a TEE questionnaire at each study visit for the treatment of bleeding 
episodes and for surgeries. All SAEs occurring after the first IMP infusion will be documented 
and reported for a patient throughout the duration of the patient’s participation in the study or 
as required to meet local regulations. Also, any concomitant medications used to treat an SAE 
will be recorded. 

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6.1.4.1 Day 1 
For subjects enrolled for surgical prevention, Day 1 is the day they undergo surgery and receive 
their first dose of Octafibrin. 
 
The following surgery-related data will be recorded: 
 
Pre-operative assessments 
The following pre-operative assessments will be performed: 
• Medical history 
• Vital signs 
• Physical examination 
• TEE questionnaire 
• Body weight (kg) 
• Blood draw for: 
– fibrinogen plasma levels (local lab–activity; central lab–antigen and activity) 
– safety lab (local—haematology and clinical chemistry) 
• Location and type of surgery 
• Severity of surgery (minor/major) 
• Expected duration of surgical procedure (start and end times, i.e., skin to skin) 
• Expected blood loss for the procedure 
• Estimate of any blood/blood product transfusions needed during the surgery 
• Any planned ancillary therapy to be used during the surgery (e.g., antifibrinolytics, pre- 
panned blood transfusions, etc.) 
 
First infusion of Octafibrin 
Following the pre-operative assessments and within 3 hours before the start of surgery, the 
subject may receive the first infusion of Octafibrin (see Section 5.4). 
NOTE: If, in the investigator’s judgement, there are no additional infusions of Octafibrin 
needed to prevent bleedings post surgery, the post-infusion assessments as detailed in the sched- 
ule for the Last Post-Operative Day should be performed instead. 
 
Intra-operative assessments 
The following assessments will be performed during or at the end of surgery: 
• Blood draw for: 
– fibrinogen plasma levels (local lab–activity; central lab–antigen and activity) 
 
Assessments at the end of surgery 
• TEE questionnaire 
• Blood draw for: 
– fibrinogen plasma levels (local lab–activity; central lab–antigen and activity) 
• Actual duration of surgical procedure (start and end times, i.e., skin to skin) 
• Details of surgery 
• Actual blood loss 

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• Details on concomitantly administered products, including any blood/blood product trans- 
fusions but excluding drugs given for routine anaesthesia 
• Intra-operative efficacy assessment at the end of surgical procedure by the surgeon (see 
Section 7.2.2.4) 
• AEs and concomitant medications 
 
6.1.4.2 Any Post-Operative Day before the Last Post-Operative Day 
On any post-operative day before the Last Post-Operative Day (see Section 6.1.4.3), the fol- 
lowing assessments will be performed: 
 
Daily post-operative assessments 
The following assessments will be on every post-operative day: 
• Vital signs 
• TEE questionnaire 
• Blood draw for: 
– fibrinogen plasma levels (local lab–activity; central lab–antigen and activity) 
– safety lab (local–haematology and clinical chemistry) 
• Wound haematomas and oozing (noting whether surgical evacuation is required and sever- 
ity and volume of oozing) 
• AEs and concomitant medications 
Octafibrin infusion, as required 
Additional dosing should occur as required depending on the actual and target plasma level and 
based on the following criteria: 
• If the actual fibrinogen plasma level is below the accepted lower limit of the target fibrino- 
gen plasma level (80 mg/dL for minor surgery, 130 mg/dL for major surgery; see Sec-  
tion 5.4), the subject should receive another infusion of Octafibrin. 
• If the fibrinogen plasma level is greater than or equal to the accepted lower limit of the 
target fibrinogen plasma level, Octafibrin should not be administered on that day. 
 
Pre- and post-infusion assessments 
If the subject receives an infusion of Octafibrin, the following pre- and post-infusion assess- 
ments will be performed: 
 
Pre-infusion assessments: 
• TEE questionnaire 
• Blood draw for: 
– fibrinogen plasma level (local lab–activity; central lab–antigen and activity) 

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1 hour (±15 minutes) after the end of each infusion: 
• Vital signs 
• TEE questionnaire 
• Blood draw for: 
– fibrinogen plasma level (local lab–activity; central lab–antigen and activity) 
– safety lab (local–haematology and clinical chemistry) 
• AEs and concomitant medications. 
 
6.1.4.3 Last Post-Operative Day 
The Last Post-Operative Day is either at least post-operative day 3 for minor and post-operative 
day 7 for major surgery or the day of the last post-operative infusion, whichever comes last. 
The assessments performed on the Last Post-Operative Day are identical to those performed on 
any other post-operative day (see Section 6.1.4.2). 
In addition, the following assessments will be performed on the Last Post-Operative Day: 
• post-operative efficacy assessment by the haematologist (see Section 7.2.2.4) 
• brief narrative describing the details of hospitalisation (start and end date, details of the 
procedure), follow-up, outcome, and efficacy of the intervention 
 
The assessments performed on the Last Post-Operative Day conclude the surgical observation 
period. No further study-related assessments will be performed, unless safety concerns (e.g., 
ongoing AEs) require follow-up. 
Patients may remain in the study until at least 12 patients have undergone PK assessments, the 
6th patient (at least 3 patients each in the specified age groups) has at least one documented 
bleeding episode, and at least 2 surgical procedures have been documented. When the study is 
closed, all subjects having received any IMP will be asked to return for a Study Completion 
Visit as summarised in Section 6.1.5. 
 
6.1.5 Study Completion Visit 
At the end of the study duration, all subjects having received any IMP will be asked to return 
for a Study Completion Visit, during which the following assessments will be performed: 
• Medical history since the last study visit 
• Physical examination 
After the Study Completion Visit, the clinical study is considered completed for the subject. 
Patients who were screened for the study but did not receive any IMP throughout the study 
duration will be notified of the end of the study. No further assessments will need to be per- 
formed. These patients will be considered ‘no treatment’ patients and reported separately. 

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6.2 Duration of Study 
 
6.2.1 Planned Duration for the Study as a Whole 
The study will be considered completed when a minimum of 12 patients have had PK assess- 
ments, 6 subjects (at least 3 subjects aged between 0 and <6 years and 3 subjects aged between 
6 and <12 years) have at least one documented bleeding episode, and a minimum of 2 surgical 
procedures have been documented. The study as a whole should be completed within 5 years. 
The estimated start of the study (enrolment of first subject) is in the 3rd quarter of 2015, and 
the estimated end of the study (last visit of last subject) is in the 3rd quarter of 2020. 
 
6.2.2 Planned Duration for an Individual Subject 
All patients will undergo a PK study after screening. This will have a duration of 14 days, after 
which a patient can be treated for a bleeding episode or planned surgical procedure when they 
occur. 
 
For subjects receiving on-demand treatment, 
• the individual subject observation and follow-up period for each documented episode 
starts with the first dose of Octafibrin administered for on-demand treatment of an acute 
bleeding episode (Day 1) and will be followed up to at least Day 30. 
• Each subject’s treatment observation period is defined according to the severity of the 
event and will last at least 3 days for minor and 7 days for major bleeding episodes. 
 
For subjects undergoing surgical prophylaxis, 
• the surgical observation period starts with the first dose of Octafibrin administered prior 
to elective surgery (Day 1) and, depending on the severity of the event, will  last  at least  
3 post-operative days for minor and 7 post-operative days for major surgeries or until the 
day of the last post-operative infusion, whichever comes last. 
During the study observation period, enrolled patients will be treated for any bleeding episodes 
or planned surgeries that can be managed under the protocol. Patients may remain in the study 
until at least 12 patients have undergone PK assessment, the 6th patient (at least 3 patients each 
in the specified age groups) has at least one documented bleeding episode, and at least 2 surgical 
procedures have been documented. 
As many bleeding episodes or surgeries as possible occurring throughout the study observation 
period will be documented. Only the first bleeding episodes will be used for the analysis of the 
primary endpoint (see Section 3.1.1). All bleeding episodes documented in the study will be 
assessed as a secondary endpoint (see Section 3.1.2). 
Patients who were screened for the study but did not receive any IMP will be considered ‘no 
treatment’ patients and reported separately. 
All patients completing the PK phase (i.e., at least 12 patients) will also be analyzed separately, 
regardless of whether they received any IMP for the treatment of a bleeding episode or surgery. 
 
6.2.3 Premature Termination of the Study 

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Both the investigator and the Sponsor reserve the right to terminate the study at any time. Should 
this be necessary, the procedures will be arranged on an individual study basis after review and 
consultation by both parties. In terminating the study, the Sponsor and the investigator will 
ensure that adequate consideration is given to the protection of the subjects’ interests. 
Furthermore, the investigator should promptly inform the Independent Ethics Committee 
(IEC)/Institutional Review Board (IRB) and provide a detailed written explanation. The perti- 
nent regulatory authorities should be informed according to national regulations. 
Early termination of the study as a whole or centre-wise may apply for the following reasons: 
• Clinical Study: At any time the study as a whole may be terminated prematurely if new 
toxicological or pharmacological findings or serious adverse events (SAEs) invalidate the 
earlier positive benefit-risk-assessment. 
• Study Centre: At any time the study may be terminated at an individual study centre if: 
− 
The centre cannot comply with the requirements of the protocol. 
− 
The centre cannot comply with Good Clinical Practice (GCP) standards. 
− 
The required recruitment rate is not met. 
Should the study be prematurely terminated, all study materials (completed, partially com- 
pleted, and blank CRFs, IMPs etc.) must be returned to the Sponsor. 

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7 ASSESSMENTS AND METHODS 
 
7.1 Background and Screening Information 
The following information will be captured on at screening: 
Demographics: sex, age, weight and height (calculated body mass index), and ethnic origin 
Medical history: obtained by interviewing the subject/legal guardian and by performing a phys- 
ical examination 
Previous and concomitant medication: obtained by interviewing the subject/legal guardian 
 
 
7.2 Efficacy Assessments 
7.2.1 Assessments for Primary Efficacy Endpoint 
The primary endpoint is the overall clinical assessment of the haemostatic efficacy of Octafibrin 
in treating the first documented bleeding episode of each patient. 
• The first bleeding episode covers the time period from the first Octafibrin infusion for the 
treatment of a bleeding episode until 24 hours (i.e., 1 day) after the last infusion or the end 
of the treatment observation period, whichever comes last. 
• The investigator’s overall clinical assessment covers the entire time period of the first 
bleeding episode as defined above. The assessment includes the clinical condition of the 
subject, laboratory values such as haematocrit and haemoglobin, as well as any additional 
haemostatic treatments. 
The investigator’s overall clinical assessment of haemostatic efficacy will be based on a 
4-point haemostatic efficacy scale (Table 2). The final efficacy assessment of each patient will 
be adjudicated by the IDMEAC. 
 
Table 2: Overall clinical assessment of haemostatic efficacy 
Category 
Definition 
 
Excellent 
Immediate and complete cessation of bleeding in the absence of other haemo- 
static intervention as clinically assessed by the treating physician; and/or <10% 
drop in haemoglobin compared to pre-infusion. 
Good 
Eventual complete cessation of bleeding in the absence of other haemostatic in- 
tervention as clinically assessed by the treating physician; and/or <20% drop in 
haemoglobin compared to pre-infusion. 
Moderate 
Incomplete cessation of bleeding and additional haemostatic intervention re- 
quired, as clinically assessed by the treating physician; and/or between 20 and 
25% drop in haemoglobin compared to pre-infusion. 
None 
No cessation of bleeding and alternative haemostatic intervention required, as 
clinically assessed by the treating physician; and/or >25% drop in haemoglobin 
  
compared to pre-infusion. 
 

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7.2.2 Assessments for Secondary Endpoints 
 
7.2.2.1 Pharmacokinetics 
The PK endpoints (i.e., AUC, incremental and classical IVR, terminal elimination half-life 
(t1/2), maximum plasma concentration (Cmax), time to reach maximum plasma concentration 
(Tmax), mean residence time (MRT), volume of distribution (Vss), and clearance (Cl) will be 
assessed after a single intravenous infusion of 70 mg/kg body weight of Octafibrin. 
 
7.2.2.2 Clot Strength 
MCF will be determined using thromboelastometry (ROTEM) and will be used as a surrogate 
marker for haemostatic efficacy. ROTEM is a method for the continuous measurement of clot 
formation and clot firmness. It utilises a mechanical detection system which is based on the 
ability of the blood or plasma clot to form a mechanical coupling over a distance of 1 mm. 
ROTEM is the continuous registration of blood clot firmness during the entire coagulation pro- 
cess (Figure 1). 
 
 
 
Figure 1: Example of thromboelastogram 
MCF (measured in mm) is a functional parameter which depends on the activation of coagula- 
tion, the platelet and fibrinogen content of the blood sample, and the polymerisation and cross- 
linking of the fibrin network. 
ROTEM has been shown in various studies to be predictive of clinical coagulopathy [16, 17, 
18, 19, 20]. ROTEM has been used as a functional marker for the assessment of fibrinogen 
content, and for the effects of fibrinogen supplementation on the clinical efficacy [21, 22, 23, 
24, 25, 26]. Therefore, the MCF parameter is regarded as an adequate surrogate marker for the 
haemostatic efficacy of fibrinogen supplementation in patients with congenital fibrinogen defi- 
ciency. 
To obtain consistent results across all study centres, with minimal centre-to-centre variability, 
MCF blood samples will be forwarded to the central laboratory. MCF will be assessed from 
frozen citrated plasma samples. 
The MCF (units: mm) at 1 hour post-infusion will be regarded as surrogate efficacy criterion. 

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7.2.2.3 Recovery 
For the first infusion of each treated bleeding episode, IVR will be determined using the fol- 
lowing approaches: 
• Incremental IVR (response): calculated as the maximum increase in plasma fibrinogen (i.e., 
Clauss data) between the pre-infusion and the 3-hour post-infusion measurement (expressed 
as absolute concentration in plasma [mg/dL]), divided by the exact dose of Octafibrin (ex- 
pressed as mg/kg dosed) 
• Classical IVR: calculated as the maximum increase in plasma fibrinogen (i.e., Clauss data) 
between the pre-infusion and the 3-hour post-infusion measurement (expressed as absolute 
concentration in plasma [mg/dL]), divided by the total dose of Octafibrin per expected 
plasma volume (expressed as mg/dL), with expected plasma volume being estimated based 
on the blood volume formula described by Nadler [27] 
 
7.2.2.4 Surgical Prophylaxis 
The efficacy of Octafibrin in surgical prophylaxis will be assessed at the end of surgery by the 
surgeon and post-operatively by the haematologist as described in Table 3. The efficacy of Oc- 
tafibrin in surgical prophylaxis will be based on an overall assessment. The overall surgical 
efficacy will be adjudicated by the IDMEAC who will evaluate the surgeons’ and investigators’ 
assessments in conjunction with a review of the surgical case. 
 
Table 3: Clinical assessment of surgical prophylaxis 
Category 
Definition 
 
Intra-operative efficacy as assessed by surgeon (at end of the surgery = after last suture) 
Excellent 
Intra-operative blood loss* was lower than or equal to the average expected 
blood loss for the type of procedure performed in a subject with normal haemo- 
stasis and of the same sex, age, and stature. 
Good 
Intra-operative blood loss* was higher than average expected blood loss but 
lower or equal to the maximal expected blood loss for the type of procedure in a 
subject with normal haemostasis. 
Moderate 
Intra-operative blood loss* was higher than maximal expected blood loss for the 
type of procedure performed in a subject with normal haemostasis, but haemostasis 
was controlled. 
None 
Haemostasis was uncontrolled necessitating a change in clotting factor replace- 
ment regimen. 
 
*Excludes unexpected blood loss due to surgical complications, i.e., 
− direct injury of a vessel (artery or vein) 
− vessel injury not adequately responding to routine surgical procedures achieving haemostasis 
− accidental injury of parenchymatous tissue (e.g., liver, lung) 

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Category 
Definition 
Post-operative efficacy as assessed by haematologist 
 
Excellent 
No post-operative bleeding or oozing that was not due to complications of sur- 
gery. All post-operative bleeding (due to complications of surgery) was con- 
trolled with Octafibrin as anticipated for the type of procedure. 
Good 
No post-operative bleeding or oozing that was not due to complications of sur- 
gery. Control of post-operative bleeding due to complications of surgery required 
increased dosing with Octafibrin or additional infusions, not originally antici- 
pated for the type of procedure. 
Moderate 
Some post-operative bleeding and oozing that was not due to complications of 
surgery; control of post-operative bleeding required increased dosing with Oc- 
tafibrin or additional infusions, not originally anticipated for the type of proce- 
dure. 
None 
Extensive uncontrolled post-operative bleeding and oozing. Control of post-oper- 
ative bleeding required use of an alternate fibrinogen concentrate. 
 
 
The IDMEAC will conduct an independent adjudication of all haemostatic efficacy results and 
adjudicate the investigator’s assessments of the intra- and post-operative assessments (‘second- 
ary adjudication’). 
The primary endpoint (‘success’ or ‘failure’) will be derived from the adjudicated intra- and 
post-operative assessments according to the agreed algorithm presented in Table 4. 
 
Table 4: 
Algorithm for the adjudicated intra- and post-operative assessments of 
haemostatic efficacy 
 
Intra-opera- 
tive assess- 
ment 
Post-operative assessment 
Excellent 
Good 
Moderate 
None 
Excellent 
Success 
Success 
Success 
Primary 
adjudication 
Good 
Success 
Success 
Primary 
adjudication 
Failure 
Moderate 
Success 
Primary 
adjudication 
Failure 
Failure 
None 
Primary 
adjudication 
Failure 
Failure 
Failure 
 
Outcomes designated as ‘primary adjudication’ will be assigned following adjudication by the 
IDMEAC. 
In documenting the adjudication process for the assessment of surgical prophylaxis, the 
IDMEAC will explicitly identify any subjects for whom they considered there to be ‘unex- 
pected blood loss due to surgical complications’ and state whether this unexpected blood loss 
altered the 4-point assessment of surgical prophylaxis. Any such cases will be analyzed both 
including (as a sensitivity analysis) and excluding the unexpected blood loss. 

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In the event that any intra- or post-operative endpoint data differ between the investigator’s 
assessment and the adjudicated assessment by the IDMEAC, the endpoint will be that based on 
the adjudicated assessments. The efficacy of Octafibrin in surgical prophylaxis will be evalu- 
ated by descriptive statistics based on an overall assessment. 
In addition, the location, severity, and type of surgery will be documented. Expected and actual 
duration of surgical procedure and details of administered dose(s) of Octafibrin (pre-, intra- 
and/or post-operatively) will be recorded. Fibrinogen plasma levels (pre-, intra-, and post-op- 
eratively) will be measured. Details of concomitantly administered products (except standard 
anaesthesia), along with a brief narrative describing the outcome of the intervention, will be 
recorded. 
 
7.3 Laboratory Assessments 
Table 5 summarises all test parameters and the laboratories responsible for analysis. 
 
Table 5: Test Parameters and Laboratories 
Test 
Material needed 
Responsible 
 
 
 
 
 
 
 
1 Any thromboembolic events reported from Day 1 to Day 30 will be documented as AEs. A final clinical evaluation of any 
signs or symptoms of potential thromboembolic events will be done at Day 30. 
 
All remaining serum and plasma volumes will be labelled and stored as retention samples at the 
central laboratory for at least 24 months after the completion of the study and until Octa- 
pharma’s written authorisation to destroy these samples. These samples may be used for addi- 
tional coagulation and viral testing, if needed. 
The flow chart of assessments for on-demand treatment is provided on page xxii. The flow chart 
of assessments for surgical prophylaxis is provided on page xxiii. 
 
7.3.1 Blood Sampling 
The actual time of blood sampling must be recorded in the CRF and on the corresponding 
laboratory requisition forms. 
If several blood samples have to be taken at one time point, the blood sampling will be done in 
the following sequence: 
1. Coagulation (citrated plasma) 
2. Haematology and virology serology (EDTA blood and serum, respectively) 
3. Clinical chemistry (serum) 
laboratory 
Fibrinogen activity (Clauss) 
Citrated plasma 
Local and central 
Fibrinogen:Ag 
Citrated plasma 
Central 
Fibrinogen inhibitor testing 
Citrated plasma 
Central 
Clinical chemistry 
Serum 
Local 
Haematology 
EDTA blood 
Local 
Maximum clot strength 
Citrated plasma 
Central 
Thrombogenicity (D-dimer, prothrombin fragment 1+2)1 
Citrated plasma 
Central 

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7.3.2 Citrated Plasma 
Blood samples taken for plasma will be centrifuged after collection as instructed in the labora- 
tory manual provided by the Sponsor. Aliquots of the supernatant are subsequently transferred 
into the tubes provided by the Sponsor and stored or shipped under conditions described in the 
laboratory manual. 
For the analysis performed in the central laboratory, samples of citrated blood will be collected 
for coagulation factor analysis and antibody testing. After collection and centrifugation as in- 
structed in laboratory manual, the plasma will be aliquoted into cryo-resistant tubes. Samples 
will be stored frozen and shipped to the central laboratory on dry-ice. 
For analyses performed locally, citrated blood as required by the local laboratory will be col- 
lected and processed in accordance with local requirements. 
Retention samples will be taken at described time points in the study for possible retesting if 
needed. 
 
7.3.3 EDTA Blood 
A sample of EDTA blood will be collected for the measurement of haematology parameters 
(red blood cell count, RBCC; white blood cell count, WBCC; haemoglobin, HB; haematocrit, 
HCT; and platelet count, PC). 
All tests will be done at the local laboratory. 
 
7.3.4 Serum 
For the determination of clinical chemistry (total bilirubin, BILI; alanine aminotransferase, 
ALT; aspartate aminotransferase, AST; blood urea nitrogen, BUN; serum creatinine, CREA; 
lactate dehydrogenase, LDH), a serum blood sample will be collected. 
All tests will be done at the local laboratory. 
Retention samples will be taken at entry into the study and at the Study Completion Visit for 
potential viral testing if there is a suspicion of infection. 
 
7.3.5 Recording of Clinically Significant Abnormal Laboratory Values as AEs/ADRs 
The investigator must assess the clinical significance of abnormal laboratory values outside the 
normal range as specified by the reference laboratory. Any clinically significant abnormalities 
should be fully investigated. 
Only laboratory abnormalities that have been rated as being clinically significant and occurred 
after the first IMP administration in the study, will be documented as AEs/ADRs. Clinically 
significant is defined as any laboratory abnormality that the investigator feels is of clinical con- 
cern and/or requires medical intervention and/or follow-up. Additional tests and other evalua- 
tions required to establish the significance or aetiology of an abnormal result or to monitor the 
course of an AE should be obtained if clinically indicated. 

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Any abnormal laboratory value that persists should be followed until resolution or for 14 days 
after the Study Completion Visit, whichever occurs first. Preferably, clinically significant la- 
boratory abnormalities should be medically diagnosed and entered as a diagnosis into the AE 
form. 
 
7.4 Safety Assessments 
Any of the following drug safety information shall be collected: 
• All AEs occurring between the start of the first Octafibrin infusion and the end of the PK 
phase, the end of each 30-day observation and follow-up period for on-demand treatment, 
or the end of the surgical observation period will be recorded. 
• All SAEs occurring after the first Octafibrin infusion will be documented and reported for 
a patient throughout the duration of the patient’s participation in the study or as required to 
meet local regulations (definitions and reporting requirements, see Section 7.4.1). 
• Post study related safety reports, drug overdose, interaction, abuse, misuse, or medication 
error (see Section 7.6). 
 
7.4.1 Adverse Events (AEs) 
 
7.4.1.1 Definitions 
• AE: An AE is any untoward medical occurrence in a study subject receiving an IMP and 
which does not necessarily have a causal relationship with this treatment. An AE can there- 
fore be any unfavourable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an IMP, whether or not related 
to the IMP. 
• Adverse drug reaction (ADR): An ADR is any noxious and unintended response to an IMP 
related to any dose. The phrase ‘response to an IMP’ means that a causal relationship be- 
tween the IMP and an AE carries at least a reasonable possibility, i.e., the relationship can- 
not be ruled out. 
• Other significant AEs: Any marked laboratory abnormalities or any AEs that lead to an 
intervention, including withdrawal of drug treatment, dose reduction or significant addi- 
tional concomitant therapy. 
• Withdrawal due to AE/ADR: Subject whose treatment with IMP is discontinued because of 
an AE or ADR. Any such events will be followed up by the investigator until the event is 
resolved or until the medical condition of the subject is stable. All follow-up information 
collected will be made available to the Sponsor. 

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7.4.1.2 Collection of AEs 
The condition of the subject will be monitored throughout the PK phase, each 30-day obser- 
vation and follow-up period for on-demand treatment or each surgical observation period 
for surgical interventions. At each visit, whether scheduled or unscheduled, AEs will be elicited 
using a standard non-leading question such as ‘How have you been since the last visit?’ 
Only AEs or ADRs which occur during the PK phase, any 30-day observation and follow-up 
period for on-demand treatment, or any surgical observation period for surgical interventions 
will be recorded in detail on the appropriate pages of the CRF. If the subject reports several 
signs or symptoms which represent a single syndrome or diagnosis, the latter should be recorded 
in the CRF. 
The investigator responsible will grade the severity of all AEs or ADRs (mild, moderate, or 
severe; see Section 7.4.1.3), the seriousness (non-serious or serious; see Section 7.4.2), and 
causality (see Section 7.4.1.4). The Sponsor is responsible to assess the expectedness of each 
ADR (expected or unexpected; see Section 7.4.1.5). 
In the event of clinically significant abnormal laboratory findings, the tests will be repeated and 
followed up until they have returned to normal and/or an adequate explanation is available. 
Diseases, signs and symptoms and/or laboratory abnormalities already existing before the first 
administration of IMP are not considered as AEs when observed at a later stage unless they 
represent an exacerbation in intensity or frequency (worsening). 
The investigator responsible should always provide detailed information concerning any abnor- 
malities and the nature of, and reasons for any necessary action(s), as well as any other obser- 
vations or comments, which are useful for the interpretation and understanding of the subjects’ 
AEs or ADRs. 
 
7.4.1.3 Severity of AEs 
The intensity/severity of all AEs will be graded as follows: 
• Mild: an AE, usually transient, which causes discomfort but does not interfere with the 
subject’s routine activities. 
• Moderate: an AE which is sufficiently discomforting to interfere with the subject’s routine 
activities. 
• Severe: an AE which is incapacitating and prevents the pursuit of the subject’s routine ac- 
tivities. 
Grading of an AE is up to the medical judgement of the investigator and will be decided on a 
case-by-case basis. 

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7.4.1.4 Causality of AEs 
The relationship of AEs to the administered IMP will be assessed by the investigator responsi- 
ble: 
• Probable: reports including good reasons and sufficient documentation to assume a causal 
relationship, in the sense of plausible, conceivable, likely, but not necessarily highly prob- 
able. A reaction that follows a reasonable temporal sequence from administration of the 
IMP; or that follows a known or expected response pattern to the suspected medicine; or 
that is confirmed by stopping or reducing the dosage of the medicine and that could not 
reasonably be explained by known characteristics of the subject’s clinical state. 
• Possible: reports containing sufficient information to accept the possibility of a causal rela- 
tionship, in the sense of not impossible and not unlikely, although the connection is uncer- 
tain or doubtful, for example because of missing data or insufficient evidence. A reaction 
that follows a reasonable temporal sequence from administration of the IMP; that follows a 
known or expected response pattern to the suspected medicine; but that could readily have 
been produced by a number of other factors. 
• Unlikely: reports not following a reasonable temporal sequence from IMP administration. 
An event which may have been produced by the subject’s clinical state or by environmental 
factors or other therapies administered. 
• Not related (unrelated): events for which sufficient information exists to conclude that the 
aetiology is unrelated to the IMP. 
• Unclassified: reports which for one reason or another are not yet assessable, e.g., because 
of outstanding information (can only be a temporary assessment). 
 
7.4.1.5 Classification of ADRs 
ADRs will be classified by the Sponsor as either expected or unexpected: 
• Expected: an AE that is listed in the current edition of the Investigator’s Brochure 
• Unexpected: an AE that is not listed in the current edition of the Investigator’s Brochure, or 
that differs because of greater severity or greater specificity 
 
7.4.1.6 Outcome of AEs 
The outcome of all reported AEs has to be documented as follows: 
1. Recovered, resolved 
2. Recovering, resolving 
3. Not recovered, not resolved 
4. Recovered, resolved with sequelae 
5. Fatal 
6. Unknown 
 
NOTE: A subject’s death per se is not an event, but an outcome. The event which resulted into 
subject’s death must be fully documented and reported, even in case the death occurs within  
4 weeks after IMP treatment end, and without respect of being considered treatment-related or 
not. 

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7.4.1.7 Action(s) Taken 
AEs requiring action or therapy must be treated with recognised standards of medical care to 
protect the health and wellbeing of the subject. Appropriate resuscitation equipment and medi- 
cines must be available to ensure the best possible treatment of an emergency situation. 
The action taken by the investigator must be documented: 
1. In general: 
− 
None 
− 
Medication (other than IMP) or other (e.g., physical) therapy started 
− 
Test performed 
− 
Other (to be specified) 
2. Regarding the IMP: 
− 
None 
− 
Product withdrawn 
− 
Dose reduced 
− 
Dose increased 
The responsible investigator will follow-up each AE until it is resolved or until the medical 
condition of the subject is stable; all relevant follow-up information will be reported to the 
Sponsor. 
 
7.4.2 Serious Adverse Events 
All reported SAEs occurring after the first administration of IMP in the study will be docu- 
mented and reported for a patient throughout the duration of the patient’s participation in the 
study. This will be designated as occurring in either an “active period” (i.e., during the treatment 
observation and follow-up period) or an “inactive period” between treatment events (i.e., bleed- 
ing or surgery). 
All related concomitant medications will also be collected for these events. 
No SAEs will be collected between screening and the first treatment unless required by local 
regulations. 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening 
• Requires hospitalisation or prolongation of existing hospitalisation 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is another important medical event 

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NOTE: The term ‘life-threatening’ refers to an event in which the subject was — in the view 
of the reporting investigator — at immediate risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it were more severe. 
In other situations, medical judgement should be exercised in deciding whether an AE/ADR is 
serious: Important AEs/ADRs that are not immediately life-threatening or do not result in death 
or hospitalisation but may jeopardise the subject or may require intervention to prevent one of 
the other outcomes listed in the definitions above, should also be considered serious. 
In addition, although not classified under the seriousness criteria, all suspected transmissions 
of an infectious agent should be reported as SAE. A suspected virus transmission means that 
virus antigen has been detected in the subject. A passive transmission of antibodies alone does 
not constitute a suspected virus transmission. 
 
7.4.3 SAE Reporting Timelines 
All SAEs, whether suspected to be related to study treatment or not, are to be reported by tele- 
phone, fax or e-mail immediately to the Clinical Project Manager or designee. Contact details 
will be communicated at the study initiation visit. 
An Octapharma ‘Serious Adverse Event Report’ must be completed  and submitted within   
24 hours after recognition of the event. 
In any case, all SAEs should also be reported to 
Octapharma’s Central Drug Safety Unit: 
OCTAPHARMA Pharmazeutika Produktionsges.m.b.H. 
Oberlaaer Strasse 235, 1100 Vienna, Austria 
Fax: +43 1 61032 9949 
E-mail: cdsu@octapharma.com 
24 hours emergency telephone number: +43 1 40 80 500 
 
Waiver from SAE expedited reporting requirement 
The following SAEs do not require expedited reporting: 
• Hospitalisation for the treatment of disease-related conditions assessed as unrelated to IMP 
treatment 
• Prolongation of an existing hospitalization due to economic or social reasons, but not med- 
ical reasons 

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7.5 Vital Signs and Physical Examination, including Thromboembolic Event 
(TEE) Questionnaire 
Vital signs including systolic and diastolic blood pressure, pulse rate, respiratory rate, and body 
temperature should be recorded using standard clinical procedures at the study centres. Vital 
signs will be assessed after 3 minutes of rest in the supine or semi-recumbent position. 
Physical examination will consist of checking the general appearance, skin condition, eyes, 
ears, nose and throat examination, heart auscultation, chest, breast and abdomen examination, 
neurological assessment, lymph node palpation, spine, and extremities examination. 
The TEE questionnaire will be completed at all study visits for the treatment of bleeding epi- 
sodes and for surgeries. 
The flow chart of assessments for on-demand treatment is provided on page xxii. The flow chart 
of assessments for surgical prophylaxis is provided on page xxiii. 
 
7.6 Other Relevant Safety Information 
 
7.6.1 Post-study Related Safety Reports 
Any ADR (i.e., any AE with a suspected causal relationship to the IMP) which occurs after the 
completion of the study should be reported by the investigator. The usual procedure for report- 
ing post marketing safety information should be followed, but relation to the clinical study 
should be stated on the report. 
If a subject/patient dies within 4 weeks after the last IMP administration, this should be reported 
as well, without being considered treatment related or not. 
 
7.6.2 Overdose, Interaction, Misuse, Medication Error 
The following safety relevant information should be reported as an AE or, if the reaction fulfils 
one of the criteria for seriousness, as a SAE. 
• Drug overdose: An overdose is a deliberate or inadvertent administration of a treatment at 
a dose higher than that specified in the protocol, and higher than the known therapeutic dose 
and of clinical relevance. The reaction must be clearly identified as an overdose. 
• Interaction: A drug interaction is a situation in which a substance/medicinal product affects 
the activity of an IMP, i.e., the effects are increased or decreased, or they produce an effect 
that none of the products exhibits on its own. The reaction must be clearly identified as drug 
interaction. 
• Misuse: Misuse is the deliberate administration or use of the medicinal product outside its 
described indication or outside the current state of the art medical practice (off-label-use). 
The reaction must be clearly identified as misuse. 
• Medication error: Medication error involves the inadvertent administration or unintended 
use of a medicinal product which may be caused by the naming, presentation of pharma- 
ceutical form/packaging, and/or instructions for use/labelling. The reaction must be clearly 
identified as a medication error. 

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7.7 Other Assessments 
Not applicable. 
 
7.8 Appropriateness of Measurements 
The clinical and laboratory measurements used to assess the efficacy and safety of Octafibrin 
are generally accepted and in accordance with published recommendations. All laboratory pa- 
rameters will be evaluated by accredited laboratory facilities using standardised and validated 
methods. 
The key laboratory investigations of the study (Clauss assay, fibrinogen specific enzyme linked 
immunosorbent assay, and MCF) will be performed by a central laboratory specialised in the 
determination of coagulation parameters. 

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8 DATA HANDLING AND RECORD KEEPING 
 
8.1 Source Data and Records 
Source data are defined as all the information related to clinical findings, observations, or other 
activities in the study, written down in original records or certified copies of original records 
allowing reconstruction and evaluation of the clinical study. 
The investigator will maintain adequate source records (e.g., case histories or subject files for 
each subject enrolled). Source records should be preserved for the maximum period of time 
required by local regulations. 
For each subject enrolled, the investigator will indicate in the source record(s) that the subject 
participates in this study. 
All data entered in the CRF must be supported by source data in the subject records with the 
exceptions listed in Section 8.2. 
The investigator will permit study-related monitoring, audit(s), IEC/IRB review(s) and regula- 
tory inspection(s), by providing direct access to source data/records. 
The investigator may authorise site staff (e.g., sub-investigators, nurses) to enter study data into 
the CRF. This must be documented in the ‘Delegation of Authority Log,’, filled in and signed 
by the investigator responsible. 
 
8.2 Case Report Forms 
For each subject enrolled, a CRF will be completed. The Principal Investigator or authorised 
investigators will sign the CRF as required on the forms. 
All forms will be filled out using an indelible (black or blue) pen, and must be legible. The 
following data will be recorded directly on the CRFs, without prior written or electronic record 
of source data, turning the CRF into source: 
• Vital signs 
• Physical examination results 
• Date and time of blood sampling 
 
8.3 Changes to Case Report Form Data 
Errors occurring in CRFs will be crossed out without obscuring the original entry, the correction 
will be written alongside the initial entry, and the change will be initialled and dated by the 
investigator or authorised study site personnel. When changes to CRF data are necessary fol- 
lowing removal of the original CRF from the study site, any such changes will be documented 
on data clarification/resolution forms, which will be submitted to the investigator for signature. 

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If reason for the change is not obvious, then a reason should be given. The Principal Investigator 
must, as a minimum, sign the final CRF page to attest the accuracy and completeness of all the 
data. Once the data have been entered onto the database, they will be checked and any discrep- 
ancies will be raised and returned to the investigator for resolution. Data will be monitored and 
tabulated in accordance with the Data Management Plan. 
Once queries have been resolved by the site staff, the resolutions are assessed by Data Manage- 
ment for incomplete or ambiguous resolutions. If the query response provided confirms the data 
as correct, the discrepancy will be closed based on the query response. If the response does not 
adequately address the question raised, a new query will be issued for further clarification. 
Manual checks are performed and programs are run throughout the study until the data is clean 
and the database is ready for lock. All discrepancies will be resolved prior to database lock. 
There will be a final run of the programmed checks to ensure all discrepancies are closed out, 
source data verification will be confirmed as complete by the monitor, and all CRFs and re- 
solved data discrepancies will be approved by the investigator prior to database lock. 
 
8.4 Information of Investigators 
An Investigator’s Brochure will be handed out to the investigator before the start of the study. 
This Brochure contains all information in the Sponsor’s possession necessary for the investiga- 
tor to be fully and accurately informed about the safety of the IMP under evaluation and the 
respective benefit-risk ratio. 
The Investigator’s Brochure will be updated by the Sponsor at regular intervals and in case new 
information concerning the IMP becomes available. 
The investigators will be informed about the methods for rating relevant study outcomes and 
for completing CRFs in order to reduce discrepancies between participating investigators and 
study sites. 
The investigator will be kept informed of important data that relate to the safe use of the IMP 
as the study proceeds. 
 
8.5 Responsibilities 
The investigator is accountable for the conduct of the clinical study. If any responsibilities are 
delegated, the investigator should maintain a list of appropriately qualified persons to whom 
he/she has delegated significant study-related duties. 
A Delegation of Authority Log will be filled in and signed by the investigator responsible. In 
accordance with this authority log study site staff (e.g., sub-investigators, nurses) is authorized 
to perform study related tasks and to enter specific data into the CRF. 

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8.5.1 Co-ordinating Investigator 
The co-ordinating investigator of this study is: 
Flora Peyvandi MD, PhD 
Associate Professor of Internal Medicine, 
A. Bianchi Bonomi Hemophilia and Thrombosis Center, 
University of Milan, 
Department of Medicine and Medical Specialties, 
IRCCS Maggiore Hospital, 
Mangiagalli and Regina Elena Foundation, 
Milan, Italy 
 
8.5.2 External Parties 
Central laboratory testing, monitoring, data management, and biostatistics will be delegated 
under an agreement of transfer of responsibilities to a central laboratory or an external Contract 
Research organisation (CRO). 
All Octapharma procedures and policies have to be met by external parties (CROs and central 
laboratories), discrepancies or exceptions are to be approved by Octapharma. All parties in- 
volved in the study are responsible to comply with local and international obligations, regula- 
tory requirements and duties in accordance with local laws, GCP guidelines, SOPs and other 
applicable regulations. 
 
8.6 Investigator’s Site File 
At each study site, the investigator is responsible for maintaining all records to enable the con- 
duct of the study to be fully documented. Essential documents as required by GCP guidelines 
and regulations (e.g., copies of the protocol, study approval letters, all original informed consent 
forms, site copies of all CRFs, drug dispensing and accountability logs, correspondence per- 
taining to the study, etc.) should be filed accurately and kept by the investigator for the maxi- 
mum period of time required by local regulations. 
The investigator is responsible for maintaining a confidential subject identification code list, 
which provides the unique link between named source records and CRF data for the Sponsor. 
The investigator must arrange for the retention of this confidential list for the maximum period 
of time required by local regulations. 
No study document should be destroyed without prior written agreement between the investi- 
gator and the Sponsor. Should the investigator elect to assign the study documents to another 
party, or move them to another location, the Sponsor must be notified in writing. 

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8.7 Provision of Additional Information 
On request, the investigator will supply the Sponsor with additional data relating to the study, 
or copies of relevant source records, ensuring that the subject’s confidentiality is maintained. 
This is particularly important when CRFs are illegible or when errors in data transcription are 
encountered. In case of particular issues or governmental queries, it is also necessary to have 
access to the complete study records, provided that the subject’s confidentiality is protected in 
accordance with applicable regulations. 
 
8.8 Independent Data Monitoring & Endpoint Adjudication Committee 
An Independent Data Monitoring & Endpoint Adjudication Committee (IDMEAC) will be es- 
tablished by the Sponsor. The IDMEAC will be composed of recognised experts in the field of 
clinical care who are not actively recruiting subjects. 
The IDMEAC will review relevant data periodically during the study and will give advice on 
the continuation, modification, or termination of the study. This committee will also be respon- 
sible for adjudicating the primary and secondary efficacy endpoints in the study. 
A IDMEAC charter will define in detail the composition, responsibilities and procedures of the 
IDMEAC. 

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9 STATISTICAL METHODS AND SAMPLE SIZE 
The statistical analysis will be delegated under an agreement of transfer of responsibilities to 
an external Contract Research Organization (CRO). All Octapharma procedures and policies 
have to be met by this CRO. Discrepancies or exceptions are to be approved by the Sponsor’s 
Manager of Biometrics. 
A statistical analysis plan (SAP) describing all details of the analyses to be performed will be 
prepared by the study statistician and approved by the Sponsor before the start of the study. 
Due to the low number of patients, all statistical analysis will be descriptive only. 
Continuous variables will be summarised using descriptive statistics (including arithmetic 
mean, standard deviation (SD), median, minimum and maximum, number of observations and 
missing observations). Categorical variables will be summarised with counts and percentages. 
 
9.1 Sample Size 
The number of subjects is limited by the very small number of patients with this indication. At 
least 12 patients will undergo PK assessments in this study. The minimum number of paediat- 
ric patients with a haemostatic outcome assessment for the on-demand treatment of a bleeding 
episode will be 6 and has been agreed upon with the paediatric committee of the EMA. No 
confirmatory test is provided. Therefore, no sample size estimation is provided. 
 
9.2 Populations for Analysis 
 
9.2.1 Safety Population 
The safety population will include all subjects who received at least one infusion of the IMP. 
The analysis of safety will be based on this population. 
 
9.2.2 Full Analysis Set 
The full analysis set (FAS) defined according to the intention-to-treat (ITT) principle will in- 
clude subjects who fulfil all of the following conditions: 
• Received at least one infusion of the IMP 
• Entered the study with a confirmed congenital fibrinogen deficiency (second inclusion cri- 
terion; see Section 4.2) 

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9.2.3 PK Analysis Population 
The PK analysis population includes all patients of the FAS who started the PK assessment and 
have at least one valid post-baseline fibrinogen activity level. 
 
9.2.4 PK-PP Population 
The PK-PP population includes patients in the PK analysis population who completed the PK 
sampling phase without significantly violating the inclusion/exclusion criteria or other aspects 
of the protocol considered to potentially affect the PK results: 
Especially patients will be excluded from this population, if they meet the following protocol 
deviations: 
• Bleeding disorder other than congenital fibrinogen deficiency, including dysfibrinogenae- 
mia 
• Any fibrinogen concentrate or other fibrinogen-containing blood product within 2 weeks 
prior to start of treatment for the PK phase 
• Diagnosis or suspicion of a neutralising anti-fibrinogen inhibitor currently or at any time 
in the past 
• Patients who use concomitant medication before or during the PK phase that may con- 
found study results 
• Patients who receive less than 90% of the planned dose (nominal) 
• Fibrinogen baseline measurement for PK assessment missing 
• More than 2 post-baseline blood samples missing for PK assessment 
 
9.2.5 FirstBLEED Population 
The FirstBLEED population will include subjects of the FAS who fulfil the following condi- 
tion: 
• Presented with at least one episode of acute bleeding (third inclusion criterion; see 
Section 4.2) treated with Octafibrin 
 
9.2.6 FirstBLEED-PP Population 
The FirstBLEED-PP population will include subjects of the FirstBLEED population who fulfil 
the following conditions: 
• Provide valid, i.e., non-missing, haemostatic efficacy data for their first bleeding 
• Received ≥90% of the planned total dose of the IMP in the first infusion for their first bleed- 
ing 
• Received ≥80% of the calculated dose (if no dose was calculated, 0% will be assumed) of 
the IMP over all further infusions of the first bleeding according to the treatment schedule 

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• Did not meet any of the following exclusion criteria: 
– Bleeding disorder other than congenital fibrinogen deficiency 
– End-stage liver disease (i.e., Child-Pugh-score B or C) 
– Suspicion of an anti-fibrinogen inhibitor as indicated by previous IVR, if available 
<0.5 (mg/dL)/(mg/kg) 
– Treatment with any fibrinogen concentrate or other fibrinogen-containing blood 
product within 2 weeks prior to start of treatment for the bleeding episode 
• Did not use any coagulation-active drug (i.e., non-steroidal anti-inflammatory drugs, war- 
farin, coumarin derivatives, platelet aggregation inhibitors) within 1 week prior to start of 
treatment for the first bleeding episode, or as a planned or expected medication during the 
time period from Day 1 until 24 hours (i.e., 1 day) after the last Octafibrin infusion 
 
9.2.7 BLEED Population 
The BLEED population will include all documented bleeding episodes treated with Octafibrin 
in subjects of the FAS. 
 
9.2.8 BLEED-PP Population 
A BLEED-PP population comprising bleeding episodes with no major protocol deviations will 
be defined in the SAP, with criteria similar to the FirstBLEED-PP population. 
 
9.2.9 SURG population 
The SURG population will include all surgical interventions with a need for at least one infusion 
of the IMP during the time period from the day of surgery until overall clinical assessment of 
haemostatic efficacy (third inclusion criterion; see Section 4.2) in subjects of the FAS. 
A SURG-PP population comprising surgical interventions with no major protocol deviations 
will be defined in the SAP with criteria similar to the FirstBLEED-PP population. 
 
NOTE: Any protocol deviations which will lead to the exclusion from an analysis population 
other than those mentioned above must be agreed upon in writing by the Sponsor and the study 
statistician, and in any case, before database closure. 
The efficacy analysis for the primary endpoint will be performed with the data from the first 
bleeding event of each patient using the FirstBLEED population (ITT analysis) as the primary 
population and using the FirstBLEED-PP population (PP analysis) as a secondary population. 
An additional analysis will be performed for all bleeding events on the BLEED and BLEED- 
PP population. The primary analysis population for the PK analysis will be the PK-PP popula- 
tion. 
 
9.2.10 Subpopulations 
Subpopulations based on the following categories will be examined: 
• Severity of bleeding: minor versus major (subpopulations of the BLEED population) 
• Age 0 to <6 years versus 6 to <12 years 

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9.3 Efficacy Analysis Plan 
 
9.3.1 Primary Endpoint 
The primary endpoint is the overall clinical assessment of haemostatic efficacy of Octafibrin in 
treating the first documented bleeding episode of each patient (FirstBLEED population). The 
first bleeding episode covers the time period from the first Octafibrin infusion until 24 hours 
(i.e., 1 day) after the last infusion or the end of the treatment observation period, whichever 
comes last (see Section 3.1.1). The final efficacy assessment of each patient will be adjudicated 
by an Independent Data Monitoring & Endpoint Adjudication Committee (IDMEAC). 
Frequency distribution will be provided for the haemostatic efficacy scale data. In addition, the 
assessment made by the investigator on the 4-point rating scale will be transformed to a dichot- 
omous endpoint with success defined as a rating of ‘excellent’ or ‘good’. A 2-sided 95% CI for 
the success rate in haemostatic efficacy (‘excellent’ or ‘good’) according to Clopper/Pearson 
will be computed. 
For the following subjects, the haemostatic efficacy outcome will be set to the worst efficacy 
category, i.e., ‘none’: 
• Subjects who withdraw from the study due to lack of efficacy 
• Subjects receiving cryoprecipitate or concentrates containing fibrinogen other than the IMP 
between first infusion and efficacy assessment (unless it is clearly documented that these 
products were administered for reasons unrelated to IMP efficacy [e.g., pharmacy error]) 
• Subjects with missing haemostatic efficacy assessment 
Haemostatic efficacy will be displayed by covariables (sex, age groups, weight, type of bleed- 
ing) in tables or with covariables in listings depending on the number per subgroup. 
 
9.3.2 Secondary Endpoints 
 
9.3.2.1 Pharmacokinetics (PK) 
The primary PK analysis will be based on the PK-PP population. 
The exact applied dose of fibrinogen concentrate (expressed as mg/kg dosed) will be calculated 
for each subject, based upon the actually administered amount of each study treatment and the 
potency of fibrinogen in the actually used batch. 
PK analysis on fibrinogen activity and antigen levels will be performed per patient with a non- 
compartmental model using standard PK software (Phoenix [28]); this includes graphical dis- 
plays of individual elimination curves. Individual endogenous baseline concentrations, if any, 
will be taken into account by subtraction from post-baseline values. The resulting PK parame- 
ters will be summarized and presented as described for continuous variables. 
The PK endpoints (i.e., area under the concentration-time curve (AUC), incremental IVR, clas- 
sical IVR, terminal elimination half-life (t1/2), maximum plasma concentration (Cmax), time to 
reach maximum plasma concentration (Tmax), mean residence time (MRT), volume of distri- 
bution (Vss), and clearance (Cl)) will be assessed after a single intravenous infusion of 70 mg/kg 
body weight of Octafibrin. 

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9.3.2.2 Clot strength (MCF) 
The analysis of MCF will be provided for the BLEED population. 
MCF before as well as MCF and fibrinogen activity 1 hour after the end of the first infusion, as 
well as changes in MCF from pre-infusion will be summarised over all bleeding episodes using 
descriptive statistics. The course of laboratory data will be presented graphically. Mean changes 
in MCF will be described with 2-sided 95% CIs based on the paired t-test. 
The same analyses or respective listings (depending on the number of observations per sub- 
group) will be provided separated for the predefined subgroups as well as separated for the 
subjects’ clinical outcome represented by each step of the 4-point haemostatic efficacy scale 
(excellent, good, moderate, none) and the dichotomised haemostatic efficacy scale (excel- 
lent/good, moderate/none). Boxplots will show MCF by haemostatic efficacy outcome, if ap- 
plicable. 
 
9.3.2.3 In-vivo recovery 
IVR will be determined for the first infusion of each bleeding episode (see Section 7.2.2.3). The 
analysis population will be the BLEED population. 
Incremental IVR (response) will be calculated as the maximum increase in plasma fibrinogen 
(i.e., Clauss data) between the pre-infusion and the 3-hour post-infusion measurement (ex- 
pressed as absolute concentration in plasma [mg/dL]), divided by the exact dose of Octafibrin 
(expressed as mg/kg dosed): 
 
Incremental IVR (response) (mg/dL increase/[mg/kg b.w.]) = 
Maximum increase in fibrinogen plasma level up to the 3-hour measurement 
post-infusion compared to pre-infusion (mg/dL) / 
(exact dose of component in IMP administered [mg]/b.w. [kg]) 
 
Classical IVR will be calculated as the maximum increase in plasma fibrinogen (i.e., Clauss 
data) between the pre-infusion and the 3-hour post-infusion measurement (expressed as abso- 
lute concentration in plasma [mg/dL]), divided by the total dose of Octafibrin per expected 
plasma volume (expressed as mg/dL, expected plasma volume being estimated based on the 
blood volume formula described by Nadler [27]): 
 
Classical IVR (%) = 
100% x actual/expected increase = 
100% x maximum increase in fibrinogen plasma level 1 and 3 hours post-infu- 
sion compared to pre-infusion (mg/dL) x plasma volume (dL) / (exact dose of 
component in IMP administered [mg]). 
 
Descriptive tables will show the distribution of IVRs separated by minor and major bleeding 
events. Fibrinogen levels before and 1 hour after each infusion will be listed. 

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9.3.2.4 Efficacy of Octafibrin in All Bleeding Episodes 
The efficacy of Octafibrin in the treatment of all bleeding episodes recorded throughout the 
study observation period will be assessed in the same way as the efficacy of Octafibrin in the 
treatment of the first bleeding episode per patient (see Section 9.3.1). 
In addition to the ‘first BE per patient approach,’ haemostatic efficacy (4-point scale) and suc- 
cess rates for the treatment of bleeding episodes will be presented descriptively for all bleeding 
episodes (BLEED population) by frequency tables. 
Success rate estimates will also be provided with two-sided 95% CIs, considering both 
• the assessments of each bleeding episode as an independent case within each subject and 
• outcomes of assessments as repeated measurements within the same patient, if applicable 
(e.g., by general estimation equations with intra-subject correlation structure). 
 
9.3.2.5 Surgical Prophylaxis 
Efficacy of Octafibrin in surgical prophylaxis will be assessed intra-operatively (at the end of 
surgery = after last suture) by the surgeon and post-operatively by the haematologist using two 
4-point efficacy scales (see Section 7.2.2.4). The primary analysis regarding haemostatic effi- 
cacy will be done on the adjudicated assessments using the algorithm described in Table 4 and 
by the IDMEAC. 
The following will be presented in frequency tables with descriptive statistics or in listings, 
depending on the number of surgeries: 
• Adjudicated overall efficacy assessment by the described algorithm and the IDMEAC 
• Efficacy evaluation by the surgeon and the haematologist (intra- and post-operatively) 
• Number of patients undergoing surgeries and number of surgeries (minor, major, total) 
• Surgery characteristics (type and site, pre-planned (yes/no), reason, severity, expected and 
actual duration, expected and actual blood loss) 
• Details on treatment with Octafibrin (before, during, and after the surgical procedure 
(number of infusions, dosing details, amount of IMP) 
• Pre-, intra-, and post-operative fibrinogen plasma levels, pre- and post-infusion 
In documenting the adjudication process for the assessment of surgical prophylaxis, the 
IDMEAC will explicitly identify any subjects for whom they considered there to be ‘unex- 
pected blood loss due to surgical complications’ and state whether this unexpected blood loss 
altered the 4-point assessment of surgical prophylaxis. Any such cases will be analyzed both 
including (as a sensitivity analysis) and excluding the unexpected blood loss. 

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9.4 Safety Analysis Plan 
The analysis of safety will be based on the safety population. 
All AEs (including events likely to be related to the underlying disease, or a concomitant illness 
or medication or clinically significant abnormalities in laboratory parameters or vital signs) will 
be displayed in summary tables and listings. 
Incidences of AEs will be given as numbers and percentages of subjects with: 
• Any AE 
• Any SAE 
• Any AE probably or possibly related to the IMP 
• Any AE temporally related (within 24 hours after end of infusion) to the IMP 
• Any severe AE 
• Any withdrawal due to AE 
• Any AE by Medical Dictionary for Regulatory Activities (MedDRA) preferred term (de- 
scending frequency) 
• Any AE temporally related (within 24 hours after end of infusion) by MedDRA preferred 
term (descending frequency) 
• Any AE by MedDRA system organ class (SOC) 
• Any AE temporally related (within 24 hours after end of infusion) by MedDRA SOC 
Summary tables for AEs will be given by SOC and preferred term. Additionally, AEs will be 
summarised by severity and relationship to the IMP 
The MedDRA coded terms and the corresponding original (verbatim) terms used by the inves- 
tigator will be listed. 
For laboratory variables (analyses of haematology, clinical chemistry, and thrombogenicity), 
the mean, standard deviation, median, and range will be presented per time point. Laboratory 
variables will also be presented graphically. Intra-individual changes between pre-infusion and 
the respective post-infusion time points will be analysed using shift tables and graphical presen- 
tations. Fibrinogen inhibitor testing data will be summarized in frequency tables. 
For vital signs, the mean, standard deviation, median, and range will be presented per time point 
(original values and intra-individual changes between pre-infusion and the respective post-in- 
fusion time points). Physical examination data will be presented in frequency tables. 

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9.5 Additional Analyses 
Octafibrin use 
Octafibrin will be individually dosed to achieve a recommended target fibrinogen plasma level 
dependent on the bleeding type (minor or major). Individual doses, achieved FVIII level after 
dosing, the target level as well as the difference between target level and achieved level will be 
listed, summarized using descriptive statistics and displayed graphically. 
The dose of the IMP used per day and in total will be summarised using descriptive statistics 
for minor and major bleeding events. Frequency of infusions and duration of treatment will also 
be summarised. 
 
9.6 Handling of Missing Data 
In general, if not stated differently, missing data will not be imputed. 
If the haemostatic efficacy assessment is missing, it will be set to ‘none’ in the ITT analysis. 
Subjects  with  missing  haemostatic  efficacy   assessment   will   be   excluded   from   the 
PP population. 
Missing PK parameters, MCF and IVR values will not be replaced. 
 
9.7 Randomisation 
Not applicable. 
 
9.8 Interim Analysis 
An administrative interim analysis will be performed after at least 12 patients have undergone 
PK assessment within the study. The interim analysis will focus on the PK data only. The results 
of the interim analysis will have no impact on the further conduct of the study. 

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10 ETHICAL, REGULATORY, LEGAL AND ADMINISTRATIVE 
ASPECTS 
 
10.1 Ethical and Regulatory Framework 
This study will be conducted in accordance with the ethical principles laid down in the Decla- 
ration of Helsinki. The study protocol and any subsequent amendment(s) will be submitted to 
an IEC/IRB and to the Regulatory Authority. The study will be conducted in compliance with 
the protocol, GCP regulations and applicable regulatory requirements. 
The regulatory application or submission for regulatory approval will be made by the Sponsor 
or designated third party (e.g., CRO), as required by national law. 
 
10.2 Approval of Study Documents 
The study protocol, a sample of the subject information and informed consent form, any other 
materials provided to the subjects, and further requested information will be submitted by the 
Sponsor or the investigator to the appropriate IEC/IRB and the Regulatory Authority. The study 
approval letter must be available before any subject is exposed to a study-related procedure. 
The Sponsor, the investigator and any third party (e.g., CRO) involved in obtaining approval, 
must inform each other in writing that all ethical and legal requirements have been met before 
the first subject is enrolled in the study. 
 
10.3 Subject Information and Informed Consent 
At screening, the investigator will obtain a freely given written consent from each subject’s 
legal guardian after an appropriate explanation of the aims, methods, anticipated benefits, po- 
tential hazards and any other aspect of the study which is relevant to the legal guardian’s deci- 
sion to have the subject participate. The informed consent form must be signed, with name and 
date and time noted by the subject’s legal guardian and the investigator, before the subject is 
exposed to any study-related procedure, including screening tests for eligibility. 
If the period between screening and treatment is more than 3 months, informed consent will be 
reviewed and confirmed prior to treatment, and details of the review process will be recorded 
in the patient chart and indicated by the investigator. 
The investigator will explain that the legal guardian is completely free to refuse to have the 
subject enter the study or to withdraw the subject from it at any time, without any consequences 
for the further care of the subject and without the need to justify. The investigator will complete 
the informed consent section of the CRF for each subject enrolled. 
Each legal guardian will be informed that the subject’s medical (source) records may be re- 
viewed by the study monitor, a quality assurance auditor or a health authority inspector, in 
accordance with applicable regulations, and that these persons are bound by confidentiality ob- 
ligations. 

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10.4 Protocol Amendments 
Any prospective change to the protocol will be agreed between the investigator (co-ordinating 
investigator in multi-centre studies) and the Sponsor prior to its implementation. Any such 
amendments will be submitted to the IEC(s/IRB) and/or competent authority responsible as 
required by applicable regulations. IEC(s)/IRB approval will at a minimum be requested for 
any change to this protocol which could affect the safety of the subjects, the objective/design 
of the study, any increase in dosage or duration of exposure to the IMP an increase in the num- 
ber of subjects treated, the addition of a new test or procedure, or the dropping of a test intended 
to monitor safety. 
 
10.5 Confidentiality of Subjects Data 
The investigator will ensure that the subject’s confidentiality is preserved. On CRFs or any 
other documents submitted to the Sponsor, the subjects will not be identified by their names, 
but by a unique subject number. Documents not for submission to the Sponsor, i.e., the confi- 
dential subject identification code list, original consent forms and source records will be main- 
tained by the investigator in strict confidence. 

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

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12 REPORTING AND PUBLICATION 
 
12.1 Clinical Study Report 
A clinical study report (in accordance with relevant guidelines and Sponsor’s SOPs) will be 
prepared by the Sponsor after the completion of the study. The co-ordinating investigator will 
approve the final study report after review. The clinical study report will be available for the 
submission to the competent authorities in the 2nd quarter of 2021. 
 
12.2 Publication Policy 
The results of this study may be published or presented at scientific meetings. If this is envis- 
aged by an investigator, the investigator agrees to inform the Sponsor and to submit all manu- 
scripts or abstracts to the Sponsor prior to submission to an editorial board or scientific review 
committee. This will allow the Sponsor to protect proprietary information and to provide com- 
ments based on information that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will support publication 
of multi-centre studies only in their entirety and not as individual centre data. Authorship will 
be determined by mutual agreement. 

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

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14 REFERENCES 
 
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15 APPENDICES 
None.