Clinical trial NCT02267226
Conditions: Congenital Fibrinogen Deficiency
Sponsor: Octapharma
Start date: 2014-09-01; Completion date: 2018-02-14
Enrollment: 25 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of the study is to assess the efficacy and safety of Octafibrin for on-demand treatment of acute bleeding in subjects with congenital fibrinogen deficiency.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Octafibrin
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_002.pdf: 
CLINICAL STUDY PROTOCOL 
FORMA-02 
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 and safety of Octafibrin for on-demand treatment of acute 
bleeding and to prevent bleeding during and after surgery in 
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-02 
EudraCT Number: 
2011-002419-27 
Development Phase: 
Phase III 
Planned Clinical Start: 
4th quarter 2014 
Planned Clinical End: 
4th quarter 2019 
Date of Protocol: 
31-Oct-2014 
Version: 
6.0, includes 
Protocol Amendment #1, 6-Aug-2014, for Russia 
Protocol Amendment #2, 31-Oct-2014 
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 
 
 
 
 
90- CSP-FORMA-02-06/DOC ID 2199 


Study Protocol 
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STUDY OUTLINE 
 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Octafibrin 
Protocol Identification Code: 
FORMA-02 
Name of Active Ingredient: 
Fibrinogen 
Date of Final Protocol: 
31-Oct-2014 
 
Title of Study: 
Prospective, open-label, uncontrolled, Phase III study to assess the efficacy and safety of 
Octafibrin for on-demand treatment of acute bleeding and to prevent bleeding during and 
after surgery in subjects with congenital fibrinogen deficiency 
Indication: Congenital fibrinogen deficiency 
Number of Study Centres: Approximately 15 study centres worldwide. 
Study Duration: 4th quarter 2014 to 4th quarter 2019 
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 show 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) that was used as a surrogate endpoint for 
haemostatic efficacy and determined via thromboelastography (TEG) in the pivotal 
pharmacokinetic (PK) study FORMA-01. Therefore, MCF as surrogate efficacy 
parameter will be determined before first infusion and 1 hour after end of first and last 
infusion. 
• 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, 
including immunogenicity, thromboembolic complications, and early signs of allergic or 
hypersensitivity reactions. 
Study Design: 
Multinational, multi-centre, prospective, open-label, uncontrolled, Phase III study. 


Study Protocol 
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Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Octafibrin 
Protocol Identification Code: 
FORMA-02 
Name of Active Ingredient: 
Fibrinogen 
Date of Final Protocol: 
31-Oct-2014 
 
Number of Subjects: 
A minimum of 24 subjects will be enrolled in the study to assess on-demand treatment of at 
least one bleeding episode. This will include at least 4 subjects aged between 12 and 18 
years (only 18 and above in Russia). This will also include an assessment of at least 4 
surgical procedures, 2 of which should be performed in subjects aged between 12 and 18 
years (only 18 and above in Russia). 
 
Subject Selection Criteria: 
 
Inclusion criteria: 
1. Aged ≥12 years (only 18 and above in Russia). 
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 
hypofibrinogenaemia. 
− 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 
planning to undergo elective surgery. 
4. Informed consent signed by the subject or 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 bleeding episode or surgery. 
− 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 
(i.e., 1 day) after the last Octafibrin infusion. 


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Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Octafibrin 
Protocol Identification Code: 
FORMA-02 
Name of Active Ingredient: 
Fibrinogen 
Date of Final Protocol: 
31-Oct-2014 
 
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. Pregnant women within the first 20 weeks of gestation. 
7. Currently breast-feeding. 
8. Known positive HIV infection with a viral load >200 particles/μL 
or >400,000 copies/mL. 
9. Polytrauma 1 year prior to start of treatment for the bleeding episode or surgery. 
10. Diagnosis or suspicion of a neutralizing anti-fibrinogen inhibitor currently or any 
time in the past. 
11. 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. 
− Subjects having evidence or a history (within the previous 12 months) of abuse 
of any licit or illicit drug substance. 
12. Participation in another interventional clinical study currently or during the past 4 
weeks. 


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Fibrinogen dose 
= 
[Target peak plasma level (mg/dL) − measured level (mg/dL)**] 
(mg/kg body weight) 
 
 
Median response* (mg/dL per mg/kg body weight) 
 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Octafibrin 
Protocol Identification Code: 
FORMA-02 
Name of Active Ingredient: 
Fibrinogen 
Date of Final Protocol: 
31-Oct-2014 
 
Test Product, Dose, Mode of Administration, and Batch Number(s): 
In this study, Octafibrin will be administered as intravenous (i.v.) bolus injection. 
Continuous infusion is not allowed. 
 
Octafibrin 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: 
*The median response in this dose calculation formula is the median incremental in vivo recovery reported in the 
interim analysis of study FORMA-01. 
**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. 
 
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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Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Octafibrin 
Protocol Identification Code: 
FORMA-02 
Name of Active Ingredient: 
Fibrinogen 
Date of Final Protocol: 
31-Oct-2014 
 
 
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 
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. 
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 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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Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Octafibrin 
Protocol Identification Code: 
FORMA-02 
Name of Active Ingredient: 
Fibrinogen 
Date of Final Protocol: 
31-Oct-2014 
 
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). 
• 3rd molar extraction or extraction of > 3 teeth. 
• 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 24 subjects have at least one 
documented bleeding episode. 
Planned duration for an individual subject: 
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 for up to 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 epi- 
sodes or planned surgeries that can be managed under the protocol. Patients may remain in 
the study until the 24th patient has at least one documented bleeding episode. 
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 


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Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Octafibrin 
Protocol Identification Code: 
FORMA-02 
Name of Active Ingredient: 
Fibrinogen 
Date of Final Protocol: 
31-Oct-2014 
 
assessed as a secondary endpoint. 
Patients who are screened for the study but do not present with a bleeding episode or 
planned surgery during the study observation period will be considered ’no treatment’ 
patients and reported separately. 
Reference Therapy, Dose, Mode of Administration, and Batch Number(s): 
Not applicable. 
Study Outcome Parameters (Primary and Secondary Endpoints): 
Efficacy: 
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 
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. 
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 
assessment 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 
haemostatic 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 
required, 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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Post-operative efficacy as assessed by haematologist 
 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Octafibrin 
Protocol Identification Code: 
FORMA-02 
Name of Active Ingredient: 
Fibrinogen 
Date of Final Protocol: 
31-Oct-2014 
 
Secondary endpoints: 
• MCF assessment before first infusion and 1 hour after end of first and last 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 of each documented bleeding episode). 
• Response as indicated by incremental IVR, calculated as the maximum increase in 
plasma fibrinogen (Clauss data) between pre-infusion and 1 and 3 hours post-infusion. 
• 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 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 
 
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 
haemostasis 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 
replacement regimen. 
 
*All 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) 
Excellent No post-operative bleeding or oozing that was not due to complications of 
surgery. All post-operative bleeding (due to complications of surgery) was 
controlled with Octafibrin as anticipated for the type of procedure. 
Good 
No post-operative bleeding or oozing that was not due to complications of 
surgery. Control of post-operative bleeding due to complications of surgery 
required increased dosing with Octafibrin or additional infusions, not 
  
originally anticipated for the type of procedure. 
 
Intra-operative efficacy as assessed by surgeon (at the end of the surgery=after last suture) 


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Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Octafibrin 
Protocol Identification Code: 
FORMA-02 
Name of Active Ingredient: 
Fibrinogen 
Date of Final Protocol: 
31-Oct-2014 
 
 
Moderate Some post-operative bleeding and oozing that was not due to complications of 
surgery; control of post-operative bleeding required increased dosing with 
Octafibrin or additional infusions, not originally anticipated for the type of 
procedure. 
None 
Extensive uncontrolled post-operative bleeding and oozing. Control of post- 
  
operative 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. 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 based on 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 Octafibrin 
(pre-, intra- and/or post-operatively) will be recorded. Fibrinogen plasma levels (pre-, 
intra-, and post-operatively) 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. 
• Safety: 
− Vital signs. 
− Physical examination. 
− Routine clinical laboratory assessment, including coagulation parameters. 
− Adverse events (AEs), including thromboembolic complications and early signs of 
allergic or hypersensitivity reactions. 
− Immunogenicity testing at Day 14 and Day 30 after the administration of Octafibrin 
for bleeding. 


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Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Octafibrin 
Protocol Identification Code: 
FORMA-02 
Name of Active Ingredient: 
Fibrinogen 
Date of Final Protocol: 
31-Oct-2014 
 
Summary of Study Procedures: 
 
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. 
• Demography, medical history (including details concerning allergic tendencies), review 
of previous therapy, and prior/concomitant medication. 
 
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. 
NOTE: All adverse events (AEs), 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. 
Concomitant medications will also be recorded throughout each 30-day observation and 
follow-up period. 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 
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. 
 
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. 


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Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Octafibrin 
Protocol Identification Code: 
FORMA-02 
Name of Active Ingredient: 
Fibrinogen 
Date of Final Protocol: 
31-Oct-2014 
 
• Physical examination. 
• 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 
− retention plasma and serum samples for potential retesting (within 30 minutes 
before infusion). 
• Urine (dip stick) or blood pregnancy test for all female subjects of childbearing 
potential. 
 
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. 
 
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. 
• Blood draw for: 
− fibrinogen plasma level (local lab–activity; central lab–antigen and activity) 
− MCF 
− safety lab (local–haematology and clinical chemistry) 
− thrombogenicity 
− retention plasma samples for potential retesting. 
3 hours (±15 minutes) after the end of infusion: 
• Vital signs. 
• Blood draw for 
− fibrinogen plasma level (central lab–antigen and activity) 


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Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Octafibrin 
Protocol Identification Code: 
FORMA-02 
Name of Active Ingredient: 
Fibrinogen 
Date of Final Protocol: 
31-Oct-2014 
 
− safety lab (local–haematology and clinical chemistry) 
− thrombogenicity 
− retention plasma samples for potential retesting. 
• 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. 
 
Daily assessments (for at least 3 days for minor bleeding or 7 days for major bleeding) 
• 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) 
− retention plasma samples for potential retesting. 
• AEs and concomitant medications. 
Octafibrin infusion, as required 
After these daily assessments, 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 
fibrinogen 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. 


Study Protocol 
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Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Octafibrin 
Protocol Identification Code: 
FORMA-02 
Name of Active Ingredient: 
Fibrinogen 
Date of Final Protocol: 
31-Oct-2014 
 
 
Pre- and post-infusion assessments 
If the subject receives an infusion of Octafibrin, the following pre- and post-infusion assess- 
ments will be done. 
Pre-infusion assessments: 
• Blood draw for (within 30 minutes before infusion): 
− fibrinogen plasma level (local lab–activity; central lab–antigen and activity) 
− retention plasma samples for potential retesting. 
1 hour (±15 minutes) after the end of each infusion: 
• Vital signs. 
• Blood draw for: 
− fibrinogen plasma level (local lab–activity; central lab–antigen and activity) 
− safety lab (local–haematology and clinical chemistry) 
− thrombogenicity 
− retention plasma samples for potential retesting. 
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 
multiple infusions are needed: 
• Blood draw for (within 30 minutes before infusion): 
− fibrinogen plasma level (local lab–activity; central lab–antigen and activity) 
− retention plasma samples for potential retesting. 
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. 


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CONFIDENTIAL 
Version 6.0 
31-Oct-2014 
xiv 
 
 
 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Octafibrin 
Protocol Identification Code: 
FORMA-02 
Name of Active Ingredient: 
Fibrinogen 
Date of Final Protocol: 
31-Oct-2014 
 
 
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. 
• Blood draw for: 
− fibrinogen plasma level (local lab–activity; central lab–antigen and activity) 
− MCF 
− safety lab (local–haematology and clinical chemistry) 
− thrombogenicity 
− retention plasma samples for potential retesting. 
3 hours (±15 minutes) after the end of last infusion: 
• Vital signs. 
• Blood draw for: 
− fibrinogen plasma level (central lab–antigen and activity) 
− safety lab (local–haematology and clinical chemistry) 
− thrombogenicity 
− retention plasma samples for potential retesting. 
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. 
• Blood draw for: 
− fibrinogen plasma level (central lab–antigen and activity) 
− safety lab (local–haematology and clinical chemistry) 
− thrombogenicity 
− retention plasma samples for potential retesting. 
• 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. 
 
Day 14 (13 days after the first infusion) 
On Day 14 (± 2 days), the following assessments will be performed: 
• Blood draw for: 


Study Protocol 
No. FORMA-02 
CONFIDENTIAL 
Version 6.0 
31-Oct-2014 
xv 
 
 
 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Octafibrin 
Protocol Identification Code: 
FORMA-02 
Name of Active Ingredient: 
Fibrinogen 
Date of Final Protocol: 
31-Oct-2014 
 
− immunogenicity 
− retention plasma samples for potential retesting. 
• AEs and concomitant medications. 
Day 30 (29 days after the first infusion)—Final Examination 
On Day 30 (± 1 week), the following assessments will be performed: 
• Physical examination. 
• Blood draw for: 
− immunogenicity 
− retention plasma samples 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 will be asked to return for a Study Completion Visit. 
If the patient experiences another bleeding event between Day 14 and 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. 
Any additional bleeding episodes will be documented in the same way as the first bleeding 
episode. They will not be used for the analysis of the primary endpoint, but they will be 
included in the analysis as a secondary endpoint. 
 
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. 
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. 


Study Protocol 
No. FORMA-02 
CONFIDENTIAL 
Version 6.0 
31-Oct-2014 
xvi 
 
 
 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Octafibrin 
Protocol Identification Code: 
FORMA-02 
Name of Active Ingredient: 
Fibrinogen 
Date of Final Protocol: 
31-Oct-2014 
 
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. 
 
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: 
• Vital signs. 
• Physical examination. 
• Body weight (kg). 
• Blood draw for: 
− fibrinogen plasma levels (local lab–activity; central lab–antigen and activity) 
− safety lab (local–haematology and clinical chemistry). 
− thrombogenicity. 
− retention plasma and serum samples for potential retesting. 
• Urine (dip stick) or blood pregnancy test for all female subjects of childbearing 
potential. 
• 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-02 
CONFIDENTIAL 
Version 6.0 
31-Oct-2014 
xvii 
 
 
 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Octafibrin 
Protocol Identification Code: 
FORMA-02 
Name of Active Ingredient: 
Fibrinogen 
Date of Final Protocol: 
31-Oct-2014 
 
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). 
− retention plasma samples for potential retesting. 
Assessments at the end of surgery 
• Blood draw for: 
− fibrinogen plasma levels (local lab–activity; central lab–antigen and activity). 
− thrombogenicity. 
− retention plasma samples for potential retesting. 
• 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. 
• Blood draw for: 
− fibrinogen plasma levels (local lab–activity; central lab–antigen and activity) 
− safety lab (local–haematology and clinical chemistry) 
− retention plasma for potential retesting. 
• Wound haematomas and oozing (noting whether surgical evacuation is required and 
severity 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: 


Study Protocol 
No. FORMA-02 
CONFIDENTIAL 
Version 6.0 
31-Oct-2014 
xviii 
 
 
 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Octafibrin 
Protocol Identification Code: 
FORMA-02 
Name of Active Ingredient: 
Fibrinogen 
Date of Final Protocol: 
31-Oct-2014 
 
• If the actual fibrinogen plasma level is below the accepted lower limit of the target 
fibrinogen 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 
assessments will be performed: 
Pre-infusion assessments: 
• Blood draw for (within 30 minutes before infusion): 
− fibrinogen plasma level (local lab–activity; central lab–antigen and activity) 
− retention plasma samples for potential retesting. 
1 hour (±15 minutes) after the end of each infusion: 
• Vital signs. 
• Blood draw for: 
– fibrinogen plasma level (local lab–activity; central lab–antigen and activity) 
– safety lab (local–haematology and clinical chemistry) 
– thrombogenicity 
– retention plasma samples for potential retesting. 
 
Last Post-Operative Day 
The Last Post-Operative Day is either 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 ‘Any post-operative day before the Last Post-Operative 
Day’ as described on page xvii). 
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 obser- 
vation period. No further study-related assessments will be performed, unless safety con- 
cerns (e.g., ongoing AEs) require follow-up. 


Study Protocol 
No. FORMA-02 
CONFIDENTIAL 
Version 6.0 
31-Oct-2014 
xix 
 
 
 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Octafibrin 
Protocol Identification Code: 
FORMA-02 
Name of Active Ingredient: 
Fibrinogen 
Date of Final Protocol: 
31-Oct-2014 
 
 
Patients may remain in the study until the 24th patient has at least one documented bleeding 
episode. When the study is closed, all subjects will be asked to return for a Study 
Completion Visit. 
 
Study Completion Visit 
At the end of the study duration, all subjects will be asked to return for a Study Completion 
Visit, during which the following assessments will be performed: 
• Blood draw for retention serum samples for potential viral testing. 
• Physical examination. 
After the Study Completion Visit, the clinical study is considered completed for the subject. 
If the subject has not been treated for bleeding or surgery, subject will be notified that the 
study has ended and will be considered a ‘no treatment’ patient and reported separately. No 
further assessments will need to be performed. 
 
Statistical analysis: 
Continuous variables will be summarised using descriptive statistics (arithmetic mean, 
standard deviation (SD), median, minimum and maximum, and number of observations and 
missing observations). Categorical variables will be summarised with counts and 
percentages. 
Efficacy analysis 
 
Primary endpoint 
For bleeding efficacy, the primary endpoint is the overall clinical assessment of the haemo- 
static 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 
until 24 hours (i.e., 1 day) after the last infusion or the end of the treatment observation 
period, whichever comes last. 
For the statistical 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 success rate will be calculated as the proportion of patients with 
success, and the two-sided 90% Blyth-Still-Casella confidence interval (CI) will be 
calculated. By comparing the lower limit of this confidence interval with a predefined 
threshold of 0.7, the hypothesis that the success rate is greater than 0.7 will be tested (H0: p 
≤ 0.7 / HA: p > 0.7). The final efficacy assessment of each patient will be adjudicated by an 
Independent Data Monitoring & Endpoint Adjudication Committee (IDMEAC). 


Study Protocol 
No. FORMA-02 
CONFIDENTIAL 
Version 6.0 
31-Oct-2014 
xx 
 
 
 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Octafibrin 
Protocol Identification Code: 
FORMA-02 
Name of Active Ingredient: 
Fibrinogen 
Date of Final Protocol: 
31-Oct-2014 
 
 
Secondary 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 first and last infusion as well as changes of MCF from pre 
infusion will be summarised using descriptive statistics and displayed graphically. In 
addition, a correlation analysis between MCF and the haemostatic efficacy assessment will 
be performed. 
 
Octafibrin use 
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. 
 
In-vivo recovery (IVR) 
Response and classical IVR will be calculated for each infusion of each subject. Descriptive 
tables will show the distributions of the 2 parameters per infusion day separated for minor 
and major bleeding events. An exploratory analysis using a repeated-measures analysis of 
covariance model will analyse whether the response/classical IVR changed over time, with 
dose associated with respective IVR as covariate in model. 
 
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. 
Safety analysis 
Safety parameters will be descriptively summarised. 
 
Interim analysis 
An interim analysis will be performed after data is available for the first bleeding episode of 
10 subjects; 2 of these subjects should be between 12 and 18 years old. Descriptive efficacy 
and safety analysis will be performed and presented to IDMEAC. 


Study Protocol 
No. FORMA-02 
CONFIDENTIAL 
Version 6.0 
31-Oct-2014 
xxi 
 
 
 
FLOW CHART OF ASSESSMENTS FOR ON-DEMAND TREATMENT OF ACUTE BLEEDING 
Screening 
30-DAY 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 14 
(± 2 days) 
Day 30 
(± 1 week) 
Pre- 
infusion 
Post-infusion 
Daily 
Pre- 
infusion [a] 
1 h post- 
infusion [a] 
(± 15 min) 
Pre- 
infusion 
Post-infusion 
or end of the 
observation 
period 
1 h 
(± 15 min) 
3 h 
(± 15 min) 
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 
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] 
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] 
x [d] 
MCF [d] 
x [b] 
x 
x 
Thrombogenicity [d] 
x 
x 
x 
x 
x 
x 
x 
Immunogenicity [d] 
x 
x 
x 
Safety lab (haematology and clinical chemistry) [c] 
x 
x 
x 
x [i] 
x 
x 
x 
x 
Retention plasma samples [e] 
x [b] 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Retention serum samples [e] 
x [b] 
x 
Urine or blood pregnancy test 
x 
Infusion of Octafibrin 
x [f] 
x [f,g] 
x 
Final haemostatic efficacy assessment 
x 
AEs [h] 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
Concomitant medications 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
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] Plasma retention sample for potential retesting; 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 


Study Protocol 
No. FORMA-02 
CONFIDENTIAL 
Version 6.0 
31-Oct-2014 
xxii 
 
 
 
FLOW CHART OF ASSESSMENTS FOR SURGICAL PROPHYLAXIS 
Screening 
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 
Pre- 
infusion 
1 h post- 
infusion 
(± 15 min) 
Daily 
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 
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] 
Thrombogenicity [c] 
x 
x 
x 
x 
Safety lab (haematology and clinical chemistry) [b] 
x 
x 
x 
x 
x 
Retention plasma samples [d] 
x 
x [a] 
x 
x 
x 
x 
x 
x 
x 
Retention serum samples [d] 
x 
x 
Urine or blood pregnancy test 
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 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
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. 


 
Study Protocol 
No. FORMA-02 
CONFIDENTIAL 
Version 6.0 
31-0ct-2014 
 
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. Sigurd Knaub, PhD 
7 
Vice President CR&D Haematology 
Octaphanna AG 
Seidenstrasse 2 
8853 Lachen 
Switzerland 
 
 
 
 
 
 
 
Signatures of the 
 
 
Signature 
Date 
Clinical Project Manager and Blostatlstlclan 
 
 
 
Bruce A. Schwartz, PhD 
Director CR&D Haematology 
Octaphanna USA 
121 River Street, Suite 1201 
Hoboken, NJ 07030 
USA 
 
 
 
Biostatistician 
Statistician 
Max Neeman Medical International 
#1, Dr Jha Marg, Okhla Phase-III 
New Delhi - 110 020 
 
 
Date 
 
 
 
 
Sig ature 
Date 
 
 
 
 
 
 
 
 
 
 
 
Pagel 
Santosh Kumar 


Study Protocol 
No. FORMA-02 
CONFIDENTIAL 
Version 6.0 
31-Oct-2014 
Page 2 
 
 
 
TABLE OF CONTENTS 
1 
INTRODUCTION ............................................................................................................ 7 
1.1 
BACKGROUND ........................................................................................................................................... 7 
1.2 
OCTAFIBRIN ............................................................................................................................................... 7 
1.3 
RATIONALE FOR CONDUCTING THE STUDY .................................................................................... 8 
1.4 
DOSE RATIONALE .................................................................................................................................... 8 
1.5 
BENEFIT-RISK STATEMENT .................................................................................................................. 9 
2 
STUDY OBJECTIVES .................................................................................................. 10 
2.1 
PRIMARY OBJECTIVE ............................................................................................................................ 10 
2.2 
SECONDARY OBJECTIVES.................................................................................................................... 10 
3 
INVESTIGATIONAL PLAN ........................................................................................ 11 
3.1 
PRIMARY AND SECONDARY ENDPOINTS ........................................................................................ 11 
3.1.1 
Primary Endpoint .......................................................................................................11 
3.1.2 
Secondary Endpoints .................................................................................................11 
3.2 
OVERALL STUDY DESIGN AND PLAN .............................................................................................. 12 
3.2.1 
On-demand Treatment of Acute Bleeding ..................................................................13 
3.2.2 
Surgical Prophylaxis ..................................................................................................13 
3.3 
DISCUSSION OF STUDY DESIGN AND CHOICE OF CONTROL GROUP(S) ......................... 14 
4 
STUDY POPULATION ................................................................................................. 15 
4.1 
POPULATION BASE ................................................................................................................................ 15 
4.2 
INCLUSION CRITERIA ............................................................................................................................ 15 
4.3 
EXCLUSION CRITERIA .......................................................................................................................... 15 
4.4 
PRIOR AND CONCOMITANT THERAPY ............................................................................................. 16 
4.4.1 
Permitted Concomitant Therapy ................................................................................16 
4.4.2 
Forbidden Concomitant Therapy ...............................................................................17 
4.5 
WITHDRAWAL AND REPLACEMENT OF SUBJECTS ...................................................................... 17 
4.5.1 
Premature Subject Withdrawal ..................................................................................17 
4.5.2 
Subject Replacement Policy .......................................................................................17 
4.6 
ASSIGNMENT OF SUBJECTS TO TREATMENT GROUPS ............................................................... 17 
4.7 
RELEVANT PROTOCOL DEVIATIONS ................................................................................................ 17 
4.8 
SUBSEQUENT THERAPY ....................................................................................................................... 17 
5 
INVESTIGATIONAL MEDICINAL PRODUCT ...................................................... 18 
5.1 
CHARACTERISATION OF INVESTIGATIONAL PRODUCT .............................................................. 18 
5.2 
PACKAGING AND LABELLING ............................................................................................................ 18 
5.3 
CONDITIONS FOR STORAGE AND USE ............................................................................................. 18 
5.4 
DOSE AND DOSING SCHEDULE .......................................................................................................... 18 
5.4.1 
Octafibrin Dose Calculation ......................................................................................19 
5.4.2 
Dosing for On-demand Treatment of Bleeding ..........................................................19 
5.4.3 
Dosing for Surgery .....................................................................................................20 
5.5 
PREPARATION AND METHOD OF ADMINISTRATION ................................................................... 21 
5.5.1 
Preparation ................................................................................................................21 
5.5.2 
Method of Administration ..........................................................................................21 
5.6 
BLINDING, EMERGENCY ENVELOPES, AND BREAKING THE STUDY BLIND ........................ 21 


Study Protocol 
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Version 6.0 
31-Oct-2014 
Page 3 
 
 
5.7 
DRUG DISPENSING AND ACCOUNTABILITY .................................................................................. 21 
5.8 
ASSESSMENT OF TREATMENT COMPLIANCE ................................................................................ 21 
6 
STUDY CONDUCT ....................................................................................................... 22 
6.1 
OBSERVATIONS PERFORMED THROUGHOUT THE STUDY ......................................................... 22 
6.1.1 
Screening Assessments ...............................................................................................22 
6.1.2 
Assessments in Subjects Undergoing On-demand Treatment of Bleeding .................22 
6.1.2.1 
Day 1 (first day of treatment) ..................................................................... 23 
6.1.2.2 
All Study Days after Day 1 (Treatment Observation Period) ..................... 24 
6.1.2.3 
Last Infusion or End of the Observation Period (whichever 
comes last) .................................................................................................. 25 
6.1.2.4 
Day 14 (13 Days after the First Infusion) ................................................... 27 
6.1.2.5 
Day 30 (29 Days after the First Infusion)—Final Examination ................. 27 
6.1.3 
Assessments in Subjects Undergoing Surgical Prophylaxis ......................................27 
6.1.3.1 
Day 1 .......................................................................................................... 28 
6.1.3.2 
Any Post-Operative Day before the Last Post-Operative Day ................... 30 
6.1.3.3 
Last Post-Operative Day ............................................................................. 31 
6.1.4 
Study Completion Visit ...............................................................................................31 
6.2 
DURATION OF STUDY ........................................................................................................................... 32 
6.2.1 
Planned Duration for the Study as a Whole ...............................................................32 
6.2.2 
Planned Duration for an Individual Subject ..............................................................32 
6.2.3 
Premature Termination of the Study ..........................................................................33 
7 
ASSESSMENTS AND METHODS .............................................................................. 34 
7.1 
BACKGROUND AND SCREENING INFORMATION .......................................................................... 34 
7.2 
EFFICACY ASSESSMENTS .................................................................................................................... 34 
7.2.1 
Assessments for Primary Efficacy Endpoint ..............................................................34 
7.2.2 
Assessments for Secondary Efficacy Endpoints .........................................................35 
7.2.2.1 
Clot Strength ............................................................................................... 35 
7.2.2.2 
Recovery ..................................................................................................... 36 
7.2.2.3 
Surgical Prophylaxis ................................................................................... 36 
7.3 
LABORATORY ASSESSMENTS ............................................................................................................ 37 
7.3.1 
Blood Sampling ..........................................................................................................38 
7.3.2 
Citrated Plasma .........................................................................................................38 
7.3.3 
EDTA Blood ...............................................................................................................38 
7.3.4 
Serum .........................................................................................................................39 
7.3.5 
Recording of Clinically Significant Abnormal Laboratory Values as AEs/ADRs ......39 
7.4 
SAFETY ASSESSMENTS ......................................................................................................................... 39 
7.4.1 
Adverse Events (AEs) .................................................................................................40 
7.4.1.1 
Definitions .................................................................................................. 40 
7.4.1.2 
Collection of AEs ....................................................................................... 40 
7.4.1.3 
Severity of AEs ........................................................................................... 41 
7.4.1.4 
Causality of AEs ......................................................................................... 41 
7.4.1.5 
Classification of ADRs ............................................................................... 41 
7.4.1.6 
Outcome of AEs ......................................................................................... 42 
7.4.1.7 
Action(s) Taken .......................................................................................... 42 
7.5 
SERIOUS ADVERSE EVENTS ............................................................................................................... 43 
7.5.1 
SAE Reporting Timelines ...........................................................................................43 
7.6 
VITAL SIGNS AND PHYSICAL EXAMINATION ................................................................................ 44 
7.7 
OTHER RELEVANT SAFETY INFORMATION ................................................................................... 44 
7.7.1.1 
Post-study Related Safety Reports .............................................................. 44 


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7.7.1.2 
Pregnancies ................................................................................................. 45 
7.7.1.3 
Overdose,  Interaction,  Misuse,  Medication  Error  and   Lack   of 
Efficacy ....................................................................................................... 45 
7.8 
OTHER ASSESSMENTS .......................................................................................................................... 45 
7.9 
APPROPRIATENESS OF MEASUREMENTS ........................................................................................ 45 
8 
DATA HANDLING AND RECORD KEEPING ......................................................... 46 
8.1 
SOURCE DATA AND RECORDS ........................................................................................................... 46 
8.2 
CASE REPORT FORMS ........................................................................................................................... 46 
8.3 
CHANGES TO CASE REPORT FORM DATA ...................................................................................... 46 
8.4 
INFORMATION OF INVESTIGATORS ................................................................................................... 47 
8.5 
RESPONSIBILITIES .................................................................................................................................. 47 
8.5.1 
Co-ordinating Investigator ........................................................................................48 
8.5.2 
External Parties ........................................................................................................ 48 
8.6 
INVESTIGATOR’S SITE FILE ................................................................................................................ 48 
8.7 
PROVISION OF ADDITIONAL INFORMATION .................................................................................. 49 
8.8 
INDEPENDENT DATA MONITORING & ENDPOINT ADJUDICATION COMMITTEE ............... 49 
9 
STATISTICAL METHODS AND SAMPLE SIZE ..................................................... 50 
9.1 
HYPOTHESIS TESTING AND DETERMINATION OF SAMPLE SIZE ............................................. 50 
9.2 
STATISTICAL ANALYSIS ...................................................................................................................... 51 
9.3 
POPULATIONS FOR ANALYSIS ............................................................................................................ 51 
9.3.1 
Safety Population .......................................................................................................51 
9.3.2 
Full Analysis Set ....................................................................................................... 51 
9.3.3 
Per-Protocol Population ........................................................................................... 52 
9.3.4 
Subpopulations .......................................................................................................... 52 
9.4 
EFFICACY ANALYSIS PLAN ................................................................................................................ 53 
9.4.1 
Primary Endpoint ...................................................................................................... 53 
9.4.2 
Secondary Endpoints ................................................................................................ 53 
9.4.2.1 
Clot strength (MCF) ................................................................................... 53 
9.4.2.2 
In-vivo recovery ......................................................................................... 54 
9.4.2.3 
Efficacy of Octafibrin in all Bleeding Episodes ......................................... 54 
9.4.2.4 
Surgical Prophylaxis ................................................................................... 55 
9.4.2.5 
Safety Analysis Plan ................................................................................... 56 
9.4.3 
Additional Analyses .................................................................................................. 57 
9.5 
HANDLING OF MISSING DATA ........................................................................................................... 57 
9.6 
RANDOMISATION ................................................................................................................................... 57 
9.7 
INTERIM ANALYSIS ............................................................................................................................... 57 
10 ETHICAL, REGULATORY, LEGAL AND ADMINISTRATIVE ASPECTS ........ 58 
10.1 ETHICAL AND REGULATORY FRAMEWORK ................................................................................... 58 
10.2 APPROVAL OF STUDY DOCUMENTS ................................................................................................. 58 
10.3 SUBJECT INFORMATION AND INFORMED CONSENT .................................................................... 58 
10.4 PROTOCOL AMENDMENTS .................................................................................................................. 59 
10.5 CONFIDENTIALITY OF SUBJECTS DATA .......................................................................................... 59 
11 QUALITY CONTROL AND QUALITY ASSURANCE ............................................ 60 
11.1 PERIODIC MONITORING ....................................................................................................................... 60 
11.2 AUDIT AND INSPECTION ...................................................................................................................... 60 


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12 REPORTING AND PUBLICATION ........................................................................... 61 
12.1 CLINICAL STUDY REPORT ................................................................................................................... 61 
12.2 PUBLICATION POLICY........................................................................................................................... 61 
13 LIABILITIES AND INSURANCE ............................................................................... 62 
14 REFERENCES ............................................................................................................... 63 
15 APPENDICES ................................................................................................................. 65 


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LIST OF ABBREVIATIONS 
AE 
Adverse event 
ADR 
Adverse drug reaction 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
b.w. 
Body weight 
CI 
Confidence interval 
CRF 
Case report form 
CRO 
Contract research organisation 
EMA 
European Medicines Agency 
EU 
European Union 
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 
PCR 
Polymerase chain reaction 
PK 
Pharmacokinetic(s) 
PP 
Per-protocol 
SAE 
Serious adverse events 
SOC 
System organ class 
SOP 
Standard Operating Procedure 
TEG 
Thromboelastography 
US 
United States 
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 
haemostasis, wound healing, fibrinolysis, inflammation, angiogenesis, cellular and matrix 
interactions, 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 
homozygotic 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 
missense mutations in the 3 fibrinogen genes have been identified as the cause of 
dysfibrinogenaemia 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 inactiva- 
tion/removal steps, i.e., solvent/detergent treatment and nanofiltration. 
Solvent/detergent treatment mode of action causes enveloped viruses to be irreversibly 
destroyed. 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). 


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The Planova 20N filter was specifically developed by Asahi Kasei Pharma Corp. to remove 
infectious agents from protein solutions on the basis of their size. Thus, this nanofiltration  
step is in principle effective for removing 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 
fibrinogen 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, 
uncontrolled study to assess the efficacy and safety of Octafibrin for on-demand treatment of 
acute bleeding in subjects with congenital fibrinogen deficiency. 
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 a questionnaire 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 
fibrinogen 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 
system bleeding, was higher (150 mg/dL). Minor episodes, like epistaxis, gum bleeding, 
menorrhagia, 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 
bleeding, increase fibrinogen plasma levels, and reduce the amount of transfusions needed 
with allogeneic 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, 
wheezing, 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 
concentrates. 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. 
Standard measures to prevent these infections include the selection of donors, screening of 
individual donations and plasma pools for specific markers of infection, and the inclusion 
of effective manufacturing steps for the inactivation/removal of viruses. Despite this, 
when medicinal products prepared from human blood or plasma are administered, the 
possibility of transmitting infective agents cannot be totally excluded. This also applies to 
unknown or emerging viruses and other pathogens. The measures taken are considered 
effective for enveloped viruses, such as 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-derived 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 show 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) that was used as a surrogate endpoint for 
haemostatic efficacy and determined via thromboelastography (TEG) in the pivotal PK 
study FORMA-01. Therefore, MCF as surrogate efficacy parameter will be determined 
before first infusion and 1 hour after end of first and last infusion. 
• 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, 
including immunogenicity, thromboembolic complications, and early signs of allergic 
or hypersensitivity 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 
Octafibrin in treating the first documented bleeding episode of each patient. 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. 
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 
assessment of each patient will be adjudicated by the Independent Data Monitoring & 
Endpoint Adjudication Committee (IDMEAC). 
In the final analysis, the number of subjects per outcome category will be assessed. 
 
3.1.2 Secondary Endpoints 
The secondary efficacy endpoints are: 
• MCF assessment before first infusion and 1 hour after end of first and last infusion of 
each documented bleeding episode (see Section 7.2.2.1). 
• 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 of each documented bleeding episode). 
• Response as indicated by incremental IVR, calculated as the maximum increase in 
plasma fibrinogen (Clauss data) between pre-infusion and 1 and 3 hours post-infusion 
(see Section 7.2.2.2). 
• 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 haemostatic 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 haemostatic efficacy scales (see Section 7.2.2.3). 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. 


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The safety endpoints are: 
• Vital signs. 
• Physical examination. 
• Routine clinical laboratory assessment, including coagulation parameters. 
• Adverse events (AEs), including thromboembolic complications and early signs of 
allergic or hypersensitivity reactions. 
• Immunogenicity testing at Day 14 and Day 30 after the administration of Octafibrin for 
bleeding. 
 
3.2 Overall Study Design and Plan 
This is a multinational, multi-centre, prospective, open-label, uncontrolled, Phase III study to 
assess the efficacy and safety of Octafibrin for on-demand treatment of acute bleeding and 
surgical prophylaxis in subjects with congenital fibrinogen deficiency. 
A total of 24 male and female subjects with congenital fibrinogen deficiency will be enrolled 
in the study. This will include at least 4 subjects aged between 12 and 18 years (only 18 and 
above in Russia). This will also include at least 4 surgeries, 2 of which should be performed in 
subjects aged between 12 and 18 years (only 18 and above in Russia). The study will be 
conducted in approximately 15 study centres worldwide. 
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 the 24th patient has at least one documented bleeding episode. The study will 
be considered completed when a minimum of 24 subjects have at least one documented 
bleeding episode. The study as a whole should be completed within 5 years. 
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. 
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. 


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3.2.1 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 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 bleeding episode (Day 1) and will be followed for up to 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 
infusions 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 
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. 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 the 24th patient has had at least one treated bleeding epi- 
sode), all patients will be asked to return for a Study Completion Visit. 
 
3.2.2 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. 


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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 judge- 
ment of the subject’s condition. 
All 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. 
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 the 24th patient has had at least one treated bleeding 
episode), all patients will be asked to return for a Study Completion Visit. 
 
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 have been obtained in study FORMA-01. 
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 interim analysis of study FORMA-01. 
Although all bleeding episodes occurring throughout the study observation period will be 
documented, 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 the 24th enrolled 
patient has at least one documented bleeding episode, potentially resulting in a large diversity 
in the number of bleeding episodes between patients. 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 
A minimum of 24 subjects with clinically diagnosed congenital fibrinogen deficiency (i.e., 
afibrinogenaemia and severe hypofibrinogenaemia) will be enrolled into the study. This will 
include at least 4 subjects aged between 12 and 18 years (only 18 and above in Russia). This 
will also include at least 4 surgeries, 2 of which should be performed in subjects aged between 
12 and 18 years (only 18 and above in Russia). 
 
4.2 Inclusion Criteria 
Subjects who meet all of the following criteria are eligible for the study: 
1. 
Aged ≥12 years (only 18 and above in Russia). 
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 
planning to undergo elective surgery. 
4. 
Informed consent signed by the subject or 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 bleeding episode or surgery 
– 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 (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 
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. 
Pregnant women within the first 20 weeks of gestation. 
7. 
Currently breast-feeding. 
8. 
Known 
positive HIV infection 
with a 
viral 
load >200 particles/μL or 
>400,000 copies/mL. 
9. 
Polytrauma 1 year prior to start of treatment for the bleeding episode or surgery. 
10. Diagnosis or suspicion of a neutralising anti-fibrinogen inhibitor currently or at any 
time in the past. 
11. 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 
– Subjects having evidence or a history (within the previous 12 months) of abuse of 
any drug licit or illicit substance. 
12. Participation in another interventional clinical study currently or during the past 4 
weeks. 
 
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. 
 
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 
follow-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 
duration 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 
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. 
 
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 (i.e., 1 day) after the last Octafibrin infusion. 
 
4.5 Withdrawal and Replacement of Subjects 
4.5.1 Premature Subject Withdrawal 
Subjects have the right to withdraw from the study at any time for any reason, without the 
need to justify their decision. The investigator also has the right to withdraw 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 
Subjects withdrawn from the study for safety reasons will not be replaced. 
 
4.6 Assignment of Subjects to Treatment Groups 
Not applicable. 
 
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 
adequate 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., 
Haemocomplettan 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 
ingredients are listed in Table 1. 
 
Table 1: Composition of Octafibrin 
Ingredients 
Quantity per mL reconstituted 
solution, 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 
reconstituted 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. 
 
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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Fibrinogen dose 
=        [Target peak plasma level (mg/dL) − measured level (mg/dL)**] 
(mg/kg body weight) 
 
Median response* (mg/dL per mg/kg body weight) 
 
 
5.4.1 Octafibrin 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: 
 
*The median response in this dose calculation formula is the median incremental in vivo recovery reported in the 
interim analysis of study FORMA-01. 
**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. 
 
5.4.2 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 organ, 
such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular, or pericardial 
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. 


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5.4.3 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 
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 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). 
• 3rd molar extraction or extraction of > 3 teeth. 
• 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. 


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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 contains 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 solutions. 
 
5.5.2 Method of Administration 
Octafibrin will be administered as intravenous (i.v.) infusion. 
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 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 
Octafibrin 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 
inclusion into the study. The screening assessments will be performed as summarised in 
Section 6.1.1. 
The observations for patients enrolled and then having on-demand treatment of an active 
bleeding episode are summarised in Section 6.1.2. The observations for patients planning to 
undergo elective surgery are summarised see Section 6.1.3. 
All treated patients will undergo a Study Completion Visit as summarised in Section 6.1.4. 
 
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. 
• Demography, medical history (including details concerning allergic tendencies), review of 
previous therapy. 
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. 
 
6.1.2 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 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 
Section 5.4.2. The flow chart of assessments  for  on-demand  treatment  is  provided  on  
page xxi. 
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. Concomitant medications will also be recorded throughout each 30-day observation 
and follow-up period. 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 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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6.1.2.1 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. 
 
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. 
• 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 
retention plasma and serum samples for potential retesting (within 30 minutes 
before infusion). 
• Urine (dip stick) or blood pregnancy test for all female subjects of childbearing 
potential. 
 
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. 
 
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). 


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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. 
• Blood draw for: 
– fibrinogen plasma level (local lab–activity; central lab–antigen and activity) 
– MCF 
– safety lab (local–haematology and clinical chemistry) 
– thrombogenicity 
– retention plasma samples for potential retesting. 
 
3 hours (±15 minutes) after the end of infusion: 
• Vital signs. 
• Blood draw for: 
– fibrinogen plasma level (central lab–antigen and activity) 
– safety lab (local–haematology and clinical chemistry) 
– thrombogenicity 
– retention plasma samples for potential retesting. 
• 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. 
 
6.1.2.2 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) 
• 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) 
– retention plasma samples for potential retesting. 
• AEs and concomitant medications. 


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Octafibrin infusion, as required 
After these daily assessments, 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 
fibrinogen plasma level (80 mg/dL for minor bleeding, 130 mg/dL for major bleeding; 
see Section 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 
assessments will be performed: 
 
Pre-infusion assessments: 
• Blood draw for (within 30 minutes before infusion): 
– fibrinogen plasma level (local lab–activity; central lab–antigen and activity) 
– retention plasma samples for potential retesting. 
1 hour (±15 minutes) after the end of each infusion: 
• Vital signs. 
• Blood draw for: 
– fibrinogen plasma level (local lab–activity; central lab–antigen and activity) 
– safety lab (local–haematology and clinical chemistry) 
– thrombogenicity 
– retention plasma samples for potential retesting. 
 
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. 
 
6.1.2.3 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 
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 
multiple infusions are needed: 
• Blood draw for (within 30 minutes before infusion): 
– fibrinogen plasma level (local lab–activity; central lab–antigen and activity) 
– retention plasma samples for potential retesting. 


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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). 
 
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. 
• Blood draw for: 
– fibrinogen plasma level (local lab–activity; central lab–antigen and activity) 
– MCF 
– safety lab (local–haematology and clinical chemistry) 
– thrombogenicity 
– retention plasma samples for potential retesting. 
 
3 hours (±15 minutes) after the end of last infusion: 
• Vital signs. 
• Blood draw for: 
– fibrinogen plasma level (central lab–antigen and activity) 
– safety lab (local–haematology and clinical chemistry) 
– thrombogenicity 
– retention plasma samples for potential retesting. 
 
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. 
• Blood draw for: 
– fibrinogen plasma levels (central lab–antigen and activity) 
– safety lab (local–haematology and clinical chemistry) 
– thrombogenicity 
– retention plasma samples for potential retesting. 
• 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. 


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6.1.2.4 Day 14 (13 Days after the First Infusion) 
On Day 14 (± 2 days), the following assessments will be performed: 
• Blood draw for: 
– immunogenicity 
– retention plasma samples for potential retesting. 
• AEs and concomitant medications. 
 
6.1.2.5 Day 30 (29 Days after the First Infusion)—Final Examination 
On Day 30 (± 1 week), the following assessments will be performed: 
• Physical examination. 
• Blood draw for: 
– immunogenicity 
– retention plasma samples 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. 
Subjects returning to the study site for another acute bleeding episode within the study 
observation period will again undergo the same Day 1 to Day 30 assessments as outlined in 
Section 6.1.2.1 through Section 6.1.2.5. At the end of the study duration, all subjects will be 
asked to return for a Study Completion Visit as summarised in Section 6.1.4. 
If a patient experiences another bleeding event between Day 14 and 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, the Day 30 evaluations will be postponed until 30 days after the start of the new 
bleeding episode. 
Any additional bleeding episodes will be documented in the same way as the first bleeding 
episode. These will not be used for the analysis of the primary endpoint, but they will be 
analysed as a secondary endpoint. 
 
6.1.3 Assessments in Subjects Undergoing Surgical Prophylaxis 
Subjects enrolled for elective surgery will undergo a treatment and assessment cycle as 
outlined in Section 6.1.3.1 through Section 6.1.3.3. 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 severity 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 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 xxii. 


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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. 
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 
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: 
• Vital signs. 
• Physical examination. 
• Body weight (kg). 


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• Blood draw for: 
– fibrinogen plasma levels (local lab–activity; central lab–antigen and activity). 
– safety lab (local—haematology and clinical chemistry). 
– thrombogenicity. 
– retention plasma and serum samples for potential retesting. 
• Urine (dip stick) or blood pregnancy test for all female subjects of childbearing 
potential. 
• 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 
schedule 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: 
– intra-operative fibrinogen plasma levels (local lab–activity; central lab–antigen and 
activity). 
– retention plasma samples for potential retesting. 
 
Assessments at the end of surgery 
• Blood draw for: 
– fibrinogen plasma levels (local lab–activity; central lab–antigen and activity). 
– thrombogenicity. 
– retention plasma samples for potential retesting. 
• 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 (see 
Section 7.2.2.3). 
• AEs and concomitant medications. 


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6.1.3.2 Any Post-Operative Day before the Last Post-Operative Day 
On any post-operative day before the Last Post-Operative Day (see Section 6.1.3.3), the 
following assessments will be performed: 
 
Daily post-operative assessments 
The following assessments will be on every post-operative day: 
• Vital signs. 
• Blood draw for: 
– fibrinogen plasma levels (local lab–activity; central lab–antigen and activity) 
– safety lab (local–haematology and clinical chemistry) 
– retention plasma samples for potential retesting. 
• Wound haematomas and oozing (noting whether surgical evacuation is required and 
severity 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 
fibrinogen plasma level (80 mg/dL for minor surgery, 130 mg/dL for major surgery; see 
Section 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: 
• Blood draw for: 
– fibrinogen plasma level (local lab–activity; central lab–antigen and activity) 
– retention plasma samples for potential retesting. 
1 hour (±15 minutes) after the end of each infusion: 
• Vital signs. 
• Blood draw for: 
– fibrinogen plasma level (local lab–activity; central lab–antigen and activity) 
– safety lab (local–haematology and clinical chemistry) 
– thrombogenicity 
– retention plasma samples for potential retesting. 


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6.1.3.3 Last Post-Operative Day 
The Last Post-Operative Day is either 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 6.1.3.2). 
In addition, the following assessments will be performed on the Last Post-Operative Day: 
• post-operative efficacy assessment by the haematologist (see Section 7.2.2.3). 
• 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 the 24th patient has at least one documented bleeding 
episode. When the study is closed, all subjects will be asked to return for a Study Completion 
Visit as summarised in Section 6.1.4. 
 
6.1.4 Study Completion Visit 
At the end of the study duration, all subjects will be asked to return for a Study Completion 
Visit, during which the following assessments will be performed: 
• Blood draw for retention serum samples for potential viral testing. 
• Physical examination. 
After the Study Completion Visit, the clinical study is considered completed for the subject. 
If the subject has not been treated for bleeding or surgery, the subject will be notified that the 
study has ended and will be considered a ‘no treatment’ patient and reported separately. No 
further assessments need to be performed. 


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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 24 subjects have at least one 
documented bleeding episode. The study as a whole should be completed within 5 years. 
The estimated start of the study (enrolment of first subject) is in the 4th quarter of 2014, and 
the estimated end of the study (last visit of last subject) is in the 4th quarter of 2019. 
 
6.2.2 Planned Duration for an Individual Subject 
 
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 for up to 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 epi- 
sodes or planned surgeries that can be managed under the protocol. Patients may remain in the 
study until the 24th patient has at least one documented bleeding episode. 
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 do not present with a bleeding episode or 
planned surgery during the study observation period will be considered ‘no treatment’ 
patients. 


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6.2.3 Premature Termination of the Study 
Both the investigator and the Sponsor reserve the right to terminate the study at any time. 
Should this be necessary, the procedures will be arranged on an individual study basis after 
review and consultation by both parties. In terminating the study, the Sponsor and the 
investigator will ensure that adequate consideration is given to the protection of the subjects’ 
interests. 
Furthermore, the investigator should promptly inform the Independent Ethics Committee 
(IEC)/Institutional Review Board (IRB) and provide a detailed written explanation. The 
pertinent 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 
completed, 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 
physical examination. 
Previous and concomitant medication: obtained by interviewing the subject. 
 
 
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 
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 
haemostatic 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 
required, 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 Efficacy Endpoints 
 
7.2.2.1 Clot Strength 
MCF will be determined using thromboelastography (TEG) and will be used as a surrogate 
marker for haemostatic efficacy. TEG 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. 
TEG is the continuous registration of blood clot firmness during the entire coagulation 
process (Figure 1). 
 
 
 
Figure 1: Example of thromboelastogram 
MCF (measured in mm) is a functional parameter which depends on the activation of 
coagulation, the platelet and fibrinogen content of the blood sample, and the polymerisation 
and cross-linking of the fibrin network. 
TEG has been shown in various studies to be predictive of clinical coagulopathy [16, 17, 18, 
19, 20]. TEG 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 
deficiency. 
To obtain consistent results across all study centres, with minimal centre-to-centre variability, 
MCF data 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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7.2.2.2 Recovery 
IVR will be determined using the following approaches: 
• Incremental IVR (response): calculated as the maximum increase in plasma fibrinogen 
(i.e., Clauss data) between pre-infusion and 1 and 3 hours post-infusion (expressed as 
absolute concentration in plasma [mg/dL]), divided by the exact dose of Octafibrin 
(expressed as mg/kg dosed). 
• Classical IVR: calculated as the maximum increase in plasma fibrinogen (i.e., Clauss 
data) between pre-infusion and 1 and 3 hours post-infusion (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]. 
 
7.2.2.3 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 
Octafibrin 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 haemostasis 
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 
replacement regimen. 
 
*All 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 
surgery. All post-operative bleeding (due to complications of surgery) was 
controlled with Octafibrin as anticipated for the type of procedure. 
Good 
No post-operative bleeding or oozing that was not due to complications of 
surgery. Control of post-operative bleeding due to complications of surgery 
required 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 
Octafibrin or additional infusions, not originally anticipated for the type of 
procedure. 
None 
Extensive uncontrolled post-operative bleeding and oozing. Control of post- 
operative bleeding required use of an alternate fibrinogen concentrate. 
 
 
 
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-operatively) 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 4 summarises all test parameters and the laboratories responsible for analysis. 
 
Table 4: 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. 
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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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 
Octapharma’s written authorisation to destroy these samples. These samples may be used for 
additional coagulation and viral testing, if needed. 
In addition, a urine or blood pregnancy test for all female subjects of childbearing potential 
will be performed before the first IMP infusion in each treatment episode (on-demand or 
surgery). 
The flow chart of assessments for on-demand treatment is provided on page xxi. The flow 
chart of assessments for surgical prophylaxis is provided on page xxii. 
 
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) 
 
7.3.2 Citrated Plasma 
Blood samples taken for plasma will be centrifuged after collection as instructed in the 
laboratory 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 instructed 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 
collected 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. 


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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 will be 
documented as AEs/ADRs. Clinically significant is defined as any laboratory abnormality that 
the investigator feels is of clinical concern and/or requires medical intervention and/or follow- 
up. Additional tests and other evaluations 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. 
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 
laboratory 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 each 30-
day observation and follow-up period for on-demand treatment or until the Last Post- 
Operative Day in surgeries 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, pregnancies, drug overdose, interaction, abuse, misuse, 
or medication error (see Section 7.7). 


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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 therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of an IMP, 
whether or not related to the IMP. 
• Adverse drug reaction (ADR): An ADR is any noxious and unintended response to an 
IMP related to any dose. The phrase ‘response to an IMP’ means that a causal 
relationship between the IMP and an AE carries at least a reasonable possibility, i.e., the 
relationship cannot be ruled out. 
• Other significant AEs: Any marked laboratory abnormalities or any AEs that lead to an 
intervention, including withdrawal of drug treatment, dose reduction or significant 
additional concomitant therapy. 
• Withdrawal due to AE/ADR: 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. 
 
7.4.1.2 Collection of AEs 
The condition of the subject will be monitored throughout each 30-day observation 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 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 7.5), 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 
abnormalities and the nature of, and reasons for any necessary action(s), as well as any other 


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observations 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 
activities. 
Grading of an AE is up to the medical judgement of the investigator and will be decided on a 
case-by-case basis. 
 
7.4.1.4 Causality of AEs 
The relationship of AEs to the administered IMP will be assessed by the investigator 
responsible: 
• Probable: reports including good reasons and sufficient documentation to assume a 
causal relationship, in the sense of plausible, conceivable, likely, but not necessarily 
highly probable. A reaction that follows a reasonable temporal sequence from 
administration of the IMP; or that follows a known or expected response pattern to the 
suspected medicine; or that is confirmed by stopping or reducing the dosage of the 
medicine and that could not reasonably be explained by known characteristics of the 
subject’s clinical state. 
• Possible: reports containing sufficient information to accept the possibility of a causal 
relationship, in the sense of not impossible and not unlikely, although the connection is 
uncertain or doubtful, for example because of missing data or insufficient evidence. A 
reaction that follows a reasonable temporal sequence from administration of the IMP; 
that follows a known or expected response pattern to the suspected medicine; but that 
could readily have been produced by a number of other factors. 
• Unlikely: reports not following a reasonable temporal sequence from IMP 
administration. An event which may have been produced by the 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. 


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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. 
 
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 well being of the subject. Appropriate resuscitation equipment and 
medicines 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. 


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7.5 Serious Adverse Events 
All reported SAEs occurring after the first administration of IMP in the study will be 
documented 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., bleeding 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. 
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. 
 
7.5.1 SAE Reporting Timelines 
All SAEs, whether suspected to be related to study treatment or not, are to be reported by 
telephone, fax or e-mail immediately to the 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. 


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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 
medical reasons. 
 
7.6 Vital Signs and Physical Examination 
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 flow chart of assessments for on-demand treatment is provided on page xxi. The flow 
chart of assessments for surgical prophylaxis is provided on page xxii. 
 
7.7 Other Relevant Safety Information 
 
7.7.1.1 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 
reporting 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. 


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7.7.1.2 Pregnancies 
Every effort will be made to avoid a pregnancy during the use of an IMP. 
Pregnancies occurring after IMP treatment is initiated (foetal exposure to the IMP) need to be 
reported. 
In case of pregnancy during the study, the investigator is asked to complete the pregnancy 
notification form and to send it (by fax) to the Clinical Project Manager or designee. 
Follow-up information on the outcome of both mother and foetus will be requested by a 
Sponsor representative. 
 
7.7.1.3 Overdose, Interaction, Misuse, Medication Error and Lack of Efficacy 
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 pharmaceutical form/packaging, and/or instructions for use/labelling. 
The reaction must be clearly identified as a medication error. 
 
7.8 Other Assessments 
Not applicable. 
 
7.9 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 
parameters 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 
regulatory 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 following 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 
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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 discrepancies 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 
Management 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 resolved 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 
investigator 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 
involved in the study are responsible to comply with local and international obligations, 
regulatory 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 
conduct of the study to be fully documented. Essential documents as required by GCP 
guidelines and regulations (e.g., copies of the protocol, study approval letters, all original 
informed consent forms, site copies of all CRFs, drug dispensing and accountability logs, 
correspondence pertaining to the study, etc.) should be filed accurately and kept by the 
investigator for the maximum period of time required by local regulations. 
The investigator is responsible for maintaining a confidential 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 
investigator and the Sponsor. Should the investigator elect to assign the study documents to 
another party, or move them to another location, the Sponsor must be notified in writing. 


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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 
established 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 
responsible 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 
 
9.1 Hypothesis Testing and Determination of Sample Size 
The following hypothesis will be tested: 
H0: p ≤ 0.7 
against the alternative 
HA: p > 0.7 
where p is the proportion of subjects with successful haemostatic efficacy (i.e., ‘excellent’ or 
‘good’). 
The null hypothesis will be tested against the alternative by comparing the lower limit of the 
two-sided 90% Blyth-Still-Casella confidence interval for the proportion of patients with 
successful haemostatic efficacy with the predefined threshold of 0.7. 
The number of subjects is limited by the very small number of patients with this indication. 
Therefore, no real sample size estimation is provided. Instead, the probabilities for different 
outcomes are provided, given a success rate of 90% for a total number of 24 subjects together 
with respective confidence intervals (CIs). 
Assuming that haemostatic treatment is successful (i.e., ‘excellent’ or ‘good’) in 90% of the 
24 subjects, the success rates and probabilities given in Table 5 will apply. 
 
Table 5: Overall clinical assessment of haemostatic efficacy 
 
Outcome 
(n/N) 
Percentage 
Probability for the outcome 
(binomial) 
90% (2-sided) confidence 
interval a 
≥20/24 
≥83.3% 
0.915 
0.681 – 0.925 
≥21/24 
≥87.5% 
0.786 
0.718 – 0.953 
≥22/24 
≥91.7% 
0.564 
0.779 – 0.978 
n = number of subjects with ‘excellent’ and ‘good’ haemostatic efficacy; N = total number of subjects. 
a Blyth-Still-Casella interval [28], realised by SAS software [29]. 
Hence, assuming that treatment with Octafibrin is associated with a true success rate of 90% 
of the 24 subjects, there will be a 78.6% probability that at least 21 of 24 subjects will have a 
successful assessment. In case of 21 successful assessments, the lower boundary of the 90% 
CI will be 0.718, i.e. >70%. 
For the purpose of analysis, the efficacy assessment made by the investigator on the 4-point 
rating scale (see Section 7.2.1) will be transformed to a dichotomous endpoint, with 
‘treatment success—yes’ defined as a rating of ‘excellent’ or ‘good’ and ‘treatment success— 
no’ defined as a rating of ‘moderate,’ ‘none,’ or a missing rating. The success rate will be 
calculated as the proportion of patients with treatment success. 


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9.2 Statistical Analysis 
The primary endpoint is the overall clinical assessment of haemostatic efficacy in acute 
bleeding, covering 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). 
In addition to the inferential evaluation of the success rate described in the preceding section, 
the haemostatic efficacy scale data will be presented descriptively by means of frequency 
counts and percentages. 
The statistical analysis of safety variables will be descriptive only. 
Continuous variables will be summarised using descriptive statistics (arithmetic mean, 
Standard Deviation (SD), median, minimum and maximum, and number of observations and 
missing observations). Categorical variables will be summarised with counts and percentages. 
Data will also be presented as bar and line graphs. 
A formal statistical analysis plan describing all details of the analyses to be performed will be 
prepared by the study statistician and approved by the Sponsor prior to the start of the 
statistical analysis. 
 
9.3 Populations for Analysis 
 
9.3.1 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. 
 
9.3.2 Full Analysis Set 
The full analysis set defined according to the intention-to-treat (ITT) principle will include 
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 
criterion; see Section 4.2). 
• Presented with an episode of acute bleeding (third inclusion criterion; see Section 4.2). 
• And/or plan to undergo a surgical procedure 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). 


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9.3.3 Per-Protocol Population 
The per-protocol (PP) population will include all subjects of the full analysis set who fulfil all 
of the following conditions: 
• Provide valid, i.e., non-missing haemostatic efficacy data. 
• Provide a 1-hour post-infusion MCF value. 
• Received ≥90% of the planned total dose of the IMP in the first infusion. 
• Received ≥80% of the calculated dose (no dose was calculated, 0% will be assumed) of 
the IMP over all further infusions according to the treatment schedule 
• 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 or 
surgery. 
• Did not use 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 (i.e., 1 day) after the last 
Octafibrin infusion. 
• Surgical procedure with a need for at least one infusion of the IMP with an overall 
clinical assessment of haemostatic efficacy. 
Any protocol deviations other than those with respect to the above conditions for the PP 
population must be agreed upon in writing by the Sponsor and the study statistician, and in 
any case, before database closure. 
The efficacy analysis will be performed for bleeding events using the full analysis set (ITT 
analysis) and for the PP population (PP analysis). An additional analysis will also be 
performed for the surgical population. 
 
9.3.4 Subpopulations 
Subpopulations based on the following categories will be examined: 
• Severity of bleeding: minor versus major. 
• Age: Paediatric (≤18 years) versus adult (18–64) versus elderly patients (≥65), if 
appropriate. 
• Sex. 


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9.4 Efficacy Analysis Plan 
 
9.4.1 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. 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). 
Frequency distribution will be provided for the haemostatic efficacy scale data. In addition, a 
90% CI for the success rate in haemostatic efficacy (excellent or good) according to Casella 
(Blyth-Still-Casella interval [28]) will be computed using SAS software [29]. 
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 
bleeding) in tables or with covariables in listings depending on the number per subgroup. 
 
9.4.2 Secondary Endpoints 
 
9.4.2.1 Clot strength (MCF) 
MCF before the first infusion and 1 hour after the end of the first and last infusion as well as 
changes of MCF from pre-infusion will be summarised using descriptive statistics and 
displayed graphically. The course of laboratory data will be presented graphically. Mean 
changes in MCF will be described with 2-sided 95% CIs. 
The same analyses will be performed 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 (excellent/good, moderate/none). Scatterplots will show MCF by 
haemostatic efficacy outcome. 
In addition, a correlation analysis between MCF and the haemostatic efficacy assessment will 
be performed. To evaluate the correlation between MCF and the primary efficacy variable, 
Spearman correlation coefficients will be estimated for the correlation of the 4-point 
haemostatic efficacy with MCF and with MCF change. 
NOTE: If there is almost no variation in haemostatic efficacy outcomes (e.g., if almost all of 
the outcomes are ‘excellent’) there will be only low discriminatory power to show an 
association between MCF and haemostatic efficacy. 


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9.4.2.2 In-vivo recovery 
IVR will be determined using incremental and classical IVR (see Section 7.2.2.2). Calculation 
and analysis of IVR will be performed for the Clauss method only. 
Response (incremental IVR) will be calculated as the maximum increase in plasma 
fibrinogen (i.e., Clauss data) between pre-infusion and 1 and 3 hours post-infusion (expressed 
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 1 and 3 hours 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 pre-infusion and 1 and 3 hours post-infusion (expressed as absolute 
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- 
infusion compared to pre-infusion (mg/dL) x plasma volume (dL) / (exact dose 
of component in IMP administered [mg]): 
∆ value  IU  
 
 IU / dL  
 dL  
IVR  
 =  
 
 
 IU / kg  
dose 
(IU) 
body weight (kg) 
 
 
Response and classical IVR will be calculated for each infusion of each subject. Descriptive 
tables will show the distributions of the 2 parameters per infusion day separated for minor and 
major bleeding. An exploratory analysis using a repeated-measures analysis of covariance 
model will analyse whether the response/classical IVR changed over time. The dose (mg/kg) 
associated with the respective IVR will be held as covariate in the model. The response/IVR 
over time and dose will also be presented in scatter plots for all subjects and by major/minor 
bleeding. 
 
9.4.2.3 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 9.4.1) 


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9.4.2.4 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. 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 evaluated by descriptive statistics based on an overall assessment. 
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 
(‘secondary 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 6. 
 
Table 6: 
Algorithm for the adjudicated intra- and post-operative assessments of 
haemostatic efficacy 
 
Intra-operative 
assessment 
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 indicated ‘IDMEAC’ will be assigned following adjudication by the IDMEAC 
(‘primary adjudication’). 


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9.4.2.5 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 
(descending 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 
investigator will be listed. 
For laboratory variables (analyses of haematology, biochemistry, and thrombogenicity), the 
mean, standard deviation, median, and range will be presented. 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 presentations. 
Physical examination data will be presented in frequency tables. 


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9.4.3 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). Target level and achieved level after 
individual dosing as well as the difference between target level and achieved level will be 
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. The frequency of unscheduled infusions will be summarised 
descriptively. 
 
9.5 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 MCF and IVR values will not be replaced. 
 
9.6 Randomisation 
Not applicable. 
 
9.7 Interim Analysis 
An interim analysis will be performed after the data is available for the first bleeding episode 
of 10 subjects; 2 of these subjects should be between 12 and 18 years old. Results will be 
included in the submission for registration. Descriptive efficacy and safety analysis will be 
performed and presented to IDMEAC. 


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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 
Declaration 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 
after an appropriate explanation of the aims, methods, anticipated benefits, potential hazards 
and any other aspect of the study which is relevant to the subject’s decision to participate. The 
informed consent form must be signed, with name and date and time noted by the subject and 
the investigator, before the subject is exposed to any study-related procedure, including 
screening tests for eligibility. 
For subjects not qualified to give legal consent, written consent must be obtained from the 
legal parent/guardian. If children are old enough to understand the risks and benefits of the 
study, they should also be informed and provide their written consent. 
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 subjects are completely free to refuse to enter the study 
or to withdraw from it at any time, without any consequences for their further care and 
without the need to justify. The investigator will complete the informed consent section of the 
CRF for each subject enrolled. 


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Each subject will be informed that his/her medical (source) records may be reviewed by the 
study monitor, a quality assurance auditor or a health authority inspector, in accordance with 
applicable regulations, and that these persons are bound by confidentiality obligations. 
 
10.4 Protocol Amendments 
Any prospective change to the protocol will be agreed between the investigator (co-ordinating 
investigator in multi-centre studies) and the Sponsor prior to its implementation. Any such 
amendments will be submitted to the IEC(s/IRB) and/or competent authority responsible as 
required by applicable regulations. IEC(s)/IRB approval will at a minimum be requested for 
any change to this protocol which could affect the safety of the subjects, the objective/design 
of the study, any increase in dosage or duration of exposure to the IMP an increase in the 
number 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 
confidential subject identification code list, original consent forms and source records will be 
maintained by the investigator in strict confidence. 


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11 QUALITY CONTROL AND QUALITY ASSURANCE 
 
11.1 Periodic Monitoring 
The monitor will contact and visit the investigator periodically to review all study-related 
source data/records, verify the adherence to the protocol and the completeness, correctness 
and accuracy of all CRF entries compared to source data. The investigator will co-operate 
with the monitor to ensure that any discrepancies identified are resolved. 
For this study, the first monitoring visit shall take place shortly after the 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 
records and reports that are important to the evaluation of the clinical study. Source data will 
be available for all data in the CRFs, including all laboratory results. 
 
11.2 Audit and Inspection 
The investigator will make all study-related source data and records available to a qualified 
quality assurance auditor mandated by the Sponsor, or to IEC/IRB/regulatory inspectors, after 
reasonable notice. The main purposes of an audit or inspection are to confirm that the rights 
and welfare of the 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. 
 
12.2 Publication Policy 
The results of this study may be published or presented at scientific meetings. If this is 
envisaged by an investigator, the investigator agrees to inform the Sponsor and to submit all 
manuscripts or abstracts to the Sponsor prior to submission to an editorial board or scientific 
review committee. This will allow the Sponsor to protect proprietary information and to 
provide comments based on information that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will support 
publication of multi-centre studies only in their entirety and not as individual centre data. 
Authorship will be determined by mutual agreement. 


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13 LIABILITIES AND INSURANCE 
In order to cover any potential damage or injury occurring to a 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 
 
1. 
Takeda Y. Studies of the metabolism and distribution of fibrinogen in healthy men with 
autologous. J Clin Invest 1966; 45:103-111 
2. 
Reeve EB, Franks JJ. Fibrinogen synthesis, distribution and degradation. Sem Thromb 
Hemostasis 1974; I:129-183 
3. 
Collen D, Tytgat GN, Claeys H, Piessens R. Metabolism and distribution of fibrinogen. 
I. Fibrinogen turnover in physiological conditions in humans. Brit J Haematology 1972; 
22:681-700 
4. 
Rausen AR, Cruchaud A, Mcmillan CW, Gitlin D. A study of fibrinogen turnover in 
classical hemophilia and congenital afibrinogemia. Blood 1961; 18:710-716 
5. 
Mammen EF. Fibinogen abnormalities. Sem Thromb Hemostasis 1983; 9:1-9 
6. 
Beck EA. Congenital abnormalities of fibrinogen. Clinical Haematology 1979; 8:169- 
181 
7. 
Micheal Laffan. Fibrinogen. Textbook of hemophilia. Blackwell Publishing 2006; 332- 
337 
8. 
Lak M, Keihani M, Elahi F, Peyvandi F, Mannucci PM. Bleeding and thrombosis in 55 
patients with inherited afibrinogemia. Brit J. Haematology 1999; 107:204-206 
9. 
Parameswaran R, Dickinson JP, De Lord S, Keeling DM, Colvin BT. Spontaneous 
intracranial bleeding in two patients with congenital afibrinogemia and the role of 
replacement therapy. Haemophilia 2000; 6:705-708 
10. 
Dang CV, Bell WR, Shuman M. The normal and morbid biology of fibrinogen. Am J 
Med 1989;87:567-576 
11. 
Kreuz WD, Krackhardt B, Ebener U, Kornhuber B. Treatment with pasteurized human 
fibrinogen concentrate. Absence of hepatitis and HIV infection in patients with a hypo 
and dys-fibrinogenemia. 34th Annual Congress of the German Society of Hematology 
and Oncology, Hanover 1989. Blut, 1989; 59:309 
12. 
Burnouf T, Radosevich M. Nanofiltration of plasma-derived biopharmaceutical 
products. Haemophilia 2003; 9(1):24-37 
13. 
Pereira A. Cryoprecipitate versus commercial fibrinogen concentrate in patients who 
occasionally require a therapeutic supply of fibrinogen: risk comparison in the case of 
an emerging transfusion-transmitted infection. Haematologica 2007; 93(2):846-849 
14. 
European Medicines Agency. Guideline on the Clinical Investigation of Recombinant 
and Human Plasma-Derived Factor IX Products (CHMP/BPWP/144552/2009). 
Available 
at: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/ 
WC500003634.pdf 
15. 
Peyvandi F, Haertel S, Knaub S, Mannucci PM. Incidence of bleeding symptoms in  
100 patients with inherited afibrinogenemia or hypofibrinogenemia. J Thromb Haemost 
2006; 4:1634-1637 


Study Protocol 
No. FORMA-02 
CONFIDENTIAL 
Version 6.0 
31-Oct-2014 
Page 64 
 
 
 
16. 
Cammerer U, Dietrich W, Rampf T, Braun SL, Richter JA. The predictive value of 
modified computerized thromboelastography and platelet function analysis for 
postoperative blood loss in routine cardiac surgery. Anesth Analg 2003; 96:51−57 
17. 
Davis CL, Chandler WL. Thromboelastography for the prediction of bleeding after 
transplant renal biopsy. J Am Soc Nephrol 1995; 6:1250−1255 
18. 
Kaufmann CR, Dwyer KM, Crews JD, Dols SJ, Trask AL. Usefulness of 
thrombelastography in assessment of trauma patient coagulation. J Trauma 1997; 
42:716−720 
19. 
Martin P, Horkay F, Rajah SM, Walker DR. Monitoring of coagulation status using 
thrombelastography during paediatric open heart surgery. Int J Clin Monit Comput 
1991; 8:183−187 
20. 
Spiess BD, Tuman KJ, McCarthy RJ, DeLaria GA, Schillo R, Ivankovich AD. 
Thromboelastography as an indicator of post-cardiopulmonary bypass coagulopathies. J 
Clin Monit 1987; 3:25−30 
21. 
De Lorenzo, Calatzis A, Welsch U, Heindl B. Fibrinogen concentrate reverses dilutional 
coagulopathy induced in vitro by saline but not by hydroxyethyl starch 6%. Anesth 
Analg 2006; 102:1194−2000 
22. 
Fenger-Eriksen 
C, 
Anker-Møller 
E, 
Heslop 
J, 
Ingersley 
J, 
Sørensen 
B. 
Thrombelastographic whole blood clot formation after ex vivo addition of plasma 
substitutes: improvements of the induced coagulopathy with fibrinogen concentrate. Br 
J Anaesth 2005; 94:324−329 
23. 
Fries D, Innerhofer P, Reif C, Streif W, Klingler A, Schobersberger W, Velik-Salchner 
C, Friesenecker B. The effect of fibrinogen substitution on reversal of dilutional 
coagulopathy: an in vitro model. Anesth Analg 2006; 102:347−351 
24. 
Fries D, Krismer A, Klingler A, Streif W, Klima G, Wenzel V, Haas T, Innerhofer 
P.Effect of fibrinogen on reversal of dilutional coagulopathy: a porcine model. Br J 
Anaesth 2005; 95: 172−177 
25. 
Rahe-Meyer N, Solomon C, Winterhalter M, Piepenbrock S, Tanaka K, Haverich A, 
Pichlmaier M. Thromboelastometry-guided administration of fibrinogen concentrate for 
the treatment of excessive intraoperative bleeding in thoracoabdominal aortic aneurysm 
surgery. J Thorac Cardiovasc Surg 2009; 138(3):694-702 
26. 
Fenger-Eriksen C, Jensen TM, Kristensen BS, Jensen KM, Tønnesen E, Ingerslev J, 
Sørensen B. Fibrinogen substitution improves whole blood clot firmness after dilution 
with hydroxyethyl starch in bleeding patients undergoing radical cystectomy: a 
randomized, placebo-controlled clinical trial. J. Thromb Haemost 2009; 7(5):795-802 
27. 
Nadler SB, Hidalgo JU, Bloch T: Prediction of blood volume in normal human adults. 
Surgery 1962; 51:224-232. 
28. 
Casella G. Refining Binomial Confidence Intervals. Canadian Journal of Statistics 1986; 
14:113-129. 
29. 
SAS Institute Inc. (2004). SAS® 9.1 for Windows, Statistical Programming Software – 
User’s Guide. 


Study Protocol 
No. FORMA-02 
CONFIDENTIAL 
Version 6.0 
31-Oct-2014 
Page 65 
 
 
 
 
15 APPENDICES 
None. 

SAP_003.pdf: 
FORMA-02 
JSS Medical Research - Data 
Management 
 
Statistical Analysis Plan 
Form Number: 
MNI-DM-BIS-01 v 6.0-T1 
Current Version 
Number: 2.0 
Previous Version Number: 
1.1 9-April-2015 
Date:11-July-2016 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Protocol Title 
: Prospective, open-label, uncontrolled, phase III study to 
assess the efficacy and safety of Octafibrin for on-demand 
treatment of acute bleeding and to prevent bleeding during 
and after surgery in subjects with congenital fibrinogen 
deficiency 
 
Protocol No. 
: 
FORMA-02 
Protocol Date 
: 
08-July-2016 
SAP Version 
: 
2.0 
Octapharma Doc ID : 
2464 
 
SAP Date 
: 11-July-2016 
 
 
PREPARED BY: 
 
JSS Medical Research, India 
Department of Data Management 
6th Floor, Vatika Mindscapes (Tower B) 
Plot 12/2, Sector 27D 
Faridabad, Haryana, India - 121003 
Ph: +91-129-6613500 
Fax: +91-129-6613520 
 
SPONSOR: 
Octapharma AG 
Seidenstrasse 2 
CH-8853 Lachen 
Switzerland 
 
 
 
Protocol No.: FORMA-02 
11-July-2016 
Confidential and Proprietary to Max Neeman International 
MNI-DM-BIS-01 v 6.0– Annexure 
Page 1 of 31 


Represented by: 
 
 
 
 
 
 
 
 
 
 
 
I hereby declare tlllat I have reviewed the StatIstIcal Analysis Plan and agree to its form and content. In 
addition, I confirm that the outlined Statistical Analysis Plan contains all relevant information for the data 
analysis to be pert rmed for Protocol No. FORMA-02 by the Biostatistics Department. 
 
 
 
 
 
 
 
 
 
Date 
 
Bruce A. Schwartz Ph D 
Director Clinical R D - Haematology 
Octapharma AG 
Seidenstrasse 2 
8853 Lachen 
Switzerland 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol No.: FORMA-  2 
11-July-2016 
Confidential and Proprietary to Max Neeman International 
MNI-DM-BIS-01 v 6.0- Annexure 
Page 2 of 31 
FORMA-02 
JSS Medical Research - Data 
Management 
JSS 
RESPONSJ E 
RE LI A BLE 
RESULTS 
Statistical Analysis Plan 
I 
Form Number: 
MNI-DM-BIS-01 v 6 .0-T1 
Current Version 
Number : 2.0 
Previous Version Number: 
1.1 9-April-2015 
Date:11-July-2016 
I 
SPONSOR SIGN, )
l  TU RE 


RESPONSIVE 
RELIABLE 
RESULTS 
Date:11-July-2016 
 
FORMA-02 
JSS Medical Research - Data 
Management 
Statistical Analysis Plan 
Form Number: 
Current Version 
Previous Version Number: 
MNI-DM-BIS-01 v 6.0-T1 
Number: 2.0 
1.1 9-April-2015 
 
 
AUTHORIZATION DOCUMENT 
 
Authorization Document: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
- 
 
I I 
' 
- . 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol No.: FORMA-02 
 
MNI-DM-BIS-01 v 6.Q-. Annexure 
 
Confidential and Proprietary to Max Neeman International 
11.July-2016 
 
Page 3 of 29 
- --- 
i' 
Sakshi Kaushik 
Biostatistician 
11 Jof J',<O/{, 
Author 
Designation 
Signature 
Date 
Dr. Ghazanfar Husain 
Lead Data Manager r; 
11 b7 7,u1£ 
j(!V//V,. 
·-. 
Reviewer 
Designation 
v 
Date 
Signature 
Data Center Head 
Koteshwar Govind 
/ 
/' < 
/) 
• ,-. v, . 
\ 
\ \ 7/ 2--0 If; 
Approver 
Designation 
C 
Signature 
Date 


Protocol No.: FORMA-02 
11-July-2016 
Confidential and Proprietary to Max Neeman International 
MNI-DM-BIS-01 v 6.0– Annexure 
Page 4 of 31 
 
 
FORMA-02 
JSS Medical Research - Data 
Management 
Statistical Analysis Plan 
Form Number: 
MNI-DM-BIS-01 v 6.0-T1 
Current Version 
Number: 2.0 
Previous Version Number: 
1.1 9-April-2015 
Date:11-July-2016 
 
REVISION HISTORY 
 
Version # 
Version Date 
Author 
Description of Modifications from 
Previous Version 
1.0 
13-Jan-2015 
Mr. Santosh Kumar 
First issue 
1.1 
09-April-2015 
Bruce Schwartz, PhD 
Reference to IDMEAC charter 
regarding statistical algorithm 
Clarification of pediatric subgroup 
Inclusion of analysis by race 
2.0 
11-July-2016 
Bruce Schwartz, PhD 
Changes to statistical analysis 


Protocol No.: FORMA-02 
11-July-2016 
Confidential and Proprietary to Max Neeman International 
MNI-DM-BIS-01 v 6.0– Annexure 
Page 5 of 31 
 
 
FORMA-02 
JSS Medical Research - Data 
Management 
Statistical Analysis Plan 
Form Number: 
MNI-DM-BIS-01 v 6.0-T1 
Current Version 
Number: 2.0 
Previous Version Number: 
1.1 9-April-2015 
Date:11-July-2016 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................................... 7 
1 
INTRODUCTION .............................................................................................................................. 8 
2 
DESCRIPTION OF THE PROTOCOL ............................................................................................. 8 
2.1 
Protocol Number and Version ........................................................................................... 8 
2.2 
Protocol Title ..................................................................................................................... 8 
2.3 
Protocol Date .................................................................................................................... 8 
3 
STUDY OBJECTIVES AND ENDPOINTS ...................................................................................... 9 
3.1 
Study Objectives ............................................................................................................... 9 
3.2 
Study Endpoints .............................................................................................................. 10 
4 
STUDY METHODS ........................................................................................................................ 13 
4.1 
Study Design ................................................................................................................... 13 
4.2 
Study Rationale ............................................................................................................... 13 
4.3 
Study Duration ................................................................................................................ 14 
4.4 
Study Population ............................................................................................................. 15 
4.5 
Flow Chart of Assessments ............................................................................................ 17 
5 
SEQUENCE OF PLANNED ANALYSES ...................................................................................... 21 
6 
GENERAL CONSIDERATIONS FOR STATISTICAL ANALYSIS ............................................... 21 
6.1 
Study Population ............................................................................................................. 21 
6.2 
Derived and Computed Variables ................................................................................... 22 
6.3 
Handling of Drop-outs and Missing Values..................................................................... 22 
6.4 
Analysis Software ........................................................................................................... 22 
7 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .......................................................... 23 
7.1 
Demographics ................................................................................................................. 23 
7.2 
Medical History ............................................................................................................... 23 
8 
EFFICACY ANALYSIS .................................................................................................................. 23 
8.1 
Primary Efficacy Analysis ................................................................................................ 23 
8.2 
Hypothesis Testing and Determination of Sample Size ................................................. 24 
8.3 
Secondary Efficacy Analyses .......................................................................................... 25 


Protocol No.: FORMA-02 
11-July-2016 
Confidential and Proprietary to Max Neeman International 
MNI-DM-BIS-01 v 6.0– Annexure 
Page 6 of 31 
 
 
FORMA-02 
JSS Medical Research - Data 
Management 
Statistical Analysis Plan 
Form Number: 
MNI-DM-BIS-01 v 6.0-T1 
Current Version 
Number: 2.0 
Previous Version Number: 
1.1 9-April-2015 
Date:11-July-2016 
9 
SAFETY ANALYSES .................................................................................................................... 27 
9.1 
Vital Signs ....................................................................................................................... 28 
9.2 
Physical Exam ................................................................................................................ 28 
10 
ADDITIONAL ANALYSES ............................................................................................................ 29 
10.1 
Data Listings ................................................................................................................... 29 
11 
PLOTS AND GRAPHS .................................................................................................................. 29 
12 
REPORTING CONVENTIONS ...................................................................................................... 30 
12.1 
Reporting of Numeric Values .......................................................................................... 30 
12.2 
Output (Tables, Listings and Graphs) Considerations .................................................... 30 
13 
REFERENCES ............................................................................................................................... 31 


Protocol No.: FORMA-02 
11-July-2016 
Confidential and Proprietary to Max Neeman International 
MNI-DM-BIS-01 v 6.0– Annexure 
Page 7 of 31 
 
 
FORMA-02 
JSS Medical Research - Data 
Management 
Statistical Analysis Plan 
Form Number: 
MNI-DM-BIS-01 v 6.0-T1 
Current Version 
Number: 2.0 
Previous Version Number: 
1.1 9-April-2015 
Date:11-July-2016 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ABBREVIATION 
DEFINITION 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
CI 
Confidence Interval 
CSR 
Clinical Study Report 
EU 
European Union 
EMA 
European Medicines Agency 
FAS 
Full Analysis Set 
IVR 
In Vivo Recovery 
IDMEAC 
Independent Data Monitoring & Endpoint Adjudication Committee 
IMP 
Investigational Medicinal Product 
ITT 
Intention to Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCF 
Maximum Clot Firmness 
PP 
Per Protocol 
PDCO 
Paul Ehrlich Institute and the Pediatric Committee 
PK 
Pharmacokinetic 
SOC 
System Organ Class 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SAE 
Serious Adverse Event 
TEG 
Thromboelastography 
TLG’s 
Tables Listings Graphs 
US 
United States 


Protocol No.: FORMA-02 
11-July-2016 
Confidential and Proprietary to Max Neeman International 
MNI-DM-BIS-01 v 6.0– Annexure 
Page 8 of 31 
 
 
FORMA-02 
JSS Medical Research - Data 
Management 
Statistical Analysis Plan 
Form Number: 
MNI-DM-BIS-01 v 6.0-T1 
Current Version 
Number: 2.0 
Previous Version Number: 
1.1 9-April-2015 
Date:11-July-2016 
 
 
1 
INTRODUCTION 
This Statistical Analysis Plan (SAP) provides a comprehensive and detailed description of 
statistical methods to be used to analyze the data for protocol FORMA-02, Version 6.0, 31-Oct- 
2014, as amended on 08-July-2016 (Version 7.0). 
The purpose of this SAP is to outline the planned analyses to be completed to support the 
completion of the Clinical Study Report (CSR) for protocol FORMA-02. In addition, this SAP will 
describe any clarifications or modifications to the endpoints and statistical methods in the 
protocol. The planned analyses identified in this SAP will supersede the statistical sections in 
protocol and will be included in regulatory submissions and/or future manuscripts. In addition, 
exploratory analyses not necessarily identified in this SAP may be performed to support the 
clinical development program. Additional exploratory analyses may be added as addendums to 
this SAP after the signoff. Any post-hoc, or unplanned, analyses not identified in this SAP 
performed will be clearly identified in the respective CSR. 
 
2 
DESCRIPTION OF THE PROTOCOL 
2.1 
Protocol Number and Version 
FORMA-02, Version 7.0 
 
2.2 
Protocol Title 
Prospective, open-label, uncontrolled, phase III study to assess the efficacy and safety of 
Octafibrin for on-demand treatment of acute bleeding and to prevent bleeding during and after 
surgery in subjects with congenital fibrinogen deficiency. 
 
2.3 
Protocol Date 
The date of protocol Version 7.0 is 08-July-2016. 


Protocol No.: FORMA-02 
11-July-2016 
Confidential and Proprietary to Max Neeman International 
MNI-DM-BIS-01 v 6.0– Annexure 
Page 9 of 31 
 
 
FORMA-02 
JSS Medical Research - Data 
Management 
Statistical Analysis Plan 
Form Number: 
MNI-DM-BIS-01 v 6.0-T1 
Current Version 
Number: 2.0 
Previous Version Number: 
1.1 9-April-2015 
Date:11-July-2016 
 
 
3 
STUDY OBJECTIVES AND ENDPOINTS 
3.1 
Study Objectives 
 
3.1.1 Primary Objective 
The primary objective of the study is: 
• 
To demonstrate the efficacy of Octafibrin for on-demand treatment of acute bleeding episode 
(spontaneous or after trauma). 
 
3.1.2 Secondary Objectives 
• 
To show 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]) that was used as a surrogate endpoint for haemostatic efficacy and 
determined via Thromboelastography (TEG) in the pivotal Pharmacokinetic (PK) study 
FORMA-01. Therefore, MCF as surrogate efficacy parameter will be determined before first 
infusion and 1 hour after the end of first and last infusion. 
• 
To achieve 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, including 
immunogenicity, thromboembolic complications, and early signs of allergic or hypersensitivity 
reactions. 


Protocol No.: FORMA-02 
11-July-2016 
Confidential and Proprietary to Max Neeman International 
MNI-DM-BIS-01 v 6.0– Annexure 
Page 10 of 31 
 
 
FORMA-02 
JSS Medical Research - Data 
Management 
Statistical Analysis Plan 
Form Number: 
MNI-DM-BIS-01 v 6.0-T1 
Current Version 
Number: 2.0 
Previous Version Number: 
1.1 9-April-2015 
Date:11-July-2016 
 
3.2 
Study Endpoints 
 
3.2.1 Primary Endpoint 
The primary endpoint is: 
• 
The primary endpoint is the overall clinical assessment of 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 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 assessment 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. 
 
Category 
Definition 
Excellent 
Immediate and complete cessation of bleeding in the absence of other haemostatic 
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 required, 
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. 


Protocol No.: FORMA-02 
11-July-2016 
Confidential and Proprietary to Max Neeman International 
MNI-DM-BIS-01 v 6.0– Annexure 
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FORMA-02 
JSS Medical Research - Data 
Management 
Statistical Analysis Plan 
Form Number: 
MNI-DM-BIS-01 v 6.0-T1 
Current Version 
Number: 2.0 
Previous Version Number: 
1.1 9-April-2015 
Date:11-July-2016 
 
 
3.2.2 
Secondary Endpoints 
The secondary efficacy endpoints are: 
• 
MCF assessment before first infusion and 1 hour after end of first and last 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 of each documented bleeding episode). 
• 
Response as indicated by incremental IVR, calculated as the maximum increase in plasma 
fibrinogen (Clauss data) between pre-infusion and 1 and 3 hours post-infusion. 
• 
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 
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 haemostasis 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 
replacement regimen. 
*All 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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11-July-2016 
Confidential and Proprietary to Max Neeman International 
MNI-DM-BIS-01 v 6.0– Annexure 
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FORMA-02 
JSS Medical Research - Data 
Management 
Statistical Analysis Plan 
Form Number: 
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Current Version 
Number: 2.0 
Previous Version Number: 
1.1 9-April-2015 
Date:11-July-2016 
 
Post-operative efficacy as assessed by haematologist 
Excellent 
No post-operative bleeding or oozing that was not due to complications of surgery. 
All post-operative bleeding (due to complications of surgery) was controlled with 
Octafibrin as anticipated for the type of procedure. 
Good 
No post-operative bleeding or oozing that was not due to complications of surgery. 
Control of post-operative bleeding due to complications of surgery required 
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 
Octafibrin or additional infusions, not originally anticipated for the type of procedure. 
None 
Extensive uncontrolled post-operative bleeding and oozing. Control of post- 
operative 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. 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 based on an agreed algorithm as 
indicated in the IDMEAC charter . 
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 Octafibrin (pre-, intra- and/or 
post-operatively) will be recorded. Fibrinogen plasma levels (pre-, intra-, and post-operatively) 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. 
 
The safety endpoints are: 
• 
Vital signs. 
• 
Physical examination. 
• 
Check of Wells criteria for deep venous thrombosis (DVT) and PE (pulmonary embolism). 
• 
Routine clinical laboratory assessment, including coagulation parameters. 
• 
Adverse events (AEs), including thromboembolic complications and early signs of allergic or 
hypersensitivity reactions. 
• 
Immunogenicity testing at Day 14 and Day 30 after the administration of Octafibrin for 
bleeding. 


Protocol No.: FORMA-02 
11-July-2016 
Confidential and Proprietary to Max Neeman International 
MNI-DM-BIS-01 v 6.0– Annexure 
Page 13 of 31 
 
 
FORMA-02 
JSS Medical Research - Data 
Management 
Statistical Analysis Plan 
Form Number: 
MNI-DM-BIS-01 v 6.0-T1 
Current Version 
Number: 2.0 
Previous Version Number: 
1.1 9-April-2015 
Date:11-July-2016 
 
 
4 
STUDY METHODS 
4.1 
Study Design 
This is a multinational, multi-centre, prospective, open-label, uncontrolled, Phase III study to 
assess the efficacy and safety of Octafibrin for on-demand treatment of acute bleeding and to 
prevent bleeding during and after surgery in subjects with congenital fibrinogen deficiency 
A minimum of 24 subjects will be enrolled in the study to assess on-demand treatment of at least 
one bleeding episode. This will include at least 4 subjects aged between 12 and 18 years (only 18 
and above in Russia). This will also include an assessment of at least 4 surgical procedures, 2 of 
which should be performed in subjects aged between 12 and 18 years (only 18 and above in 
Russia). The study will be conducted in approximately 15 centres worldwide. 
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 
the 24th patient has at least one documented bleeding episode. The study will be considered 
completed when a minimum of 24 subjects have at least one documented bleeding episode. The 
study as a whole should be completed within 5 years. 
 
4.2 
Study Rationale 
It is estimated that there are 500 to 1000 subjects with congenital fibrinogen deficiency in the 
European Union (EU). Historically, the principal source for the treatment of congenital fibrinogen 
deficiency has been cryoprecipitate. 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. 
The introduction of Octafibrin will present an additional and safe option, providing more choices of 
supply for the benefit of the medical community and subjects affected by congenital fibrinogen 
deficiency. 
This phase III study is designed as a multinational, multi-centre, prospective, open-label, 
uncontrolled study to assess the efficacy and safety of Octafibrin for on-demand treatment of 
acute bleeding in subjects with congenital fibrinogen deficiency. 
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) and discussions with the Paul Ehrlich Institute 
and the Paediatric Committee (PDCO) of the EMA. 


Protocol No.: FORMA-02 
11-July-2016 
Confidential and Proprietary to Max Neeman International 
MNI-DM-BIS-01 v 6.0– Annexure 
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FORMA-02 
JSS Medical Research - Data 
Management 
Statistical Analysis Plan 
Form Number: 
MNI-DM-BIS-01 v 6.0-T1 
Current Version 
Number: 2.0 
Previous Version Number: 
1.1 9-April-2015 
Date:11-July-2016 
 
4.3 
Study Duration 
 
4.3.1 Planned Duration for an Individual Subject 
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 for up to 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 epi-sodes 
or planned surgeries that can be managed under the protocol. Patients may remain in the study 
until the 24th patient has at least one documented bleeding episode. 
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 3.2.1). All bleeding episodes documented in the study will be 
assessed as a secondary endpoint (see Section 3.2.2). 
Patients who were screened for the study but do not present with a bleeding episode or planned 
surgery during the study observation period will be considered ‘no treatment’ patients. 
The individual observation period by subject starts with the first dose of Octafibrin administered 
for on-demand treatment of an acute bleeding episode or prior to elective surgery (Day 1). 
Subjects enrolled will be treated for any bleeding episodes or planned surgeries during the study 
observation period. They may remain in the study until the 24th subject has at least one 
documented bleeding episode. 
 
4.3.2 Planned Duration for the Study as a Whole 
The study will be considered completed when a minimum of 24 subjects have at least one 
documented bleeding episode. The study as a whole should be completed within 5 years. 
The estimated start of the study (enrolment of first subject) is in the 4th quarter of 2014, and the 
estimated end of the study (last visit of last subject) is in the 4th quarter of 2019. 


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MNI-DM-BIS-01 v 6.0– Annexure 
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FORMA-02 
JSS Medical Research - Data 
Management 
Statistical Analysis Plan 
Form Number: 
MNI-DM-BIS-01 v 6.0-T1 
Current Version 
Number: 2.0 
Previous Version Number: 
1.1 9-April-2015 
Date:11-July-2016 
 
4.4 
Study Population 
 
4.4.1 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 the safety population. 
 
4.4.2 Full Analysis Set (FAS) 
The full analysis set defined according to the intention-to-treat (ITT) principle will include subjects 
who fulfill all of the following conditions: 
• 
Received at least one infusion of the IMP. 
• 
Entered the study with a confirmed congenital fibrinogen deficiency (second inclusion 
criterion). 
• 
Presented with an episode of acute bleeding (third inclusion criterion). 
• 
And/or plan to undergo a surgical procedure with a need for at least one infusion of the IMP 
(third inclusion criterion). 
 
4.4.3 The Per Protocol (PP) Population 
The per-protocol (PP) population will include all subjects of the full analysis set who fulfill all of the 
following conditions: 
• 
Provide valid, i.e., non-missing haemostatic efficacy data. 
• 
Provide a 1-hour post-infusion MCF value. 
• 
Received ≥90% of the planned total dose of the IMP in the first infusion. 
• 
Received ≥80% of the calculated dose (no dose was calculated, 0% will be assumed) of the 
IMP over all further infusions according to the treatment schedule 
• 
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 or surgery. 
• 
Did not use 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 (i.e., 1 day) after the last Octafibrin infusion. 
• 
Surgical procedure with a need for at least one infusion of the IMP with an overall clinical 
assessment of haemostatic efficacy. 


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MNI-DM-BIS-01 v 6.0– Annexure 
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FORMA-02 
JSS Medical Research - Data 
Management 
Statistical Analysis Plan 
Form Number: 
MNI-DM-BIS-01 v 6.0-T1 
Current Version 
Number: 2.0 
Previous Version Number: 
1.1 9-April-2015 
Date:11-July-2016 
 
Any protocol deviations other than those with respect to the above conditions for the PP 
population must be agreed upon in writing by the Sponsor and the study statistician, and in any 
case, before database closure. 
The efficacy analysis will be performed for bleeding events using the full analysis set (ITT 
analysis) and for the PP population (PP analysis). An additional analysis will also be performed 
for the surgical population. 
 
4.4.4 Surgical Prophylaxis Population 
The full analysis set defined according to the intention-to-treat (ITT) principle will include subjects 
who fulfill all of the following conditions: 
• 
Received at least one infusion of the IMP. 
• 
Entered the study with a confirmed congenital fibrinogen deficiency (second inclusion 
criterion). 
• 
Presented with an episode of acute bleeding (third inclusion criterion). 
• 
And plan to undergo a surgical procedure with a need for at least one infusion of the IMP 
(third inclusion criterion). 
 
4.4.5 Subpopulations 
Subpopulations based on the following categories will be examined: 
• 
Severity of bleeding: minor versus major. 
• 
Age: Paediatric (≤18 years) versus adult (18–64) versus elderly patients (≥65), if appropriate. 
• 
Sex. 


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MNI-DM-BIS-01 v 6.0– Annexure 
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FORMA-02 
JSS Medical Research - Data Management 
Statistical Analysis Plan 
Form Number: 
MNI-DM-BIS-01 v 6.0-T1 
Current Version Number: 
2.0 
Previous Version Number: 1.1 9- 
April-2015 
Date: 11-July-2016 
 
4.5 
Flow Chart of Assessments 
 
4.5.1 Flow Chart of Assessments for On-Demand Treatment of Acute Bleeding 
 
Observations performed for each bleeding episode 
Screening 
Day 1 
All study days 
after Day 1 
(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 14 
(± 2 days) 
Day 30 
(± 1 week) 
Study 
Completion 
Visit 
Pre- 
infusion 
Post-infusion 
Daily 
Pre- 
infusion [a] 
1 h post- 
infusion [a] 
(± 15 min) 
Pre- 
infusion 
Post-infusion 
1 h 
(± 15 min) 
3 h 
(± 15 min) 
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 
x 
Wells criteria for DVT and PE 
x 
x 
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] 
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] 
x [d] 
MCF [d] 
x [b] 
x 
x 
Thrombogenicity [d] 
x 
x 
x 
x 
x 
x 
x 
Immunogenicity [d] 
x 
x 
x 
Safety lab (haematology and clinical chemistry) [c] 
x 
x 
x 
x [i] 
x 
x 
x 
x 
Retention plasma samples [e] 
x [b] 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Retention serum samples [e] 
x 
x 
Urine or blood pregnancy test 
x 
Infusion of Octafibrin 
x [f] 
x [f,g] 
x 
Final haemostatic efficacy assessment 
x 
AEs [h] 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
Concomitant medications 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 


Protocol No.: FORMA-02 
11-July-2016 
Confidential and Proprietary to Max Neeman International 
MNI-DM-BIS-01 v 6.0– Annexure 
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FORMA-02 
JSS Medical Research - Data Management 
Statistical Analysis Plan 
Form Number: 
MNI-DM-BIS-01 v 6.0-T1 
Current Version Number: 
2.0 
Previous Version Number: 1.1 9- 
April-2015 
Date: 11-July-2016 
 
 
 
DVT = deep venous thrombosis; PE = pulmonary embolism; 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] Plasma retain sample for potential retesting; serum retain 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 completion of the Wells criteria for assessment of possible DVT and PE or any thromboembolic events or hypersensitivity reactions. 
[i] Haematology only 


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MNI-DM-BIS-01 v 6.0– Annexure 
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FORMA-02 
JSS Medical Research - Data Management 
Statistical Analysis Plan 
Form Number: 
MNI-DM-BIS-01 v 6.0-T1 
Current Version Number: 
2.0 
Previous Version Number: 1.1 9- 
April-2015 
Date: 11-July-2016 
 
4.5.2 Flow Chart of Assessments for Surgical Prophylaxis 
 
Screening 
Observations performed for each surgical intervention 
Study 
Completion 
Visit 
Before surgery 
Day 1 
Surgery 
Any POP day 
(i.e., up to 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 
Pre- 
infusion 
1 h post- 
infusion 
(± 15 min) 
Daily 
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 
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 
Wells criteria for DVT and PE 
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] 
Thrombogenicity [c] 
x 
x 
x 
x 
Safety lab (haematology and clinical chemistry) [b] 
x 
x 
x 
x 
x 
Retention plasma samples [d] 
x 
x [a] 
x 
x 
x 
x 
x 
x 
x 
Retention serum samples [d] 
x 
x 
Urine or blood pregnancy test 
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 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 


Protocol No.: FORMA-02 
11-July-2016 
Confidential and Proprietary to Max Neeman International 
MNI-DM-BIS-01 v 6.0– Annexure 
Page 20 of 31 
 
 
FORMA-02 
JSS Medical Research - Data Management 
Statistical Analysis Plan 
Form Number: 
MNI-DM-BIS-01 v 6.0-T1 
Current Version Number: 
2.0 
Previous Version Number: 1.1 9- 
April-2015 
Date: 11-July-2016 
 
 
DVT = deep venous thrombosis; PE = pulmonary embolism; 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 completion completion of the Wells criteria for assessment of possible DVT and PE or any thromboembolic events and hypersensitivity reactions. 


Protocol No.: FORMA-02 
11-July-2016 
Confidential and Proprietary to Max Neeman International 
MNI-DM-BIS-01 v 6.0– Annexure 
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FORMA-02 
JSS Medical Research - Data 
Management 
Statistical Analysis Plan 
Form Number: 
MNI-DM-BIS-01 v 6.0-T1 
Current Version 
Number: 2.0 
Previous Version Number: 
1.1 9-April-2015 
Date: 11-July-2016 
 
4.5.3 Schedule of Visits/Summary of Study Procedures 
Refer to Section 6.1 of protocol – Observations performed throughout the study. 
 
5 
SEQUENCE OF PLANNED ANALYSES 
An interim analysis will be performed after the data is available for the first bleeding episode of 10 
subjects. Two of these subjects should be between 12 and 18 years old. Results will be included 
in the submission for registration. Descriptive efficacy and safety analysis will be performed and 
presented to IDMEAC. 
 
6 
GENERAL CONSIDERATIONS FOR STATISTICAL ANALYSIS 
The descriptive statistics for continuous variables will be presented with number (n) of non- 
missing observations, mean, Standard Deviation (SD), median, minimum and maximum (or 
range). For categorical variables, descriptive statistics will be presented with number of eligible 
subjects and number (n) with percentage of observations in the various categories of the 
endpoint, where percentage will be based on the eligible subjects in the respective analysis set. 
 
6.1 
Study Population 
 
6.1.1 Number of Subjects 
A minimum of 24 subjects will be enrolled in the study to assess on-demand treatment of at least 
one bleeding episode. This will include at least 4 subjects aged between 12 and 18 years (only 18 
and above in Russia). This will also include an assessment of at least 4 surgical procedures, 2 of 
which should be performed in subjects aged between 12 and 18 years (only 18 and above in 
Russia). The study will be conducted in approximately 15 centres worldwide. 
 
6.1.2 Subpopulations 
Subpopulations based on the following categories will be examined: 
• 
Severity of bleeding: minor versus major. 
• 
Age: Paediatric (<18 years) versus adult (18–64) versus elderly patients (≥65), if appropriate. 
• 
Sex 
• 
Race 
• 
Surgical population 
 
6.1.3 Sample Size Rationale 
The number of subjects is limited by the very small number of subjects in this indication. 
Therefore no real sample size estimation is provided. Instead, the probabilities for different 
outcomes are provided, given a success rate of 95% for a total number of 24 subjects together 
with respective confidence intervals (CIs). 


Protocol No.: FORMA-02 
11-July-2016 
Confidential and Proprietary to Max Neeman International 
MNI-DM-BIS-01 v 6.0– Annexure 
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FORMA-02 
JSS Medical Research - Data 
Management 
Statistical Analysis Plan 
Form Number: 
MNI-DM-BIS-01 v 6.0-T1 
Current Version 
Number: 2.0 
Previous Version Number: 
1.1 9-April-2015 
Date: 11-July-2016 
 
6.2 
Derived and Computed Variables 
It is expected that variables will be derived and computed. The SAP will not be amended for 
additional variables that are not related to the primary or key secondary variables. 
For analysis purpose the assessment made by the investigator on the 4-point rating scale will be 
transformed to a dichotomous endpoint with success as “Yes” defined as a rating of excellent or 
good and “No” as Moderate or Non or Missing). The success rate will be calculated as the 
proportion of patients with success. 
Any additional derived variables will be identified and documented in the Statistical Analysis 
System (SAS®) programs that create analysis files. 
The following variable will be calculated for the analysis tables: BMI 
 
Variable 
Name 
Description 
Valid Values 
(Ranges) 
Computation Methods, Notes, or 
Equation(s) 
BMI 
Body Mass Index 
— 
BMI = {Weight (in Kg) / (Height (in 
meters))2} 
Success 
Overall clinical 
assessment of 
haemostatic efficacy 
Yes/No 
if value is ‘excellent; or ‘good’, then 
Success = “Yes” 
if value is ‘Moderate ‘or ‘None’ or 
‘Missing’, then Success = “No” 
Body Mass Index (BMI) = {Weight (in Kg) / (Height (in meters)) 2} 
 
6.3 
Handling of Drop-outs and Missing Values 
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 per-protocol  
PP population. LOCF (Last observation carried forward) approach will be used for body weight 
measurement for all analysis involving dose/kg BW. 
Missing MCF and IVR values will not be replaced. 
 
6.4 
Analysis Software 
All the Statistical Reports including Summary Tables, Listings and Graphs (TLGs) will be 
generated using a customized reporting SAS Version 9.3 for windows, SAS Institute, Cary, North 
Carolina, United States of America (USA). 


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11-July-2016 
Confidential and Proprietary to Max Neeman International 
MNI-DM-BIS-01 v 6.0– Annexure 
Page 23 of 31 
 
 
FORMA-02 
JSS Medical Research - Data 
Management 
Statistical Analysis Plan 
Form Number: 
MNI-DM-BIS-01 v 6.0-T1 
Current Version 
Number: 2.0 
Previous Version Number: 
1.1 9-April-2015 
Date: 11-July-2016 
 
 
7 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
The following information will be captured on enrolment: 
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 
physical examination. 
Previous and concomitant medication: obtained by interviewing the subject. 
 
7.1 
Demographics 
Demographic variables and will be summarized descriptively. Demographic variables will include 
age, weight, sex, height, BMI and ethnic origin. Variables that are measured on a continuous 
scale, such as the age of the subject at the time of enrollment, the number of non-missing 
observations (n), mean, median, SD, minimum, and maximum will be tabulated for Octafibrin. 
Variables that are measured on a categorical scale will be summarized using frequencies and 
percentages of Octafibrin. 
 
7.2 
Medical History 
Medical history will be listed by body system coded by MedDRA version 17.1 or higher with 
Preferred Term. 
 
8 
EFFICACY ANALYSIS 
8.1 
Primary Efficacy Analysis 
For bleeding efficacy, 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 until 24 hours 
(i.e., 1 day) after the last infusion or the end of the treatment observation period, whichever 
comes last. Frequency distribution will be provided for the haemostatic efficacy scale data. In 
addition, a 95% CI for the success rate in haemostatic efficacy (excellent or good) according to 
Casella (Blyth-Still-Casella interval) will be computed using StatXact® software. 
For the following subjects the haemostatic efficacy outcome will be set to the worst 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 efficacy [e.g., pharmacy error]). 
• 
Subjects with missing haemostatic efficacy assessment. 
Haemostatic efficacy will be displayed by co variables (sex, age groups, race, weight and type of 
bleeding) in tables or with co variables in listings depending on the number per subgroup. 


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11-July-2016 
Confidential and Proprietary to Max Neeman International 
MNI-DM-BIS-01 v 6.0– Annexure 
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FORMA-02 
JSS Medical Research - Data 
Management 
Statistical Analysis Plan 
Form Number: 
MNI-DM-BIS-01 v 6.0-T1 
Current Version 
Number: 2.0 
Previous Version Number: 
1.1 9-April-2015 
Date: 11-July-2016 
 
8.2 
Hypothesis Testing and Determination of Sample Size 
The following hypothesis will be tested: 
H0: p ≤ 0.6 
Against the alternative 
HA: p > 0.6 
Where p is the proportion of subjects with successful haemostatic efficacy (i.e.; ‘excellent’ or 
‘good’). 
The null hypothesis will be tested against the alternative by comparing the lower limit of the two- 
sided 95% Blyth-Still-Casella confidence interval for the proportion of patients with successful 
haemostatic efficacy with the predefined threshold of 0.6. 
Due to practical limitations in subject enrolment and total study duration due to the very small 
number of patients with this indication, no real sample size calculation was performed on basis of 
statistical power considerations. Instead, the probabilities and associated confidence intervals 
(CIs) for different outcomes are provided, assuming a true success rate of 0.95. 
Assuming that the study treatment is successful (i.e. the haemostatic efficacy assessment is 
‘excellent’ or ‘good’) in 95% of the subjects, the success rates given in Table 1 will be observed in 
the 24 study subjects with the following probabilities: 
Table 1: Overall clinical assessment of haemostatic efficacy 
 
Outcome 
(n/N) 
Percentage 
Probability for 
the outcome (binomial) 
95% (2-sided) 
confidence intervala 
≥19/24 
≥79.1% 
0.999 
0.594–0.914 
≥20/24 
≥83.3% 
0.994 
0.633–0.941 
≥21/24 
≥87.5% 
0.970 
0.691–0.965 
≥22/24 
≥91.7% 
0.884 
0.744–0.985 
n = number of subjects with ‘excellent’ and ‘good’ haemostatic efficacy; N = total number of subjects. 
a Blyth-Still-Casella interval, realised by StatXact® software. 
Hence, assuming that treatment with Octafibrin is associated with a true success rate of 95% of 
the 24 subjects, there will be a 99.4% probability that at least 20 of 24 subjects will have a 
successful assessment. In case of 20 successful assessments, the lower boundary of the 95% CI 
will be 0.633, i.e., > 60%. 


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FORMA-02 
JSS Medical Research - Data 
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Form Number: 
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Current Version 
Number: 2.0 
Previous Version Number: 
1.1 9-April-2015 
Date: 11-July-2016 
 
For the purpose of analysis, the efficacy assessment made by the investigator on the 4-point 
rating scale will be transformed to a dichotomous endpoint, with ‘treatment success—yes’ defined 
as a rating of ‘excellent’ or ‘good’ and ‘treatment success—no’ defined as a rating of ‘moderate,’ 
‘none,’ or a missing rating. The success rate will be calculated as the proportion of patients with 
treatment success. 
 
8.3 
Secondary Efficacy Analyses 
 
8.3.1 Clot strength (MCF) 
• 
Fibrinogen levels 1 hour after infusions of the IMP, MCF at baseline and at 1 hour after first 
and last infusion as well as changes of MCF from baseline will be summarized using 
descriptive statistics and displayed graphically. The course of laboratory data will be 
presented graphically. Mean changes in MCF will be described with 2-sided 95% CIs. 
• 
Statistical analyses will also be performed separately 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 dichotomized 
haemostatic efficacy scale (excellent/good, moderate/none). Scatter plots will show MCF by 
haemostatic efficacy outcome. 
 
Correlation with MCF and MCF Change: 
• 
In addition, a correlation analysis between MCF and the haemostatic efficacy assessment will 
be performed. To evaluate the correlation between MCF and the primary efficacy variable 
Spearman correlation coefficients will be estimated for the correlation of the 4-point 
haemostatic efficacy with MCF and with MCF change. 
Note: If there is almost no variation in haemostatic efficacy outcomes (e.g., if almost all of the 
outcomes are “excellent”) there will be only low discriminatory power to show an association 
between MCF and haemostatic efficacy. 
Octafibrin use 
• 
The dose of the IMP used per day and in total will be summarized using descriptive statistics 
for minor and major bleeding events. Frequency of infusions and duration of treatment will 
also be summarized. The frequency of unscheduled infusions will be summarized 
descriptively. 
 
8.3.2 Fibrinogen Levels 
Fibrinogen plasma level before and 1 hour after the end of each subsequent infusion and at the 
time of the overall clinical assessment of haemostatic efficacy. 
Fibrinogen at baseline and at 1 hour after first and last infusion as well as changes of Fibrinogen 
from baseline will be summarized using descriptive statistics and displayed graphically. 


Protocol No.: FORMA-02 
11-July-2016 
Confidential and Proprietary to Max Neeman International 
MNI-DM-BIS-01 v 6.0– Annexure 
Page 26 of 31 
 
 
FORMA-02 
JSS Medical Research - Data 
Management 
Statistical Analysis Plan 
Form Number: 
MNI-DM-BIS-01 v 6.0-T1 
Current Version 
Number: 2.0 
Previous Version Number: 
1.1 9-April-2015 
Date: 11-July-2016 
 
 
 
Octafibrin will be individually dosed to achieve a recommended target fibrinogen plasma level 
dependent on the bleeding type (minor or major). Target level and achieved level after individually 
dosed as well as difference of Target level and achieved level will be summarized using 
descriptive statistics and displayed graphically. 
 
8.3.3 In-Vivo Recovery 
• 
Calculation and analysis of IVR will be performed for the Clauss method only. 
• 
Response (incremental IVR) will be calculated as the maximum increase in plasma fibrinogen 
(i.e., Clauss data) as compared to pre-infusion, within the 12 hours (will usually refer either to 
the 60 minutes or the 3 hours after the first and the last infusion and refer to the 60 minutes 
time point after the other infusions) following infusion (expressed 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 within 12 hours 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) 
as compared to pre-infusion, within 12 hours (will usually refer either to the 60 minutes or the 3 
hours after the first and the last infusion and refer to the 60 minutes time point after the other 
infusions) following infusion (expressed as absolute 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. 
Classical IVR (%) = 
100% x actual/expected increase = 
100% x maximum increase in fibrinogen plasma level within 12 hours compared to pre- 
infusion (mg/dL) x plasma volume (dL) / (exact dose of component in IMP administered 
[mg]): 
 
 
 IU / dL  
∆ value  IU  
dL 
IVR  
 =  
 
 
 IU / kg  
dose (IU) body weight (kg) 
 
Response and classical IVR will be calculated for each infusion of each subject. Descriptive 
tables will show the distributions of the 2 parameters per infusion day separated for minor and 
major bleeding. An exploratory analysis using a repeated-measures analysis of covariance model 
will analyze whether the response/classical IVR changed over time. The dose (mg/kg) associated 
with the respective IVR will be held as covariate in the model. The response/IVR over time and 
dose will also be presented in scatter plots for all subjects and by major/minor bleeding. 


Protocol No.: FORMA-02 
11-July-2016 
Confidential and Proprietary to Max Neeman International 
MNI-DM-BIS-01 v 6.0– Annexure 
Page 27 of 31 
 
 
FORMA-02 
JSS Medical Research - Data 
Management 
Statistical Analysis Plan 
Form Number: 
MNI-DM-BIS-01 v 6.0-T1 
Current Version 
Number: 2.0 
Previous Version Number: 
1.1 9-April-2015 
Date: 11-July-2016 
 
8.3.4 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 9.4.1). 
 
8.3.5 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. 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 primary 
endpoint will be that based on the adjudicated assessments. The efficacy of Octafibrin in surgical 
prophylaxis will be evaluated by descriptive statistics based on an overall assessment. 
In the documentation of the adjudication process for the assessment of surgical prophylaxis the 
DMEAC will explicitly identify any subjects for whom they considered there to be “unexpected 
blood loss due to surgical complications” and if that consideration altered the 4-point assessment 
of surgical prophylaxis. This information will be analyze both including (as a sensitivity analysis) 
and excluding unexpected blood loss if it occurs. 
 
9 
SAFETY ANALYSES 
AEs and SAEs will be coded by latest version 17 or higher of MedDRA body system and 
preferred term, and tabulated by indicating number and percentage of subjects and number of 
events. Number and percentage of subjects who experience any Adverse Drug Reaction (ADR) 
will be summarized. 
AEs will be collected and evaluated for relation to test article, seriousness, intensity, frequency, 
measures taken and outcome. 
Descriptive statistics and subject listing will be presented for concomitant medications. 
The analysis of safety will be based on the safety population. 
All AEs occurring after initiation of study treatments (including events likely to be related to the 
underlying disease, or a concomitant illness or medication or clinical significant abnormalities in 
laboratory parameters or vital signs) will be displayed in summary tables and listings. 
Treatment emergent AEs will be those occurring during infusion or in the 45-day observation 
period after the first infusion. ADRs will be classified by the Sponsor as either expected or 
unexpected 


Protocol No.: FORMA-02 
11-July-2016 
Confidential and Proprietary to Max Neeman International 
MNI-DM-BIS-01 v 6.0– Annexure 
Page 28 of 31 
 
 
FORMA-02 
JSS Medical Research - Data 
Management 
Statistical Analysis Plan 
Form Number: 
MNI-DM-BIS-01 v 6.0-T1 
Current Version 
Number: 2.0 
Previous Version Number: 
1.1 9-April-2015 
Date: 11-July-2016 
 
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 (descending 
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 
summarized by severity and relationship to the IMP. 
The MedDRA coded terms and the corresponding original (verbatim) terms used by the 
investigator will be listed. 
For laboratory variables (analyses of haematology, biochemistry, and thrombogenicity), the 
mean, standard deviation, median, and range will be presented. Laboratory variables will also be 
presented graphically. Intra-individual changes between baseline and the respective post- 
baseline time points will be analyzed using shift tables and graphical presentations. Virus safety 
variables and physical examination will be evaluated via frequency tables. 
 
9.1 
Vital Signs 
Vital signs including systolic and diastolic blood pressure, pulse rate, respiratory rate, and body 
temperature will be recorded using standard clinical procedures at the study centers. Vital signs 
will be assessed after 3 minutes of rest in the supine or semi-recumbent position. 
 
9.2 
Physical Exam 
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 Wells criteria for assessing the probability for possible DVT and PE will be documented 
for all study and planned follow-up visits of any patients treated in the study (see Section 7.6 of 
the study protocol). 


Protocol No.: FORMA-02 
11-July-2016 
Confidential and Proprietary to Max Neeman International 
MNI-DM-BIS-01 v 6.0– Annexure 
Page 29 of 31 
 
 
FORMA-02 
JSS Medical Research - Data 
Management 
Statistical Analysis Plan 
Form Number: 
MNI-DM-BIS-01 v 6.0-T1 
Current Version 
Number: 2.0 
Previous Version Number: 
1.1 9-April-2015 
Date: 11-July-2016 
 
 
10 
ADDITIONAL ANALYSES 
If any additional statistical analyses required during the final analysis, appropriate methods will be 
used, and any changes, including the rationale for use, will be documented in the Clinical Study 
Report (CSR). 
 
11 
DATA LISTINGS 
All Case Report Form (CRF) data, as well as any outcomes derived from the data, will be 
summarized in detailed data listings. Subject data listings will be presented for all subjects 
randomized into the study. 
 
12 
PLOTS AND GRAPHS 
• 
The plots and graphs will be presented to illustrate the efficacy variables. 
• 
A bar graph will be prepared for Haemostatic Efficacy. 
• 
A line graph will be prepared for mean MCF at baseline and at 1 hour after first and last 
infusion as well 
as mean change of MCF from baseline. 
• 
A line graph will be prepared for mean Fibrinogen at baseline and at 1 hour after first and last 
infusion as well as mean change of Fibrinogen from baseline. 
• 
A line graph will be prepared for mean MCF Vs Time and Fibrinogen levels Vs Time. 
• 
A bar graph will be prepared for Intra-operative efficacy as assessed by surgeon (at the end 
of the surgery = after last suture). 
• 
A bar graph will be prepared for Post-operative efficacy as assessed by haematologist. 
• 
A scatter plot will be prepared for MCF and the haemostatic efficacy. 
• 
A scatter plot will be prepared for response/IVR over time and dose for all subjects and by 
major/minor bleeding. 


Protocol No.: FORMA-02 
11-July-2016 
Confidential and Proprietary to Max Neeman International 
MNI-DM-BIS-01 v 6.0– Annexure 
Page 30 of 31 
 
 
FORMA-02 
JSS Medical Research - Data 
Management 
Statistical Analysis Plan 
Form Number: 
MNI-DM-BIS-01 v 6.0-T1 
Current Version 
Number: 2.0 
Previous Version Number: 
1.1 9-April-2015 
Date: 11-July-2016 
 
 
13 
REPORTING CONVENTIONS 
13.1 Reporting of Numeric Values 
All raw data will be presented to the original number of decimal places. The mean and medians 
will be presented with 1 decimal place more than raw data. The SD will be presented with two 
decimal places more than raw data. Percentages will be presented in xx.x % format. Precision of 
p-values will be four decimal places. p-values less than 0.0001 will be presented as <.0001 and if 
equal to 1 then ≥ 0.9999. Missing values for both numeric and character variables will be 
presented as blanks in a table or data listing. 
 
13.2 Output (Tables, Listings and Graphs) Considerations 
The ICH numbering convention is to be used for all tables, figures and data listings. The default 
Tables, Listings and Graphs layout will be as follows: 
 
Orientation 
As per the size of the tables page orientation will be landscape 
Paper Size 
Letter size (11” x 8.5”) 
Margins 
Top: 1.25 in, if landscape [1.0 in, if Portrait] 
Bottom: 0.75 in, if landscape [0.75 in, if Portrait] 
Left: 0.75 in, if landscape [1.25 in, if Portrait] 
Right: 0.5 in, if landscape [0.5 in, if Portrait] 
Font 
Font style (preferably Courier New) of the Text with size 8 or higher 
Headers 
Titles of Table/Listing will be center 
Left: 
Sponsor: 
Study Name: 
Protocol No: 
Right: 
Status: Draft or Final 
Data Status/Date: Eg. Draft, Dummy Treatment Code, Datalock Date 
Footers 
Left: 
Analysts Initials: 
Program Name: 
Program Run date: time: 
Right: 
Datasets used: 
Page XXX of YYY 


Protocol No.: FORMA-02 
11-July-2016 
Confidential and Proprietary to Max Neeman International 
MNI-DM-BIS-01 v 6.0– Annexure 
Page 31 of 31 
 
 
FORMA-02 
JSS Medical Research - Data 
Management 
Statistical Analysis Plan 
Form Number: 
MNI-DM-BIS-01 v 6.0-T1 
Current Version 
Number: 2.0 
Previous Version Number: 
1.1 9-April-2015 
Date: 11-July-2016 
 
The margin may be reduced as necessary to allow additional rows to be presented, but not at the 
expense of clarity. Also the orientation may be changed to portrait if appropriate. The date format 
for all presentations will be ‘DDMMMYYYY’. 
Population(s) represented on the tables or listings will be clearly identified in the title as 
“Population: <name of population>” where <name of population> is any of the analysis population 
names or abbreviations defined in the SAP. 
All observed time values and time durations will be reported using a 24-hour clock HH:MM 
format. The use of decimal notation to present (display) time durations should be avoided (e.g. 
0.083h = 5min) unless it is necessary to show the computation of time differences in a table, 
figure, or data listing, in which case both notations may be used to display the time duration. 
 
14 
REFERENCES 
• 
ICH E3: Structure and content of Clinical Study Reports, July, CPMP. 
• 
ICH E9: Statistical Principles for Clinical Trials, September 1998, CPMP.