Extension Study for Patients Who Completed GENA-05 (NuProtect)- to Investigate Immunogenicity, Efficacy and Safety of Treatment With Human-cl rhFVIII
Phase: PHASE3
Conditions: Severe Hemophilia A
Sponsor: Octapharma

CLINICAL STUDY PROTOCOL 
NOTE: This document contains confidential and proprietary information of Octapharma. Do not copy or distribute 
without written permission. 
 
 
 
Extension Study for Patients who completed GENA-05 
(NuProtect) – to Investigate Immunogenicity, Efficacy and 
Safety of Treatment with Human-cl rhFVIII 
 
 
 
Investigational Product 
Human-cl rhFVIII 
Indication 
Severe Haemophilia A 
Study Design 
Prospective, multicentre, multinational, open-label, non- 
controlled 
Sponsor 
Octapharma Pharmazeutika Produktionsges.m.b.H. 
Oberlaaer Strasse 235, A-1100 Vienna, Austria 
Study Number 
GENA-15 
EudraCT and/or 
IND Number 
2013-003997-28 
BB-IND 13722 
Development Phase 
Phase IIIb 
Planned Clinical Start 
1st Quarter 2014 
Planned Clinical End 
1st Quarter 2016 
Date of Protocol 
18-Sep-2013 
Version 
01 
Co-ordinating Investigator 
Raina J Liesner, MD 
Great Ormond Street Hospital for Children, NHS Trust 
Haemophilia Centre 
Great Ormond Street 
London WC1N 3JH 
 
 
 
 
 
 
 
 
 
 
 
090-CSP-GENA-15/DOC ID 1985 

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STUDY OUTLINE 
Name of Sponsor/Company: 
Octapharma Pharmazeutika Produktions GmbH, Vienna, Austria 
Name of Investigational Product: 
Human-cl rhFVIII 
Protocol Identification Code: 
GENA-15 
Name of Active Ingredient: 
Coagulation FVIII 
Date of Final Protocol: 
18-Sep-2013 
Title of Study: 
Extension Study for Patients who completed GENA-05 (NuProtect) – to Investigate 
Immunogenicity, Efficacy and Safety of Treatment with Human-cl rhFVIII 
Indication: 
Severe Haemophilia A (FVIII coagulation activity [FVIII:C] <1%) 
Number of Study Centre(s): 
Around 20-30 centres worldwide are planned to participate in this study 
Study Duration: 
This study is planned to start in the 1st quarter 2014 and 
will be completed by 1st quarter 2016 at the latest 
Development Phase: IIIb 
Objectives: 
• To investigate the immunogenicity of Human-cl rhFVIII in patients who 
completed GENA-05 in accordance with the study protocol 
• To assess the efficacy of Human-cl rhFVIII during prophylactic treatment (based 
on the frequency of spontaneous break-through bleeds) 
• To assess the efficacy of Human-cl rhFVIII during treatment of bleeds 
• To assess the efficacy of Human-cl rhFVIII in surgical prophylaxis 
• To assess the safety and tolerability of Human-cl rhFVIII 
Study Design: 
Prospective, multicentre, multinational, open-label, non-controlled 
Number of Patients: 
Only patients who completed GENA-05 in accordance with the study protocol may be 
enrolled (max. 100) 
Patient Selection Criteria: 
The patient population will mainly be young children; however, there was no age 
limitation in the preceding GENA-05 study. 
Inclusion criteria: 
1. Patients who completed GENA-05 in accordance with the study protocol 
2. Voluntarily given, fully informed written and signed consent obtained before any 
study-related procedures are conducted (obtained from the patient’s parent/legal 
guardian) 
Exclusion criteria: 
1. Severe liver or kidney disease (alanine amino transferase (ALT) or aspartate 
transaminase (AST) levels >5 times of upper limit of normal, creatinine >120 
µmol/L); 
2. Concomitant treatment with any systemic immunosuppressive drug; 
3. Other FVIII concentrate than Human-cl rhFVIII was received between completion 
visit of GENA-05 and start of GENA-15 (except emergency cases). 
Test Product, Dose, Mode of Administration, and Batch Number(s): 
Human-cl rhFVIII is a purified B-domain deleted FVIII glycoprotein that is synthesised 

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Name of Sponsor/Company: 
Octapharma Pharmazeutika Produktions GmbH, Vienna, Austria 
Name of Investigational Product: 
Human-cl rhFVIII 
Protocol Identification Code: 
GENA-15 
Name of Active Ingredient: 
Coagulation FVIII 
Date of Final Protocol: 
18-Sep-2013 
by a genetically engineered human embryonic kidney cell line (HEK 293F). Human-cl 
rhFVIII will be provided in single use vials containing a nominal potency of 250, 500, 
1000 or 2000 International Units (IU) each of freeze-dried recombinant FVIII (rFVIII) 
concentrate to be reconstituted in 2.5 mL of water for injection. 
Human-cl rhFVIII is to be used as intravenous injection only (maximally 4 mL/minute). 
Dose: 
Prophylactic treatment is recommended. However, the Investigator will have final 
discretion whether patients will be treated prophylactically or on-demand. Patients may 
switch from on-demand to prophylactic treatment, or from prophylactic to on-demand 
treatment during the course of the study. 
Prophylactic treatment: 
Patients will be treated prophylactically with a recommended dose of >20 IU FVIII/kg 
body weight (BW). The frequency of treatment will depend on the patient’s clinical 
situation. In cases of inadequate response, Human-cl rhFVIII administration frequency or 
dose adjustments can be made at Investigator’s discretion. 
On-demand treatment: 
In case of a bleed, the patients can be treated on-demand. The dosage and duration of 
treatment of spontaneous or traumatic bleeds depend on the location and the extent of the 
bleeding as well as on the clinical situation of the patient. Dosage recommendations are 
given as follows: 
• Minor haemorrhage: 20-30 IU FVIII/kg BW to achieve an intended target peak 
level of about 40% to 60%. Repeat dose every 8-24 hours until BE is resolved. 
• Moderate to major haemorrhage: 30-40 IU FVIII/kg BW to achieve an intended 
target peak level of about 60% to 80%. Repeat dose every 6-24 hours until BE is 
resolved. 
• Major to life-threatening haemorrhage: initial dose of 50-80 IU FVIII/kg BW to 
achieve an intended target peak level of 100% to 120%. Repeat dose of >20 IU 
FVIII/kg BW every 6-12 hours until BE is resolved. 
Surgical prophylaxis: 
The dosage and duration of treatment with Human-cl rhFVIII will depend on the type of 
surgery and the patient’s individual incremental recovery. Dosage recommendations are 
given as follows: 
• Minor surgeries including tooth extractions: 25-30 IU FVIII/kg BW starting within 
3 hours prior to surgery to achieve an intended target peak level of >30%. Repeat 
one dose every 12-24 hours if needed. Trough levels should be maintained at ≥ 
30%. 
• Major surgeries: > 50 IU FVIII/kg BW within 3 hours prior to surgery to achieve 
an intended target peak level of approximately 100%. Repeat if necessary after 6- 
12 hours initially and for at least 6 to 14 days until healing is complete and 
recurrence to regular prophylactic treatment is possible. Trough levels should be 
maintained at > 50%. 
Batch Number(s): 
Several batches of Human-cl rhFVIII will be used. 

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Name of Sponsor/Company: 
Octapharma Pharmazeutika Produktions GmbH, Vienna, Austria 
Name of Investigational Product: 
Human-cl rhFVIII 
Protocol Identification Code: 
GENA-15 
Name of Active Ingredient: 
Coagulation FVIII 
Date of Final Protocol: 
18-Sep-2013 
Duration of Treatment: 
The patients are planned to stay in the study until the IMP is registered and launched in 
the individual countries, or for a maximum period of 2 years from screening, whichever 
comes first. 
Reference Therapy, Dose, Mode of Administration, and Batch Number(s): 
Not applicable 
Study Outcome Parameters / Endpoints): 
Immunogenicity: 
Inhibitor activity will be determined by the modified Bethesda assay (Nijmegen 
modification), using congenital FVIII-deficient human plasma spiked with Human-cl 
rhFVIII at the following time points: 
• At Screening Visit, which can be the same sampling time-point as the completion 
visit of GENA-05 
• Once every 6 months during the open treatment phase 
• At study completion 
• Any time in the case of suspicion of inhibitor development. 
In case of a positive inhibitor result, an inhibitor re-test using a second separately drawn 
sample should be performed, centrally. 
Efficacy: 
Efficacy of prophylactic treatment: The efficacy of Human-cl rhFVIII in the prophylactic 
treatment will be assessed based on the frequency of spontaneous break-through bleeds 
under prophylactic treatment. The dates and times of study drug infusions, details of 
dose(s) and product batch numbers used for the prophylactic treatment will be 
documented. Details of any BEs occurring under prophylactic treatment will be 
documented. Study drug consumption data (FVIII IU/kg per month, per year) per patient 
and in total will be evaluated. 
Efficacy of treatment of bleeds: The efficacy of Human-cl rhFVIII in the treatment of 
bleeds will be assessed based on an objective haemostatic efficacy scale. Details of the 
bleed (type, site and severity of the bleed, and the start and end date and time of the 
bleed), the amount of Human-cl rhFVIII needed and the number of injections necessary to 
stop the bleed will be documented. 
Efficacy of surgical prophylaxis: The efficacy of Human-cl rhFVIII in surgical 
prophylaxis will be assessed based on: 
• Overall efficacy assessment (taking the intra- and post-operative assessment into 
account) after the end of the surgical prophylactic treatment phase, done together 
by the surgeon and the haematologist. 
• Average and maximum expected estimated blood loss compared to the actual 
estimated blood loss. 
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 Human-cl 
rhFVIII (pre-, intra- and/or post-operatively) will be recorded. FVIII plasma levels (pre-, 
intra-, and post-operatively) will be measured. Details of concomitantly administered 
products (except standard anaesthetics) along with a brief narrative describing the 

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Name of Sponsor/Company: 
Octapharma Pharmazeutika Produktions GmbH, Vienna, Austria 
Name of Investigational Product: 
Human-cl rhFVIII 
Protocol Identification Code: 
GENA-15 
Name of Active Ingredient: 
Coagulation FVIII 
Date of Final Protocol: 
18-Sep-2013 
outcome of the intervention will be recorded. 
Safety: 
Vital signs: Blood pressure, heart rate, respiratory rate and body temperature will be 
assessed at screening, thereafter every 6 months (±2 weeks) and at study completion. In 
case IMP is injected at study site during these visits, one pre- and one post-treatment 
measurement is obligatory. 
Safety laboratory parameters: The following routine safety laboratory parameters will be 
tested at screening (GENA-05 study completion values can be copied), at 6-monthly (± 2 
weeks) follow-up visits, and at completion visit: haematological parameters (red blood 
cell count, white blood cell count, haemoglobin, haematocrit, platelet count) and clinical 
chemistry (ALT, AST, serum creatinine). Samples are analysed in the local laboratory. 
Tolerability: The occurrence of any adverse event (AE) will be monitored throughout the 
study. 
Summary of Study Procedures and Statistical Analysis Plan: 
Study Procedures: 
All administrations of Human-cl rhFVIII, the occurrence of bleeds, the occurrence of AEs 
and the administration of concomitant medication during the entire study period will be 
thoroughly documented to assess the exposure to FVIII, the efficacy in the prevention of 
and the treatment of bleeds, and the overall safety and tolerability. 
Screening Visit: 
Patients’ parent(s)/legal guardian(s) will be informed about the study details and will be 
required to give written informed consent before any investigations and any assessments 
can be performed. The majority of data required will be available from the preceding 
GENA-05 study, so that only the following information needs to be documented/assessed: 
• Check of inclusion- and exclusion criteria 
• Height 
• Body weight 
The Investigator will hand out the patient diary and instruct the patient/legal guardian how 
to document details of treatment with Human-cl rhFVIII, bleeds, AEs and concomitant 
medication. The patient/legal guardian will receive a sufficient amount of study product 
for home treatment and will be instructed on proper storage and administration. Details of 
home treatment (e.g. parents’ home treatment training, the involvement of a general 
practitioner or a study nurse) are documented. 
6-Monthly (± 2 weeks) Follow-Up Visits: 
These visits will include additional investigations, i.e. assessment of safety laboratory 
parameters and – in case IMP is injected after blood sampling – vital signs pre- and 30-60 
minutes post-injection. 
At such visits, patients’ body weight will be checked, and blood samples will be obtained 
for FVIII inhibitor screen (after a wash-out period of at least 2, but preferably 3 days after 
the previous IMP administration). The patient diary will be reviewed and data will be 
transferred into the CRF. The occurrence of AEs and changes in concomitant medication 
will be checked and documented. A physical examination is performed. 
Surgical Visits: 

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Name of Sponsor/Company: 
Octapharma Pharmazeutika Produktions GmbH, Vienna, Austria 
Name of Investigational Product: 
Human-cl rhFVIII 
Protocol Identification Code: 
GENA-15 
Name of Active Ingredient: 
Coagulation FVIII 
Date of Final Protocol: 
18-Sep-2013 
Study subjects may undergo surgical interventions during the course of the study. 
Depending on the type of surgery, subjects may or may not be hospitalised (in case of 
certain minor surgeries with low risk of post-operative bleeding) at the discretion of the 
Investigator. Details of surgery, Human-cl rhFVIII dosing, expected and actual blood loss, 
concomitant treatment (including need for additional blood transfusions), and lab 
investigations will be documented, as well as details of hospitalisation (start and end date, 
regular ward, intensive care unit stay). 
Completion Visit: 
For each patient, the study will be completed once the IMP is registered and launched in 
the respective country, but no later than 2 years from the screening visit. 
At these visits, patients’ body weight will be checked, and blood samples will be obtained 
for FVIII inhibitor screen (after a wash-out period of at least 2, preferably 3 days after the 
previous IMP administration) and for the safety panel. Vital signs will be checked and a 
physical examination will be performed. The occurrence of AEs and changes in 
concomitant medication will be checked and documented. 
At this visit, the patient diary will be reviewed and data transferred into the CRF. 
Statistical Analysis: 
No inferential analysis involving formal testing is planned in this non-controlled trial. The 
patients are offered to continue treatment after the completion of the preceding GENA-05 
study in accordance with the study protocol; no formal sample size estimation is 
performed. The statistical analyses of the endpoints will be descriptive. 

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The study assessments and scheduled time points are summarised in the Flow Chart: 
 
FLOW CHART 
 

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PROTOCOL SIGNATURES 
 
Signature of the Sponsor's Representative 
 
 
This study is intended to be conducted in compliance with the protocol, 
Good Clinical Practice and the applicable regulatory requirements. 
 
 
 
 
 
 
 
 
 
 
 
 
 
On behalf of the Sponsor 
 
 
 
Senior Vice President CR&D 
Signature 
Octapharma Pharmazeutika Produktionsges.m.b.H. 
Oberlaaer Strasse 235 
A-1100 Vienna 
Austria 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Wolfgang Frenzel, MD 

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Signature of the Vice President Clinical Research &Development Haematology 
 
This study is intended to be conducted in compliance with the protocol, Good Clinical 
Practice and the applicable regulatory requirements. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vice President CR&D Haematology 
Octapharma AG 
Seidenstrasse 2 
CH-8853 Lachen 
Switzerland 
> 
Signature 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sigurd Knaub, PhD 

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I
 
 
Signature of the Author of the Protocol/ Clinical Project Manager 
 
 
This study is intended to be conducted in compliance with the protocol, Good Clinical 
Practice and the applicable regulatory requirements. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Martina Jansen 
di?. Se£>- 20A3 
Author of the Protocol 
& Senior Clinical Project Manager 
Octapharma Pharmazeutika Produktionsges.m.b.H. 
Oberlaaerstrasse 235 
A-1100 Vienna, Austria 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

11 
 
 
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Signature of the Biostatistician 
 
 
This study is intended to be conducted in compliance with the protocol, 
Good Clinical Practice and the applicable regulatory requirements. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hans-Peter Hucke, PhD 
 
Senior Statistician 
GASDmbH 
Am Konvent 8-10 
41460 Neuss, Germany 
Signature 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Signature of the Coordinating Investigator 
 
 
This study is intended to be conducted in compliance with the protocol, 
Good Clinical Practice and the applicable regulatory requirements. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Raina J Liesner, MD 
 
 
Coordinating Investigator 
Signature 
Great Ormond Street Hospital for Children, NHS Trust 
Haemophilia Centre 
Great Ormond Street 
UK-London WCIN 3JH 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
1 
INTRODUCTION. ......................................................................................................... 17 
1.1 RATIONALE FOR CONDUCTING THE STUDY .................................................................................... 17 
1.2 BENEFIT-RISK STATEMENT .................................................................................................................. 18 
2 
STUDY OBJECTIVES ................................................................................................... 18 
3 
INVESTIGATIONAL PLAN ........................................................................................ 19 
3.1 STUDY ENDPOINTS .................................................................................................................................. 19 
3.2 OVERALL STUDY DESIGN AND PLAN ................................................................................................ 20 
3.3 DISCUSSION OF STUDY DESIGN .......................................................................................................... 23 
3.3.1 Study Design ......................................................................................................... 23 
3.3.2 Control Group(s) .................................................................................................. 23 
3.3.3 Target Parameters ................................................................................................ 23 
4 
STUDY POPULATION ................................................................................................. 23 
4.1 POPULATION BASE .................................................................................................................................. 23 
4.1.1 Inclusion Criteria .................................................................................................. 24 
4.1.2 Exclusion Criteria ................................................................................................. 24 
4.2 PRIOR AND CONCOMITANT THERAPY ............................................................................................... 24 
4.2.1 Permitted Concomitant Therapy ........................................................................... 24 
4.2.2 Forbidden Concomitant Therapy .......................................................................... 24 
4.3 WITHDRAWAL AND REPLACEMENT OF PATIENTS......................................................................... 25 
4.3.1 Premature Patient Withdrawal ............................................................................. 25 
4.3.2 Patient Replacement Policy .................................................................................. 25 
4.4 ASSIGNMENT OF PATIENTS TO TREATMENT GROUPS .................................................................. 25 
4.5 RELEVANT PROTOCOL DEVIATIONS .................................................................................................. 25 
4.6 SUBSEQUENT THERAPY ......................................................................................................................... 25 
5 
INVESTIGATIONAL MEDICINAL PRODUCT(S) .................................................. 25 
5.1 CHARACTERISATION OF INVESTIGATIONAL PRODUCT(S) ............................................... 25 
5.2 PACKAGING AND LABELLING .............................................................................................................. 25 
5.3 CONDITIONS FOR STORAGE AND USE ............................................................................................... 26 
5.4 DOSE AND DOSING SCHEDULE ............................................................................................................ 26 
5.5 PREPARATION AND METHOD OF ADMINISTRATION ..................................................................... 27 
5.6 BLINDING, EMERGENCY ENVELOPES AND BREAKING THE STUDY BLIND ........................... 27 
5.7 TREATMENT COMPLIANCE ................................................................................................................... 27 
5.7.1 Drug Dispensing and Accountability .................................................................... 27 
5.7.2 Assessment of Treatment Compliance .................................................................. 27 
6 
STUDY CONDUCT ........................................................................................................ 28 
6.1 OBSERVATIONS BY VISIT ...................................................................................................................... 28 
6.1.1 Screening (Visit 1) ................................................................................................. 28 
6.1.2 Procedures During the Follow-Up Part of the Study ........................................... 28 
6.2 DURATION OF STUDY ............................................................................................................................. 29 
6.2.1 Planned Duration for an Individual Patient ......................................................... 29 
6.2.2 Planned Duration for the Study as a Whole ......................................................... 29 
6.2.3 Premature Termination of the Study ..................................................................... 29 

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7 
ASSESSMENTS AND METHODS ...............................................................................29 
7.1 BACKGROUND / BASELINE INFORMATION ...................................................................................... 29 
7.2 EFFICACY/IMMUNOGENICITY ASSESSMENTS ................................................................................. 30 
7.2.1 Assessments for Endpoint ..................................................................................... 30 
7.3 SAFETY ASSESSMENTS ........................................................................................................................... 34 
7.3.1 Adverse Events ...................................................................................................... 34 
7.3.2 Serious Adverse Events ......................................................................................... 37 
7.3.3 Laboratory Safety Tests ....................................................................................... 38 
7.3.4 Vital Signs and Physical Examination .................................................................. 40 
7.3.5 Other Relevant Safety Information ....................................................................... 40 
7.4 APPROPRIATENESS OF MEASUREMENTS .......................................................................................... 41 
8 
DATA HANDLING AND RECORD KEEPING ......................................................... 41 
8.1 DOCUMENTATION OF DATA ................................................................................................................. 41 
8.1.1 Source Data and Records ..................................................................................... 41 
8.1.2 Case Report Forms ............................................................................................... 42 
8.1.3 Changes to Case Report Form Data ..................................................................... 42 
8.2 INFORMATION OF INVESTIGATORS ..................................................................................................... 42 
8.3 RESPONSIBILITIES .................................................................................................................................... 42 
8.4 INVESTIGATOR’S SITE FILE .................................................................................................................. 43 
8.5 PROVISION OF ADDITIONAL INFORMATION .................................................................................... 43 
8.6 INDEPENDENT DATA MONITORING COMMITTEE .......................................................................... 43 
9 
STATISTICAL METHODS AND SAMPLE SIZE .................................................... 43 
9.1 DETERMINATION OF SAMPLE SIZE ..................................................................................................... 44 
9.2 STATISTICAL ANALYSIS ......................................................................................................................... 44 
9.2.1 Population for Analysis. ........................................................................................ 44 
9.2.2 Efficacy Analysis Plan .......................................................................................... 45 
9.2.3 Safety Analysis Plan .............................................................................................. 45 
9.2.4 Handling of Missing Data .....................................................................................46 
9.3 INTERIM ANALYSIS ................................................................................................................................. 46 
10 ETHICAL / REGULATORY, LEGAL AND ADMINISTRATIVE ASPECTS .......46 
10.1 ETHICAL / REGULATORY FRAMEWORK ............................................................................................ 46 
10.2 APPROVAL OF STUDY DOCUMENTS ................................................................................................... 47 
10.3 PATIENT INFORMATION AND INFORMED CONSENT ...................................................................... 47 
10.4 PROTOCOL AMENDMENTS .................................................................................................................... 47 
10.5 CONFIDENTIALITY OF PATIENTS´ DATA........................................................................................... 47 
11 QUALITY CONTROL AND QUALITY ASSURANCE ............................................48 
11.1 PERIODIC MONITORING ......................................................................................................................... 48 
11.2 AUDIT AND INSPECTION ........................................................................................................................ 48 
12 REPORTING AND PUBLICATION ........................................................................... 48 
12.1 CLINICAL STUDY REPORT ..................................................................................................................... 48 
12.2 PUBLICATION POLICY ............................................................................................................................. 48 
13 LIABILITIES AND INSURANCE ...............................................................................48 
14 REFERENCES ................................................................................................................ 49 

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LIST OF TABLES 
Table 1 Screening Visit (majority of data need to be transferred from GENA-05) ............... 21 
Table 2 Six-Monthly (± 2 weeks) Visits ................................................................................ 21 
Table 3 Bleeding Episodes (BE) ............................................................................................ 21 
Table 4 Completion Visit ....................................................................................................... 22 
Table 5 Surgery ...................................................................................................................... 22 
Table 6 Time-Points and Approximate Blood Volume for Laboratory Parameters .............. 39 
Table 7 Test Parameters and Laboratories ............................................................................. 40 

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LIST OF ABBREVIATIONS 
 
 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate transaminase 
BE 
Bleeding episode 
BLEED 
Study population of BEs 
BMI 
Body mass index 
BU 
Bethesda unit 
BW 
Body weight 
CHO 
Chinese hamster ovary (cells) 
CHR 
Chromogenic 
CHMP 
Committee for Medicinal Products for Human Use 
CRO 
Contract Research Organisation 
CVAD 
Central Venous Access Device 
ED 
Exposure day 
EMA 
European Medicines Agency 
FVIII 
Coagulation factor VIII 
FVIII:C 
Factor VIII coagulation activity 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HEK 
Human Embryonic Kidney 
HLA 
Human Leukocyte Antigen 
ICU 
Intensive care unit 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
ITI 
Immune tolerance induction 
ITT 
Intention to treat 
IU 
International Unit 
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
OC 
Observed cases 
OS 
One-stage 
PBMC 
Peripheral blood mononuclear cells 
PP 
Per protocol 
PROPH 
Study population of subjects with prophylaxis 
PTP 
Previously-treated patient 
PUP 
Previously-untreated patient 
RBC 
Red blood cell 
rFVIII 
Recombinant FVIII 
SAEs 
Serious adverse events 
SAP 
Statistical analysis plan 
SOC 
System organ class 
SOP 
Standard operating procedure 
SURG 
Study population of surgeries 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WFI 
Water for injection 

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1 
INTRODUCTION 
Haemophilia A is an inherited gender-related coagulation disorder in which affected males do 
not produce functional coagulation factor VIII (FVIII) in sufficient quantities to achieve 
satisfactory haemostasis. Therefore, patients suffer from bleeding diathesis. Most bleeding 
episodes (BEs) occur in joints and muscles. Without adequate treatment these repeated 
haemarthroses and haematoma lead to long-term sequelae with severe disability. Other 
bleeding sites, although less frequent but more severe, are the central nervous system, the 
urinary or gastrointestinal tract, eyes and the retro-peritoneum. Hence, affected patients are at 
high risk to develop major and life-threatening bleeds after surgical procedures, even after 
minor ones such as tooth extraction. 
The optimal effective treatment of the disorder is the replacement of FVIII by using FVIII 
concentrate either obtained by fractionation of human plasma or manufactured by 
recombinant DNA technology. 
All commercially available recombinant rFVIII concentrates are exclusively produced in 
hamster cells, either in baby hamster kidney (BHK) cells (e.g. Kogenate FS) or in Chinese 
hamster ovary (CHO) cells (e.g. Advate, ReFacto). The intrinsic immunogenicity of current 
rFVIII products may be increased due to incorporation of non-human glycan  structures 
during post-translational protein processing in mammalian cell lines. 
Human-cl rhFVIII is a B-domain deleted rhFVIII expressed in genetically modified human 
embryonic kidney (HEK) 293F cells. Using a human cell line for the expression of rFVIII 
ensures that non-human immunogenic epitopes are absent, in contrast to rFVIII expressed in 
hamster cells. For example, N-glycolylneuraminic acid, which is reported to be antigenic in 
man (1) and present in recombinant glycoproteins expressed by CHO cells (2), was not 
detected in Human-cl rhFVIII. Furthermore, the antigenic carbohydrate epitope Galα1,3Gal, 
which has been reported to be present in recombinant proteins such as full-length FVIII from 
BHK cells (3), is not present in Human-cl rhFVIII either (4). The use of a human cell-line for 
the expression of rFVIII is expected to provide a more genuine human glycosylation pattern 
than achieved with murine cell-lines. This may result in an improved function and reduced 
immunogenicity of the rFVIII expressed from human cell-lines. 
Clinical data on efficacy and safety of Human-cl rhFVIII in the targeted indications in adult 
and paediatric previously treated patients (PTPs) are available. Since previously untreated 
patients (PUPs) may respond differently to FVIII treatments than PTPs, European Medicines 
Agency (EMA) CHMP guidelines (5) specify that the clinical development strategy for FVIII 
products in paediatric patients should follow a stepwise approach, in order to gain experience 
in older patients before investigations are initiated in younger patients and finally in 
previously untreated patients. The ongoing study GENA-05 is assessing immunogenicity, 
efficacy and safety of Human-cl rhFVIII in previously untreated patients (PUPs) with severe 
Haemophilia A. 
A summary of findings from non-clinical as well as clinical investigations can be found in the 
Clinical Investigator’s Brochure. 
1.1 
Rationale for Conducting the Study 
 
The present study has been designed to investigate the long-term immunogenicity, tolerability 
and efficacy of Human-cl rhFVIII in patients originally included into the preceding study 
GENA-05 as PUP (previously untreated patients) with severe Haemophilia A (FVIII:C <1%). 
Study participation is offered to all subjects who completed the foregoing GENA-05 study in 

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accordance with the study protocol, provided the IMP is not registered and ready for launch 
in the respective country. However, the maximum study participation is two years from time 
of screening. 
GENA-15 is a prospective, open-label, uncontrolled, international, multi-centre Phase IIIb 
study with the objective of collecting long-term data on the immunogenicity, tolerability and 
efficacy of Human-cl rhFVIII. 
Participation will be offered to all GENA-05 subjects who meet the eligibility criteria and are 
willing to continue prophylactic or on-demand treatment with Human-cl rhFVIII until they 
can switch to marketed product. 
Dose Rationale 
Human-cl rhFVIII will be provided in single use vials containing a nominal potency of 250, 
500, 1000 or 2000 International Units (IU) each of freeze-dried rFVIII concentrate to be 
reconstituted in 2.5 mL of water for injection (WFI). Human-cl rhFVIII is to be used as 
intravenous injection only (maximum infusion speed: 4 mL/minute). 
Dose and frequency adjustments are based on the individual patients’ needs and are subject to 
the Investigators’ clinical judgement. 
1.2 
Benefit-Risk Statement 
 
On the basis of data already available for adults and children (PTPs), the half-life and the 
recovery of Human-cl rhFVIII are similar to other already licensed rFVIII preparations. It can 
be concluded that Human-cl rhFVIII is efficacious in the prevention and in the treatment of 
BEs and during surgical prophylaxis in patients with inherited FVIII deficiency. 
Comparable to other rFVIII preparations, the following adverse drug reactions (ADRs) may 
occur when using Human-cl rhFVIII: 
1. 
Allergic or anaphylactic types of reactions. Observed symptoms may include fever, 
chills, nausea, urticaria, pruritus, dizziness, chest tightness, shortness of breath, and – 
very rarely – anaphylactic shock. 
2. 
Development of antibodies (inhibitors) against FVIII. 
In conclusion, the hitherto existing clinical and pre-clinical data allow the conclusion that 
participating in this study does not represent any additional risk for the included patients in 
terms of immunogenicity and safety. 
 
2 
STUDY OBJECTIVES 
Objectives of this trial are: 
• To investigate the immunogenicity of Human-cl rhFVIII in patients who completed 
GENA-05 in accordance with the study protocol 
• To assess the efficacy of Human-cl rhFVIII during prophylactic treatment (based on 
the frequency of spontaneous break-through bleeds) 
• To assess the efficacy of Human-cl rhFVIII during treatment of bleeds 
• To assess the efficacy of Human-cl rhFVIII in surgical prophylaxis 

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3 
INVESTIGATIONAL PLAN 
3.1 
Study Endpoints 
 
Immunogenicity of Human-cl rhFVIII 
Inhibitor activity will be determined by the modified Bethesda assay (Nijmegen 
modification), using congenital FVIII-deficient human plasma, spiked with Human-cl 
rhFVIII, at the following time points: 
• At Screening Visit, which will most likely be the same sampling time-point as the 
completion visit of GENA-05 
• Once every 6 months in the course of the follow-up visits 
• At study completion 
• Any time in the case of a suspicion of inhibitor development. 
In case of a positive inhibitor result, an inhibitor retesting, using a second separately drawn 
sample, should be performed. A FVIII inhibitor is defined as “positive”, if the retesting 
confirms the positive result, otherwise the result is considered as “negative”. 
Efficacy of prophylactic treatment  
The efficacy of Human-cl rhFVIII in the prophylactic treatment will be investigated by 
calculating the frequency of spontaneous break-through bleeds under prophylactic treatment 
(see Section 7.2.1.2). Study drug consumption data (FVIII IU/kg per month, per year) per 
patient and in total will be evaluated. The dates and times of study drug infusions, the details 
of dose(s), and the product batch numbers used for the prophylactic treatment will be 
documented. 
Efficacy of treatment of bleeds  
The efficacy of Human-cl rhFVIII in the treatment of bleeds will be investigated by using a 
4-point ordinal haemostatic efficacy scale (see Section 7.2.1.3). Details of the bleed, the 
amount of Human-cl rhFVIII needed and the number of injections necessary to stop the bleed 
will be documented. 
Efficacy of surgical prophylaxis 
In surgical procedures, the following parameters will be documented: 
• One overall efficacy assessment (taking into account the intra- and post-operative 
assessment) after the end of surgical prophylactic treatment phase, agreed upon between 
the surgeon and the haematologist (see Section 7.2.1.4) 
• Average and maximum expected estimated blood loss, compared to the actual estimated 
blood loss 
• Details on surgical procedure (see Section 7.2.1.4): location, severity, type, expected and 
actual duration 
• Pre-, intra-, and post-operative FVIII plasma levels, if appropriate 
• Details of administered dose(s) of Human-cl rhFVIII given pre-, intra- and/or post- 
operatively including dates, times and batch numbers 
• Details on concomitantly administered drugs, including all blood and blood product 
transfusions, excluding standard anaesthetic drugs 
• Details on all wound haematomas in terms of capturing, analysing, and reporting these, 

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including any need for surgical evacuation 
• Outcome of the intervention, described by means of a brief narrative. 
Safety and tolerability 
Safety and tolerability will be assessed by monitoring vital signs, standard laboratory 
parameters, and by monitoring adverse events (AEs). 
3.2 
Overall Study Design and Plan 
 
This study is designed as a prospective, multicentre, multinational, open-label, non-controlled 
phase IIIb study in patients who completed GENA-05 in accordance with the study protocol. 
Around 20-30 centres worldwide are planned to participate in this study. 
For each patient, the exposure to Human-cl rhFVIII, the efficacy of Human-cl rhFVIII in the 
prevention and the treatment of bleeds, the frequency of break-through bleeds in case of 
prophylactic treatment, the efficacy in surgical prophylaxis, and the overall safety and 
tolerability of Human-cl rhFVIII will be thoroughly assessed. In the course of the follow-up 
visits scheduled to be performed every 6 months (± 2 weeks) after the Screening Visit, FVIII 
inhibitor levels will be assessed for each patient. 
The occurrence of AEs and changes in concomitant medication will be checked and 
documented at each follow-up visit. A patient completes the study by switching to marketed 
Factor VIII concentrate, the latest 2 years after his screening visit. 
In patients undergoing surgical interventions, treatment details will be documented for the 
pre-, intra-, and post-operative phase, respectively. 
This study is planned to start in the 1st quarter 2014 and will be completed by 1st quarter 2016 
at the latest. 
The tables below summarise the assessments to be performed at the individual visits: 

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Table 1 
Screening Visit (majority of data need to be transferred from GENA-05) 
 
Written informed consent for patients’ parents / guardians 
 
Inclusion/exclusion criteria check 
 
Body weight and height measurement 
 
IMP injection after blood sampling (not mandatory) 
 
Diary & IMP instructions 
 
 
Table 2 
Six-Monthly (± 2 weeks) Visits 
 
Before IMP injection 
Time after end of IMP injection§ 
Body weight measurement 
 
FVIII inhibitor screen 
 
Safety lab tests 
 
IMP injection after blood 
sampling (not mandatory) 
 
Vital signs 
 
30-60 minutes 
(in case IMP is injected) 
Physical examination 
 
Review of diary 
 
AE monitoring & changes 
in concomitant medication 
<throughout whole period> 
§ Actual time points are to be documented. 
 
Table 3 
Bleeding Episodes (BE) 
 
Treatment details 
 
Efficacy assessment at the end of the BE 
 
Type of bleeding (spontaneous, traumatic, post-operative, other) 
 
Site of bleeding 
 
Start date and time of occurrence/of noticing the bleed 
 
Severity of the bleed (minor, moderate to major, or major to life threatening) 
 
Date and time of end of BE 
 

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Table 4 
Completion Visit 
 
Before 
Time after end of infusion§ 
Body weight measurement 
 
Physical examination 
 
FVIII inhibitor screen 
 
Safety lab tests 
 
IMP injection after blood sampling (not 
mandatory) 
 
Vital signs 
 
30-60 minutes 
(in case IMP is injected) 
Review of diary 
 
AE monitoring & changes in concomitant 
medication 
<throughout whole period> 
§ Actual time points are to be documented. 
Table 5 
Surgery 
 
within 
12 hours 
before start 
within 
3 hours 
before start 
Surgery 
POP 
Day 1 
any POP 
Day 
last POP 
Day 
start intra-op 
end 
Body weight 
 
Estimation blood loss & 
Duration of surgery 
 
Details on surgery (location, 
type, severity, duration) 
 
Actual blood loss 
 
Concomitant medications 
<------------------------------- throughout whole period ---------------------------- > 
Details study drug 
injection(s) 
  
( ) 
( ) 
( ) 
( ) 
( ) 
( ) 
Major surgery: FVIII level 
(mandatory for the first 3 
postoperative infusions)* 
 
 
 
 
 
 
Minor surgery: FVIII level* 
 
() 
() 
() 
() 
() 
Efficacy assessment 
 
 
Safety laboratory tests 
 
 
() 
() 
Vital signs 
 
 
 
Wound haematomas 
 
 
 
Narrative of outcome 
 
AE monitoring 
<------------------------------ throughout whole period ------------------------------- > 
POP = post-operative, ( ) = optional administration; () optional investigation; * <30 minutes prior to and after each study 
drug administration. 

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3.3 
Discussion of Study Design 
 
3.3.1 Study Design 
The present study is an extension study of GENA-05, a study in which the immunogenicity, 
clinical efficacy, and safety of Human-cl rhFVIII in PUPs has been studied. 
GENA-15 is a prospective, open-label, uncontrolled, international, multi-centre Phase IIIb 
study with the objective to collect further long-term data on the immunogenicity, safety and 
efficacy of Human-cl rhFVIII. 
Provided the inclusion- and exclusion criteria are met, all subjects wishing to continue 
treatment with the IMP until Human-cl rhFVIII is registered and ready for being launched in 
the respective country may be included into GENA-15, if they completed GENA-05 in 
accordance with the study protocol. Thus, individual study participation period varies from 
country to country, but may not exceed 2 years individual duration from start of screening. 
3.3.2 Control Group(s) 
Not applicable. 
3.3.3 Target Parameters 
The following measurements and assessments are requested to be carried out, grouped by the 
different target parameters: 
Immunogenicity 
FVIII inhibitor screen 
Prophylactic Treatment 
Frequency of spontaneous breakthrough bleeds under prophylactic treatment, and in case of 
surgical prophylaxis 
Efficacy 
Efficacy assessment at the end of each BE (based on the efficacy scale described in Section 
7.2.1.3) 
Safety 
Vital signs (blood pressure, heart rate, respiratory rate and body temperature) 
Safety laboratory parameters (red blood cell [RBC] count, white blood cell [WBC] count, 
haemoglobin, haematocrit, platelet count, alanine amino transferase [ALT], aspartate 
transaminase [AST], serum creatinine) 
Tolerability (occurrence of any AE will be monitored throughout the study) 
 
4 
STUDY POPULATION 
4.1 
Population Base 
The patient population will mainly be young children; however, there was no age limitation 
in the preceding GENA-05 study. 
In total, patients from approximately 20-30 centres from around the world may be enrolled. 

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4.1.1 Inclusion Criteria 
In order to qualify for study enrolment, the following criteria must be fulfilled before study 
entry: 
1. patients who completed GENA-05 in accordance with the study protocol 
2. Voluntarily given, fully informed written and signed consent obtained before any 
study-related procedures are conducted (obtained from the patient’s parent/legal 
guardian) 
4.1.2 Exclusion Criteria 
Patients will not be included if any of the following exclusion criteria are met: 
1. Severe liver or kidney disease (alanine amino transferase (ALT) or aspartate 
transaminase (AST) levels >5 times of upper limit of normal, creatinine >120 
µmol/L); 
2. Concomitant treatment with any systemic immunosuppressive drug; 
3. Other FVIII concentrate than Human-cl rhFVIII was received between completion 
visit of GENA-05 and start of GENA-15 (except emergency cases). 
4.2 
Prior and Concomitant Therapy 
 
As this study is conducted in patients who completed the preceding GENA-05 study, patients 
should not have received any other FVIII concentrates except our IMP for the last 100 EDs. 
4.2.1 Permitted Concomitant Therapy 
Concomitant administration of therapies not interfering with the objectives of the study is 
permitted. Details of any concomitant therapies must be recorded in the Case Report Form 
(CRF). 
Vaccinations are permitted prior and during the study, and immunisations should be given as 
recommended by the country standards. However a subcutaneous administration on a day 
without FVIII administration is recommended. 
Patients may only receive anti-fibrinolytics if this is medically indicated / standard of care, 
e.g. in the course of tooth extractions or other surgeries. 
4.2.2 Forbidden Concomitant Therapy 
No FVIII concentrates other than Human-cl rhFVIII must be administered (except for 
emergency situations). 
Patients permanently switching to another FVIII product within the study participation period 
are subsequently withdrawn from the study and a completion visit has to be completed. 
Patients will be assessed as treatment failures in the efficacy analyses. However, there are 
exceptions to this rule. Patients will hence not be considered treatment failures in the efficacy 
analyses, if: 
• the use of another FVIII concentrate was due to an emergency case (example: 
accident requiring treatment with FVIII without patient or intensive care unit [ICU] 
personnel) having access to Investigational Medicinal Product [IMP]) 
• the IMP was not available for the patient in time (example: patient experiences a 
severe bleed but does not have enough product available). 
The reason for a patient switching to another FVIII product should be clearly documented in 
the CRF (and patient diary, if appropriate). 

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Patients 
may 
not 
receive 
immuno-modulating 
drugs 
(other 
than 
anti-retroviral 
chemotherapy), such as alpha-interferon, prednisone (equivalent to >10 mg/day), or similar 
drugs. 
4.3 
Withdrawal and Replacement of Patients 
 
4.3.1 Premature Patient Withdrawal 
Subjects have the right to withdraw from the study at any time for any reason, without the 
need to justify. The Investigator also has the right to withdraw subjects in case of AEs, 
protocol violations, or for administrative reasons. Since an excessive rate of withdrawals can 
render the study non-interpretable, the unnecessary withdrawal of subjects must be avoided. 
The Investigator will obtain all the required withdrawal details and document the reason(s) 
for discontinuation in the CRF. Should the reason for removal of a subject be 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. 
4.3.2 Patient Replacement Policy 
Patients withdrawn from the study will not be replaced. 
4.4 
Assignment of Patients to Treatment Groups 
 
As this is a single-arm study, assignment of patients to treatment groups is not necessary. 
4.5 
Relevant Protocol Deviations 
 
In case of any major protocol deviation or violation, the Investigator and Octapharma will 
decide on the further participation of the patient in this study after having discussed all 
relevant aspects. 
4.6 
Subsequent Therapy 
 
Not applicable. 
 
5 
INVESTIGATIONAL MEDICINAL PRODUCT(S) 
5.1 
Characterisation of Investigational Product(s) 
 
Human-cl rhFVIII is a B-domain deleted, human cell-line derived recombinant FVIII 
concentrate for intravenous use and will be provided in single use vials containing a nominal 
potency of 250, 500, 1000 or 2000 IU each of freeze-dried rFVIII concentrate to be 
reconstituted in 2.5 mL of WFI. 
Several batches of the product will be used in the study. 
The final product will be released by the responsible Octapharma Quality Control 
Department, in accordance with 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 with respect to treatment information. Thus, the IMP will be packed and 
labelled according to local regulations, together with a pre-filled syringe containing 2.5 mL 

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WFI (which will be transferred to the product vial), 1 disposable syringe (10 mL), 1 vial 
adapter, 1 butterfly needle and 2 alcohol swabs. 
Details regarding master labelling can be found in Appendix 1. 
5.3 
Conditions for Storage and Use 
 
The product has to be stored at 2-8°C protected from light. The product must not be frozen. 
The Investigators must ensure that the investigational product is stored under appropriate 
conditions with restricted access. The Investigators will inform the patients’ parent(s)/legal 
guardian(s) of necessary storage conditions once the patients start home treatment. 
5.4 
Dose and Dosing Schedule 
 
Prophylactic treatment is recommended, but finally, it is the decision of the responsible 
treating physician whether patients will be treated prophylactically or on-demand. Patients 
may switch from on-demand to prophylactic treatment, or from prophylactic to on-demand 
treatment during the course of the study. 
Prophylactic Treatment 
In case prophylactic treatment is chosen, the patients will be treated with a recommended 
dose of >20 IU FVIII/kg body weight (BW). 
The frequency of treatment will mainly depend on the patient’s clinical situation. In cases of 
inadequate response, Human-cl rhFVIII administration frequency or dose adjustments can be 
considered at Investigator’s discretion. 
On-demand Treatment 
In case of bleeds, the patients can be treated on-demand. The dosage and duration of 
treatment of spontaneous or traumatic bleeds depend on the location and the extent of 
bleeding as well as on the clinical situation of the patient. Dosage recommendations are given 
as follows: 
• Minor haemorrhage (superficial muscle or soft tissue and oral bleeds): 20-30 IU 
FVIII/kg BW to achieve an intended target peak level of about 40% to 60%. Repeat 
dose every 8-24 hours until BE is resolved. 
• Moderate to major haemorrhage (haemorrhage into muscles, into oral cavity; 
haemarthrosis, known trauma): 30-40 IU FVIII/kg BW to achieve an intended target 
peak level of about 60% to 80%. Repeat dose every 6-24 hours until BE is resolved. 
• Major to life-threatening haemorrhage (intracranial, intra-abdominal, gastro-intestinal 
or intrathoracic bleeds, central nervous system bleeds, bleeding in retropharyngeal 
spaces or iliopsoas sheath, eyes/retina, fractures or head trauma): initial dose of 50-80 
IU FVIII/kg BW to achieve an intended target peak level of 100% to 120%. Repeat 
dose of >20 IU FVIII/kg BW every 6-12 hours until BE is resolved. 
Surgical Prophylaxis 
The dosage and duration of treatment with Human-cl rhFVIII will depend on the type of 
surgery and the patient’s individual incremental recovery. Dosage recommendations are 
given as follows: 
• Minor surgeries including tooth extractions: 25-30 IU FVIII/kg BW starting within 3 
hours prior to surgery to achieve an intended target peak level of >30%. Repeat one 
dose every 12-24 hours if needed. Trough levels should be maintained at ≥30%. 

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• Major surgeries: >50 IU FVIII/kg BW within 3 hours prior to surgery to achieve an 
intended target peak level of approximately 100%. Repeat if necessary after 6-12 
hours initially and for at least 6 to 14 days until healing is complete and recurrence to 
regular prophylactic treatment is possible. Trough levels should be maintained at 
>50%. 
5.5 
Preparation and Method of Administration 
 
Human-cl rhFVIII will be provided in single use vials containing a nominal potency of 250, 
500, 1000 or 2000 IU each of freeze-dried rFVIII concentrate to be reconstituted in 2.5 mL of 
WFI. 
Prior to injection, the solution must have reached room temperature, without taking any 
specific warming-up measures. The preparation should be administered within 3 hours after 
reconstitution at one single occasion. The solution is a clear or slightly opalescent colourless 
solution. Solutions that are cloudy or have deposits must not be used. Human-cl rhFVIII 
should be injected intravenously by bolus injection (maximally 4 mL/minute) by using 
aseptic technique. 
5.6 
Blinding, Emergency Envelopes and Breaking the Study Blind 
 
Not applicable. 
5.7 
Treatment Compliance 
 
5.7.1 Drug Dispensing and Accountability 
A drug dispensing log will be kept up to date by the Investigator, detailing the dates, batch 
numbers, and quantities of investigational product dispensed to each patient. The inventory 
will be available to the Study Monitor in order to verify drug accountability in the course of 
the study. Patients’ parent(s)/legal guardian(s) will be advised to return any empty vials and 
unused investigational product on the occasion of the study visits. 
Any unused investigational product not dispensed, or returned by the patient, will be counted 
and returned to the Sponsor. 
In certain cases, unused supplies might have to be destroyed at the study site. However, this  
is only applicable after drug accountability has been verified and fully re-conciliated, and 
after written approval from the Sponsor has been obtained. 
The Investigator will ensure that such a disposition does not expose patients to risks linked to 
the investigational product. The Investigator and the Sponsor will maintain records of any 
such alternate disposition to permit accurate drug accountability. 
5.7.2 Assessment of Treatment Compliance 
Patients will usually undergo at-home treatment (treatment will likely be administered by 
parents/guardians due to the expected young age of the patients or by general practitioners or 
nurses, if accepted by national regulations). At the first visit, the Investigator will provide a 
sufficient amount of study medication and a diary to the parents. The Investigator will advise 
the parents/guardians on how to fill in the diary. The diary will include detailed written 
instructions for all assessments to be made. Furthermore, the efficacy rating criteria and the 
criteria for assessing the severity of a bleed will be explained. The Investigator will 
emphasise the necessity of a careful documentation of all treatment details. The recording of 
at-home injections will include the date and time, dose, batch number, and reason for 

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injection (i.e. prophylaxis, BE treatment). IMP is provided with tear-off labels that must be 
placed in the diary. 
In case of treatment of BEs, the patient’s parents/guardians will document the site and 
severity of the bleed, the start and end dates and time, and carry out an efficacy assessment 
according to the explanation provided in the diary. 
Study product administrations that are overseen by the Investigator (e.g. treatment in relation 
to severe BEs treated at the study site), are to be documented in the patient’s journal (by the 
Investigator), as well as in the patient's diary (by the parents/guardians). 
In addition, the patient’s parents/guardians will record any concomitant medications taken 
during the study period in their diaries. 
For each follow-up visit at the study site, the parents/guardians must bring all diaries to be 
reviewed and validated by site personnel. 
 
6 
STUDY CONDUCT 
6.1 
Observations by Visit 
 
6.1.1 Screening (Visit 1) 
Parents/guardians have to be informed about the study details and have to give their written 
informed consent before any investigations and assessments can be performed. The majority 
of data required are available from the preceding GENA-05 study, and only the following 
information will be documented/assessed: 
• Check of inclusion- and exclusion criteria 
• Height 
• Body weight 
The Investigator will hand out the patient diary and instruct the parent(s)/legal guardian(s) on 
how to document details of treatment with Human-cl rhFVIII, bleeds, AEs and concomitant 
medication. The parent(s)/legal guardian(s) will receive a sufficient amount of study product 
for home treatment and will be instructed on how to store and administer it. 
6.1.2 Procedures During the Follow-Up Part of the Study 
Follow-Up Visits (every 6 months ± 2 weeks): 
The patients will visit the study site every 6 months (± 2 weeks). At these visits, blood 
samples will be obtained for FVIII inhibitor screen (after a wash-out period of at least 2, 
preferably 3 days after the previous IMP administration). Samples are analysed in the central 
laboratory. The safety laboratory parameters will be assessed (samples are analysed locally) 
and vital signs will be measured pre- and – in case IMP was injected – 30-60 minutes post- 
injection and the patient’s BW will be measured. A physical examination is performed. 
At these visits, the patient diary will be reviewed, and data are transferred into the CRF. The 
occurrence of AEs and changes in weight and concomitant medication will be checked and 
documented. 
Surgical Visits: 
Study subjects may undergo surgical interventions during the course of the study. Depending 
on the type of surgery, subjects may be hospitalised or not (in case of certain minor surgeries 
with low risk of post-operative bleeding) at the discretion of the Investigator. Patient’s BW 

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will be recorded within 12 hour before the start of surgery. Estimations of blood loss and 
duration of surgery will be recorded. Details of Human-cl rhFVIII dosing, concomitant 
treatment (including need for additional blood transfusions, excluding anaesthetic drugs), 
AEs (if any) and vital signs will be documented throughout the surgery. Details of surgery, 
actual blood loss, efficacy assessment, presence of wound haematomas and narratives of 
outcomes will be recorded after the surgery. 
Completion Visit: 
For each patient, the study is completed once the IMP is registered and ready for launch in 
the individual country of study conduct, but latest after 2 years individual study duration - 
from screening. 
At this visit, blood samples will be obtained for FVIII inhibitor screen (after a wash-out 
period of at least 2, preferably 3 days after the previous IMP administration) and the safety 
panel. Samples for FVIII inhibitor screen are analysed in the central laboratory. 
The vital signs and a physical examination will be performed. The patient’s BW will be 
measured. The occurrence of AEs and changes in concomitant medication are checked and 
documented. 
At these visits, the patient diary will be reviewed, and data are transferred into the CRF. 
6.2 
Duration of Study 
 
6.2.1 Planned Duration for an Individual Patient 
The patients may stay in the study until the IMP is registered and ready for launch in the 
individual country of study conduct, but latest after 2 years individual study duration - from 
screening. 
6.2.2 Planned Duration for the Study as a Whole 
The study will be considered completed when the registration of the IMP is achieved. This 
study is planned to start in the 1st quarter 2014 and will be completed by 1st quarter 2016 at 
the latest. 
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 required procedures will be arranged on an individual basis  
after review and consultation by both parties. In terminating the study, the Sponsor and the 
Investigator will ensure that adequate consideration is given to the protection of the patients' 
interests. 
 
7 
ASSESSMENTS AND METHODS 
7.1 
Background / Baseline Information 
 
The majority of required background / baseline information is known from the preceding 
study GENA-05, and does not need to be documented, again, but will be transferred from the 
GENA-05 database. 
Demographics: date of birth, patient number in GENA-05 

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After parents (or legal guardians) have given their written informed consent, subjects keep 
the same unique subject numbers as used in the preceding study GENA-05, except that '05' 
will be replaced by '15'. 
Medical history: obtained from existing medical charts and by interviewing the 
parent(s)/legal guardian(s) and by performing a physical examination 
7.2 
Efficacy/Immunogenicity Assessments 
 
7.2.1 Assessments for Endpoint 
 
7.2.1.1 Immunogenicity 
 
The objective is to investigate the immunogenicity of Human-cl rhFVIII. 
Inhibitor activity will be determined centrally by the modified Bethesda assay (Nijmegen 
modification), using congenital FVIII-deficient human plasma spiked with Human-cl rhFVIII 
at the following time points: 
• At Screening Visit, which is most likely the same sampling time-point as the 
completion visit of GENA-05 
• Once every 6 months during the open treatment phase 
• At study completion 
• Any time in the case of a suspicion of inhibitor development. 
In case of a positive inhibitor result, an inhibitor re-testing using a second separately drawn 
sample should be performed centrally. The definitions for thresholds are ≥ 0.6 to < 5 BU for a 
"low titre" inhibitor and ≥5 BU for a "high-titre" inhibitor. 
 
7.2.1.2 Prophylactic treatment 
 
The following parameters will be documented: 
• Dates and times of study product injections 
• Details of dose(s) (in IU) and product batch numbers 
• Details of BEs (if any) occurring under prophylactic treatment 
Study drug consumption data (FVIII IU/kg per month, per year) per patient and in total (for 
patients on prophylactic treatment) will be evaluated. 
Efficacy Assessment of Prophylactic Treatment 
The efficacy of Human-cl rhFVIII in prophylactic treatment will be evaluated based on the 
frequency of spontaneous breakthrough bleeds per months under three times weekly or every 
other day prophylactic treatment and will be calculated and assessed as excellent, good, 
moderate or poor: 
Excellent:        Less than 0.75 spontaneous BEs per month 
Good: 
Between 0.75 and 1 spontaneous BEs per month 
Moderate: 
Between more than 1 and 1.5 spontaneous BEs per month 
Poor: 
More than 1.5 spontaneous BEs per month 
The time period for prophylactic treatment will comprise the time periods between first 
prophylactic treatment with Human-cl rhFVIII until the administration of the last 

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prophylactic treatment + 2 days or completion visit whichever comes first) minus time 
periods from start of a surgery until final assessment of the surgery, and minus time period of 
on demand treatment, if any. 
The frequency of treatment will mainly depend on the patient’s clinical situation and may 
vary from every other day to once weekly injections. In cases of inadequate response, 
Human-cl rhFVIII administration frequency or dose adjustments can be considered at 
Investigator’s discretion. 
The number of BEs counted for prophylactic treatment efficacy assessment will comprise all 
BEs starting during the time periods for prophylactic treatment defined above, i.e. BEs 
occurring between start of surgery until final assessment of the surgery will not be included  
in the prophylactic treatment assessment. 
 
7.2.1.3 Bleeding episodes 
 
For all BEs occurring within the study period, the following data will be documented: 
• Type of bleeding (spontaneous, traumatic, post-operative, other) 
• Site of bleeding 
• Start date and time of occurrence/of noticing the bleed 
• Severity of the bleed (minor, moderate, major or life threatening, see Section 5.4) 
• Date and time of end of BE* 
• Efficacy assessment at the end of the BE (definitions see below) 
• Details of dose(s) and batch number used to treat BE (in IU) 
• Dates and times of study product injections 
* If the treatment of a BE in one bleeding site is interrupted for more than 48 hours, two 
separate BEs will have to be recorded; if another – in addition to the original – bleeding site 
is affected, the events will be recorded as separate BEs at any time. 
All above listed parameters will be documented by the parents/guardians (together with the 
Investigator in case of on-site treatments) in the patient's diary. Patients experiencing a major 
or life-threatening BE should preferably be treated at the study site. 
After the end of a BE the patient is intended to return to his regular prophylactic treatment 
regimen. 
Efficacy Assessment of Bleeding Episodes 
At the end of a BE, the following efficacy assessment will be made by the patient’s 
parent(s)/legal guardian(s) (together with the Investigator in case of on-site treatment): 
Excellent: Abrupt pain relief and/or unequivocal improvement in objective  signs  of  
bleeding within approximately 8 hours after a single infusion 
Good: 
Definite pain relief and/or improvement in signs of bleeding within 
approximately 8 – 12 hours after an infusion requiring up to 2 infusions for 
complete resolution 
Moderate:    Probable or slight beneficial effect within approximately 12 hours after the    
first infusion requiring more than two infusions for complete resolution 

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None: 
No improvement within 12 hours, or worsening of symptoms, requiring more 
than 2 infusions for complete resolution 
The assessment will be made at the end of a BE. 
 
7.2.1.4 Surgical Prophylaxis 
 
In case surgical procedures are performed, the following data will be documented: 
• Location and type (planned or emergency) of surgery 
• Severity of surgery (minor or major, definitions see below) 
• Expected duration of surgical procedure 
• Actual BW prior to surgery (kg) 
• Actual duration of surgical procedure (start and end times, i.e. skin to skin) 
• Pre-, intra-, and post-operative FVIII plasma levels (time-points see below) 
• Expected and actual blood loss (see below) 
•  All wound haematomas, incl. capture, analysis, and reporting, noting whether surgical 
evacuation is required 
• Laboratory tests (haematology, chemistry: before and 24 hours after end of surgery) 
• Details on concomitantly administered products including any blood/blood product 
transfusions but excluding drugs given for routine anaesthesia 
•  Details of administered dose(s) of Human-cl rhFVIII given pre-, intra- and/or post- 
operatively (definitions see below) including dates, times, and batch number 
• A brief narrative describing the outcome and efficacy of the intervention 
• Overall efficacy assessment at the end of surgical prophylaxis by the surgeon and the 
haematologist (definitions see below) 
Classification of Surgeries 
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 patient's life is at stake 
The classification is made prospectively. All other surgeries are classified as minor. 
FVIII Plasma Level 
FVIII plasma level (both assays, local and central lab) will be documented at the following 
time-points: 

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• Immediately (≤30 minutes) before and after pre-operative injection of study drug 
•  Immediately (≤30 minutes) before and after each intra-operative bolus dose (if any); not 
mandatory for minor BEs 
•  Immediately (≤30 minutes) before and after each post-operative dose (if any); in case of 
major surgery: mandatory for the first 3 post-operative doses 
Continuous infusion is not allowed in this study, only bolus injections are permitted. 
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 patient 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 patient with normal haemostasis, of the same sex, 
age, and stature. 
Following the surgery, the actual blood loss will be estimated by the surgeon. 
Definitions of Pre-, Intra-, and Post-Operative Doses 
A pre-operative  administration is defined as any dose of Human-cl rhFVIII  applied within   
3 hours prior to surgery start. 
An intra-operative administration is defined as any injection of Human-cl rhFVIII applied 
during surgery. 
A post-operative administration is defined as any dose of Human-cl rhFVIII applied after the 
end of the surgery (“end of surgery” is defined as “last suture”), for at least 2 days (minor 
surgeries), or for at least 6 to 14 days (major surgeries), respectively, until healing is  
achieved and recurrence to the regular prophylactic treatment regimen. 
Efficacy Assessment of Surgical Prophylaxis 
Efficacy will be assessed (1) at the end of surgery by the surgeon, and (2) post-operatively by 
the haematologist, and finally (3) overall by an agreed upon assessment from the surgeon and 
the haematologist using the following scales: 
Intra-operatively (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 compared with the same type of procedure performed in a patient 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 compared with the same type of procedure in 
a patient with normal haemostasis. 
• Moderate: Intra-operative blood loss was higher than maximal expected blood loss 
compared with the same type of procedure performed in a patient with normal 
haemostasis, but haemostasis was controlled. 
• None: Haemostasis was uncontrolled necessitating a change in clotting factor replacement 
regimen. 

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Post-operatively: 
• 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 Human-cl rhFVIII, 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 Human-cl rhFVIII 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 Human-cl 
rhFVIII 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 FVIII concentrate. 
An overall efficacy assessment taking both the intra- and post-operative assessment into 
account will be done by the surgeon and the haematologist. 
The conclusion of the post-operative phase of a major surgery is defined as follows: date of 
discharge, or at least post-operative Day 6, whichever occurs later. 
At the end of a surgical prophylactic treatment period the patient is intended to return to his 
regular prophylactic treatment regimen. 
7.3 
Safety Assessments 
 
7.3.1 Adverse Events 
All AEs and SAEs will be monitored and recorded throughout the study. 
7.3.1.1 Definitions 
 
Adverse event (AE): An AE is any untoward medical occurrence in a study patient receiving 
an IMP and which does not necessarily have a causal relationship with this treatment. An AE 
can therefore be any 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: Is a patient 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 patient is stable. All follow-up information 
collected will be made available to the Sponsor. 

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7.3.1.2 Collection 
 
The condition of the patient will be monitored throughout the study. At each visit, whether 
scheduled or unscheduled, AEs will be elicited using a standard non-leading question such as 
“How have you been since the last visit / during the previous study period?” In addition, the 
patient diaries (if applicable) will be checked by the Investigator for any documented event. 
Any AE or ADR which occurs during the study will be noted in detail on the appropriate 
pages of the CRF. If the patient reports several signs or symptoms, 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), the seriousness (non- 
serious or serious) and causality, as defined below (Sections 7.3.1.3, 7.3.1.4 and 7.3.2). The 
Sponsor is responsible to assess the expectedness of each ADR (expected or unexpected), as 
defined below (Section 7.3.1.4). 
In the event of clinically significant abnormal laboratory findings, the tests will be 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 
observations or comments, which are useful for the interpretation and understanding of the 
patients’ AEs or ADRs. 
7.3.1.3 Severity 
 
The intensity/severity of all AEs will be graded as follows: 
• mild: an AE, usually transient, which causes discomfort but does not interfere with  
the patient’s routine activities; 
• moderate: an AE which is sufficiently discomforting to interfere with the patient’s 
routine activities; 
• severe: an AE which is incapacitating and prevents the pursuit of the patient’s routine 
activities. 
Grading of an AE is up to the medical judgement of the Investigator and will be decided on a 
case by case basis. 
7.3.1.4 Causality 
 
The relationship of AEs to the administered IMP will be assessed by the Investigator 
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 
patient’s clinical state. 

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• possible: reports containing sufficient information to accept the possibility of a causal 
relationship, in the sense of not impossible and not unlikely, although the connection 
is uncertain or doubtful, for example because of missing data or insufficient evidence. 
A reaction that follows a reasonable temporal sequence from administration of the 
IMP; that follows a known or expected response pattern to the suspected medicine; 
but that could readily have been produced by a number of other factors. 
• unlikely: reports not following a reasonable temporal sequence from IMP 
administration. An event which may have been produced by the patient’s clinical state 
or by environmental factors or other therapies administered. 
• not related (unrelated): events for which sufficient information exists to conclude that 
the 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). 
Classification of ADRs: 
ADRs will be classified by the Sponsor as either expected or unexpected: 
• expected: an AE that is listed in the “Reference Safety Information” of the current 
edition of the Investigator's Brochure. 
• unexpected: an AE that is not listed in the current edition of the Investigator's 
Brochure, or that differs because of greater severity or greater specificity. 
7.3.1.5 Outcome 
 
The outcome of all reported AEs has to be documented as follows: 
1. recovered, resolved 
2. recovering, resolving 
3. not recovered, not resolved 
4. recovered, resolved with sequelae 
5. fatal 
6. unknown 
NOTE: A patient’s death per se is not an event, but an outcome. The event which resulted 
into patient’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. 
7.3.1.6 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 patient. 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: 
In general 
• none 

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• medication (other than IMP) or other (e.g., physical) therapy started 
• test performed 
• other (to be specified) 
On 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 patient is stable, and all relevant follow-up information will be reported to 
the Sponsor. 
7.3.2 Serious Adverse Events 
An SAE is any untoward medical occurrence that at any dose: 
• results in death, 
• is life-threatening, 
• requires hospitalisation or prolongation of existing hospitalisation, 
• results in persistent or significant disability/incapacity, 
• is a congenital anomaly/birth defect, 
• is another important medical event. 
In addition, each FVIII inhibitor development is regarded as an SAE. 
NOTE: The term "life-threatening" refers to an event in which the patient was — in the view 
of the reporting Investigator — at immediate risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it were more severe. 
Medical judgment should be exercised in deciding whether an AE/reaction is serious in other 
situations: Important AEs/ADRs that are not immediately life-threatening or do not result in 
death or hospitalisation but may jeopardise the patient or may require intervention to prevent 
one of the other outcomes listed in the definitions above, should also be considered serious. 
In addition, although not classified under the seriousness criteria, all suspected transmissions 
of an infectious agent should be reported as SAE. A suspected virus transmission means that 
virus antigen has been detected in the patient. A passive transmission of antibodies alone  
does not constitute a suspected virus transmission. 
SAE reporting timelines 
All SAEs, whether suspected to be related to study treatment or not, are to be reported by 
telephone, fax or e-mail immediately to the Clinical Project Manager or designee. 
Contact details for SAEs reporting are available on the “Serious Adverse Event Report” and 
below. 
An Octapharma "Serious Adverse Event Report" must be completed and submitted within 24 
hours after recognition of the event. 

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All SAEs should additionally be reported to: 
Martina Jansen 
Senior Clinical Project Manager 
e-mail: martina.jansen@octapharma.com 
 
 
Octapharma’s Central Drug Safety Unit 
 
e-mail: cdsu@octapharma.com 
OCTAPHARMA Pharmazeutika Produktionsges.m.b.H. 
Oberlaaer Strasse 235, 1100 Vienna, Austria 
Fax: +43 1 61032-9249 
24 hours emergency telephone number: +43 1 40 80 500 
Waiver from SAE reporting requirement: 
The following SAEs do not require reporting in expedited manner: 
• Hospitalisation for the treatment of a (disease-related) BE assessed as unrelated to 
IMP treatment. 
These exceptions/waivers include surgeries that are elective or planned, and prolongation of 
the existing hospitalisations due to economic or social reasons, but not medical reasons. 
These should not be considered as SAEs. 
7.3.3 Laboratory Safety Tests 
Blood Sampling 
The actual date and time of any blood sampling must be recorded in the CRF, on the label of 
the laboratory tubes and on the corresponding laboratory shipment forms. 
If several blood samples have to be taken at one time point, the blood sampling will be done 
in the following sequence: 
1. Haematology: RBC count, WBC count, haemoglobin, haematocrit, platelet count 
(EDTA blood) 
2. Coagulation: FVIII plasma level and FVIII inhibitor control (citrated plasma) 
3. Biochemistry: ALT, AST, serum creatinine (serum) 
It is essential that blood sampling after the injection of Human-cl rhFVIII is done from the 
other arm. 
Blood samples taken for citrate plasma will be centrifuged after collection for 15 to 20 
minutes at 1500 to 2000 g (about 3000 rpm). Aliquots of the supernatant are subsequently 
transferred into the tubes provided by the central laboratory (pre-labelled with date and time 
point of sampling, type of sample, patient identification and study number) and stored, 
respectively shipped under adequate conditions. 
EDTA Blood 
A 1 mL sample (or less, as required by the local laboratory) of EDTA blood will be collected 
for the measurement of haematology parameters (RBC count, WBC count, haemoglobin, 
haematocrit, platelet count). All haematology tests are to be done at the local laboratory. 
Citrated Plasma 
For the analysis of FVIII (if applicable) and inhibitor screen, both performed in the central 
laboratory in the US, citrated blood will be collected. After collection and centrifugation, the 

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plasma will be aliquoted into cryo-resistant tubes. Samples will be stored at ≤-70°C and 
shipped to the central laboratory on dry-ice. 
For analysis performed locally, e.g. at screening and pre-, intra, and post-surgery, citrated 
blood as required by the local laboratory will be collected and processed in accordance with 
local requirements. 
Serum 
For the determination of clinical chemistry (ALT, AST, serum creatinine) a blood sample of 
about 0.5 mL (or less, as required by the local laboratory) will be collected. All tests are to be 
done at the local laboratory. 
 
The “Ethical Considerations for Clinical Trials on Medicinal Products conducted with the 
Paediatric Population” (6) are followed during the conduct of GENA-15. The Committee 
recommends the below blood volume limits for sampling: 
Per individual, the trial-related blood loss should not exceed 3 % of the total blood volume 
during a period of four weeks, and should not exceed 1% at any single time. The total volume 
of blood is estimated at 80 to 90 ml/kg body weight; 3% is 2.4 ml blood per kg body weight. 
Time-points and required blood / plasma volume needed for laboratory parameters are 
estimated as follows (please note that the exact amount needed for the analysis performed in 
the central laboratory can be found in the laboratory manual, only): 
Table 6 
Time-Points and Approximate Blood Volume for Laboratory Parameters 
 
Screening 
Follow-Up 
Surgery 
Results from GENA-05 
completion visit are 
transferred – no additional 
blood sampling 
6-Months Visits 
(+ 2 weeks) 
Completion Visit 
(Pre-, intra- and post- 
surgery) 
FVIII inhibitor screen 
1.4 mL/0.7 mL 
1.4 mL/0.7 mL 
Haematology 
~1 mL 
EDTA blood 
~1 mL 
EDTA blood 
~1 mL 
EDTA blood 
Clinical chemistry 
~0.5 mL 
serum 
~0.5 mL 
serum 
~0.5 mL 
serum 
FVIII:C 
1.4 mL/0.7 mL 
1.4 mL/0.7 mL 
1.4 mL/0.7 mL 
 
All treatment-emergent rise in AST or ALT to >3 x ULN will be followed by assessing liver 
function tests until their return to normal; or (in case of a priori increased values) until their 
return to the individual's baseline; or until a definite diagnosis is determined. 
If the abnormal values persist for more than 1 week, viral serology (hepatitis B virus, 
hepatitis C virus, and/or others) and PCR testing will be performed by the local laboratory. In 
addition, PCR testing of the corresponding batches will be performed by the central lab. 
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. 

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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 final study visit, whichever occurs first. Preferably, 
clinically significant lab abnormalities should be medically diagnosed and entered as a 
diagnosis into the AE form, if not already present at baseline. 
The following table summarises all test parameters and the laboratory responsible for 
analysis: 
Table 7 
Test Parameters and Laboratories 
 
Test 
Material needed 
Responsible laboratory 
FVIII:C*‡ 
(one-stage and chromogenic assay) 
Citrated plasma 
LabCorp Clinical Trials 
Laboratory Services 
8490 Upland Dr, Ste. 100 
Englewood, CO 80112, USA 
Inhibitors to FVIII 
(modified Bethesda assay - Nijmegen 
modification) 
Citrated plasma 
Haematology 
EDTA blood 
Local laboratory 
Clinical chemistry 
Serum 
Local laboratory 
PCR testing of Human-cl rhFVIII batches† 
Human-cl rhFVIII 
Octapharma AB 
Elersvägen 40 
11275 Stockholm, Sweden 
* Performed locally when required, e.g. pre-, intra- and post-surgery. 
† Performed if abnormal AST or ALT values persist for more than 1 week. 
 
All remaining serum and plasma volumes will be labelled and stored as retention samples at 
the central laboratory for at least 2 years after the completion of the study and until 
Octapharma’s written authorisation to destroy these samples. 
7.3.4 Vital Signs and Physical Examination 
Vital signs (blood pressure, heart rate, respiratory rate, body temperature) will be assessed at 
the following time-points: at screening (results are to be transferred from GENA-05’s 
completion visit), prior and – in case IMP was injected – 30-60 minutes after the end of the 
injection at 6-monthly (± 2 weeks) visits, and prior and – in case IMP was injected – 30-60 
minutes after the end of the injection at the completion visit. During surgical procedures vital 
signs will be assessed before, during and at the first post-operative day. 
A physical examination needs to be performed at screening (results are to be transferred from 
GENA-05’s completion visit), once every 6 months and at study completion. 
7.3.5 Other Relevant Safety Information 
Post study related safety reports: 
Any ADR (i.e., any AE with a suspected causal relationship to the IMP) that 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. 

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If a patient dies within 4 weeks after the last IMP administration, this should be reported as 
well, without being considered treatment-related or not. 
Overdose, interaction, abuse, 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, 
instructions for use/labelling. The reaction must be clearly identified as a medication error. 
7.4 
Appropriateness of Measurements 
 
All measurements used for the assessment of the immunogenicity, safety, and efficacy of 
Human-cl rhFVIII are in compliance with the requirements set up in the CHMP “Guideline 
on the clinical investigation of recombinant and human plasma-derived factor VIII products” 
(EMA/CHMP/BPWP/144533/2009) (5). 
All FVIII inhibitor and FVIII plasma level samples obtained in the course of this study will 
be evaluated by an accredited central laboratory using validated methods and assays. 
If clinically indicated, FVIII and inhibitor testing can additionally be performed in the local 
laboratory. The results obtained locally will be recorded in the CRFs. 
 
8 
DATA HANDLING AND RECORD KEEPING 
8.1 
Documentation of Data 
 
8.1.1 Source Data and Records 
Source data are defined as all the information related to clinical findings, observations, or 
other activities in the study, 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 patient files for 
each patient enrolled). Source records should be preserved for the maximum period of time 
required by local regulations. 

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For each patient enrolled, the Investigator will indicate in the source record(s) that the patient 
participates in this study. 
All data entered in the CRF must be supported by source data in the patient records with the 
exceptions listed in Section 8.1.2. 
The Investigator will permit study-related monitoring, audit(s), Independent Ethics 
Committee [IEC]/ Institutional Review Board [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. 
8.1.2 Case Report Forms 
For each patient enrolled, a CRF will be completed and signed by the Investigator or an 
authorised Co-Investigator. All forms will be filled out using an indelible pen, and must be 
legible. 
8.1.3 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 
Investigator for signature. 
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. 
8.2 
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. 
8.3 
Responsibilities 
 
The Co-ordinating Investigator of this study is Dr Raina J Liesner, Great Ormond Street 
Hospital for Children, NHS Trust, Haemophilia Centre, Great Ormond Street, London WC1N 
3JH, United Kingdom. 

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The central laboratory for all coagulation parameters and inhibitor testing is LabCorp Clinical 
Trials, Laboratory Services, 8490 Upland Dr, Ste. 100, Englewood, CO 80112, USA. 
Statistical advice during the planning phase, study data management and statistics of the 
study will be delegated under an agreement of transfer of responsibilities to GASD mbH, Am 
Konvent 8-10, 41460 Neuss, Germany. 
All Octapharma SOPs, procedures and policies have to be met by external parties (Contract 
Research Organisations [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, using the 
principles of good clinical practice (GCP) and good laboratory practice (GLP) guidelines, 
SOPs and complying with all other applicable regulations. 
8.4 
Investigator’s Site File 
 
At each study site, the Investigator is responsible for maintaining all records to enable the 
conduct of the study to be fully documented. Essential documents as required by GCP 
guidelines and regulations (e.g., copies of the protocol, study approval letters, all original 
informed consent forms, site copies of all CRFs, drug dispensing and accountability logs, 
correspondence pertaining to the study, etc.) should be filed accurately and kept by the 
Investigator for the maximum period of time required by local regulations. 
The Investigator is responsible for maintaining a confidential patient identification code list, 
which provides the unique link between named source records and CRF data for the Sponsor. 
The Investigator must arrange for the retention of this confidential list for the maximum 
period of time required by local regulations. 
No study document should be destroyed without prior written agreement between the 
Investigator and the Sponsor. Should the Investigator elect to assign the study documents to 
another party, or move them to another location, the Sponsor must be notified in writing. 
8.5 
Provision of Additional Information 
 
On request, the Investigator will supply the Sponsor with additional data relating to the study, 
or copies of relevant source records, ensuring that the patient’s confidentiality is maintained. 
This is particularly important when CRFs are illegible or when errors in data transcription are 
encountered. In case of particular issues or governmental queries, it is also necessary to have 
access to the complete study records, provided that the patient’s confidentiality is protected in 
accordance with applicable regulations. 
8.6 
Independent Data Monitoring Committee 
 
GENA-05 is monitored by an Independent Data Monitoring Committee (IDMC). GENA-15 
is an extension study of GENA-05and is not monitored by the IDMC. 
 
9 
STATISTICAL METHODS AND SAMPLE SIZE 
The statistical analysis will be delegated under an agreement of transfer of responsibilities to 
an external CRO. All Octapharma procedures and policies have to be met by this CRO. 
Discrepancies or exceptions are to be approved by the Sponsor’s Manager of Biometrics. 

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9.1 
Determination of Sample Size 
 
No inferential analysis involving formal testing is planned in this non-controlled extension 
study. Consequently, no formal sample size estimation was performed. 
9.2 
Statistical Analysis 
 
A formal statistical analysis plan (SAP) describing all details of the analyses to be performed 
will be prepared by the study statistician and approved by the Sponsor prior to the start of the 
study. 
The statistical analysis of the endpoints is to be understood in the exploratory sense. No 
confirmatory hypothesis testing is planned. 
9.2.1 Population for Analysis 
For the analysis of this study, the following populations will be considered: 
• Safety analysis population: All subjects who received at least one dose of Human-cl 
rhFVIII; 
• Intent to Treat (ITT) analysis population: All subjects in the safety analysis population for 
whom any data was collected post treatment with Human-cl rhFVIII; 
• Efficacy: Per Protocol (PP) analysis population: All subjects in the ITT  analysis  
population who completed the trial without significantly violating the inclusion/exclusion 
criteria or other aspects of the protocol considered to potentially affect the efficacy 
results. 
Especially the following subjects will be excluded from this population: 
• Subjects who fulfil the following exclusion criteria: 
- severe liver or kidney disease (ALT and AST levels >5 times of ULN, creatinine 
>120 μmol/L), 
- concomitant treatment with any systemic immunosuppressive drug 
- subjects who use concomitant medication that may confound study results, like 
e.g. alpha-interferon or prednisone 
- other FVIII concentrate than Human-cl rhFVIII was received between completion 
visit of GENA-05 and start of GENA-15 (except emergency cases) 
•  Subjects with significant non-compliances with the protocol such as non-compliance   
to complete the diary in a proper manner or more than 30% of haemostatic efficacy 
assessments missing. 
• Subjects with dosing or treatment errors like e.g. the use of other FVIII products  
(except for emergencies as mentioned above) or several unexplained and significant 
deviations from the recommended dose regimen. 
• Population of subjects on prophylactic treatment schedule (PROPH): All subjects in the 
ITT population who have at least one prophylactic treatment 
• Per-protocol population of subjects on prophylactic treatment schedules (PROPH-PP): 
All subjects in the PP population who have no significant dosing or treatment errors, like 
e.g. unexplained interruptions of the prophylaxis with Human-cl rhFVIII 
• Population of bleedings (BLEED): All documented bleeds - except those occurring 
during and after surgery - of subjects in the ITT population for which 
• any amount of treatment with Human-cl rhFVIII is documented and which 
• start between first BE treated with Human-cl rhFVIII and the completion visit. 

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• Population of bleedings per protocol (BLEED-PP): All documented bleeds in the BLEED 
population of subjects in the PP population. 
• Surgery population (SURG): All documented surgical interventions of subjects in the ITT 
population for which 
• any amount of Human-cl rhFVIII prior to, during or after the surgery is documented 
and 
• no other FVIII concentrate is documented within 24 hours prior to surgery. 
• Surgery per-protocol population (SURG-PP): All documented surgical interventions of 
subjects in the PP population for which 
• any amount of Human-cl rhFVIII prior to, during or after the surgery is documented 
and 
• no other FVIII concentrate is documented within 72 hours prior to, during or after the 
surgery (until resuming regular prophylactic treatment or until discharge from hospital 
in case of a subject with on-demand treatment). 
The subject disposition, i.e. the identification of significant violations to consider for the PP 
populations and the assignment of each subject, bleeding and surgery to these analysis 
populations, will be the joined decision of the trial statistician and the responsible medical 
expert prior to database lock. 
The ITT population is considered to be the most relevant for analysis of immunogenicity 
data; the PROPH population is considered to be the most relevant for analysis of efficacy  
data on prophylaxis; the BLEED population is considered to be the most relevant for analysis 
of efficacy data on bleedings and the SURG population is considered to be the most relevant 
for analysis of efficacy data on surgeries. To evaluate the robustness of the study results, 
efficacy analyses will also be done on basis of the respective PP population. 
9.2.2 Efficacy Analysis Plan 
Efficacy will be evaluated by descriptive statistics. 
• On bleeding rates (efficacy of prophylaxis) overall and by intensity of prophylaxis 
• On efficacy assessments per bleed, basic bleed characteristics including severity, site 
and type 
• On efficacy assessments per surgery 
The frequency of bleeds, the number of infusions needed to treat a BE, the number of EDs, 
and study drug consumption data (FVIII IU/kg per infusion, per BE, per month, per year) per 
patient and in total will be evaluated. Furthermore, increased and decreased doses of Human- 
cl rhFVIII used to treat individual BEs (frequency and relative magnitude of dose changes) 
will be evaluated, as well as changes in the doses per infusion and changes in the total dose 
used to treat subsequent BEs of the same type (e.g. elbow, knee, etc.) in the same patient 
(frequency and relative magnitude of dose changes). 
9.2.3 Safety Analysis Plan 
All AEs and any changes in physical examination findings during study 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, listings and figures. 
Incidences of AEs will be given as numbers and percentages of patients and infusions with: 

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• Any AE. 
• Any serious AE. 
• Any AE probably or possibly related to the trial drug. 
• Any AE that begins within 24 hours of the end of an infusion. 
• Any severe AE. 
• Any withdrawal due to AE. 
• Any AE by MedDRA preferred term. 
• Any AE by MedDRA System Organ Class (SOC). 
Summary tables for AEs will be given by SOC and preferred term. Additionally, AEs will be 
summarised by severity and relationship to study treatment. These summary tables will 
feature total counts and counts by age group, sex, prior EDs to Human-cl rhFVIII (including 
EDs within GENA-05) and total amount of Human-cl rhFVIII (including amount used within 
GENA-05) used prior to the AE to evaluate the need of further investigation of any apparent 
pattern or trend in AE rates. 
The MedDRA coded terms and the corresponding original (verbatim) terms used by the 
Investigator will be listed. 
Vital signs 
Blood pressure (systolic/diastolic), heart rate, respiratory rate and body temperature will be 
tabulated, and the sample characteristics will be presented by time point. 
Routine laboratory data 
Routine laboratory parameters (haematology, clinical chemistry) will be listed for all patients, 
using indicators for values outside the associated reference ranges. Changes from baseline 
(screening) will be provided where appropriate. 
9.2.4 Handling of Missing Data 
In general, missing data will not be imputed: calculations pertaining to person-year 
computations will be based on observed values only. Only in case of missing BW, the last 
available weight measurement will be used for calculating the dose per kg bodyweight (last 
observation carried forward). 
9.3 
Interim Analysis 
 
No interim analysis is planned. 
 
10 ETHICAL / REGULATORY, LEGAL AND ADMINISTRATIVE ASPECTS 
10.1 Ethical / Regulatory Framework 
 
This study will be conducted in accordance with the ethical principles laid down in the 
Declaration of Helsinki. The study protocol and any subsequent amendment(s) will be 
submitted to an 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. 

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10.2 Approval of Study Documents 
 
The study protocol, a sample of the patient information and informed consent form, any other 
materials provided to the patients, and further requested information will be submitted by the 
Sponsor or the Investigator to the appropriate IEC/IRB and the Regulatory Authority. The 
study approval letter must be available before any patient is exposed to a study-related 
procedure. 
The Sponsor, the Investigator and any third party (e.g., CRO) involved in obtaining approval, 
must inform each other in writing that all ethical and legal requirements have been met before 
the first patient is enrolled in the study. 
10.3 Patient Information and Informed Consent 
 
The investigator will obtain a freely given written consent from each patient/parent/legal 
guardian 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 noted by the 
patient/parent/legal guardian, before the patient is exposed to any study-related procedure, 
including screening tests for eligibility. 
For patients not qualified to give legal consent, written consent must be obtained from the 
legal parent or 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. 
The investigator will explain that the patient/parent/legal guardian are completely free to 
refuse to enter the study or to withdraw from it at any time, without any consequences for the 
patient's further care and without the need to justify. The investigator will complete the 
informed consent section of the CRF for each subject enrolled. 
Each patient/parent/legal guardian will be informed that the patient's 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 patients, the 
objective/design of the study, any increase in dosage or duration of exposure to the IMP an 
increase in the number of patients treated, the addition of a new test or procedure, or the 
dropping of a test intended to monitor safety. 
10.5 Confidentiality of Patients´ Data 
 
The Investigator will ensure that the patient's confidentiality is preserved. On CRFs or any 
other documents submitted to the Sponsor, the patients will not be identified by their names, 
but by a unique patient number. Documents not for submission to the Sponsor, i.e., the 
confidential patient identification code list, original consent forms and source records will be 
maintained by the Investigator in strict confidence. 

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11 QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 Periodic Monitoring 
 
The monitor will contact and visit the Investigator periodically to review all study-related 
source data/records, verify the adherence to the protocol and the completeness, correctness 
and accuracy of all CRF entries compared to source data. The Investigator will co-operate 
with the monitor to ensure that any discrepancies identified are resolved. 
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 patients have been adequately protected, and that all data relevant for the 
assessment of safety and effectiveness of the IMP have been reported to the Sponsor. 
 
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. 
 
13 LIABILITIES AND INSURANCE 
In order to cover any potential damage or injury occurring to a patient in association with the 
IMP or the participation in the study, Octapharma will contract insurance in accordance with 
local regulations. 

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The Investigator is responsible for dispensing the IMP according to this protocol, and for its 
secure storage and safe handling throughout the study. 
 
14 REFERENCES 
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Curr Opin Organ Transplant 2006;11:1541-59. 
(2) Hokke CH, Bergwerff AA, van Dedem GWK, van Oostrum J, Kamerling JP, and 
Vliegenthart JFG. Sialylated carbohydrate chains of recombinant human 
glycoproteins expressed in Chinese hamster ovary cells contain traces of N- 
glycolylneuraminic acid. FEBS Lett 1990;275:9-14. 
(3) Hironaka T, Furukawa K, Esmon PC, Fournel MA, Sawada S, Kato M, et al. 
Comparative study of the sugar chains of factor VIII purified from human plasma 
and from the culture media of recombinant baby hamster kidney cells. J Biol 
Chem 1992;267:8012-20. 
(4) Kannicht Ch, Ramström M, Kohla G, Tiemeyer M, Casademunt E, Walter O, 
Sandberg H. Characterisation of the post-translational modifications of a novel, 
human cell line-derived recombinant human factor VIII. Thrombosis Research 
2013, 131: 78–88 
(5) Guideline on the clinical Investigation of Recombinant and Human Plasma- 
Derived Factor VIII Products (EMEA/CHMP/BPWP/144533/2009), London, 21 
July 2011 
(6) Ethical Considerations for Clinical Trials on Medicinal Products conducted with 
the Paediatric Population. Recommendations of the ad hoc group for the 
development of implementing guidelines for Directive 2001/20/EC relating to 
good clinical practice in the conduct of clinical trials on medicinal products for 
human use, Final 2008