Prospective, Multinational, Non-interventional Post-authorisation Study to Document the Long-term Immunogenicity, Safety, and Efficacy of Human-cl rhFVIII (Simoctocog Alfa) in Patients With Haemophilia A Treated in Routine Clinical Practice
Conditions: Hemophilia A
Sponsor: Octapharma

Human-cl rhFVIII 
Post-Authorisation Study 
 
Gita Pezeshki, PhD 
Clinical Trial Manager - Haematology 
Octapharma USA Inc. 
Email: gita.pezeshki@octapharma.com 
GENA-99 
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Title 
Prospective, multinational, non-interventional post- 
authorisation study to document the long-term 
immunogenicity, safety, and efficacy of Human-cl rhFVIII 
(simoctocog alfa) in patients with haemophilia A treated in 
routine clinical practice 
Protocol number 
GENA-99 
Protocol version 
05 
Date of protocol 
26 Sep 2017 
Active substance 
Coagulation FVIII 
Medicinal product 
Human-cl rhFVIII (simoctocog alfa) 
Commercial name: Nuwiq® 
Indications 
Treatment and prevention of bleeding episodes (also during and 
after surgery) in patients with haemophilia A 
Research question 
and objectives 
To collect additional clinical data and to ensure consistency in 
the long-term between the outcome from pre-authorisation 
clinical studies (in 135 previously treated paediatric and adult 
patients) and routine clinical practice. 
Besides aspects such as general product safety and efficacy, 
there will be a focus on immunogenicity, particularly on 
inhibitor development. The diagnosis of FVIII inhibitor will be 
based on clinical observations and confirmed by FVIII inhibitor 
testing in the laboratory. 
Countries 
Countries from across the EU and other countries where Nuwiq® 
is commercially available 
Marketing 
authorisation holder 
Octapharma AG 
Seidenstrasse 2 
8853 Lachen 
Switzerland 
Author 
 
 
 
 
090-NIS-GENA-99-Version-05/DOC ID2660 

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STUDY OUTLINE 
 
Title of Study: Prospective, multinational, non-interventional post-authorisation study to 
document the long-term immunogenicity, safety, and efficacy of Human-cl rhFVIII in 
patients with haemophilia A treated in routine clinical practice 
Study Rationale: Data from pre-authorisation studies are insufficient to estimate all 
aspects of therapy with FVIII products, especially with respect to immunogenicity. 
Therefore, to estimate the likelihood of rare side effects, such as the occurrence of FVIII 
inhibitors, and to bridge between the outcome from clinical trials and long-term clinical 
use, the purpose of this study is to assess the long-term immunogenicity, safety, and 
efficacy of Nuwiq® in patients with haemophilia A treated in routine clinical practice. 
Specifically, the study is designed to meet the requirements for post-authorisation studies 
as outlined in the ‘Guideline on the clinical investigation of recombinant and human 
plasma-derived factor VIII products’ by the European Medicines Agency (EMA), 
EMA/CHMP/BPWP/144533/2009. 
Study Objectives: In addition to general product safety and efficacy, the focus of this 
study will be on immunogenicity, particularly on inhibitor development 
(EMA/CHMP/BPWP/144533/2009). The objectives of this study are: 
• To assess the long-term immunogenicity and safety of Nuwiq® in treating or 
preventing bleeding episodes (BEs) in patients with haemophilia A 
• To assess the long-term efficacy of Nuwiq® in treating or preventing BEs in patients 
with haemophilia A 
Study Design: Prospective, multinational, non-interventional post-authorisation study 
Study Population 
According to Guideline EMA/CHMP/BPWP/144533/2009, the number of patients 
typically needed in a post-authorisation study with FVIII to cover immunogenicity aspects 
is 200. 
• The goal is to collect data on 200 previously treated male patients of any age with 
haemophilia (FVIII:C ≤ 2%). 
• Of the 200 enrolled patients, at least 100 patients should have severe haemophilia A 
(FVIII:C < 1%). 
• The age distribution of enrolled patients should be evenly balanced; thus, approx. 
60 patients should be < 12 years of age; also, at least 10 patients should be aged 
between 14–18 years. 
• Patients with severe haemophilia A after successful immune tolerance induction 
(ITI) can also be included; the proportion of ITI patients should not exceed 25% of 
the entire cohort. 

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Data on patients having participated in pre-authorisation studies with Nuwiq® and patients 
starting treatment with Nuwiq® in additional clinical Good Clinical Practice (GCP) 
studies may be combined with data from patients agreeing to participate in this non- 
interventional study to count towards the required 200 patients. 
Eligibility Criteria 
Inclusion Criteria 
(a) Haemophilia A (FVIII:C ≤ 2%) based on medical history; at least 100 patients 
should have severe haemophilia A (FVIII:C < 1%) 
(b) Male patients of any age 
(c) Previous treatment with a FVIII concentrate for more than 150 exposure days 
(EDs) 
(d) Availability of detailed documentation (patient diary) covering either the last 50 
EDs or the last 2 years per patient to confirm treatment modality (i.e., prophylaxis, 
on-demand, recent surgery, or immune tolerance induction) 
(e) Inhibitor negative (< 0.6 BU) at study entry as confirmed by a recovery test with 
previous FVIII product and inhibitor test in a central laboratory 
(f) Immunocompetence (CD4+ count > 200/µL), HIV-negative, or having a viral load 
< 200 particles/µL or < 400,000 copies/mL 
(g) Decision to prescribe Nuwiq® before enrolment into the study 
(h) Written informed consent by the patient or the patient’s parent or legal guardian 
Exclusion Criteria 
Patients treated with any investigational medicinal product (IMP) except FVIII IMP 
within 30 days prior to the Screening Visit or patients planning to undergo treatment with 
any IMP other than Nuwiq® are not eligible for enrolment into the study. 
Outcome Parameters 
Immunogenicity and Safety 
The study objective of assessing the long-term immunogenicity and safety of Nuwiq® will 
be evaluated using the following outcome parameters: 
• Incidence of FVIII inhibitors, with the diagnosis 
– based on clinical observations and 
– confirmed by FVIII inhibitor testing in the laboratory 
• Incidence of adverse drug reactions (ADRs), including hypersensitivity reactions 

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Efficacy 
The study objective of assessing the long-term efficacy of Nuwiq® will be evaluated using 
the following outcome parameters: 
• Prophylactic treatment 
– Annualised rate of breakthrough bleeding episodes (BEs) 
– FVIII consumption data 
 Number of EDs 
 Number of infusions (needed to treat a breakthrough BE) 
 FVIII IU/kg per infusion, per BE, per month, per year 
• On-demand treatment of bleeding episodes 
– Annualised rate of bleeding episodes (BEs) 
– FVIII consumption data 
 Number of EDs 
 Number of infusions needed to treat a BE 
 FVIII IU/kg per infusion, per BE, per month, per year 
– Assessment of the effectiveness of treatment at the end of a BE by the patient 
• Surgical prophylaxis 
– Details of the surgical intervention 
– FVIII consumption data 
– Details on concomitantly administered products, including any blood or blood 
product transfusions or colloidal plasma substitutes (such as albumin, 
hydroxyl starch, dextran, and gelatine) 
– Estimated and actual perioperative and postoperative bleeding volumes 
– Overall assessment of the effectiveness of surgical prophylaxis by the treating 
physicians 
 
Patient characteristics 
• Age, sex, ethnic origin 
• Medical history (including age at first treatment with FVIII) 
• FVIII inhibitor history 
• FVIII genotype 
• Family history of haemophilia 
• HIV status 
• Comorbidities that may significantly impact on blood coagulation/immune reaction 
• Previous medication(s) and FVIII treatment regimen(s) 
• Concomitant medication(s) and current FVIII treatment regimen 

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Optional PK assessment 
An optional PK assessment to determine prophylactic treatment regimen of a patient may 
be conducted at the discretion of the treating physician. The dose and dosing interval will 
be calculated in the frame of this non-interventional study either based on an individual 
PK with 6 - 10 time points or on a population-based PK using 1-3 time points (including 
the possibility to combine 1 to 2 time-points from different infusions of Nuwiq® at the 
dose patient is routinely treated with). The population-PK option uses WAPPS (wapps- 
hemo.org) to model collected FVIII activity data from the withdrawn time-points and to 
provide an estimation of the patient PK. WAPPS is developed and provided online by 
McMaster University (Hamilton, Ontario Canada). Patients will consent to participate in 
this optional assessment. 
Optional Quality of Life assessment (SF-36 Health Survey) 
Patient’s health-related quality of life may be measured using SF-36 health survey. This 
assessment will be performed only in countries where it is not considered interventional. 
Patients will consent prior to receiving the questionnaire. SF-36 health survey will be 
done at screening, every 6 months after enrolment and at completion visit. 
Duration of Treatment: Patients from pre-authorisation studies can be followed up to at 
least 100 EDs, newly enrolled patients have to be treated and followed for at least 100 
EDs. The overall duration of this post-authorisation study will be approximately 4 years. 
The study will be completed once 200 patients have been treated and followed up for at 
least 100 EDs, provided that: 
• Age distribution is balanced (approx. 60 patients < 12 years of age; at least 10 
patients aged between 14–18 years) 
• At least 100 patients have severe haemophilia A (FVIII:C <1%) 
• The proportion of ITI patients does not exceed 25% of the entire cohort 
Data Analysis: Descriptive statistics 
Milestones: 
Start of data collection 
End of data collection 
Study progress report 
Final study report 
Q1 2016 
Q2 2019 
2 years after marketing authorisation 
Q1 2020 

 
SigurdKnaub,PhD 
/_ 
f .@  J O. 
A-1--- 
._. 
Vice President CR&D Haematology 
Signature 
Date 
Octapharma AG 
Seidenstrasse 2 
CH-8853 Lachen 
Study Protocol 
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PROTOCOL   SIGNATURES 
 
Signature of the Sponsor's Representative 
 
 
This study is to be conducted in compliance with this protocol 
and applicable regulatory requirements. 

 
Gita Pezeshki, PhD 
·  . to. 11-
Author of the Protocol 
Date 
Clinical Trial Manager - Haematology 
Octapharma USA Inc. 
121River Street, Suite 1201 
Hoboken, New Jersey 07030 
/ 
 
Study Protocol 
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Signature of the Author of the Protocol & Clinical Project Manager 
 
 
This study is to be conducted in compliance with this protocol 
and applicable regulatory requirements. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 

 
Dr Balazs Toth 
Qualified Person Pharmacovigilance 
Signature 
Date 
Drug Safety Physician 
Octapharma Pharmazeutika 
Produktionsges.m.b.H 
Oberlaaer Strasse 235 
A-1100 Vienna 
Austria 
Study Protocol 
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Signature of the Qualified Person Pharmacovigilance/Drug Safety Physician 
 
 
This study is to be conducted in compliance with this protocol 
and applicable regulatory requirements. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3 

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TABLE OF CONTENTS 
STUDY OUTLINE ............................................................................................................. II 
PROTOCOL SIGNATURES ............................................................................................. 1 
1 
MILESTONES ............................................................................................................. 8 
2 
RATIONALE AND BACKGROUND ....................................................................... 8 
2.1 
TREATMENT OF HAEMOPHILIA A ......................................................................... 8 
2.2 
PRODUCT DESCRIPTION .............................................................................................................. 8 
2.2.1 
Results from Clinical Studies for Market Authorisation ................................... 9 
2.2.2 
Therapeutic Indications .................................................................................... 9 
2.2.3 
Benefit-Risk Statement ...................................................................................... 9 
2.3 
STUDY RATIONALE ................................................................................................................... 11 
3 
STUDY OBJECTIVES AND OUTCOME PARAMETERS ................................ 12 
3.1 
STUDY OBJECTIVES .................................................................................................................. 12 
3.2 
OUTCOME PARAMETERS ......................................................................................................... 12 
3.2.1 
Outcome parameters for assessing the long-term immunogenicity and 
safety of Human-cl rhFVIII ............................................................................. 12 
3.2.2 
Outcome parameters for assessing the long-term efficacy of Human-cl 
rhFVIII ............................................................................................................ 13 
3.2.3 
Patient characteristics .................................................................................... 14 
4 
STUDY DESIGN ....................................................................................................... 14 
5 
STUDY POPULATION ............................................................................................ 14 
5.1 
INCLUSION CRITERIA ............................................................................................................... 15 
5.2 
EXCLUSION CRITERIA .............................................................................................................. 15 
5.3 
WITHDRAWAL OF PATIENTS .................................................................................................. 15 
6 
MEDICINAL PRODUCT ........................................................................................ 16 
6.1 
CHARACTERISATION OF MEDICINAL PRODUCT .............................................................. 16 
6.2 
PACKAGING ................................................................................................................................. 16 
6.3 
CONDITIONS FOR STORAGE AND USE ................................................................................. 16 
6.4 
METHOD OF ADMINISTRATION ............................................................................................. 17 
6.5 
TREATMENT REGIMEN, DOSE, AND DOSING INTERVAL ............................................... 17 
6.6 
CONCOMITANT THERAPY ....................................................................................................... 18 
6.7 
TREATMENT COMPLIANCE ..................................................................................................... 19 
7 
STUDY CONDUCT .................................................................................................. 19 
7.1 
FLOW CHARTS OF ASSESSMENTS ......................................................................................... 20 
7.2 
DATA RECORDED DURING EACH VISIT ............................................................................. 21 
7.2.1 
Screening Visit ................................................................................................ 21 
7.2.2 
Follow-up Visits and Study Completion Visit ................................................. 22 
7.2.3 
Optional PK assessment for individual prophylaxis regimen ......................... 22 

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7.3 
PATIENT CODES ......................................................................................................................... 23 
7.4 
TREATMENT DIARIES ............................................................................................................... 23 
7.5 
STUDY DURATION ..................................................................................................................... 23 
7.5.1 
Planned Duration of the Study ........................................................................ 23 
7.5.2 
Planned Duration by Patient ........................................................................... 24 
7.6 
OPTIONAL QUALITY OF LIFE ASSESSMENT (SF-36 HEALTH SURVEY) ................ 24 
8 
ASSESSMENTS AND METHODS ......................................................................... 25 
8.1 
EFFECTIVENESS ASSESSMENTS ............................................................................................. 25 
8.1.1 
Prophylactic Treatment ................................................................................... 25 
8.1.2 
Bleeding Episodes (BEs) ................................................................................. 25 
8.1.3 
Surgical Prophylaxis ....................................................................................... 26 
8.2 
SAFETY ASSESSMENTS ............................................................................................................ 28 
8.2.1 
Definition of (serious) adverse drug reaction and other safety 
information ...................................................................................................... 28 
8.2.2 
Other relevant drug safety information ........................................................... 29 
8.2.3 
Specifically monitored ADRs .......................................................................... 30 
8.2.4 
Reporting of adverse drug reactions (ADRs) and other safety 
information ...................................................................................................... 31 
8.3 
OPTIONAL PK EVALUATION ...................................................................................................... 32 
8.4 
LABORATORY ASSESSMENTS ................................................................................................ 33 
8.4.1 
General Laboratory Assessments .................................................................... 33 
8.4.2 
Immunogenicity ............................................................................................... 33 
9 
DATA MANAGEMENT ........................................................................................... 34 
9.1 
DOCUMENTATION OF DATA ................................................................................................... 34 
9.2 
RESPONSIBILITIES ...................................................................................................................... 34 
10 DATA ANALYSIS..................................................................................................... 35 
10.1 DETERMINATION OF SAMPLE SIZE ....................................................................................... 35 
10.2 ANALYSIS PLAN ......................................................................................................................... 35 
10.3 PROGRESS STUDY REPORTS ................................................................................................... 35 
10.4 OPTIONAL PK EVALUATION ...................................................................................................... 35 
11 ETHICAL AND REGULATORY ASPECTS ......................................................... 36 
11.1 ETHICAL AND REGULATORY FRAMEWORK....................................................................... 36 
11.2 SUBMISSION OF STUDY DOCUMENTS TO IEC AND/OR REGULATORY 
AUTHORITY ................................................................................................................................. 36 
11.3 PATIENT INFORMATION AND INFORMED CONSENT ........................................................ 36 
11.4 PROTOCOL AMENDMENTS ...................................................................................................... 37 
11.5 CONFIDENTIALITY OF PATIENT DATA ................................................................................ 37 
12 REPORTING AND PUBLICATION ...................................................................... 37 
12.1 FINAL STUDY REPORT ............................................................................................................. 37 
12.2 PUBLICATION POLICY .............................................................................................................. 37 

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13 REFERENCES .......................................................................................................... 38 
APPENDIX 
APPENDIX 1: CASE SAFETY REPORT FORM ......................................................................................... 39 
CASE SAFETY REPORT FORM - ANNEX 1: FVIII INHIBITOR DEVELOPMENT .................... 43 
CASE SAFETY REPORT FORM - ANNEX 2: 
HYPERSENSITIVITY/ANAPHYLACTIC REACTIONS .......................................................... 47 
CASE SAFETY REPORT FORM - ANNEX 3: THROMBOEMBOLIC EVENTS ............................. 50 

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LIST OF ABBREVIATIONS 
 
 
ADR 
adverse drug reaction 
AE 
adverse event 
AUC 
area under the curve 
BE 
bleeding episode 
BU 
Bethesda Unit 
CI 
confidence interval 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
ED 
exposure day 
EMA 
European Medicines Agency 
FVIII 
factor VIII 
FVIII:C 
FVIII coagulant activity 
GCP 
Good Clinical Practice 
HIV 
human immunodeficiency virus 
IEC 
Independent Ethics Committee 
IMP 
investigational medicinal product 
ITI 
immune tolerance induction 
IU 
International Unit 
PK 
pharmacokinetics 
PTP 
previously treated patient 
QoL 
Quality of life 
rFVIII 
recombinant FVIII 
rhFVIII 
recombinant human factor VIII 
SADR 
serious adverse drug reaction 
SAE 
serious adverse event 
SF-36 
Short Form Health Survey 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SPC 
Summary of Product Characteristics 
VWF 
von Willebrand factor 
VWFAg 
von Willebrand factor antigen 
WFI 
water for injections 

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1 MILESTONES 
 
 
Milestone 
Planned date 
Start of data collection 
Q1 2016 
End of data collection 
Q2 2019 
Study progress report 
2 years after marketing authorisation 
Final study report 
Q1 2020 
 
2 RATIONALE AND BACKGROUND 
 
2.1 Treatment of Haemophilia A 
 
The optimal treatment of haemophilia A is replacement of FVIII using FVIII concentrate 
either obtained by fractionation of human plasma or manufactured by recombinant DNA 
technology. The transmission of viruses by plasma-derived coagulation factor concentrates 
in the 1970s and early 1980s sparked increased interest in producing FVIII products by 
recombinant DNA technology, and since the early 1990s, recombinant FVIII products have 
been commercially available [1]. 
Thus far, commercial unmodified recombinant FVIII (rFVIII) concentrates have been 
expressed in hamster cells. However, products derived from hamster cells may contain 
contaminants of non-human origin that may give rise to immune reactions. Also, the post- 
translational modifications of these proteins expressed in hamster cells are not identical to 
those of native human FVIII, potentially leading to immunogenic reactions and the 
development of inhibitors against rFVIII [2, 3]. 
Octapharma has developed Nuwiq® (simoctocog alfa), a fourth-generation recombinant 
human factor VIII (rhFVIII) concentrate for the control and prevention of bleeding 
episodes (BEs) and for surgical prophylaxis in patients with haemophilia A. In Europe, 
marketing authorisation for Nuwiq® was obtained through the centralised procedure on 22 
July 2014.. 
 
2.2 Product Description 
 
Nuwiq® is a B-domain deleted rhFVIII produced in human embryonic kidney cells (HEK 
293F) [4]. Nuwiq® has been shown to be highly pure, with host-cell protein and DNA 
traces comparable to, or lower than, other marketed rFVIII products [5]. Nuwiq® has a high 
specific FVIII activity and characteristics similar to full-length rFVIII products. Nuwiq® 
displayed a higher binding capacity with von Willebrand factor (VWF) than comparator 

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products, thus minimizing circulating unbound FVIII and further reducing the potential risk 
of inhibitor development [5]. 
For rhFVIII, glycosylation and sulfation are vital for functionality and VWF binding 
affinity. Nuwiq® has been shown to be sulfated and glycosylated in ways comparable to 
human-plasma-derived FVIII. Most importantly, Nuwiq® is devoid of the antigenic 
Neu5Gc or alpha-Gal epitopes observed in Chinese Hamster Ovary- and Baby Hamster 
Kidney-derived rFVIII products. Both the avoidance of non-human glycan structures and 
the achievement of complete sulfation are proposed to lower the intrinsic immunogenicity 
of Nuwiq® compared with current rFVIII products [6]. 
For more detailed product information, refer to Section 6 and the Summary of Product 
Characteristics (SPC) of Human-cl rhFVIII. 
 
2.2.1 Results from Clinical Studies for Market Authorisation 
The clinical study program for market authorisation was developed with consideration of 
both EU and USA guidelines. Final results are available from 5 studies in a total of 135 
previously treated patients. Nuwiq® was bioequivalent to the licensed full-length rFVIII 
Kogenate FS, with the ratio of the geometric means [90% CI] for AUCnorm (Nuwiq® 
relative to Kogenate FS) within the accepted range for bioequivalence of 0.8 to 1.25, and it 
was safe and efficacious in preventing and treating BEs. In particular, no inhibitor was 
detected, and no unexpected adverse event (AE) or related SAEs were reported in any of 
the studies. 
 
2.2.2 Therapeutic Indications 
Nuwiq® is indicated for the treatment and prophylaxis of bleeding in paediatric and adult 
patients with haemophilia A (congenital factor VIII deficiency). 
 
2.2.3 Benefit-Risk Statement 
Based on the available clinical evidence, Nuwiq® is safe and effective in the prevention and 
treatment of BEs and during surgical prophylaxis in patients with inherited FVIII 
deficiency. 

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Summary of safety profile 
• Hypersensitivity or allergic reactions (which may include angioedema, burning and 
stinging at the infusion site, chills, flushing, generalised urticaria, headache, hives, 
hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, 
tingling, vomiting, wheezing) have rarely been observed with FVIII preparations and 
may in some cases progress to severe anaphylaxis (including shock). 
• Patients with haemophilia A may develop neutralising antibodies (inhibitors) to factor 
VIII. If such inhibitors occur, the condition will manifest as an insufficient clinical 
response. In such cases, the patient should contact the study site. 
 
Tabulation of ADRs seen in the clinical development program of Human-cl rhFVIII 
In clinical studies with Nuwiq® in previously treated paediatric (2 to 11 years, n = 58), 
adolescent (12 to 17 years, n = 3) and adult patients (n = 74) with severe haemophilia A, a 
total of 8 adverse drug reactions (ADRs) (6 in adults, 2 in children) were reported in 5 
patients (3 adults, 2 children). 
Table 1 is sorted by MedDRA System Organ Class (SOC) and Preferred Term (PT). 
 
Table 1 
Occurrence of adverse drug reactions (ADRs, n=8) in clinical studies with Nuwiq® 
in 135 previously treated patients with severe haemophilia A 
 
MedDRA Standard System Organ Class 
Adverse reaction (Preferred Term) 
Frequency* 
Nervous system disorders 
Parasthesia 
Headache 
Uncommon 
General disorders and administration site 
conditions 
Injection site inflammation 
Injection site pain 
Uncommon 
Investigations 
Non-neutralising anti factor VIII 
antibody positive 
Uncommon 
Musculoskeletal and connective tissue disorders 
Back pain 
Uncommon 
Ear and labyrinth disorders 
Vertigo 
Uncommon 
Gastrointestinal disorders 
Dry mouth 
Uncommon 
* All ADRs occurred only once. With a total number of studied patients of 135, the frequency classification of 
an ADR occurring only once cannot be less than ‘uncommon.’ 
Frequencies have been evaluated according to the following convention: very common (≥1/10); common 
(≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not 
known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are 
presented in order of decreasing seriousness. 

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Description of selected ADRs 
One case of non-neutralizing anti-factor VIII antibody was detected in one adult patient 
(see Table 1). The sample was tested by the central laboratory at eight dilutions. The result 
was positive only at dilution factor 1, and the antibody titre was very low. Inhibitory 
activity, as measured by the modified Bethesda assay, was not detected in this patient. 
Clinical efficacy and in-vivo recovery of Nuwiq® was not affected in this patient. 
 
Paediatric population 
The frequency, type, and severity of ADRs in children are assumed to be the same as in 
adults. 
 
2.3 Study Rationale 
 
The number of patients enrolled in the pre-authorisation clinical studies with Nuwiq® was 
135 (see Section 2.2.1), which is considered adequate to provide relevant information on 
general safety aspects and to demonstrate the efficacy of Nuwiq® in terms of its ability to 
restore factor VIII levels and stop or prevent bleeding. However, data from pre- 
authorisation studies are insufficient to estimate all aspects of therapy with FVIII products, 
especially with respect to immunogenicity (EMA/CHMP/BPWP/144533/2009). 
Therefore, to estimate the likelihood of rare side effects, such as the occurrence of FVIII 
inhibitors, and to bridge between the outcome from clinical trials and long-term clinical 
use, the purpose of this study is to assess the long-term immunogenicity, safety, and 
efficacy of Nuwiq® in patients with haemophilia A treated in routine clinical practice. 
Specifically, the study is designed to meet the requirements for post-authorisation studies as 
outlined in ‘Guideline on the clinical investigation of recombinant and human plasma- 
derived factor VIII products’ by the European Medicines Agency (EMA), 
EMA/CHMP/BPWP/144533/2009. 

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3 STUDY OBJECTIVES AND OUTCOME PARAMETERS 
 
3.1 Study Objectives 
 
The overall objective of this study is to collect clinical data in addition to those obtained 
during the clinical study program and to ensure the consistency, in the long-term, between 
the outcome from pre-authorisation clinical studies (in 135 previously treated paediatric and 
adult patients) and routine clinical practice. 
In addition to general product safety and efficacy, the focus of this study will be on 
immunogenicity, particularly on inhibitor development 
(EMA/CHMP/BPWP/144533/2009). 
The objectives of this study are: 
• To assess the long-term immunogenicity and safety of Nuwiq® in treating or 
preventing bleeding episodes (BEs) in patients with haemophilia A 
• To assess the long-term efficacy of Nuwiq® in treating or preventing BEs in patients 
with haemophilia A 
The study will be performed in countries from across the EU and other countries where 
Nuwiq® is intended to be marketed. 
 
3.2 Outcome Parameters 
 
3.2.1 Outcome parameters for assessing the long-term immunogenicity and 
safety of Human-cl rhFVIII 
The study objective of assessing the long-term immunogenicity and safety of Nuwiq® in 
treating or preventing BEs in patients with haemophilia A will be evaluated using the 
following outcome parameters: 
• Incidence of FVIII inhibitors, with the diagnosis 
– based on clinical observations and 
– confirmed by FVIII inhibitor testing in the laboratory 
• Incidence of adverse drug reactions (ADRs), including hypersensitivity reactions 

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3.2.2 Outcome parameters for assessing the long-term efficacy of Human-cl 
rhFVIII 
The study objective of assessing the long-term efficacy of Nuwiq® in treating or preventing 
BEs in patients with haemophilia A will be evaluated using the following outcome 
parameters: 
• Prophylactic treatment 
– Annualised rate of breakthrough BEs 
– FVIII consumption data 
 Number of EDs 
 Number of infusions (needed to treat a breakthrough BE) 
 FVIII IU/kg per infusion, per BE, per month, per year 
• On-demand treatment of bleeding episodes 
– Annualised rate of BEs 
– FVIII consumption data 
 Number of EDs 
 Number of infusions needed to treat a BE 
 FVIII IU/kg per infusion, per BE, per month, per year 
– Assessment of the effectiveness of treatment at the end of a BE by the patient 
(see Section 8.1.2) 
• Surgical prophylaxis 
– Details of the surgical intervention (see Section 8.1.3) 
– FVIII consumption data (see Section 8.1.3) 
– Details on concomitantly administered products, including any blood or blood 
product transfusions or colloidal plasma substitutes (such as albumin, hydroxyl 
starch, dextran, or gelatine) 
– Estimated and actual perioperative and postoperative bleeding volumes 
– Overall assessment of the effectiveness of surgical prophylaxis by the treating 
physicians (see Section 8.1.3) 
• Optional PK Analysis 
– FVIII consumption data following PK-based changes in prophylaxis regimen 
(see Section 8.3) 
– Annualised rate of BEs following PK-based changes in prophylaxis regimen 
 
• Optional quality of life (QoL) assessment 
– Health-related QoL(SF-36) in haemophilia A patients using Nuwiq® 
– Health-related QoL (SF-36) following PK-based changes in prophylaxis 
regimen 

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3.2.3 Patient characteristics 
For patient characteristics to be recorded, refer to Section 7.2.1. 
 
4 STUDY DESIGN 
This is a prospective, multinational, non-interventional post-authorisation study designed to 
assess the long-term immunogenicity, safety, and efficacy of Nuwiq® in patients with 
haemophilia A treated in routine clinical practice. 
The study design complies with Guideline EMA/CHMP/BPWP/144533/2009. In brief, 
200 male patients of any age with haemophilia (FVIII:C ≤ 2%) will be treated and followed 
for at least 100 EDs. Of the 200 enrolled patients, at least 100 patients should have severe 
haemophilia A (FVIII:C < 1%). The overall duration of this study will be approximately 4 
years. The testing schedule for FVIII inhibitors as predefined in Guideline 
EMA/CHMP/BPWP/144533/2009 is given in Table 3. 
 
5 STUDY POPULATION 
According to Guideline EMA/CHMP/BPWP/144533/2009, the number of patients typically 
needed in a post-authorisation study with FVIII to cover immunogenicity aspects is 200. In 
a cohort of 200 patients and assuming an inhibitor incidence of 1.5% or higher, there is at 
least 95% probability to observe antibodies in one or more patients. 
An EMA expert meeting on FVIII products and inhibitor development agreed that the risk 
of inhibitor formation related to an individual product should be evaluated in previously 
treated patients (PTPs), because patients with a high degree of previous exposure should be 
immunotolerant to FVIII and are considered to be a better suited study population 
(EMA/CHMP/BPWP/144533/2009). 
• Therefore, the goal is to collect data on 200 previously treated male patients of any 
age with haemophilia (FVIII:C ≤ 2%). Data from patients having participated in pre- 
authorisation studies with Nuwiq® and data from patients starting treatment with 
Nuwiq® in additional clinical Good Clinical Practice (GCP) studies may be combined 
with data from patients agreeing to participate in this non-interventional study to 
count towards the required 200 patients (see Section 7.5.2). Patients from pre- 
authorisation studies can be followed up to at least 100 EDs. Newly enrolled 
patients have to be treated and followed for at least 100 EDs. 
• Of the 200 enrolled patients, at least 100 patients should have severe haemophilia A 
(FVIII:C < 1%). 
• Because the results of a clinical study in children was evaluated as part of the 
marketing authorisation procedure, patients of every age group are eligible to be 
included in this study. The age distribution of enrolled patients should be evenly 

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balanced. Thus, of the 200 enrolled patients, approx. 60 patients should be < 12 years 
of age. Also, at least 10 patients should be aged between 14–18 years. 
• Patients with severe haemophilia A after successful immune tolerance induction (ITI) 
can also be included; the proportion of these ITI patients should not exceed 25% of 
the entire cohort. 
 
5.1 Inclusion Criteria 
 
Patients who meet all of the following criteria are eligible for the study: 
(a) Haemophilia A (FVIII:C ≤ 2%) based on medical history; at least 100 patients 
should have severe haemophilia A (FVIII:C < 1%) 
(b) Male patients of any age 
(c) Previous treatment with a FVIII concentrate for more than 150 EDs 
(d) Availability of detailed documentation (patient diary, log book, etc.) covering either 
the last 50 EDs or the last 2 years per patient to confirm treatment modality (i.e., 
prophylaxis, on-demand, recent surgery, or immune tolerance induction) 
(e) Inhibitor negative (< 0.6 BU) at study entry as confirmed by a recovery test with 
previous FVIII product and inhibitor test in a central laboratory 
(f) Immunocompetence (CD4+ count > 200/µL), HIV-negative, or having a viral load 
< 200 particles/µL or < 400,000 copies/mL 
(g) Decision to prescribe Nuwiq® before enrolment into the study 
(h) Written informed consent by the patient or the patient’s parent or legal guardian 
 
5.2 Exclusion Criteria 
 
Patients treated with any investigational medicinal product (IMP) except FVIII IMP within 
30 days prior to the Screening Visit or patients planning to undergo treatment with any IMP 
other than Nuwiq® are not eligible for enrolment into the study. 
 
5.3 Withdrawal of Patients 
 
Patients have the right to withdraw from the study at any time for any reason without the 
need to justify their decision. The treating physician also has the right to withdraw patients 
in case of ADRs or for other reasons. 
In case of any withdrawal after study entry, the treating physician will make every possible 
effort to collect any required data and document the reason(s) for withdrawal in the CRF. If 
the reason for withdrawal of a patient is an ADR, the main specific event or laboratory test 
will be recorded in the CRF, and the treating physician will make every possible effort to 
clearly document the outcome. 

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6 
MEDICINAL PRODUCT 
 
6.1 Characterisation of Medicinal Product 
 
Nuwiq® is formulated as a powder and solvent for solution for injection. Each vial of 
Nuwiq® contains either 250, 500, 1000, 2000, 2500, 3000 and 4000international units (IU) 
of freeze-dried simoctocog alfa concentrate, each to be reconstituted in 2.5 mL of sterilised 
water for injections (WFI). Complete product information is given in the SPC of Nuwiq®. 
 
6.2 Packaging 
 
In this non-interventional study, commercially available Nuwiq® will be used. 
Nuwiq® is filled and lyophilised in glass vials. The solvent for reconstitution of the drug 
product, 2.5 mL sterilised WFI, is provided in prefilled syringes. 
Each drug product vial is provided with a kit containing: 
• One sterile vial adapter for reconstitution 
• One butterfly needle 
• Two alcohol swabs 
Only the provided injection sets should be used because treatment failure can occur as a 
consequence of human coagulation factor VIII adsorption to the internal surfaces of some 
injection equipment. 
 
6.3 Conditions for Storage and Use 
 
Nuwiq® has a shelf life of 24 months at 2°C to 8°C. For further details on specific storage 
conditions, please refer to your country specific package insert. After reconstitution, 
chemical and physical in-use stability has been demonstrated for 24 hours when stored at 
room temperature. From a microbiological point of view, the product should be used 
immediately or within 3 hours after reconstitution. Keep the reconstituted solution at room 
temperature. Do not refrigerate after reconstitution. If not used immediately, in-use storage 
times and conditions prior to use are the responsibility of the user. 
The powder should only be reconstituted with the supplied solvent (2.5 mL water for 
injections) using the supplied injection set. The vial should be gently rotated until all 
powder is dissolved. After reconstitution, the solution should be drawn back into the 
syringe. 
 
Reconstituted medicinal product should be visually inspected for particulate matter and 
discoloration prior to administration. The reconstituted medicinal product is a clear, 

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colourless solution, free from foreign particles and has a pH of 6.5 to 7.5. Do not use 
solutions that are cloudy or have deposits. 
 
6.4 Method of Administration 
 
Nuwiq® should be administered by intravenous bolus injection. The infusion rate should 
not exceed 4 mL per minute. 
The reconstituted solution should be used immediately or within 3 hours after 
reconstitution. Also, the reconstituted solution should be kept at room temperature. 
The solution is normally clear or slightly opalescent and colourless. Solutions which are 
cloudy or have deposits must not be used. For further details please refer to your country 
specific package insert. 
 
6.5 Treatment Regimen, Dose, and Dosing Interval 
 
The treatment regimen (i.e., prophylactic treatment, on-demand treatment, ITI, or surgical 
prophylaxis) as well as the doses, dosing intervals, or dose adjustments will be determined 
at the discretion of the treating physician and should be recorded in the CRF. If deemed 
appropriate by the treating physician for the respective patient, options for individual 
adjustment of the prophylaxis regimen may be calculated from the results of a PK 
assessment. 
 
Prophylactic treatment 
For long-term prophylaxis against bleeding in patients with severe haemophilia A, the usual 
doses are 20 to 40 IU of factor VIII per kg body weight at intervals of 2 to 3 days. In some 
cases, especially in younger patients, shorter dosage intervals or higher doses may be 
necessary. For further details please refer to your country specific package insert. 
 
On-demand treatment of bleeding episodes 
The following table can be used to guide dosing in bleeding episodes. For further details 
please refer to your country specific package insert. 
 
 
Degree of haemorrhage 
Factor VIII level 
required (%) (IU/dL) 
Frequency of doses (hours) and 
duration of therapy (days) 
Early haemarthrosis, muscle 
bleeding, or oral bleeding 
20–40 
Repeat every 12–24 hours. At least 1 
day, until the bleeding episode as 
indicated by pain is resolved or healing 
is achieved. 

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Degree of haemorrhage 
Factor VIII level 
required (%) (IU/dL) 
Frequency of doses (hours) and 
duration of therapy (days) 
More extensive haemarthrosis, 
muscle bleeding, or haematoma 
30–60 
Repeat infusion every 12–24 hours for 3 
to 4 days or more until pain and acute 
disability are resolved. 
Life threatening haemorrhages 
60–100 
Repeat infusion every 8 to 24 hours until 
threat is resolved. 
 
Surgical prophylaxis 
The following table can be used to guide dosing in surgery. For further details please refer to 
your country specific package insert. 
 
 
Type of surgical procedure 
Factor VIII level required 
(%) (IU/dL) 
Frequency of doses (hours) and 
duration of therapy (days) 
Minor surgery 
including tooth extraction 
30–60 
Every 24 hours, at least 1 day, until 
healing is achieved. 
Major surgery 
80–100 
(pre- and postoperative) 
Repeat infusion every 8–24 hours until 
adequate wound healing, then therapy 
for at least another 7 days to maintain a 
factor VIII activity of 30% to 60% (IU/dL). 
 
Optional individual PK evaluation 
The recommended dose for individual PK-injection is 60±5 IU/kg. 
The dose for population PK Nuwiq® is the dose the patient is routinely treated (or actual 
prophylaxis infusion). 
 
6.6 Concomitant Therapy 
 
Concomitant therapies are at the discretion of the treating physician. 
Patients should be asked to keep their treating physicians informed of any concomitant 
medications, FVIII products other than Nuwiq® (including the reason for using an 
alternative FVIII product), and significant non-drug therapies (including physical therapy 
and blood transfusions) they may be receiving and/or to record them in their treatment 
diaries (see Section 7.4). Any concomitant therapies will be recorded in the CRF. 
In patients undergoing surgical prophylaxis, details on concomitantly administered 
products, including any blood or blood product transfusions or colloidal plasma substitutes 
(such as albumin, hydroxyl starch, dextran, or gelatine) will be documented. 

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6.7 Treatment Compliance 
 
There will not be any specific procedures to monitor the patients’ compliance with 
treatment. Compliance will be monitored by the treating physician as part of routine clinical 
practice and supported by the information in the treatment diary (see Section 7.4). 
The treating physician should promote compliance by instructing the patient (or the 
patient’s parent or legal guardian) to administer Nuwiq® exactly as prescribed and by 
emphasising that compliance is necessary for the patient’s safety. The patient should be 
asked to contact his treating physician if he is unable, for any reason, to administer Nuwiq® 
as prescribed. 
 
7 STUDY CONDUCT 
Patient eligibility for enrolment into the study will be determined at the Screening Visit, 
during which demographic and baseline data will be recorded (Table 2). 
Before patient inclusion, there should be no clinical suspicion of FVIII inhibitors, and a 
recovery and inhibitor test in a central laboratory is recommended to confirm that the 
patient is negative at study entry. An inhibitor test which is not negative should be 
confirmed by testing a second separately drawn sample in central laboratory. The 
recommended testing schedule for FVIII inhibitors is predefined in Guideline 
EMA/CHMP/BPWP/144533/2009 and is presented in Table 3. 
An optional PK assessment to determine individualized or population based prophylactic 
treatment regimen of a patient may be conducted at the discretion of the treating physician. 
The dose and dosing interval will be calculated in the frame of this non-interventional study 
either based on an individual PK with 6 - 10 time points or a population PK with 1- 3 time 
points – (see Section 8.3 and Table 5). 
Treatment regimen of a patient may be conducted at the discretion of the treating physician. 
The individual dose and dosing interval will be calculated in the frame of this non- 
interventional study. 
Patient diaries will be evaluated for the total number of exposures per year and the mean 
dose per kg per patient/year (consumption). The intended treatment regimen for every 
patient at study entry and the reason for each ED will also be documented. 
In case of bleeding, the particulars of the event will be documented, along with drug 
consumption data and the severity and treatment outcome assessed by both the clinician and 
the patient. 
In case of surgery, details of the intervention will be collected, such as type of surgery 
(planned or emergency), mode of administration, drug consumption, and any complications 
that may occur. 

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Any adverse drug reactions (ADRs) will also be monitored. 
The frequency of clinical and laboratory monitoring throughout the study will be at the 
discretion of the treating physician based on clinical requirements. Therefore, study visits 
will generally coincide with routine follow-up visits or with any emergency visits that may 
become necessary. The data that should be recorded at each Follow-up Visit until study 
completion are summarized in Table 2. 
 
7.1 Flow Charts of Assessments 
 
The flow chart of recommended assessments is given in Table 2, and the flow chart of 
inhibitor testing as recommended by Guideline EMA/CHMP/BPWP/144533/2009 is given 
in Table 3. 
Table 2 Flow Chart of Assessments 
 
Data to be recorded 
Screening Visit 
Follow-up and Study 
Completion Visits 
Informed consent 
X 
Eligibility criteria* (see also Table 3) 
X 
Demographics 
X 
Medical history 
X 
Bleeding history in the previous 6 months 
X 
FVIII inhibitor history 
X 
FVIII genotype 
X 
Family history of haemophilia (including FVIII inhibitor 
history) 
X 
Body weight 
X 
Body height 
X 
Immunocompetence and viral status* 
X 
Comorbidities2 
X 
X 
Previous medication(s) 
X 
Concomitant medication(s) 
X 
X 
Previous FVIII treatment regimen(s) 
X 
Current FVIII treatment regimen 
X 
X 
Completion of SF-36† 
X 
X‡ 
Documentation of occupational physical demand 
X 
PK analysis § 
Any time during the study (Table 5) 
Bleeding episode data 
throughout the study 
Surgery data 
throughout the study 
Monitoring of SADRs and ADRs 
throughout the study 
FVIII inhibitor status 
see Table 3 
* Patients must be immunocompetent (CD4 lymphocytes >200/µL), HIV-negative, or have a viral load 
< 200 particles/µL or < 400 000 copies/mL). 
† For patients 14 years of age and older who have consented for the optional assessment 
‡ At follow up visits every 6 months after screening and completion visit 
§ Optional, if deemed beneficial by treating physician and after patient’s consent 

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The data that should be recorded during each patient visit are summarised in Section 7.2. 
 
Table 3 
Flow Chart of Inhibitor Testing as Recommended by Guideline 
EMA/CHMP/BPWP/144533/2009 
 
Assessments 
Previous FVIII 
product2 
Human-cl rhFVIII5 
ED 1 
ED 10–15 
ED 50–75 
ED ̴100 
Inhibitor1 
x3 
x4 
x 
x 
x 
Recovery 
x3 
x 
x 
x 
x 
1 After washout period; storage of backup sample is recommended. 
Inhibitor tests should be performed when the plasma factor VIII level has reached a pre-substitution nadir 
(documentation for the last infusion should be provided). 
Inhibitor re-testing using a second separately drawn sample as confirmatory measurement should be 
performed in the central laboratory. 
2 New patients, i.e., patients not recruited for pre-authorisation studies 
3 According to Guideline EMA/CHMP/BPWP/144533/2009, there should not be any clinical suspicion of 
inhibitors before inclusion into the study, and a recovery and inhibitor test in a central laboratory should 
confirm that the patient is inhibitor-negative at study entry. 
4 Baseline inhibitor testing before infusion of Nuwiq® at a central laboratory 
5 In addition to the tests specified in the table, testing should be carried out if there is any suspicion of 
inhibitors. 
 
Details on the laboratory testing for FVIII inhibitors are given in Section 8.3.2. 
 
7.2 Data Recorded During Each Visit 
 
7.2.1 Screening Visit 
The following data will be recorded: 
• Informed consent 
• Eligibility criteria 
• Demographic data 
– Age 
– Ethnic origin 
• Medical history (including age at first treatment with FVIII) 
• Bleeding history in the previous 6 months (frequency of BEs) 
• FVIII inhibitor history 
• FVIII genotype 
• Family history of haemophilia (including FVIII inhibitor history) 
• Body weight 
• Body height 
• Immunocompetence (CD4+ count > 200/µL), HIV negative, or having a viral load 
< 200 particles/µL or < 400,000 copies/mL 
• Viral status 

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• Comorbidities that may significantly impact on blood coagulation or immune reaction 
• Previous medication(s) 
• Concomitant medication(s) 
• Previous FVIII treatment regimen(s) based on treatment diary covering either the last 
50 EDs or the last 2 years per patient to confirm treatment modality (e.g., 
prophylaxis, on-demand, recent surgery, immune tolerance induction) 
– Doses and dosing frequency 
– Name of previous FVIII product(s) 
• Current FVIII treatment regimen (e.g., prophylaxis on-demand) 
– Doses and dosing frequency 
– Name of current FVIII product 
• Completion of Short Form Health Survey (SF-36): as the study is non-interventional 
completion of this form is optional and only patients who consent to participate in 
this assessment will be asked to complete this form. 
• Documentation of occupational physical demand 
Eligible patients agreeing to enter the study will receive and be asked to fill in a treatment 
diary (see Section 7.4). 
 
7.2.2 Follow-up Visits and Study Completion Visit 
Follow-up visits will be performed at the discretion of the treating physician (e.g., every 2– 
4 months) and/or at the time points specified in Table 3. 
The following data will be documented: 
• Current FVIII treatment regimen (e.g., prophylaxis, on-demand) 
– Doses and dosing frequency 
• In case of bleeding episodes, see Section 8.1.2 
• In case of surgery, see Section 8.1.3 
• Concomitant medication(s) 
• Monitoring of SADRs and ADRs 
• FVIII inhibitor status 
• SF-36 (optional) every 6 months after screening and at completion visit 
 
7.2.3 Optional PK assessment for individual prophylaxis regimen 
An optional PK analysis to determine individual prophylaxis regimen for a patient is 
offered in this non-interventional study. FVIII plasma level measurements will be 
performed at the discretion of the treating physician and if patient has given consent. 
FVIII:C levels measured after infusion of Nuwiq® up to 6 months prior to enrolment in the 
study are acceptable to perform the PK analysis, if no significant changes in patient’s health 
or weight have been recorded .The dose and dosing interval will be calculated in the frame 

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of this non-interventional study either based on an individual PK with 6 - 10 time points or 
on a population-based PK using 1-3 time points (including the possibility to combine 1 to 2 
time-points from different infusions of Nuwiq® at the dose the patient is routinely treated 
with). The population-PK option uses WAPPS (wapps-hemo.org) to model collected FVIII 
activity data from the withdrawn time-points and to provide an estimation of the patient PK. 
WAPPS is developed and provided online by McMaster University (Hamilton, Ontario 
Canada) [7]. 
 
7.3 Patient Codes 
 
Each patient enrolled into this non-interventional study will be uniquely identifiable by a 
patient code consisting of the study code, centre code, and patient number. The centre code 
is assigned to the study site by Octapharma. At each site, enrolled patients will be 
numbered consecutively. Once assigned to a patient, a patient number will not be reused. 
 
7.4 Treatment Diaries 
 
Documenting treatment and bleeding data is an integral part of home treatment for 
haemophilia. In this study, patients will be provided with a treatment diary during the 
Screening Visit after inclusion into the study. Patients will be asked to complete their 
treatment diaries and to bring them along for review to each Follow-up Visit. 
The following data can be recorded in the treatment diary: 
• Infusion-related data: date and time of administration, dose, batch number, reason for 
infusion (i.e., prophylaxis, BE treatment). 
• For BE data that can be documented (including patient assessment of treatment 
efficacy), see Section 8.1.1. 
• Concomitant medications 
• Adverse drug reactions (ADRs), including hypersensitivity reactions 
 
During or after each follow-up visit, the information recorded in the patient diaries will be 
transcribed to the CRFs. The patient diaries are considered source data, and the originals 
will be included in the patient’s medical record. 
 
7.5 Study Duration 
 
7.5.1 Planned Duration of the Study 
The overall duration of this post-authorisation study will be approximately 4 years. 

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The study will be considered completed once 200 patients have been treated and followed 
for at least 100 EDs (see Section 5), provided that 
• Age distribution is balanced (approx. 60 patients < 12 years of age; at least 
10 patients aged between 14–18 years) 
• At least 100 patients have severe haemophilia A (FVIII:C <1%) 
• The proportion of ITI patients does not exceed 25% of the entire cohort 
Also, all CRFs must have been completed and submitted to the Sponsor. 
 
7.5.2 Planned Duration by Patient 
Patients from pre-authorisation studies as well as patients from other interventional Phase 
III studies with Nuwiq® can be followed until they have completed at least 100 EDs. 
Patients enrolled into this non-interventional study will be treated and followed for at least 
100 EDs. 
 
7.6 Optional Quality of Life assessment (SF-36 Health Survey) 
 
An optional quality of life assessment is offered in this non-interventional study. Hence, 
this assessment will be performed only in countries where it is not considered 
interventional. Patients need to additionally consent in order to receive the questionnaire. 
SF-36 health survey is a set of generic, coherent, and easily administered quality-of-life 
measures which relies upon patient self-reporting for routine monitoring and assessment of 
care outcomes in patients. 
SF-36 will be completed by patients 14 years of age or older at screening, every 6 months 
after enrolment in the study and at completion visit who have consented to participate in 
this optional assessment. 

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8 ASSESSMENTS AND METHODS 
A complete list of data recorded throughout the study is given in Section 7.2. This section 
provides details on individual data recorded as well as on assessment methods used. 
 
8.1 Effectiveness Assessments 
8.1.1 Prophylactic Treatment 
FVIII consumption data to be documented 
• Dates and times the IMP was infused 
• IMP dose(s) and batch number(s) 
 
8.1.2 Bleeding Episodes (BEs) 
 
BE data to be documented in the treatment diary 
For any BE occurring during the study, the following data should be recorded: 
• BE type (spontaneous, traumatic, postoperative, other) 
• BE site 
• BE severity (minor, moderate, major) 
• Date and time the BE first occurred or was first noticed 
• Date and time the BE ended 
 
FVIII consumption data to be documented 
• Dates and times the IMP was infused 
• IMP dose(s) and batch number(s) 
 
Assessment of the efficacy of treatment at the end of a BE 
At the end of a BE, treatment efficacy will be assessed either by the patient (or the patient’s 
parent or legal guardian) or by the treating physician in case of on-site treatment using a 
scale including the four items ‘excellent,’ ‘good,’ moderate,’ and ‘none.’ Based on this 
efficacy assessment, all efficacy ratings assessed as either ‘excellent’ or ‘good’ will be 
considered ‘successfully treated.’ 

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8.1.3 Surgical Prophylaxis 
For any surgical procedure performed during the study, the following data should be 
recorded: 
• Type of surgery (planned or emergency) 
• Location of surgery 
• Severity of surgery (minor, major); see item (a) below 
• Details on dose(s) of Nuwiq® given pre-, intra-, or postoperatively; see item (b) 
below 
• Pre-, intra-, and postoperative FVIII plasma levels, if routinely done; see item (c) 
below 
• Estimated and actual perioperative and postoperative bleeding volumes 
• Overall efficacy assessment at the end of surgical prophylaxis by the surgeon and the 
haematologist; see item (d) below 
• Details on concomitantly administered products, including any blood or blood 
product transfusions or colloidal plasma substitutes (such as albumin, hydroxyl 
starch, dextran, and gelatine), but excluding drugs given for routine anaesthesia 
• Monitoring of ADRs 
 
Definitions of periods and time points before, during, and after surgery: 
• Preoperative is defined as the time period of up to 3 hours before the start of surgery. 
• The end of surgery is defined as the time immediately after the last surgical suture. 
• Postoperative is the period from the end of surgery to the time the patient returns to 
his regular FVIII treatment regimen. 
• The end of the postoperative period is the time the patient returns to his regular 
FVIII treatment regimen. 

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(a) Severity of surgery 
Surgeries are defined as major if any of the following criteria are met: 
• General or spinal/epidural anaesthesia required 
• Opening into the great body cavities required 
• Severe haemorrhage during surgery possible 
• Haemostatic therapy for at least 6 days required 
• 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. 
 
(b) Pre-, intra-, and postoperative doses of Nuwiq® 
Details on the pre-, intra-, and postoperative administration of Nuwiq® will be recorded in 
the CRF and include the dates and times of administration as well as the batch numbers. 
 
(c) FVIII plasma levels 
If pre-, intra-, and postoperative FVIII plasma levels are routinely assessed at a given 
centre, they should also be recorded in the CRF, detailing when they were assessed (i.e., 
pre-, intra-, and/or postoperatively). The following time points for the determination of 
FVIII plasma levels are recommended: 
• Immediately ( 30 min) before and 30 ± 15 min after preoperative infusion of 
Nuwiq® 
• Immediately ( 30 min) before and 30 ± 15 min after each intraoperative bolus dose, 
if any 
• Immediately ( 30 min) before and 30 ± 15 min after each postoperative dose, if any 
 
(d) Assessment of the efficacy of surgical prophylaxis 
At the end of the postoperative period, an overall assessment of the efficacy of treatment in 
the pre-, peri-, and postoperative periods using the ‘excellent,’ ‘good,’ moderate,’ and 
‘none’ scale will be done jointly by the surgeon and the haematologist. Based on this 
overall efficacy assessment, all efficacy ratings assessed as either ‘excellent’ or ‘good’ will 
be considered ‘successfully treated.’ 

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Table 4 Flow Chart of Assessments Performed for Surgical Interventions During the Study 
Period 
 
Any time 
before 
surgery 
Within 
3 hours 
before 
start 
Intra- 
operatively 
Enda 
POP 
day 1 
Any 
POP 
day 
At the 
end of 
POP 
periodb 
Type of surgery 
x 
Location of surgery 
x 
Severity of surgery 
x 
Administration of Human-cl rhFVIII 
x 
(x) 
(x) 
(x) 
(x) 
(x) 
FVIII plasma levels 
# 
(#) 
(#) 
(#) 
(#) 
(#) 
Estimated bleeding volumes 
x 
x 
Overall efficacy assessment 
SH 
Concomitant medications 
throughout observation period 
ADR monitoring 
throughout observation period 
POP, postoperative; ( ) optional; # samples should be taken before ( 30 min) and 30 ± 15 min after Nuwiq® 
administration 
a time immediately after the last surgical suture 
b time the patient returns to his regular FVIII treatment regimen 
SH, performed by surgeon and haematologist 
 
 
8.2 Safety Assessments 
 
To allow continuous monitoring of the product safety, all adverse drug reactions (ADRs) 
and other safety information as defined below have to be documented and reported to 
Octapharma. 
8.2.1 Definition of (serious) adverse drug reaction and other safety information 
Adverse drug reaction (ADR) 
An ADR is a response to a medicinal product which is noxious and unintended [Directive 
2001/83/EC Art 1(11)]. 
‘Response’ in this context means that a causal relationship between a medicinal product and 
an adverse event is at least a reasonable possibility (see Annex IV, ICH-E2A Guideline). 
ADRs may arise from use of the product within or outside the terms of the marketing 
authorisation or from occupational exposure [Directive 2001/83/EC Art 101(1)]. Conditions 
of use outside the marketing authorisation include off-label use, overdose, misuse, abuse 
and medication errors. 

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Serious adverse drug reaction (SADR) 
SADRs are ADRs that fulfil at least one of the following criteria: 
• results in death 
• is life-threatening (this implies that the patient was at risk of death at the time of the 
event; it does not refer to a reaction that hypothetically might have caused death if 
more severe) 
• requires in-patient hospitalisation or prolongation of existing in-patient 
hospitalisation (hospitalisation does not refer to the treatment of an ADR on an out- 
patient status) 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect 
• is a medically important event, e.g., 
– suspected transmission via a medicinal product of an infectious agent, 
– inhibitor development, 
– thromboembolic events, or 
– other reactions that should be reported in an expedited manner although they 
did not immediately result in one of the above seriousness criteria, e.g., 
intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalisation or development of dependency or abuse 
 
8.2.2 Other relevant drug safety information 
Any safety information relating to 
• drug abuse (persistent, sporadic or intentional excessive use of a medicinal product 
inconsistent with the SPC or acceptable medical practice), 
• misuse (situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the authorised product information) 
• overdose (administration of a quantity of a medicinal product given per 
administration or cumulatively which is above the maximum recommended dose 
according to the authorised product information. Clinical judgement should always be 
applied.), 
• medication errors (prescribing or dispensing error), 
• interactions with other medicinal products or devices 
• occupational exposure (an exposure to a medicinal product as a result of one’s 
professional or non-professional occupation) associated with Human-cl rhFVIII, even 
if no ADR occurred. 

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8.2.3 Specifically monitored ADRs 
ADRs of particular interest, i.e., hypersensitivity reactions and FVIII inhibitor development 
(see Section 2.2.3) as well as thromboembolic events, will be specifically monitored 
throughout the study using specific CRF pages. 
 
Hypersensitivity reactions 
As with any intravenous protein product, allergic type hypersensitivity reactions are 
possible. Nuwiq® contains traces of human host cell proteins other than factor VIII. Early 
signs of hypersensitivity reactions include hives, generalised urticaria, tightness of the 
chest, wheezing, hypotension, and anaphylaxis. A sample CRF for hypersensitivity 
reactions is provided in the Appendix 1: Case Safety Report Form, Case Safety Report 
Form - Annex 1: FVIII Inhibitor Development. 
 
FVIII inhibitors 
The diagnosis of factor VIII inhibitor will be based on clinical observations and be 
confirmed by factor VIII inhibitor testing in the central laboratory. The recommended 
laboratory testing schedule is given in Table 3. Items to be recorded include details on 
when blood samples were obtained for inhibitor testing and recovery tests (including dose), 
results of these tests and assay methodology, description of clinical symptoms suggesting 
inhibitor development, e.g. ineffective prophylaxis, need to increase dose and/or decrease 
prophylactic treatment interval, need to increase dose and/or number of infusions to treat a 
bleed. A sample CRF for FVIII inhibitor testing is provided in the Appendix 1: Case Safety 
Report Form, Case Safety Report Form - Annex 2: Hypersensitivity/Anaphylactic 
Reactions. 
The occurrence of FVIII inhibitors is considered a serious adverse drug reaction (SADR). 
The sampling time points and inhibitor levels should be recorded and included in the SADR 
report. For SADR reporting requirements, see Section 8.2.4. 
 
Thromboembolic events 
A sample CRF for thromboembolic events is provided in the Appendix 1: Case Safety 
Report Form, Case Safety Report Form - Annex 3: Thromboembolic Events. 

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Oberlaaer Strasse 235 
1100 Vienna 
Austria 
Fax: +43/1/61032-9949 
Email: cdsu@octapharma.com 
24-hour emergency telephone number: +43 1 40 80 500 
 
 
8.2.4 Reporting of adverse drug reactions (ADRs) and other safety information 
All suspected ADRs and other safety information associated with the administration of 
Nuwiq® have to be reported in the Case Safety Report Form and be sent to: 
 
Octapharma Central Drug Safety Unit 
OCTAPHARMA Pharmazeutika Produktionsges.m.b.H. 
 
 
Reporting requirements for SADRs 
SADRs have to be reported immediately by fax or email (within 24 hrs). Non-serious 
ADRs and other safety information should be reported to Octapharma upon recognition but 
no later than 10 days after their occurrence. 
Patients who carry out home-treatment should be asked to immediately inform the treating 
physician of any ADR or other relevant safety information. The treating physician has to 
assess the causal relationship for ADRs and report ADRs and other relevant drug safety 
information. 
For information about possible ADRs and other safety information, please refer to the local 
Summary of Product Characteristics of Nuwiq®. 

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8.3 Optional PK evaluation 
Individual dosing and dosing interval can be calculated at the beginning or during patients 
are on this study if deemed potentially beneficial by the treating physician. The treating 
physician can decide whether an individual or population approach will be used to perform 
the PK analysis. For the PK evaluation the information listed in Table 5 should be 
collected. 
 
Table 5 Flow Chart of Assessments Performed for Individual or Population based PK 
Analysis 
 
Individual PK 
Population PK 
- 
Current body weight 
- 
Current body weight 
- 
Current height 
- 
FVIII:C levels measured locally or 
centrally (as applicable per country) 
before and at least 5 times after 
Nuwiq® infusion of a recommended 
dose of 60±5 IU/kg. 
- 
The following time points are 
recommended: 
• 
Before ( 30 min) infusion of 
Nuwiq® 
• 
30 minutes, 6, 24, 48 and 72 
hours after infusion of Nuwiq® 
• 
For a complete PK additionally 
1, 3, 9 and 30 hours after the 
infusion are recommended. 
- 
FVIII:C levels measured locally or 
centrally (as applicable per country) at 
1 to 3 time points* (prior and) after 
infusion of Nuwiq®. Sampling time 
points can be combined from multiple 
infusions of Nuwiq® at a dose patient 
is routinely treated with. 
- 
The following time points for the 
determination of FVIII plasma levels 
are recommended: 
• 1-3 time points at least 12h apart 
between 4-48h. Example: between 4- 
8h (e.g. 6h), 16-28h (e.g. 24h†) and 
40-60h (e.g. 48h) § 
*inclusion of a pre-infusion sample is recommended. 
†24h is the sample providing the most information. 
§ If patient is known to have a longer half-life with Nuwiq®, a sample between 60 and 84h 
is recommended (e.g. 72h). 
 
- 
FVIII:C levels measured after infusion of Nuwiq® up to 6 months prior to 
enrolment in the study are acceptable to perform the PK analysis, if no significant 
changes in patient’s health or weight have been recorded . 
 
- 
Patients must consent to this optional assessment. 
 
- 
Patients should be preferably not bleeding at the time of blood sampling for PK. 

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8.4 Laboratory Assessments 
 
8.4.1 General Laboratory Assessments 
General laboratory assessments, such as FVIII:C measurements in case of surgery will be 
done by the local laboratories. 
FVIII:C measurement for PK analysis will be done either at local laboratories or central 
laboratory as applicable per specific countries. 
 
8.4.2 Immunogenicity 
The occurrence of antibodies against FVIII is a major complication of haemophilia A 
treatment. The risk of inhibitor occurrence is higher in patients with severe haemophilia A 
than in patients with moderate and mild disease, and the genotype (high risk: inversions, 
large deletions or nonsense mutations of the FVIII gene) and ethnic background of the 
patient is also of relevance. 
In addition, risk may be associated with commencing treatment in previously untreated 
patients, when changing treatment, or when the antigenicity of a product has been altered 
due to changes in the manufacturing process. 
Previously treated patients, the population to be enrolled into this study, are the most 
suitable candidates to test the product-related immunogenicity of a factor VIII product 
(Guideline EMA/CHMP/BPWP/144533/2009). 
• According to Guideline EMA/CHMP/BPWP/144533/2009, there should not be any 
clinical suspicion of inhibitors before inclusion into the study, and a recovery and 
inhibitor test in a central laboratory should confirm that the patient is inhibitor- 
negative at study entry. 
• In addition, testing should be carried out if there is any suspicion of an inhibitor. 
• Inhibitor tests should be performed when the plasma factor VIII level has reached a 
pre-substitution nadir (documentation for the last infusion should be provided). 
• Inhibitor re-testing using a second separately drawn sample as confirmatory 
measurement should be performed in the central laboratory. 
• The flow chart of inhibitor testing is as recommended by Guideline 
EMA/CHMP/BPWP/144533/2009 is given in Table 3. 
FVIII inhibitors will be assessed by the following central laboratory using validated test: 
Esoterix Coagulation 
8490 Upland Drive 
Suite 100 
Englewood, Colorado 80112, USA 

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FVIII inhibitor test used 
Inhibitor activity will be determined by the modified Bethesda assay (Nijmegen 
modification). 
 
FVIII inhibitor status definitions 
The FVIII inhibitor status is defined as follow: 
• Negative: < 0.6 BU 
• Low-titre inhibitors: < 5 BU 
• High-titre inhibitors: ≥ 5 BU 
A rise in the circulating FVIII level of less than 1% per FVIII IU/kg administered will be 
considered an indication for inhibitor development. A rise of less than 1.5% per IU/kg 
administered will be considered suggestive for inhibitor development. 
The flow chart of FVIII inhibitor testing as recommended by Guideline 
EMA/CHMP/BPWP/144533/2009 is given in Table 3. 
The occurrence of FVIII inhibitors is considered a serious adverse drug reaction (SADR). 
The sampling time points and inhibitor levels should be recorded and included in the SADR 
report. For SADR reporting requirements, see Section 8.2.4. 
 
9 DATA MANAGEMENT 
 
9.1 Documentation of Data 
 
For each patient enrolled, a Case Report Form (CRF) will be completed and approved by 
the treating physician or other authorised personnel. Study site staff will be responsible for 
entering all patient data into the CRF. 
If any errors in the CRFs are found during the data review process, queries will be 
generated by either a monitor or Data Management and submitted to the site personnel or 
monitor. Once the query has been answered, Data Management or the monitor will review 
the new or changed data to ensure an appropriate response and close the query. 
 
9.2 Responsibilities 
 
The treating physician is accountable for the conduct of the study. On request, the treating 
physician will supply the Sponsor with additional data relating to the study, ensuring that 
the patient’s confidentiality is maintained. This is particularly important when errors in data 
transcription are encountered. In case of particular issues or queries by regulatory 

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authorities, 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. 
 
10 DATA ANALYSIS 
The statistical analysis will be delegated under an agreement of transfer of responsibilities 
to an external Contract Research Organization (CRO). The CRO has to comply with all 
Octapharma procedures and policies. Discrepancies or exceptions are to be approved by the 
Sponsor’s Manager of Biometrics. 
 
10.1 Determination of Sample Size 
 
No formal sample size determination was performed. According to Guideline 
EMA/CHMP/BPWP/144533/2009, the number of patients typically needed in a post- 
authorisation study with FVIII to cover immunogenicity aspects is 200. 
 
10.2 Analysis Plan 
 
The data recorded in the CRF will be analysed using descriptive statistical methods. An 
analysis plan detailing the analyses to be performed will be prepared by the study 
statistician and approved by the Sponsor before the start of the study. 
 
10.3 Progress Study Reports 
 
A progress study report will be prepared 2 years after marketing authorisation, detailing the 
recruitment status and progress of the study. 
 
10.4 Optional PK evaluation 
 
Individual PKs will be assessed based on the availability of individual patient data using 
either a 1- or 2-compartment model or the WAPPS-Hemo (Web-Accessible Population 
Pharmacokinetics Service Hemophilia) model. Based on the estimated PK parameters, 
potential treatment options will be calculated. The calculated PK parameters will be 
analysed descriptively. 

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11 ETHICAL AND REGULATORY ASPECTS 
 
11.1 Ethical and Regulatory Framework 
This study will be conducted in accordance with the ethical principles laid down in the 
Declaration of Helsinki and applicable national requirements for non-interventional studies. 
 
11.2 Submission of Study Documents to IEC and/or Regulatory Authority 
 
If required by national regulations pertaining to the performance of non-interventional 
studies, 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 treating physician to the appropriate IEC and/or the 
Regulatory Authority. 
The Sponsor, the treating physician, and any third party (e.g., CRO) involved in notifying 
the IEC and/or Regulatory Authority must inform each other in writing that all ethical and 
legal requirements have been met before the first patient is enrolled in the study. 
 
11.3 Patient Information and Informed Consent 
 
The treating physician will obtain freely given written consent from each patient after an 
appropriate explanation of the aims, methods, anticipated benefits, potential hazards, and 
any other aspects of the study that are relevant to the patient’s decision to participate. The 
informed consent form must be signed, with the patient’s name and the date and time added 
by the patient, before the patient is exposed to any study-related procedure, including 
screening for eligibility. 
For patients not qualified to give legal consent, written consent must be obtained from the 
legal guardian. 

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The treating physician will explain that the patients are completely free to refuse to enter 
the study or to withdraw from it at any time, without any consequences for their further care 
and without the need to justify. The treating physician will complete the informed consent 
section of the CRF for each patient enrolled. 
Each patient will be informed that his medical (source) records may be reviewed by the 
study monitor, a quality assurance auditor, or a health authority inspector in accordance 
with applicable regulations, and that these persons are bound by confidentiality obligations. 
 
11.4 Protocol Amendments 
 
Any amendments will be submitted to the IEC(s) and/or competent authority if required by 
national regulations. 
 
11.5 Confidentiality of Patient Data 
 
The treating physician 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 code (see Section 7.3). Documents not intended for 
submission to the Sponsor, i.e., a confidential patient identification code list, original 
consent forms, and patient records, will be maintained by the treating physician in strict 
confidence. 
 
12 REPORTING AND PUBLICATION 
 
12.1 Final Study Report 
 
A final study report (in accordance with relevant guidelines and the Sponsor’s SOPs) will 
be prepared by the Sponsor after completion of the study. 
 
12.2 Publication Policy 
 
The results of this study may be published or presented at scientific meetings. If this is 
envisaged by a physician, the physician 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 author. 

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In accordance with standard editorial and ethical practice, the Sponsor will support 
publication of multicentre studies only in their entirety and not as individual centre data. 
Authorship will be determined by mutual agreement. 
 
13 REFERENCES 
 
1. Mannucci PM. Back to the future: a recent history of haemophilia treatment. 
Haemophilia 2008;14 Suppl 3:10-18. 
2. Hironaka T, Furukawa K, Esmon PC 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;267:8012-8020. 
3. Hokke CH, Bergwerff AA, Van Dedem GW, van OJ, Kamerling JP, Vliegenthart JF. 
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. 
4. Casademunt E, Martinelle K, Jernberg M et al. The first recombinant human 
coagulation factor VIII of human origin: human cell line and manufacturing 
characteristics. Eur J Haematol 2012;89:165-176. 
5. Sandberg H, Kannicht C, Stenlund P et al. Functional characteristics of the novel, 
human-derived recombinant FVIII protein product, human-cl rhFVIII. Thromb Res 
2012;130:808-817. 
6. Kannicht C, Ramstrom M, Kohla G et al. Characterisation of the post-translational 
modifications of a novel, human cell line-derived recombinant human factor VIII. 
Thromb Res 2013;131:78-88. 
7. https://www.wapps-hemo.org/Default.aspx 
 
 
 
 
 
 
 
 
APPENDIX 
APPENDIX 1: CASE SAFETY REPORT FORM ......................................................................................... 39 
CASE SAFETY REPORT FORM - ANNEX 1: FVIII INHIBITOR DEVELOPMENT .................... 43 
CASE SAFETY REPORT FORM - ANNEX 2: 
HYPERSENSITIVITY/ANAPHYLACTIC REACTIONS .......................................................... 47 
CASE SAFETY REPORT FORM - ANNEX 3: THROMBOEMBOLIC EVENTS ............................. 50 

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Appendix 1: Case Safety Report Form 

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Case Safety Report Form - Annex 1: FVIII Inhibitor Development 

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Case Safety Report Form - Annex 2: Hypersensitivity/Anaphylactic 
Reactions 

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Case Safety Report Form - Annex 3: Thromboembolic Events 

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