Surveillance of Safety and Efficacy of Wilate in Patients With Von Willebrand Disease
Conditions: Von Willebrand Disease
Sponsor: Octapharma

 
 
 
 
 
Clinical Research & Development 
 
 
wilate® 
 
 
WIL-20 
 
 
Surveillance of the Safety and Efficacy of wilate® in 
patients with von Willebrand disease 
 
 
 
 
Author: 
Dr. Bruce A Schwartz 
 
Document Type: 
Observational Surveillance Protocol 
Development Phase: 
Post-marketing 
Marketing authorisation holder 
Octapharma AG 
Seidenstrasse 2 
8853 Lachen 
Switzerland 
Version Number: 
04 (with Protocol Amendment No.2 and 3 
incorporated) US country specific version 
 
Release Date: 
[28.08.2012] 
 
 
 
 
 
Property of Octapharma 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Octapharma 
090-CTP-WIL-20_version4_ 28-Aug-2012/DOC ID 1834 

 
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PROTOCOL AUTHORIZATION 
 
This observational surveillance will be conducted in compliance with the protocol, 
and the applicable regulatory requirements. 
 
 
 
Dr Sigurd Knaub 
C.- 
-)  
 
..-•· 
? o; (."'".'J. ,/ 
  
---:,_-_·c_...  
[ 
._.  
t_<S 
Vice President CR&D Haematology 
Signature 
Date 
Octaphanna AG 
Seidenstrasse 2 
8853 Lachen 
Switzerland 
 
 
 
Dr Bruce A. Schwartz 
 
Author of the Protocol 
Director Clinical Research, Hematology 
121 River Street, 
Suite 1201 
Hoboken, New Jersey, 07030 
USA 
Date 
 
 
 
Dr. Hans-Peter Hucke 
 
Biostatistician 
and Data Manager 
GASD, Gesellschaft fllr Angewandte Statistik + Datenanalyse mbH 
Am Konvent 8-10 
41460 Neuss 
Germany 
 
 
 
 
 
 
 
 
8-28-12 

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Table of contents 
Table of contents................................................................................................... 3 
List of tables .......................................................................................................... 4 
List of abbreviations .............................................................................................. 5 
Surveillance protocol synopsis .............................................................................. 6 
1 
Background ........................................................................................................... 7 
2 
Purpose of the surveillance ................................................................................... 7 
3 
Objectives ............................................................................................................. 8 
3.1 
Primary objective ........................................................................................ 8 
3.2 
Secondary objective(s) ............................................................................... 8 
4 
Surveillance endpoints .......................................................................................... 8 
4.1 
Primary surveillance endpoint ..................................................................... 8 
4.2 
Secondary surveillance endpoints .............................................................. 8 
5 
Surveillance design and duration .......................................................................... 8 
6 
Population ............................................................................................................. 8 
7 
Treatment .............................................................................................................. 9 
7.1 
Patient numbering ...................................................................................... 9 
7.2 
Observational drug ..................................................................................... 9 
7.3 
Treating the patient ..................................................................................... 9 
7.3.1 
Dispensing wilate® ....................................................................... 9 
7.3.2 
Instructions for prescribing and taking wilate® ............................. 9 
7.3.3 
wilate® dose adjustments and interruptions ............................... 10 
7.3.4 
Other concomitant treatment ..................................................... 10 
7.3.5 
wilate® discontinuation ............................................................... 10 
7.3.6 
Observation completion ............................................................. 10 
8 
Visit schedule and assessments ......................................................................... 11 
8.1 
Patient Diary ............................................................................................. 13 
8.2 
Patient demographics/other baseline characteristics ................................ 13 
8.3 
Treatment exposure ................................................................................. 14 
8.4 
Immunogenicity ........................................................................................ 14 
8.5 
Thrombogenicity ....................................................................................... 14 
8.6 
Outcome Assessment .............................................................................. 15 
8.7 
Bleeding Tendency ................................................................................... 16 
8.8 
General patient assessment and previous treatment with FVIII/VWF ....... 16 
8.8.1 
Laboratory evaluations .............................................................. 16 
8.8.2 
Days lost from school or work .................................................... 17 

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8.9 
Assessments in case of hemostasis management before, during or 
after interventional procedure ................................................................... 17 
8.9.1 
Assessment of blood loss / Transfusion ..................................... 17 
8.10 Safety / Tolerability ................................................................................... 17 
8.10.1 
Virus Safety ............................................................................... 17 
9 
Safety monitoring ................................................................................................ 18 
9.1 
Definition of adverse drug reaction and other safety information .............. 18 
9.2 
Reporting of adverse drug reactions and other safety information ............ 19 
10 Data analysis....................................................................................................... 19 
10.1 Statistical Analysis .................................................................................... 19 
10.2 Interim analysis ......................................................................................... 19 
11 Reference ........................................................................................................... 19 
Appendix I:  Local drug safety unit of Octapharma .............................................. 20 
Appendix II:  Wilate US Package Insert .............................................................. 24 
 
 
 
List of tables 
Table 1 
Assessment schedule ............................................................................... 11 
Table 2 
Optional immunogenicity and thrombogenicity assessment schedule ...... 12 

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List of abbreviations 
 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALT 
Alanine transaminase 
AST 
Aspartate aminotransferase 
CRF 
Case Report/Record Form 
CRP 
C reactive protein 
DD 
D-dimer 
DDAVP 
1-deamino-8-D-arginine vasopressin 
ED 
Exposure days 
ELISA 
Enzyme-linked immunosorbent assay 
ESR 
Erythrocyte sedimentation rate 
F1+2 
Prothrombin fragments 1 and 2 
FVIII 
Factor VIII 
GCP 
Good clinical Practice 
HAV 
Hepatitis A virus 
Hb 
Hemoglobin 
HBV 
Hepatitis B virus 
Hc 
Hematocrit 
HIV 
Human immunodeficiency virus 
IN 
Investigator notification 
IU 
International Unit 
PTPs 
Previously treated patients 
PUPs 
Previously untreated patients 
RBC 
Red blood count 
SAE 
Serious adverse event 
SPC 
Summary of product characteristics 
VRS 
Verbal rating scale 
VWD 
Von Willebrand disease 
VWF 
Von Willebrand factor 
VWF:Ag 
VWF antigen 
VWF:RCo 
VWF Ristocetin Co-factor activity 
WBC 
White blood count 

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Surveillance protocol synopsis 
Title: 
Surveillance of Safety and Efficacy of wilate® in patients with von Willebrand disease 
Objectives: 
Primary objective: 
Primary objective is to collect information concerning t the safety and tolerability of wilate® in routine 
clinical use. 
Secondary objective: 
Secondary objective is to collect information concerning the clinical outcome of wilate® administration 
in routine clinical use. 
Population: 
VWD patients of any gender, age, or VWD type, previously treated (PTPs) or previously untreated 
patients (PUPs), who have been prescribed wilate ® in the course of the physician’s medical practice. 
Investigational and reference therapy: 
wilate® - human coagulation factor VIII and human von Willebrand factor (VWF) 
Design: 
Open-label, prospective, multicentre, multinational, post-marketing, observational, non-interventional 
surveillance 
Efficacy assessments: 
Assessment of the outcome of wilate® administration will be based on a 4-point hemostatic efficacy 
scale as “excellent”, “good” “moderate” or “none”. The frequency of bleeding episodes in total and per 
bleeding site, days of treatment of bleeding episodes in total and per bleeding site, exposure days and 
consumption of wilate® per event, per patient and in total will be calculated. 
Safety/Tolerability assessments: 
Assessment of safety will be based on recorded Adverse Drug Reactions during the full course of the 
observation. Assessment of tolerability will be based on a 3 point Verbal Rating Scale. 
Immunogenicity 
As a recommended assessment, this study will observe development of inhibitors against VWF in 
response to wilate® treatment (by an ELISA assay). Inhibitor assessment is recommended to be 
performed before and after first wilate® application, and then the every 3 months during the full course 
of observation. 
Thrombogenicity 
As a recommended assessment, this study will observe the coagulation parameters based on 
assessment of prothrombin fragments 1 and 2 (F1+2) and D-dimer (DD) by latex enhanced 
immunoturbimetric test. Thrombogenicity assessment is recommended to be performed before first 
wilate® application, 1 hour after application, 3 and 24 hours after application and every 3 months 
during the full course of observation. It is also recommended to perform thrombogenicity assessment 
for all interventional procedures. 
Data analysis: 
Descriptive statistics will be used as method for data analysis. 

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1 
Background 
wilate® is a freeze-dried preparation consisting of the two active ingredients: human 
plasma-derived coagulation Factor VIII (FVIII) and von Willebrand Factor (VWF). In 
the United States wilate® is indicated for the treatment of spontaneous and trauma- 
induced bleeding episodes in patients with severe von Willebrand disease (VWD) as 
well as patients with mild or moderate VWD in whom the use of desmopressin is 
known or suspected to be ineffective or contraindicated. (1) wilate® has not been 
granted the indication for the prophylaxis of spontaneous bleeding episodes, or the 
prevention of excessive bleeding during and after surgery in VWD patients or the 
treatment of Hemophilia A. Full prescribing information for wilate® in the US is 
provided in Appendix II. 
The hereditary form of von Willebrand’s disease (VWD) is a common coagulation 
disorder with an estimated worldwide prevalence of 0.9-1.3%. Only a part of this 
patient population requires treatment, as there is great variability of geno- and 
phenotypes. The three main types of VWD are: type 1, 2 and 3. They are associated 
with quantitative (type 1 and 3) and qualitative defects (type 2) of the VWF. 
VWF/FVIII concentrates are administered mainly to patients with type 3, but patients 
with type 1 or 2 may also need regular or occasional substitution. Generally, the 
substitution frequency is very variable. 
New biotechnological methods and chromatographic materials have been introduced 
in the development and production of wilate®. The result is a highly purified 
concentrate that contains FVIII/VWF complex in its natural form and in its 
physiological ratio of close to 1:1. wilate® is virtually free from low-molecular 
impurities. 
wilate® is double virus-inactivated using the solvent/detergent method and a dry 
heating process (PermaHeat, 100°C for 2 hours). See appendix II for the approved 
US package insert. 
 
2 
Purpose of the surveillance 
This post-marketing surveillance is designed to collect information concerning safety, 
tolerability, and outcome of wilate® administration in routine clinical use. 
Documentation of the administration of wilate® in clinical practice will not only improve 
the efficacy and tolerability knowledge database, but will produce findings that cannot 
be obtained in the same way in controlled clinical studies. This surveillance will help 
support the safe and effective use of wilate® thus bringing benefit for both physicians 
and patients. 

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3 
Objectives 
3.1 
Primary objective 
Primary objective is to collect information concerning the safety and tolerability of 
wilate® in routine clinical use. 
3.2 
Secondary objective(s) 
Secondary objective is to collect information concerning the (outcome) of wilate® in 
routine clinical use. 
 
4 
Surveillance endpoints 
4.1 
Primary surveillance endpoint 
Incidence of recorded adverse drug reactions (side effects) and wilate® 
 
 
 
tolerability 
results assessed by 3 point Verbal Rating Scale (see section 
endpoints. 
 
4.2 
Secondary surveillance endpoints 
8.10) define primary 
The secondary endpoint is defined as the percentage of the effectiveness ratings 
“excellent” and “good” based on a 4-point hemostatic efficacy scale (see section 8.6). 
 
5 
Surveillance design and duration 
This is open-label, prospective, multinational, post-marketing, non-interventional 
observational surveillance. The observation was started Q4 2009 and to be 
completed after 5 years, with an individual observation period of 2 years. 
 
6 
Population 
The surveillance will include 50 subjects. The observed population will consist of 
clinically diagnosed VWD patients of any type, previously treated (PTPs) or 
previously untreated patients (PUPs). The surveillance will observe male and female 
subjects without age limitation. It will include subjects who have been prescribed 
wilate® by their physician in the course of medical practice. 

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7 
Treatment 
7.1 
Patient numbering 
Each patient is uniquely identified in the study by a combination of his/her center 
number and patient number. Octapharma assigns the center number to the 
investigative site. At each site the first patient is assigned patient number 1, and 
subsequent patients are assigned consecutive numbers (e.g., the second patient is 
assigned patient number 2, the third patient is assigned patient number 3. Once 
assigned to a patient, a patient number will not be reused. 
 
7.2 
Observational drug 
wilate® is available in the US as a lyophilized powder with a special solvent (water for 
injection containing 0.1% Polysorbate 80) in the following strengths: 500 IU/vial (+ 5 
ml solvent), 1000 IU/vial (+ 10 ml solvent), containing nominally 500 IU FVIII:C/500 
VWF:RCo or 1000 IU FVIII:C/1000 VWF:RCo per vial, respectively. 
 
7.3 
Treating the patient 
7.3.1 
Dispensing wilate® 
This is an observational, post-marketing surveillance. Subjects documented in this 
surveillance will receive commercially available wilate®. 
7.3.2 
Instructions for prescribing and taking wilate® 
Patients are treated with wilate® according to the investigator’s prescription. For 
dosage recommendations please refer to the local wilate® package leaflet. 
The dosage and duration of treatment depend on the severity of the VWD as well as 
on the location and extent of bleeding and the patient’s clinical condition. The 
therapeutic decision is at the investigators` discretion. 
The ratio of factor VIII:VWF Ristocetin cofactor activity is approximately 1:1. Usual 
dosage of wilate® to achieve sufficient hemostasis is 20-60 IU/ kg body weight 
depending on the severity of the bleeding. This should increase the FVIII:C and 
VWF:RCo plasma level by about 30-50% which will vary depending on individual 
patient pharmacokinetic characteristics. 
The investigator should promote compliance by instructing the patient to take wilate® 
exactly as prescribed and by stating that compliance is necessary for the patient’s 
safety. The patient should be instructed to contact the investigator if he/she is unable 
for any reason to receive wilate® as prescribed. 
All dosages prescribed and dispensed to the patient and all dose changes during this 
observational surveillance should be recorded on the Dosage Administration Record 
CRF. 

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7.3.3 
wilate® dose adjustments and interruptions 
Any drug dose adjustment and interruptions are at the discretion of the investigator, 
according to the location, extent of bleeding and patient’s clinical condition. 
All changes in wilate® dosage or interruptions should be recorded on the Dosage 
Administration Record CRF. 
7.3.4 
Other concomitant treatment 
Any other concomitant treatment is at the discretion of the investigator. No 
interactions with other medicinal products are known (wilate® SPC). 
In case of PTPs, a washout period of 7 days after the last infusion of the previous 
concentrate is recommended before the start of wilate® application. 
The investigator should instruct the patient to notify the observational site about any 
new medications he/she takes after the start of wilate® application. All medications 
and significant non-drug therapies (including physical therapy and blood transfusions) 
administered after the patient starts treatment with wilate® should be listed on the 
Concomitant Medications/Significant Non-drug Therapies CRF. 
7.3.5 
wilate® discontinuation 
If, for any reason, the investigator or the patient decides to discontinue the treatment 
the observation of this patient will be terminated. 
However, the investigator should make the best efforts to complete and report all 
observations. The investigator will document the reason(s) for termination in the CRF 
and complete a Termination Form. 
If the reason for discontinuing wilate® 
therapy is an adverse drug reaction, the 
specific reaction will also be recorded and is recommended that the investigator 
make thorough efforts to clearly document the outcome. All serious adverse drug 
reactions shall be reported to Octapharma to facilitate the Octapharma’s compliance 
with any reporting obligations. 
7.3.6 
Observation completion 
The observation is planned to be finalized after complete documentation of 50 
subjects and after completion and submission of all CRFs. 
The investigator must also provide follow-up medical care for all patients who are 
prematurely withdrawn from this observation, or must refer them for appropriate 
ongoing care. 
When the patient has completed all observational assessments, the investigator 
should inform Octapharma within 10 days and record the core study patient 
completion in the CRF. 

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8 
Visit schedule and assessments 
Table 1 lists all of the assessments recommended by this observation and indicates 
with an “X” the visits when they should be performed. 
 
Table 1 
Assessment schedule 
 
 
Visits 
Assessments 
Observation 
Entry 
Subsequent 
Visits 
Terminal 
Visit 
Interventional 
treatment 1 
Anamnestic data 2 
X 
XB 
Weight 
X 
X 
XB, A 
Residual activity of FVIII / VWF 3 
X 
XB 
Response to DDAVP 
X 
XB 
Patient general condition 
X 
XB 
Bleeding tendency with severity 
X 
XB 
Regularly administered medication(s) 
X 
XB, D, A 
Previous treatment with FVIII / VWF 
X 
XB 
Concomitant medication 4 
X 
X 
X 
XB, D, A 
Viral status 5 
X 
X10 
X10 
XB 
Vaccination status 6 
X 
X 
XB 
Laboratory evaluation 7 
X 
X 
X 
XB, D, A 
FVIII / VWF measurements before and after 
wilate® application 
X 
X 
XB, A 
Current bleeding episodes 
-Site, Severity, Duration and Efficacy 
X 
X 
XD. A 
wilate® application 8 
X 
X 
XB, D, A 
General wilate® assesment 
X 
XA 
Documentation of interventional procedure 
XB 
Assessment of blood loss due to intervention 
XD. A 
Transfusion of blood / components 
XD. A 
Assessment of haemostatic efficacy and 
tolerability of wilate® 9 
X 
X 
XA 
Adverse drug reactions 
X 
X 
XD. A 
1 - e.g. minor/major surgery, dental care, invasive diagnostic procedures etc.. 
2 - Anamnestic data include year of birth, gender, height, weight, blood group, general patient condition, VWD type and date of 
diagnosis 
3 - %VWF:RCo; VWF:Ag; FVIII:C 
4 - Including all medication taken in the last 7 days before observation entry 
5- Hepatitis A, B, C, Parvovirus anbd., HIV anbd. 
6 - HAV, HBV vaccine 
7 - Hb, Hc, RBC, WBC, Platelets, ALT, AST, Bilirubin, Creatinine, CRP, Erythrocyte Sedimentation Rate (ESR) 
8 - Date of administration, batch number, total dose, reason for treatment, tolerability 
9 - Assessment of efficacy should be done after each bleeding episode for on demand treatment 
10 - Only B19 Parvovirus antb. 
B - Before intervention 
D - During intervention 
A - After intervention 
 
 
 
 
 
 
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Table 2 
Recommended immunogenicity and thrombogenicity assessment 
schedule 
 
 
Week one 
3 months 6 months 9 months 12 months 15 months 18 months 21 months 24 months 
Before first 
application 
After first 
application 
Inhibitor testing 
 
VWF Inhibitor 
X 
X 1 
X 1 
X 1 
X 1 
X 1 
X 1 
X 1 
X 1 
X 1 
Thrombogenicity testing 
F1+2 and D-dimer 
X 
X 2 
X 2 
X 2 
X 2 
X 2 
X 2 
X 2 
X 2 
X 2 
Note: All tests will be performed in a central laboratory 
 
1-Inhibitor test should be performed 3 to 4 days (preferably 7 days) after wilate® application 
2-Blood samples collected 1 hour, 3 hours and 24 hours after wilate® application 
It is recommended that all data obtained from the assessments listed in Table 1 
should be documented in the patient’s CRFs. 
Due to the nature of this non-interventional, observational study design, strict pre- 
defined visit and time schedule is not required, however the study recommendation is 
to perform subsequent visits on regular 3 months intervals. 
Before patient inclusion there should not be a clinical suspicion for an inhibitor. 
Recommendation is to perform a VWF inhibitor test to confirm that the patient is 
inhibitor negative at study entry. 
At observation entry the physician will inform the patient about the conduct, 
implications and goal of this post marketing surveillance. If a patient agrees to 
participate and provide informed consent, he will receive a patient diary. The 
physician will explain how to use it and advise patients to bring it at each visit. 
Patients will be instructed that they should contact the physician in case of any 
problems that could be related to treatment with wilate®- including all adverse drug 
reactions - during the whole observation period. 
Before the 1st treatment with wilate®, the physician should record all baseline 
characteristics on appropriate pages of the CRF. These include demographic data, 
diagnosis, the patient's date of enrolment and intended therapy with VWF/FVIII 
concentrate, any relevant concomitant medication, medical history, and available 
baseline laboratory data, including viral markers for HIV and hepatitis A, B, and C. It 
is recommended that available results should be recorded in the CRF. For PTPs the 
number of previous exposure days (ED) should be recorded. It is also recommended 
to document details of patient’s treatment of the last 6 months before starting the 
observation. 
It is recommended that any substitution, intolerability, adverse reaction, concomitant 
medication, major inter-current illness, bleeding episode and surgical procedure 
throughout the 2-Year observation period should be documented in appropriate CRF 
sections. 

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In case interventional procedures (e.g. minor/major surgery, dental care, invasive 
diagnostic procedures etc.) are performed, available related information will be 
obtained and documented on the respective forms. The information of interest 
includes a description of the surgical procedure, substitutive treatment, relevant 
concomitant medication, course and outcome of the surgical procedure, assessment 
of overall haemostatic effect, details regarding continuous infusion as well as relevant 
laboratory data. 
 
8.1 
Patient Diary 
Patients are asked to document data as specified below. For this purpose they will 
receive a patient diary. 
It is recommended to record every treatment with wilate® 
in the patient diary, 
regardless whether patients treat themselves at home or receive injections at the 
participating observational centre. The information of interest is: date and time of 
each injection, number of units used, batch number(s), indication, patient’s and 
physician’s assessment of outcome and of acute tolerability. 
Similarly, patients are asked to record all concomitant medication. 
The surveillance will observe documented bleeding episodes, indicating the bleeding 
site, start and stop date of bleeding, severity of bleeding (minor, moderate, or severe) 
and if appropriate, the amount of wilate® required to treat that episode. 
Patients or their parents should assess the outcome of their wilate® treatment in case 
of bleeding episodes (on demand treatment), using the 4-point hemostatic efficacy 
scale (see section 8.6): 
The tolerability of wilate® injections is assessed by the 3-point Verbal Rating Scale- 
VRS (see section 8.10). 
In addition, each suspected adverse drug reaction related to wilate® therapy should 
be documented. 
 
8.2 
Patient demographics/other baseline characteristics 
Before first wilate® 
application it is recommended to observe and document 
anamnestic data, (year of birth, gender, height, weight, blood group, general patient 
condition) VWD type and date of diagnosis, residual plasma level (%) of VWF:RCo, 
VWF:Ag, and FVIII:C, bleeding time and response to DDAVP. 
Bleeding tendency with severity and frequency will also be observed as well as 
regularly applied medications, previous FVIII/VWF treatment(s), concomitant 
medications at the start with wilate® treatment and viral status (Hepatitis A, B and C, 
antibodies against parvovirus B19, HIV antibodies). 
Vaccination status (against Hepatitis A and B) and clinical chemistry tests 
(hemoglobin, hematocrit, RBC, WBC, platelet count, ALT, AST, bilirubin, creatinine, 
CRP and Erythrocyte Sedimentation Rate-ESR) before wilate® treatment will also be 
observed if available. 

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8.3 
Treatment exposure 
Every wilate® application with date of administration, batch number, total dose 
applied, and reason for the wilate® treatment and wilate® treatment tolerability will be 
observed. Laboratory analyses (if performed) before and after first wilate® application 
and then during the full course of this surveillance will also be observed. 
In case of application before, during or after an interventional treatment, date, time, 
dosage and batch number of wilate® will be observed as well as the wilate® 
application method (bolus injections or continuous infusion in pre-operative, intra- 
operative or post-operative application). Above described laboratory sampling in case 
of wilate® application in pre-operative treatment will also be observed. 
Concomitant medication applied during full course of the surveillance will be 
observed and documented with the generic name of concomitant medication, dosage 
and mode of administration, with start, end or ongoing concomitant therapy 
notification. Concomitant medication applied in the last 7 days before the start of 
observation will be documented. 
 
8.4 
Immunogenicity 
As recommended assessment, the surveillance will observe inhibitor activity 
determined by ELISA performed in the central laboratory after the first exposure day 
(ED), and then on every 3 months during the full course of observation (see table 2). 
Additional testing should be performed at any time during the course of surveillance if 
inhibitor development is suspected. 
Octapharma will reimburse the costs of laboratory tests performed in the designated 
central laboratory and all shipment costs. 
Before inhibitor testing, a period of at least 3-4 days without injection is 
recommended, if clinically acceptable. In order to safely exclude the presence of any 
low titer inhibitors, an injection free period of 7-8 days is preferable. For patients at 
high risk of bleeding, the injection free period is reduced appropriately. 
 
8.5 
Thrombogenicity 
As recommended assessment, the study will observe activation of coagulation 
parameters performed in the central laboratory, based on assessment of prothrombin 
fragments 1 and 2 (F1+2) and D-dimer (DD) by latex enhanced immunoturbimetric 
test. Thrombogenicity assessment should be performed before first wilate® 
application, 1 hour after application, 3 and 24 hours after application and then 
onwards every 3 months during the full course of observation by the same schedule 
(1h, 3h and 24 hours after application). It is also recommended to perform 
thrombogenicity assessment for all interventional procedures. 
Octapharma will reimburse the costs of laboratory tests performed in the designated 
central laboratory and all shipment costs. 

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8.6 
Outcome Assessment 
Assessment of the outcome of wilate® 
 
administration in treatment of bleeding 
episodes (on demand treatment) and in interventional procedures will be based on a 
4-point haemostatic efficacy scale. 
a) Hemostatic efficacy scale applied in treatment of bleeding episodes (on 
demand treatment) assessed by patients or their parents at the end of each 
bleeding episode: 
 Excellent: bleeding was completely stopped within a reasonable period of time 
 Good: bleeding was completely stopped, but time and/or dose slightly 
exceeded expectation 
 Moderate: bleeding could only be stopped by significantly exceeding time 
and/or dose expectation 
 None: bleeding could only be stopped by using other FVIII/VWF-containing 
products. 
b) Hemostatic efficacy scale applied in interventional procedures assessed by 
physician at the end of the procedure: 
 Excellent: Hemostasis clinically not significantly different from normal 
 Good: Mildly abnormal hemostasis in terms of quantity and/or quality (e.g., 
slight oozing) 
 Moderate/Poor: Moderately abnormal hemostasis in terms of quantity and/or 
quality (e.g., moderate, controllable bleeding) 
 None: Severely abnormal hemostasis in terms of quantity and/or quality (e.g., 
severe hemorrhage that is difficult to control) 
The frequency of bleeding episodes in total and per bleeding site, days of treatment 
and numbers of infusions per bleeding episode in total and per bleeding site, 
exposure days and consumption of wilate® per patient and in total will be calculated. 
In addition a comparison of wilate® with previously applied FVIII/VWF preparations 
should  be  performed  (see  also  8.7),  based  on  following  parameters:  bleeding 
frequency, concentrate FVIII/VWF consumption and clinical rating. 
If the dataset allows, the dose used in different types and severities of bleeds will be 
correlated to the efficacy and duration of the treatment. 

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8.7 
Bleeding Tendency 
Before the first application of wilate® the surveillance will observe and document 
previous bleeding frequency (number of bleeds per week, per month, per year) and 
severity of this episodes (severe, moderate, mild). Locations that are affected more 
frequently will also be observed. 
During the course of the observation current bleeding episodes with date of start,  
site, severity (mild, moderate, severe), duration and outcome should be documented 
in CRF. 
 
8.8 
General patient assessment and previous treatment with 
FVIII/VWF 
At the start of the surveillance anamnestic data together with general patient 
condition and other clinically relevant diseases will be observed and documented 
(see section 8.2). Previous treatment with FVIII/VWD concentrates recordings should 
include concentrates applied in the last 6 months before the observation baseline. 
These data should include concentrate use for prophylactic or “on demand” treatment 
with usual dose and application frequency. Total consumption of FVIII/VWF 
concentrate applied in the last six months and exposure days during the same time 
will be observed and documented as well as tolerability assessment of previous 
treatment. Following definition of a 3-point Verbal Rating Scale (VRS) assesses the 
tolerability of previous treatment: 
• Excellent: very good or good overall feeling within or after previous therapy 
• Satisfactory: moderate overall feeling within or after previous therapy and/or 
occurrence of mild reactions (e.g. mild headache, mild dizziness etc.) 
• Unsatisfactory: bad overall feeling within or after previous therapy and/or 
occurrence of moderate or severe adverse drug reactions. 
It is recommended to document patients viral and vaccination status at the baseline 
(see section 8.2). Any changes in vaccination status during the observation period 
should be recorded. 
 
8.8.1 
Laboratory evaluations 
The surveillance will follow subsequent laboratory values: Hemoglobin, Hematocrit, 
WBC, RBC, Platelets, ALT, AST, Bilirubin, Creatinine, CRP and Erythrocyte 
Sedimentation Rate-ESR. The date and time selection for blood sampling for 
laboratory evaluations are at the full discretion of the investigator. 
The observation will record measurements of FVIII/VWF activity before and after 
wilate® application, but the choice of laboratory assays used for FVIII/VWF 
measurements are at the full discretion of the physician. However, its recommended 
to use VWF:RCo, VWF:Ag and FVIII:C analytical methods. 

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8.8.2 
Days lost from school or work 
The surveillance will follow the number of days the patient was not able to attend 
school or work retrospectively if available at the beginning of observation (estimation 
is possible, if no precise data are available) and then during the rest of the 
observation period. 
 
8.9 
Assessments in case of hemostasis management before, during 
or after interventional procedure 
8.9.1 
Assessment of blood loss / Transfusion 
The surveillance will observe and document: date and time of intervention, type and 
description of intervention (planned or emergency), mode of wilate® administration, 
consumption, the quantity of blood lost during intervention and in the following five 
days as well as presence of drainage and quantity of blood lost in drainage system. 
Any presence of hematoma will also be observed if available. 
In case of blood or blood components transfusion; type and volume (ml.) of 
transfusion (whole blood, RBC, platelets, plasma) applied before, during and/or 5 
days after intervention will be observed. 
 
8.10 
Safety / Tolerability 
Each suspected adverse drug reaction (ADR) during or after wilate® therapy noticed 
during the full course of the observation should be documented. The documented 
ADRs will be assessed and reported by the treating physician (for reporting details 
see section 9.2.). 
The tolerability of wilate® injections are assessed by using the following definitions of 
a 3-point Verbal Rating Scale (VRS): 
• Excellent: very good or good overall feeling within or after the wilate® therapy 
and no adverse drug reactions registered 
• Satisfactory: moderate overall feeling within or after the wilate® therapy and/or 
occurrence of mild reactions (e.g. mild headache, mild dizziness etc.) 
• Unsatisfactory: bad overall feeling within or after the wilate® 
occurrence of moderate or severe adverse drug reactions. 
 
8.10.1 
Virus Safety 
therapy and/or 
The surveillance will observe and document the possibility of parvovirus B19 
seroconversion after wilate® application. It is recommended to perform B19 testing 
during subsequent visits including the final visit (see Table 1 Assessment schedule). 

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9 
Safety monitoring 
To allow continuous monitoring of the product safety all adverse drug reactions and 
other safety information as defined below have to be documented and reported to 
Octapharma. 
 
9.1 
Definition of adverse drug reaction and other safety information 
Adverse drug reaction (ADR): 
Is defined as any adverse event associated with the use of wilate®, whether or not 
considered drug related. 
Serious adverse drug reaction: 
ADRs that fulfill at least one of the following criteria: 
 results in death 
 is life-threatening (this implies that the patient was at an immediate risk of 
death at the time of the event, and not a hypothetical situation of what could or 
would have happened if, for example, no treatment had been administered) 
 requires in-patient hospitalization or prolongation of existing in-patient 
hospitalization (hospitalization 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 condition (e.g. suspected transmission 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) 
Other relevant drug safety information: 
Any safety information relating to 
 pregnancies/breastfeeding, 
 drug abuse (persistent, sporadic or intentional excessive use of a medicinal 
product inconsistent with the SPC or acceptable medical practice), 
 overdose (treatment exceeding the medically recommended dose), 
 medication errors (prescribing or dispensing error), 
 interactions with other medicinal products or devices associated with wilate®, 
even if no adverse drug reaction occurred. 

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9.2 
Reporting of adverse drug reactions and other safety information 
All suspected adverse reactions and other safety information associated with the 
administration of wilate® have to be reported to the Octapharma Unit using the Case 
Safety Report Form (see Appendix I). 
Serious adverse drug reactions have to be reported immediately by fax or email 
(within 24 hrs). Non-serious adverse drug reactions and other safety information 
should be reported to Octapharma, if possible, upon recognition but no later than 10 
days. 
Patients who carry out home-treatment with wilate® should be asked to inform the 
treating physician of any adverse drug reaction or other relevant safety information, 
immediately. The treating physician has to assess the causal relationship for ADRs 
and report adverse drug reactions and other relevant drug safety information. 
More information about possible ADRs and other safety information can be found in 
the local Summary of Product Characteristics (see Appendix II). 
 
10 
Data analysis 
10.1 
Statistical Analysis 
The responsibility for the statistical analyses presented in the final report belongs to: 
contract research organisation: GASD, Gesellschaft für Angewandte Statistik + 
Datenanalyse mbH, Am Konvent 8 - 10, 41460 Neuss, Germany. 
This is a prospective post-licensure surveillance that will be conducted as an 
international multi-centre non-interventional surveillance. All items of the CRF will be 
analyzed by means of descriptive statistical methods. 
Standard Patients treatments will be evaluated on total number of wilate® exposure 
days per year and mean wilate® dose per kg per patient per year. 
10.2 
Interim analysis 
The first interim analysis will take place two years after the enrolment of the first 
patient, provided that there will be a reasonable number of documented patient- 
months available. Further interim analyses are planned once a year until surveillance 
completion. 
 
11 
Reference 
1. E. Berntorp, J. Windiga and the European Wilate Study Group; Treatment and 
prevention of acute bleedings in von Willebrand disease--efficacy and safety of 
Wilate, a new generation von Willebrand factor/factor VIII concentrate. Haemophilia. 
2009 Jan;15(1):122-30 

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Appendix I: Local Drug Safety nit of Octapharma 
 
Case Safety Report Form (CSRF) 

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Appendix II: Wilate US Package Insert 

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