Clinical Study to Investigate the Efficacy, Pharmacokinetics, Immunogenicity and Safety of Wilate in Severe Von Willebrand Disease Patients Under the Age of 6 Years
Phase: PHASE3
Conditions: Von Willebrand Disease
Sponsor: Octapharma

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2022-12-05_090-CSP-WIL-33_Final 03 / DOC ID 3534 
 
CLINICAL STUDY PROTOCOL 
CLINICAL STUDY TO INVESTIGATE THE EFFICACY, 
PHARMACOKINETICS, IMMUNOGENICITY AND 
SAFETY OF WILATE IN SEVERE VON WILLEBRAND 
DISEASE PATIENTS UNDER THE AGE OF 6 YEARS 
Investigational Product: 
VWF/FVIII concentrate from plasma of human 
donors (wilate) 
Indication: 
Routine prophylaxis in children under the age of 6 
years with severe VWD 
Study Design: 
Open-label, 
prospective, 
non-controlled, 
international, multi-centre phase 3 study 
Sponsor: 
Octapharma Pharmazeutika Produktionsges.m.b.H. 
Oberlaaer Strasse 235 
A-1100 Vienna 
Austria 
Study Number: 
WIL-33 
EudraCT and/or IND Number: EudraCT: 2020-004344-28 
IND: 011303 
Development Phase: 
Phase 3  
Planned Clinical Start: 
Quarter 3 2021 
Planned Clinical End: 
Quarter 2 2024 
Initial Study Protocol V01: 
Protocol Amendment 1.0: 
Amended Protocol V02: 
Supplemental Amendment 2.0 
Protocol Amendment 3.0: 
Amended Protocol V03: 
15-Jan-2021 
20-Aug-2021 (Moldova only, based on V01) 
31-Aug-2021 
31-Aug-2021 (supplementing Protocol V02) 
20-Nov-2022 (Germany only, based on V02) 
05-Dec-2022 
Version: 
Version 03 
Co-ordinating Investigator: 
 
Paediatric Haematologist-Oncologist 
Loma Linda University Health 
 
250 E Caroline St 
San Bernardino 
CA 92408, United States 
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Copying or distribution of this document is only permitted with the written permission of Octapharma. 
Any commercial use of the information is subject to the permission of Octapharma and a license fee. 

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Study Protocol No. WIL-33 
 
Version 03 
CONFIDENTIAL 
 
05-Dec-2022 
 
Page 1 of 78 
STUDY OUTLINE  
Name of Sponsor/Company: 
Octapharma Pharmazeutika Produktionsges.m.b.H. 
Name of Investigational Product: 
wilate 
Protocol Identification Code: 
WIL-33 
Name of Active Ingredient: 
VWF/FVIII concentrate human 
Date of Final Protocol: 
05-Dec-2022 
 
Title of Study: 
Clinical Study to Investigate the Efficacy, Pharmacokinetics, Immunogenicity and Safety of 
wilate in Severe von Willebrand Disease Patients under the Age of 6 Years 
Indication: 
Routine prophylaxis in children under 6 years of age with severe VWD 
Number of Study Centre(s): 
Up to 15 sites worldwide 
Objectives: 
Primary Objective: 
The primary objective of this study is to determine the efficacy of wilate in the prophylactic 
treatment of up to 12 paediatric patients (eight evaluable) with severe VWD (defined as 
screening von Willebrand factor ristocetin cofactor activity [VWF:RCo] <20%)  under the 
age of 6 years, for a period of 12 months. 
Secondary Objectives: 
The secondary objectives of this study are to: 
• Determine the pharmacokinetics (PK) of wilate for VWF:Ac (VWF:RCo) and FVIII:C 
(one-stage [OS]) 
• Determine incremental in-vivo recovery (IVR) of wilate over time 
• Evaluate the rate of traumatic and spontaneous breakthrough bleeds under 
prophylactic treatment, including the corresponding treatment efficacy 
• Assess the treatment response in minor and major bleeds and surgeries 
• Determine wilate consumption data for prophylactic treatment, on-demand treatment, 
and surgeries 
• Investigate the immunogenic potential of wilate by screening for VWF and FVIII 
inhibitors 
• Investigate the thrombogenic potential of wilate 
• Assess the patients’ joint status with the Haemophilia Joint Health Score (HJHS) 
• Assess the safety and tolerability of wilate 

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Study Protocol No. WIL-33 
 
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Name of Sponsor/Company: 
Octapharma Pharmazeutika Produktionsges.m.b.H. 
Name of Investigational Product: 
wilate 
Protocol Identification Code: 
WIL-33 
Name of Active Ingredient: 
VWF/FVIII concentrate human 
Date of Final Protocol: 
05-Dec-2022 
 
Exploratory Objectives: 
The exploratory objective of this study is to investigate the VWF multimer composition in the 
hereditary type 3 VWD paediatric patients. 
Study Design: 
Open-label, prospective, non-controlled, international, multi-centre phase 3 study 
Number of Subjects/Patients: 
12 patients (eight evaluable) with VWD under the age of 6 years suffering from severe VWD 
defined as screening VWF:RCo <20%, regardless of prior treatment. At least four of these 
patients should be suffering from hereditary type 3 VWD. The remaining patients can be 
diagnosed with severe type 2 (except 2N) or severe type 1 VWD. 
Subject/Patient Selection Criteria: 
Inclusion Criteria: 
1. Patients aged <6 years at the time of screening  
2. Type 3 (at least four patients), severe type 2 (except 2N) or severe type 1 VWD (any 
of which with VWF:RCo <20%) according to medical history, requiring substitution 
therapy with a VWF-containing product 
3. Minimum body weight 12.5 kg at the time of screening 
4. Voluntarily given, fully informed written and signed consent obtained before any 
study-related procedures are conducted (obtained from the patient’s parent(s)/ legal 
guardian(s)) 
Exclusion Criteria: 
1. History, or current suspicion of VWF or FVIII inhibitors 
2. Injection of DDAVP or VWF-containing product within 72 hours prior to inclusion 
3. Medical history of a thromboembolic event 
4. Platelet count <100,000/µL at screening (except for VWD type 2B) 
5. Patients receiving, or scheduled to receive, immunosuppressant drugs (other than 
antiretroviral chemotherapy), such as prednisone (equivalent to >10 mg/day), or 
similar drugs 

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Page 3 of 78 
Name of Sponsor/Company: 
Octapharma Pharmazeutika Produktionsges.m.b.H. 
Name of Investigational Product: 
wilate 
Protocol Identification Code: 
WIL-33 
Name of Active Ingredient: 
VWF/FVIII concentrate human 
Date of Final Protocol: 
05-Dec-2022 
 
6. Treatment with any investigational medicinal product (IMP) in another interventional 
clinical study currently or within four weeks before enrolment 
7. Other coagulation disorders or bleeding disorders 
8. Known hypersensitivity to any of the components of the study drug 
Test Product, Dose, and Mode of Administration: 
The VWF/FVIII concentrate wilate, produced from the plasma of human donors, is presented 
as a powder and solvent for intravenous injection containing nominally 500 IU or 1000 IU 
human VWF and human FVIII per vial. At least three different wilate batches will be used. 
wilate Dosage for PK Assessment: 
Single dose of 80 IU/kg body-weight (BW). The exact dose calculated according to the 
nominal potency should be administered, with 70–85 IU/kg BW as the acceptable range. 
wilate Dosage Recommendations for Prophylactic Treatment: 
For prophylactic treatment, wilate should be administered 2–3 times per week at a 
recommended dose of  30–50 IU/kg BW over 12 months. The prophylactic dose and 
frequency for each patient will be determined by the responsible treating Investigator, based 
on the individual patient’s clinical condition.  
In case of unacceptably frequent breakthrough bleeding events (BEs) (i.e. two or more BEs 
within a 30-day period or one major BE), the dose of wilate should be increased by 
approximately 5 IU/kg BW (depending on the vial size of the additional vial(s) that need(s) 
to be injected) and/or the treatment frequency can be increased. 
wilate Dosage Recommendations for the Treatment of BEs: 
Dose Type 
Minor haemorrhage 
Major haemorrhage 
Loading dose 
30–50 IU/kg BW 
50–80 IU/kg BW 
Maintenance dose 
30–40 IU/kg BW every 12–24 hours 
30–50 IU/kg BW every 12–24 
hours 
Therapeutic goal 
Maintain VWF:Ac and FVIII:C 
trough levels >30% 
Maintain VWF:Ac and FVIII:C 
trough levels >50% 
 
 

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Study Protocol No. WIL-33 
 
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Name of Sponsor/Company: 
Octapharma Pharmazeutika Produktionsges.m.b.H. 
Name of Investigational Product: 
wilate 
Protocol Identification Code: 
WIL-33 
Name of Active Ingredient: 
VWF/FVIII concentrate human 
Date of Final Protocol: 
05-Dec-2022 
 
wilate Dosage Recommendations for Surgical Prophylaxis: 
Dose type 
Minor surgeries (including tooth 
extractions) 
Major surgeries 
Loading dose 
40–60 IU/kg BW 
60–80 IU/kg BW 
Maintenance dose 
20–30 IU/kg BW, or half the 
loading dose, every 12–24 hours 
for up to 3 days 
30–40 IU/kg BW, or half the 
loading dose, every 12–24 hours 
for up to 6 days or longer 
Therapeutic goal 
Achieve VWF:Ac peak levels of 
50% after loading dose and trough 
levels of >30% during maintenance 
doses 
Achieve VWF:Ac peak level of 
100% after loading dose and trough 
levels of >50% during maintenance 
doses 
Duration of Treatment: 
The planned prophylactic treatment duration per patient is 12 months (+2 weeks time-
window). 
The study will be considered clinically completed when all enrolled patients have completed 
the planned observation period (i.e. last visit of last patient). 
Reference Therapy, Dose, Mode of Administration: 
None. 
Study Outcome Parameters (Primary and Secondary Endpoints): 
Efficacy Parameters: 
Primary Endpoint: 
The primary endpoint of this study is to determine the total annualised bleeding rate (tABR) 
during prophylactic treatment with wilate. 
Secondary Endpoints: 
The secondary endpoints of this study are to determine: 
• PK profile characteristics of VWF:Ac (VWF:RCo) and FVIII:C (OS) based on blood 
samples taken pre-dose (baseline), 15 minutes, 3, 9, 24, 48 and 72 hours after dosing 
of 80 IU/kg BW wilate. 
• Incremental in-vivo recovery (IVR) of wilate for VWF:Ac (VWF:RCo) and FVIII:C 
(OS) over time (at baseline and at 1, 2, 3, 6, 9, and 12 months of treatment) 

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Study Protocol No. WIL-33 
 
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Name of Sponsor/Company: 
Octapharma Pharmazeutika Produktionsges.m.b.H. 
Name of Investigational Product: 
wilate 
Protocol Identification Code: 
WIL-33 
Name of Active Ingredient: 
VWF/FVIII concentrate human 
Date of Final Protocol: 
05-Dec-2022 
 
• Efficacy of wilate in the prevention and treatment of spontaneous and traumatic 
breakthrough BEs based on their rate and the proportion of spontaneous and traumatic 
BEs successfully treated with wilate as assessed by the use of a 4-point ordinal 
haemostatic efficacy scale (excellent – good – moderate – none), respectively 
• The overall efficacy of wilate in perioperative prophylaxis against excessive bleeding 
as assessed at the end of the postoperative period by the responsible treating 
Investigator. A 4-point ordinal haemostatic efficacy scale (excellent – good – 
moderate – none) will be used 
• wilate consumption data for prophylactic treatment, for on-demand treatment and 
during surgical prophylaxis 
Safety Parameters: 
Secondary Endpoints: 
• Incidence of VWF and FVIII inhibitors  
• Incidence of thromboembolic events  
• Joint Health Status determination by the use of the HJHS, given the patient’s age and 
constitutional development allow this assessment 
• Safety and tolerability of wilate by monitoring adverse events (AEs) throughout the 
study 
Exploratory Endpoint: 
The exploratory endpoint of this study, which is solely investigated in the hereditary type 3 
VWD patients with ≥14.5 kg body weight, is a VWF multimer analysis from the PK samples 
taken at 15 minutes, and 24 hours after wilate injection, by using multimer analysis using low- 
and high resolution electrophoresis gels. 
 

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Study Protocol No. WIL-33 
 
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Page 6 of 78 
Name of Sponsor/Company: 
Octapharma Pharmazeutika Produktionsges.m.b.H. 
Name of Investigational Product: 
wilate 
Protocol Identification Code: 
WIL-33 
Name of Active Ingredient: 
VWF/FVIII concentrate human 
Date of Final Protocol: 
05-Dec-2022 
 
Study Procedures: 
Patients will participate in the following visits: 
Study Visits: 
Visit 1: Screening Visit 
At the Screening Visit, the following assessments will be performed: 
• Obtain voluntarily given signed and dated informed consent 
• Inclusion and exclusion criteria 
• Collect demographic characteristics and medical history, incl. target joints 
• Physical examination, collect vital signs and Haemophilia Joint Health Score (HJHS) 
• Collect haematology blood samples for the local laboratory and blood samples for the 
central laboratory tests which include VWF:Ac (VWF:RCo), VWF and FVIII 
inhibitor testing and VWF multimer analysis, as well as the retention sample for 
possible virus testing  
• During the Screening Visit, the patient’s parents will receive a patient diary. The 
Investigator will explain how to fill in the diary and emphasise the importance of 
carefully documenting any BEs, treatment details, AEs, and concomitant medication. 
Patients may continue treatment with their previous VWF-containing product for up to four 
weeks, awaiting confirmation of the VWD diagnosis from the central laboratory. The PK visit 
must be initiated within four weeks after the Screening Visit. 
Visit 2: PK Visit 
During the PK Visit, patients will receive wilate at a dose of 80 IU/kg BW after a washout 
period of at least 72 hours from the patient’s previous administration of a VWF-containing 
product. The exact dose calculated according to the nominal potency should be administered, 
with 70–85 IU/kg BW as the acceptable range. Blood samples will be taken pre-dose 
(baseline), 15 minutes, 3, 9, 24, 48 and 72 hours after administration of wilate.  
During the PK Visit the following assessments will be performed: 
• Confirmation of inclusion and exclusion criteria 
• Before injection: measure body weight 
• Before injection and at 15 min (±5 min) after injection: vital signs  

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Study Protocol No. WIL-33 
 
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05-Dec-2022 
 
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Name of Sponsor/Company: 
Octapharma Pharmazeutika Produktionsges.m.b.H. 
Name of Investigational Product: 
wilate 
Protocol Identification Code: 
WIL-33 
Name of Active Ingredient: 
VWF/FVIII concentrate human 
Date of Final Protocol: 
05-Dec-2022 
 
• 
Within 60 min before and 15 min (±5 min), 3 (±1 hour) and 9, 24, 48, and 72 hours 
(each ±2 hours) after injection: PK blood samples – VWF:Ac (VWF:RCo), FVIII:C 
(OS) 
• At 15 min (±5 min) and 24 hours (±2 hours) after injection: VWF multimer analysis 
in type 3 VWD patients with ≥14.5 kg body weight 
• During the visit: patient diary review, bleeding episodes monitoring, AE monitoring, 
concomitant medication 
Patients must not be experiencing acute bleeding during the course of the PK visit.  
During this visit, the future prophylactic dose and dosing interval of wilate will be determined 
by the treating Investigator, based on the patient’s clinical condition. 
The patient’s parents will be trained in how to correctly prepare and administer wilate, which 
will be re-supplied whenever necessary during the study. The Investigator will discuss wilate 
dose and frequency of administration with the patients’ parents, both for regular prophylaxis 
and for treatment of BEs. 
The first prophylactic dose will be administered after completion of the PK Assessment, i.e. 
after the 72-hour sample has been collected), and should be administered at the study site 
before patients return to home treatment. Where applicable, external home-care companies 
with experience in conducting clinical studies will be contracted, with trained nurses 
supporting patients’ parents by providing training, re-training, and oversight through home-
care visit support throughout the study. 
Visit 3: 1-Month IVR Visit 
The 1-Month IVR Visit will take place 1 month (±3 days) after the first prophylactic injection 
of wilate has been received. The following assessments will be performed: 
• Before injection: measure body weight 
• Within 60 min before and 15 min after (±5 min) injection: IVR blood sampling 
(VWF:Ac [VWF:RCo] and FVIII:C [OS]) and vital signs 
• During the visit: patient diary review, review of compliance, bleeding episodes 
monitoring, AE monitoring, concomitant medication, AB0 blood group testing (if 
unknown, can also be shifted to a later timepoint) 
 

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Page 8 of 78 
Name of Sponsor/Company: 
Octapharma Pharmazeutika Produktionsges.m.b.H. 
Name of Investigational Product: 
wilate 
Protocol Identification Code: 
WIL-33 
Name of Active Ingredient: 
VWF/FVIII concentrate human 
Date of Final Protocol: 
05-Dec-2022 
 
Visit 4: 2-Month IVR Visit 
The 2-Month IVR Visit will take place 2 months (±3 days) after the first prophylactic injection 
of wilate has been received. The following assessments will be performed: 
• Before injection: measure body weight  
• Within 60 min before and 15 min after (±5 min) injection: IVR blood sampling 
(VWF:Ac [VWF:RCo] and FVIII:C [OS]) and vital signs 
• During the visit: patient diary review, review of compliance, bleeding episodes 
monitoring, AE monitoring, concomitant medication 
Visits 5–7: 3-Monthly IVR Visits 
The 3-Monthly IVR Visits will take place after 3 (±1 week), 6 (±2 weeks), and 9 months (±2 
weeks) after the first prophylactic injection of wilate has been received. The following 
assessments will be performed: 
• Before injection: measure body weight, blood sampling for VWF and FVIII inhibitor 
testing 
• Within 60 min before and 15 min after (±5 min) injection: IVR blood sampling 
(VWF:Ac [VWF:RCo] and FVIII:C [OS]) and vital signs 
• During the visit: patient diary review, review of compliance, bleeding episodes 
monitoring, AE monitoring, concomitant medication 
Visit 8: Study Completion (12-Month) Visit 
The Study Completion Visit will take place 12 months (+2 weeks) after the first prophylactic 
injection of wilate. The following assessments will be performed: 
• Before injection: measure body weight, blood sampling for VWF and FVIII inhibitor 
testing, and for haematology parameters at local laboratory. 
• Within 60 min before and 15 min after (±5 min) injection: IVR blood sampling 
(VWF:Ac [VWF:RCo] and FVIII:C [OS]) and vital signs 
• During the visit: patient diary review, review of compliance, HJHS, physical 
examination, bleeding episodes monitoring, AE monitoring, concomitant medication, 
target joints. 
Compliance calls 
Parents should be contacted by telephone every 5–7 weeks after the 3-monthly IVR visits at 
3, 6, and 9 months. The compliance calls will check the following: 

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Study Protocol No. WIL-33 
 
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Name of Sponsor/Company: 
Octapharma Pharmazeutika Produktionsges.m.b.H. 
Name of Investigational Product: 
wilate 
Protocol Identification Code: 
WIL-33 
Name of Active Ingredient: 
VWF/FVIII concentrate human 
Date of Final Protocol: 
05-Dec-2022 
 
• Patient’s overall condition and wellbeing 
• Adherence to the treatment regimen (dose and frequency) 
• Bleeding episodes and their treatment 
• Requirement of any prophylactic treatment adjustment 
• Adverse events 
• Concomitant medication 
• Answer parents’ questions or concerns, if any 
Unscheduled Visits and Additional Measures 
If an inhibitor development is suspected (e.g. based on an unexplained need to increase the 
dose, a lack of efficacy of wilate injections seen in more frequent spontaneous bleeds, or 
prolonged bleeding), VWF and FVIII inhibitor tests will be performed at the central 
laboratory. In case of positive inhibitor results, inhibitor re-testing using a second, separately 
drawn sample should be performed, preferably within 15 days of becoming aware of the 
positive result. 
Other reasons for unscheduled visits may be the occurrence of serious AEs or hospitalisations 
for BEs or surgical interventions. 
Statistical Analysis Plan: 
No formal sample size calculation was performed for the study. The sample size of up to 12 
patients, including at least four patients with type 3 VWD, is based on a communication with 
the FDA and on EU guideline CPMP/BPWG/220/02 calling for a trial in at least eight children 
with VWD under the age of 6 years, three of whom should have type 3 VWD and was selected 
to accommodate for drop-outs. 
The tABR will be evaluated over all types of VWD. The frequency and severity of BEs and 
the total, traumatic and spontaneous ABR will be calculated from patients’ dosing and 
treatment frequency in different VWD types. 
The haemostatic efficacy of wilate in the treatment of BEs will be assessed, and a frequency 
distribution of all successfully treated BEs will be presented overall and by severity, along 
with an exploratory 95% confidence interval (CI). Statistical analyses of other secondary 
endpoints will be descriptive, including exploratory 95% CIs. 
The PK and recovery assessments will be summarised using descriptive statistics and the 
presentation of concentration vs. time plots. The results of IVR assessments over time will be 

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Study Protocol No. WIL-33 
 
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Name of Sponsor/Company: 
Octapharma Pharmazeutika Produktionsges.m.b.H. 
Name of Investigational Product: 
wilate 
Protocol Identification Code: 
WIL-33 
Name of Active Ingredient: 
VWF/FVIII concentrate human 
Date of Final Protocol: 
05-Dec-2022 
 
presented per time point and as differences to baseline, along with 95% CIs for the mean 
differences. 
Safety analysis will be based on the occurrence of AEs, e.g. results of immunogenicity 
screening, thrombogenicity monitoring for sustained excessive FVIII plasma levels (and an 
increased risk of thrombotic events), and safety laboratory testing. Analysis of AEs will focus 
on treatment-emergent adverse events (TEAEs). 
Time profiles of VWF and FVIII inhibitor testing results will be analysed by presenting 
sampling statistics for the values as well as frequency tables for positive findings, along with 
95% Pearson-Clopper CIs. 
 

Study Protocol No. WIL-33 
 
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FLOW CHART FOR PK ASSESSMENT AND PROPHYLACTIC TREATMENT 
Table 1 
Flow Chart of Assessments Performed Throughout the Study 
ASSESSMENTS 
Screening 
Visit 
PK Visit 
(within 4 
weeks after 
Screening) 
1-Month Visit 
(±3 days) 
2-Month Visit 
(±3 days) 
3-Month Visit 
(±1 week) 
Compliance 
Call 1 [1] 
(5–7 weeks 
after 3-Month 
Visit) 
6-Month Visit 
(±2 weeks) 
Compliance 
Call 2 [1] 
(5–7 weeks 
after 6-Month 
Visit) 
9-Month 
Visit 
(±2 weeks) 
Compliance 
Call 3 [1] 
(5–7 weeks 
after 9-Month 
Visit) 
Study 
Completion 
(12-Month) 
Visit 
(+2 weeks) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Medical history and prior medication 
X 
 
 
 
 
 
 
 
 
 
 
Family history of VWD 
X 
 
 
 
 
 
 
 
 
 
 
Vital signs (blood pressure, heart rate, body 
temperature, respiratory rate) [2] 
X 
X  
X 
X 
X 
 
X 
 
X 
 
X 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
X 
Injections at study site 
 
 
 
 
 
 
 
 
 
 
 
 
PK injection (80 IU/kg BW) [10] 
 
X 
 
 
 
 
 
 
 
 
 
 
IVR injection  
 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
Start of prophylactic treatment phase [8] 
 
X 
 
 
 
 
 
 
 
 
 
Local laboratory assessments 
 
 
 
 
 
 
 
 
 
 
 
 
Routine safety laboratory (haematology) 
X  
 
 
 
 
 
 
 
 
 
X [3] 
 
Determination of AB0 blood group 
 
 
X [4] 
 
 
 
 
 
 
 
 
Central laboratory assessments 
 
 
 
 
 
 
 
 
 
 
 
 
VWF:Ac (VWF:RCo) 
X 
X [6] 
X [2] 
X [2] 
X [2] 
 
X [2] 
 
X [2] 
 
X [2] 
 
FVIII:C (OS) 
 
X [6] 
X [2] 
X [2] 
X [2] 
 
X [2] 
 
X [2] 
 
X [2] 
 
VWF and FVIII inhibitors [5]  
X 
 
 
 
X [3] 
 
X [3]   
 
X [3]   
 
X [3]  
 
Retention samples for virus marker 
 
testing 
X 
 
 
 
 
 
 
 
 
 
 
 
VWF multimer analysis 
X 
X [7] 
 
 
 
 
 
 
 
 
 
Haemophilia Joint Health Score (HJHS) [9]  
X 
 
 
 
 
 
 
 
 
 
X  
Assessment of compliance and adherence to 
treatment regimen  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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ASSESSMENTS 
Screening 
Visit 
PK Visit 
(within 4 
weeks after 
Screening) 
1-Month Visit 
(±3 days) 
2-Month Visit 
(±3 days) 
3-Month Visit 
(±1 week) 
Compliance 
Call 1 [1] 
(5–7 weeks 
after 3-Month 
Visit) 
6-Month Visit 
(±2 weeks) 
Compliance 
Call 2 [1] 
(5–7 weeks 
after 6-Month 
Visit) 
9-Month 
Visit 
(±2 weeks) 
Compliance 
Call 3 [1] 
(5–7 weeks 
after 9-Month 
Visit) 
Study 
Completion 
(12-Month) 
Visit 
(+2 weeks) 
Bleeding Episodes monitoring 
Throughout the study 
Concomitant Medication monitoring 
Throughout the study 
Adverse event monitoring 
Throughout the study 
 
VWD = von Willebrand disease, FVIII = factor VIII, FVIII:C = factor VIII procoagulant activity, OS = one-stage assay 
[1] Parents should be contacted by telephone 5–7 weeks after the 3-monthly IVR visits at 3, 6, and 9 months.to check the patient’s status of bleedings, AEs, concomitant medications, compliance and adherence 
with treatment regimen, including the evaluation of the need to adjust the prophylactic treatment, completing diary. 
[2] Within 60 min before and 15 ±5 min after wilate injection. 
[3] Before injection. 
[4] To be determined unless known.  
[5] At the given time-points and at any time if inhibitor development is suspected. 
[6] Blood samples for PK and recovery assessment to be taken before injection, and after 15 minutes, 3, 9, 24, 48 and 72 hours after injection (central laboratory). At least three different wilate batches should 
be used. 
  
[7] Multimer analysis will be performed in all patients at Screening. At the PK Visit, the VWF multimer analysis will only be performed in type 3 VWD patients with ≥14.5 kg body weight: the samples taken  
at 15 minutes, and 24 hours after the injection will be used to investigate the VWF multimer distribution of the VWF by multimeric sizing analysis using low- and high resolution electrophoreses gels. 
[8] Start of prophylactic treatment phase: first IMP injection after collection of the last PK sample (i.e. the 72-hour sample), which is administered at the study site before patients return to home treatment 
[9] Given the patient’s age and constitutional development allow this assessment. 
[10] The exact dose calculated according to the nominal potency should be administered, with 70– 85 IU/kg BW as the acceptable range. 
 
 
 
 
 
 
 

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PROTOCOL SIGNATURES 
Signature of the Sponsor's Representative 
Version 03 
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This study is intended to be conducted in compliance with the protocol, 
Good Clinical Practice and applicable regulatory requirements. 
--
- A_t1~i_~-~v~< 
 
Octapharma AG 
Seidenstrasse 2 
8853 Lachen, Switzerland 
Signature 
Date 
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Signature of the Author of the Protocol/Clinical Project Manager 
This study is intended to be conducted in compliance with the protocol, Good Clinical 
Practice and applicable regulatory requirements. 
 
 
Octapharma Pharmazeutika Produtionsges.m.b.H. 
Oberlaaer Strasse 235 
A-1100 Vienna, Austria 
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Date 
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Study Protocol No. WIL-33 
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Signature of the Study Medical Expert 
Version 03 
05-Dec-2022 
This study is intended to be conducted in compliance with the protocol, Good Clinical 
Practice and applicable regulatory requirements. 
 
Octapharma AG 
Seidenstrasse 2 
8853 Lachen, Switzerland 
Signature 
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Date 
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Study Protocol No. WIL-33 
CONFIDENTIAL 
Signature of the Biostatistician 
Version 03 
05-Dec-2022 
This study is intended to be conducted in compliance with the protocol, 
Good Clinical Practice and applicable regulatory requirements. 
 
Ergomed CDS 
Im Mediapark 2 
D-50670 Cologne, Germany 
Signature 
Date 
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Study Protocol No. WIL-33 
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Signature of the Coordinating Investigator 
Version 03 
05-Dec-2022 
This study is intended to be conducted in compliance with the protocol, 
Good Clinical Practice and applicable regulatory requirements. 
250 E Caroline St 
San Bemandino 
CA 92408, United States 
Signature 
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TABLE OF CONTENTS 
STUDY OUTLINE .................................................................................................................................1 
FLOW CHART FOR PK ASSESSMENT AND PROPHYLACTIC TREATMENT ...................11 
PROTOCOL SIGNATURES ..............................................................................................................13 
TABLE OF CONTENTS .....................................................................................................................18 
INDEX OF TABLES ............................................................................................................................21 
LIST OF ABBREVIATIONS ..............................................................................................................22 
1 
INTRODUCTION .......................................................................................................................23 
1.1 
RATIONALE FOR CONDUCTING THE STUDY ............................................................. 24 
1.2 
DOSE RATIONALE ................................................................................................... 25 
1.3 
BENEFIT-RISK STATEMENT..................................................................................... 25 
1.4 
COVID-19 BENEFIT-RISK STATEMENT .................................................................. 26 
2 
STUDY OBJECTIVES ...............................................................................................................27 
2.1 
PRIMARY OBJECTIVE(S) .......................................................................................... 27 
2.2 
SECONDARY OBJECTIVE(S) ..................................................................................... 27 
2.3 
EXPLORATORY OBJECTIVE(S) ................................................................................. 27 
3 
INVESTIGATIONAL PLAN .....................................................................................................28 
3.1 
PRIMARY AND SECONDARY ENDPOINTS ................................................................. 28 
3.1.1 
Primary Endpoint .................................................................................................28 
3.1.2 
Secondary Endpoints ............................................................................................28 
3.1.3 
Safety Parameters .................................................................................................28 
3.1.4 
Exploratory Endpoint ...........................................................................................28 
3.2 
OVERALL STUDY DESIGN AND PLAN ...................................................................... 28 
3.3 
DISCUSSION OF STUDY DESIGN AND CHOICE OF CONTROL GROUP(S) .................... 29 
3.3.1 
Study Design .........................................................................................................29 
3.3.2 
Control Group(s) ..................................................................................................29 
3.3.3 
Study Parameters ..................................................................................................29 
4 
STUDY POPULATION ..............................................................................................................33 
4.1 
POPULATION BASE ................................................................................................. 33 
4.1.1 
Inclusion Criteria ..................................................................................................33 
4.1.2 
Exclusion Criteria .................................................................................................33 
4.2 
PRIOR AND CONCOMITANT THERAPY ..................................................................... 34 
4.2.1 
Permitted Concomitant Therapy ...........................................................................34 
4.2.2 
Forbidden Concomitant Therapy ..........................................................................34 
4.3 
WITHDRAWAL AND REPLACEMENT OF SUBJECTS/PATIENTS................................... 34 
4.3.1 
Premature Subject/Patient Withdrawal ................................................................34 
4.3.2 
Subject/Patient Replacement Policy .....................................................................34 
4.4 
ASSIGNMENT OF SUBJECTS/PATIENTS TO TREATMENT GROUPS ............................. 35 
4.5 
RELEVANT PROTOCOL DEVIATIONS ....................................................................... 35 
4.6 
SUBSEQUENT THERAPY .......................................................................................... 35 
 

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5 
INVESTIGATIONAL MEDICINAL PRODUCT(S) ...............................................................36 
5.1 
CHARACTERISATION OF INVESTIGATIONAL PRODUCT(S) ........................................ 36 
5.2 
PACKAGING AND LABELLING ................................................................................. 36 
5.3 
CONDITIONS FOR STORAGE AND USE...................................................................... 36 
5.4 
DOSE AND DOSING SCHEDULE ................................................................................ 36 
5.4.1 
wilate Dosage for PK Assessment ........................................................................36 
5.4.2 
wilate Dosage for Prophylactic Treatment ...........................................................36 
5.4.3 
wilate Dose for the Treatment of Bleeding Episodes (BEs) ..................................37 
5.4.4 
wilate Dose for Surgical Prophylaxis ...................................................................38 
5.5 
PREPARATION AND METHOD OF ADMINISTRATION ................................................. 38 
5.6 
BLINDING, EMERGENCY ENVELOPES, AND BREAKING THE STUDY BLIND .............. 38 
5.7 
TREATMENT COMPLIANCE ...................................................................................... 38 
5.7.1 
Drug Dispensing and Accountability ....................................................................38 
5.7.2 
Assessment of Treatment Compliance ..................................................................39 
6 
STUDY CONDUCT ....................................................................................................................40 
6.1 
OBSERVATIONS BY VISIT ........................................................................................ 40 
6.1.1 
Screening Visit (Visit 1) ........................................................................................40 
6.1.2 
PK Visit (Visit 2) ...................................................................................................41 
6.1.3 
1-Month Visit (Visit 3) ..........................................................................................42 
6.1.4 
2-Month Visit (Visit 4) ..........................................................................................43 
6.1.5 
3-Month Visit (Visit 5) ..........................................................................................43 
6.1.6 
6-Month and 9-Month Visit (Visit 6 and 7) ...........................................................44 
6.1.7 
Study Completion (12-Month) Visit (Last visit) ....................................................44 
6.1.8 
Compliance Calls ..................................................................................................45 
6.1.9 
Unscheduled Visits and Additional Measures ......................................................46 
6.1.10 Surgical Visits .......................................................................................................46 
6.2 
DURATION OF STUDY ............................................................................................. 46 
6.2.1 
Planned Duration for an Individual Subject/Patient ............................................46 
6.2.2 
Planned Duration for the Study as a Whole .........................................................46 
6.2.3 
Premature Termination of the Study .....................................................................46 
7 
ASSESSMENTS AND METHODS ...........................................................................................48 
7.1 
DEMOGRAPHIC AND BASELINE INFORMATION ........................................................ 48 
7.1.1 
Demographic and baseline characteristics ..........................................................48 
7.1.2 
Medical history and prior/concomitant medications ............................................48 
7.2 
EFFICACY ASSESSMENTS ........................................................................................ 48 
7.2.1 
Assessments for Primary Efficacy Endpoint(s) .....................................................48 
7.2.2 
Assessments for Secondary Efficacy Endpoint(s) .................................................49 
7.3 
PHARMACOKINETIC ASSESSMENTS ......................................................................... 53 
7.4 
SAFETY ASSESSMENTS ........................................................................................... 54 
7.4.1 
Assessments for Safety Endpoints .........................................................................54 
7.4.2 
Adverse Events (AEs) ............................................................................................54 
7.4.3 
Serious Adverse Events (SAEs) .............................................................................57 
7.4.4 
SAE Reporting Timelines ......................................................................................57 
7.4.5 
Laboratory Tests ...................................................................................................58 
7.4.6 
Virus Safety Tests ..................................................................................................61 

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7.4.7 
Vital Signs and Physical Examination ..................................................................61 
7.4.8 
Other Relevant Safety Information .......................................................................62 
7.5 
APPROPRIATENESS OF MEASUREMENTS ................................................................. 63 
8 
DATA HANDLING AND RECORD KEEPING......................................................................64 
8.1 
DOCUMENTATION OF DATA .................................................................................... 64 
8.1.1 
Source Data and Records .....................................................................................64 
8.1.2 
Case Report Forms ...............................................................................................64 
8.1.3 
Changes to electronic Case Report Form (eCRF) Data .......................................65 
8.2 
INFORMATION TO INVESTIGATORS .......................................................................... 65 
8.3 
RESPONSIBILITIES ................................................................................................... 65 
8.4 
INVESTIGATOR’S SITE FILE ..................................................................................... 66 
8.5 
PROVISION OF ADDITIONAL INFORMATION ............................................................. 66 
8.6 
INDEPENDENT DATA MONITORING COMMITTEE ..................................................... 66 
9 
STATISTICAL METHODS AND SAMPLE SIZE .................................................................67 
9.1 
DETERMINATION OF SAMPLE SIZE .......................................................................... 67 
9.2 
STATISTICAL ANALYSIS .......................................................................................... 67 
9.2.1 
Populations for Analysis .......................................................................................67 
9.2.2 
Efficacy Analysis Plan ..........................................................................................68 
9.2.3 
Safety Analysis Plan..............................................................................................69 
9.2.4 
Handling of Missing Data .....................................................................................70 
9.3 
RANDOMISATION, STRATIFICATION, AND CODE RELEASE ...................................... 70 
9.4 
INTERIM ANALYSIS (IF APPLICABLE) ...................................................................... 70 
10 
ETHICAL/REGULATORY, LEGAL AND ADMINISTRATIVE ASPECTS ......................71 
10.1 ETHICAL/REGULATORY FRAMEWORK .................................................................... 71 
10.2 APPROVAL OF STUDY DOCUMENTS ........................................................................ 71 
10.3 PATIENT INFORMATION AND INFORMED CONSENT ................................................. 71 
10.4 PROTOCOL AMENDMENTS ...................................................................................... 72 
10.5 CONFIDENTIALITY OF SUBJECT/PATIENT DATA ...................................................... 72 
11 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................................73 
11.1 PERIODIC MONITORING .......................................................................................... 73 
11.2 AUDIT AND INSPECTION .......................................................................................... 73 
12 
REPORTING AND PUBLICATION ........................................................................................74 
12.1 CLINICAL STUDY REPORT ....................................................................................... 74 
12.2 PUBLICATION POLICY ............................................................................................. 74 
13 
LIABILITIES AND INSURANCE ............................................................................................75 
14 
REFERENCES ............................................................................................................................76 
15 
APPENDICES..............................................................................................................................78 
 
 
 

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INDEX OF TABLES 
 
Table 1 
Flow Chart of Assessments Performed Throughout the Study ............................. 11 
Table 2 
Definition of the Severity of Bleeding................................................................... 30 
Table 3 
Efficacy Assessment of the Treatment of Breakthrough BEs ............................... 31 
Table 4 
wilate Dosage Recommendations for the Treatment of BEs ................................. 37 
Table 5 
wilate Dosage Recommendations for Surgical Prophylaxis .................................. 38 
Table 6 
Assessments for Perioperative Prophylaxis ........................................................... 51 
Table 7 
Efficacy Assessment at the End of Surgery ........................................................... 52 
Table 8 
Efficacy Assessment at the End of the Postoperative Period ................................ 52 
Table 9 
Algorithm for the Overall Efficacy Assessment for Surgical Prophylaxis............ 53 
Table 10 
Laboratory Sampling Flowchart ............................................................................ 58 
 
 

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LIST OF ABBREVIATIONS 
 
Abbreviation 
Description 
ABR 
Annualised Bleeding Rate 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
Ag 
Antigen 
BE 
Bleeding Episode 
BW 
Body Weight 
CI 
Confidence Interval 
CRF 
Clinical Report Form 
CRO 
Contract Research Organisation 
DDAVP 
Desmopressin (1-deamino-8-D-arginine vasopressin) 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EDTA 
Ethylenediaminetetraacetic acid 
FAS 
Full Analysis Set 
FVIII 
Factor VIII 
FVIII:C 
Factor VIII procoagulant activity 
GCP 
Good Clinical Practice 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
HJHS 
Haemophilia Joint Health Score 
IB 
Investigator’s Brochure 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
PP 
Per Protocol 
RBC 
Red Blood Count 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SURG 
Surgery (Population) 
TABR 
Total Annualised Bleeding Rate 
TEAE 
Treatment-Emergent Adverse Event 
VWD 
Von Willebrand Disease 
VWF 
Von Willebrand Factor 
VWF:Ac 
Von Willebrand Factor Activity 
VWF:RCo 
Von Willebrand ristocetin cofactor activity 
WBC 
White blood cell count 

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1 
INTRODUCTION 
Von Willebrand Disease 
Inherited von Willebrand disease (VWD) is the most common inherited haemorrhagic 
disorder, and many cases are diagnosed in childhood, with an estimated prevalence of 1 in every 
100 individuals of either sex [1]. There is wide geno- and phenotypic variability of the disease, 
and not all patients with VWD require treatment. 
Three types of inherited VWD are known. Whereas type 1 and type 3 disease are characterised 
by a quantitative deficiency of von Willebrand factor (VWF), VWD type 2 arises from a 
qualitative deficiency of VWF. There are various subtypes within the three inherited types of 
VWD. Von Willebrand disease may also be acquired. 
Of the inherited forms, type 1 is the most common, accounting for 70–80% of cases, followed 
by type 2, which affects approximately 20% of patients. Type 3, the most severe form of VWD 
characterised by a complete absence of VWF, is rare and affects about 1–3% of all patients [2]. 
Clinical symptoms of VWD include predominantly mild mucosal bleeding; surgical bleeding 
may occur with specific challenges and joint bleeding can occur in the most severe forms [3].  
Treatment of VWD depends on the type and severity of the disease. Whereas mild to moderate 
forms of type 1 and type 2A disease often respond adequately to treatment with desmopressin 
(1-deamino-8-D-arginine vasopressin, DDAVP), this approach is contraindicated in type 2B 
and not effective in type 3 disease. Treatment with DDAVP may also be contraindicated for 
other clinical reasons or may be associated with significant side effects. Immediate potential 
complications of DDAVP include flushing, hypotension/hypertension, gastrointestinal upset, 
and headache. Repeated dosing of this antidiuretic-hormone mimicking drug can lead to 
hyponatremia and seizures [3]. Although some responses have been seen in other type 2 
patients, they are usually either too small or not sufficiently sustained to be effective. DDAVP 
is not effective in type 3 patients and is usually contraindicated in type 2B patients because it 
may promote thrombocytopenia, although it has been effective in selected type 2B patients [4]. 
DDAVP is not recommended for patients under the age of 2 due to poor response [5]. 
The appropriate treatments for patients in whom DDAVP is ineffective or contraindicated are 
VWF/factor VIII (FVIII) concentrates, which have become the mainstay of VWD treatment. 
Cryoprecipitate, which is screened for viruses but not treated to inactivate them, is also rich in 
VWF, but is likely to be less safe than viral-attenuated concentrates [6]. 
wilate 
wilate is a plasma-derived, stable, highly purified, double virus inactivated concentrate of 
freeze-dried active VWF and FVIII prepared from cryoprecipitate and intended for the 
treatment of patients with VWD and/or haemophilia A. By introducing new biotechnological 
methods and optimised chromatographic media into the wilate manufacturing process, it has 
been possible to manufacture a preparation containing the FVIII/VWF complex in its native 
form and almost devoid of lower molecular weight proteins. Therefore, antigenicity and 
immunogenicity due to co-purified proteins are reduced to a minimum. 
Overall, 16 prospective clinical studies with wilate have been completed, eight in patients with 
VWD and eight in patients with haemophilia A. A summary of findings from nonclinical and 
clinical studies with wilate, including in paediatric patients, is provided in the product’s 
Investigator’s Brochure (IB) [7]. 

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wilate received its first marketing authorisation in Germany in February 2005; to date, wilate 
has been licensed in 72 countries worldwide. 
1.1 Rationale for Conducting the Study 
The purpose of this study is to obtain additional data on the efficacy, PK, immunogenicity, and 
safety of wilate in paediatric patients below the age of 6 years with severe VWD undergoing 
regular prophylaxis, thus supplementing the existing body of data to obtain approval of wilate 
in the prophylactic treatment of severe VWD in this patient population. Other studies have 
demonstrated a beneficial effect of prophylaxis with VWF treatment in patients with severe 
VWD, including paediatric patients. These reported reduced mucosal and joint bleeding rates, 
decreased median ABR, a reduced incidence of major bleeds, and good tolerability: 
• Treatment of mucosal bleeding (epistaxis and gastrointestinal bleeding) and joint bleeding 
remains problematic in clinically severe VWD. Patients are often unresponsive to treatment 
(e.g. desmopressin or antifibrinolytic therapy) and may require VWF replacement therapy. 
A prospective, treatment escalation design study evaluated the effect of escalating dose 
prophylaxis in 11 patients with severe VWD (median age 34.6 years). Use of prophylaxis 
with VWF concentrates reduced mucosal and joint bleeding rates. The median ABR 
decreased from 25 to 6.1 (95% confidence interval [CI] of the rate difference: -51.6 to -1.7) 
[8]. 
• A recent phase 3, multi-centre, open-label trial included 17 previously treated children <12 
years old with severe type 1, 2A, or 3 VWD (VWF:RCo <20% at screening or a documented 
history of VWF:RCo <10%), for whom DDAVP treatment had been ineffective, 
contraindicated, or unavailable. Participants received on-demand treatment of nonsurgical 
bleeds, were undergoing a surgical procedure, or were treated on a predefined prophylactic 
regimen with a plasma-derived VWF/FVIII concentrate. The duration of study participation 
ranged from 12 to 13 months. Pharmacokinetic parameters for VWF markers were generally 
comparable to adults but showed lower VWF:RCo exposure, as indicated by a lower 
incremental recovery, shorter half-life, and faster clearence. Incidence of major bleeds was 
lower for prophylaxis (3.3%) than on-demand therapy (27.1%); joint bleeds were also lower 
(3.3% vs 11.5%, respectively). Investigator-reported excellent/good haemostatic efficacy 
against nonsurgical bleeds was 100%. No clinically relevant differences in PK, haemostatic 
efficacy, or safety were observed between age groups (<6 years and 6 to <12 years). The 
treatment was well tolerated. Adverse events were mild to moderate and consistent with the 
adult safety profile. No cases of anaphylactic reactions or angioedema, development of 
FVIII/VWF inhibitors, thromboembolic events, or viral infections were reported [9].  
• A study found that 23% (184/804) of VWD patients self-reported joint bleeds. These 184 
patients reported joint damage more often (54% vs. 18%, p<0.001) and had lower health-
related QoL (SF-36, p<0.05) compared to VWD patients not reporting joint bleeds. Of 55 
patients with available joint bleed data, 65% had the first joint bleed in childhood. These 55 
patients used more clotting factor concentrate (p<0.001), more often had X-ray joint 
damage (44% vs. 11%, p=0.001] and chronic joint pain (44% vs. 18%, p=0.008) compared 
to 55 control VWD patients without joint bleeds [10]. Therefore, it was considered valuable 
to measure the HJHS score in the enrolled paediatric patients, because although the HJHS 
score has been validated in adult patients [11], there are no validated tools to determine QoL 
or disease-specific tools to assess the musculoskeletal status in paediatric patients with 
severe VWD. 

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Since there are insufficient data on use of wilate in paediatric patients with severe VWD below 
the age of 6 years, Octapharma plans to evaluate the efficacy of wilate in bleeding prophylaxis 
in these patients. 
1.2 Dose Rationale 
Doses of wilate vary based on the indication. The doses for prophylaxis (30–50 IU/kg BW 
administered 2–3 times per week), the treatment of BEs, and perioperative prophylaxis are 
detailed in Section 5.2. Because there are currently insufficient data to recommend the use of 
wilate in children under 6 years of age, the dose rationale was based on recommended doses in 
adults and children over 6 years of age [12, 13], with some adjustments allowing for the fact 
that, contrary to adults, 1 IU/kg BW VWF:Ac and FVIII:C may not raise the plasma level by 
as much as 1.5–2% of normal activity for the respective proteins in children below the age of 6 
years. 
1.3 Benefit-Risk Statement 
The following adverse drug reactions (ADRs) are known to occur with other VWF/FVIII 
preparations and may also occur with the use of wilate [7]: 
• 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 been observed upon use of wilate and may, in some cases, 
progress to severe anaphylaxis (including shock) with or without fever. On rare occasions, 
fever has been observed. 
• Patients with VWD, especially type 3 patients, may develop neutralising antibodies 
(inhibitors) to VWF and/or FVIII. If expected VWF:Ac and/or FVIII:C activity plasma 
levels are not attained or bleeding is not controlled with an appropriate dose, an appropriate 
assay should be performed to determine whether a VWF inhibitor and/or factor VIII 
inhibitor is present. In patients with high titres of inhibitor, VWF therapy may not be 
effective, and other therapeutic options should be considered. 
• As for all medicinal products prepared from human blood or plasma, infectious diseases 
due to transmission of infective agents cannot be totally excluded. This also applies to 
pathogens of hitherto unknown origin. The manufacturing process of wilate, which includes 
two viral inactivation steps with different chemical/physical action principles, represents a 
high standard for plasma-derived concentrates in terms of pathogen safety. The measures 
taken are considered effective for enveloped viruses such as human immunodeficiency virus 
(HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV), and for the non-enveloped 
hepatitis A virus. The measures taken may be of limited value against non-enveloped 
viruses such as parvovirus B19. 
• Thrombotic events. When using a FVIII-containing VWF product, the treating physician 
should be aware that continued treatment may cause an excessive rise in FVIII:C. Patients 
receiving FVIII-containing VWF products should be monitored for sustained excessive 
FVIII:C plasma levels, which may increase the risk of thrombotic events. The risk of 
occurrence of thrombotic events in patients using FVIII-containing VWF products is 

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particularly increased in patients with known clinical or laboratory risk factors. Therefore, 
patients at risk must be monitored for early signs of thrombosis. Prophylaxis against venous 
thromboembolism should be instituted in accordance with current recommendations. 
In view of its state-of-the-art manufacturing process and available clinical and post-marketing 
evidence, the benefit-risk evaluation of wilate is positive, including paediatric patients. 
1.4 COVID-19 Benefit-Risk Statement 
For the WIL-33 study, patients and their parents are required to come into the treatment centre 
for 8 visits over a period of approximately 12 months in order to participate in the study. There 
is therefore a risk that the parents may become exposed to COVID-19 and potentially even 
infected. The standard safety measures will be in place at the treatment centres in line with the 
local requirements. 
Potential COVID-19 related risks for site management and project management will be 
evaluated in advance and options such as alternative monitoring approaches will be 
implemented. In addition, for the support of the study processes (e.g. provision of the study 
medication and transport of the blood samples), only well-established service providers are 
selected which have strong regional expertise and strict risk and quality guidelines in place, 
including with regards to potential COVID-19-related risks. The current regulations regarding 
transport and logistics will be continuously monitored for the countries participating in the 
study, and flexible solutions and longer lead times will be implemented wherever appropriate. 
In order to address the risk of delays in study visits, exceeding the permitted time windows for 
visits on grounds of COVID-19-infection on the part of patients/parents or study staff at the 
sites is excluded from classification as major protocol deviation in all cases. Also, the number 
of patients as required by the EU guideline CPMP/BPWG/2220/02 [15], which requires at least 
8 patients with severe VWD under the age of 6 years, has been increased by 150% to 12 patients, 
not least to counteract possible COVID-19-related drop-outs. 
The potential impact of COVID-19 on the patients, the patient’s parents and the study 
performance was weighed up against the negative impact of not doing the study, i.e. that wilate 
treatment will not be adequately assessed for use in paediatric patients. Overall, the benefit-risk 
evaluation of wilate and of performing this study is positive.  

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2 
STUDY OBJECTIVES 
2.1  Primary Objective(s) 
The primary objective of this study is to determine the efficacy of wilate in the prophylactic 
treatment of up to 12 paediatric patients (eight evaluable) with severe VWD (defined as 
screening von Willebrand factor ristocetin cofactor activity [VWF:RCo] <20%) under the age 
of 6 years, for a period of 12 months. 
2.2 Secondary Objective(s) 
The secondary objectives of this study are to: 
• Determine the pharmacokinetics (PK) of wilate for VWF:Ac (VWF:RCo) and FVIII:C 
(one-stage [OS]) 
• Determine incremental in-vivo recovery (IVR) of wilate over time 
• Evaluate the rate of traumatic and spontaneous breakthrough bleeds under prophylactic 
treatment, including the corresponding treatment efficacy 
• Assess the treatment response in minor and major bleeds and surgeries 
• Determine wilate consumption data for prophylactic treatment, on-demand treatment, 
and surgeries 
• Investigate the immunogenic potential of wilate by screening for VWF and FVIII 
inhibitors 
• Investigate the thrombogenic potential of wilate 
• Assess the patients’ joint status with the Haemophilia Joint Health Score (HJHS) 
• Assess the safety and tolerability of wilate 
 
2.3 Exploratory Objective(s) 
The exploratory objective of this study is to investigate the VWF multimer composition in the 
hereditary type 3 VWD paediatric patient group. 

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3 
INVESTIGATIONAL PLAN 
3.1 Primary and Secondary Endpoints 
3.1.1 Primary Endpoint 
The primary endpoint of this study is to determine the total annualised bleeding rate (tABR) 
during prophylactic treatment with wilate. 
3.1.2 Secondary Endpoints 
The secondary endpoints of this study are to determine: 
• PK profile characteristics of VWF:Ac (VWF:RCo) and FVIII:C (OS) based on blood 
samples taken pre-dose (baseline), 15 minutes, 3, 9, 24, 48 and 72 hours after dosing of 
80 IU/kg BW wilate 
• Incremental in-vivo recovery (IVR) of wilate for VWF:Ac (VWF:RCo) and FVIII:C 
(OS) over time (at baseline and at 1, 2, 3, 6, 9, and 12 months of treatment)  
• Efficacy of wilate in the prevention and treatment of spontaneous and traumatic 
breakthrough BEs based on on their rate the proportion of spontaneous and traumatic 
BEs successfully treated with wilate as assessed by the use of a 4-point ordinal 
haemostatic efficacy scale (excellent – good – moderate – none), respectively 
• The overall efficacy of wilate in perioperative prophylaxis against excessive bleeding 
as assessed at the end of the postoperative period by the responsible treating 
Investigator. A 4-point ordinal haemostatic efficacy scale (excellent – good – moderate 
– none) will be used 
• wilate consumption data for prophylactic treatment, for on-demand treatment and 
during surgical prophylaxis  
3.1.3 Safety Parameters 
 
Secondary Endpoints 
• Incidence of VWF and FVIII inhibitors  
• Incidence of thromboembolic events 
• Joint Health Status determination by the use of the HJHS, given the patient’s age and 
constitutional development allow this assessment 
• Safety and tolerability of wilate assessed by monitoring AEs throughout the study 
3.1.4 Exploratory Endpoint 
The exploratory endpoint of this study, which is solely investigated in the hereditary type 3 
VWD patient group with ≥14.5 kg body weight, is a VWF multimer analysis from the PK 
samples taken at 15 minutes, and 24 hours after wilate injection, by using multimer analysis 
using low- and high resolution electrophoresis gels. 
3.2 Overall Study Design and Plan 
This is an open, prospective, non-controlled, international, multi-centre phase 3 study 
investigating the efficacy, pharmacokinetics, immunogenicity, and safety of wilate in paediatric 

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patients below the age of 6 years at the time of screening with severe VWD (defined as 
VWF:RCo <20%, regardless of prior treatment) undergoing regular prophylaxis. The study is 
estimated to start in Q3 2021 and to be completed by Q2 2024 resulting in an overall duration 
of 2 years and 6 months. 
"Regardless of prior treatment" in this context means that both subjects  previously treated with 
VWF/FVIII-containing products (either on-demand treatment or regular prophylactic 
treatment) and  previously untreated patients (PUPs) can be included in the study. 
Overall, 12 patients (eight evaluable) will be enrolled by up to 15 sites worldwide. At least four 
of these patients should be suffering from hereditary type 3 VWD. The remaining patients can 
be diagnosed with severe type 2 (except 2N) or severe type 1 VWD. 
Of the 12 patients, at least eight patients should be evaluable for the primary endpoint. 
The planned prophylactic treatment duration per patient is 12 months. 
Patients will participate in the following visits: Screening Visit, PK Visit, 1-Month, 2-Month, 
3-Month, 6-Month, and 9-Month Visits, and a Study Completion (12-Month) Visit. Moreover, 
“Compliance Calls” will be performed every 5–7 weeks after the 3-monthly IVR visits at 3, 6, 
and 9 months (detailed in Section 6.1 and in the flow chart of assessments by study visit [Table 
1]). 
The start of the prophylactic treatment phase is defined as the first IMP injection after collection 
of the last PK sample (i.e. the 72-hour sample), which is administered at the study site before 
patients return to home treatment. Parents will receive product for home treatment and will be 
instructed on proper storage and administration. Involvement of a physician or a study nurse 
will be documented. 
Where needed, external home-care companies with experience in conducting clinical trials will 
be contracted, with trained nurses supporting patients’ parents by providing training, re-
training, and oversight through home-care visit support throughout the study or as needed. 
3.3 Discussion of Study Design and Choice of Control Group(s) 
3.3.1 Study Design 
This open-label, prospective, non-controlled, international, multi-centre phase 3 study is 
designed to evaluate the efficacy of wilate in bleeding prophylaxis in paediatric patients below 
6 years of age with severe VWD. 
There is currently no data available on the tABR of patients <6 years of age with VWD 
undergoing regular prophylaxis. Description of the effect of prophylaxis on the tABR of 
patients with inherited coagulation disorders has been used as an efficacy endpoint to evaluate 
the clinical benefit of this intervention.  
3.3.2 Control Group(s) 
Not applicable. 
3.3.3 Study Parameters 
For the evaluation of efficacy endpoints, the following parameters will be documented: 
 

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1. wilate Consumption Data 
 Dates and times of wilate injections 
 Doses of wilate in IU and wilate batch numbers. IU/kg BW per injection, per month, 
and per year will be calculated. 
 Purpose of wilate injection (PK/incremental in vivo recovery [IVR], prophylaxis, 
prophylaxis to avoid re-bleeding, treatment of BE, surgical prophylaxis) 
2. Assessment of Adherence with the Treatment Regimen 
Adherence with the treatment regimen will be assessed throughout the study. Any change of 
the prophylactic dose as determined by the responsible treating Investigator during the PK 
Visit will be documented in the patient records and electronic Case Report Form (eCRF), 
including start and end dates of each dose and the reason for dose change. 
3. Efficacy Assessment in Treatment of BEs 
Details of each (treated and not treated) BE will be recorded: 
 BE type (spontaneous, traumatic, postoperative, other) 
 BE location 
 BE severity (minor or major) (Table 2) 
 Date and time the BE first occurred or was first noticed 
 Date and time the BE ended 
 wilate administration data, if applicable 
 Assessment of the efficacy of treatment at the end of the BE, if applicable 
All parameters will be documented in a patient diary by the patient’s parent(s)/legal 
guardian(s) (hereafter referred to as “parents”), or in the case of on-site treatments with the 
responsible treating Investigator, and in the case of use of a home-care service together with 
the nurse. 
Table 2 
Definition of the Severity of Bleeding 
Bleeding severity 
Description 
Minor 
Mild haemarthrosis (mild swelling, ‘aura,’ pain, warmth of the skin 
over the joint, change in range of motion, decrease in mobility and 
activity, slight difficulty in using the limb compared with baseline), 
superficial muscle bleed (pain and/or swelling and functional 
impairment compared with baseline), soft-tissue bleeding (scrapes, 
superficial cuts such as those cause by shaving razor, knife, or scissors, 
bleeding episodes that require frequent bandage changes, cutaneous 
bleeds with numerous bruises >1 cm), oral bleeding (superficial mouth 
bleeds, oozing or bleeding related to tooth eruption or extraction, 
spontaneous or after brushing/flossing, gum bleeding, bleeding after 
bites to lip or tongue), and most nose bleeds (i.e., those causing distress 
or interference with daily or social activities). 
 
 
 

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Bleeding severity 
Description 
Major 
Generally requires hospitalisation; causes incapacity, significant pain, 
and substantial decrease in range of motion of affected joint (in case of 
joint bleeds); includes symptomatic bleeding in a critical area or organ 
(such as intracranial, intraspinal, intraocular, retroperitoneal, 
intraabdominal, intraarticular, or pericardial bleeds), intramuscular 
bleeds with compartment syndrome, bleeds of the pelvic muscles, 
periorbital bleeds, gastrointestinal bleeds, central nervous system 
bleeds, bleeding in the area of the neck or throat or pharynx, other 
major trauma, or bleeding causing a decrease in haemoglobin levels by 
20 g/L (1.24 mmol/L) or more. 
The amount of wilate needed and the number of injections necessary to stop the bleed will be 
documented. The required IU/kg BW per bleeding event will be calculated. 
Efficacy of wilate will be assessed for all treated BEs, using a 4-point objective haemostatic 
efficacy scale (i.e. excellent – good – moderate – none) detailed in Table 3. In case of minor 
bleeds treated at home, the assessment should be made by the patients’ parents. Major BEs 
should preferably be treated at the study site. An efficacy assessment will be made by the 
responsible treating Investigator after the end of the bleeding event, based on the 4-point 
objective haemostatic efficacy scale.  
Table 3 
Efficacy Assessment of the Treatment of Breakthrough BEs 
Excellent 
Bleeding was completely stopped within 3 days in case of minor bleeds, 
within 7 days in case of major bleeds, and within 10 days in case of 
gastrointestinal bleeds 
Good 
Bleeding was completely stopped, but time and/or dose slightly exceeded 
expectations  
Moderate Bleeding could be stopped only by significantly exceeding time and/or 
dose expectations 
None 
Bleeding could be stopped only by using other VWF-containing products 
 
Based on these data, the frequency of BEs, the total, traumatic, and spontaneous ABR under 
prophylactic treatment will be calculated. 
The proportion of BEs successfully treated with wilate will be evaluated for all BEs in total 
and further differentiated by BE severity. All efficacy ratings assessed as either “excellent” or 
“good” according to the 4-point objective haemostatic efficacy scale will be considered 
successfully treated. 
 
 

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4. Efficacy Assessment in Perioperative Prophylaxis 
The following surgery-related parameters will be documented for major surgeries (parameters 
marked with * are obligatory also for minor surgeries, while the unmarked parameters can be 
collected for minor surgeries depending on availability).   
 Type of surgery (planned or emergency)* 
 Location of surgery* 
 Severity of surgery (minor, major)* 
 Expected and actual duration of surgery 
 Expected average/maximum and actual blood loss 
 Pre-, intra-, and postoperative wilate administration data* 
 Pre-, intra-, and postoperative VWF:Ac ( VWF:RCo) and FVIII plasma levels 
 Routine safety laboratory 
 Presence of wound haematomas 
 Vital signs (blood pressure, heart rate, body temperature, and respiratory rate) 
 Details on concomitantly administered medications (except standard anaesthetics)* 
 Blood transfusion requirements 
 Brief narrative describing the outcome of the intervention* 
 Overall efficacy assessment at the end of the postoperative period by the responsible 
treating Investigator. Predefined assessment criteria will be used* 
 Monitoring of AEs* 
Surgeries are defined as major if any of the following criteria are met: 
 General or spinal 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) 
 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. 

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4 
STUDY POPULATION 
4.1 Population Base 
Overall, 12 patients (eight evaluable) with VWD under the age of 6 years suffering from 
severe VWD defined as screening VWF:RCo <20%, regardless of prior treatment will be 
enrolled into this study. At least four of these patients should be suffering from hereditary 
type 3 VWD. The remaining patients can be diagnosed with severe type 2 (except 2N) or 
severe type 1 VWD. 
"Regardless of prior treatment" in this context means that both subjects  previously treated with 
VWF/FVIII-containing products (either on-demand treatment or regular prophylactic 
treatment) and  previously untreated patients (PUPs) can be included in the study. 
4.1.1 Inclusion Criteria 
Patients who meet all of the following criteria are eligible for the study: 
1. Patients aged <6 years at the time of screening  
2. Type 3 (at least four patients), severe type 2 (except 2N) or severe type 1 VWD (any of 
which with VWF:RCo <20%) according to medical history, requiring substitution 
therapy with a VWF-containing product 
3. Minimum body weight 12.5 kg at the time of screening 
4. Voluntarily given, fully informed written and signed consent obtained before any study-
related procedures are conducted (obtained from the patient’s parent(s)/legal 
guardian(s) 
4.1.2 Exclusion Criteria 
Patients who meet any of the following criteria are not eligible for the study: 
1. History, or current suspicion of VWF or FVIII inhibitors 
2. Injection of DDAVP or VWF-containing product within 72 hours prior to inclusion 
3. Medical history of a thromboembolic event 
4. Platelet count <100,000/µL at screening (except for VWD type 2B) 
5. Patients receiving, or scheduled to receive, immunosuppressant drugs (other than 
antiretroviral chemotherapy), such as prednisone (equivalent to >10 mg/day), or similar 
drugs 
6. Treatment with any IMP in another interventional clinical study currently or within four 
weeks before enrolment 
7. Other coagulation disorders or bleeding disorders 
8. Known hypersensitivity to any of the components of the study drug 

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4.2 Prior and Concomitant Therapy 
4.2.1 Permitted Concomitant Therapy 
Vaccination against hepatitis A and B (or the presence of antibodies resulting from a previous 
infection, or other evidence of immunisation) is strongly recommended before repeated 
treatment with a VWF/FVIII concentrate such as wilate. 
Patients receiving, or scheduled to receive, immunosuppressant drugs (other than antiretroviral 
chemotherapy), such as prednisone (equivalent to >10 mg/day), or similar drugs may not be 
enrolled. 
Concomitant therapies not interfering with the objectives of the study are permitted. Details of 
any concomitant medication must be recorded in the electronic Case Report Form (eCRF). 
4.2.2 Forbidden Concomitant Therapy 
No VWF/FVIII concentrates other than wilate must be administered (except for emergency 
situations). Patients permanently switching to other VWF/FVIIII products within the study 
participation period will be assessed as treatment failures in the efficacy analyses.  
However, there are exceptions to this rule. Patients will hence not be considered treatment 
failures in the efficacy analyses, if: 
• the use of another VWF/FVIII concentrate was due to an emergency case (example: in 
the case of an accident causing a bleeding that requires treatment with VWF concentrate 
but without access to the IMP, a different concentrate may be used instead) 
• the IMP was not available for the patient in time (example: patient experiences a severe 
bleed but parents do not have enough product available). 
4.3 Withdrawal and Replacement of Subjects/Patients 
4.3.1 Premature Subject/Patient Withdrawal 
Parents have the right to withdraw their children from the study at any time for any reason, 
without the need to justify their decision. The Investigator also has the right to withdraw 
subjects/patients in case of AEs, poor compliance, or other reasons. Since an excessive rate of 
withdrawals can render the study noninterpretable, any unnecessary withdrawal of 
subjects/patients should be avoided. 
For any withdrawals after study entry, the Investigator will obtain all the required details and 
document the reason(s) for discontinuation. If the reason for withdrawal of a patient is an AE, 
the main specific event or laboratory test will be recorded, and the Investigator will make 
thorough efforts to clearly document the outcome. 
4.3.2 Subject/Patient Replacement Policy 
Patients withdrawn from the study for safety reasons will not be replaced. 

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4.4 Assignment of Subjects/Patients to Treatment Groups 
The Investigator will enter a unique identifier (consisting of the study code (SC), centre code 
(CC), and patient number (PN), in the format “SC-CC-PN”) of each patient in both the CRF 
and the confidential patient identification list. The Investigator will inform the monitor of new 
patients enrolled. 
Under no circumstances are patients who enrol in the study permitted to re-enrol. 
4.5 Relevant Protocol Deviations 
Deviations from the protocol should be avoided at all times throughout the study. If deviations 
occur, the Investigator should promptly inform the monitor, and the implication of the deviation 
must be assessed and discussed. Any deviation must be documented, stating the reason and date 
and the action taken. The documentation must be kept in the Investigator’s study file and the 
Sponsor’s study master file. A complete list of all critical, major and minor deviations will be 
compiled and regularly updated by the Project Manager and provided for preparation of the 
Clinical Study Report (CSR).  
All cases where the time windows for visits to the study centres are exceeded due to COVID-
19-related illness on the part of patients/parents or study staff will be defined as a minor 
deviation. 
In case of any major protocol deviation, the Investigator and Octapharma will decide on the 
further participation of the subject/patient in this study after having discussed all relevant 
aspects. 
Examples of critical/major protocol deviations are:  
• Patients who entered the study even though they did not satisfy the eligibility criteria.  
• Patients who received the wrong treatment or incorrect dose (also see Section 5.4). 
• Patients with substantial deviations from the prophylactic treatment regimen. 
• Patients who received forbidden concomitant medication. 
4.6 Subsequent Therapy 
All patients who leave the study – be it prematurely or per protocol (PP) – will continue VWD 
treatment as per the discretion of the responsible treating Investigator. 
 

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5 
INVESTIGATIONAL MEDICINAL PRODUCT(S) 
5.1 Characterisation of Investigational Product(s) 
The VWF/FVIII concentrate wilate, produced from the plasma of human donors, is presented 
as a powder and solvent for intravenous injection containing nominally 500 IU or 1000 IU 
human VWF and human FVIII per vial. The ratio between VWF ristocetin co-factor activity 
(VWF:RCo) and FVIII:C is 1:1. 
The product contains approximately 100 IU/mL human VWF when reconstituted with 
5 mL/10 mL water for injections with 0.1% polysorbate 80. The specific activity of wilate is 
≥67 IU VWF:RCo/mg protein. 
The injection or infusion rate should not exceed 2–3 mL per minute. 
5.2 Packaging and Labelling 
Final labelling of the IMP will comply with the national requirements of each country where 
the study is conducted. 
5.3 Conditions for Storage and Use 
The powder and solvent vials must be stored in a refrigerator at +2°C to +8°C (36°F to 46°F). 
The vials must be kept in the outer carton to protect from light and must not be frozen. 
As an accepted exception to the storage conditions, the product can be stored at room 
temperature (max. +25°C or 77°F) for a maximum of 2 months. 
After reaching room temperature, however, no return to refrigerated conditions is permitted. 
2 months after the product is taken out of the refrigerator for the first time it must not be used 
any more and must be destroyed following local rules. 
The Investigator and any authorised personnel at the site will ensure that the IMP is stored in 
appropriate conditions with restricted access and in compliance with national regulations. 
5.4 Dose and Dosing Schedule 
5.4.1 wilate Dosage for PK Assessment 
For the PK Assessment, a single dose of 80 IU/kg BW will be administered, based on the weight 
measured at the beginning of the visit. The exact dose calculated according to the nominal 
potency should be administered, with 70–85 IU/kg BW as the acceptable range. The injection 
or infusion rate should not exceed 2–3 mL per minute. At least three different wilate batches 
will be used. 
As regards determining incremental in-vivo recovery over time, a single dose of wilate is 
administered at the dose of regular prophylactic treatment. 
5.4.2 wilate Dosage for Prophylactic Treatment 
For prophylactic treatment, wilate should be administered 2–3 times per week at a 
recommended dose of 30–50 IU/kg BW over 12 months. The prophylactic dose and frequency 

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for each patient will be determined by the responsible treating Investigator, based on the 
individual patient’s clinical condition. 
After each body weight measurement during the study, dose adjustments based on the patient's 
actual weight should be considered. 
The first prophylactic dose will be administered after completion of the PK Assessment, i.e. 
after the 72-hour sample has been collected), and should be administered at the study site before 
patients return to home treatment. The same venipuncture as that used to collect the sample can 
be used for administration (taking into account prior rinsing with NaCl).  
It is recommended to aim for a dose that supports the administration of full vials of wilate 
during home treatment. However, the administration of partial vials is permitted if clinically 
indicated, as long as the recommended dose range is respected. Such cases must be carefully 
discussed and explained in detail with the patients’ parents and must be accurately documented 
in the patient's diary and in the eCRF. Parents should be trained in the administration of partial 
vials and their return after use. 
In case of unacceptably frequent breakthrough BEs (i.e. two or more BEs within a 30-day period 
or one major BE), the dose of wilate should be increased by approximately 5 IU/kg BW 
(depending on the vial size of the additional vial(s) that need(s) to be injected) and/or the 
treatment frequency can be increased. This rule applies irrespective of whether one or more 
bleeding sites are affected, and for BEs that occur on the same day. 
5.4.3 wilate Dose for the Treatment of Bleeding Episodes (BEs) 
The dose (and duration) of treatment of BEs will depend on the location and extent of bleeding 
and on the clinical condition of the patient. 
Generally, 1 IU/kg BW VWF:Ac and FVIII:C raises the plasma level by 1.5–2% of normal 
activity for the respective protein, but this increase may be lower in children below the age of 
6 years. Usually, about 20–50 IU/kg BW wilate are necessary to achieve adequate haemostasis. 
This will raise the VWF:Ac and FVIII:C in the patients by approximately 30–100% [12]. 
Recommendations for the dosing in the treatment of BEs in paediatric patients under 6 years of 
age has been adapted from the US Package Insert [13] and is shown in Table 4. 
Table 4 
wilate Dosage Recommendations for the Treatment of BEs 
Dose Type 
Minor haemorrhage 
Major haemorrhage 
Loading dose 
30–50 IU/kg BW 
50–80 IU/kg BW 
Maintenance dose 
30–40 IU/kg BW every 12–24 hours 
30–50 IU/kg BW every 12–24 
hours 
Therapeutic goal 
Maintain VWF:Ac and FVIII:C 
trough levels >30%  
Maintain VWF:Ac and FVIII:C 
trough levels >50% 
After the initial treatment phase of a BE, any further treatment to avoid re-bleeding is to be 
documented as “prophylactic treatment to avoid re-bleeding” until the transition to the regular 
prophylactic treatment schedule. 

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5.4.4 wilate Dose for Surgical Prophylaxis 
For prevention of bleeding in case of surgery, VWF:Ac peak levels of 50% should be achieved 
for minor surgeries and VWF:Ac peak level of 100% should be achieved for major surgeries. 
An appropriate dose should be re-administered every 12–24 hours of treatment. The dose and 
duration of the treatment depend on the clinical status of the patient, the type and severity of 
bleeding, VWF:Ac and FVIII:C levels. 
In patients receiving FVIII-containing VWF products, plasma levels of FVIII:C should be 
monitored to reveal sustained excessive FVIII:C plasma levels, which may increase the risk of 
thrombotic events. Accordingly, FVIII activity levels should not exceed 200%. 
Recommendations for the dosing in in surgical prophylaxis in paediatric patients under 6 years 
of age has been adapted from the US Package Insert [13] and is shown in Table 5. 
Table 5 
wilate Dosage Recommendations for Surgical Prophylaxis 
Dose type 
Minor surgeries (including tooth 
extractions) 
Major surgeries 
Loading dose 
40–60 IU/kg BW 
60–80 IU/kg BW 
Maintenance 
dose 
20–30 IU/kg BW, or half the loading 
dose, every 12–24 hours for up to 3 days 
30–40 IU/kg BW, or half the 
loading dose, every 12–24 hours 
for up to 6 days or longer 
Therapeutic goal 
Achieve VWF:Ac peak levels of 50% 
after loading dose and trough levels of 
>30% during maintenance doses 
Achieve VWF:Ac peak level of 
100% after loading dose and 
trough levels of >50% during 
maintenance doses  
  
5.5 Preparation and Method of Administration 
For more information on the method of administration of wilate, please see the European 
Summary of Product Characteristics [12]. 
Throughout the study, several batches of wilate will be used, and these will be recorded in the 
clinical study report. 
5.6 Blinding, Emergency Envelopes, and Breaking the Study Blind 
Not applicable. 
5.7 Treatment Compliance 
5.7.1 Drug Dispensing and Accountability 
Any wilate provided to the site will be accounted for. This includes wilate received at the site, 
wilate dispensed to patients, and wilate returned used or unused by the patient’s parents. 
Supplies and re-supplies of wilate for home treatment of patients are carefully calculated and 
should suffice for the next home treatment period, before the patients return to the study site 
for their next visit. The agreed number of vials will be handed out to the patient's parents, who 

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will be advised that all used, partially used and expired vials must be returned on the next visit. 
During the completion visit, all unused vials must also be returned to the study centre for 
accountability of the IMP. 
A Drug Inventory and Dispensing Log will be kept current by the Investigator, detailing the 
dates and quantities of wilate received and dispensed to each patient and the remaining quantity.  
The inventory and dispensing log will be available to the monitor to verify drug accountability 
during the study.  
Used and partially used vials which were either kept at site or returned by patients’ parents need 
to be verified and counted by the study monitor who will in turn approve their destruction after 
completion of the accountability process. 
Unused wilate should be destroyed at the study site in accordance with local regulations. If this 
is not possible, arrangements shall be made to return them to the Sponsor for destruction. 
Destruction of unused vials can be initiated only after accountability has been verified and fully 
reconciled by the monitor and after the Sponsor has granted written permission for destruction. 
5.7.2 Assessment of Treatment Compliance 
For all IVR and PK Assessments, wilate will be administered at the study site, with compliance 
under the control of the treating Investigator. 
Adherence with the treatment regimen will be assessed throughout the study. Any change of 
the prophylactic dose as determined by the responsible treating Investigator during the Baseline 
Visit will be documented in the patient records and eCRF, including start and end dates of each 
dose and the reason for dose change.  
Parents should be conducted by telephone every 5–7 weeks after the start of the prophylactic 
treatment phase, and every 5–7 weeks after the 3-monthly IVR visits at 3, 6, and 9 months.  
 

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6 
STUDY CONDUCT  
The flow chart of assessments by study visit is given in Table 1. Details on the individual 
assessments and methods are provided in Section 7. 
6.1 Observations by Visit 
All enrolled patients will participate in the following study visits: 
• Screening Visit (Visit 1) 
• PK Visit (Visit 2) 
• 1-Month Visit (Visit 3) 
• 2-Month Visit (Visit 4) 
• 3-Month Visit (Visit 5) 
• 6-Month Visit (Visit 6) 
• 9-Month Visit (Visit 7) 
• Study Completion (12-Month) Visit (Visit 8) 
• “Compliance Calls” will be performed every 5–7 weeks after the 3-monthly IVR visits 
at 3, 6, and 9 months. 
Parents will receive product for home treatment and will be instructed on proper storage and 
administration. Involvement of a physician or a study nurse will be documented. 
Where needed, external home-care companies with experience in conducting clinical studies 
will be contracted, with trained nurses supporting patients’ parents by providing training, re-
training, and oversight through home-care visit support throughout the study. 
6.1.1 Screening Visit (Visit 1) 
The following assessments will be performed during the Screening Visit, which should take 
place within 4 weeks before the first administration of IMP: 
• Obtaining voluntarily given, written (signed and dated) informed consent 
• Inclusion and exclusion criteria 
• Demographic and baseline characteristics 
• Medical history and prior medication, including VWD type (including e.g. historical 
values of VWF:Ac (VWF:RCo), VWF:Ag, multimer analyses, FVIII-binding tests), 
prior VWD specific treatment, and family history of VWD 
• Vital signs (blood pressure, heart rate, body temperature, and respiratory rate) 
• Physical examination 
• Blood samples 
o Routine safety laboratory [local laboratory] 
o VWF:Ac (VWF:RCo) [central laboratory] 
o VWF and FVIII inhibitor testing [central laboratory] 
o VWF multimer analysis [central laboratory] 
o Retention samples for possible virus marker testing [central laboratory] 

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• Assess the patients’ joint status using the Haemophilia Joint Health Score (HJHS) and 
any target joints (defined as three or more sponatenouos BEs in a single joint within six 
consecutive months preceding the Screening Visit). 
• Documentation of concomitant medication 
During the Screening Visit, the patients’ parents will receive a patient diary. The Investigator 
will explain how to fill in the diary and emphasise the importance of carefully documenting any 
BEs, treatment details, AEs, and concomitant medication. 
Patients may continue treatment with their previous VWF-containing product for up to four 
weeks, awaiting confirmation of the VWD diagnosis from the central laboratory. 
The PK visit must be initiated within four weeks after the Screening Visit. 
Any treatment with previously used VWF-containing product, any BEs and AEs occurring 
between the Screening Visit and the PK Visit will be documented in the patient diary. 
6.1.2 PK Visit (Visit 2) 
During the PK Visit, patients will receive wilate at a dose of 80 IU/kg BW after a washout 
period of at least 72 hours from the patient’s previous administration of a VWF-containing 
product. The exact dose calculated according to the nominal potency should be administered, 
with 70–85 IU/kg BW as the acceptable range. Patients must be bleed-free when visiting the 
study site for PK. Blood samples will be taken pre-dose (baseline), 15 minutes, 3, 9, 24, 48 and 
72 hours after dosing of 80 IU/kg BW wilate 
The following assessments will be performed: 
• Before any other assessments 
o Confirmation of inclusion and exclusion criteria 
• Before injection 
o Body weight 
o Vital signs (blood pressure, heart rate, body temperature, and respiratory rate 
should be monitored during the PK assessment: at baseline and at 15 min [±5 
min] after injection) 
• Within 60 min before and 15 min (±5 min), 3 (± 1 hour) and 9, 24, 48, and 72 hours 
(each ±2 hours) after injection 
o PK blood samples: 
 VWF:Ac (VWF:RCo) [central laboratory] 
 FVIII:C (OS) [central laboratory] 
• At 15 min (±5min) and 24 hours (±2hours) after injection 
o VWF multimer analysis in type 3 VWD patients ≥14.5 kg body weight by using 
the PK samples taken at 15 minutes and 24 hours after the injection [central 
laboratory] 
 

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• During the visit 
o Patient diary review 
o Bleeding episodes monitoring 
o Monitoring of AEs 
o Concomitant medication 
During this visit, the future prophylactic dose and dosing interval of wilate will be determined 
by the treating Investigator based on the patient’s clinical condition. 
The patients’ parents will be trained in how to correctly prepare and administer wilate, which 
will be re-supplied whenever necessary during the study. The Investigator will discuss wilate 
dose and frequency of administration with the patients’ parents, both for regular prophylaxis 
and for treatment of BEs. 
The first prophylactic dose will be administered after completion of the PK Assessment, i.e. 
after the 72-hour samples have been collected), and should be administered at the study site 
before patients return to home treatment. 
Where applicable, external home-care companies with experience in conducting clinical studies 
will be contracted, with trained nurses supporting patients’ parents by providing training, re-
training, and oversight through home-care visit support throughout the study. 
6.1.3 1-Month Visit (Visit 3) 
The 1-Month IVR visit will take place 1 month (±3 days) after the first prophylactic injection 
of wilate has been received. 
The following assessments will be performed: 
• Before injection 
o Body weight 
o Vital signs (blood pressure, heart rate, body temperature, and respiratory rate 
should be monitored during the IVR Assessment: baseline, 15±5 min after 
injection) 
• Within 60 min before and 15 min after (±5 min) injection 
o VWF:Ac (VWF:RCo) [central laboratory] 
o FVIII:C (OS) [central laboratory] 
• During the visit 
o Patient diary review 
o Review of compliance and adherence to the treatment regimen 
o Bleeding episodes monitoring 
o AE monitoring 
o Concomitant medication 
o AB0 blood group testing, unless already known, and if blood volume restrictions 
allow (otherwise sample to be drawn at any further time point during the study 
[local laboratory] 
During this visit, a prophylactic injection of wilate will be administered. 

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6.1.4 2-Month Visit (Visit 4) 
The 2-Month IVR visit will take place 2 months (±3 days) after the first prophylactic injection 
of wilate has been received. 
The following assessments will be performed: 
• Before injection 
o Body weight 
o Vital signs (blood pressure, heart rate, body temperature, and respiratory rate 
should be monitored during the IVR Assessment: baseline, 15±5 min after 
injection) 
• Within 60 min before and 15 min after (±5 min) injection 
o VWF:Ac (VWF:RCo) [central laboratory] 
o FVIII:C (OS) [central laboratory] 
• During the visit 
o Patient diary review 
o Review of compliance and adherence to the treatment regimen 
o Bleeding episodes monitoring 
o AE monitoring 
o Concomitant medication 
During this visit, a prophylactic injection of wilate will be administered. 
6.1.5 3-Month Visit (Visit 5) 
The first of the 3-Monthly Visits will take place 3 months (±1 week) after the first prophylactic 
injection of wilate has been received. 
The following assessments will be performed: 
• Before injection 
o Body weight 
o Vital signs (blood pressure, heart rate, body temperature, and respiratory rate 
should be monitored during the IVR Assessment: at baseline, and at 15±5 min 
after injection) 
o Blood samples 
 VWF and FVIII inhibitor testing [central laboratory] 
• Within 60 min before and 15 min after (±5 min) injection 
o VWF:Ac (VWF:RCo) [central laboratory] 
o FVIII:C (OS) [central laboratory] 
• During the visit 
o Patient diary review 
o Review of compliance and adherence to the treatment regimen 

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o Bleeding episodes monitoring 
o Monitoring of AEs 
o Concomitant medication 
During this visit, a prophylactic injection of wilate will be administered. 
6.1.6 6-Month and 9-Month Visit (Visit 6 and 7) 
The following 3-Monthly visits will take place 6 (±2 weeks), and 9 months (±2 weeks) after the 
first prophylactic injection of wilate was received. 
The following assessments will be performed: 
• Before injection 
o Body weight 
o Vital signs (blood pressure, heart rate, body temperature, and respiratory rate 
should be monitored during the IVR Assessment: at baseline, and at 15±5 min 
after injection) 
o Blood samples 
 VWF and FVIII inhibitor testing [central laboratory] 
• Within 60 min before and 15 min after (±5 min) injection 
o VWF:Ac (VWF:RCo) [central laboratory] 
o FVIII:C (OS) [central laboratory] 
• During the visit 
o Patient diary review 
o Review of compliance and adherence to the treatment regimen 
o Bleeding episodes monitoring 
o Monitoring of AEs 
o Concomitant medication 
During these visits, a prophylactic injection of wilate will be administered. 
6.1.7 Study Completion (12-Month) Visit (Last visit) 
The Study Completion Visit will take place 12 months (+2 weeks) after the first prophylactic 
injection of wilate. 
The following assessments will be performed: 
• During the visit 
o Before injection 
 Body weight 
 Vital signs (blood pressure, heart rate, body temperature, and respiratory 
rate should be monitored during the IVR Assessment: baseline, 15±5 min 
after injection) 
 
 

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 Blood sampling  
• Routine safety laboratory [local laboratory] 
• VWF and FVIII inhibitor testing [central laboratory] 
o Within 60 min before and 15 min after (±5 min) injection 
 IVR blood sampling 
• VWF:Ac (VWF:RCo) [central laboratory] 
• FVIII:C (OS) [central laboratory] 
o During the visit 
 Patient diary review 
 Review of compliance and adherence to the treatment regimen 
 HJHS 
 Target Joints (three or more sponatenouos BEs in a single joint within 
six consecutive months preceding the Completion Visit) 
 Physical examination 
 Bleeding episodes monitoring 
 Monitoring of AEs 
 Concomitant medication 
 
All used and unused wilate vials will be returned by the parents or their home-care providers. 
Patients prematurely withdrawing from the study for any reason will be invited to attend the 
Study Completion Visit at the time of withdrawal. 
After the final examination, the clinical study is considered completed for the subject/patient. 
No further study-related assessments will be performed, unless safety concerns (e.g. ongoing 
AEs) require follow-up. 
6.1.8 Compliance Calls 
Parents should be contacted by telephone every 5–7 weeks after the 3-monthly IVR visits at 3, 
6, and 9 months. 
The compliance calls will check the following: 
• Patient’s overall condition and wellbeing 
• Adherence to the treatment regimen (dose and frequency) 
• Bleeding episodes and their treatment 
• Requirement of any prophylactic treatment adjustment 
• Adverse events 
• Concomitant medication 
• Answer parents’ questions or concerns, if any 
 
If any issues with completing the diaries or adhering to the infusion regimen are identified, the 
Investigator or home-care provider will re-train the patient accordingly. 

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6.1.9 Unscheduled Visits and Additional Measures 
If inhibitor development is suspected (e.g. based on an unexplained need to increase the dose, 
a lack of efficacy of wilate injections seen in more frequent spontaneous bleeds, or prolonged 
bleeding), VWF and FVIII inhibitor tests will be performed at the central laboratory and will 
be documented accordingly (see Section 7.4.5.1). 
In case of positive inhibitor result, inhibitor re-testing using a second, separately drawn sample 
should be performed, preferably within 15 days of becoming aware of the positive result, and 
further measures will need to be discussed on an individual basis. If the result is confirmed, the 
patient will be discontinued from the study. 
Other reasons for unscheduled visits may be the occurrence of serious AEs or hospitalisations 
for BEs or surgical interventions. 
6.1.10 Surgical Visits 
Patients may undergo surgical interventions in the course of the study. Whether or not these 
patients are hospitalised will depend on the type and severity of the surgery and is at the 
discretion of the treating physician. 
In patients undergoing major surgeries, standard methods of postsurgical thromboprophylaxis 
such as gradated compression stockings and early mobilisation, should be used to prevent 
venous thromboembolism. 
For details on the surgery data to be documented and the surgical efficacy assessments to be 
performed, see Section 7.2.2. 
6.2 Duration of Study 
6.2.1 Planned Duration for an Individual Subject/Patient 
The duration of the planned prophylactic treatment for each patient will be 12 months (+2-
weeks). 
6.2.2 Planned Duration for the Study as a Whole 
The study will be considered completed when all patients have completed the planned 
observation period, including the Study Completion Visit. 
The estimated start of the study (enrolment of first patient) is Q3 2021, and the estimated end 
of the study (last visit of last patient) is Q2 2024. 
6.2.3 Premature Termination of the Study 
Both the Investigator and the Sponsor reserve the right to terminate the study at any time. In 
this event, any necessary procedures will be arranged on an individual study basis after review 
and consultation by both parties. In terminating the study, the Sponsor and the Investigator will 
ensure that adequate consideration is given to the protection of the patients’ interests. 
Patients prematurely withdrawing from the study for any reason will be invited to attend the 
Study Completion Visit at the time of withdrawal (see Section 6.1.7). 

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Regulatory authorities and IECs/IRBs should be informed in accordance with national 
regulations. 
Early termination of the study as a whole or by centre may apply for the following reasons: 
6.2.3.1 Early Termination of the Entire Clinical Study 
At any time, the study as a whole will be terminated prematurely if new toxicological or 
pharmacological findings or safety reports invalidate the earlier positive benefit-risk-
assessment. 
6.2.3.2 Early Termination at an Individual Study Centre 
At any time, the study can be terminated at an individual centre if: 
• The centre cannot comply with the requirements of the protocol. 
• The centre cannot comply with GCP standards. 
• The required recruitment rate is not met. 
Should the study be prematurely terminated, all study materials (completed, partially 
completed, and blank CRFs, etc.) must be returned to the Sponsor. Unused wilate will be 
destroyed at the study site in accordance with local requirements, following completion of the 
appropriate drug account and after release by the Sponsor. 

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7 
ASSESSMENTS AND METHODS 
7.1 Demographic and Baseline Information 
Demographic and baseline information will be recorded during the Screening Visit 
7.1.1 Demographic and baseline characteristics 
The demographic and baseline characteristics are age, ethnic origin, height, weight, and AB0 
blood group. 
7.1.2 Medical history and prior/concomitant medications 
The medical history will be obtained by interviewing the patient’s parent. Records of past 
diseases and treatments (e.g. hospital records) will be obtained for the study files, if available. 
Prior and concomitant medications will be obtained by interview. 
The history or presence of VWF or FVIII inhibitor activity is an exclusion criterion (see Section 
4.1.2). 
7.2 Efficacy Assessments 
This section summarises the assessments to be performed for the calculation of the primary, 
secondary and exploratory endpoints of this study (see Section 3.1). 
For details on laboratory analyses, see Section 7.4.5. 
7.2.1 Assessments for Primary Efficacy Endpoint(s) 
The primary endpoint of this study is to determine the total annualised bleeding rate (tABR) 
during prophylactic treatment with wilate. BEs will be monitored throughout the study. The 
parents of study participants will be instructed by the Investigator on recording all BEs and in 
how to record them. The following details of each (treated and not treated) bleeding episode 
will be recorded: 
 BE type (spontaneous, traumatic, postoperative, other) 
 BE location 
 BE severity (minor or major) 
 Date and time the BE first occurred or was first noticed 
 Date and time the BE ended 
 wilate administration data, if applicable 
 Assessment of the efficacy of treatment at the end of the BE, if applicable 
All of these parameters will be documented in the patient diary by the patient’s parents, together 
with the responsible treating Investigator in case of on-site treatments, or with the nurse in case 
a home-care service is used. 
The amount of wilate needed and the number of injections necessary to stop the bleed will be 
documented. The required IU/kg BW per bleeding event will be calculated. 
 

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7.2.2 Assessments for Secondary Efficacy Endpoint(s) 
Consumption of wilate  
The following parameters will be documented: 
 Dates and times of wilate injections 
 Doses of wilate in IU and wilate batch numbers. IU/kg BW per injection, per month 
and per year will be calculated. 
 Purpose of wilate injection (PK/IVR, prophylaxis, prophylaxis to avoid re-bleeding, 
treatment of BE, surgical prophylaxis) 
Injections administered for the purpose of prophylaxis of recurrent bleeding are those injections 
administered after bleeding cessation and in advance of the patient’s next regular prophylactic 
dose. 
Efficacy of wilate for treatment of BEs 
Efficacy of wilate will be assessed for all treated BEs, using a 4-point objective haemostatic 
efficacy scale (i.e. excellent – good – moderate – none) using the predefined criteria detailed in 
Section 3.3.3. In case of minor bleeds treated at home, the assessment should be made by the 
patients’ parents. For major bleeds, which should preferably be treated at the study site, an 
efficacy assessment will made by the responsible treating Investigator after the end of the 
bleeding event, based on the objective haemostatic efficacy scale.  
Based on these data, the frequency of BEs and the total, traumatic and spontaneous ABR under 
prophylactic treatment will be calculated. 
The proportion of BEs successfully treated with wilate will be evaluated for all BEs in total, 
and further differentiated by BE severity. All efficacy ratings assessed as either “excellent” or 
“good” will be considered successfully treated. 
The proportion of BEs successfully treated with wilate will be evaluated for all BEs and by BE 
severity. All efficacy ratings assessed as either “excellent” or “good” will be considered 
successfully treated. To assess the haemostatic efficacy of wilate in the treatment of 
breakthrough BEs, a frequency distribution of all successfully treated BEs will be presented 
overall and by severity, along with an exploratory 95% CI. Statistical analyses of other 
secondary endpoints will be descriptive, including exploratory 95% CIs. 
 
Treatment of Surgeries 
The following surgery-related parameters will be documented for major surgeries (parameters 
marked with * are obligatory also for minor surgeries, while the unmarked parameters can be 
collected for minor surgeries depending on availability): 
• Type of surgery (planned or emergency)* 
• Location of surgery* 
• Severity of surgery (minor, major) (see definitions under (a) below)* 
• Expected and actual duration of surgery 
• Expected average/maximum and actual blood loss 

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• Pre-, intra-, and postoperative wilate administration data (see definitions under (b) 
below)* 
• Pre-, intra-, and postoperative VWF:Ac (VWF:RCo) and FVIII plasma levels (see 
definitions under (b) below) 
• Routine safety laboratory 
• Presence of wound haematomas 
• Vital signs (blood pressure, heart rate, body temperature, and respiratory rate) 
• Details on concomitantly administered medications (except standard anaesthetics)* 
• Blood transfusion requirements 
• Brief narrative describing the outcome of the intervention* 
• Overall efficacy assessment at the end of the postoperative period by the responsible 
treating Investigator. Predefined assessment criteria will be used (see below)* 
• Monitoring of AEs* 
Details regarding the time points of data collection and assessments for surgical prophylaxis 
are described below in Table 6. 
The efficacy of wilate will be assessed at end of the postoperative period by the responsible 
treating Investigator, using predefined assessment criteria. 
(a) Severity of surgery 
Surgeries are defined as major if any of the following criteria are met: 
• General or spinal 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) 
• 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) 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 
or her regular VWF treatment regimen. 
• The end of the postoperative period is the time the patient returns to his or her regular 
VWF treatment regimen. 
 
 

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Table 6 
Assessments for Perioperative Prophylaxis 
 
 
Assessment 
For 
details, 
see 
Section 
Within 
12 hours 
before 
start 
Within 
3 hours 
before 
start 
Surgery 
POP 
day 1 
Any 
POP 
day 
End of 
POP 
period 
Intra- 
operativ
ely 
End 
[1] 
Body weight 
 
x 
 
 
 
 
 
 
Type of surgery 
7.2.2 
x 
 
 
 
 
 
 
Location of surgery 
7.2.2 
x 
 
 
 
 
 
 
Severity of surgery 
7.2.2 
x 
 
 
 
 
 
 
Expected duration of surgery 
7.2.2 
x 
 
 
 
 
 
 
Actual duration of surgery 
7.2.2 
 
 
 
x 
 
 
 
Expected average/maximum blood loss 
during surgery 
7.2.2 
x 
 
 
 
 
 
 
Actual blood loss and transfusions 
during surgery 
7.2.2 
 
 
 
x 
 
 
 
Administration of wilate 
5.4 
 
x 
(x) 
(x) 
(x) 
(x) 
(x) 
FVIII:C  
7.4.5 
 
# L 
(#) L 
(#) L 
(#) [2] 
L 
(#) L 
(#) L 
VWF:Ac (VWF:RCo) 
7.4.5 
 
# L 
(#) L 
(#) L 
(#) [2] 
L 
(#) L 
(#) L 
Routine safety laboratory 
7.4.5 
x 
 
 
 
(x) 
(x) 
(x) 
Presence of wound haematomas 
7.4.2 
 
 
 
 
x 
x 
x 
Vital signs 
7.4.7 
x 
 
x 
 
x 
 
 
Efficacy assessments 
7.2.2 
 
 
 
S 
 
 
H 
Overall efficacy assessment 
7.2.2 
 
 
 
 
 
 
I 
Brief narrative of outcome of the 
intervention 
7.2.2 
 
 
 
 
 
 
x 
Concomitant medications 
7.4.2 
Throughout observation period 
Adverse event monitoring 
7.4.2 
Throughout observation period 
POP = postoperative, FVIII:C = factor VIII procoagulant activity, VWF:Ac = VWF activity, VWF:RCo= von Willebrand ristocetin 
cofactor activity), S = performed by surgeon, H = performed by haematologist, I = performed by Investigator, L= can be performed 
in an optional manner by the local laboratory  
( ) Optional 
# Samples to be taken immediately before (≤30 min) and 30±15 min after wilate administration 
[1] Immediately after the last surgical suture 
[2] For major surgeries, mandatory for the first three postoperative doses 
 
Efficacy in Perioperative Prophylaxis 
Following major surgeries, efficacy will be assessed at the end of surgery by the Surgeon and 
at the end of the postoperative period by the responsible Haematologist/Investigator (see 
above). In both cases, predefined assessment criteria will be used. 
In addition, an overall assessment of efficacy will be made for all minor and major surgeries at 
the end of the postoperative period by the Investigator. 
 
At the End of Surgery 
At the end of surgery (defined as the time immediately after the last surgical suture), the 
haemostatic efficacy of wilate will be assessed by the responsible Investigator using the criteria 
listed in Table 7. 
 
 

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Table 7 
Efficacy Assessment at the End of Surgery 
Excellent 
Intraoperative blood loss was lower than or equal to the average expected blood loss 
for the type of procedure performed in a patient with normal haemostasis and of the 
same sex, age, and stature 
Good 
Intraoperative blood loss was higher than the average expected blood loss but lower or 
equal to the maximum expected blood loss for the type of procedure in a patient with 
normal haemostasis 
Moderate 
Intraoperative blood loss was higher than the maximum expected blood loss for the 
type of procedure performed in a patient with normal haemostasis, but haemostasis was 
controlled  
None 
Haemostasis was uncontrolled, necessitating a change in the clotting factor replacement 
regimen 
 
At the End of the Postoperative Period 
At the end of the postoperative period (defined as the time the patient returns to his or her 
regular VWF treatment regimen), the haemostatic efficacy of wilate will be assessed by the 
responsible Investigator using the criteria listed in Table 8. 
Table 8 
Efficacy Assessment at the End of the Postoperative Period 
Excellent 
No postoperative bleeding or oozing that was not due to complications of surgery. All 
postoperative bleeding (due to complications of surgery) was controlled with wilate as 
anticipated for the type of procedure 
Good 
No postoperative bleeding or oozing that was not due to complications of surgery. 
Control of postoperative bleeding due to complications of surgery required increased 
dosing with wilate or additional injections not originally anticipated for the type of 
procedure 
Moderate 
Some postoperative bleeding and oozing that was not due to complications of surgery. 
Control of postoperative bleeding required increased dosing with wilate or additional 
injections not originally anticipated for the type of procedure 
None 
Extensive uncontrolled postoperative bleeding and oozing. Control of postoperative 
bleeding required use of an alternate VWF-containing product 
 
Overall Efficacy Assessment at the End of the Postoperative Period 
As for major surgeries, the overall efficacy will be assessed by the responsible Investigator 
using the excellent, good, moderate, and none scale, taking both the intra- and postoperative 
assessments into account, based on the following algorithm in Table 9.  
 
 

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Table 9 
Algorithm for the Overall Efficacy Assessment for Surgical Prophylaxis 
Algorithm for the Overall Efficacy Assessment for Surgical Prophylaxis 
Intraoperative 
assessment 
Postoperative assessment 
Excellent 
Good 
Moderate 
None 
Excellent 
Excellent 
Good 
Good 
Moderate 
Good 
Good 
Good 
Moderate 
Moderate 
Moderate 
Good 
Moderate 
Moderate 
None 
None 
Moderate  
Moderate 
None 
None 
For minor surgeries, the overall assessment of perioperative prophylaxis will be assessed by the 
responsible Investigator using the excellent, good, moderate, and none scale, taking the 
postoperative assessment in to account as shown in Table 8. 
 
Joint Health Status 
Joint health will be assessed using the Haemophilia Joint Health Score (HJHS) [16], which has 
been specifically validated for the assessment of clinical outcome in adult patients with VWD 
(mean age 46 years [range 18–80]) [11]. 
The HJHS has shown excellent reliability and good validity in both adults and children with 
haemophilia [16-18].  
Target joint(s) will also be documented. Target joint(s) are defined as having three or more 
spontaneous BEs into a single joint within six consecutive months preceding either the 
Screening Visit or the Study Completion Visit. 
7.3 Pharmacokinetic Assessments 
Pharmacokinetic parameters will be assessed for VWF:Ac (VWF:RCo) and FVIII:C (one-stage, 
OS) assays based on actual wilate potencies. 
The following PK parameters will be assessed: 
• Area under the curve (AUC) and AUC normalised for the administered dose (AUCnorm) 
• In vivo half-life (T1/2) 
• Maximum plasma concentration (Cmax) 
• Time to reach maximum plasma concentration (Tmax) 
• Mean residence time (MRT) 
• Volume of distribution (Vd) 
• Clearance (CL) 
• Incremental in vivo recovery (IVR) 
To account for residual VWF:Ac and FVIII:C levels the listed parameters will be computed on 
pre-dose-adjusted concentration vs. time profiles. 
For details on the laboratory analyses, see Section 7.4.5. 

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7.4 Safety Assessments 
7.4.1 Assessments for Safety Endpoints 
Any of the following drug safety information shall be collected: 
• Adverse events (AEs) and serious adverse events (SAEs) temporally associated with the 
administration of IMP, comparator, or placebo  
• Pregnancies, drug overdose, interaction, medication error, lack of efficacy, and post-
study SAEs  
7.4.2 Adverse Events (AEs) 
7.4.2.1 Definitions 
• Adverse event (AE): An AE is any untoward medical occurrence in a study patient 
receiving an IMP and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use 
of an IMP, whether or not related to the IMP. 
• Treatment-emergent adverse event (TEAE): A TEAE is an AE that started or 
worsened after the start of IMP injection. 
• Adverse drug reaction (ADR): An ADR is any noxious and unintended response to an 
IMP related to any dose. The phrase ‘response to an IMP’ means that a causal 
relationship between the IMP and an AE carries at least a reasonable possibility, i.e., 
the relationship cannot be ruled out. 
• Other significant AEs: Any marked laboratory abnormalities or any AEs that lead to 
an intervention, including withdrawal of drug treatment, dose reduction, or significant 
additional concomitant therapy. 
• Withdrawal due to AE/ADR: AE/ADR leading to discontinuation of treatment with 
IMP. Any such events will be followed up by the Investigator until the event is resolved 
or until the medical condition of the subject/patient is stable. All follow-up information 
collected will be made available to the Sponsor. 
7.4.2.2 Collection of AEs 
The condition of the patient will be monitored throughout the study. At each visit, whether 
scheduled or unscheduled, AEs will be elicited using a standard nonleading question such as 
“How have you been since the last visit/during the previous study period?” In addition, the 
Investigator will check the subject/patient diaries (if applicable) for any documented event. 
Any AE or ADR which occurs during the study will be noted in detail on the appropriate pages 
of the CRF. If the subject/patient reports several signs or symptoms representing a single 
syndrome or diagnosis, the diagnosis should be recorded in the CRF. The Investigator will grade 
the severity of all AEs or ADRs (mild, moderate, or severe), the seriousness (non-serious or 
serious), and the causality. The Sponsor is responsible for assessing the expectedness of each 
ADR (expected or unexpected). 

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In the event of clinically significant abnormal laboratory findings, the tests will be confirmed 
and the patient followed up until the laboratory values have returned to normal and/or an 
adequate explanation for the abnormality has become available. 
Diseases, signs and symptoms, and/or laboratory abnormalities already present before the first 
administration of IMP will not be considered AEs unless an exacerbation in intensity or 
frequency (worsening) occurs. 
The Investigator will provide detailed information about any abnormalities and about the nature 
of and reasons for any action taken as well as any other observations or comments that may be 
useful for the interpretation and understanding of an AE or ADR. 
7.4.2.3 Severity of AEs 
The intensity/severity of AEs will be graded as follows: 
• Mild: an AE, usually transient, which causes discomfort but does not interfere with the 
patient’s routine activities 
• Moderate: an AE which is sufficiently discomforting to interfere with the patient’s 
routine activities 
• Severe: an AE which is incapacitating and prevents the pursuit of the patient’s routine 
activities 
The grading of an AE is up to the medical judgement of the Investigator and will be decided on 
a case-by-case basis. 
7.4.2.4 Causality of AEs 
The relationship of AEs to the administered IMP will be assessed by the Investigator: 
• Probable: reports including good reasons and sufficient documentation to assume a 
causal relationship, in the sense of plausible, conceivable, likely, but not necessarily 
highly probable. A reaction that follows a reasonable temporal sequence from 
administration of the IMP; or that follows a known or expected response pattern to the 
suspected medicine; or that is confirmed by stopping or reducing the dosage of the 
medicine and that could not reasonably be explained by known characteristics of the 
subject’s/patient’s clinical state. 
• Possible: reports containing sufficient information to accept the possibility of a causal 
relationship, in the sense of not impossible and not unlikely, although the connection is 
uncertain or doubtful, for example because of missing data or insufficient evidence. A 
reaction that follows a reasonable temporal sequence from administration of the IMP; 
that follows a known or expected response pattern to the suspected medicine; but that 
could readily have been produced by a number of other factors. 
• Unlikely: reports not following a reasonable temporal sequence from IMP 
administration. An event which may have been produced by the subject’s/patient’s 
clinical state or by environmental factors or other therapies administered. 
• Not related (unrelated): events for which sufficient information exists to conclude that 
the aetiology is unrelated to the IMP. 
• Unclassified: reports which for one reason or another are not yet assessable, e.g., 
because of outstanding information (can only be a temporary assessment). 

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7.4.2.5 Classification of ADRs by Expectedness 
ADRs will be classified by the Sponsor as either expected or unexpected: 
• Expected: an ADR that is listed in the current edition of the Investigator’s Brochure or 
other reference safety information. 
• Unexpected: an ADR that is not listed in the current edition of the Investigator’s 
Brochure or other reference safety information, or that differs because of greater 
severity or greater specificity. 
7.4.2.6 Outcome of AEs 
The outcome of all reported AEs has to be documented as follows: 
1. Recovered, resolved 
2. Recovering, resolving 
3. Not recovered, not resolved 
4. Recovered, resolved with sequelae 
5. Fatal 
6. Unknown 
NOTE: A patient’s death per se is not an event, but an outcome. The event which resulted in 
the patient’s death must be fully documented and reported, even in case the death occurs within 
4 weeks after IMP treatment end and regardless of whether or not it is considered treatment-
related. 
7.4.2.7 Action(s) taken 
AEs requiring action or therapy must be treated with recognised standards of medical care to 
protect the health and well being of the subject/patient. Appropriate resuscitation equipment 
and medicines must be available to ensure the best possible treatment in an emergency situation. 
The action taken by the Investigator must be documented: 
a) General actions taken in the event of an AE 
– None 
– Medication (other than IMP) or other (e.g., physical) therapy started 
– Test performed 
– Other (to be specified) 
b) IMP-related actions taken in the event of an AE 
– None 
– Product withdrawn 
– Dose reduced 
– Dose increased 

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The Investigator will follow up on each AE until it has resolved or until the medical condition 
of the subject/patient has stabilised. Any relevant follow-up information will be reported to the 
Sponsor. 
7.4.3 Serious Adverse Events (SAEs) 
A serious AE (SAE) is any untoward medical occurrence that at any dose: 
• results in death, 
• is life-threatening (see below), 
• requires hospitalisation or prolongation of existing hospitalisation, 
• results in persistent or significant disability/incapacity, 
• is a congenital anomaly/birth defect, 
• is another important medical event. 
NOTE: The term ‘life-threatening’ refers to an event in which the patient was, in the view of 
the reporting Investigator, at immediate risk of death at the time of the event; it does not refer 
to an event which may hypothetically have caused death had it been more severe. 
In deciding whether an AE/ADR is serious, medical judgment should be exercised. Thus, 
important AEs/ADRs that are not immediately life-threatening or do not result in death or 
hospitalisation but may jeopardise the subject/patient or may require intervention to prevent 
one of the other outcomes listed in the definitions above should also be considered serious.  
In addition, although not classified under the seriousness criteria, all suspected transmissions 
of an infectious agent should be reported as SAE. A suspected virus transmission means that 
virus antigen has been detected in the patient. A passive transmission of antibodies alone does 
not constitute a suspected virus transmission. Another such ‘important medical event’ that has 
to be reported as an SAE is the development of VWF or FVIII inhibitors. 
Hospitalisation is not considered an SAE in the case where: 
• the hospitalization takes place because of study-related procedure 
(e.g. PK assessment) 
• of any planned surgical procedure (e.g. for the implementation of a port-a-cath) 
7.4.4 SAE Reporting Timelines 
All SAEs, whether or not they are suspected to be related to study treatment, are to be reported 
immediately by telephone, fax, or email to the Clinical Project Manager or designee: 
  
 
Clinical Resarch & Development Haematology 
Fax: 
 
Email: 
 
The contact details will also be communicated at the study initiation visit. 
In addition, within 24 hours after recognition of the event, an Octapharma Serious Adverse 
Event Report must be completed and submitted to: 

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Octapharma’s Central Drug Safety Unit 
OCTAPHARMA Pharmazeutika Produktionsges.m.b.H. 
Oberlaaer Strasse 235, 1100 Vienna, Austria 
 
 
24 hours emergency telephone number: 
 
Waivers the from SAE Reporting Requirement 
Waivers from the SAE reporting requirement include hospitalisation for the treatment of a 
(disease related) BE assessd as unrelated to IMP treatment, and surgeries that are elective or 
were planned before study entry or prolongations of existing hospitalisations for economic or 
social, but not medical, reasons. Such surgeries or prolongations of hospitalisations should not 
be considered SAEs. 
7.4.5 Laboratory Tests 
The laboratory parameters shown in Table 10 will be investigated during the study at the time 
points specified in Section 6.1. 
Table 10 
Laboratory Sampling Flowchart 
 
Laboratory Assessments 
Screening Visit 
PK Visits 
1-Month IVR Visit 
2-Month IVR Visit 
3-Month IVR Visit 
6-Month IVR Visit 
9-Month IVR Visit 
Study Completion 
(12-Month) IVR Visit 
LOCAL LAB 
 
 
 
 
 
 
 
 
  Determination of AB0 blood group, unless derivable from medical history 
 
 
x [1] 
 
 
 
 
 
  Routine safety laboratory 
x 
 
 
 
 
 
 
x [2] 
CENTRAL LAB 
 
 
 
 
 
 
 
 
  VWF:Ac (VWF:RCo) 
x 
x [3]  
x [4] 
x [4] 
x [4] 
x [4] 
x [4] 
x [4] 
  FVIII:C (OS)  
 
x [3] 
x [4] 
x [4] 
x [4] 
x [4] 
x [4] 
x [4] 
  VWF and FVIII inhibitors 
x 
 
 
 
x [2] 
x [2] 
x [2]  
x [2] 
  VWF multimer analysis 
x 
x [5] 
 
 
 
 
 
 
  Retention samples for possible virus marker testing 
x 
 
 
 
 
 
 
 
[1] 
If unknown, can also be shifted to a later timepoint 
[2] 
Before injection 
[3] 
Before injection and at 15 min, 3 hr, 9 hr, 24 hr, 48 hr and 72 hrs after injection 
[4]  
Within 60 min before and 15±5 min after injection 
[5] 
For VWD type 3 patients ≥14.5 kg BW, samples from 15 min and 24 hrs will be used for additional multimer analysis 
An effort was made in this study to avoid invasive procedures and repeated blood sampling in 
paediatric patients, in agreement with EU guidelines. The Ethical Considerations for Clinical 
Trials on Medicinal Products conducted with the Paediatric Population will be followed during 
the conduct of WIL-33. 
For sampling, the Committee recommends that per individual, trial-related blood loss should 
not exceed 3% of the total blood volume during a period of four weeks and should not exceed 
1% at any single time. The total volume of blood is estimated at 90 ml/kg BW; in mean 3% is 
around 2.7 mL blood per kg BW [19]. 

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Blood Sampling 
The actual date and time of any blood sampling must be recorded in the eCRF, on the label of 
the laboratory tubes and on the corresponding laboratory shipment forms. The exact sampling 
volumes needed, and further specific processes will be desribed in the laboratory manual. 
EDTA Blood 
Around 2 mL (or less, as required by the local laboratory) of EDTA blood will be collected for 
the measurement of haematology parameters (RBC count, WBC count, haemoglobin, 
haematocrit, platelet count) at the screening and at completion visit. All haematology tests are 
to be done at the local laboratory in accordance with local requirements. 
Citrated Plasma 
For the analysis of FVIII:C, VWF:Ac, FVIII inhibitor screen, and VWF inhibitor screen citrated 
blood is collected and sent to the main central laboratory, from where it is further distributed as 
required. As the only exception, samples collected for multimer analysis must be sent separately 
to the specialised laboratory as indicated below. 
After collection and centrifugation, the plasma will be aliquoted into cryo-resistant tubes. 
Samples will be stored at ≤-70°C and shipped to the central laboratory on dry-ice. The samples 
from the screening visit must be sent to the laboratories within 2 working days. The frequency 
of further shipments depends on the number of patients and other local factors, and will be 
individually specified. 
The blood volumes needed for the regular study visits range from a minimum of approximately 
5.6 mL per visit day (at Visits 3-4: Monthly IVR Visits) to 9.7 mL (at Visits 5–7: 3-Monthly 
IVR Visits). 
As for the PK Visit, the needed volumes per day range from approximately 2.8 mL (at PK days 
3 and 4) to 11.2 mL (at PK day 1), whereas additional multimer analysis in severe VWD Type 
3 patients requires sampling volumes of up to 13.0 mL on one day (VWD Type 3 patients with 
≥14.5 kg body weight). 
These assumptions are based on the smallest possible collection tube volumes, details of which 
are provided in the laboratory manual that will be made available to all participating study 
centres. 
For analysis performed locally, e.g. at screening and pre-, intra, and post-surgery, citrated blood 
as required by the local laboratory will be collected and processed in accordance with local 
requirements. 
Serum 
AB0 blood group analysis is only indicated in cases where the blood group is not known from 
medical history at the time of screening, and can be done at the 1-Month visit or at any other 
time during the study by the local laboratory.  
For retention samples for possible later virus testing, a serum sample of another approximately 
2.5 mL  is taken (at Screening Visit only) and sent frozen to the central main blood sample 
reception laboratory. 

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All collection tubes and materials required as well as exact shipping information are provided 
by the central laboratory in advance. 
Laboratory Abnormalities 
The Investigator must assess the clinical significance of abnormal laboratory values outside the 
normal range as specified by the reference laboratory. Any clinically significant abnormalities 
should be fully investigated. 
Only laboratory abnormalities that have been rated as being clinically significant will be 
documented as AEs/ADRs. Clinically significant is defined as any laboratory abnormality that 
the Investigator feels is of clinical concern, and/or requires medical intervention and/or follow-
up. Additional tests and other evaluations required to establish the significance, or aetiology of 
an abnormal result or to monitor the course of an AE should be obtained if clinically indicated. 
Any abnormal laboratory value that persists should be followed until resolution or for 14 days 
after the final study visit, whichever occurs first. Preferably, clinically significant laboratory 
abnormalities should be medically diagnosed and entered as a diagnosis into the AE form, if 
not already present at baseline. 
All remaining serum and plasma volumes will be labelled and stored as retention samples at the 
central laboratory for at least 2 years after the completion of the study and until Octapharma’s 
written authorisation to destroy these samples. 
7.4.5.1 Central Laboratory 
The following laboratory parameters will be determined in accordance with the time points 
specified in Table 1 and in Section 6, and as shown in the Laboratory Sampling Flowchart in 
Table 10: 
• FVIII:C (one-stage) in wilate batches used for PK/IVR evaluations will be determined 
(for VWF:Ac (VWF:RCo), potency will be obtained from the Certificates of Analysis). 
• FVIII:C will be measured in plasma at pre-specified time points using the OS assay. 
• VWF:Ac will be measured in plasma at pre-specified time points by VWF:RCo. 
• For VWF and FVIII inhibitor titre testing, a sample will be analysed at the central 
laboratory. In addition, VWF and FVIII inhibitor testing will be performed testing at 
baseline, every 3 months, and in case of inhibitor suspicion. 
• A retention sample is to be drawn for possible virus marker testing.  
• Multimer distribution of the VWF by multimer analysis using low- and high resolution 
electrophoresis gels (preferably 1% and >2% gels) in paediatric patients with VWD type 
3 and a body weight ≥14.5 kg; VWF multimers will be determined by a quantitative 
method. 
 
 
Central laboratory facilities: 
 
 
Main blood sample reception laboratory for EMEA countries: 
 
Labcorp Central Laboratory Services S.à.r.l. 
 
7, rue Moïse-Marcinhes 
 
1217 Meyrin, Geneva, Switzerland 
 

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Main blood sample reception laboratory for US / CA: 
 
Labcorp Central Laboratory Services 
 
Limited Partnership 
 
8211 SciCorDrive 
 
Indianapolis, IN, 46214, US 
 
 
Analysis of central laboratory parameters: 
 
VWF:Ac (RCo), FVIII (OS), VWF Inhibitors, FVIII Inhibitors; 
 
LabCorp Esoterix Coagulation Laboratory 
 
8490 Upland Drive 
 
Suite 100 
 
Englewood, Colorado 80112, US 
 
 
Analysis of central laboratory parameter: 
 
VWF Multimer Analysis 
 
MEDILYS Laborgesellschaft mbH 
 
Paul-Ehrlich-Straße 1 
 
22763 Hamburg, Germany 
Laboratory kits for all required central laboratory tests are provided by Labcorp Central 
Laboratory Services in Indianapolis, US. 
7.4.5.2 Local Laboratory 
The following routine safety laboratory tests will be done by the local laboratories of each study 
site: 
 Haematology: red blood cell count, white blood cell count, haemoglobin, haematocrit, 
and platelet count 
 AB0 blood-group testing, if unknown. Should the blood group not have been 
previously determined, this can be done at any time during the study, by however 
respecting blood volume restrictions. 
 VWF:Ac (VWF:RCo) and FVIII:C measurements in case of BEs or surgeries will 
also be done by the local laboratories, if clinically indicated. 
 VWF / FVIII inhibitor determination if an inhibitor is suspected, and if laboratory 
facilities allow.  
The analyses of the local laboratories are carried out according to local regulations. 
7.4.6 Virus Safety Tests 
Retention samples will be taken for possible virus marker testing in the central laboratory. 
7.4.7 Vital Signs and Physical Examination 
The vital signs obtained at the time points specified in Section 6 are blood pressure, body 
temperature, pulse rate, and respiratory rate. 

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Physical examinations will be performed at the visits specified in Section 6. Both height and 
weight will be measured at screening. In addition, weight will be measured at all visits prior to 
wilate dosing and serve as a basis for continuous dose adjustments, if appropriate. 
7.4.8 Other Relevant Safety Information 
a) Post-study related safety reports 
Any SAE which occurs up to 4 weeks after the last IMP administration should be reported by 
the Investigator to the Sponsor in case the Investigator becomes aware of it. Proactive 
monitoring for post-study SAEs is not required. 
In case a post-study SAE is identified, the Investigator should complete an SAE form and also 
state the relation to the clinical study in the report and transmit it to the Clinical Trial Manager 
and to Octopharma’s Corporate Drug Safety Unit (see Section 7.4.4). 
Deaths occurring within 4 weeks after the last IMP administration should also be reported, 
regardless of whether or not they are considered treatment-related. 
 
Overdose, interaction, medication error and lack of efficacy 
The following safety relevant information should be reported as AE or, if the reaction fulfils 
one of the criteria for seriousness, as SAE. 
b) Drug overdose 
An overdose is a deliberate or inadvertent administration of a treatment at a dose higher than 
specified in the protocol and higher than the known therapeutic dose that is of clinical relevance. 
The reaction must be clearly identified as an overdose. 
c) Drug interaction 
A drug interaction is a situation in which a substance or medicinal product affects the activity 
of an IMP, i.e., increases or decreases its effects, or produces an effect that none of the products 
would exhibit on its own. The reaction must be clearly identified as a drug interaction. 
d) Medication error 
A medication error involves the inadvertent administration or unintended use of a medicinal 
product which may be caused by the naming, presentation of pharmaceutical form/packaging, 
or instructions for use/labelling. The reaction must be clearly identified as a medication error. 
e) Lack of efficacy 
Lack of efficacy is suspected when the therapeutic result is not as expected. One example of a 
lack of efficacy may be continued bleeding in a patient with VWD despite administration of 
coagulation factor. Lack of efficacy should be reported as an AE or, if the reaction fulfils one 
of the criteria for seriousness, as an SAE. 

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7.5 Appropriateness of Measurements 
The criteria for assessing the safety and efficacy of wilate in the treatment of BEs as well as in 
surgical prophylaxis are identical to those used in similar previous studies with wilate. 
Evaluation of the tABR of patients with coagulation bleeding disorders such as haemophilia A 
has been used as an efficacy endpoint to reliably demonstrate the impact of prophylaxis on the 
bleeding rates of these patients (see Section 1.2). 

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8 
DATA HANDLING AND RECORD KEEPING 
8.1 Documentation of Data 
8.1.1 Source Data and Records 
Source data are defined as all information related to clinical findings, observations, or other 
activities in the study, written down in original records or certified copies of original records, 
allowing reconstruction and evaluation of the clinical study. 
The Investigator will maintain adequate source records (e.g., case histories or subject/patient 
files for each subject/patient enrolled). Source records should be preserved for the maximum 
period of time required by local regulations. 
For each patient enrolled, the Investigator will indicate in the source record(s) that the patient 
participates in this study and document any further study-related details, such as patient 
information and consent process (whose signature was retrieved, date and time of consent), any 
details communicated regarding IMP administration and IMP handling (i.e. training of parents 
for home-treatment, including any potential external home-treatment planned). 
All data entered in the eCRF must be supported by source data in the subject/patient records, 
with exceptions listed in Section 8.1.2. 
The Investigator will permit study-related monitoring, audit(s), IEC/IRB review(s), and 
regulatory inspection(s), by providing direct access to the source data/records. 
Patients will usually be treated at home by their parents or by their home physician. Parents 
will, therefore, be provided with a sufficient amount of wilate and a patient diary, which should 
also be documented in the patient’s source data records on an ongoing basis. 
The patient diary will be handed to the patient during the Screening Visit after inclusion into 
the study. The Investigator will explain to the patients’ parents how to fill in the diary and 
emphasise the importance of careful documentation. 
At each follow-up visit at the study site, the patients’ parents will bring along the patient diary 
for review and validation by site personnel. 
During or after each follow-up visit, the information recorded in the patient diaries will be 
transcribed to the eCRFs. The patient diaries are classified as source data, and the originals will 
be included in the patient’s medical record. 
The Investigator may authorise site staff (e.g., sub-Investigators, nurses) to enter study data into 
the eCRF. This must be documented in the Delegation of Authority Log signed by the 
Investigator. 
8.1.2 Case Report Forms 
For each patient enrolled, an electronic CRF (eCRF) will be completed within the Electronic 
Data Capture (EDC) system and approved by the Investigator or an authorised sub-Investigator.  
Study site staff (e.g., research nurse) will be responsible for entering patient data into the 
validated EDC system. All site personnel will be trained on the EDC system and study specific 
eCRFs prior to receiving access to the live database for data entry. 

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The site is also provided with the approved eCRF Completion Guidelines which will assist in 
data entry and data issues/questions. The site will be notified once the database is active to 
begin data entry. Additional site training may be provided as refreshers throughout the study, if 
needed. All persons allowed to enter or change eCRF data must be listed in the Delegation of 
Authority Log. 
8.1.3 Changes to electronic Case Report Form (eCRF) Data 
Monitors will perform source data verification (SDV) as defined for the study. 
If any errors or discrepancies in the eCRFs are found during data entry or review, discrepancies 
will be generated programmatically within the EDC system, and ‘manual’ queries will be 
generated by either a monitor or Data Management.  
Discrepancies and queries can only be corrected by the Investigator(s) or other authorised site 
personnel. An audit trail documents all changes to the data over the entire study period. If the 
reason for a change is not obvious, a comment must be supplied in the query’s response, stating 
the reason for the change, prior to closing. The study monitor should provide guidance to 
Investigator(s) and the Investigator(s)’ designated representatives on making such corrections.  
Once queries have been resolved by the site staff, the resolutions are assessed by Data 
Management. If the query response provided confirms the data as correct, the discrepancy will 
be closed. If the response does not adequately address the question raised, a new query will be 
issued for further clarification. 
Manual checks are performed and programs are run throughout the study until the data is clean 
and the database is ready for lock. All discrepancies will be resolved prior to database lock. 
There will be a final run of the programmed checks to ensure all discrepancies are closed out, 
SDV will be confirmed as complete by the monitor, and all eCRFs will be approved by the 
Investigator prior to database lock. 
8.2 Information to Investigators 
An Investigator’s Brochure (IB) will be handed out to the Investigator before the start of the 
study. The IB contains all information in the Sponsor’s possession necessary for the Investigator 
to be fully and accurately informed about the safety of the IMP under evaluation and the 
respective benefit-risk ratio. 
The IB will be updated by the Sponsor at regular intervals and whenever relevant new 
information concerning the IMP becomes available. 
The Investigator will be informed about the methods for rating relevant study outcomes and for 
completing CRFs to reduce discrepancies between participating Investigator and study sites. 
The Investigator will be kept informed of important data that relate to the safe use of the IMP 
as the study proceeds. 
8.3 Responsibilities 
The Principal Investigator is accountable for the conduct of the clinical study. Responsibilities 
may be delegated to appropriately qualified persons. 

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A Delegation of Authority Log will be filled in and signed by the Principal Investigator. In 
accordance with this authority log, study site staff (e.g., sub-Investigators, nurses) is authorised 
to perform tasks relating to the study. 
8.4 Investigator’s Site File 
At each study site, the Investigator is responsible for maintaining all records to enable the 
conduct of the study to be fully documented. Essential documents as required by GCP 
guidelines and regulations (e.g., copies of the protocol, study approval letters, all original 
informed consent forms, site copies of all CRFs, drug dispensing and accountability logs, 
correspondence pertaining to the study, etc.) should be filed accurately and kept by the 
Investigator for the maximum period of time required by local regulations. 
The Investigator is responsible for maintaining a confidential subject/patient identification code 
list, which provides the unique link between named source records and CRF data for the 
Sponsor. The Investigator must arrange for the retention of this confidential list for the 
maximum period of time required by local regulations. 
No study document should be destroyed without prior written agreement between the 
Investigator and the Sponsor. Should the Investigator elect to assign the study documents to 
another party, or move them to another location, the Sponsor must be notified in writing. 
8.5 Provision of Additional Information 
On request, the Investigator will supply the Sponsor with additional data relating to the study, 
or copies of relevant source records, ensuring that the subject’s/patient’s confidentiality is 
maintained. This is particularly important when CRFs are illegible or when errors in data 
transcription are encountered. In case of particular issues or governmental queries, it is also 
necessary to have access to the complete study records, provided that the subject’s/patient’s 
confidentiality is protected in accordance with applicable regulations. 
8.6 Independent Data Monitoring Committee 
Not applicable. 

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9 
STATISTICAL METHODS AND SAMPLE SIZE 
The statistical analysis will be delegated under an agreement of transfer of responsibilities to 
an external contract research organisation (CRO) that agrees to meet all Octapharma procedures 
and policies. 
9.1 Determination of Sample Size 
No formal sample size calculation was performed for the study. 
The sample size of up to 12 patients, including at least four patients with VWD type 3, is based 
on a communication from the FDA and on EU guideline CPMP/BPWG/220/02 calling for a 
trial in at least eight children with VWD under the age of six years, three of whom should have 
type 3 VWD and was selected to accommodate for drop-outs. 
9.2 Statistical Analysis 
The primary approach to statistical analysis will be descriptive, presenting sampling statistics 
(n, mean, standard deviation, quartiles, and ranges) for continuous measurements and absolute 
and relative frequency counts for categorical/ordinal data. Geometric means and standard 
deviations will presented in addition for PK concentrations and parameters. This will be 
complemented by the presentation of exploratory CIs for means or proportions. 
A formal statistical analysis plan describing all details of the analyses to be performed will be 
prepared by the study statistician and approved by the Sponsor prior to the start of the statistical 
analysis. 
9.2.1 Populations for Analysis 
The safety set will include all patients who received at least one dose of wilate. 
The full analysis set defined according to the intention-to-treat (ITT) principle will include all 
enrolled patients who received at least one dose of wilate after the PK Visit. 
The per-protocol (PP) set, i.e., a subset of the full analysis set, will exclude patients with major 
protocol deviations which may have an impact on the evaluation of the primary study outcome 
parameter(s). Examples of major and minor protocol deviations will be described in the 
Statistical Analysis Plan. 
The surgery (SURG) set will be a subset of the FAS, containing all patients who underwent a 
surgical procedure treated with wilate during their prophylactic treatment phase. 
The pharmacokinetic (PK) set will be a subset of the SAF, containing all patients for whom a 
valid PK profile was obtained at the PK Visit. 
A final decision about the classification of protocol deviations and their consequences regarding 
assignment of patients to analysis sets will be made during the data review meeting. Decisions 
and outcome will be approved by the Sponsor. 
The analysis of safety will be based on the safety set. 
The evaluation of primary endpoint will be performed on the full analysis set (ITT analysis) 
and the PP set (PP analysis). 

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For secondary and explarotary endpoints, ITT and PP analyses will be carried out, unless the 
two analysis sets differ by no more than 1 patient. 
Analysis and efficacy of wilate in surgeries will be based on the SURG set. 
Analysis of the PK properties of wilate will be based on the PK set. 
9.2.2 Efficacy Analysis Plan 
The analysis of the efficacy of prophylactic treatment with wilate will be based on the FAS and 
the PP set. 
Primarily, all obtained data on treatment characteristics (wilate dosages, frequencies, total 
consumption), VWF:Ac and FVIII:C incremental IVR of wilate over time and BEs (duration, 
frequency, efficacy assessment) will be described using summary statistics. 
9.2.2.1 Efficacy of wilate in Prophylactic Treatment 
The haemostatic efficacy of wilate will be assessed by evaluating tABR over all types of VWD. 
The frequency and severity of BEs and the total, traumatic and spontaneous ABR will be 
calculated from patients’ dosing and treatment frequency in different VWD types. Efficacy of 
prophylactic treatment with wilate will be statistically evaluated by analysing the primary 
endpoint. 
The tABR will be calculated as the total number of spontaneous bleeds, traumatic bleeds, and 
other bleeds occurring in the time period between first prophylactic dose of wilate and the Study 
Completion Visit, divided by the duration (in years) between first prophylactic dose of wilate 
and the Study Completion Visit. Bleeding episodes occurring within surgery periods will be 
excluded from the calculation of tABR. 
9.2.2.2 Efficacy of wilate in the Treatment of Breakthrough Bleedings 
To assess the haemostatic efficacy of wilate in the treatment of breakthrough BEs during 
prophylaxis, a frequency distribution of all treated BEs that were successfully treated will be 
presented overall and by severity, along with an exploratory 95% CI for the proportion of 
successfully treated BEs. 
9.2.2.3 Pharmacokinetic Analysis/Recovery Assessments 
All PK analyses will be based on the PK set. The following PK parameters for will be analysed: 
• Area under the curve (AUC) and AUCnorm (normalised for the administered dose) 
• In vivo half-life (T1/2) 
• Maximum plasma concentration (Cmax) 
• Time to reach maximum plasma concentration (Tmax) 
• Mean residence time (MRT) 
• Volume of distribution (Vd) 
• Clearance (CL) 
• Incremental in vivo recovery (IVR) 

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Pharmacokinetic parameters will be computed for VWF:Ac and FVIII:C. The one-stage (OS) 
assay for FVIII, actual wilate potencies, and actual sampling times will be used in the 
calculations. Pharmacokinetic parameters will be derived by non-compartmental methods. 
To account for residual VWF:Ac and FVIII:C levels, the listed parameters will be computed on 
pre-dose-adjusted concentration vs. time profiles. 
The PK profiles of VWF:Ac and FVIII:C, the PK parameters derived and recovery assessments 
will be summarised using descriptive statistics (including geometric means and standard 
deviations) as well as the presentation of concentration vs time plots (individual values and 
means). The results of IVR assessments over time will be presented per time point and as 
differences to baseline, along with 95% CIs for the mean differences. 
9.2.2.4 Efficacy of wilate in Surgical Prophylaxis 
To assess the efficacy of wilate in surgical prophylaxis, a frequency distribution of the efficacy 
rating for all surgical procedures will be presented. All other surgery data (e.g., severity, type, 
wilate consumption) will be presented descriptively. 
9.2.2.5 Analysis of Other Endpoints 
The statistical analysis of other endpoints will be descriptive, including exploratory 95% CIs. 
9.2.3 Safety Analysis Plan 
All safety analyses will be based on the SAF population. 
The analysis of safety will be based on the occurrence of AEs, e.g. results of immunogenicity 
screening, thrombogenicity monitoring for sustained excessive FVIII plasma levels (and an 
increased risk of thrombotic events), and safety laboratory testing. Analysis of AEs will focus 
on TEAEs. 
Adverse events will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA) in the version current at the clinical start of the study. The analysis will include 
only treatment-emergent adverse events (TEAEs), i.e., AEs that started or worsened after the 
first IMP injection. All TEAEs, related TEAEs (i.e., TEAEs probably or possibly related to the 
IMP), and serious TEAEs will be summarised and tabulated according to MedDRA primary 
system organ class and preferred term. 
Patient listings will be provided for patients with SAEs, AEs leading to withdrawal from study, 
and AEs leading to death. 
Time profiles of the safety laboratory parameters will be analysed by presenting sampling 
statistics for the values as well as frequency tables for positive findings, along with 95% 
Pearson-Clopper CIs. 
Similarly, time profiles of VWF and FVIII inhibitor testing results will be analysed by 
presenting sampling statistics for the values as well as frequency tables for positive findings, 
along with 95% Pearson-Clopper CIs. 
Other safety parameters (e.g., changes in physical examination findings) will be analysed by 
summary tables or listings. 

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9.2.4 Handling of Missing Data 
In general, missing data will not be imputed. Calculations pertaining to the derivation of the 
tABR will be based on documented time periods only. Only in case of missing body weight 
will the last available weight measurement be used for calculating the dose per kg bodyweight 
(last observation carried forward, LOCF). 
9.3 Randomisation, Stratification, and Code Release 
Not applicable 
9.4 Interim Analysis (if Applicable) 
Not applicable 

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10 ETHICAL/REGULATORY, LEGAL AND ADMINISTRATIVE ASPECTS 
10.1 Ethical/Regulatory Framework 
This study will be conducted in in compliance with the protocol and its amendments, the ICH 
Guideline for Good Clinical Practice (GCP) E6 (R2) (EMA/CHMP/ICH/135/1995), the Ethical 
considerations for clinical trials on medicinal products conducted with the paediatric 
population, applicable regulatory requirements, and in accordance with the ethical principles 
laid down in the Declaration of Helsinki.  
The study protocol and any subsequent amendment(s) will be submitted to an Independent 
Ethics Committee (IEC)/Institutional Review Board (IRB) and to the Regulatory Authority. 
The study will be conducted in compliance with the protocol, GCP guidelines, and applicable 
regulatory requirements. 
The regulatory application or submission for regulatory approval will be made by the Sponsor, 
the Investigator, or designated third party (e.g., CRO) as required by national law. 
10.2 Approval of Study Documents 
The study protocol, a sample of the patient information and informed consent form, any other 
materials provided to the patients, and further requested information will be submitted by the 
Sponsor or the Investigator to the appropriate IEC/IRB and the Regulatory Authority. The study 
must be approved by the IEC/IRB and the Regulatory Authority before any IMP may be shipped 
to the study sites and any subject/patient is exposed to a study-related procedure. 
The Sponsor, the Investigator, and any third party (e.g., CRO) involved in obtaining approval 
must inform each other in writing that all ethical and legal requirements have been met before 
the first subject/patient is enrolled in the study. 
10.3 Patient Information and Informed Consent 
The Investigator will obtain freely given written consent from each patient’s legal 
parent/guardian after an appropriate explanation of the aims, methods, anticipated benefits, 
potential hazards, and any other aspect of the study which is relevant to the patient’s decision 
to participate. The informed consent form must be signed, with name and date and time noted 
by the patient’s legal parent/guardian, before the patient is exposed to any study-related 
procedure, including screening tests for eligibility. If the children are old enough to understand 
the risks and benefits of the study, they should also be informed and provide their written 
consent. 
The Investigator will explain that the patients’legal parents/guardians are completely free to 
refuse to enter the study or to withdraw from it at any time, without any consequences for their 
further care and without the need to justify. The Investigator will complete the informed consent 
section of the CRF for each patient enrolled. 
Each patient’s legal parent/guardian will be informed that his/her medical (source) records may 
be reviewed by the study monitor, a quality assurance auditor, or a health authority inspector, 
in accordance with applicable regulations, and that these persons are bound by confidentiality 
obligations. 

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

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

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

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

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14 REFERENCES 
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Bowman M, Hopman WM, Rapson D, Lillicrap D, Silva M, James P. A prospective 
evaluation of the prevalence of symptomatic von Willebrand disease (VWD) in a 
pediatric primary care population. Pediatr Blood Cancer. 2010;55(1):171-3. 
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Sadler JE. A revised classification of von Willebrand disease. For the Subcommittee on 
von Willebrand Factor of the Scientific and Standardization Committee of the 
International Society on Thrombosis and Haemostasis. Thromb Haemost. 
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3. 
Neff AT, Sidonio RF, Jr. Management of VWD. Hematology Am Soc Hematol Educ 
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Nichols WL, Hultin MB, James AH, Manco-Johnson MJ, Montgomery RR, Ortel TL, 
et al. von Willebrand disease (VWD): evidence-based diagnosis and management 
guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report 
(USA). Haemophilia. 2008;14(2):171-232. 
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Revel-Vilk S, Schmugge M, Carcao MD, Blanchette P, Rand ML, Blanchette VS. 
Desmopressin (DDAVP) responsiveness in children with von Willebrand disease. J 
Pediatr Hematol Oncol. 2003;25(11):874-9. 
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Rodeghiero F, Castaman G, Tosetto A. How I treat von Willebrand disease. Blood. 
2009;114(6):1158-65. 
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Wilate. Clinical Investigator's Brochure No. 20. 03 November 2021. 
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Abshire T, Cox-Gill J, Kempton CL, Leebeek FW, Carcao M, Kouides P, et al. 
Prophylaxis escalation in severe von Willebrand disease: a prospective study from the 
von Willebrand Disease Prophylaxis Network. J Thromb Haemost. 2015;13(9):1585-9. 
9. 
Auerswald G, Djambas KC, Stasyshyn O, Iosava G, Romashevskaya I, López MJ, et al. 
Pharmacokinetics, Efficacy and Safety of a Plasma-Derived VWF/FVIII Concentrate 
(Formulation V) in Pediatric Patients with von Willebrand Disease (SWIFTLY-VWD 
Study). J Blood Med. 2020;11:213-25. 
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van Galen KP, Sanders YV, Vojinovic U, Eikenboom J, Cnossen MH, Schutgens RE, 
et al. Joint bleeds in von Willebrand disease patients have significant impact on quality 
of life and joint integrity: a cross-sectional study. Haemophilia. 2015;21(3):e185-92. 
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van Galen KPM, Timmer MA, de Kleijn P, Fischer K, Foppen W, Schutgens REG, et 
al. Joint assessment in von Willebrand disease. Validation of the Haemophilia Joint 
Health score and Haemophilia Activities List. Thromb Haemost. 2017;117(8):1465-70. 
12. 
Wilate 500, 500 IU VWF/500 IUFVIII, powder and solvent for solution for injection, 
Summary of Product Characteristics, Updated 29 June 2020, Octapharma Limited. 
13. 
WILATE, von Willebrand Factor/Coagulation Factor VIII Complex (Human) 
Lyophilized Powder for Solution for Intravenous Injection, Package Insert, Issued 
September 2019, Octapharma USA, Inc. 
14. 
Obsolete in the meantime due to the deletion of the entire underlying paragraph, but 
retained for the purpose of continuing the previous numbering of references: 
Viner RM, Mytton OT, Bonell C, Melendez-Torres GJ, Ward J, Hudson L, et al. 
Susceptibility to SARS-CoV-2 Infection Among Children and Adolescents Compared 
With Adults: A Systematic Review and Meta-analysis. JAMA Pediatrics. 2020. 

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15. 
EMA Committee for medicinal products for human use. CPMP/BPWG/220/02: Clinical 
investigation of human plasma-derived von Willebrand factor products 2006 [Available 
from: 
https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-
clinical-investigation-human-plasma-derived-von-willebrand-factor-products-
cpmp/bpwg/220/02_en.pdf. 
16. 
Feldman BM, Funk SM, Bergstrom BM, Zourikian N, Hilliard P, van der Net J, et al. 
Validation of a new pediatric joint scoring system from the International Hemophilia 
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Hilliard P, Funk S, Zourikian N, Bergstrom BM, Bradley CS, McLimont M, et al. 
Hemophilia joint health score reliability study. Haemophilia. 2006;12(5):518-25. 
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Fischer K, de Kleijn P. Using the Haemophilia Joint Health Score for assessment of 
teenagers and young adults: exploring reliability and validity. Haemophilia. 
2013;19(6):944-50. 
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Ethical considerations for clinical trials on medicinal products conducted with the 
paediatric population. Recommendations of the ad hoc group for the development of 
implementing guidelines for Directive 2001/20/EC relating to good clinical practice in 
the conduct of clinical trials on medicinal products for human use. Available from: 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/ethical_considerations_en.pdf (accessed 24 June 2020) 2008. 
 

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15 APPENDICES 
Not applicable.