Clinical trial NCT04052698
Conditions: Von Willebrand Diseases
Sponsor: Octapharma
Start date: 2020-06-18; Completion date: 2022-04-23
Enrollment: 43 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a prospective, non-controlled, international, multi-center phase 3 study investigating the efficacy and safety of Wilate in previously treated adult patients with VWD, to obtain additional data on the safety and efficacy of Wilate in previously treated patients with VWD undergoing regular prophylaxis.

Detailed description:

Arms: arm 1: Patients with type 3, type 2 (except 2N), or severe type 1 VWD aged ≥6 years at screening receiving Wilate for prophylactic treatment.
Interventions: intervention 1: Wilate
Intervention descriptions: intervention 1: Produced from the plasma of human donors, Wilate is presented as a powder or solvent for intravenous injection containing normally 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 5ml/10mL water for injection 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 2-3mL per minute.

Protocol documents:
Prot_000.pdf: 
Property of Octapharma. Do not copy or distribute without written permission.
090-CSP-WIL-31-V07
DOC ID  3302 
CLINICAL STUDY PROTOCOL 
CLINICAL STUDY TO INVESTIGATE THE 
EFFICACY AND SAFETY OF WILATE 
DURING PROPHYLAXIS IN PREVIOUSLY TREATED PATIENTS 
WITH VON WILLEBRAND DISEASE (VWD) 
Investigational Product: 
Wilate 
Indication: 
Routine prophylaxis in patients with VWD
Study Design: 
Prospective, non-controlled, international, multi-cen-
tre phase 3 study
Sponsor: 
Octapharma AG
Seidenstrasse 2
CH-8853 Lachen
Switzerland
Study Number: 
WIL-31
EudraCT and/or IND Number: 
EudraCT 2018-004675-13, IND 011303
Development Phase: 
Phase 3  
Planned Clinical Start: 
Q2 2020 
Planned Clinical End:
Q1 2022 
Date of Protocol: 
01-Mar-2021
Version: 
07 
Previous Protocol Versions:
06—26-Feb-2020 (for Ukraine only) 
05—25-Feb-2020 
04—23-Aug-2019 (for Ukraine only) 
03—22-Aug-2019 
02—13-Jun-2019 
01—04-Feb-2019 
Coordinating Investigator: 
Aflac Cancer and Blood Disorders 
Emory University School of Medicine 
1760 Haygood Drive 
HSRB W340 
Atlanta, Georgia 30322, USA 
This document contains confidential and proprietary information of Octapharma AG. 
Do not copy or distribute without written permission. 
This document contains confidential and proprietary information of Octapharma. 
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 
CONFIDENTIAL 
Version 07
No. WIL-31 
01-Mar-2021
Page 1 of 86 
STUDY OUTLINE 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Wilate 
Protocol Identification Code: 
WIL-31 
Name of Active Ingredient: 
Factor VIII/VWF concentrate human 
Date of Final Protocol: 
01-Mar-2021
Title of Study: Clinical Study to Investigate the Efficacy and Safety of Wilate during Prophy-
laxis in Previously Treated Patients with VWD 
Number of Study Centre(s): Up to 14 sites worldwide 
OBJECTIVES: 
Primary Objective: 
The primary objective of this study is to determine the efficacy of Wilate in the prophylactic 
treatment of previously treated patients (PTPs) with type 3, type 2 (except 2N), or severe type 
1 VWD 
Secondary Objectives: 
The secondary objectives of this study are to: 

Assess the incremental IVR of Wilate for VWF:Ac and FVIII:C over time

Determine the pharmacokinetics (PK) of Wilate for VWF:Ac and FVIII:C in paedi-
atric patients aged 6–16 years

Assess the safety and tolerability of Wilate

Determine Wilate consumption data
Additional Objectives: 
Additional objectives of this study are to: 

Determine the efficacy of Wilate in the treatment of breakthrough bleeding episodes
(BEs)

Determine the efficacy of Wilate in surgical prophylaxis

Assess patients’ quality of life (QoL) during prophylaxis with Wilate

Assess the patients’ joint status using the Hemophilia Joint Health Score (HJHS)

Assess the menstrual bleeding intensity of female patients of child-bearing potential
(based on PBAC score)
Study Design: Prospective, non-controlled, international, multi-centre phase 3 study 


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Study Protocol 
CONFIDENTIAL 
Version 07
No. WIL-31 
01-Mar-2021
Page 2 of 86 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Wilate 
Protocol Identification Code: 
WIL-31 
Name of Active Ingredient: 
Factor VIII/VWF concentrate human 
Date of Final Protocol: 
01-Mar-2021
Number of Patients: Around 40 patients, including at least 5 patients with VWD type 3, at 
least 6 patients aged 6–11 years, and at least 6 patients aged 12–16 years 
Paediatric patients will undergo a 4-day PK assessment starting at the Baseline PK Visit, 
with the aim to obtain evaluable PK data from at least 6 patients aged 6–11 years (of which 
at least 4 evaluable) and at least 6 patients aged 12–16 years (of which at least 4 evaluable). 
Drop-outs will not be replaced. 
PATIENT SELECTION CRITERIA: 
Inclusion Criteria: 
1. Patients aged ≥6 years at the time of screening
2. VWD type 1 (baseline von Willebrand factor activity [VWF:RCo], <30 IU/dL), 2A, 2B,
2M, or 3 according to medical history, requiring substitution therapy with a VWF-
containing product to control bleeding
3. Currently receiving on-demand treatment with a VWF-containing product AND having
experienced at least 6 BEs (excluding menstrual bleeds) over a period of 6 months, with
at least 2 of these BEs treated with a VWF-containing product AND having records
available to reliably evaluate the type, frequency, and treatment of BEs in this 6-month
period
OR
Having switched to prophylactic treatment with a VWF-containing product within the
past 2 years AND having records available to reliably evaluate the type, frequency, and
treatment of BEs over a period of 6 months of on-demand treatment
4. Female patients of child-bearing potential must have a negative urine pregnancy test at
screening and agree to use adequate birth control measures; in case hormonal contracep-
tion is used, the medication class should remain unchanged for the duration of the study
5. Voluntarily given, fully informed written and signed consent obtained before any study-
related procedures are conducted
Exclusion Criteria: 
1. Having received on-demand or prophylactic treatment with a VWF-containing product,
but having no records available to reliably evaluate the type, frequency, and treatment of
BEs over a period of at least 6 months of on-demand treatment
2. History, or current suspicion, of VWF or FVIII inhibitors
3. Medical history of a thromboembolic event within 1 year before enrolment


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Study Protocol 
CONFIDENTIAL 
Version 07
No. WIL-31 
01-Mar-2021
Page 3 of 86 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Wilate 
Protocol Identification Code: 
WIL-31 
Name of Active Ingredient: 
Factor VIII/VWF concentrate human 
Date of Final Protocol: 
01-Mar-2021
4. Severe liver or kidney diseases (alanine aminotransferase [ALAT] and aspartate trans-
aminase [ASAT] levels >5 times of upper limit of normal, creatinine >120 µmol/L)
5. Platelet count <100,000/µL at screening (except for VWD type 2B)
6. Body weight <20 kg at screening
7. Patients receiving, or scheduled to receive, immunosuppressant drugs (other than an-
tiretroviral chemotherapy), such as prednisone (equivalent to >10 mg/day), or similar
drugs
8. Pregnant or breast-feeding at the time of enrolment
9. Cervical or uterine conditions causing abnormal uterine bleeding (including infection,
dysplasia)
10. Treatment with any investigational medicinal product (IMP) in another interventional
clinical study currently or within 4 weeks before enrolment
11. Other coagulation disorders or bleeding disorders due to anatomical reasons
12. Known hypersensitivity to any of the components of the study drug
TEST PRODUCT, DOSE, AND MODE OF ADMINISTRATION: 
The FVIII/VWF 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. 
Wilate Dosage for Baseline PK Assessment in Paediatric Patients (6–16 years): 
Single dose of 60 ± 10 IU/kg 
Wilate Dosage for Prophylactic Treatment: 
For prophylactic treatment, Wilate should be administered 2–3 times per week at a dose of 
20–40 IU/kg BW for 12 months. 
The prophylactic dose for each patient will be determined by the Principal Investigator based 
on each patient’s clinical condition and at the following time points: 

At the Baseline IVR Visit in adult patients (≥17 years)
In adult patients, the first prophylactic dose will be administered at the time of the
baseline IVR assessment.

At the Baseline PK Visit in paediatric patients (6–16 years)
In paediatric patients, the first prophylactic dose will be administered after comple-
tion of the PK phase.


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Study Protocol 
CONFIDENTIAL 
Version 07
No. WIL-31 
01-Mar-2021
Page 4 of 86 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Wilate 
Protocol Identification Code: 
WIL-31 
Name of Active Ingredient: 
Factor VIII/VWF concentrate human 
Date of Final Protocol: 
01-Mar-2021
In case of unacceptably frequent spontaneous breakthrough BEs (i.e., more than 2 spontane-
ous BEs or 1 major spontaneous BE within a 30-day period), the dose of Wilate should be 
increased by approximately 5 IU/kg (depending on the entire content of the additional vial(s) 
that need(s) to be reconstituted). If, after a dose increase, patients still experience more than 
2 spontaneous bleeding episodes, the dosing interval should be shortened from 2 times per 
week to 3 times per week.  
Wilate Dosage for the Treatment of Breakthrough BEs: 
The following should be used to guide dosing in the treatment of BEs: 
Dose Type 
Minor haemorrhage* 
Major haemorrhage 
Loading dose 
20–40 IU/kg 
40–60 IU/kg 
Maintenance dose 
20–30 IU/kg every 12–24 hours 
20–40 IU/kg every 12–24 hours 
Therapeutic goal 
Maintain VWF:Ac (VWF:RCo) and FVIII:C 
trough levels >30% 
Maintain VWF:Ac (VWF:RCo) and 
FVIII:C trough levels >50% 
*Menstrual bleeds of regular intensity (i.e., minor menstrual haemorrhage) will be considered normal and are not
expected to require therapy unless deemed necessary by the investigator and/or the patient.
Surgical Prophylaxis: 
The following should be used to guide dosing in surgical prophylaxis: 
Dose type 
Minor surgeries (incl. tooth extractions) 
Major surgeries 
Loading dose 
30–60 IU/kg 
40–60 IU/kg 
Maintenance dose 
15–30 IU/kg, or half the loading dose, every 
12–24 hours for up to 3 days 
20–40 IU/kg, or half the loading dose, 
every 12–24 hours for up to 6 days or 
longer 
Therapeutic goal 
Achieve VWF:Ac (VWF:RCo) peak levels of 
50% after loading dose and trough levels of 
>30% during maintenance doses
Achieve VWF:Ac (VWF:RCo) peak 
level of 100% after loading dose and 
trough levels of >50% during mainte-
nance doses 
DURATION OF TREATMENT: 
The planned treatment duration per patient is 12 months 
The study will be considered clinically completed when all enrolled patients have completed 
the planned observation period, including the Study Completion Visit. 
The estimated start of the study (enrolment of first patient) is Q2 2020, and the estimated end 


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Study Protocol 
CONFIDENTIAL 
Version 07
No. WIL-31 
01-Mar-2021
Page 5 of 86 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Wilate 
Protocol Identification Code: 
WIL-31 
Name of Active Ingredient: 
Factor VIII/VWF concentrate human 
Date of Final Protocol: 
01-Mar-2021
of the study is Q1 2022. 
Reference Therapy, Dose, Mode of Administration: None 


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Study Protocol 
CONFIDENTIAL 
Version 07
No. WIL-31 
01-Mar-2021
Page 6 of 86 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Wilate 
Protocol Identification Code: 
WIL-31 
Name of Active Ingredient: 
Factor VIII/VWF concentrate human 
Date of Final Protocol: 
01-Mar-2021
STUDY ENDPOINTS: 
Primary Endpoint: 
The primary endpoint of this study is to demonstrate that prophylactic treatment with 
WILATE lowers the patients’ total annualized bleeding rate (TABR) observed during on-
demand treatment by more than 50%.Secondary Endpoints: 

Spontaneous annualised bleeding rate (SABR), calculated in analogy with TABR

Incremental IVR of Wilate for VWF:Ac (VWF:RCo and VWF:GPIbm) and FVIII:C
(OS and CHR) over time (at baseline and at 1, 2, 3, 6, 9, and 12 months of treat-
ment)

For paediatric patients, baseline PK profile characteristics of VWF:Ac (VWF:RCo)
and FVIII:C (OS and CHR) based on blood samples taken pre-dose and 1, 3, 9, 24,
48, and 72 hours after dosing

Safety and tolerability of Wilate by monitoring adverse events (AEs) throughout the
study

Wilate consumption data (VWF/FVIII IU/kg per month per patient) for prophylaxis
Exploratory Endpoints: 

Efficacy of Wilate in the treatment of breakthrough BEs based on the proportion of
BEs successfully treated with Wilate

Efficacy of Wilate in surgical prophylaxis based on the proportion of surgeries suc-
cessfully treated with Wilate

QoL based on the scores of PROMIS-29 for all patients, SF-36v2 for patients aged
≥16 years, and SF-10 for patients aged 6–15 years

Hemophilia Joint Health Score (HJHS)

Pictorial Blood Loss Assessment Chart (PBAC) score for menstrual bleeds

Annual rate of heavy (i.e., major) menstrual bleeds


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Study Protocol 
CONFIDENTIAL 
Version 07
No. WIL-31 
01-Mar-2021
Page 7 of 86 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Wilate 
Protocol Identification Code: 
WIL-31 
Name of Active Ingredient: 
Factor VIII/VWF concentrate human 
Date of Final Protocol: 
01-Mar-2021
EFFICACY PARAMETERS: 
For the evaluation of efficacy, the following parameters will be documented: 
IMP Administration Data 
The following parameters will be documented: 

Dates and times of IMP injections

Doses of IMP in IU and IU/kg and IMP batch numbers

Purpose of IMP injection (IVR, prophylaxis, prophylaxis of recurrent bleeding,
treatment of BE, surgery, prophylaxis after surgery, or menstrual bleeds)
Bleeding Episode (BE) Data 
Study participants will be instructed by the investigator on recording all BEs and in how to 
record them. For any BE occurring during the study, the following data will be recorded: 

BE type (spontaneous, traumatic, postoperative, other)

BE site

BE severity (minor or major, based on predefined criteria)

Date and time the BE first occurred or was first noticed

Date and time the BE ended

IMP administration data

Assessment of the efficacy of treatment at the end of the BE
All of these parameters will be documented by the patient (together with the investigator in 
case of on-site treatments or together with the nurse in case a home-care service is used) in 
the patient diary. Patients who experience a major BE should be treated at the study site, if 
possible. 
Based on these data, the frequency of BEs and the TABR and SABR under prophylactic treat-
ment will be calculated. 
Assessment of Adherence with the Infusion Regimen 
Throughout the study, adherence with the infusion regimen will be assessed. Any change of 
the prophylactic dose as determined by the Principal Investigator during the Baseline Visit 
will be documented in the patient records and eCRF, including start and end dates of each 
dose, reasons for dose change, or reasons for not implementing a required dose change. 


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Study Protocol 
CONFIDENTIAL 
Version 07
No. WIL-31 
01-Mar-2021
Page 8 of 86 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Wilate 
Protocol Identification Code: 
WIL-31 
Name of Active Ingredient: 
Factor VIII/VWF concentrate human 
Date of Final Protocol: 
01-Mar-2021
Efficacy of the Treatment of Breakthrough BEs 
At the end of a BE, treatment efficacy will be assessed by the patient (together with the in-
vestigator in case of on-site treatment) using the following predefined criteria: 
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 
The proportion of BEs successfully treated with IMP will be evaluated for all BEs taken 
together and by BE severity. All efficacy ratings assessed as either ‘excellent’ or ‘good’ will 
be considered ‘successfully treated.’ 
Surgical Prophylaxis Data 
The following surgery-related parameters will be documented: 

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 IMP administration data

Pre-, intra-, and postoperative FVIII and VWF:Ac plasma levels

Routine safety laboratory

Presence of wound haematomas

Vital signs

Details on concomitantly administered medications

Blood transfusion requirements

Brief narrative describing the outcome of the intervention

Efficacy assessment at the end of surgery by surgeon

Efficacy assessment at the end of the postoperative period by haematologist

Overall efficacy assessment at the end of the postoperative period by the
investigator

Monitoring of AEs


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Study Protocol 
CONFIDENTIAL 
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No. WIL-31 
01-Mar-2021
Page 9 of 86 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Wilate 
Protocol Identification Code: 
WIL-31 
Name of Active Ingredient: 
Factor VIII/VWF concentrate human 
Date of Final Protocol: 
01-Mar-2021
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)

3rd molar extraction or extraction of ≥3 teeth

Surgeries/conditions in which the patient’s life is at stake
The classification is made prospectively. All other surgeries are classified as minor. 
Efficacy in Surgical Prophylaxis 
Efficacy will be assessed at the end of surgery by the surgeon and at end of the postoperative 
period by the haematologist. In both cases, predefined assessment criteria will be used. In 
addition, an overall assessment of efficacy will be made at the end of the postoperative period 
by the investigator. 
At the End of Surgery (by Surgeon) 
At the end of surgery, the haemostatic efficacy of Wilate will be assessed by the surgeon using 
the following predefined criteria: 
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 stat-
ure.  
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 proce-
dure 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 (by Haematologist) 
At the end of the postoperative period, the haemostatic efficacy of Wilate will be assessed by 
the haematologist using the following predefined criteria: 


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Study Protocol 
CONFIDENTIAL 
Version 07
No. WIL-31 
01-Mar-2021
Page 10 of 86 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Wilate 
Protocol Identification Code: 
WIL-31 
Name of Active Ingredient: 
Factor VIII/VWF concentrate human 
Date of Final Protocol: 
01-Mar-2021
Efficacy Assessment at the End of the Postoperative Period 
Excellent 
No postoperative bleeding or oozing that was not due to complications of surgery. All postopera-
tive 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 post-
operative bleeding due to complications of surgery required increased dosing with Wilate or addi-
tional 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 re-
quired use of an alternate VWF-containing product. 
Overall Efficacy Assessment at the End of the Postoperative Period (by Investigator) 
Overall efficacy using the ‘excellent,’ ‘good,’ moderate,’ and ‘none’ scale taking both the 
intra- and postoperative assessments into account will be determined by the investigator based 
on the following algorithm: 
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 
QoL Questionnaires 
For the assessment of quality of life, PROMIS-29 will be used for all patients. In addition, 
version 2 of the 36-Item Short Form Health Survey (SF-36v2) will be used for patients aged 
≥16 years, and SF-10 will be used for patients aged 6–15 years. At each visit requiring QoL 
assessments, the questionnaires should be completed before starting any other visit assess-
ment. 


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Study Protocol 
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Version 07
No. WIL-31 
01-Mar-2021
Page 11 of 86 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Wilate 
Protocol Identification Code: 
WIL-31 
Name of Active Ingredient: 
Factor VIII/VWF concentrate human 
Date of Final Protocol: 
01-Mar-2021
PK PARAMETERS: 
PK parameters will be assessed for VWF:Ac (VWF:RCo) and FVIII:C (OS and CHR) assays 
based on actual IMP potencies. 
The following PK parameters will be assessed: 

Area under the curve (AUC) and AUC normalized 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)
SAFETY PARAMETERS: 
The following drug safety information will be collected: 

Adverse events (AEs) and serious adverse events (SAEs)

Pregnancy, drug overdose, interaction, medication error, lack of efficacy, and post-
study SAEs
Laboratory Tests 
The following laboratory parameters will be determined at the time points specified in the 
flow charts of assessments. 
Central Laboratory 

VWF:Ac (VWF:RCo and VWF:GPIbm)

FVIII:C (OS and CHR)

Retention samples for possible virus marker and VWF/FVIII inhibitor testing

VWF and FVIII inhibitor testing, in case inhibitor development is suspected

Anti-parvovirus B19 antibody testing

VWF multimers for patients with VWD type 2A and genotype for patients with
VWD type 2B


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Study Protocol 
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Version 07
No. WIL-31 
01-Mar-2021
Page 12 of 86 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Wilate 
Protocol Identification Code: 
WIL-31 
Name of Active Ingredient: 
Factor VIII/VWF concentrate human 
Date of Final Protocol: 
01-Mar-2021
Local Laboratory 

Haematology: red blood cell count, white blood cell count, haemoglobin, haemato-
crit, and platelet count

Chemistry: total bilirubin, alanine amino transferase, aspartate transaminase, blood
urea nitrogen or Urea, serum creatinine

Urine pregnancy test (in female patients of child-bearing potential)
AB0 blood-type testing as well as VWF:Ac and FVIII:C measurements in case of BEs or 
surgery will also be done by the local laboratories. 
STUDY PROCEDURES: 
Because all paediatric patients (6–16 years old) enrolled in the study will undergo PK assess-
ment, whereas adult patients (≥17 years old) will not, the first two study visits differ between 
these two age cohorts. 
Patients will participate in the following visits: 

Screening Visit
– For adult patients
– For paediatric patients

Baseline Visit
– Baseline IVR Visit for adult patients
– Baseline PK Visit for paediatric patients

1-Month IVR Visit

2-Month IVR Visit

3-Month IVR Visit

6-Month IVR Visit

9-Month IVR Visit

Study Completion (12-Month) Visit
Between the 3- and 6-Month Visits, the 6- and 9-Month Visits, and the 9- and 12-Month 
Visits, monthly telephone contacts will be performed. 
Where needed, external home-care companies with experience in conducting clinical trials 
will be contracted, with trained nurses supporting patients by providing training, re-training, 
and oversight through home-care visit support throughout the study. 


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Study Protocol 
CONFIDENTIAL 
Version 07
No. WIL-31 
01-Mar-2021
Page 13 of 86 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Wilate 
Protocol Identification Code: 
WIL-31 
Name of Active Ingredient: 
Factor VIII/VWF concentrate human 
Date of Final Protocol: 
01-Mar-2021
SCREENING AND BASELINE VISITS FOR ADULT PATIENTS (≥17 YEARS OLD) 
Screening Visit (Adult Patients) 
The following assessments will be performed: 
Obtaining voluntarily given, written (signed and dated) informed consent
Inclusion and exclusion criteria
Demographic and baseline characteristics
Weight
Height
Medical history, including:
— VWD type 
— Prior medications 
— Birth control measures (for female patients of child-bearing potential) 
— History of heavy menstrual bleeding (for female patients) 
Family history of VWD
Vital signs
Physical examination
Blood samples for the following assessments:
— AB0 blood group, unless derivable from the baseline characteristics [local lab] 
— Routine safety laboratory [local lab] 
Urine pregnancy test (in female patients of child-bearing potential)
Concomitant medications
During the Screening Visit, patients will also receive a patient diary. The investigator will 
explain to the patient how to fill in the diary and emphasize the importance of carefully doc-
umenting any BEs, treatment details, AEs, and concomitant medications. Menstrual bleeds 
will be documented in the Pictorial Blood Loss Assessment Chart (PBAC). Therefore, fe-
male patients of child-bearing potential will also be instructed in completing the PBAC. 
After the Screening Visit, eligible patients will participate in the Baseline IVR Visit, during 
which the IVR injection of Wilate will be administered. 
For adult patients, the Screening Visit and the Baseline IVR Visit may coincide; however, 
note that administration of the first prophylactic dose of Wilate during the Baseline IVR Visit 
requires a washout period of at least 72 hours from the patient’s previous administration of 
a VWF-containing product. If possible, the interval between the Screening Visit and the Base-
line IVR Visit should not exceed 2 weeks. 


Property of Octapharma. Do not copy or distribute without written permission.
Study Protocol 
CONFIDENTIAL 
Version 07
No. WIL-31 
01-Mar-2021
Page 14 of 86 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Wilate 
Protocol Identification Code: 
WIL-31 
Name of Active Ingredient: 
Factor VIII/VWF concentrate human 
Date of Final Protocol: 
01-Mar-2021
Between the Screening Visit and the Baseline IVR Visit, on-demand treatment of BEs or 
prophylactic treatment should be continued with the patient’s previously used VWF-
containing product.  
Baseline IVR Visit (Adult Patients) 
During the Baseline IVR Visit, the prophylactic dose and dosing interval of Wilate for each 
adult patient will be determined by the Principal Investigator based on the patient’s clinical 
condition, and the first prophylactic dose will be administered after a washout period of at 
least 72 hours from the patient’s latest administration of a VWF-containing product. Patients 
must not be experiencing any bleeding.  
The following assessments will be performed: 
BEFORE ANY OTHER ASSESSMENTS 
Confirm inclusion and exclusion criteria (to be documented in patient records)
QoL questionnaires (PROMIS-29 for all patients, SF-36v2 or SF-10 as applicable)
BEFORE INJECTION 
Weight
Blood samples
— VWF multimer pattern for VWD type 2A and genotype for VWD type 2B [central lab]
— Anti-parvovirus B19 antibodies [central lab] 
— Retention samples for possible virus marker and VWF/FVIII inhibitor testing 
[central lab] 
WITHIN 60 MIN BEFORE AND 60±5 MIN AFTER INJECTION 
Vital signs
Blood samples
— VWF:Ac (VWF:RCo and VWF:GPIbm) for IVR [central lab]
— FVIII:C (OS and CHR) for IVR [central lab] 
ANY TIME 
Patient diary review, with documentation of PBAC data and calculation of PBAC score by inves-
tigator (in female patients of child-bearing potential)
Hemophilia Joint Health Score (HJHS)
Target joint(s)
Re-confirm commitment to using birth control measures (in female patients of child-bearing poten-
tial)
Monitoring of adverse events (AEs)
Concomitant medications
In adult patients, the first prophylactic injection of Wilate is administered during the 
Baseline IVR Visit. 


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Study Protocol 
CONFIDENTIAL 
Version 07
No. WIL-31 
01-Mar-2021
Page 15 of 86 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Wilate 
Protocol Identification Code: 
WIL-31 
Name of Active Ingredient: 
Factor VIII/VWF concentrate human 
Date of Final Protocol: 
01-Mar-2021
In case of home treatment, patients will be trained in how to correctly administer the IMP 
and provided with IMP. Patients will be re-supplied with IMP whenever necessary during the 
study. 
SCREENING AND BASELINE VISITS FOR PAEDIATRIC PATIENTS 
Screening Visit (Paediatric Patients) 
The following assessments will be performed: 
Obtaining voluntarily given, written (signed and dated) informed consent
Inclusion and exclusion criteria
Demographic and baseline characteristics
Weight
Height
Medical history, including:
— VWD type 
— Prior medications 
— Birth control measures (for female patients of child-bearing potential) 
— History of heavy menstrual bleeding (for female patients) 
Family history of VWD
Vital signs
Physical examination
Blood samples for the following assessments:
— AB0 blood group, unless derivable from the baseline characteristics [local lab] 
— Routine safety laboratory [local lab] 
— VWF multimer pattern for VWD type 2A and genotype for VWD type 2B [central lab] 
— VWF:Ac (VWF:RCo and VWF:GPIbm) [central lab] 
— FVIII:C (OS and CHR) [central lab] 
— Anti-parvovirus B19 antibodies [central lab] 
— Retention samples for possible virus marker and VWF/FVIII inhibitor testing [central lab] 
Urine pregnancy test (in female patients of child-bearing potential)
Concomitant medications
During the Screening Visit, patients will also receive a patient diary. The investigator will 
explain to the patient how to fill in the diary and emphasize the importance of carefully doc-
umenting any BEs, treatment details, AEs, and concomitant medications. Menstrual bleeds 
will be documented in the Pictorial Blood Loss Assessment Chart (PBAC). Therefore, fe-
male patients of child-bearing potential will also be instructed in completing the PBAC. 


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Study Protocol 
CONFIDENTIAL 
Version 07
No. WIL-31 
01-Mar-2021
Page 16 of 86 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Wilate 
Protocol Identification Code: 
WIL-31 
Name of Active Ingredient: 
Factor VIII/VWF concentrate human 
Date of Final Protocol: 
01-Mar-2021
After the Screening Visit, eligible children will participate in the Baseline PK Visit.. The 
Screening Visit and the Baseline PK Visit must not occur on the same day. If possible, the 
interval between the Screening Visit and the Baseline PK Visit should not exceed 2 weeks. 
Between the Screening Visit and the Baseline PK Visit, on-demand treatment of BEs or 
prophylactic treatment should be continued with the patient’s previously used VWF-
containing product.. 
Baseline PK Visit (Paediatric Patients) 
During the Baseline PK Visit, paediatric patients will receive Wilate at a dose of 
60 ± 10 IU/kg after a washout period of at least 72 hours from the patient’s previous admin-
istration of a VWF-containing product. Patients must not be experiencing any bleeding.  
The following assessments will be performed: 
BEFORE ANY OTHER ASSESSMENTS 
Confirm inclusion and exclusion criteria (to be documented in patient records)
QoL questionnaires (PROMIS-29 for all patients, SF-36v2 or SF-10 as applicable)
BEFORE INJECTION 
Weight
WITHIN 60 MIN BEFORE AND 60±5 MIN AFTER INJECTION 
Vital signs
WITHIN 60 MIN BEFORE AND 60±5 MIN, 3 H±30 MIN, 9±1 H, 24±2 H, 48±2 H, and 72±2 H AFTER 
INJECTION 
Blood samples
— VWF:Ac (VWF:RCo) for PK [central lab]
— FVIII:C (OS and CHR) for PK [central lab] 
ANY TIME 
Patient diary review, with documentation of PBAC data and calculation of PBAC score by inves-
tigator (in female patients of child-bearing potential)
Hemophilia Joint Health Score (HJHS)
Target joint(s)
Re-confirm commitment to using birth control measures (in female patients of child-bearing poten-
tial)
Monitoring of adverse events (AEs)
Concomitant medications
During this visit, the prophylactic dose and dosing interval of Wilate will be determined by 
the Principal Investigator based on the patient’s clinical condition. 
In paediatric patients, the first prophylactic injection of Wilate is administered after 


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Study Protocol 
CONFIDENTIAL 
Version 07
No. WIL-31 
01-Mar-2021
Page 17 of 86 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Wilate 
Protocol Identification Code: 
WIL-31 
Name of Active Ingredient: 
Factor VIII/VWF concentrate human 
Date of Final Protocol: 
01-Mar-2021
completion of the Baseline PK Visit. 
In case of home treatment, patients will be trained in how to correctly administer the IMP 
and provided with IMP. Patients will be re-supplied with IMP whenever necessary during the 
study. 
SUBSEQUENT VISITS FOR ALL PATIENTS 
1-Month IVR Visit
The 1-Month IVR Visit will take place 1 month (±1 week) after the first prophylactic injection 
of Wilate.  
During this visit, a prophylactic injection of Wilate will be administered. Patients should ar-
rive at the centre within 3 hours before their next planned prophylactic dose. Patients must 
not be experiencing any bleeding. 
The following assessments will be performed: 
BEFORE INJECTION 
Weight
Blood samples
— For VWF and FVIII inhibitor testing, only if inhibitor development is suspected
WITHIN 60 MIN BEFORE AND 60±5 MIN AFTER INJECTION 
Vital signs
Blood samples
— VWF:Ac (VWF:RCo and VWF:GPIbm) for IVR [central lab]
— FVIII:C (OS and CHR) for IVR [central lab] 
ANY TIME 
Patient diary review, with documentation of PBAC data and calculation of PBAC score by inves-
tigator (in female patients of child-bearing potential)
Review of compliance and adherence to the infusion regimen
Re-confirm commitment to using birth control measures (in female patients of child-bearing poten-
tial)
Monitoring of adverse events (AEs)
Concomitant medications
At the end of this and each of the following visits, IMP for home treatment will be given to 
patients as applicable. 


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Study Protocol 
CONFIDENTIAL 
Version 07
No. WIL-31 
01-Mar-2021
Page 18 of 86 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Wilate 
Protocol Identification Code: 
WIL-31 
Name of Active Ingredient: 
Factor VIII/VWF concentrate human 
Date of Final Protocol: 
01-Mar-2021
2-Month IVR Visit
The 2-Month IVR Visit will take place 2 months (±1 week) after the first prophylactic injec-
tion of Wilate. 
During this visit, a prophylactic injection of Wilate will be administered. Patients should ar-
rive at the centre within 3 hours before their next planned prophylactic dose. Patients must 
not be experiencing any bleeding. 
The following assessments will be performed: 
Same assessments are for the 1-Month IVR Visit
3-Month IVR Visit
The 3-Month IVR Visit will take place 3 months (±1 week) after the first prophylactic injec-
tion of Wilate. 
During this visit, a prophylactic injection of Wilate will be administered. Patients should ar-
rive at the centre within 3 hours before their next planned prophylactic dose. Patients must 
not be experiencing any bleeding. 
The following assessments will be performed: 
Same assessments are for the 1-Month IVR Visit
Urine pregnancy test (in female patients of child-bearing potential)
6-Month IVR Visit
The 6-Month IVR Visit will take place 6 months (±2 weeks) after the first prophylactic injec-
tion of Wilate. 
During this visit, a prophylactic injection of Wilate will be administered. Patients should ar-
rive at the centre within 3 hours before their next planned prophylactic dose. Patients must 
not be experiencing any bleeding. 
The following assessments will be performed: 
BEFORE ANY OTHER ASSESSMENTS 
QoL questionnaires (PROMIS-29 for all patients, SF-36v2 or SF-10 as applicable)
Same assessments as for 1-Month IVR Visit
Urine pregnancy test (in female patients of child-bearing potential)


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Study Protocol 
CONFIDENTIAL 
Version 07
No. WIL-31 
01-Mar-2021
Page 19 of 86 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Wilate 
Protocol Identification Code: 
WIL-31 
Name of Active Ingredient: 
Factor VIII/VWF concentrate human 
Date of Final Protocol: 
01-Mar-2021
9-Month IVR Visit
The 9-Month IVR Visit will take place 9 months (±2 weeks) after the first prophylactic injec-
tion of Wilate. 
During this visit, a prophylactic injection of Wilate will be administered. Patients should ar-
rive at the centre within 3 hours before their next planned prophylactic dose. Patients must 
not be experiencing any bleeding. 
The following assessments will be performed: 
Same assessments are for the 1-Month IVR Visit
Study Completion (12-Month) Visit 
The Study Completion Visit will take place 12 months (+2 weeks) after the first prophylactic 
injection of Wilate. 
During this visit, a prophylactic injection of Wilate will be administered. Patients should ar-
rive at the centre within 3 hours before their next planned prophylactic dose. Patients must 
not be experiencing any bleeding. 
The following assessments will be performed: 
BEFORE ANY OTHER ASSESSMENTS 
QoL questionnaires (PROMIS-29 for all patients, SF-36v2 or SF-10 as applicable)
BEFORE INJECTION 
Weight
Blood samples
— Routine safety laboratory [local lab]
— For VWF and FVIII inhibitor testing, only if inhibitor development is suspected [central lab] 
— Anti-parvovirus B19 antibodies [central lab], only if the sample at the Baseline Visit was nega-
tive, or if it was equivocal on both original and re-testing 
WITHIN 60 MIN BEFORE AND 60±5 MIN AFTER INJECTION 
Vital signs
Blood samples
— VWF:Ac (VWF:RCo and VWF:GPIbm) for IVR [central lab]
— FVIII:C (OS and CHR) for IVR [central lab] 
ANY TIME 
Patient diary review, with documentation of PBAC data and calculation of PBAC score by inves-
tigator (in female patients of child-bearing potential)
Review of compliance and adherence to the infusion regimen
Hemophilia Joint Health Score (HJHS)
Target joint(s)


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Study Protocol 
CONFIDENTIAL 
Version 07
No. WIL-31 
01-Mar-2021
Page 20 of 86 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Wilate 
Protocol Identification Code: 
WIL-31 
Name of Active Ingredient: 
Factor VIII/VWF concentrate human 
Date of Final Protocol: 
01-Mar-2021
Physical examination
Urine pregnancy test (in female patients of child-bearing potential)
Monitoring of adverse events (AEs)
Concomitant medications
All used and unused IMP vials will be returned by the patients or their home-care providers. 
Monthly Telephone Contacts 
Monthly telephone contacts will be performed 4, 5, 7, 8, 10, and 11 months (±1 week) after 
the first prophylactic injection of Wilate. Should a patient visit the study centre at the time 
any of these telephone contacts are scheduled, the required assessments may also be per-
formed during this visit. 
The following assessments will be performed: 

Review of compliance with correctly completing the patient diary, including
completing the PBAC (for female patients of child-bearing potential)

Review of adherence to the infusion regimen

Monitoring of adverse events (AEs)

Concomitant medications
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. 
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 IMP injections, or prolonged bleeding), VWF and FVIII inhibitor tests 
will be performed at the central laboratory and documented. 
In case of positive inhibitor results, inhibitor retesting using a second, separately drawn sam-
ple 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. 


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Study Protocol 
CONFIDENTIAL 
Version 07
No. WIL-31 
01-Mar-2021
Page 21 of 86 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Wilate 
Protocol Identification Code: 
WIL-31 
Name of Active Ingredient: 
Factor VIII/VWF concentrate human 
Date of Final Protocol: 
01-Mar-2021
Surgical Visits 
Patients may undergo surgical interventions in the course of the study. Whether or not these 
patients will be hospitalised will depend on the type and severity of the surgery and be at the 
discretion of the investigator. 
STATISTICAL ANALYSIS PLAN: 
Determination of Sample Size 
Assuming a mean TABR ratio (TABRpr / TABRod) of 0.25 with a correlation of 0.5 between 
the two treatment regimens, a coefficient of variation of 10 in on-demand treatment, and a 
coefficient of variation of 10 in prophylactic treatment, 25 patients will be needed to reject 
the null hypothesis with a power of 80% using a paired t-test for log-transformed data 
The primary approach to statistical analysis will be descriptive, complemented by exploratory 
confidence intervals (CIs) for means or proportions.  
Efficacy of Prophylactic Treatment with Wilate 
The primary endpoint of this study is to demonstrate that the TABR during prophylactic treat-
ment with Wilate lowers the patients’ TABR observed during on-demand treatment by more 
than 50%. To test whether the mean TABR during prophylactic treatment (TABRpr) is less 
than half the mean TABR during on-demand treatment (TABRod), the following pair of hy-
potheses will be tested using a paired t-test assuming log-normally distributed data: 
H0: mean(TABRpr / TABRod) ≥0.5 vs H1: mean(TABRpr / TABRod) <0.5 
at a one-sided alpha level of 2.5%. Corresponding two-sided 95% CIs for TABR will also be 
presented.  
To assess the qualitative robustness of the inferential result the hypothesis will additionally 
be tested with the Wilcoxon (matched-pair signed rank) test on the log-transformed bleeding 
rate as a distribution-free alternative. Also, a 95% Hodges-Lehmann CI for the median dif-
ference will be reported.  
In addition, intra-individual comparisons with each patient’s documented historical TABR 
will be performed. 


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Study Protocol 
CONFIDENTIAL 
Version 07
No. WIL-31 
01-Mar-2021
Page 22 of 86 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Wilate 
Protocol Identification Code: 
WIL-31 
Name of Active Ingredient: 
Factor VIII/VWF concentrate human 
Date of Final Protocol: 
01-Mar-2021
Efficacy of Wilate in the Treatment of BEs 
To assess the haemostatic efficacy of Wilate in the treatment of breakthrough BEs, a fre-
quency 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. 
IVR Assessments 
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. 
PK Assessments in Paediatric Patients 
The PK parameters will be summarized using descriptive statistics and the presentation of 
concentration vs time plots. 
Safety Analysis 
The analysis of safety will be based on the occurrence of AEs, results of safety laboratory 
testing, and the occurrence of parvovirus B19 seroconversions. 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 sam-
pling statistics for the values as well as frequency tables for positive findings, along with 95% 
Pearson-Clopper CIs. Incidences of parvovirus B19 seroconversions between baseline and 
the end of study will be estimated, along with 95% Pearson-Clopper CIs. 


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Study Protocol 
CONFIDENTIAL 
Version 07 
No. WIL-31 
01-Mar-2021 
Page 23 of 86 
FLOW CHART FOR IVR ASSESSMENT AND PROPHYLACTIC TREATMENT (ADULT PATIENTS, ≥17 YEARS) 
Assessment 
For 
details, 
see 
Section 
Screening 
Visit 
Baseline 
IVR Visit 
(may coincide with, 
and should if possible 
take place within 2 
weeks after, Screen-
ing Visit) 
1-Month 
IVR Visit
(±1 week) 
2-Month 
IVR Visit
(±1 week) 
3-Month 
IVR Visit
(±1 week)
4-Month Call
5-Month-Call
6-Month 
IVR Visit
(±2 weeks)
7-Month Call
8-Month Call
9-Month 
IVR Visit
(±2 weeks)
10-Month Call
11-Month Call
Study 
Completion 
(12-Month) 
IVR Visit 
(+2 weeks) 
Informed consent 
10.3 
x [4] 
COMPLIANCE CALL* 
COMPLIANCE CALL* 
COMPLIANCE CALL* 
Inclusion and exclusion criteria 
 4.1 
x 
x 
Demographics 
7.1.1 
x 
Weight 
x 
x [1] 
x [1] 
x [1] 
x [1] 
x [1] 
x [1] 
x [1] 
Height 
x 
Medical history and prior medications 
7.1.2 
x 
Family history of VWD 
x 
Vital signs 
7.4.6 
x 
x [2] 
x [2] 
x [2] 
x [2] 
x [2] 
x [2] 
x [2] 
Physical examination 
7.4.6 
x 
x 
Laboratory assessments 
   LOCAL LAB 
 Determination of AB0 blood group, unless derivable from medical history 
7.1.1 
x 
 Routine safety laboratory 
7.4.5 
x 
x [1] 
   CENTRAL LAB 
 VWF multimer pattern for VWD type 2A and genotype for VWD type 2B 
7.4.5 
x 
 VWF:Ac ( VWF:RCo  and VWF:GPIbm) for IVR 
7.4.5 
x [2] 
x [2] 
x [2] 
x [2] 
x [2] 
x [2] 
x [2] 
 FVIII:C (OS and CHR) for IVR 
7.4.5 
x [2] 
x [2] 
x [2] 
x [2] 
x [2] 
x [2] 
x [2] 
 Anti-parvovirus B19 antibodies 
7.4.5 
x [1] 
x [3] 
 VWF and FVIII inhibitors (•) 
7.4.5 
(•) [1] 
(•) [1] 
(•) [1] 
(•) [1] 
(•) [1] 
(•) [1] 
 Retention samples for possible virus marker and VWF/FVIII inhibitor testing 
7.4.5 
x [1] 
Quality of life using PROMIS-29 and SF-36v2 or SF-10, as applicable 
7.2.6 
x [4] 
x [4] 
x [4] 
Hemophilia Joint Health Score (HJHS) 
7.2.7 
x [1] 
x [1] 
Documentation of target joint(s) [5] 
7.2.7 
x [1] 
x [1] 
Urine pregnancy test [6] 
x 
x 
x 
x 
Re-confirm commitment to using birth control measures [6] 
x 
x 
x 
x 
x 
x 
Patient diary review, including PBAC [6] completion 
7.2.8 
x 
x 
x 
x 
x 
x 
x 
Assessment of compliance and adherence to infusion regimen  
5.7.2 
x 
x 
x 
x 
x  
x 
Adverse event monitoring 
7.3 
x 
x 
x 
x 
x 
x 
x 
Concomitant medications 
7.1.2 
x  
x 
x 
x 
x 
x 
x 
x 


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Study Protocol 
CONFIDENTIAL 
Version 07 
No. WIL-31 
01-Mar-2021 
Page 24 of 86 
FLOW CHART FOR IVR ASSESSMENT AND PROPHYLACTIC TREATMENT (ADULT PATIENTS)—Continued 
IVR = in vivo recovery, VWD = von Willebrand disease, VWF:Ac = VWF activity, GP1b = glycoprotein 1b, FVIII = factor VIII, FVIII:C = factor VIII procoagulant activity, OS = one-
stage assay, CHR = chromogenic assay, PBAC = Pictorial Blood Loss Assessment Chart, PROMIS = Patient-Reported Outcomes Measurement Information System, SF-36v2 
= 36-Item Short Form Health Survey (version 2), SF-10 = 10-Item Short Form Health Survey 
LEGEND TO THE FLOW CHART FOR IVR ASSESSMENT AND PROPHYLACTIC TREATMENT (ADULT PATIENTS) 
*
COMPLIANCE CALL: monthly telephone calls to take place ±1 week to review compliance with completing diary, obtaining PBAC (for female patients of
child-bearing potential), adherence with infusion regimen, AEs, and concomitant medications (see Section 6.1.11)
(•) If inhibitor development is suspected 
[1]
Before injection
[2]
Within 60 min before and 60±5 min after injection
[3]
Before injection, if sample at the Baseline IVR Visit was negative, or if it was equivocal on both original and re-testing
[4]
Before starting any other visit assessment
[5]
Target joint(s) are defined as having 3 or more spontaneous bleeding episodes into a single joint within 6 consecutive months preceding the Baseline
Visit or the Study Completion Visit
[6]
In female patients of child-bearing potential


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Study Protocol 
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Version 07 
No. WIL-31 
01-Mar-2021 
Page 25 of 86 
FLOW CHART FOR PK ASSESSMENT AND PROPHYLACTIC TREATMENT (PAEDIATRIC PATIENTS, 6–16 YEARS) 
Assessment 
For 
details, 
see 
Section 
Screening 
Visit 
Baseline 
PK Visit 
(must not coincide 
with, and should if 
possible take place 
within 2 weeks after, 
Screening Visit) 
1-Month 
IVR Visit
(±1 week)
2-Month 
IVR Visit
(±1 week)
3-Month 
IVR Visit
(±1 week)
4-Month Call*
5-Month-Call*
6-Month 
IVR Visit
(±2 weeks)
7-Month Call*
8-Month Call*
9-Month 
IVR Visit
(±2 weeks)
10-Month Call*
11-Month Call*
Study 
Completion 
(12-Month) 
IVR Visit 
(+2 weeks) 
Informed consent 
10.3 
x [5] 
COMPLIANCE CALL* 
COMPLIANCE CALL* 
COMPLIANCE CALL* 
Inclusion and exclusion criteria 
 4.1 
x 
x 
Demographics 
7.1.1 
x 
Weight 
x 
x [1] 
x [1] 
x [1] 
x [1] 
x [1] 
x [1] 
x [1] 
Height 
x 
Medical history and prior medications 
7.1.2 
x 
Family history of VWD 
x 
Vital signs 
7.4.6 
x 
x [2] 
x [2] 
x [2] 
x [2] 
x [2] 
x [2] 
x [2] 
Physical examination 
7.4.6 
x 
x 
Laboratory assessments 
  LOCAL LAB 
 Determination of AB0 blood group, unless derivable from medical history 
7.1.1 
x 
 Routine safety laboratory 
7.4.5 
x 
x [1] 
  CENTRAL LAB 
 VWF multimer pattern for VWD type 2A and genotype for VWD type 2B 
7.4.5 
x 
 VWF:Ac (VWF:RCo and VWF:GPIbm) for IVR 
7.4.5 
x 
x [2] 
x [2] 
x [2] 
x [2] 
x [2] 
x [2] 
 FVIII:C (OS and CHR) for IVR 
7.4.5 
x 
x [2] 
x [2] 
x [2] 
x [2] 
x [2] 
x [2] 
  PK injection (60 ± 10 IU/kg) 
5.4.1 
x 
  PK blood sampling for VWF:Ac (VWF:RCo) and FVIII:C (OS and CHR) 
7.3 
x [3] 
 Anti-parvovirus B19 antibodies 
7.4.5 
x 
x [4] 
 VWF and FVIII inhibitors (•) 
7.4.5 
(•) [1] 
(•) [1] 
(•) [1] 
(•) [1] 
(•) [1] 
(•) [1] 
 Retention samples for possible virus marker and VWF/FVIII inhibitor testing 
7.4.5 
x 
Quality of life using PROMIS-29 and SF-36v2 or SF-10, as applicable 
7.2.6 
x [5] 
x [5] 
x [5] 
Hemophilia Joint Health Score (HJHS) 
7.2.7 
x [1] 
x [1] 
Documentation of target joint(s) [6] 
7.2.7 
x [1] 
x [1] 
Urine pregnancy test [7] 
x 
x 
x 
x 
Re-confirm commitment to using birth control measures [7] 
x 
x 
x 
x 
x 
x 
Patient diary review, including PBAC [7] completion 
7.2.8 
x 
x 
x 
x 
x 
x 
x 
Assessment of compliance and adherence to infusion regimen  
5.7.2 
x 
x 
x 
x 
x  
x 
Adverse event monitoring 
7.3 
x 
x 
x 
x 
x 
x 
x 
Concomitant medications 
7.1.2 
x  
x 
x 
x 
x 
x 
x 
x 


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FLOW CHART FOR PK ASSESSMENT AND PROPHYLACTIC TREATMENT (PAEDIATRIC PATIENTS)—Continued 
IVR = in vivo recovery, VWD = von Willebrand disease, VWF:Ac = VWF activity, GP1b = glycoprotein 1b, FVIII = factor VIII, FVIII:C = factor VIII procoagulant activity, OS = one-
stage assay, CHR = chromogenic assay, PBAC = Pictorial Blood Loss Assessment Chart, PROMIS = Patient-Reported Outcomes Measurement Information System, SF-36v2 
= 36-Item Short Form Health Survey (version 2), SF-10 = 10-Item Short Form Health Survey 
LEGEND TO THE FLOW CHART FOR PK ASSESSMENT AND PROPHYLACTIC TREATMENT (PAEDIATRIC PATIENTS) 
*
COMPLIANCE CALL: monthly telephone calls to take place ±1 week to review compliance with completing diary, obtaining PBAC (for female patients of
child-bearing potential), adherence with infusion regimen, AEs, and concomitant medications (see Section 6.1.11)
(•) If inhibitor development is suspected 
[1]
Before injection
[2]
Within 60 min before and 60±5 min after injection
[3]
Blood samples for PK assessment to be taken within 60 min before injection and 60±5 min, 3 h (±30 min), 9±1 h, 24±2 h, 48±2 h, and 72±2 h after injec-
tion (central laboratory)
[4]
Before injection, if sample at the Baseline PK Visit was negative, or if it was equivocal on both original and re-testing
[5]
Before starting any other visit assessment
[6]
Target joint(s) are defined as having 3 or more spontaneous bleeding episodes into a single joint within 6 consecutive months preceding the Baseline
Visit or the Study Completion Visit.
[7]
In female patients of child-bearing potential


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FLOW CHART OF ASSESSMENTS FOR SURGICAL 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- 
operatively 
End [1] 
Body weight 
x 
Type of surgery 
7.2.4 
x 
Location of surgery 
7.2.4 
x 
Severity of surgery 
7.2.4 
x 
Expected duration of surgery 
7.2.4 
x 
Actual duration of surgery 
7.2.4 
x 
Expected average/maximum blood loss during surgery 
7.2.4 
x 
Actual blood loss and transfusions during surgery 
7.2.4 
x 
Administration of Wilate 
7.2.1 
x 
(x) 
(x) 
(x) 
(x) 
(x) 
FVIII:C plasma levels 
7.2.4 
# L 
(#) L 
(#) L 
(#) [2] L 
(#) L 
(#) L 
VWF:Ac plasma levels 
7.4.5 
# L 
(#) L 
(#) L 
(#) [2] L 
(#) L 
(#) L 
Routine safety laboratory 
7.4.5 
x 
(x) 
(x) 
(x) 
Presence of wound haematomas 
7.2.4 
x 
x 
x 
Vital signs 
7.2.4 
x 
x 
x 
Efficacy assessments 
7.2.5 
S 
H 
Overall efficacy assessment 
7.2.5 
I 
Brief narrative of outcome of the intervention 
7.2.4 
x 
Concomitant medications 
7.2.4 
Throughout observation period 
Adverse event monitoring 
7.3 
Throughout observation period 
POP = postoperative, FVIII:C = factor VIII procoagulant activity, VWF:Ac = VWF 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 IMP administration 
[1] Immediately after the last surgical suture
[2] For major surgeries, mandatory for the first 3 postoperative doses


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PROTOCOLSIGNATURES 
Version 07 
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This study is intended to be conducted in compliance with the protocol, 
Good Clinical Practice and applicable regulatory requirements. 
Signature ofthe Sponsor's Representative 
Octaphanna AG 
Seidenstrasse 2 
8853 Lachen· 
Switzerland 
Octapbanna USA, c. 
117 West Century Road 
Paramus, NJ 07652 
USA 
Signature 
Signature of the Protocol Author 
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(!)'"2_' 0-S, {(J v( 
Date 
0 \ mc 
!.{ J 
Date 
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Study Protocol 
No. WIL-31 
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PROTOCOL SIGNA TURES 
Version 07 
01-Mar-2021
This study is intended tobe conducted in c mpliance wiLh the protocol, 
Goocl C!inical Practice and applicable regulatory reqllirements. 
---
Co-ordinating investigator 
Aflac Cancer and Blood Disorders 
Emory University School of Medicine 
1760 Haygood Drive 
HSRB W340 
Atlanta, Georgia 30322 
USA 
Signature 
ERGOMED 
Im Mediapark 2 
50670 Köln 
Ge1many 
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Date 
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Study Protocol 
No. WIL-31 
CONFIDENTIAL 
PROTOCOL SIGNATURES 
Version 07 
01-Mar-2021
This study is intended to be conducted in compliance with the protocol, 
Good Clinical Practice and applicable regulatory requirements . 
Co-ordinating investigator 
Signature 
Aflac Cancer and Blood Disorders 
Emory University School of Medicine 
1760 Haygood Drive 
HSRB W340 
Atlanta, Georgia 30322 
USA 
ERGOMED 
Im Mediapark 2 
50670 Köln 
Germany 
Signature 
Page 29 of86
Date 
2d24-0l-02 
Date 
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TABLE OF CONTENTS 
STUDY OUTLINE ................................................................................................................................ 1 
FLOW CHART FOR IVR ASSESSMENT AND PROPHYLACTIC TREATMENT 
(ADULT PATIENTS, ≥17 YEARS) ................................................................................................... 23 
FLOW CHART FOR PK ASSESSMENT AND PROPHYLACTIC TREATMENT 
(PAEDIATRIC PATIENTS, 6–16 YEARS)...................................................................................... 25 
FLOW CHART OF ASSESSMENTS FOR SURGICAL PROPHYLAXIS .................................. 27 
LIST OF ABBREVIATIONS ............................................................................................................. 33 
1 
INTRODUCTION ...................................................................................................................... 35 
1.1 
VON WILLEBRAND DISEASE ................................................................................... 35 
1.2 
WILATE ................................................................................................................... 36 
1.3 
RATIONALE FOR CONDUCTING THE STUDY ............................................................ 36 
1.4 
DOSE RATIONALE ................................................................................................... 36 
1.5 
BENEFIT-RISK STATEMENT .................................................................................... 36 
2 
STUDY OBJECTIVES .............................................................................................................. 38 
2.1 
PRIMARY OBJECTIVE .............................................................................................. 38 
2.2 
SECONDARY OBJECTIVES ....................................................................................... 38 
2.3 
ADDITIONAL OBJECTIVES ....................................................................................... 38 
3 
INVESTIGATIONAL PLAN .................................................................................................... 39 
3.1 
STUDY ENDPOINTS ................................................................................................. 39 
3.1.1 
Primary Endpoint................................................................................................. 39 
3.1.2 
Secondary Endpoints ........................................................................................... 39 
3.1.3 
Exploratory Endpoints ......................................................................................... 39 
3.2 
OVERALL STUDY DESIGN AND PLAN ...................................................................... 40 
3.3 
DISCUSSION OF STUDY DESIGN .............................................................................. 41 
4 
STUDY POPULATION ............................................................................................................. 41 
4.1 
POPULATION BASE ................................................................................................. 41 
4.1.1 
Number of Patients .............................................................................................. 41 
4.1.2 
Inclusion Criteria ................................................................................................. 41 
4.1.3 
Exclusion Criteria ................................................................................................ 42 
4.2 
PRIOR AND CONCOMITANT THERAPY ..................................................................... 42 
4.3 
WITHDRAWAL AND REPLACEMENT OF PATIENTS ................................................... 43 
4.3.1 
Premature Patient Withdrawal ............................................................................ 43 
4.3.2 
Patient Replacement Policy ................................................................................. 44 
4.3.3 
Assignment of Patients to Treatment ................................................................... 44 
4.4 
RELEVANT PROTOCOL DEVIATIONS ....................................................................... 44 
5 
INVESTIGATIONAL MEDICINAL PRODUCT ................................................................... 44 
5.1 
CHARACTERISATION OF WILATE ............................................................................. 44 
5.2 
PACKAGING AND LABELLING ................................................................................. 44 
5.3 
CONDITIONS FOR STORAGE AND USE ..................................................................... 45 


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5.4 
DOSE AND DOSING SCHEDULE ............................................................................... 45 
5.4.1 
Wilate Dosage for PK Assessment in Paediatric Patients ................................... 45 
5.4.2 
Wilate Dosage for Prophylactic Treatment ......................................................... 45 
5.4.3 
Wilate Dose for the Treatment of Breakthrough BEs .......................................... 45 
5.4.4 
Surgical Prophylaxis ............................................................................................ 46 
5.5 
PREPARATION AND METHOD OF ADMINISTRATION ................................................ 46 
5.6 
BLINDING, EMERGENCY ENVELOPES, AND BREAKING THE STUDY BLIND .............. 46 
5.7 
TREATMENT COMPLIANCE ..................................................................................... 47 
5.7.1 
Drug Dispensing and Accountability ................................................................... 47 
5.7.2 
Assessment of Treatment Compliance and Adherence with Infusion Regimen .... 47 
6 
STUDY CONDUCT ................................................................................................................... 47 
6.1 
OBSERVATIONS BY VISIT FOR PROPHYLACTIC TREATMENT ................................... 48 
6.1.1 
Screening Visit (Adult Patients) ........................................................................... 48 
6.1.2 
Baseline IVR Visit (Adult Patients) ...................................................................... 50 
6.1.3 
Screening Visit (Paediatric Patients) ................................................................... 51 
6.1.4 
Baseline PK Visit (Paediatric Patients) ............................................................... 52 
6.1.5 
1-Month IVR Visit ................................................................................................ 53
6.1.6 
2-Month IVR Visit ................................................................................................ 53
6.1.7 
3-Month IVR Visit ................................................................................................ 54
6.1.8 
6-Month IVR Visit ................................................................................................ 54
6.1.9 
9-Month IVR Visit ................................................................................................ 54
6.1.10 Study Completion (12-Month) Visit ..................................................................... 55 
6.1.11 Monthly Telephone Contacts ............................................................................... 56 
6.1.12 Unscheduled Visits and Additional Measures ..................................................... 56 
6.1.13 Surgical Visits ...................................................................................................... 56 
6.2 
DURATION OF STUDY ............................................................................................. 57 
6.2.1 
Planned Duration for an Individual Patient ........................................................ 57 
6.2.2 
Planned Duration for the Study as a Whole ........................................................ 57 
6.2.3 
Premature Termination of the Study .................................................................... 57 
7 
ASSESSMENTS AND METHODS ........................................................................................... 58 
7.1 
DEMOGRAPHIC AND BASELINE INFORMATION ........................................................ 58 
7.1.1 
Demographic and Baseline Characteristics ........................................................ 58 
7.1.2 
Medical History and Prior Medications .............................................................. 58 
7.2 
EFFICACY ASSESSMENTS ........................................................................................ 58 
7.2.1 
IMP Administration Data .................................................................................... 59 
7.2.2 
Bleeding Episode (BE) Data ................................................................................ 59 
7.2.3 
Efficacy of the Treatment of Breakthrough BEs .................................................. 60 
7.2.4 
Surgical Prophylaxis Data ................................................................................... 61 
7.2.5 
Efficacy in Surgical Prophylaxis.......................................................................... 62 
7.2.6 
Quality of Life ...................................................................................................... 63 
7.2.7 
Joint Health Status ............................................................................................... 64 
7.2.8 
Pictorial Blood Assessment Chart ....................................................................... 64 
7.3 
PK ASSESSMENTS .................................................................................................. 64 
7.4 
SAFETY ASSESSMENTS ........................................................................................... 65 
7.4.1 
Assessments for Safety Endpoints ........................................................................ 65 


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7.4.2 
Adverse Events (AEs) ........................................................................................... 65 
7.4.3 
Serious Adverse Events (SAEs) ............................................................................ 68 
7.4.4 
AE and SAE Reporting Timelines ........................................................................ 69 
7.4.5 
Laboratory Tests .................................................................................................. 69 
7.4.6 
Vital Signs and Physical Examination ................................................................. 72 
7.4.7 
Other Relevant Safety Information ...................................................................... 72 
7.5 
APPROPRIATENESS OF MEASUREMENTS ................................................................. 73 
8 
DATA HANDLING AND RECORD KEEPING ..................................................................... 73 
8.1 
DOCUMENTATION OF DATA .................................................................................... 73 
8.1.1 
Source Data and Records .................................................................................... 73 
8.1.2 
Case Report Forms .............................................................................................. 74 
8.1.3 
Changes to Case Report Form (CRF) Data ......................................................... 74 
8.2 
INFORMATION FOR INVESTIGATORS ........................................................................ 75 
8.3 
RESPONSIBILITIES ................................................................................................... 75 
8.4 
INVESTIGATOR’S SITE FILE ..................................................................................... 75 
8.5 
PROVISION OF ADDITIONAL INFORMATION ............................................................ 76 
9 
STATISTICAL METHODS AND SAMPLE SIZE ................................................................. 76 
9.1 
DETERMINATION OF SAMPLE SIZE .......................................................................... 76 
9.2 
STATISTICAL ANALYSIS ......................................................................................... 77 
9.2.1 
Populations for Analysis ...................................................................................... 77 
9.2.2 
Efficacy Analysis Plan ......................................................................................... 77 
9.2.3 
Safety Analysis Plan ............................................................................................. 80 
9.2.4 
Handling of Missing Data .................................................................................... 80 
9.3 
RANDOMISATION, STRATIFICATION, AND CODE RELEASE ...................................... 80 
9.4 
INTERIM ANALYSIS ................................................................................................ 80 
10 
ETHICAL/REGULATORY, LEGAL AND ADMINISTRATIVE ASPECTS ..................... 81 
10.1 ETHICAL/REGULATORY FRAMEWORK .................................................................... 81 
10.2 APPROVAL OF STUDY DOCUMENTS ........................................................................ 81 
10.3 PATIENT INFORMATION AND INFORMED CONSENT ................................................. 81 
10.4 PROTOCOL AMENDMENTS ...................................................................................... 82 
10.5 CONFIDENTIALITY OF PATIENT DATA .................................................................... 82 
11 
QUALITY CONTROL AND QUALITY ASSURANCE ........................................................ 83 
11.1 PERIODIC MONITORING .......................................................................................... 83 
11.2 AUDIT AND INSPECTION ......................................................................................... 83 
12 
REPORTING AND PUBLICATION ....................................................................................... 83 
12.1 CLINICAL STUDY REPORT ...................................................................................... 83 
12.2 PUBLICATION POLICY ............................................................................................. 83 
13 
LIABILITIES AND INSURANCE ........................................................................................... 84 
14 
REFERENCES ........................................................................................................................... 85 
15 
APPENDICES ............................................................................................................................. 86 


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LIST OF ABBREVIATIONS 
Abbreviation 
Description 
ABR 
Annualised Bleeding Rate 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALAT 
Alanine Aminotransferase 
ASAT 
Aspartate Transaminase 
BE 
Bleeding Episode 
BU 
Bethesda Units 
BW 
Body Weight 
CHR 
Chromogenic (Assay) 
CI 
Confidence Interval 
CRO 
Contract Research Organisation 
DDAVP 
Desmopressin (1-deamino-8-D-arginine vasopressin) 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FVIII 
Factor VIII 
GP1b 
Glycoprotein 1b 
GCP 
Good Clinical Practice 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
ITT 
Intention-To-Treat 
IU 
International Units 
IVR 
In Vivo Recovery 
MedDRA 
Medical Dictionary for Regulatory Activities 
OS 
One-Stage (Assay) 
PBAC 
Pictorial Blood Loss Assessment Chart 
PP 
Per Protocol 


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Abbreviation 
Description 
PROMIS 
The Patient-Reported Outcomes Measurement Information System® 
PTP 
Previously Treated Patient 
PUP 
Previously Untreated Patient 
QoL 
Quality of Life 
RCo 
Ristocetin Co-factor 
SABR 
Spontaneous Annualised Bleeding Rate 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SAR 
Suspected Adverse Reaction 
SF-36v2 
36-Item Short Form Health Survey, version 2
SF-10 
10-Item Short Form Health Survey
SURG 
Surgery (Population)
TABR 
Total Annualised Bleeding Rate
TEAE 
Treatment-Emergent Adverse Event
USA 
United States of America
VWD 
Von Willebrand Disease
VWF 
Von Willebrand Factor
VWF:Ac 
Von Willebrand Factor Activity
VWF:GPIbm 
Assay based on the spontaneous binding of VWF to a gain-of-function mutant GP1b 
fragment [1] 
VWF:GP1bR 
Assay based on the ristocetin-induced binding of VWF to a recombinant wild-type GP1b 
fragment [1] 
VWF:RCo 
VWF:RCo Ristocetin cofactor activity; assay that uses platelets and ristocetin 


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1 
INTRODUCTION 
1.1 Von Willebrand Disease 
Inherited von Willebrand disease (VWD) is the most common inherited haemorrhagic disor-
der, with an estimated prevalence of 1 in every 100 individuals of either sex. There is wide 
geno- and phenotypic variability of the disease, and not all patients with VWD require treat-
ment. 
Three types of inherited VWD are known. Thus, whereas type 1 and type 3 disease are charac-
terised 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. VWD 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]. 
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), DDAVP is contraindicated in type 2B and not 
effective in type 3 disease. Treatment with DDAVP may also be contraindicated for other clin-
ical reasons or may be associated with significant side effects. 
The appropriate treatment for the 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 the viral-attenuated concentrates [3]. 
VWD affects all ethnic groups and both sexes. Women are more likely to experience symptoms 
of VWD and may pose a special treatment challenge because of the physiological events related 
to menstruation, pregnancy, and birth [4]. If untreated, pregnant women with VWD are at in-
creased risk of postpartum bleeding. In women with VWD types 1 or 2, the levels of VWF and 
FVIII rise 2- to 3-fold during the second and third trimesters, but fall to baseline levels soon 
after delivery. By contrast, in VWD type 2B, the increase of the abnormal VWF can cause or 
worsen thrombocytopenia. In women with VWD type 3, VWF and FVIII do not increase during 
pregnancy, so that administration of VWF-containing products may be required during preg-
nancy and at birth [4]. 


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1.2 Wilate 
Wilate is a plasma-derived, stable, highly purified, double virus inactivated concentrate of 
freeze-dried active von Willebrand factor (VWF) and factor VIII (FVIII) prepared from cryo-
precipitate 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 mini-
mum. 
Overall, 15 prospective clinical studies with Wilate have been completed, 8 in patients with 
VWD and 7 in patients with haemophilia A. A summary of findings from nonclinical and clin-
ical studies with Wilate is provided in the product’s Investigator’s Brochure (IB). 
Wilate received its first market authorisation in Germany in February 2005. By November 2018, 
Wilate had been licensed in 68 countries worldwide. 
1.3 Rationale for Conducting the Study 
The purpose of this study is to obtain additional data on the safety and efficacy of Wilate in 
previously treated patients with VWD undergoing regular prophylaxis, thus supplementing the 
existing body of data to obtain approval of Wilate in the prophylactic treatment of patients with 
VWD in the USA. 
1.4 Dose Rationale 
The doses for prophylaxis (20–40 IU/kg Wilate/kg BW administered 2–3 times per week), the 
treatment of BEs, and perioperative prophylaxis (see Section 5.4) are as recommended in the 
product’s European Summary of Product Characteristics. 
1.5 Benefit-Risk Statement 
The following adverse drug reactions (ADRs) are known to occur with other VWF/FVIII prep-
arations and may also occur with the use of Wilate: 

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.


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
Patients with VWD, especially type 3 patients, may develop neutralising antibodies
(inhibitors) to VWF and/or FVIII. If expected VWF:RCo 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 applies also
to pathogens of hitherto unknown origin. The manufacturing process of Wilate, which
includes 2 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 im-
munodeficiency 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 physi-
cian 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 particularly increased in patients with known clinical or laboratory risk fac-
tors. 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. 


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2 
STUDY OBJECTIVES 
2.1 Primary Objective 
The primary objective of this study is to determine the efficacy of Wilate in the prophylactic 
treatment of previously treated patients (PTPs) with type 3, type 2 (except 2N), or severe type 
1 VWD. 
2.2 Secondary Objectives 
The secondary objectives of this study are to: 

Assess the incremental IVR of Wilate for VWF:Ac and FVIII:C over time

Determine the pharmacokinetics (PK) of Wilate for VWF:Ac and FVIII:C in paediatric
patients aged 6–16 years

Assess the safety and tolerability of Wilate

Determine Wilate consumption data
2.3 Additional Objectives 
Additional objectives of this study are to: 

Determine the efficacy of Wilate in the treatment of breakthrough bleeding episodes
(BEs)

Determine the efficacy of Wilate in surgical prophylaxis

Assess patients’ quality of life (QoL) during prophylaxis with Wilate

Assess the patients’ joint status using the Hemophilia Joint Health Score (HJHS)

Assess the menstrual bleeding intensity of female patients of child-bearing potential
(based on PBAC score)


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3 
INVESTIGATIONAL PLAN 
3.1 Study Endpoints 
3.1.1 Primary Endpoint 
The primary endpoint of this study is to demonstrate that prophylactic treatment with Wilate 
lowers the patients’ total annualized bleeding rate (TABR) observed during on-demand treat-
ment by more than 50%.The TABR will be calculated as the total number of spontaneous 
bleeds, traumatic bleeds, and other bleeds (except menstrual bleeds) occurring in the time pe-
riod between first dose of the investigational medicinal product (IMP) and the Study Comple-
tion Visit, divided by the duration (in years) between first dose of IMP and the Study Comple-
tion Visit. Surgery periods, and BEs occurring within these surgery periods, will be excluded 
from the calculation of TABR. 
Similar calculation rules will be applied for the computation of the TABR during the previously 
documented on-demand treatment regimen. 
3.1.2 Secondary Endpoints 
The secondary endpoints of this study are the: 

Spontaneous annualised bleeding rate (SABR), calculated in analogy with TABR

Incremental IVR of Wilate for VWF:Ac (VWF:RCo and VWF:GPIbm) and FVIII:C
(OS and CHR) over time (at baseline and at 1, 2, 3, 6, 9, and 12 months of treatment)

For paediatric patients, baseline PK profile characteristics of VWF:Ac (VWF:RCo)
and FVIII:C (OS and CHR) based on blood samples taken pre-dose and 1, 3, 9, 24,
48, and 72 hours after dosing

Safety and tolerability of Wilate by monitoring adverse events (AEs) throughout the
study

Wilate consumption data (VWF/FVIII IU/kg per month per patient) for prophylaxis
3.1.3 Exploratory Endpoints 
The exploratory endpoints of this study are: 

Efficacy of Wilate in the treatment of breakthrough BEs based on the proportion of
BEs successfully treated with Wilate

Efficacy of Wilate in surgical prophylaxis based on the proportion of surgeries suc-
cessfully treated with Wilate

QoL based on the score of PROMIS-29 for all patients, SF-36v2 for patients aged
≥16 years, and SF-10 for patients aged 6–15 years

Hemophilia Joint Health Score (HJHS)

Pictorial Blood Loss Assessment Chart (PBAC) score for menstrual bleeds

Annual rate of heavy (i.e., major) menstrual bleeds


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3.2 Overall Study Design and Plan 
This is a prospective, non-controlled, international, multi-centre phase 3 study investigating the 
efficacy and safety of Wilate in previously treated patients with type 3, type 2 (except 2N), or 
severe type 1 VWD aged ≥6 years at the time of screening. 
Overall, around 40 patients will be enrolled by approximately 14 study sites worldwide. Of the 
40 patients, at least 5 patients should have type 3 VWD, at least 6 patients should be aged 6–11 
years, and at least 6 patients should be aged 12–16 years. 
Of the 40 patients, at least 25 patients should be evaluable for the primary endpoint. 
Paediatric patients will undergo a 4-day PK assessment at the time of the Baseline PK Visit, 
with the aim to obtain evaluable PK data from at least 6 patients aged 6–11 years (of which at 
least 4 evaluable) and at least  6 patients aged 12–16 years (of which at least 4 evaluable).  
The planned treatment duration per patient is 12 months. 
The primary objective of this study is to determine the efficacy of Wilate in the prophylactic 
treatment of previously treated patients with type 3, type 2 (except 2N), or severe type 1 VWD. 
The efficacy of prophylactic treatment with Wilate will be assessed by comparing each patient’s 
individual total annualized bleeding rate (TABR) under prophylactic treatment in this study 
with the TABR recorded for the same patient under at least 6 months of on-demand treatment.  
The secondary objectives are to assess the incremental IVR of Wilate for VWF:Ac and FVIII:C 
over time (at baseline and at 1, 2, 3, 6, 9, and 12 months of treatment), the VWF:Ac and FVIII:C 
pharmacokinetics at baseline in paediatric patients aged 6–16 years,  the product’s safety and 
tolerability, and Wilate consumption data. 
Additional objectives are to determine the efficacy of Wilate in the treatment of breakthrough 
bleeding episodes (BEs) and in surgical prophylaxis and to assess the patients’ QoL during 
prophylaxis with Wilate, joint status, and menstrual bleeding intensity (in female patients of 
child-bearing potential). 
Where needed, external home-care companies with experience in conducting clinical trials will 
be contracted, with trained nurses supporting patients by providing training, re-training, and 
oversight through home-care visit support throughout the study. 


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3.3 Discussion of Study Design 
This prospective, non-controlled, international, multi-centre phase 3 study is designed to 
demonstrate that Wilate is efficacious in bleeding prophylaxis in patients with VWD. 
Reduction of the annual bleeding rate (ABR) 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. 
In addition, it is expected that the quality of life of patients with VWD is considerably compro-
mised. Therefore, it was considered valuable to investigate the QoL profile of enrolled patients, 
despite there not being any validated tools to determine QoL in patients with VWD. 
4 
STUDY POPULATION 
4.1 Population Base 
4.1.1 Number of Patients 
Overall, around 40 PTPs aged ≥6 years at the time of screening will be enrolled into this study. 
Of the 40 patients, at least 5 patients should have type 3 VWD, at least 6 patients should be 
aged 6–11 years, and at least 6 patients should be aged 12–16 years. 
4.1.2 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. VWD type 1 (baseline von Willebrand factor activity [VWF:RCo] <30 IU/dL), 2A, 2B,
2M, or 3 according to medical history requiring substitution therapy with a VWF-
containing product to control bleeding
3. Currently receiving on-demand treatment with a VWF-containing product AND hav-
ing experienced at least 6 BEs (excluding menstrual bleeds) over a period of 6 months,
with at least 2 of these BEs treated with a VWF-containing product AND having rec-
ords available to reliably evaluate the type, frequency, and treatment of BEs in this 6-
month period
OR
Having switched to prophylactic treatment with a VWF-containing product within the
past 2 years AND having records available to reliably evaluate the type, frequency,
and treatment of BEs over a period of 6 months of on-demand treatment
4. Female patients of child-bearing potential must have a negative urine pregnancy test at
screening and agree to use adequate birth control measures; in case hormonal contracep-
tion is used, the medication class should remain unchanged for the duration of the study
5. Voluntarily given, fully informed written and signed consent obtained before any study-
related procedures are conducted


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4.1.3 Exclusion Criteria 
Patients who meet any of the following criteria are not eligible for the study: 
1. Having received on-demand or prophylactic treatment with a VWF-containing product
but having no records available to reliably evaluate the type, frequency, and treatment
of BEs over a period of at least 6 months of on-demand treatment
2. History, or current suspicion, of VWF or FVIII inhibitors
3. Medical history of a thromboembolic event within 1 year before enrolment
4. Severe liver or kidney diseases (alanine aminotransferase [ALAT] and aspartate trans-
aminase [ASAT] levels >5 times of upper limit of normal, creatinine >120 µmol/L)
5. Platelet count <100,000/µL at screening (except for VWD type 2B)
6. Body weight <20 kg at screening
7. Patients receiving, or scheduled to receive, immunosuppressant drugs (other than an-
tiretroviral chemotherapy), such as prednisone (equivalent to >10 mg/day), or similar
drugs
8. Pregnant or breast-feeding at the time of enrolment
9. Cervical or uterine conditions causing abnormal uterine bleeding (including infection,
dysplasia)
10. Treatment with any IMP in another interventional clinical study currently or within 4
weeks before enrolment
11. Other coagulation disorders or bleeding disorders due to anatomical reasons
12. Known hypersensitivity to any of the components of the study drug
4.2 Prior and Concomitant Therapy 
Patients receiving, or scheduled to receive, immunosuppressant drugs (other than antiretroviral 
chemotherapy), such as prednisone (equivalent to >10 mg/day), or similar drugs, and women 
having changed their hormonal contraception within 6 months before enrolment may not be 
enrolled. 
Concomitant therapies not interfering with the objectives of the study are permitted. Details of 
any concomitant medications must be recorded in the electronic Case Report Form (eCRF). 
Forbidden Medication 
No VWF/FVIII concentrates other than Wilate must be administered (except for emergency 
situations). 
Patients permanently switching to another product 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: 


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•
the use of another VWF/FVIII concentrate was due to an emergency case (example:
accident requiring treatment with VWF without patient or treating facility having access
to Investigational Medicinal Product [IMP])
•
the IMP was not available for the patient in time (example: patient experiences a severe
bleed but does not have enough product available).
The reason for a patient switching to another VWF product should be clearly documented in 
the CRF (and patient diary, if appropriate). 
4.3 Withdrawal and Replacement of Patients 
4.3.1 Premature Patient Withdrawal 
Patients have the right to withdraw from the study at any time for any reason, without the need 
to justify their decision. The investigator also has the right to withdraw patients in case of AEs, 
poor compliance, or other reasons. 


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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 thor-
ough efforts to clearly document the outcome. 
4.3.2 Patient Replacement Policy 
Drop-outs will not be replaced. 
4.3.3  Assignment of Patients to Treatment 
The investigator will enter a unique identifier for each patient (consisting of the study code, 
centre code, and patient number) in both the eCRF and the confidential patient identification 
list and inform the monitor of any new patient enrolled. 
Patients who enrol in the study will not be permitted to re-enrol. 
4.4 Relevant Protocol Deviations 
In case of any major protocol deviation, the investigator and Octapharma will decide on the 
further participation of the patient in this study after having discussed all relevant aspects. 
5 
INVESTIGATIONAL MEDICINAL PRODUCT 
5.1 Characterisation of Wilate 
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 will comply with the national requirements of each country where the study is 
conducted. 


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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. 
The product can be stored at room temperature (max. of +25°C or 77°F) for 2 months. In this 
case, the shelf-life expires 2 months after the product has been taken out of the refrigerator for 
the first time. 
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 in Paediatric Patients 
For the PK assessment in paediatric patients (6–16 years), a single dose of 60 ± 10 IU/kg will 
be administered. 
5.4.2 Wilate Dosage for Prophylactic Treatment 
For prophylactic treatment, Wilate should be administered 2–3 times per week at a dose of 
20–40 IU/kg BW for 12 months. 
The prophylactic dose for each patient will be determined by the Principal Investigator based 
on each patient’s clinical condition and at the following time points: 

At the Baseline IVR Visit (see Section 6.1.2) in adult patients (≥17 years)
In adult patients, the first prophylactic dose will be administered at the time of the
baseline IVR assessment.

At the Baseline PK Visit (see Section 6.1.4) in paediatric patients (6–16 years)
In paediatric patients, the first prophylactic dose will be administered after comple-
tion of the PK phase.
In case of unacceptably frequent spontaneous breakthrough BEs (i.e., more than 2 spontaneous 
BEs or 1 major spontaneous BE within a 30-day period), the dose of Wilate should be increased 
by approximately 5 IU/kg (depending on the entire content of the additional vials that need to 
be reconstituted). If, after a dose increase, patients still experience more than 2 spontaneous 
bleeding episodes, the dosing interval should be shortened from 2 times per week to 3 times per 
week.  
5.4.3 Wilate Dose for the Treatment of Breakthrough BEs 
The dose (and duration) of treatment of BEs will depend on the location and extent of bleed-
ing and on the clinical condition of the patient. 
Generally, 1 IU/kg BW VWF:Ac (VWF:RCo) and FVIII:C raises the plasma level by 
1.5–2% of normal activity for the respective protein. Usually, about 20–50 IU Wilate/kg BW 
are necessary to achieve adequate haemostasis. This will raise the VWF:Ac (VWF:RCo) and 


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FVIII:C in the patients by approx. 30–100%. 
The following should be used to guide dosing in the treatment of BEs: 
Dose type 
Minor haemorrhage* 
Major haemorrhage 
Loading dose 
20–40 IU/kg 
40–60 IU/kg 
Maintenance dose 
20–30 IU/kg every 12–24 hours 
20–40 IU/kg every 12–24 hours 
Therapeutic goal 
Maintain 
VWF:Ac 
(VWF:RCo) 
and 
FVIII:C trough levels >30% 
Maintain VWF:Ac (VWF:RCo) and FVIII:C 
trough levels >50% 
*Menstrual bleeds of regular intensity (i.e., minor menstrual haemorrhage) will be considered normal and are not
expected to require therapy unless deemed necessary by the investigator and/or the patient.
5.4.4 Surgical Prophylaxis 
For prevention of bleeding in case of surgery, levels of VWF:Ac (VWF:RCo) ≥60 IU/dL 
(≥60%) and FVIII:C levels ≥40 IU/dL (≥40%) should be achieved. 
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, and VWF:Ac (VWF:RCo) and FVIII:C levels. 
In patients receiving FVIII-containing VWF products, plasma levels of FVIII:C should be mon-
itored to reveal sustained excessive FVIII:C plasma levels, which may increase the risk of 
thrombotic events. 
The following should be used to guide dosing in surgical prophylaxis: 
Dose type 
Minor surgeries (incl. tooth extractions) 
Major surgeries 
Loading dose 
30–60 IU/kg 
40–60 IU/kg 
Maintenance dose 
15–30 IU/kg, or half the loading dose, every 
12–24 hours for up to 3 days 
20–40 IU/kg, or half the loading dose, 
every 12–24 hours for up to 6 days or 
longer 
Therapeutic goal 
Achieve VWF:Ac (VWF:RCo) peak levels of 
50% after loading dose and trough levels of 
>30% during maintenance doses
Achieve VWF:Ac (VWF:RCo) 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 Sum-
mary of Product Characteristics or the US Prescribing Information. 
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. 


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5.7 Treatment Compliance 
5.7.1 Drug Dispensing and Accountability 
Any IMP provided to the site will be accounted for. This includes IMP received at the site, IMP 
dispensed to patients, and used or unused IMP returned by patients. 
A Drug Inventory and Dispensing Log will be kept current by the investigator, detailing the 
dates and quantities of IMP 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. 
Unused IMP can be destroyed at the study site or returned to the Sponsor for destruction. De-
struction can be initiated only after accountability has been verified and fully reconciled by the 
monitor and after the Sponsor has granted written approval of destruction. 
5.7.2 Assessment of Treatment Compliance and Adherence with Infusion Regimen 
For all IVR assessments as well as for the PK assessment in paediatric patients, Wilate will be 
administered at the study site, with compliance under the control of the investigator. 
Assessment of Adherence with the Infusion Regimen 
Throughout the study, adherence with the infusion regimen will be assessed. Any change of the 
prophylactic dose as determined by the Principal Investigator during the Baseline Visit will be 
documented in the patient records and eCRF, including start and end dates of each dose, reasons 
for dose change, or reasons for not implementing a required dose change. 
6 
STUDY CONDUCT 
The flow charts of assessments for prophylactic treatment by study visit are given on pages 23 
and 25. The flow chart of assessments for surgical prophylaxis is given on page 27. Details on 
the individual assessments and methods are provided in Section 7. 


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6.1 Observations by Visit for Prophylactic Treatment 
Because all paediatric patients enrolled in the study will undergo PK assessment, whereas adult 
patients will not, the first two study visits differ between these two age cohorts. 
All enrolled patients will participate in the following study visits: 

Screening Visit
– For adult patients
– For paediatric patients

Baseline Visit
– Baseline IVR Visit for adult patients
– Baseline PK Visit for paediatric patients

1-Month IVR Visit

2-Month IVR Visit

3-Month IVR Visit

6-Month IVR Visit

9-Month IVR Visit

Study Completion (12-Month) Visit
Between the 3- and 6-Month Visits, the 6- and 9-Month Visits, and the 9- and 12-Month Visits, 
monthly telephone contacts will be performed. 
Where needed, external home-care companies with experience in conducting clinical trials 
will be contracted, with trained nurses supporting patients by providing training, re-training, 
and oversight through home-care visit support throughout the study. 
SCREENING AND BASELINE VISITS FOR ADULT PATIENTS (≥17 YEARS) 
6.1.1 Screening Visit (Adult Patients) 
The Screening Visit should take place at least 72 hours from the patient’s latest administration 
of a VWF-containing product. 


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The following assessments will be performed: 

Obtaining voluntarily given, written (signed and dated) informed consent

Inclusion and exclusion criteria

Demographic and baseline characteristics

Weight

Height

Medical history, including:
— VWD type
— Prior medications 
— Birth control measures (for female patients of child-bearing potential) 
— History of heavy menstrual bleeding (for female patients) 

Family history of VWD

Vital signs

Physical examination

Blood samples for the following assessments:
— AB0 blood group, unless derivable from the baseline characteristics [local
lab] 
— Routine safety laboratory [local lab] 

Urine pregnancy test (in female patients of child-bearing potential)

Concomitant medications
During the Screening Visit, patients will also receive a patient diary. The investigator will 
explain to the patient how to fill in the diary and emphasize the importance of carefully docu-
menting any BEs, treatment details, AEs, and concomitant medications. Menstrual bleeds will 
be documented in the Pictorial Blood Loss Assessment Chart (PBAC). Therefore, female 
patients of child-bearing potential will also be instructed in completing the PBAC (see Section 
7.2.8). 
After the Screening Visit, eligible patients will participate in the Baseline IVR Visit, during 
which the first prophylactic dose of Wilate will be administered. 
For adult patients, the Screening Visit and the Baseline IVR Visit may coincide; however, note 
that administration of the first prophylactic dose of Wilate during the Baseline IVR Visit re-
quires a washout period of at least 72 hours from the patient’s previous administration of a 
VWF-containing product. If possible, the interval between the Screening Visit and the Baseline 
IVR Visit should not exceed 2 weeks. 
Between the Screening Visit and the Baseline IVR Visit, on-demand treatment of BEs or 
prophylactic treatment should be continued with the patient’s previously used VWF-
containing product. Any BEs occurring between the Screening Visit and the Baseline IVR 
Visit will be documented in the patient diary (menstrual bleeds in the PBAC). Also, any 
infusions with the patient’s previous VWF-containing product during this time will be docu-
mented in the patient diary as concomitant medication.  


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6.1.2 Baseline IVR Visit (Adult Patients) 
During the Baseline IVR Visit, the prophylactic dose and dosing interval of Wilate for each 
adult patient will be determined by the Principal Investigator based on the patient’s clinical 
condition, and the first prophylactic dose will be administered after a washout period of at least 
72 hours from the patient’s latest administration of a VWF-containing product. Patients must 
not be experiencing any bleeding.  
The following assessments will be performed: 
BEFORE ANY OTHER ASSESSMENTS 

Confirm inclusion and exclusion criteria (to be documented in patient
records)

QoL questionnaires (PROMIS-29 for all patients, SF-36v2 or SF-10 as ap-
plicable)
BEFORE INJECTION 

Weight

Blood samples
— VWF multimer pattern for VWD type 2A and genotype for VWD type 2B
[central lab] 
— Anti-parvovirus B19 antibodies [central lab] 
— Retention samples for possible virus marker and VWF/FVIII inhibitor 
testing [central lab] 
WITHIN 60 MIN BEFORE AND 60±5 MIN AFTER INJECTION 

Vital signs

Blood samples
— VWF:Ac (VWF:RCo and VWF:GPIbm) for IVR [central lab]
— FVIII:C (OS and CHR) for IVR [central lab] 
ANY TIME 

Patient diary review, with documentation of PBAC data and calculation
of PBAC score by investigator (in female patients of child-bearing potential)

Hemophilia Joint Health Score (HJHS)

Target joint(s)

Re-confirm commitment to using birth control measures (in female pa-
tients of child-bearing potential)

Monitoring of adverse events (AEs)

Concomitant medications
In adult patients, the first prophylactic injection of Wilate is administered during the 
Baseline IVR Visit. 
In case of home treatment, patients will be trained in how to correctly administer the IMP and 
provided with IMP. Patients will be re-supplied with IMP whenever necessary during the study. 


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SCREENING AND BASELINE VISITS FOR PAEDIATRIC PATIENTS (6–16 YEARS) 
6.1.3 Screening Visit (Paediatric Patients) 
The following assessments will be performed: 

Obtaining voluntarily given, written (signed and dated) informed consent

Inclusion and exclusion criteria

Demographic and baseline characteristics

Weight

Height

Medical history, including:
— VWD type
— Prior medications 
— Birth control measures (for female patients of child-bearing potential) 
— History of heavy menstrual bleeding (for female patients) 

Family history of VWD

Vital signs

Physical examination

Blood samples for the following assessments:
— AB0 blood group, unless derivable from the baseline characteristics [local
lab] 
— Routine safety laboratory [local lab] 
— VWF multimer pattern for VWD type 2A and genotype for VWD type 2B 
[central lab] 
— VWF:Ac (VWF:RCo and VWF:GPIbm) [central lab] 
— FVIII:C (OS and CHR) [central lab] 
— Anti-parvovirus B19 antibodies [central lab] 
— Retention samples for possible virus marker and VWF/FVIII inhibitor testing 
[central lab] 

Urine pregnancy test (in female patients of child-bearing potential)

Concomitant medications
During the Screening Visit, patients will also receive a patient diary. The investigator will 
explain to the patient how to fill in the diary and emphasize the importance of carefully docu-
menting any BEs, treatment details, AEs, and concomitant medications. Menstrual bleeds will 
be documented in the Pictorial Blood Loss Assessment Chart (PBAC). Therefore, female 
patients of child-bearing potential will also be instructed in completing the PBAC (see Section 
7.2.8). 
After the Screening Visit, eligible children will participate in the Baseline PK Visit. The Screen-
ing Visit and the Baseline PK Visit must not occur on the same day. If possible, the interval 
between the Screening Visit and the Baseline PK Visit should not exceed 2 weeks. 
Between the Screening Visit and the Baseline PK Visit, on-demand treatment of BEs or prophy-
lactic treatment should be continued with the patient’s previously used VWF-containing 
product. Any BEs occurring between the Screening Visit and the Baseline PK Visit will be 
documented in the patient diary (menstrual bleeds in the PBAC). Also, any infusions with 


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the patient’s previous VWF-containing product during this time will be documented in the 
patient diary as concomitant medication. 
6.1.4 Baseline PK Visit (Paediatric Patients) 
During the Baseline PK Visit, paediatric patients will receive Wilate at a dose of 60 ± 10 IU/kg 
after a washout period of at least 72 hours from the patient’s previous administration of a 
VWF-containing product. Patients must not be experiencing any bleeding.  
The following assessments will be performed: 
BEFORE ANY OTHER ASSESSMENTS 

Confirm inclusion and exclusion criteria (to be documented in patient
records)

QoL questionnaires (PROMIS-29 for all patients, SF-36v2 or SF-10, as ap-
plicable)
BEFORE INJECTION 

Weight
WITHIN 60 MIN BEFORE AND 60±5 MIN AFTER INJECTION 

Vital signs
WITHIN 60 MIN BEFORE AND 60±5 MIN, 3 H±30 MIN, 9±1 H, 24±2 H, 48±2 H, 
and 72±2 H AFTER INJECTION 

Blood samples
−VWF:Ac (VWF:RCo) for PK [central lab]
−FVIII:C (OS and CHR) for PK [central lab]
ANY TIME 

Patient diary review, with documentation of PBAC data and calculation
of PBAC score by investigator (in female patients of child-bearing potential)

Hemophilia Joint Health Score (HJHS)

Target joint(s)

Re-confirm commitment to using birth control measures (in female pa-
tients of child-bearing potential)

Monitoring of adverse events (AEs)

Concomitant medications
During this visit, the prophylactic dose and dosing interval of Wilate will be determined by the 
Principal Investigator based on the patient’s clinical condition. 
In paediatric patients, the first prophylactic injection of Wilate is administered after the 
Baseline PK Visit. 
In case of home treatment, patients will be trained in how to correctly administer the IMP and 
provided with IMP. Patients will be re-supplied with IMP whenever necessary during the study. 
After the Baseline IVR Visit in adults and the Baseline PK Visit in children, 
all subsequent visits will be the same for both age cohorts. 


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SUBSEQUENT VISITS FOR ALL PATIENTS 
6.1.5 1-Month IVR Visit 
The 1-Month IVR Visit will take place 1 month (±1 week) after the first prophylactic injection 
of Wilate. 
During this visit, a prophylactic injection of Wilate will be administered. Patients should arrive 
at the centre within 3 hours before their next planned prophylactic dose. Patients must not be 
experiencing any bleeding.  
The following assessments will be performed: 
BEFORE INJECTION 

Weight

Blood samples
— For VWF and FVIII inhibitor testing, only if inhibitor development is sus-
pected 
WITHIN 60 MIN BEFORE AND 60±5 MIN AFTER INJECTION 

Vital signs

Blood samples
— VWF:Ac (VWF:RCo and VWF:GPIbm) for IVR [central lab]
— FVIII:C (OS and CHR) for IVR [central lab] 
ANY TIME 

Patient diary review, with documentation of PBAC data and calculation
of PBAC score by investigator (in female patients of child-bearing potential)

Review of compliance and adherence to the infusion regimen

Re-confirm commitment to using birth control measures (in female pa-
tients of child-bearing potential)

Monitoring of adverse events (AEs)

Concomitant medications
At the end of this and each of the following visits, IMP for home treatment will be given to 
patients as applicable. 
6.1.6 2-Month IVR Visit 
The 2-Month IVR visit will take place 2 months (±1 week) after the first prophylactic injection 
of Wilate. 
During this visit, a prophylactic injection of Wilate will be administered. Patients should arrive 
at the centre within 3 hours before their next planned prophylactic dose. Patients must not be 
experiencing any bleeding. 
The following assessments will be performed: 

Same assessments are for the 1-Month IVR Visit


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6.1.7 3-Month IVR Visit 
The 3-Month IVR Visit will take place 3 months (±1 week) after the first prophylactic injection 
of Wilate. 
During this visit, a prophylactic injection of Wilate will be administered. Patients should arrive 
at the centre within 3 hours before their next planned prophylactic dose. Patients must not be 
experiencing any bleeding. 
The following assessments will be performed: 

Same assessments as for the 1-Month IVR Visit

Urine pregnancy test (in female patients of child-bearing potential)
6.1.8 6-Month IVR Visit 
The 6-Month IVR Visit will take place 6 months (±2 weeks) after the first prophylactic injection 
of Wilate. 
During this visit, a prophylactic injection of Wilate will be administered. Patients should arrive 
at the centre within 3 hours before their next planned prophylactic dose. Patients must not be 
experiencing any bleeding. 
The following assessments will be performed: 
BEFORE ANY OTHER ASSESSMENTS 

QoL questionnaires (PROMIS-29 for all patients, SF-36v2 or SF-10 as ap-
plicable)

Same assessments as for 1-Month IVR Visit

Urine pregnancy test (in female patients of child-bearing potential)
6.1.9 9-Month IVR Visit 
The 9-Month IVR Visit will take place 9 months (±2 weeks) after the first prophylactic injection 
of Wilate. 
During this visit, a prophylactic injection of Wilate will be administered. Patients should arrive 
at the centre within 3 hours before their next planned prophylactic dose. Patients must not be 
experiencing any bleeding. 
The following assessments will be performed: 

Same assessments are for the 1-Month IVR Visit


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6.1.10 Study Completion (12-Month) Visit 
The Study Completion Visit will take place 12 months (+2 weeks) after the first prophylactic 
injection of Wilate. 
During this visit, a prophylactic injection of Wilate will be administered. Patients should arrive 
at the centre within 3 hours before their next planned prophylactic dose. Patients must not be 
experiencing any bleeding. 
The following assessments will be performed: 
BEFORE ANY OTHER ASSESSMENTS 

QoL questionnaires (PROMIS-29 for all patients, SF-36v2 or SF-10 as ap-
plicable)
BEFORE INJECTION 

Weight

Blood samples
— Routine safety laboratory [local lab]
— For VWF and FVIII inhibitor testing, only if inhibitor development is sus-
pected [central lab] 
— Anti-parvovirus B19 antibodies [central lab], only if the sample at the 
Baseline Visit was negative, or if it was equivocal on both original and 
re-testing 
WITHIN 60 MIN BEFORE AND 60±5 MIN AFTER INJECTION 

Vital signs

Blood samples
— VWF:Ac (VWF:RCo and VWF:GPIbm) for IVR [central lab]
— FVIII:C (OS and CHR) for IVR [central lab] 
ANY TIME 

Patient diary review, with documentation of PBAC data and calculation
of PBAC score by investigator (in female patients of child-bearing potential)

Review of compliance and adherence to the infusion regimen

Hemophilia Joint Health Score (HJHS)

Target joint(s)

Physical examination

Urine pregnancy test (in female patients of child-bearing potential)

Monitoring of adverse events (AEs)

Concomitant medications
All used and unused IMP vials will be returned by the patients or their home-care providers. 
Patients prematurely withdrawing from the study for any reason will also be invited to attend 
the Study Completion Visit. 


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6.1.11 Monthly Telephone Contacts 
Monthly telephone contacts will be performed 4, 5, 7, 8, 10, and 11 months (± 1 week) after 
first prophylactic injection of Wilate. Should a patient visit the study centre at the time any of 
these telephone contacts are scheduled, the required assessments may also be performed during 
this visit. 
The following assessments will be performed: 

Review of compliance with correctly completing the patient diary and PBAC (for
female patients of child-bearing potential)

Review of adherence with the infusion regimen

Monitoring of adverse events (AEs)

Concomitant medications
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. 
6.1.12 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 IMP injections, or prolonged bleeding), VWF and FVIII inhibitor tests will 
be performed at the central laboratory and documented (see Section 7.4.5.1). 
In case of positive inhibitor results, inhibitor retesting 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. 
6.1.13 Surgical Visits 
Patients may undergo surgical interventions in the course of the study. Whether or not these 
patients will be hospitalised will depend on the type and severity of the surgery and be at the 
discretion of the investigator. 
In patients undergoing major surgeries, standard methods of postsurgical thromboprophylaxis, 
such as gradated compression stockings and early mobilisation, should be used to prevent ve-
nous thromboembolism. 
For the flow chart of assessments for surgical prophylaxis, see page 27. 
For details on the surgery data to be documented and the surgical efficacy assessments to be 
performed, see Section 7.2.4 and Section 7.2.5. 


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6.2 Duration of Study 
6.2.1 Planned Duration for an Individual Patient 
The planned treatment duration per patient is 12 months. 
6.2.2 Planned Duration for the Study as a Whole 
The study will be considered clinically completed when all enrolled patients have completed 
the planned observation period, including the Study Completion Visit. 
The estimated start of the study (enrolment of first patient) is Q2 2020, and the estimated end 
of the study is Q1 2022. 
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. 
Regulatory authorities and IECs/IRBs should be informed in accordance with national regula-
tions. Early termination of the study as a whole or by centre may apply for the reasons described 
below. 
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 phar-
macological 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 and partially com-
pleted CRFs, IMPs, etc.) must be returned to the Sponsor. 


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7 
ASSESSMENTS AND METHODS 
7.1 Demographic and Baseline Information 
The following information will be recorded during the Screening Visit (see Section 6.1.1): 
7.1.1 Demographic and Baseline Characteristics 
The demographic and baseline characteristics are age, ethnic origin, weight, height, and AB0 
blood group. 
7.1.2 Medical History and Prior Medications 
The medical history will be obtained by patient interview and by collecting records of past 
diseases and treatments (e.g., hospital records), if available. Concomitant medications will also 
be obtained by interview. 
For female patients of child-bearing potential, the birth control measures used within 6 months 
before enrolment will be documented. For all female patients, any history of heavy menstrual 
bleeding will be recorded. The Pictorial Blood Chart Assessment (PBAC) score calculated dur-
ing the 6 months previous to Screening will be obtained in an observational study preceding 
this study, if applicable. 
In addition, information about the patients’ treatment with VWF-containing product will be 
collected. To be eligible for the study, complete records on the type, frequency, and treatment 
of BEs for at least 6 months of on-demand treatment must be available (see Section 4.1.2). 
The history or (suspected) presence of VWF or FVIII inhibitor activity is an exclusion criterion 
(see Section 4.1.3). 
7.2 Efficacy Assessments 
This section summarises the assessments to be performed for the calculation of the primary 
endpoint (see Section 3.1.1) as well as the secondary (see Section 3.1.2) and exploratory end-
points (see Section 3.1.3) of this study. 
For details on laboratory analyses, see Section 7.4.5. 


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7.2.1 IMP Administration Data 
The following parameters will be documented: 

Dates and times of IMP injections

Doses of IMP in IU and IU/kg and IMP batch numbers

Purpose of IMP injection (IVR, prophylaxis, prophylaxis of recurrent bleeding, treat-
ment of BE, surgery, prophylaxis after surgery, or menstrual bleeds)
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. 
7.2.2 Bleeding Episode (BE) Data 
Study participants will be instructed by the investigator on recording all BEs and in how to 
record them. For any BE occurring during the study, the following data will be recorded: 

BE type (spontaneous, traumatic, postoperative, other)

BE site

BE severity (minor or major) (see Table 1)

Date and time the BE first occurred or was first noticed

Date and time the BE ended

IMP administration data (see Section 7.2.1)

Assessment of the efficacy of treatment at the end of the BE (see Section 7.2.3)
All of these parameters will be documented by the patient (together with the investigator in case 
of on-site treatments or together with the nurse in case a home-care service is used) in the patient 
diary. Patients who experience a major BE should be treated at the study site, if possible. 
Based on these data, the frequency of BEs and the TABR and SABR under prophylactic treat-
ment will be calculated. 
If the treatment of a BE in one bleeding site is interrupted for more than 48 hours, two separate 
BEs will have to be recorded; if, in addition to the original bleeding site, another bleeding site 
is affected, these events will be recorded as separate BEs at any time. 
Menstrual bleedings will not be counted towards the TABR. 
BE severity and the severity of menstrual bleeds will be assessed using the criteria given in 
Table 1. 


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Table 1 
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 diffi-
culty 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, cutane-
ous 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). 
Major 
Generally requires hospitalization; 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 pericar-
dial bleeds), intramuscular bleeds with compartment syndrome, bleeds of the 
pelvic muscles, periorbital bleeds, gastrointestinal bleeds, central nervous sys-
tem bleeds, heavy menstrual bleeding,* bleeding in the area of the neck or 
throat or pharynx, other major trauma, or bleeding causing a decrease in hae-
moglobin levels by 20 g/L (1.24 mmol/L) or more. 
*Heavy menstrual bleeding is any menstrual bleeding that impedes the abil-
ity to perform daily activities such as work, housework, exercise, or social activi-
ties during menstrual periods and should be considered ‘major.’ Criteria for
heavy (i.e., major) menstrual bleeding may also include any of the following:
changing pads/tampons more frequently than hourly; menstrual bleeding lasting
7 or more days; and the presence of clots >1 cm combined with a history of
flooding or a PBAC score ≥185.
7.2.3 Efficacy of the Treatment of Breakthrough BEs 
At the end of a BE, treatment efficacy will be assessed by the patient (together with the inves-
tigator in case of on-site treatment) using the predefined criteria detailed in Table 2. 
Table 2 
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 
The proportion of BEs successfully treated with IMP will be evaluated for all BEs taken 
together and by BE severity. All efficacy ratings assessed as either ‘excellent’ or ‘good’ will be 
considered ‘successfully treated.’ 


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7.2.4 Surgical Prophylaxis Data 
The following surgery-related parameters will be documented: 

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

Pre-, intra-, and postoperative IMP administration data (see definitions under (b) be-
low)

Pre-, intra-, and postoperative FVIII and VWF:Ac plasma levels (see definitions un-
der (b) below)

Routine safety laboratory

Presence of wound haematomas

Vital signs

Details on concomitantly administered products

Blood transfusion requirements

Brief narrative describing the outcome of the intervention

Efficacy assessment at the end of surgery by surgeon (see Section 7.2.5.1)

Efficacy assessment at the end of the postoperative period by haematologist (see
Section 7.2.5.2)

Overall efficacy assessment at the end of the postoperative period by the investigator
(see Section 7.2.5.3)

Monitoring of AEs
For details regarding the time points of data collection, refer to the flow chart of assessments 
for surgical prophylaxis on page 27. 
(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)

3rd molar extraction or extraction of ≥3 teeth

Surgeries/conditions in which the patient’s life is at stake
The classification is made prospectively. All other surgeries are classified as minor. 


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(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 regu-
lar VWF treatment regimen.
7.2.5 Efficacy in Surgical Prophylaxis 
Efficacy will be assessed at the end of surgery by the surgeon (see Section 7.2.5.1) and at the 
end of the postoperative period by the haematologist (see Section 7.2.5.2). In both cases, pre-
defined assessment criteria will be used. In addition, an overall assessment of efficacy will be 
made at the end of the postoperative period by the investigator (see Section 7.2.5.3). 
7.2.5.1 At the End of Surgery (by Surgeon) 
At the end of surgery, the haemostatic efficacy of Wilate will be assessed by the surgeon using 
the criteria listed in Table 3. 
Table 3 
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 haemosta-
sis 
Moderate 
Intraoperative blood loss was higher than the maximum expected blood loss for the type of pro-
cedure performed in a patient with normal haemostasis, but haemostasis was controlled  
None 
Haemostasis was uncontrolled, necessitating a change in the clotting factor replacement regi-
men 
7.2.5.2 At the End of the Postoperative Period (by Haematologist) 
At the end of the postoperative period, the haemostatic efficacy of Wilate will be assessed by 
the haematologist using the criteria listed in Table 4. 


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Table 4 
Efficacy Assessment at the End of the Postoperative Period 
Excellent 
No postoperative bleeding or oozing that was not due to complications of surgery. All postoper-
ative 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 orig-
inally 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 
7.2.5.3 Overall Efficacy Assessment at the End of the Postoperative Period (by 
Investigator) 
Overall efficacy using the ‘excellent,’ ‘good,’ moderate,’ and ‘none’ scale taking both the intra- 
and postoperative assessments into account will be assessed by the investigator based on the 
algorithm given in Table 5. 
Table 5 
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 
7.2.6 Quality of Life 
For the assessment of QoL, the following instruments will be used: 

Patient-Reported Outcomes Measurement Information System (PROMIS)-29 [5–7]
for patients of all ages. For patients 6–7 years of age, the questionnaire will be com-
pleted by the parent/legal guardian. Self-reported measures will be used for patients
≥8 years old.

36-Item Short Form Health Survey, version 2 (SF-36v2, [8]), for patients ≥16 years,

10-Item Short From Health Survey (SF-10, [9]) will be used for patients 6–15 years
of age.
At each visit requiring QoL assessments, the questionnaires should be administered before start-
ing any other visit assessment. 


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7.2.7 Joint Health Status 
Joint health will be assessed using the Hemophilia Joint Health Score (HJHS) [10], which has 
been specifically validated for the assessment of clinical outcome in VWD [11]. 
Target joint(s) will also be documented. Target joint(s) are defined as having three or more 
spontaneous BEs into a single joint within 6 consecutive months preceding either the Baseline 
Visit or the Study Completion Visit. 
7.2.8 Pictorial Blood Assessment Chart 
Bleeding information from each menstrual period in this study will be collected in the Pictorial 
Blood Assessment Chart (PBAC) [12,13]. The PBAC will be provided to all female patients of 
child-bearing potential. 
The investigator will train all relevant patients in how to complete the PBAC. At each study 
visit, the investigator will review the completed PBAC and calculate the PBAC score. In addi-
tion, the investigator will review, together with the patient, the severity assessment of the men-
strual bleed using the criteria given in Table 1, Section 7.2.2 . The data documented in the 
PBAC and the investigator-calculated final score will be recorded in the eCRF. 
7.3 PK Assessments 
PK parameters will be assessed for VWF:Ac (VWF:RCo) and FVIII:C using both the chromo-
genic (CHR) and one-stage (OS) assays based on actual IMP potencies. 
The following PK parameters will be assessed: 

Area under the curve (AUC) and AUC normalized 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)


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7.4 Safety Assessments 
7.4.1 Assessments for Safety Endpoints 
The following drug safety information will be collected: 

Adverse events (AEs) and serious adverse events (SAEs) (for definitions and report-
ing requirements, see Sections 7.4.2, 7.4.3, and 7.4.4)

Pregnancies, drug overdose, interaction, medication error, lack of efficacy, and post-
study SAEs (see Section 7.4.7)
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 wors-
ened after the start of IMP infusion.

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 rela-
tionship 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 led 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 re-
solved or until the medical condition of the patient is stable. All follow-up infor-
mation 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 non-leading question such as 
“How have you been since the last visit/during the previous study period?” In addition, the 
investigator will check the patient diaries for any documented event. 
Any AE or ADR which occurs during the study will be noted in detail on the appropriate pages 
of the eCRF. If the patient reports several signs or symptoms representing a single syndrome or 
diagnosis, the diagnosis should be recorded in the eCRF. The investigator will grade the sever-
ity of all AEs or ADRs (mild, moderate, or severe), the seriousness (non-serious or serious), 


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and the causality as defined in Sections 7.4.2.3, 7.4.3, and 7.4.2.4. The Sponsor is responsible 
for assessing the expectedness of each ADR (expected or unexpected) as defined in Sec-
tion 7.4.2.5. 
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 ade-
quate 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 fre-
quency (worsening) occurs. Seroconversion for parvovirus B19 will be reported as an AE. 
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 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 rou-
tine activities
The grading of an AE is up to the medical judgment 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 admin-
istration of the IMP; or that follows a known or expected response pattern to the sus-
pected medicine; or that is confirmed by stopping or reducing the dosage of the medi-
cine and that could not reasonably be explained by known characteristics of the pa-
tient’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.


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
Unlikely: reports not following a reasonable temporal sequence from IMP admin-
istration. An event which may have been produced by the patient’s clinical state or by
environmental factors or other therapies administered.

Not related (unrelated): events for which sufficient information exists to conclude
that the aetiology is unrelated to the IMP.

Unclassified: reports which, for whatever reason, are not yet assessable, e.g., because
of still outstanding information (can only be a temporary assessment).
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 IB.

Unexpected: an ADR that is not listed in the current edition of the IB 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 wellbeing of the patient. Appropriate resuscitation equipment and medi-
cines must be available to ensure the best possible treatment in an emergency situation. 
The actions 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)


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(b) IMP-related actions taken in the event of an AE
– None
– Product withdrawn
– Dose reduced
– Dose increased
The investigator will follow up on each AE until it has resolved or until the medical condition 
of the 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 (see below).
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, im-
portant AEs/ADRs that are not immediately life-threatening or do not result in death or hospi-
talisation but may jeopardise the patient or may require intervention to prevent one of the other 
outcomes listed in the definitions above should also be considered serious. 
Examples of ‘important medical events’ are all suspected transmissions of an infectious agent, 
which therefore have to 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. 


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7.4.4 AE and SAE Reporting Timelines 
All SAEs, whether or not they are suspected to be related to study treatment, are to be reported 
immediately by telephone or email to the clinical study team. 
Phone: 
Mobile: 
Email: 
The contact details will also be communicated at the study initiation visit. 
In addition, within 24 hours after recognition of an SAE, an Octapharma Serious Adverse Event 
Report must be completed and submitted to: 
Octapharma’s Corporate Drug Safety Unit 
OCTAPHARMA Pharmazeutika Produktionsges.m.b.H. 
Oberlaaer Straße 235, 1100 Vienna, Austria 
Email: 
24-hour emergency telephone number:
Waivers the from SAE Reporting Requirement 
Waivers from the SAE reporting requirement include 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 following laboratory parameters will be determined at the time points specified in the flow 
charts of assessments on pages 23, 25 and 27, in Section 6, and in Table 6 and Table 7. 
7.4.5.1 Central Laboratory 
The following laboratory tests will be done at the central laboratory: 

VWF:Ac in vials used for baseline IVR injections as well as in plasma will be deter-
mined using VWF:RCo and VWF:GPIbm.

FVIII:C will be measured in plasma at pre-specified time points using OS and CHR
assays.


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
For VWF and FVIII inhibitor testing, a retention sample will be collected and
stored at the central laboratory. In addition, VWF and FVIII inhibitor testing will be
performed at any time during the study in case inhibitor development is suspected.
For the determination of VWF inhibitors, a mixing study based on VWF:RCo will be
used. For the determination of FVIII inhibitors, the modified Bethesda assay (Nijme-
gen modification) using the OS assay will be used.

Virus safety will be evaluated by taking a plasma sample for anti-parvovirus B19 an-
tibody testing before the first injection of Wilate. All patients negative at baseline will
be tested again at the Study Completion Visit. For patients with equivocal results at
baseline, the same sample will be re-tested. If re-testing also yields an equivocal re-
sult, the patient will be tested again at the Study Completion Visit. In addition, a re-
tention serum sample for possible virus marker testing will be taken and stored at the
central laboratory.

For patients with VWD type 2A, VWF multimers will be determined by a quantita-
tive method.

For patients with VWD type 2B, bidirectional sequencing of exon 28 and its intron-
exon boundaries will be performed to confirm the VWD type. If no mutation is identi-
fied, an additional molecular testing will be performed to exclude pseudo-VWD
Central laboratory: 
Covance Central Laboratory Services 
Rue Moise-Marcinhes 7 
1217 Geneva 
Meyrin, Switzerland 
SYNLAB Analytics & Services Germany GmbH 
Responsible for testing of VWF:GPIbm only 
Bayerstr. 53 
80335 Munich, Germany 
7.4.5.2 Local Laboratory 
The following routine safety laboratory tests will be done by the local laboratories of each site: 

Haematology: red blood cell count, white blood cell count, haemoglobin, haemato-
crit, and platelet count

Chemistry: total bilirubin, alanine amino transferase, aspartate transaminase, blood
urea nitrogen or urea, serum creatinine

Urine pregnancy test (in female patients of child-bearing potential)
AB0 blood-type testing as well as VWF:Ac (VWF:RCo) and FVIII:C measurements in case of 
BEs or surgery will also be done by the local laboratories. 


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Table 6 
Laboratory Assessments in Adult Patients (≥17 Years) 
Laboratory Assessments 
Screening Visit 
Baseline IVR Visit 
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 
x 
   Routine safety laboratory 
x 
x [1] 
   Urine pregnancy test [4] 
x 
x 
x 
x 
CENTRAL LAB 
   VWF multimer pattern for VWD type 2A and genotype for VWD type 2B 
x 
   VWF:Ac ( VWF:RCo  and VWF:GPIbm) for IVR 
x [2] 
x [2] 
x [2] 
x [2] 
x [2] 
x [2] 
x [2] 
   FVIII:C (OS and CHR) for IVR 
x [2] 
x [2] 
x [2] 
x [2] 
x [2] 
x [2] 
x [2] 
   Anti-parvovirus B19 antibodies 
x [1] 
x [3] 
   VWF and FVIII inhibitors (•) 
(•) [1] 
(•) [1] 
(•) [1] 
(•) [1] 
(•) [1] 
(•) [1] 
   Retention samples for possible virus marker and VWF/FVIII inhibitor testing 
x [1] 
(•) 
If inhibitor development is suspected 
[1]
Before injection
[2]
Within 60 min before and 60±5 min after injection
[3]
Before injection, if sample at the Baseline IVR Visit was negative, or if it was equivocal on both original and re-testing
[4]
In female patients of child-bearing potential
Table 7 
Laboratory Assessments in Paediatric Patients (6–16 Years) 
Laboratory Assessments 
Screening Visit 
Baseline PK Visit 
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 
  Routine safety laboratory 
x 
x [1] 
  Urine pregnancy test [4] 
x 
x 
x 
x 
CENTRAL LAB 
  VWF multimer pattern for VWD type 2A and genotype for VWD type 2B 
x 
  VWF:Ac (VWF:RCo and VWF:GPIbm) for IVR 
x 
x [2] 
x [2] 
x [2] 
x [2] 
x [2] 
x [2] 
  FVIII:C (OS and CHR) for IVR 
x 
x [2] 
x [2] 
x [2] 
x [2] 
x [2] 
x [2] 
  PK blood sampling for VWF:Ac (VWF:RCo) and FVIII:C (OS and CHR) 
x [3] 
  Anti-parvovirus B19 antibodies 
x 
x [4] 
  VWF and FVIII inhibitors (•) 
(•) [1] (•) [1] (•) [1] (•) [1] (•) [1] 
(•) [1] 
  Retention samples for possible virus marker and VWF/FVIII inhibitor testing 
x 
(•) 
If inhibitor development is suspected 
[1]
Before injection
[2]
Within 60 min before and 60±5 min after injection
[3]
Blood samples for PK assessment to be taken within 60 min before injection and 60±5 min, 3 h (±30 min), 9±1 h, 24±2 h,
48±2 h, and 72±2 h after injection (central laboratory)
[4]
Before injection, if sample at the Baseline PK Visit was negative, or if it was equivocal on both original and re-testing


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7.4.6 Vital Signs and Physical Examination 
The vital signs obtained at the time points specified in Section 6 are blood pressure, body tem-
perature, heart rate, and respiratory rate. 
Physical examinations will be performed at the visits specified in Section 6. Both height and 
weight will be measured during screening. In addition, weight will be measured at all visits 
prior to dosing. 
7.4.7 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 mon-
itoring for post-study SAEs is not required. 
If any such post-study event is identified, the investigator will complete an SAE form and trans-
mit it to the Clinical Trial Manager and to Octapharma’s Corporate Drug Safety Unit (see Sec-
tion 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. 
(b) Pregnancies
Every effort will be made to avoid a pregnancy during the use of an IMP. Pregnancies occurring 
during the study (foetal exposure to the IMP) must be reported. 
If a pregnancy occurs during the study, the investigator should complete the Pregnancy Notifi-
cation Form and transmit it to the Clinical Trial Manager and to Octapharma’s Corporate Drug 
Safety Unit (see Section 7.4.4). 
Follow-up information on the outcome of both mother and foetus will be requested by a Sponsor 
representative. 
Overdose, interaction, medication error 
The following safety relevant information should be reported as AE or, if the reaction fulfils 
one of the criteria for seriousness, as SAE. 
(c) 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. 


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(d) 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. 
(e) 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. 
(f) 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. 
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 studies with Wilate. 
Reduction of ABR 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. 
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 patient files for 
each 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. 
All data entered in the eCRF must be supported by source data in the patient records. 


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The investigator will permit study-related monitoring, audits, IEC/IRB reviews, and regulatory 
inspections, by providing direct access to the source data/records. 
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. 
Patients will usually treat themselves at home, and they will therefore be provided with a suffi-
cient amount of IMP and a patient diary as well as the PBAC (women of child-bearing poten-
tial).  
The patient diary/PBAC will be handed to the patient during the Screening Visit after inclusion 
into the study. The investigator will explain to the patient how to fill in the diary/PBAC and 
emphasize the importance of careful documentation. 
At each follow-up visit at the study site, the patient will bring along the patient diary/PBAC for 
review and validation by site personnel. 
During or after each follow-up visit, the information recorded in the patient diaries/PBACs will 
be transcribed to the eCRFs. The patient diaries/PBACs are classified as source data, and the 
originals will be included in the patient’s medical record. 
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 vali-
dated 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. 
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 Case Report Form (CRF) 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 gen-
erated 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 


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the reason for the change, prior to closing. The study monitor should provide guidance to in-
vestigator(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 Manage-
ment. 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 for 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 re-
spective benefit-risk ratio. 
The IB will be updated by the Sponsor at regular intervals and whenever relevant new infor-
mation concerning the IMP becomes available. 
The investigator will be informed about the methods for rating relevant study outcomes and for 
completing eCRFs 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. 
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 con-
duct 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 
and assent forms, 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. 


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The investigator is responsible for maintaining a confidential patient identification code list, 
which provides the unique link between named source records and CRF data for the Sponsor. 
The investigator must arrange for the retention of this confidential list for the maximum period 
of time required by local regulations. 
No study document should be destroyed without prior written agreement between the investi-
gator and the Sponsor. Should the investigator elect to assign the study documents to another 
party, or move them to another location, the Sponsor must be notified in writing. 
8.5 Provision of Additional Information 
On request, the investigator will supply the Sponsor with additional data relating to the study, 
or copies of relevant source records, ensuring that the patient’s confidentiality is maintained. 
This is particularly important when CRFs are illegible or when errors in data transcription are 
encountered. In case of particular issues or governmental queries, it is also necessary to have 
access to the complete study records, provided that the patient’s confidentiality is protected in 
accordance with applicable regulations. 
9 
STATISTICAL METHODS AND SAMPLE SIZE 
The statistical analysis will be delegated under an agreement of transfer of responsibilities to 
an external CRO that agrees to meet all Octapharma procedures and policies. 
9.1 Determination of Sample Size 
Assuming a mean TABR ratio (TABRpr / TABRod) of 0.25 with a correlation of 0.5 between 
the two treatment regimens, a coefficient of variation of 10 in on-demand treatment, and a co-
efficient of variation of 10 in prophylactic treatment, 25 patients will be needed to reject the 
null hypothesis 
H0: mean(TABRpr / TABRod) ≥0.5 
in favour of 
H1: mean(TABRpr / TABRod) <0.5 
with a type one error of 0.025 and a power of 80% using a paired t-test on log-transformed data. 


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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. This will be complemented by the 
presentation of exploratory confidence intervals (CIs) for means or proportions. 
A formal Statistical Analysis Plan (SAP) describing all details of the analyses to be performed 
will be prepared by the study statistician and approved by the Sponsor prior to the start of the 
statistical analysis. 
9.2.1 Populations for Analysis 
The safety set (SAF) will include all patients who received at least one dose of IMP. 
The full analysis set (FAS), defined according to the intention-to-treat (ITT) principle, will 
include all enrolled patients who received at least one dose of IMP after the Baseline IVR Visit 
in adults or the Baseline PK Visit in children. 
The per-protocol (PP) set, i.e., a subset of the FAS, will exclude patients with major protocol 
deviations which may have an impact on the evaluation of the primary study outcome parame-
ter. Examples of major and minor protocol deviations will be described in the SAP. 
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 FAS, containing all patients for whom a 
valid PK profile was obtained at baseline. 
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 SAF set.

The evaluation of the primary endpoint will be performed on the FAS (ITT analysis)
and on the PP set (PP analysis).

For secondary and exploratory endpoints, ITT and PP analyses will be carried out, un-
less these analysis sets differ by no more than 5% of patients.

Analysis of the efficacy and safety 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. 


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Primarily, all obtained data on treatment characteristics (IMP dosages, frequencies, total con-
sumption), VWF:Ac and FVIII:C incremental IVR of Wilate over time and BEs (duration, fre-
quency, efficacy assessment) will be described using summary statistics. 
Whenever sufficient reliable and comparable data on secondary endpoints (see Section 3.1.2) 
or exploratory endpoints (see Section 3.1.3) are available for similar historical on-demand treat-
ment periods, exploratory statistical comparisons of these endpoints to on-demand treatment 
periods will be considered.  
Efficacy of Prophylactic Treatment with Wilate 
The efficacy of prophylactic treatment with Wilate will be assessed by comparing each patient’s 
individual ABR under prophylactic treatment in this study with the ABR recorded for the same 
patient in a previous, non-interventional, study or with the ABR that can reliably be obtained 
from the patient’s bleeding documentation. 
Efficacy of prophylactic treatment with Wilate will be statistically evaluated by analysing the 
primary endpoint, i.e., demonstration that the TABR during prophylactic treatment lowers the 
patients’ TABR during on-demand treatment by more than 50%. 
To test whether the mean TABR during prophylactic treatment (TABRpr) is less than half the 
historical mean TABR during on-demand treatment (TABRod), the following pair of hypotheses 
will be tested using a paired t-test assuming log-normally distributed data: 
H0: mean(TABRpr / TABRod) ≥0.5 vs H1: mean(TABRpr / TABRod) <0.5 
at a one-sided alpha level of 2.5%. A corresponding two-sided 95% CI for the TABR will also 
be provided. 
To assess the qualitative robustness of the inferential result, the hypothesis will additionally be 
tested with the Wilcoxon (matched-pair signed rank) test on the log-transformed bleeding rate 
as a distribution-free alternative. Also, a 95% Hodges-Lehmann CI for the median difference 
will be reported. 
In addition to the comparison of the patients’ TABR during on-demand and prophylactic treat-
ment, intra-individual comparisons with each patient’s documented historical TABR will be 
performed. For this, descriptive statistics for historical TABR and TABR during prophylactic 
treatment and their intra-individual differences will be tabulated. Descriptive statistics will also 
be presented for the SABR. 
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 suc-
cessfully treated BEs. 


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Pharmacokinetic Analysis 
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 (normalized for the administered dose)

In vivo half-life (T½)

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)
PK parameters will be computed for VWF:Ac (VWF:RCo) and FVIII:C. Both chromogenic 
(CHR) and one-stage (OS) assays, actual IMP potencies, and actual sampling times will be used 
in the calculations. PK parameters will be derived by non-compartmental methods. 
The PK profiles of VWF:Ac and FVIII:C and the PK parameters derived from them will be 
summarized by descriptive statistics (including geometric means and standard deviations) as 
well as the presentation of concentration vs time plots (individual values and means). 
Subgroup Analyses 
Analyses of the primary endpoint assessing the efficacy of prophylactic treatment with Wilate 
and the secondary endpoint assessing the efficacy of Wilate in the treatment of breakthrough 
bleedings will be presented for the following subgroups: 

Age (6–11 years,’ ‘12–16 years,’ and ‘≥17 years’)

Race (‘American Indian or Alaska Native,’ ‘Asian,’ ‘Black or African American,’
‘Native Hawaiian or Other Pacific Islander,’ ‘White,’ ‘Other’)

Geographical region (‘patients in the US,’ ‘patients outside the US’)

Sex (‘female,’ ‘male’)
Analysis of PK parameters will be presented by age (‘6–11 years’ and ‘12–16 years’). 
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, 
IMP consumption) will be presented descriptively. 
Efficacy of Wilate in Menstrual Bleeding 
To assess the relative haemostatic efficacy of Wilate in the treatment of menstrual bleeding 
during prophylaxis compared to on-demand treatment, changes in the PBAC score will be an-
alysed based on complete cycle data. Only women of childbearing potential will be included in 
the analysis, which will include estimates and 95% CIs for PBAC score changes. 


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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, the results of the safety laboratory 
tests, and the occurrence of parvovirus B19 seroconversions. 
AEs will be coded according to the latest Medical Dictionary for Regulatory Activities 
(MedDRA) version. The analysis will include only treatment-emergent adverse events 
(TEAEs), i.e., AEs that started or worsened after the first IMP infusion. All TEAEs, related 
TEAEs (i.e., TEAEs probably or possibly related to the IMP), and serious TEAEs will be sum-
marised 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 sta-
tistics for the values as well as their difference to baseline at each time point. Additionally, 
frequency tables for values outside the normal ranges will be presented. 
Similarly, time profiles of VWF and FVIII inhibitor testing results will be analysed by present-
ing sampling statistics for the values as well as frequency tables for positive findings, along 
with 95% Pearson-Clopper CIs. 
To assess the viral safety of Wilate, incidences of parvovirus B19 seroconversions between 
baseline and end of study will be estimated along with 95% Pearson-Clopper CIs. 
Other safety parameters (e.g., changes in physical examination findings) will be analysed by 
summary tables or listings. 
The analysis of the safety parameters recorded during surgery (lab values) will be purely de-
scriptive and presented as summary tables or listings. 
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 
Not applicable. 


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10 ETHICAL/REGULATORY, LEGAL AND ADMINISTRATIVE ASPECTS 
10.1 Ethical/Regulatory Framework 
This study will be conducted in accordance with the ethical principles laid down in the Decla-
ration 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 Regula-
tory 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 
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 patient is exposed to a study-related procedure. 
The Sponsor, the investigator, and any third party (e.g., CRO) involved in obtaining approval 
must inform each other in writing that all ethical and legal requirements have been met before 
the first patient is enrolled in the study. 
10.3 Patient Information and Informed Consent 
The investigator will obtain freely given written consent from each patient 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, before the patient is exposed 
to any study-related procedure, including screening tests for eligibility. 
For patients not qualified to give legal consent, written consent must be obtained from the le-
gal parent/guardian. If children are old enough to understand the risks and benefits of the 
study, they should also be informed and provide their oral or written assent. 
The investigator will explain that the patients are completely free to refuse to enter the study or 
to withdraw from it at any time, without any consequences for their further care and without 
the need to justify. The investigator will complete the informed consent section of the eCRF for 
each patient enrolled. 
Each patient will be informed that his medical (source) records may be reviewed by the study 
monitor, a quality assurance auditor, or a health authority inspector, in accordance with appli-
cable 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 Co-ordinating Investigator 
and the Sponsor prior to its implementation. Any such amendments will be submitted to the 
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 patients, the objective/design of the study, any increase in dosage or 
duration of exposure to the IMP, an increase in the number of patients treated, the addition of a 
new test or procedure, or the dropping of a test intended to monitor safety. 
10.5 Confidentiality of 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 patient identification code list, original consent and assent forms, and source rec-
ords, 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 eCRF 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 
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 rec-
ords and reports that are important to the evaluation of the clinical study. Source data will be 
available for all data in the eCRFs, including all laboratory results. 
11.2 Audit and Inspection 
The investigator will make all study-related source data and records available to a qualified 
quality assurance auditor mandated by the Sponsor, or to IEC/IRB/regulatory inspectors, after 
reasonable notice. The main purposes of an audit or inspection are to confirm that the rights 
and welfare of the patients have been adequately protected, and that all data relevant for the 
assessment of safety and efficacy of the IMP have been reported to the Sponsor. 
12 REPORTING AND PUBLICATION 
12.1 Clinical Study Report 
A clinical study report (in accordance with relevant guidelines and the Sponsor’s Standard Op-
erating Procedures) 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 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 
1.
Bodó I, Eikenboom J, Montgomery R, Patzke J, Schneppenheim R, Di Paola J. Platelet-
dependent von Willebrand factor activity. Nomenclature and methodology: communica-
tion from the SSC of the ISTH. Journal of Thrombosis and Haemostasis 2015; 13(7): 1345–
50.
2.
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 1994; 71(4):520–5.
3.
Rodeghiero F, Castaman G, Tosetto A. How I treat von Willebrand disease. Blood 2009;
114(6):1158–65.
4.
Castaman G, Goodeve A, Eikenboom J. Principles of care for the diagnosis and treatment
of von Willebrand disease. Haematologica 2013; 98(5):667–74.
5.
U. S. Department of Health and Human Services. Health Measures. Available at
http://www.healthmeasures.net/explore-measurement-systems/promis.
6 
Ader DN. Developing the Patient-Reported Outcomes Measurement Information System 
(PROMIS). Medical Care 2007; 45(Suppl 1): S1-S2. 
7 
Hays RD, Spritzer KL, Schalet BD, Cella D. PROMIS®-29 v2.0 profile physical and men-
tal health summary scores. Quality of Life Research. An International Journal of Quality 
of Life Aspects of Treatment, Care and Rehabilitation 2018; 27(7): 1885–91. 
8.
Maruish M. User’s manual for the SF-36v2 Health Survey (3rd edition). Optum Incorpo-
rated; 2011.
9.
Saris-Baglama, R,DeRosa, M, Raczek, A, Bjorner, J,Turner-Bowker, D, Ware, J. The SF-
10™ Health Survey for Children: A User’s Guide. QualityMetric Incorporated; 2007.
10 Feldman BM, Funk SM, Bergstrom B-M et al. Validation of a new pediatric joint scoring 
system from the International Hemophilia Prophylaxis Study Group: validity of the hemo-
philia joint health score. Arthritis Care & Research 2011; 63(2): 223–30. 
11 van Galen KPM, Timmer MA, Kleijn P de et al. Joint assessment in von Willebrand dis-
ease. Validation of the Haemophilia Joint Health score and Haemophilia Activities List. 
Thrombosis and Haemostasis 2017; 117(8): 1465–70. 
12 Janssen CA, Scholten PC, Heintz AP. A simple visual assessment technique to discriminate 
between menorrhagia and normal menstrual blood loss. Obstetrics and Gynecology 1995; 
85(6): 977–82. 
13. Higham JM, O'Brien PM, Shaw RW. Assessment of menstrual blood loss using a pictorial
chart. British Journal of Obstetrics and Gynaecology 1990; 97(8): 734–9.


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Study Protocol 
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15 APPENDICES 
Not applicable. 

SAP_001.pdf: 
Property of Octapharma. Do not copy or distribute without written permission.
FRM/BS/001.03 
Version 4.0, Effective Aug-2019 
Statistical Analysis Plan Version 6.0 
Page 1 of 24 
Sponsor 
Octapharma 
Protocol No 
WIL-31 
Statistical Analysis Plan (SAP) 
Sponsor: 
Octapharma 
Study Title: 
Clinical Study to Investigate the Efficacy and Safety of Wilate dur-
ing Prophylaxis in Previously Treated Patients with VWD 
Protocol 
Version/Date: 
Ver. 07, 2021-03-01; Ver. 08, 2021-03-01 (Ukraine only) 
SAP 
Version/Date: 
Ver. 6.0, 2022-09-23 
Supersedes SAP Ver-
sion: 
Ver. 5.0, 2022-05-18 
Appendices 
(external documents): 
1.
List of Tables, Listing, Figures (TLFs)
Approval 
The Trial Statistician hereby confirms that the SAP was prepared in conformance with the pro-
cedures and principles set forth in the indicated protocol version and all established relevant
guidelines. 
Name 
Affiliation, Function 
Signature:
Date: 
Ergomed, Trial Statistician
By signing hereafter, I confirm that this Statistical Analysis Plan adequately describes the sta-
tistical analyses to be performed in the context of this study.
Name
Affiliation, Function 
Signature: 
Date: 
 Octapharma 
Octapharma 
This document contains confidential and proprietary information of Octapharma. 
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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FRM/BS/001.03 
Version 4.0, Effective Aug-2019 
 
Statistical Analysis Plan Version 6.0 
 
Page 2 of 24 
Sponsor 
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Protocol No 
WIL-31 
 
Revision history 
 
SAP Version 
Version 
date 
Reason(s) for change 
1.0 
2018-12-18 
Initial version 
1.1 
2019-02-08 
Trial Flow Charts were adapted. 
2.0 
2019-06-21 
- adding age and race subgroup analyses 
- adding non-parametric test for primary endpoint TABR 
- adapting to new IVR visit schedule 
- addressing handling of menstrual bleeds 
- adding comparisons with historical data obtained dur-
ing on-demand treatment periods 
3.0 
2020-03-26 
- changing to new SAP template, 
- addressing changes in protocol versions 05 and 06 re-
spectively protocol amendment #3 and #1-UKA 
4.0 
2022-05-10 
- Modifications and addition of definitions/formulas for 
derived variables in section 6.1.  
- Definition for modified FAS and PK PP set added.  
- For comparison of annualized bleeding rates, instead of 
a paired t-test for the log-transformed data a negative 
binomial counting regression model (GLIM) will be 
used (section 2.2) 
- Usage of on-demand run-in trial data defined in detail 
and adapted to the fact that all subjects participated in 
previous WIL-29 study (usage of retrospective meas-
urements is not applicable) 
- Further changes after cross-check with protocol and as 
requested by sponsor as well as minor changes in 
wording 
5.0 
2022-05-18 
- Protocol Version/Date on page 1 set to current versions  
07 (2021-03-01) and 08 Ukraine only (2021-03-01) 
6.0 
2022-09-23 
- The primary analysis set for efficacy was changed 
from FAS to mFAS to exclude subjects for whom la-
boratory results did not confirm patient's eligibility re-
garding inclusion criterion 2 from primary efficacy 
analysis 
- Calculation of changes to baseline is not needed for In-
cremental IVR of Wilate over time 
- Calculation of PK parameters is based on concentra-
tions adjusted for residual pre-dose levels 
- Deletion of analysis: frequency distribution of severity 
for breakthrough bleedings with 95% CIs  
 
 


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Protocol No 
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TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS ......................................................................................................................... 4 
1 Study information ........................................................................................................................................ 6 
1.1 Primary objective .......................................................................................................................................... 6 
1.2 Secondary objective ...................................................................................................................................... 6 
1.3 Additional objective ...................................................................................................................................... 6 
1.4 Study design.................................................................................................................................................. 6 
1.5 Planned sample size ...................................................................................................................................... 6 
2 General Information .................................................................................................................................... 7 
2.1 Background details ....................................................................................................................................... 7 
2.2 Deviations from the trial protocol with regard to statistical analyses ........................................................... 7 
2.3 Individual protocol deviations ...................................................................................................................... 7 
3 Analysis Populations .................................................................................................................................... 8 
3.1 Safety Set ...................................................................................................................................................... 8 
3.2 Full Analysis Set ........................................................................................................................................... 8 
3.3 Modified Full Analysis Set ........................................................................................................................... 8 
3.4 Per Protocol Set ............................................................................................................................................ 9 
3.5 Surgery Set.................................................................................................................................................... 9 
3.6 Pharmacokinetic Set ..................................................................................................................................... 9 
3.7 Pharmacokinetic Per-Protocol Set ................................................................................................................ 9 
3.8 Subgroup analyses ........................................................................................................................................ 9 
4 Statistical Analyses ...................................................................................................................................... 10 
4.1 Conventions ................................................................................................................................................ 11 
4.1.1 
Baseline definition ........................................................................................................................... 11 
4.1.2 
Missing data ..................................................................................................................................... 11 
4.1.3 
Pooling of centers ............................................................................................................................. 11 
4.1.4 
Use of measurements from on-demand non-interventional run-in study (WIL-29) ......................... 11 
4.2 Demographic and other background data ................................................................................................... 11 
4.3 IMP exposure, compliance ......................................................................................................................... 12 
4.4 Medical history, physical examination ....................................................................................................... 13 
4.5 Prior and concomitant medication .............................................................................................................. 13 
4.6 Concomitant non-pharmacological measures, pre-medication ................................................................... 13 
4.7 Efficacy ....................................................................................................................................................... 13 
4.7.1 
Primary Endpoint ............................................................................................................................. 14 
4.7.2 
Secondary Endpoints ........................................................................................................................ 14 
4.7.3 
Exploratory Endpoints...................................................................................................................... 15 
4.8 Pharmacokinetics / Pharmacodynamics ...................................................................................................... 17 
4.9 Safety .......................................................................................................................................................... 18 
4.9.1 
Adverse events ................................................................................................................................. 18 
4.9.2 
Vital Signs ........................................................................................................................................ 19 
4.9.3 
Safety Laboratory variables ............................................................................................................. 19 
4.9.4 
Other safety variables ....................................................................................................................... 19 
4.10 Other variables ............................................................................................................................................ 20 
4.11 Interim analyses .......................................................................................................................................... 20 
5 Quality Control ........................................................................................................................................... 20 
6 Derivations and Transformations ............................................................................................................... 21 
6.1 Formulas for derived variables ................................................................................................................... 21 
6.2 Algorithm for the Overall Efficacy Assessment for Surgical Prophylaxis ................................................. 23 
7 References ................................................................................................................................................... 23 
Appendices ..................................................................................................................................................... 24 
1. 
List of Tables, Listings, Figures ................................................................................................................. 24 
 
 


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Protocol No 
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LIST OF ABBREVIATIONS 
 
Abbreviation 
Description 
ABRod 
Annualized bleeding rate under on-demand treatment (WIL-29 run-in 
study) 
ABRpr 
Annualized bleeding rate under prophylactic treatment (study WIL-31) 
ADR 
Adverse drug reaction 
AE 
Adverse Event 
ALAT 
ALanine Amino Transferase 
ASAT 
ASpartate Transaminase 
BE 
Bleeding Episode 
BMI 
Body Mass Index 
BW 
Body Weight 
CHR 
Chromogenic assay 
CI 
Confidence Interval 
CL 
Clearance 
C0 
Last concentration before IMP administration 
Cmax 
Maximum Plasma Concentration 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
DMP 
Data Management Plan 
DRM 
Database Review Meeting 
DVP 
Data Validation Plan 
ED 
Exposure Day 
eCRF 
Electronic Case Report Form 
FAS 
Full Analysis Set 
FVIII 
Coagulation Factor VIII 
FVIII:C 
Factor VIII-coagulant 
HJHS 
Hemophilia Joint Health Score 
HMABR 
Heavy Menstrual Annualized Bleeding Rate 
ID 
Identifier 
IMP 
Investigational Medicinal Product 
ITT 
Intention-To-Treat 
IU 
International Unit 
IV 
Intravenous 
IVR 
Incremental in Vivo Recovery 
LOCF 
Last Observation Carried Forward 
mFAS 
modified Full Analysis Set 
PK-PP 
Pharmacokinetic Per-Protocol set 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRT 
Mean Residence Time 
N 
Number of Subjects/Observations 
OS 
One-stage assay 
POP 
Postoperative 
PBAC 
Pictorial Blood Assessment Chart 
PK 
Pharmacokinetic, Pharmacokinetic set 
PP 
Per-Protocol 
PT 
Preferred Term 


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Protocol No 
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Abbreviation 
Description 
PROMIS-29 
Patient-Reported Outcomes Measurement Information System 
PT 
Preferred Term 
QC 
Quality Control 
RBC 
Red Blood Cell count 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software package 
SD 
Standard Deviation 
SP 
Statistical Programmer 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SABR 
Spontaneous Annualized Bleeding Rate 
SURG 
Surgery analysis set 
TABR 
Total Annualized Bleeding Rate 
TRABR 
Traumatic Annualized Bleeding Rate 
TEAE 
Treatment Emergent Adverse Event 
TLFs 
Tables, Listings, Figures 
TS 
Trial Statistician 
VWD 
Von Willebrand Disease 
VWF 
Von Willebrand Factor 
VWF:Ac 
VWF activity  
VWF:GP1bM Assay based on the spontaneous binding of VWF to a gain-of-function mu-
tant GP1b fragment 
VWF:RCo 
Ristocetin cofactor activity; assay that uses platelets and ristocetin 
WBC 
White Blood Cell count 
WHO 
World Health Organization 
 
 
 


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1 STUDY INFORMATION 
1.1 Primary objective 
The primary objective of this study is to determine the efficacy of Wilate in the prophy-
lactic treatment of previously treated patients with type 3, type 2 except N, and severe type 
1 VWD. 
 
1.2 Secondary objective 
The secondary objectives of this study are: 
• Assess the incremental IVR of VWF:Ac and FVIII:C over time (at baseline, and at 1, 
2, 3, 6, 9 and 12 months of treatment)  
• Determine the pharmacokinetics (PK) of Wilate for VWF:Ac and FVIII:C in paediat-
ric patients aged 6–16 years 
• Assess the safety and tolerability of Wilate during prophylaxis 
• Determine Wilate consumption data 
 
1.3 Additional objective 
Additional objectives of this study are to: 
• Determine the efficacy of Wilate in the treatment of breakthrough bleeding episodes 
(BEs) 
• Determine the efficacy of Wilate in surgical prophylaxis 
• Assess patients’ Quality of Life (QoL) during prophylaxis with Wilate 
• Assess patients’ joint status using the Hemophilia Joint Health Score (HJHS) 
• Assess the menstrual bleeding intensity of female patients of child-bearing potential 
(based on PBAC score) 
 
1.4 Study design 
This study is designed as a prospective, non-controlled, international, multi-center phase 
3 study.  
It is intended to compare the prospectively obtained assessments under a prophylactic 
treatment regimen with similar assessment under an on-demand treatment regimen. To 
achieve this, retrospective data from the patient’s medical records or patient data obtained 
in a similar (prospective) study with an on-demand treatment regimen will be used for the 
analysis. 
Further details are given in the overview on next page. 
 
1.5 Planned sample size 
Overall, 28 patients will be enrolled in this study, including at least 5 patients with VWD 
type 3, at least 5 patients aged 6–11 years, and at least 5 patients aged 12–16. 
Assuming a mean total annualized bleeding rate (TABR) ratio (TABRpr / TABRod) of 0.25 
with a correlation of 0.5 between the two treatment regimes, a coefficient of variation of 
10 in on-demand treatment, and a coefficient of variation of 10 in prophylactic treatment, 
25 patients will be needed to reject the null hypothesis  


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H0: mean(TABRpr / TABRod) ≥ 0.5 
in favor of  
H1: mean(TABRpr / TABRod) < 0.5 
with a type one error of 0.025  and power of 80% using a paired t-test for log-transformed 
data. 
TABRpr is defined as the total annual bleeding rate in the prophylactic treatment and 
TABRod is defined as the total annual bleeding rate in the matching on-demand treatment 
period. 
 
 
2 GENERAL INFORMATION 
2.1 Background details 
All study data will be transferred to a SAS database (version 9.4 or later) for statistical 
analysis purposes. Data will be imported from the Data Capture System OPVerdi via val-
idated SAS programs. If applicable external data will also be transferred to SAS for 
presentation of these data in the statistical analyses. 
The SAP will be finalized before database review meeting after agreement with the Spon-
sor. 
 
2.2 Deviations from the trial protocol with regard to statistical analyses 
Due to the reporting of non-confirmed eligibility, the primary and secondary efficacy anal-
yses will also be performed for the mFAS (see section 3.3). 
Contrary to initial assumptions, patients may have documented 0 bleeding episodes during 
the prophylactic treatment phase. This would contradict the assumption of a log-normally 
distributed TABR and make the calculation of logarithms of the TABRs impossible. 
Hence, instead of the originally planned paired t-test for the log-transformed data, now the 
use of a negative binomial counting regression model (GLIM) with treatment regimen as 
main effect and treatment period as offset parameter is implemented for the analysis of the 
primary efficacy parameter.  
Such counting regression models will also be used for the analysis of similarly defined 
secondary and exploratory endpoints (e.g. SABR). 
 
2.3 Individual protocol deviations 
Any deviation from protocol will be discussed case by case before database lock whether 
the deviation has to be regarded as minor or as major, and whether an observed deviation 
will lead to exclusion from particular analysis populations. 
Examples for minor protocol violations may be deviations from scheduled investigation 
time. 
Criteria for important protocol violations will at least include: 
• Any substantial violation of in- or exclusion criteria. 
• Use of concomitant medication that may interfere with the assessment of efficacy. 


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• Substantial deviations in frequency, duration and/or dosing of the prophylactic 
treatment regimen. 
The final decision about the classification of individual protocol deviations and their con-
sequences regarding assignment of subjects to analysis sets will be made during the data 
review meeting (DRM). A complete listing of protocol deviations and the judgment for 
assessment of subject disposition will be approved by the Sponsor and signed before da-
tabase lock. All deviations as well as the disposition of each subject will be recorded in 
separate database members that will become part of the study database. A description of 
all important protocol violations will be included in the table part of the CSR. 
 
 
3 ANALYSIS POPULATIONS 
The disposition of patients will be displayed according to the following analysis popula-
tions: 
• Safety (SAF) set 
• Full Analysis set (FAS) 
• Modified Full Analysis set (mFAS) 
• Per-Protocol (PP) set 
• Surgery (SURG) set 
• Pharmacokinetic (PK) set 
• Pharmacokinetic Per-Protocol (PK PP) set 
Membership of subjects will be decided upon in a DRM with the Sponsor before database 
lock. The proper flags for analysis sets exclusion (e.g., exclusion from PP set), will be 
included in the analysis datasets.  
 
3.1 Safety Set 
The safety (SAF) set will include all subjects who received at least one dose of IMP. 
 
3.2 Full Analysis Set 
The full analysis set (FAS) defined according to the intention-to-treat (ITT) principle will 
include all enrolled subjects who received at least one dose of IMP after the Baseline IVR 
Visit in adults or the Baseline PK Visit in children. 
 
3.3 Modified Full Analysis Set 
The modified full analysis set (mFAS) will be a subset of the FAS excluding all subjects 
for whom laboratory results did not confirm patient's eligibility, i.e. severe VWD type 1, 
2A, 2B, 2M or 3 not confirmed. 
 


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3.4 Per Protocol Set 
The per-protocol (PP) set, i.e. a subset of the FAS, will exclude subjects with major pro-
tocol deviations which may have an impact on the evaluation of the primary study outcome 
parameter (major protocol deviations as defined during DRM). 
 
3.5 Surgery Set 
The surgery (SURG) set will be a subset of the FAS, containing all subjects who under-
went a surgical procedure treated with IMP prior to start of surgery during their Prophy-
lactic Treatment Phase. 
 
3.6 Pharmacokinetic Set 
The pharmacokinetic (PK) set will be a subset of the FAS containing all subjects with a 
pharmacokinetic assessment. 
 
3.7 Pharmacokinetic Per-Protocol Set 
The pharmacokinetic Per-Protocol (PK PP) set will be a subset of the PK, excluding all 
subjects for whom laboratory results did not confirm patient's eligibility, i.e. severe VWD 
type 1, 2A, 2B, 2M or 3 not confirmed and excluding patients with an inhibitor to von 
Willebrand factor or factor FVIII at PK visit. Invalid samples/PK profiles (e.g. hemolyzed 
samples) will be excluded from PK-analysis as defined during DRM. 
 
3.8 Subgroup analyses 
The analyses of the efficacy endpoints ‘efficacy of prophylactic treatment’ and ‘efficacy 
in treatment of breakthrough BEs’ will be presented in the following subgroups: 
• Age groups (‘6 to 11, 12 to 16 and >16 years’). 
• VWD type (‘severe type 1’, ‘type 2’ and ‘type 3’) 
• Sex (‘Female’, ‘Male’) 
• Race, according to CDISC Controlled Terminology (dependent on the number of 
subjects per race) 
 
 
The safety analysis will be presented by the following subgroup:  
• Age groups (‘6 to 11, 12 to 16 and >16 years’). 
 
 
 
 


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4 STATISTICAL ANALYSES 
All statistical analyses will be performed using the SAS® software (Version 9.4 or later). 
Pharmacokinetic parameters will be calculated using the WinNonlin software for Win-
dows, version 7.0 or later using a non-compartment model (for definitions see section 8.1 
of this SAP): 
Descriptive statistics will always be given for the entire population. 
The analysis of safety will be based on the SAF set.  
Analysis of the primary endpoint will be performed on the FAS, mFAS and PP set, where 
the primary analysis set will be the mFAS. 
For secondary and other endpoints (except endpoints regarding surgeries), FAS, mFAS and 
PP analyses will be carried out, unless the latter analysis sets differ by no more than 5% of 
patients in the mFAS. 
Analysis of the efficacy and safety of Wilate in surgeries will be based on the SURG set. 
If not stated otherwise the following standard descriptive statistics will be presented:  
Descriptive statistics for continuous data 
Number of subjects (N), arithmetic mean, standard deviation (SD), minimum, lower quar-
tile, median, upper quartile and maximum will be presented. These descriptive statistics 
will be determined for measured values and for differences to baseline. 
Descriptive statistics for categorical data 
Absolute frequencies (N) will be presented with 0, relative frequencies (%) with at least 1 
decimal. For changes from baseline, shift tables may be generated.  
Inferential statistics 
If not stated otherwise all statistical tests will be performed as described in the correspond-
ing sections below.  
All p-values will be rounded to 4 decimals (p<0.0001 will be displayed if the p-values are 
less than 0.0001). Unless otherwise specified, statistical significance will be declared if 
the rounded p-value will be less than 0.05.  
All confidence intervals (CI) will be derived two-sided and at a confidence probability of 
1-α = 0.95.  
Listings 
All subject data will be listed by subject. Identification variable will be the subject ID 
(composed of study, center and subject number separated by a hyphen, e.g. ’31-01-01’. 
Any derived data listed will also be stored permanently and will be calculated as outlined 
in section 6.1 of this SAP.  
 
 
 


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4.1 Conventions 
4.1.1 Baseline definition 
Assessments at screening visit or the first IVR measurement (at PK or IVR visit, respec-
tively) whatever is closest to start of prophylaxis are considered as baseline.  
 
4.1.2 Missing data 
In case of missing body weight documentation, data will be imputed using the Last Ob-
servation Carried Forward (LOCF) approach to calculate the dose per kg body weight 
(IU/kg).  
In case of missing date/time documentations for IVR and PK samplings the corresponding 
scheduled time point will be used for analysis. 
No further imputations for missing data will be performed. 
Calculations pertaining to the derivation of annual bleeding rates will be based on docu-
mented time periods only. 
 
4.1.3 Pooling of centers 
All tables will be presented in total over all participating countries and centers. The distri-
bution of number of subjects per country and center will be presented in the disposition 
section of the report. 
 
4.1.4 Use of measurements from on-demand non-interventional run-in study (WIL-29) 
Apart from analyzing the efficacy of Wilate in the prophylactic treatment of VWD based 
on annualized bleeding rates, it is also of interest to compare data with annualized bleeding 
rated of the same patients under an on-demand treatment schedule. To achieve this, data 
from those patients that also participated in a previous on-demand run-in study (WIL-29) 
will be used in the analysis data for the current study. This includes duration of On-demand 
phase, number of bleeding episodes and annualized bleeding rates for total, spontaneous, 
traumatic, and heavy menstrual bleeds.  
For females with childbearing potential, it is of interest to compare their differences in 
median PBAC scores under prophylaxis with scores under on-demand treatment. For this 
purpose, all total PBAC scores collected during study WIL-29 will be stored in the WIL-
31 database and the Wilcoxon matched pair sign-rank test will be used for statistical com-
parison. 
The statistical methods for such exploratory comparisons of on-demand to prophylactic 
treatment schedule will be based on paired, or repeated-measurement data.  
 
4.2 Demographic and other background data 
The disposition of subjects (cf. Section 3) will be tabulated for the entire population. De-
tails on protocol deviations will be listed. 
Discontinued subjects will be described by frequency distributions including the reasons 
and in individual listings. 


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Demographic data (age, weight, height, BMI, race, ethnic group) will be summarized in 
tables and presented for the SAF, FAS and mFAS population. Other baseline or back-
ground data, e.g. disease-specific information, will comprise descriptive tables for the SAF 
and FAS population for the following variables: 
• ABO blood group 
• VWF:Ac and FVIII levels at screening, VWF multimer pattern for VWD type 2A, 
and genotype for VWD type 2B 
• Vital Signs (Systolic and diastolic blood pressure, pulse, respiratory rate, and body 
temperature) at screening 
• Physical examination (normal/abnormal) at screening 
• Results of Parvovirus B19 antibodies at baseline IVR visit 
• Urine pregnancy test (in female patients of child-bearing potential) 
• Historical annual bleeding rates (ABR)  
• Hemophilia Joint Health Score (HJHS) at baseline 
• Target joint(s) at baseline 
Historical PBAC scores (total scores documented under on-demand treatment from run-
in study WIL-29)  
 
4.3 IMP exposure, compliance 
Prophylactic treatment will be administered 2 – 3 times per week at a dose of 20 – 40 
IU/kg BW for 12 months.  
In case of unacceptably frequent spontaneous breakthrough BEs (i.e., more than 2 sponta-
neous BEs or 1 major spontaneous BE within a 30-day period), the dose of Wilate should 
be increased by approximately 5 IU/kg (depending on the entire content of the additional 
vial(s) that need(s) to be reconstituted).  
Overall summaries will be provided for  
• Number of Injections 
• Number of Exposure Days 
• Total Dose (IU) 
• Dose (IU/kg.) 
• Reason for Administration 
 
For the FAS  and the mFAS population the following parameters will be summarized by 
frequency tables of descriptive statistics: 
• Number of subjects treated prophylactically among all enrolled subjects 
• Treatment regimen, dosage, changes, or interruptions in prophylactic treatments 
• Number of injections  
• Overall period of exposure (from first- to last dose of IMP)  
• Number of exposure days 


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• Amount (IU) of Wilate used (per month, per year, exposure day and injection, and 
in total) 
• Normalized dose (IU/kg) of Wilate used (per month, per year, exposure day and 
injection, and in total) 
• Frequency and relative magnitude of dose changes: increased and decreased doses 
of Wilate used to treat individual BEs 
• Frequency and relative magnitude of dose changes: in the doses per injection and changes 
in the total dose used to treat subsequent BEs of the same site (e.g. elbow, knee, etc.) in the 
same patient 
All IMP treatment details will be listed for the FAS population. 
Furthermore, the Wilate batches and their actual potencies will be included in the listing of 
individual doses. 
 
4.4 Medical history, physical examination 
Data on medical history will only be listed. Medical history will be coded according to the 
Medical Dictionary for Regulatory Activities (MedDRA). Codes will be reviewed by a 
Medical Expert and approved by the sponsor before data base lock.  
 
4.5 Prior and concomitant medication 
Any relevant medication taken at time of screening and all new medications taken by the 
subject during the study period are defined as ‘Concomitant’. Any changes of medications 
during the study period will also be recorded. 
All details of concomitant medications will be listed including, the route, dose, frequency, 
start and stop date and indication. 
Concomitant medications will be coded using the WHO Drug Global thesaurus in the ver-
sion current at the time of study start. Coding will be performed by the CRO and agreed 
upon with the sponsor before data base lock. (cf. DMP). For concomitant medications ta-
bles will show the frequencies of subjects by WHO Drug Global preferred term. 
 
4.6 Concomitant non-pharmacological measures, pre-medication 
Not applicable. 
 
4.7 Efficacy 
The analysis of the efficacy of prophylactic treatment with Wilate will be based on the 
FAS, mFAS and additionally on the PP set if the latter populations differ by >5% of the 
mFAS. 
The efficacy of Wilate in prophylactic treatment will be presented based on the total an-
nualized bleeding rate (TABR) – see section 4.7.1. 
Primarily, all obtained data on treatment characteristics (IMP dosages, frequencies, total 
consumption) and BEs (duration, frequency, efficacy assessment) will be described by 
providing summary statistics. 


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4.7.1 Primary Endpoint 
Primary objective of this study is to demonstrate that the total annualized bleeding rate 
(TABR) during prophylactic treatment lowers the patients’ TABR during on-demand 
treatment by more than 50%. 
TABR will be calculated as the total number of spontaneous, traumatic and other bleeds 
(excluding menstrual bleeds) in the time period between first prophylactic dose of IMP 
and the day of the last dose of IMP (+ 2 days wash-out), divided by the duration (in years) 
between first dose of prophylactic IMP  and the day of last dose of IMP (+ 2 days wash-
out). Surgery periods, and BEs occurring within these periods, will be excluded from the 
calculation of TABR. Menstrual bleeds of any severity will not be included in this calcu-
lation. In female patients with child-bearing potential heavy menstrual bleeds will be re-
ported and analyzed separately. 
For this efficacy assessment the individual annualized bleeding rates under prophylactic 
treatment in this study will be compared to the annualized bleeding rates recorded for the 
same patient during a previous, non-interventional study, (WIL-29). 
To test whether the mean TABR during prophylactic treatment (TABRpr) is less than half 
the historical mean TABR during on-demand treatment (TABRod), the following pair of 
hypotheses will be tested in the context of negative binomial counting regression model: 
(*) H0: mean(TABRpr / TABRod) ≥ 0.5       vs       H1: mean(TABRpr / TABRod) < 0.5 
at a one-sided alpha level of 2.5%. A corresponding two-sided 95% CI for the different 
TABRs and their ratio will also be provided.  
 
4.7.2 Secondary Endpoints 
Secondary endpoints are: 
• Spontaneous annualized bleeding rate (SABR), calculated in analogy with TABR 
• Incremental IVR of Wilate for VWF:Ac (VWF:Rco and VWF:GP1bM) and 
FVIII:C (OS and CHR) over time (at baseline and at 1, 2, 3, 6, 9, and 12 months 
of treatment) 
• For paediatric patients, baseline PK profile characteristics of VWF:Ac (VWF:Rco) 
and FVIII:C (OS and CHR) based on blood samples taken pre-dose and 1, 3, 9, 24, 
48, and 72 hours after dosing 
• Wilate consumption data (VWF/FVIII IU/kg per month per patient) for prophy-
laxis 
The statistical analysis of the secondary endpoints will be descriptive, including explora-
tory 95% confidence intervals. 
For the secondary endpoint SABR descriptive statistics will be tabulated. Comparisons 
with on-demand treatment similar to TABR analysis will be performed. 
 
Regarding the IMP administration data, the following parameters will be listed: 
• Dates and times of IMP injections 
• Doses of IMP in IU and IU/kg and IMP batch numbers 
• Reason for IMP injection (prophylaxis, treatment of BE, surgery) 


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Descriptive statistics will be determined for time in study, exposure days, number of infu-
sions and dosages of IMP overall and by reason for IMP injection. 
Descriptive statistics including changes to pre-infusion will be tabulated for VWF:Ac 
(VWF:Rco and VWF:GP1bM) at  baseline IVR visit, at 1, 2, 3, 6, 9 months IVR visit and 
at study completion visit. 
 
4.7.3 Exploratory Endpoints 
Exploratory endpoints are: 
• Efficacy of Wilate in the treatment of breakthrough BEs based on the proportion 
of BEs successfully treated with Wilate 
• Efficacy of Wilate in surgical prophylaxis based on the proportion of surgeries 
successfully treated with Wilate 
• QoL based on the scores of PROMIS-29 for all patients, SF-36v2 for patients aged 
≥16 years, and SF-10 for patients aged 6–15 years 
• Hemophilia Joint Health Score (HJHS) 
• Pictorial Blood Loss Assessment Chart (PBAC) score for menstrual bleeds  
• Traumatic annualized bleeding rate (TRABR), calculated in analogy with TABR 
• Heavy Menstrual Annualized Bleeding Rate (HMABR) for females with child-
bearing potential, calculated in analogy with TABR 
 
Annualized bleeding rates 
Comparisons with bleeding rates (TRABR, HMABR) under on-demand treatment will 
follow the same approach as for TABR. 
 
Sensitivity analyses 
ABR endpoints may be influenced by patient’s medical conditions that by themselves are 
associated with an increased rate of spontaneous bleedings. Hence the robustness of the  
primary results will be investigated by additionally presenting the ABR analysis (descrip-
tive as well as inferential) when subjects with such identified bleedings are excluded. 
To study the sensitivity of results with respect to bleedings that are scheduled to occur 
very frequently but are mainly caused by an underlying medical condition other than VWD 
(gastrointestinal bleeds related to Ulcer and spontaneous oral cavity bleeds related to Gin-
givitis) a separate analysis for TABR and SABR will be performed comparing the ABRs 
under on-demand and prophylaxis excluding subjects suffering from those types of bleed-
ing episodes. 
 
Efficacy in the Treatment of Breakthrough BEs 
For any BE occurring during study, the following data will be recorded: 
• BE type (spontaneous, traumatic, postoperative, other) 
• BE site 
• BE severity (minor, major) 
• Date and time the BE first occurred or was first noticed 


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• Date and time the BE ended 
• IMP administration data 
Descriptive statistics will be provided for the number of bleedings overall and by site. 
Absolute and relative frequencies for the bleeding site, the bleeding type and the bleeding 
severity will be tabulated.  
At the end of each BE treated with Wilate, treatment efficacy will be assessed by the pa-
tient (together with the investigator in case of on-site treatment). The efficacy assessment 
of treatment of BEs includes the categories ‘excellent’, ‘good’, ‘moderate’ and ‘none’. All 
efficacy ratings assessed as either ‘excellent’ or ‘good’ will be considered ‘successfully 
treated.’ 
 
Efficacy in the surgical prophylaxis 
Efficacy in surgical prophylaxis will be analyzed descriptively, presenting summary tables 
and listing on all aspects of surgical treatment and procedures as well as efficacy ratings. 
The following surgery-related parameters will be presented: 
• Location, severity (minor or major, for definitions see protocol), and type (planned 
or emergency) of surgery 
• Expected and actual duration of surgical procedure 
• Expected average/maximum and actual blood loss 
• Pre-, intra-, and/or postoperative IMP administration data (only listed) 
• Pre-, intra-, and postoperative FVIII:C and VWF:Ac plasma levels (dependent on 
the availability of data) 
• Routine safety laboratory 
• Details on concomitantly administered products, except standard anesthetic prod-
ucts (only listed) 
• Blood transfusion requirements (only listed) 
• 
Brief narrative describing the outcome of the intervention (only listed) 
• Assessment of efficacy of surgical prophylaxis: 
1. at the end of surgery by the surgeon 
2. at end of the postoperative period by the hematologist 
3. overall efficacy assessment taking both the intra- and postoperative assess-
ments into account, assessed by the Investigator. 
• Number of successfully treated surgeries (‘excellent’ or ‘good’ overall efficacy 
rating) 
 
Procedures that meet the following criteria are considered as ‘major’ surgeries. All other 
procedures are considered ‘minor’ 
• 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, shoul-
der) 
• 3rd molar extraction or extraction of ≥3 teeth 
• Surgeries/conditions in which the patient’s life is at stake 
Time periods relative to surgical procedures are defined as: 


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• Preoperative is defined as the time period of up to 3 hours before the start of sur-
gery. 
• 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 Wilate treatment regimen. 
 
QoL questionnaires 
The results for the QoL scales (PROMIS-29, SF-36; SF-10 for patients <16 years of age) 
and different categories will be scored according to the analysis manual. Summary tables 
will be provided for baseline, 6-months and 12-months visit including changes to baseline. 
 
HJHS questionnaires 
The results for the HJH-scores over time will be summarized in descriptive tables for each 
visit including changes to baseline. 
 
PBAC score (only female patients) 
For female patients, the results of the PBAC score over time will be summarized in de-
scriptive tables for each complete menstrual cycle. Additionally, the differences in intra-
individual median PBAC scores under prophylaxis will be compared with scores under on-
demand treatment (see also section 4.1.4). 
 
Annualized rate of heavy (i.e. major) menstrual bleeds  
For the exploratory endpoint Annualized rate of heavy menstrual bleeds descriptive sta-
tistics will be tabulated. The annualized rate of heavy menstrual bleeds will be calculated 
in analogy with TABR. 
If possible, the annualized rates of heavy menstrual bleeds under prophylactic treatment 
in this study will be compared to the annualized rates of heavy menstrual bleeds recorded 
for the same patient during the previous, non-interventional run-in study.  
 
4.8 Pharmacokinetics / Pharmacodynamics 
For IVR assessments VWF:Ac (VWF:Rco and VWF:GP1bM) and FVIII:C (measured by 
both, the chromogenic (CHR) and one-stage assay (OS)) will be analyzed based on actual 
IMP potency. 
Incremental IVR of Wilate over time (at baseline, 1, 2, 3, 6, 9 and at 12 months of treatment) 
will be analyzed in summary tables for each time point . For IVR analysis at baseline the 
IVRs derived from the paediatric PK profiles will also be included. 
For children aged 6 to < 16 concentration versus time profiles will be obtained for VWF:Ac 
(VWF:Rco and VWF:GP1bM) and FVIII:C (OS and CHR) assays. 
Calculation of PK parameters will be based on actual IMP potencies, on concentrations 
adjusted for residual pre-dose levels and actual time after end of infusion. 
The following PK parameters will be derived from the adjusted concentration profiles.  
 : 


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• Area under the curve (AUC) and AUC normalized for the administered dose 
(AUCnorm) 
• In vivo half-life (T½) 
• 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) 
The PK profiles and the PK parameters derived from them will be summarized by descrip-
tive statistics (including geometric means and standard deviations, except for Tmax) as well 
as the presentation of concentration vs. time plots. All derived PK parameters will be pre-
sented in by-patient displays. 
PK profiles will additionally be presented graphically on original as well as semi-logarith-
mic scales as concentration-time curves, individually in spaghetti plots, and overall, show-
ing the sample characteristic by time-point. 
As PK data are only collected for children, the mentioned PK results will be presented in 
total and separately by age groups (‘6 to <11’ and ’12 to <16’ years) as well as by VWD 
type. 
 
4.9 Safety 
All safety analyses will be based on the SAF population. 
The safety and tolerability of Wilate will be assessed by monitoring adverse events (AEs) 
throughout the study. The analysis of safety will include the occurrence of AEs, the results 
of the safety laboratory tests, immunogenicity measurements and the occurrence of par-
vovirus B19 seroconversions. 
 
4.9.1 Adverse events 
Adverse events (AEs) will be coded by the Data Management of the CRO according to 
the Medical Dictionary for Regulatory Activities (MedDRA). Coding will be agreed upon 
with the Sponsor before database lock (cf. DMP). 
All adverse events occurring during study will be listed in appendix 16.2 of the report.  
The analysis will include only treatment-emergent adverse events (TEAEs), i.e. all docu-
mented AEs that started or worsened after the start of the first IMP infusion. It is assumed 
that for each increase in intensity of an AE a new entry of the AE will be done by the 
investigator; hence such cases will be analyzed like different phases of the same AE.  
A descriptive analysis will be performed. Incidences will be presented by SOC and inci-
dences of PT within primary SOC sorted according to the Internationally Agreed Order. 
Multiple counts within a PT or SOC (repeated or different included terms or changes in 
descriptors) will be counted only once for the calculation of incidences. 


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Global incidences will be calculated for: 
• All TEAE irrespective of the causality assessment 
• Related TEAEs (‘Probably’ or ‘Possible’), i.e. Adverse Drug reactions (ADRs) 
• TEAEs by worst severity 
• Serious TEAEs 
A listing of “special cases” containing subject identification, age, sex, AE descriptors, start 
and end of treatment will be prepared for the following types of TEAEs: 
• Serious adverse events (SAE) 
• Adverse events which led to death 
• Adverse events which led to discontinuation 
Serious non-treatment emergent AEs will be listed separately. 
 
4.9.2 Vital Signs 
Vital signs parameters (systolic/diastolic blood pressure, pulse, body weight, respiratory 
rates, body temperature) will be assessed at screening, IVR baseline,  after 1, 2, 3, 6 and 9 
months IVR visit, and at study completion visit. Body weight will also be documented 
within 12 hours before start of surgery. 
Descriptive analyses of values will be performed and changes from baseline (before IMP 
administration) will be analyzed for vital signs parameters at visits. 
 
4.9.3 Safety Laboratory variables 
The analysis of the safety lab values for  
Hematology:  
 
RBCs, WBCs, haemoglobin, haematocrit, and platelet count 
Clinical chemistry: 
Total bilirubin, ALT, AST, blood urea nitrogen, serum create
 
 
 
 
nine 
recorded during visits (screening and study completion visit), urine pregnancy test results 
recorded during visits (screening, 3, 6 and 12 months) and at surgery will be purely de-
scriptive and presented as summary tables or listings. 
Time profiles of the safety laboratory parameters will be analyzed by presenting sampling 
statistics for the values as well as their difference to baseline (before IMP administration) 
at each time point. Additionally, frequency tables for values outside the normal ranges will 
be presented. 
Similarly, time profiles of VWF- and FVIII-inhibitor testing results will be analyzed by 
presenting sampling statistics for the values as well as frequency tables for positive find-
ings, along with 95% Pearson-Clopper CIs. 
To assess the viral safety of Wilate incidences of parvovirus B19 seroconversions between 
IVR baseline and end of study will be estimated along with 95% Pearson-Clopper CIs. 
 
4.9.4 Other safety variables 
Other safety parameters (e.g., changes in physical examination findings) will be analyzed 
by summary tables or listings. All abnormal findings from the physical examination will 
be listed. 


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The analysis of the safety parameters recorded during surgery (lab values) will be purely 
descriptive and presented as summary tables or listings. 
 
4.10 Other variables 
Not applicable. 
 
4.11 Interim analyses 
Not applicable.  
 
 
5 QUALITY CONTROL 
The SAP was reviewed by the trial statistician (TS) before signature. Particularly the TS 
has checked the consistency of the described methods and outputs with the actual version 
of the study protocol. In addition, a sponsor representative has reviewed the SAP before 
final approval. 
Log files of all SAS® programs used in the analysis will be checked for errors, warnings 
and suspicious notes by the statistical programmer. All findings will be either eliminated 
or commented upon. The final version of each program will be stored along with its log 
file in the electronic archive.  
All programs will be validated by the program author or an independent statistical pro-
grammer depending on the requested validation level selected in the List of TLFs.  
The agreement of the program outputs with the SAP, their consistency and plausibility 
will be checked by the TS. Moreover, the TS will review the outputs regarding complete-
ness, readability and comprehensibility. 
The described process is associated with the 'normal' level of program validation. Addi-
tional levels of quality control can be specified in the List of TLFs (see Appendix, 1) for 
individual outputs. 
 
 


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6 DERIVATIONS AND TRANSFORMATIONS 
6.1 Formulas for derived variables 
Variable 
Description 
Durations between 
two dates 
Later date minus earlier date plus 1, expressed in days. (Remark: 
Duration will be 1, if both dates are the same.) 
On-Demand period 
(days) 
(Date of study completion – date of screening + 1) - Surgery pe-
riod. 
Applicable for historical data from WIL-29 
Surgery Periodod 
(days) 
Formula for surgery period under on-demand treatment correspond 
to formula for surgery period under prophylactic treatment but re-
placing “IMP” by “VCP (von Willebrand factor containing prod-
uct)”. Applicable for historical data from WIL-29 
Prophylactic treat-
ment phase (days) 
( (last date of IMP + 2 OR completion date, whatever occurred ear-
lier) – first date of prophylactic IMP +1) – Surgery period.  
Surgery Period 
(days) 
Individual surgery period: last date of IMP in context of surgery 
(reason = “Prophylaxis after surgery” or “Surgery”) –  date of sur-
gery + 1 or 1 day (i.e. day of surgery) in case surgery not 
treated/no treatment information available. 
Surgery period: Sum of individual surgery periods per subject. 
All BEs at day of surgery with onset after start of surgery and all 
BEs occurring under post-operative prophylaxis (reason = “Prophy-
laxis after surgery”) will be excluded from the calculation of ABRs 
Annualized Bleed-
ing Rates On-De-
mand (ABRod) 
Formulas for ABR under on-demand treatment correspond to for-
mulas for ABR under prophylactic treatment but replacing 
“prophylactic treatment phase” by “on-demand period”. 
Individual annualized bleeding rates under on-demand period will 
be taken from calculated rates in study WIL-29 for all subjects 
along with total number of bleedings   
Total Annualized 
Bleeding Rate 
Prophylaxis 
(TABRpr) 
Number of bleedings under prophylactic treatment phase (except 
menstrual bleedings) / (prophylactic treatment phase /365.25) 
 
Spontaneous Annu-
alized Bleeding Rate 
Prophylaxis 
(SABRpr) 
Number of spontaneous bleedings under prophylactic treatment 
phase /(prophylactic treatment phase/365.25) 
Traumatic Annual-
ized Bleeding Rate 
Prophylaxis 
(TRABR pr) 
Number of traumatic bleedings under prophylactic treatment phase 
/ (prophylactic treatment phase/365.25) 
 
Heavy Menstrual 
Annualized Bleed-
ing Rate Prophy-
laxis (HMABR pr) 
Heavy Menstrual Annualized Bleeding Rate: Number of heavy 
menstrual bleedings under prophylactic treatment phase / (prophy-
lactic treatment phase/365.25) 


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FRM/BS/001.03 
Version 4.0, Effective Aug-2019 
 
Statistical Analysis Plan Version 6.0 
 
Page 22 of 24 
Sponsor 
Octapharma 
Protocol No 
WIL-31 
 
Variable 
Description 
ED 
Exposure day = each calendar day the subject received IMP 
C0  
Last concentration before IMP administration 
Cmax  
Maximum plasma concentration. Maximal measured concentration 
after end of IMP infusion (peak concentration) 
Tmax 
Time to reach Cmax (Timing starts at end of injection) 
T1/2 
In vivo half-life 𝑇𝑇1 2
ൗ=
𝑙𝑙𝑙𝑙(2)
𝐾𝐾 
K = elimination rate constant, determined as the slope of the re-
gression line) using linear regression on the terminal phase of the 
logarithm of the concentration 
AUC 
Area under the curve from baseline to infinity 
𝐴𝐴𝐴𝐴𝐴𝐴= ෍൬(𝐶𝐶𝑛𝑛+ 𝐶𝐶𝑛𝑛+1)
2
⋅𝛥𝛥𝛥𝛥൰+ 𝐶𝐶𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙
𝐾𝐾 
(Clast is the last available measurement) 
AUCnorm 
AUC normalized for the administered dose 
AUMC 
Area under the moment curve (from baseline to infinity) 
𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴= ෍൬(𝑡𝑡𝑛𝑛⋅𝐶𝐶𝑛𝑛+ 𝑡𝑡𝑛𝑛+1𝐶𝐶𝑛𝑛+1)
2
⋅𝛥𝛥𝛥𝛥൰+ 𝐶𝐶𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙
𝐾𝐾2 + 𝑡𝑡𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙⋅𝐶𝐶𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙
𝐾𝐾
 
MRT 
Mean residence time 𝑀𝑀𝑀𝑀𝑀𝑀=
𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴
𝐴𝐴𝐴𝐴𝐴𝐴 
CL 
Clearance 𝐶𝐶𝐶𝐶=
𝐷𝐷
𝐴𝐴𝐴𝐴𝐴𝐴 where D is the actual dose administered 
Vd 
Volume of distribution at steady state: 𝑉𝑉𝑉𝑉= 𝐶𝐶𝐶𝐶⋅𝑀𝑀𝑀𝑀𝑀𝑀 
Incremental in vivo 
recovery (IVR) 
D
BW
C
C
IVR
⋅
−
=
)
(
0
max
 
where BW = body weight in kg and D = dose of IMP  
Hemostatic success 
(in treatment of 
bleeding episodes 
and surgeries) 
Success: efficacy rating is ‘excellent’ or ‘good’ 
Non-Success: efficacy rating ‘moderate’ or ‘none’ or ‘missing’ 
Duplicate test re-
sults 
If more than one blood sample for the same time point and test has 
been taken and two valid results are available/have been captured 
into the database, the mean of the values will be used in analysis 
 
 
 


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FRM/BS/001.03 
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Statistical Analysis Plan Version 6.0 
 
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Sponsor 
Octapharma 
Protocol No 
WIL-31 
 
6.2 Algorithm for the Overall Efficacy Assessment for Surgical Prophylaxis 
The evaluation of overall efficacy of the treatment in surgeries based on the intraoperative 
and postoperative assessment is defined as described below: 
 
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 
 
 
 
7 REFERENCES 
No specific references were used. 
 
 
 
 


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FRM/BS/001.03 
Version 4.0, Effective Aug-2019 
 
Statistical Analysis Plan Version 6.0 
 
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Sponsor 
Octapharma 
Protocol No 
WIL-31 
 
APPENDICES 
1. List of Tables, Listings, Figures 
A complete List of tables, listings, figures (TLFs) will be given in a separate document 
which can be updated without updating the SAP. The List will serve as a reference for 
both the Sponsor, the TS and the SP and describes the entire set of statistical output to be 
produced. Therefore, this List will be versioned and approved by both Ergomed and Spon-
sor before commencing the statistical programming. 
Each output page will have an appropriate heading specifying the study ID and abbreviated 
study title. 
Each output page will show a common date and page numbers in the form 'Page [x / y]' 
where x denotes the current page within an output and y the total number of pages of that 
output. The output pages will not contain any other sequential page numbering. 
All statistical output will identify the underlying analysis set(s) and indicate the number 
of subjects/events in this set (N) and the number of subjects/events actually contributing 
to the particular output (n). 
All subject listings will contain in addition to the subject identification the analysis set.  
TFLs will follow the numbering scheme of the ICH E3 guideline.