A PROSPECTIVE, PHASE 3, OPEN-LABEL, INTERNATIONAL MULTICENTER STUDY ON EFFICACY AND SAFETY OF PROPHYLAXIS WITH rVWF IN SEVERE VON WILLEBRAND DISEASE
Phase: PHASE3
Conditions: Von Willebrand Disease
Sponsor: Takeda

CLINICAL STUDY PROTOCOL 
NCT Number: 
NCT02973087 
Study Title: 
A PROSPECTIVE, PHASE 3, OPEN-LABEL, INTERNATIONAL 
MULTICENTER STUDY ON EFFICACY AND SAFETY OF PROPHYLAXIS 
WITH rVWF IN SEVERE VON WILLEBRAND DISEASE 
Study Number: 
071301 
Protocol Version and Date: 
Original Protocol: 
19 Feb 2014 
Amendment 1: 
08 Apr 2016 
Amendment 2: 
15 Dec 2016 
Amendment 3: 
03 Aug 2017 
Amendment 6: 
12 Mar 2018 

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CLINICAL STUDY PROTOCOL
PRODUCT: Recombinant Von Willebrand Factor (rVWF)
STUDY TITLE: A PROSPECTIVE, PHASE 3, OPEN LABEL, INTERNATIONAL 
MULTICENTER STUDY ON EFFICACY AND SAFETY OF PROPHYLAXIS 
WITH rVWF IN SEVERE VON WILLEBRAND DISEASE
STUDY SHORT TITLE: rVWF IN PROPHYLAXIS
PROTOCOL IDENTIFIER: 071301
CLINICAL TRIAL PHASE 3
ORIGINAL: 2014 FEB 19
OTHER ID(s)
NCT Number: to be determined
EudraCT Number: to be determined
IND NUMBER: to be determined
Study Sponsor(s):
Baxter Healthcare Corporation
One Baxter Way
Westlake Village, CA  91362
Baxter Innovations GmbH
Industriestrasse 67
A-1221 Vienna, AUSTRIA
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1. STUDY PERSONNEL
1.1 Authorized Representative (Signatory) / Responsible Party
, MD
, Global Clinical Development
Baxter Healthcare Corporation
1.2 Study Organization
The name and contact information of the responsible party and individuals involved with 
the study (e.g. investigator(s), sponsor’s medical expert and study monitor, sponsor’s 
representative(s), laboratories, steering committees, and oversight committees [including 
ethics committees (ECs)], as applicable) will be maintained by the sponsor and provided 
to the investigator.
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2. SERIOUS ADVERSE EVENT REPORTING
The investigator will comply with applicable laws/requirements for reporting serious 
adverse events (SAEs) to the ECs. 
ALL SAEs ARE TO BE REPORTED ON THE 
SERIOUS ADVERSE EVENT REPORT (SAER) FORM AND 
TRANSMITTED TO THE SPONSOR 
WITHIN 24 HOURS AFTER BECOMING AWARE OF THE EVENT
See SAER form for contact information. 
Further details are also available in the study team roster.
For definitions and information on the assessment of these events refer to the following:
AE, Section 12.1
SAE, Section 12.1.1.1
Assessment of AEs, Section 12.1.2.
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3. SYNOPSIS 
INVESTIGATIONAL PRODUCT
Name of Investigational Product (IP)
Recombinant von Willebrand factor (rVWF)
Name(s) of Active Ingredient(s)
Recombinant von Willebrand factor (rVWF)
CLINICAL CONDITION(S)/INDICATION(S)
Subjects with severe von Willebrand disease (VWD) requiring prophylactic treatment with coagulation 
factor replacement
PROTOCOL ID
071301
PROTOCOL TITLE
A PROSPECTIVE, PHASE 3, OPEN LABEL, 
INTERNATIONAL MULTICENTER STUDY ON EFFICACY 
AND SAFETY OF PROPHYLAXIS WITH rVWF IN SEVERE 
VON WILLEBRAND DISEASE
Short Title
rVWF IN PROPHYLAXIS
STUDY PHASE
Ph3
PLANNED STUDY PERIOD
Initiation
2014 DEC
Primary Completion
2016 OCT
Study Completion
2016 OCT
Duration
22 months
STUDY OBJECTIVES AND PURPOSE
Study Purpose
The purpose of this phase 3 study is to investigate the efficacy and safety, including immunogenicity and 
thrombogenicity, and 
of prophylactic treatment with rVWF in 
subjects with severe VWD.
Primary Objective
The primary objective of this study is to prospectively evaluate the overall annualized bleeding rate (ABR) 
for spontaneous bleeding episodes while on prophylactic treatment with rVWF and to retrospectively 
evaluate the subjects’ historical ABR for spontaneous bleeding episodes during on-demand treatment. 
Secondary Objective(s)
Secondary Objectives are 

Additional efficacy assessments of prophylactic treatment, 

Safety, 

Pharmacokinetics (PK), 

Efficacy of the treatment of bleeding episodes 
Exploratory Objective(s)
STUDY DESIGN
Study Type/ Classification/ Discipline
Efficacy and Safety 
Control Type
No control
Study Indication Type
Prophylaxis and treatment of bleeding episodes
Intervention model 
Single-group
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INVESTIGATIONAL PRODUCT(S), DOSE AND MODE OF ADMINISTRATION
Active Product
Dosage form: lyophilized powder and solvent for solution for injection
Dosage frequency:
Prophylactic Treatment
The standard prophylactic regimen will consist of BAX 111 (rVWF) infusions 
administered three times weekly at doses of 50±10 IU/kg rVWF:RCo. Dosage may be 
individualized within this range based on:

the PK data

type and severity of bleeding episodes the subject has experienced in the past

monitoring of appropriate clinical and laboratory measures. 
Any further adjustment will have to be agreed with the sponsor in advance.
Treatment of Bleeding Episodes:
Dosage must be individualized based on the subject’s weight, type and severity of 
bleeding episode and monitoring of appropriate clinical and laboratory measures. In 
general, an initial dose of 40-60 IU/kg VWF:RCo with 30-45 IU rFVIII 
[ADVATE]/kg) is recommended (rVWF:rFVIII ratio of 1.3:1: ±0.2). In cases of major 
bleeding episodes, a dose of up to 80 IU/kg VWF:RCo may be infused. Subsequent 
doses, if necessary, will be administered with or without ADVATE to maintain 
VWF:RCo and FVIII levels for as long as deemed necessary by the investigator.
Mode of Administration: intravenous
SUBJECT SELECTION
Targeted Accrual
Approximately 15 evaluable subjects with severe VWD
Number of Groups/Arms/Cohorts
Single-group
Inclusion Criteria
Subjects who meet ALL of the following criteria are eligible for this study:
1.
Subject has a documented diagnosis of severe VWD which : 
a. is confirmed by genetic testing and multimer analysis, documented in patient history or at 
screening
b. requires prophylactic replacement treatment with VWF containing concentrate to control 
bleeding. This includes:
- subjects already on prophylactic treatment 
- subjects currently on-demand treatment for whom prophylactic treatment is recommended 
according to standard of care at the center
c. a minimum of documented 3 spontaneous bleeds requiring VWF treatment within 12 months 
prior to prophylactic treatment. 
2.
Availability of records to reliably evaluate type, frequency and treatment of bleeding episodes 
prior to onset of prophylactic treatment for at least 12 months
3.
Subject is ≥ 18 years old at the time of screening.
4.
If female of childbearing potential, subject presents with a negative blood/urine pregnancy test at 
screening and agrees to employ adequate birth control measures for the duration of the study.
5.
Subject is willing and able to comply with the requirements of the protocol
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Exclusion Criteria
Subjects who meet ANY of the following criteria are not eligible for this study:
1.
The subject has been diagnosed with pseudo VWD or another hereditary or acquired coagulation 
disorder other than VWD (e.g. qualitative and quantitative platelet disorders or elevated
prothrombin time (PT)/ international normalized ratio [INR] 1.4).
2.
The subject has a history or presence of a VWF inhibitor at screening.
3.
The subject has a history or presence of a FVIII inhibitor with a titer ≥ 0.4 BU (by Nijmegen 
modified Bethesda assay) or ≥ 0.6 BU (by Bethesda assay).
4.
The subject has a known hypersensitivity to any of the components of the study drugs, such as to 
mouse or hamster proteins.
5.
The subject has a medical history of immunological disorders, excluding seasonal allergic 
rhinitis/conjunctivitis, mild asthma, food allergies or animal allergies.
6.
The subject has a medical history of a thromboembolic event.
7.
The subject is HIV positive with an absolute Helper T cell (CD4) count 200/mm3.
8.
The subject has been diagnosed with significant liver disease as evidenced by any of the following: 
serum alanine aminotransferase (ALT) 5 times the upper limit of normal; hypoalbuminemia; portal 
vein hypertension (e.g., presence of otherwise unexplained splenomegaly, history of esophageal 
varices).
9.
The subject has been diagnosed with renal disease, with a serum creatinine level ≥ 2.5 mg/dL.
10. The subject has been treated with an immunomodulatory drug, excluding topical treatment (e.g., 
ointments, nasal sprays), within 30 days prior to signing the informed consent.
11. The subject is pregnant or lactating at the time of enrollment.
12. The subject has participated in another clinical study involving another investigational product (IP)
or investigational device within 30 days prior to enrollment or is scheduled to participate in another 
clinical study involving an IP or investigational device during the course of this study.
13. The subject has a progressive fatal disease and/or life expectancy of less than 15 months.
14. The subject is identified by the investigator as being unable or unwilling to cooperate with study 
procedures.
15. The subject suffers from a mental condition rendering him/her unable to understand the nature, 
scope and possible consequences of the study and/or evidence of an uncooperative attitude.
16. The subject is in prison or compulsory detention by regulatory and/or juridical order
17. The subject is member of the study team or in a dependent relationship with one of the study team 
members which includes close relatives (i.e., children, partner/spouse, siblings and parents) as well 
as employees.
Delay criteria
1.
If the subject presents with an acute bleeding episodes or acute illness (e.g., influenza, flu-like 
syndrome, allergic rhinitis/conjunctivitis, non-seasonal asthma) the screening visit will be 
postponed until the subject has recovered.
STATISTICAL ANALYSIS
Sample Size Calculation
The determination of the sample size for this study is not based on strict statistical considerations.
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4. TABLE OF CONTENTS
1. STUDY PERSONNEL.................................................................................................. 2
1.1 Authorized Representative (Signatory) / Responsible Party .............................. 2
1.2 Study Organization................................................................................................. 2
2. SERIOUS ADVERSE EVENT REPORTING........................................................... 3
3. SYNOPSIS..................................................................................................................... 4
4. TABLE OF CONTENTS ............................................................................................. 9
5. LIST OF ABBREVIATIONS .................................................................................... 15
6. BACKGROUND INFORMATION .......................................................................... 18
6.1 Description of Investigational Product ............................................................... 18
6.2 Clinical Condition/Indication .............................................................................. 18
6.3 The role of prophylaxis in the management of VWD........................................ 19
6.4 Population to be Studied ...................................................................................... 21
6.5 Findings from Nonclinical and Clinical Studies................................................. 21
6.5.1 Findings from Nonclinical Studies ............................................................... 21
6.5.1.1 Primary Pharmacodynamics ................................................................. 21
6.5.1.2 Safety Pharmacology.............................................................................. 22
6.5.1.3 Pharmacokinetics.................................................................................... 22
6.5.1.4 Toxicology................................................................................................ 22
6.5.2 Findings from Clinical Studies ..................................................................... 23
6.5.2.1 Study 070701 ........................................................................................... 24
6.5.2.2 Study 071104 ........................................................................................... 25
6.6 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) 
to Human Subjects................................................................................................ 26
6.7 Compliance Statement.......................................................................................... 26
7. STUDY PURPOSE AND OBJECTIVES ................................................................. 27
7.1 Study Purpose ....................................................................................................... 27
7.2 Primary Objective................................................................................................. 27
7.3 Secondary Objectives ........................................................................................... 27
7.4 Exploratory Objectives......................................................................................... 27
7.4.1
........................................................................................................... 27
8. STUDY DESIGN......................................................................................................... 28
8.1 Brief Summary...................................................................................................... 28
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8.2 Overall Study Design............................................................................................ 28
8.3 Duration of Study Period(s) and Subject Participation .................................... 28
8.4 Outcome Measures ............................................................................................... 28
8.4.1 Primary Outcome Measure........................................................................... 28
8.4.2 Secondary Outcome Measures ..................................................................... 29
8.4.2.1 Efficacy .................................................................................................... 29
8.4.2.2 Safety........................................................................................................ 29
8.4.2.3 Pharmacokinetics.................................................................................... 29
8.4.2.4 Efficacy of the Treatment of Bleeding Episodes.................................. 29
8.4.3 Exploratory Outcomes Measure................................................................... 30
8.5 Randomization and Blinding............................................................................... 30
8.6 Study Stopping Rules............................................................................................ 30
8.7 Investigational Product(s) .................................................................................... 31
8.7.1 Packaging, Labeling, and Storage................................................................ 31
8.7.1.1 rVWF (Recombinant von Willebrand Factor)..................................... 31
8.7.1.2 rFVIII (Recombinant FactorVIII /ADVATE)..................................... 31
8.7.2 Reconstitution................................................................................................. 31
8.7.3 Administration ............................................................................................... 32
8.7.4 Description of Treatment.............................................................................. 33
8.7.4.1 Baseline Visit (PK-Assessment Treatment).......................................... 33
8.7.4.2 Prophylaxis Initiation Treatment.......................................................... 33
8.7.4.3 Prophylaxis Treatment........................................................................... 34
8.7.4.4 Treatment of Bleeding Episodes............................................................ 35
8.7.5 Investigational Product Accountability ....................................................... 38
8.8 Source Data ........................................................................................................... 38
9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION .......... 39
9.1 Inclusion Criteria.................................................................................................. 39
9.2 Exclusion Criteria................................................................................................. 39
9.3 Delay Criteria........................................................................................................ 40
9.4 Withdrawal and Discontinuation ........................................................................ 41
10. STUDY PROCEDURES .......................................................................................... 42
10.1 Informed Consent and Enrollment ................................................................... 42
10.2 Subject Identification Code................................................................................ 42
10.3 Screening and Study Visits................................................................................. 42
10.3.1 Screening Visit.............................................................................................. 42
10.3.2 Baseline Visit - PK-Assessment Visit ......................................................... 43
10.3.3 Prophylaxis Initiation Visit......................................................................... 44
10.3.3.1 Surgical Prophylaxis............................................................................. 44
10.3.4 Treatment of Bleeding Episodes................................................................. 45
10.3.5 Follow-Up Visits (1 Month ± 1 Week, 2 Months ± 1 Week, 3 Months 
± 2 Weeks, 6 Months ± 2 Weeks, 9 Months ± 2 Weeks)............................. 45
10.3.6 Unscheduled Visits....................................................................................... 46
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10.3.7 Study Termination Visit (12 months ± 2 weeks)....................................... 47
10.4 Medications and Non-Drug Therapies.............................................................. 47
10.5 Subject Diary....................................................................................................... 48
10.6 Subject Completion/Discontinuation ................................................................ 48
10.7 Procedures for Monitoring Subject Compliance ............................................. 49
11. ASSESSMENT OF EFFICACY AND PHARMACOKINETICS........................ 50
11.1 Assessment of Spontaneous Bleeding Episodes/Annualized Bleed Rate........ 50
11.2 Evaluation of ABR before rVWF Prophylaxis and ABR under rVWF 
prophylactic treatment......................................................................................... 51
11.3 Number of Infusions and Total Weight Adjusted Consumption of rVWF and 
ADVATE................................................................................................................ 51
11.4 Assessment of Efficacy for Treatment of Bleeding Episode ........................... 51
11.5 Pharmacokinetic Assessment............................................................................. 51
12. ASSESSMENT OF SAFETY................................................................................... 52
12.1 Adverse Events.................................................................................................... 52
12.1.1 Definitions..................................................................................................... 52
12.1.1.1 Serious Adverse Event.......................................................................... 52
12.1.1.2 Non-Serious Adverse Event ................................................................. 53
12.1.1.3 Unexpected Adverse Events................................................................. 53
12.1.1.4 Preexisting Disease................................................................................ 53
12.1.2 Assessment of Adverse Events.................................................................... 53
12.1.2.1 Severity .................................................................................................. 55
12.1.2.2 Causality................................................................................................ 55
12.2 Urgent Safety Measures ..................................................................................... 56
12.3 Untoward Medical Occurrences........................................................................ 57
12.4 Non-Medical Complaints ................................................................................... 57
12.5 Medical, Medication, and Non-Drug Therapy History................................... 57
12.6 Physical Examinations........................................................................................ 58
12.6.1 Thromboembolic events .............................................................................. 58
12.6.2 Anaphylactic reactions ................................................................................ 59
12.7 Vital Signs............................................................................................................ 60
12.8 Electrocardiogram.............................................................................................. 60
12.9 Clinical Laboratory Parameters........................................................................ 61
12.9.1 rVWF and endogenous FVIII Pharmacokinetics ..................................... 61
12.9.2 Hematology and Clinical Chemistry.......................................................... 62
12.9.3 Immunology.................................................................................................. 62
12.9.3.1 Antibodies to VWF and FVIII............................................................. 62
12.9.3.2 Inhibitory and Total Binding Anti-VWF Antibodies........................ 63
12.9.3.3 Binding antibodies to VWF.................................................................. 63
12.9.3.4 Neutralizing antibodies to VWF.......................................................... 64
12.9.3.5 Binding Antibodies to FVIII................................................................ 65
12.9.3.6 Neutralizing antibodies (inhibitors) to FVIII..................................... 65
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13.6 Planned Interim Analysis of the Study ............................................................. 78
14. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .................................... 79
15. QUALITY CONTROL AND QUALITY ASSURANCE...................................... 80
15.1 Investigator’s Responsibility.............................................................................. 80
15.1.1 Investigator Report and Final Clinical Study Report.............................. 80
15.2 Training ............................................................................................................... 80
15.3 Monitoring........................................................................................................... 80
15.4 Auditing ............................................................................................................... 80
15.5 Non-Compliance with the Protocol ................................................................... 81
15.6 Laboratory and Reader Standardization ......................................................... 81
16. ETHICS ..................................................................................................................... 82
16.1 Subject Privacy ................................................................................................... 82
16.2 Ethics Committee and Regulatory Authorities................................................ 82
16.3 Informed Consent ............................................................................................... 82
16.4 Data Monitoring Committee.............................................................................. 83
17. DATA HANDLING AND RECORD KEEPING................................................... 84
17.1 Confidentiality Policy ......................................................................................... 84
17.2 Study Documentation and Case Report Forms ............................................... 84
17.3 Document and Data Retention........................................................................... 84
18. FINANCING AND INSURANCE........................................................................... 85
19. PUBLICATION POLICY........................................................................................ 85
20. SUPPLEMENTS....................................................................................................... 86
20.1 Study Flow Chart................................................................................................ 86
20.2 Schedule of Study Procedures and Assessments.............................................. 87
20.3 Clinical Laboratory Assessments ...................................................................... 89
21. REFERENCES.......................................................................................................... 91
22. SUMMARY OF CHANGES.................................................................................... 94
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Tables
Table 1. rVWF Dosing Schedule Examples: Schedules 1 and 2 ..................................... 34
Table 2 rVWF:RCo Dosing Recommendations for the Treatment of Bleedings due to 
VWD................................................................................................................... 37
Table 3 Hemostatic Efficacy Rating Scale ...................................................................... 51
Table 4 Schedule of Study Procedures and Assessments ................................................ 87
Table 5. Clinical Laboratory Assessment ........................................................................ 89
Figures
Figure 1 Study Design for Baxter Clinical Study 071301 ............................................... 86
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5. LIST OF ABBREVIATIONS
Abbreviation
Definition
ABR
Annualized bleeding rate
ADAMTS13
A Disintegrin And Metalloproteinase with a ThromboSpondin type 1 motif, number 13
AE
Adverse event
ALT
Alanine aminotransferase
AP
Alkaline phosphatase
AST
Aspartate aminotransferase
AUC0-∞
Area under the plasma concentration /time curve from time 0 to infinity
AUC0-72h/Dose
Area under the plasma concentration/time curve from time 0 to 72 hours 
post-infusion/dose
AUC0-∞/Dose
Area under the plasma concentration/time curve from time 0 to infinity/dose
AUC/Dose
Area under the curve/dose
AUMC
Area under moment curve
AUMC0-∞/Dose
Area under the first moment curve from time 0 to infinity/dose
aPTT
Activated partial thromboplastin time
B19V
Parvovirus B19
BILI
Bilirubin
BP
Blood pressure
BU
Bethesda Unit
BUN
Blood urea nitrogen
BW
Body weight
CAM
Cell adhesion molecule
CB
Collagen binding activity
CBC
Complete blood count
CD4
Helper T cell
CHO
Chinese hamster ovary
Cl
Chloride
CL
Clearance
Cmax
Maximum plasma concentration
CR
Creatinine
eCRF
Electronic case report form
DMC
Data monitoring committee
DIC
Disseminated intravascular coagulation
DVT
Deep vein thrombosis
EC
Ethics committee
ECG
Electrocardiogram 
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Abbreviation
Definition
EDTA
Ethylenediaminetetraacetic acid
ELISA
Enzyme-linked immunosorbent assay
FAS
Full analysis set
FVIII
Factor VIII
FVIII:C
Factor VIII clotting activity
GCP
Good Clinical Practice
GI
Gastrointestinal
Glu
Glucose
GPIb
Glycoprotein Ib
HAMA
Human anti- mouse antibodies
HAV
Hepatitis A virus
HB
Hepatitis B
HBs
Hepatitis B surface
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HEV
Hepatitis E virus
HIV
Human immunodeficiency virus 
HLA
Human leukocyte antigen
HRP
Horseradish peroxidase
IB
Investigator's brochure
ICH
International Conference on Harmonisation
Ig
Immunoglobulin
INR
International normalized ratio
IP
Investigational product
IQR
Interquartil range
IR
Incremental recovery
i.v.
Intravenous
K
Potassium
k.o.
Knock out
LDH
Lactate Dehydrogenase
Na
Sodium
NMC
Non-medical complaint
NOAEL
No observed adverse effect level
MRI
Magnetic resonance imaging
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Abbreviation
Definition
MRT
Mean residence time
pdVWF
Plasma derived VWF product
pdVWF/FVIII
Plasma derived VWF product containing fractions of FVIII
PCR
Polymerase Chain Reaction
PEF
Peak expiratory flow
PK
Pharmacokinetic
PKFAS
Pharmacokinetic Full Analysis Set
PKPPAS
Pharmacokinetic Per Protocol Analysis Set
PP
Per protocol 
PT
Prothrombin time
Q1, Q3
Quartile
rFVIII
Recombinant factor VIII
rVWF
Recombinant von Willebrand factor
RBC
Red blood cell count
SAE
Serious adverse event
SAER
Serious adverse event report
SDS-PAGE
Sodium dodecyl sulfate polyacrylamide gel electrophoresis
SIC
Subject identification code
sP-selectin
Soluble P-selectin
T 1/2
Elimination phase half life
TIA
Transient ischemic attack
Tmax
Time to reach the maximum concentration
TTP
Thrombotic thrombocytopenic purpura
ULMW
Ultra-large molecular weight 
Vss
Volume of distribution at steady state
VTE
Venous thromboembolism (VTE)
VWD
von Willebrand disease
VWF
Von Willebrand factor
VWF:Ag
Von Willebrand factor antigen
VWF Ac
VWF activity measured INNOVANCE VWF Ac assay
VWF:CB
Von Willebrand Factor collagen binding
VWF:RCo
Von Willebrand factor: Ristocetin cofactor activity
WBC
White blood cell
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6. BACKGROUND INFORMATION
6.1 Description of Investigational Product
Baxter Healthcare Corporation (hereafter referred to as Baxter or sponsor) has developed 
a human recombinant von Willebrand Factor (rVWF), which is co-expressed with 
recombinant factor VIII (rFVIII) in a Chinese hamster ovary (CHO) cell line and
separated during the subsequent downstream process. To address concerns regarding the 
risk of transmission of blood-borne pathogens that may be introduced by human plasma, 
no exogenously added raw materials of human or animal origin are employed in the cell 
culture, purification, or formulation of the final container product. The only proteins 
present in the final container product other than rVWF are trace quantities of murine 
immunoglobulin (IgG, from the immunoaffinity purification), host cell (i.e., CHO) 
protein, rFurin (used to further process rVWF). rVWF is intended for the treatment of 
von Willebrand disease (VWD).
rVWF has been developed under the Baxter internal code BAX111 and is used as 
investigational product (IP) in this study. rVWF may be used with or without ADVATE 
(rFVIII) for the treatment of bleeding episodes (see Section 8.7.4.4). See Section 8.7 for 
further information on the IPs and their usage in this study). A detailed description of 
rVWF is also provided in the Investigator’s Brochure (IB).
6.2 Clinical Condition/Indication 
Von Willebrand Factor (VWF) is a large multimeric glycoprotein with a molecular 
weight that varies from 500 to 20,000 kDa. VWF is normally found in plasma and 
produced in the alpha-granules of platelets and in endothelial cell organelles known as the 
Weibel-Palade bodies. VWF mediates platelet adhesion and aggregation at sites of 
vascular injury, one of the key functions in primary hemostasis. VWF also serves to 
stabilize coagulation factor VIII (FVIII), where FVIII is an essential cofactor of 
secondary hemostasis, which leads to fibrin clot formation.1 Qualitative and/or 
quantitative deficiencies of VWF lead to a highly variable bleeding diathesis known as 
VWD, the most common of the hereditary coagulation factor deficiencies. Penetrance of 
VWD is highly variable, with only a small fraction of mildly affected patients displaying 
clinical symptoms or a family history of a bleeding diathesis.
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The current biochemical-based classification distinguishes disorders arising from partial 
quantitative (type 1), qualitative (type 2), or virtually complete (type 3) deficiencies of 
VWF. Up to 70% of VWD patients are diagnosed with type 1 VWD, which may also be 
associated with minor functional defects in the molecule. In general, patients with type 1 
VWD display mild clinical symptoms. Approximately 20 to 30% of VWD patients are 
diagnosed with type 2 VWD. Type 2 VWD is further divided into 4 subtypes (A, B, N, 
and M), reflecting distinct classes of functional abnormalities. These defects result in 
abnormal functional and/or multimeric distribution patterns that facilitate their diagnosis. 
The bleeding diathesis is usually moderate and primarily affects the mucosal tissues. 
Type 2N VWD patients are sometimes misdiagnosed as mild hemophilia A. Finally, 
approximately 1% percent of VWD patients exhibit a total or near total absence of VWF, 
which is classified as type 3 VWD. The incidence of type 3 VWD is estimated at 
0.5-1.0 x 106. This type is also associated with a very low FVIII level (typically < 5%) 
because the VWF carrier function for FVIII is lost. Replacement of VWF alone stabilizes 
endogenous FVIII, resulting in hemostatic levels within several hours post-infusion.   
Published results from studies of a plasma-derived VWF concentrate demonstrated an 
increase of FVIII at an approximate rate of 5.8 1 IU dL-1 h-1.2 Type 3 VWD patients 
display severe hemorrhagic symptoms with bleeding predominantly in mucosal tissues, 
muscle and joints. All VWD patients, particularly those with type 2 or type 3 VWD, are 
at an increased risk for life-threatening bleeding episodes.
6.3 The role of prophylaxis in the management of VWD
The goals of long term prophylaxis in VWD are to maintain VWF and FVIII at sufficient 
levels to reduce the frequency and duration of bleeding episodes, the need for red blood 
cell transfusions, and the risk of complications, such as arthropathy.3 In contrast to 
hemophilia, routine prophylaxis is not as established in VWD, although prophylaxis for 
patients with severe VWD have already been in use in Sweden during the 1950s 4. In 
those early days of VWD treatment plasma FVIII concentrates containing VWF fractions 
were applied for replacement therapy, which then were followed by plasma derived VWF 
products containing fractions of FVIII (pdVWF/FVIII). 
A Swedish cohort including 37 patients with type 3 VWD under prophylactic median 
treatment of 11 years (range 2 to 45 years) was retrospectively analyzed 5;6. The doses 
used for prophylaxis, given once weekly for at least 45 weeks per year, were calculated 
based on 12 to 50 IU/kg body weight (BW) of factor VIII clotting activity (FVIII:C)
which approximately corresponded to 24-100 IU/kg von Willebrand factor: Ristocetin 
cofactor activity (VWF:RCo) considering that mainly Haemate with a known 
VWF:RCo/FVIII:C ratio of about 2 was used. An escalation of doses from one to three 
dose levels was allowed depending on the frequency and severity of bleedings. 
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The results demonstrate that under long-term prophylaxis the number of bleeds could be 
reduced dramatically. Whereas the median value for bleeds per year was about 10 before 
prophylaxis this value could be reduced to less than 1 bleed per year during prophylaxis.
The benefit of prophylaxis for such indications was retrospectively also demonstrated in a 
cohort of Italian patients including type 3, 2A, 2M and type 1 patients. Prophylaxis was 
started after severe gastrointestinal or joint bleedings and completely prevented bleedings 
in 8 of these 11 patients and largely reduced the need of blood transfusions in the 
remaining three. A regimen of 40 IU rVWF:RCo/kg was applied every other day or twice 
a week. A prospective study on prophylaxis, the PRO.WILL study, has been initiated in 
Italy 7.
The results of a prospective study investigating the prophylaxis in children and young 
adults showed a significantly reduced bleeding frequency and bleeding score ( 3 vs. 0.07; 
3 vs. 0. p<0.001) compared to the pre-prophylaxis values. The median dose was 40 
(20-47) IU/kg VWF:RCo administered mainly twice weekly in 23 patients, three times a 
week in 7 patients and four times a week in 2 children 8. 
The VWD Prophylaxis Network initiated the VWD International Prophylaxis (VIP) trial 
to investigate the role of prophylaxis in patients with severe VWD including Type 1, 2 
and 3. The dose of the factor replacement product was 50 IU /kgVWF:RCo. The 
frequency of the dose depended on the type of bleeding and could be increased from once 
weekly to twice weekly or three times per week. For the treatment of menorrhagia the 
dose of 50 IU/kg VWF:RCo was given on the first day of menses for 2 cycles. The 
frequency could be increased to day 1 and 2 for 2 cycles or to day 1, 2, and 3 of menses.
The study contains both retrospective and prospective study components. Results from 
the retrospective study component were published, including sixty-one subjects on 
prophylactic regimen in the past 6 months prior to enrollment or subjects with a history of 
prophylaxis over at least 6 month 9. Differences in annualized bleeding rates (ABR) 
within individuals (during prophylaxis – before prophylaxis) were significant for those 
with primary indications of epistaxis (P = 0.0005), joint bleeding (P = 0.002) and 
gastrointestinal (GI) bleeding (P = 0.001). The difference in the group whose primary 
indication for treatment was abnormally heavy bleeding at menstruation (n = 4) was not 
significant (P = 0.25). The reduction of mucosal bleeding likely not only dependents on 
normal circulating levels of active VWF, but also on the presence of discrete 
concentrations of normal VWF inside the platelets and within endothelial matrices. The 
low subject number (n=4) and the treatment scheme for menorrhagia on days 1, 2, and 3 
of menses which might represent rather on-demand than prophylactic treatment may also 
account for the outcome in this study. 
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The results of the VIP study and previous investigations suggest that VWD patients with 
recurrent bleedings and severe menorrhagia will benefit from a prophylactic VWF 
replacement therapy. There is evidence that up to 40 % of patients with type 3 VWD 
experience joint bleeding which can lead to hemophilic arthropathy. Other potential 
indications for prophylaxis include patients with type 2A or 2B VWD with recurrent 
gastrointestinal bleeding, menorrhagia or frequent epistaxis 3. Long-term prophylaxis for 
most patients with type 3 VWD and in some patients with type 1 or 2 VWD, depending 
on the pattern of bleeding, may be the treatment option of choice. Although the main 
experience with long-term prophylaxis is with secondary prophylaxis, primary 
prophylaxis starting at young age is recommended to prevent arthropathy in patients with 
severe VWD.10
However, further studies are needed to develop evidence-based guidelines for 
prophylactic treatment in VWD.
6.4 Population to be Studied
A total of approximately 18 eligible, adult subjects to achieve approximately 15 evaluable 
subjects with severe VWD are planned to be enrolled, of which a subset of at least 
5 subjects will have type 3 VWD. Enrolled subjects (i.e., subjects who have signed the 
informed consent form) will be eligible to participate in the study if they meet all of the 
inclusion criteria (see Section 9.1) and none of the exclusion criteria (see Section 9.2).
6.5 Findings from Nonclinical and Clinical Studies
The following summarizes the key findings from relevant nonclinical studies as well as 
from the completed clinical Phase 1 study 070701 and 071104. Potential risks and 
efficacy of rVWF:ADVATE are summarized in the following sections. For additional 
information on nonclinical and clinical Phase 1 results refer to the rVWF IB.
6.5.1 Findings from Nonclinical Studies
6.5.1.1 Primary Pharmacodynamics
Efficacy of rVWF combined with ADVATE was shown in VWD animal models, which 
have also low endogenous FVIII levels. Time to occlusion and stable thrombus formation 
was assessed in the carotid occlusion model in VWD mice. The results demonstrated that 
rVWF in combination with ADVATE acted efficiently in a dose-dependent manner and 
had higher efficacy than rVWF alone or plasma derived (pd)VWF. These results were 
confirmed in an additional study assessing blood loss and survival in a tail tip bleeding 
model in VWD mice. In a VWD dog rVWF stabilized canine FVIII in the circulation and 
significantly reduced the bleeding time. 
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6.5.1.2 Safety Pharmacology
The anaphylactoid and thrombogenic potential of the co-infusion of ADVATE and rVWF 
and the co-infused product’s effects on blood pressure, cardiac and respiratory function 
and parameters of coagulation activation were investigated in four in vivo studies in 
different animal models. Safety Pharmacology Studies in rats, guinea pigs, rabbits and 
dogs revealed no risks for anaphylactoid and thrombogenic potential of ADVATE in 
combination with rVWF. All observations in safety pharmacology studies are considered 
to lie within the biological variability of animal models or occurred due to known 
species-specific anaphylactoid effects of excipients.
6.5.1.3 Pharmacokinetics
Pharmacokinetic studies of both rVWF alone and combined with human rFVIII 
(rVWF+ADVATE) were conducted in VWD mice, VWD dogs, VWD pigs, rats and 
cynomolgus monkeys. Human rVWF stabilized the endogenous FVIII in VWD mice, 
VWD pigs and VWD dogs. Furthermore, the hypotheses that the area under the curve 
(AUC) with rVWF alone and rVWF+ADVATE is not inferior to the AUC with pdVWF 
(Haemate P) was tested and confirmed statistically in normal rats. The pharmacokinetic 
(PK) characteristics of ADVATE were not affected by co-administration of rVWF in 
cynomolgus monkeys. The PK data in the FVIII knock out (k.o.) mice model are 
inconclusive and might not be relevant for the clinical situation. However, a stabilizing 
effect of VWF on FVIII could be shown in a double knock out model in a dose dependent 
manner.
6.5.1.4 Toxicology
Single dose toxicity studies were conducted in C57BL/6J-mice, VWD mice, rats, rabbits,
and cynomolgus monkeys. Rats, rabbits, and cynomolgus monkeys showed no signs of
toxicity. Signs of microthrombosis, an exaggerated pharmacological effect, were
observed in mice. Mice are not capable of sufficiently cleaving the rVWF subunit as
murine disintegrin and metalloproteinase with a thrombospondin type 1 motif, number 13
(ADAMTS13) does not decrease the ultra-large molecular weight multimers of rVWF 11. 
The observed symptoms of microthrombosis are interpreted as a species-specific 
exaggerated pharmacological effect. Studies evaluating the safety of repeated 
administration of rVWF with or without ADVATE (daily over 14 days) were performed 
in a rodent (rat) and non-rodent (cynomolgus monkey) species. Reversible signs of 
exaggerated pharmacological effects (regenerative anemia, thrombocytopenia, and 
treatment-related histopathologic changes in the heart, liver, and spleen) were observed in 
rats that were administered 1400 U VWF:RCo/kg /day + 1080 IU ADVATE/kg/day 
intravenously once daily for 14 days. Also, these findings are interpreted as a species-
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specific exaggerated pharmacological effect due to the low susceptibility of human rVWF 
to cleavage by rodent ADAMTS13 11. No toxicologically relevant changes were evident 
for clinical observations, body weight, feed consumption, ophthalmology, urinalysis, 
coagulation and serum chemistry parameters, platelet aggregation, and gross pathology.
rVWF combined with ADVATE was well tolerated in cynomolgus monkeys after daily 
intravenous (i.v.) (bolus) administration of 100 U VWF:RCo/kg rVWF combined with 
77 IU/kg ADVATE over a period of 14 days. No adverse effects could be detected in this
species. There were no signs of hemolysis, thrombosis or thrombocytopenia after
repeated intravenous application of rVWF with or without ADVATE. Therefore, 
100 U VWF:RCo/kg/day rVWF with or without 77 IU/kg ADVATE was considered the 
no observed adverse effect level (NOAEL) in this study, which was the highest dose 
tested. Anti-drug antibodies, however, were formed in both species and resulted in a 
significant reduction in drug exposure after 14 applications as compared to a single 
application. These antibodies substantially reduced the systemic exposure to the test 
substance as compared to a single dose administration. No adverse effects due to 
antibody formation were observed in both species. rVWF combined with ADVATE was 
well tolerated locally and no genotoxic potential was evident after two in vitro and one in 
vivo genotoxicity study. A study on the influence of co-administration of VWF and 
ADVATE on the immunogenicity of ADVATE in three different hemophilic mouse 
models (E17 hemophilic Balb/c mice, E17 hemophilic C57BL/6J mice and E17 
hemophilic human F8 transgenic mice) showed that rVWF does not negatively impact the 
immunogenicity of ADVATE in any of the three different hemophilic mouse models. 
6.5.2 Findings from Clinical Studies
Two phase 1 studies with rVWF either alone or co-administrated with ADVATE in 
patients with VWD 070701 and Hemophilia A 071104 have been conducted and the 
results were analyzed and evaluated. Details on study design, populations enrolled and 
safety and efficacy outcomes of these two phase 1 studies are presented in Section 6.5.2.1
and Section 6.5.2.2. 
Refer to rVWF IB for periodic updates from other rVWF studies. 
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6.5.2.1 Study 070701
Phase 1 clinical study 070701 was a multicenter, controlled, randomized, single-blind 
prospective 3-step, dose escalation study to investigate safety, tolerability and PK of 
rVWF combined at a fixed ratio with ADVATE (VWF:RCo/FVIII:C of 1.3 ± 0.2:1) in 
adults with severe VWD. Subjects were enrolled in sequential cohorts in a dose 
escalating manner: Cohort 1, 2 and 3 received a single intravenous infusion of 
rVWF:ADVATE at the following doses: 2 IU/kg VWF:RCo (Cohort 1), 7.5 IU/kg 
VWF:RCo (Cohort 2), and 20 IU/kg VWF:RCo (Cohort 3). Subjects in Cohort 4 received 
a single intravenous infusion of rVWF:ADVATE and pdVWF/ADVATE at 50 IU/kg 
VWF:RCo in random order.
The primary endpoint was the tolerability and safety after single dose injections of 
rVWF:ADVATE at 2, 7.5, 20 and 50 IU/kg VWF:RCo for up to 30 days after the last IP 
infusion. The data generated in this phase 1 study suggest that rVWF:ADVATE up to the 
highest investigated dose of 50 IU/kg VWF:RCo is well tolerated and safe in adults with 
severe VWD. No thrombogenic risk or TTP-like syndrome was observed, and no 
inhibitory antibodies to VWF or FVIII were identified. There were no deaths or other 
serious adverse reactions, and no infusions were interrupted or stopped due to an AE.
Overall, the reported AE profile was similar between the recombinant and plasma-
derived concentrates.
Secondary endpoints were the PK assessment of VWF:RCo, von Willebrand factor 
antigen (VWF:Ag) and multimeric composition of rVWF as well as FVIII:C at 
standardized time points after single injections of rVWF:ADVATE and pdVWF:FVIII. 
The median VWF:RCo half-life (T1/2) of rVWF at the 50 IU/kg dose was 16 hours. T1/2 
with pdVWF:FVIII at the same dose level appeared shorter at 12.58 hours, however, the 
limits of the 90% CI were similar (11.73 to 17.7 hours vs. 11.87 to 18.03 hours). The 
median half-lives of VWF:RCo were shorter with the lower investigated doses: 
7.13 hours and 13.23 hours with the 7.5 IU/kg and 20 IU/kg doses, although these data 
were derived from a much smaller number of subjects.
In consequence of the missing ADAMTS13 cleavage ultra-large molecular weight 
(ULMW) multimers are contained in the rVWF final product. The immediate cleavage of 
these ultra-large multimers by ADAMTS13 upon release into the circulation could be 
demonstrated applying Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-
PAGE)/Immunoblot with polyclonal anti-VWF antibodies to detect the resulting rVWF 
subunit cleavage fragments.
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Overall the data generated in this phase 1 study suggest that rVWF:ADVATE is well 
tolerated and safe in adults with severe VWD.
6.5.2.2 Study 071104
This study was a prospective, uncontrolled, non-randomized, multicenter proof of 
concept study to assess safety and PK of the addition of rVWF to ADVATE treatment in 
12 evaluable subjects with severe hemophilia A. All subjects underwent 3 PK analyses: 
the first after infusion with ADVATE alone, the second after infusion with ADVATE
plus 10 IU/kg rVWF and the third after infusion with ADVATE plus 50 IU/kg rVWF. 
The PK analysis was performed at intervals of approximately 8 to 14 days. Before each 
infusion for PK assessment there was a wash-out period of at least 5 days and the subjects 
were not actively bleeding. 
Primary outcome measures indicate that co-administration of rVWF slightly sustain 
ADVATE activity with the highest observed ADVATE half-life of 13.74 h (CI 11.44 to 
16.52) after co-infusion of 50 IU/kg ADVATE plus 50 IU/kg rVWF:RCo. The highest 
improvement in ADVATE circulating half-life was observed in subjects with VWF:Ag 
levels below 100% which indicates an association between baseline VWF:Ag levels and 
ADVATE half-life increase. 
No treatment related adverse events (AEs) or serious adverse events (SAEs) were 
reported. No subject withdrew due to an AE and there were no deaths. No binding 
antibodies to VWF, CHO and rFurin were detectable in the confirmatory assay and no 
signs of a hypersensitivity to rVWF or ADVATE antigen were observed. Laboratory 
values over time did not indicate any potential safety risk for hemophilia A patients 
treated with rVWF and ADVATE in combination. 
In summary, the data indicate that rVWF co-administered with ADVATE up to the
highest dose of 50 IU/kg VWF:RCo is well tolerated and safe in hemophilia A patients.
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6.6 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) to
Human Subjects
Current treatment of VWD patients relies on desmopressin and VWF products 
manufactured from pooled human plasma. Human VWF produced by recombinant 
technology could offer a new perspective in treatment of VWD. The benefit for the 
individual subject is anticipated to be significant during this clinical study. He/she may 
benefit from a product that minimizes excessive FVIII administration. Variations in VWF 
multimeric composition may lead to variability with respect to treating or preventing 
bleeds in VWD subjects, especially mucosal bleeds which are especially problematic. 
rVWF product manufactured by Baxter consistently contains ultra-large molecular weight 
(ULMW) VWF multimers due to the fact that the product has not been exposed to 
ADAMTS13. The initial presence of these ULMW VWF multimers, which are 
subsequently cleaved by the subject’s endogenous ADAMTS13, may result in improved 
platelet and collagen binding and therefore provide more predictable treatment outcomes. 
By using a recombinant product, the risk of contamination with blood derived viruses or 
variant Creutzfeldt-Jakob Disease associated with the use of products of human or animal 
origin has been virtually eliminated. At this stage of product development, the key 
societal benefit is a better understanding of advanced treatment options for VWD and 
enhanced product availability.
These benefits outweigh the following potential risks of rVWF:
allergic type hypersensitivity reactions as with any intravenous protein product
the occurrence of thrombotic events
the development of neutralizing antibodies to VWF 
Refer to the IB for further details on benefits and risks of the IP.
6.7 Compliance Statement
This study will be conducted in accordance with this protocol, the International 
Conference on Harmonisation Guideline for Good Clinical Practice E6 (ICH GCP, April 
1996), Title 21 of the US Code of Federal Regulations (US CFR), the European Clinical 
Trial Directive (2001/20/EC and 2005/28/EC), and applicable national and local 
regulatory requirements.
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7. STUDY PURPOSE AND OBJECTIVES
7.1 Study Purpose
The purpose of this phase 3 study is to investigate the efficacy and safety, including 
immunogenicity and thrombogenicity, and 
of 
prophylactic treatment with rVWF in subjects with severe VWD.
7.2 Primary Objective
The primary objective of this study is to prospectively evaluate the overall annualized 
bleeding rate (ABR) for spontaneous bleeding episodes while on prophylactic treatment 
with rVWF and to retrospectively evaluate the patients historical ABR for spontaneous 
bleeding episodes during on-demand treatment. 
7.3 Secondary Objectives
Secondary Objectives are:
Additional efficacy assessments of prophylactic treatment, 
Safety,
Pharmacokinetics (PK), 
Efficacy of the treatment of bleeding episodes
7.4 Exploratory Objectives
7.4.1
 
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8. STUDY DESIGN
8.1 Brief Summary
8.2 Overall Study Design 
This is a prospective, open label, uncontrolled, non-randomized, international, 
multicenter phase 3 study to evaluate efficacy, safety, including immunogenicity and 
thrombogenicity and 
of a prophylactic treatment regimen with rVWF in patients 
with severe VWD. 
The dose of rVWF for prophylaxis will be in the range of 50 ±10 IU/kg rVWF:RCo 
administered 3 times weekly. The dose may be adjusted within this range based on the 
subject’s history of bleeding episodes, the clinical response and the results from clinical 
and laboratory assessments (see Section 8.7.4.2).
The overall duration of prophylactic treatment per subject will be 12 months.
During this period any bleeding episodes requiring substitution therapy with VWF 
concentrate to control bleeding will be treated with rVWF with or without ADVATE. 
The dose will be according to the bleeding severity and it will be adjusted to the clinical 
response (see Section 10.3.4).
The overall study design is illustrated in Figure 1.
8.3 Duration of Study Period(s) and Subject Participation
The overall duration of the study is approximately 22 months from study initiation (i.e., 
first subject enrolled) to study completion (i.e., last subject last visit). The subject 
participation period is approximately 16 months from enrollment to completion (i.e, last 
study visit), unless the subject is prematurely discontinued.
8.4 Outcome Measures
8.4.1 Primary Outcome Measure
The primary outcome measure is

Efficacy:
Prospectively recorded overall ABR for spontaneous bleedings during 
prophylactic treatment with rVWF and the subjects‘ historical ABR for 
spontaneous bleedings during on-demand treatment.
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8.4.2 Secondary Outcome Measures
8.4.2.1 Efficacy 

Number of subjects with reduction of ABR for spontaneous bleeding episodes 
during prophylaxis compared to the subjects’ own historical control during on-
demand treatment

Number of subjects with 0 bleeds during prophylactic treatment with rVWF

Number of infusions and total weight adjusted consumption of rVWF and
ADVATE per month and per year
8.4.2.2 Safety

AEs

Incidence of thrombotic events 

Incidence of severe allergic reactions (e.g. anaphylaxis) 

Development of inhibitory antibodies to VWF and FVIII

Development of total binding antibodies to VWF and FVIII

Development of antibodies to Chinese hamster ovary (CHO) proteins, mouse 
immunoglobulin G (IgG) and rFurin
8.4.2.3 Pharmacokinetics

Incremental recovery (IR), terminal half-life (T1/2), mean residence time (MRT), 
area under the curve/dose (AUC/dose), area under moment curve/dose 
(AUMC/dose), volume of distribution at steady state (Vss) and clearance (CL) 
based on Von Willebrand factor Ristocetin cofactor activity (VWF:RCo), Von 
Willebrand factor antigen (VWF:Ag), Von Willebrand collagen binding activity 
(VWF:CB) , INNOVANCE VWF Ac (exploratory assay) and time course (72
hours) of FVIII clotting activity (FVIII:C) levels.  
8.4.2.4 Efficacy of the Treatment of Bleeding Episodes

Number of infusions of rVWF and ADVATE per bleeding episode

Weight-adjusted consumption of rVWF and ADVATE per bleeding episode

Overall hemostatic efficacy rating at resolution of bleed 
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8.4.3 Exploratory Outcomes Measure
8.5 Randomization and Blinding
This is a non-randomized open-label, active treatment clinical study. 
8.6 Study Stopping Rules 
This study will be stopped if 1 or more of the following criteria are met:
1. Two subjects develop a thrombosis, other than superficial thrombosis
2. Two subjects develop anaphylactoid reactions (e.g. hives, generalized urticaria, 
tightness of the chest, wheezing, hypotension, or anaphylaxis)
3. Two subjects develop signs and symptoms, suggestive of a thrombotic 
thrombocytopenic purpura-like syndrome (subjects with type 2B VWD developing 
thrombocytopenia or changes of the platelet count as described below, will be 
evaluated on case by case, whether they need to be accounted for), such as 

A drop in platelet count of 50% of subject’s baseline or less than 100.000 per 
microliter

3 fold increase in Lactate dehydrogenase (LDH)

Impaired renal function as determined by: 
Creatinine increase of 1.5 fold from baseline levels
Blood urea nitrogen (BUN) increase from normal levels to a level 
> 60 mg/dL
4. Two subjects develop rVWF inhibitory antibodies
The study may be stopped at any time by the sponsor.
The sponsor ultimately will decide whether to terminate, temporarily halt or modify the 
study based on the Data monitoring committee (DMC) recommendation.
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8.7 Investigational Product(s)
8.7.1 Packaging, Labeling, and Storage
8.7.1.1 rVWF (Recombinant von Willebrand Factor)
rVWF will be packaged in boxes with 2 glass vials, one containing the lyophilized 
rVWF, and the second vial containing the diluent. Further details are provided in the IB 
and Pharmacy Manual. The rVWF label will include, at a minimum, the actual 
VWF:RCo potency and the date of expiration.
rVWF should be refrigerated (2°-8°C [36°-46°F]) in lyophilized form. Deviations from 
the storage condition have to be communicated and followed up with the sponsor.
Inadequately stored product will have to be placed on quarantine and may only be used 
after written investigational product administration authorization by the sponsor.
After removal of the product from the refrigerator the product must not be returned to the 
refrigerator and has to be used immediately. rVWF must not be used beyond the 
expiration date printed on the vial. Avoid freezing at all times. 
8.7.1.2 rFVIII (Recombinant FactorVIII /ADVATE)
ADVATE will be packaged in boxes with 2 glass vials, one containing the lyophilized 
rFVIII, and the second vial containing the diluent. Further details are provided in the IB 
and Pharmacy Manual. The ADVATE label will include, at a minimum, the actual 
FVIII:C potency and the date of expiration. 
ADVATE should be refrigerated (2°-8°C [36°-46°F]) in powder form and should not be 
used beyond the expiration date printed on the vial. Deviations from the storage condition 
have to be communicated and followed up with the sponsor. Inadequately stored product 
will have to be placed on quarantine and may only be used after written investigational 
product administration authorization by the sponsor. After removal of the product from 
the refrigerator the product must not be returned to the refrigerator and has to be used 
immediately. Avoid freezing at all times.
8.7.2 Reconstitution
The reconstitution procedures for both rVWF and ADVATE products are detailed in the 
Pharmacy Manual. 
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8.7.3 Administration
Following reconstitution, rVWF and ADVATE (in case of bleeding episode treatment) 
should be administered to study subjects at room temperature and within 3 hours of 
reconstitution. The reconstituted rVWF and ADVATE, should be inspected for 
particulate matter and discoloration prior to administration, whenever the solution and 
container permit. The solution should be clear and colorless in appearance. If not, do not 
administer the product. Plastic syringes provided by the sponsor must be used since 
coagulation factors tend to stick to the surface of glass syringes.
IP infusions should be given at a rate which should not exceed 4 mL/minute. The 
investigator/ subject shall ensure that no visible residual volume remains in the syringe(s) 
and that the complete content is administered. Upon completion of the infusion, the 
butterfly catheter should be flushed with at least 2 mL of saline solution. In case of a 
(central) venous access device, the flush should be with at least 10 mL of saline solution.
Only the actual potencies of rVWF and ADVATE as stated on the vial labels and 
described in the Pharmacy Manual should be used. A variation of up to 10% of the 
intended dose for prophylactic infusions and of the intended dose for treatment of 
bleeding episodes is permissible and the exact dose should be recorded on the Case 
Report Form (CRF).
At study visits where recovery analysis is being done, vials with the same lot numbers 
should be used throughout the PK IP infusion per subject.
For treatment of bleeding episodes there are two options for the preparation of rVWF and 
ADVATE for infusion if needed. 
Preferably sequential administration will be done: separate syringes of the appropriate 
dose of rVWF and ADVATE will be prepared for sequential infusion. rVWF should be 
infused first sequentially followed preferably within 10 minutes by infusion  of 
ADVATE. Only the actual potencies of rVWF and ADVATE as stated on the vial labels 
and described in the Pharmacy Manual should be used. 
Alternatively, premixed solutions can be administered: rVWF and ADVATE will be pre-
mixed in a single syringe to achieve the appropriate dose. The contents of each vial of 
rVWF or ADVATE can be drawn into one syringe by using a separate unused 
reconstitution device as described in the Pharmacy Manual. 
The final dose of rVWF:ADVATE should be at a ratio of 1.3:1 ± 0.2.
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8.7.4 Description of Treatment
8.7.4.1 Baseline Visit (PK-Assessment Treatment)
The first IP infusion for PK assessment should be within 60 days after the completion of 
screening procedures and confirmation of eligibility.
At the baseline visit the subjects will receive a dose of 50± 5IU/kg rVWF:RCo for PK 
assessment. Blood samples will be drawn within 30 minutes pre-infusion, and at 7 time 
points post-infusion (305 minutes, 605 minutes, 61 hours, 12 1 hours, 242 hours, 
482 hours, 722 hours). 
If a subject is already on a prophylactic treatment scheme using a pdVWF a washout 
period of at least 5 days is required prior to infusion of rVWF for PK assessment.
Subjects previously enrolled in rVWF studies 070701 or 071001 and having previously 
undergone PK assessments in these studies are required to repeat the PK assessment due 
to different dose and time points used in these former studies (see Section 12.9.1 and , 
Section 20.3 A washout period of at least 5 days is required prior to infusion of rVWF 
for PK assessment for subjects previously treated with rVWF.
Subjects who participated in the surgery study 071101 will not need an additional PK 
assessment if they transfer to this study. Identical PK dose and time points are used for 
both studies 071101 and 071301. 
8.7.4.2 Prophylaxis Initiation Treatment 
The prophylaxis initiation treatment visit will coincide with the 722 h PK assessment. 
At this visit subjects will receive their prophylaxis initiation dose of 50 ± 10 IU/kg
rVWF:RCo after the blood draw for the 722 hours post-infusion PK assessment. If 
subjects do not need an additional PK assessment (e.g. subject has transferred from the 
surgery study 071101), subjects must receive the IP for prophylaxis initiation treatment 
within 60 days after screening and confirmation of eligibility. The exact standard 
prophylaxis dose may range between 40 and 60 IU/kg based on:

available historical PK data

type and severity of bleeding episodes the subject has experienced in the past and

monitoring of appropriate clinical and laboratory measures.
Dose adjustments during the continued prophylactic treatment are described in
Section 8.7.4.3.
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The subject will be trained on IP reconstitution and administration and may then qualify
for home treatment (see Section 8.7.4.3.1). Refer to Table 4 for study procedures and
Table 5 for clinical laboratory assessments.
8.7.4.3 Prophylaxis Treatment
The standard prophylaxis is an infusion of 50 ±10 IU/kg rVWF:RCo administered three 
times per week. Examples of possible dosing schedule are given in Table 1.
Table 1.
rVWF Dosing Schedule Examples: Schedules 1 and 2
Example
Mon
Tues
Wed
Thurs
Fri
Sat
Sun
Schedule 1
X
X
X
Schedule 2
X
X
X
Any further dose and frequency adjustment will be agreed with the sponsor in advance
unless it constitutes an urgent safety measure. Dose adjustments to higher doses (not 
exceeding the upper dose limit of 80 IU/kg rVWF:RCo) and adjustments to 4 times 
weekly administration will only be allowed in cases of persisting high bleeding rates due 
to insufficient therapeutic response.
Dose and frequency reduction will only be allowed in case plasma VWF or FVIII levels
are exceeding the recommended ranges. 
If a subject does not adequately respond to rVWF therapy, he/she will be evaluated for 
the presence of inhibitory and total binding anti-VWF antibodies (see Section 12.9.3.2).
It is essential for the success of this study that the subjects adhere to treatment regimens. 
Therefore, procedures for monitoring subject’s compliance are implemented (see 
Section 10.7).
If one infusion of IP is missed, the subject may administer the IP as soon as possible. The 
subject should then adhere to the standard prophylaxis treatment scheme ensuring a 
minimum interval of 12 hours between this and the previous IP infusion. For example, a
subject routinely infuses IP on Monday, Wednesday and Friday, he/she misses the 
Wednesday time point and therefore may infuse the IP on the next day (Thursday) and 
thereafter proceed with infusing the IP on Friday (considering a minimum 12 hours 
between the infusions) and return to the initially chosen schedule.
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If more than 30% of infusions of IP are missed within the visit interval of 3 months the 
subject will be discontinued from the study (see Section 9.4).
8.7.4.3.1 General Instructions for Home Treatment for Prophylaxis
At the discretion of the investigator, a subject may be considered suitable for home 
treatment only after the subject has received at least 1 infusion of IP in the clinic, either 
during planned IP exposure (PK or prophylaxis) or during the treatment of bleeding 
episodes, and meets the following additional criteria:
1.
Fully understands the concept of a clinical study and related documentation 
(documented training of at least 30 minutes), 
2.
Has a history of previous experience with home treatment including self-
administration and treatment with VWF containing concentrates, 
3.
Has adequate time for initial training of the study drug preparation (preparation, 
mixing and infusion of the IP(s) (documented training of at least 30 minutes).
In the event a healthcare professional is required to administer IP, he/she must be trained 
and qualified by the sponsor on the above procedures prior to the decision for home 
treatment. A Subject Guideline detailing all instructions and information listed above will 
be provided to each subject. 
8.7.4.4 Treatment of Bleeding Episodes
8.7.4.4.1 General Instructions for Home Treatment of Bleeding Episodes
If a subject experiences a bleeding episode, he/she should contact the study site 
immediately and the site investigator should provide instructions on the treatment 
regimen. If the subject initiates the treatment at home, he/she should at least follow up 
with the study site if a visit is needed as per hospital standard.
In the event a healthcare professional is required to administer treatment at the subject’s 
home, he/she must be trained and qualified by the sponsor on the above procedures prior 
to the decision for home treatment. Once a subject has received 1 infusion of rVWF in the 
clinic (either during planned IP exposure or during the treatment of a bleeding episode) 
and meets the criteria for home treatment, the treatment of bleeding episodes with IP can 
be conducted at home (see Section 8.7.4.3.1).
If a subject is not qualified for home treatment, rVWF infusions must be administered at 
the study site.
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If a subject experiences a bleeding episode that requires treatment between the screening 
and the prophylaxis initiation visit, the subject will be treated with IP (rVWF with or 
without ADVATE). Treatment with IP must occur at the study site unless the subject has 
previously qualified for home treatment with rVWF. If rVWF treatment is not feasible, 
the subject may use his/her standard of care, such as commercial pdVWF/FVIII products.
In any case a washout period of at least 5 days is required prior to rVWF PK infusion at
the PK assessment visit.
If a subject experiences a bleeding episode requiring treatment during the PK assessment, 
rVWF will be used to treat the bleed. Blood draws for PK assessment will be stopped and 
the PK assessments will be repeated once the bleed has resolved and the subject is free of 
any symptoms related with the bleeding episode. Dose and frequency of rVWF infusions 
or any other replacement therapy to stop the bleed should be recorded in the e-CRF.
8.7.4.4.2 Dosing Recommendations for Treatment of Bleeding Episodes 
If an acute bleeding episode occurs, the subject will be treated with rVWF with or 
without ADVATE. In general initially, an infusion of rVWF: ADVATE at a rVWF:
ADVATE ratio of 1.3:1±0.2 will be administered. Subsequent infusions may either use 
rVWF alone or with ADVATE, based on FVIII levels, if available. 
If FVIII levels are not available, dosing is at the discretion of the investigator based upon 
the individual subject’s PK data. Using ADVATE in addition to rVWF in subsequent 
doses carries the risk of an excessive rise in FVIII:C. Therefore, reduced doses of 
ADVATE and/or prolongation of the dose interval should be considered.
In general the aim of the initial dose should be full replacement of VWF with VWF:RCo 
levels of > 0.6 IU/ml (60%) and FVIII:C of > 0.4 IU/mL (40%). In major bleeding 
episodes, subsequent doses should keep the trough level of VWF:RCo >50% for 3 days 
and then as deemed necessary by the investigator for subsequent days. In moderate 
bleeding episodes, the dose and trough level may be reduced to >30% for as long as 
deemed necessary by the investigator. Treatment for minor bleeding episodes will 
generally consist of only 1 or 2 doses of rVWF IP. 
If the VWF:RCo level is above 150%, a planned treatment should be delayed by at least 
12 hours; if the VWF:RCo level is above 200%, a planned treatment should be delayed 
by at least 24 hours. In either case, a lower subsequent dose (e.g., 20 IU/kg VWF:RCo) 
may be appropriate.
Dosing recommendations are listed in Table 2. 
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Dosage must be individualized based on the subject’s weight, VWD type and the severity 
of the bleeding episode, as well as on monitoring of appropriate clinical and laboratory 
measures. In the phase 1 study 070701, 1.0 IU/kg VWF:RCo raised the circulating level 
of VWF:RCo by 0.017 IU/mL (1.7 %). In the same study, the observed mean half-life for 
rVWF was 19.3 hours, with a standard deviation of 10.9 hours.
Table 2
rVWF:RCo Dosing Recommendations for the Treatment of Bleedings due to VWD
Classification of 
VWD 
Hemorrhage 
Dosage (IU VWF:RCo/kg body weight) 
Type 1 
Severe (Baseline 
VWF:RCo activity 
typically <20%) 
Minor (e.g. epistaxis, oral 
bleeding, menorrhagia) 
40 to 50 IU/kg (1 or 2 doses)
Major (e.g. severe or refractory 
epistaxis, menorrhagia, GI 
bleeding, CNS trauma, 
hemarthrosis, or traumatic 
hemorrhage)
Initial dose 50 to 75 IU/kg, then 40 to 60 IU/kg 
every 8 to 12 hours for 3 days to keep the trough 
level of VWF:RCo >50%; then 40 to 60 IU/kg 
daily for a total of up to 7 days of treatment.
Type 2 (all variants) 
and Type 3 
Minor (clinical indications 
above) 
40 to 50 IU/kg (1 or 2 doses) 
Major (clinical indications 
above)
Initial dose of 60 to 80 IU/kg, then 40 to 60 IU/kg 
every 8 to 12 hours for 3 days to keep the trough 
level of VWF:RCo >50%; then 40 to 60 IU/kg 
daily for a total of up to 7 days of treatment. 
Variances of up to 10% in dosing are permissible during treatment of bleeding episodes, 
but rounding to the nearest vial size should be avoided.
Subjects with non-neutralizing binding anti-VWF antibodies should initially be treated 
with a dose known to be efficacious based on the subject’s medical treatment history
which may differ from the recommendations provided in Table 2. Subjects should be 
monitored for lack of efficacy as well as for FVIII (mandatory), VWF:RCo (mandatory), 
and VWF:Ag (optional where testing is not available) levels after 3 - 6 hours. Re-dosing 
with rVWF in combination with ADVATE using the same (initial) dose and adaptation of 
the dosing frequency should be considered until cessation of the bleed, if the FVIII and/or 
VWF:RCo levels drop below 30%-50% depending on bleeding severity.
The number of subsequent infusions and the dosage levels prescribed will be determined 
by the investigator on the basis of the clinical severity, response to current therapy, 
available laboratory data, and the subject’s historical treatment for similar bleeding 
episodes. 
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8.7.5 Investigational Product Accountability
The investigator will ensure that the IP(s) is stored as specified in the protocol and that 
the storage area is secured, with access limited to authorized study personnel. The 
investigator will maintain records that the IP(s) was received, including the date received, 
drug identity code, date of manufacture or expiration date, amount received and 
disposition. IP(s) must be dispensed only at the study site or other suitable location (e.g. 
infusion center; home, as applicable per study design), as specified in the protocol (see 
Section 10). Records will be maintained that includes the subject identification code 
(SIC), dispensation date, and amount dispensed. All remaining partially used and/or 
unused IP(s) will be returned to the sponsor or sponsor’s representative after study 
completion/termination, or destroyed with the permission of the sponsor in accordance 
with applicable laws and study site procedures. If IP(s) is to be destroyed, the investigator 
will provide documentation in accordance with sponsor’s specifications.
8.8 Source Data
Per ICH GCP, source data are defined as all information in original records and certified 
copies of original records of clinical findings, observations, or other activities in a clinical 
trial that are necessary for the reconstruction and evaluation of the trial. Source data are 
contained in source documents (original records or certified copies), which may be in 
paper and/or electronic format. Source data for this study comprise the following:
hospital records, medical records, clinical and office charts, laboratory notes, memoranda, 
subjects' diaries or evaluation checklists, outcomes reported by subjects, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate copies, microfiches, photographic negatives, 
microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at 
the laboratories and at medico-technical departments involved in the clinical study.
For additional information on study documentation and CRFs refer to Section 17.2. The 
use of subject diaries is described in Section 10.5.
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9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION
9.1 Inclusion Criteria
Subjects who meet ALL of the following criteria are eligible for this study:
1.
Subject has a documented diagnosis of severe VWD which 
a)
is confirmed by genetic testing and multimer analysis, documented in 
patient history or at screening
b)
requires prophylactic replacement treatment with VWF containing 
concentrate to control bleeding. This includes:
- subjects already on prophylactic treatment
-  subjects currently on-demand treatment for whom prophylactic treatment 
is recommended according to standard of care at the center
c)
a minimum of documented 3 spontaneous bleeds requiring VWF treatment
within 12 months prior to prophylactic treatment. 
2.
Availability of records to reliably evaluate type,  frequency and treatment of 
bleeding episodes prior to onset of prophylactic treatment for at least 12 months
3.
Subject is ≥ 18 years old at the time of screening.
4.
If female of childbearing potential, subject presents with a negative pregnancy test 
at screening and agrees to employ adequate birth control measures for the duration 
of the study.
5.
Subject is willing and able to comply with the requirements of the protocol.
9.2 Exclusion Criteria
Subjects who meet ANY of the following criteria are not eligible for this study:
1.
The subject has been diagnosed with pseudo VWD or another hereditary or 
acquired coagulation disorder other than VWD (eg qualitative and quantitative 
platelet disorders or elevated PT/ international normalized ratio [INR] 1.4).
2.
The subject has a history or presence of a VWF inhibitor at screening.
3.
The subject has a history or presence of a FVIII inhibitor with a titer ≥ 0.4 BU (by 
Nijmegen modified Bethesda assay) or ≥ 0.6 BU (by Bethesda assay).
4.
The subject has a known hypersensitivity to any of the components of the study 
drugs, such as to mouse or hamster proteins.
5.
The subject has a medical history of immunological disorders, excluding seasonal 
allergic rhinitis/conjunctivitis, mild asthma, food allergies or animal allergies.
6.
The subject has a medical history of a thromboembolic event.
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7.
The subject is HIV positive with an absolute Helper T cell (CD4) count 
200/mm3.
8.
The subject has been diagnosed with significant liver disease as evidenced by any 
of the following: serum alanine aminotransferase (ALT) 5 times the upper limit of 
normal; hypoalbuminemia; portal vein hypertension (e.g., presence of otherwise 
unexplained splenomegaly, history of esophageal varices).
9.
The subject has been diagnosed with renal disease, with a serum creatinine level 
≥2.5 mg/dL.
10. The subject has been treated with an immunomodulatory drug, excluding topical 
treatment (e.g., ointments, nasal sprays), within 30 days prior to signing the 
informed consent.
11. The subject is pregnant or lactating at the time of enrollment.
12. The subject has participated in another clinical study involving another IP or 
investigational device within 30 days prior to enrollment or is scheduled to 
participate in another clinical study involving an IP or investigational device 
during the course of this study.
13. The subject has a progressive fatal disease and/or life expectancy of less than 
15 months.
14. The subject is identified by the investigator as being unable or unwilling to 
cooperate with study procedures.
15. The subject suffers from a mental condition rendering him/her unable to 
understand the nature, scope and possible consequences of the study and/or 
evidence of an uncooperative attitude.
16. The subject is in prison or compulsory detention by regulatory and/or juridical 
order
17. The subject is member of the study team or in a dependent relationship with one 
of the study team members which includes close relatives (i.e., children, 
partner/spouse, siblings and parents) as well as employees.
9.3 Delay Criteria
1.
If the subject has an acute bleeding episodes or presents with an acute illness (e.g., 
influenza, flu-like syndrome, allergic rhinitis/conjunctivitis, non-seasonal asthma) 
the screening visit will be postponed until the subject has recovered.
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9.4 Withdrawal and Discontinuation
Any subject may voluntarily withdraw (i.e., reduce the degree of participation in the 
study) consent for continued participation and data collection. The reason for withdrawal 
will be recorded on the End of Study CRF. Assessments to be performed at the 
termination visit (including cases of withdraw or discontinuation) are described in 
Section 10.6 and Section 20.2. 
Discontinuation (i.e., complete withdrawal from study participation) may be due to 
dropout (i.e., active discontinuation by subject) or loss to follow-up (ie, discontinuation 
by subject without notice or action). Additionally, the investigator and sponsor have the 
discretion to discontinue any subject from the study if, in their judgment, continued 
participation would pose an unacceptable risk for the subject.
Subjects also will be withdrawn from treatment or discontinued from further study 
participation for the following reasons:
The subject is scheduled for an extended treatment period 3 months with non-
topical immunomodulating drugs other than anti-retroviral chemotherapy (e.g., 
-interferon, corticosteroid agents [equivalent to hydrocortisone greater than 10 mg 
/day]) during the course of the study.
Subjects with chronic hepatitis B or C develop ALT/aspartate aminotransferase 
(AST) levels exceeding 5 times the upper limit of normal for 1 month.
Subjects who experience severe allergic reactions, e.g., anaphylaxis upon exposure 
to rVWF. 
Subjects who develop a neutralizing inhibitor to rVWF and/or ADVATE
(biological assays).
Subjects who demonstrate clinical signs of thrombotic events.
The subject becomes pregnant. IP exposure will be discontinued. Attempts will be 
made to follow the subject through completion of the pregnancy and up to 1 year 
post delivery, if feasible. The investigator will record a narrative description of the 
course of the pregnancy and its outcome.
The subject begins lactating. IP exposure will be discontinued.  The investigator 
will record a narrative description of the course of the baby’s development. 
The subject is not compliant with the prophylactic treatment regimen and does not 
adhere to the frequency of IP administration. Once >30% of infusions are missed
within a visit interval (3 months), the subject will be discontinued from further 
participation in the study. 
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10. STUDY PROCEDURES
10.1 Informed Consent and Enrollment
Any patient who provides informed consent (i.e., signs and dates the informed consent 
form and assent form, if applicable) is considered enrolled in the study.
10.2 Subject Identification Code
The following series of numbers will comprise the SIC: protocol identifier (e.g., 090701) 
to be provided by the sponsor, 2- or 3-digit number study site number (e.g., 02) to be 
provided by the sponsor, and 3- or 4-digit subject number (e.g., 0003) reflecting the order 
of enrollment (i.e., signing the informed consent form). For example, the third subject 
who signed an informed consent form at study site 02 will be identified as Subject 
090701-020003. All study documents (e.g., CRFs, clinical documentation, sample
containers, drug accountability logs, etc.) will be identified with the SIC. Additionally, a 
uniquely coded SIC(s) is permitted as long as it does not contain a combination of 
information that allows identification of a subject (e.g., collection of a subject’s initials 
and birth date would not be permitted), in compliance with laws governing data privacy.
10.3 Screening and Study Visits
The study site is responsible for maintaining an enrollment/screening log that includes all 
subjects enrolled. The log also will serve to document the reason for screening failure. 
All screening data will be collected and reported in CRFs, regardless of screening 
outcome. If a subject is re-screened, the End of Study CRF should be completed, and a 
new ICF, new SIC and new CRF are required for that subject.
The overall study design is illustrated in the Figure 1. Details on the procedures to be 
performed at each study visit, including screening, are provided in Supplement 20.2
Schedule of Study Procedures and Assessments and Supplement 20.3 Clinical Laboratory 
Assessments.
10.3.1 Screening Visit
Written informed consent must be obtained from each subject before any study 
related procedures are performed. To initiate screening procedures, at least 72 hours 
must have elapsed since the last VWF administration and the subject must not be 
actively bleeding at the time of screening. The screening visit will be delayed if the 
subjects presents with an acute bleeding episodes or acute illness (e.g. influenza, flu-
like symptoms, inflammatory diseases) until the event has resolved. All screening 
procedures and confirmation of eligibility shall take place within 60 days prior to 
the first infusion of IP for PK assessments. If the IP is not infused within 60 days,
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all screening assessments except blood group, human leucocyte antigen (HLA), genetics, 
multimeric pattern and 
, must be repeated to reconfirm eligibility. Refer to 
Supplement 20.2 and Supplement 20.3. Upon completion of screening procedures, 
subject eligibility will be confirmed by the sponsor on a subject eligibility form before 
additional study procedures are undertaken. The subject will maintain a diary that will 
include infusion logs, AEs, and concomitant medications (see Section 10.5). The 
allocation of IP will be initiated after the subject has qualified for home treatment (see 
Section 8.7.4.3.1).
In the event of a subject experiencing a bleeding episode that requires treatment between 
the screening visit and the baseline visit (PK assessment), the subject will be treated with
rVWF. If rVWF is not available for any reason, e.g.: subject not yet trained  on IP 
administration, study site visit for IP administration not feasible, etc., the subject may use 
his/her standard of care, such as commercial pdVWF/FVIII products. Subject currently 
on standard prophylaxis regimen with a commercial pdVWF/FVIII product may continue 
his/her regimen until initiation of rVWF prophylaxis (baseline – PK assessment visit) at 
the discretion of the investigator. In such cases, a minimum washout period of at least 
5 days is required prior to infusion of rVWF for PK assessment (see Section 10.3.2 and 
Section 10.3.3).
10.3.2 Baseline Visit - PK-Assessment Visit 
After screening and confirmation of eligibility each subject will undergo a PK 
assessment. Subjects transitioning from the surgery study 071101 will not need to 
undergo a PK baseline assessment again, provided valid PK data from 071101 is 
available. These subjects may proceed directly with the prophylaxis initiation visit (refer 
to Section 10.3.3) All subjects will receive a dose of 50± 5 IU/kg rVWF:RCo to 
determine VWF and FVIII levels. Blood samples will be drawn within 30 minutes pre-
infusion, and at 7 time points post-infusion (305 minutes, 605 minutes, 61 hours, 12 
1 hours, 242 hours, 482 hours, 722 hours). IP infusion vials from the same lot 
number should be used for all PK-assessments per subject. Refer to Section 20.2 and 
Section 20.3. Samples for measurement of FVIII and VWF activity taken through to 
6 hours post-infusion will be obtained from an extremity different from that used for the 
infusion of IP. Where needed, the phlebotomy site will be kept patent via an infusion of 
normal saline. In this event, at least 5 mL of blood will be collected and discarded before 
collection of the next test sample into a fresh syringe.
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If the subject has a central venous catheter, the central line should be used to administer 
the infusion and a peripheral venipuncture should be used to collect the blood samples. 
In the event that a blood sample must be drawn through the central line used for 
administration of IP, the line must first be flushed with at least 10 mL normal saline or 
other suitable catheter flush solution that does not contain anticoagulant. At least 5 mL of 
whole blood must be collected and discarded prior to obtaining the sample. 
If a subject experiences a bleeding episode during the PK assessment no subsequent
blood sample will be drawn in that specific PK period. The guidance provided in 
Section 8.7.4.4 has to be followed for the treatment of the bleeding episode. The subject 
once recovered is eligible to repeat the PK assessment. 
10.3.3 Prophylaxis Initiation Visit
After the blood sample for the 72 h PK assessment is drawn the subject will receive the 
first rVWF prophylactic dose of 50±10 IU/kg rVWF: RCo. Details on dose are provided
in Section 8.7.4.3. 
If a subject did not undergo PK assessment (for example the subject has transitioned from 
the surgery study 071101 and has undergone PK in this study, refer to Section 10.3.3.1),
procedures and assessments at this visit include: adverse events, bleeding episodes,
medications taken, non-drug therapies and laboratory assessment. Independent of 
previous PK assessment visits, within 2 hours prior the IP infusion, a physical 
examination will be performed. Vital signs will be assessed within 30 minutes prior to IP
rVWF infusion and 30 minutes ±15 minutes after IP infusion. For subjects with a 
previous PK assessment in the course of the surgery study, incremental recovery (IR) will 
be determined based on VWF: RCo activity assessed prior and after IP infusion. Further 
details are provided in Supplement 20.2 and Supplement 20.3.
10.3.3.1 Surgical Prophylaxis
Subjects who require surgery during the study can be temporarily transferred to study 
071101 (Surgery study) for their peri-operative and post-operative hemostatic 
management. The subject will be transferred to the Surgery study once Informed Consent
for the Surgery study has been signed. Refer to the Surgery study protocol for further 
details. 
The two studies are managed separately and the amount of transferrable data is limited. 
However, to minimize subject efforts and the number of blood draws, coinciding of 
study visits is feasible. For example, the screening visit for the Surgery study may be 
aligned with one of the foreseen follow-up visits of this prophylaxis study. 
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In this case, assessment results and laboratory values obtained at this consolidated study 
visit will be made available for both studies. Subjects transferred to the Surgery study 
071101 will stop prophylactic treatment in this current prophylaxis study and adhere to 
the treatment regimen in the Surgery study (preoperative priming and loading dose, intra-
and postoperative dosing) as described in the Surgery protocol. Subjects are expected to 
participate in the Surgery study for 8 to 15 weeks.. The termination visit of the Surgery 
Study may be used to confirm eligibility for transferring the subject back to this
prophylactic study 071301. Thereafter, the subject shall continue with the infusion of IP 
according to the prophylactic treatment regimen. The regular follow-up visits for the 
071301 study will be re-scheduled accordingly, calculating from the time point the 
subject has restarted his/her previous prophylactic treatment regimen. The safety and 
efficacy data recorded while the subject was enrolled in the Surgery study will only be 
considered for the evaluation and assessment of the final results and conclusion of the
Surgery study, but not for the assessment of efficacy and safety of this prophylaxis study.
10.3.4 Treatment of Bleeding Episodes
Treatment of bleeding episodes is described in detail in Section 8.7.4.4.
10.3.5 Follow-Up Visits (1 Month ± 1 Week, 2 Months ± 1 Week, 3 Months
± 2 Weeks, 6 Months ± 2 Weeks, 9 Months ± 2 Weeks)
Visits will be performed after the prophylaxis  initiation visit at 1 month ± 1 week, 
2 months ± 1 week and 3 months± 2 weeks and thereafter every three months± 2 weeks. 
Additional visits may occur if clinically indicated (see Section 10.3.6).
Within 2 hours prior to the rVWF IP infusion , a physical examination will be performed. 
Vital signs will be assessed within 30 minutes prior to IP infusion and 30 minutes
±15 minutes after IP infusion. Incremental recovery (IR) will be determined at each 
follow-up visit based on VWF:RCo activity assessed prior to and after IP infusion. 
The blood sample for incremental recovery (IR) analysis will be drawn within 30 minutes 
prior to IP infusion and 30 minutes ±5 minutes after IP infusion. rVWF will be infused at 
the regular prophylactic dose, i. e 50 ± 10 IU/kg rVWF:RCo. For each subject’s recovery 
analysis IP infusion, vials from the same lot number should be used. 
Testing for VWF:RCo VWF:CB, rVWF:Ag, INNOVANCE VWF:Ac (exploratory) and 
FVIII:C level will be performed using the blood sample obtained before and after IP 
infusion. 
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The blood sample prior to IP infusion will also be used for the assessment ofinhibitory 
and binding antibodies, clinical chemistry and hematology. A washout period of at least 
72 hours after the last infusion applies before the blood draw for the immunogenicity 
assays. Bleeding episodes, the hemostatic efficacy and AEs will be evaluated based on 
the review of the patient diary. Refer to Section 20.2 and Section 20.3. The evaluation of 
IP consumption and treatment compliance will be performed based on subject’s diary 
entries. If a subject is not compliant with the prophylactic treatment regimen and does not 
adhere to the required frequency of administration of IP infusions [>30% of infusions
were missed within a visit interval (3 months)] the subject will be withdrawn from the 
study.
At the 6 months ± 2 week visit an electrocardiogram (ECG) will be performed and 
data will be collected. For the hemostatic efficacy assessment the following 
information will be recorded by the subject or by authorized study site personnel in the 
patient diary: bleeding location, type, severity, onset and resolution date and time, 
infusion date and time, clinical efficacy according to the rating scale. If at any time 
during the study a subject’s bleeding episode does not adequately respond to rVWF 
therapy, he/she will be evaluated for the presence of inhibitory and total binding 
antibodies. Refer to Section 12.9.3.2.
Further guidance on completing the subject’s diary will be provided to the subjects during 
training for home treatment (see Section 8.7.4.3.1).
10.3.6 Unscheduled Visits
For any unscheduled visit (except for collection of IP) a clinical assessment will be 
performed as per the scheduled follow-up visits with the exception of 
, ECG and 
IR determination (refer to Supplement 20.2 and Supplement 20.3.).
Subjects who have more than one bleeding episode in 3 months, or an increased 
frequency of bleeding, should go to the study site for an unscheduled visit.
Follow-Up visits after the subject has experienced a bleed may be requested by the 
investigator. Additional assessments may be required which are at the discretion of the 
investigator. 
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10.3.7 Study Termination Visit (12 months ± 2 weeks)
A washout period of at least 72 hours is required between the last infusion and the study 
termination visit. The following assessments will be performed after the last infusion of 
rVWF and at the time of early termination, if possible: vital signs, physical examination, 
clinical chemistry, hematology, rVWF:RCo, rVWF:CB, rVWF:Ag assays and FVIII:C
and immunogenicity assays (refer to Supplement 20.2 and Supplement 20.3). A review of 
all AEs, bleeding episodes and the subject’s diary and the 
will be conducted at 
the termination visit.
10.4 Medications and Non-Drug Therapies 
The following medications and non-drug therapies are not permitted within 30 days 
before study entry and during the course of the study:
Medications:
Immunomodulating drugs other than anti-retroviral chemotherapy 
(e.g. -interferon, or corticosteroid agents at a dose equivalent to hydrocortisone 
greater than 10 mg/day) and an extended treatment period 3 months.
Another investigational and/or interventional study drug (except rVWF and FVIII 
administered under the surgery protocol).
A subject who has taken any of these medications or received any of these non-drug 
therapies during the study will be withdrawn from the study. 
The following medications are permitted during the course of the study:
Antifibrinolytics (e.g., tranexamic acid, -amino caproic acid) or topical
hemostats as needed, according to each institution’s standard of care
Emergent use of a VWF concentrate other than rVWF may be permissible
under certain circumstances (see Section 8.7.4.4.1)
Details of all adjunctive hemostatic medication used, including dose and reason for use, 
will be recorded in the eCRFs.
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10.5 Subject Diary
1.
An electronic subject diary will be provided to each subject at the baseline visit to
record the following information:

IP infusions to include date, start and stop times of the infusion, number of 
vials utilized, infusion volume, potency and lot numbers for prophylactic 
treatment or treatment of bleeding episodes, including IP infusion for PK 
analysis and other infusions at the study site 
2.
Details of bleeding episodes (site and type of bleeding) and response to treatment 
as described in Section 8.7.4.4
3.
Subjective hemostatic efficacy assessments
4.
Body weight 
5.
All AEs 
6.
Concomitant medications taken (including immunizations and infusions other 
than IP) and non-drug therapy.
7.
Drug accountability (number of unused vials of investigational product remaining 
in the subject’s refrigerator including refrigerator temperature as recorded, prior to 
each study visit).
Subjects and/or their legally authorized representatives will be trained on use of the diary. 
The diary will be provided in electronic format and remain with the subject for the 
duration of the study. The investigator will review the diary for completeness and request 
missing information periodically and in a timely manner. Untoward events recorded in 
the diary will be reported as AEs according to the investigator’s discretion and clinical 
judgment.
Subject entries in the diary will serve as source records. During study participation the 
investigator has access to the database holding the subject diary data. After study closure, 
the investigator will receive the diary records for their subjects, including audit trail 
records, in PDF format. The data will be transmitted to the CRF by a validated transfer. 
10.6 Subject Completion/Discontinuation
A subject is considered to have completed the study when he/she ceases active 
participation in the study because the subject has, or is presumed to have completed all 
study procedures according with the protocol (with or without protocol deviations).
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Reasons for completion/discontinuation will be reported on the 
Completion/Discontinuation CRF, including: completed, screen failure, AE (e.g., death), 
discontinuation by subject (e.g., lost to follow-up [defined as 3 documented unsuccessful 
attempts to contact the subject], dropout), physician decision (e.g., pregnancy, 
progressive disease, non-compliance with IP/protocol violation(s), recovery), study 
terminated by sponsor, or other (reason to be specified by the investigator, e.g., technical 
problems). Regardless of the reason, all data available for the subject up to the time of 
completion/discontinuation should be recorded on the appropriate CRF. 
Every effort will be made to have discontinued subjects complete the study 
completion/termination visit. If the completion/termination visit is done as an additional, 
unscheduled visit, the assessment results shall be recorded with the 
completion/termination visit. If a subject terminates participation in the study and does 
not return for completion/termination visit, his/her last recorded assessments shall remain
with the last visit. The reason for discontinuation will be recorded, and the data collected 
up to the time of discontinuation will be used in the analysis and included in the clinical 
study report. If additional assessments are required, the assessments shall be recorded 
separately. Assessments to be performed at the termination visit (including in cases of 
withdraw or discontinuation) can be found in Supplement 20.2 Schedule of Study 
Procedures and Assessments and Supplement 20.3 Clinical Laboratory Assessments.
In the event of subject discontinuation due to an AE, clinical and/or laboratory 
investigations that are beyond the scope of the required study observations/assessments 
may be performed as part of the evaluation of the event. These investigations will take 
place under the direction of the investigator in consultation with the sponsor, and the 
details of the outcome may be reported to the appropriate regulatory authorities by the 
sponsor. 
10.7 Procedures for Monitoring Subject Compliance
Subject compliance with the procedures of this study (treatment regimens and study 
visits) will be monitored by the investigator or/a licensed healthcare professional at the 
study site.
During the regular scheduled follow-up visits a direct review of the subject’s source data 
(e-diaries) will be performed at the sites and evaluated against the protocol requirements. 
In addition drug accountability will be evaluated at each follow-up study visit and the 
study termination visit by comparing the infusions recorded in the subject diary with
empty vials returned by each subject to the study site, and the study site’s dispensing 
record. Protocol deviations will be noted in the final report. 
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11. ASSESSMENT OF EFFICACY AND PHARMACOKINETICS
11.1 Assessment of Spontaneous Bleeding Episodes/Annualized Bleed Rate 
The annualized bleed rate (ABR) will be assessed based upon each individual 
spontaneous bleed, requiring coagulation factor replacement therapy, i.e. rVWF 
treatment. The following details on bleeding episodes will be recorded by the subject (for 
home treatment), the subject’s healthcare provider (for treatments away from the primary 
investigative site), or by authorized, qualified personnel at the participating site (for 
hospital-based treatment) in the subject’s diary:
Location of bleed; i.e., joint, menorrhagia, epistaxis, gastrointestinal, soft tissue, 
muscle, body cavity, intracranial, etc.
Type of bleed; i.e., spontaneous, traumatic, unknown
Severity of bleed; i.e., minor, moderate, and major 
Date and time of onset of bleed
Date and time of each infusion of rVWF or rVWF-ADVATE used to treat a 
bleeding episode
Date and time of resolution of the bleeding episode
Type and number of analgesics as well as additional hemostatic treatments required 
Other concomitant medications
Non-drug therapies
AEs (refer to Section 12.1)
Study site personnel are qualified after they have undergone training during the 
qualification of the site. 
All types of bleeds, including traumatic bleeds, will be recorded, however only 
spontaneous bleeds requiring VWF treatment will be considered for the assessment of 
ABRs used for primary outcome assessment . 
Bleeds occurring at the same anatomical location (e.g., right knee) with the same etiology 
(i.e., spontaneous versus injury) within 24 hours after onset of the first bleed will be 
considered a single bleed. Bleeding occurring at multiple locations related to the same 
injury (e.g., knee and ankle bleeds following a fall) will be counted as a single bleeding 
episode. 
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All efforts should be made to use rVWF for treatment of bleeding episodes. If needed the 
use of a VWF concentrate other than IP for the treatment of bleeding episodes will not 
disqualify the subject from further participation in the study and will not be considered a 
protocol deviation. 
11.2 Evaluation of ABR before rVWF Prophylaxis and ABR under rVWF
prophylactic treatment
At screening, the subject’s medical history will be recorded, including the number of all 
spontaneous bleeding episodes within the past 12 months on-demand treatment. The 
ABR during the 12 months before prophylactic treatment will be the baseline for 
evaluation of ABR under rVWF prophylactic treatment. If applicable, the ABR 
determined during previous prophylactic treatment using a commercial pdVWF/FVIII 
product will also be recorded. The maximum interval of bleed-free periods as well as 
trauma induced bleeding episodes will also be recorded.
11.3 Number of Infusions and Total Weight Adjusted Consumption of rVWF and 
ADVATE
The number of rVWF and ADVATE (in case of bleeding episode treatment) infusions 
will be logged in the subject diary. Based on these entries the weight adjusted 
consumption will be calculated per month and per year. 
11.4 Assessment of Efficacy for Treatment of Bleeding Episode
Investigators will be asked to assess and record hemostatic efficacy after resolution of 
each bleeding episode using the 4-scale rating system outlined in Table 3. 
Table 3
Hemostatic Efficacy Rating Scale 12
Rating Scale
Definition
Excellent
Hemostasis achieved/complete cessation of bleeding
Good
Slight oozing/partial but adequate control of bleeding did not require 
additional product for unplanned treatment
Moderate
Moderate bleeding/moderate control of bleeding; required additional 
product for unplanned treatment
None
Severe uncontrolled bleeding
11.5 Pharmacokinetic Assessment
Details on pharmacokinetic assessments are provided in Section 12.9.1.
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12. ASSESSMENT OF SAFETY
12.1 Adverse Events
12.1.1 Definitions
An AE is defined as any untoward medical occurrence in a subject administered IP that 
does not necessarily have a causal relationship with the treatment. An AE can therefore 
be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom
(e.g., rash, pain, discomfort, fever, dizziness, etc.), disease (e.g., peritonitis, bacteremia,
etc.), or outcome of death temporally associated with the use of an IP, whether or not 
considered causally related to the IP.
12.1.1.1 Serious Adverse Event
A serious adverse event (SAE) is defined as an untoward medical occurrence that at any 
dose meets one or more of the following criteria:
Outcome is fatal/results in death (including fetal death)
Is life-threatening – defined as an event in which the subject was, in the judgment 
of the investigator, at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death had it been more severe.
Requires inpatient hospitalization or results in prolongation of an existing 
hospitalization – inpatient hospitalization refers to any inpatient admission, 
regardless of length of stay.
Results in persistent or significant disability/incapacity (i.e., a substantial disruption 
of a person’s ability to conduct normal life functions)
Is a congenital anomaly/birth defect
Is a medically important event – a medical event that may not be immediately life-
threatening or result in death or require hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the definitions above. Examples of such events are: 

Intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias, or convulsions that do not result in 
hospitalization, or development of drug dependence or drug abuse 

Reviewed and confirmed seroconversion for human immunodeficiency virus
(HIV), hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus
(HCV), hepatitis E virus (HEV), or parvovirus B19 (B19V)

Development of inhibitory VWF antibodies

Development of inhibitory antibodies to FVIII (titer ≥ 0.4 BU (by Nijmegen-
modified Bethesda assay) or ≥0.6 BU (by Bethesda assay))
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
Thromboembolic events (e.g., myocardial infarction, stroke, transient ischemic 
attack (TIA), deep vein thrombosis (DVT) or pulmonary embolism)

Anaphylactic type hypersensitivity reactions (for definition, refer to
Section 12.6.2)
Uncomplicated pregnancies, following maternal or paternal exposure to IP are not 
considered an (S)AE; however, any pregnancy complication or pregnancy termination by 
therapeutic, elective, or spontaneous abortion shall be considered an SAE.
12.1.1.2 Non-Serious Adverse Event
A non-serious AE is an AE that does not meet the criteria of an SAE.
12.1.1.3 Unexpected Adverse Events
An unexpected adverse event is an AE whose nature, severity, specificity, or outcome is 
not consistent with the term, representation, or description used in the Reference Safety 
Information (e.g., IB, package insert). “Unexpected” also refers to the AEs that are 
mentioned in the IB as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring 
with the particular drug under investigation.
12.1.1.4 Preexisting Disease
Preexisting diseases that are present before entry in to the study are described in the 
medical history, and those that manifest with the same severity, frequency, or duration 
after IP exposure will not be recorded as AEs. However, when there is an increase in the 
severity, duration, or frequency of a preexisting disease, the event must be described on 
the AE CRF.
12.1.2 Assessment of Adverse Events
For the purposes of this study, the following will not be considered as AEs and will not 
be included in the analysis of AEs.
Bleeding episodes are part of the underlying disease and therefore are not AEs; they 
will be evaluated in the context of efficacy. If a bleeding episode was caused by an 
injury, the injury would not be reported as an AE, unless it resulted in a medical 
finding other than a bleeding episode (e.g., abrasion of skin). Therefore, any VWD-
related bleeding event (e.g., epistaxis, gastrointestinal bleeding, musculo-skeletal 
bleeding, menorrhagia) will not be reported as AEs. However, the investigator may 
decide that the event is an AE if the event also would have occurred in a healthy 
individual under the same circumstances.
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Seroconversion after documented HAV/HBV vaccination prior to or during the 
study period.
Each AE from the first IP exposure to the study completion date will be described on the 
AE CRF using the medical diagnosis (preferred), or, if no diagnosis could be established 
at the time of reporting the AE, a symptom or sign, in standard medical terminology in 
order to avoid the use of vague, ambiguous, or colloquial expressions (see definition in 
Section 12.1). Each AE will be evaluated by the investigator for:
Seriousness as defined in Section 12.1.1.1
Severity as defined in Section 12.1.2.1
Causal relationship to IP exposure or study procedure as defined in Section 12.1.2.2
For each AE, the outcome (i.e., recovering/resolving, recovered/resolved, 
recovered/resolved with sequelae, not recovered/not resolved, fatal, unknown) and if 
applicable action taken (i.e., dose increased, dose not changed, dose reduced, drug 
interrupted, drug withdrawn, not applicable, or unknown) will also be recorded on the AE 
CRF. Recovering/resolving AEs will be followed until resolution.
If the severity rating for an ongoing AE changes before the event resolves, the original 
AE report will be revised (i.e., the event will not be reported as separate AE). During the 
course of any AE, the highest severity rating will be reported.
Deviations from the protocol-specified dosage (including underdosing /overdosing
[< 20 IU/kg rVWF:RCo or > 100 rVWF:RCo], abuse, and withdrawal, treatment errors 
(including incorrect route of administration, use of an incorrect product, and deviations 
from the protocol-defined dosing schedule), failures of expected pharmacological actions, 
and unexpected therapeutic or clinical benefits will be followed with regard to occurrence 
of AEs, lack of efficacy, and/or other observations because these events may be 
reportable to regulatory authorities. 
Any pregnancy that occurs after administration of IP will be reported on a Pregnancy
Form and followed-up at 1 year post-delivery, if feasible. 
If an investigator becomes aware of an SAE occurring in a subject after study completion, 
the SAE must be reported on the SAE Form within 24 hours after awareness: no 
additional reporting on CRFs is necessary.
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12.1.2.1 Severity
The investigator will assess the severity of each AE using his/her clinical expertise and 
judgment based on the most appropriate description below:
Mild
The AE is a transient discomfort and does not interfere in a significant manner 
with the subject’s normal functioning level.
The AE resolves spontaneously or may require minimal therapeutic
intervention.
Moderate
The AE produces limited impairment of function and may require therapeutic
intervention.
The AE produces no sequela/sequelae.
Severe
The AE results in a marked impairment of function and may lead to temporary 
inability to resume usual life pattern.

The AE produces sequela/sequelae, which require (prolonged) therapeutic
intervention.
These severity definitions will also be used to assess the severity of an AE with a study-
related procedure(s), if necessary.
12.1.2.2 Causality
Causality is a determination of whether there is a reasonable possibility that the IP is 
etiologically related to/associated with the AE. Causality assessment includes, e.g., 
assessment of temporal relationships, dechallenge/rechallenge information, association 
(or lack of association) with underlying disease, presence (or absence) of a more likely 
cause, and physiological plausibility. For each AE, the investigator will assess the causal 
relationship between the IP and the AE using his/her clinical expertise and judgment 
according to the following most appropriate algorithm for the circumstances of the AE:
Not related (both circumstances must be met)

Is due to underlying or concurrent illness, complications, concurrent 
treatments, or effects of concurrent drugs

Is not associated with the IP (i.e., does not follow a reasonable temporal 
relationship to the administration of IP or has a much more likely alternative 
etiology). 
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Unlikely related (either 1 or both circumstances are met)
Has little or no temporal relationship to the IP 
A more likely alternative etiology exists
Possibly related (both circumstances must be met)
Follows a reasonable temporal relationship to the administration of IP
An alternative etiology is equally or less likely compared to the potential 
relationship to the IP
Probably related (both circumstances must be met)
Follows a strong temporal relationship to the administration of IP, which may 
include but is not limited to the following: 
o
Reappearance of a similar reaction upon re-administration (positive 
re-challenge)
o
Positive results in a drug sensitivity test (skin test, etc.)
o
Toxic level of the IP as evidenced by measurement of the IP 
concentrations in the blood or other bodily fluid
Another etiology is unlikely or significantly less likely
For events assessed as not related or unlikely related and occurring within 5 days after IP 
infusion, the investigator shall provide the alternative etiology. These causality 
definitions will also be used to assess the relationship of an AE with a study-related 
procedure(s), if necessary.
12.2 Urgent Safety Measures
An urgent safety measure is an immediate action taken, which is not defined by the 
protocol, in order to protect subjects participating in a clinical trial from immediate harm. 
Urgent safety measures may be taken by the sponsor or clinical investigator, and may 
include any of the following: 
Immediate change in study design or study procedures
Temporary or permanent halt of a given clinical trial or trials
Any other immediate action taken in order to protect clinical trial participants from 
immediate hazard to their health and safety
The investigator may take appropriate urgent safety measures in order to protect subjects 
against any immediate hazard to their health or safety. The measures should be taken 
immediately and may be taken without prior authorization from the sponsor. 
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In the event(s) of an apparent immediate hazard to the subject, the investigator will notify 
the sponsor immediately by phone and confirm notification to the sponsor in writing as 
soon as possible, but within 1 calendar day after the change is implemented. The sponsor 
will also ensure the responsible ethics committee is notified of the urgent measures taken 
in such cases according to local regulations.
12.3 Untoward Medical Occurrences
Untoward medical occurrences occurring before the first exposure to IP are not 
considered AEs (according to the definition of AE, see Section 12.1.1). However, each 
serious untoward medical occurrence experienced before the first IP exposure (i.e., from 
the time of signed informed consent up to but not including the first IP exposure) will be 
described on the SAE Report. These events will not be considered as SAEs and will not 
be included in the analysis of SAEs. 
12.4 Non-Medical Complaints
A non-medical complaint (NMC) is any alleged product deficiency that relates to 
identity, quality, durability, reliability, safety and performance of the product but did not 
result in an AE. NMCs include but are not limited to the following:

A failure of a product to exhibit its expected pharmacological activity and/or 
design function, e.g. reconstitution difficulty

Missing components

Damage to the product or unit carton

A mislabeled product (e.g., potential counterfeiting/tampering)

A bacteriological, chemical, or physical change or deterioration of the product 
causing it to malfunction or to present a hazard or fail to meet label claims
Any NMCs of the product will be documented on an NMC form and reported to the 
sponsor within 1 business day. If requested, defective product(s) will be returned to the 
sponsor for inspection and analysis according to procedures.
12.5 Medical, Medication, and Non-Drug Therapy History
At screening, the subject’s medical history will be described for the following body 
systems including severity (defined in Section 12.1.2.1) or surgery and start and end 
dates, if known: eyes, ears, nose, and throat; respiratory; cardiovascular; gastrointestinal; 
musculoskeletal; neurological; endocrine; hematopoietic/lymphatic; dermatological; and 
genitourinary. The subject’s medical history will also include documented history of on-
demand and prophylactic treatment for the past 12 months and a documented history, 
e.g., patient charts and prescription information, of all bleeding episodes within the past 
12 months.
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All medications taken and non-drug therapies received in the 2 weeks prior to study entry 
and all concomitant medications and non-drug therapies during study will be recorded on 
the CRFs.
Data on medical history, drug and non-drug therapy history of those subjects who 
transition from surgery rVWF study will be used from the eCRF of the main studies, will 
be updated, if applicable, and transcribed into the respective eCRF of the prophy study.
12.6 Physical Examinations
At screening and subsequent study visits (as described in Section 10.3), a physical 
examination will be performed on the following body systems: general appearance, head 
and neck, eyes and ears, nose and throat, chest, lungs, heart, abdomen, extremities and 
joints, lymph nodes, skin, and neurological. At screening, if an abnormal condition is 
detected, the condition will be described on the medical history CRF. At study visits, if a 
new abnormal or worsened abnormal pre-existing condition is detected, the condition will 
be described on the AE CRF. If the abnormal value was not deemed an AE because it 
was due to an error, due to a preexisting disease (described in Section 12.1.1.4), not 
clinically significant, a symptom of a new/worsened condition already recorded as an AE, 
or due to another issue that will be specified, the investigator will record the justification 
on the source record.
12.6.1 Thromboembolic events
Thromboembolic events are considered a potential risk of rVWF treatment, hence,
indices of thromboembolic events such as clinical evidence of thrombosis will be 
monitored during the study. In the case of clinical signs of any thrombotic event other 
than superficial thrombosis, additional diagnostic procedures are required according to 
each institution’s standard of care which may consist of, but are not limited to the 
following:

For deep vein thrombosis (DVT): Magnetic Resonance Imaging (MRI), 
compression ultrasound or impedance plethysmography.

For pulmonary embolism: ECG, chest radiography, perfusion/scintiscan or MRI. 

For myocardial infarction: ECG, cardiac enzymes, echocardiography

For stroke: diffusion-weighted magnetic resonance imaging or computed 
tomography, ABCD scoring, carotid imaging
Results of diagnostic procedures may be forwarded to the sponsor to be reviewed by an 
independent external expert panel, such as the DMC, if applicable.
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12.6.2 Anaphylactic reactions
Anaphylaxis is highly likely when any of the following 3 criteria are fulfilled:
1) Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue or both (e.g, generalized hives, pruritus or flushing, swollen lips-
tongue-uvula) and at least one of the following:
a. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced peak expiratory flow [PEF], hypoxemia)
b. Reduced blood pressure (BP) or associated symptoms of end-organ 
dysfunction (e.g., hypotonia [collapse], syncope, incontinence)
2) Two or more of the following that occur rapidly after exposure to a likely allergen 
for that patient (minutes to several hours):
a. Involvement of the skin or mucosal tissue (e.g., generalized hives, pruritus 
or flushing, swollen lips-tongue-uvula)
b. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced PEF, hypoxemia)
c. Reduced BP or associated symptoms (hypotonia [collapse], syncope, 
incontinence)
d. Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, 
vomiting)
3) Reduced BP after exposure to a known allergen for that patient (minutes to 
several hours):
a. Infants and children: low systolic BP (age specific) or greater than 30% 
decrease in systolic BP
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease 
from that person’s baseline BP
If a subject develops a severe allergic reaction (e.g., anaphylaxis) in the course of the 
clinical study this needs to be reported as SAE (Section 12.1.1.1). Additional blood draws 
for Anti-VWF IgE antibody testing will be drawn (Section 12.9.13).
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12.7 Vital Signs
Vital signs will be assessed pre and post-infusion at each visit, if not stated otherwise:
Height (cm) and weight (kg)
Blood pressure: Systolic/diastolic blood pressure (mmHg) baseline measurements 
will be measured after a 10-minute rest in the supine/semi-recumbent position.
Pulse rate: Pulse rate (beats/min) will be measured at the distal radial arteries under 
the same conditions as above.
Respiratory rate: Respiratory rate (breaths/min) will be measured over a period of 1 
minute under the same conditions as above.
Temperature: Body temperature (oC or oF) may be determined by oral, rectal, 
axillary, or tympanic measurement at the discretion of the investigator. However, 
the same method should be used for all measurements in 1 subject.
Vital signs (pulse rate, respiratory rate, and blood pressure) should be recorded within 
30 min before and after IP administration. The assessment of vital signs per planned 
study visit is outlined in Supplement 20.2.
Vital sign values are to be recorded on the physical examination eCRF. For each vital 
sign value, the investigator will determine whether the value is considered an AE (see 
definition in Section 12.1). If assessed as an AE, the medical diagnosis (preferably), 
symptom, or sign, will be recorded on the AE eCRF. Additional tests and other 
evaluations required to establish the significance or etiology of an abnormal result, or to 
monitor the course of an AE, should be obtained when clinically indicated. Any abnormal 
value that persists should be followed at the discretion of the investigator.
12.8 Electrocardiogram 
A standard 12-lead ECG at rest will be performed at screening, at the 6 month follow-up 
visit and at the study termination visit and evaluated for medical significance by the
investigator.
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12.9 Clinical Laboratory Parameters
Refer to the Laboratory Manual for information on collection and processing of samples.
In general all laboratory tests will be performed at central laboratories, except the 
pregnancy and blood group test which will be performed at the local laboratory. In 
addition, relevant critical safety laboratory tests for complete blood count (CBC), serum 
chemistry and/or coagulation parameters such as VWF and FVIII activity may also be 
performed in the local laboratory to ensure that results will be available immediately to 
the investigator. In principle, results from the central laboratory will be used for data 
analysis purposes. The assays performed in the central laboratories are specified in the 
Laboratory Manual. The investigator will supply the sponsor with a list of the normal 
ranges and units of measurement for the laboratory variables to be determined at the site. 
Laboratory values such as antibodies to other proteins are not required immediately and 
will be assessed later during the course of the study. Any remaining samples not required 
for the purpose of this study may be used for non-commercial dedicated VWF and/or 
VWD research to improve the diagnosis and treatment.
Abnormal laboratory values deemed clinically significant by the investigator are to be 
recorded as AEs (see Section 12.1.2).
12.9.1 rVWF and endogenous FVIII Pharmacokinetics
PK assessments using a dose of 50 IU±5 IU/kg rVWF:RCo will be performed at the 
baseline visit. If the subject is on prophylactic treatment using a commercial 
pdVWF/FVIII product or is on on-demand treatment and has received VWF replacement 
therapy a washout period of at least 5 days is required before the infusion of rVWF for 
PK assessment can be administered. If a subject is on prophylactic treatment using a 
pdVWF product as standard care, the subject has to terminate the prophylactic treatment 
using rVWF immediately at least 5 days before the PK assessment is started (see further 
details in Section 10.3.1). 
Blood samples will be drawn within 30 minutes pre-infusion, and at 7 time points post-
infusion (305 minutes, 605 minutes, 61 hours, 12 1 hours, 242 hours, 48
2 hours and722 hours) VWF activity will be determined using the VWF:RCo, 
VWF:CB and the VWF: Ag assay. The Innovance assay will be used as an exploratory 
assay to provide supportive data and to compare the results of this new assay with results 
from the established VWF:RCo assay. 
Endogenous FVIII activity will be measured using the 1-stage clotting assay. 
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The following parameters will be used as part of the PK assessment:

Incremental recovery of VWF:RCo, VWF:Ag, VWF:CB and INNOVANCE 
VWF Ac (exploratory assay)

AUC/dose, area under moment curve (AUMC/dose, clearance (CL), Volume of 
distribution at steady state (Vss), mean residence time (MRT), of 
VWF:RCo ,VWF:Ag, VWF:CB and INNOVANCE VWF Ac (exploratory assay)

Half-life of VWF:RCo, VWF:Ag, VWF:CB and INNOVANCE VWF Ac 
(exploratory assay)

Time course of the FVIII:C levels

VWF collagen binding (VWF:CB) levels
12.9.2 Hematology and Clinical Chemistry
The hematology panel will consist of CBC [hemoglobin, hematocrit, erythrocytes (ie, red 
blood cell count [RBC]), and leukocytes (i.e., white blood cell count [WBC])] with 
differential (i.e., basophils, eosinophils, lymphocytes, monocytes, neutrophils) and 
platelet counts.
The clinical chemistry panel will consist of sodium (Na), potassium (K), chloride (Cl), 
alanine aminotransferase (ALT), lactate dehydrogenase (LDH), aspartate 
aminotransferase (AST), bilirubin (BILI), alkaline phosphatase (AP), blood urea nitrogen
(BUN), creatinine (CR), and glucose (Glu).
Blood will be obtained for assessment of hematology and clinical chemistry parameters at 
screening, during PK-assessment prior to rVWF IP infusion, after 24 ± 2 hours, 48 ±
2 hours and 72 ± 2 hours post rVWF IP infusion, at all follow-up visits as per schedule 
(refer to Supplement 20.3 Clinical Laboratory Assessments), i.e., 4 weeks ± 1week, 
8 weeks ± 1 week and every 3 months ± 2 weeks, and at study completion/termination. 
Hematology and clinical chemistry assessments will be performed on 
Ethylenediaminetetraacetic acid (EDTA)-anticoagulated whole blood and serum, 
respectively, at the central laboratory.
12.9.3 Immunology
12.9.3.1 Antibodies to VWF and FVIII
All subjects will be tested for binding and inhibitory antibodies to VWF and FVIII at 
screening, at baseline PK assessment, at each of the scheduled follow-up visits and at the 
study completion visit. Testing will be done prior to IP infusion and with at least a 
72 hour wash out period since the last IP infusion. If there is any suspicion of inhibitor 
development (e.g. excessive bleeding) binding and inhibitory antibodies to VWF and 
FVIII may be tested at the discretion of the investigator. 
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12.9.3.2 Inhibitory and Total Binding Anti-VWF Antibodies
The assays to establish the presence of neutralizing and total binding anti-VWF 
antibodies have been established in the absence of international standards and with only 
limited numbers of positive controls. Therefore, caution is advised in interpreting positive 
results. In particular, any clinical association, changes in the natural history of the 
disease, effect of therapy, etc. needs to be taken into account for final judgment. 
The sponsor’s Medical Director should be consulted for additional advice. As part of the 
AE follow-up, any sample testing positive needs to be confirmed after 2-4 weeks for 
central laboratory testing. Only confirmed neutralizing anti -VWF antibodies are 
considered inhibitors (see Section 12.9.3.4). These subjects need to be closely monitored 
and therapy adjusted accordingly. 
12.9.3.3 Binding antibodies to VWF 
The presence of total binding anti-VWF antibodies will be determined by an enzyme-
linked immunosorbent assay (ELISA) employing polyclonal anti-human Immunoglobulin
(Ig) antibodies (IgG, IgM and IgA). For this assay (ELISA), recombinant human VWF 
will be coated onto a microtiter plate, then incubated with dilutions of the positive 
control, the negative control or test sample. Antibodies against human VWF that are 
present in the samples bind to the coated antigen and will be detected with a horseradish 
peroxidase (HRP)-coupled goat anti-human antibody (secondary antibody). The positive 
control for this assay will be a human monoclonal antibody specific for human VWF 
spiked into the negative control. The negative control for this assay is pooled normal 
human plasma.
Plasma samples are analyzed for binding antibodies against the specific antigen in two 
steps. First, the sample is screened for antibodies and the titer of binding antibodies is 
determined. Second, the specificity of positive antibody results is confirmed.13 In brief, 
all samples are serially diluted (initial dilution 1:20 and further diluted 1:2). The titer 
endpoint, defined as the highest dilution that still gives a positive signal above cut off 
level, is determined in two independent duplicates. The cut off level is established based 
on background signal level of healthy plasma donors (n=160) and set to include 5% false 
positives to be as sensitive as possible (95% percentile). The ELISA assay is validated 
allowing an assay variability of ± 1 titer step. Therefore, differences ≤2 titers steps may 
be due to variability of the ELISA assay. Specificity has to be confirmed in a competition 
assay when a sample has a titer of 1:80 or higher in the screening assay. Based on the 
validation criteria samples tested in the screening assay at 1:20 or 1:40 cannot be 
confirmed in the competition assay. A positive screening value is confirmed if the 
difference between the titers determined for the subject sample (re-screen) and for the 
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subject sample with pre-incubation (confirmation sample) is > 2 titer steps. Antibody 
titers of subject samples will only be reported as positive, if the results of the screening 
and confirmatory analysis fulfill these acceptance criteria. The titer to be reported is 
always the one determined in the original screening procedure (independent of the result 
of the re-screening in the confirmation procedure). 
A more detailed test procedure will be supplied upon request or pro-actively if a sample 
tests positive. A treatment related increase of the binding anti-VWF antibodies is 
expected, if the titer increases by more than 2 titration steps. These subjects need to be 
closely monitored and therapy adjusted accordingly.
12.9.3.4 Neutralizing antibodies to VWF
Three functional VWF assays, collagen binding (VWF:CB) assay, Ristocetin cofactor 
(VWF:RCo) and FVIII binding (VWF:FVIIIB), will be used to test for the presence of 
inhibitory anti-VWF antibodies. Neutralizing antibodies to VWF:RCo, VWF:CB and 
VWF:FVIIIB activities will be measured by assays based on the Bethesda assay 
established for quantitative analysis of FVIII inhibitors (Nijmegen modification of the 
Bethesda assay).14 The amount of inhibitor is expressed as Bethesda units (BU) per mL.  
One BU is thereby defined as the amount of inhibitor that decreases the measured activity 
in the assays to 50% of that of the negative control samples. The assays were validated 
using human plasma samples from two type 3 VWD patients with low (1-2 BU/mL) and 
high (~10 BU/mL) titer inhibitors and plasma samples from non-human primates 
immunized with human rVWF (>100 BU/mL)
If a subject has a measurable baseline level of VWF activity in the respective assay, it is 
taken into account in the calculation of the residual activity. However, if baseline levels 
are too high (>15% VWF:RCo), inhibitors may not be reliably detected.
To exclude false positive results, the detection limit for anti-VWF inhibitors was set to 
1 BU/ml for all 3 assays. The rationale for this cut-off value is the relatively high 
confidence interval of the underlying assays, making determinations at the end of the 
evaluation range of the Bethesda reference curve uncertain.15
A more detailed test procedure may be requested to further characterize the anti-VWF 
inhibitors, if detected.
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12.9.3.5 Binding Antibodies to FVIII
Binding antibodies against FVIII will be analyzed using a proprietary enzyme 
immunoassay. The testing strategy will be as described for binding anti- VWF antibodies. 
Antibody-containing samples will be identified in a screening assay followed by a 
confirmatory assay to exclude false positive results.
12.9.3.6 Neutralizing antibodies (inhibitors) to FVIII 
Neutralizing antibodies (inhibitors) to FVIII will be assessed by the Nijmegen 
modification of the Bethesda assay in a central laboratory. To verify a FVIII inhibitor, 
additional testing (such as tests for Lupus anticoagulants) may be initiated. Positive FVIII 
inhibitor tests will be defined as ≥0.4 BU by the Nijmegen-modified Bethesda assay that 
is confirmed by a second test performed on an independent sample obtained 2-4 weeks 
following the first test. Only confirmed positive FVIII inhibitor test result will be 
reported as an SAE.
12.9.4 Antibodies to Other Proteins
Plasma will be assayed for the presence of antibodies against CHO protein (total Ig), 
murine IgG and human Furin (total Ig) using proprietary enzyme immunoassays. The 
testing strategy will be as described for binding anti- VWF antibodies. Antibody-
containing samples will be identified in a screening assay followed by a confirmatory 
assay to exclude false positive results.
12.9.4.1 Anti-CHO Protein
Total Ig antibodies (IgG, IgA, IgM) against CHO protein will be analyzed. For this assay 
(ELISA), CHO protein derived from cultures of untransfected cells and propagated under 
the identical cell culture conditions used for ADVATE production will be coated onto a 
microtiter plate, then incubated with dilutions of the positive control, negative control or 
test sample. Antibodies against CHO protein that are present in the samples bind to the 
coated antigen and will be detected with a horseradish peroxidase (HRP)-coupled goat 
anti-human antibody (secondary antibody). The positive control for this assay will be a 
polyclonal goat anti-CHO protein antibody spiked into the negative control. The negative 
control for this assay is pooled normal human plasma.
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12.9.4.2 Anti-Murine IgG
A commercially available ELISA (Medac, Hamburg, Germany) will be used to detect and 
to quantify IgG antibodies originating from human plasma that are directed against 
mouse-IgG (HAMA: human anti- mouse antibodies). Microtiter plates coated with mouse 
IgG will be incubated with dilutions of the standard, the positive control, the negative 
control or the test sample. Antibodies against mouse IgG that are present in the samples 
bind to the coated antigen and form a bridge to a peroxidase coupled mouse IgG antibody 
that will be used for detection (bridging format of the ELISA assay). The positive control 
for this assay will be a polyclonal goat anti-murine IgG spiked into the negative control. 
The negative control for this assay is pooled normal human plasma.
12.9.4.3 Antibodies to human Furin
Total Ig antibodies (IgG, IgA, IgM) against human Furin will be analyzed. For this assay 
(ELISA), recombinant human Furin will be coated onto a microtiter plate, then incubated 
with dilutions of the positive control, the negative control or test sample. Antibodies 
against human Furin that are present in the samples bind to the coated antigen and will be 
detected with a horseradish peroxidase (HRP)-coupled goat anti-human antibody 
(secondary antibody). The positive control for this assay will be a human monoclonal 
antibody specific for human Furin spiked into the negative control. The negative control 
for this assay is pooled normal human plasma.
12.9.5 Viral Serology
The following viral seromarkers will be assessed at screening:

HIV: anti-HIV 1, HIV 2 

HAV: anti-HAV (IgG and immunoglobulin M [IgM])

HBV: Hepatitis B surface antigen (HbsAg), anti-Hepatitis B (HB) core, anti-HBs

HCV: anti-HCV ELISA

Parvovirus B19: anti-B19V (IgG and IgM)
Virus serology will be established during the screening period. The relevant confirmatory 
Polymerase Chain Reaction (PCR) testing may be performed from appropriate left-over 
samples as needed. 
12.9.6 Urinalysis (Dipstick)
The urinalysis will include assessments for erythrocytes, specific gravity, urobilinogen, 
ketones, glucose, protein, bilirubin, nitrite and pH and will be performed at the central 
laboratory.
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12.9.7 Pregnancy Test
A pregnancy test for females of child-bearing potential will be performed at the local 
laboratory primarily from urine. If no urine sample is available, the pregnancy testing will 
be done from serum. The pregnancy test may need to be repeated during the course of 
study in countries where mandated by national law.
12.9.8 VWD Mutational Analysis, Multimer Analysis and Human Leukocyte 
Antigen Genotyping 
A cell pellet (buffy coat and erythrocytes) will be retained for VWD gene mutational 
analysis and HLA genotype determination if the information is not already available in 
the subject’s medical history. Results from multimer analysis (see Section 12.9.10.1) may 
contribute to VWD gene mutational analysis. The genetic testing will be done, when the 
subject consents to the genetic testing. 
12.9.9 Blood Group Analysis
The blood group needs to be determined during the screening period. If the information is 
not already available in the subject’s medical history, it has to be determined at the local 
lab.
12.9.10 Additional Laboratory Testing in case of Thrombotic Events
rVWF contains ultra large molecular weight (ULMW) multimers because of a lack of 
exposure to endogenous VWF protease (a disintegrin and metalloproteinase with a 
thrombospondin type 1 motif, member 13 (ADAMTS13) during the manufacturing 
process. In vitro and in vivo cleavage of these ultralarge molecular fractions by 
ADAMTS13 and generation of characteristic satellite bands has been extensively 
demonstrated during nonclinical and clinical development. Nevertheless, the potential 
elevated risk of thrombosis and/or other thromboembolic complications due to the 
administration of ultra large molecular VWF multimers in subjects with normal levels of 
VWF cannot be completely excluded. Therefore VWF multimer analysis will not only be 
performed routinely at screening but in case of thrombotic events both VWF multimer 
analysis as well as ADAMTS13 activity will be determined to assess any relatedness of 
these occurrences with IP treatment. 
12.9.10.1 VWF multimers analysis
The VWF multimers pattern will be assessed using low-resolution sodium dodecyl sulfate 
(SDS)–agarose gel electrophoresis. High-resolution SDS–agarose gel electrophoresis, 
with agarose concentrations 1.5%, will be used to determine the satellite band structure 
of VWF. These analyses will employ Western blot with luminescence video imaging.
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12.9.10.2 ADAMTS13 activity 
VWF73 was identified as the 73 amino acid minimal region of the VWF A2 domain 
required for ADAMTS13 cleavage. The cleavage of this substrate will be detected by a 
commercially available ELISA-based Chromogenic assay (Technoclone Austria):
Cleavage of immobilized VWF73 substrate is detected by a HRP-labeled antibody 
directed against the cleavage site of VWF73. The amount of bound antibody, which is the 
function of the ADAMTS13 cleavage is detected by a chromogenic substrate.
12.9.11 Soluble P-Selectin (sP-Selectin)
sP-selectin is a cell adhesion molecule (CAM) found in granules in endothelial cells (cells 
lining blood vessels) and activated platelets. Data for an association between the sP-
selectin concentration, thrombotic thrombocytopenic purpura (TTP) and venous 
thromboembolism (VTE) are limited and the predictive value has not yet established. A 
commercial ELISA assay will be employed as an exploratory test. sP-selectin will be 
determined at the Screening visit and used as indicator for an increased thrombotic risk.
12.9.12 D-Dimer
D-dimer will be used as a marker for DVT and disseminated intravascular coagulation
(DIC). While a negative result practically rules out thrombosis, a positive result can 
indicate thrombosis but does not rule out other potential etiologies, including a recent 
hemorrhage. Its main use, therefore, is to exclude thromboembolic disease where the 
probability is low. D-Dimer will be measured at the Screening visit and used as indicator 
for an increased thrombotic risk.
12.9.13 Additional Laboratory Testing in Case of Severe Allergic Reactions (e.g. 
Anaphylaxis)
If a subject develops a severe allergic reaction (e.g. anaphylaxis) in the course of the 
clinical study, additional blood draws for anti-VWF IgE antibody testing will be drawn.
The presence of anti-VWF IgE will be determined by using the ImmunoCAP®, a VWF-
specific IgE blood test (Thermo Scientific). The basis of the ImmunoCAP® technology is 
a cellulose polymer as solid phase in a plastic capsule providing a large surface for 
protein binding. rVWF as antigen is covalently coupled to the cellulose polymer. 
Detection of specific anti-VWF IgE bound to the antigen will be accomplished by a 
secondary enzyme-labeled anti-human IgE antibody. Testing for binding anti-human 
VWF IgE antibodies will be done with 0.5 mL plasma. Antibody containing samples will 
be identified and quantified in a screening assay followed by a confirmatory assay to 
exclude false positive results.
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12.9.14 Exploratory Assay 
The INNOVANCE VWF Ac: an assay, which will eventually replace the VWF:RCo test 
in the future, will be done using the same time points/blood draws incl. PK assessment as 
outlined for the VWF:RCo assessments. The VWF Ac assay is a sensitive test for direct 
determination of VWF activity. It employs an advanced new technology, allowing the 
assay to mimic the reaction in which VWF binds to glycoprotein Ib (GPIb), the major 
VWF receptor protein on platelets. Latex particles are coated with an antibody against 
GPIb, to which recombinant GPIb is added.
12.9.15 Assessment of Laboratory Values
12.9.15.1 Assessment of Abnormal Laboratory Values 
For VWF and FVIII laboratory assessments no evaluation of clinical significance is 
necessary.
Each other laboratory value (except results to determine genetics of the underlying VWD 
disease and blood group) has to be assessed by the investigator and the assessment will be 
recorded on the eCRF. The investigator will determine for each abnormal laboratory 
value whether the value is considered clinically significant or not. For clinically 
significant values, the investigator will indicate if the value constitutes a new AE (see 
definition in Section 12.1) and record the sign, symptom, or medical diagnosis on the AE 
CRF, is a symptom or related to a previously recorded AE, is due to a pre-existing 
disease (described in Section 12.1.1.4), or is due to another issue that will be specified. If 
the abnormal value was not clinically significant, the investigator will indicate the reason, 
i.e. because it is due to a preexisting disease, due to a lab error, due to variation or due to 
another issue that will be specified. Additional tests and other evaluations required to 
establish the significance or etiology of an abnormal value, or to monitor the course of an 
AE should be obtained when clinically indicated. Any abnormal value that persists should 
be followed at the discretion of the investigator.
Any seroconversion result for human immunodeficiency virus (HIV), hepatitis A virus 
(HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis E virus (HEV), or 
parvovirus B19 (B19V) shall be re-tested.
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12.9.16 Biobanking
Backup samples should be taken and stored appropriately for additional analysis, if 
necessary. These samples may be used for re-testing, further evaluation of an AE, or 
follow-up of other test results.
The following samples are planned:
Citrated plasma samples (minimum of 2,5 ml per sample) taken at:
Screening
Baseline Visit –PK assessment (within 30 minutes prior to IP infusion start
and at 7 time points post infusion: 30 ± 5 minutes; 60 ± 5 minutes; 
6 ± 1 hours; 12 ± 1 hours; 24 ± 2 hours; 48 ± 2 hours; 72 ± 2 hours);
Prophylaxis initiation visit
Follow-up visits ( 1 month ± 1 week, 2 months ± 1 week, 3 months ± 
2 weeks, 6 months ± 2 weeks, 9 months ± 2 weeks after the Prophylaxis 
initiation visit)
Study completion/termination visit
Backup samples that remain after study testing is done may be stored and used for 
additional testing (e.g., further evaluation of an abnormal test, an AE or assay 
development) and further assay developments. Samples will be stored in a coded form for
a maximum of 2 years after the final study report has been completed and then the 
samples will subsequently be destroyed.
12.10
12.10.1
 
 
 
 
 
 
 
 
 
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12.10.2
 
 
 
 
 
 
 
 
 
 
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13. STATISTICS
13.1 Sample Size and Power Calculations
The determination of the sample size for this study is not based on strict statistical 
considerations.
13.2 Datasets and Analysis Cohorts
13.2.1 Safety Analysis Set
The Safety Analysis Set will be comprised of all subjects who received any amount of IP, 
rVWF:ADVATE or rVWF alone. 
13.2.2 Full Analysis Dataset
The Full Analysis Set (FAS) will be comprised of all subjects who received prophylaxis 
IP infusion for at least 6 months.
13.2.3 Per-Protocol Analysis Set
The Per-Protocol (PP) Analysis Set will be comprised of subjects who are at least 70% 
compliant regarding required prophylactic infusions. Only subjects who met all study 
entry criteria and who had no major protocol violations that might impact efficacy 
assessments will be included in the PP analysis set.
13.2.4 PK Full Analysis Set
The Pharmacokinetic Full Analysis Set (PKFAS) will be comprised of all subjects who 
received the PK infusion and who provided acceptable data for PK analysis. Acceptable 
PK data will be defined in the Statistical Analysis Plan. 
13.2.5 PK Per Protocol Analysis Set 
The Pharmacokinetic Per Protocol Analysis Set (PKPPAS) is defined as a subset of the 
PKFAS. Subjects who met the following additional criteria will be included in the 
PKPPAS: had no major violation of affecting the PK period of the study as defined in the
detailed Statistical Analysis Plan.
13.3 Handling of Missing, Unused, and Spurious Data
13.3.1 General
Statistical techniques will not be used to identify and exclude any observations as outliers 
from the analyses. If data are considered spurious, e.g. for lack of biological plausibility, 
it will be documented to include the reason for exclusion and the analyses from which the 
data were excluded.
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13.3.2 Other
1) Regarding missing data in PK records:
Body weight: If a subject’s weight is missing from the PK infusion record, the 
subject’s last recorded weight will be used to calculate the weight-adjusted dose.
Concentration:
Baseline concentration levels reported as below the limit of quantification will be 
considered to be 0. Missing VWF baseline concentration levels (VWF: RCo, VWF: 
AG or VWF: CB) for Type 3 subjects will be set to 0.
Time:
If start time of infusion is missing (but stop time is available) and actual 
collection time is available, then stop time of infusion will be taken for 
further calculation (i.e. time difference between actual end date/time of 
infusion and date/time blood sample drawn).
If actual collection date/time is missing and planned collection date/time is 
missing, then this PK time point will be taken out from the PK analysis (i.e. 
no data entry for this time point). 
For all other scenarios, the planned collection date/time will be taken for 
further calculation.
2) Regarding missing data in AE records:
Handling of unknown causality assessment:
If a subject experiences an AE with a missing causality assessment, the 
relationship of the AE will be counted as “related.”
Handling of unknown severity grades:
If a subject experiences more than one AE categorized under the same 
preferred term, one of them is categorized as “severe” and one of them is 
categorized as “unknown”, then the maximum severity for this preferred term 
should be counted as “severe” for this subject.
If a subject experiences more than one AE categorized under the same 
preferred term, one of them is categorized as “mild” or “moderate” and one 
of them is categorized as “unknown”, then the maximum severity for this 
preferred term should be counted as “unknown” for this subject.
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13.4 Methods of Analysis
13.4.1 Primary Outcome Measure
The focus of the statistical analysis will be descriptive.
For the prospectively recorded overall annualized bleeding rate (ABR) of spontaneous 
bleedings during prophylactic treatment as well as for the historical ABR of spontaneous 
bleedings, means and corresponding 90% two-sided confidence intervals based on the 
negative binomial distribution will be estimated. The confidence intervals will be 
calculated within a generalized linear model framework (with a logarithmic link function 
which is the default for the negative binomial distribution), accounting for the logarithm 
of follow-up time (in years) as an offset.
The annualized rate of bleeding episodes will be calculated as (Number of bleeding 
episodes/observed treatment period in days) * 365.25. 
The primary efficacy analysis will be based on the FAS. As a supportive analysis, the 
same analysis will also be carried out on the PP.
13.4.2 Secondary Outcome Measures 
13.4.2.1 Efficacy
For the number of infusions and for the total weight adjusted consumption of rVWF and 
ADVATE per month and per year, summary statistics will be carried out.
For the number of subjects with reduction of ABR as well as for the number of subjects 
with 0 bleeds, proportions and corresponding 90% two-sided confidence intervals will be 
performed.
The secondary efficacy analysis will be performed on the FAS only.
13.4.2.2 Efficacy of the Treatment of Bleeding Episodes
For the number of infusions of rVWF and ADVATE per bleeding episode, for the weight 
adjusted consumption of rVWF and ADVATE per bleeding event as well as for the 
overall hemostatic efficacy rating at resolution of bleed, summary statistics will be 
carried out.
The analysis will be performed on the FAS.
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13.4.2.3 Pharmacokinetic Analysis
All PK analyses will use the actual sampling times, not nominal times specified in the 
protocol, wherever possible. Actual sampling times will be defined as time from the start 
of infusion to the blood sample collection time. A deviation from the protocol-specified 
blood sample drawing time window will not be a reason to exclude an observation from 
the analysis. Samples with unknown actual and planned collection date/time or where the 
concentration could not be determined, or where results were biologically implausible 
will be eliminated from the analysis.
If any concentration data are considered spurious (e.g. lack of biological plausibility), the 
reason for exclusion from the analysis and the analysis from which the data point was 
excluded will be documented.
To ensure that values at baseline (pre-infusion) are not affecting the estimation of PK 
parameters, post-infusion concentration data will be adjusted for baseline as follows:
t
Measured,
C
)
Tmax
Measured,
C
infusion
pre
Measured,
C
(1
t
Corrected,
C




After adjustment of the post-infusion concentration data, any pre-infusion data will be set 
to 0.
CCorrected will be set to missing, if:
Samples have an unknown draw time or where the concentration could not be 
determined, or where results were deemed to be unreliable due to analytical issues.
Any concentration data are considered spurious (e.g. lack of biological plausibility).
Handling of concentrations that are below the quantification limit: 
Baseline concentration values reported as below the limit of quantification will be 
considered to be 0 (CCorrected = Concentration value)
Post-infusion concentration values reported as below the limit of quantification or 
missing repeated concentration values will be set to missing (CCorrected = missing)
The area under the plasma concentration/time curve from time 0 to infinity (AUC0-) and 
the area under the first moment curve from time 0 to infinity (AUMC0-) will be 
calculated as the sum of AUC or AUMC from time 0 to the time of last quantifiable 
concentration plus a tail area correction calculated as Ct/z and Ct/z(t + 1/z), 
respectively, where Ct is the last quantifiable concentration, t is the time of last 
quantifiable concentration and z is the terminal or disposition rate constant.
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The area under the plasma concentration/time curve from time 0 to 72 hours post-infusion 
(AUC0-72h) will be computed using the linear trapezoidal rule. For the calculation of 
AUC0-72h the levels at 72 hours will be linearly interpolated/ extrapolated from the 
2 nearest sampling time points.
Elimination phase half-life (HL) in hours will be calculated as:
where the elimination rate constant (z) will be obtained by loge-linear fitting using least 
squares deviations to at least the last 3 quantifiable concentrations above pre-infusion 
level.
The Mean Residence Time (MRT) in hours will be calculated as total area under the 
moment curve divided by the total area under the curve:
Systemic clearance in dL/kg/h will be calculated as the dose in IU/kg divided by the 
total AUC: 
Apparent steady state volume of distribution (Vss) in dL/kg will be calculated as:
The maximum concentration, Cmax, will be calculated as the maximum concentration 
post-infusion.
The time to reach the maximum concentration, Tmax, in hours was defined as the time 
to reach Cmax. 
Incremental recovery (IR) in (IU/dL)/(IU VWF:RCo/kg) will be calculated as:
where Cmax and Cpre-infusion are the unadjusted concentration values.
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The PK parameters AUC0-72h/Dose, AUC0-∞/Dose, AUMC0-∞/Dose, MRT (mean 
residence time), CL (clearance), IR (incremental recovery), T1/2 (elimination phase half-
life), Vss (Volume of distribution at steady state), Cmax (maximum concentration) and
Tmax (time to reach the maximum concentration) will be summarized by median and 
corresponding 90% confidence intervals, mean and corresponding 90% confidence 
intervals, standard deviation, Q1, Q3, IQR, geometric mean and corresponding 90% 
confidence intervals.
Descriptive statistics will be used to summarize VWF:RCo levels for each nominal time 
point on the PK curve. 
PK analysis as described above will be carried out on the PKFAS as well as on the 
PKPPAS.
For all subjects in the PKFAS concentration vs. time curves will be prepared.
PK parameters will be derived using non-compartmental methods in WinNonlin.
The analysis will be performed on the FAS.
13.4.2.4 Safety
AEs that occurred during or after first IP infusion will be presented in summary tables. 
Summary tables shall indicate the number of subjects who experienced adverse events. 
Separate tables will be carried out for temporally associated adverse events; and for 
temporally associated or causally related adverse events. 
In addition, tables will be prepared to list each AE, the number of subjects who 
experienced an AE at least once, and the rate of subjects with AE(s). AEs will be grouped 
by system organ class. Each event will then be divided into defined severity grades (mild, 
moderate, severe). The tables will also divide the AEs into those considered related (a 
“possibly related” or a “probably related” AE will be considered as a “related AE”) to the 
treatment and those considered unrelated (an “unlikely related” or a “not related” AE will 
be considered as an “unrelated” AE). These tables will also be carried out for temporally 
associated adverse events; and for temporally associated or causally related adverse 
events. 
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All AEs; temporally associated AEs; causally related AEs; and temporally associated or 
causally related AEs will also be summarized by system organ class, preferred term, 
including the number of AEs, the number (%) of unique subjects, the frequency category 
(very common: ≥10%, common: ≥1% to <10%, uncommon: ≥0.1% to <1%, rare: ≥0.01% 
to <0.1%, very rare: <0.01%) and the number of IP-infusions associated with an AE.
Temporally associated AEs are defined as AEs that begin during infusion or within 
24 hours (or 1 day where time of onset is not available) after completion of infusion, 
irrespective of being related or not related to treatment.
AEs and SAEs for each subject, including the same event on several occasions, will be 
listed separately, giving both MedDRA preferred term and the original term used by the 
investigator, system organ class, severity grade, seriousness, relation to the treatment, 
onset date, and stop date.
AEs that occurred before first IP infusion will be listed separately.
Incidences of thrombotic events and severe allergic reactions will be listed. For the 
development of antibodies, proportions will be carried out.
The safety analyses will be based on the safety analysis set. 
13.5 Exploratory Outcome Measures
 
 
13.6 Planned Interim Analysis of the Study
No formal interim analysis is planned for this study. However, a descriptive summary 
report for this study is planned after all subjects have completed at least 6 months of
prophylactic treatment with rVWF.
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14. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
The investigator/study site will cooperate and provide direct access to study documents 
and data, including source documentation for monitoring by the study monitor, audits by 
the sponsor or sponsor’s representatives, review by the EC, and inspections by applicable 
regulatory authorities, as described in the Clinical Study Agreement. If contacted by an 
applicable regulatory authority, the investigator will notify the sponsor of contact, 
cooperate with the authority, provide the sponsor with copies of all documents received 
from the authority, and allow the sponsor to comment on any responses, as described in 
the Clinical Study Agreement.
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15. QUALITY CONTROL AND QUALITY ASSURANCE
15.1 Investigator’s Responsibility
The investigator will comply with the protocol (which has been approved/given favorable 
opinion by the EC), ICH GCP, and applicable regulatory requirements as described in the 
Clinical Study Agreement. The investigator is ultimately responsible for the conduct of 
all aspects of the study at the study site and verifies by signature the integrity of all data 
transmitted to the sponsor. The term “investigator” as used in this protocol as well as in 
other study documents, refers to the investigator or authorized study personnel that the 
investigator has designated to perform certain duties. Sub-investigators or other 
authorized study personnel are eligible to sign for the investigator, except where the 
investigator’s signature is specifically required.
15.1.1 Investigator Report and Final Clinical Study Report 
The investigator, or coordinating investigator(s) for multicenter studies, will sign the 
clinical study report. The coordinating investigator will be selected before study start.
15.2 Training
The study monitor will ensure that the investigator and study site personnel understand all 
requirements of the protocol, the investigational status of the IP, and his/her regulatory 
responsibilities as an investigator. Training may be provided at an investigator’s meeting, 
at the study site, and/or by instruction manuals. In addition, the study monitor will be 
available for consultation with the investigator and will serve as the liaison between the 
study site and the sponsor.
15.3 Monitoring
The study monitor is responsible for ensuring and verifying that each study site conducts 
the study according to the protocol, standard operating procedures other written 
instructions/agreements, ICH GCP, and applicable regulatory guidelines/requirements. 
The investigator will permit the study monitor to visit the study site at appropriate 
intervals, as described in the Clinical Study Agreement. Monitoring processes specific to 
the study will be described in the clinical monitoring plan. 
15.4 Auditing
The sponsor and/or sponsor’s representatives may conduct audits to evaluate study 
conduct and compliance with the protocol, standard operating procedures, other written 
instructions/agreements, ICH GCP, and applicable regulatory guidelines/requirements. 
The investigator will permit auditors to visit the study site, as described in the Clinical 
Study Agreement. Auditing processes specific to the study will be described in the 
auditing plan.
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15.5 Non-Compliance with the Protocol
The investigator may deviate from the protocol to eliminate an apparent immediate 
hazard to the subject. In the event(s) of an apparent immediate hazard to the subject, the 
investigator will notify the sponsor immediately by phone and confirm notification to the 
sponsor in writing as soon as possible, but within 1 calendar day after the change is 
implemented. The sponsor (Baxter) will also ensure the responsible ethics committee
(EC) is notified of the urgent measures taken in such cases according to local regulations.
If monitoring and/or auditing identify serious and/or persistent non-compliance with the 
protocol, the sponsor may terminate the investigator’s participation. The sponsor will 
notify the EC and applicable regulatory authorities of any investigator termination.
15.6 Laboratory and Reader Standardization
A central laboratory/reader will be used for all clinical assessments except for pregancy 
testing and blood group test (refer to Section 12.9). Local laboratories are requested to 
provide their laboratory specifications of the individual tests that are also being tested 
locally.
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16. ETHICS 
16.1 Subject Privacy
The investigator will comply with applicable subject privacy regulations/guidance as 
described in the Clinical Study Agreement.
16.2 Ethics Committee and Regulatory Authorities
Before enrollment of patients into this study, the protocol, informed consent form, any 
promotional material/advertisements, and any other written information to be provided 
will be reviewed and approved/given favorable opinion by the EC and applicable 
regulatory authorities. The IB will be provided for review. The EC’s composition or a 
statement that the EC’s composition meets applicable regulatory criteria will be 
documented. The study will commence only upon the sponsor’s receipt of 
approval/favorable opinion from the EC and, if required, upon the sponsor’s notification 
of applicable regulatory authority(ies) approval, as described in the Clinical Study 
Agreement.
If the protocol or any other information given to the subject is amended, the revised 
documents will be reviewed and approved/given favorable opinion by the EC and 
applicable regulatory authorities, where applicable. The protocol amendment will only be 
implemented upon the sponsor’s receipt of approval and, if required, upon the sponsor’s 
notification of applicable regulatory authority(ies) approval.
16.3 Informed Consent
Investigators will choose patients for enrollment considering the study eligibility criteria. 
The investigator will exercise no selectivity so that no bias is introduced from this source. 
All patients and/or their legally authorized representative must sign an informed consent 
form before entering into the study according to applicable regulatory requirements and 
ICH GCP. An assent form may be provided and should be signed by patients less than 18 
years of age. Before use, the informed consent form will be reviewed by the sponsor and 
approved by the EC and regulatory authority(ies), where applicable, (see Section 16.2). 
The informed consent form will include a comprehensive explanation of the proposed 
treatment without any exculpatory statements, in accordance with the elements required 
by ICH GCP and applicable regulatory requirements. Patients or their legally-authorized 
representative(s) will be allowed sufficient time to consider participation in the study. By 
signing the informed consent form, patients or their legally authorized representative(s) 
agree that they will complete all evaluations required by the study, unless they withdraw 
voluntarily or are terminated from the study for any reason.
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The sponsor will provide to the investigator in written form any new information that 
significantly bears on the subjects’ risks associated with IP exposure. The informed 
consent will be updated, if necessary. This new information and/or revised informed 
consent form, which have been approved by the applicable EC and regulatory authorities, 
will be provided by the investigator to the subjects who consented to participate in the 
study 
16.4 Data Monitoring Committee
This study will be monitored by Data Monitoring Committee (DMC). The DMC is a 
group of individuals with pertinent expertise that reviews on a regular basis accumulating 
data from an ongoing clinical study. For this study, the DMC will be composed of 
recognized experts in the field of VWD clinical care and research who are not actively 
recruiting subjects, and an independent statistician. The DMC can stop a trial if it finds 
toxicities or if treatment is proven to be not beneficial. Details will be defined in the 
DMC charter. 
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17. DATA HANDLING AND RECORD KEEPING
17.1 Confidentiality Policy
The investigator will comply with the confidentiality policy as described in the Clinical 
Study Agreement. 
17.2 Study Documentation and Case Report Forms
The investigator will maintain complete and accurate paper format study documentation 
in a separate file. Study documentation may include information defined as “source data” 
(see Section 8.8), records detailing the progress of the study for each subject, signed 
informed consent forms, correspondence with the EC and the study monitor/sponsor, 
enrollment and screening information, CRFs, SAE reports (SAERs), laboratory reports (if 
applicable), and data clarifications requested by the sponsor.
The investigator will comply with the procedures for data recording and reporting. Any 
corrections to paper study documentation must be performed as follows: 1) the first entry 
will be crossed out entirely, remaining legible; and 2) each correction must be dated and 
initialed by the person correcting the entry; the use of correction fluid and erasing are 
prohibited.
The investigator is responsible for the procurement of data and for the quality of data 
recorded on the CRFs. CRFs will be provided in electronic form. 
If electronic format CRFs are provided by the sponsor, only authorized study site 
personnel will record or change data on the CRFs. If data is not entered on the CRFs 
during the study visit the data will be recorded on paper and this documentation will be 
considered source documentation. Changes to a CRF will require documentation of the 
reason for each change. An identical (electronic/paper) version of the complete set of 
CRFs for each subject will remain in the investigator file at the study site in accordance 
with the data retention policy (see Section 17.3).
The handling of data by the sponsor, including data quality assurance, will comply with 
regulatory guidelines (e.g., ICH GCP) and the standard operating procedures of the 
sponsor. Data management and control processes specific to the study will be described 
in the data management plan.
17.3 Document and Data Retention 
The investigator will retain study documentation and data (paper and electronic forms) in 
accordance with applicable regulatory requirements and the document and data retention 
policy, as described in the Clinical Study Agreement.
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18. FINANCING AND INSURANCE
The investigator will comply with investigator financing, investigator/sponsor insurance, 
and subject compensation policies, if applicable, as described in the Clinical Study 
Agreement.
19. PUBLICATION POLICY
The investigator will comply with the publication policy as described in the Clinical 
Study Agreement. 
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20. SUPPLEMENTS
20.1 Study Flow Chart
Figure 1
Study Design for Baxter Clinical Study 071301
Screening Visit
Baseline Visit
(PK-Assessment Visit)
within 60 days post Screening Visit 
Prophylaxis Initiation Visit
72 hours post Baseline Visit
Follow-Up Visits
1, 2, 3, 6, 9 months 
post Prophylaxis Initiation Visit 
Study Termination Visit
12 months
post Prophylaxis Initiation Visit 
Surgery Study 071101
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20.2 Schedule of Study Procedures and Assessments
Table 4
Schedule of Study Procedures and Assessments
Procedures/
Assessments
Screening Visit
Baseline Visit 
(PK-assessment 
visit)
Prophylaxis
Initiation Visit
Interval/Follow-Up 
Study Visits
Study Completion/
Termination
Visit
Pre-
infusion
Infusion
Post-
infusiong
1 month± 
1 Week
2 month± 
1 Week 
3 month± 
2 Weeks
6 month± 
2 Weeks 
9 month± 
2 Weeks
12 month± 
2 Weeks
Informed Consent a
X
Eligibility Criteria
X
Medical Historyb
X
X
Medicationsc
X
X
X
X
X
X
X
X
X
Non-drug Therapiesc
X
X
X
X
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
Bleedings
X
X
X
X
X
X
X
X
X
Laboratories 
X
X
X
X
X
X
X
X
X
Vital Signsd
X
X
X
X
X
X
X
X
X
X
ECG
X
X
X
IP Treatmente
X
X
X
X
X
X
X
X
IP Consumption/Treat-
ment Compliance
X
X
X
X
X
X
Subject Diary
X
X
X
X
X
X
X
Xf
X
X
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Continued
a) Occurs at enrollment (before screening).
b) Including documented history of on-demand and prophylactic treatment for the past 12 months and a documented history, e.g., patient charts and 
prescription information, of all bleeding episodes within the past 12 months
c) Including all medications and non- drug therapies taken in the 2 weeks prior to study entry and all the concomitant medications and non-drug therapies 
during the course of the study.
d) Vital signs (pulse rate, respiratory rate, and blood pressure): within 30 minutes before infusion start and 30 ± 15 minutes post-infusion.
e) IP treatment after the prophylactic treatment initiation visit at the site will be continued as home-treatment if the subject qualifies; a wash-out period of at 
least 72 hours is required after the last IP infusion before the follow-up visit. IP infusion will be given at the study site after the blood sample for 
immunology testing and IR determination is drawn.
f) Can be done either at the screening or the baseline visit.
g) Time points for blood draws post infusion: 30 ± 5 minutes; 60 ± 5 minutes; 6 ± 1 hours; 12 ± 1 hours; 24 ± 2 hours; 48 ± 2 hours; 72 ± 2 hours
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20.3 Clinical Laboratory Assessments
Table 5.
Clinical Laboratory Assessment
Procedures/
Assessments
Screening Visit
Baseline Visit (PK-
assessment visit)
Interval/Follow-Up 
Study Visits
Study Completion/
Termination Visit
Pre-
Infusion
Post-
Infusion/
Prophyaxis 
Initiation
Visit k
1 month± 
1 Week
2 month± 
1 Week 
3 month± 
2 Weeks
6 month± 
2 Weeks 
9 month± 
2 Weeks
12 month± 2 Weeks
Hematology a
X
X
X
X
X
X
X
X
X
Clinical Chemistry b
X
X
X
X
X
X
X
X
X
Coagulation Panel/PK 
assessmentc
X
X
X
X
X
X
X
X
X
Immunogenicityd
X
X
Xl
X
X
X
X
X
X
Viral Serologye
X
Urinalysisf
X
VWD Gene Mutational 
Analysis / HLA genotype 
analysis and Analysis of 
VWF multimers g
X
sP-selectin and 
D-dimer
Xh
Blood Groupi
X
Pregnancy Testj
X
Exploratory Tests
X
X
X
X
X
X
X
X
X
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Continued
a) Hematology assessments include: complete blood count [hemoglobin, hematocrit, erythrocytes (i.e. red blood cell count), mean corpuscular volume 
(MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), leukocytes (i.e. white blood cell count)] with 
differential (i.e. basophils, eosinophils, lymphocytes, monocytes, neutrophils) and platelet counts. Hematology assessments during PK assessments will be 
determined prior IP infusion and 24±2 hours, 48±2 hours and 72±2 hours thereafter.
b) Clinical chemistry assessments include: Sodium, potassium, chloride, glucose, creatinine, blood urea nitrogen (BUN), aspartate aminotransferase (AST), 
alanine aminotransferase (ALT) lactate dehydrogenase (LDH), alkaline phosphatase (AP), bilirubin. Clinical chemistry will be determined at baseline, 
after 24±2 h, 48±2 hours and 72±2 hours during the PK assessments. 
c) Coagulation panel/PK assessment: INR/aPTT, VWF:RCo, VWF:Ag, VWF:CB, FVIII:C, VWF Innovance (exploratory assay); during the PK assessment 
at the baseline visit blood samples will be drawn 30 min prior PK infusion; once the PK infusion is completed 30 5 minutes; 60 ± 5 minutes; 6 hours 
± 1 hour ; 12 ± 0.5 hours; 24 ± 2 hours, 48 ± 2 hours; 72 ± 2 hours and VWF:RCo, VWF:CB, VWF:Ag, VWF Ac, FVIII:C will be determined; in case of 
thrombotic event VWF multimers and ADAMTS13 will be analyzed to judge on a possibly relatedness to UHMW fractions of the IP.
d) Immunogenicity assessment includes Neutralizing Antibodies (Ab) to FVIII – Inhibitory and Neutralizing Ab to VWF:RCo, Neutralizing Ab to VWF:CB, 
Neutralizing Ab to VWF:FVIII, Binding Ab to VWF and FVIII, Binding Ab to CHO-Protein, Binding Ab to rFurin, Binding Ab to Murine IgG; .CD4* In 
case of an SAE hypersensitivity reaction IgE antibodies to VWF will be determined. A washout period of at least 72 hours after the last IP infusion is 
required before blood samples for immunogenicity assessments can be drawn. 
e) Viral Serology Hepatitis A Antibody, Total - Hepatitis A Antibody, IgM - Hepatitis B Surface Antibody - Hepatitis B Core Ab, Total - Hepatitis B Surface 
Antigen - Hepatitis C Virus Antibody; Parvovirus B19; HIV-1/HIV-2 Antibodies
f) Urinalysis comprehends: erythrocytes, specific gravity, urobilinogen, ketones, glucose, protein, bilirubin, nitrite, and pH
g) Not required if available in the subject’s medical history; VWF multimers: additionally in case of thrombotic events
h) At screening and in case of thrombotic events
i) Blood group assessment major blood group (local laboratory) only if not available in the subject’s medical history
j) Serum pregnancy test (in females of child-bearing potential if no urine sample is available)
k) The 72 h post-infusion laboratory assessments coincidence with the initiation visit for prophylactic treatment. After the blood samples are drawn for 
laboratory assessment for the 72 h post infusion PK assessment, the subject receives the first IP infusion for prophylactic treatment (prophylactic treatment 
initiation visit). 
l) Only needed for subjects without PK assessment prior to their first IP infusion in this study.
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21. REFERENCES
1. Mannucci PM. Treatment of von Willebrand's Disease. N.Engl.J.Med. 
2004;351:683-694.
2. Goudemand J, Scharrer I, Berntorp E et al. Pharmacokinetic studies on Wilfactin, 
a von Willebrand factor concentrate with a low factor VIII content treated with 
three virus-inactivations/removal methods. J.Thromb.Haemost. 2005;3:2219-
2227.
3. Abshire T. The role of prophylaxis in the management of von Willebrand disease: 
today and tomorrow. Thromb.Res. 2009;124 Suppl 1:S15-S19.
4. Nilsson IM, Blombäck M, Jorpes E, Blombäck B, Johansson SA. V.Willebrand's 
Disease and its Correction with Human Plasma Fraction 1-0. Acta Med.Scand. 
1957;159:179-188.
5. Berntorp E, Petrini P. Long-term prophylaxis in von Willebrand disease. Blood 
Coagul.Fibrinolysis 2005;16 Suppl 1:S23-S26.
6. Berntorp E. Prophylaxis and treatment of bleeding complications in von 
Willebrand disease type 3. Semin.Thromb.Hemost. 2006;32:621-625.
7. Federici AB. Highly purified VWF/FVIII concentrates in the treatment and 
prophylaxis of von Willebrand disease: the PRO.WILL Study. Haemophilia. 
2007;13 Suppl 5:15-24.
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8. Halimeh S, Krümpel A, Rott H et al. Long-term secondary prophylaxis in 
children, adolescents and young adults with von Willebrand disease. Results of a 
cohort study. Thromb.Haemost. 2011;105:597-604.
9. Abshire TC, Federici AB, Alvárez MT et al. Prophylaxis in severe forms of von 
Willebrand's disease: results from the von Willebrand Disease Prophylaxis 
Network (VWD PN). Haemophilia. 2013;19:76-81.
10. Berntorp E. Prophylaxis in von Willebrand disease. Haemophilia. 2008;14 Suppl 
5:47-53.
11. Varadi K, Rottensteiner H, Vejda S et al. Species-dependent variability of 
ADAMTS13-mediated proteolysis of human recombinant von Willebrand factor. 
J.Thromb.Haemost. 2009;7:1134-1142.
12. Kessler CM, Windyga J, Schwartz BA, Knaub S. Use of objective efficacy 
criteria for evaluation of von Willebrand factor/factor VIII concentrates. Blood 
Coagul.Fibrinolysis 2012;23:262-267.
13. Committee for Medicinal Products for Human Use. Guideline on immunogenicity 
assessment of biotechnology-derived therapeutic proteins. 
CHMP/BMWP/14327/2006, 18. 13-12-2007. London, European Medicines 
Agency (EMEA - EMA). 
Link to Publisher´s Site: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/20
09/09/WC500003946.pdf
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14. Kasper CK. Laboratory tests for factor VIII inhibitors, their variation, significance 
and interpretation. Blood Coagul.Fibrinolysis 1991;2 Suppl 1:7-10.
15. Lillicrap D. Von Willebrand Factor. International Society for Thrombhosis and 
Hemostasis (ISTH) 54th Annual Scientific and Standardization Committee 
Meeting. 2008:60-64.
Link to Publisher´s Site: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/20
09/09/WC500003946.pdf
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22. SUMMARY OF CHANGES 
Not applicable. 
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INVESTIGATOR ACKNOWLEDGEMENT
RECOMBINANT VON WILLEBRAND FACTOR (rVWF)
A prospective, phase 3, open label, international multicenter study on efficacy and 
safety of prophylaxis with rVWF in severe von Willebrand Disease
PROTOCOL IDENTIFIER: 071301
CLINICAL TRIAL PHASE 3
ORIGINAL: 2014 FEB 19
OTHER PROTOCOL ID(s)
NCT Number: to be determined
EudraCT Number: to be determined
IND/IDE NUMBER: to be determined
By signing below, the investigator acknowledges that he/she has read and understands 
this protocol, and will comply with the requirements for obtaining  informed consent 
from all study subjects prior to initiating any protocol-specific procedures, obtaining 
written initial and ongoing EC(s) protocol review and approval, understands and abides 
by the requirements for maintenance of source documentation, and provides assurance 
that this study will be conducted according to all requirements as defined in this protocol, 
clinical study agreement, ICH GCP guidelines, and all applicable regulatory 
requirements.
Signature of Principal Investigator
Date
Print Name of Principal Investigator
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INVESTIGATOR ACKNOWLEDGEMENT
RECOMBINANT VON WILLEBRAND FACTOR (rVWF)
A prospective, phase 3, open label, international multicenter study on efficacy and 
safety of prophylaxis with rVWF in severe von Willebrand Disease
PROTOCOL IDENTIFIER: 071301
CLINICAL TRIAL PHASE 3
ORIGINAL: 2014 FEB 19
OTHER PROTOCOL ID(s)
NCT Number: to be determined
EudraCT Number: to be determined
IND/IDE NUMBER: to be determined
By signing below, the investigator acknowledges that he/she has read and understands 
this protocol, and provides assurance that this study will be conducted according to all 
requirements as defined in this protocol, clinical study agreement, ICH GCP guidelines, 
and all applicable regulatory requirements.
Signature of Coordinating Investigator
Date
Print Name and Title of Coordinating Investigator
Signature of Sponsor Representative
Date
, MD
, Global Clinical Development
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CLINICAL STUDY PROTOCOL
PRODUCT: Recombinant Von Willebrand Factor (rVWF)
STUDY TITLE: A PROSPECTIVE, PHASE 3, OPEN LABEL, INTERNATIONAL 
MULTICENTER STUDY ON EFFICACY AND SAFETY OF PROPHYLAXIS 
WITH rVWF IN SEVERE VON WILLEBRAND DISEASE
STUDY SHORT TITLE: rVWF IN PROPHYLAXIS
PROTOCOL IDENTIFIER: 071301
CLINICAL TRIAL PHASE 3
AMENDMENT 1: 2016 APR 08
Replaces: ORIGINAL: 2014 FEB 19
OTHER ID(s)
NCT Number: to be determined
EudraCT Number: 2016-001478-14
IND NUMBER: to be determined
Study Sponsor(s):
Baxalta US Inc.
One Baxter Way
Westlake Village, CA  91362,
UNITED STATES
Baxalta Innovations GmbH
Industriestrasse 67
A-1221 Vienna,
AUSTRIA
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1. STUDY PERSONNEL
1.1 Authorized Representative (Signatory) / Responsible Party
, MD
, Global Clinical Development
Baxalta US Inc.
1.2 Study Organization
The name and contact information of the responsible party and individuals involved with 
the study (e.g. investigator(s), sponsor’s medical expert and study monitor, sponsor’s 
representative(s), laboratories, steering committees, and oversight committees [including 
ethics committees (ECs)], as applicable) will be maintained by the sponsor and provided 
to the investigator.
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2. SERIOUS ADVERSE EVENT REPORTING
The investigator will comply with applicable laws/requirements for reporting serious 
adverse events (SAEs) and suspected unexpected serious adverse events (SUSARs) to the 
ECs.
ALL SAEs, INCLUDING SUSARs, ARE TO BE REPORTED ON THE ADVERSE 
EVENT ELECTRONIC CASE REPORT FORM (eCRF) 
WITHIN 24 HOURS AFTER BECOMING AWARE OF THE EVENT. IF THE 
eCRF IS NOT AVAILABLE THEN THE SAE MUST BE REPORTED ON THE 
SERIOUS ADVERSE EVENT REPORT (SAER) FORM AND 
TRANSMITTED TO THE SPONSOR TO MEET THE 24 HOUR TIMELINE 
REQUIREMENT.
Bleeding events that meet seriousness criteria (death, life-threatening, 
hospitalizing/prolongation of hospitalization, disability, congenital anomaly, or medically 
significant and if not urgently treated would result in one of the above) should be reported 
on the SAE eCRF or SAE Report form as an SAE.
Drug Safety contact information: see SAE Report form 
Refer to SAE Protocol Sections and the study team roster for further information.
For definitions and information on the assessment of these events, refer to the following:
AE, Section 12.1
SAE, Section 12.1.1.1
SUSARs, Section 12.1.1.2
Assessment of AEs, Section 12.1.2
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3. SYNOPSIS 
INVESTIGATIONAL PRODUCT
Name of Investigational Product (IP)
Recombinant von Willebrand factor (rVWF)
Name(s) of Active Ingredient(s)
Recombinant von Willebrand factor (rVWF)
CLINICAL CONDITION(S)/INDICATION(S)
Subjects with severe von Willebrand disease (VWD) requiring prophylactic treatment with coagulation 
factor replacement
PROTOCOL ID
071301
PROTOCOL TITLE
A prospective, phase 3, open label, international multicenter 
study on efficacy and safety of prophylaxis with rVWF in severe 
von willebrand disease
Short Title
rVWF in prophylaxis
STUDY PHASE
Ph3
PLANNED STUDY PERIOD
Initiation
2016 JUN
Primary Completion
2018 Q1
Study Completion
2018 Q1
Duration
22 months
STUDY OBJECTIVES AND PURPOSE
Study Purpose
The purpose of this phase 3 study is to investigate the efficacy and safety, including immunogenicity and 
thrombogenicity, and 
of prophylactic treatment with rVWF in 
subjects with severe VWD.
Primary Objective
The primary objective of this study is to prospectively evaluate the annualized bleeding rate (ABR) for
spontaneous bleeding episodes while on prophylactic treatment with rVWF and to compare it to the 
subject’s historical ABR for spontaneous bleeding episodes during on-demand treatment. 
Secondary Objectives
Secondary Objectives are 

Additional efficacy assessments of prophylactic treatment

Safety and immunogenicity

Pharmacokinetics (PK)

Efficacy of the treatment of bleeding episodes 
Exploratory Objectives
 
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STUDY DESIGN
Study Type/ Classification/ Discipline
Efficacy and Safety 
Control Type
No control
Study Indication Type
Prophylaxis and treatment of bleeding episodes
Intervention model 
Single-group
Blinding/Masking
Open-label
Study Design
This is a phase 3, prospective, open-label, non-randomized, 
international multicenter study evaluating efficacy, safety, 
including immunogenicity and thrombogenicity, and 
of 
prophylactic treatment regimen with rVWF for subjects with 
severe VWD.
Subjects will be offered the option to continue to receive 
BAX111 in a long-term continuation study.
Planned Duration of Subject 
Participation
Approximately 15 months 
Primary Outcome Measure 
Efficacy

Prospectively recorded ABR for spontaneous (not related to trauma) bleeding episodes during 
prophylactic treatment with rVWF and the subjects’ historical ABR for spontaneous bleeding
episodes during on-demand treatment.
Secondary Outcome Measure(s)
Efficacy

Number (proportion) of subjects with reduction of ABR for spontaneous (not related to trauma) 
bleeding episodes during prophylaxis relative to the subjects’ own historical ABR during on-demand
treatment

Number (proportion) of subjects with 0 bleeds during prophylactic treatment with rVWF

Number of infusions and total weight adjusted consumption of rVWF and ADVATE (recombinant 
factor VIII/rFVIII) per month and per year during on-demand treatment
Safety

Adverse events (AEs)

Incidence of thromboembolic events 

Incidence of severe hypersensitivity reactions

Development of neutralizing antibodies to VWF and FVIII 

Development of total binding antibodies to VWF and FVIII

Development of antibodies to Chinese hamster ovary (CHO) proteins, mouse immunoglobulin G 
(IgG) and rFurin
Pharmacokinetic

Incremental recovery (IR), terminal half-life (T1/2), mean residence time (MRT), area under the 
curve/dose (AUC/dose), area under moment curve/dose (AUMC/dose), volume of distribution at 
steady state (Vss) and clearance (CL) based on Von Willebrand factor Ristocetin cofactor activity
(VWF:RCo), Von Willebrand factor antigen (VWF:Ag), Von Willebrand collagen binding activity 
(VWF:CB) , INNOVANCE VWF Ac (exploratory assay) and time course (72 hours) of FVIII 
clotting activity (FVIII:C) levels.
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Inclusion Criteria
Subjects who meet ALL of the following criteria are eligible for this study:
1. Subject has a documented diagnosis of severe VWD (baseline VWF:RCo <20 IU/dL) with a history 
of requiring substitution therapy with von Willebrand factor concentrate to control bleeding:
a. Type 1 (VWF:RCo <20 IU/dL) or,
b. Type 2A (as verified by multimer pattern), Type 2B (as diagnosed by genotype), Type 2M or,
c. Type 3 (VWF:Ag ≤3 IU/dL).
2. Diagnosis is confirmed by genetic testing and multimer analysis, documented in patient history or at 
screening.
3. Subject currently receiving on-demand treatment for whom prophylactic treatment is recommended 
according to standard of care at the center.
4. Has ≥3 documented spontaneous bleeds requiring VWF treatment during the past 12 months 
5. Availability of records to reliably evaluate type, frequency and treatment of bleeding episodes 
during 12 months of on-demand treatment prior to enrollment.
6. Subject is ≥18 years old at the time of screening and has a body mass index ≥15 but <40 kg/m2.
7. If female of childbearing potential, subject presents with a negative blood/urine pregnancy test at 
screening and agrees to employ adequate birth control measures for the duration of the study.
8. Subject is willing and able to comply with the requirements of the protocol.
Exclusion Criteria
Subjects who meet ANY of the following criteria are not eligible for this study:
1. The subject has been diagnosed with Type 2N VWD, pseudo VWD, or another hereditary or 
acquired coagulation disorder other than VWD (e.g., qualitative and quantitative platelet disorders 
or elevated prothrombin time (PT)/international normalized ratio [INR] 1.4).
2. The subject has received prophylaxis treatment in the 12 months prior to screening (including those 
who received treatment once a month for menorrhagia but were not treated for any other bleeds).
3. The subject is currently receiving prophylaxis treatment.
4. The subject has a history or presence of a VWF inhibitor at screening.
5. The subject has a history or presence of a FVIII inhibitor with a titer ≥0.4 BU (by Nijmegen 
modified Bethesda assay) or ≥0.6 BU (by Bethesda assay).
6. The subject has a known hypersensitivity to any of the components of the study drugs, such as to 
mouse or hamster proteins.
7. The subject has a medical history of immunological disorders, excluding seasonal allergic 
rhinitis/conjunctivitis, mild asthma, food allergies or animal allergies.
8. The subject has a medical history of a thromboembolic event.
9. The subject is HIV positive with an absolute Helper T cell (CD4) count 200/mm3.
10. The subject has been diagnosed with significant liver disease as evidenced by any of the following: 
serum alanine aminotransferase (ALT) 5 times the upper limit of normal; hypoalbuminemia; portal 
vein hypertension (e.g., presence of otherwise unexplained splenomegaly, history of esophageal 
varices).
11. The subject has been diagnosed with renal disease, with a serum creatinine level ≥2.5 mg/dL.
12. The subject has a platelet count <100,000/mL at screening.
13. The subject has been treated with an immunomodulatory drug, excluding topical treatment (e.g., 
ointments, nasal sprays), within 30 days prior to signing the informed consent.
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14. The subject is pregnant or lactating at the time of enrollment.
15. Patient has cervical or uterine conditions causing menorrhagia or metrorrhagia (including infection,
dysplasia).
16. The subject has participated in another clinical study involving another investigational product (IP)
or investigational device within 30 days prior to enrollment or is scheduled to participate in another
clinical study involving an IP or investigational device during the course of this study.
17. The subject has a progressive fatal disease and/or life expectancy of less than 15 months.
18. The subject is identified by the investigator as being unable or unwilling to cooperate with study
procedures.
19. The subject has a mental condition rendering him/her unable to understand the nature, scope and
possible consequences of the study and/or evidence of an uncooperative attitude.
20. The subject is in prison or compulsory detention by regulatory and/or juridical order
21. The subject is member of the study team or in a dependent relationship with one of the study team
members which includes close relatives (i.e., children, partner/spouse, siblings and parents) as well
as employees.
Delay criteria
1. If the subject presents with an acute bleeding episodes or acute illness (e.g., influenza, flu-like
syndrome, allergic rhinitis/conjunctivitis, non-seasonal asthma) the screening visit will be postponed 
until the subject has recovered.
STATISTICAL ANALYSIS
Sample Size Calculation
The determination of the sample size for this study is not based on strict statistical considerations. The 
sample size of a subset of at least 15 subjects with severe VWD, 5 of whom must have Type 3 VWD, is 
based on the Guideline on the Clinical Investigation of Human Plasma Derived von Willebrand Factor 
Products (CPMP/BPWG/220/02).1
Planned Statistical Analysis
Primary Outcome Measure:
The statistical analysis will provide descriptive summaries.
The prospectively recorded annualized bleeding rate (ABR) of spontaneous (not related to trauma) bleeding
episodes during prophylactic treatment will be assessed using negative binomial distribution. Mean ABR of 
spontaneous bleeding episodes together with the corresponding 95% two-sided confidence intervals (CIs) 
will be reported for the prospective counts as well as those based on historical data. 
Secondary Outcome Measures:
Efficacy:
For the number of infusions and for the total weight adjusted consumption of rVWF and ADVATE per 
month and per year during on-demand treatment for bleeding episodes, summary statistics will be carried 
out.
For the number (proportion) of subjects with reduction of ABR relative to historic ABR as well as for the 
number (proportion) of subjects with 0 bleeds, proportions and corresponding 95% two-sided CIs will be 
performed.
The cause, type, localization and severity of bleeding episodes will also be recorded and summarized.
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4. TABLE OF CONTENTS
1. STUDY PERSONNEL.................................................................................................. 2
1.1 Authorized Representative (Signatory) / Responsible Party .............................. 2
1.2 Study Organization................................................................................................. 2
2. SERIOUS ADVERSE EVENT REPORTING........................................................... 3
3. SYNOPSIS..................................................................................................................... 4
4. TABLE OF CONTENTS ........................................................................................... 10
5. LIST OF ABBREVIATIONS .................................................................................... 16
6. BACKGROUND INFORMATION .......................................................................... 20
6.1 Description of Investigational Product ............................................................... 20
6.2 Clinical Condition/Indication .............................................................................. 20
6.3 The role of prophylaxis in the management of VWD........................................ 21
6.4 Population to be Studied ...................................................................................... 23
6.5 Findings from Nonclinical and Clinical Studies................................................. 24
6.5.1 Findings from Nonclinical Studies ............................................................... 24
6.5.1.1 Primary Pharmacodynamics ................................................................. 24
6.5.1.2 Safety Pharmacology.............................................................................. 24
6.5.1.3 Pharmacokinetics.................................................................................... 24
6.5.1.4 Toxicology................................................................................................ 25
6.5.2 Findings from Clinical Studies ..................................................................... 26
6.5.2.1 Study 070701 ........................................................................................... 26
6.5.2.2 Study 071104 ........................................................................................... 27
6.5.2.3 Study 071001 ........................................................................................... 28
6.5.2.4 Study 071401: Single Subject with von Willebrand Disease............... 30
6.6 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) 
to Human Subjects................................................................................................ 30
6.7 Compliance Statement.......................................................................................... 31
7. STUDY PURPOSE AND OBJECTIVES ................................................................. 32
7.1 Study Purpose ....................................................................................................... 32
7.2 Primary Objective................................................................................................. 32
7.3 Secondary Objectives ........................................................................................... 32
7.4 Exploratory Objectives......................................................................................... 32
7.4.1
........................................................................................................... 32
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8. STUDY DESIGN......................................................................................................... 33
8.1 Brief Summary...................................................................................................... 33
8.2 Overall Study Design............................................................................................ 33
8.3 Duration of Study Period(s) and Subject Participation .................................... 33
8.4 Outcome Measures ............................................................................................... 33
8.4.1 Primary Outcome Measure........................................................................... 33
8.4.2 Secondary Outcome Measures ..................................................................... 34
8.4.2.1 Efficacy .................................................................................................... 34
8.4.2.2 Safety........................................................................................................ 34
8.4.2.3 Pharmacokinetics.................................................................................... 34
8.4.2.4 Efficacy of the Treatment of Bleeding Episodes.................................. 34
8.4.3 Exploratory Outcomes Measure................................................................... 35
8.5 Randomization and Blinding............................................................................... 35
8.6 Study Stopping Rules............................................................................................ 35
8.7 Investigational Product(s) .................................................................................... 36
8.7.1 Packaging, Labeling, and Storage................................................................ 36
8.7.1.1 rVWF (Recombinant von Willebrand Factor)..................................... 36
8.7.1.2 rFVIII (Recombinant FactorVIII /ADVATE)..................................... 37
8.7.2 Reconstitution................................................................................................. 37
8.7.3 Administration ............................................................................................... 37
8.7.4 Description of Treatment.............................................................................. 38
8.7.4.1 Baseline Visit (PK-Assessment Treatment).......................................... 38
8.7.4.2 Prophylaxis Initiation Treatment.......................................................... 39
8.7.4.3 Prophylaxis Treatment........................................................................... 39
8.7.4.4 Treatment of Bleeding Episodes............................................................ 42
8.7.5 Investigational Product Accountability ....................................................... 45
8.8 Source Data ........................................................................................................... 45
9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION .......... 46
9.1 Inclusion Criteria.................................................................................................. 46
9.2 Exclusion Criteria................................................................................................. 46
9.3 Delay Criteria........................................................................................................ 48
9.4 Withdrawal and Discontinuation ........................................................................ 48
10. STUDY PROCEDURES .......................................................................................... 50
10.1 Informed Consent and Enrollment ................................................................... 50
10.2 Subject Identification Code................................................................................ 50
10.3 Screening and Study Visits................................................................................. 50
10.3.1 Screening Visit.............................................................................................. 50
10.3.2 Baseline Visit - PK-Assessment Visit ......................................................... 51
10.3.3 Prophylaxis Initiation Visit......................................................................... 52
10.3.4 Treatment of Bleeding Episodes................................................................. 52
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10.3.5 Follow-Up Visits (1 Month ± 1 Week, 2 Months ± 1 Week, 3 Months 
± 2 Weeks, 6 Months ± 2 Weeks, 9 Months ± 2 Weeks)............................. 52
10.3.6 Unscheduled Visits....................................................................................... 54
10.3.7 Study Termination Visit (12 months ± 2 weeks)....................................... 54
10.4 Medications and Non-Drug Therapies.............................................................. 55
10.5 Subject Diary....................................................................................................... 55
10.6 Subject Completion/Discontinuation ................................................................ 56
10.7 Procedures for Monitoring Subject Compliance ............................................. 57
11. ASSESSMENT OF EFFICACY AND PHARMACOKINETICS........................ 58
11.1 Assessment of Spontaneous Bleeding Episodes/Annualized Bleed Rate........ 58
11.2 Evaluation of ABR before rVWF Prophylaxis and ABR under rVWF 
prophylactic treatment......................................................................................... 59
11.3 Number of Infusions and Total Weight Adjusted Consumption of rVWF and 
ADVATE................................................................................................................ 59
11.4 Assessment of Efficacy for Treatment of Bleeding Episode ........................... 59
11.5 Pharmacokinetic Assessment............................................................................. 60
12. ASSESSMENT OF SAFETY................................................................................... 61
12.1 Adverse Events.................................................................................................... 61
12.1.1 Definitions..................................................................................................... 61
12.1.1.1 Serious Adverse Event.......................................................................... 61
12.1.1.2 Suspected Unexpected Serious Adverse Reaction (SUSAR)............. 62
12.1.1.3 Non-Serious Adverse Event ................................................................. 62
12.1.1.4 Unexpected Adverse Events................................................................. 62
12.1.1.5 Preexisting Disease................................................................................ 63
12.1.2 Assessment of Adverse Events.................................................................... 63
12.1.2.1 Severity .................................................................................................. 64
12.1.2.2 Causality................................................................................................ 65
12.1.2.3 Safety Reporting ................................................................................... 66
12.2 Urgent Safety Measures ..................................................................................... 67
12.3 Untoward Medical Occurrences........................................................................ 68
12.4 Non-Medical Complaints ................................................................................... 68
12.5 Medical, Medication, and Non-Drug Therapy History................................... 68
12.6 Physical Examinations........................................................................................ 69
12.6.1 Thromboembolic events .............................................................................. 69
12.6.2 Anaphylaxis.................................................................................................. 70
12.7 Vital Signs............................................................................................................ 71
12.8 Electrocardiogram.............................................................................................. 71
12.9 Clinical Laboratory Parameters........................................................................ 72
12.9.1 rVWF and endogenous FVIII Pharmacokinetics ..................................... 72
12.9.2 Hematology and Clinical Chemistry.......................................................... 73
12.9.3 Immunology.................................................................................................. 74
12.9.3.1 Antibodies to VWF and FVIII............................................................. 74
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13.4.2.2 Efficacy of the Treatment of Bleeding Episodes................................ 85
13.4.2.3 Pharmacokinetic Analysis.................................................................... 85
13.4.2.4 Safety...................................................................................................... 88
13.5 Exploratory Outcome Measures........................................................................ 89
13.6 Planned Interim Analysis of the Study ............................................................. 89
14. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .................................... 89
15. QUALITY CONTROL AND QUALITY ASSURANCE...................................... 90
15.1 Investigator’s Responsibility.............................................................................. 90
15.1.1 Investigator Report and Final Clinical Study Report.............................. 90
15.2 Training ............................................................................................................... 90
15.3 Monitoring........................................................................................................... 90
15.4 Auditing ............................................................................................................... 90
15.5 Non-Compliance with the Protocol ................................................................... 91
15.6 Laboratory and Reader Standardization ......................................................... 91
16. ETHICS ..................................................................................................................... 92
16.1 Subject Privacy ................................................................................................... 92
16.2 Ethics Committee and Regulatory Authorities................................................ 92
16.3 Informed Consent ............................................................................................... 92
16.4 Data Monitoring Committee.............................................................................. 93
17. DATA HANDLING AND RECORD KEEPING................................................... 94
17.1 Confidentiality Policy ......................................................................................... 94
17.2 Study Documentation and Case Report Forms ............................................... 94
17.3 Document and Data Retention........................................................................... 94
18. FINANCING AND INSURANCE........................................................................... 95
19. PUBLICATION POLICY........................................................................................ 95
20. SUPPLEMENTS....................................................................................................... 96
20.1 Study Flow Chart................................................................................................ 96
20.2 Schedule of Study Procedures and Assessments.............................................. 97
20.3 Clinical Laboratory Assessments ...................................................................... 99
21. REFERENCES........................................................................................................ 101
22. SUMMARY OF CHANGES.................................................................................. 104
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Tables
Table 1 rVWF Dosing Schedule Examples: Schedules, A, B, and C.............................. 39
Table 2 Criteria for escalation specific to each bleeding indication................................ 40
Table 3 rVWF:RCo Dosing Recommendations for the Treatment of Bleeding Episodes 
due to VWD.............................................................................................................. 44
Table 4 Efficacy Rating Scale.......................................................................................... 59
Table 5 Schedule of Study Procedures and Assessments ................................................ 97
Table 6 Clinical Laboratory Assessments........................................................................ 99
Figures
Figure 1 Study Design for Baxalta Clinical Study 071301.............................................. 96
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5. LIST OF ABBREVIATIONS
Abbreviation
Definition
ABR
Annualized bleeding rate
ADAMTS13
A Disintegrin And Metalloproteinase with a ThromboSpondin type 1 motif, number 13
AE
Adverse event
ALT
Alanine aminotransferase
AP
Alkaline phosphatase
AST
Aspartate aminotransferase
AUC0-∞
Area under the plasma concentration /time curve from time 0 to infinity
AUC0-72h/Dose
Area under the plasma concentration/time curve from time 0 to 72 hours 
post-infusion/dose
AUC0-∞/Dose
Area under the plasma concentration/time curve from time 0 to infinity/dose
AUC/Dose
Area under the curve/dose
AUMC
Area under moment curve
AUMC0-∞/Dose
Area under the first moment curve from time 0 to infinity/dose
aPTT
Activated partial thromboplastin time
B19V
Parvovirus B19
BILI
Bilirubin
BP
Blood pressure
BU
Bethesda Unit
BUN
Blood urea nitrogen
BW
Body weight
CAM
Cell adhesion molecule
CB
Collagen binding activity
CBC
Complete blood count
CD4
Helper T cell
CHO
Chinese hamster ovary
CI
Confidence interval
Cl
Chloride
CL
Clearance
Cmax
Maximum plasma concentration
CR
Creatinine
CTA
Clinical Trial Agreement
eCRF
Electronic case report form
DMC
Data monitoring committee
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Abbreviation
Definition
DIC
Disseminated intravascular coagulation
DVT
Deep vein thrombosis
EC
Ethics committee
ECG
Electrocardiogram 
EDC
Electronic Data Capture
EDTA
Ethylenediaminetetraacetic acid
ELISA
Enzyme-linked immunosorbent assay
FAS
Full analysis set
FVIII
Factor VIII
FVIII:C
Factor VIII clotting activity
GCP
Good Clinical Practice
GI
Gastrointestinal
Glu
Glucose
GPIb
Glycoprotein Ib
HAMA
Human anti- mouse antibodies
HAV
Hepatitis A virus
HB
Hepatitis B
HBs
Hepatitis B surface
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HEV
Hepatitis E virus
HIV
Human immunodeficiency virus 
HLA
Human leukocyte antigen
HRP
Horseradish peroxidase
IB
Investigator's brochure
ICH
International Council for Harmonisation
Ig
Immunoglobulin
INR
International normalized ratio
IP
Investigational product
IQR
Interquartil range
IR
Incremental recovery
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Abbreviation
Definition
i.v.
Intravenous
K
Potassium
k.o.
Knock out
LDH
Lactate Dehydrogenase
Na
Sodium
NMC
Non-medical complaint
NOAEL
No observed adverse effect level
MRI
Magnetic resonance imaging
MRT
Mean residence time
pdVWF
Plasma derived VWF product
pdVWF/FVIII
Plasma derived VWF product containing fractions of FVIII
PBAC
Pictorial Blood Assessment Chart
PCR
Polymerase Chain Reaction
PEF
Peak expiratory flow
PK
Pharmacokinetic
PKFAS
Pharmacokinetic Full Analysis Set
PKPPAS
Pharmacokinetic Per Protocol Analysis Set
PP
Per protocol 
PT
Prothrombin time
Q1, Q3
Quartile
rFVIII
Recombinant factor VIII
rVWF
Recombinant von Willebrand factor
RBC
Red blood cell count
SAE
Serious adverse event
SAER
Serious adverse event report
SDS-PAGE
Sodium dodecyl sulfate polyacrylamide gel electrophoresis
SIC
Subject identification code
sP-selectin
Soluble P-selectin
SUSAR
Suspected unexpected serious adverse reaction
T1/2
Elimination phase half life
TIA
Transient ischemic attack
Tmax
Time to reach the maximum concentration
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Abbreviation
Definition
TTP
Thrombotic thrombocytopenic purpura
ULMW
Ultra-large molecular weight 
ULN
Upper limit of normal
Vss
Volume of distribution at steady state
VTE
Venous thromboembolism (VTE)
VWD
von Willebrand disease
VWF
Von Willebrand factor
VWF:Ag
Von Willebrand factor antigen
VWF Ac
VWF activity measured INNOVANCE VWF Ac assay
VWF:CB
Von Willebrand Factor collagen binding
VWF:RCo
Von Willebrand factor: Ristocetin cofactor activity
WBC
White blood cell
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6. BACKGROUND INFORMATION
6.1 Description of Investigational Product
Baxalta US Inc. (hereafter referred to as Baxalta or sponsor) has developed a human 
recombinant von Willebrand Factor (rVWF), which is co-expressed with recombinant 
factor VIII (rFVIII) in a Chinese hamster ovary (CHO) cell line and separated during the 
subsequent downstream process. To address concerns regarding the risk of transmission 
of blood-borne pathogens that may be introduced by human plasma, no exogenously 
added raw materials of human or animal origin are employed in the cell culture, 
purification, or formulation of the final container product. The only proteins present in 
the final container product other than rVWF are trace quantities of murine 
immunoglobulin (IgG, from the immunoaffinity purification), host cell (i.e., CHO) 
protein, rFurin (used to further process rVWF). rVWF is intended for the treatment of 
von Willebrand disease (VWD).
rVWF has been developed under the Baxalta internal code BAX111 and is used as 
investigational product (IP) in this study. rVWF may be used with or without ADVATE 
(rFVIII) for the treatment of bleeding episodes (see Section 8.7.4.4). See Section 8.7 for 
further information on the IPs and their usage in this study. A detailed description of 
rVWF is also provided in the Investigator’s Brochure (IB).
rVWF was granted licensure in the United States in December 2015 under the brand 
name VONVENDI for the on-demand treatment and control of bleeding episodes in 
adults diagnosed with VWD; as of the date of this protocol VONVENDI is not yet 
available on the market.
6.2 Clinical Condition/Indication
Von Willebrand Factor (VWF) is a large multimeric glycoprotein with a molecular 
weight that varies from 500 to 20,000 kDa. VWF is normally found in plasma and 
produced in the alpha-granules of platelets and in endothelial cell organelles known as the 
Weibel-Palade bodies. VWF mediates platelet adhesion and aggregation at sites of 
vascular injury, one of the key functions in primary hemostasis. VWF also serves to 
stabilize coagulation factor VIII (FVIII), where FVIII is an essential cofactor of 
secondary hemostasis, which leads to fibrin clot formation.2 Qualitative and/or 
quantitative deficiencies of VWF lead to a highly variable bleeding diathesis known as 
VWD, the most common of the hereditary coagulation factor deficiencies. Penetrance of 
VWD is highly variable, with only a small fraction of mildly affected patients displaying 
clinical symptoms or a family history of a bleeding diathesis.
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The current biochemical-based classification distinguishes disorders arising from partial 
quantitative (type 1), qualitative (type 2), or virtually complete (type 3) deficiencies of 
VWF. Up to 70% of VWD patients are diagnosed with type 1 VWD, which may also be 
associated with minor functional defects in the molecule. In general, patients with type 1 
VWD display mild clinical symptoms. Approximately 20 to 30% of VWD patients are 
diagnosed with type 2 VWD. Type 2 VWD is further divided into 4 subtypes (A, B, N, 
and M), reflecting distinct classes of functional abnormalities. These defects result in 
abnormal functional and/or multimeric distribution patterns that facilitate their diagnosis. 
The bleeding diathesis is usually moderate and primarily affects the mucosal tissues. 
Type 2N VWD patients are sometimes misdiagnosed as mild hemophilia A. Finally, 
approximately 1% percent of VWD patients exhibit a total or near total absence of VWF, 
which is classified as type 3 VWD. The incidence of type 3 VWD is estimated at 
0.5-1.0 x 106. This type is also associated with a very low FVIII level (typically <5%) 
because the VWF carrier function for FVIII is lost. Replacement of VWF alone stabilizes 
endogenous FVIII, resulting in hemostatic levels within several hours post-infusion. 
Published results from studies of a plasma-derived VWF concentrate demonstrated an 
increase of FVIII at an approximate rate of 5.8 1 IU dL-1 h-1.3 Type 3 VWD patients 
display severe hemorrhagic symptoms with bleeding predominantly in mucosal tissues, 
muscle and joints. All VWD patients, particularly those with type 2 or type 3 VWD, are 
at an increased risk for life-threatening bleeding episodes.
6.3 The role of prophylaxis in the management of VWD
The goals of long term prophylaxis in VWD are to maintain VWF and FVIII at sufficient 
levels to reduce the frequency and duration of bleeding episodes, the need for red blood 
cell transfusions, and the risk of complications, such as arthropathy.4 In contrast to 
hemophilia, routine prophylaxis is not as established in VWD, although prophylaxis for 
patients with severe VWD have already been in use in Sweden during the 1950s.5 In 
those early days of VWD treatment plasma FVIII concentrates containing VWF fractions 
were applied for replacement therapy, which then were followed by plasma derived VWF 
products containing fractions of FVIII (pdVWF/FVIII). 
A Swedish cohort including 37 patients with type 3 VWD under prophylactic median 
treatment of 11 years (range 2 to 45 years) was retrospectively analyzed.6;7 The 
doses used for prophylaxis, given once weekly for at least 45 weeks per year, were
calculated based on 12 to 50 IU/kg body weight (BW) of FVIII clotting activity (FVIII:C)
which approximately corresponded to 24-100 IU/kg von Willebrand factor: Ristocetin 
cofactor activity (VWF:RCo) considering that mainly Haemate with a known 
VWF:RCo/FVIII:C ratio of about 2 was used. An escalation of doses from 1 to 3 dose 
levels was allowed depending on the frequency and severity of bleeding episodes. 
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The results demonstrate that under long-term prophylaxis the number of bleeds could be 
reduced dramatically. Whereas the median value for bleeds per year was about 10 before 
prophylaxis this value could be reduced to less than 1 bleed per year during prophylaxis.
The benefit of prophylaxis for such indications was retrospectively also demonstrated in a 
cohort of Italian patients including type 3, 2A, 2M and type 1 patients. Prophylaxis was 
started after severe gastrointestinal or joint bleeding episodes and completely prevented 
bleeding episodes in 8 of these 11 patients and largely reduced the need of blood 
transfusions in the remaining 3. A regimen of 40 IU rVWF:RCo/kg was applied every 
other day or twice a week. A prospective study on prophylaxis, the PRO.WILL study, has 
been initiated in Italy.8
The results of a prospective study investigating the prophylaxis in children and young 
adults showed a significantly reduced bleeding frequency and bleeding score (3 vs. 0.07; 
3 vs. 0. p<0.001) compared to the pre-prophylaxis values. The median dose was 
40 (20-47) IU/kg VWF:RCo administered mainly twice weekly in 23 patients, 3 times a 
week in 7 patients and 4 times a week in 2 children.9
The VWD Prophylaxis Network initiated the VWD International Prophylaxis (VIP) trial 
to investigate the role of prophylaxis in patients with severe VWD including Type 1, 2,
and 3. The dose of the factor replacement product was 50 IU /kgVWF:RCo. The 
frequency of the dose depended on the type of bleeding and could be increased from once 
weekly to twice weekly or 3 times per week. For the treatment of menorrhagia the dose of 
50 IU/kg VWF:RCo was given on the first day of menses for 2 cycles. The frequency 
could be increased to Day 1 and 2 for 2 cycles or to Day 1, 2, and 3 of menses.
The study contains both retrospective and prospective study components. Results from 
the retrospective study component were published, including 61 subjects on prophylactic 
regimen in the past 6 months prior to enrollment or subjects with a history of prophylaxis 
over at least 6 month.10 Differences in annualized bleeding rates (ABR) within 
individuals (during prophylaxis – before prophylaxis) were significant for those with 
primary indications of epistaxis (P = 0.0005), joint bleeding (P = 0.002) and 
gastrointestinal (GI) bleeding (P = 0.001). The difference in the group whose primary 
indication for treatment was abnormally heavy bleeding at menstruation (n = 4) was not 
significant (P = 0.25). The reduction of mucosal bleeding likely not only dependents on 
normal circulating levels of active VWF, but also on the presence of discrete 
concentrations of normal VWF inside the platelets and within endothelial matrices. The 
low subject number (n=4) and the treatment scheme for menorrhagia on Days 1, 2, and 3 
of menses which might represent rather on-demand than prophylactic treatment may also 
account for the outcome in this study. 
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Results from the prospective study component were reported recently.11 Eleven subjects 
completed the study. Six subjects had type 2A, and 5 subjects had type 3 VWD. 
Six subjects presented with epistaxis, 3 with GI bleeding, and 2 with joint bleeding. 
Seven subjects had dose escalation above the first level. Among the 10 subjects with 
evaluable bleeding log data, the use of prophylaxis decreased the median ABR from 25 to 
6.1 (95% confidence interval [CI] of the rate difference: -51.6 to -1.7), and the median 
ABR was even lower (4.0; 95% CI: -57.5 to -5.3) when the subjects reached their final 
dosing level. The authors concluded that this was the first prospective study to 
demonstrate that prophylaxis with VWF concentrates is highly effective in reducing 
mucosal and joint bleeding rates in clinically severe VWD.
The results of the VIP study and previous investigations suggest that VWD patients with 
recurrent bleeding episodes and severe menorrhagia will benefit from a prophylactic 
VWF replacement therapy. There is evidence that up to 40% of patients with type 3 
VWD experience joint bleeding which can lead to hemophilic arthropathy. Other 
potential indications for prophylaxis include patients with type 2A or 2B VWD with 
recurrent gastrointestinal bleeding, menorrhagia or frequent epistaxis.4 Long-term 
prophylaxis for most patients with type 3 VWD and in some patients with type 1 or 2 
VWD, depending on the pattern of bleeding, may be the treatment option of choice.
Although the main experience with long-term prophylaxis is with secondary prophylaxis, 
primary prophylaxis starting at young age is recommended to prevent arthropathy in 
patients with severe VWD.12
However, further studies are needed to develop evidence-based guidelines for 
prophylactic treatment in VWD.
6.4 Population to be Studied
A total of approximately 18 eligible, adult subjects to achieve approximately 15 evaluable 
subjects with severe VWD are planned to be enrolled, of which a subset of at least 
5 subjects will have type 3 VWD. Enrolled subjects (i.e., subjects who have signed the 
informed consent form) will be eligible to participate in the study if they meet all of the 
inclusion criteria (see Section 9.1) and none of the exclusion criteria (see Section 9.2).
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6.5 Findings from Nonclinical and Clinical Studies
The following summarizes the key findings from relevant nonclinical studies as well as 
from the completed clinical studies 070701 (Phase 1 PK and safety in VWD), 071001
(Phase 3 safety and efficacy in the treatment of bleeding episodes in VWD), 071104
(Phase 1 safety and PK in hemophilia A), and 071401 (Phase 3, expanded access in a 
single subject with VWD). Potential risks and efficacy of rVWF:ADVATE are 
summarized in the following sections. For additional information on nonclinical and 
clinical Phase 1 results refer to the rVWF IB.
6.5.1 Findings from Nonclinical Studies
6.5.1.1 Primary Pharmacodynamics
Efficacy of rVWF combined with ADVATE was shown in VWD animal models, which 
have also low endogenous FVIII levels. Time to occlusion and stable thrombus formation 
was assessed in the carotid occlusion model in VWD mice. The results demonstrated that 
rVWF in combination with ADVATE acted efficiently in a dose-dependent manner and 
had higher efficacy than rVWF alone or plasma derived (pd)VWF. These results were 
confirmed in an additional study assessing blood loss and survival in a tail tip bleeding 
model in VWD mice. In a VWD dog rVWF stabilized canine FVIII in the circulation and 
significantly reduced the bleeding time. 
6.5.1.2 Safety Pharmacology
The anaphylactoid and thrombogenic potential of the co-infusion of ADVATE and rVWF 
and the co-infused product’s effects on blood pressure, cardiac and respiratory function 
and parameters of coagulation activation were investigated in 4 in vivo studies in 
different animal models. Safety pharmacology studies in rats, guinea pigs, rabbits, and 
dogs revealed no risks for anaphylactoid and thrombogenic potential of ADVATE in 
combination with rVWF. All observations in safety pharmacology studies are considered 
to lie within the biological variability of animal models or occurred due to known 
species-specific anaphylactoid effects of excipients.
6.5.1.3 Pharmacokinetics
Pharmacokinetic studies of both rVWF alone and combined with human rFVIII 
(rVWF+ADVATE) were conducted in VWD mice, VWD dogs, VWD pigs, rats, and 
cynomolgus monkeys. Human rVWF stabilized the endogenous FVIII in VWD mice, 
VWD pigs, and VWD dogs. Furthermore, the hypotheses that the area under the curve 
(AUC) with rVWF alone and rVWF+ADVATE is not inferior to the AUC with 
pdVWF (Haemate P) was tested and confirmed statistically in normal rats.
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The pharmacokinetic (PK) characteristics of ADVATE were not affected by co-
administration of rVWF in cynomolgus monkeys. The PK data in the FVIII knock out
(k.o.) mice model are inconclusive and might not be relevant for the clinical situation. 
However, a stabilizing effect of VWF on FVIII could be shown in a double knock out 
model in a dose dependent manner.
6.5.1.4 Toxicology
Single dose toxicity studies were conducted in C57BL/6J-mice, VWD mice, rats, rabbits,
and cynomolgus monkeys. Rats, rabbits, and cynomolgus monkeys showed no signs of
toxicity. Signs of microthrombosis, an exaggerated pharmacological effect, were
observed in mice. Mice are not capable of sufficiently cleaving the rVWF subunit as
murine disintegrin and metalloproteinase with a thrombospondin type 1 motif, number 13
(ADAMTS13) does not decrease the ultra-large molecular weight multimers of rVWF.13
The observed symptoms of microthrombosis are interpreted as a species-specific 
exaggerated pharmacological effect. Studies evaluating the safety of repeated 
administration of rVWF with or without ADVATE (daily over 14 days) were performed 
in a rodent (rat) and non-rodent (cynomolgus monkey) species. Reversible signs of 
exaggerated pharmacological effects (regenerative anemia, thrombocytopenia, and 
treatment-related histopathologic changes in the heart, liver, and spleen) were observed in 
rats that were administered 1400 U VWF:RCo/kg /day + 1080 IU ADVATE/kg/day 
intravenously once daily for 14 days. Also, these findings are interpreted as a 
species-specific exaggerated pharmacological effect due to the low susceptibility of 
human rVWF to cleavage by rodent ADAMTS13.13 No toxicologically relevant changes 
were evident for clinical observations, body weight, feed consumption, ophthalmology, 
urinalysis, coagulation, and serum chemistry parameters, platelet aggregation, and gross 
pathology. rVWF combined with ADVATE was well tolerated in cynomolgus monkeys
after daily intravenous (i.v.) (bolus) administration of 100 U VWF:RCo/kg rVWF 
combined with 77 IU/kg ADVATE over a period of 14 days. No adverse effects could be 
detected in this species. There were no signs of hemolysis, thrombosis, or 
thrombocytopenia after repeated intravenous application of rVWF with or without 
ADVATE. Therefore, 100 U VWF:RCo/kg/day rVWF with or without 77 IU/kg 
ADVATE was considered the no observed adverse effect level (NOAEL) in this study, 
which was the highest dose tested. Anti-drug antibodies, however, were formed in both 
species and resulted in a significant reduction in drug exposure after 14 applications as 
compared to a single application. These antibodies substantially reduced the systemic 
exposure to the test substance as compared to a single dose administration. No 
adverse effects due to antibody formation were observed in both species.
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rVWF combined with ADVATE was well tolerated locally and no genotoxic potential 
was evident after 2 in vitro and 1 in vivo genotoxicity study. A study on the influence of 
co-administration of VWF and ADVATE on the immunogenicity of ADVATE in 
3 different hemophilic mouse models (E17 hemophilic Balb/c mice, E17 hemophilic 
C57BL/6J mice, and E17 hemophilic human F8 transgenic mice) showed that rVWF does 
not negatively impact the immunogenicity of ADVATE in any of the three different 
hemophilic mouse models. 
6.5.2 Findings from Clinical Studies
Two phase 1 studies with rVWF either alone or co-administrated with ADVATE in 
patients with VWD 070701 and Hemophilia A 071104 and 1 phase 3 study with rVWF in 
patients with VWD 071001 have been conducted and the results were analyzed and 
evaluated. Details on study design, populations enrolled, and safety and efficacy 
outcomes of these 2 phase 1 studies are presented in Section 6.5.2.1 and Section 6.5.2.2,
and the phase 3 study in Section 6.5.2.3. Information on a single subject with VWD in 
Study 071401 is presented in Section 6.5.2.4.
Refer to rVWF IB for periodic updates from other rVWF studies. 
6.5.2.1 Study 070701
Phase 1 clinical study 070701 was a multicenter, controlled, randomized, single-blind,
prospective 3-step, dose escalation study to investigate safety, tolerability, and PK of 
rVWF combined at a fixed ratio with ADVATE (VWF:RCo/FVIII:C of 1.3 ± 0.2:1) in 
adults with severe VWD.14 Subjects were enrolled in sequential cohorts in a dose 
escalating manner: Cohort 1, 2, and 3 received a single intravenous infusion of 
rVWF:ADVATE at the following doses: 2 IU/kg VWF:RCo (Cohort 1), 7.5 IU/kg 
VWF:RCo (Cohort 2), and 20 IU/kg VWF:RCo (Cohort 3). Subjects in Cohort 4 received 
a single intravenous infusion of rVWF:ADVATE and pdVWF/ADVATE at 50 IU/kg 
VWF:RCo in random order.
The primary endpoint was the tolerability and safety after single dose injections of 
rVWF:ADVATE at 2, 7.5, 20, and 50 IU/kg VWF:RCo for up to 30 days after the last IP 
infusion. The data generated in this phase 1 study suggest that rVWF:ADVATE up to the 
highest investigated dose of 50 IU/kg VWF:RCo is well tolerated and safe in adults with 
severe VWD. No thrombogenic risk or TTP-like syndrome was observed, and no 
neutralizing antibodies to VWF or FVIII were identified. There were no deaths or other 
serious adverse reactions, and no infusions were interrupted or stopped due to an AE.
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Overall, the reported AE profile was similar between the recombinant and 
plasma-derived concentrates.
Secondary endpoints were the PK assessment of VWF:RCo, von Willebrand factor 
antigen (VWF:Ag) and multimeric composition of rVWF as well as FVIII:C at 
standardized time points after single injections of rVWF:ADVATE and pdVWF:FVIII. 
The median VWF:RCo half-life (T1/2) of rVWF at the 50 IU/kg dose was 16 hours. 
T1/2 with pdVWF:FVIII at the same dose level appeared shorter at 12.58 hours, however,
the limits of the 90% CI were similar (11.73 to 17.7 hours vs. 11.87 to 18.03 hours). 
The median half-lives of VWF:RCo were shorter with the lower investigated doses: 
7.13 hours and 13.23 hours with the 7.5 IU/kg and 20 IU/kg doses, although these data 
were derived from a much smaller number of subjects.
In consequence of the missing ADAMTS13 cleavage, ultra-large molecular weight 
(ULMW) multimers are contained in the rVWF final product. The immediate cleavage of 
these ultra-large multimers by ADAMTS13 upon release into the circulation could be 
demonstrated applying sodium dodecyl sulfate polyacrylamide gel electrophoresis
(SDS-PAGE)/Immunoblot with polyclonal anti-VWF antibodies to detect the resulting 
rVWF subunit cleavage fragments.
Overall the data generated in this phase 1 study suggest that rVWF:ADVATE is well 
tolerated and safe in adults with severe VWD.
6.5.2.2 Study 071104
This study was a prospective, uncontrolled, non-randomized, multicenter proof of 
concept study to assess safety and PK of the addition of rVWF to ADVATE treatment in 
12 evaluable subjects with severe hemophilia A. All subjects underwent 3 PK analyses: 
the first after infusion with ADVATE alone, the second after infusion with ADVATE
plus 10 IU/kg rVWF and the third after infusion with ADVATE plus 50 IU/kg rVWF. 
The PK analysis was performed at intervals of approximately 8 to 14 days. Before each 
infusion for PK assessment, there was a wash-out period of at least 5 days and the 
subjects were not actively bleeding. 
Primary outcome measures indicate that co-administration of rVWF slightly sustain 
ADVATE activity with the highest observed ADVATE half-life of 13.74 h (CI 
11.44 to 16.52) after co-infusion of 50 IU/kg ADVATE plus 50 IU/kg rVWF:RCo.
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The highest improvement in ADVATE circulating half-life was observed in subjects 
with VWF:Ag levels below 100% which indicates an association between baseline 
VWF:Ag levels and ADVATE half-life increase. 
No treatment related adverse events (AEs) or serious adverse events (SAEs) were 
reported. No subject withdrew due to an AE and there were no deaths. No binding 
antibodies to VWF, CHO, and rFurin were detectable in the confirmatory assay and no 
signs of a hypersensitivity to rVWF or ADVATE antigen were observed. Laboratory 
values over time did not indicate any potential safety risk for hemophilia A patients 
treated with rVWF and ADVATE in combination.
In summary, the data indicate that rVWF co-administered with ADVATE up to the
highest dose of 50 IU/kg VWF:RCo is well tolerated and safe in hemophilia A patients.
6.5.2.3 Study 071001
This was a phase 3, multicenter, open-label, part-randomized clinical study to assess the 
PK, safety, and efficacy of rVWF:rFVIII and rVWF in the treatment of bleeding episodes
in adult subjects with severe type 3 and severe non-type 3 VWD.15 A total of 49 subjects 
were enrolled (signed informed consent) and screened, 18 subjects were randomized 
(Arm 1 and Arm 2 [PK 50] only), 37 subjects were treated with IP (all study arms), and 
30 subjects completed the study. 
The study consisted of 2 parts (Part A and Part B). Part A consisted of PK assessments 
alone (Arm 2: PK50 only [without treatment of bleeding episodes]), or PK assessments 
(Arm 1: PK50 and Arm 3: PK80) plus on-demand treatment period(s) of 6 months for 
bleeding episodes, or on-demand treatment for bleeding episodes only (Arm 4). Subjects 
receiving treatment for PK assessments and/or bleeding episodes in Part A were to be 
entered into Part B to continue on-demand treatment for bleeding episodes for 
6 additional months for a total of 12 months in the study. 
The primary outcome measure was the number of subjects with “treatment success”
(extent of control of bleeding episodes), which was defined as a mean efficacy rating 
score of <2.5 for a subject’s IP-treated bleeding episodes during the study. The rate of 
subjects with treatment success was 100% (Clopper-Pearson exact 90% CI: 84.7 to 
100.0) for bleeds where the assessments were made prospectively and excluding GI 
bleeds. Sensitivity analyses confirmed the results of the primary analysis.
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Crossover results at 50 IU/kg VWF:RCo showed that the PK profile for rVWF 
VWF:RCo was independent of administration alone or with rFVIII (ADVATE) (T1/2:
19.4 hours for rVWF and 16.6 hours for rVWF:rFVIII; IR: 1.8 U/dL per IU/kg infused 
for both rVWF and rVWF:rFVIII; MRT: 26.7 hours for rVWF and 25.2 hours for 
rVWF:rFVIII). FVIII levels increased substantially with a median peak at 24 hours of 
111.0 U/dL for rVWF:rFVIII and 86.0 U/dL after rVWF alone, indicating that rVWF 
induces a sustained increase in endogenous FVIII activity. The rVWF PK profile was 
comparable at 50 IU/kg and 80 IU/kg VWF:RCo, and repeated PK at 80 IU/kg 
VWF:RCo showed close agreement between pretreatment and end-of-study results.
Further analysis of the PK data from the 071001 study supports the initial use of 50 IU/kg 
twice weekly for prophylaxis dosing in the present study for those subjects who are 
moving from on-demand to prophylaxis. Using 50 IU/kg for PK measurements, subjects 
in the 071001 study exhibiting a T1/2 for rVWF of 14, 16, or 19 hours had BAX111 
plasma concentrations at 72 hours after administration of 2.55, 4.01, and 6.49% above 
baseline, respectively, and plasma concentrations at 96 hours after administration of 0.78, 
1.40, and 2.71% above baseline, respectively. Subjects who have significant spontaneous 
bleeding while on twice weekly prophylaxis will have their regimen increased to 
50 IU/kg 3 times per week (see Section 8.7.4.2).
A total of 125 AEs occurred in 25/37 (67.7%) subjects (62/318 infusions [19.5%]) during 
or after infusion with IP. Of these, 116/125 were non-serious (all mild or moderate; none 
were severe), and 9 SAEs were reported in 7 subjects. Of 125 total AEs, 38 were 
temporally associated with IP; 8 AEs were considered causally related to IP: 
6 non-serious related AEs (tachycardia, infusion site paraesthesia, electrocardiogram 
[ECG] t-wave inversion, dysgeusia, generalized pruritis, and hot flush) occurred in 
4 subjects, and 2 related SAEs (chest discomfort and increased heart rate) occurred in 
1 subject. No deaths occurred during this study. 
None of the subjects developed anti-VWF or anti-FVIII neutralizing antibodies and no 
binding antibodies to VWF or rFurin, or antibodies against CHO protein or anti-Murine 
IgG were observed. No clinical or subclinical signs or symptoms of a thrombogenic event 
were observed in this study. Following an initial increase in ultralarge VWF multimers 
after administration of rVWF, a notable decrease in the proportion of large VWF 
multimers occurred between 12 and 24 hours post infusion, due to degradation by the 
endogenous ADAMTS13 followed by a continued decline until the end of the 96-hour 
follow-up period. 
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Overall, the data support the safe and effective use of rVWF with or without FVIII 
(ADVATE) in the treatment of bleeds in patients with VWD.
6.5.2.4 Study 071401: Single Subject with von Willebrand Disease
One subject who exhibited allergic reactions to currently marketed pdVWF products was 
treated in the single-subject study 071401 with rVWF only for the bleed treatment of 
continued hematuria, and for biopsy and surgical resection of a left-kidney mass.
For the initial rVWF infusion, the subject received a test dose of 5% of the total dose of 
60 IU/kg rVWF:RCo at an infusion rate of 1 mL/min. After a 10 to 15-minute
observation period, no adverse symptoms or signs were noted and the subject received 
the remaining 95% of the total dose. The subject was monitored for any signs of an 
allergic reaction, and none were noted. Treatment with rVWF every 12 to 24 hours was 
to continue at the discretion of the investigator based on VWF levels and clinical 
symptomatology. The subject had an excellent response and recovery, which allowed for 
daily dosing of rVWF and, within 24 hours, the subject’s bleeding had stopped. Daily 
dosing of rVWF was maintained and the subject received his last dose on 
.
The subject also received rVWF for 7 days for prophylaxis for surgery (surgical resection 
of a left-kidney mass). The subject experienced no hemorrhagic complications and no 
AEs that were considered related to the use of rVWF.
6.6 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) to
Human Subjects
Current treatment of VWD patients relies on desmopressin and VWF products 
manufactured from pooled human plasma. Human VWF produced by recombinant 
technology could offer a new perspective in treatment of VWD. The benefit for the 
individual subject is anticipated to be significant during this clinical study. He/she may 
benefit from a product that minimizes excessive FVIII administration. Variations in VWF 
multimeric composition may lead to variability with respect to treating or preventing 
bleeds in VWD subjects, especially mucosal bleeds which are especially problematic. 
rVWF product manufactured by Baxalta consistently contains ultra-large molecular 
weight (ULMW) VWF multimers due to the fact that the product has not been exposed to 
ADAMTS13. The initial presence of these ULMW VWF multimers, which are 
subsequently cleaved by the subject’s endogenous ADAMTS13, may result in improved 
platelet and collagen binding and therefore provide more predictable treatment outcomes.
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By using a recombinant product, the risk of contamination with blood derived viruses or 
variant Creutzfeldt-Jakob Disease associated with the use of products of human or animal 
origin has been virtually eliminated. At this stage of product development, the key 
societal benefit is a better understanding of advanced treatment options for VWD and 
enhanced product availability.
These benefits outweigh the following potential risks of rVWF:

allergic-type hypersensitivity reactions as with any intravenous protein product

the occurrence of thromboembolic events

the development of neutralizing antibodies to VWF
Refer to the IB for further details on benefits and risks of the IP.
6.7 Compliance Statement
This study will be conducted in accordance with this protocol, the International Council 
for Harmonisation Guideline for Good Clinical Practice E6 (ICH GCP, April 1996), 
Title 21 of the US Code of Federal Regulations (US CFR), the EU Directives 2001/20/EC 
and 2005/28/EC, and applicable national and local regulatory requirements.
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7. STUDY PURPOSE AND OBJECTIVES
7.1 Study Purpose
The purpose of this phase 3 study is to investigate the efficacy and safety, including 
immunogenicity and thrombogenicity, and 
of 
prophylactic treatment with rVWF in subjects with severe VWD.
7.2 Primary Objective
The primary objective of this study is to prospectively evaluate the annualized bleeding 
rate (ABR) for spontaneous bleeding episodes while on prophylactic treatment with 
rVWF and to compare it to the subject’s historical ABR for spontaneous bleeding 
episodes during on-demand treatment. 
7.3 Secondary Objectives
Secondary Objectives are:

Additional efficacy assessments of prophylactic treatment

Safety and immunogenicity

Pharmacokinetics

Efficacy of the treatment of bleeding episodes
7.4 Exploratory Objectives
7.4.1
 
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8. STUDY DESIGN
8.1 Brief Summary
8.2 Overall Study Design 
This is a prospective, open label, uncontrolled, non-randomized, international, 
multicenter phase 3 study to evaluate efficacy, safety, including immunogenicity and 
thrombogenicity, and 
of a prophylactic treatment regimen with rVWF in patients 
with severe VWD. 
Subjects transitioning either from on-demand treatment or from prophylactic treatment 
will be infused twice weekly with BAX 111 (rVWF) at doses of 50 ± 10 IU/kg 
rVWF:RCo. The dose may be adjusted within this range based on the PK data, subject’s 
history of bleeding episodes, and the results from clinical and laboratory assessments (see 
Section 8.7.4.2).
The overall duration of prophylactic treatment per subject will be 12 months.
During this period any bleeding episodes requiring substitution therapy with VWF 
concentrate to control bleeding will be treated with rVWF with or without ADVATE. 
The dose will be according to the bleeding severity and it will be adjusted to the clinical 
response (see Section 8.7.4.4.2).
The overall study design is illustrated in Figure 1.
8.3 Duration of Study Period(s) and Subject Participation
The overall duration of the study is approximately 22 months from study initiation 
(i.e., first subject enrolled) to study completion (i.e., last subject last visit). The subject 
participation period is approximately 15 months from enrollment to completion (i.e, last 
study visit), unless the subject is prematurely discontinued.
Subjects will be offered the option to continue to receive BAX111 in a long-term 
continuation study.
8.4 Outcome Measures
8.4.1 Primary Outcome Measure
The primary outcome measure is
Efficacy:
Prospectively recorded ABR for spontaneous (not related to trauma) bleeding
episodes during prophylactic treatment with rVWF and the subjects’ historical 
ABR for spontaneous bleeding episodes during on-demand treatment.
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8.4.2 Secondary Outcome Measures
8.4.2.1 Efficacy 

Number (proportion) of subjects with reduction of ABR for spontaneous (not 
related to trauma) bleeding episodes during prophylaxis relative to the subjects’
own historical ABR during on-demand treatment

Number (proportion) of subjects with 0 bleeds during prophylactic treatment with 
rVWF

Number of infusions and total weight adjusted consumption of rVWF and
ADVATE per month and per year during on-demand treatment
8.4.2.2 Safety

AEs

Incidence of thromboembolic events 

Incidence of severe hypersensitivity reactions

Development of neutralizing antibodies to VWF and FVIII

Development of total binding antibodies to VWF and FVIII

Development of antibodies to Chinese hamster ovary (CHO) proteins, mouse 
immunoglobulin G (IgG) and rFurin
8.4.2.3 Pharmacokinetics

Incremental recovery (IR), terminal half-life (T1/2), mean residence time (MRT), 
area under the curve/dose (AUC/dose), area under moment curve/dose
(AUMC/dose), volume of distribution at steady state (Vss) and clearance (CL) 
based on Von Willebrand factor Ristocetin cofactor activity (VWF:RCo), Von 
Willebrand factor antigen (VWF:Ag), Von Willebrand collagen binding activity 
(VWF:CB) , INNOVANCE VWF Ac (exploratory assay) and time course 
(72 hours) of FVIII clotting activity (FVIII:C) levels.
8.4.2.4 Efficacy of the Treatment of Bleeding Episodes

Number of infusions of rVWF and ADVATE (rFVIII) per spontaneous bleeding 
episode

Number of infusions of rVWF and ADVATE (rFVIII) per traumatic bleeding 
episode
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
Weight-adjusted consumption of rVWF and ADVATE (rFVIII) per spontaneous 
bleeding episode

Weight-adjusted consumption of rVWF and ADVATE (rFVIII) per traumatic 
bleeding episode

Overall hemostatic efficacy rating at resolution of bleed 
8.4.3 Exploratory Outcomes Measure
 
8.5 Randomization and Blinding
This is a non-randomized open-label, active treatment clinical study. 
8.6 Study Stopping Rules 
This study will be stopped if 1 or more of the following criteria are met:
1. Two subjects develop a thromboembolic event
2. Two subjects develop severe hypersensitivity reactions (e.g., clinically significant 
localized urticaria, generalized urticaria, wheezing, or anaphylaxis); or infusion 
related tightness of the chest or hypotension
3. Two subjects develop signs and symptoms, suggestive of a thrombotic 
thrombocytopenic purpura-like syndrome (subjects with type 2B VWD developing 
thrombocytopenia or changes of the platelet count as described below, will be 
evaluated on case by case, whether they need to be accounted for), such as 

A drop in platelet count of 50% of subject’s baseline or less than 100.000 per 
microliter

3-fold increase in lactate dehydrogenase (LDH)

Impaired renal function as determined by: 

Creatinine increase of 1.5-fold from baseline levels
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
Blood urea nitrogen (BUN) increase from normal levels to a level 
> 60 mg/dL
4. Any subject has abnormal liver function:
Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) 
elevations >5 times upper limit of normal (ULN) in the absence of a concomitant 
bilirubin increase
ALT and/or AST elevations >3 times ULN in the presence of a total bilirubin 
increase >2 times ULN or an international normalized ratio (INR) >1.5 without 
findings of cholestasis or other alternate etiology to explain the elevations 
(i.e., “Hy’s Law cases”)
ALT and/or AST elevations >3 times ULN with the appearance of fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or 
eosinophilia (>5%)
5. Two subjects develop rVWF neutralizing antibodies
The study may be stopped at any time by the sponsor.
The sponsor ultimately will decide whether to terminate, temporarily halt or modify the 
study based on the data monitoring committee (DMC) recommendation.
8.7 Investigational Product(s)
8.7.1 Packaging, Labeling, and Storage
8.7.1.1 rVWF (Recombinant von Willebrand Factor)
rVWF will be packaged in boxes with 2 glass vials, one containing the lyophilized 
rVWF, and the second vial containing the diluent. Further details are provided in the IB 
and Pharmacy Manual. The rVWF label will include, at a minimum, the actual 
VWF:RCo potency and the date of expiration.
rVWF should be refrigerated (2-8°C [36-46°F]) in lyophilized form. Deviations from the 
storage condition have to be communicated and followed up with the sponsor.
Inadequately stored product will have to be placed in quarantine and may only be used 
after written investigational product administration authorization by the sponsor. After
removal of the product from the refrigerator the product must not be returned to the 
refrigerator and has to be used immediately. rVWF must not be used beyond the 
expiration date printed on the vial. Avoid freezing at all times.
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8.7.1.2 rFVIII (Recombinant Factor VIII /ADVATE)
ADVATE will be packaged in boxes with 2 glass vials, one containing the lyophilized 
rFVIII, and the second vial containing the diluent. Further details are provided in the IB 
and Pharmacy Manual. The ADVATE label will include, at a minimum, the actual 
FVIII:C potency and the date of expiration. 
ADVATE should be refrigerated (2-8°C [36-46°F]) in powder form and should not be 
used beyond the expiration date printed on the vial. Deviations from the storage condition 
have to be communicated and followed up with the sponsor. Inadequately stored product 
will have to be placed in quarantine and may only be used after written investigational 
product administration authorization by the sponsor. After removal of the product from 
the refrigerator the product must not be returned to the refrigerator and has to be used 
immediately. Avoid freezing at all times.
8.7.2 Reconstitution
The reconstitution procedures for both rVWF and ADVATE products are detailed in the 
Pharmacy Manual. 
8.7.3 Administration
Following reconstitution, rVWF and ADVATE (in case of bleeding episode treatment) 
should be administered to study subjects at room temperature and within 3 hours of 
reconstitution. The reconstituted rVWF and ADVATE, should be inspected for 
particulate matter and discoloration prior to administration, whenever the solution and 
container permit. The solution should be clear and colorless in appearance. If not, do not 
administer the product. Plastic syringes provided by the sponsor must be used since 
coagulation factors tend to stick to the surface of glass syringes.
Investigational product infusions should be given at a rate which should not exceed 
4 mL/minute. The investigator/ subject shall ensure that no visible residual volume 
remains in the syringe(s) and that the complete content is administered. Upon completion 
of the infusion, the butterfly catheter should be flushed with at least 2 mL of saline 
solution. In case of a (central) venous access device, the flush should be with at least 
10 mL of saline solution. The IP infusions should be administered over a duration of 2 to 
15 minutes, depending on the volume.
Only the actual potencies of rVWF and ADVATE as stated on the vial labels and 
described in the Pharmacy Manual should be used. A variation of up to 10% of the 
intended dose for prophylactic infusions and of the intended dose for treatment of 
bleeding episodes is permissible and the exact dose should be recorded on the Case 
Report Form (CRF).
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At study visits where recovery analysis is being done, vials with the same lot numbers 
should be used throughout the PK IP infusion per subject.
For treatment of bleeding episodes there are 2 options for the preparation of rVWF and 
ADVATE for infusion if needed. 
Preferably sequential administration will be done: separate syringes of the appropriate 
dose of rVWF and ADVATE will be prepared for sequential infusion. rVWF should be 
infused first sequentially followed preferably within 10 minutes by infusion of ADVATE. 
Only the actual potencies of rVWF and ADVATE as stated on the vial labels and 
described in the Pharmacy Manual should be used. 
Alternatively, premixed solutions can be administered: rVWF and ADVATE will be an 
i.v. admixture in a single syringe to achieve the appropriate dose. The contents of each 
vial of rVWF or ADVATE can be drawn into 1 syringe by using a separate unused 
reconstitution device as described in the Pharmacy Manual. 
The final dose of rVWF:ADVATE should be at a ratio of 1.3:1 ± 0.2.
8.7.4 Description of Treatment
8.7.4.1 Baseline Visit (PK-Assessment Treatment)
The first IP infusion for PK assessment should be within 42 days after the completion of 
screening procedures and confirmation of eligibility.
At the baseline visit the subjects will receive a dose of 50 ± 5 IU/kg rVWF:RCo for PK 
assessment. Blood samples will be drawn within 30 minutes pre-infusion, and at 7 time 
points post-infusion (30 5 minutes, 60 5 minutes, 6 1 hours, 12 1 hours, 
24 2 hours, 48 2 hours, 72 2 hours). 
Subjects previously enrolled in rVWF studies 070701 or 071001 and having previously 
undergone PK assessments in these studies are required to repeat the PK assessment due 
to different dose and time points used in these former studies (see Section 12.9.1 and 
Section 20.3). A washout period of at least 5 days is required prior to infusion of rVWF 
for PK assessment for subjects previously treated with rVWF.
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Subjects who participated and had a major procedure performed in the surgery study 
071101 will not need an additional PK assessment. Identical PK dose and time points are 
used for both studies 071101 and 071301. Subjects who participated and had a minor 
procedure performed in the surgery study 071101 will need a PK assessment.
8.7.4.2 Prophylaxis Initiation Treatment 
The prophylaxis initiation treatment visit will coincide with the 72 2 h PK assessment. 
At this visit subjects will receive their prophylaxis initiation dose of 50 ± 10 IU/kg
rVWF:RCo after the blood draw for the 72 2 hours post-infusion PK assessment. If 
subjects do not need an additional PK assessment (e.g., subject has participated in the 
surgery study 071101 and had a major procedure performed), subjects must receive the IP 
for prophylaxis initiation treatment within 42 days after screening and confirmation of 
eligibility. The exact standard prophylaxis dose may range between 40 and 60 IU/kg 
based on:

available historical PK data

type and severity of bleeding episodes the subject has experienced in the past and

monitoring of appropriate clinical and laboratory measures
Dose adjustments during the continued prophylactic treatment are described in
Section 8.7.4.3.
The subject will be trained on IP reconstitution and administration and may then qualify
for home treatment (see Section 8.7.4.3.2). Refer to Table 5 for study procedures and
Table 6 for clinical laboratory assessments.
8.7.4.3 Prophylaxis Treatment
The standard prophylactic dose is 50 ± 10 IU/kg rVWF:RCo. All subjects will initially
receive BAX111 (rVWF) twice per week (Table 1, Schedule A). Examples of all dosing 
schedules are provided in Table 1.
Table 1
rVWF Dosing Schedule Examples: Schedules, A, B, and C
Example
M
T
W
Th
F
Sat
Sun
M
T
W
Th
F
Sat
Sun
Schedule A
X
X
X
X
Schedule B
X
X
X
X
X
X
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Dose and frequency adjustments will be agreed with the sponsor in advance unless it 
constitutes an urgent safety measure. Dose adjustments to higher doses (not exceeding the 
upper dose limit of 80 IU/kg rVWF:RCo) and adjustments to frequency will only be 
allowed in cases of persisting high bleeding rates due to insufficient therapeutic response.
8.7.4.3.1 Treatment escalation
Criteria for dose and frequency escalation are specific to each bleeding indication 
(Table 2) but, overall, involve 1 significant breakthrough bleeding episode despite 
compliant prophylaxis. Subjects entering the study will begin prophylaxis treatment 
according to Schedule A (Table 1) and will remain at this dose and frequency until 
meeting the criteria for escalation to the next higher schedule: for example, from 
2 infusions of 50 ± 10 IU VWF:RCo/kg/week to 3 infusions of 50 ± 10 IU 
VWF:RCo/kg/week (Schedule B) to achieve adequate prophylaxis.
Table 2
Criteria for escalation specific to each bleeding indication
Schedule A
Schedule B
Joint bleeding
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) twice per week. In the event a 
spontaneous joint bleeding episode occurs 
while on this regimen, the subject will escalate 
to Schedule B following its resolution
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week.
GI bleeding
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) twice per week. In the event a 
severe GI bleeding episode occurs while on 
this regimen, the subject will escalate to 
Schedule B following its resolution
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week.
Menorrhagia
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) on days 1 and 2 of menses for 
2 cycles. Menstrual flow will be monitored by 
the PBAC score. If the average pictorial chart 
score is > 185, then the subject will escalate to 
Schedule B
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) on days 1, 2, 
and 3 of menses. Menstrual flow 
will be monitored by the PBAC 
score.
Epistaxis
50 ± 10 IU VWF:RCo/kg (rounded up to the
nearest vial) twice per week. The subject will 
escalate to Schedule B in the event of 
1 occurrence of breakthrough bleeding 
requiring intervention such as iron 
replacement therapy, transfusion, packing, 
hospitalization; or 2 bleeding events that 
require treatment with factor replacement
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week. 
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Table 2
Criteria for escalation specific to each bleeding indication
Schedule A
Schedule B
Oral and Other 
Mucosa
50 ± 10 IU VWF:RCo/kg (rounded up to the
nearest vial) twice per week. The subject will 
escalate to Schedule B in the event of
1 occurrence of breakthrough bleeding 
requiring intervention such as iron 
replacement therapy, transfusion, packing, 
hospitalization; or 2 bleeding events that 
require treatment with factor replacement.
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week.
Muscle and Soft 
Tissue
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) twice per week. In the event a 
spontaneous bleeding episode occurs while on 
this schedule, the subject will escalate to 
Schedule B following its resolution.
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week.
GI: gastrointestinal; PBAC: Pictorial Blood Assessment Chart
Dose and frequency reduction will only be allowed in case plasma VWF or FVIII levels
are exceeding the recommended ranges. 
If a subject does not adequately respond to rVWF therapy, he/she will be evaluated for 
the presence of neutralizing and total binding anti-VWF antibodies (see Section 12.9.3.2).
If a subject experiences a bleed while receiving rVWF three times per week, the 
investigator should treat the bleed with rVWF at doses up to 80 IU VWF:RCo/kg at a 
frequency determined by the investigator until the bleed resolves.  Upon resolution of the 
bleeding event, the subject will return to their assigned prophylaxis regimen. 
It is essential for the success of this study that the subjects adhere to treatment regimens. 
Therefore, procedures for monitoring subject’s compliance are implemented (see 
Section 10.7).
If 1 infusion of IP is missed, the subject may administer the IP as soon as possible. The 
subject should adhere to their treatment scheme ensuring a minimum interval of 12 hours 
between this and the previous IP infusion. For example, a subject routinely infuses IP on 
Monday and Thursday, he/she misses the Monday time point and therefore may infuse 
the IP on the next day (Tuesday) and thereafter proceed with infusing the IP on Thursday
(considering a minimum 12 hours between the infusions) and return to the initial
schedule.
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If more than 30% of infusions of IP are missed within the visit interval of 3 months the 
subject will be discontinued from the study (see Section 9.4).
8.7.4.3.2 General Instructions for Home Treatment for Prophylaxis
At the discretion of the investigator, a subject may be considered suitable for home 
treatment only after the subject has received at least 1 infusion of IP in the clinic, either 
during planned IP exposure (PK or prophylaxis) or during the treatment of bleeding 
episodes, and meets the following additional criteria:
1.
Fully understands the concept of a clinical study and related documentation 
(documented training of at least 30 minutes), 
2.
Has a history of previous experience with home treatment including 
self-administration and treatment with VWF containing concentrates, 
3.
Has adequate time for initial training of the study drug preparation (preparation, 
mixing and infusion of the IP(s) (documented training of at least 30 minutes).
In the event a healthcare professional is required to administer IP, he/she must be trained 
and qualified by the sponsor on the above procedures prior to the decision for home 
treatment. A Subject Guideline detailing all instructions and information listed above will 
be provided to each subject. 
8.7.4.4 Treatment of Bleeding Episodes
8.7.4.4.1 General Instructions for Home Treatment of Bleeding Episodes
If a subject experiences a bleeding episode, he/she should contact the study site 
immediately and the site investigator should provide instructions on the treatment 
regimen. If the subject initiates the treatment at home, he/she should at least follow up 
with the study site if a visit is needed as per the standard of care at the center.
In the event a healthcare professional is required to administer treatment at the subject’s 
home, he/she must be trained and qualified by the site investigator on the above 
procedures prior to the decision for home treatment. Once a subject has received 
1 infusion of rVWF in the clinic (either during planned IP exposure or during the 
treatment of a bleeding episode) and meets the criteria for home treatment, the treatment 
of bleeding episodes with IP can be conducted at home (see Section 8.7.4.3.2).
If a subject is not qualified for home treatment, rVWF infusions must be administered at 
the study site.
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If a subject experiences a bleeding episode that requires treatment between the screening 
and the prophylaxis initiation visit, the subject will be treated with IP (rVWF with or 
without ADVATE). Treatment with IP must occur at the study site unless the subject has 
previously qualified for home treatment with rVWF. If rVWF treatment is not feasible, 
the subject may use his/her standard of care, such as commercial pdVWF/FVIII products.
In any case a washout period of at least 5 days is required prior to rVWF PK infusion at
the PK assessment visit.
If a subject experiences a bleeding episode requiring treatment during the PK assessment, 
rVWF will be used to treat the bleed. Blood draws for PK assessment will be stopped and 
the PK assessments will be repeated once the bleed has resolved and the subject is free of 
any symptoms related with the bleeding episode. Dose and frequency of rVWF infusions 
or any other replacement therapy to stop the bleed should be recorded in the e-CRF.
8.7.4.4.2 Dosing Recommendations for Treatment of Bleeding Episodes 
If an acute bleeding episode occurs, the subject will be treated with rVWF with or 
without ADVATE. In general initially, an infusion of rVWF: ADVATE at an rVWF:
ADVATE ratio of 1.3:1± 0.2 will be administered. Subsequent infusions may either use 
rVWF alone or with ADVATE, based on FVIII levels, if available. 
If FVIII levels are not available, dosing is at the discretion of the investigator based upon 
the individual subject’s PK data. Using ADVATE in addition to rVWF in subsequent 
doses carries the risk of an excessive rise in FVIII:C. Therefore, reduced doses of 
ADVATE and/or prolongation of the dose interval should be considered.
In general the aim of the initial dose should be full replacement of VWF with VWF:RCo 
levels of >0.6 IU/ml (60%) and FVIII:C of >0.4 IU/mL (40%). In major bleeding 
episodes, subsequent doses should keep the trough level of VWF:RCo >50% for 3 days 
and then as deemed necessary by the investigator for subsequent days. In moderate 
bleeding episodes, the dose and trough level may be reduced to >30% for as long as 
deemed necessary by the investigator. Treatment for minor bleeding episodes will 
generally consist of only 1 or 2 doses of rVWF IP. 
If the VWF:RCo level is above 150%, a planned treatment should be delayed by at least 
12 hours; if the VWF:RCo level is above 200%, a planned treatment should be delayed 
by at least 24 hours. In either case, a lower subsequent dose (e.g., 20 IU/kg VWF:RCo) 
may be appropriate.
Dosing recommendations are listed in Table 3.
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Dosage must be individualized based on the subject’s weight, VWD type, and the 
severity of the bleeding episode, as well as on monitoring of appropriate clinical and 
laboratory measures. In the phase 1 study 070701, 1.0 IU/kg VWF:RCo raised the 
circulating level of VWF:RCo by 0.017 IU/mL (1.7 %). In the same study, the observed 
mean half-life for rVWF was 19.3 hours, with a standard deviation of 10.9 hours.
Table 3
rVWF:RCo Dosing Recommendations for the Treatment of Bleeding Episodes due to VWD
Classification of 
VWD 
Hemorrhage 
Dosage (IU VWF:RCo/kg body weight) 
Type 1 
Severe (Baseline 
VWF:RCo activity 
typically <20%) 
Minor (e.g., epistaxis, oral 
bleeding, menorrhagia*) 
40 to 50 IU/kg (1 or 2 doses)
Major (e.g., severe or 
refractory epistaxis, 
menorrhagia*, GI bleeding, 
CNS trauma, hemarthrosis, 
or traumatic hemorrhage)
Initial dose 50 to 75 IU/kg, then 40 to 60 IU/kg 
every 8 to 12 hours for 3 days to keep the trough 
level of VWF:RCo >50%; then 40 to 60 IU/kg daily 
for a total of up to 7 days of treatment
Type 2 (all variants) 
and Type 3 
Minor (clinical indications 
above) 
40 to 50 IU/kg (1 or 2 doses)
Major (clinical indications 
above)
Initial dose of 60 to 80 IU/kg, then 40 to 60 IU/kg 
every 8 to 12 hours for 3 days to keep the trough 
level of VWF:RCo >50%; then 40 to 60 IU/kg daily 
for a total of up to 7 days of treatment
* Menorrhagia is defined as excessive bleeding during menstruation. A diagnosis of menorrhagia will be 
defined by a prospectively completed Pictorial Blood Assessment Chart (PBAC) score >185 and normal 
cervical cytology or requiring use of a VWF-containing concentrate for treatment of excessive menstrual 
bleeding for at least one menstrual cycle during the prior year.
Variances of up to 10% in dosing are permissible during treatment of bleeding episodes, 
but rounding to the nearest vial size should be avoided.
Subjects with non-neutralizing binding anti-VWF antibodies should initially be treated 
with a dose known to be efficacious based on the subject’s medical treatment history
which may differ from the recommendations provided in Table 3. Subjects should be 
monitored for lack of efficacy as well as for FVIII (mandatory), VWF:RCo (mandatory), 
and VWF:Ag (optional where testing is not available) levels after 3 to 6 hours. Re-dosing 
with rVWF in combination with ADVATE using the same (initial) dose and adaptation of 
the dosing frequency should be considered until cessation of the bleed, if the FVIII and/or 
VWF:RCo levels drop below 30%-50% depending on bleeding severity.
The number of subsequent infusions and the dosage levels prescribed will be determined 
by the investigator on the basis of the clinical severity, response to current therapy, 
available laboratory data, and the subject’s historical treatment for similar bleeding 
episodes.
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8.7.5 Investigational Product Accountability
The investigator will ensure that the IP(s) is stored as specified in the Pharmacy Manual
and that the storage area is secured, with access limited to authorized study personnel. 
The investigator will maintain records that the IP(s) was received, including the date 
received, drug identity code, date of manufacture or expiration date, amount received and 
disposition. The IP(s) must be dispensed only at the study site or other suitable location 
(e.g., infusion center; home, as applicable per study design), as specified in the protocol 
(see Section 10). Records will be maintained that includes the subject identification code 
(SIC), dispensation date, and amount dispensed. All remaining partially used and/or 
unused IP(s) will be returned to the sponsor or sponsor’s representative after study 
completion/termination, or destroyed with the permission of the sponsor in accordance 
with applicable laws and study site procedures. If IP(s) is to be destroyed, the investigator 
will provide documentation in accordance with sponsor’s specifications.
8.8 Source Data
Per ICH GCP, source data are defined as all information in original records and certified 
copies of original records of clinical findings, observations, or other activities in a clinical 
trial that are necessary for the reconstruction and evaluation of the trial. Source data are 
contained in source documents (original records or certified copies), which may be in 
paper and/or electronic format. Source data for this study comprise the following:
hospital records, medical records, clinical and office charts, laboratory notes, memoranda, 
subjects' diaries or evaluation checklists, outcomes reported by subjects, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate copies, microfiches, photographic negatives, 
microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at 
the laboratories and at medico-technical departments involved in the clinical study.
No data will be entered directly onto the CRF.
For additional information on study documentation and CRFs refer to Section 17.2. The 
use of subject diaries is described in Section 10.5.
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9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION
9.1 Inclusion Criteria
Subjects who meet ALL of the following criteria are eligible for this study:
1.
Subject has a documented diagnosis of severe VWD (baseline VWF:RCo 
<20 IU/dL) with a history of requiring substitution therapy with von Willebrand 
factor concentrate to control bleeding
a. Type 1 (VWF:RCo <20 IU/dL) or,
b. Type 2A (as verified by multimer pattern), Type 2B (as diagnosed by 
genotype), Type 2M or,
c. Type 3 (VWF:Ag ≤3 IU/dL).
2.
Diagnosis is confirmed by genetic testing and multimer analysis, documented in 
patient history or at screening.
3.
Subject currently receiving on-demand treatment for whom prophylactic treatment 
is recommended according to standard of care at the center.
4.
Has ≥3 documented spontaneous bleeds requiring VWF treatment during the past 
12 months 
5.
Availability of records to reliably evaluate type, frequency and treatment of 
bleeding episodes during 12 months of on-demand treatment prior to enrollment.
6.
Subject is ≥18 years old at the time of screening and has a body mass index 
≥15 but <40 kg/m2.
7.
If female of childbearing potential, subject presents with a negative blood/urine 
pregnancy test at screening and agrees to employ adequate birth control measures 
for the duration of the study.
8.
Subject is willing and able to comply with the requirements of the protocol.
9.2 Exclusion Criteria
Subjects who meet ANY of the following criteria are not eligible for this study:
1.
The subject has been diagnosed with Type 2N VWD, pseudo VWD, or another 
hereditary or acquired coagulation disorder other than VWD (eg qualitative and 
quantitative platelet disorders or elevated PT/INR 1.4).
2.
The subject has received prophylaxis treatment in the 12 months prior to 
screening (including those who received treatment once a month for menorrhagia 
but were not treated for any other bleeds).
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3.
The subject is currently receiving prophylaxis treatment.
4.
The subject has a history or presence of a VWF inhibitor at screening.
5.
The subject has a history or presence of a FVIII inhibitor with a titer ≥0.4 BU (by 
Nijmegen modified Bethesda assay) or ≥0.6 BU (by Bethesda assay).
6.
The subject has a known hypersensitivity to any of the components of the study 
drugs, such as to mouse or hamster proteins.
7.
The subject has a medical history of immunological disorders, excluding seasonal 
allergic rhinitis/conjunctivitis, mild asthma, food allergies or animal allergies.
8.
The subject has a medical history of a thromboembolic event.
9.
The subject is HIV positive with an absolute Helper T cell (CD4) count 
200/mm3.
10. The subject has been diagnosed with significant liver disease as evidenced by any 
of the following: serum ALT 5 times the ULN; hypoalbuminemia; portal vein 
hypertension (e.g., presence of otherwise unexplained splenomegaly, history of 
esophageal varices).
11. The subject has been diagnosed with renal disease, with a serum creatinine level 
≥2.5 mg/dL.
12. The subject has a platelet count <100,000/mL at screening.
13. The subject has been treated with an immunomodulatory drug, excluding topical 
treatment (e.g., ointments, nasal sprays), within 30 days prior to signing the 
informed consent.
14. The subject is pregnant or lactating at the time of enrollment.
15. Patient has cervical or uterine conditions causing menorrhagia or metrorrhagia 
(including infection, dysplasia).
16. The subject has participated in another clinical study involving another IP or 
investigational device within 30 days prior to enrollment or is scheduled to 
participate in another clinical study involving an IP or investigational device 
during the course of this study.
17. The subject has a progressive fatal disease and/or life expectancy of less than 
15 months.
18. The subject is identified by the investigator as being unable or unwilling to 
cooperate with study procedures.
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19. The subject has a mental condition rendering him/her unable to understand the 
nature, scope and possible consequences of the study and/or evidence of an 
uncooperative attitude.
20. The subject is in prison or compulsory detention by regulatory and/or juridical 
order.
21. The subject is member of the study team or in a dependent relationship with one 
of the study team members which includes close relatives (i.e., children, 
partner/spouse, siblings and parents) as well as employees.
9.3 Delay Criteria
1.
If the subject has an acute bleeding episode or presents with an acute illness 
(e.g., influenza, flu-like syndrome, allergic rhinitis/conjunctivitis, non-seasonal 
asthma) the screening visit will be postponed until the subject has recovered.
9.4 Withdrawal and Discontinuation
Any subject may voluntarily withdraw (i.e., reduce the degree of participation in the 
study) consent for continued participation and data collection. The reason for withdrawal 
will be recorded on the End of Study CRF. Assessments to be performed at the 
termination visit (including cases of withdraw or discontinuation) are described in 
Section 10.6 and Section 20.2. 
Discontinuation (i.e., complete withdrawal from study participation) may be due to 
dropout (i.e., active discontinuation by subject) or loss to follow-up (i.e., discontinuation 
by subject without notice or action). Additionally, the investigator and sponsor have the 
discretion to discontinue any subject from the study if, in their judgment, continued 
participation would pose an unacceptable risk for the subject.
Subjects also will be withdrawn from treatment or discontinued from further study 
participation for the following reasons:
1.
The subject is scheduled for an extended treatment period 3 months with 
non-topical immunomodulating drugs other than anti-retroviral chemotherapy 
(e.g., -interferon, corticosteroid agents [equivalent to hydrocortisone greater than 
10 mg/day]) during the course of the study
2.
Subjects with chronic hepatitis B or C develop ALT/AST levels exceeding 5 times 
the ULN for 1 month
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3.
Subjects who experience severe hypersensitivity reactions, e.g., anaphylaxis upon 
exposure to rVWF
4.
Subjects who develop a neutralizing inhibitor to rVWF and/or ADVATE
(biological assays)
5.
Subjects who demonstrate clinical signs of thromboembolic events
6.
The subject becomes pregnant. IP exposure will be discontinued. Attempts will be 
made to follow the subject through completion of the pregnancy and up to 1 year 
post delivery, if feasible. The investigator will record a narrative description of 
the course of the pregnancy and its outcome.
7.
The subject begins lactating. IP exposure will be discontinued. The investigator 
will record a narrative description of the course of the baby’s development. 
8.
The subject is not compliant with the prophylactic treatment regimen and does not 
adhere to the frequency of IP administration. Once >30% of infusions are missed
within a visit interval (3 months), the subject will be discontinued from further 
participation in the study. 
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10. STUDY PROCEDURES
10.1 Informed Consent and Enrollment
Any patient who provides informed consent (i.e., signs and dates the informed consent 
form) is considered a subject in the study.
10.2 Subject Identification Code
The following series of numbers will comprise the SIC: protocol identifier (e.g., 090701) 
to be provided by the sponsor, 2- or 3-digit number study site number (e.g., 02) to be 
provided by the sponsor, and 3- or 4-digit subject number (e.g., 0003) reflecting the order 
of enrollment (i.e., signing the informed consent form). For example, the third subject 
who signed an informed consent form at study site 02 will be identified as Subject 
090701-020003. All study documents (e.g., CRFs, clinical documentation, sample 
containers, drug accountability logs, etc.) will be identified with the SIC. Additionally, a 
uniquely coded SIC(s) is permitted as long as it does not contain a combination of 
information that allows identification of a subject (e.g., collection of a subject’s initials 
and birth date would not be permitted), in compliance with laws governing data privacy.
10.3 Screening and Study Visits
The study site is responsible for maintaining a screening log that includes all subjects 
who provided informed consent. The log also will serve to document the reason for 
screening failure. All screening data will be collected and reported in CRFs, regardless of 
screening outcome. If a subject is re-screened, the End of Study CRF should be 
completed, and a new ICF, new SIC and new CRF are required for that subject.
The overall study design is illustrated in the Figure 1. Details on the procedures to be 
performed at each study visit, including screening, are provided in Supplement 20.2
Schedule of Study Procedures and Assessments and Supplement 20.3 Clinical Laboratory 
Assessments.
10.3.1 Screening Visit
Written informed consent must be obtained from each subject before any study 
related procedures are performed. To initiate screening procedures, at least 72 hours 
must have elapsed since the last VWF administration and the subject must not be 
actively bleeding at the time of screening. Multimer analysis and VWD gene mutation 
analysis should be performed at screening if not available in the subject’s medical history.
The screening visit will be delayed if the subjects presents with an acute bleeding 
episodes or acute illness (e.g., influenza, flu-like symptoms, inflammatory diseases) until 
the event has resolved. All screening procedures and confirmation of eligibility shall take 
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place within 42 days prior to the first infusion of IP for PK assessments. If the IP is not 
infused within 42 days, all screening assessments except blood group, human leucocyte 
antigen (HLA), genetics, multimeric pattern and 
, must be repeated to reconfirm 
eligibility. Refer to Supplement 20.2 and Supplement 20.3. Upon completion of screening 
procedures, subject eligibility will be confirmed by the sponsor on a subject eligibility 
form before additional study procedures are undertaken. The subject will maintain a diary 
that will include infusion logs (see Section 10.5). The allocation of IP will be initiated 
after the subject has qualified for home treatment (see Section 8.7.4.3.2).
In the event of a subject experiencing a bleeding episode that requires treatment between 
the screening visit and the baseline visit (PK assessment visit), the subject will be treated
with rVWF. If rVWF is not available for any reason, e.g., subject not yet trained on IP 
administration, study site visit for IP administration not feasible, etc., the subject may use 
his/her standard of care, such as commercial pdVWF/FVIII products.
10.3.2 Baseline Visit - PK-Assessment Visit 
After screening and confirmation of eligibility each subject will undergo a PK 
assessment. Subjects who participated in the surgery study 071101 will not need to 
undergo a PK baseline assessment again if they had a major procedure performed, 
provided valid PK data from 071101 is available. These subjects may proceed directly 
with the prophylaxis initiation visit (refer to Section 10.3.3). All subjects will receive a 
dose of 50 ± 5 IU/kg rVWF:RCo to determine VWF and FVIII levels. Blood samples will 
be drawn within 30 minutes pre-infusion, and at 7 time points post-infusion 
(30 5 minutes, 60 5 minutes, 6 1 hours, 12 1 hours, 24 2 hours, 48 2 hours, 
72 2 hours). Refer to Section 20.2 and Section 20.3. IP infusion vials from the same lot 
number should be used for all PK-assessments per subject. Samples for measurement of 
FVIII and VWF activity taken through to 6 hours post-infusion will be obtained from an 
extremity different from that used for the infusion of IP. Where needed, the phlebotomy 
site will be kept patent via an infusion of normal saline. In this event, at least 5 mL of 
blood will be collected and discarded before collection of the next test sample into a fresh 
syringe.
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If the subject has a central venous catheter, the central line should be used to administer 
the infusion and a peripheral venipuncture should be used to collect the blood samples. 
In the event that a blood sample must be drawn through the central line used for 
administration of IP, the line must first be flushed with at least 10 mL normal saline or 
other suitable catheter flush solution that does not contain anticoagulant. At least 5 mL of 
whole blood must be collected and discarded prior to obtaining the sample. 
If a subject experiences a bleeding episode during the PK assessment no subsequent 
blood sample will be drawn in that specific PK period. The guidance provided in 
Section 8.7.4.4 has to be followed for the treatment of the bleeding episode. The subject 
once recovered is eligible to repeat the PK assessment. 
10.3.3 Prophylaxis Initiation Visit
After the blood sample for the 72 hour PK assessment is drawn the subject will receive 
the first rVWF prophylactic dose of 50 ± 10 IU/kg rVWF: RCo. Details on dose are 
provided in Section 8.7.4.3. 
If a subject did not undergo PK assessment (for example the subject has participated in
the surgery study 071101 and has undergone PK in Study 071101 and had a major 
procedure performed, refer to Section 8.7.4.2), procedures and assessments at this visit 
include: adverse events, bleeding episodes, medications taken, non-drug therapies and 
laboratory assessment. Independent of previous PK assessment visits, within 2 hours 
prior the IP infusion, a physical examination will be performed. Vital signs will be 
assessed within 30 minutes prior to IP rVWF infusion and 30 minutes ± 15 minutes after 
IP infusion. For subjects with a previous PK assessment in the course of the surgery 
study, incremental recovery (IR) will be determined based on VWF: RCo activity 
assessed prior and after IP infusion. Further details are provided in Supplement 20.2 and 
Supplement 20.3.
10.3.4 Treatment of Bleeding Episodes
Treatment of bleeding episodes is described in detail in Section 8.7.4.4.
10.3.5 Follow-Up Visits (1 Month ± 1 Week, 2 Months ± 1 Week, 
3 Months ± 2 Weeks, 6 Months ± 2 Weeks, 9 Months ± 2 Weeks)
Visits will be performed after the prophylaxis initiation visit at 1 month ± 1 week, 
2 months ± 1 week, and 3 months ± 2 weeks and thereafter every three months
± 2 weeks. Additional visits may occur if clinically indicated (see Section 10.3.6).
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When possible, site visits should be scheduled on days when the subject is expected to 
infuse BAX111. Within 2 hours prior to the rVWF IP infusion , a physical examination 
will be performed. Vital signs will be assessed within 30 minutes prior to IP infusion and 
30 minutes ± 15 minutes after IP infusion. Incremental recovery (IR) will be determined 
at each follow-up visit based on VWF:RCo activity assessed prior to and after IP 
infusion. 
The blood sample for IR analysis will be drawn within 30 minutes prior to IP infusion
and 30 minutes ± 5 minutes after IP infusion. rVWF will be infused at the regular 
prophylactic dose, i.e., 50 ± 10 IU/kg rVWF:RCo. For each subject’s recovery analysis IP
infusion, vials from the same lot number should be used. 
Testing for VWF:RCo VWF:CB, rVWF:Ag, INNOVANCE VWF:Ac (exploratory) and 
FVIII:C level will be performed using the blood sample obtained before and after IP 
infusion. 
The blood sample prior to IP infusion will also be used for the assessment of neutralizing
and binding antibodies, clinical chemistry and hematology. A washout period of at least 
72 hours after the last infusion applies before the blood draw for the immunogenicity 
assays. Bleeding episodes and the hemostatic efficacy will be evaluated based on the 
review of the patient diary. Refer to Section 20.2 and Section 20.3. The evaluation of IP 
consumption and treatment compliance will be performed based on subject’s diary 
entries. If a subject is not compliant with the prophylactic treatment regimen and does not 
adhere to the required frequency of administration of IP infusions (>30% of infusions
were missed within a visit interval [3 months]) the subject will be withdrawn from the 
study.
At the 6 months ± 2 week visit an electrocardiogram (ECG) will be performed and 
data will be collected. 
For the hemostatic efficacy assessment the following information will be recorded by the 
subject in the patient diary: bleeding location, type, severity, onset and resolution date 
and time, infusion date and time, clinical efficacy according to the rating scale. If at any 
time during the study a subject’s bleeding episode does not adequately respond to rVWF 
therapy, he/she will be evaluated for the presence of neutralizing and total binding 
antibodies. Refer to Section 12.9.3.2.
Further guidance on completing the subject’s diary will be provided to the subjects during 
training for home treatment (see Section 8.7.4.3.2).
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10.3.6 Unscheduled Visits
For any unscheduled visit (except for collection of IP) a clinical assessment will be 
performed as per the scheduled follow-up visits with the exception of 
, ECG, and 
IR determination (refer to Supplement 20.2 and Supplement 20.3).
Subjects who have more than one bleeding episode in 3 months, or an increased 
frequency of bleeding, should go to the study site for an unscheduled visit.
Follow-up visits after the subject has experienced a bleed may be requested by the 
investigator. Additional assessments may be required which are at the discretion of the 
investigator. 
10.3.7 Study Termination Visit (12 months ± 2 weeks)
At the 12 month ± 2 week visit, a full PK analysis, as per the baseline PK assessment, 
will be performed. Blood samples will be drawn within 30 minutes pre-infusion, and at 
7 time points post-infusion (30 ± 5 minutes, 60 ± 5 minutes, 6 ± 1 hours, 12 ± 1 hours, 
24 ± 2 hours, 48 ± 2 hours, 72 ± 2 hours). If a subject experiences a bleeding episode 
during the PK assessment no subsequent blood sample will be drawn in that specific PK 
period. The guidance provided in Section 8.7.4.4 has to be followed for the treatment of 
the bleeding episode. The subject once recovered is eligible to repeat the PK assessment.
The following parameters will be used as part of the PK assessment:

Incremental recovery of VWF:RCo, VWF:Ag, VWF:CB, and INNOVANCE 
VWF Ac (exploratory assay)

AUC/dose, area under moment curve (AUMC/dose, clearance (CL), Volume of 
distribution at steady state (Vss), mean residence time (MRT), of 
VWF:RCo ,VWF:Ag, VWF:CB, and INNOVANCE VWF Ac (exploratory assay) 

Half-life of VWF:RCo, VWF:Ag, VWF:CB, and INNOVANCE VWF Ac 
(exploratory assay)

Time course of the FVIII:C levels

VWF collagen binding (VWF:CB) levels
Refer to Supplement 20.2 and Supplement 20.3 for the other assessments to be performed 
at the PK assessment and study completion visits.
A washout period of at least 72 hours is required between the PK infusion and the study 
termination visit (at the time of the 72 hour postinfusion PK assessment). 
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Refer to Supplement 20.2 and Supplement 20.3 for the list of assessments to be 
performed at the termination visit.
Subjects will be offered the option to continue to receive BAX111 in a long-term 
continuation study.
10.4 Medications and Non-Drug Therapies 
The following medications and non-drug therapies are not permitted within 30 days 
before study entry and during the course of the study:
Medications:

Immunomodulating drugs other than anti-retroviral chemotherapy (e.g.,
-interferon, or corticosteroid agents at a dose equivalent to hydrocortisone 
greater than 10 mg/day) and an extended treatment period 3 months.

Another investigational and/or interventional study drug (except rVWF and FVIII 
administered under the surgery protocol).
A subject who has taken any of these medications or received any of these non-drug 
therapies during the study will be withdrawn from the study. 
The following medications are permitted during the course of the study:

Antifibrinolytics (e.g., tranexamic acid, -amino caproic acid) or topical
hemostats as needed, according to each institution’s standard of care

Emergent use of a VWF concentrate other than rVWF may be permissible under
certain circumstances (see Section 8.7.4.4.1)
Details of all adjunctive hemostatic medication used, including dose and reason for use, 
will be recorded in the electronic Case Report Form (eCRF).
10.5 Subject Diary
1.
An electronic subject diary will be provided to each subject at the baseline visit to
record the following information:

IP infusions to include date, start and stop times of the infusion, number of 
vials utilized, and infusion volume for prophylactic treatment or treatment of 
spontaneous and traumatic bleeding episodes 
2.
Details of bleeding episodes (site and type of bleeding) and response to treatment 
as described in Section 8.7.4.4
3.
Subjective hemostatic efficacy assessments.
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Subjects and/or their legally authorized representatives will be trained on use of the diary. 
The diary will be provided in electronic format and remain with the subject for the 
duration of the study. The investigator will review the diary for completeness and request 
missing information periodically and in a timely manner. 
Infusions performed at the study site will be recorded in the site’s source documents and 
not in the patient diary.
Subject entries in the diary will serve as source records. During study participation the 
investigator has access to the database holding the subject diary data. After study closure, 
the investigator will receive the diary records for their subjects, including audit trail 
records, in PDF format. The data will be transmitted to the CRF by a validated transfer. 
10.6 Subject Completion/Discontinuation
A subject is considered to have completed the study when he/she ceases active 
participation in the study because the subject has, or is presumed to have completed all 
study procedures according with the protocol (with or without protocol deviations).
Reasons for completion/discontinuation will be reported on the 
Completion/Discontinuation CRF, including: completed, screen failure, AE (e.g., death), 
discontinuation by subject (e.g., lost to follow-up [defined as 3 documented unsuccessful 
attempts to contact the subject], dropout), physician decision (e.g., pregnancy, 
progressive disease, non-compliance with IP/protocol violation(s), recovery), study 
terminated by sponsor, or other (reason to be specified by the investigator, e.g., technical 
problems). Regardless of the reason, all data available for the subject up to the time of 
completion/discontinuation should be recorded on the appropriate CRF. 
Every effort will be made to have discontinued subjects complete the study termination 
visit. If the termination visit is done as an additional, unscheduled visit, the assessment
results shall be recorded with the termination visit. If a subject terminates participation in 
the study and does not return for termination visit, his/her last recorded assessments shall 
remain with the last visit. The reason for discontinuation will be recorded, and the data 
collected up to the time of discontinuation will be used in the analysis and included in the 
clinical study report. If additional assessments are required, the assessments shall be 
recorded separately. Assessments to be performed at the termination visit (including in 
cases of withdraw or discontinuation) can be found in Supplement 20.2 Schedule of 
Study Procedures and Assessments and Supplement 20.3 Clinical Laboratory 
Assessments.
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In the event of subject discontinuation due to an AE, clinical and/or laboratory 
investigations that are beyond the scope of the required study observations/assessments 
may be performed as part of the evaluation of the event. These investigations will take
place under the direction of the investigator in consultation with the sponsor, and the 
details of the outcome may be reported to the appropriate regulatory authorities by the 
sponsor. 
10.7 Procedures for Monitoring Subject Compliance
Subject compliance with the procedures of this study (treatment regimens and study 
visits) will be monitored by the investigator or/a licensed healthcare professional at the 
study site.
During the regular scheduled follow-up visits a direct review of the subject’s source data 
(e-diaries) will be performed at the sites and evaluated against the protocol requirements. 
In addition drug accountability will be evaluated at each follow-up study visit and the 
study termination visit by comparing the infusions recorded in the subject diary with
empty vials returned by each subject to the study site, and the study site’s dispensing 
record. Protocol deviations will be noted in the final report. 
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11. ASSESSMENT OF EFFICACY AND PHARMACOKINETICS
11.1 Assessment of Spontaneous Bleeding Episodes/Annualized Bleed Rate 
The annualized bleed rate (ABR) will be assessed based upon each individual 
spontaneous bleed, requiring coagulation factor replacement therapy, i.e., rVWF 
treatment. The following details on bleeding episodes will be recorded by the subject in 
the electronic diary (for home treatment), the subject’s healthcare provider in the site’s 
source documents (for treatments away from the primary investigative site), or by 
authorized, qualified personnel at the participating site in the subject’s medical records 
(for hospital-based treatment):

Location of bleed; i.e., joint, menorrhagia, epistaxis, gastrointestinal, soft tissue, 
muscle, body cavity, intracranial, etc.

Type of bleed; i.e., spontaneous, traumatic, unknown

Severity of bleed; i.e., minor, moderate, and major (see Table 3)

Date and time of onset of bleed

Date and time of each infusion of rVWF or rVWF-ADVATE used to treat a 
bleeding episode

Date and time of resolution of the bleeding episode
Study site personnel are qualified after they have undergone training during the 
qualification of the site.
All types of bleeds, including traumatic bleeds, will be recorded. Bleeding episodes 
should be organized by where they occur in addition to whether they occurred 
spontaneously or due to a traumatic event.
Bleeds occurring at the same anatomical location (e.g., right knee) with the same etiology 
(i.e., spontaneous versus injury) within 24 hours after onset of the first bleed will be 
considered a single bleed. Bleeding occurring at multiple locations related to the same 
injury (e.g., knee and ankle bleeds following a fall) will be counted as a single bleeding 
episode.
All efforts should be made to use rVWF for treatment of bleeding episodes. If needed, the 
use of a VWF concentrate other than IP for the treatment of bleeding episodes will not 
disqualify the subject from further participation in the study.
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11.2 Evaluation of ABR before rVWF Prophylaxis and ABR under rVWF
prophylactic treatment
At screening, the subject’s medical history will be recorded, including the number of all 
spontaneous and traumatic bleeding episodes within the past 12 months. The maximum 
interval of bleed-free periods as well as trauma induced bleeding episodes will also be 
recorded (prospectively and retrospectively).
11.3 Number of Infusions and Total Weight Adjusted Consumption of rVWF and 
ADVATE
The number of rVWF and ADVATE (in case of bleeding episode treatment) infusions 
will be logged in the subject diary. Based on these entries the weight adjusted 
consumption will be calculated per month and per year. 
11.4 Assessment of Efficacy for Treatment of Bleeding Episode
Investigators will be asked to assess and record hemostatic efficacy after resolution of 
each bleeding episode using the 4-scale rating system outlined in Table 4. 
Table 4
Efficacy Rating Scale
Rating
Efficacy Rating Criterion
Minor and Moderate Bleeding Events
Major Bleeding Events
Excellent (=1)
Actual number of infusions ≤ estimated 
number of infusions required to treat that 
bleeding episode
No additional VWF containing 
coagulation factor containing product 
required
Actual number of infusions ≤ estimated 
number of infusions required to treat that 
bleeding episode
No additional VWF containing coagulation 
factor containing product required
Good (=2)
1-2 infusions greater than estimated 
required to control that bleeding episode
No additional VWF containing 
coagulation factor containing product 
required
< 1.5 x infusions greater than estimated 
required to control that bleeding episode
No additional VWF containing coagulation 
factor containing product required
Moderate (=3)
3 or more infusions greater than estimated 
required to control that bleeding episode
No additional VWF containing 
coagulation factor containing product 
required
≥1.5 x infusions greater than estimated 
required to control that bleeding episode
No additional VWF containing coagulation 
factor containing product required
None (=4)
Severe uncontrolled bleeding or intensity 
of bleeding not changed
Additional VWF containing coagulation 
factor containing product required
Severe uncontrolled bleeding or intensity 
of bleeding not changed
Additional VWF containing coagulation 
factor containing product required
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11.5 Pharmacokinetic Assessment
Details on pharmacokinetic assessments are provided in Section 12.9.1.
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12. ASSESSMENT OF SAFETY
12.1 Adverse Events
12.1.1 Definitions
An AE is defined as any untoward medical occurrence in a subject administered IP that 
does not necessarily have a causal relationship with the treatment. An AE can therefore 
be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom
(e.g., rash, pain, discomfort, fever, dizziness, etc.), disease (e.g., peritonitis, bacteremia, 
etc.), or outcome of death temporally associated with the use of an IP, whether or not 
considered causally related to the IP.
12.1.1.1 Serious Adverse Event
An SAE is defined as an untoward medical occurrence that at any dose meets one or 
more of the following criteria:

Outcome is fatal/results in death (including fetal death)

Is life-threatening – defined as an event in which the subject was, in the judgment 
of the investigator, at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death had it been more severe.

Requires inpatient hospitalization or results in prolongation of an existing 
hospitalization – inpatient hospitalization refers to any inpatient admission, 
regardless of length of stay.

Results in persistent or significant disability/incapacity (i.e., a substantial 
disruption of a person’s ability to conduct normal life functions)

Is a congenital anomaly/birth defect

Is a medically important event – a medical event that may not be immediately 
life-threatening or result in death or require hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the definitions above. Examples of such events are: 

Intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias, or convulsions that do not result in 
hospitalization, or development of drug dependence or drug abuse 

Reviewed and confirmed seroconversion for human immunodeficiency 
virus
(HIV), hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus
(HCV), hepatitis E virus (HEV), or parvovirus B19 (B19V)
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
Development of neutralizing VWF antibodies

Development of neutralizing antibodies to FVIII (titer ≥0.4 BU [by 
Nijmegen- modified Bethesda assay] or ≥0.6 BU [by Bethesda assay])

Thromboembolic events (e.g., myocardial infarction, stroke, transient 
ischemic attack [TIA], deep vein thrombosis [DVT] or pulmonary 
embolism)

Anaphylaxis (for definition, refer to Section 12.6.2) or severe 
hypersensitivity reactions
Uncomplicated pregnancies, following maternal or paternal exposure to IP are not 
considered an (S)AE; however, any pregnancy complication or pregnancy termination by 
therapeutic, elective, or spontaneous abortion shall be considered an SAE.
12.1.1.2 Suspected Unexpected Serious Adverse Reaction (SUSAR)
Any suspected adverse reaction to study treatment (i.e., including active comparators) 
that is both serious and unexpected. 
The event(s) must meet all of the following:

Suspected adverse reaction

Serious

Unexpected

Assessed as related to study treatment
Once determined to meet the criteria for a SUSAR, an SAE should be submitted to 
regulatory agencies expeditiously. 
12.1.1.3 Non-Serious Adverse Event
A non-serious AE is an AE that does not meet the criteria of an SAE.
12.1.1.4 Unexpected Adverse Events
An unexpected adverse event is an AE whose nature, severity, specificity, or outcome is 
not consistent with the term, representation, or description used in the Reference Safety 
Information (e.g., IB, package insert). “Unexpected” also refers to the AEs that are 
mentioned in the IB as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring 
with the particular drug under investigation.
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12.1.1.5 Preexisting Disease
Preexisting diseases that are present before entry in to the study are described in the 
medical history, and those that manifest with the same severity, frequency, or duration 
after IP exposure will not be recorded as AEs. However, when there is an increase in the 
severity, duration, or frequency of a preexisting disease, the event must be described on 
the AE CRF.
12.1.2 Assessment of Adverse Events
For the purposes of this study, the following will not be considered as AEs and will not 
be included in the analysis of AEs.

Bleeding episodes are part of the underlying disease and therefore are not AEs; 
they will be evaluated in the context of efficacy.

For non-serious bleeding episodes caused by an injury, the injury would not 
be reported as an AE, unless it resulted in a medical finding other than a 
bleeding episode (e.g., abrasion of skin). Therefore, any VWD-related 
bleeding event (e.g., epistaxis, gastrointestinal bleeding, musculo-skeletal 
bleeding, menorrhagia) that is non-serious will not be reported as an AE. 
However, the investigator may decide that the event is an AE if the event also 
would have occurred in a healthy individual under the same circumstances.

For SAEs: Bleeding events that meet seriousness criteria (death, 
life-threatening, hospitalizing/prolongation of hospitalization, disability, 
congenital anomaly, or medically significant and if not urgently treated would 
result in one of the above) should be reported on the SAE eCRF or SAE 
Report form as an SAE.

Seroconversion after documented HAV/HBV vaccination prior to or during the 
study period.
Each AE from the first IP exposure to the study completion date will be described on the 
AE CRF using the medical diagnosis (preferred), or, if no diagnosis could be established 
at the time of reporting the AE, a symptom or sign, in standard medical terminology in 
order to avoid the use of vague, ambiguous, or colloquial expressions (see definition in 
Section 12.1). Each AE will be evaluated by the investigator for:

Seriousness as defined in Section 12.1.1.1

Severity as defined in Section 12.1.2.1

Causal relationship to IP exposure or study procedure as defined in 
Section 12.1.2.2
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For each AE, the outcome (i.e., recovering/resolving, recovered/resolved, 
recovered/resolved with sequelae, not recovered/not resolved, fatal, unknown) and if 
applicable action taken (i.e., dose increased, dose not changed, dose reduced, drug 
interrupted, drug withdrawn, not applicable, or unknown) will also be recorded on the AE 
CRF. Recovering/resolving AEs will be followed until resolution.
If the severity rating for an ongoing AE changes before the event resolves, the original 
AE report will be revised (i.e., the event will not be reported as separate AE). During the 
course of any AE, the highest severity rating will be reported.
Deviations from the protocol-specified dosage (including underdosing /overdosing
[<20 IU/kg rVWF:RCo or >100 rVWF:RCo], abuse, and withdrawal, treatment errors 
(including incorrect route of administration, use of an incorrect product, and deviations 
from the protocol-defined dosing schedule), failures of expected pharmacological actions, 
and unexpected therapeutic or clinical benefits will be followed with regard to occurrence 
of AEs, lack of efficacy, and/or other observations because these events may be 
reportable to regulatory authorities. 
Any pregnancy that occurs after administration of IP will be reported on a Pregnancy
Form and followed-up at 1 year post-delivery, if feasible. 
If an investigator becomes aware of an SAE occurring in a subject after study completion, 
the SAE must be reported on the SAE Form within 24 hours after awareness: no 
additional reporting on CRFs is necessary.
12.1.2.1 Severity
The investigator will assess the severity of each AE using his/her clinical expertise and 
judgment based on the most appropriate description below:

Mild
The AE is a transient discomfort and does not interfere in a significant manner 
with the subject’s normal functioning level.
The AE resolves spontaneously or may require minimal therapeutic
intervention.

Moderate
The AE produces limited impairment of function and may require therapeutic
intervention.
The AE produces no sequela/sequelae.
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
Severe
The AE results in a marked impairment of function and may lead to temporary 
inability to resume usual life pattern.
The AE produces sequela/sequelae, which require (prolonged) therapeutic
intervention.
These severity definitions will also be used to assess the severity of an AE with a study-
related procedure(s), if necessary.
12.1.2.2 Causality
Causality is a determination of whether there is a reasonable possibility that the IP is 
etiologically related to/associated with the AE. Causality assessment includes, e.g., 
assessment of temporal relationships, dechallenge/rechallenge information, association 
(or lack of association) with underlying disease, presence (or absence) of a more likely 
cause, and physiological plausibility. For each AE, the investigator will assess the causal 
relationship between the IP and the AE using his/her clinical expertise and judgment 
according to the following most appropriate algorithm for the circumstances of the AE:

Not related (both circumstances must be met)
Is due to underlying or concurrent illness, complications, concurrent 
treatments, or effects of concurrent drugs
Is not associated with the IP (i.e., does not follow a reasonable temporal 
relationship to the administration of IP or has a much more likely alternative 
etiology). 

Unlikely related (either 1 or both circumstances are met)
Has little or no temporal relationship to the IP 
A more likely alternative etiology exists

Possibly related (both circumstances must be met)
Follows a reasonable temporal relationship to the administration of IP
An alternative etiology is equally or less likely compared to the potential 
relationship to the IP

Probably related (both circumstances must be met)
Follows a strong temporal relationship to the administration of IP, which may 
include but is not limited to the following: 
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o
Reappearance of a similar reaction upon re-administration (positive re-
challenge)
o
Positive results in a drug sensitivity test (skin test, etc.)
o
Toxic level of the IP as evidenced by measurement of the IP 
concentrations in the blood or other bodily fluid
Another etiology is unlikely or significantly less likely
For events assessed as not related or unlikely related and occurring within 5 days after IP 
infusion, the investigator shall provide the alternative etiology. These causality 
definitions will also be used to assess the relationship of an AE with a study-related 
procedure(s), if necessary.
12.1.2.3 Safety Reporting
Adverse events/SAEs will be assessed at all study visits as outlined in the Schedule of 
Study Procedures and Assessments (see Table 5) and Section 12.1.2.
Adverse Events/SAEs are to be recorded on the AE page of the eCRF. Each event should 
be recorded separately.
Any SAE, including death due to any cause, which occurs during this study, whether or 
not related to the investigational product, must be reported immediately (within 24 hours 
of the study center’s first knowledge of the event). All SAEs must be reported via the 
Electronic Data Capture (EDC) system by completing the relevant eCRF page(s) in 
English. For instances in which the EDC may become unavailable, SAEs must be 
reported using the back-up paper SAE report (SAER) form to meet the 24-hour timeline 
requirement (for contacts and instructions refer to the SAER form). Once the EDC 
becomes available, the site must enter all SAE data as reported on the back-up paper 
SAER form on the applicable eCRF pages.
The initial SAE information reported on the applicable eCRF pages (or back-up SAER 
Form, if applicable) must at least include the following:
1.
Protocol Number
2.
Subject identification number and demographics (gender, age at onset of event 
and/or date of birth)
3.
Investigational product exposure
4.
Medical Term for Event (Diagnosis preferably) 
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5.
Description of the (S)AE, including:

Date of onset

(S)AE treatment (drug, dose, route of administration)

Causal relationship by the Investigator

Measures taken (i.e., action taken regarding investigational product in direct 
relationship to the AE)
6.
Seriousness criteria (ie, death, life-threatening, or other criterion)
7.
Cause of death
8.
Autopsy findings (if available)
9.
Name, address, fax number, email, and telephone number of the reporting
Investigator (for paper SAER Forms) 
12.2 Urgent Safety Measures
An urgent safety measure is an immediate action taken, which is not defined by the 
protocol, in order to protect subjects participating in a clinical trial from immediate harm. 
Urgent safety measures may be taken by the sponsor or clinical investigator, and may 
include any of the following: 

Immediate change in study design or study procedures

Temporary or permanent halt of a given clinical trial or trials

Any other immediate action taken in order to protect clinical trial participants 
from immediate hazard to their health and safety
The investigator may take appropriate urgent safety measures in order to protect subjects 
against any immediate hazard to their health or safety. The measures should be taken 
immediately and may be taken without prior authorization from the sponsor. 
In the event(s) of an apparent immediate hazard to the subject, the investigator will notify 
the sponsor immediately by phone and confirm notification to the sponsor in writing as 
soon as possible, but within 1 calendar day after the change is implemented. The sponsor 
will also ensure the responsible ethics committees (ECs) and relevant competent 
authority(s) are notified of the urgent measures taken in such cases according to local 
regulations.
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12.3 Untoward Medical Occurrences
Untoward medical occurrences occurring before the first exposure to IP are not 
considered AEs (according to the definition of AE, see Section 12.1.1). However, each 
serious untoward medical occurrence experienced before the first IP exposure (i.e., from 
the time of signed informed consent up to but not including the first IP exposure) will be 
described on the SAER. These events will not be considered as SAEs and will not be 
included in the analysis of SAEs. 
12.4 Non-Medical Complaints
A non-medical complaint (NMC) is any alleged product deficiency that relates to 
identity, quality, durability, reliability, safety and performance of the product but did not 
result in an AE. NMCs include but are not limited to the following:

A failure of a product to exhibit its expected pharmacological activity and/or 
design function, e.g. reconstitution difficulty

Missing components

Damage to the product or unit carton

A mislabeled product (e.g., potential counterfeiting/tampering)

A bacteriological, chemical, or physical change or deterioration of the product 
causing it to malfunction or to present a hazard or fail to meet label claims
Any NMCs of the product will be documented on an NMC form and reported to the 
sponsor within 1 business day. If requested, defective product(s) will be returned to the 
sponsor for inspection and analysis according to procedures.
12.5 Medical, Medication, and Non-Drug Therapy History
At screening, the subject’s medical history will be described for the following body 
systems including severity (defined in Section 12.1.2.1) or surgery and start and end 
dates, if known: eyes, ears, nose, and throat; respiratory; cardiovascular; gastrointestinal; 
musculoskeletal; neurological; endocrine; hematopoietic/lymphatic; dermatological; and 
genitourinary. The subject’s medical history will also include documented history of 
on-demand treatment for the past 12 months and a documented history, e.g., patient 
charts and prescription information, of all bleeding episodes within the past 12 months.
All medications taken and non-drug therapies received in the 2 weeks prior to study entry 
and all concomitant medications and non-drug therapies during study will be recorded on 
the CRFs.
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Data on medical history, drug and non-drug therapy history of those subjects who 
transition from surgery rVWF study will be used from the eCRF of the main studies, will 
be updated, if applicable, and transcribed into the respective eCRF of the prophy study.
12.6 Physical Examinations
At screening and subsequent study visits (as described in Section 10.3), a physical 
examination will be performed on the following body systems: general appearance, head 
and neck, eyes and ears, nose and throat, chest, lungs, heart, abdomen, extremities and 
joints, lymph nodes, skin, and neurological. At screening, if an abnormal condition is 
detected, the condition will be described on the medical history CRF. At study visits, if a 
new abnormal or worsened abnormal pre-existing condition is detected, the condition will 
be described on the AE CRF. If the abnormal value was not deemed an AE because it 
was due to an error, due to a preexisting disease (described in Section 12.1.1.5), not 
clinically significant, a symptom of a new/worsened condition already recorded as an AE, 
or due to another issue that will be specified, the investigator will record the justification 
on the source record.
12.6.1 Thromboembolic events
Thromboembolic events are considered a potential risk of rVWF treatment, hence,
clinical evidence of thrombosis will be monitored during the study. In the case of clinical 
signs of any thromboembolic event other than superficial thrombosis, additional 
diagnostic procedures are required according to each institution’s standard of care which 
may consist of, but are not limited to the following:

For deep vein thrombosis (DVT): Magnetic Resonance Imaging (MRI), 
compression ultrasound or impedance plethysmography.

For pulmonary embolism: ECG, chest radiography, perfusion/scintiscan or MRI. 

For myocardial infarction: ECG, cardiac enzymes, echocardiography

For stroke: diffusion-weighted magnetic resonance imaging or computed 
tomography, ABCD scoring, carotid imaging
Results of diagnostic procedures may be forwarded to the sponsor to be reviewed by an 
independent external expert panel, such as the DMC, if applicable.
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12.6.2 Anaphylaxis
The diagnosis of anaphylaxis is highly likely when any of the following 3 criteria are 
fulfilled:
1.
Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue or both (e.g, generalized urticaria, pruritus or flushing, swollen 
lips-tongue-uvula) and at least one of the following:
a. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced peak expiratory flow [PEF], hypoxemia)
b. Reduced blood pressure (BP) or associated symptoms of end-organ 
dysfunction (e.g., hypotonia [collapse], syncope, incontinence)
2.
Two or more of the following that occur rapidly after exposure to a likely allergen 
for that patient (minutes to several hours):
a. Involvement of the skin or mucosal tissue (e.g., generalized urticaria, pruritus 
or flushing, swollen lips-tongue-uvula)
b. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced PEF, hypoxemia)
c. Reduced BP or associated symptoms (hypotonia [collapse], syncope, 
incontinence)
d. Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)
3.
Reduced BP after exposure to a known allergen for that patient (minutes to 
several hours):
a. Infants and children: low systolic BP (age specific) or greater than 30% 
decrease in systolic BP
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from 
that person’s baseline BP
If a subject develops anaphylaxis in the course of the clinical study this needs to be 
reported as SAE (Section 12.1.1.1). Additional blood draws for Anti-VWF IgE antibody 
testing will be drawn (Section 12.9.13).
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12.7 Vital Signs
Vital signs will be assessed pre and post-infusion at each visit, if not stated otherwise:

Height (cm) and weight (kg) (pre-infusion only)

Blood pressure: Systolic/diastolic blood pressure (mmHg) baseline measurements 
will be measured after a 10-minute rest in the supine/semi-recumbent position.

Pulse rate: Pulse rate (beats/min) will be measured at the distal radial arteries 
under the same conditions as above.

Respiratory rate: Respiratory rate (breaths/min) will be measured over a period of 
1 minute under the same conditions as above.

Temperature: Body temperature (oC or oF) may be determined by oral, rectal, 
axillary, or tympanic measurement at the discretion of the investigator. However, 
the same method should be used for all measurements in 1 subject.
Vital signs (pulse rate, respiratory rate, and blood pressure) should be recorded within 
30 min before and after IP administration. The assessment of vital signs per planned 
study visit is outlined in Supplement 20.2.
Vital sign values are to be recorded on the physical examination eCRF. For each vital 
sign value, the investigator will determine whether the value is considered an AE (see 
definition in Section 12.1). If assessed as an AE, the medical diagnosis (preferably), 
symptom, or sign, will be recorded on the AE eCRF. Additional tests and other 
evaluations required to establish the significance or etiology of an abnormal result, or to 
monitor the course of an AE, should be obtained when clinically indicated. Any abnormal 
value that persists should be followed at the discretion of the investigator.
12.8 Electrocardiogram 
A standard 12-lead ECG at rest will be performed at screening, at the 6 month follow-up 
visit and at the study termination visit and evaluated for medical significance by the 
investigator.
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12.9 Clinical Laboratory Parameters
Refer to the Laboratory Manual for information on collection and processing of samples.
In general all laboratory tests will be performed at central laboratories, except the 
pregnancy and blood group test which will be performed at the local laboratory. In 
addition, relevant critical safety laboratory tests for complete blood count (CBC), serum 
chemistry and/or coagulation parameters such as VWF and FVIII activity may also be 
performed in the local laboratory to ensure that results will be available immediately to 
the investigator. In principle, results from the central laboratory will be used for data 
analysis purposes. The assays performed in the central laboratories are specified in the 
Laboratory Manual. The investigator will supply the sponsor with a list of the normal 
ranges and units of measurement for the laboratory variables to be determined at the site. 
Laboratory values such as antibodies to other proteins are not required immediately and 
will be assessed later during the course of the study. 
Abnormal laboratory values deemed clinically significant by the investigator are to be 
recorded as AEs (see Section 12.1.2).
12.9.1 rVWF and endogenous FVIII Pharmacokinetics
PK assessments using a dose of 50 IU ± 5 IU/kg rVWF:RCo will be performed at the 
baseline visit. If the subject is on on-demand treatment and has received VWF 
replacement therapy a washout period of at least 5 days is required before the infusion of 
rVWF for PK assessment can be administered. 
Blood samples will be drawn within 30 minutes pre-infusion, and at 7 time points 
post-infusion (30 5 minutes, 60 5 minutes, 6 1 hours, 12 1 hours, 24 2 hours, 
48 2 hours and 72 2 hours) VWF activity will be determined using the VWF:RCo, 
VWF:CB and the VWF: Ag assay. The Innovance assay will be used as an exploratory 
assay to provide supportive data and to compare the results of this new assay with results 
from the established VWF:RCo assay. 
Endogenous FVIII activity will be measured using the 1-stage clotting assay. 
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At the 12 month ± 2 week visit, a full PK analysis will also be performed. Blood samples 
will be drawn within 30 minutes pre-infusion, and at 7 time points post-infusion 
(30 ± 5 minutes, 60 ± 5 minutes, 6 ± 1 hours, 12 ± 1 hours, 24 ± 2 hours, 48 ± 2 hours, 
72 ± 2 hours). If a subject experiences a bleeding episode during the PK assessment no 
subsequent blood sample will be drawn in that specific PK period. The guidance provided 
in Section 8.7.4.4 has to be followed for the treatment of the bleeding episode. The 
subject once recovered is eligible to repeat the PK assessment.
The following parameters will be used as part of the PK assessment:

Incremental recovery of VWF:RCo, VWF:Ag, VWF:CB and INNOVANCE 
VWF Ac (exploratory assay)

AUC/dose, area under moment curve (AUMC/dose, clearance (CL), Volume of 
distribution at steady state (Vss), mean residence time (MRT), of 
VWF:RCo ,VWF:Ag, VWF:CB and INNOVANCE VWF Ac (exploratory assay)

Half-life of VWF:RCo, VWF:Ag, VWF:CB and INNOVANCE VWF Ac 
(exploratory assay)

Time course of the FVIII:C levels

VWF collagen binding (VWF:CB) levels
12.9.2 Hematology and Clinical Chemistry
The hematology panel will consist of CBC [hemoglobin, hematocrit, erythrocytes (ie, red 
blood cell count [RBC]), and leukocytes (i.e., white blood cell count [WBC])] with 
differential (i.e., basophils, eosinophils, lymphocytes, monocytes, neutrophils) and 
platelet counts.
The clinical chemistry panel will consist of sodium (Na), potassium (K), chloride (Cl), 
alanine aminotransferase (ALT), lactate dehydrogenase (LDH), aspartate 
aminotransferase (AST), bilirubin (BILI), alkaline phosphatase (AP), blood urea nitrogen
(BUN), creatinine (CR), and glucose (Glu).
Blood will be obtained for assessment of hematology and clinical chemistry parameters 
at screening, during PK-assessment prior to rVWF IP infusion, after 24 ± 2 hours, 
48 ± 2 hours and 72 ± 2 hours post rVWF IP infusion, at all follow-up visits as per 
schedule (refer to Supplement 20.3 Clinical Laboratory Assessments), i.e., 4 weeks
± 1week, 8 weeks ± 1 week and every 3 months ± 2 weeks, and at study completion. 
Hematology and clinical chemistry assessments will be performed on 
Ethylenediaminetetraacetic acid (EDTA)-anticoagulated whole blood and serum, 
respectively, at the central laboratory.
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12.9.3 Immunology
12.9.3.1 Antibodies to VWF and FVIII
All subjects will be tested for binding and neutralizing antibodies to VWF and FVIII at 
screening, at baseline PK assessment, at each of the scheduled follow-up visits and at the 
study completion visit. Testing will be done prior to IP infusion and with at least a 
72 hour wash out period since the last IP infusion. If there is any suspicion of inhibitor 
development (e.g. excessive bleeding) binding and neutralizing antibodies to VWF and 
FVIII may be tested at the discretion of the investigator. 
12.9.3.2 Neutralizing and Total Binding Anti-VWF Antibodies
The assays to establish the presence of neutralizing and total binding anti-VWF 
antibodies have been established in the absence of international standards and with only 
limited numbers of positive controls. Therefore, caution is advised in interpreting positive 
results. In particular, any clinical association, changes in the natural history of the 
disease, effect of therapy, etc. needs to be taken into account for final judgment. 
The sponsor’s Medical Director should be consulted for additional advice. As part of the 
AE follow-up, any sample testing positive needs to be confirmed after 2-4 weeks for 
central laboratory testing. Only confirmed neutralizing anti -VWF antibodies are 
considered inhibitors (see Section 12.9.3.4). These subjects need to be closely monitored 
and therapy adjusted accordingly. 
12.9.3.3 Binding antibodies to VWF 
The presence of total binding anti-VWF antibodies will be determined by an enzyme-
linked immunosorbent assay (ELISA) employing polyclonal anti-human Immunoglobulin
(Ig) antibodies (IgG, IgM and IgA). For this assay (ELISA), recombinant human VWF 
will be coated onto a microtiter plate, then incubated with dilutions of the positive 
control, the negative control or test sample. Antibodies against human VWF that are 
present in the samples bind to the coated antigen and will be detected with a horseradish 
peroxidase (HRP)-coupled goat anti-human antibody (secondary antibody). The positive 
control for this assay will be a human monoclonal antibody specific for human VWF 
spiked into the negative control. The negative control for this assay is pooled normal 
human plasma.
Plasma samples are analyzed for binding antibodies against the specific antigen in two 
steps. First, the sample is screened for antibodies and the titer of binding antibodies is 
determined. Second, the specificity of positive antibody results is confirmed.16
In brief, all samples are serially diluted (initial dilution 1:20 and further diluted 1:2). 
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The titer endpoint, defined as the highest dilution that still gives a positive signal above 
cut off level, is determined in two independent duplicates. The cut off level is established 
based on background signal level of healthy plasma donors (n=160) and set to include 5% 
false positives to be as sensitive as possible (95% percentile). The ELISA assay is 
validated allowing an assay variability of ± 1 titer step. Therefore, differences ≤2 titers 
steps may be due to variability of the ELISA assay. Specificity has to be confirmed in a 
competition assay when a sample has a titer of 1:80 or higher in the screening assay. 
Based on the validation criteria samples tested in the screening assay at 1:20 or 1:40 
cannot be confirmed in the competition assay. A positive screening value is confirmed if 
the difference between the titers determined for the subject sample (re-screen) and for the 
subject sample with pre-incubation (confirmation sample) is > 2 titer steps. Antibody 
titers of subject samples will only be reported as positive, if the results of the screening 
and confirmatory analysis fulfill these acceptance criteria. The titer to be reported is 
always the one determined in the original screening procedure (independent of the result 
of the re-screening in the confirmation procedure). 
A more detailed test procedure will be supplied upon request or pro-actively if a sample 
tests positive. A treatment related increase of the binding anti-VWF antibodies is 
expected, if the titer increases by more than 2 titration steps. These subjects need to be 
closely monitored and therapy adjusted accordingly.
12.9.3.4 Neutralizing antibodies to VWF
Three functional VWF assays, collagen binding (VWF:CB) assay, Ristocetin cofactor 
(VWF:RCo) and FVIII binding (VWF:FVIIIB), will be used to test for the presence of 
neutralizing anti-VWF antibodies. Neutralizing antibodies to VWF:RCo, VWF:CB and 
VWF:FVIIIB activities will be measured by assays based on the Bethesda assay 
established for quantitative analysis of FVIII inhibitors (Nijmegen modification of the 
Bethesda assay).17 The amount of inhibitor is expressed as Bethesda units (BU) per mL.
One BU is thereby defined as the amount of inhibitor that decreases the measured activity 
in the assays to 50% of that of the negative control samples. The assays were validated 
using human plasma samples from two type 3 VWD patients with low (1-2 BU/mL) and 
high (~10 BU/mL) titer inhibitors and plasma samples from non-human primates 
immunized with human rVWF (>100 BU/mL) 
If a subject has a measurable baseline level of VWF activity in the respective assay, it is 
taken into account in the calculation of the residual activity. However, if baseline levels 
are too high (>15% VWF:RCo), inhibitors may not be reliably detected.
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To exclude false positive results, the detection limit for anti-VWF inhibitors was set to 
1 BU/ml for all 3 assays. The rationale for this cut-off value is the relatively high CI of 
the underlying assays, making determinations at the end of the evaluation range of the 
Bethesda reference curve uncertain.18
A more detailed test procedure may be requested to further characterize the anti-VWF 
inhibitors, if detected.
12.9.3.5 Binding Antibodies to FVIII
Binding antibodies against FVIII will be analyzed using a proprietary enzyme 
immunoassay. The testing strategy will be as described for binding anti-VWF antibodies. 
Antibody-containing samples will be identified in a screening assay followed by a 
confirmatory assay to exclude false positive results.
12.9.3.6 Neutralizing antibodies (inhibitors) to FVIII 
Neutralizing antibodies (inhibitors) to FVIII will be assessed by the Nijmegen 
modification of the Bethesda assay in a central laboratory. To verify a FVIII inhibitor, 
additional testing (such as tests for Lupus anticoagulants) may be initiated. Positive FVIII 
inhibitor tests will be defined as ≥0.4 BU by the Nijmegen-modified Bethesda assay that 
is confirmed by a second test performed on an independent sample obtained 2-4 weeks 
following the first test. Only confirmed positive FVIII inhibitor test result will be 
reported as an SAE.
12.9.4 Antibodies to Other Proteins
Plasma will be assayed for the presence of antibodies against CHO protein (total Ig), 
murine IgG and human Furin (total Ig) using proprietary enzyme immunoassays. The 
testing strategy will be as described for binding anti- VWF antibodies. 
Antibody-containing samples will be identified in a screening assay followed by a 
confirmatory assay to exclude false positive results.
12.9.4.1 Anti-CHO Protein
Total Ig antibodies (IgG, IgA, IgM) against CHO protein will be analyzed. For this assay 
(ELISA), CHO protein derived from cultures of untransfected cells and propagated under 
the identical cell culture conditions used for ADVATE production will be coated onto a 
microtiter plate, then incubated with dilutions of the positive control, negative control or 
test sample. Antibodies against CHO protein that are present in the samples bind to the 
coated antigen and will be detected with a horseradish peroxidase (HRP)-coupled goat 
anti-human antibody (secondary antibody). The positive control for this assay will be a 
polyclonal goat anti-CHO protein antibody spiked into the negative control. The negative 
control for this assay is pooled normal human plasma.
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12.9.4.2 Anti-Murine IgG
A commercially available ELISA (Medac, Hamburg, Germany) will be used to detect and 
to quantify IgG antibodies originating from human plasma that are directed against 
mouse-IgG (HAMA: human anti- mouse antibodies). Microtiter plates coated with 
mouse IgG will be incubated with dilutions of the standard, the positive control, the 
negative control or the test sample. Antibodies against mouse IgG that are present in 
the samples bind to the coated antigen and form a bridge to a peroxidase coupled mouse 
IgG antibody that will be used for detection (bridging format of the ELISA assay). 
The positive control for this assay will be a polyclonal goat anti-murine IgG spiked into 
the negative control. The negative control for this assay is pooled normal human plasma.
12.9.4.3 Antibodies to human Furin
Total Ig antibodies (IgG, IgA, IgM) against human Furin will be analyzed. For this assay 
(ELISA), recombinant human Furin will be coated onto a microtiter plate, then incubated 
with dilutions of the positive control, the negative control or test sample. Antibodies 
against human Furin that are present in the samples bind to the coated antigen and will be 
detected with a horseradish peroxidase (HRP)-coupled goat anti-human antibody 
(secondary antibody). The positive control for this assay will be a human monoclonal 
antibody specific for human Furin spiked into the negative control. The negative control 
for this assay is pooled normal human plasma.
12.9.5 Viral Serology
The following viral seromarkers will be assessed at screening:

HIV: anti-HIV 1, HIV 2 

HAV: anti-HAV (IgG and immunoglobulin M [IgM])

HBV: Hepatitis B surface antigen (HbsAg), anti-Hepatitis B (HB) core, anti-HBs

HCV: anti-HCV ELISA

Parvovirus B19: anti-B19V (IgG and IgM)
Virus serology will be established during the screening period. The relevant confirmatory 
Polymerase Chain Reaction (PCR) testing may be performed from appropriate left-over 
samples as needed. 
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12.9.6 Urinalysis (Dipstick)
The urinalysis will include assessments for erythrocytes, specific gravity, urobilinogen, 
ketones, glucose, protein, bilirubin, nitrite and pH and will be performed at the central 
laboratory.
12.9.7 Pregnancy Test
A pregnancy test for females of child-bearing potential will be performed at the local 
laboratory primarily from urine. If no urine sample is available, the pregnancy testing will 
be done from serum. The pregnancy test may need to be repeated during the course of 
study in countries where mandated by national law.
12.9.8 VWD Mutational Analysis, Multimer Analysis and Human Leukocyte 
Antigen Genotyping 
A cell pellet (buffy coat and erythrocytes) will be retained at the screening visit for VWD 
gene mutational analysis, VWF multimer analysis and HLA genotype determination if the 
information is not already available in the subject’s medical history. Results from 
multimer analysis (see Section 12.9.10.1) may contribute to VWD gene mutational 
analysis. The genetic testing will be done, when the subject consents to the genetic 
testing. 
12.9.9 Blood Group Analysis
The blood group needs to be determined during the screening period. If the information is 
not already available in the subject’s medical history, it has to be determined at the local 
lab.
12.9.10 Additional Laboratory Testing in case of Thromboembolic Events
rVWF contains ultra large molecular weight (ULMW) multimers because of a lack of 
exposure to endogenous VWF protease (a disintegrin and metalloproteinase with a 
thrombospondin type 1 motif, member 13 (ADAMTS13) during the manufacturing 
process. In vitro and in vivo cleavage of these ultralarge molecular fractions by 
ADAMTS13 and generation of characteristic satellite bands has been extensively 
demonstrated during nonclinical and clinical development. Nevertheless, the potential 
elevated risk of thrombosis and/or other thromboembolic complications due to the 
administration of ultra large molecular VWF multimers in subjects with normal levels of 
VWF cannot be completely excluded. Therefore VWF multimer analysis will not only be 
performed routinely at screening but in case of thromboembolic events both VWF 
multimer analysis as well as ADAMTS13 activity will be determined to assess any 
relatedness of these occurrences with IP treatment. 
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12.9.10.1 VWF multimer analysis
The VWF multimer pattern will be assessed using low-resolution sodium dodecyl sulfate 
(SDS)–agarose gel electrophoresis. High-resolution SDS–agarose gel electrophoresis, 
with agarose concentrations 1.5%, will be used to determine the satellite band structure 
of VWF. These analyses will employ Western blot with luminescence video imaging.
12.9.10.2 ADAMTS13 activity 
VWF73 was identified as the 73 amino acid minimal region of the VWF A2 domain 
required for ADAMTS13 cleavage. The cleavage of this substrate will be detected by a 
commercially available ELISA-based Chromogenic assay (Technoclone Austria):
Cleavage of immobilized VWF73 substrate is detected by a HRP-labeled antibody 
directed against the cleavage site of VWF73. The amount of bound antibody, which is the 
function of the ADAMTS13 cleavage is detected by a chromogenic substrate.
12.9.11 Soluble P-Selectin (sP-Selectin)
sP-selectin is a cell adhesion molecule (CAM) found in granules in endothelial cells 
(cells lining blood vessels) and activated platelets. Data for an association between the 
sP-selectin concentration, thrombotic thrombocytopenic purpura (TTP) and venous 
thromboembolism (VTE) are limited and the predictive value has not yet established. 
A commercial ELISA assay will be employed as an exploratory test. sP-selectin will be 
determined at the Screening visit and used as indicator for an increased thrombotic risk.
12.9.12 D-Dimer
D-dimer will be used as a marker for DVT and disseminated intravascular coagulation
(DIC). While a negative result practically rules out thrombosis, a positive result can 
indicate thrombosis but does not rule out other potential etiologies, including a recent 
hemorrhage. Its main use, therefore, is to exclude thromboembolic disease where the 
probability is low. D-Dimer will be measured at the Screening visit and used as indicator 
for an increased thrombotic risk.
12.9.13 Additional Laboratory Testing in Case of Severe Hypersensitivity Reactions
If a subject develops a severe hypersensitivity reaction in the course of the clinical study, 
additional blood draws for anti-VWF IgE antibody testing will be drawn. The presence of 
anti-VWF IgE will be determined by using the ImmunoCAP®, a VWF-specific IgE 
blood test (Thermo Scientific). The basis of the ImmunoCAP® technology is a cellulose 
polymer as solid phase in a plastic capsule providing a large surface for protein binding. 
rVWF as antigen is covalently coupled to the cellulose polymer. Detection of specific 
anti-VWF IgE bound to the antigen will be accomplished by a secondary enzyme-labeled 
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anti-human IgE antibody. Testing for binding anti-human VWF IgE antibodies will be 
done with 0.5 mL plasma. Antibody containing samples will be identified and quantified 
in a screening assay followed by a confirmatory assay to exclude false positive results.
12.9.14 Exploratory Assay 
The INNOVANCE VWF Ac: an assay, which will eventually replace the VWF:RCo test 
in the future, will be done using the same time points/blood draws including PK 
assessment as outlined for the VWF:RCo assessments. The VWF Ac assay is a sensitive 
test for direct determination of VWF activity. It employs an advanced new technology, 
allowing the assay to mimic the reaction in which VWF binds to glycoprotein Ib (GPIb), 
the major VWF receptor protein on platelets. Latex particles are coated with an antibody 
against GPIb, to which recombinant GPIb is added.
12.9.15 Assessment of Laboratory Values
12.9.15.1 Assessment of Abnormal Laboratory Values 
For VWF and FVIII laboratory assessments no evaluation of clinical significance is 
necessary.
Each other laboratory value (except results to determine genetics of the underlying VWD 
disease and blood group) has to be assessed by the investigator and the assessment will be 
recorded on the eCRF. The investigator will determine for each abnormal laboratory 
value whether the value is considered clinically significant or not. For clinically 
significant values, the investigator will indicate if the value constitutes a new AE (see 
definition in Section 12.1) and record the sign, symptom, or medical diagnosis on the AE 
CRF, is a symptom or related to a previously recorded AE, is due to a pre-existing 
disease (described in Section 12.1.1.5), or is due to another issue that will be specified. If 
the abnormal value was not clinically significant, the investigator will indicate the reason, 
i.e. because it is due to a preexisting disease, due to a lab error, due to variation or due to 
another issue that will be specified. Additional tests and other evaluations required to 
establish the significance or etiology of an abnormal value, or to monitor the course of an 
AE should be obtained when clinically indicated. Any abnormal value that persists should 
be followed at the discretion of the investigator.
Any seroconversion result for human immunodeficiency virus (HIV), hepatitis A virus 
(HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis E virus (HEV), or 
parvovirus B19 (B19V) shall be re-tested.
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12.10
12.10.1
 
 
 
 
 
 
 
 
 
 
12.10.2
 
 
 
 
 
 
 
 
 
 
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13. STATISTICS
13.1 Sample Size and Power Calculations
The determination of the sample size for this study is not based on strict statistical 
considerations. The sample size of a subset of at least 15 subjects with severe VWD, 5 of 
whom must have Type 3 VWD, is based on the Guideline on the Clinical Investigation of 
Human Plasma Derived von Willebrand Factor Products (CPMP/BPWG/220/02).1
13.2 Datasets and Analysis Cohorts
13.2.1 Safety Analysis Set
The Safety Analysis Set will be composed of all subjects who received any amount of IP, 
rVWF:ADVATE or rVWF alone. 
13.2.2 Full Analysis Dataset
The Full Analysis Set (FAS) will be composed of all subjects with available bleeding 
data gathered during prophylaxis IP treatment.
13.2.3 Per-Protocol Analysis Set
The Per-Protocol (PP) Analysis Set will be composed of subjects who are at least 70% 
compliant regarding required prophylactic infusions. Only subjects who met all study 
entry criteria and who had no major protocol violations that might impact efficacy 
assessments will be included in the PP analysis set.
13.2.4 PK Full Analysis Set
The Pharmacokinetic Full Analysis Set (PKFAS) will be composed of all subjects who 
received the PK infusion and who provided acceptable data for PK analysis. Acceptable 
PK data will be defined in the Statistical Analysis Plan. 
13.2.5 PK Per Protocol Analysis Set 
The Pharmacokinetic Per Protocol Analysis Set (PKPPAS) is defined as a subset of the 
PKFAS. Subjects who met the following additional criteria will be included in the 
PKPPAS: had no major violation of affecting the PK period of the study as defined in the
detailed Statistical Analysis Plan.
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13.3 Handling of Missing, Unused, and Spurious Data
13.3.1 General
Statistical techniques will not be used to identify and exclude any observations as outliers 
from the analyses. If data are considered spurious, e.g. for lack of biological plausibility, 
it will be documented to include the reason for exclusion and the analyses from which the 
data were excluded.
13.3.2 Other
1.
Regarding missing data in PK records:

Body weight: If a subject’s weight is missing from the PK infusion record, the 
subject’s last recorded weight will be used to calculate the weight-adjusted 
dose.

Concentration:

Baseline concentration levels reported as below the limit of quantification will 
be considered to be 0. Missing VWF baseline concentration levels (VWF: RCo, 
VWF: AG or VWF: CB) for Type 3 subjects will be set to 0.

Time:

If start time of infusion is missing (but stop time is available) and actual 
collection time is available, then stop time of infusion will be taken for further 
calculation (i.e. time difference between actual end date/time of infusion and 
date/time blood sample drawn).

If actual collection date/time is missing and planned collection date/time is 
missing, then this PK time point will be taken out from the PK analysis 
(i.e. no data entry for this time point). 

For all other scenarios, the planned collection date/time will be taken for 
further calculation.
2.
Regarding missing data in AE records:

Handling of unknown causality assessment:

If a subject experiences an AE with a missing causality assessment, the 
relationship of the AE will be counted as “related.”

Handling of unknown severity grades:

If a subject experiences more than one AE categorized under the same 
preferred term, one of them is categorized as “severe” and one of them is 
categorized as “unknown”, then the maximum severity for this preferred 
term should be counted as “severe” for this subject.
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
If a subject experiences more than one AE categorized under the same 
preferred term, one of them is categorized as “mild” or “moderate” and 
one of them is categorized as “unknown”, then the maximum severity for 
this preferred term should be counted as “unknown” for this subject.
13.4 Methods of Analysis
The study success criteria are the objectives as stated in Section 7. “Treatment success” 
was defined as the extent of control of bleeding episodes achieved during this study.
13.4.1 Primary Outcome Measure
The statistical analysis will provide descriptive summaries.
For the number of infusions and for the total weight adjusted consumption of rVWF and 
ADVATE per month and per year during on-demand treatment, summary statistics will 
be carried out.
For the number (proportion) of subjects with reduction of ABR relative to historic ABR 
as well as for the number (proportion) of subjects with 0 bleeds, proportions and 
corresponding 95% two-sided CIs will be performed.
The annualized rate of bleeding episodes will be calculated as (Number of bleeding 
episodes/observed treatment period in days) * 365.25. 
The primary efficacy analysis will be based on the FAS. As a supportive analysis, the 
same analysis will also be carried out on the PP.
The two time periods (prior to prophylaxis treatment and while on prophylaxis) will be 
compared within each subject in terms of mean ABR using a generalized estimating 
equations model framework (with a logarithmic link function which was the default for 
the negative binomial distribution), accounting for the fixed effect of the two time 
periods. The follow-up time (in years) will be specified as an offset and an unstructured 
working correlation matrix will be used to account for the correlated data. Ratios between 
the two time period means (95% CI) will be estimated within this model by SAS 
procedure GENMOD.
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13.4.2 Secondary Outcome Measures 
13.4.2.1 Efficacy
For the number of infusions and for the total weight adjusted consumption of rVWF and 
ADVATE per month and per year during on-demand treatment for bleeding episodes, 
summary statistics will be carried out.
For the number (proportion) of subjects with reduction of ABR relative to historic ABR 
as well as for the number (proportion) of subjects with 0 bleeds, proportions and 
corresponding 95% two-sided CIs will be performed.
The cause, type, localization and severity of bleeding episodes will also be recorded and 
summarized. Bleeding episodes should be organized by where they occur in addition to 
whether they occurred spontaneously or due to a traumatic event.
The secondary efficacy analysis will be performed on the FAS only.
13.4.2.2 Efficacy of the Treatment of Bleeding Episodes
For the number of infusions of rVWF and ADVATE per bleeding episode, for the weight 
adjusted consumption of rVWF and ADVATE per bleeding event as well as for the 
overall hemostatic efficacy rating at resolution of bleed, summary statistics will be 
carried out.
The severity and localization of bleeding episodes will also be recorded and summarized.
The analysis will be performed on the FAS.
13.4.2.3 Pharmacokinetic Analysis
All PK analyses will use the actual sampling times, not nominal times specified in the 
protocol, wherever possible. Actual sampling times will be defined as time from the start 
of infusion to the blood sample collection time. A deviation from the protocol-specified 
blood sample drawing time window will not be a reason to exclude an observation from 
the analysis. Samples with unknown actual and planned collection date/time or where the 
concentration could not be determined, or where results were biologically implausible 
will be eliminated from the analysis.
If any concentration data are considered spurious (e.g. lack of biological plausibility), the 
reason for exclusion from the analysis and the analysis from which the data point was 
excluded will be documented.
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To ensure that values at baseline (pre-infusion) are not affecting the estimation of PK 
parameters, post-infusion concentration data will be adjusted for baseline as follows:
After adjustment of the post-infusion concentration data, any pre-infusion data will be set 
to 0.
CCorrected will be set to missing, if:

Samples have an unknown draw time or where the concentration could not be 
determined, or where results were deemed to be unreliable due to analytical 
issues.

Any concentration data are considered spurious (e.g. lack of biological 
plausibility).
Handling of concentrations that are below the quantification limit: 

Baseline concentration values reported as below the limit of quantification will be 
considered to be 0 (CCorrected = Concentration value)

Post-infusion concentration values reported as below the limit of quantification or 
missing repeated concentration values will be set to missing (CCorrected = 
missing)
The area under the plasma concentration/time curve from time 0 to infinity (AUC0-) and 
the area under the first moment curve from time 0 to infinity (AUMC0-) will be 
calculated as the sum of AUC or AUMC from time 0 to the time of last quantifiable 
concentration plus a tail area correction calculated as Ct/z and Ct/z(t + 1/z), 
respectively, where Ct is the last quantifiable concentration, t is the time of last 
quantifiable concentration and z is the terminal or disposition rate constant.
The area under the plasma concentration/time curve from time 0 to 72 hours post-infusion 
(AUC0-72h) will be computed using the linear trapezoidal rule. For the calculation of 
AUC0-72h the levels at 72 hours will be linearly interpolated/ extrapolated from the 
2 nearest sampling time points.
Elimination phase half-life (HL) in hours will be calculated as:
/ = 	
(2)/
t
Measured,
C
)
Tmax
Measured,
C
infusion
pre
Measured,
C
(1
t
Corrected,
C




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where the elimination rate constant (z) will be obtained by loge-linear fitting using least 
squares deviations to at least the last 3 quantifiable concentrations above pre-infusion 
level.
The Mean Residence Time (MRT) in hours will be calculated as total area under the 
moment curve divided by the total area under the curve:
MRT = ∞[ℎ ∗/]
∞[ℎ∗/]
Systemic clearance in dL/kg/h will be calculated as the dose in IU/kg divided by the 
total AUC: 
 = 
!
"#[/$]
%[ℎ∗/]
Apparent steady state volume of distribution (Vss) in dL/kg will be calculated as:
&"" = !
"#[ $
⁄
] × %[ℎ ∗/]
%

[ℎ ∗/]
The maximum concentration, Cmax, will be calculated as the maximum concentration 
post-infusion.
The time to reach the maximum concentration, Tmax, in hours was defined as the time 
to reach Cmax. 
Incremental recovery (IR) in (IU/dL)/(IU VWF:RCo/kg) will be calculated as:
) = *+,[ 
⁄
] −./01234051[/]

"# 6#7 $ 8
9 :#;ℎ< [/$]
where Cmax and Cpre-infusion are the unadjusted concentration values.
The PK parameters AUC0-72h/Dose, AUC0-∞/Dose, AUMC0-∞/Dose, MRT (mean 
residence time), CL (clearance), IR (incremental recovery), T1/2 (elimination phase half-
life), Vss (Volume of distribution at steady state), Cmax (maximum concentration) and
Tmax (time to reach the maximum concentration) will be summarized by mean, standard 
deviation and the corresponding 90% CIs, median, Q1, Q3, IQR and range.
Descriptive statistics will be used to summarize VWF:RCo levels for each nominal time 
point on the PK curve. 
PK analysis as described above will be carried out on the PKFAS as well as on the 
PKPPAS.
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For all subjects in the PKFAS concentration vs. time curves will be prepared.
PK parameters will be derived using non-compartmental methods in WinNonlin.
The analysis will be performed on the FAS.
13.4.2.4 Safety
AEs that occurred during or within 24 hours after first IP infusion will be presented in 
summary tables. Summary tables shall indicate the number of subjects who experienced 
adverse events. Separate tables will be carried out for temporally associated adverse 
events; and for temporally associated or causally related adverse events. 
In addition, tables will be prepared to list each AE, the number of subjects who 
experienced an AE at least once, and the rate of subjects with AE(s). AEs will be grouped 
by system organ class. Each event will then be divided into defined severity grades (mild, 
moderate, severe). The tables will also divide the AEs into those considered related (a 
“possibly related” or a “probably related” AE will be considered as a “related AE”) to the 
treatment and those considered unrelated (an “unlikely related” or a “not related” AE will 
be considered as an “unrelated” AE). These tables will also be carried out for temporally 
associated adverse events; and for temporally associated or causally related adverse 
events. 
All AEs; temporally associated AEs; causally related AEs (by investigator assessment); 
and temporally associated or causally related AEs will also be summarized by system 
organ class, preferred term, including the number of AEs, the number (%) of unique 
subjects, the frequency category (very common: ≥10%, common: ≥1% to <10%, 
uncommon: ≥0.1% to <1%, rare: ≥0.01% to <0.1%, very rare: <0.01%) and the number 
of IP-infusions associated with an AE.
Temporally associated AEs are defined as AEs that begin during infusion or within
24 hours (or 1 day where time of onset is not available) after completion of infusion, 
irrespective of being related or not related to treatment.
AEs and SAEs for each subject, including the same event on several occasions, will be 
listed separately, giving both MedDRA preferred term and the original verbatim term 
used by the investigator, system organ class, severity grade, seriousness, relation to the 
treatment (by investigator assessment; for SAEs this will be by investigator and sponsor 
assessment), onset date, and stop date.
AEs that occurred before first IP infusion will be listed separately.
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Incidences of thromboembolic events and hypersensitivity reactions will be tabulated and 
also listed per subject. For the development of antibodies, proportions will be carried out.
The safety analyses will be based on the safety analysis set. 
13.5 Exploratory Outcome Measures
 
 
 
 
 
 
 
 
13.6 Planned Interim Analysis of the Study
No formal interim analysis is planned for this study. However, a descriptive summary 
report for this study is planned after all subjects have completed at least 6 months of
prophylactic treatment with rVWF.
14. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
The investigator/study site will cooperate and provide direct access to study documents 
and data, including source documentation for monitoring by the study monitor, audits by 
the sponsor or sponsor’s representatives, review by the EC, and inspections by applicable 
regulatory authorities, as described in the Clinical Trial Agreement (CTA). If contacted 
by an applicable regulatory authority, the investigator will notify the sponsor of contact, 
cooperate with the authority, provide the sponsor with copies of all documents received 
from the authority, and allow the sponsor to comment on any responses, as described in 
the CTA.
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15. QUALITY CONTROL AND QUALITY ASSURANCE
15.1 Investigator’s Responsibility
The investigator will comply with the protocol (which has been approved/given favorable 
opinion by the EC), ICH GCP, and applicable national and local regulatory requirements 
as described in the CTA. The investigator is ultimately responsible for the conduct of all 
aspects of the study at the study site and verifies by signature the integrity of all data 
transmitted to the sponsor. The term “investigator” as used in this protocol as well as in 
other study documents, refers to the investigator or authorized study personnel that the 
investigator has designated to perform certain duties. Sub-investigators or other 
authorized study personnel are eligible to sign for the investigator, except where the 
investigator’s signature is specifically required.
15.1.1 Investigator Report and Final Clinical Study Report 
The investigator, or coordinating investigator(s) for multicenter studies, will sign the 
clinical study report. The coordinating investigator will be selected before study start.
15.2 Training
The study monitor will ensure that the investigator and study site personnel understand all 
requirements of the protocol, the investigational status of the IP, and his/her regulatory 
responsibilities as an investigator. Training may be provided at an investigator’s meeting, 
at the study site, and/or by instruction manuals. In addition, the study monitor will be 
available for consultation with the investigator and will serve as the liaison between the 
study site and the sponsor.
15.3 Monitoring
The study monitor is responsible for ensuring and verifying that each study site conducts 
the study according to the protocol, standard operating procedures other written 
instructions/agreements, ICH GCP, and applicable national and local regulatory 
guidelines/requirements. The investigator will permit the study monitor to visit the study 
site at appropriate intervals, as described in the CTA. Monitoring processes specific to the 
study will be described in the clinical monitoring plan. 
15.4 Auditing
The sponsor and/or sponsor’s representatives may conduct audits to evaluate study 
conduct and compliance with the protocol, standard operating procedures, other written 
instructions/agreements, ICH GCP, and applicable national and local regulatory 
guidelines/requirements. The investigator will permit auditors to visit the study site, as 
described in the CTA. Auditing processes specific to the study will be described in the 
audit plan.
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15.5 Non-Compliance with the Protocol
The investigator may deviate from the protocol only to eliminate an apparent immediate 
hazard to the subject. In the event(s) of an apparent immediate hazard to the subject, the 
investigator will notify the sponsor immediately by phone and confirm notification to the 
sponsor in writing as soon as possible, but within 1 calendar day after the change is 
implemented. The sponsor (Baxalta) will also ensure the responsible EC and relevant 
competent authority are notified of the urgent measures taken in such cases according to 
local regulations.
If monitoring and/or auditing identify serious and/or persistent non-compliance with the 
protocol, the sponsor may terminate the investigator’s participation. The sponsor will 
notify the EC and applicable regulatory authorities of any investigator termination.
15.6 Laboratory and Reader Standardization
A central laboratory/reader will be used for all clinical assessments except for pregnancy
testing and blood group test (refer to Section 12.9). Local laboratories are requested to 
provide their laboratory specifications of the individual tests that are also being tested 
locally.
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16. ETHICS 
16.1 Subject Privacy
The investigator will comply with applicable subject privacy regulations/guidance as 
described in the CTA.
16.2 Ethics Committee and Regulatory Authorities
Before enrollment of patients into this study, the protocol, informed consent form, any 
promotional material/advertisements, and any other written information to be provided 
will be reviewed and approved/given favorable opinion by the EC and applicable 
regulatory authorities. The IB will be provided for review. The EC’s composition or a 
statement that the EC’s composition meets applicable regulatory criteria will be 
documented. The study will commence only upon the sponsor’s receipt of 
approval/favorable opinion from the EC and, if required, upon the sponsor’s notification 
of applicable regulatory authority(ies) approval, as described in the CTA.
If the protocol or any other information given to the subject is amended, the revised 
documents will be reviewed and approved/given favorable opinion by the EC and 
applicable regulatory authorities, where applicable. The protocol amendment will only be 
implemented upon the sponsor’s receipt of approval and, if required, upon the sponsor’s 
notification of applicable regulatory authority(ies) approval.
16.3 Informed Consent
Investigators will choose patients for enrollment considering the study eligibility criteria. 
The investigator will exercise no selectivity so that no bias is introduced from this source. 
All patients and/or their legally authorized representative must sign an informed consent 
form before entering into the study according to applicable national and local regulatory 
requirements and ICH GCP. Before use, the informed consent form will be reviewed by 
the sponsor and approved by the EC and regulatory authority(ies), where applicable, (see 
Section 16.2). The informed consent form will include a comprehensive explanation of 
the proposed treatment without any exculpatory statements, in accordance with the 
elements required by ICH GCP and applicable national and local regulatory 
requirements. Patients or their legally-authorized representative(s) will be allowed 
sufficient time to consider participation in the study. By signing the informed consent 
form, patients or their legally authorized representative(s) agree that they will complete 
all evaluations required by the study, unless they withdraw voluntarily or are terminated 
from the study for any reason.
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The sponsor will provide to the investigator in written form any new information that 
significantly bears on the subjects’ risks associated with IP exposure. The informed 
consent will be updated, if necessary. This new information and/or revised informed 
consent form, which have been approved by the applicable EC and regulatory authorities, 
will be provided by the investigator to the subjects who consented to participate in the 
study 
16.4 Data Monitoring Committee
This study will be monitored by Data Monitoring Committee (DMC). The DMC is a 
group of individuals with pertinent expertise that reviews on a regular basis accumulating 
data from an ongoing clinical study. For this study, the DMC will be composed of 
recognized experts in the field of VWD clinical care and research who are not actively 
recruiting subjects, and an independent statistician. The DMC can stop a trial if it finds 
toxicities or if treatment is proven to be not beneficial. Details will be defined in the 
DMC charter. 
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17. DATA HANDLING AND RECORD KEEPING
17.1 Confidentiality Policy
The investigator will comply with the confidentiality policy as described in the CTA. 
17.2 Study Documentation and Case Report Forms
The investigator will maintain complete and accurate paper format study documentation 
in a separate file. Study documentation may include information defined as “source data” 
(see Section 8.8), records detailing the progress of the study for each subject, signed 
informed consent forms, correspondence with the EC and the study monitor/sponsor, 
enrollment and screening information, CRFs, SAERs, laboratory reports (if applicable),
and data clarifications requested by the sponsor.
The investigator will comply with the procedures for data recording and reporting. Any 
corrections to paper study documentation must be performed as follows: 1) the first entry 
will be crossed out entirely, remaining legible; and 2) each correction must be dated and 
initialed by the person correcting the entry; the use of correction fluid and erasing are 
prohibited.
The investigator is responsible for the procurement of data and for the quality of data 
recorded on the CRFs. CRFs will be provided in electronic form. 
If electronic format CRFs are provided by the sponsor, only authorized study site 
personnel will record or change data on the CRFs. If data is not entered on the CRFs 
during the study visit the data will be recorded on paper and this documentation will be 
considered source documentation. Changes to a CRF will require documentation of the 
reason for each change. An identical (electronic/paper) version of the complete set of 
CRFs for each subject will remain in the investigator file at the study site in accordance 
with the data retention policy (see Section 17.3).
The handling of data by the sponsor, including data quality assurance, will comply with 
regulatory guidelines (e.g., ICH GCP) and the standard operating procedures of the 
sponsor. Data management and control processes specific to the study will be described 
in the data management plan.
17.3 Document and Data Retention 
The investigator will retain study documentation and data (paper and electronic forms) in 
accordance with applicable regulatory requirements and the document and data retention 
policy, as described in the CTA.
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18. FINANCING AND INSURANCE
The investigator will comply with investigator financing, investigator/sponsor insurance, 
and subject compensation policies, if applicable, as described in the CTA.
19. PUBLICATION POLICY
The investigator will comply with the publication policy as described in the CTA. 
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20. SUPPLEMENTS
20.1 Study Flow Chart
Figure 1
Study Design for Baxalta Clinical Study 071301
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20.2 Schedule of Study Procedures and Assessments
Table 5
Schedule of Study Procedures and Assessments
Procedures/
Assessments
Screening Visit
Baseline Visit 
(PK-assessment visit)
Prophylaxis Initiation 
Visit
Interval/Follow-Up 
Study Visits
PK Assessment and 
Study Completion
Termination 
Visit
Pre-infusion
Infusion
Post-infusiong
1 month ± 
1 week
2 month ± 
1 week 
3 month ± 
2 weeks
6 month ± 
2 weeks 
9 month ± 
2 weeks
Pre-
infusion
Infusion
Post-
infusiong
Conducted 
at the 
72 hour 
postinfusion 
PK 
Assessment
12 month± 
2 weeks
Informed Consent a
X
Eligibility Criteria
X
Medical Historyb
X
X
X
Medicationsc
X
X
X
X
X
X
X
X
X
X
Non-drug Therapiesc
X
X
X
X
X
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
Bleeding Episodes
X
X
X
X
X
X
X
X
X
X
Laboratories 
X
X
X
Xh
X
X
X
X
X
X
X
X
Vital Signsd
X
X
X
X
X
X
X
X
X
X
X
X
ECG
X
X
X
IP Treatmente
X
X
X
X
X
X
X
X
IP Consumption / Treatment 
Compliance 
X
X
X
X
X
Subject Diary
X
X
X
X
X
X
Xf
X
X
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Continued
a) Occurs at enrollment (before screening).
b) Including documented history of on-demand treatment for the past 12 months and a documented history, e.g., patient charts and prescription information, 
of all bleeding episodes within the past 12 months. 
c) Including all medications and non- drug therapies taken in the 2 weeks prior to study entry and all the concomitant medications and non-drug therapies 
during the course of the study.
d) Vital signs (pulse rate, respiratory rate, and blood pressure): within 30 minutes before infusion start and 30 ± 15 minutes post-infusion.
e) IP treatment after the prophylactic treatment initiation visit at the site will be continued as home-treatment if the subject qualifies; a wash-out period of at 
least 72 hours is required after the last IP infusion before the follow-up visit. IP infusion will be given at the study site after the blood sample for 
immunology testing and IR determination is drawn.
f) Can be done either at the screening or the baseline visit.
g) Time points for blood draws post infusion: 30 ± 5 minutes; 60 ± 5 minutes; 6 ± 1 hours; 12 ± 1 hours; 24 ± 2 hours; 48 ± 2 hours; 72 ± 2 hours. 
h) If a subject did not undergo PK assessment (for example the subject has participated in the surgery study 071101 and has undergone PK in Study 071101), 
laboratory assessments will be performed at this visit.
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20.3 Clinical Laboratory Assessments
Table 6
Clinical Laboratory Assessments
Procedures/
Assessments
Screening Visit
Baseline Visit 
(PK-assessment visit)
Prophylaxis Initiation 
Visitk
Interval/Follow-Up 
Study Visits
PK Assessment and 
Study Completion
Termination 
Visit
Pre-infusion
Infusion
Post-infusiong
1 month ± 
1 week
2 month ± 
1 week 
3 month ± 
2 weeks
6 month ± 
2 weeks 
9 month ± 
2 weeks
Pre-
infusion
Infusion
Post-
infusiong
Conducted 
at the 
72 hour 
postinfusion 
PK 
Assessment
12 month± 
2 weeks
Hematology a
X
X
X
X
X
X
X
X
X
Xm
X
Clinical Chemistryb
X
X
X
X
X
X
X
X
X
X
X
Coagulation Panel/PK 
assessmentc
X
X
X
X
X
X
X
X
X
X
X
Immunogenicityd
X
X
X
Xl
X
X
X
X
X
X
X
Viral Serologye
X
Urinalysisf
X
VWD Gene Mutational 
Analysis / HLA genotype 
analysis and Analysis of 
VWF multimersg
X
sP-selectin and 
D-dimer
Xh
Blood Groupi
X
X
Pregnancy Testj
X
Exploratory Tests
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Continued
a) Hematology assessments include: complete blood count [hemoglobin, hematocrit, erythrocytes (i.e. red blood cell count), mean corpuscular volume 
(MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), leukocytes (i.e. white blood cell count)] with 
differential (i.e. basophils, eosinophils, lymphocytes, monocytes, neutrophils) and platelet counts. Hematology assessments during PK assessments will be 
determined prior IP infusion and 24 ± 2 hours, 48 ± 2 hours and 72 ± 2 hours thereafter.
b) Clinical chemistry assessments include: Sodium, potassium, chloride, glucose, creatinine, blood urea nitrogen (BUN), aspartate aminotransferase (AST), 
alanine aminotransferase (ALT) lactate dehydrogenase (LDH), alkaline phosphatase (AP), bilirubin. Clinical chemistry will be determined at baseline, 
after 24 ± 2 h, 48 ± 2 hours and 72 ± 2 hours during the PK assessments. 
c) Coagulation panel/PK assessment: INR/aPTT, VWF:RCo, VWF:Ag, VWF:CB, FVIII:C, VWF Innovance (exploratory assay); during the PK assessment 
at the baseline visit blood samples will be drawn 30 min prior PK infusion; once the PK infusion is completed 30 5 minutes; 60 ± 5 minutes; 6 hours 
± 1 hour ; 12 ± 0.5 hours; 24 ± 2 hours, 48 ± 2 hours; 72 ± 2 hours and VWF:RCo, VWF:CB, VWF:Ag, VWF Ac, FVIII:C will be determined; in case of 
thromboembolic event VWF multimers and ADAMTS13 will be analyzed to judge on a possibly relatedness to UHMW fractions of the IP.
d) Immunogenicity assessment includes Neutralizing Antibodies (Ab) to FVIII – Neutralizing and Neutralizing Ab to VWF:RCo, Neutralizing Ab to 
VWF:CB, Neutralizing Ab to VWF:FVIII, Binding Ab to VWF and FVIII, Binding Ab to CHO-Protein, Binding Ab to rFurin, Binding Ab to Murine IgG; 
.CD4* In case of an SAE hypersensitivity reaction IgE antibodies to VWF will be determined. A washout period of at least 72 hours after the last IP 
infusion is required before blood samples for immunogenicity assessments can be drawn. 
e) Viral Serology Hepatitis A Antibody, Total - Hepatitis A Antibody, IgM - Hepatitis B Surface Antibody - Hepatitis B Core Ab, Total - Hepatitis B Surface 
Antigen - Hepatitis C Virus Antibody; Parvovirus B19; HIV-1/HIV-2 Antibodies
f) Urinalysis comprehends: erythrocytes, specific gravity, urobilinogen, ketones, glucose, protein, bilirubin, nitrite, and pH
g) Not required if available in the subject’s medical history; VWF multimers: additionally in case of thromboembolic events
h) At screening and in case of thromboembolic events
i) Blood group assessment major blood group (local laboratory) only if not available in the subject’s medical history
j) Serum pregnancy test (in females of child-bearing potential if no urine sample is available)
k) The 72 h post-infusion laboratory assessments coincidence with the initiation visit for prophylactic treatment. After the blood samples are drawn for 
laboratory assessment for the 72 h post infusion PK assessment, the subject receives the first IP infusion for prophylactic treatment (prophylactic treatment 
initiation visit). 
l) Only needed for subjects without PK assessment prior to their first IP infusion in this study.
m) A full PK analysis will be performed. Blood samples will be drawn within 30 minutes pre-infusion, and at 7 time points post-infusion (30 ± 5 minutes,
60 ± 5 minutes, 6 ± 1 hours, 12 ± 1 hours, 24 ± 2 hours, 48 ± 2 hours, 72 ± 2 hours).
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21. REFERENCES
1. Committee for Medicinal Products for Human Use. Guideline on clinical 
investigation of human plasma derived von Willebrand factor products. 
CPMP/BPWG/220/02, 12. 11-17-2005. London, European Medicines Agency 
(EMEA) (EMA). 
Link to Publisher´s Site: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/201
0/01/WC500067126.pdf
2. Mannucci PM. Treatment of von Willebrand's Disease. N.Engl.J.Med. 
2004;351:683-694.
3. Goudemand J, Scharrer I, Berntorp E et al. Pharmacokinetic studies on Wilfactin, a 
von Willebrand factor concentrate with a low factor VIII content treated with three 
virus-inactivations/removal methods. J.Thromb.Haemost. 2005;3:2219-2227.
4. Abshire T. The role of prophylaxis in the management of von Willebrand disease: 
today and tomorrow. Thromb.Res. 2009;124 Suppl 1:S15-S19.
5. Nilsson IM, Blombäck M, Jorpes E, Blombäck B, Johansson SA. V. Willebrand's 
disease and its correction with human plasma fraction 1-0. Acta Med.Scand. 
1957;159:179-188.
6. Berntorp E, Petrini P. Long-term prophylaxis in von Willebrand disease. Blood 
Coagul.Fibrinolysis 2005;16 Suppl 1:S23-S26.
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7. Berntorp E. Prophylaxis and treatment of bleeding complications in von Willebrand 
disease type 3. Semin.Thromb.Hemost. 2006;32:621-625.
8. Federici AB. Highly purified VWF/FVIII concentrates in the treatment and 
prophylaxis of von Willebrand disease: the PRO.WILL Study. Haemophilia. 
2007;13 Suppl 5:15-24.
9. Halimeh S, Krümpel A, Rott H et al. Long-term secondary prophylaxis in children, 
adolescents and young adults with von Willebrand disease. Results of a cohort 
study. Thromb.Haemost. 2011;105:597-604.
10. Abshire TC, Federici AB, Alvárez MT et al. Prophylaxis in severe forms of von 
Willebrand's disease: results from the von Willebrand Disease Prophylaxis Network 
(VWD PN). Haemophilia. 2013;19:76-81.
11. Abshire T, Cox-Gill J, Kempton CL et al. Prophylaxis escalation in severe von 
Willebrand disease: A prospective study from the von Willebrand Disease 
Prophylaxis Network. J.Thromb.Haemost. 2015;13:1585-1589.
12. Berntorp E. Prophylaxis in von Willebrand disease. Haemophilia. 2008;14 Suppl 
5:47-53.
13. Varadi K, Rottensteiner H, Vejda S et al. Species-dependent variability of 
ADAMTS13-mediated proteolysis of human recombinant von Willebrand factor. 
J.Thromb.Haemost. 2009;7:1134-1142.
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14. Mannucci PM, Kempton C, Millar C et al. Pharmacokinetics and safety of a novel 
recombinant human von Willebrand factor manufactured with a plasma-free 
method: a prospective clinical trial. Blood. 2013;122:648-657.
15. Gill JC, Castaman G, Windyga J et al. Hemostatic efficacy, safety and 
pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand 
disease. Blood. 2015;126:2038-2046.
16. Committee for Medicinal Products for Human Use. Guideline on immunogenicity 
assessment of biotechnology-derived therapeutic proteins. 
CHMP/BMWP/14327/2006, 18. 12-13-2007. London, European Medicines Agency 
(EMEA - EMA). 
Link to Publisher´s Site: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/200
9/09/WC500003946.pdf
17. Kasper CK. Laboratory tests for factor VIII inhibitors, their variation, significance 
and interpretation. Blood Coagul.Fibrinolysis 1991;2 Suppl 1:7-10.
18. Lillicrap D. Von Willebrand Factor. International Society for Thrombhosis and 
Hemostasis (ISTH) 54th Annual Scientific and Standardization Committee 
Meeting. 2008:60-64.
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22. SUMMARY OF CHANGES 
Protocol 071301: Amendment 1: 2016 APR 08
Replaces: Original: 2014 FEB 19
In this section, changes from the previous version of the Protocol, dated 2014 FEB 19, 
are described and their rationale is given.
1.
Throughout the document
Description of Change: Minor edits and formatting corrections. The sponsor name 
was updated from ‘Baxter’ to ‘Baxalta’ and the dates of the planned study period 
were updated. The term ‘inhibitory antibodies’ was updated to ‘neutralizing 
antibodies’ and ‘thrombotic’ was updated to ‘thromboembolic’, throughout the 
protocol. The abbreviation 
 was corrected to 
 throughout the 
protocol. The term ‘allergic’ was changed to ‘hypersensitivity’ for consistency 
across program documents. Some updates were made as a result of a newly 
available protocol template. EudraCT number added.
Purpose for Change: Administrative.
2.
Synopsis, Primary Objective; Synopsis, Primary Outcome Measure; 
Section 7.2 Primary Objective; Section 8.4.1 Primary Outcome Measure; 
Section 13.4.1 Primary Outcome Measure
Description of Change: The description of ABR for the primary objective was 
updated. It was clarified that spontaneous bleeding episodes were those not related 
to trauma.
Purpose for Change: Administrative.
3.
Synopsis, Secondary Objectives; Section 7.3 Secondary Objectives
Description of Change: Immunogenicity was added to the list of secondary 
objectives for consistency with the listed secondary outcome measures.
Purpose for Change: Administrative.
4.
Synopsis, Exploratory Objectives; Synopsis, Exploratory Outcome Measures; 
Section 7.4 Exploratory Objectives; Section 8.4.3 Exploratory Outcomes 
Measures; Section 13.5 Exploratory Outcomes Measures
Description of Change: 
 were added as 
an exploratory objective and exploratory outcome measures.
Purpose for Change: Administrative.
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5.
Synopsis, Study Design; Section 8.3 Duration of Study Periods and Subject 
Participation
Description of Change: The planned duration of the participation period for 
subjects was updated from 16 months to 15 months.
Purpose for Change: Administrative.
6.
Synopsis, Study Design; Section 8.3 Duration of Study Periods and Subject 
Participation
Description of Change: Language was included regarding an option for subjects to 
enrol into a continuation study once all visits in 071301 have been completed: 
“Subjects will be offered the option to continue to receive BAX111 in a long-term 
continuation study”.
Purpose for Change: It would be unethical to remove access to the study drug
while it remains unapproved for commercial, prophylactic use, hence a long-term 
continuation study will allow continued access to BAX111 and additionally allow 
longer term data to be collected.
7.
Synopsis, Secondary Outcome Measures; Synopsis, Planned Statistical Analysis, 
Section 8.4.2.1 Efficacy, Section 8.4.8.4 Efficacy of the Treatment of Bleeding 
Episodes; Section 13.4.2.1 Efficacy
Description of Change: To clarify that the secondary outcome measure of 
“Number of infusions and total weight adjusted consumption of rVWF and 
ADVATE (recombinant factor VIII/rFVIII) per month and per year” referred to 
on-demand treatment and not prophylactic treatment. It was also clarified that 
spontaneous bleeding episodes were those that were unrelated to trauma. The 
number of infusions and weight-adjusted consumption of rVWF and ADVATE 
per traumatic bleeding episode were added as secondary outcome measures for 
the efficacy of the treatment of bleeding episodes.
Purpose for Change: Clarification of secondary outcome measure due to FDA 
feedback.
8.
Synopsis, Active Product; Section 8.2 Overall Study Design; 
Section 8.7.4.3 Prophylaxis Treatment
Description of Change: The dosage frequency was changed and clarified for those 
subjects transitioning from on-demand treatment on entry to the study.
A new subsection (Section 8.7.4.3.1) was added to describe the criteria for 
treatment escalations.
Purpose for Change: Administrative.
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9.
Synopsis, Targeted Accrual
Description of Change: The text was updated to clarify that approximately 18 
subjects would be enrolled to achieve 15 evaluable subjects with severe VWD.
Purpose for Change: Administrative.
10. Synopsis, Inclusion Criteria; Section 9.1 Inclusion Criteria
Description of Change: The definition of severe VWD was added to the protocol.
Inclusion criteria regarding diagnosis of VWD and prior treatment were clarified.
Clarification was added regarding past documented spontaneous bleeds requiring 
VWF treatment. An acceptable body mass index range was added to the inclusion 
criteria.
Purpose for Change: EMA feedback.
11. Synopsis, Inclusion Criteria; Synopsis, Exclusion Criteria; Section 
9.1 Inclusion Criteria; Section 9.2 Exclusion Criteria
Description of Change: Study entry criteria were amended to exclude subjects 
receiving prophylaxis prior to entering the study. The study aims to demonstrate a 
change in ABR from pre-study to prophylaxis with BAX111 and having patients 
already on prophylaxis would negatively impact this possibility.
Purpose for Change: Due to the low number of patients involved in the trial, only 
half of the subjects would be on-demand treatment at the time of enrollment.
12. Synopsis, Exclusion Criteria; Section 9.2 Exclusion Criteria
Description of Change: An exclusion criterion was added for those who have 
received prophylaxis treatment in the 12 months prior to screening (including 
those who received treatment once a month for menorrhagia but were not treated 
for any other bleeds). 
Purpose for Change: In light of the small number of subjects, the protocol was 
revised in order to evaluate only subjects currently receiving on-demand therapy.
13. Synopsis, Exclusion Criteria; Section 9.2 Exclusion Criteria
Description of Change: Subjects with Type 2N VWD are to be excluded from the 
study. Subjects with cervical or uterine conditions causing menorrhagia or 
metrorrhagia (including infection, dysplasia) are to be excluded from the study. It 
was added that subjects with a low platelet count should be excluded from the 
study. It was also added that subjects receiving prophylaxis treatment at a dosing 
frequency of once per week would be excluded from the study.
Purpose for Change: EMA feedback.
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14. Synopsis, Sample Size Calculation; Section 13.1 Sample size and Power 
Calculation, Section 22 References
Description of Change: The following text was added to clarify the choice of 
sample size, and the corresponding reference was added to the protocol:
New text: The sample size of a subset of at least 15 subjects with severe VWD, 
5 of whom must have Type 3 VWD, is based on the Guideline on the Clinical 
Investigation of Human Plasma Derived von Willebrand Factor Products 
(CPMP/BPWG/220/02).
Purpose for Change: To justify the sample size chosen for the protocol.
15. Synopsis, Planned Statistical Analysis; Section 11.1 Assessment of Spontaneous 
Bleeding Episodes/Annualized Bleed Rate; Section 13.4.2.1 Efficacy
Description of Change: Bleeding episodes should be organized by where they 
occur in addition to whether they occurred spontaneously or due to a traumatic
event.
Purpose for Change: Bleeding episodes due to traumatic events should not be 
included in the calculation of ABR.
16. Synopsis, Planned Statistical Analysis; Section 13.4.1 Primary Outcome Measure; 
Section 13.4.2.1 Efficacy
Description of Change: The 90% CIs for the primary and secondary outcome 
measures were updated to 95% CIs. Text was added to Section 13.4.1 to describe 
the difference between prospective and historical ABR.
Purpose for Change: EMA request to change. 
17. Synopsis, Planned Statistical Analysis; Section 13.4.2.1 Efficacy
Description of Change: It was clarified that the number of infusions and the total 
weight adjusted comparison of rVWF and ADVATE (per month/year) will be 
calculated during on-demand treatment for bleeding episodes.
Purpose for Change: Administrative.
18. Synopsis, Planned Statistical Analysis; Section 13.4.2.1 Efficacy; 
Section 13.4.2.2 Efficacy of the Treatment of Bleeding Episodes
Description of Change: It was added that the cause, type, localization and severity 
of spontaneous bleeds were to be documented throughout the study.
Purpose for Change: EMA feedback.
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19. Section 2 Serious Adverse Event Reporting, Section 12.1.2 Assessment of 
Adverse Events
Description of Change: Text added to clarify that bleeding events meeting 
seriousness criteria (death, life-threatening, hospitalizing/prolongation of 
hospitalization, disability, congenital anomaly, or medically significant and if not 
urgently treated would result in one of the above) should be reported on the SAE 
eCRF or SAE Report form as an SAE.
Purpose for Change: Compliance with Baxalta SOP for reporting cases that meet 
CIOMS criteria for seriousness.
20. Section 6.1 Description on Investigational Product
Description of Change: Text was added to describe the licensure of rVWF in the 
US.
Purpose for Change: Administrative.
21. Section 6.3 The role of prophylaxis in the management of VWD; Section 22 
References
Description of Change: Further details of the prospective component of the VIP 
trial recently became available so a summary of the results were added along with 
the corresponding reference.
Purpose for Change: Administrative.
22. Section 6.5 Findings from Nonclinical and Clinical Studies;
Section 6.5.2 Findings from Clinical Studies; Section 22 References
Description of Change: Details from the completed phase 3 study 071001 were 
added to the protocol. Section 6.5.2 was amended to include Study 071001 and 
the corresponding reference was added to the protocol.
New sub-sections were added to include a summary of the study design and 
results for 071001(Section 6.5.2.3) and to add details of expanded access in a 
single subject with VWD in 071401 (Section 6.5.2.4).
Purpose for Change: Updated list of completed studies.
23. Section 8.6 Study Stopping Rules
Description of Change: A new study stopping criterion was added for those 
subjects with abnormal liver function.
Purpose for Change: Administrative.
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24. Section 8.7.3 Administration
Description of Change: It was added that the IP infusions should be administered 
over a duration of 2 to 15 minutes, depending on the volume.
Purpose for Change: Administrative.
25. Section 8.7.4.1 Baseline Visit (PK-Assessment Treatment); 
Section 8.7.4.2 Prophylaxis Initiation Treatment; Section 10.3.1 Screening Visit; 
Section 20.1 Study Flow Chart 
Description of Change: The duration of the screening period was changed from 
60 days to 42 days.
Purpose for Change: Administrative.
26. Section 8.7.4.1 Baseline Visit (PK-Assessment Treatment); 
Section 8.7.4.2 Prophylaxis Initiation Treatment; Section 10.3.3.1 Surgical 
Prophylaxis; Section 10.3.2 Baseline Visit – PK-Assessment Visit; 
Section 20.2 Study Flow Chart
Description of Change: The text regarding subjects transitioning from the surgery 
study 071101 was updated to reflect the fact that the surgery study will have 
completed enrollment prior to this study enrolling the first subject. Subjects who 
participated and had a major procedure performed in the surgery study 071101 
will not need an additional PK assessment in this study. Subjects who participated 
and had a minor procedure performed in the surgery study 071101 will need a PK 
assessment. Section 10.3.3.1 was removed from the protocol.
Purpose for Change: The surgery study will complete enrollment prior to this study 
enrolling the first subject.
27. Section 8.7.4.3 Prophylaxis Treatment; Table 1 rVWF Dosing Schedule 
Examples: Schedules, A, B, and C; Section 8.7.4.3.1 Treatment escalation; 
Table 2 Criteria for escalation specific to each bleeding indication
Description of Change: Schedule C removed.
Purpose for Change: Since the study no longer offers an every other day dosing 
frequency, this schedule has been removed.
28. Section 8.7.4.3.1 Treatment escalation; Table 2 Criteria for escalation specific to 
each bleeding indication
Description of Change: Text added to instruct investigators how to treat a bleed if 
it occurs when the subject is receiving BAX111 3 times per week.
Purpose for Change: Details added since the every other day dosing frequency was 
removed.
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29. Section 8.7.4.4.2 Dosing Recommendations for Treatment of Bleeding Episodes
Description of Change: A definition of menorrhagia was added to the protocol.
Purpose for Change: Administrative.
30. Section 10.3.1 Screening Visit; Section 12.9.8 VWD Mutational Analysis, 
Multimer Analysis and Human Leukocyte Antigen Genotyping
Description of Change: It was clarified that VWD has to be confirmed by genetic 
testing and multimer analysis, either by the subjects’s medical history or by 
sample assessment during screening.
Purpose for Change: Clarification of screening assessments.
31. Section 10.3.1 Screening Visit; Section 10.3.5 Follow-Up Visits (1 Month ± 1 
Week, 2 Months ± 1 Week, 3 Months ± 2 Weeks, 6 Months ± 2 Weeks, 9 Months 
± 2 Weeks); Section 10.5 Subject Diary; Section 11.1 Assessment of Spontaneous 
Bleeding Episodes/Annualized Bleed Rate
Description of Change: The information to be recorded in the subject diary was 
updated; potency, lot numbers, weight, AEs, concomitant medication and drug 
accountability were removed and it was clarified that the treatment of both 
spontaneous and traumatic bleeding episodes were to be recorded. It was also 
added that infusions performed at the study site will be recorded in the site’s 
source documents and not in the patient diary. Additional clarification was added 
on where bleeding episodes will be recorded. It was added that, when possible, 
site visits should be scheduled on days when the subject is expected to infuse 
BAX 111.
Purpose for Change: Administrative.
32. Section 10.3.7 Study termination Visit (12 months ± 2 weeks); 
Section 12.9.1 rVWF and Endogenous FVIII Pharmacokinetics; 
Section 20.2 Schedule of Study Procedures and Assessments; 
Section 20.3 Clinical Laboratory Assessments
Description of Change: Full PK analysis was added at the end of the study to 
allow comparison to the baseline PK parameters.
The full PK assessments and a study termination visit to coincide with the 72-hour 
postinfusion PK analysis was added to Table 5 and Table 6.
Purpose for Change: To allow comparative analysis of PK parameters at baseline 
and at the end of the study.
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33. Section 10.3.7 Study termination Visit (12 months ± 2 weeks)
Description of Change: Subjects will be offered the option to continue to receive 
BAX111 in a long-term continuation study.
Purpose for Change: Strategic decision to allow access to BAX111 for subjects 
who wish to continue receiving study drug after completion of this study. The 
option to continue receiving drug will be a separate stand alone continuation 
study.
34. Section 11.2 Evaluation of ABR before rVWF Prophylaxis and ABR under rVWF 
Prophylactic Treatment
Description of Change: The text regarding bleeding episode history was updated 
to cover those subjects on-demand therapy prior to enrollment in the study.
Purpose for Change: Administrative.
35. Section 11.4 Assessment of Efficacy for Treatment of Bleeding Episode; Section 
21 References
Description of Change: The table detailing the hemostatic efficacy rating scale 
was replaced with more detailed efficacy rating criteria for minor/moderate and 
major bleeding events. The corresponding reference was deleted from Section 21.
Purpose for Change: Administrative.
36. Section 12.7 Vital Signs
Description of Change: It was clarified that height and weight would be measured 
pre-infusion only.
Purpose for Change: Administrative.
37. Section 12.9.16 Biobanking
Description of Change: For this study, no back-up samples will be taken or stored 
long-term in a biobank for future analyses. This section describing biobanking 
procedures was removed from the protocol.
Purpose for Change: Administrative.
38. Section 13.2.2 Full Analysis Dataset
Description of Change: The definition of the Full Analysis Set was updated to 
include all subjects with available bleeding data gathered during prophylaxis, 
instead of those with a minimum of 6 months data.
Purpose for Change: To allow estimation of ABR on all available bleeding data.
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39. Section 13.4 Methods of Analysis
Description of Change: Study success criteria were defined in the protocol.
New text: The study success criteria are the objectives as stated in Section 7. 
“Treatment success” was defined as the extent of control of bleeding episodes 
achieved during this study.
Purpose for Change: Administrative.
40. Section 13.4.2.3 Pharmacokinetic Analysis
Description of Change: The proposed analysis was updated to reduce the number 
of descriptive statistics being reported.
Purpose for Change: Administrative.
41. Section 13.4.2.4 Safety
Description of Change: Some minor wording updates were made to clarify the 
timing of AEs and the assessments of causality for AEs and SAEs.
Purpose for Change: Administrative.
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INVESTIGATOR ACKNOWLEDGEMENT
RECOMBINANT VON WILLEBRAND FACTOR (rVWF)
A prospective, phase 3, open label, international multicenter study on efficacy and 
safety of prophylaxis with rVWF in severe von Willebrand Disease
PROTOCOL IDENTIFIER: 071301
CLINICAL TRIAL PHASE 3
AMENDMENT 1: 2016 APR 08
Replaces: ORIGINAL: 2014 FEB 19
OTHER PROTOCOL ID(s)
NCT Number: to be determined
EudraCT Number: 2016-001478-14
IND/IDE NUMBER: to be determined
By signing below, the investigator acknowledges that he/she has read and understands 
this protocol, and will comply with the requirements for obtaining informed consent from 
all study subjects prior to initiating any protocol-specific procedures, obtaining written 
initial and ongoing EC(s) protocol review and approval, understands and abides by the 
requirements for maintenance of source documentation, and provides assurance that this 
study will be conducted according to all requirements as defined in this protocol, Clinical 
Trial Agreement, ICH GCP guidelines, and all applicable national and local regulatory 
requirements.
Signature of Principal Investigator
Date
Print Name of Principal Investigator
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INVESTIGATOR ACKNOWLEDGEMENT
RECOMBINANT VON WILLEBRAND FACTOR (rVWF)
A prospective, phase 3, open label, international multicenter study on efficacy and 
safety of prophylaxis with rVWF in severe von Willebrand Disease
PROTOCOL IDENTIFIER: 071301
CLINICAL TRIAL PHASE 3
AMENDMENT 1: 2016 APR 08
Replaces: ORIGINAL: 2014 FEB 19
OTHER PROTOCOL ID(s)
NCT Number: to be determined
EudraCT Number: 2016-001478-14
IND/IDE NUMBER: to be determined
By signing below, the investigator acknowledges that he/she has read and understands 
this protocol, and provides assurance that this study will be conducted according to all 
requirements as defined in this protocol, Clinical Trial Agreement, ICH GCP guidelines, 
and all applicable national and local regulatory requirements.
Signature of Coordinating Investigator
Date
Print Name and Title of Coordinating Investigator
Signature of Sponsor Representative
Date
, MD
, Global Clinical Development
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BAXALTA CONFIDENTIAL – RESTRICTED: DO NOT DISTRIBUTE WITHOUT PRIOR APPROVAL
CLINICAL STUDY PROTOCOL
PRODUCT: Recombinant Von Willebrand Factor (rVWF)
STUDY TITLE: A PROSPECTIVE, PHASE 3, OPEN-LABEL, INTERNATIONAL 
MULTICENTER STUDY ON EFFICACY AND SAFETY OF PROPHYLAXIS 
WITH rVWF IN SEVERE VON WILLEBRAND DISEASE
STUDY SHORT TITLE: rVWF IN PROPHYLAXIS
PROTOCOL IDENTIFIER: 071301
CLINICAL TRIAL PHASE 3
AMENDMENT 2: 2016 DEC 15
Replaces: AMENDMENT 1: 2016 APR 08
OTHER ID(s)
NCT Number: NCT02973087
EudraCT Number: 2016-001478-14
IND NUMBER: to be determined
Study Sponsor(s):
Baxalta US Inc.
One Baxter Way
Westlake Village, CA  91362
UNITED STATES
Baxalta Innovations GmbH
Industriestrasse 67
A-1221 Vienna
AUSTRIA
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1. STUDY PERSONNEL
1.1 Authorized Representative (Signatory) / Responsible Party
, MD
Global Clinical Development Operations
Baxalta US Inc./Baxalta Innovations GmbH
1.2 Study Organization
The name and contact information of the responsible party and individuals involved with 
the study (e.g. investigator(s), sponsor’s medical expert and study monitor, sponsor’s 
representative(s), laboratories, steering committees, and oversight committees [including 
ethics committees (ECs)], as applicable) will be maintained by the sponsor and provided 
to the investigator.
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2. SERIOUS ADVERSE EVENT REPORTING
The investigator will comply with applicable laws/requirements for reporting serious 
adverse events (SAEs) and suspected unexpected serious adverse events (SUSARs) to the 
ECs.
ALL SAEs, INCLUDING SUSARs, ARE TO BE REPORTED ON THE SERIOUS 
ADVERSE EVENT REPORT (SAER) FORM AND TRANSMITTED TO THE 
SPONSOR WITHIN 24 HOURS AFTER BECOMING AWARE OF THE EVENT.
Bleeding events that meet seriousness criteria (death, life-threatening, 
hospitalizing/prolongation of hospitalization, disability, congenital anomaly, or medically 
significant and if not urgently treated would result in one of the above) should be reported 
on the SAE eCRF or SAE Report form as an SAE.
Drug Safety contact information: see SAE Report form 
Refer to SAE Protocol Sections and the study team roster for further information.
For definitions and information on the assessment of these events, refer to the following:
AE, Section 12.1
SAE, Section 12.1.1.1
SUSARs, Section 12.1.1.2
Assessment of AEs, Section 12.1.2
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3. SYNOPSIS 
INVESTIGATIONAL PRODUCT
Name of Investigational Product (IP)
Recombinant von Willebrand factor (rVWF)
Name(s) of Active Ingredient(s)
Recombinant von Willebrand factor (rVWF)
CLINICAL CONDITION(S)/INDICATION(S)
Subjects with severe von Willebrand disease (VWD) requiring prophylactic treatment with coagulation 
factor replacement
PROTOCOL ID
071301
PROTOCOL TITLE
A prospective, phase 3, open-label, international multicenter 
study on efficacy and safety of prophylaxis with rVWF in severe 
von Willebrand disease
Short Title
rVWF in prophylaxis
STUDY PHASE
Ph3
PLANNED STUDY PERIOD
Initiation
2016 JUN
Primary Completion
2018 Q1
Study Completion
2018 Q1
Duration
22 months
STUDY OBJECTIVES AND PURPOSE
Study Purpose
The purpose of this phase 3 study is to investigate the efficacy and safety, including immunogenicity and 
thrombogenicity, and 
of prophylactic treatment with rVWF in 
subjects with severe VWD.
Primary Objective
The primary objective of this study is to prospectively evaluate the annualized bleeding rate (ABR) for
spontaneous bleeding episodes while on prophylactic treatment with rVWF and to compare it to the 
subject’s historical ABR for spontaneous bleeding episodes during on-demand treatment. 
Secondary Objectives
Secondary Objectives are 

Additional efficacy assessments of prophylactic treatment

Safety and immunogenicity

Pharmacokinetics (PK)

Efficacy of the treatment of bleeding episodes 
Exploratory Objectives
 
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STUDY DESIGN
Study Type/ Classification/ Discipline
Efficacy and Safety 
Control Type
No control
Study Indication Type
Prophylaxis and treatment of bleeding episodes
Intervention model 
Single-group
Blinding/Masking
Open-label
Study Design
This is a phase 3, prospective, open-label, non-randomized, 
international multicenter study evaluating efficacy, safety, 
including immunogenicity and thrombogenicity, and 
of 
prophylactic treatment regimen with rVWF for subjects with 
severe VWD.
Subjects will be offered the option to continue to receive 
BAX111 in a long-term continuation study.
Planned Duration of Subject 
Participation
Approximately 15 months 
Primary Outcome Measure 
Efficacy

Prospectively recorded ABR for spontaneous (not related to trauma) bleeding episodes during 
prophylactic treatment with rVWF and the subjects’ historical ABR for spontaneous bleeding 
episodes during on-demand treatment.
Secondary Outcome Measure(s)
Efficacy

Number (proportion) of subjects with reduction of ABR for spontaneous (not related to trauma) 
bleeding episodes during prophylaxis relative to the subjects’ own historical ABR during on-demand
treatment

Number (proportion) of subjects with 0 bleeds during prophylactic treatment with rVWF

Number of infusions and total weight adjusted consumption of rVWF and ADVATE (recombinant 
factor VIII/rFVIII) per month and per year during on-demand treatment
Safety

Adverse events (AEs)

Incidence of thromboembolic events 

Incidence of severe hypersensitivity reactions

Development of neutralizing antibodies to VWF and FVIII 

Development of total binding antibodies to VWF and FVIII

Development of antibodies to Chinese hamster ovary (CHO) proteins, mouse immunoglobulin G 
(IgG) and rFurin
Pharmacokinetic

Incremental recovery (IR), terminal half-life (T1/2), mean residence time (MRT), area under the 
curve/dose (AUC/dose), area under moment curve/dose (AUMC/dose), volume of distribution at 
steady state (Vss) and clearance (CL) based on Von Willebrand factor Ristocetin cofactor activity
(VWF:RCo), Von Willebrand factor antigen (VWF:Ag), Von Willebrand collagen binding activity 
(VWF:CB), INNOVANCE VWF Ac (exploratory assay) and time course (72 hours) of FVIII 
clotting activity (FVIII:C) levels.
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Inclusion Criteria
Subjects who meet ALL of the following criteria are eligible for this study:
1. Subject has a documented diagnosis of severe VWD (baseline VWF:RCo <20 IU/dL) with a history 
of requiring substitution therapy with von Willebrand factor concentrate to control bleeding:
a. Type 1 (VWF:RCo <20 IU/dL) or,
b. Type 2A (as verified by multimer pattern), Type 2B (as diagnosed by genotype), Type 2M or,
c. Type 3 (VWF:Ag ≤3 IU/dL).
2. Diagnosis is confirmed by genetic testing and multimer analysis, documented in patient history or at 
screening.
3. Subject currently receiving on-demand treatment for whom prophylactic treatment is recommended 
according to standard of care at the center.
4. Has ≥3 documented spontaneous bleeds requiring VWF treatment during the past 12 months 
5. Availability of records to reliably evaluate type, frequency and treatment of bleeding episodes 
during 12 months of on-demand treatment prior to enrollment.
6. Subject is ≥18 years old at the time of screening and has a body mass index ≥15 but <40 kg/m2.
7. If female of childbearing potential, subject presents with a negative blood/urine pregnancy test at 
screening and agrees to employ adequate birth control measures for the duration of the study.
8. Subject is willing and able to comply with the requirements of the protocol.
Exclusion Criteria
Subjects who meet ANY of the following criteria are not eligible for this study:
1. The subject has been diagnosed with Type 2N VWD, pseudo VWD, or another hereditary or 
acquired coagulation disorder other than VWD (e.g., qualitative and quantitative platelet disorders 
or elevated prothrombin time (PT)/international normalized ratio [INR] 1.4).
2. The subject has received prophylaxis treatment in the 12 months prior to screening (including those 
who received treatment once a month for menorrhagia but were not treated for any other bleeds).
3. The subject is currently receiving prophylaxis treatment.
4. The subject has a history or presence of a VWF inhibitor at screening.
5. The subject has a history or presence of a FVIII inhibitor with a titer ≥0.4 BU (by Nijmegen 
modified Bethesda assay) or ≥0.6 BU (by Bethesda assay).
6. The subject has a known hypersensitivity to any of the components of the study drugs, such as to 
mouse or hamster proteins.
7. The subject has a medical history of immunological disorders, excluding seasonal allergic 
rhinitis/conjunctivitis, mild asthma, food allergies or animal allergies.
8. The subject has a medical history of a thromboembolic event.
9. The subject is HIV positive with an absolute Helper T cell (CD4) count 200/mm3.
10. The subject has been diagnosed with significant liver disease as evidenced by any of the following: 
serum alanine aminotransferase (ALT) 5 times the upper limit of normal; hypoalbuminemia; portal 
vein hypertension (e.g., presence of otherwise unexplained splenomegaly, history of esophageal 
varices).
11. The subject has been diagnosed with renal disease, with a serum creatinine level ≥2.5 mg/dL.
12. The subject has a platelet count <100,000/mL at screening.
13. The subject has been treated with an immunomodulatory drug, excluding topical treatment (e.g., 
ointments, nasal sprays), within 30 days prior to signing the informed consent.
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14. The subject is pregnant or lactating at the time of enrollment.
15. Patient has cervical or uterine conditions causing menorrhagia or metrorrhagia (including infection, 
dysplasia).
16. The subject has participated in another clinical study involving another investigational product (IP)
or investigational device within 30 days prior to enrollment or is scheduled to participate in another 
clinical study involving an IP or investigational device during the course of this study.
17. The subject has a progressive fatal disease and/or life expectancy of less than 15 months.
18. The subject is identified by the investigator as being unable or unwilling to cooperate with study 
procedures.
19. The subject has a mental condition rendering him/her unable to understand the nature, scope and 
possible consequences of the study and/or evidence of an uncooperative attitude.
20. The subject is in prison or compulsory detention by regulatory and/or juridical order
21. The subject is member of the study team or in a dependent relationship with one of the study team 
members which includes close relatives (i.e., children, partner/spouse, siblings and parents) as well 
as employees.
Delay criteria
1. If the subject presents with an acute bleeding episodes or acute illness (e.g., influenza, flu-like 
syndrome, allergic rhinitis/conjunctivitis, non-seasonal asthma) the screening visit will be postponed 
until the subject has recovered.
STATISTICAL ANALYSIS
Sample Size Calculation
The determination of the sample size for this study is not based on strict statistical considerations. The 
sample size of a subset of at least 15 subjects with severe VWD, 5 of whom must have Type 3 VWD, is 
based on the Guideline on the Clinical Investigation of Human Plasma Derived von Willebrand Factor 
Products (CPMP/BPWG/220/02).1
Planned Statistical Analysis
Primary Outcome Measure:
The statistical analysis will provide descriptive summaries.
The prospectively recorded annualized bleeding rate (ABR) of spontaneous (not related to trauma) bleeding 
episodes during prophylactic treatment will be assessed using negative binomial distribution. Mean ABR of 
spontaneous bleeding episodes together with the corresponding 95% two-sided confidence intervals (CIs) 
will be reported for the prospective counts as well as those based on historical data. 
Secondary Outcome Measures:
Efficacy:
For the number of infusions and for the total weight adjusted consumption of rVWF and ADVATE per 
month and per year during on-demand treatment for bleeding episodes, summary statistics will be carried 
out.
For the number (proportion) of subjects with reduction of ABR relative to historic ABR as well as for the 
number (proportion) of subjects with 0 bleeds, proportions and corresponding 95% two-sided CIs will be 
performed.
The cause, type, localization and severity of bleeding episodes will also be recorded and summarized.
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4. TABLE OF CONTENTS
1. STUDY PERSONNEL.................................................................................................. 2
1.1 Authorized Representative (Signatory) / Responsible Party .............................. 2
1.2 Study Organization................................................................................................. 2
2. SERIOUS ADVERSE EVENT REPORTING........................................................... 3
3. SYNOPSIS..................................................................................................................... 4
4. TABLE OF CONTENTS ........................................................................................... 10
5. LIST OF ABBREVIATIONS .................................................................................... 16
6. BACKGROUND INFORMATION .......................................................................... 20
6.1 Description of Investigational Product ............................................................... 20
6.2 Clinical Condition/Indication .............................................................................. 20
6.3 The Role of Prophylaxis in the Management of VWD...................................... 21
6.4 Population to be Studied ...................................................................................... 23
6.5 Findings from Nonclinical and Clinical Studies................................................. 23
6.5.1 Findings from Nonclinical Studies ............................................................... 24
6.5.1.1 Primary Pharmacodynamics ................................................................. 24
6.5.1.2 Safety Pharmacology.............................................................................. 24
6.5.1.3 Pharmacokinetics.................................................................................... 24
6.5.1.4 Toxicology................................................................................................ 25
6.5.2 Findings from Clinical Studies ..................................................................... 26
6.5.2.1 Study 070701 ........................................................................................... 26
6.5.2.2 Study 071104 ........................................................................................... 27
6.5.2.3 Study 071001 ........................................................................................... 28
6.5.2.4 Study 071401: Single Subject with von Willebrand Disease............... 29
6.6 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) 
to Human Subjects................................................................................................ 30
6.7 Compliance Statement.......................................................................................... 31
7. STUDY PURPOSE AND OBJECTIVES ................................................................. 31
7.1 Study Purpose ....................................................................................................... 31
7.2 Primary Objective................................................................................................. 31
7.3 Secondary Objectives ........................................................................................... 31
7.4 Exploratory Objectives......................................................................................... 32
7.4.1
........................................................................................................... 32
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8. STUDY DESIGN......................................................................................................... 32
8.1 Brief Summary...................................................................................................... 32
8.2 Overall Study Design............................................................................................ 32
8.3 Duration of Study Period(s) and Subject Participation .................................... 32
8.4 Outcome Measures ............................................................................................... 33
8.4.1 Primary Outcome Measure........................................................................... 33
8.4.2 Secondary Outcome Measures ..................................................................... 33
8.4.2.1 Efficacy .................................................................................................... 33
8.4.2.2 Safety........................................................................................................ 33
8.4.2.3 Pharmacokinetics.................................................................................... 34
8.4.2.4 Efficacy of the Treatment of Bleeding Episodes.................................. 34
8.4.3 Exploratory Outcomes Measure................................................................... 34
8.5 Randomization and Blinding............................................................................... 34
8.6 Study Stopping Rules............................................................................................ 34
8.7 Investigational Product(s) .................................................................................... 36
8.7.1 Packaging, Labeling, and Storage................................................................ 36
8.7.1.1 rVWF (Recombinant von Willebrand Factor)..................................... 36
8.7.1.2 rFVIII (Recombinant Factor VIII /ADVATE).................................... 36
8.7.2 Reconstitution................................................................................................. 36
8.7.3 Administration ............................................................................................... 36
8.7.4 Description of Treatment.............................................................................. 38
8.7.4.1 Baseline Visit (PK-Assessment Treatment).......................................... 38
8.7.4.2 Prophylaxis Initiation Treatment.......................................................... 38
8.7.4.3 Prophylaxis Treatment........................................................................... 39
8.7.4.4 Treatment of Bleeding Episodes............................................................ 42
8.7.5 Investigational Product Accountability ....................................................... 44
8.8 Source Data ........................................................................................................... 45
9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION .......... 45
9.1 Inclusion Criteria.................................................................................................. 45
9.2 Exclusion Criteria................................................................................................. 46
9.3 Delay Criteria........................................................................................................ 48
9.4 Withdrawal and Discontinuation ........................................................................ 48
10. STUDY PROCEDURES .......................................................................................... 49
10.1 Informed Consent and Enrollment ................................................................... 49
10.2 Subject Identification Code................................................................................ 49
10.3 Screening and Study Visits................................................................................. 49
10.3.1 Screening Visit.............................................................................................. 50
10.3.2 Baseline Visit - PK-Assessment Visit ......................................................... 50
10.3.3 Prophylaxis Initiation Visit......................................................................... 51
10.3.4 Treatment of Bleeding Episodes................................................................. 51
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10.3.5 Follow-Up Visits (1 Month ± 1 Week, 2 Months ± 1 Week, 
3 Months ± 2 Weeks, 6 Months ± 2 Weeks, 9 Months ± 2 Weeks)............ 52
10.3.6 Unscheduled Visits....................................................................................... 53
10.3.7 Study Termination Visit (12 Months ± 2 Weeks)...................................... 53
10.4 Medications and Non-Drug Therapies.............................................................. 54
10.5 Subject Diary....................................................................................................... 55
10.6 Subject Completion/Discontinuation ................................................................ 55
10.7 Procedures for Monitoring Subject Compliance ............................................. 56
11. ASSESSMENT OF EFFICACY AND PHARMACOKINETICS........................ 57
11.1 Assessment of Spontaneous Bleeding Episodes/Annualized Bleed Rate........ 57
11.2 Evaluation of ABR Before rVWF Prophylaxis and ABR Under rVWF 
Prophylactic Treatment........................................................................................ 58
11.3 Number of Infusions and Total Weight Adjusted Consumption of rVWF and 
ADVATE................................................................................................................ 58
11.4 Assessment of Efficacy for Treatment of Bleeding Episode ........................... 58
11.5 Pharmacokinetic Assessment............................................................................. 59
12. ASSESSMENT OF SAFETY................................................................................... 59
12.1 Adverse Events.................................................................................................... 59
12.1.1 Definitions..................................................................................................... 59
12.1.1.1 Serious Adverse Event.......................................................................... 59
12.1.1.2 Suspected Unexpected Serious Adverse Reaction (SUSAR)............. 60
12.1.1.3 Non-Serious Adverse Event ................................................................. 60
12.1.1.4 Unexpected Adverse Events................................................................. 61
12.1.1.5 Preexisting Disease................................................................................ 61
12.1.2 Assessment of Adverse Events.................................................................... 61
12.1.2.1 Severity .................................................................................................. 63
12.1.2.2 Causality................................................................................................ 63
12.1.2.3 Safety Reporting ................................................................................... 64
12.2 Urgent Safety Measures ..................................................................................... 65
12.3 Untoward Medical Occurrences........................................................................ 66
12.4 Non-Medical Complaints ................................................................................... 66
12.5 Medical, Medication, and Non-Drug Therapy History................................... 67
12.6 Physical Examinations........................................................................................ 67
12.6.1 Thromboembolic Events ............................................................................. 68
12.6.2 Anaphylaxis.................................................................................................. 68
12.7 Vital Signs............................................................................................................ 69
12.8 Electrocardiogram.............................................................................................. 70
12.9 Clinical Laboratory Parameters........................................................................ 70
12.9.1 rVWF and Endogenous FVIII Pharmacokinetics .................................... 70
12.9.2 Hematology and Clinical Chemistry.......................................................... 71
12.9.3 Immunology.................................................................................................. 72
12.9.3.1 Antibodies to VWF and FVIII............................................................. 72
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13.4.2.1 Efficacy .................................................................................................. 83
13.4.2.2 Efficacy of the Treatment of Bleeding Episodes................................ 83
13.4.2.3 Pharmacokinetic Analysis.................................................................... 83
13.4.2.4 Safety...................................................................................................... 86
13.5 Exploratory Outcome Measures........................................................................ 87
13.6 Planned Interim Analysis of the Study ............................................................. 87
14. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .................................... 87
15. QUALITY CONTROL AND QUALITY ASSURANCE...................................... 88
15.1 Investigator’s Responsibility.............................................................................. 88
15.1.1 Investigator Report and Final Clinical Study Report.............................. 88
15.2 Training ............................................................................................................... 88
15.3 Monitoring........................................................................................................... 88
15.4 Auditing ............................................................................................................... 88
15.5 Non-Compliance with the Protocol ................................................................... 89
15.6 Laboratory and Reader Standardization ......................................................... 89
16. ETHICS ..................................................................................................................... 89
16.1 Subject Privacy ................................................................................................... 89
16.2 Ethics Committee and Regulatory Authorities................................................ 89
16.3 Informed Consent ............................................................................................... 90
16.4 Data Monitoring Committee.............................................................................. 90
17. DATA HANDLING AND RECORD KEEPING................................................... 91
17.1 Confidentiality Policy ......................................................................................... 91
17.2 Study Documentation and Case Report Forms ............................................... 91
17.3 Document and Data Retention........................................................................... 91
18. FINANCING AND INSURANCE........................................................................... 92
19. PUBLICATION POLICY........................................................................................ 92
20. SUPPLEMENTS....................................................................................................... 93
20.1 Study Flow Chart................................................................................................ 93
20.2 Schedule of Study Procedures and Assessments.............................................. 94
20.3 Clinical Laboratory Assessments ...................................................................... 96
20.4 Contraceptive Methods for Female Subjects of Childbearing Potential....... 98
21. REFERENCES.......................................................................................................... 99
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22. SUMMARY OF CHANGES.................................................................................. 102
Tables
Table 1 rVWF Dosing Schedule Examples: Schedules, A, B, and C.............................. 39
Table 2 Criteria for Escalation Specific to Each Bleeding Indication............................. 40
Table 3 rVWF:RCo Dosing Recommendations for the Treatment of Bleeding Episodes 
Due to VWD ............................................................................................................. 44
Table 4 Efficacy Rating Scale.......................................................................................... 58
Table 5 Schedule of Study Procedures and Assessments ................................................ 94
Table 6 Clinical Laboratory Assessments........................................................................ 96
Figures
Figure 1 Study Design for Baxalta Clinical Study 071301.............................................. 93
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5. LIST OF ABBREVIATIONS
Abbreviation
Definition
ABR
Annualized bleeding rate
ADAMTS13
A Disintegrin And Metalloproteinase with a Thrombospondin type 1 motif, number 13
AE
Adverse event
ALT
Alanine aminotransferase
AP
Alkaline phosphatase
AST
Aspartate aminotransferase
AUC0-∞
Area under the plasma concentration /time curve from time 0 to infinity
AUC0-72h/Dose 
Area under the plasma concentration/time curve from time 0 to 72 hours 
post-infusion/dose
AUC0-∞/Dose
Area under the plasma concentration/time curve from time 0 to infinity/dose
AUC/Dose
Area under the curve/dose
AUMC
Area under moment curve
AUMC0-∞/Dose
Area under the first moment curve from time 0 to infinity/dose
aPTT
Activated partial thromboplastin time
B19V
Parvovirus B19
BILI
Bilirubin
BP
Blood pressure
BU
Bethesda Unit
BUN
Blood urea nitrogen
BW
Body weight
CAM
Cell adhesion molecule
CB
Collagen binding activity
CBC
Complete blood count
CD4
Helper T cell
CHO
Chinese hamster ovary
CI
Confidence interval
Cl
Chloride
CL
Clearance
Cmax
Maximum plasma concentration
CR
Creatinine
CTA
Clinical Trial Agreement
eCRF
Electronic case report form
DMC
Data monitoring committee
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Abbreviation
Definition
DIC
Disseminated intravascular coagulation
DVT
Deep vein thrombosis
EC
Ethics committee
ECG
Electrocardiogram 
EDC
Electronic Data Capture
EDTA
Ethylenediaminetetraacetic acid
ELISA
Enzyme-linked immunosorbent assay
FAS
Full analysis set
FVIII
Factor VIII
FVIII:C
Factor VIII clotting activity
GCP
Good Clinical Practice
GI
Gastrointestinal
Glu
Glucose
GPIb
Glycoprotein Ib
HAMA
Human anti- mouse antibodies
HAV
Hepatitis A virus
HB
Hepatitis B
HBs
Hepatitis B surface
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HEV
Hepatitis E virus
HIV
Human immunodeficiency virus 
HLA
Human leukocyte antigen
HRP
Horseradish peroxidase
IB
Investigator's brochure
ICH
International Council for Harmonisation
Ig
Immunoglobulin
INR
International normalized ratio
IP
Investigational product
IQR
Interquartil range
IR
Incremental recovery
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Abbreviation
Definition
i.v.
Intravenous
K
Potassium
k.o.
Knock out
LDH
Lactate Dehydrogenase
Na
Sodium
NMC
Non-medical complaint
NOAEL
No observed adverse effect level
MRI
Magnetic resonance imaging
MRT
Mean residence time
pdVWF
Plasma derived VWF product
pdVWF/FVIII
Plasma derived VWF product containing fractions of FVIII
PBAC
Pictorial Blood Assessment Chart
PCR
Polymerase Chain Reaction
PEF
Peak expiratory flow
PK
Pharmacokinetic
PKFAS
Pharmacokinetic Full Analysis Set
PKPPAS
Pharmacokinetic Per Protocol Analysis Set
PP
Per protocol 
PT
Prothrombin time
Q1, Q3
Quartile
rFVIII
Recombinant factor VIII
rVWF
Recombinant von Willebrand factor
RBC
Red blood cell count
SAE
Serious adverse event
SAER
Serious adverse event report
SDS-PAGE
Sodium dodecyl sulfate polyacrylamide gel electrophoresis
SIC
Subject identification code
sP-selectin
Soluble P-selectin
SUSAR
Suspected unexpected serious adverse reaction
T1/2
Elimination phase half life
TIA
Transient ischemic attack
Tmax
Time to reach the maximum concentration
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Abbreviation
Definition
TTP
Thrombotic thrombocytopenic purpura
ULMW
Ultra-large molecular weight 
ULN
Upper limit of normal
Vss
Volume of distribution at steady state
VTE
Venous thromboembolism (VTE)
VWD
von Willebrand disease
VWF
Von Willebrand factor
VWF:Ag
Von Willebrand factor antigen
VWF Ac
VWF activity measured INNOVANCE VWF Ac assay
VWF:CB
Von Willebrand Factor collagen binding
VWF:RCo
Von Willebrand factor: Ristocetin cofactor activity
WBC
White blood cell
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6. BACKGROUND INFORMATION
6.1 Description of Investigational Product
Baxalta US Inc. (hereafter referred to as Baxalta or sponsor) has developed a human 
recombinant von Willebrand Factor (rVWF), which is co-expressed with recombinant 
factor VIII (rFVIII) in a Chinese hamster ovary (CHO) cell line and separated during the 
subsequent downstream process. To address concerns regarding the risk of transmission 
of blood-borne pathogens that may be introduced by human plasma, no exogenously 
added raw materials of human or animal origin are employed in the cell culture, 
purification, or formulation of the final container product. The only proteins present in 
the final container product other than rVWF are trace quantities of murine 
immunoglobulin (IgG, from the immunoaffinity purification), host cell (i.e., CHO) 
protein, rFurin (used to further process rVWF). rVWF is intended for the treatment of 
von Willebrand disease (VWD).
rVWF has been developed under the Baxalta internal code BAX111 and is used as 
investigational product (IP) in this study. rVWF may be used with or without ADVATE 
(rFVIII) for the treatment of bleeding episodes (see Section 8.7.4.4). See Section 8.7 for 
further information on the IPs and their usage in this study. A detailed description of 
rVWF is also provided in the Investigator’s Brochure (IB).
rVWF was granted licensure in the United States in December 2015 under the brand 
name VONVENDI for the on-demand treatment and control of bleeding episodes in 
adults diagnosed with VWD; as of the date of this protocol VONVENDI is not yet 
available on the market.
6.2 Clinical Condition/Indication
Von Willebrand Factor (VWF) is a large multimeric glycoprotein with a molecular 
weight that varies from 500 to 20,000 kDa. VWF is normally found in plasma and 
produced in the alpha-granules of platelets and in endothelial cell organelles known as the 
Weibel-Palade bodies. VWF mediates platelet adhesion and aggregation at sites of 
vascular injury, one of the key functions in primary hemostasis. VWF also serves to 
stabilize coagulation factor VIII (FVIII), where FVIII is an essential cofactor of 
secondary hemostasis, which leads to fibrin clot formation.2 Qualitative and/or 
quantitative deficiencies of VWF lead to a highly variable bleeding diathesis known as 
VWD, the most common of the hereditary coagulation factor deficiencies. Penetrance of 
VWD is highly variable, with only a small fraction of mildly affected patients displaying 
clinical symptoms or a family history of a bleeding diathesis.
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The current biochemical-based classification distinguishes disorders arising from partial 
quantitative (type 1), qualitative (type 2), or virtually complete (type 3) deficiencies of 
VWF. Up to 70% of VWD patients are diagnosed with type 1 VWD, which may also be 
associated with minor functional defects in the molecule. In general, patients with type 1 
VWD display mild clinical symptoms. Approximately 20 to 30% of VWD patients are 
diagnosed with type 2 VWD. Type 2 VWD is further divided into 4 subtypes (A, B, N, 
and M), reflecting distinct classes of functional abnormalities. These defects result in 
abnormal functional and/or multimeric distribution patterns that facilitate their diagnosis. 
The bleeding diathesis is usually moderate and primarily affects the mucosal tissues. 
Type 2N VWD patients are sometimes misdiagnosed as mild hemophilia A. Finally, 
approximately 1% percent of VWD patients exhibit a total or near total absence of VWF, 
which is classified as type 3 VWD. The incidence of type 3 VWD is estimated at 
0.5-1.0 x 106. This type is also associated with a very low FVIII level (typically <5%) 
because the VWF carrier function for FVIII is lost. Replacement of VWF alone stabilizes 
endogenous FVIII, resulting in hemostatic levels within several hours post-infusion. 
Published results from studies of a plasma-derived VWF concentrate demonstrated an 
increase of FVIII at an approximate rate of 5.8 1 IU dL-1 h-1.3 Type 3 VWD patients 
display severe hemorrhagic symptoms with bleeding predominantly in mucosal tissues, 
muscle and joints. All VWD patients, particularly those with type 2 or type 3 VWD, are 
at an increased risk for life-threatening bleeding episodes.
6.3 The Role of Prophylaxis in the Management of VWD
The goals of long term prophylaxis in VWD are to maintain VWF and FVIII at sufficient 
levels to reduce the frequency and duration of bleeding episodes, the need for red blood 
cell transfusions, and the risk of complications, such as arthropathy.4 In contrast to 
hemophilia, routine prophylaxis is not as established in VWD, although prophylaxis for 
patients with severe VWD have already been in use in Sweden during the 1950s.5 In 
those early days of VWD treatment plasma FVIII concentrates containing VWF fractions 
were applied for replacement therapy, which then were followed by plasma derived VWF 
products containing fractions of FVIII (pdVWF/FVIII). 
A Swedish cohort including 37 patients with type 3 VWD under prophylactic median 
treatment of 11 years (range 2 to 45 years) was retrospectively analyzed.6;7 The 
doses used for prophylaxis, given once weekly for at least 45 weeks per year, were 
calculated based on 12 to 50 IU/kg body weight (BW) of FVIII clotting activity (FVIII:C)
which approximately corresponded to 24-100 IU/kg von Willebrand factor: Ristocetin 
cofactor activity (VWF:RCo) considering that mainly Haemate with a known 
VWF:RCo/FVIII:C ratio of about 2 was used. An escalation of doses from 1 to 3 dose 
levels was allowed depending on the frequency and severity of bleeding episodes. 
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The results demonstrate that under long-term prophylaxis the number of bleeds could be 
reduced dramatically. Whereas the median value for bleeds per year was about 10 before 
prophylaxis this value could be reduced to less than 1 bleed per year during prophylaxis.
The benefit of prophylaxis for such indications was retrospectively also demonstrated in a 
cohort of Italian patients including type 3, 2A, 2M and type 1 patients. Prophylaxis was 
started after severe gastrointestinal or joint bleeding episodes and completely prevented 
bleeding episodes in 8 of these 11 patients and largely reduced the need of blood 
transfusions in the remaining 3. A regimen of 40 IU rVWF:RCo/kg was applied every 
other day or twice a week. A prospective study on prophylaxis, the PRO.WILL study, has 
been initiated in Italy.8
The results of a prospective study investigating the prophylaxis in children and young 
adults showed a significantly reduced bleeding frequency and bleeding score (3 vs. 0.07; 
3 vs. 0. p<0.001) compared to the pre-prophylaxis values. The median dose was 
40 (20-47) IU/kg VWF:RCo administered mainly twice weekly in 23 patients, 3 times a 
week in 7 patients and 4 times a week in 2 children.9
The VWD Prophylaxis Network initiated the VWD International Prophylaxis (VIP) trial 
to investigate the role of prophylaxis in patients with severe VWD including Type 1, 2,
and 3. The dose of the factor replacement product was 50 IU /kgVWF:RCo. The 
frequency of the dose depended on the type of bleeding and could be increased from once 
weekly to twice weekly or 3 times per week. For the treatment of menorrhagia the dose of 
50 IU/kg VWF:RCo was given on the first day of menses for 2 cycles. The frequency 
could be increased to Day 1 and 2 for 2 cycles or to Day 1, 2, and 3 of menses.
The study contains both retrospective and prospective study components. Results from 
the retrospective study component were published, including 61 subjects on prophylactic 
regimen in the past 6 months prior to enrollment or subjects with a history of prophylaxis 
over at least 6 month.10 Differences in annualized bleeding rates (ABR) within 
individuals (during prophylaxis – before prophylaxis) were significant for those with 
primary indications of epistaxis (P = 0.0005), joint bleeding (P = 0.002) and 
gastrointestinal (GI) bleeding (P = 0.001). The difference in the group whose primary 
indication for treatment was abnormally heavy bleeding at menstruation (n = 4) was not 
significant (P = 0.25). The reduction of mucosal bleeding likely not only dependents on 
normal circulating levels of active VWF, but also on the presence of discrete 
concentrations of normal VWF inside the platelets and within endothelial matrices. The 
low subject number (n=4) and the treatment scheme for menorrhagia on Days 1, 2, and 3 
of menses which might represent rather on-demand than prophylactic treatment may also 
account for the outcome in this study. 
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Results from the prospective study component were reported recently.11 Eleven subjects 
completed the study. Six subjects had type 2A, and 5 subjects had type 3 VWD. 
Six subjects presented with epistaxis, 3 with GI bleeding, and 2 with joint bleeding. 
Seven subjects had dose escalation above the first level. Among the 10 subjects with 
evaluable bleeding log data, the use of prophylaxis decreased the median ABR from 25 to 
6.1 (95% confidence interval [CI] of the rate difference: -51.6 to -1.7), and the median 
ABR was even lower (4.0; 95% CI: -57.5 to -5.3) when the subjects reached their final 
dosing level. The authors concluded that this was the first prospective study to 
demonstrate that prophylaxis with VWF concentrates is highly effective in reducing 
mucosal and joint bleeding rates in clinically severe VWD.
The results of the VIP study and previous investigations suggest that VWD patients with 
recurrent bleeding episodes and severe menorrhagia will benefit from a prophylactic 
VWF replacement therapy. There is evidence that up to 40% of patients with type 3 
VWD experience joint bleeding which can lead to hemophilic arthropathy. Other 
potential indications for prophylaxis include patients with type 2A or 2B VWD with 
recurrent gastrointestinal bleeding, menorrhagia or frequent epistaxis.4 Long-term 
prophylaxis for most patients with type 3 VWD and in some patients with type 1 or 2 
VWD, depending on the pattern of bleeding, may be the treatment option of choice.
Although the main experience with long-term prophylaxis is with secondary prophylaxis, 
primary prophylaxis starting at young age is recommended to prevent arthropathy in 
patients with severe VWD.12
However, further studies are needed to develop evidence-based guidelines for 
prophylactic treatment in VWD.
6.4 Population to be Studied
A total of approximately 18 eligible, adult subjects to achieve approximately 15 evaluable 
subjects with severe VWD are planned to be enrolled, of which a subset of at least 
5 subjects will have type 3 VWD. Enrolled subjects (i.e., subjects who have signed the 
informed consent form) will be eligible to participate in the study if they meet all of the 
inclusion criteria (see Section 9.1) and none of the exclusion criteria (see Section 9.2).
6.5 Findings from Nonclinical and Clinical Studies
The following summarizes the key findings from relevant nonclinical studies as well as 
from the completed clinical studies 070701 (Phase 1 PK and safety in VWD), 071001
(Phase 3 safety and efficacy in the treatment of bleeding episodes in VWD), 071104
(Phase 1 safety and PK in hemophilia A), and 071401 (Phase 3, expanded access in a 
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single subject with VWD). Potential risks and efficacy of rVWF:ADVATE are 
summarized in the following sections. For additional information on nonclinical and 
clinical Phase 1 results refer to the rVWF IB.
6.5.1 Findings from Nonclinical Studies
6.5.1.1 Primary Pharmacodynamics
Efficacy of rVWF combined with ADVATE was shown in VWD animal models, which 
have also low endogenous FVIII levels. Time to occlusion and stable thrombus formation 
was assessed in the carotid occlusion model in VWD mice. The results demonstrated that 
rVWF in combination with ADVATE acted efficiently in a dose-dependent manner and 
had higher efficacy than rVWF alone or plasma derived (pd)VWF. These results were 
confirmed in an additional study assessing blood loss and survival in a tail tip bleeding 
model in VWD mice. In a VWD dog rVWF stabilized canine FVIII in the circulation and 
significantly reduced the bleeding time. 
6.5.1.2 Safety Pharmacology
The anaphylactoid and thrombogenic potential of the co-infusion of ADVATE and rVWF 
and the co-infused product’s effects on blood pressure, cardiac and respiratory function 
and parameters of coagulation activation were investigated in 4 in vivo studies in 
different animal models. Safety pharmacology studies in rats, guinea pigs, rabbits, and 
dogs revealed no risks for anaphylactoid and thrombogenic potential of ADVATE in 
combination with rVWF. All observations in safety pharmacology studies are considered 
to lie within the biological variability of animal models or occurred due to known 
species-specific anaphylactoid effects of excipients.
6.5.1.3 Pharmacokinetics
Pharmacokinetic studies of both rVWF alone and combined with human rFVIII 
(rVWF+ADVATE) were conducted in VWD mice, VWD dogs, VWD pigs, rats, and 
cynomolgus monkeys. Human rVWF stabilized the endogenous FVIII in VWD mice, 
VWD pigs, and VWD dogs. Furthermore, the hypotheses that the area under the curve 
(AUC) with rVWF alone and rVWF+ADVATE is not inferior to the AUC with 
pdVWF (Haemate P) was tested and confirmed statistically in normal rats. The
pharmacokinetic (PK) characteristics of ADVATE were not affected by co-administration 
of rVWF in cynomolgus monkeys. The PK data in the FVIII knock out (k.o.) mice model 
are inconclusive and might not be relevant for the clinical situation. However, a 
stabilizing effect of VWF on FVIII could be shown in a double knock out model in a dose 
dependent manner.
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6.5.1.4 Toxicology
Single dose toxicity studies were conducted in C57BL/6J-mice, VWD mice, rats, rabbits,
and cynomolgus monkeys. Rats, rabbits, and cynomolgus monkeys showed no signs of
toxicity. Signs of microthrombosis, an exaggerated pharmacological effect, were
observed in mice. Mice are not capable of sufficiently cleaving the rVWF subunit as
murine disintegrin and metalloproteinase with a thrombospondin type 1 motif, number 13
(ADAMTS13) does not decrease the ultra-large molecular weight multimers of rVWF.13
The observed symptoms of microthrombosis are interpreted as a species-specific 
exaggerated pharmacological effect. Studies evaluating the safety of repeated 
administration of rVWF with or without ADVATE (daily over 14 days) were performed 
in a rodent (rat) and non-rodent (cynomolgus monkey) species. Reversible signs of 
exaggerated pharmacological effects (regenerative anemia, thrombocytopenia, and 
treatment-related histopathologic changes in the heart, liver, and spleen) were observed in 
rats that were administered 1400 U VWF:RCo/kg /day + 1080 IU ADVATE/kg/day 
intravenously once daily for 14 days. Also, these findings are interpreted as a 
species-specific exaggerated pharmacological effect due to the low susceptibility of 
human rVWF to cleavage by rodent ADAMTS13.13 No toxicologically relevant changes 
were evident for clinical observations, body weight, feed consumption, ophthalmology, 
urinalysis, coagulation, and serum chemistry parameters, platelet aggregation, and gross 
pathology. rVWF combined with ADVATE was well tolerated in cynomolgus monkeys
after daily intravenous (i.v.) (bolus) administration of 100 U VWF:RCo/kg rVWF 
combined with 77 IU/kg ADVATE over a period of 14 days. No adverse effects could be 
detected in this species. There were no signs of hemolysis, thrombosis, or 
thrombocytopenia after repeated intravenous application of rVWF with or without 
ADVATE. Therefore, 100 U VWF:RCo/kg/day rVWF with or without 77 IU/kg 
ADVATE was considered the no observed adverse effect level (NOAEL) in this study, 
which was the highest dose tested. Anti-drug antibodies, however, were formed in both 
species and resulted in a significant reduction in drug exposure after 14 applications as 
compared to a single application. These antibodies substantially reduced the systemic 
exposure to the test substance as compared to a single dose administration. No 
adverse effects due to antibody formation were observed in both species.
rVWF combined with ADVATE was well tolerated locally and no genotoxic potential 
was evident after 2 in vitro and 1 in vivo genotoxicity study. A study on the influence of 
co-administration of VWF and ADVATE on the immunogenicity of ADVATE in 
3 different hemophilic mouse models (E17 hemophilic Balb/c mice, E17 hemophilic 
C57BL/6J mice, and E17 hemophilic human F8 transgenic mice) showed that rVWF does 
not negatively impact the immunogenicity of ADVATE in any of the three different 
hemophilic mouse models. 
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6.5.2 Findings from Clinical Studies
Two phase 1 studies with rVWF either alone or co-administrated with ADVATE in 
patients with VWD 070701 and Hemophilia A 071104 and 1 phase 3 study with rVWF in 
patients with VWD 071001 have been conducted and the results were analyzed and 
evaluated. Details on study design, populations enrolled, and safety and efficacy 
outcomes of these 2 phase 1 studies are presented in Section 6.5.2.1 and Section 6.5.2.2,
and the phase 3 study in Section 6.5.2.3. Information on a single subject with VWD in 
Study 071401 is presented in Section 6.5.2.4.
Refer to rVWF IB for periodic updates from other rVWF studies. 
6.5.2.1 Study 070701
Phase 1 clinical study 070701 was a multicenter, controlled, randomized, single-blind,
prospective 3-step, dose escalation study to investigate safety, tolerability, and PK of 
rVWF combined at a fixed ratio with ADVATE (VWF:RCo/FVIII:C of 1.3 ± 0.2:1) in 
adults with severe VWD.14 Subjects were enrolled in sequential cohorts in a dose 
escalating manner: Cohort 1, 2, and 3 received a single intravenous infusion of 
rVWF:ADVATE at the following doses: 2 IU/kg VWF:RCo (Cohort 1), 7.5 IU/kg 
VWF:RCo (Cohort 2), and 20 IU/kg VWF:RCo (Cohort 3). Subjects in Cohort 4 received 
a single intravenous infusion of rVWF:ADVATE and pdVWF/ADVATE at 50 IU/kg 
VWF:RCo in random order.
The primary endpoint was the tolerability and safety after single dose injections of 
rVWF:ADVATE at 2, 7.5, 20, and 50 IU/kg VWF:RCo for up to 30 days after the last IP 
infusion. The data generated in this phase 1 study suggest that rVWF:ADVATE up to the 
highest investigated dose of 50 IU/kg VWF:RCo is well tolerated and safe in adults with 
severe VWD. No thrombogenic risk or TTP-like syndrome was observed, and no 
neutralizing antibodies to VWF or FVIII were identified. There were no deaths or other 
serious adverse reactions, and no infusions were interrupted or stopped due to an AE. 
Overall, the reported AE profile was similar between the recombinant and 
plasma-derived concentrates.
Secondary endpoints were the PK assessment of VWF:RCo, von Willebrand factor 
antigen (VWF:Ag) and multimeric composition of rVWF as well as FVIII:C at 
standardized time points after single injections of rVWF:ADVATE and pdVWF:FVIII. 
The median VWF:RCo half-life (T1/2) of rVWF at the 50 IU/kg dose was 16 hours. 
T1/2 with pdVWF:FVIII at the same dose level appeared shorter at 12.58 hours, however, 
the limits of the 90% CI were similar (11.73 to 17.7 hours vs. 11.87 to 18.03 hours). 
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The median half-lives of VWF:RCo were shorter with the lower investigated doses: 
7.13 hours and 13.23 hours with the 7.5 IU/kg and 20 IU/kg doses, although these data 
were derived from a much smaller number of subjects.
In consequence of the missing ADAMTS13 cleavage, ultra-large molecular weight 
(ULMW) multimers are contained in the rVWF final product. The immediate cleavage of 
these ultra-large multimers by ADAMTS13 upon release into the circulation could be 
demonstrated applying sodium dodecyl sulfate polyacrylamide gel electrophoresis
(SDS-PAGE)/Immunoblot with polyclonal anti-VWF antibodies to detect the resulting 
rVWF subunit cleavage fragments.
Overall the data generated in this phase 1 study suggest that rVWF:ADVATE is well 
tolerated and safe in adults with severe VWD.
6.5.2.2 Study 071104
This study was a prospective, uncontrolled, non-randomized, multicenter proof of 
concept study to assess safety and PK of the addition of rVWF to ADVATE treatment in 
12 evaluable subjects with severe hemophilia A. All subjects underwent 3 PK analyses: 
the first after infusion with ADVATE alone, the second after infusion with ADVATE
plus 10 IU/kg rVWF and the third after infusion with ADVATE plus 50 IU/kg rVWF. 
The PK analysis was performed at intervals of approximately 8 to 14 days. Before each 
infusion for PK assessment, there was a wash-out period of at least 5 days and the 
subjects were not actively bleeding. 
Primary outcome measures indicate that co-administration of rVWF slightly sustain 
ADVATE activity with the highest observed ADVATE half-life of 13.74 h (CI 
11.44 to 16.52) after co-infusion of 50 IU/kg ADVATE plus 50 IU/kg rVWF:RCo.
The highest improvement in ADVATE circulating half-life was observed in subjects with 
VWF:Ag levels below 100% which indicates an association between baseline VWF:Ag 
levels and ADVATE half-life increase. 
No treatment related adverse events (AEs) or serious adverse events (SAEs) were 
reported. No subject withdrew due to an AE and there were no deaths. No binding 
antibodies to VWF, CHO, and rFurin were detectable in the confirmatory assay and no 
signs of a hypersensitivity to rVWF or ADVATE antigen were observed. Laboratory 
values over time did not indicate any potential safety risk for hemophilia A patients 
treated with rVWF and ADVATE in combination.
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In summary, the data indicate that rVWF co-administered with ADVATE up to the 
highest dose of 50 IU/kg VWF:RCo is well tolerated and safe in hemophilia A patients. 
6.5.2.3 Study 071001
This was a phase 3, multicenter, open-label, part-randomized clinical study to assess the 
PK, safety, and efficacy of rVWF:rFVIII and rVWF in the treatment of bleeding episodes 
in adult subjects with severe type 3 and severe non-type 3 VWD.15 A total of 49 subjects 
were enrolled (signed informed consent) and screened, 18 subjects were randomized 
(Arm 1 and Arm 2 [PK 50] only), 37 subjects were treated with IP (all study arms), and 
30 subjects completed the study. 
The study consisted of 2 parts (Part A and Part B). Part A consisted of PK assessments 
alone (Arm 2: PK50 only [without treatment of bleeding episodes]), or PK assessments 
(Arm 1: PK50 and Arm 3: PK80) plus on-demand treatment period(s) of 6 months for 
bleeding episodes, or on-demand treatment for bleeding episodes only (Arm 4). Subjects 
receiving treatment for PK assessments and/or bleeding episodes in Part A were to be 
entered into Part B to continue on-demand treatment for bleeding episodes for 
6 additional months for a total of 12 months in the study. 
The primary outcome measure was the number of subjects with “treatment success” 
(extent of control of bleeding episodes), which was defined as a mean efficacy rating 
score of <2.5 for a subject’s IP-treated bleeding episodes during the study. The rate of 
subjects with treatment success was 100% (Clopper-Pearson exact 90% CI: 84.7 to 
100.0) for bleeds where the assessments were made prospectively and excluding GI 
bleeds. Sensitivity analyses confirmed the results of the primary analysis. 
Crossover results at 50 IU/kg VWF:RCo showed that the PK profile for rVWF 
VWF:RCo was independent of administration alone or with rFVIII (ADVATE) (T1/2:
19.4 hours for rVWF and 16.6 hours for rVWF:rFVIII; IR: 1.8 U/dL per IU/kg infused 
for both rVWF and rVWF:rFVIII; MRT: 26.7 hours for rVWF and 25.2 hours for 
rVWF:rFVIII). FVIII levels increased substantially with a median peak at 24 hours of 
111.0 U/dL for rVWF:rFVIII and 86.0 U/dL after rVWF alone, indicating that rVWF 
induces a sustained increase in endogenous FVIII activity. The rVWF PK profile was 
comparable at 50 IU/kg and 80 IU/kg VWF:RCo, and repeated PK at 80 IU/kg 
VWF:RCo showed close agreement between pretreatment and end-of-study results.
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Further analysis of the PK data from the 071001 study supports the initial use of 50 IU/kg 
twice weekly for prophylaxis dosing in the present study for those subjects who are 
moving from on-demand to prophylaxis. Using 50 IU/kg for PK measurements, subjects 
in the 071001 study exhibiting a T1/2 for rVWF of 14, 16, or 19 hours had BAX111 
plasma concentrations at 72 hours after administration of 2.55, 4.01, and 6.49% above 
baseline, respectively, and plasma concentrations at 96 hours after administration of 0.78, 
1.40, and 2.71% above baseline, respectively. Subjects who have significant spontaneous 
bleeding while on twice weekly prophylaxis will have their regimen increased to 
50 IU/kg 3 times per week (see Section 8.7.4.2).
A total of 125 AEs occurred in 25/37 (67.7%) subjects (62/318 infusions [19.5%]) during 
or after infusion with IP. Of these, 116/125 were non-serious (all mild or moderate; none 
were severe), and 9 SAEs were reported in 7 subjects. Of 125 total AEs, 38 were 
temporally associated with IP; 8 AEs were considered causally related to IP: 
6 non-serious related AEs (tachycardia, infusion site paraesthesia, electrocardiogram 
[ECG] t-wave inversion, dysgeusia, generalized pruritis, and hot flush) occurred in 
4 subjects, and 2 related SAEs (chest discomfort and increased heart rate) occurred in 
1 subject. No deaths occurred during this study. 
None of the subjects developed anti-VWF or anti-FVIII neutralizing antibodies and no 
binding antibodies to VWF or rFurin, or antibodies against CHO protein or anti-Murine 
IgG were observed. No clinical or subclinical signs or symptoms of a thrombogenic event 
were observed in this study. Following an initial increase in ultralarge VWF multimers 
after administration of rVWF, a notable decrease in the proportion of large VWF 
multimers occurred between 12 and 24 hours post infusion, due to degradation by the 
endogenous ADAMTS13 followed by a continued decline until the end of the 96-hour 
follow-up period. 
Overall, the data support the safe and effective use of rVWF with or without FVIII 
(ADVATE) in the treatment of bleeds in patients with VWD.
6.5.2.4 Study 071401: Single Subject with von Willebrand Disease
One subject who exhibited allergic reactions to currently marketed pdVWF products was 
treated in the single-subject study 071401 with rVWF only for the bleed treatment of 
continued hematuria, and for biopsy and surgical resection of a left-kidney mass.
For the initial rVWF infusion, the subject received a test dose of 5% of the total dose of 
60 IU/kg rVWF:RCo at an infusion rate of 1 mL/min. After a 10 to 15-minute 
observation period, no adverse symptoms or signs were noted and the subject received 
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the remaining 95% of the total dose. The subject was monitored for any signs of an 
allergic reaction, and none were noted. Treatment with rVWF every 12 to 24 hours was 
to continue at the discretion of the investigator based on VWF levels and clinical 
symptomatology. The subject had an excellent response and recovery, which allowed for 
daily dosing of rVWF and, within 24 hours, the subject’s bleeding had stopped. Daily 
dosing of rVWF was maintained and the subject received his last dose on 
.
The subject also received rVWF for 7 days for prophylaxis for surgery (surgical resection 
of a left-kidney mass). The subject experienced no hemorrhagic complications and no 
AEs that were considered related to the use of rVWF.
6.6 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) to
Human Subjects
Current treatment of VWD patients relies on desmopressin and VWF products 
manufactured from pooled human plasma. Human VWF produced by recombinant 
technology could offer a new perspective in treatment of VWD. The benefit for the 
individual subject is anticipated to be significant during this clinical study. He/she may 
benefit from a product that minimizes excessive FVIII administration. Variations in VWF 
multimeric composition may lead to variability with respect to treating or preventing 
bleeds in VWD subjects, especially mucosal bleeds which are especially problematic. 
rVWF product manufactured by Baxalta consistently contains ultra-large molecular 
weight (ULMW) VWF multimers due to the fact that the product has not been exposed to 
ADAMTS13. The initial presence of these ULMW VWF multimers, which are 
subsequently cleaved by the subject’s endogenous ADAMTS13, may result in improved 
platelet and collagen binding and therefore provide more predictable treatment outcomes.
By using a recombinant product, the risk of contamination with blood derived viruses or 
variant Creutzfeldt-Jakob Disease associated with the use of products of human or animal 
origin has been virtually eliminated. At this stage of product development, the key 
societal benefit is a better understanding of advanced treatment options for VWD and 
enhanced product availability.
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These benefits outweigh the following potential risks of rVWF:

allergic-type hypersensitivity reactions as with any intravenous protein product

the occurrence of thromboembolic events

the development of neutralizing antibodies to VWF
Refer to the IB for further details on benefits and risks of the IP.
6.7 Compliance Statement
This study will be conducted in accordance with this protocol, the International Council 
for Harmonisation Guideline for Good Clinical Practice E6 (ICH GCP, April 1996), 
Title 21 of the US Code of Federal Regulations (US CFR), the EU Directives 2001/20/EC 
and 2005/28/EC, and applicable national and local regulatory requirements.
7. STUDY PURPOSE AND OBJECTIVES
7.1 Study Purpose
The purpose of this phase 3 study is to investigate the efficacy and safety, including 
immunogenicity and thrombogenicity, and 
of 
prophylactic treatment with rVWF in subjects with severe VWD.
7.2 Primary Objective
The primary objective of this study is to prospectively evaluate the annualized bleeding 
rate (ABR) for spontaneous bleeding episodes while on prophylactic treatment with 
rVWF and to compare it to the subject’s historical ABR for spontaneous bleeding 
episodes during on-demand treatment. 
7.3 Secondary Objectives
Secondary Objectives are:

Additional efficacy assessments of prophylactic treatment

Safety and immunogenicity

Pharmacokinetics

Efficacy of the treatment of bleeding episodes
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7.4 Exploratory Objectives
7.4.1
 
8. STUDY DESIGN
8.1 Brief Summary
8.2 Overall Study Design 
This is a prospective, open label, uncontrolled, non-randomized, international, 
multicenter phase 3 study to evaluate efficacy, safety, including immunogenicity and 
thrombogenicity, and 
of a prophylactic treatment regimen with rVWF in patients 
with severe VWD. 
Subjects transitioning either from on-demand treatment or from prophylactic treatment 
will be infused twice weekly with BAX 111 (rVWF) at doses of 50 ± 10 IU/kg 
rVWF:RCo. The dose may be adjusted within this range based on the PK data, subject’s 
history of bleeding episodes, and the results from clinical and laboratory assessments (see 
Section 8.7.4.2).
The overall duration of prophylactic treatment per subject will be 12 months.
During this period any bleeding episodes requiring substitution therapy with VWF 
concentrate to control bleeding will be treated with rVWF with or without ADVATE. 
The dose will be according to the bleeding severity and it will be adjusted to the clinical 
response (see Section 8.7.4.4.2).
The overall study design is illustrated in Figure 1.
8.3 Duration of Study Period(s) and Subject Participation
The overall duration of the study is approximately 22 months from study initiation 
(i.e., first subject enrolled) to study completion (i.e., last subject last visit). The subject 
participation period is approximately 15 months from enrollment to completion (i.e, last 
study visit), unless the subject is prematurely discontinued.
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Subjects will be offered the option to continue to receive BAX111 in a long-term 
continuation study.
8.4 Outcome Measures
8.4.1 Primary Outcome Measure
The primary outcome measure is
Efficacy:
Prospectively recorded ABR for spontaneous (not related to trauma) bleeding 
episodes during prophylactic treatment with rVWF and the subjects’ historical 
ABR for spontaneous bleeding episodes during on-demand treatment.
8.4.2 Secondary Outcome Measures
8.4.2.1 Efficacy

Number (proportion) of subjects with reduction of ABR for spontaneous (not 
related to trauma) bleeding episodes during prophylaxis relative to the subjects’
own historical ABR during on-demand treatment

Number (proportion) of subjects with 0 bleeds during prophylactic treatment with 
rVWF

Number of infusions and total weight adjusted consumption of rVWF and
ADVATE per month and per year during on-demand treatment
8.4.2.2 Safety

AEs

Incidence of thromboembolic events 

Incidence of severe hypersensitivity reactions

Development of neutralizing antibodies to VWF and FVIII

Development of total binding antibodies to VWF and FVIII

Development of antibodies to Chinese hamster ovary (CHO) proteins, mouse 
immunoglobulin G (IgG) and rFurin
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8.4.2.3 Pharmacokinetics

Incremental recovery (IR), terminal half-life (T1/2), mean residence time (MRT), 
area under the curve/dose (AUC/dose), area under moment curve/dose 
(AUMC/dose), volume of distribution at steady state (Vss) and clearance (CL) 
based on Von Willebrand factor Ristocetin cofactor activity (VWF:RCo), Von 
Willebrand factor antigen (VWF:Ag), Von Willebrand collagen binding activity 
(VWF:CB), INNOVANCE VWF Ac (exploratory assay) and time course 
(72 hours) of FVIII clotting activity (FVIII:C) levels.
8.4.2.4 Efficacy of the Treatment of Bleeding Episodes

Number of infusions of rVWF and ADVATE (rFVIII) per spontaneous bleeding 
episode

Number of infusions of rVWF and ADVATE (rFVIII) per traumatic bleeding 
episode

Weight-adjusted consumption of rVWF and ADVATE (rFVIII) per spontaneous 
bleeding episode

Weight-adjusted consumption of rVWF and ADVATE (rFVIII) per traumatic 
bleeding episode

Overall hemostatic efficacy rating at resolution of bleed 
8.4.3 Exploratory Outcomes Measure
 
8.5 Randomization and Blinding
This is a non-randomized open-label, active treatment clinical study. 
8.6 Study Stopping Rules 
This study will be stopped if 1 or more of the following criteria are met:
1. Two subjects develop a thromboembolic event
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2. Two subjects develop severe hypersensitivity reactions (e.g., clinically significant 
localized urticaria, generalized urticaria, wheezing, or anaphylaxis); or infusion 
related tightness of the chest or hypotension
3. Two subjects develop signs and symptoms, suggestive of a thrombotic 
thrombocytopenic purpura-like syndrome (subjects with type 2B VWD developing 
thrombocytopenia or changes of the platelet count as described below, will be 
evaluated on case by case, whether they need to be accounted for), such as 

A drop in platelet count of 50% of subject’s baseline or less than 100.000 per 
microliter

3-fold increase in lactate dehydrogenase (LDH)

Impaired renal function as determined by: 

Creatinine increase of 1.5-fold from baseline levels

Blood urea nitrogen (BUN) increase from normal levels to a level 
> 60 mg/dL
4. Any subject has abnormal liver function:
Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) 
elevations >5 times upper limit of normal (ULN) in the absence of a concomitant 
bilirubin increase
ALT and/or AST elevations >3 times ULN in the presence of a total bilirubin 
increase >2 times ULN or an international normalized ratio (INR) >1.5 without 
findings of cholestasis or other alternate etiology to explain the elevations 
(i.e., “Hy’s Law cases”)
ALT and/or AST elevations >3 times ULN with the appearance of fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or 
eosinophilia (>5%)
5. Two subjects develop rVWF neutralizing antibodies
The study may be stopped at any time by the sponsor.
The sponsor ultimately will decide whether to terminate, temporarily halt or modify the 
study based on the data monitoring committee (DMC) recommendation.
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8.7 Investigational Product(s)
8.7.1 Packaging, Labeling, and Storage
8.7.1.1 rVWF (Recombinant von Willebrand Factor)
rVWF will be packaged in boxes with 2 glass vials, one containing the lyophilized 
rVWF, and the second vial containing the diluent. Further details are provided in the IB 
and Pharmacy Manual. The rVWF label will include, at a minimum, the actual 
VWF:RCo potency and the date of expiration.
rVWF should be refrigerated (2-8°C [36-46°F]) in lyophilized form. Deviations from the 
storage condition have to be communicated and followed up with the sponsor.
Inadequately stored product will have to be placed in quarantine and may only be used 
after written investigational product administration authorization by the sponsor. After
removal of the product from the refrigerator the product must not be returned to the 
refrigerator and has to be used immediately. rVWF must not be used beyond the 
expiration date printed on the vial. Avoid freezing at all times.
8.7.1.2 rFVIII (Recombinant Factor VIII /ADVATE)
ADVATE will be packaged in boxes with 2 glass vials, one containing the lyophilized 
rFVIII, and the second vial containing the diluent. Further details are provided in the IB 
and Pharmacy Manual. The ADVATE label will include, at a minimum, the actual 
FVIII:C potency and the date of expiration. 
ADVATE should be refrigerated (2-8°C [36-46°F]) in powder form and should not be 
used beyond the expiration date printed on the vial. Deviations from the storage condition 
have to be communicated and followed up with the sponsor. Inadequately stored product 
will have to be placed in quarantine and may only be used after written investigational 
product administration authorization by the sponsor. After removal of the product from 
the refrigerator the product must not be returned to the refrigerator and has to be used 
immediately. Avoid freezing at all times.
8.7.2 Reconstitution
The reconstitution procedures for both rVWF and ADVATE products are detailed in the 
Pharmacy Manual. 
8.7.3 Administration
Following reconstitution, rVWF and ADVATE (in case of bleeding episode treatment) 
should be administered to study subjects at room temperature and within 3 hours of 
reconstitution. The reconstituted rVWF and ADVATE, should be inspected for 
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particulate matter and discoloration prior to administration, whenever the solution and 
container permit. The solution should be clear and colorless in appearance. If not, do not
administer the product. Plastic syringes provided by the sponsor must be used since 
coagulation factors tend to stick to the surface of glass syringes.
Investigational product infusions should be given at a rate which should not exceed 
4 mL/minute. The investigator/ subject shall ensure that no visible residual volume 
remains in the syringe(s) and that the complete content is administered. Upon completion 
of the infusion, the butterfly catheter should be flushed with at least 2 mL of saline 
solution. In case of a (central) venous access device, the flush should be with at least 
10 mL of saline solution. The IP infusions should be administered over a duration of 2 to 
15 minutes, depending on the volume.
Only the actual potencies of rVWF and ADVATE as stated on the vial labels and 
described in the Pharmacy Manual should be used. A variation of up to 10% of the 
intended dose for prophylactic infusions and of the intended dose for treatment of 
bleeding episodes is permissible and the exact dose should be recorded on the Case 
Report Form (CRF).
At study visits where recovery analysis is being done, vials with the same lot numbers 
should be used throughout the PK IP infusion per subject.
For treatment of bleeding episodes there are 2 options for the preparation of rVWF and 
ADVATE for infusion if needed. 
Preferably sequential administration will be done: separate syringes of the appropriate 
dose of rVWF and ADVATE will be prepared for sequential infusion. rVWF should be 
infused first sequentially followed preferably within 10 minutes by infusion of ADVATE. 
Only the actual potencies of rVWF and ADVATE as stated on the vial labels and 
described in the Pharmacy Manual should be used. 
Alternatively, premixed solutions can be administered: rVWF and ADVATE will be an 
i.v. admixture in a single syringe to achieve the appropriate dose. The contents of each 
vial of rVWF or ADVATE can be drawn into 1 syringe by using a separate unused 
reconstitution device as described in the Pharmacy Manual. 
The final dose of rVWF:ADVATE should be at a ratio of 1.3:1 ± 0.2.
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8.7.4 Description of Treatment
8.7.4.1 Baseline Visit (PK-Assessment Treatment)
The first IP infusion for PK assessment should be within 42 days after the completion of 
screening procedures and confirmation of eligibility.
At the baseline visit the subjects will receive a dose of 50 ± 5 IU/kg rVWF:RCo for PK 
assessment. Blood samples will be drawn within 30 minutes pre-infusion, and at 7 time 
points post-infusion (30 5 minutes, 60 5 minutes, 6 1 hours, 12 1 hours, 
24 2 hours, 48 2 hours, 72 2 hours). 
Subjects previously enrolled in rVWF studies 070701 or 071001 and having previously 
undergone PK assessments in these studies are required to repeat the PK assessment due 
to different dose and time points used in these former studies (see Section 12.9.1 and 
Section 20.3). A washout period of at least 5 days is required prior to infusion of rVWF 
for PK assessment for subjects previously treated with rVWF.
Subjects who participated and had a major procedure performed in the surgery study 
071101 will not need an additional PK assessment. Identical PK dose and time points are 
used for both studies 071101 and 071301. Subjects who participated and had a minor 
procedure performed in the surgery study 071101 will need a PK assessment.
8.7.4.2 Prophylaxis Initiation Treatment 
The prophylaxis initiation treatment visit will coincide with the 72 2 h PK assessment. 
At this visit subjects will receive their prophylaxis initiation dose of 50 ± 10 IU/kg
rVWF:RCo after the blood draw for the 72 2 hours post-infusion PK assessment. If 
subjects do not need an additional PK assessment (e.g., subject has participated in the 
surgery study 071101 and had a major procedure performed), subjects must receive the IP 
for prophylaxis initiation treatment within 42 days after screening and confirmation of 
eligibility. The exact standard prophylaxis dose may range between 40 and 60 IU/kg 
based on:

available historical PK data

type and severity of bleeding episodes the subject has experienced in the past and

monitoring of appropriate clinical and laboratory measures
Dose adjustments during the continued prophylactic treatment are described in
Section 8.7.4.3.
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The subject will be trained on IP reconstitution and administration and may then qualify
for home treatment (see Section 8.7.4.3.2). Refer to Table 5 for study procedures and
Table 6 for clinical laboratory assessments.
8.7.4.3 Prophylaxis Treatment
The standard prophylactic dose is 50 ± 10 IU/kg rVWF:RCo. All subjects will initially
receive BAX111 (rVWF) twice per week (Table 1, Schedule A). Examples of all dosing 
schedules are provided in Table 1.
Table 1
rVWF Dosing Schedule Examples: Schedules, A, B, and C
Example
M
T
W
Th
F
Sat
Sun
M
T
W
Th
F
Sat
Sun
Schedule A
X
X
X
X
Schedule B
X
X
X
X
X
X
Dose and frequency adjustments will be agreed with the sponsor in advance unless it 
constitutes an urgent safety measure. Dose adjustments to higher doses (not exceeding the 
upper dose limit of 80 IU/kg rVWF:RCo) and adjustments to frequency will only be 
allowed in cases of persisting high bleeding rates due to insufficient therapeutic response. 
8.7.4.3.1 Treatment Escalation
Criteria for dose and frequency escalation are specific to each bleeding indication 
(Table 2) but, overall, involve 1 significant breakthrough bleeding episode despite 
compliant prophylaxis. Subjects entering the study will begin prophylaxis treatment 
according to Schedule A (Table 1) and will remain at this dose and frequency until 
meeting the criteria for escalation to the next higher schedule: for example, from 
2 infusions of 50 ± 10 IU VWF:RCo/kg/week to 3 infusions of 50 ± 10 IU 
VWF:RCo/kg/week (Schedule B) to achieve adequate prophylaxis.
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Table 2
Criteria for Escalation Specific to Each Bleeding Indication
Schedule A
Schedule B
Joint bleeding
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) twice per week. In the event a 
spontaneous joint bleeding episode occurs 
while on this regimen, the subject will escalate 
to Schedule B following its resolution
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week.
GI bleeding
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) twice per week. In the event a 
severe GI bleeding episode occurs while on 
this regimen, the subject will escalate to 
Schedule B following its resolution
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week.
Menorrhagia
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) on days 1 and 2 of menses for 
2 cycles. Menstrual flow will be monitored by 
the PBAC score. If the average pictorial chart 
score is > 185, then the subject will escalate to 
Schedule B
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) on days 1, 2, 
and 3 of menses. Menstrual flow 
will be monitored by the PBAC 
score.
Epistaxis
50 ± 10 IU VWF:RCo/kg (rounded up to the
nearest vial) twice per week. The subject will 
escalate to Schedule B in the event of 
1 occurrence of breakthrough bleeding 
requiring intervention such as iron 
replacement therapy, transfusion, packing, 
hospitalization; or 2 bleeding events that 
require treatment with factor replacement
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week. 
Oral and Other 
Mucosa
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) twice per week. The subject will 
escalate to Schedule B in the event of
1 occurrence of breakthrough bleeding 
requiring intervention such as iron 
replacement therapy, transfusion, packing, 
hospitalization; or 2 bleeding events that 
require treatment with factor replacement.
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week.
Muscle and Soft 
Tissue
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) twice per week. In the event a 
spontaneous bleeding episode occurs while on 
this schedule, the subject will escalate to 
Schedule B following its resolution.
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week.
Abbreviations:  GI: gastrointestinal; PBAC: Pictorial Blood Assessment Chart.
Dose and frequency reduction will only be allowed in case plasma VWF or FVIII levels
are exceeding the recommended ranges. 
If a subject does not adequately respond to rVWF therapy, he/she will be evaluated for 
the presence of neutralizing and total binding anti-VWF antibodies (see Section 12.9.3.2).
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If a subject experiences a bleed while receiving rVWF three times per week, the 
investigator should treat the bleed with rVWF at doses up to 80 IU VWF:RCo/kg at a 
frequency determined by the investigator until the bleed resolves. Upon resolution of the 
bleeding event, the subject will return to their assigned prophylaxis regimen. 
It is essential for the success of this study that the subjects adhere to treatment regimens. 
Therefore, procedures for monitoring subject’s compliance are implemented (see 
Section 10.7).
If 1 infusion of IP is missed, the subject may administer the IP as soon as possible. The 
subject should adhere to their treatment scheme ensuring a minimum interval of 12 hours 
between this and the previous IP infusion. For example, a subject routinely infuses IP on 
Monday and Thursday, he/she misses the Monday time point and therefore may infuse 
the IP on the next day (Tuesday) and thereafter proceed with infusing the IP on Thursday
(considering a minimum 12 hours between the infusions) and return to the initial
schedule.
If more than 30% of infusions of IP are missed within the visit interval of 3 months the 
subject will be discontinued from the study (see Section 9.4).
8.7.4.3.2 General Instructions for Home Treatment for Prophylaxis
At the discretion of the investigator, a subject may be considered suitable for home 
treatment only after the subject has received at least 1 infusion of IP in the clinic, either 
during planned IP exposure (PK or prophylaxis) or during the treatment of bleeding 
episodes, and meets the following additional criteria:
1.
Fully understands the concept of a clinical study and related documentation 
(documented training of at least 30 minutes), 
2.
Has a history of previous experience with home treatment including 
self-administration and treatment with VWF containing concentrates, 
3.
Has adequate time for initial training of the study drug preparation (preparation, 
mixing and infusion of the IP(s) (documented training of at least 30 minutes).
In the event a healthcare professional is required to administer IP, he/she must be trained
and qualified by the sponsor on the above procedures prior to the decision for home 
treatment. A Subject Guideline detailing all instructions and information listed above will 
be provided to each subject. 
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8.7.4.4 Treatment of Bleeding Episodes
8.7.4.4.1 General Instructions for Home Treatment of Bleeding Episodes
If a subject experiences a bleeding episode, he/she should contact the study site 
immediately and the site investigator should provide instructions on the treatment 
regimen. If the subject initiates the treatment at home, he/she should at least follow up 
with the study site if a visit is needed as per the standard of care at the center.
In the event a healthcare professional is required to administer treatment at the subject’s 
home, he/she must be trained and qualified by the site investigator on the above 
procedures prior to the decision for home treatment. Once a subject has received 
1 infusion of rVWF in the clinic (either during planned IP exposure or during the 
treatment of a bleeding episode) and meets the criteria for home treatment, the treatment 
of bleeding episodes with IP can be conducted at home (see Section 8.7.4.3.2).
If a subject is not qualified for home treatment, rVWF infusions must be administered at 
the study site.
If a subject experiences a bleeding episode that requires treatment between the screening 
and the prophylaxis initiation visit, the subject will be treated with IP (rVWF with or 
without ADVATE). Treatment with IP must occur at the study site unless the subject has 
previously qualified for home treatment with rVWF. If rVWF treatment is not feasible, 
the subject may use his/her standard of care, such as commercial pdVWF/FVIII products. 
In any case a washout period of at least 5 days is required prior to rVWF PK infusion at 
the PK assessment visit.
If a subject experiences a bleeding episode requiring treatment during the PK assessment, 
rVWF will be used to treat the bleed. Blood draws for PK assessment will be stopped and 
the PK assessments will be repeated once the bleed has resolved and the subject is free of 
any symptoms related with the bleeding episode. Dose and frequency of rVWF infusions 
or any other replacement therapy to stop the bleed should be recorded in the e-CRF.
8.7.4.4.2 Dosing Recommendations for Treatment of Bleeding Episodes 
If an acute bleeding episode occurs, the subject will be treated with rVWF with or 
without ADVATE. In general initially, an infusion of rVWF: ADVATE at an rVWF:
ADVATE ratio of 1.3:1± 0.2 will be administered. Subsequent infusions may either use 
rVWF alone or with ADVATE, based on FVIII levels, if available. 
If FVIII levels are not available, dosing is at the discretion of the investigator based upon 
the individual subject’s PK data. Using ADVATE in addition to rVWF in subsequent 
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doses carries the risk of an excessive rise in FVIII:C. Therefore, reduced doses of 
ADVATE and/or prolongation of the dose interval should be considered.
In general the aim of the initial dose should be full replacement of VWF with VWF:RCo 
levels of >0.6 IU/ml (60%) and FVIII:C of >0.4 IU/mL (40%). In major bleeding 
episodes, subsequent doses should keep the trough level of VWF:RCo >50% for 3 days 
and then as deemed necessary by the investigator for subsequent days. In moderate 
bleeding episodes, the dose and trough level may be reduced to >30% for as long as 
deemed necessary by the investigator. Treatment for minor bleeding episodes will 
generally consist of only 1 or 2 doses of rVWF IP. 
If the VWF:RCo level is above 150%, a planned treatment should be delayed by at least 
12 hours; if the VWF:RCo level is above 200%, a planned treatment should be delayed 
by at least 24 hours. In either case, a lower subsequent dose (e.g., 20 IU/kg VWF:RCo) 
may be appropriate.
Dosing recommendations are listed in Table 3.
Dosage must be individualized based on the subject’s weight, VWD type, and the 
severity of the bleeding episode, as well as on monitoring of appropriate clinical and 
laboratory measures. In the phase 1 study 070701, 1.0 IU/kg VWF:RCo raised the 
circulating level of VWF:RCo by 0.017 IU/mL (1.7 %). In the same study, the observed 
mean half-life for rVWF was 19.3 hours, with a standard deviation of 10.9 hours.
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Table 3
rVWF:RCo Dosing Recommendations for the Treatment of Bleeding Episodes Due to VWD
Classification of 
VWD
Hemorrhage
Dosage (IU VWF:RCo/kg Body Weight)
Type 1 
Severe (Baseline 
VWF:RCo activity 
typically <20%) 
Minor (e.g., epistaxis, oral 
bleeding, menorrhagiaa) 
40 to 50 IU/kg (1 or 2 doses)
Major (e.g., severe or 
refractory epistaxis, 
menorrhagia*, GI bleeding, 
CNS trauma, hemarthrosis, 
or traumatic hemorrhage)
Initial dose 50 to 75 IU/kg, then 40 to 60 IU/kg 
every 8 to 12 hours for 3 days to keep the trough 
level of VWF:RCo >50%; then 40 to 60 IU/kg daily 
for a total of up to 7 days of treatment
Type 2 (all variants) 
and Type 3 
Minor (clinical indications 
above) 
40 to 50 IU/kg (1 or 2 doses)
Major (clinical indications 
above)
Initial dose of 60 to 80 IU/kg, then 40 to 60 IU/kg 
every 8 to 12 hours for 3 days to keep the trough 
level of VWF:RCo >50%; then 40 to 60 IU/kg daily 
for a total of up to 7 days of treatment
a Menorrhagia is defined as excessive bleeding during menstruation. A diagnosis of menorrhagia will be 
defined by a prospectively completed Pictorial Blood Assessment Chart (PBAC) score >185 and normal 
cervical cytology or requiring use of a VWF-containing concentrate for treatment of excessive 
menstrual bleeding for at least one menstrual cycle during the prior year.
Variances of up to 10% in dosing are permissible during treatment of bleeding episodes, 
but rounding to the nearest vial size should be avoided.
Subjects with non-neutralizing binding anti-VWF antibodies should initially be treated 
with a dose known to be efficacious based on the subject’s medical treatment history
which may differ from the recommendations provided in Table 3. Subjects should be 
monitored for lack of efficacy as well as for FVIII (mandatory), VWF:RCo (mandatory), 
and VWF:Ag (optional where testing is not available) levels after 3 to 6 hours. Re-dosing 
with rVWF in combination with ADVATE using the same (initial) dose and adaptation of 
the dosing frequency should be considered until cessation of the bleed, if the FVIII and/or 
VWF:RCo levels drop below 30%-50% depending on bleeding severity.
The number of subsequent infusions and the dosage levels prescribed will be determined 
by the investigator on the basis of the clinical severity, response to current therapy, 
available laboratory data, and the subject’s historical treatment for similar bleeding 
episodes.
8.7.5 Investigational Product Accountability
The investigator will ensure that the IP(s) is stored as specified in the Pharmacy Manual
and that the storage area is secured, with access limited to authorized study personnel. 
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The investigator will maintain records that the IP(s) was received, including the date 
received, drug identity code, date of manufacture or expiration date, amount received and 
disposition. The IP(s) must be dispensed only at the study site or other suitable location 
(e.g., infusion center; home, as applicable per study design), as specified in the protocol 
(see Section 10). Records will be maintained that includes the subject identification code 
(SIC), dispensation date, and amount dispensed. All remaining partially used and/or 
unused IP(s) will be returned to the sponsor or sponsor’s representative after study 
completion/termination, or destroyed with the permission of the sponsor in accordance 
with applicable laws and study site procedures. If IP(s) is to be destroyed, the investigator 
will provide documentation in accordance with sponsor’s specifications.
8.8 Source Data
Per ICH GCP, source data are defined as all information in original records and certified 
copies of original records of clinical findings, observations, or other activities in a clinical 
trial that are necessary for the reconstruction and evaluation of the trial. Source data are 
contained in source documents (original records or certified copies), which may be in 
paper and/or electronic format. Source data for this study comprise the following:
hospital records, medical records, clinical and office charts, laboratory notes, memoranda, 
subjects' diaries or evaluation checklists, outcomes reported by subjects, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate copies, microfiches, photographic negatives, 
microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at 
the laboratories and at medico-technical departments involved in the clinical study.
No data will be entered directly onto the CRF.
For additional information on study documentation and CRFs refer to Section 17.2. The 
use of subject diaries is described in Section 10.5.
9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION
9.1 Inclusion Criteria
Subjects who meet ALL of the following criteria are eligible for this study:
1.
Subject has a documented diagnosis of severe VWD (baseline VWF:RCo 
<20 IU/dL) with a history of requiring substitution therapy with von Willebrand 
factor concentrate to control bleeding
a. Type 1 (VWF:RCo <20 IU/dL) or,
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b. Type 2A (as verified by multimer pattern), Type 2B (as diagnosed by 
genotype), Type 2M or,
c. Type 3 (VWF:Ag ≤3 IU/dL).
2.
Diagnosis is confirmed by genetic testing and multimer analysis, documented in 
patient history or at screening.
3.
Subject currently receiving on-demand treatment for whom prophylactic treatment 
is recommended according to standard of care at the center.
4.
Has ≥3 documented spontaneous bleeds requiring VWF treatment during the past 
12 months 
5.
Availability of records to reliably evaluate type, frequency and treatment of 
bleeding episodes during 12 months of on-demand treatment prior to enrollment.
6.
Subject is ≥18 years old at the time of screening and has a body mass index 
≥15 but <40 kg/m2.
7.
If female of childbearing potential, subject presents with a negative blood/urine 
pregnancy test at screening and agrees to employ adequate birth control measures 
for the duration of the study.i
8.
Subject is willing and able to comply with the requirements of the protocol.
9.2 Exclusion Criteria
Subjects who meet ANY of the following criteria are not eligible for this study:
1.
The subject has been diagnosed with Type 2N VWD, pseudo VWD, or another 
hereditary or acquired coagulation disorder other than VWD (eg qualitative and 
quantitative platelet disorders or elevated PT/INR 1.4).
2.
The subject has received prophylaxis treatment in the 12 months prior to 
screening (including those who received treatment once a month for menorrhagia 
but were not treated for any other bleeds).
3.
The subject is currently receiving prophylaxis treatment.
4.
The subject has a history or presence of a VWF inhibitor at screening.
5.
The subject has a history or presence of a FVIII inhibitor with a titer ≥0.4 BU (by 
Nijmegen modified Bethesda assay) or ≥0.6 BU (by Bethesda assay).
                                                
i Refer to Section 20.4 for a list of adequate contraceptive methods for females of childbearing potential.
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6.
The subject has a known hypersensitivity to any of the components of the study 
drugs, such as to mouse or hamster proteins.
7.
The subject has a medical history of immunological disorders, excluding seasonal 
allergic rhinitis/conjunctivitis, mild asthma, food allergies or animal allergies.
8.
The subject has a medical history of a thromboembolic event.
9.
The subject is HIV positive with an absolute Helper T cell (CD4) count 
200/mm3.
10. The subject has been diagnosed with significant liver disease as evidenced by any 
of the following: serum ALT 5 times the ULN; hypoalbuminemia; portal vein 
hypertension (e.g., presence of otherwise unexplained splenomegaly, history of 
esophageal varices).
11. The subject has been diagnosed with renal disease, with a serum creatinine level 
≥2.5 mg/dL.
12. The subject has a platelet count <100,000/mL at screening.
13. The subject has been treated with an immunomodulatory drug, excluding topical 
treatment (e.g., ointments, nasal sprays), within 30 days prior to signing the 
informed consent.
14. The subject is pregnant or lactating at the time of enrollment.
15. Patient has cervical or uterine conditions causing menorrhagia or metrorrhagia 
(including infection, dysplasia).
16. The subject has participated in another clinical study involving another IP or 
investigational device within 30 days prior to enrollment or is scheduled to 
participate in another clinical study involving an IP or investigational device 
during the course of this study.
17. The subject has a progressive fatal disease and/or life expectancy of less than 
15 months.
18. The subject is identified by the investigator as being unable or unwilling to 
cooperate with study procedures.
19. The subject has a mental condition rendering him/her unable to understand the 
nature, scope and possible consequences of the study and/or evidence of an 
uncooperative attitude.
20. The subject is in prison or compulsory detention by regulatory and/or juridical 
order.
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21. The subject is member of the study team or in a dependent relationship with one 
of the study team members which includes close relatives (i.e., children, 
partner/spouse, siblings and parents) as well as employees.
9.3 Delay Criteria
1.
If the subject has an acute bleeding episode or presents with an acute illness 
(e.g., influenza, flu-like syndrome, allergic rhinitis/conjunctivitis, non-seasonal 
asthma) the screening visit will be postponed until the subject has recovered.
9.4 Withdrawal and Discontinuation
Any subject may voluntarily withdraw (i.e., reduce the degree of participation in the 
study) consent for continued participation and data collection. The reason for withdrawal 
will be recorded on the End of Study CRF. Assessments to be performed at the 
termination visit (including cases of withdraw or discontinuation) are described in 
Section 10.6 and Section 20.2. 
Discontinuation (i.e., complete withdrawal from study participation) may be due to 
dropout (i.e., active discontinuation by subject) or loss to follow-up (i.e., discontinuation 
by subject without notice or action). Additionally, the investigator and sponsor have the 
discretion to discontinue any subject from the study if, in their judgment, continued 
participation would pose an unacceptable risk for the subject.
Subjects also will be withdrawn from treatment or discontinued from further study 
participation for the following reasons:
1.
The subject is scheduled for an extended treatment period 3 months with 
non-topical immunomodulating drugs other than anti-retroviral chemotherapy 
(e.g., -interferon, corticosteroid agents [equivalent to hydrocortisone greater than 
10 mg/day]) during the course of the study
2.
Subjects with chronic hepatitis B or C develop ALT/AST levels exceeding 5 times 
the ULN for 1 month
3.
Subjects who experience severe hypersensitivity reactions, e.g., anaphylaxis upon 
exposure to rVWF
4.
Subjects who develop a neutralizing inhibitor to rVWF and/or ADVATE
(biological assays)
5.
Subjects who demonstrate clinical signs of thromboembolic events
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6.
The subject becomes pregnant. IP exposure will be discontinued. Attempts will be 
made to follow the subject through completion of the pregnancy and up to 1 year 
post delivery, if feasible. The investigator will record a narrative description of 
the course of the pregnancy and its outcome. 
7.
The subject begins lactating. IP exposure will be discontinued. The investigator 
will record a narrative description of the course of the baby’s development. 
8.
The subject is not compliant with the prophylactic treatment regimen and does not 
adhere to the frequency of IP administration. Once >30% of infusions are missed 
within a visit interval (3 months), the subject will be discontinued from further 
participation in the study. 
10. STUDY PROCEDURES
10.1 Informed Consent and Enrollment
Any patient who provides informed consent (i.e., signs and dates the informed consent 
form) is considered a subject in the study.
10.2 Subject Identification Code
The following series of numbers will comprise the SIC: protocol identifier (e.g., 090701) 
to be provided by the sponsor, 2- or 3-digit number study site number (e.g., 02) to be 
provided by the sponsor, and 3- or 4-digit subject number (e.g., 0003) reflecting the order 
of enrollment (i.e., signing the informed consent form). For example, the third subject 
who signed an informed consent form at study site 02 will be identified as Subject 
090701-020003. All study documents (e.g., CRFs, clinical documentation, sample 
containers, drug accountability logs, etc.) will be identified with the SIC. Additionally, a 
uniquely coded SIC(s) is permitted as long as it does not contain a combination of 
information that allows identification of a subject (e.g., collection of a subject’s initials 
and birth date would not be permitted), in compliance with laws governing data privacy.
10.3 Screening and Study Visits
The study site is responsible for maintaining a screening log that includes all subjects 
who provided informed consent. The log also will serve to document the reason for 
screening failure. All screening data will be collected and reported in CRFs, regardless of 
screening outcome. If a subject is re-screened, the End of Study CRF should be 
completed, and a new ICF, new SIC and new CRF are required for that subject.
The overall study design is illustrated in the Figure 1. Details on the procedures to be 
performed at each study visit, including screening, are provided in Supplement 20.2
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Schedule of Study Procedures and Assessments and Supplement 20.3 Clinical Laboratory 
Assessments.
10.3.1 Screening Visit
Written informed consent must be obtained from each subject before any study 
related procedures are performed. To initiate screening procedures, at least 72 hours 
must have elapsed since the last VWF administration and the subject must not be 
actively bleeding at the time of screening. Multimer analysis and VWD gene mutation 
analysis should be performed at screening if not available in the subject’s medical history.
The screening visit will be delayed if the subjects presents with an acute bleeding 
episodes or acute illness (e.g., influenza, flu-like symptoms, inflammatory diseases) until 
the event has resolved. All screening procedures and confirmation of eligibility shall take 
place within 42 days prior to the first infusion of IP for PK assessments. If the IP is not 
infused within 42 days, all screening assessments except blood group, human leucocyte 
antigen (HLA), genetics, multimeric pattern and 
, must be repeated to reconfirm 
eligibility. Refer to Supplement 20.2 and Supplement 20.3. Upon completion of screening 
procedures, subject eligibility will be confirmed by the sponsor on a subject eligibility 
form before additional study procedures are undertaken. The subject will maintain a diary 
that will include infusion logs (see Section 10.5). The allocation of IP will be initiated 
after the subject has qualified for home treatment (see Section 8.7.4.3.2).
In the event of a subject experiencing a bleeding episode that requires treatment between 
the screening visit and the baseline visit (PK assessment visit), the subject will be treated
with rVWF. If rVWF is not available for any reason, e.g., subject not yet trained on IP 
administration, study site visit for IP administration not feasible, etc., the subject may use 
his/her standard of care, such as commercial pdVWF/FVIII products.
10.3.2 Baseline Visit - PK-Assessment Visit 
After screening and confirmation of eligibility each subject will undergo a PK 
assessment. Subjects who participated in the surgery study 071101 will not need to 
undergo a PK baseline assessment again if they had a major procedure performed, 
provided valid PK data from 071101 is available. These subjects may proceed directly 
with the prophylaxis initiation visit (refer to Section 10.3.3). All subjects will receive a 
dose of 50 ± 5 IU/kg rVWF:RCo to determine VWF and FVIII levels. Blood samples will 
be drawn within 30 minutes pre-infusion, and at 7 time points post-infusion 
(30 5 minutes, 60 5 minutes, 6 1 hours, 12 1 hours, 24 2 hours, 48 2 hours, 
72 2 hours). See Section 20.2 and Section 20.3. IP infusion vials from the same lot 
number should be used for all PK-assessments per subject. Samples for measurement of 
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FVIII and VWF activity taken through to 6 hours post-infusion will be obtained from an 
extremity different from that used for the infusion of IP. Where needed, the phlebotomy 
site will be kept patent via an infusion of normal saline. In this event, at least 5 mL of 
blood will be collected and discarded before collection of the next test sample into a fresh 
syringe.
If the subject has a central venous catheter, the central line should be used to administer 
the infusion and a peripheral venipuncture should be used to collect the blood samples. 
In the event that a blood sample must be drawn through the central line used for 
administration of IP, the line must first be flushed with at least 10 mL normal saline or 
other suitable catheter flush solution that does not contain anticoagulant. At least 5 mL of 
whole blood must be collected and discarded prior to obtaining the sample. 
If a subject experiences a bleeding episode during the PK assessment no subsequent 
blood sample will be drawn in that specific PK period. The guidance provided in 
Section 8.7.4.4 has to be followed for the treatment of the bleeding episode. The subject 
once recovered is eligible to repeat the PK assessment. 
10.3.3 Prophylaxis Initiation Visit
After the blood sample for the 72 hour PK assessment is drawn the subject will receive 
the first rVWF prophylactic dose of 50 ± 10 IU/kg rVWF: RCo. Details on dose are 
provided in Section 8.7.4.3. 
If a subject did not undergo PK assessment (for example the subject has participated in
the surgery study 071101 and has undergone PK in Study 071101 and had a major 
procedure performed, refer to Section 8.7.4.2), procedures and assessments at this visit 
include: adverse events, bleeding episodes, medications taken, non-drug therapies and 
laboratory assessment. Independent of previous PK assessment visits, within 2 hours 
prior the IP infusion, a physical examination will be performed. Vital signs will be 
assessed within 30 minutes prior to IP rVWF infusion and 30 minutes ± 15 minutes after 
IP infusion. For subjects with a previous PK assessment in the course of the surgery 
study, incremental recovery (IR) will be determined based on VWF: RCo activity 
assessed prior and after IP infusion. Further details are provided in Supplement 20.2 and 
Supplement 20.3.
10.3.4 Treatment of Bleeding Episodes
Treatment of bleeding episodes is described in detail in Section 8.7.4.4.
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10.3.5 Follow-Up Visits (1 Month ± 1 Week, 2 Months ± 1 Week, 
3 Months ± 2 Weeks, 6 Months ± 2 Weeks, 9 Months ± 2 Weeks)
Visits will be performed after the prophylaxis initiation visit at 1 month ± 1 week, 
2 months ± 1 week, and 3 months ± 2 weeks and thereafter every three months
± 2 weeks. Additional visits may occur if clinically indicated (see Section 10.3.6).
When possible, site visits should be scheduled on days when the subject is expected to 
infuse BAX111. Within 2 hours prior to the rVWF IP infusion, a physical examination 
will be performed. Vital signs will be assessed within 30 minutes prior to IP infusion and 
30 minutes ± 15 minutes after IP infusion. Incremental recovery (IR) will be determined 
at each follow-up visit based on VWF:RCo activity assessed prior to and after IP 
infusion. 
The blood sample for IR analysis will be drawn within 30 minutes prior to IP infusion 
and 30 minutes ± 5 minutes after IP infusion. rVWF will be infused at the regular 
prophylactic dose, i.e., 50 ± 10 IU/kg rVWF:RCo. For each subject’s recovery analysis IP 
infusion, vials from the same lot number should be used. 
Testing for VWF:RCo VWF:CB, rVWF:Ag, INNOVANCE VWF:Ac (exploratory) and 
FVIII:C level will be performed using the blood sample obtained before and after IP 
infusion. 
The blood sample prior to IP infusion will also be used for the assessment of neutralizing
and binding antibodies, clinical chemistry and hematology. A washout period of at least 
72 hours after the last infusion applies before the blood draw for the immunogenicity 
assays. Bleeding episodes and the hemostatic efficacy will be evaluated based on the 
review of the patient diary. See Section 20.2 and Section 20.3. The evaluation of IP 
consumption and treatment compliance will be performed based on subject’s diary 
entries. If a subject is not compliant with the prophylactic treatment regimen and does not 
adhere to the required frequency of administration of IP infusions (>30% of infusions
were missed within a visit interval [3 months]) the subject will be withdrawn from the 
study.
At the 6 months ± 2 week visit an electrocardiogram (ECG) will be performed and 
data will be collected. 
For the hemostatic efficacy assessment the following information will be recorded by the 
subject in the patient diary: bleeding location, type, severity, onset and resolution date 
and time, infusion date and time, clinical efficacy according to the rating scale. If at any 
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time during the study a subject’s bleeding episode does not adequately respond to rVWF 
therapy, he/she will be evaluated for the presence of neutralizing and total binding 
antibodies. Refer to Section 12.9.3.2.
Further guidance on completing the subject’s diary will be provided to the subjects during 
training for home treatment (see Section 8.7.4.3.2).
10.3.6 Unscheduled Visits
For any unscheduled visit (except for collection of IP) a clinical assessment will be 
performed as per the scheduled follow-up visits with the exception of 
, ECG, and 
IR determination (refer to Supplement 20.2 and Supplement 20.3).
Subjects who have more than one bleeding episode in 3 months, or an increased 
frequency of bleeding, should go to the study site for an unscheduled visit.
Follow-up visits after the subject has experienced a bleed may be requested by the 
investigator. Additional assessments may be required which are at the discretion of the 
investigator. 
10.3.7 Study Termination Visit (12 Months ± 2 Weeks)
At the 12 month ± 2 week visit, a full PK analysis, as per the baseline PK assessment, 
will be performed. Blood samples will be drawn within 30 minutes pre-infusion, and at 
7 time points post-infusion (30 ± 5 minutes, 60 ± 5 minutes, 6 ± 1 hours, 12 ± 1 hours, 
24 ± 2 hours, 48 ± 2 hours, 72 ± 2 hours). If a subject experiences a bleeding episode 
during the PK assessment no subsequent blood sample will be drawn in that specific PK 
period. The guidance provided in Section 8.7.4.4 has to be followed for the treatment of 
the bleeding episode. The subject once recovered is eligible to repeat the PK assessment.
The following parameters will be used as part of the PK assessment:

Incremental recovery of VWF:RCo, VWF:Ag, VWF:CB, and INNOVANCE 
VWF Ac (exploratory assay)

AUC/dose, area under moment curve (AUMC/dose, clearance (CL), Volume of 
distribution at steady state (Vss), mean residence time (MRT), of 
VWF:RCo ,VWF:Ag, VWF:CB, and INNOVANCE VWF Ac (exploratory assay) 

Half-life of VWF:RCo, VWF:Ag, VWF:CB, and INNOVANCE VWF Ac 
(exploratory assay)
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
Time course of the FVIII:C levels

VWF collagen binding (VWF:CB) levels
Refer to Supplement 20.2 and Supplement 20.3 for the other assessments to be performed 
at the PK assessment and study completion visits.
A washout period of at least 72 hours is required between the PK infusion and the study 
termination visit (at the time of the 72 hour postinfusion PK assessment). 
Refer to Supplement 20.2 and Supplement 20.3 for the list of assessments to be 
performed at the termination visit.
Subjects will be offered the option to continue to receive BAX111 in a long-term 
continuation study.
10.4 Medications and Non-Drug Therapies 
The following medications and non-drug therapies are not permitted within 30 days 
before study entry and during the course of the study:
Medications:

Immunomodulating drugs other than anti-retroviral chemotherapy (e.g.,
-interferon, or corticosteroid agents at a dose equivalent to hydrocortisone 
greater than 10 mg/day) and an extended treatment period 3 months.

Another investigational and/or interventional study drug (except rVWF and FVIII 
administered under the surgery protocol).
A subject who has taken any of these medications or received any of these non-drug 
therapies during the study will be withdrawn from the study. 
The following medications are permitted during the course of the study:

Antifibrinolytics (e.g., tranexamic acid, -amino caproic acid) or topical
hemostats as needed, according to each institution’s standard of care

Emergent use of a VWF concentrate other than rVWF may be permissible under
certain circumstances (see Section 8.7.4.4.1)
Details of all adjunctive hemostatic medication used, including dose and reason for use, 
will be recorded in the electronic Case Report Form (eCRF).
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10.5 Subject Diary
1.
An electronic subject diary will be provided to each subject at the baseline visit to
record the following information:

IP infusions to include date, start and stop times of the infusion, number of 
vials utilized, and infusion volume for prophylactic treatment or treatment of 
spontaneous and traumatic bleeding episodes 
2.
Details of bleeding episodes (site and type of bleeding) and response to treatment 
as described in Section 8.7.4.4
3.
Subjective hemostatic efficacy assessments.
Subjects and/or their legally authorized representatives will be trained on use of the diary. 
The diary will be provided in electronic format and remain with the subject for the 
duration of the study. The investigator will review the diary for completeness and request 
missing information periodically and in a timely manner. 
Infusions performed at the study site will be recorded in the site’s source documents and 
not in the patient diary.
Subject entries in the diary will serve as source records. During study participation the 
investigator has access to the database holding the subject diary data. After study closure, 
the investigator will receive the diary records for their subjects, including audit trail 
records, in PDF format. The data will be transmitted to the CRF by a validated transfer. 
10.6 Subject Completion/Discontinuation
A subject is considered to have completed the study when he/she ceases active 
participation in the study because the subject has, or is presumed to have completed all 
study procedures according with the protocol (with or without protocol deviations).
Reasons for completion/discontinuation will be reported on the 
Completion/Discontinuation CRF, including: completed, screen failure, AE (e.g., death), 
discontinuation by subject (e.g., lost to follow-up [defined as 3 documented unsuccessful 
attempts to contact the subject], dropout), physician decision (e.g., pregnancy, 
progressive disease, non-compliance with IP/protocol violation(s), recovery), study 
terminated by sponsor, or other (reason to be specified by the investigator, e.g., technical 
problems). Regardless of the reason, all data available for the subject up to the time of 
completion/discontinuation should be recorded on the appropriate CRF. 
Every effort will be made to have discontinued subjects complete the study termination 
visit. If the termination visit is done as an additional, unscheduled visit, the assessment
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results shall be recorded with the termination visit. If a subject terminates participation in 
the study and does not return for termination visit, his/her last recorded assessments shall 
remain with the last visit. The reason for discontinuation will be recorded, and the data 
collected up to the time of discontinuation will be used in the analysis and included in the 
clinical study report. If additional assessments are required, the assessments shall be 
recorded separately. Assessments to be performed at the termination visit (including in 
cases of withdraw or discontinuation) can be found in Supplement 20.2 Schedule of 
Study Procedures and Assessments and Supplement 20.3 Clinical Laboratory 
Assessments.
In the event of subject discontinuation due to an AE, clinical and/or laboratory 
investigations that are beyond the scope of the required study observations/assessments 
may be performed as part of the evaluation of the event. These investigations will take 
place under the direction of the investigator in consultation with the sponsor, and the 
details of the outcome may be reported to the appropriate regulatory authorities by the 
sponsor. 
10.7 Procedures for Monitoring Subject Compliance
Subject compliance with the procedures of this study (treatment regimens and study 
visits) will be monitored by the investigator or/a licensed healthcare professional at the 
study site.
During the regular scheduled follow-up visits a direct review of the subject’s source data 
(e-diaries) will be performed at the sites and evaluated against the protocol requirements. 
In addition drug accountability will be evaluated at each follow-up study visit and the 
study termination visit by comparing the infusions recorded in the subject diary with
empty vials returned by each subject to the study site, and the study site’s dispensing 
record. Protocol deviations will be noted in the final report. 
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11. ASSESSMENT OF EFFICACY AND PHARMACOKINETICS
11.1 Assessment of Spontaneous Bleeding Episodes/Annualized Bleed Rate 
The annualized bleed rate (ABR) will be assessed based upon each individual 
spontaneous bleed, requiring coagulation factor replacement therapy, i.e., rVWF 
treatment. The following details on bleeding episodes will be recorded by the subject in 
the electronic diary (for home treatment), the subject’s healthcare provider in the site’s 
source documents (for treatments away from the primary investigative site), or by 
authorized, qualified personnel at the participating site in the subject’s medical records 
(for hospital-based treatment):

Location of bleed; i.e., joint, menorrhagia, epistaxis, gastrointestinal, soft tissue, 
muscle, body cavity, intracranial, etc.

Type of bleed; i.e., spontaneous, traumatic, unknown

Severity of bleed; i.e., minor, moderate, and major (see Table 3)

Date and time of onset of bleed

Date and time of each infusion of rVWF or rVWF-ADVATE used to treat a 
bleeding episode

Date and time of resolution of the bleeding episode
Study site personnel are qualified after they have undergone training during the 
qualification of the site.
All types of bleeds, including traumatic bleeds, will be recorded. Bleeding episodes 
should be organized by where they occur in addition to whether they occurred 
spontaneously or due to a traumatic event.
Bleeds occurring at the same anatomical location (e.g., right knee) with the same etiology 
(i.e., spontaneous versus injury) within 24 hours after onset of the first bleed will be 
considered a single bleed. Bleeding occurring at multiple locations related to the same 
injury (e.g., knee and ankle bleeds following a fall) will be counted as a single bleeding 
episode.
All efforts should be made to use rVWF for treatment of bleeding episodes. If needed, the 
use of a VWF concentrate other than IP for the treatment of bleeding episodes will not 
disqualify the subject from further participation in the study.
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11.2 Evaluation of ABR Before rVWF Prophylaxis and ABR Under rVWF
Prophylactic Treatment
At screening, the subject’s medical history will be recorded, including the number of all 
spontaneous and traumatic bleeding episodes within the past 12 months. The maximum 
interval of bleed-free periods as well as trauma induced bleeding episodes will also be 
recorded (prospectively and retrospectively).
11.3 Number of Infusions and Total Weight Adjusted Consumption of rVWF and 
ADVATE
The number of rVWF and ADVATE (in case of bleeding episode treatment) infusions 
will be logged in the subject diary. Based on these entries the weight adjusted 
consumption will be calculated per month and per year. 
11.4 Assessment of Efficacy for Treatment of Bleeding Episode
Investigators will be asked to assess and record hemostatic efficacy after resolution of 
each bleeding episode using the 4-scale rating system outlined in Table 4. 
Table 4
Efficacy Rating Scale
Rating
Efficacy Rating Criterion
Minor and Moderate Bleeding Events
Major Bleeding Events
Excellent (=1)
Actual number of infusions ≤ estimated 
number of infusions required to treat that 
bleeding episode
No additional VWF containing 
coagulation factor containing product 
required
Actual number of infusions ≤ estimated 
number of infusions required to treat that 
bleeding episode
No additional VWF containing coagulation 
factor containing product required
Good (=2)
1-2 infusions greater than estimated 
required to control that bleeding episode
No additional VWF containing 
coagulation factor containing product 
required
< 1.5 x infusions greater than estimated 
required to control that bleeding episode
No additional VWF containing coagulation 
factor containing product required
Moderate (=3)
3 or more infusions greater than estimated 
required to control that bleeding episode
No additional VWF containing 
coagulation factor containing product 
required
≥1.5 x infusions greater than estimated 
required to control that bleeding episode
No additional VWF containing coagulation 
factor containing product required
None (=4)
Severe uncontrolled bleeding or intensity 
of bleeding not changed
Additional VWF containing coagulation 
factor containing product required
Severe uncontrolled bleeding or intensity 
of bleeding not changed
Additional VWF containing coagulation 
factor containing product required
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11.5 Pharmacokinetic Assessment
Details on pharmacokinetic assessments are provided in Section 12.9.1.
12. ASSESSMENT OF SAFETY
12.1 Adverse Events
12.1.1 Definitions
An AE is defined as any untoward medical occurrence in a subject administered IP that 
does not necessarily have a causal relationship with the treatment. An AE can therefore 
be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom
(e.g., rash, pain, discomfort, fever, dizziness, etc.), disease (e.g., peritonitis, bacteremia, 
etc.), or outcome of death temporally associated with the use of an IP, whether or not 
considered causally related to the IP.
12.1.1.1 Serious Adverse Event
An SAE is defined as an untoward medical occurrence that at any dose meets one or 
more of the following criteria:

Outcome is fatal/results in death (including fetal death)

Is life-threatening – defined as an event in which the subject was, in the judgment 
of the investigator, at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death had it been more severe.

Requires inpatient hospitalization or results in prolongation of an existing 
hospitalization – inpatient hospitalization refers to any inpatient admission, 
regardless of length of stay.

Results in persistent or significant disability/incapacity (i.e., a substantial 
disruption of a person’s ability to conduct normal life functions)

Is a congenital anomaly/birth defect

Is a medically important event – a medical event that may not be immediately 
life-threatening or result in death or require hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the definitions above. Examples of such events are: 

Intensive treatment in an emergency room or at home for allergic
bronchospasm, blood dyscrasias, or convulsions that do not result in 
hospitalization, or development of drug dependence or drug abuse 
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
Reviewed and confirmed seroconversion for human immunodeficiency 
virus
(HIV), hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus
(HCV), hepatitis E virus (HEV), or parvovirus B19 (B19V)

Development of neutralizing VWF antibodies

Development of neutralizing antibodies to FVIII (titer ≥0.4 BU [by 
Nijmegen- modified Bethesda assay] or ≥0.6 BU [by Bethesda assay])

Thromboembolic events (e.g., myocardial infarction, stroke, transient 
ischemic attack [TIA], deep vein thrombosis [DVT] or pulmonary 
embolism)

Anaphylaxis (for definition, refer to Section 12.6.2) or severe 
hypersensitivity reactions
Uncomplicated pregnancies, following maternal or paternal exposure to IP are not 
considered an (S)AE; however, any pregnancy complication or pregnancy termination by 
therapeutic, elective, or spontaneous abortion shall be considered an SAE.
12.1.1.2 Suspected Unexpected Serious Adverse Reaction (SUSAR)
Any suspected adverse reaction to study treatment (i.e., including active comparators) 
that is both serious and unexpected. 
The event(s) must meet all of the following:

Suspected adverse reaction

Serious

Unexpected

Assessed as related to study treatment
Once determined to meet the criteria for a SUSAR, the sponsor will ensure expedited 
SUSAR reporting in line with the regulatory requirements in participating countries as 
outlined in the Safety Management Plan.
12.1.1.3 Non-Serious Adverse Event
A non-serious AE is an AE that does not meet the criteria of an SAE.
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12.1.1.4 Unexpected Adverse Events
An unexpected adverse event is an AE whose nature, severity, specificity, or outcome is 
not consistent with the term, representation, or description used in the Reference Safety 
Information (e.g., IB, package insert). “Unexpected” also refers to the AEs that are 
mentioned in the IB as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring 
with the particular drug under investigation.
12.1.1.5 Preexisting Disease
Preexisting diseases that are present before entry in to the study are described in the 
medical history, and those that manifest with the same severity, frequency, or duration 
after IP exposure will not be recorded as AEs. However, when there is an increase in the 
severity, duration, or frequency of a preexisting disease, the event must be described on 
the AE CRF.
12.1.2 Assessment of Adverse Events
For the purposes of this study, the following will not be considered as AEs and will not 
be included in the analysis of AEs.

Bleeding episodes are part of the underlying disease and therefore are not AEs; 
they will be evaluated in the context of efficacy.

For non-serious bleeding episodes caused by an injury, the injury would not 
be reported as an AE, unless it resulted in a medical finding other than a 
bleeding episode (e.g., abrasion of skin). Therefore, any VWD-related 
bleeding event (e.g., epistaxis, gastrointestinal bleeding, musculo-skeletal 
bleeding, menorrhagia) that is non-serious will not be reported as an AE. 
However, the investigator may decide that the event is an AE if the event also 
would have occurred in a healthy individual under the same circumstances.

For SAEs: Bleeding events that meet seriousness criteria (death, 
life-threatening, hospitalizing/prolongation of hospitalization, disability, 
congenital anomaly, or medically significant and if not urgently treated would 
result in one of the above) should be reported on the SAE eCRF or SAE 
Report form as an SAE.

Seroconversion after documented HAV/HBV vaccination prior to or during the 
study period.
Each AE from the first IP exposure to the study completion date will be described on the 
AE CRF using the medical diagnosis (preferred), or, if no diagnosis could be established 
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at the time of reporting the AE, a symptom or sign, in standard medical terminology in 
order to avoid the use of vague, ambiguous, or colloquial expressions (see definition in 
Section 12.1). Each AE will be evaluated by the investigator for:

Seriousness as defined in Section 12.1.1.1

Severity as defined in Section 12.1.2.1

Causal relationship to IP exposure or study procedure as defined in 
Section 12.1.2.2
For each AE, the outcome (i.e., recovering/resolving, recovered/resolved, 
recovered/resolved with sequelae, not recovered/not resolved, fatal, unknown) and if 
applicable action taken (i.e., dose increased, dose not changed, dose reduced, drug 
interrupted, drug withdrawn, not applicable, or unknown) will also be recorded on the AE 
CRF. Recovering/resolving AEs will be followed until resolution.
If the severity rating for an ongoing AE changes before the event resolves, the original 
AE report will be revised (i.e., the event will not be reported as separate AE). During the 
course of any AE, the highest severity rating will be reported.
Deviations from the protocol-specified dosage (including underdosing /overdosing
[<20 IU/kg rVWF:RCo or >100 rVWF:RCo], abuse, and withdrawal, treatment errors 
(including incorrect route of administration, use of an incorrect product, and deviations 
from the protocol-defined dosing schedule), failures of expected pharmacological actions, 
and unexpected therapeutic or clinical benefits will be followed with regard to occurrence 
of AEs, lack of efficacy, and/or other observations because these events may be 
reportable to regulatory authorities. 
Any pregnancy that occurs after administration of IP will be reported on a Pregnancy 
Form and followed-up at 1 year post-delivery, if feasible. 
If an investigator becomes aware of an SAE occurring in a subject after study completion, 
the SAE must be reported on the SAE Form within 24 hours after awareness: no 
additional reporting on CRFs is necessary.
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12.1.2.1 Severity
The investigator will assess the severity of each AE using his/her clinical expertise and 
judgment based on the most appropriate description below:

Mild
The AE is a transient discomfort and does not interfere in a significant manner 
with the subject’s normal functioning level.
The AE resolves spontaneously or may require minimal therapeutic 
intervention.

Moderate
The AE produces limited impairment of function and may require therapeutic 
intervention.
The AE produces no sequela/sequelae.

Severe
The AE results in a marked impairment of function and may lead to temporary 
inability to resume usual life pattern.
The AE produces sequela/sequelae, which require (prolonged) therapeutic 
intervention.
These severity definitions will also be used to assess the severity of an AE with a study-
related procedure(s), if necessary.
12.1.2.2 Causality
Causality is a determination of whether there is a reasonable possibility that the IP is 
etiologically related to/associated with the AE. Causality assessment includes, e.g., 
assessment of temporal relationships, dechallenge/rechallenge information, association 
(or lack of association) with underlying disease, presence (or absence) of a more likely 
cause, and physiological plausibility. For each AE, the investigator will assess the causal 
relationship between the IP and the AE using his/her clinical expertise and judgment 
according to the following most appropriate algorithm for the circumstances of the AE:

Not related (both circumstances must be met)
Is due to underlying or concurrent illness, complications, concurrent 
treatments, or effects of concurrent drugs
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Is not associated with the IP (i.e., does not follow a reasonable temporal 
relationship to the administration of IP or has a much more likely alternative 
etiology). 

Unlikely related (either 1 or both circumstances are met)
Has little or no temporal relationship to the IP 
A more likely alternative etiology exists

Possibly related (both circumstances must be met)
Follows a reasonable temporal relationship to the administration of IP
An alternative etiology is equally or less likely compared to the potential 
relationship to the IP

Probably related (both circumstances must be met)
Follows a strong temporal relationship to the administration of IP, which may 
include but is not limited to the following: 
o
Reappearance of a similar reaction upon re-administration (positive re-
challenge)
o
Positive results in a drug sensitivity test (skin test, etc.)
o
Toxic level of the IP as evidenced by measurement of the IP 
concentrations in the blood or other bodily fluid
Another etiology is unlikely or significantly less likely
For events assessed as not related or unlikely related and occurring within 5 days after IP 
infusion, the investigator shall provide the alternative etiology. These causality 
definitions will also be used to assess the relationship of an AE with a study-related 
procedure(s), if necessary.
12.1.2.3 Safety Reporting
Adverse events/SAEs will be assessed at all study visits as outlined in the Schedule of 
Study Procedures and Assessments (see Table 5) and Section 12.1.2.
Adverse Events/SAEs are to be recorded on the AE page of the eCRF. Each event should 
be recorded separately.
Any SAE, including death due to any cause, which occurs during this study, whether or 
not related to the investigational product, must be reported immediately (within 24 hours 
of the study center’s first knowledge of the event). All SAEs must be reported via the 
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Electronic Data Capture (EDC) system by completing the relevant eCRF page(s) in 
English. For instances in which the EDC may become unavailable, SAEs must be 
reported using the back-up paper SAE report (SAER) form to meet the 24-hour timeline 
requirement (for contacts and instructions refer to the SAER form). Once the EDC 
becomes available, the site must enter all SAE data as reported on the back-up paper 
SAER form on the applicable eCRF pages.
The initial SAE information reported on the applicable eCRF pages (or back-up SAER 
Form, if applicable) must at least include the following:
1.
Protocol Number
2.
Subject identification number and demographics (gender, age at onset of event 
and/or date of birth)
3.
Investigational product exposure
4.
Medical Term for Event (Diagnosis preferably) 
5.
Description of the (S)AE, including:

Date of onset

(S)AE treatment (drug, dose, route of administration)

Causal relationship by the Investigator

Measures taken (i.e., action taken regarding investigational product in direct 
relationship to the AE)
6.
Seriousness criteria (ie, death, life-threatening, or other criterion)
7.
Cause of death
8.
Autopsy findings (if available)
9.
Name, address, fax number, email, and telephone number of the reporting
Investigator (for paper SAER Forms) 
12.2 Urgent Safety Measures
An urgent safety measure is an immediate action taken, which is not defined by the 
protocol, in order to protect subjects participating in a clinical trial from immediate harm. 
Urgent safety measures may be taken by the sponsor or clinical investigator, and may 
include any of the following: 

Immediate change in study design or study procedures
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
Temporary or permanent halt of a given clinical trial or trials

Any other immediate action taken in order to protect clinical trial participants 
from immediate hazard to their health and safety
The investigator may take appropriate urgent safety measures in order to protect subjects 
against any immediate hazard to their health or safety. The measures should be taken 
immediately and may be taken without prior authorization from the sponsor. 
In the event(s) of an apparent immediate hazard to the subject, the investigator will notify 
the sponsor immediately by phone and confirm notification to the sponsor in writing as 
soon as possible, but within 1 calendar day after the change is implemented. The sponsor 
will also ensure the responsible ethics committees (ECs) and relevant competent 
authority(s) are notified of the urgent measures taken in such cases according to local 
regulations.
12.3 Untoward Medical Occurrences
Untoward medical occurrences occurring before the first exposure to IP are not 
considered AEs (according to the definition of AE, see Section 12.1.1). However, each 
serious untoward medical occurrence experienced before the first IP exposure (i.e., from 
the time of signed informed consent up to but not including the first IP exposure) will be 
described on the SAER. These events will not be considered as SAEs and will not be 
included in the analysis of SAEs. 
12.4 Non-Medical Complaints
A non-medical complaint (NMC) is any alleged product deficiency that relates to 
identity, quality, durability, reliability, safety and performance of the product but did not 
result in an AE. NMCs include but are not limited to the following:

A failure of a product to exhibit its expected pharmacological activity and/or 
design function, e.g. reconstitution difficulty

Missing components

Damage to the product or unit carton

A mislabeled product (e.g., potential counterfeiting/tampering)

A bacteriological, chemical, or physical change or deterioration of the product 
causing it to malfunction or to present a hazard or fail to meet label claims
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Any NMCs of the product will be documented on an NMC form and reported to the 
sponsor within 1 business day. If requested, defective product(s) will be returned to the 
sponsor for inspection and analysis according to procedures.
12.5 Medical, Medication, and Non-Drug Therapy History
At screening, the subject’s medical history will be described for the following body 
systems including severity (defined in Section 12.1.2.1) or surgery and start and end 
dates, if known: eyes, ears, nose, and throat; respiratory; cardiovascular; gastrointestinal; 
musculoskeletal; neurological; endocrine; hematopoietic/lymphatic; dermatological; and 
genitourinary. The subject’s medical history will also include documented history of 
on-demand treatment for the past 12 months and a documented history, e.g., patient 
charts and prescription information, of all bleeding episodes within the past 12 months.
All medications taken and non-drug therapies received in the 2 weeks prior to study entry 
and all concomitant medications and non-drug therapies during study will be recorded on 
the CRFs.
Data on medical history, drug and non-drug therapy history of those subjects who 
transition from surgery rVWF study will be used from the eCRF of the main studies, will 
be updated, if applicable, and transcribed into the respective eCRF of the prophy study. 
12.6 Physical Examinations
At screening and subsequent study visits (as described in Section 10.3), a physical 
examination will be performed on the following body systems: general appearance, head 
and neck, eyes and ears, nose and throat, chest, lungs, heart, abdomen, extremities and 
joints, lymph nodes, skin, and neurological. At screening, if an abnormal condition is 
detected, the condition will be described on the medical history CRF. At study visits, if a 
new abnormal or worsened abnormal pre-existing condition is detected, the condition will 
be described on the AE CRF. If the abnormal value was not deemed an AE because it 
was due to an error, due to a preexisting disease (described in Section 12.1.1.5), not 
clinically significant, a symptom of a new/worsened condition already recorded as an AE, 
or due to another issue that will be specified, the investigator will record the justification 
on the source record.
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12.6.1 Thromboembolic Events
Thromboembolic events are considered a potential risk of rVWF treatment, hence,
clinical evidence of thrombosis will be monitored during the study. In the case of clinical 
signs of any thromboembolic event other than superficial thrombosis, additional 
diagnostic procedures are required according to each institution’s standard of care which 
may consist of, but are not limited to the following:

For deep vein thrombosis (DVT): Magnetic Resonance Imaging (MRI), 
compression ultrasound or impedance plethysmography.

For pulmonary embolism: ECG, chest radiography, perfusion/scintiscan or MRI. 

For myocardial infarction: ECG, cardiac enzymes, echocardiography

For stroke: diffusion-weighted magnetic resonance imaging or computed 
tomography, ABCD scoring, carotid imaging 
Results of diagnostic procedures may be forwarded to the sponsor to be reviewed by an 
independent external expert panel, such as the DMC, if applicable.
12.6.2 Anaphylaxis
The diagnosis of anaphylaxis is highly likely when any of the following 3 criteria are 
fulfilled:
1.
Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue or both (e.g, generalized urticaria, pruritus or flushing, swollen 
lips-tongue-uvula) and at least one of the following:
a. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced peak expiratory flow [PEF], hypoxemia)
b. Reduced blood pressure (BP) or associated symptoms of end-organ 
dysfunction (e.g., hypotonia [collapse], syncope, incontinence)
2.
Two or more of the following that occur rapidly after exposure to a likely allergen 
for that patient (minutes to several hours):
a. Involvement of the skin or mucosal tissue (e.g., generalized urticaria, pruritus 
or flushing, swollen lips-tongue-uvula)
b. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced PEF, hypoxemia)
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c. Reduced BP or associated symptoms (hypotonia [collapse], syncope, 
incontinence)
d. Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)
3.
Reduced BP after exposure to a known allergen for that patient (minutes to 
several hours):
a. Infants and children: low systolic BP (age specific) or greater than 30% 
decrease in systolic BP
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from 
that person’s baseline BP
If a subject develops anaphylaxis in the course of the clinical study this needs to be 
reported as SAE (Section 12.1.1.1). Additional blood draws for Anti-VWF IgE antibody 
testing will be drawn (Section 12.9.13).
12.7 Vital Signs
Vital signs will be assessed pre and post-infusion at each visit, if not stated otherwise:

Height (cm) and weight (kg) (pre-infusion only)

Blood pressure: Systolic/diastolic blood pressure (mmHg) baseline measurements 
will be measured after a 10-minute rest in the supine/semi-recumbent position.

Pulse rate: Pulse rate (beats/min) will be measured at the distal radial arteries 
under the same conditions as above.

Respiratory rate: Respiratory rate (breaths/min) will be measured over a period of 
1 minute under the same conditions as above.

Temperature: Body temperature (oC or oF) may be determined by oral, rectal, 
axillary, or tympanic measurement at the discretion of the investigator. However, 
the same method should be used for all measurements in 1 subject.
Vital signs (pulse rate, respiratory rate, and blood pressure) should be recorded within 
30 min before and after IP administration. The assessment of vital signs per planned 
study visit is outlined in Supplement 20.2.
Vital sign values are to be recorded on the physical examination eCRF. For each vital 
sign value, the investigator will determine whether the value is considered an AE (see 
definition in Section 12.1). If assessed as an AE, the medical diagnosis (preferably), 
symptom, or sign, will be recorded on the AE eCRF. Additional tests and other 
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evaluations required to establish the significance or etiology of an abnormal result, or to 
monitor the course of an AE, should be obtained when clinically indicated. Any abnormal 
value that persists should be followed at the discretion of the investigator.
12.8 Electrocardiogram 
A standard 12-lead ECG at rest will be performed at screening, at the 6 month follow-up 
visit and at the study termination visit and evaluated for medical significance by the 
investigator.
12.9 Clinical Laboratory Parameters
Refer to the Laboratory Manual for information on collection and processing of samples.
In general all laboratory tests will be performed at central laboratories, except the 
pregnancy and blood group test which will be performed at the local laboratory. In 
addition, relevant critical safety laboratory tests for complete blood count (CBC), serum 
chemistry and/or coagulation parameters such as VWF and FVIII activity may also be 
performed in the local laboratory to ensure that results will be available immediately to 
the investigator. In principle, results from the central laboratory will be used for data 
analysis purposes. The assays performed in the central laboratories are specified in the 
Laboratory Manual. The investigator will supply the sponsor with a list of the normal 
ranges and units of measurement for the laboratory variables to be determined at the site. 
Laboratory values such as antibodies to other proteins are not required immediately and 
will be assessed later during the course of the study. 
Abnormal laboratory values deemed clinically significant by the investigator are to be 
recorded as AEs (see Section 12.1.2).
12.9.1 rVWF and Endogenous FVIII Pharmacokinetics
PK assessments using a dose of 50 IU ± 5 IU/kg rVWF:RCo will be performed at the 
baseline visit. If the subject is on on-demand treatment and has received VWF 
replacement therapy a washout period of at least 5 days is required before the infusion of 
rVWF for PK assessment can be administered. 
Blood samples will be drawn within 30 minutes pre-infusion, and at 7 time points 
post-infusion (30 5 minutes, 60 5 minutes, 6 1 hours, 12 1 hours, 24 2 hours, 
48 2 hours and 72 2 hours) VWF activity will be determined using the VWF:RCo, 
VWF:CB and the VWF: Ag assay. The Innovance assay will be used as an exploratory 
assay to provide supportive data and to compare the results of this new assay with results 
from the established VWF:RCo assay. 
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Endogenous FVIII activity will be measured using the 1-stage clotting assay. 
At the 12 month ± 2 week visit, a full PK analysis will also be performed. Blood samples 
will be drawn within 30 minutes pre-infusion, and at 7 time points post-infusion 
(30 ± 5 minutes, 60 ± 5 minutes, 6 ± 1 hours, 12 ± 1 hours, 24 ± 2 hours, 48 ± 2 hours, 
72 ± 2 hours). If a subject experiences a bleeding episode during the PK assessment no 
subsequent blood sample will be drawn in that specific PK period. The guidance provided 
in Section 8.7.4.4 has to be followed for the treatment of the bleeding episode. The 
subject once recovered is eligible to repeat the PK assessment.
The following parameters will be used as part of the PK assessment:

Incremental recovery of VWF:RCo, VWF:Ag, VWF:CB and INNOVANCE 
VWF Ac (exploratory assay)

AUC/dose, area under moment curve (AUMC/dose, clearance (CL), Volume of 
distribution at steady state (Vss), mean residence time (MRT), of 
VWF:RCo ,VWF:Ag, VWF:CB and INNOVANCE VWF Ac (exploratory assay)

Half-life of VWF:RCo, VWF:Ag, VWF:CB and INNOVANCE VWF Ac 
(exploratory assay)

Time course of the FVIII:C levels

VWF collagen binding (VWF:CB) levels
12.9.2 Hematology and Clinical Chemistry
The hematology panel will consist of CBC [hemoglobin, hematocrit, erythrocytes (ie, red 
blood cell count [RBC]), and leukocytes (i.e., white blood cell count [WBC])] with 
differential (i.e., basophils, eosinophils, lymphocytes, monocytes, neutrophils) and 
platelet counts.
The clinical chemistry panel will consist of sodium (Na), potassium (K), chloride (Cl), 
alanine aminotransferase (ALT), lactate dehydrogenase (LDH), aspartate 
aminotransferase (AST), bilirubin (BILI), alkaline phosphatase (AP), blood urea nitrogen
(BUN), creatinine (CR), and glucose (Glu).
Blood will be obtained for assessment of hematology and clinical chemistry parameters 
at screening, during PK-assessment prior to rVWF IP infusion, after 24 ± 2 hours, 
48 ± 2 hours and 72 ± 2 hours post rVWF IP infusion, at all follow-up visits as per 
schedule (refer to Supplement 20.3 Clinical Laboratory Assessments), i.e., 4 weeks
± 1 week, 8 weeks ± 1 week and every 3 months ± 2 weeks, and at study completion. 
Hematology and clinical chemistry assessments will be performed on 
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Ethylenediaminetetraacetic acid (EDTA)-anticoagulated whole blood and serum, 
respectively, at the central laboratory.
12.9.3 Immunology
12.9.3.1 Antibodies to VWF and FVIII
All subjects will be tested for binding and neutralizing antibodies to VWF and FVIII at 
screening, at baseline PK assessment, at each of the scheduled follow-up visits and at the 
study completion visit. Testing will be done prior to IP infusion and with at least a 
72 hour wash out period since the last IP infusion. If there is any suspicion of inhibitor 
development (e.g. excessive bleeding) binding and neutralizing antibodies to VWF and 
FVIII may be tested at the discretion of the investigator. 
12.9.3.2 Neutralizing and Total Binding Anti-VWF Antibodies
The assays to establish the presence of neutralizing and total binding anti-VWF 
antibodies have been established in the absence of international standards and with only 
limited numbers of positive controls. Therefore, caution is advised in interpreting positive 
results. In particular, any clinical association, changes in the natural history of the 
disease, effect of therapy, etc. needs to be taken into account for final judgment. 
The sponsor’s Medical Director should be consulted for additional advice. As part of the 
AE follow-up, any sample testing positive needs to be confirmed after 2-4 weeks for 
central laboratory testing. Only confirmed neutralizing anti -VWF antibodies are 
considered inhibitors (see Section 12.9.3.4). These subjects need to be closely monitored 
and therapy adjusted accordingly. 
12.9.3.3 Binding antibodies to VWF 
The presence of total binding anti-VWF antibodies will be determined by an enzyme-
linked immunosorbent assay (ELISA) employing polyclonal anti-human Immunoglobulin
(Ig) antibodies (IgG, IgM and IgA). For this assay (ELISA), recombinant human VWF 
will be coated onto a microtiter plate, then incubated with dilutions of the positive 
control, the negative control or test sample. Antibodies against human VWF that are 
present in the samples bind to the coated antigen and will be detected with a horseradish 
peroxidase (HRP)-coupled goat anti-human antibody (secondary antibody). The positive 
control for this assay will be a human monoclonal antibody specific for human VWF 
spiked into the negative control. The negative control for this assay is pooled normal 
human plasma.
Plasma samples are analyzed for binding antibodies against the specific antigen in two 
steps. First, the sample is screened for antibodies and the titer of binding antibodies is 
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determined. Second, the specificity of positive antibody results is confirmed.16
In brief, all samples are serially diluted (initial dilution 1:20 and further diluted 1:2). 
The titer endpoint, defined as the highest dilution that still gives a positive signal above 
cut off level, is determined in two independent duplicates. The cut off level is established 
based on background signal level of healthy plasma donors (n=160) and set to include 5% 
false positives to be as sensitive as possible (95% percentile). The ELISA assay is 
validated allowing an assay variability of ± 1 titer step. Therefore, differences ≤ 2 titers 
steps may be due to variability of the ELISA assay. Specificity has to be confirmed in a 
competition assay when a sample has a titer of 1:80 or higher in the screening assay. 
Based on the validation criteria samples tested in the screening assay at 1:20 or 1:40 
cannot be confirmed in the competition assay. A positive screening value is confirmed if 
the difference between the titers determined for the subject sample (re-screen) and for the 
subject sample with pre-incubation (confirmation sample) is > 2 titer steps. Antibody 
titers of subject samples will only be reported as positive, if the results of the screening 
and confirmatory analysis fulfill these acceptance criteria. The titer to be reported is 
always the one determined in the original screening procedure (independent of the result 
of the re-screening in the confirmation procedure). 
A more detailed test procedure will be supplied upon request or pro-actively if a sample 
tests positive. A treatment related increase of the binding anti-VWF antibodies is 
expected, if the titer increases by more than 2 titration steps. These subjects need to be 
closely monitored and therapy adjusted accordingly.
12.9.3.4 Neutralizing Antibodies to VWF
Three functional VWF assays, collagen binding (VWF:CB) assay, Ristocetin cofactor 
(VWF:RCo) and FVIII binding (VWF:FVIIIB), will be used to test for the presence of 
neutralizing anti-VWF antibodies. Neutralizing antibodies to VWF:RCo, VWF:CB and 
VWF:FVIIIB activities will be measured by assays based on the Bethesda assay 
established for quantitative analysis of FVIII inhibitors (Nijmegen modification of the 
Bethesda assay).17 The amount of inhibitor is expressed as Bethesda units (BU) per mL.
One BU is thereby defined as the amount of inhibitor that decreases the measured activity 
in the assays to 50% of that of the negative control samples. The assays were validated 
using human plasma samples from two type 3 VWD patients with low (1-2 BU/mL) and 
high (~10 BU/mL) titer inhibitors and plasma samples from non-human primates 
immunized with human rVWF (>100 BU/mL) 
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If a subject has a measurable baseline level of VWF activity in the respective assay, it is 
taken into account in the calculation of the residual activity. However, if baseline levels 
are too high (>15% VWF:RCo), inhibitors may not be reliably detected.
To exclude false positive results, the detection limit for anti-VWF inhibitors was set to 
1 BU/ml for all 3 assays. The rationale for this cut-off value is the relatively high CI of 
the underlying assays, making determinations at the end of the evaluation range of the 
Bethesda reference curve uncertain.18
A more detailed test procedure may be requested to further characterize the anti-VWF 
inhibitors, if detected.
12.9.3.5 Binding Antibodies to FVIII
Binding antibodies against FVIII will be analyzed using a proprietary enzyme 
immunoassay. The testing strategy will be as described for binding anti-VWF antibodies. 
Antibody-containing samples will be identified in a screening assay followed by a 
confirmatory assay to exclude false positive results.
12.9.3.6 Neutralizing Antibodies (Inhibitors) to FVIII 
Neutralizing antibodies (inhibitors) to FVIII will be assessed by the Nijmegen 
modification of the Bethesda assay in a central laboratory. To verify a FVIII inhibitor, 
additional testing (such as tests for Lupus anticoagulants) may be initiated. Positive FVIII 
inhibitor tests will be defined as ≥0.4 BU by the Nijmegen-modified Bethesda assay that 
is confirmed by a second test performed on an independent sample obtained 2-4 weeks 
following the first test. Only confirmed positive FVIII inhibitor test result will be 
reported as an SAE.
12.9.4 Antibodies to Other Proteins
Plasma will be assayed for the presence of antibodies against CHO protein (total Ig), 
murine IgG and human Furin (total Ig) using proprietary enzyme immunoassays. The 
testing strategy will be as described for binding anti- VWF antibodies. 
Antibody-containing samples will be identified in a screening assay followed by a 
confirmatory assay to exclude false positive results.
12.9.4.1 Anti-CHO Protein
Total Ig antibodies (IgG, IgA, IgM) against CHO protein will be analyzed. For this assay 
(ELISA), CHO protein derived from cultures of untransfected cells and propagated under 
the identical cell culture conditions used for ADVATE production will be coated onto a 
microtiter plate, then incubated with dilutions of the positive control, negative control or 
test sample. Antibodies against CHO protein that are present in the samples bind to the 
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coated antigen and will be detected with a horseradish peroxidase (HRP)-coupled goat 
anti-human antibody (secondary antibody). The positive control for this assay will be a 
polyclonal goat anti-CHO protein antibody spiked into the negative control. The negative 
control for this assay is pooled normal human plasma.
12.9.4.2 Anti-Murine IgG
A commercially available ELISA (Medac, Hamburg, Germany) will be used to detect and 
to quantify IgG antibodies originating from human plasma that are directed against 
mouse-IgG (HAMA: human anti- mouse antibodies). Microtiter plates coated with 
mouse IgG will be incubated with dilutions of the standard, the positive control, the 
negative control or the test sample. Antibodies against mouse IgG that are present in 
the samples bind to the coated antigen and form a bridge to a peroxidase coupled mouse 
IgG antibody that will be used for detection (bridging format of the ELISA assay). 
The positive control for this assay will be a polyclonal goat anti-murine IgG spiked into 
the negative control. The negative control for this assay is pooled normal human plasma.
12.9.4.3 Antibodies to Human Furin
Total Ig antibodies (IgG, IgA, IgM) against human Furin will be analyzed. For this assay 
(ELISA), recombinant human Furin will be coated onto a microtiter plate, then incubated 
with dilutions of the positive control, the negative control or test sample. Antibodies 
against human Furin that are present in the samples bind to the coated antigen and will be 
detected with a horseradish peroxidase (HRP)-coupled goat anti-human antibody 
(secondary antibody). The positive control for this assay will be a human monoclonal 
antibody specific for human Furin spiked into the negative control. The negative control 
for this assay is pooled normal human plasma.
12.9.5 Viral Serology
The following viral seromarkers will be assessed at screening:

HIV: anti-HIV 1, HIV 2 

HAV: anti-HAV (IgG and immunoglobulin M [IgM])

HBV: Hepatitis B surface antigen (HbsAg), anti-Hepatitis B (HB) core, anti-HBs

HCV: anti-HCV ELISA

Parvovirus B19: anti-B19V (IgG and IgM)
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Virus serology will be established during the screening period. The relevant confirmatory 
Polymerase Chain Reaction (PCR) testing may be performed from appropriate left-over 
samples as needed. 
12.9.6 Urinalysis (Dipstick)
The urinalysis will include assessments for erythrocytes, specific gravity, urobilinogen, 
ketones, glucose, protein, bilirubin, nitrite and pH and will be performed at the central 
laboratory.
12.9.7 Pregnancy Test
A pregnancy test for females of child-bearing potential will be performed at the local 
laboratory primarily from urine. If no urine sample is available, the pregnancy testing will 
be done from serum. The pregnancy test may need to be repeated during the course of 
study in countries where mandated by national law.
12.9.8 VWD Mutational Analysis, Multimer Analysis and Human Leukocyte 
Antigen Genotyping 
A cell pellet (buffy coat and erythrocytes) will be retained at the screening visit for VWD 
gene mutational analysis, VWF multimer analysis and HLA genotype determination if the 
information is not already available in the subject’s medical history. Results from 
multimer analysis (see Section 12.9.10.1) may contribute to VWD gene mutational 
analysis. The genetic testing will be done, when the subject consents to the genetic 
testing. 
12.9.9 Blood Group Analysis
The blood group needs to be determined during the screening period. If the information is 
not already available in the subject’s medical history, it has to be determined at the local 
lab.
12.9.10 Additional Laboratory Testing in Case of Thromboembolic Events
rVWF contains ultra large molecular weight (ULMW) multimers because of a lack of 
exposure to endogenous VWF protease (a disintegrin and metalloproteinase with a 
thrombospondin type 1 motif, member 13 (ADAMTS13) during the manufacturing 
process. In vitro and in vivo cleavage of these ultralarge molecular fractions by 
ADAMTS13 and generation of characteristic satellite bands has been extensively 
demonstrated during nonclinical and clinical development. Nevertheless, the potential 
elevated risk of thrombosis and/or other thromboembolic complications due to the 
administration of ultra large molecular VWF multimers in subjects with normal levels of 
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VWF cannot be completely excluded. Therefore VWF multimer analysis will not only be 
performed routinely at screening but in case of thromboembolic events both VWF 
multimer analysis as well as ADAMTS13 activity will be determined to assess any 
relatedness of these occurrences with IP treatment. 
12.9.10.1 VWF Multimer Analysis 
The VWF multimer pattern will be assessed using low-resolution sodium dodecyl sulfate 
(SDS)–agarose gel electrophoresis. High-resolution SDS–agarose gel electrophoresis, 
with agarose concentrations 1.5%, will be used to determine the satellite band structure 
of VWF. These analyses will employ Western blot with luminescence video imaging.
12.9.10.2 ADAMTS13 Activity 
VWF73 was identified as the 73 amino acid minimal region of the VWF A2 domain 
required for ADAMTS13 cleavage. The cleavage of this substrate will be detected by a 
commercially available ELISA-based Chromogenic assay (Technoclone Austria):
Cleavage of immobilized VWF73 substrate is detected by a HRP-labeled antibody 
directed against the cleavage site of VWF73. The amount of bound antibody, which is the 
function of the ADAMTS13 cleavage is detected by a chromogenic substrate.
12.9.11 Soluble P-Selectin (sP-Selectin)
sP-selectin is a cell adhesion molecule (CAM) found in granules in endothelial cells 
(cells lining blood vessels) and activated platelets. Data for an association between the 
sP-selectin concentration, thrombotic thrombocytopenic purpura (TTP) and venous 
thromboembolism (VTE) are limited and the predictive value has not yet established. 
A commercial ELISA assay will be employed as an exploratory test. sP-selectin will be 
determined at the Screening visit and used as indicator for an increased thrombotic risk.
12.9.12 D-Dimer
D-dimer will be used as a marker for DVT and disseminated intravascular coagulation
(DIC). While a negative result practically rules out thrombosis, a positive result can 
indicate thrombosis but does not rule out other potential etiologies, including a recent 
hemorrhage. Its main use, therefore, is to exclude thromboembolic disease where the 
probability is low. D-Dimer will be measured at the Screening visit and used as indicator 
for an increased thrombotic risk.
12.9.13 Additional Laboratory Testing in Case of Severe Hypersensitivity Reactions
If a subject develops a severe hypersensitivity reaction in the course of the clinical study, 
additional blood draws for anti-VWF IgE antibody testing will be drawn. The presence of 
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anti-VWF IgE will be determined by using the ImmunoCAP®, a VWF-specific IgE 
blood test (Thermo Scientific). The basis of the ImmunoCAP® technology is a cellulose 
polymer as solid phase in a plastic capsule providing a large surface for protein binding. 
rVWF as antigen is covalently coupled to the cellulose polymer. Detection of specific 
anti-VWF IgE bound to the antigen will be accomplished by a secondary enzyme-labeled 
anti-human IgE antibody. Testing for binding anti-human VWF IgE antibodies will be 
done with 0.5 mL plasma. Antibody containing samples will be identified and quantified 
in a screening assay followed by a confirmatory assay to exclude false positive results.
12.9.14 Exploratory Assay 
The INNOVANCE VWF Ac: an assay, which will eventually replace the VWF:RCo test 
in the future, will be done using the same time points/blood draws including PK 
assessment as outlined for the VWF:RCo assessments. The VWF Ac assay is a sensitive 
test for direct determination of VWF activity. It employs an advanced new technology, 
allowing the assay to mimic the reaction in which VWF binds to glycoprotein Ib (GPIb), 
the major VWF receptor protein on platelets. Latex particles are coated with an antibody 
against GPIb, to which recombinant GPIb is added.
12.9.15 Assessment of Laboratory Values
12.9.15.1 Assessment of Abnormal Laboratory Values 
For VWF and FVIII laboratory assessments no evaluation of clinical significance is 
necessary.
Each other laboratory value (except results to determine genetics of the underlying VWD 
disease and blood group) has to be assessed by the investigator and the assessment will be 
recorded on the eCRF. The investigator will determine for each abnormal laboratory 
value whether the value is considered clinically significant or not. For clinically 
significant values, the investigator will indicate if the value constitutes a new AE (see 
definition in Section 12.1) and record the sign, symptom, or medical diagnosis on the AE 
CRF, is a symptom or related to a previously recorded AE, is due to a pre-existing 
disease (described in Section 12.1.1.5), or is due to another issue that will be specified. If 
the abnormal value was not clinically significant, the investigator will indicate the reason, 
i.e. because it is due to a preexisting disease, due to a lab error, due to variation or due to 
another issue that will be specified. Additional tests and other evaluations required to 
establish the significance or etiology of an abnormal value, or to monitor the course of an 
AE should be obtained when clinically indicated. Any abnormal value that persists should 
be followed at the discretion of the investigator.
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Any seroconversion result for human immunodeficiency virus (HIV), hepatitis A virus
(HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis E virus (HEV), or 
parvovirus B19 (B19V) shall be re-tested.
12.10
12.10.1
 
 
 
 
 
 
 
 
 
 
12.10.2
 
 
 
 
 
 
 
 
 
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13. STATISTICS
13.1 Sample Size and Power Calculations
The determination of the sample size for this study is not based on strict statistical 
considerations. The sample size of a subset of at least 15 subjects with severe VWD, 5 of 
whom must have Type 3 VWD, is based on the Guideline on the Clinical Investigation of 
Human Plasma Derived von Willebrand Factor Products (CPMP/BPWG/220/02).1
13.2 Datasets and Analysis Cohorts
13.2.1 Safety Analysis Set
The Safety Analysis Set will be composed of all subjects who received any amount of IP, 
rVWF:ADVATE or rVWF alone. 
13.2.2 Full Analysis Dataset
The Full Analysis Set (FAS) will be composed of all subjects with available bleeding 
data gathered during prophylaxis IP treatment.
13.2.3 Per-Protocol Analysis Set
The Per-Protocol (PP) Analysis Set will be composed of subjects who are at least 70% 
compliant regarding required prophylactic infusions. Only subjects who met all study 
entry criteria and who had no major protocol violations that might impact efficacy 
assessments will be included in the PP analysis set.
13.2.4 PK Full Analysis Set
The Pharmacokinetic Full Analysis Set (PKFAS) will be composed of all subjects who 
received the PK infusion and who provided acceptable data for PK analysis. Acceptable 
PK data will be defined in the Statistical Analysis Plan. 
13.2.5 PK Per Protocol Analysis Set
The Pharmacokinetic Per Protocol Analysis Set (PKPPAS) is defined as a subset of the 
PKFAS. Subjects who met the following additional criteria will be included in the 
PKPPAS: had no major violation of affecting the PK period of the study as defined in the
detailed Statistical Analysis Plan.
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13.3 Handling of Missing, Unused, and Spurious Data
13.3.1 General
Statistical techniques will not be used to identify and exclude any observations as outliers 
from the analyses. If data are considered spurious, e.g. for lack of biological plausibility, 
it will be documented to include the reason for exclusion and the analyses from which the 
data were excluded.
13.3.2 Other
1.
Regarding missing data in PK records:

Body weight: If a subject’s weight is missing from the PK infusion record, the 
subject’s last recorded weight will be used to calculate the weight-adjusted 
dose.

Concentration:

Baseline concentration levels reported as below the limit of quantification will 
be considered to be 0. Missing VWF baseline concentration levels (VWF: RCo,
VWF: AG or VWF: CB) for Type 3 subjects will be set to 0.

Time:

If start time of infusion is missing (but stop time is available) and actual 
collection time is available, then stop time of infusion will be taken for further 
calculation (i.e. time difference between actual end date/time of infusion and 
date/time blood sample drawn).

If actual collection date/time is missing and planned collection date/time is 
missing, then this PK time point will be taken out from the PK analysis 
(i.e. no data entry for this time point). 

For all other scenarios, the planned collection date/time will be taken for 
further calculation.
2.
Regarding missing data in AE records:

Handling of unknown causality assessment:

If a subject experiences an AE with a missing causality assessment, the 
relationship of the AE will be counted as “related.”

Handling of unknown severity grades:

If a subject experiences more than one AE categorized under the same 
preferred term, one of them is categorized as “severe” and one of them is 
categorized as “unknown”, then the maximum severity for this preferred 
term should be counted as “severe” for this subject.
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
If a subject experiences more than one AE categorized under the same 
preferred term, one of them is categorized as “mild” or “moderate” and
one of them is categorized as “unknown”, then the maximum severity for 
this preferred term should be counted as “unknown” for this subject.
13.4 Methods of Analysis
The study success criteria are the objectives as stated in Section 7. “Treatment success” 
was defined as the extent of control of bleeding episodes achieved during this study.
13.4.1 Primary Outcome Measure
The statistical analysis will provide descriptive summaries.
For the number of infusions and for the total weight adjusted consumption of rVWF and 
ADVATE per month and per year during on-demand treatment, summary statistics will 
be carried out.
For the number (proportion) of subjects with reduction of ABR relative to historic ABR 
as well as for the number (proportion) of subjects with 0 bleeds, proportions and 
corresponding 95% two-sided CIs will be performed.
The annualized rate of bleeding episodes will be calculated as (Number of bleeding 
episodes/observed treatment period in days) * 365.25. 
The primary efficacy analysis will be based on the FAS. As a supportive analysis, the 
same analysis will also be carried out on the PP.
The two time periods (prior to prophylaxis treatment and while on prophylaxis) will be 
compared within each subject in terms of mean ABR using a generalized estimating 
equations model framework (with a logarithmic link function which was the default for 
the negative binomial distribution), accounting for the fixed effect of the two time 
periods. The follow-up time (in years) will be specified as an offset and an unstructured 
working correlation matrix will be used to account for the correlated data. Ratios between 
the two time period means (95% CI) will be estimated within this model by SAS 
procedure GENMOD.
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13.4.2 Secondary Outcome Measures 
13.4.2.1 Efficacy
For the number of infusions and for the total weight adjusted consumption of rVWF and 
ADVATE per month and per year during on-demand treatment for bleeding episodes, 
summary statistics will be carried out.
For the number (proportion) of subjects with reduction of ABR relative to historic ABR 
as well as for the number (proportion) of subjects with 0 bleeds, proportions and 
corresponding 95% two-sided CIs will be performed.
The cause, type, localization and severity of bleeding episodes will also be recorded and 
summarized. Bleeding episodes should be organized by where they occur in addition to 
whether they occurred spontaneously or due to a traumatic event.
The secondary efficacy analysis will be performed on the FAS only.
13.4.2.2 Efficacy of the Treatment of Bleeding Episodes
For the number of infusions of rVWF and ADVATE per bleeding episode, for the weight 
adjusted consumption of rVWF and ADVATE per bleeding event as well as for the 
overall hemostatic efficacy rating at resolution of bleed, summary statistics will be 
carried out.
The severity and localization of bleeding episodes will also be recorded and summarized.
The analysis will be performed on the FAS.
13.4.2.3 Pharmacokinetic Analysis
All PK analyses will use the actual sampling times, not nominal times specified in the 
protocol, wherever possible. Actual sampling times will be defined as time from the start 
of infusion to the blood sample collection time. A deviation from the protocol-specified 
blood sample drawing time window will not be a reason to exclude an observation from 
the analysis. Samples with unknown actual and planned collection date/time or where the 
concentration could not be determined, or where results were biologically implausible 
will be eliminated from the analysis.
If any concentration data are considered spurious (e.g. lack of biological plausibility), the 
reason for exclusion from the analysis and the analysis from which the data point was 
excluded will be documented.
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To ensure that values at baseline (pre-infusion) are not affecting the estimation of PK 
parameters, post-infusion concentration data will be adjusted for baseline as follows:
After adjustment of the post-infusion concentration data, any pre-infusion data will be set 
to 0.
CCorrected will be set to missing, if:

Samples have an unknown draw time or where the concentration could not be 
determined, or where results were deemed to be unreliable due to analytical 
issues.

Any concentration data are considered spurious (e.g. lack of biological 
plausibility).
Handling of concentrations that are below the quantification limit: 

Baseline concentration values reported as below the limit of quantification will be 
considered to be 0 (CCorrected = Concentration value)

Post-infusion concentration values reported as below the limit of quantification or 
missing repeated concentration values will be set to missing (CCorrected = 
missing)
The area under the plasma concentration/time curve from time 0 to infinity (AUC0-) and 
the area under the first moment curve from time 0 to infinity (AUMC0-) will be 
calculated as the sum of AUC or AUMC from time 0 to the time of last quantifiable 
concentration plus a tail area correction calculated as Ct/z and Ct/z(t + 1/z), 
respectively, where Ct is the last quantifiable concentration, t is the time of last 
quantifiable concentration and z is the terminal or disposition rate constant.
The area under the plasma concentration/time curve from time 0 to 72 hours post-infusion 
(AUC0-72h) will be computed using the linear trapezoidal rule. For the calculation of 
AUC0-72h the levels at 72 hours will be linearly interpolated/ extrapolated from the 
2 nearest sampling time points.
Elimination phase half-life (HL) in hours will be calculated as:
/ = 	
(2)/
t
Measured,
C
)
Tmax
Measured,
C
infusion
pre
Measured,
C
(1
t
Corrected,
C




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where the elimination rate constant (z) will be obtained by loge-linear fitting using least 
squares deviations to at least the last 3 quantifiable concentrations above pre-infusion 
level.
The Mean Residence Time (MRT) in hours will be calculated as total area under the 
moment curve divided by the total area under the curve:
MRT = ∞[ℎ ∗/]
∞[ℎ∗/]
Systemic clearance in dL/kg/h will be calculated as the dose in IU/kg divided by the 
total AUC: 
 = 
!
"#[/$]
%[ℎ∗/]
Apparent steady state volume of distribution (Vss) in dL/kg will be calculated as:
&"" = !
"#[ $
⁄
] × %[ℎ ∗/]
%

[ℎ ∗/]
The maximum concentration, Cmax, will be calculated as the maximum concentration 
post-infusion.
The time to reach the maximum concentration, Tmax, in hours was defined as the time 
to reach Cmax. 
Incremental recovery (IR) in (IU/dL)/(IU VWF:RCo/kg) will be calculated as:
) = *+,[ 
⁄
] −./01234051[/]

"# 6#7 $ 8
9 :#;ℎ< [/$]
where Cmax and Cpre-infusion are the unadjusted concentration values.
The PK parameters AUC0-72h/Dose, AUC0-∞/Dose, AUMC0-∞/Dose, MRT (mean 
residence time), CL (clearance), IR (incremental recovery), T1/2 (elimination phase half-
life), Vss (Volume of distribution at steady state), Cmax (maximum concentration) and
Tmax (time to reach the maximum concentration) will be summarized by mean, standard 
deviation and the corresponding 90% CIs, median, Q1, Q3, IQR and range.
Descriptive statistics will be used to summarize VWF:RCo levels for each nominal time 
point on the PK curve. 
PK analysis as described above will be carried out on the PKFAS as well as on the 
PKPPAS.
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For all subjects in the PKFAS concentration vs. time curves will be prepared.
PK parameters will be derived using non-compartmental methods in WinNonlin.
The analysis will be performed on the FAS.
13.4.2.4 Safety
AEs that occurred during or within 24 hours after first IP infusion will be presented in 
summary tables. Summary tables shall indicate the number of subjects who experienced 
adverse events. Separate tables will be carried out for temporally associated adverse 
events; and for temporally associated or causally related adverse events. 
In addition, tables will be prepared to list each AE, the number of subjects who 
experienced an AE at least once, and the rate of subjects with AE(s). AEs will be grouped 
by system organ class. Each event will then be divided into defined severity grades (mild, 
moderate, severe). The tables will also divide the AEs into those considered related (a 
“possibly related” or a “probably related” AE will be considered as a “related AE”) to the 
treatment and those considered unrelated (an “unlikely related” or a “not related” AE will 
be considered as an “unrelated” AE). These tables will also be carried out for temporally 
associated adverse events; and for temporally associated or causally related adverse 
events. 
All AEs; temporally associated AEs; causally related AEs (by investigator assessment); 
and temporally associated or causally related AEs will also be summarized by system 
organ class, preferred term, including the number of AEs, the number (%) of unique 
subjects, the frequency category (very common: ≥10%, common: ≥1% to <10%, 
uncommon: ≥0.1% to <1%, rare: ≥0.01% to <0.1%, very rare: <0.01%) and the number 
of IP-infusions associated with an AE.
Temporally associated AEs are defined as AEs that begin during infusion or within
24 hours (or 1 day where time of onset is not available) after completion of infusion, 
irrespective of being related or not related to treatment.
AEs and SAEs for each subject, including the same event on several occasions, will be 
listed separately, giving both MedDRA preferred term and the original verbatim term 
used by the investigator, system organ class, severity grade, seriousness, relation to the 
treatment (by investigator assessment; for SAEs this will be by investigator and sponsor 
assessment), onset date, and stop date.
AEs that occurred before first IP infusion will be listed separately.
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Incidences of thromboembolic events and hypersensitivity reactions will be tabulated and 
also listed per subject. For the development of antibodies, proportions will be carried out.
The safety analyses will be based on the safety analysis set. 
13.5 Exploratory Outcome Measures
 
 
 
 
 
 
 
 
13.6 Planned Interim Analysis of the Study
No formal interim analysis is planned for this study. However, a descriptive summary 
report for this study is planned after all subjects have completed at least 6 months of
prophylactic treatment with rVWF.
14. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
The investigator/study site will cooperate and provide direct access to study documents 
and data, including source documentation for monitoring by the study monitor, audits by 
the sponsor or sponsor’s representatives, review by the EC, and inspections by applicable 
regulatory authorities, as described in the Clinical Trial Agreement (CTA). If contacted 
by an applicable regulatory authority, the investigator will notify the sponsor of contact, 
cooperate with the authority, provide the sponsor with copies of all documents received 
from the authority, and allow the sponsor to comment on any responses, as described in 
the CTA.
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15. QUALITY CONTROL AND QUALITY ASSURANCE
15.1 Investigator’s Responsibility
The investigator will comply with the protocol (which has been approved/given favorable 
opinion by the EC), ICH GCP, and applicable national and local regulatory requirements 
as described in the CTA. The investigator is ultimately responsible for the conduct of all 
aspects of the study at the study site and verifies by signature the integrity of all data 
transmitted to the sponsor. The term “investigator” as used in this protocol as well as in 
other study documents, refers to the investigator or authorized study personnel that the 
investigator has designated to perform certain duties. Sub-investigators or other 
authorized study personnel are eligible to sign for the investigator, except where the 
investigator’s signature is specifically required.
15.1.1 Investigator Report and Final Clinical Study Report 
The investigator, or coordinating investigator(s) for multicenter studies, will sign the 
clinical study report. The coordinating investigator will be selected before study start. 
15.2 Training
The study monitor will ensure that the investigator and study site personnel understand all 
requirements of the protocol, the investigational status of the IP, and his/her regulatory 
responsibilities as an investigator. Training may be provided at an investigator’s meeting, 
at the study site, and/or by instruction manuals. In addition, the study monitor will be 
available for consultation with the investigator and will serve as the liaison between the 
study site and the sponsor.
15.3 Monitoring
The study monitor is responsible for ensuring and verifying that each study site conducts 
the study according to the protocol, standard operating procedures other written 
instructions/agreements, ICH GCP, and applicable national and local regulatory 
guidelines/requirements. The investigator will permit the study monitor to visit the study 
site at appropriate intervals, as described in the CTA. Monitoring processes specific to the 
study will be described in the clinical monitoring plan. 
15.4 Auditing
The sponsor and/or sponsor’s representatives may conduct audits to evaluate study 
conduct and compliance with the protocol, standard operating procedures, other written 
instructions/agreements, ICH GCP, and applicable national and local regulatory 
guidelines/requirements. The investigator will permit auditors to visit the study site, as 
described in the CTA. Auditing processes specific to the study will be described in the 
audit plan.
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15.5 Non-Compliance with the Protocol
The investigator may deviate from the protocol only to eliminate an apparent immediate 
hazard to the subject. In the event(s) of an apparent immediate hazard to the subject, the 
investigator will notify the sponsor immediately by phone and confirm notification to the 
sponsor in writing as soon as possible, but within 1 calendar day after the change is 
implemented. The sponsor (Baxalta) will also ensure the responsible EC and relevant 
competent authority are notified of the urgent measures taken in such cases according to 
local regulations.
If monitoring and/or auditing identify serious and/or persistent non-compliance with the 
protocol, the sponsor may terminate the investigator’s participation. The sponsor will 
notify the EC and applicable regulatory authorities of any investigator termination.
15.6 Laboratory and Reader Standardization
A central laboratory/reader will be used for all clinical assessments except for pregnancy
testing and blood group test (refer to Section 12.9). Local laboratories are requested to 
provide their laboratory specifications of the individual tests that are also being tested 
locally.
16. ETHICS 
16.1 Subject Privacy
The investigator will comply with applicable subject privacy regulations/guidance as 
described in the CTA.
16.2 Ethics Committee and Regulatory Authorities
Before enrollment of patients into this study, the protocol, informed consent form, any 
promotional material/advertisements, and any other written information to be provided 
will be reviewed and approved/given favorable opinion by the EC and applicable 
regulatory authorities. The IB will be provided for review. The EC’s composition or a 
statement that the EC’s composition meets applicable regulatory criteria will be 
documented. The study will commence only upon the sponsor’s receipt of 
approval/favorable opinion from the EC and, if required, upon the sponsor’s notification 
of applicable regulatory authority(ies) approval, as described in the CTA.
If the protocol or any other information given to the subject is amended, the revised 
documents will be reviewed and approved/given favorable opinion by the EC and 
applicable regulatory authorities, where applicable. The protocol amendment will only be 
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implemented upon the sponsor’s receipt of approval and, if required, upon the sponsor’s 
notification of applicable regulatory authority(ies) approval.
16.3 Informed Consent
Investigators will choose patients for enrollment considering the study eligibility criteria. 
The investigator will exercise no selectivity so that no bias is introduced from this source. 
All patients and/or their legally authorized representative must sign an informed consent 
form before entering into the study according to applicable national and local regulatory 
requirements and ICH GCP. Before use, the informed consent form will be reviewed by 
the sponsor and approved by the EC and regulatory authority(ies), where applicable, (see 
Section 16.2). The informed consent form will include a comprehensive explanation of 
the proposed treatment without any exculpatory statements, in accordance with the 
elements required by ICH GCP and applicable national and local regulatory 
requirements. Patients or their legally-authorized representative(s) will be allowed 
sufficient time to consider participation in the study. By signing the informed consent 
form, patients or their legally authorized representative(s) agree that they will complete 
all evaluations required by the study, unless they withdraw voluntarily or are terminated 
from the study for any reason.
The sponsor will provide to the investigator in written form any new information that 
significantly bears on the subjects’ risks associated with IP exposure. The informed 
consent will be updated, if necessary. This new information and/or revised informed 
consent form, which have been approved by the applicable EC and regulatory authorities, 
will be provided by the investigator to the subjects who consented to participate in the 
study 
16.4 Data Monitoring Committee
This study will be monitored by Data Monitoring Committee (DMC). The DMC is a 
group of individuals with pertinent expertise that reviews on a regular basis accumulating 
data from an ongoing clinical study. For this study, the DMC will be composed of 
recognized experts in the field of VWD clinical care and research who are not actively 
recruiting subjects, and an independent statistician. The DMC can stop a trial if it finds 
toxicities or if treatment is proven to be not beneficial. Details will be defined in the 
DMC charter. 
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17. DATA HANDLING AND RECORD KEEPING
17.1 Confidentiality Policy
The investigator will comply with the confidentiality policy as described in the CTA. 
17.2 Study Documentation and Case Report Forms
The investigator will maintain complete and accurate paper format study documentation 
in a separate file. Study documentation may include information defined as “source data” 
(see Section 8.8), records detailing the progress of the study for each subject, signed 
informed consent forms, correspondence with the EC and the study monitor/sponsor, 
enrollment and screening information, CRFs, SAERs, laboratory reports (if applicable),
and data clarifications requested by the sponsor.
The investigator will comply with the procedures for data recording and reporting. Any 
corrections to paper study documentation must be performed as follows: 1) the first entry 
will be crossed out entirely, remaining legible; and 2) each correction must be dated and 
initialed by the person correcting the entry; the use of correction fluid and erasing are 
prohibited.
The investigator is responsible for the procurement of data and for the quality of data 
recorded on the CRFs. CRFs will be provided in electronic form. 
If electronic format CRFs are provided by the sponsor, only authorized study site 
personnel will record or change data on the CRFs. If data is not entered on the CRFs 
during the study visit the data will be recorded on paper and this documentation will be 
considered source documentation. Changes to a CRF will require documentation of the 
reason for each change. An identical (electronic/paper) version of the complete set of 
CRFs for each subject will remain in the investigator file at the study site in accordance 
with the data retention policy (see Section 17.3).
The handling of data by the sponsor, including data quality assurance, will comply with 
regulatory guidelines (e.g., ICH GCP) and the standard operating procedures of the 
sponsor. Data management and control processes specific to the study will be described 
in the data management plan.
17.3 Document and Data Retention 
The investigator will retain study documentation and data (paper and electronic forms) in 
accordance with applicable regulatory requirements and the document and data retention 
policy, as described in the CTA.
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18. FINANCING AND INSURANCE
The investigator will comply with investigator financing, investigator/sponsor insurance, 
and subject compensation policies, if applicable, as described in the CTA.
19. PUBLICATION POLICY
The investigator will comply with the publication policy as described in the CTA. 
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20. SUPPLEMENTS
20.1 Study Flow Chart
Figure 1
Study Design for Baxalta Clinical Study 071301
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20.2 Schedule of Study Procedures and Assessments
Table 5
Schedule of Study Procedures and Assessments
Procedures/
Assessments
Screening Visit
Baseline Visit 
(PK-assessment visit)
Prophylaxis Initiation 
Visit
Interval/Follow-Up 
Study Visits
PK Assessment and 
Study Completion
Termination 
Visit
Pre-infusion
Infusion
Post-infusiong
1 month ± 
1 week
2 month ± 
1 week 
3 month ± 
2 weeks
6 month ± 
2 weeks 
9 month ± 
2 weeks
Pre-
infusion
Infusion
Post-
infusiong
Conducted 
at the 
72 hour 
postinfusion 
PK 
Assessment
12 month± 
2 weeks
Informed Consent a
X
Eligibility Criteria
X
Medical Historyb
X
X
X
Medicationsc
X
X
X
X
X
X
X
X
X
X
Non-drug Therapiesc
X
X
X
X
X
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
Bleeding Episodes
X
X
X
X
X
X
X
X
X
X
Laboratories 
X
X
X
Xh
X
X
X
X
X
X
X
X
Vital Signsd
X
X
X
X
X
X
X
X
X
X
X
X
ECG
X
X
X
IP Treatmente
X
X
X
X
X
X
X
X
IP Consumption / Treatment 
Compliance 
X
X
X
X
X
Subject Diary
X
X
X
X
X
X
Xf
X
X
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Continued
a) Occurs at enrollment (before screening).
b) Including documented history of on-demand treatment for the past 12 months and a documented history, e.g., patient charts and prescription information, 
of all bleeding episodes within the past 12 months. 
c) Including all medications and non- drug therapies taken in the 2 weeks prior to study entry and all the concomitant medications and non-drug therapies 
during the course of the study.
d) Vital signs (pulse rate, respiratory rate, and blood pressure): within 30 minutes before infusion start and 30 ± 15 minutes post-infusion.
e) IP treatment after the prophylactic treatment initiation visit at the site will be continued as home-treatment if the subject qualifies; a wash-out period of at 
least 72 hours is required after the last IP infusion before the follow-up visit. IP infusion will be given at the study site after the blood sample for 
immunology testing and IR determination is drawn.
f) Can be done either at the screening or the baseline visit.
g) Time points for blood draws post infusion: 30 ± 5 minutes; 60 ± 5 minutes; 6 ± 1 hours; 12 ± 1 hours; 24 ± 2 hours; 48 ± 2 hours; 72 ± 2 hours. 
h) If a subject did not undergo PK assessment (for example the subject has participated in the surgery study 071101 and has undergone PK in Study 071101), 
laboratory assessments will be performed at this visit.
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20.3 Clinical Laboratory Assessments
Table 6
Clinical Laboratory Assessments
Procedures/
Assessments
Screening Visit
Baseline Visit 
(PK-assessment visit)
Prophylaxis Initiation 
Visitk
Interval/Follow-Up 
Study Visits
PK Assessment and 
Study Completion
Termination 
Visit
Pre-infusion
Infusion
Post-infusiong
1 month ± 
1 week
2 month ± 
1 week 
3 month ± 
2 weeks
6 month ± 
2 weeks 
9 month ± 
2 weeks
Pre-
infusion
Infusion
Post-
infusiong
Conducted 
at the 
72 hour 
postinfusion 
PK 
Assessment
12 month± 
2 weeks
Hematology a
X
X
X
X
X
X
X
X
X
Xm
X
Clinical Chemistryb
X
X
X
X
X
X
X
X
X
X
X
Coagulation Panel/PK 
assessmentc
X
X
X
X
X
X
X
X
X
X
X
Immunogenicityd
X
X
X
Xl
X
X
X
X
X
X
X
Viral Serologye
X
Urinalysisf
X
VWD Gene Mutational 
Analysis / HLA genotype 
analysis and Analysis of 
VWF multimersg
X
sP-selectin and 
D-dimer
Xh
Blood Groupi 
X
X
Pregnancy Testj
X
Exploratory Tests
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Continued
a) Hematology assessments include: complete blood count [hemoglobin, hematocrit, erythrocytes (i.e. red blood cell count), mean corpuscular volume 
(MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), leukocytes (i.e. white blood cell count)] with 
differential (i.e. basophils, eosinophils, lymphocytes, monocytes, neutrophils) and platelet counts. Hematology assessments during PK assessments will be 
determined prior IP infusion and 24 ± 2 hours, 48 ± 2 hours and 72 ± 2 hours thereafter.
b) Clinical chemistry assessments include: Sodium, potassium, chloride, glucose, creatinine, blood urea nitrogen (BUN), aspartate aminotransferase (AST), 
alanine aminotransferase (ALT) lactate dehydrogenase (LDH), alkaline phosphatase (AP), bilirubin. Clinical chemistry will be determined at baseline, 
after 24 ± 2 h, 48 ± 2 hours and 72 ± 2 hours during the PK assessments. 
c) Coagulation panel/PK assessment: INR/aPTT, VWF:RCo, VWF:Ag, VWF:CB, FVIII:C, VWF Innovance (exploratory assay); during the PK assessment 
at the baseline visit blood samples will be drawn 30 min prior PK infusion; once the PK infusion is completed 30 5 minutes; 60 ± 5 minutes; 6 hours 
± 1 hour ; 12 ± 0.5 hours; 24 ± 2 hours, 48 ± 2 hours; 72 ± 2 hours and VWF:RCo, VWF:CB, VWF:Ag, VWF Ac, FVIII:C will be determined; in case of 
thromboembolic event VWF multimers and ADAMTS13 will be analyzed to judge on a possibly relatedness to UHMW fractions of the IP.
d) Immunogenicity assessment includes Neutralizing Antibodies (Ab) to FVIII – Neutralizing and Neutralizing Ab to VWF:RCo, Neutralizing Ab to 
VWF:CB, Neutralizing Ab to VWF:FVIII, Binding Ab to VWF and FVIII, Binding Ab to CHO-Protein, Binding Ab to rFurin, Binding Ab to Murine IgG; 
.CD4* In case of an SAE hypersensitivity reaction IgE antibodies to VWF will be determined. A washout period of at least 72 hours after the last IP 
infusion is required before blood samples for immunogenicity assessments can be drawn. 
e) Viral Serology Hepatitis A Antibody, Total - Hepatitis A Antibody, IgM - Hepatitis B Surface Antibody - Hepatitis B Core Ab, Total - Hepatitis B Surface 
Antigen - Hepatitis C Virus Antibody; Parvovirus B19; HIV-1/HIV-2 Antibodies
f) Urinalysis comprehends: erythrocytes, specific gravity, urobilinogen, ketones, glucose, protein, bilirubin, nitrite, and pH
g) Not required if available in the subject’s medical history; VWF multimers: additionally in case of thromboembolic events
h) At screening and in case of thromboembolic events
i) Blood group assessment major blood group (local laboratory) only if not available in the subject’s medical history
j) Serum pregnancy test (in females of child-bearing potential if no urine sample is available)
k) The 72 h post-infusion laboratory assessments coincidence with the initiation visit for prophylactic treatment. After the blood samples are drawn for 
laboratory assessment for the 72 h post infusion PK assessment, the subject receives the first IP infusion for prophylactic treatment (prophylactic treatment 
initiation visit). 
l) Only needed for subjects without PK assessment prior to their first IP infusion in this study.
m) A full PK analysis will be performed. Blood samples will be drawn within 30 minutes pre-infusion, and at 7 time points post-infusion (30 ± 5 minutes,
60 ± 5 minutes, 6 ± 1 hours, 12 ± 1 hours, 24 ± 2 hours, 48 ± 2 hours, 72 ± 2 hours).
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20.4 Contraceptive Methods for Female Subjects of Childbearing Potential
In this study, subjects who are women of childbearing potential must agree to utilize a 
highly effective contraceptive measure throughout the course of the study and for 30 days 
after the last administration of investigational product. In accordance with the Clinical 
Trial Facilitation Group (CTFG) recommendations related to contraception and 
pregnancy testing in clinical trials (version 2014-09-15),ii birth control methods which 
may be considered as highly effective include the following:
Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation:
oral
intravaginal
transdermal
Progestogen-only hormonal contraception associated with inhibition of ovulation:
oral
injectable
implantableiii
Intrauterine device (IUD)iii
Intrauterine hormone-releasing system (IUS) iii
Bilateral tubal occlusioniii
Vasectomised partner(s)iii
Sexual abstinence during the entire study period
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhoea method (LAM) are 
not acceptable methods of contraception. Female condom and male condom should not 
be used together.
                                                
ii Clinical Trial Facilitation Group (CTFG) recommendations related to contraception and pregnancy testing 
in clinical trials: http://www.hma.eu/fileadmin/dateien/ 
Human_Medicines/01About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf.
iii Contraception methods that are considered to have low user dependency.
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21. REFERENCES
1. Committee for Medicinal Products for Human Use. Guideline on clinical 
investigation of human plasma derived von Willebrand factor products. 
CPMP/BPWG/220/02, 12. 11-17-2005. London, European Medicines Agency 
(EMEA) (EMA). Link to Publisher´s Site: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/201
0/01/WC500067126.pdf.
2. Mannucci PM. Treatment of von Willebrand's Disease. N.Engl.J.Med. 
2004;351:683-694.
3. Goudemand J, Scharrer I, Berntorp E et al. Pharmacokinetic studies on Wilfactin, a 
von Willebrand factor concentrate with a low factor VIII content treated with three 
virus-inactivations/removal methods. J.Thromb.Haemost. 2005;3:2219-2227.
4. Abshire T. The role of prophylaxis in the management of von Willebrand disease: 
today and tomorrow. Thromb.Res. 2009;124 Suppl 1:S15-S19.
5. Nilsson IM, Blombäck M, Jorpes E, Blombäck B, Johansson SA. V. Willebrand's 
disease and its correction with human plasma fraction 1-0. Acta Med.Scand. 
1957;159:179-188.
6. Berntorp E, Petrini P. Long-term prophylaxis in von Willebrand disease. Blood 
Coagul.Fibrinolysis 2005;16 Suppl 1:S23-S26.
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7. Berntorp E. Prophylaxis and treatment of bleeding complications in von Willebrand 
disease type 3. Semin.Thromb.Hemost. 2006;32:621-625.
8. Federici AB. Highly purified VWF/FVIII concentrates in the treatment and 
prophylaxis of von Willebrand disease: the PRO.WILL Study. Haemophilia. 
2007;13 Suppl 5:15-24.
9. Halimeh S, Krümpel A, Rott H et al. Long-term secondary prophylaxis in children, 
adolescents and young adults with von Willebrand disease. Results of a cohort 
study. Thromb.Haemost. 2011;105:597-604.
10. Abshire TC, Federici AB, Alvárez MT et al. Prophylaxis in severe forms of von 
Willebrand's disease: results from the von Willebrand Disease Prophylaxis Network 
(VWD PN). Haemophilia. 2013;19:76-81.
11. Abshire T, Cox-Gill J, Kempton CL et al. Prophylaxis escalation in severe von 
Willebrand disease: A prospective study from the von Willebrand Disease 
Prophylaxis Network. J.Thromb.Haemost. 2015;13:1585-1589.
12. Berntorp E. Prophylaxis in von Willebrand disease. Haemophilia. 2008;14 Suppl 
5:47-53.
13. Varadi K, Rottensteiner H, Vejda S et al. Species-dependent variability of 
ADAMTS13-mediated proteolysis of human recombinant von Willebrand factor. 
J.Thromb.Haemost. 2009;7:1134-1142.
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14. Mannucci PM, Kempton C, Millar C et al. Pharmacokinetics and safety of a novel 
recombinant human von Willebrand factor manufactured with a plasma-free 
method: a prospective clinical trial. Blood. 2013;122:648-657.
15. Gill JC, Castaman G, Windyga J et al. Hemostatic efficacy, safety and 
pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand 
disease. Blood. 2015;126:2038-2046.
16. Committee for Medicinal Products for Human Use. Guideline on immunogenicity 
assessment of biotechnology-derived therapeutic proteins. 
CHMP/BMWP/14327/2006, 18. 12-13-2007. London, European Medicines Agency 
(EMEA - EMA). Link to Publisher´s Site: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/200
9/09/WC500003946.pdf.
17. Kasper CK. Laboratory tests for factor VIII inhibitors, their variation, significance 
and interpretation. Blood Coagul.Fibrinolysis 1991;2 Suppl 1:7-10.
18. Lillicrap D. Von Willebrand Factor. International Society for Thrombhosis and 
Hemostasis (ISTH) 54th Annual Scientific and Standardization Committee 
Meeting. 2008:60-64.
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22. SUMMARY OF CHANGES 
Protocol 071301: Amendment 2: 2016 DEC 15
Replaces: Amendment 1: 2016 APR 08
In this section, changes from the previous version of the Protocol, dated 2016 APR 08, 
are described and their rationale is given.
1. Throughout the document
Description of Change: Minor grammatical and/or administrative changes have 
been made.
Purpose for Change: To improve the readability and/or clarity of the protocol.
2. Title page; Investigator Acknowledgement Page
Description of Change: NCT number was added.
Purpose for Change: Administrative.
3.
Section 1.1; Investigator Acknowledgement Page
Description of Change: Changed authorized representative (signatory) / 
responsible party.
Purpose for Change: Administrative.
4.
Section 2
Description of Change: Revised reporting method for SAEs to paper SAE form.
Purpose for Change: Administrative.
5.
Section 12.1.1.2
Description of Change: 
Original text:
Once determined to meet the criteria for a SUSAR, an SAE should be submitted 
to regulatory agencies expeditiously.
New text:
Once determined to meet the criteria for a SUSAR, an SAE should be submitted 
to regulatory agencies expeditiously. the sponsor will ensure expedited 
SUSAR reporting in line with the regulatory requirements in participating 
countries as outlined in the Safety Management Plan.
Purpose for Change: Administrative.
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6.
Section 20.4
Description of Change: New section added: “Contraceptive Methods for Female 
Subjects of Childbearing Potential”
Purpose for Change: Section added in order to list what constitutes adequate birth 
control measures to be used by females of childbearing potential, in line with 
Clinical Trials Facilitation Group guidance on effective contraception. 
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INVESTIGATOR ACKNOWLEDGEMENT
RECOMBINANT VON WILLEBRAND FACTOR (rVWF)
A prospective, phase 3, open-label, international multicenter study on efficacy and 
safety of prophylaxis with rVWF in severe von Willebrand Disease
PROTOCOL IDENTIFIER: 071301
CLINICAL TRIAL PHASE 3
AMENDMENT 2: 2016 DEC 15
Replaces: AMENDMENT 1: 2016 APR 08
OTHER PROTOCOL ID(s)
NCT Number: NCT02973087
EudraCT Number: 2016-001478-14
IND NUMBER: to be determined
By signing below, the investigator acknowledges that he/she has read and understands 
this protocol, and will comply with the requirements for obtaining informed consent from 
all study subjects prior to initiating any protocol-specific procedures, obtaining written 
initial and ongoing EC(s) protocol review and approval, understands and abides by the 
requirements for maintenance of source documentation, and provides assurance that this 
study will be conducted according to all requirements as defined in this protocol, Clinical 
Trial Agreement, ICH GCP guidelines, and all applicable national and local regulatory 
requirements.
Signature of Principal Investigator
Date
Print Name of Principal Investigator
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INVESTIGATOR ACKNOWLEDGEMENT
RECOMBINANT VON WILLEBRAND FACTOR (rVWF)
A prospective, phase 3, open-label, international multicenter study on efficacy and 
safety of prophylaxis with rVWF in severe von Willebrand Disease
PROTOCOL IDENTIFIER: 071301
CLINICAL TRIAL PHASE 3
AMENDMENT 2: 2016 DEC 15
Replaces: AMENDMENT 1: 2016 APR 08
OTHER PROTOCOL ID(s)
NCT Number: NCT02973087
EudraCT Number: 2016-001478-14
IND NUMBER: to be determined
By signing below, the investigator acknowledges that he/she has read and understands 
this protocol, and provides assurance that this study will be conducted according to all 
requirements as defined in this protocol, Clinical Trial Agreement, ICH GCP guidelines, 
and all applicable national and local regulatory requirements.
Signature of Coordinating Investigator
Date
Print Name and Title of Coordinating Investigator
Signature of Sponsor Representative
Date
, MD
Global Clinical Development Operations
Baxalta US Inc./Baxalta Innovations GmbH
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CLINICAL STUDY PROTOCOL
PRODUCT: Recombinant Von Willebrand Factor (rVWF)
STUDY TITLE: A PROSPECTIVE, PHASE 3, OPEN-LABEL, INTERNATIONAL 
MULTICENTER STUDY ON EFFICACY AND SAFETY OF PROPHYLAXIS 
WITH rVWF IN SEVERE VON WILLEBRAND DISEASE
STUDY SHORT TITLE: rVWF IN PROPHYLAXIS
PROTOCOL IDENTIFIER: 071301
CLINICAL TRIAL PHASE 3
GLOBAL AMENDMENT 3: 2017 AUG 03
Replaces: AMENDMENT 2: 2016 DEC 15
ALL VERSIONS: 
Amendment 3: 2017 AUG 03
Amendment 2: 2016 DEC 15
Amendment 1: 2016 APR 08
Original: 2014 FEB 09
OTHER ID(s)
NCT Number: NCT02973087
EudraCT Number: 2016-001478-14
IND NUMBER: 013657
Study Sponsor(s):
Baxalta US Inc.
One Baxter Way
Westlake Village, CA  91362
UNITED STATES
Baxalta Innovations GmbH
Industriestrasse 67
A-1221 Vienna
AUSTRIA
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1. STUDY PERSONNEL
1.1 Authorized Representative (Signatory) / Responsible Party
, MD
Global Clinical Development Operations
Baxalta Innovations GmbH
1.2 Study Organization
The name and contact information of the responsible party and individuals involved with 
the study (e.g. investigator(s), sponsor’s medical expert and study monitor, sponsor’s 
representative(s), laboratories, steering committees, and oversight committees [including 
ethics committees (ECs)], as applicable) will be maintained by the sponsor and provided 
to the investigator.
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2. SERIOUS ADVERSE EVENT REPORTING
The investigator will comply with applicable laws/requirements for reporting serious 
adverse events (SAEs) and suspected unexpected serious adverse events (SUSARs) to the 
ECs.
ALL SAEs, INCLUDING SUSARs, ARE TO BE REPORTED ON THE SERIOUS 
ADVERSE EVENT REPORT (SAER) FORM AND TRANSMITTED TO THE 
SPONSOR WITHIN 24 HOURS AFTER BECOMING AWARE OF THE EVENT.
Bleeding events that meet seriousness criteria (death, life-threatening, 
hospitalizing/prolongation of hospitalization, disability, congenital anomaly, or medically 
significant and if not urgently treated would result in one of the above) should be reported 
on the SAE eCRF or SAE Report form as an SAE.
Drug Safety contact information: see SAE Report form 
Refer to SAE Protocol Sections and the study team roster for further information.
For definitions and information on the assessment of these events, refer to the following:

AE, Section 12.1

SAE, Section 12.1.1.1

SUSARs, Section 12.1.1.2

Assessment of AEs, Section 12.1.2
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3. SYNOPSIS 
INVESTIGATIONAL PRODUCT
Name of Investigational Product (IP)
Recombinant von Willebrand factor (rVWF)
Name(s) of Active Ingredient(s)
Recombinant von Willebrand factor (rVWF)
CLINICAL CONDITION(S)/INDICATION(S)
Subjects with severe von Willebrand disease (VWD) requiring prophylactic treatment with coagulation 
factor replacement
PROTOCOL ID
071301
PROTOCOL TITLE
A prospective, phase 3, open-label, international multicenter 
study on efficacy and safety of prophylaxis with rVWF in severe 
von Willebrand disease
Short Title
rVWF in prophylaxis
STUDY PHASE
Ph3
PLANNED STUDY PERIOD
Initiation
2016 JUN
Primary Completion
2018 Q1
Study Completion
2018 Q1
Duration
22 months
STUDY OBJECTIVES AND PURPOSE
Study Purpose
The purpose of this phase 3 study is to investigate the efficacy and safety, including immunogenicity and 
thrombogenicity, and 
of prophylactic treatment with rVWF in 
subjects with severe VWD.
Primary Objective
The primary objective of this study is to prospectively evaluate the annualized bleeding rate (ABR) for
spontaneous bleeding episodes while on prophylactic treatment with rVWF and to compare it to the 
subject’s historical ABR for spontaneous bleeding episodes during on-demand treatment. 
Secondary Objectives
Secondary Objectives are 

Additional efficacy assessments of prophylactic treatment

Safety and immunogenicity

Pharmacokinetics (PK)

Efficacy of the treatment of bleeding episodes 

Efficacy of the treatment of perioperative bleeding management, if surgery is required
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Exploratory Objectives
 
STUDY DESIGN
Study Type/ Classification/ Discipline
Efficacy and Safety 
Control Type
No control
Study Indication Type
Prophylaxis and treatment of bleeding episodes
Intervention model 
Single-group
Blinding/Masking
Open-label
Study Design
This is a phase 3, prospective, open-label, non-randomized, 
international multicenter study evaluating efficacy, safety, 
including immunogenicity and thrombogenicity, and 
of 
prophylactic treatment regimen with rVWF for subjects with 
severe VWD.
Subjects will be offered the option to continue to receive 
BAX111 in a long-term continuation study.
Planned Duration of Subject 
Participation
Approximately 15 months 
Primary Outcome Measure 
Efficacy

Prospectively recorded ABR for spontaneous (not related to trauma) bleeding episodes during 
prophylactic treatment with rVWF and the subjects’ historical ABR for spontaneous bleeding 
episodes during on-demand treatment.
Secondary Outcome Measure(s)
Efficacy

Number (proportion) of subjects with reduction of ABR for spontaneous (not related to trauma) 
bleeding episodes during prophylaxis relative to the subjects’ own historical ABR during on-demand
treatment. An ABR reduction of >25% is considered relevant.

Number (proportion) of subjects with 0 bleeds during prophylactic treatment with rVWF

Number of infusions and total weight adjusted consumption of rVWF and ADVATE (recombinant
factor VIII/rFVIII) per month and per year during prophylactic treatment as well as during on-
demand treatment
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Safety

Adverse events (AEs)

Incidence of thromboembolic events 

Incidence of severe hypersensitivity reactions

Development of neutralizing antibodies to VWF and FVIII 

Development of total binding antibodies to VWF and FVIII

Development of antibodies to Chinese hamster ovary (CHO) proteins, mouse immunoglobulin G 
(IgG) and rFurin
Pharmacokinetic

Incremental recovery (IR), terminal half-life (T1/2), mean residence time (MRT), area under the 
curve/dose (AUC/dose), area under moment curve/dose (AUMC/dose), volume of distribution at 
steady state (Vss) and clearance (CL) based on Von Willebrand factor Ristocetin cofactor activity
(VWF:RCo), Von Willebrand factor antigen (VWF:Ag), Von Willebrand collagen binding activity 
(VWF:CB), and time course (72 hours) of FVIII clotting activity (FVIII:C) levels.
Efficacy of the treatment of bleeding episodes

Number of infusions of rVWF and ADVATE (rFVIII) per spontaneous bleeding episode

Number of infusions of rVWF and ADVATE (rFVIII) per traumatic bleeding episode

Weight-adjusted consumption of rVWF and ADVATE (rFVIII) per spontaneous bleeding episode

Weight-adjusted consumption of rVWF and ADVATE (rFVIII) per traumatic bleeding episode

Overall hemostatic efficacy rating at resolution of bleed 
Efficacy of treatment of perioperative bleeding management, if surgery is required

Intraoperative actual versus predicted blood loss (assessed by the operating surgeon) at completion 
of surgery

Intraoperative hemostatic efficacy score on a scale of excellent, good, moderate or none (assessed by 
the operating surgeon) at completion of surgery

For elective surgery: an overall assessment of hemostatic efficacy 24 hours after the last 
perioperative infusion of rVWF, assessed by the Investigator

Daily intra- and postoperative weight-adjusted dose of rVWF with or without ADVATE through 
postoperative day 14.
Exploratory Outcome Measures
 
 
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INVESTIGATIONAL PRODUCT(S), DOSE AND MODE OF ADMINISTRATION
Active Product
Dosage form: lyophilized powder and solvent for solution for injection
Dosage frequency:
Prophylactic Treatment
Subjects transitioning from on-demand treatment will be infused twice weekly
with BAX 111 (rVWF) at doses of 50 ± 10 IU/kg rVWF:RCo. Dosage may be 
individualized within this range based on:

the PK data

type and severity of bleeding episodes the subject has experienced in the 
past

monitoring of appropriate clinical and laboratory measures
Any further adjustment will have to be agreed with the sponsor in advance.
Treatment of Bleeding Episodes:
Dosage must be individualized based on the subject’s weight, type and severity 
of bleeding episode and monitoring of appropriate clinical and laboratory 
measures. In general, an initial dose of 40-60 IU/kg VWF:RCo with 30-45 IU 
rFVIII [ADVATE]/kg) is recommended (rVWF:rFVIII ratio of 1.3:1: ± 0.2). In 
cases of major bleeding episodes, a dose of up to 80 IU/kg VWF:RCo may be 
infused. Subsequent doses, if necessary, will be administered with or without 
ADVATE to maintain VWF:RCo and FVIII levels for as long as deemed 
necessary by the investigator.
Mode of Administration: intravenous
SUBJECT SELECTION
Targeted Accrual
Approximately 18 subjects to achieve 15 evaluable subjects with severe VWD
Number of Groups/
Arms/ Cohorts
Single-group
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Inclusion Criteria
Subjects who meet ALL of the following criteria are eligible for this study:
1. Subject has a documented diagnosis of severe VWD (baseline VWF:RCo <20 IU/dL) with a history 
of requiring substitution therapy with von Willebrand factor concentrate to control bleeding:
a. Type 1 (VWF:RCo <20 IU/dL) or,
b. Type 2A (as verified by multimer pattern), Type 2B (as diagnosed by genotype), Type 2M or,
c. Type 3 (VWF:Ag ≤3 IU/dL).
2. Diagnosis is confirmed by genetic testing and multimer analysis, documented in patient history or at 
screening.
3. Subject currently receiving on-demand treatment for whom prophylactic treatment is recommended 
according to standard of care at the center.
4. Has ≥3 documented spontaneous bleeds requiring VWF treatment during the past 12 months 
5. Availability of records to reliably evaluate type, frequency and treatment of bleeding episodes 
during 12 months of on-demand treatment prior to enrollment.
6. Subject is ≥18 years old at the time of screening and has a body mass index ≥15 but <40 kg/m2.
7. If female of childbearing potential, subject presents with a negative blood/urine pregnancy test at 
screening and agrees to employ adequate birth control measures for the duration of the study.
8. Subject is willing and able to comply with the requirements of the protocol.
Exclusion Criteria
Subjects who meet ANY of the following criteria are not eligible for this study:
1. The subject has been diagnosed with Type 2N VWD, pseudo VWD, or another hereditary or 
acquired coagulation disorder other than VWD (e.g., qualitative and quantitative platelet disorders 
or elevated prothrombin time (PT)/international normalized ratio [INR] 1.4).
2. The subject has received prophylaxis treatment in the 12 months prior to screening (including those 
who received treatment once a month for menorrhagia but were not treated for any other bleeds).
3. The subject is currently receiving prophylaxis treatment.
4. The subject has a history or presence of a VWF inhibitor at screening.
5. The subject has a history or presence of a FVIII inhibitor with a titer ≥0.4 BU (by Nijmegen 
modified Bethesda assay) or ≥0.6 BU (by Bethesda assay).
6. The subject has a known hypersensitivity to any of the components of the study drugs, such as to 
mouse or hamster proteins.
7. The subject has a medical history of immunological disorders, excluding seasonal allergic 
rhinitis/conjunctivitis, mild asthma, food allergies or animal allergies.
8. The subject has a medical history of a thromboembolic event.
9. The subject is HIV positive with an absolute Helper T cell (CD4) count 200/mm3.
10. The subject has been diagnosed with significant liver disease as evidenced by any of the following: 
serum alanine aminotransferase (ALT) 5 times the upper limit of normal; hypoalbuminemia; portal 
vein hypertension (e.g., presence of otherwise unexplained splenomegaly, history of esophageal 
varices).
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11. The subject has been diagnosed with renal disease, with a serum creatinine level ≥2.5 mg/dL.
12. The subject has a platelet count <100,000/mL at screening.
13. The subject has been treated with an immunomodulatory drug, excluding topical treatment (e.g., 
ointments, nasal sprays), within 30 days prior to signing the informed consent.
14. The subject is pregnant or lactating at the time of enrollment.
15. Patient has cervical or uterine conditions causing menorrhagia or metrorrhagia (including infection, 
dysplasia).
16. The subject has participated in another clinical study involving another investigational product (IP)
or investigational device within 30 days prior to enrollment or is scheduled to participate in another 
clinical study involving an IP or investigational device during the course of this study.
17. The subject has a progressive fatal disease and/or life expectancy of less than 15 months.
18. The subject is identified by the investigator as being unable or unwilling to cooperate with study 
procedures.
19. The subject has a mental condition rendering him/her unable to understand the nature, scope and 
possible consequences of the study and/or evidence of an uncooperative attitude.
20. The subject is in prison or compulsory detention by regulatory and/or juridical order
21. The subject is member of the study team or in a dependent relationship with one of the study team 
members which includes close relatives (i.e., children, partner/spouse, siblings and parents) as well 
as employees.
Delay criteria
1. If the subject presents with an acute bleeding episodes or acute illness (e.g., influenza, flu-like 
syndrome, allergic rhinitis/conjunctivitis, non-seasonal asthma) the screening visit will be postponed 
until the subject has recovered.
STATISTICAL ANALYSIS
Sample Size Calculation
The determination of the sample size for this study is not based on strict statistical considerations. The 
sample size of a subset of at least 15 subjects with severe VWD, 5 of whom must have Type 3 VWD, is 
based on the Guideline on the Clinical Investigation of Human Plasma Derived von Willebrand Factor 
Products (CPMP/BPWG/220/02).1
Planned Statistical Analysis
Primary Outcome Measure:
The statistical analysis will provide descriptive summaries.
The prospectively recorded annualized bleeding rate (ABR) of spontaneous (not related to trauma) bleeding 
episodes during prophylactic treatment will be assessed using negative binomial distribution. Mean ABR of 
spontaneous bleeding episodes together with the corresponding 95% two-sided confidence intervals (CIs) 
will be reported for the prospective counts as well as those based on historical data. 
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Secondary Outcome Measures:
Efficacy:
For the number of infusions and for the total weight adjusted consumption of rVWF and ADVATE per 
month and per year during prophylactic treatment as well as during on-demand treatment for bleeding 
episodes, summary statistics will be carried out.
For the number (proportion) of subjects with reduction of ABR relative to historic ABR as well as for the 
number (proportion) of subjects with 0 bleeds, proportions and corresponding 95% two-sided CIs will be 
performed. An ABR reduction of >25% is considered relevant.
The cause, type, localization and severity of bleeding episodes will also be recorded and summarized.
Efficacy of the Treatment of Bleeding Episodes:
For the number of infusions of rVWF and ADVATE per bleeding episode, for the weight adjusted 
consumption of rVWF and ADVATE per bleeding episode as well as for the overall hemostatic efficacy 
rating at resolution of bleed, summary statistics will be carried out.
The severity and localization of bleeding episodes will also be recorded and summarized. Bleeding 
episodes should be organized by where they occur in addition to whether they occurred spontaneously 
or due to a traumatic event.
Efficacy of the Treatment of Perioperative Bleeding Management, if Surgery is Required:
Intraoperative actual versus predicted blood loss and intraoperative hemostatic efficacy score on a scale 
of excellent, good, moderate or none will be assessed at completion of surgery by the operating 
surgeon. For elective surgery, an overall assessment of hemostatic efficacy 24 hours after the last 
perioperative infusion of rVWF will be assessed by the Investigator. Daily intra- and postoperative 
weight-adjusted dose of rVWF with or without ADVATE will be recorded through postoperative 
day 14.
Pharmacokinetic:
The PK parameters AUC0-72h/Dose, AUC0-∞/Dose, AUMC0-∞/Dose, MRT (mean residence time), CL 
(clearance), IR (incremental recovery), T1/2 (elimination phase half-life), Vss (Volume of distribution at 
steady state), Cmax (maximum concentration) and Tmax (time to reach the maximum concentration) will be 
summarized by mean, standard deviation and the corresponding 90% CIs, median, Q1, Q3, IQR and range.
Descriptive statistics will be used to summarize VWF:RCo levels for each nominal time point on the PK 
curve. 
For all subjects concentration vs. time curves will be prepared.
Safety:
The number of subjects who experienced SAEs and the number of SAEs will be tabulated. In addition, the 
number of subjects who experienced AEs assessed as related to IP by the investigator and by the sponsor, 
and the number of IP-related AEs will be tabulated and subcategorized for thromboembolic events, 
neutralizing and total binding antibodies to VWF and FVIII, and hypersensitivity reactions by severity, as 
well as antibodies to Chinese hamster ovary (CHO) proteins, antibodies to mouse immunoglobulin G (IgG) 
and antibodies to rFurin.
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A listing of all AEs will be presented by subject identifier, age, sex, preferred term and reported term of the 
AE, duration, severity, seriousness, action taken, outcome, causality assessment by investigator, onset date, 
stop date and medication or non-drug therapy to treat the AE. An overview table for AEs will be provided, 
presenting the number of AEs, the number of subjects with AEs and the corresponding percent of subjects 
in total and by seriousness and relationship to study treatment. An additional summary table will present 
the total number of (mild, moderate, severe) AEs by system organ class and preferred term with 
relationship to IP.
Exploratory Outcome Measures:
 
 
 
 
 
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4. TABLE OF CONTENTS
1. STUDY PERSONNEL.................................................................................................. 2
1.1 Authorized Representative (Signatory) / Responsible Party .............................. 2
1.2 Study Organization................................................................................................. 2
2. SERIOUS ADVERSE EVENT REPORTING........................................................... 3
3. SYNOPSIS..................................................................................................................... 4
4. TABLE OF CONTENTS ........................................................................................... 12
5. LIST OF ABBREVIATIONS .................................................................................... 18
6. BACKGROUND INFORMATION .......................................................................... 22
6.1 Description of Investigational Product ............................................................... 22
6.2 Clinical Condition/Indication .............................................................................. 22
6.3 The Role of Prophylaxis in the Management of VWD...................................... 23
6.4 Population to be Studied ...................................................................................... 25
6.5 Findings from Nonclinical and Clinical Studies................................................. 26
6.5.1 Findings from Nonclinical Studies ............................................................... 26
6.5.1.1 Primary Pharmacodynamics ................................................................. 26
6.5.1.2 Safety Pharmacology.............................................................................. 26
6.5.1.3 Pharmacokinetics.................................................................................... 26
6.5.1.4 Toxicology................................................................................................ 27
6.5.2 Findings from Clinical Studies ..................................................................... 28
6.5.2.1 Study 070701 ........................................................................................... 28
6.5.2.2 Study 071104 ........................................................................................... 29
6.5.2.3 Study 071001 ........................................................................................... 30
6.5.2.4 Study 071401: Single Subject with von Willebrand Disease............... 32
6.6 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) 
to Human Subjects................................................................................................ 32
6.7 Compliance Statement.......................................................................................... 33
7. STUDY PURPOSE AND OBJECTIVES ................................................................. 34
7.1 Study Purpose ....................................................................................................... 34
7.2 Primary Objective................................................................................................. 34
7.3 Secondary Objectives ........................................................................................... 34
7.4 Exploratory Objectives......................................................................................... 34
7.4.1
........................................................................................................... 34
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8. STUDY DESIGN......................................................................................................... 35
8.1 Overall Study Design............................................................................................ 35
8.2 Duration of Study Period(s) and Subject Participation .................................... 35
8.3 Outcome Measures ............................................................................................... 35
8.3.1 Primary Outcome Measure........................................................................... 35
8.3.2 Secondary Outcome Measures ..................................................................... 36
8.3.2.1 Efficacy .................................................................................................... 36
8.3.2.2 Safety........................................................................................................ 36
8.3.2.3 Pharmacokinetics.................................................................................... 36
8.3.2.4 Efficacy of the Treatment of Bleeding Episodes.................................. 36
8.3.2.5 Efficacy of treatment of perioperative bleeding management, if 
surgery is required.................................................................................. 37
8.3.3 Exploratory Outcomes Measure................................................................... 37
8.4 Randomization and Blinding............................................................................... 37
8.5 Study Stopping Rules............................................................................................ 38
8.6 Investigational Product(s) .................................................................................... 39
8.6.1 Packaging, Labeling, and Storage................................................................ 39
8.6.1.1 rVWF (Recombinant von Willebrand Factor)..................................... 39
8.6.1.2 rFVIII (Recombinant Factor VIII /ADVATE).................................... 39
8.6.2 Reconstitution................................................................................................. 39
8.6.3 Administration ............................................................................................... 40
8.6.4 Description of Treatment.............................................................................. 41
8.6.4.1 Baseline Visit (PK-Assessment Treatment).......................................... 41
8.6.4.2 Prophylaxis Initiation Treatment.......................................................... 41
8.6.4.3 Prophylaxis Treatment........................................................................... 42
8.6.4.4 Treatment of Bleeding Episodes............................................................ 45
8.6.4.5 Treatment of Surgical Bleeding............................................................. 48
8.6.4.6 Thrombosis Prophylaxis ........................................................................ 50
8.6.5 Investigational Product Accountability ....................................................... 50
8.7 Source Data ........................................................................................................... 51
9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION .......... 52
9.1 Inclusion Criteria.................................................................................................. 52
9.2 Exclusion Criteria................................................................................................. 52
9.3 Delay Criteria........................................................................................................ 54
9.4 Withdrawal and Discontinuation ........................................................................ 54
10. STUDY PROCEDURES .......................................................................................... 56
10.1 Informed Consent and Enrollment ................................................................... 56
10.2 Subject Identification Code................................................................................ 56
10.3 Screening and Study Visits................................................................................. 56
10.3.1 Screening Visit.............................................................................................. 56
10.3.2 Baseline Visit - PK-Assessment Visit ......................................................... 57
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10.3.3 Prophylaxis Initiation Visit......................................................................... 58
10.3.4 Treatment of Bleeding Episodes................................................................. 58
10.3.5 Perioperative Visits (only applicable is surgery is needed)...................... 58
10.3.6 Follow-Up Visits (1 Month ± 1 Week, 2 Months ± 1 Week, 
3 Months ± 2 Weeks, 6 Months ± 2 Weeks, 9 Months ± 2 Weeks)............ 58
10.3.7 Unscheduled Visits....................................................................................... 59
10.3.8 Study Termination Visit (12 Months ± 2 Weeks)...................................... 60
10.4 Medications and Non-Drug Therapies.............................................................. 61
10.5 Subject Diary....................................................................................................... 61
10.6 Subject Completion/Discontinuation ................................................................ 62
10.7 Procedures for Monitoring Subject Compliance ............................................. 63
11. ASSESSMENT OF EFFICACY AND PHARMACOKINETICS........................ 64
11.1 Assessment of Spontaneous Bleeding Episodes/Annualized Bleed Rate........ 64
11.2 Evaluation of ABR Before rVWF Prophylaxis and ABR Under rVWF 
Prophylactic Treatment........................................................................................ 65
11.3 Number of Infusions and Total Weight Adjusted Consumption of rVWF and 
ADVATE................................................................................................................ 65
11.4 Assessment of Efficacy for Treatment of Bleeding Episode ........................... 65
11.5 Assessment of Efficacy for Treatment for Surgical Bleeding......................... 66
11.6 Pharmacokinetic Assessment............................................................................. 66
12. ASSESSMENT OF SAFETY................................................................................... 67
12.1 Adverse Events.................................................................................................... 67
12.1.1 Definitions..................................................................................................... 67
12.1.1.1 Serious Adverse Event.......................................................................... 67
12.1.1.2 Suspected Unexpected Serious Adverse Reaction (SUSAR)............. 68
12.1.1.3 Non-Serious Adverse Event ................................................................. 68
12.1.1.4 Unexpected Adverse Events................................................................. 68
12.1.1.5 Preexisting Disease................................................................................ 69
12.1.2 Assessment of Adverse Events.................................................................... 69
12.1.2.1 Severity .................................................................................................. 70
12.1.2.2 Causality................................................................................................ 71
12.1.2.3 Safety Reporting ................................................................................... 72
12.2 Urgent Safety Measures ..................................................................................... 73
12.3 Untoward Medical Occurrences........................................................................ 74
12.4 Non-Medical Complaints ................................................................................... 74
12.5 Medical, Medication, and Non-Drug Therapy History................................... 74
12.6 Physical Examinations........................................................................................ 75
12.6.1 Thromboembolic Events ............................................................................. 75
12.6.2 Anaphylaxis.................................................................................................. 76
12.7 Vital Signs............................................................................................................ 77
12.8 Electrocardiogram.............................................................................................. 77
12.9 Clinical Laboratory Parameters........................................................................ 78
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13.4.1 Primary Outcome Measure......................................................................... 90
13.4.2 Secondary Outcome Measures ................................................................... 91
13.4.2.1 Efficacy .................................................................................................. 91
13.4.2.2 Efficacy of the Treatment of Bleeding Episodes................................ 91
13.4.2.3 Efficacy of the Treatment of Peroperative Bleeding Management, if 
Surgery is Required................................................................................ 91
13.4.2.4 Pharmacokinetic Analysis.................................................................... 92
13.4.2.5 Safety...................................................................................................... 94
13.5 Exploratory Outcome Measures........................................................................ 95
13.6 Planned Interim Analysis of the Study ............................................................. 96
14. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .................................... 96
15. QUALITY CONTROL AND QUALITY ASSURANCE...................................... 97
15.1 Investigator’s Responsibility.............................................................................. 97
15.1.1 Investigator Report and Final Clinical Study Report.............................. 97
15.2 Training ............................................................................................................... 97
15.3 Monitoring........................................................................................................... 97
15.4 Auditing ............................................................................................................... 97
15.5 Non-Compliance with the Protocol ................................................................... 98
15.6 Laboratory and Reader Standardization ......................................................... 98
16. ETHICS ..................................................................................................................... 99
16.1 Subject Privacy ................................................................................................... 99
16.2 Ethics Committee and Regulatory Authorities................................................ 99
16.3 Informed Consent ............................................................................................... 99
16.4 Data Monitoring Committee............................................................................ 100
17. DATA HANDLING AND RECORD KEEPING................................................. 101
17.1 Confidentiality Policy ....................................................................................... 101
17.2 Study Documentation and Case Report Forms ............................................. 101
17.3 Document and Data Retention......................................................................... 101
18. FINANCING AND INSURANCE......................................................................... 102
19. PUBLICATION POLICY...................................................................................... 102
20. SUPPLEMENTS..................................................................................................... 103
20.1 Study Flow Chart.............................................................................................. 103
20.2 Schedule of Study Procedures and Assessments............................................ 104
20.2.1 Summary Schedule of Visit Assesments for Surgical Bleeding............. 106
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20.3 Clinical Laboratory Assessments .................................................................... 107
20.3.1 Laboratory Sampling for Surgical Bleeding ........................................... 109
20.4 Contraceptive Methods for Female Subjects of Childbearing Potential..... 110
21. REFERENCES........................................................................................................ 111
22. SUMMARY OF CHANGES.................................................................................. 113
Tables
Table 1 rVWF Dosing Schedule Examples: Schedules A and B..................................... 42
Table 2 Criteria for Escalation Specific to Each Bleeding Indication............................. 43
Table 3 rVWF:RCo Dosing Recommendations for the Treatment of Bleeding Episodes 
Due to VWD ............................................................................................................. 47
Table 4 Efficacy Rating Scale.......................................................................................... 65
Table 5 Assessment of Hemostatic Efficacy ................................................................... 66
Table 6 Schedule of Study Procedures and Assessments .............................................. 104
Table 7 Summary Schedule of Visit Assesments for Surgical Bleeding....................... 106
Table 8 Clinical Laboratory Assessments...................................................................... 107
Table 9 Laboratory Sampling for Surgical Bleeding..................................................... 109
Figures
Figure 1 Study Design for Baxalta Clinical Study 071301............................................ 103
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5. LIST OF ABBREVIATIONS
Abbreviation
Definition
ABR
Annualized bleeding rate
ADAMTS13
A Disintegrin And Metalloproteinase with a Thrombospondin type 1 motif, number 13
AE
Adverse event
ALT
Alanine aminotransferase
AP
Alkaline phosphatase
AST
Aspartate aminotransferase
AUC0-∞
Area under the plasma concentration /time curve from time 0 to infinity
AUC0-72h/Dose 
Area under the plasma concentration/time curve from time 0 to 72 hours 
post-infusion/dose
AUC0-∞/Dose
Area under the plasma concentration/time curve from time 0 to infinity/dose
AUC/Dose
Area under the curve/dose
AUMC
Area under moment curve
AUMC0-∞/Dose
Area under the first moment curve from time 0 to infinity/dose
aPTT
Activated partial thromboplastin time
B19V
Parvovirus B19
BILI
Bilirubin
BP
Blood pressure
BU
Bethesda Unit
BUN
Blood urea nitrogen
BW
Body weight
CAM
Cell adhesion molecule
CB
Collagen binding activity
CBC
Complete blood count
CD4
Helper T cell
CHO
Chinese hamster ovary
CI
Confidence interval
Cl
Chloride
CL
Clearance
Cmax
Maximum plasma concentration
CR
Creatinine
CTA
Clinical Trial Agreement
eCRF
Electronic case report form
DMC
Data monitoring committee
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Abbreviation
Definition
DIC
Disseminated intravascular coagulation
DVT
Deep vein thrombosis
EC
Ethics committee
ECG
Electrocardiogram 
EDC
Electronic Data Capture
EDTA
Ethylenediaminetetraacetic acid
ELISA
Enzyme-linked immunosorbent assay
FAS
Full analysis set
FVIII
Factor VIII
FVIII:C
Factor VIII clotting activity
GCP
Good Clinical Practice
GI
Gastrointestinal
Glu
Glucose
GPIb
Glycoprotein Ib
HAMA
Human anti- mouse antibodies
HAV
Hepatitis A virus
HB
Hepatitis B
HBs
Hepatitis B surface
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HEV
Hepatitis E virus
HIV
Human immunodeficiency virus 
HLA
Human leukocyte antigen
HRP
Horseradish peroxidase
IB
Investigator's brochure
ICH
International Council for Harmonisation
Ig
Immunoglobulin
INR
International normalized ratio
IP
Investigational product
IQR
Interquartil range
IR
Incremental recovery
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Abbreviation
Definition
i.v.
Intravenous
K
Potassium
k.o.
Knock out
LDH
Lactate Dehydrogenase
Na
Sodium
NMC
Non-medical complaint
NOAEL
No observed adverse effect level
MRI
Magnetic resonance imaging
MRT
Mean residence time
pdVWF
Plasma derived VWF product
pdVWF/FVIII
Plasma derived VWF product containing fractions of FVIII
PBAC
Pictorial Blood Assessment Chart
PCR
Polymerase Chain Reaction
PEF
Peak expiratory flow
PK
Pharmacokinetic
PKFAS
Pharmacokinetic Full Analysis Set
PKPPAS
Pharmacokinetic Per Protocol Analysis Set
PP
Per protocol 
PT
Prothrombin time
Q1, Q3
Quartile
rFVIII
Recombinant factor VIII
rVWF
Recombinant von Willebrand factor
RBC
Red blood cell count
SAE
Serious adverse event
SAER
Serious adverse event report
SDS-PAGE
Sodium dodecyl sulfate polyacrylamide gel electrophoresis
SIC
Subject identification code
sP-selectin
Soluble P-selectin
SUSAR
Suspected unexpected serious adverse reaction
T1/2
Elimination phase half life
TIA
Transient ischemic attack
Tmax
Time to reach the maximum concentration
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Abbreviation
Definition
TTP
Thrombotic thrombocytopenic purpura
ULMW
Ultra-large molecular weight 
ULN
Upper limit of normal
Vss
Volume of distribution at steady state
VTE
Venous thromboembolism (VTE)
VWD
von Willebrand disease
VWF
Von Willebrand factor
VWF:Ag
Von Willebrand factor antigen
VWF:CB
Von Willebrand Factor collagen binding
VWF:RCo
Von Willebrand factor: Ristocetin cofactor activity
WBC
White blood cell
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6. BACKGROUND INFORMATION
6.1 Description of Investigational Product
Baxalta US Inc. (hereafter referred to as Baxalta or sponsor) has developed a human 
recombinant von Willebrand Factor (rVWF), which is co-expressed with recombinant 
factor VIII (rFVIII) in a Chinese hamster ovary (CHO) cell line and separated during the 
subsequent downstream process. To address concerns regarding the risk of transmission 
of blood-borne pathogens that may be introduced by human plasma, no exogenously 
added raw materials of human or animal origin are employed in the cell culture, 
purification, or formulation of the final container product. The only proteins present in 
the final container product other than rVWF are trace quantities of murine 
immunoglobulin (IgG, from the immunoaffinity purification), host cell (i.e., CHO) 
protein, rFurin (used to further process rVWF). rVWF is intended for the treatment of 
von Willebrand disease (VWD).
rVWF has been developed under the Baxalta internal code BAX111 and is used as 
investigational product (IP) in this study. rVWF may be used with or without ADVATE 
(rFVIII) for the treatment of bleeding episodes (see Section 8.6.4.4). See Section 8.6 for 
further information on the IPs and their usage in this study. A detailed description of 
rVWF is also provided in the Investigator’s Brochure (IB).
rVWF was granted licensure in the United States in December 2015 under the brand 
name VONVENDI for the on-demand treatment and control of bleeding episodes in 
adults diagnosed with VWD; as of the date of this protocol VONVENDI is not yet 
available on the market.
6.2 Clinical Condition/Indication
Von Willebrand Factor (VWF) is a large multimeric glycoprotein with a molecular 
weight that varies from 500 to 20,000 kDa. VWF is normally found in plasma and 
produced in the alpha-granules of platelets and in endothelial cell organelles known as the 
Weibel-Palade bodies. VWF mediates platelet adhesion and aggregation at sites of 
vascular injury, one of the key functions in primary hemostasis. VWF also serves to 
stabilize coagulation factor VIII (FVIII), where FVIII is an essential cofactor of 
secondary hemostasis, which leads to fibrin clot formation.2 Qualitative and/or 
quantitative deficiencies of VWF lead to a highly variable bleeding diathesis known as 
VWD, the most common of the hereditary coagulation factor deficiencies. Penetrance of 
VWD is highly variable, with only a small fraction of mildly affected patients displaying 
clinical symptoms or a family history of a bleeding diathesis.
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The current biochemical-based classification distinguishes disorders arising from partial 
quantitative (type 1), qualitative (type 2), or virtually complete (type 3) deficiencies of 
VWF. Up to 70% of VWD patients are diagnosed with type 1 VWD, which may also be 
associated with minor functional defects in the molecule. In general, patients with type 1 
VWD display mild clinical symptoms. Approximately 20 to 30% of VWD patients are 
diagnosed with type 2 VWD. Type 2 VWD is further divided into 4 subtypes (A, B, N, 
and M), reflecting distinct classes of functional abnormalities. These defects result in 
abnormal functional and/or multimeric distribution patterns that facilitate their diagnosis. 
The bleeding diathesis is usually moderate and primarily affects the mucosal tissues. 
Type 2N VWD patients are sometimes misdiagnosed as mild hemophilia A. Finally, 
approximately 1% percent of VWD patients exhibit a total or near total absence of VWF, 
which is classified as type 3 VWD. The incidence of type 3 VWD is estimated at 
0.5-1.0 x 106. This type is also associated with a very low FVIII level (typically <5%) 
because the VWF carrier function for FVIII is lost. Replacement of VWF alone stabilizes 
endogenous FVIII, resulting in hemostatic levels within several hours post-infusion. 
Published results from studies of a plasma-derived VWF concentrate demonstrated an 
increase of FVIII at an approximate rate of 5.8 1 IU dL-1 h-1.3 Type 3 VWD patients 
display severe hemorrhagic symptoms with bleeding predominantly in mucosal tissues, 
muscle and joints. All VWD patients, particularly those with type 2 or type 3 VWD, are 
at an increased risk for life-threatening bleeding episodes.
6.3 The Role of Prophylaxis in the Management of VWD
The goals of long term prophylaxis in VWD are to maintain VWF and FVIII at sufficient 
levels to reduce the frequency and duration of bleeding episodes, the need for red blood 
cell transfusions, and the risk of complications, such as arthropathy.4 In contrast to 
hemophilia, routine prophylaxis is not as established in VWD, although prophylaxis for 
patients with severe VWD have already been in use in Sweden during the 1950s.5 In 
those early days of VWD treatment plasma FVIII concentrates containing VWF fractions 
were applied for replacement therapy, which then were followed by plasma derived VWF 
products containing fractions of FVIII (pdVWF/FVIII). 
A Swedish cohort including 37 patients with type 3 VWD under prophylactic median 
treatment of 11 years (range 2 to 45 years) was retrospectively analyzed.6,7 The 
doses used for prophylaxis, given once weekly for at least 45 weeks per year, were 
calculated based on 12 to 50 IU/kg body weight (BW) of FVIII clotting activity (FVIII:C)
which approximately corresponded to 24-100 IU/kg von Willebrand factor: Ristocetin 
cofactor activity (VWF:RCo) considering that mainly Haemate with a known 
VWF:RCo/FVIII:C ratio of about 2 was used. An escalation of doses from 1 to 3 dose 
levels was allowed depending on the frequency and severity of bleeding episodes. 
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The results demonstrate that under long-term prophylaxis the number of bleeds could be 
reduced dramatically. Whereas the median value for bleeds per year was about 10 before 
prophylaxis this value could be reduced to less than 1 bleed per year during prophylaxis.
The benefit of prophylaxis for such indications was retrospectively also demonstrated in a 
cohort of Italian patients including type 3, 2A, 2M and type 1 patients. Prophylaxis was 
started after severe gastrointestinal or joint bleeding episodes and completely prevented 
bleeding episodes in 8 of these 11 patients and largely reduced the need of blood 
transfusions in the remaining 3. A regimen of 40 IU rVWF:RCo/kg was applied every 
other day or twice a week. A prospective study on prophylaxis, the PRO.WILL study, has 
been initiated in Italy.8
The results of a prospective study investigating the prophylaxis in children and young 
adults showed a significantly reduced bleeding frequency and bleeding score (3 vs. 0.07; 
3 vs. 0. p<0.001) compared to the pre-prophylaxis values. The median dose was 
40 (20-47) IU/kg VWF:RCo administered mainly twice weekly in 23 patients, 3 times a 
week in 7 patients and 4 times a week in 2 children.9
The VWD Prophylaxis Network initiated the VWD International Prophylaxis (VIP) trial 
to investigate the role of prophylaxis in patients with severe VWD including Type 1, 2,
and 3. The dose of the factor replacement product was 50 IU /kgVWF:RCo. The 
frequency of the dose depended on the type of bleeding and could be increased from once 
weekly to twice weekly or 3 times per week. For the treatment of menorrhagia the dose of 
50 IU/kg VWF:RCo was given on the first day of menses for 2 cycles. The frequency 
could be increased to Day 1 and 2 for 2 cycles or to Day 1, 2, and 3 of menses.
The study contains both retrospective and prospective study components. Results from 
the retrospective study component were published, including 61 subjects on prophylactic 
regimen in the past 6 months prior to enrollment or subjects with a history of prophylaxis 
over at least 6 month.10 Differences in annualized bleeding rates (ABR) within 
individuals (during prophylaxis – before prophylaxis) were significant for those with 
primary indications of epistaxis (P = 0.0005), joint bleeding (P = 0.002) and 
gastrointestinal (GI) bleeding (P = 0.001). The difference in the group whose primary 
indication for treatment was abnormally heavy bleeding at menstruation (n = 4) was not 
significant (P = 0.25). The reduction of mucosal bleeding likely not only dependents on 
normal circulating levels of active VWF, but also on the presence of discrete 
concentrations of normal VWF inside the platelets and within endothelial matrices. The 
low subject number (n=4) and the treatment scheme for menorrhagia on Days 1, 2, and 3 
of menses which might represent rather on-demand than prophylactic treatment may also 
account for the outcome in this study. 
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Results from the prospective study component were reported recently.11 Eleven subjects 
completed the study. Six subjects had type 2A, and 5 subjects had type 3 VWD. 
Six subjects presented with epistaxis, 3 with GI bleeding, and 2 with joint bleeding. 
Seven subjects had dose escalation above the first level. Among the 10 subjects with 
evaluable bleeding log data, the use of prophylaxis decreased the median ABR from 25 to 
6.1 (95% confidence interval [CI] of the rate difference: -51.6 to -1.7), and the median 
ABR was even lower (4.0; 95% CI: -57.5 to -5.3) when the subjects reached their final 
dosing level. The authors concluded that this was the first prospective study to 
demonstrate that prophylaxis with VWF concentrates is highly effective in reducing 
mucosal and joint bleeding rates in clinically severe VWD.
The results of the VIP study and previous investigations suggest that VWD patients with 
recurrent bleeding episodes and severe menorrhagia will benefit from a prophylactic 
VWF replacement therapy. There is evidence that up to 40% of patients with type 3 
VWD experience joint bleeding which can lead to hemophilic arthropathy. Other 
potential indications for prophylaxis include patients with type 2A or 2B VWD with 
recurrent gastrointestinal bleeding, menorrhagia or frequent epistaxis.4 Long-term 
prophylaxis for most patients with type 3 VWD and in some patients with type 1 or 2 
VWD, depending on the pattern of bleeding, may be the treatment option of choice.
Although the main experience with long-term prophylaxis is with secondary prophylaxis, 
primary prophylaxis starting at young age is recommended to prevent arthropathy in 
patients with severe VWD.12
However, further studies are needed to develop evidence-based guidelines for 
prophylactic treatment in VWD.
6.4 Population to be Studied
A total of approximately 18 eligible, adult subjects to achieve approximately 15 evaluable 
subjects with severe VWD are planned to be enrolled, of which a subset of at least 
5 subjects will have type 3 VWD. Enrolled subjects (i.e., subjects who have signed the 
informed consent form) will be eligible to participate in the study if they meet all of the 
inclusion criteria (see Section 9.1) and none of the exclusion criteria (see Section 9.2).
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6.5 Findings from Nonclinical and Clinical Studies
The following summarizes the key findings from relevant nonclinical studies as well as 
from the completed clinical studies 070701 (Phase 1 PK and safety in VWD), 071001
(Phase 3 safety and efficacy in the treatment of bleeding episodes in VWD), 071104
(Phase 1 safety and PK in hemophilia A), and 071401 (Phase 3, expanded access in a 
single subject with VWD). Potential risks and efficacy of rVWF:ADVATE are 
summarized in the following sections. For additional information on nonclinical and 
clinical Phase 1 results refer to the rVWF IB.
6.5.1 Findings from Nonclinical Studies
6.5.1.1 Primary Pharmacodynamics
Efficacy of rVWF combined with ADVATE was shown in VWD animal models, which 
have also low endogenous FVIII levels. Time to occlusion and stable thrombus formation 
was assessed in the carotid occlusion model in VWD mice. The results demonstrated that 
rVWF in combination with ADVATE acted efficiently in a dose-dependent manner and 
had higher efficacy than rVWF alone or plasma derived (pd)VWF. These results were 
confirmed in an additional study assessing blood loss and survival in a tail tip bleeding 
model in VWD mice. In a VWD dog rVWF stabilized canine FVIII in the circulation and 
significantly reduced the bleeding time. 
6.5.1.2 Safety Pharmacology
The anaphylactoid and thrombogenic potential of the co-infusion of ADVATE and rVWF 
and the co-infused product’s effects on blood pressure, cardiac and respiratory function 
and parameters of coagulation activation were investigated in 4 in vivo studies in 
different animal models. Safety pharmacology studies in rats, guinea pigs, rabbits, and 
dogs revealed no risks for anaphylactoid and thrombogenic potential of ADVATE in 
combination with rVWF. All observations in safety pharmacology studies are considered 
to lie within the biological variability of animal models or occurred due to known 
species-specific anaphylactoid effects of excipients.
6.5.1.3 Pharmacokinetics
Pharmacokinetic studies of both rVWF alone and combined with human rFVIII 
(rVWF+ADVATE) were conducted in VWD mice, VWD dogs, VWD pigs, rats, and 
cynomolgus monkeys. Human rVWF stabilized the endogenous FVIII in VWD mice, 
VWD pigs, and VWD dogs. Furthermore, the hypotheses that the area under the curve 
(AUC) with rVWF alone and rVWF+ADVATE is not inferior to the AUC with 
pdVWF (Haemate P) was tested and confirmed statistically in normal rats.
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The pharmacokinetic (PK) characteristics of ADVATE were not affected by co-
administration of rVWF in cynomolgus monkeys. The PK data in the FVIII knock out
(k.o.) mice model are inconclusive and might not be relevant for the clinical situation. 
However, a stabilizing effect of VWF on FVIII could be shown in a double knock out 
model in a dose dependent manner.
6.5.1.4 Toxicology
Single dose toxicity studies were conducted in C57BL/6J-mice, VWD mice, rats, rabbits,
and cynomolgus monkeys. Rats, rabbits, and cynomolgus monkeys showed no signs of
toxicity. Signs of microthrombosis, an exaggerated pharmacological effect, were
observed in mice. Mice are not capable of sufficiently cleaving the rVWF subunit as
murine disintegrin and metalloproteinase with a thrombospondin type 1 motif, number 13
(ADAMTS13) does not decrease the ultra-large molecular weight multimers of rVWF.13
The observed symptoms of microthrombosis are interpreted as a species-specific 
exaggerated pharmacological effect. Studies evaluating the safety of repeated 
administration of rVWF with or without ADVATE (daily over 14 days) were performed 
in a rodent (rat) and non-rodent (cynomolgus monkey) species. Reversible signs of 
exaggerated pharmacological effects (regenerative anemia, thrombocytopenia, and 
treatment-related histopathologic changes in the heart, liver, and spleen) were observed in 
rats that were administered 1400 U VWF:RCo/kg /day + 1080 IU ADVATE/kg/day 
intravenously once daily for 14 days. Also, these findings are interpreted as a 
species-specific exaggerated pharmacological effect due to the low susceptibility of 
human rVWF to cleavage by rodent ADAMTS13.13 No toxicologically relevant changes 
were evident for clinical observations, body weight, feed consumption, ophthalmology, 
urinalysis, coagulation, and serum chemistry parameters, platelet aggregation, and gross 
pathology. rVWF combined with ADVATE was well tolerated in cynomolgus monkeys
after daily intravenous (i.v.) (bolus) administration of 100 U VWF:RCo/kg rVWF 
combined with 77 IU/kg ADVATE over a period of 14 days. No adverse effects could be 
detected in this species. There were no signs of hemolysis, thrombosis, or 
thrombocytopenia after repeated intravenous application of rVWF with or without 
ADVATE. Therefore, 100 U VWF:RCo/kg/day rVWF with or without 77 IU/kg 
ADVATE was considered the no observed adverse effect level (NOAEL) in this study, 
which was the highest dose tested. Anti-drug antibodies, however, were formed in both 
species and resulted in a significant reduction in drug exposure after 14 applications as 
compared to a single application. These antibodies substantially reduced the systemic 
exposure to the test substance as compared to a single dose administration. No 
adverse effects due to antibody formation were observed in both species.
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rVWF combined with ADVATE was well tolerated locally and no genotoxic potential 
was evident after 2 in vitro and 1 in vivo genotoxicity study. A study on the influence of 
co-administration of VWF and ADVATE on the immunogenicity of ADVATE in 
3 different hemophilic mouse models (E17 hemophilic Balb/c mice, E17 hemophilic 
C57BL/6J mice, and E17 hemophilic human F8 transgenic mice) showed that rVWF does 
not negatively impact the immunogenicity of ADVATE in any of the three different 
hemophilic mouse models. 
6.5.2 Findings from Clinical Studies
Two phase 1 studies with rVWF either alone or co-administrated with ADVATE in 
patients with VWD 070701 and Hemophilia A 071104 and 1 phase 3 study with rVWF in 
patients with VWD 071001 have been conducted and the results were analyzed and 
evaluated. Details on study design, populations enrolled, and safety and efficacy 
outcomes of these 2 phase 1 studies are presented in Section 6.5.2.1 and Section 6.5.2.2,
and the phase 3 study in Section 6.5.2.3. Information on a single subject with VWD in 
Study 071401 is presented in Section 6.5.2.4.
Refer to rVWF IB for periodic updates from other rVWF studies. 
6.5.2.1 Study 070701
Phase 1 clinical study 070701 was a multicenter, controlled, randomized, single-blind,
prospective 3-step, dose escalation study to investigate safety, tolerability, and PK of 
rVWF combined at a fixed ratio with ADVATE (VWF:RCo/FVIII:C of 1.3 ± 0.2:1) in 
adults with severe VWD.14 Subjects were enrolled in sequential cohorts in a dose 
escalating manner: Cohort 1, 2, and 3 received a single intravenous infusion of 
rVWF:ADVATE at the following doses: 2 IU/kg VWF:RCo (Cohort 1), 7.5 IU/kg 
VWF:RCo (Cohort 2), and 20 IU/kg VWF:RCo (Cohort 3). Subjects in Cohort 4 received 
a single intravenous infusion of rVWF:ADVATE and pdVWF/ADVATE at 50 IU/kg 
VWF:RCo in random order.
The primary endpoint was the tolerability and safety after single dose injections of 
rVWF:ADVATE at 2, 7.5, 20, and 50 IU/kg VWF:RCo for up to 30 days after the last IP 
infusion. The data generated in this phase 1 study suggest that rVWF:ADVATE up to the 
highest investigated dose of 50 IU/kg VWF:RCo is well tolerated and safe in adults with 
severe VWD. No thrombogenic risk or TTP-like syndrome was observed, and no 
neutralizing antibodies to VWF or FVIII were identified. There were no deaths or other 
serious adverse reactions, and no infusions were interrupted or stopped due to an AE. 
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Overall, the reported AE profile was similar between the recombinant and 
plasma-derived concentrates.
Secondary endpoints were the PK assessment of VWF:RCo, von Willebrand factor 
antigen (VWF:Ag) and multimeric composition of rVWF as well as FVIII:C at 
standardized time points after single injections of rVWF:ADVATE and pdVWF:FVIII. 
The median VWF:RCo half-life (T1/2) of rVWF at the 50 IU/kg dose was 16 hours. 
T1/2 with pdVWF:FVIII at the same dose level appeared shorter at 12.58 hours, however, 
the limits of the 90% CI were similar (11.73 to 17.7 hours vs. 11.87 to 18.03 hours). 
The median half-lives of VWF:RCo were shorter with the lower investigated doses: 
7.13 hours and 13.23 hours with the 7.5 IU/kg and 20 IU/kg doses, although these data 
were derived from a much smaller number of subjects.
In consequence of the missing ADAMTS13 cleavage, ultra-large molecular weight 
(ULMW) multimers are contained in the rVWF final product. The immediate cleavage of 
these ultra-large multimers by ADAMTS13 upon release into the circulation could be 
demonstrated applying sodium dodecyl sulfate polyacrylamide gel electrophoresis
(SDS-PAGE)/Immunoblot with polyclonal anti-VWF antibodies to detect the resulting 
rVWF subunit cleavage fragments.
Overall the data generated in this phase 1 study suggest that rVWF:ADVATE is well 
tolerated and safe in adults with severe VWD.
6.5.2.2 Study 071104
This study was a prospective, uncontrolled, non-randomized, multicenter proof of 
concept study to assess safety and PK of the addition of rVWF to ADVATE treatment in 
12 evaluable subjects with severe hemophilia A. All subjects underwent 3 PK analyses: 
the first after infusion with ADVATE alone, the second after infusion with ADVATE
plus 10 IU/kg rVWF and the third after infusion with ADVATE plus 50 IU/kg rVWF. 
The PK analysis was performed at intervals of approximately 8 to 14 days. Before each 
infusion for PK assessment, there was a wash-out period of at least 5 days and the 
subjects were not actively bleeding. 
Primary outcome measures indicate that co-administration of rVWF slightly sustain 
ADVATE activity with the highest observed ADVATE half-life of 13.74 h (CI 
11.44 to 16.52) after co-infusion of 50 IU/kg ADVATE plus 50 IU/kg rVWF:RCo.
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The highest improvement in ADVATE circulating half-life was observed in subjects with 
VWF:Ag levels below 100% which indicates an association between baseline VWF:Ag 
levels and ADVATE half-life increase. 
No treatment related adverse events (AEs) or serious adverse events (SAEs) were 
reported. No subject withdrew due to an AE and there were no deaths. No binding 
antibodies to VWF, CHO, and rFurin were detectable in the confirmatory assay and no 
signs of a hypersensitivity to rVWF or ADVATE antigen were observed. Laboratory 
values over time did not indicate any potential safety risk for hemophilia A patients 
treated with rVWF and ADVATE in combination.
In summary, the data indicate that rVWF co-administered with ADVATE up to the 
highest dose of 50 IU/kg VWF:RCo is well tolerated and safe in hemophilia A patients. 
6.5.2.3 Study 071001
This was a phase 3, multicenter, open-label, part-randomized clinical study to assess the 
PK, safety, and efficacy of rVWF:rFVIII and rVWF in the treatment of bleeding episodes 
in adult subjects with severe type 3 and severe non-type 3 VWD.15 A total of 49 subjects 
were enrolled (signed informed consent) and screened, 18 subjects were randomized 
(Arm 1 and Arm 2 [PK 50] only), 37 subjects were treated with IP (all study arms), and 
30 subjects completed the study. 
The study consisted of 2 parts (Part A and Part B). Part A consisted of PK assessments 
alone (Arm 2: PK50 only [without treatment of bleeding episodes]), or PK assessments 
(Arm 1: PK50 and Arm 3: PK80) plus on-demand treatment period(s) of 6 months for 
bleeding episodes, or on-demand treatment for bleeding episodes only (Arm 4). Subjects 
receiving treatment for PK assessments and/or bleeding episodes in Part A were to be 
entered into Part B to continue on-demand treatment for bleeding episodes for 
6 additional months for a total of 12 months in the study. 
The primary outcome measure was the number of subjects with “treatment success” 
(extent of control of bleeding episodes), which was defined as a mean efficacy rating 
score of <2.5 for a subject’s IP-treated bleeding episodes during the study. The rate of 
subjects with treatment success was 100% (Clopper-Pearson exact 90% CI: 84.7 to 
100.0) for bleeds where the assessments were made prospectively and excluding GI 
bleeds. Sensitivity analyses confirmed the results of the primary analysis. 
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Crossover results at 50 IU/kg VWF:RCo showed that the PK profile for rVWF 
VWF:RCo was independent of administration alone or with rFVIII (ADVATE) (T1/2:
19.4 hours for rVWF and 16.6 hours for rVWF:rFVIII; IR: 1.8 U/dL per IU/kg infused 
for both rVWF and rVWF:rFVIII; MRT: 26.7 hours for rVWF and 25.2 hours for 
rVWF:rFVIII). FVIII levels increased substantially with a median peak at 24 hours of 
111.0 U/dL for rVWF:rFVIII and 86.0 U/dL after rVWF alone, indicating that rVWF 
induces a sustained increase in endogenous FVIII activity. The rVWF PK profile was 
comparable at 50 IU/kg and 80 IU/kg VWF:RCo, and repeated PK at 80 IU/kg 
VWF:RCo showed close agreement between pretreatment and end-of-study results.
Further analysis of the PK data from the 071001 study supports the initial use of 50 IU/kg 
twice weekly for prophylaxis dosing in the present study for those subjects who are 
moving from on-demand to prophylaxis. Using 50 IU/kg for PK measurements, subjects 
in the 071001 study exhibiting a T1/2 for rVWF of 14, 16, or 19 hours had BAX111 
plasma concentrations at 72 hours after administration of 2.55, 4.01, and 6.49% above 
baseline, respectively, and plasma concentrations at 96 hours after administration of 0.78, 
1.40, and 2.71% above baseline, respectively. Subjects who have significant spontaneous 
bleeding while on twice weekly prophylaxis will have their regimen increased to 
50 IU/kg 3 times per week (see Section 8.6.4.2).
A total of 125 AEs occurred in 25/37 (67.7%) subjects (62/318 infusions [19.5%]) during 
or after infusion with IP. Of these, 116/125 were non-serious (all mild or moderate; none 
were severe), and 9 SAEs were reported in 7 subjects. Of 125 total AEs, 38 were 
temporally associated with IP; 8 AEs were considered causally related to IP: 
6 non-serious related AEs (tachycardia, infusion site paraesthesia, electrocardiogram 
[ECG] t-wave inversion, dysgeusia, generalized pruritis, and hot flush) occurred in 
4 subjects, and 2 related SAEs (chest discomfort and increased heart rate) occurred in 
1 subject. No deaths occurred during this study. 
None of the subjects developed anti-VWF or anti-FVIII neutralizing antibodies and no 
binding antibodies to VWF or rFurin, or antibodies against CHO protein or anti-Murine 
IgG were observed. No clinical or subclinical signs or symptoms of a thrombogenic event 
were observed in this study. Following an initial increase in ultralarge VWF multimers 
after administration of rVWF, a notable decrease in the proportion of large VWF 
multimers occurred between 12 and 24 hours post infusion, due to degradation by the 
endogenous ADAMTS13 followed by a continued decline until the end of the 96-hour 
follow-up period. 
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Overall, the data support the safe and effective use of rVWF with or without FVIII 
(ADVATE) in the treatment of bleeds in patients with VWD.
6.5.2.4 Study 071401: Single Subject with von Willebrand Disease
One subject who exhibited allergic reactions to currently marketed pdVWF products was 
treated in the single-subject study 071401 with rVWF only for the bleed treatment of 
continued hematuria, and for biopsy and surgical resection of a left-kidney mass.
For the initial rVWF infusion, the subject received a test dose of 5% of the total dose of 
60 IU/kg rVWF:RCo at an infusion rate of 1 mL/min. After a 10 to 15-minute 
observation period, no adverse symptoms or signs were noted and the subject received 
the remaining 95% of the total dose. The subject was monitored for any signs of an 
allergic reaction, and none were noted. Treatment with rVWF every 12 to 24 hours was 
to continue at the discretion of the investigator based on VWF levels and clinical 
symptomatology. The subject had an excellent response and recovery, which allowed for 
daily dosing of rVWF and, within 24 hours, the subject’s bleeding had stopped. Daily 
dosing of rVWF was maintained and the subject received his last dose on 
.
The subject also received rVWF for 7 days for prophylaxis for surgery (surgical resection 
of a left-kidney mass). The subject experienced no hemorrhagic complications and no 
AEs that were considered related to the use of rVWF.
6.6 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) to
Human Subjects
Current treatment of VWD patients relies on desmopressin and VWF products 
manufactured from pooled human plasma. Human VWF produced by recombinant 
technology could offer a new perspective in treatment of VWD. The benefit for the 
individual subject is anticipated to be significant during this clinical study. He/she may 
benefit from a product that minimizes excessive FVIII administration. Variations in VWF 
multimeric composition may lead to variability with respect to treating or preventing 
bleeds in VWD subjects, especially mucosal bleeds which are especially problematic. 
rVWF product manufactured by Baxalta consistently contains ultra-large molecular 
weight (ULMW) VWF multimers due to the fact that the product has not been exposed to 
ADAMTS13. The initial presence of these ULMW VWF multimers, which are 
subsequently cleaved by the subject’s endogenous ADAMTS13, may result in improved 
platelet and collagen binding and therefore provide more predictable treatment outcomes.
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By using a recombinant product, the risk of contamination with blood derived viruses or 
variant Creutzfeldt-Jakob Disease associated with the use of products of human or animal 
origin has been virtually eliminated. At this stage of product development, the key 
societal benefit is a better understanding of advanced treatment options for VWD and 
enhanced product availability.
These benefits outweigh the following potential risks of rVWF:

allergic-type hypersensitivity reactions as with any intravenous protein product

the occurrence of thromboembolic events

the development of neutralizing antibodies to VWF
Refer to the IB for further details on benefits and risks of the IP.
6.7 Compliance Statement
This study will be conducted in accordance with this protocol, the International Council 
for Harmonisation Guideline for Good Clinical Practice E6 (ICH GCP, April 1996), 
Title 21 of the US Code of Federal Regulations (US CFR), the EU Directives 2001/20/EC 
and 2005/28/EC, and applicable national and local regulatory requirements.
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7. STUDY PURPOSE AND OBJECTIVES
7.1 Study Purpose
The purpose of this phase 3 study is to investigate the efficacy and safety, including 
immunogenicity and thrombogenicity, and 
of 
prophylactic treatment with rVWF in subjects with severe VWD.
7.2 Primary Objective
The primary objective of this study is to prospectively evaluate the annualized bleeding 
rate (ABR) for spontaneous bleeding episodes while on prophylactic treatment with 
rVWF and to compare it to the subject’s historical ABR for spontaneous bleeding 
episodes during on-demand treatment. 
7.3 Secondary Objectives
Secondary Objectives are:

Additional efficacy assessments of prophylactic treatment

Safety and immunogenicity

Pharmacokinetics

Efficacy of the treatment of bleeding episodes

Efficacy of the treatment of perioperative bleeding management, if surgery is 
required
7.4 Exploratory Objectives
7.4.1
 
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8. STUDY DESIGN
8.1 Overall Study Design 
This is a prospective, open label, uncontrolled, non-randomized, international, 
multicenter phase 3 study to evaluate efficacy, safety, including immunogenicity and 
thrombogenicity, and 
of a prophylactic treatment regimen with rVWF in patients 
with severe VWD. 
Subjects transitioning from on-demand treatment will be infused twice weekly with 
BAX 111 (rVWF) at doses of 50 ± 10 IU/kg rVWF:RCo. The dose may be adjusted 
within this range based on the PK data, subject’s history of bleeding episodes, and the 
results from clinical and laboratory assessments (see Section 8.6.4.2).
The overall duration of prophylactic treatment per subject will be 12 months.
During this period any bleeding episodes requiring substitution therapy with VWF 
concentrate to control bleeding will be treated with rVWF with or without ADVATE. 
The dose will be according to the bleeding severity and it will be adjusted to the clinical 
response (see Section 8.6.4.4.2).
The overall study design is illustrated in Figure 1.
8.2 Duration of Study Period(s) and Subject Participation
The overall duration of the study is approximately 22 months from study initiation 
(i.e., first subject enrolled) to study completion (i.e., last subject last visit). The subject 
participation period is approximately 15 months from enrollment to completion (i.e, last 
study visit), unless the subject is prematurely discontinued.
Subjects will be offered the option to continue to receive BAX111 in a long-term 
continuation study.
8.3 Outcome Measures
8.3.1 Primary Outcome Measure
The primary outcome measure is

Efficacy:
Prospectively recorded ABR for spontaneous (not related to trauma) bleeding 
episodes during prophylactic treatment with rVWF and the subjects’ historical 
ABR for spontaneous bleeding episodes during on-demand treatment.
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8.3.2 Secondary Outcome Measures
8.3.2.1 Efficacy 

Number (proportion) of subjects with reduction of ABR for spontaneous (not 
related to trauma) bleeding episodes during prophylaxis relative to the subjects’
own historical ABR during on-demand treatment. An ABR reduction of >25% is 
considered relevant.

Number (proportion) of subjects with 0 bleeds during prophylactic treatment with 
rVWF

Number of infusions and total weight adjusted consumption of rVWF and
ADVATE per month and per year during prophylactic treatment as well as during 
on-demand treatment.
8.3.2.2 Safety

AEs

Incidence of thromboembolic events 

Incidence of severe hypersensitivity reactions

Development of neutralizing antibodies to VWF and FVIII

Development of total binding antibodies to VWF and FVIII

Development of antibodies to Chinese hamster ovary (CHO) proteins, mouse 
immunoglobulin G (IgG) and rFurin
8.3.2.3 Pharmacokinetics

Incremental recovery (IR), terminal half-life (T1/2), mean residence time (MRT), 
area under the curve/dose (AUC/dose), area under moment curve/dose 
(AUMC/dose), volume of distribution at steady state (Vss) and clearance (CL) 
based on Von Willebrand factor Ristocetin cofactor activity (VWF:RCo), Von 
Willebrand factor antigen (VWF:Ag), Von Willebrand collagen binding activity 
(VWF:CB), and time course (72 hours) of FVIII clotting activity (FVIII:C) levels.
8.3.2.4 Efficacy of the Treatment of Bleeding Episodes

Number of infusions of rVWF and ADVATE (rFVIII) per spontaneous bleeding 
episode

Number of infusions of rVWF and ADVATE (rFVIII) per traumatic bleeding 
episode
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
Weight-adjusted consumption of rVWF and ADVATE (rFVIII) per spontaneous 
bleeding episode

Weight-adjusted consumption of rVWF and ADVATE (rFVIII) per traumatic 
bleeding episode

Overall hemostatic efficacy rating at resolution of bleed 
8.3.2.5 Efficacy of treatment of perioperative bleeding management, if surgery is 
required

Intraoperative actual versus predicted blood loss (assessed by the operating 
surgeon) at completion of surgery

Intraoperative hemostatic efficacy score on a scale of excellent, good, moderate or 
none (assessed by the operating surgeon) at completion of surgery

For elective surgery: an overall assessment of hemostatic efficacy 24 hours after 
the last perioperative infusion of rVWF, assessed by the Investigator

Daily intra- and postoperative weight-adjusted dose of rVWF with or without 
ADVATE through postoperative day 14.
8.3.3 Exploratory Outcomes Measure
 
8.4 Randomization and Blinding
This is a non-randomized open-label, active treatment clinical study. 
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8.5 Study Stopping Rules 
This study will be stopped if 1 or more of the following criteria are met:
1.
Two subjects develop a thromboembolic event
2.
Two subjects develop severe hypersensitivity reactions (e.g., clinically significant 
localized urticaria, generalized urticaria, wheezing, or anaphylaxis); or infusion 
related tightness of the chest or hypotension
3.
Two subjects develop signs and symptoms, suggestive of a thrombotic 
thrombocytopenic purpura-like syndrome (subjects with type 2B VWD developing 
thrombocytopenia or changes of the platelet count as described below, will be 
evaluated on case by case, whether they need to be accounted for), such as 

A drop in platelet count of 50% of subject’s baseline or less than 100.000 per 
microliter

3-fold increase in lactate dehydrogenase (LDH)

Impaired renal function as determined by: 

Creatinine increase of 1.5-fold from baseline levels

Blood urea nitrogen (BUN) increase from normal levels to a level 
> 60 mg/dL
4.
Any subject has abnormal liver function:
Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) 
elevations >5 times upper limit of normal (ULN) in the absence of a concomitant 
bilirubin increase
ALT and/or AST elevations >3 times ULN in the presence of a total bilirubin 
increase >2 times ULN or an international normalized ratio (INR) >1.5 without 
findings of cholestasis or other alternate etiology to explain the elevations 
(i.e., “Hy’s Law cases”)
ALT and/or AST elevations >3 times ULN with the appearance of fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or 
eosinophilia (>5%)
5.
Two subjects develop rVWF neutralizing antibodies
The study may be stopped at any time by the sponsor.
The sponsor ultimately will decide whether to terminate, temporarily halt or modify the 
study based on the data monitoring committee (DMC) recommendation.
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8.6 Investigational Product(s)
8.6.1 Packaging, Labeling, and Storage
8.6.1.1 rVWF (Recombinant von Willebrand Factor)
rVWF will be packaged in boxes with 2 glass vials, one containing the lyophilized 
rVWF, and the second vial containing the diluent. Further details are provided in the IB 
and Pharmacy Manual. The rVWF label will include, at a minimum, the actual 
VWF:RCo potency and the date of expiration.
rVWF should be refrigerated (2-8°C [36-46°F]) in lyophilized form. Deviations from the 
storage condition have to be communicated and followed up with the sponsor.
Inadequately stored product will have to be placed in quarantine and may only be used 
after written investigational product administration authorization by the sponsor. After
removal of the product from the refrigerator the product must not be returned to the 
refrigerator and has to be used immediately. rVWF must not be used beyond the 
expiration date printed on the vial. Avoid freezing at all times.
8.6.1.2 rFVIII (Recombinant Factor VIII /ADVATE)
ADVATE will be packaged in boxes with 2 glass vials, one containing the lyophilized 
rFVIII, and the second vial containing the diluent. Further details are provided in the IB 
and Pharmacy Manual. The ADVATE label will include, at a minimum, the actual 
FVIII:C potency and the date of expiration. 
ADVATE should be refrigerated (2-8°C [36-46°F]) in powder form and should not be 
used beyond the expiration date printed on the vial. Deviations from the storage condition 
have to be communicated and followed up with the sponsor. Inadequately stored product 
will have to be placed in quarantine and may only be used after written investigational 
product administration authorization by the sponsor. After removal of the product from 
the refrigerator the product must not be returned to the refrigerator and has to be used 
immediately. Avoid freezing at all times.
8.6.2 Reconstitution
The reconstitution procedures for both rVWF and ADVATE products are detailed in the 
Pharmacy Manual. 
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8.6.3 Administration
Following reconstitution, rVWF and ADVATE (in case of bleeding episode treatment) 
should be administered to study subjects at room temperature and within 3 hours of 
reconstitution. The reconstituted rVWF and ADVATE, should be inspected for 
particulate matter and discoloration prior to administration, whenever the solution and 
container permit. The solution should be clear and colorless in appearance. If not, do not 
administer the product. Plastic syringes provided by the sponsor must be used since 
coagulation factors tend to stick to the surface of glass syringes.
Investigational product infusions should be given at a rate which should not exceed 
4 mL/minute. The investigator/ subject shall ensure that no visible residual volume 
remains in the syringe(s) and that the complete content is administered. Upon completion 
of the infusion, the butterfly catheter should be flushed with at least 2 mL of saline 
solution. In case of a (central) venous access device, the flush should be with at least 
10 mL of saline solution. The IP infusions should be administered over a duration of 2 to 
15 minutes, depending on the volume.
Only the actual potencies of rVWF and ADVATE as stated on the vial labels and 
described in the Pharmacy Manual should be used. A variation of up to 10% of the 
intended dose for prophylactic infusions and of the intended dose for treatment of 
bleeding episodes is permissible and the exact dose should be recorded on the Case 
Report Form (CRF).
At study visits where recovery analysis is being done, vials with the same lot numbers 
should be used throughout the PK IP infusion per subject.
For treatment of bleeding episodes there are 2 options for the preparation of rVWF and 
ADVATE for infusion if needed. 
Preferably sequential administration will be done: separate syringes of the appropriate 
dose of rVWF and ADVATE will be prepared for sequential infusion. rVWF should be 
infused first sequentially followed preferably within 10 minutes by infusion of ADVATE. 
Only the actual potencies of rVWF and ADVATE as stated on the vial labels and 
described in the Pharmacy Manual should be used. 
Alternatively, premixed solutions can be administered: rVWF and ADVATE will be an 
i.v. admixture in a single syringe to achieve the appropriate dose. The contents of each 
vial of rVWF or ADVATE can be drawn into 1 syringe by using a separate unused 
reconstitution device as described in the Pharmacy Manual. 
The final dose of rVWF:ADVATE should be at a ratio of 1.3:1 ± 0.2.
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8.6.4 Description of Treatment
8.6.4.1 Baseline Visit (PK-Assessment Treatment)
The first IP infusion for PK assessment should be within 42 days after the completion of 
screening procedures and confirmation of eligibility.
At the baseline visit the subjects will receive a dose of 50 ± 5 IU/kg rVWF:RCo for PK 
assessment. Blood samples will be drawn within 30 minutes pre-infusion, and at 11 time 
points post-infusion (15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 
6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours
and 96 ± 2 hours). 
Subjects previously enrolled in rVWF studies 070701, 071001 or 071101 and having
previously undergone PK assessments in these studies are required to repeat the PK 
assessment due to different dose and time points used in these former studies (see 
Section 12.9.1 and Section 20.3). A washout period of at least 5 days is required prior to 
infusion of rVWF for PK assessment for subjects previously treated with rVWF.
8.6.4.2 Prophylaxis Initiation Treatment 
The prophylaxis initiation treatment visit will coincide with the 96 2 h PK assessment. 
At this visit subjects will receive their prophylaxis initiation dose of 50 ± 10 IU/kg
rVWF:RCo after the blood draw for the 96 2 hours post-infusion PK assessment. If 
subjects do not need an additional PK assessment, subjects must receive the IP for 
prophylaxis initiation treatment within 42 days after screening and confirmation of 
eligibility. The exact standard prophylaxis dose may range between 40 and 60 IU/kg 
based on:

available historical PK data

type and severity of bleeding episodes the subject has experienced in the past and

monitoring of appropriate clinical and laboratory measures
Dose adjustments during the continued prophylactic treatment are described in
Section 8.6.4.3.
The subject will be trained on IP reconstitution and administration and may then qualify
for home treatment (see Section 8.6.4.3.2). Refer to Table 6 for study procedures and
Table 8 for clinical laboratory assessments.
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8.6.4.3 Prophylaxis Treatment
The standard prophylactic dose is 50 ± 10 IU/kg rVWF:RCo. All subjects will initially
receive BAX111 (rVWF) twice per week (Table 1, Schedule A). Examples of all dosing 
schedules are provided in Table 1.
Table 1
rVWF Dosing Schedule Examples: Schedules A and B
Example
M
T
W
Th
F
Sat
Sun
M
T
W
Th
F
Sat
Sun
Schedule A
X
X
X
X
Schedule B
X
X
X
X
X
X
Dose and frequency adjustments will be agreed with the sponsor in advance unless it 
constitutes an urgent safety measure. Dose adjustments to higher doses (not exceeding the 
upper dose limit of 80 IU/kg rVWF:RCo) and adjustments to frequency will only be 
allowed in cases of persisting high bleeding rates due to insufficient therapeutic response. 
8.6.4.3.1 Treatment Escalation
Criteria for dose and frequency escalation are specific to each bleeding indication 
(Table 2) but, overall, involve 1 significant breakthrough bleeding episode despite 
compliant prophylaxis. Subjects entering the study will begin prophylaxis treatment 
according to Schedule A (Table 1) and will remain at this dose and frequency until 
meeting the criteria for escalation to the next higher schedule: for example, from 
2 infusions of 50 ± 10 IU VWF:RCo/kg/week to 3 infusions of 50 ± 10 IU 
VWF:RCo/kg/week (Schedule B) to achieve adequate prophylaxis.
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Table 2
Criteria for Escalation Specific to Each Bleeding Indication
Schedule A
Schedule B
Joint bleeding
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) twice per week. In the event a 
spontaneous joint bleeding episode occurs 
while on this regimen, the subject will escalate 
to Schedule B following its resolution
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week.
GI bleeding
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) twice per week. In the event a 
severe GI bleeding episode occurs while on 
this regimen, the subject will escalate to 
Schedule B following its resolution
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week.
Menorrhagia
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) on days 1 and 2 of menses for 
2 cycles. Menstrual flow will be monitored by 
the PBAC score. If the average pictorial chart 
score is > 185, then the subject will escalate to 
Schedule B
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) on days 1, 2, 
and 3 of menses. Menstrual flow 
will be monitored by the PBAC 
score.
Epistaxis
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) twice per week. The subject will 
escalate to Schedule B in the event of 
1 occurrence of breakthrough bleeding 
requiring intervention such as iron 
replacement therapy, transfusion, packing, 
hospitalization; or 2 bleeding events that 
require treatment with factor replacement
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week. 
Oral and Other 
Mucosa
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) twice per week. The subject will 
escalate to Schedule B in the event of 
1 occurrence of breakthrough bleeding 
requiring intervention such as iron 
replacement therapy, transfusion, packing, 
hospitalization; or 2 bleeding events that 
require treatment with factor replacement.
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week.
Muscle and Soft 
Tissue
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) twice per week. In the event a 
spontaneous bleeding episode occurs while on 
this schedule, the subject will escalate to 
Schedule B following its resolution.
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week.
Abbreviations:  GI: gastrointestinal; PBAC: Pictorial Blood Assessment Chart.
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Dose and frequency reduction will only be allowed in case plasma VWF or FVIII levels
are exceeding the recommended ranges. 
If a subject does not adequately respond to rVWF therapy, he/she will be evaluated for 
the presence of neutralizing and total binding anti-VWF antibodies (see Section 12.9.3.2).
If a subject experiences a bleed while receiving rVWF three times per week, the 
investigator should treat the bleed with rVWF at doses up to 80 IU VWF:RCo/kg at a 
frequency determined by the investigator until the bleed resolves. Upon resolution of the 
bleeding event, the subject will return to their assigned prophylaxis regimen. 
It is essential for the success of this study that the subjects adhere to treatment regimens. 
Therefore, procedures for monitoring subject’s compliance are implemented (see 
Section 10.7).
If 1 infusion of IP is missed, the subject may administer the IP as soon as possible. The 
subject should adhere to their treatment scheme ensuring a minimum interval of 12 hours 
between this and the previous IP infusion. For example, a subject routinely infuses IP on 
Monday and Thursday, he/she misses the Monday time point and therefore may infuse 
the IP on the next day (Tuesday) and thereafter proceed with infusing the IP on Thursday
(considering a minimum 12 hours between the infusions) and return to the initial
schedule.
If more than 30% of infusions of IP are missed within the visit interval of 3 months the 
subject will be discontinued from the study (see Section 9.4).
8.6.4.3.2 General Instructions for Home Treatment for Prophylaxis
At the discretion of the investigator, a subject may be considered suitable for home 
treatment only after the subject has received at least 1 infusion of IP in the clinic, either 
during planned IP exposure (PK or prophylaxis) or during the treatment of bleeding 
episodes, and meets the following additional criteria:
1.
Fully understands the concept of a clinical study and related documentation 
(documented training of at least 30 minutes), 
2.
Has a history of previous experience with home treatment including 
self-administration and treatment with VWF containing concentrates, 
3.
Has adequate time for initial training of the study drug preparation (preparation, 
mixing and infusion of the IP(s) (documented training of at least 30 minutes).
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In the event a healthcare professional is required to administer IP, he/she must be trained 
and qualified by the sponsor on the above procedures prior to the decision for home 
treatment. A Subject Guideline detailing all instructions and information listed above will 
be provided to each subject. 
8.6.4.4 Treatment of Bleeding Episodes
8.6.4.4.1 General Instructions for Home Treatment of Bleeding Episodes
If a subject experiences a bleeding episode, he/she should contact the study site 
immediately and the site investigator should provide instructions on the treatment 
regimen. If the subject initiates the treatment at home, he/she should at least follow up 
with the study site if a visit is needed as per the standard of care at the center.
In the event a healthcare professional is required to administer treatment at the subject’s 
home, he/she must be trained and qualified by the site investigator on the above 
procedures prior to the decision for home treatment. Once a subject has received 
1 infusion of rVWF in the clinic (either during planned IP exposure or during the 
treatment of a bleeding episode) and meets the criteria for home treatment, the treatment 
of bleeding episodes with IP can be conducted at home (see Section 8.6.4.3.2).
If a subject is not qualified for home treatment, rVWF infusions must be administered at 
the study site.
If a subject experiences a bleeding episode that requires treatment between the screening 
and the prophylaxis initiation visit, the subject will be treated with IP (rVWF with or 
without ADVATE). Treatment with IP must occur at the study site unless the subject has 
previously qualified for home treatment with rVWF. If rVWF treatment is not feasible, 
the subject may use his/her standard of care, such as commercial pdVWF/FVIII products. 
In any case a washout period of at least 5 days is required prior to rVWF PK infusion at 
the PK assessment visit.
If a subject experiences a bleeding episode requiring treatment during the PK assessment, 
rVWF will be used to treat the bleed. Blood draws for PK assessment will be stopped and 
the PK assessments will be repeated once the bleed has resolved and the subject is free of 
any symptoms related with the bleeding episode. Dose and frequency of rVWF infusions 
or any other replacement therapy to stop the bleed should be recorded in the e-CRF.
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8.6.4.4.2 Dosing Recommendations for Treatment of Bleeding Episodes 
If an acute bleeding episode occurs, the subject will be treated with rVWF with or 
without ADVATE. In general initially, an infusion of rVWF: ADVATE at an rVWF:
ADVATE ratio of 1.3:1± 0.2 will be administered. Subsequent infusions will be with 
rVWF:RCo 40 to 60 IU/kg with or without 30 to 45 IU/kg ADVATE (only to be 
administered if plasma FVIII levels fall below 30 IU/L during the treatment period). 
If FVIII levels are not available, dosing is at the discretion of the investigator based upon 
the individual subject’s PK data. Using ADVATE in addition to rVWF in subsequent 
doses carries the risk of an excessive rise in FVIII:C. Therefore, reduced doses of 
ADVATE and/or prolongation of the dose interval should be considered.
In general the aim of the initial dose should be full replacement of VWF with VWF:RCo 
levels of >0.6 IU/ml (60%) and FVIII:C of >0.4 IU/mL (40%). In major bleeding 
episodes, subsequent doses should keep the trough level of VWF:RCo >50% for 3 days 
and then as deemed necessary by the investigator for subsequent days. In moderate 
bleeding episodes, the dose and trough level may be reduced to >30% for as long as 
deemed necessary by the investigator. Treatment for minor bleeding episodes will 
generally consist of only 1 or 2 doses of rVWF IP. 
If the VWF:RCo level is above 150%, a planned treatment should be delayed by at least 
12 hours; if the VWF:RCo level is above 200%, a planned treatment should be delayed 
by at least 24 hours. In either case, a lower subsequent dose (e.g., 20 IU/kg VWF:RCo) 
may be appropriate.
Dosing recommendations are listed in Table 3.
Dosage must be individualized based on the subject’s weight, VWD type, and the 
severity of the bleeding episode, as well as on monitoring of appropriate clinical and 
laboratory measures. In the phase 1 study 070701, 1.0 IU/kg VWF:RCo raised the 
circulating level of VWF:RCo by 0.017 IU/mL (1.7 %). In the same study, the observed 
mean half-life for rVWF was 19.3 hours, with a standard deviation of 10.9 hours.
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Table 3
rVWF:RCo Dosing Recommendations for the Treatment of Bleeding Episodes Due to VWD
Classification of 
VWD
Hemorrhage
Dosage (IU VWF:RCo/kg Body Weight)
Type 1 
Severe (Baseline 
VWF:RCo activity 
typically <20%) 
Minor (e.g., epistaxis, oral 
bleeding, menorrhagiaa) 
40 to 50 IU/kg (1 or 2 doses)
Major (e.g., severe or 
refractory epistaxis, 
menorrhagia*, GI bleeding, 
CNS trauma, hemarthrosis, 
or traumatic hemorrhage)
Initial dose 50 to 75 IU/kg, then 40 to 60 IU/kg 
every 8 to 12 hours for 3 days to keep the trough 
level of VWF:RCo >50%; then 40 to 60 IU/kg daily 
for a total of up to 7 days of treatment
Type 2 (all variants) 
and Type 3 
Minor (clinical indications 
above) 
40 to 50 IU/kg (1 or 2 doses)
Major (clinical indications 
above)
Initial dose of 60 to 80 IU/kg, then 40 to 60 IU/kg 
every 8 to 12 hours for 3 days to keep the trough 
level of VWF:RCo >50%; then 40 to 60 IU/kg daily 
for a total of up to 7 days of treatment
a Menorrhagia is defined as excessive bleeding during menstruation. A diagnosis of menorrhagia will be 
defined by a prospectively completed Pictorial Blood Assessment Chart (PBAC) score >185 and normal 
cervical cytology or requiring use of a VWF-containing concentrate for treatment of excessive 
menstrual bleeding for at least one menstrual cycle during the prior year.
Variances of up to 10% in dosing are permissible during treatment of bleeding episodes, 
but rounding to the nearest vial size should be avoided.
Subjects with non-neutralizing binding anti-VWF antibodies should initially be treated 
with a dose known to be efficacious based on the subject’s medical treatment history
which may differ from the recommendations provided in Table 3. Subjects should be 
monitored for lack of efficacy as well as for FVIII (mandatory), VWF:RCo (mandatory), 
and VWF:Ag (optional where testing is not available) levels after 3 to 6 hours. Re-dosing 
with rVWF in combination with ADVATE using the same (initial) dose and adaptation of 
the dosing frequency should be considered until cessation of the bleed, if the FVIII and/or 
VWF:RCo levels drop below 30%-50% depending on bleeding severity.
The number of subsequent infusions and the dosage levels prescribed will be determined 
by the investigator on the basis of the clinical severity, response to current therapy, 
available laboratory data, and the subject’s historical treatment for similar bleeding 
episodes.
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8.6.4.5 Treatment of Surgical Bleeding
Subjects enrolled in this study who require surgery or dental procedures will be treated 
with investigational product to manage their surgical bleeding then afterwards will 
resume their prophylactic rVWF treatment schedule.
8.6.4.5.1 Major, Minor and Oral Surgery Definition
The following definitions and criteria are used to serve as a guidance for major, minor 
and oral surgery.
Major surgeries generally refer to major orthopedic surgery (e.g., joint replacement, 
arthroscopic or open synovectomy, arthrodesis, hardware removals like plates or 
intramedullary nails, etc.), major abdominal surgery (e.g. open or laparoscopic 
hernioplasty, cholecystectomy, colon or small bowel resection, etc.), major gynecological 
surgery (e.g. open or laparoscopic myomectomy, hysterectomy, removal of 
endometriosis, polyps, cysts, adhesiolysis, etc.), major head and neck surgery (e.g.: 
tonsillectomy, adenoidectomy, rhinoplasty, lymphadenectomy, thyroidectomy, 
parotidectomy. etc.), any intracranial , cardiovascular or spinal surgery and any other 
surgery which has a significant risk of large volume blood loss or blood loss into a 
confined anatomical space. Extraction of impacted third molars is generally also 
considered major surgery due to the expected difficulty of surgery and the expected blood 
loss.
Minor surgeries generally refer to interventions such as placement of intravenous access 
devices, removal of small skin lesions, arthroscopy, gastroscopy, colonoscopy or 
conisation.
Oral surgeries comprise extractions of fewer than three teeth, if the teeth are non-molars 
and have no bony involvement.
A summary schedule of visit assessments and laboratory sampling is included in 
Supplement tables in Section 20.2.1 and Section 20.3.1.
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8.6.4.5.2 Preoperative Priming Dose
12- 24 hours prior to surgery, a priming dose with rVWF, using the rVWF and ADVATE 
IR and T1/2 for this subject , will be infused to allow the endogenous FVIII levels to raise 
to at least 30 IU/dL (minor, oral surgery), or 60 IU/dL (major surgery) before the loading 
dose of rVWF is infused.
As a general guidance a priming dose of 40-60 IU/kg rVWF:RCo will be administered.
8.6.4.5.3 Preoperative Loading Dose
An rVWF loading dose should be administed within 3 hours before surgery. 
The preoperative loading dose will be calculated as the difference in the target peak and 
baseline plasma VWF:RCo levels divided by the IR. For minor and oral surgery, the 
target peak is 50-60 IU/dL VWF:RCo and 40-50 IU/dL FVIII. For major surgery, the 
target peak is 100IU/dL VWF:RCo and 80-100 IU/dL FVIII.
If FVIII levels prior to loading dose administration are not at least 30 IU/dL (minor, oral 
surgery), or 60 IU/dL (major surgery) ADVATE will be administered in addition to 
rVWF in order to raise FVIII:C levels to recommended levels.
The surgery may only start after normalization of the activated partial 
thromboplastin time (aPTT).
8.6.4.5.4 Intra- and Postoperative (maintenance) Dosing
After the preoperative loading dose(s), subjects who have not achieved the desired 
postinfusion recovery will continue to receive rVWF with or without ADVATE as a 
bolus infusion, depending on VWF and FVIII levels. The peri- and postoperative 
substitution regimen will be individualized according to the PK results, intensity and 
duration of the hemostatic challenge, and the institution’s standard of care.
Subjects undergoing minor surgery will be infused with rVWF every 12-24 hours or 
every other day, targerting >30IU/dL (rVWF and FVIII) for at least the first 48 hours.
Subjects undergoing oral surgery will be infused with rVWF at least once within the first 
8-12 hours, targeting >30 IU/dL (rVWF and FVIII).
Subjects undergoing major surgery will be infused with rVWF every 12-24 hours for at 
least the first 72 hours post-surgery, targeting a VWF:RCo and FVIII:C trough plasma 
level >50 IU/dL, followed by further treatment post-72 hours for as long as deemed 
necessary by the Investigator, targeting a VWF:RCo and FVIII:C trough plasma level of 
>30 IU/dL.
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Dose modifications based on pre-infusion VWF/FVIII levels will be performed as 
needed. For subsequent infusions post surgery, in case pre-infusion levels are not 
available prior to the consecutive infusion in a timely manner, pre-infusion levels from 
the previous dose may be used by the investigator for dosing guidance.
Peak plasma level guidance is matching to Section 8.6.4.4.2
A schedule of all perioperative visit assessments and laboratory sampling can be found in 
supplement tables in Section 20.2.1 and Section 20.3.1.
8.6.4.6 Thrombosis Prophylaxis
Thromboembolic events have been reported in patients who have VWD, especially in the 
setting of known risk factors for thrombosis. Hence, in all patients who have VWD and 
are receiving VWF concentrate, attention should be given to avoid exceeding maximal 
recommended plasma activity levels of VWF:RCo (250 IU/dL) and FVIII (250 IU/dL), 
perform proper thrombotic-risk assessment, and institute appropriate preventive 
strategies.
Anticoagulation measures, such as heparin, are acceptable and should follow study site 
standards. The investigator will record the use and reasons for such measures/agents on 
the appropriate CRF.
8.6.5 Investigational Product Accountability
The investigator will ensure that the IP(s) is stored as specified in the Pharmacy Manual
and that the storage area is secured, with access limited to authorized study personnel. 
The investigator will maintain records that the IP(s) was received, including the date 
received, drug identity code, date of manufacture or expiration date, amount received and 
disposition. The IP(s) must be dispensed only at the study site or other suitable location 
(e.g., infusion center; home, as applicable per study design), as specified in the protocol 
(see Section 10). Records will be maintained that includes the subject identification code 
(SIC), dispensation date, and amount dispensed. All remaining partially used and/or 
unused IP(s) will be returned to the sponsor or sponsor’s representative after study 
completion/termination, or destroyed with the permission of the sponsor in accordance 
with applicable laws and study site procedures. If IP(s) is to be destroyed, the investigator 
will provide documentation in accordance with sponsor’s specifications.
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8.7 Source Data
Per ICH GCP, source data are defined as all information in original records and certified 
copies of original records of clinical findings, observations, or other activities in a clinical 
trial that are necessary for the reconstruction and evaluation of the trial. Source data are 
contained in source documents (original records or certified copies), which may be in 
paper and/or electronic format. Source data for this study comprise the following:
hospital records, medical records, clinical and office charts, laboratory notes, memoranda, 
subjects' diaries or evaluation checklists, outcomes reported by subjects, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate copies, microfiches, photographic negatives, 
microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at 
the laboratories and at medico-technical departments involved in the clinical study.
No data will be entered directly onto the CRF.
For additional information on study documentation and CRFs refer to Section 17.2. The 
use of subject diaries is described in Section 10.5.
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9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION
9.1 Inclusion Criteria
Subjects who meet ALL of the following criteria are eligible for this study:
1.
Subject has a documented diagnosis of severe VWD (baseline VWF:RCo 
<20 IU/dL) with a history of requiring substitution therapy with von Willebrand 
factor concentrate to control bleeding
a. Type 1 (VWF:RCo <20 IU/dL) or,
b. Type 2A (as verified by multimer pattern), Type 2B (as diagnosed by 
genotype), Type 2M or,
c. Type 3 (VWF:Ag ≤3 IU/dL).
2.
Diagnosis is confirmed by genetic testing and multimer analysis, documented in 
patient history or at screening.
3.
Subject currently receiving on-demand treatment for whom prophylactic treatment 
is recommended according to standard of care at the center.
4.
Has ≥3 documented spontaneous bleeds requiring VWF treatment during the past 
12 months 
5.
Availability of records to reliably evaluate type, frequency and treatment of 
bleeding episodes during 12 months of on-demand treatment prior to enrollment.
6.
Subject is ≥18 years old at the time of screening and has a body mass index 
≥15 but <40 kg/m2.
7.
If female of childbearing potential, subject presents with a negative blood/urine 
pregnancy test at screening and agrees to employ adequate birth control measures 
for the duration of the study.i
8.
Subject is willing and able to comply with the requirements of the protocol.
9.2 Exclusion Criteria
Subjects who meet ANY of the following criteria are not eligible for this study:
1.
The subject has been diagnosed with Type 2N VWD, pseudo VWD, or another 
hereditary or acquired coagulation disorder other than VWD (eg qualitative and 
quantitative platelet disorders or elevated PT/INR 1.4).
                                                
i Refer to Section 20.4 for a list of adequate contraceptive methods for females of childbearing potential.
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2.
The subject has received prophylaxis treatment in the 12 months prior to 
screening (including those who received treatment once a month for menorrhagia 
but were not treated for any other bleeds).
3.
The subject is currently receiving prophylaxis treatment.
4.
The subject has a history or presence of a VWF inhibitor at screening.
5.
The subject has a history or presence of a FVIII inhibitor with a titer ≥0.4 BU (by 
Nijmegen modified Bethesda assay) or ≥0.6 BU (by Bethesda assay).
6.
The subject has a known hypersensitivity to any of the components of the study 
drugs, such as to mouse or hamster proteins.
7.
The subject has a medical history of immunological disorders, excluding seasonal 
allergic rhinitis/conjunctivitis, mild asthma, food allergies or animal allergies.
8.
The subject has a medical history of a thromboembolic event.
9.
The subject is HIV positive with an absolute Helper T cell (CD4) count 
200/mm3.
10. The subject has been diagnosed with significant liver disease as evidenced by any 
of the following: serum ALT 5 times the ULN; hypoalbuminemia; portal vein 
hypertension (e.g., presence of otherwise unexplained splenomegaly, history of 
esophageal varices).
11. The subject has been diagnosed with renal disease, with a serum creatinine level 
≥2.5 mg/dL.
12. The subject has a platelet count <100,000/mL at screening.
13. The subject has been treated with an immunomodulatory drug, excluding topical 
treatment (e.g., ointments, nasal sprays), within 30 days prior to signing the 
informed consent.
14. The subject is pregnant or lactating at the time of enrollment.
15. Patient has cervical or uterine conditions causing menorrhagia or metrorrhagia 
(including infection, dysplasia).
16. The subject has participated in another clinical study involving another IP or 
investigational device within 30 days prior to enrollment or is scheduled to 
participate in another clinical study involving an IP or investigational device 
during the course of this study.
17. The subject has a progressive fatal disease and/or life expectancy of less than 
15 months.
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18. The subject is identified by the investigator as being unable or unwilling to 
cooperate with study procedures.
19. The subject has a mental condition rendering him/her unable to understand the 
nature, scope and possible consequences of the study and/or evidence of an 
uncooperative attitude.
20. The subject is in prison or compulsory detention by regulatory and/or juridical 
order.
21. The subject is member of the study team or in a dependent relationship with one 
of the study team members which includes close relatives (i.e., children, 
partner/spouse, siblings and parents) as well as employees.
9.3 Delay Criteria
1.
If the subject has an acute bleeding episode or presents with an acute illness 
(e.g., influenza, flu-like syndrome, allergic rhinitis/conjunctivitis, non-seasonal 
asthma) the screening visit will be postponed until the subject has recovered.
9.4 Withdrawal and Discontinuation
Any subject may voluntarily withdraw (i.e., reduce the degree of participation in the 
study) consent for continued participation and data collection. The reason for withdrawal 
will be recorded on the End of Study CRF. Assessments to be performed at the 
termination visit (including cases of withdraw or discontinuation) are described in 
Section 10.6 and Section 20.2. 
Discontinuation (i.e., complete withdrawal from study participation) may be due to 
dropout (i.e., active discontinuation by subject) or loss to follow-up (i.e., discontinuation 
by subject without notice or action). Additionally, the investigator and sponsor have the 
discretion to discontinue any subject from the study if, in their judgment, continued 
participation would pose an unacceptable risk for the subject.
Subjects also will be withdrawn from treatment or discontinued from further study 
participation for the following reasons:
1.
The subject is scheduled for an extended treatment period 3 months with 
non-topical immunomodulating drugs other than anti-retroviral chemotherapy 
(e.g., -interferon, corticosteroid agents [equivalent to hydrocortisone greater than 
10 mg/day]) during the course of the study
2.
Subjects with chronic hepatitis B or C develop ALT/AST levels exceeding 5 times 
the ULN for 1 month
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3.
Subjects who experience severe hypersensitivity reactions, e.g., anaphylaxis upon 
exposure to rVWF
4.
Subjects who develop a neutralizing inhibitor to rVWF and/or ADVATE
(biological assays)
5.
Subjects who demonstrate clinical signs of thromboembolic events
6.
The subject becomes pregnant. IP exposure will be discontinued. Attempts will be 
made to follow the subject through completion of the pregnancy and up to 1 year 
post delivery, if feasible. The investigator will record a narrative description of 
the course of the pregnancy and its outcome. 
7.
The subject begins lactating. IP exposure will be discontinued. The investigator 
will record a narrative description of the course of the baby’s development. 
8.
The subject is not compliant with the prophylactic treatment regimen and does not 
adhere to the frequency of IP administration. Once >30% of infusions are missed 
within a visit interval (3 months), the subject will be discontinued from further 
participation in the study. 
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10. STUDY PROCEDURES
10.1 Informed Consent and Enrollment
Any patient who provides informed consent (i.e., signs and dates the informed consent 
form) is considered a subject in the study.
10.2 Subject Identification Code
The following series of numbers will comprise the SIC: protocol identifier (e.g., 090701) 
to be provided by the sponsor, 2- or 3-digit number study site number (e.g., 02) to be 
provided by the sponsor, and 3- or 4-digit subject number (e.g., 0003) reflecting the order 
of enrollment (i.e., signing the informed consent form). For example, the third subject 
who signed an informed consent form at study site 02 will be identified as Subject 
090701-020003. All study documents (e.g., CRFs, clinical documentation, sample 
containers, drug accountability logs, etc.) will be identified with the SIC. Additionally, a 
uniquely coded SIC(s) is permitted as long as it does not contain a combination of 
information that allows identification of a subject (e.g., collection of a subject’s initials 
and birth date would not be permitted), in compliance with laws governing data privacy.
10.3 Screening and Study Visits
The study site is responsible for maintaining a screening log that includes all subjects
who provided informed consent. The log also will serve to document the reason for 
screening failure. All screening data will be collected and reported in CRFs, regardless of 
screening outcome. If a subject is re-screened, the End of Study CRF should be 
completed, and a new ICF, new SIC and new CRF are required for that subject.
The overall study design is illustrated in the Figure 1. Details on the procedures to be 
performed at each study visit, including screening, are provided in Supplement 20.2
Schedule of Study Procedures and Assessments and Supplement 20.3 Clinical Laboratory 
Assessments.
10.3.1 Screening Visit
Written informed consent must be obtained from each subject before any study related
procedures are performed. To initiate screening procedures, at least 72 hours must have 
elapsed since the last VWF administration and the subject must not be actively bleeding 
at the time of screening. Multimer analysis and VWD gene mutation analysis should be 
performed at screening if not available in the subject’s medical history. The screening visit 
will be delayed if the subjects presents with an acute bleeding episodes or acute illness 
(e.g., influenza, flu-like symptoms, inflammatory diseases) until the event has resolved. 
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All screening procedures and confirmation of eligibility shall take place within 42 days 
prior to the first infusion of IP for PK assessments. If the IP is not infused within 42 days,
all screening assessments except blood group, human leucocyte antigen (HLA), genetics, 
multimeric pattern and 
, must be repeated to reconfirm eligibility. Refer to 
Supplement 20.2 and Supplement 20.3. Upon completion of screening procedures, 
subject eligibility will be confirmed by the sponsor on a subject eligibility form before 
additional study procedures are undertaken. The subject will maintain a diary that will 
include infusion logs (see Section 10.5). The allocation of IP will be initiated after the 
subject has qualified for home treatment (see Section 8.6.4.3.2).
In the event of a subject experiencing a bleeding episode that requires treatment between 
the screening visit and the baseline visit (PK assessment visit), the subject will be treated
with rVWF. If rVWF is not available for any reason, e.g., subject not yet trained on IP 
administration, study site visit for IP administration not feasible, etc., the subject may use 
his/her standard of care, such as commercial pdVWF/FVIII products.
10.3.2 Baseline Visit - PK-Assessment Visit 
After screening and confirmation of eligibility each subject will undergo a PK 
assessment. All subjects will receive a dose of 50 ± 5 IU/kg rVWF:RCo to determine 
VWF and FVIII levels. Blood samples will be drawn within 30 minutes pre-infusion, and 
at 11 time points post-infusion (15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 3 ± 0.5 
hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 
72 2 hours and 96 ± 2 hours). See Section 20.2 and Section 20.3. IP infusion vials from 
the same lot number should be used for all PK-assessments per subject. Samples for 
measurement of FVIII and VWF activity taken through to 6 hours post-infusion will be 
obtained from an extremity different from that used for the infusion of IP. Where needed, 
the phlebotomy site will be kept patent via an infusion of normal saline. In this event, at 
least 5 mL of blood will be collected and discarded before collection of the next test 
sample into a fresh syringe.
If the subject has a central venous catheter, the central line should be used to administer 
the infusion and a peripheral venipuncture should be used to collect the blood samples. 
In the event that a blood sample must be drawn through the central line used for 
administration of IP, the line must first be flushed with at least 10 mL normal saline or 
other suitable catheter flush solution that does not contain anticoagulant. At least 5 mL of 
whole blood must be collected and discarded prior to obtaining the sample. 
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If a subject experiences a bleeding episode during the PK assessment no subsequent 
blood sample will be drawn in that specific PK period. The guidance provided in 
Section 8.6.4.4 has to be followed for the treatment of the bleeding episode. The subject 
once recovered is eligible to repeat the PK assessment. 
10.3.3 Prophylaxis Initiation Visit
After the blood sample for the 96 hour PK assessment is drawn the subject will receive 
the first rVWF prophylactic dose of 50 ± 10 IU/kg rVWF: RCo. Details on dose are 
provided in Section 8.6.4.3. 
Procedures and assessments at this visit include: adverse events, bleeding episodes,
medications taken, and non-drug therapies. Independent of previous PK assessment visits, 
within 2 hours prior the IP infusion, a physical examination will be performed. Vital 
signs will be assessed within 30 minutes prior to IP rVWF infusion and 30 minutes ± 15 
minutes after IP infusion. Further details are provided in Supplement 20.2 and 
Supplement 20.3.
10.3.4 Treatment of Bleeding Episodes
Treatment of bleeding episodes is described in detail in Section 8.6.4.4 and treatment of 
perioperative bleeding is described in detail in Section 8.6.4.5.
10.3.5 Perioperative Visits (only applicable is surgery is needed)
The perioperative visits from priming dose through postoperative day 14 will be required 
to check daily intra- and postoperative weight-adjusted dose of rVWF with or without 
ADVATE. Details on the procedures and assessments performed at each visit can be 
found in supplement tables in Section 20.2.1 and Section 20.3.1.
10.3.6 Follow-Up Visits (1 Month ± 1 Week, 2 Months ± 1 Week, 
3 Months ± 2 Weeks, 6 Months ± 2 Weeks, 9 Months ± 2 Weeks)
Visits will be performed after the prophylaxis initiation visit at 1 month ± 1 week, 
2 months ± 1 week, and 3 months ± 2 weeks and thereafter every three months
± 2 weeks. Additional visits may occur if clinically indicated (see Section 10.3.7).
When possible, site visits should be scheduled on days when the subject is expected to 
infuse BAX111. Within 2 hours prior to the rVWF IP infusion, a physical examination 
will be performed. Vital signs will be assessed within 30 minutes prior to IP infusion and 
30 minutes ± 15 minutes after IP infusion. Incremental recovery (IR) will be determined 
at each follow-up visit based on VWF:RCo activity assessed prior to and after IP 
infusion. 
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The blood sample for IR analysis will be drawn within 30 minutes prior to IP infusion 
and 30 minutes ± 5 minutes after IP infusion. rVWF will be infused at the regular 
prophylactic dose, i.e., 50 ± 10 IU/kg rVWF:RCo. For each subject’s recovery analysis IP 
infusion, vials from the same lot number should be used. 
Testing for VWF:RCo VWF:CB, rVWF:Ag, and FVIII:C level will be performed using 
the blood sample obtained before and after IP infusion. 
The blood sample prior to IP infusion will also be used for the assessment of neutralizing
and binding antibodies, clinical chemistry and hematology. A washout period of at least 
72 hours after the last infusion applies before the blood draw for the immunogenicity 
assays. Bleeding episodes and the hemostatic efficacy will be evaluated based on the 
review of the patient diary. See Section 20.2 and Section 20.3. The evaluation of IP 
consumption and treatment compliance will be performed based on subject’s diary 
entries. If a subject is not compliant with the prophylactic treatment regimen and does not 
adhere to the required frequency of administration of IP infusions (>30% of infusions
were missed within a visit interval [3 months]) the subject will be withdrawn from the 
study.
At the 6 months ± 2 week visit an electrocardiogram (ECG) will be performed and 
data will be collected. 
For the hemostatic efficacy assessment the following information will be recorded by the 
subject in the patient diary: bleeding location, type, severity, onset and resolution date 
and time, infusion date and time, clinical efficacy according to the rating scale. If at any 
time during the study a subject’s bleeding episode does not adequately respond to rVWF 
therapy, he/she will be evaluated for the presence of neutralizing and total binding 
antibodies. Refer to Section 12.9.3.2.
Further guidance on completing the subject’s diary will be provided to the subjects during 
training for home treatment (see Section 8.6.4.3.2).
10.3.7 Unscheduled Visits
For any unscheduled visit (except for collection of IP) a clinical assessment will be 
performed as per the scheduled follow-up visits with the exception of 
, ECG, and 
IR determination (refer to Supplement 20.2 and Supplement 20.3).
Subjects who have more than one bleeding episode in 3 months, or an increased 
frequency of bleeding, should go to the study site for an unscheduled visit.
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Follow-up visits after the subject has experienced a bleed may be requested by the 
investigator. Additional assessments may be required which are at the discretion of the 
investigator. 
10.3.8 Study Termination Visit (12 Months ± 2 Weeks)
At the 12 month ± 2 week visit, a full PK analysis, as per the baseline PK assessment, 
will be performed. Blood samples will be drawn within 30 minutes pre-infusion, and 
at 11 time points post-infusion (15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 
3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 
72 2 hours and 96 ± 2 hours). If a subject experiences a bleeding episode during the PK 
assessment no subsequent blood sample will be drawn in that specific PK period. The 
guidance provided in Section 8.6.4.4 has to be followed for the treatment of the bleeding 
episode. The subject once recovered is eligible to repeat the PK assessment.
The following parameters will be used as part of the PK assessment:

Incremental recovery of VWF:RCo, VWF:Ag, and VWF:CB

AUC/dose, area under moment curve (AUMC/dose, clearance (CL), Volume of 
distribution at steady state (Vss), mean residence time (MRT), of 
VWF:RCo ,VWF:Ag, and VWF:CB 

Half-life of VWF:RCo, VWF:Ag, and VWF:CB

Time course of the FVIII:C levels

VWF collagen binding (VWF:CB) levels
Refer to Supplement 20.2 and Supplement 20.3 for the other assessments to be performed 
at the PK assessment and study completion visits.
A washout period of at least 72 hours is required between the PK infusion and the study 
termination visit (at the time of the 96 hour postinfusion PK assessment). 
Refer to Supplement 20.2 and Supplement 20.3 for the list of assessments to be 
performed at the termination visit.
Subjects will be offered the option to continue to receive BAX111 in a long-term 
continuation study.
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10.4 Medications and Non-Drug Therapies 
The following medications and non-drug therapies are not permitted within 30 days 
before study entry and during the course of the study:
Medications:

Immunomodulating drugs other than anti-retroviral chemotherapy (e.g.,
-interferon, or corticosteroid agents at a dose equivalent to hydrocortisone 
greater than 10 mg/day) and an extended treatment period 3 months.

Another investigational and/or interventional study drug (except rVWF and FVIII 
administered under the surgery protocol).
A subject who has taken any of these medications or received any of these non-drug 
therapies during the study will be withdrawn from the study. 
The following medications are permitted during the course of the study:

Antifibrinolytics (e.g., tranexamic acid, -amino caproic acid) or topical
hemostats as needed, according to each institution’s standard of care

Emergent use of a VWF concentrate other than rVWF may be permissible under
certain circumstances (see Section 8.6.4.4.1)
Details of all adjunctive hemostatic medication used, including dose and reason for use, 
will be recorded in the electronic Case Report Form (eCRF).
10.5 Subject Diary
1.
An electronic subject diary will be provided to each subject at the baseline visit to
record the following information:

IP infusions to include date, start and stop times of the infusion, number of 
vials utilized, and infusion volume for prophylactic treatment or treatment of 
spontaneous and traumatic bleeding episodes 
2.
Details of bleeding episodes (site and type of bleeding) and response to treatment 
as described in Section 8.6.4.4
3.
Subjective hemostatic efficacy assessments.
Subjects and/or their legally authorized representatives will be trained on use of the diary. 
The diary will be provided in electronic format and remain with the subject for the 
duration of the study. The investigator will review the diary for completeness and request 
missing information periodically and in a timely manner. 
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Infusions performed at the study site will first be recorded in the site’s source documents 
and not in the patient diary.
Subject entries in the diary will serve as source records. During study participation the 
investigator has access to the database holding the subject diary data. After study closure, 
the investigator will receive the diary records for their subjects, including audit trail 
records, in PDF format. The data will be transmitted to the CRF by a validated transfer. 
Paper diary may be utilized in rare case where electronic diary use is not possible.
10.6 Subject Completion/Discontinuation
A subject is considered to have completed the study when he/she ceases active 
participation in the study because the subject has, or is presumed to have completed all 
study procedures according with the protocol (with or without protocol deviations).
Reasons for completion/discontinuation will be reported on the 
Completion/Discontinuation CRF, including: completed, screen failure, AE (e.g., death), 
discontinuation by subject (e.g., lost to follow-up [defined as 3 documented unsuccessful 
attempts to contact the subject], dropout), physician decision (e.g., pregnancy, 
progressive disease, non-compliance with IP/protocol violation(s), recovery), study 
terminated by sponsor, or other (reason to be specified by the investigator, e.g., technical 
problems). Regardless of the reason, all data available for the subject up to the time of 
completion/discontinuation should be recorded on the appropriate CRF. 
Every effort will be made to have discontinued subjects complete the study termination 
visit. If the termination visit is done as an additional, unscheduled visit, the assessment
results shall be recorded with the termination visit. If a subject terminates participation in 
the study and does not return for termination visit, his/her last recorded assessments shall 
remain with the last visit. The reason for discontinuation will be recorded, and the data 
collected up to the time of discontinuation will be used in the analysis and included in the 
clinical study report. If additional assessments are required, the assessments shall be 
recorded separately. Assessments to be performed at the termination visit (including in 
cases of withdraw or discontinuation) can be found in Supplement 20.2 Schedule of 
Study Procedures and Assessments and Supplement 20.3 Clinical Laboratory 
Assessments.
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In the event of subject discontinuation due to an AE, clinical and/or laboratory 
investigations that are beyond the scope of the required study observations/assessments 
may be performed as part of the evaluation of the event. These investigations will take 
place under the direction of the investigator in consultation with the sponsor, and the 
details of the outcome may be reported to the appropriate regulatory authorities by the 
sponsor. 
10.7 Procedures for Monitoring Subject Compliance
Subject compliance with the procedures of this study (treatment regimens and study 
visits) will be monitored by the investigator or/a licensed healthcare professional at the 
study site.
During the regular scheduled follow-up visits a direct review of the subject’s source data 
(e-diaries) will be performed at the sites and evaluated against the protocol requirements. 
In addition drug accountability will be evaluated at each follow-up study visit and the 
study termination visit by comparing the infusions recorded in the subject diary with
empty vials returned by each subject to the study site, and the study site’s dispensing 
record. Protocol deviations will be noted in the final report. 
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11. ASSESSMENT OF EFFICACY AND PHARMACOKINETICS
11.1 Assessment of Spontaneous Bleeding Episodes/Annualized Bleed Rate 
The annualized bleed rate (ABR) will be assessed based upon each individual 
spontaneous bleed, requiring coagulation factor replacement therapy, i.e., rVWF 
treatment. The following details on bleeding episodes will be recorded by the subject in 
the electronic diary (for home treatment), the subject’s healthcare provider in the site’s 
source documents (for treatments away from the primary investigative site), or by 
authorized, qualified personnel at the participating site in the subject’s medical records 
(for hospital-based treatment):

Location of bleed; i.e., joint, menorrhagia, epistaxis, gastrointestinal, soft tissue, 
muscle, body cavity, intracranial, etc.

Type of bleed; i.e., spontaneous, traumatic, unknown

Severity of bleed; i.e., minor, moderate, and major (see Table 3)

Date and time of onset of bleed

Date and time of each infusion of rVWF or rVWF-ADVATE used to treat a 
bleeding episode

Date and time of resolution of the bleeding episode
Study site personnel are qualified after they have undergone training during the 
qualification of the site.
All types of bleeds, including traumatic bleeds, will be recorded. Bleeding episodes 
should be organized by where they occur in addition to whether they occurred 
spontaneously or due to a traumatic event.
Bleeds occurring at the same anatomical location (e.g., right knee) with the same etiology 
(i.e., spontaneous versus injury) within 24 hours after onset of the first bleed will be 
considered a single bleed. Bleeding occurring at multiple locations related to the same 
injury (e.g., knee and ankle bleeds following a fall) will be counted as a single bleeding 
episode.
All efforts should be made to use rVWF for treatment of bleeding episodes. If needed, the 
use of a VWF concentrate other than IP for the treatment of bleeding episodes will not 
disqualify the subject from further participation in the study.
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11.2 Evaluation of ABR Before rVWF Prophylaxis and ABR Under rVWF
Prophylactic Treatment
At screening, the subject’s medical history will be recorded, including the number of all 
spontaneous and traumatic bleeding episodes within the past 12 months. The maximum 
interval of bleed-free periods as well as trauma induced bleeding episodes will also be 
recorded (prospectively and retrospectively).
11.3 Number of Infusions and Total Weight Adjusted Consumption of rVWF and 
ADVATE
The number of rVWF and ADVATE (in case of bleeding episode treatment) infusions 
will be logged in the subject diary. Based on these entries the weight adjusted 
consumption will be calculated per month and per year. 
11.4 Assessment of Efficacy for Treatment of Bleeding Episode
Investigators will be asked to assess and record hemostatic efficacy after resolution of 
each bleeding episode using the 4-scale rating system outlined in Table 4. 
Table 4
Efficacy Rating Scale
Rating
Efficacy Rating Criterion
Minor and Moderate Bleeding Events
Major Bleeding Events
Excellent (=1)
Actual number of infusions ≤ estimated 
number of infusions required to treat that 
bleeding episode
No additional VWF containing 
coagulation factor containing product 
required
Actual number of infusions ≤ estimated 
number of infusions required to treat that 
bleeding episode
No additional VWF containing coagulation 
factor containing product required
Good (=2)
1-2 infusions greater than estimated 
required to control that bleeding episode
No additional VWF containing 
coagulation factor containing product 
required
< 1.5 x infusions greater than estimated 
required to control that bleeding episode
No additional VWF containing coagulation 
factor containing product required
Moderate (=3)
3 or more infusions greater than estimated 
required to control that bleeding episode
No additional VWF containing 
coagulation factor containing product 
required
≥1.5 x infusions greater than estimated 
required to control that bleeding episode
No additional VWF containing coagulation 
factor containing product required
None (=4)
Severe uncontrolled bleeding or intensity 
of bleeding not changed
Additional VWF containing coagulation 
factor containing product required
Severe uncontrolled bleeding or intensity 
of bleeding not changed
Additional VWF containing coagulation 
factor containing product required
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11.5 Assessment of Efficacy for Treatment for Surgical Bleeding
For those undergoing surgery, the operating surgeon will be asked to assess and record 
actual versus predicated blood loss and intraoperative hemostatic efficacy immediately 
after surgery. 
The investigator will be asked to assess and record an overall assessment of hemostatic 
efficacy 24 hours after the last perioperative rVWF infusion and on Day 7 and Day 14 
using the 4-scale rating system described in Table 5.
Table 5
Assessment of Hemostatic Efficacy
Rating
Overall Assessment of Hemostatic Efficacy 24 Hours After the Last Perioperative
rVWF Infusion
Excellent (1)
Intra- and post-operative hemostasis achieved with rVWF with or without ADVATE 
was as good or better than that expected for the type of surgical procedure performed in 
a hemostatically normal subject
Good (2)
Intra- and post-operative hemostasis achieved with rVWF with or without ADVATE 
was probably as good as that expected for the type of surgical procedure performed in a 
hemostatically normal subject
Moderate (3)
Intra- and post-operative hemostasis with rVWF with or without ADVATE was clearly 
less than optimal for the type of procedure performed but was maintained without the 
need to change the rVWF concentrate
None (4)
Subject experienced uncontrolled bleeding that was the result of inadequate therapeutic 
response despite proper dosing, necessitating a change of rVWF concentrate
11.6 Pharmacokinetic Assessment
Details on pharmacokinetic assessments are provided in Section 12.9.1.
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12. ASSESSMENT OF SAFETY
12.1 Adverse Events
12.1.1 Definitions
An AE is defined as any untoward medical occurrence in a subject administered IP that 
does not necessarily have a causal relationship with the treatment. An AE can therefore 
be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom
(e.g., rash, pain, discomfort, fever, dizziness, etc.), disease (e.g., peritonitis, bacteremia, 
etc.), or outcome of death temporally associated with the use of an IP, whether or not 
considered causally related to the IP.
12.1.1.1 Serious Adverse Event
An SAE is defined as an untoward medical occurrence that at any dose meets one or 
more of the following criteria:

Outcome is fatal/results in death (including fetal death)

Is life-threatening – defined as an event in which the subject was, in the judgment 
of the investigator, at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death had it been more severe.

Requires inpatient hospitalization or results in prolongation of an existing 
hospitalization – inpatient hospitalization refers to any inpatient admission, 
regardless of length of stay.

Results in persistent or significant disability/incapacity (i.e., a substantial 
disruption of a person’s ability to conduct normal life functions)

Is a congenital anomaly/birth defect

Is a medically important event – a medical event that may not be immediately 
life-threatening or result in death or require hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the definitions above. Examples of such events are: 

Intensive treatment in an emergency room or at home for allergic
bronchospasm, blood dyscrasias, or convulsions that do not result in 
hospitalization, or development of drug dependence or drug abuse 

Reviewed and confirmed seroconversion for human immunodeficiency 
virus
(HIV), hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus
(HCV), hepatitis E virus (HEV), or parvovirus B19 (B19V)
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
Development of neutralizing VWF antibodies

Development of neutralizing antibodies to FVIII (titer ≥0.4 BU [by 
Nijmegen- modified Bethesda assay] or ≥0.6 BU [by Bethesda assay])

Thromboembolic events (e.g., myocardial infarction, stroke, transient 
ischemic attack [TIA], deep vein thrombosis [DVT] or pulmonary 
embolism)

Anaphylaxis (for definition, refer to Section 12.6.2) or severe 
hypersensitivity reactions
Uncomplicated pregnancies, following maternal or paternal exposure to IP are not 
considered an (S)AE; however, any pregnancy complication or pregnancy termination by 
therapeutic, elective, or spontaneous abortion shall be considered an SAE.
12.1.1.2 Suspected Unexpected Serious Adverse Reaction (SUSAR)
Any suspected adverse reaction to study treatment (i.e., including active comparators) 
that is both serious and unexpected. 
The event(s) must meet all of the following:

Suspected adverse reaction

Serious

Unexpected

Assessed as related to study treatment
Once determined to meet the criteria for a SUSAR, the sponsor will ensure expedited 
SUSAR reporting in line with the regulatory requirements in participating countries as 
outlined in the Safety Management Plan.
12.1.1.3 Non-Serious Adverse Event
A non-serious AE is an AE that does not meet the criteria of an SAE.
12.1.1.4 Unexpected Adverse Events
An unexpected adverse event is an AE whose nature, severity, specificity, or outcome is 
not consistent with the term, representation, or description used in the Reference Safety 
Information (e.g., IB, package insert). “Unexpected” also refers to the AEs that are 
mentioned in the IB as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring 
with the particular drug under investigation.
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12.1.1.5 Preexisting Disease
Preexisting diseases that are present before entry in to the study are described in the 
medical history, and those that manifest with the same severity, frequency, or duration 
after IP exposure will not be recorded as AEs. However, when there is an increase in the 
severity, duration, or frequency of a preexisting disease, the event must be described on 
the AE CRF.
12.1.2 Assessment of Adverse Events
For the purposes of this study, the following will not be considered as AEs and will not 
be included in the analysis of AEs.

Bleeding episodes are part of the underlying disease and therefore are not AEs; 
they will be evaluated in the context of efficacy.

For non-serious bleeding episodes caused by an injury, the injury would not 
be reported as an AE, unless it resulted in a medical finding other than a 
bleeding episode (e.g., abrasion of skin). Therefore, any VWD-related 
bleeding event (e.g., epistaxis, gastrointestinal bleeding, musculo-skeletal 
bleeding, menorrhagia) that is non-serious will not be reported as an AE. 
However, the investigator may decide that the event is an AE if the event also 
would have occurred in a healthy individual under the same circumstances.

For SAEs: Bleeding events that meet seriousness criteria (death, 
life-threatening, hospitalizing/prolongation of hospitalization, disability, 
congenital anomaly, or medically significant and if not urgently treated would 
result in one of the above) should be reported on the SAE eCRF or SAE 
Report form as an SAE.

Seroconversion after documented HAV/HBV vaccination prior to or during the 
study period.
Each AE from the first IP exposure to the study completion date will be described on the 
AE CRF using the medical diagnosis (preferred), or, if no diagnosis could be established 
at the time of reporting the AE, a symptom or sign, in standard medical terminology in 
order to avoid the use of vague, ambiguous, or colloquial expressions (see definition in 
Section 12.1). Each AE will be evaluated by the investigator for:

Seriousness as defined in Section 12.1.1.1

Severity as defined in Section 12.1.2.1

Causal relationship to IP exposure or study procedure as defined in 
Section 12.1.2.2
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For each AE, the outcome (i.e., recovering/resolving, recovered/resolved, 
recovered/resolved with sequelae, not recovered/not resolved, fatal, unknown) and if 
applicable action taken (i.e., dose increased, dose not changed, dose reduced, drug 
interrupted, drug withdrawn, not applicable, or unknown) will also be recorded on the AE 
CRF. Recovering/resolving AEs will be followed until resolution.
If the severity rating for an ongoing AE changes before the event resolves, the original 
AE report will be revised (i.e., the event will not be reported as separate AE). During the 
course of any AE, the highest severity rating will be reported.
Deviations from the protocol-specified dosage (including underdosing /overdosing
[<20 IU/kg rVWF:RCo or >100 rVWF:RCo], abuse, and withdrawal, treatment errors 
(including incorrect route of administration, use of an incorrect product, and deviations 
from the protocol-defined dosing schedule), failures of expected pharmacological actions, 
and unexpected therapeutic or clinical benefits will be followed with regard to occurrence 
of AEs, lack of efficacy, and/or other observations because these events may be 
reportable to regulatory authorities. 
Any pregnancy that occurs after administration of IP will be reported on a Pregnancy 
Form and followed-up at 1 year post-delivery, if feasible. 
If an investigator becomes aware of an SAE occurring in a subject after study completion, 
the SAE must be reported on the SAE Form within 24 hours after awareness: no 
additional reporting on CRFs is necessary.
12.1.2.1 Severity
The investigator will assess the severity of each AE using his/her clinical expertise and 
judgment based on the most appropriate description below:

Mild
The AE is a transient discomfort and does not interfere in a significant manner 
with the subject’s normal functioning level.
The AE resolves spontaneously or may require minimal therapeutic 
intervention.

Moderate
The AE produces limited impairment of function and may require therapeutic 
intervention.
The AE produces no sequela/sequelae.
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
Severe
The AE results in a marked impairment of function and may lead to temporary 
inability to resume usual life pattern.
The AE produces sequela/sequelae, which require (prolonged) therapeutic 
intervention.
These severity definitions will also be used to assess the severity of an AE with a study-
related procedure(s), if necessary.
12.1.2.2 Causality
Causality is a determination of whether there is a reasonable possibility that the IP is 
etiologically related to/associated with the AE. Causality assessment includes, e.g., 
assessment of temporal relationships, dechallenge/rechallenge information, association 
(or lack of association) with underlying disease, presence (or absence) of a more likely 
cause, and physiological plausibility. For each AE, the investigator will assess the causal 
relationship between the IP and the AE using his/her clinical expertise and judgment 
according to the following most appropriate algorithm for the circumstances of the AE:

Not related (both circumstances must be met)
Is due to underlying or concurrent illness, complications, concurrent 
treatments, or effects of concurrent drugs
Is not associated with the IP (i.e., does not follow a reasonable temporal 
relationship to the administration of IP or has a much more likely alternative 
etiology). 

Unlikely related (either 1 or both circumstances are met)
Has little or no temporal relationship to the IP 
A more likely alternative etiology exists

Possibly related (both circumstances must be met)
Follows a reasonable temporal relationship to the administration of IP
An alternative etiology is equally or less likely compared to the potential 
relationship to the IP

Probably related (both circumstances must be met)
Follows a strong temporal relationship to the administration of IP, which may 
include but is not limited to the following: 
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o
Reappearance of a similar reaction upon re-administration (positive re-
challenge)
o
Positive results in a drug sensitivity test (skin test, etc.)
o
Toxic level of the IP as evidenced by measurement of the IP 
concentrations in the blood or other bodily fluid
Another etiology is unlikely or significantly less likely
For events assessed as not related or unlikely related and occurring within 5 days after IP 
infusion, the investigator shall provide the alternative etiology. These causality 
definitions will also be used to assess the relationship of an AE with a study-related 
procedure(s), if necessary.
12.1.2.3 Safety Reporting
Adverse events/SAEs will be assessed at all study visits as outlined in the Schedule of 
Study Procedures and Assessments (see Table 6) and Section 12.1.2.
Adverse Events/SAEs are to be recorded on the AE page of the eCRF. Each event should 
be recorded separately.
Any SAE, including death due to any cause, which occurs during this study, whether or 
not related to the investigational product, must be reported immediately (within 24 hours 
of the study center’s first knowledge of the event). All SAEs must be reported via the 
Electronic Data Capture (EDC) system by completing the relevant eCRF page(s) in 
English. For instances in which the EDC may become unavailable, SAEs must be 
reported using the back-up paper SAE report (SAER) form to meet the 24-hour timeline 
requirement (for contacts and instructions refer to the SAER form). Once the EDC 
becomes available, the site must enter all SAE data as reported on the back-up paper 
SAER form on the applicable eCRF pages.
The initial SAE information reported on the applicable eCRF pages (or back-up SAER 
Form, if applicable) must at least include the following:
1.
Protocol Number
2.
Subject identification number and demographics (gender, age at onset of event 
and/or date of birth)
3.
Investigational product exposure
4.
Medical Term for Event (Diagnosis preferably) 
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5.
Description of the (S)AE, including:

Date of onset

(S)AE treatment (drug, dose, route of administration)

Causal relationship by the Investigator

Measures taken (i.e., action taken regarding investigational product in direct 
relationship to the AE)
6.
Seriousness criteria (ie, death, life-threatening, or other criterion)
7.
Cause of death
8.
Autopsy findings (if available)
9.
Name, address, fax number, email, and telephone number of the reporting
Investigator (for paper SAER Forms) 
12.2 Urgent Safety Measures
An urgent safety measure is an immediate action taken, which is not defined by the 
protocol, in order to protect subjects participating in a clinical trial from immediate harm. 
Urgent safety measures may be taken by the sponsor or clinical investigator, and may 
include any of the following: 

Immediate change in study design or study procedures

Temporary or permanent halt of a given clinical trial or trials

Any other immediate action taken in order to protect clinical trial participants 
from immediate hazard to their health and safety
The investigator may take appropriate urgent safety measures in order to protect subjects 
against any immediate hazard to their health or safety. The measures should be taken 
immediately and may be taken without prior authorization from the sponsor. 
In the event(s) of an apparent immediate hazard to the subject, the investigator will notify 
the sponsor immediately by phone and confirm notification to the sponsor in writing as 
soon as possible, but within 1 calendar day after the change is implemented. The sponsor 
will also ensure the responsible ethics committees (ECs) and relevant competent 
authority(s) are notified of the urgent measures taken in such cases according to local 
regulations.
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12.3 Untoward Medical Occurrences
Untoward medical occurrences occurring before the first exposure to IP are not 
considered AEs (according to the definition of AE, see Section 12.1.1). However, each 
serious untoward medical occurrence experienced before the first IP exposure (i.e., from 
the time of signed informed consent up to but not including the first IP exposure) will be 
described on the SAER. These events will not be considered as SAEs and will not be 
included in the analysis of SAEs. 
12.4 Non-Medical Complaints
A non-medical complaint (NMC) is any alleged product deficiency that relates to 
identity, quality, durability, reliability, safety and performance of the product but did not 
result in an AE. NMCs include but are not limited to the following:

A failure of a product to exhibit its expected pharmacological activity and/or 
design function, e.g. reconstitution difficulty

Missing components

Damage to the product or unit carton

A mislabeled product (e.g., potential counterfeiting/tampering)

A bacteriological, chemical, or physical change or deterioration of the product 
causing it to malfunction or to present a hazard or fail to meet label claims
Any NMCs of the product will be documented on an NMC form and reported to the 
sponsor within 1 business day. If requested, defective product(s) will be returned to the 
sponsor for inspection and analysis according to procedures.
12.5 Medical, Medication, and Non-Drug Therapy History
At screening, the subject’s medical history will be described for the following body 
systems including severity (defined in Section 12.1.2.1) or surgery and start and end 
dates, if known: eyes, ears, nose, and throat; respiratory; cardiovascular; gastrointestinal; 
musculoskeletal; neurological; endocrine; hematopoietic/lymphatic; dermatological; and 
genitourinary. The subject’s medical history will also include documented history of 
on-demand treatment for the past 12 months and a documented history, e.g., patient 
charts and prescription information, of all bleeding episodes within the past 12 months.
All medications taken and non-drug therapies received in the 2 weeks prior to study entry 
and all concomitant medications and non-drug therapies during study will be recorded on 
the CRFs.
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Data on medical history, drug and non-drug therapy history of those subjects who 
transition from surgery rVWF study will be used from the eCRF of the main studies, will 
be updated, if applicable, and transcribed into the respective eCRF of the prophy study. 
12.6 Physical Examinations
At screening and subsequent study visits (as described in Section 10.3), a physical 
examination will be performed on the following body systems: general appearance, head 
and neck, eyes and ears, nose and throat, chest, lungs, heart, abdomen, extremities and 
joints, lymph nodes, skin, and neurological. At screening, if an abnormal condition is 
detected, the condition will be described on the medical history CRF. At study visits, if a 
new abnormal or worsened abnormal pre-existing condition is detected, the condition will 
be described on the AE CRF. If the abnormal value was not deemed an AE because it 
was due to an error, due to a preexisting disease (described in Section 12.1.1.5), not
clinically significant, a symptom of a new/worsened condition already recorded as an AE, 
or due to another issue that will be specified, the investigator will record the justification 
on the source record.
12.6.1 Thromboembolic Events
Thromboembolic events are considered a potential risk of rVWF treatment, hence,
clinical evidence of thrombosis will be monitored during the study. In the case of clinical 
signs of any thromboembolic event other than superficial thrombosis, additional 
diagnostic procedures are required according to each institution’s standard of care which 
may consist of, but are not limited to the following:

For deep vein thrombosis (DVT): Magnetic Resonance Imaging (MRI), 
compression ultrasound or impedance plethysmography.

For pulmonary embolism: ECG, chest radiography, perfusion/scintiscan or MRI. 

For myocardial infarction: ECG, cardiac enzymes, echocardiography

For stroke: diffusion-weighted magnetic resonance imaging or computed 
tomography, ABCD scoring, carotid imaging 
Results of diagnostic procedures may be forwarded to the sponsor to be reviewed by an 
independent external expert panel, such as the DMC, if applicable.
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12.6.2 Anaphylaxis
The diagnosis of anaphylaxis is highly likely when any of the following 3 criteria are 
fulfilled:
1.
Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue or both (e.g, generalized urticaria, pruritus or flushing, swollen 
lips-tongue-uvula) and at least one of the following:
a. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced peak expiratory flow [PEF], hypoxemia)
b. Reduced blood pressure (BP) or associated symptoms of end-organ 
dysfunction (e.g., hypotonia [collapse], syncope, incontinence)
2.
Two or more of the following that occur rapidly after exposure to a likely allergen 
for that patient (minutes to several hours):
a. Involvement of the skin or mucosal tissue (e.g., generalized urticaria, pruritus 
or flushing, swollen lips-tongue-uvula)
b. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced PEF, hypoxemia)
c. Reduced BP or associated symptoms (hypotonia [collapse], syncope, 
incontinence)
d. Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)
3.
Reduced BP after exposure to a known allergen for that patient (minutes to 
several hours):
a. Infants and children: low systolic BP (age specific) or greater than 30% 
decrease in systolic BP
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from 
that person’s baseline BP
If a subject develops anaphylaxis in the course of the clinical study this needs to be 
reported as SAE (Section 12.1.1.1). Additional blood draws for Anti-VWF IgE antibody 
testing will be drawn (Section 12.9.13).
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12.7 Vital Signs
Vital signs will be assessed pre and post-infusion at each visit, if not stated otherwise:

Height (cm) and weight (kg) (pre-infusion only)

Blood pressure: Systolic/diastolic blood pressure (mmHg) baseline measurements 
will be measured after a 10-minute rest in the supine/semi-recumbent position.

Pulse rate: Pulse rate (beats/min) will be measured at the distal radial arteries 
under the same conditions as above.

Respiratory rate: Respiratory rate (breaths/min) will be measured over a period of 
1 minute under the same conditions as above.

Temperature: Body temperature (oC or oF) may be determined by oral, rectal, 
axillary, or tympanic measurement at the discretion of the investigator. However, 
the same method should be used for all measurements in 1 subject.
Vital signs (pulse rate, respiratory rate, and blood pressure) should be recorded within 
30 min before and after IP administration. The assessment of vital signs per planned 
study visit is outlined in Supplement 20.2.
Vital sign values are to be recorded on the physical examination eCRF. For each vital 
sign value, the investigator will determine whether the value is considered an AE (see 
definition in Section 12.1). If assessed as an AE, the medical diagnosis (preferably), 
symptom, or sign, will be recorded on the AE eCRF. Additional tests and other 
evaluations required to establish the significance or etiology of an abnormal result, or to 
monitor the course of an AE, should be obtained when clinically indicated. Any abnormal 
value that persists should be followed at the discretion of the investigator.
12.8 Electrocardiogram 
A standard 12-lead ECG at rest will be performed at screening, at the 6 month follow-up 
visit and at the study termination visit and evaluated for medical significance by the 
investigator.
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12.9 Clinical Laboratory Parameters
Refer to the Laboratory Manual for information on collection and processing of samples.
In general all laboratory tests will be performed at central laboratories, except the 
pregnancy and blood group test which will be performed at the local laboratory. In 
addition, relevant critical safety laboratory tests for complete blood count (CBC), serum 
chemistry and/or coagulation parameters such as VWF and FVIII activity may also be 
performed in the local laboratory to ensure that results will be available immediately to 
the investigator. In principle, results from the central laboratory will be used for data 
analysis purposes. The assays performed in the central laboratories are specified in the 
Laboratory Manual. The investigator will supply the sponsor with a list of the normal 
ranges and units of measurement for the laboratory variables to be determined at the site. 
Laboratory values such as antibodies to other proteins are not required immediately and 
will be assessed later during the course of the study. 
Abnormal laboratory values deemed clinically significant by the investigator are to be 
recorded as AEs (see Section 12.1.2).
12.9.1 rVWF and Endogenous FVIII Pharmacokinetics
PK assessments using a dose of 50 IU ± 5 IU/kg rVWF:RCo will be performed at the 
baseline visit. If the subject is on on-demand treatment and has received VWF 
replacement therapy a washout period of at least 5 days is required before the infusion of 
rVWF for PK assessment can be administered. 
Blood samples will be drawn within 30 minutes pre-infusion, and at 11 time points 
post-infusion (15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 
6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours
and 96 ± 2 hours) VWF activity will be determined using the VWF:RCo, VWF:CB and 
the VWF: Ag assay.
Endogenous FVIII activity will be measured using the 1-stage clotting assay. 
At the 12 month ± 2 week visit, a full PK analysis will also be performed. Blood samples 
will be drawn within 30 minutes pre-infusion, and at 11 time points post-infusion 
(15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 
12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours and 
96 ± 2 hours). If a subject experiences a bleeding episode during the PK assessment 
no subsequent blood sample will be drawn in that specific PK period. The guidance 
provided in Section 8.6.4.4 has to be followed for the treatment of the bleeding episode. 
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The subject once recovered is eligible to repeat the PK assessment.
The following parameters will be used as part of the PK assessment:

Incremental recovery of VWF:RCo, VWF:Ag, and VWF:CB)

AUC/dose, area under moment curve (AUMC/dose, clearance (CL), Volume of 
distribution at steady state (Vss), mean residence time (MRT), of 
VWF:RCo ,VWF:Ag, and VWF:CB 

Half-life of VWF:RCo, VWF:Ag, and VWF:CB

Time course of the FVIII:C levels

VWF collagen binding (VWF:CB) levels
12.9.2 Hematology and Clinical Chemistry
The hematology panel will consist of CBC [hemoglobin, hematocrit, erythrocytes (ie, red 
blood cell count [RBC]), and leukocytes (i.e., white blood cell count [WBC])] with 
differential (i.e., basophils, eosinophils, lymphocytes, monocytes, neutrophils) and 
platelet counts.
The clinical chemistry panel will consist of sodium (Na), potassium (K), chloride (Cl), 
alanine aminotransferase (ALT), lactate dehydrogenase (LDH), aspartate 
aminotransferase (AST), bilirubin (BILI), alkaline phosphatase (AP), blood urea nitrogen
(BUN), creatinine (CR), and glucose (Glu).
Blood will be obtained for assessment of hematology and clinical chemistry parameters 
at screening, during PK-assessment prior to rVWF IP infusion, after 24 ± 2 hours, 
48 ± 2 hours and 72 ± 2 hours post rVWF IP infusion, at all follow-up visits as per 
schedule (refer to Supplement 20.3 Clinical Laboratory Assessments), i.e., 4 weeks
± 1 week, 8 weeks ± 1 week and every 3 months ± 2 weeks, and at study completion. 
Hematology and clinical chemistry assessments will be performed on 
Ethylenediaminetetraacetic acid (EDTA)-anticoagulated whole blood and serum, 
respectively, at the central laboratory.
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12.9.3 Immunology
12.9.3.1 Antibodies to VWF and FVIII
All subjects will be tested for binding and neutralizing antibodies to VWF and FVIII at 
screening, at baseline PK assessment, at each of the scheduled follow-up visits and at the 
study completion visit. Testing will be done prior to IP infusion and with at least a 
72 hour wash out period since the last IP infusion. If there is any suspicion of inhibitor 
development (e.g. excessive bleeding) binding and neutralizing antibodies to VWF and 
FVIII may be tested at the discretion of the investigator. 
12.9.3.2 Neutralizing and Total Binding Anti-VWF Antibodies
The assays to establish the presence of neutralizing and total binding anti-VWF 
antibodies have been established in the absence of international standards and with only 
limited numbers of positive controls. Therefore, caution is advised in interpreting positive 
results. In particular, any clinical association, changes in the natural history of the 
disease, effect of therapy, etc. needs to be taken into account for final judgment. 
The sponsor’s Medical Director should be consulted for additional advice. As part of the 
AE follow-up, any sample testing positive needs to be confirmed after 2-4 weeks for 
central laboratory testing. Only confirmed neutralizing anti -VWF antibodies are 
considered inhibitors (see Section 12.9.3.4). These subjects need to be closely monitored 
and therapy adjusted accordingly. 
12.9.3.3 Binding antibodies to VWF 
The presence of total binding anti-VWF antibodies will be determined by an enzyme-
linked immunosorbent assay (ELISA) employing polyclonal anti-human Immunoglobulin
(Ig) antibodies (IgG, IgM and IgA). For this assay (ELISA), recombinant human VWF 
will be coated onto a microtiter plate, then incubated with dilutions of the positive 
control, the negative control or test sample. Antibodies against human VWF that are 
present in the samples bind to the coated antigen and will be detected with a horseradish 
peroxidase (HRP)-coupled goat anti-human antibody (secondary antibody). The positive 
control for this assay will be a human monoclonal antibody specific for human VWF 
spiked into the negative control. The negative control for this assay is pooled normal 
human plasma.
Plasma samples are analyzed for binding antibodies against the specific antigen in two 
steps. First, the sample is screened for antibodies and the titer of binding antibodies is 
determined. Second, the specificity of positive antibody results is confirmed.16
In brief, all samples are serially diluted (initial dilution 1:20 and further diluted 1:2). 
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The titer endpoint, defined as the highest dilution that still gives a positive signal above 
cut off level, is determined in two independent duplicates. The cut off level is established 
based on background signal level of healthy plasma donors (n=160) and set to include 5% 
false positives to be as sensitive as possible (95% percentile). The ELISA assay is 
validated allowing an assay variability of ± 1 titer step. Therefore, differences ≤ 2 titers 
steps may be due to variability of the ELISA assay. Specificity has to be confirmed in a 
competition assay when a sample has a titer of 1:80 or higher in the screening assay. 
Based on the validation criteria samples tested in the screening assay at 1:20 or 1:40 
cannot be confirmed in the competition assay. A positive screening value is confirmed if 
the difference between the titers determined for the subject sample (re-screen) and for the 
subject sample with pre-incubation (confirmation sample) is > 2 titer steps. Antibody 
titers of subject samples will only be reported as positive, if the results of the screening 
and confirmatory analysis fulfill these acceptance criteria. The titer to be reported is 
always the one determined in the original screening procedure (independent of the result 
of the re-screening in the confirmation procedure). 
A more detailed test procedure will be supplied upon request or pro-actively if a sample 
tests positive. A treatment related increase of the binding anti-VWF antibodies is 
expected, if the titer increases by more than 2 titration steps. These subjects need to be 
closely monitored and therapy adjusted accordingly.
12.9.3.4 Neutralizing Antibodies to VWF
Three functional VWF assays, collagen binding (VWF:CB) assay, Ristocetin cofactor 
(VWF:RCo) and FVIII binding (VWF:FVIIIB), will be used to test for the presence of 
neutralizing anti-VWF antibodies. Neutralizing antibodies to VWF:RCo, VWF:CB and 
VWF:FVIIIB activities will be measured by assays based on the Bethesda assay 
established for quantitative analysis of FVIII inhibitors (Nijmegen modification of the 
Bethesda assay).17 The amount of inhibitor is expressed as Bethesda units (BU) per mL.
One BU is thereby defined as the amount of inhibitor that decreases the measured activity 
in the assays to 50% of that of the negative control samples. The assays were validated 
using human plasma samples from two type 3 VWD patients with low (1-2 BU/mL) and 
high (~10 BU/mL) titer inhibitors and plasma samples from non-human primates 
immunized with human rVWF (>100 BU/mL) 
If a subject has a measurable baseline level of VWF activity in the respective assay, it is 
taken into account in the calculation of the residual activity. However, if baseline levels 
are too high (>15% VWF:RCo), inhibitors may not be reliably detected.
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To exclude false positive results, the detection limit for anti-VWF inhibitors was set to 
1 BU/ml for all 3 assays. The rationale for this cut-off value is the relatively high CI of 
the underlying assays, making determinations at the end of the evaluation range of the 
Bethesda reference curve uncertain.18
A more detailed test procedure may be requested to further characterize the anti-VWF 
inhibitors, if detected.
12.9.3.5 Binding Antibodies to FVIII
Binding antibodies against FVIII will be analyzed using a proprietary enzyme 
immunoassay. The testing strategy will be as described for binding anti-VWF antibodies. 
Antibody-containing samples will be identified in a screening assay followed by a 
confirmatory assay to exclude false positive results.
12.9.3.6 Neutralizing Antibodies (Inhibitors) to FVIII 
Neutralizing antibodies (inhibitors) to FVIII will be assessed by the Nijmegen 
modification of the Bethesda assay in a central laboratory. To verify a FVIII inhibitor, 
additional testing (such as tests for Lupus anticoagulants) may be initiated. Positive FVIII 
inhibitor tests will be defined as ≥0.4 BU by the Nijmegen-modified Bethesda assay that 
is confirmed by a second test performed on an independent sample obtained 2-4 weeks 
following the first test. Only confirmed positive FVIII inhibitor test result will be 
reported as an SAE.
12.9.4 Antibodies to Other Proteins
Plasma will be assayed for the presence of antibodies against CHO protein (total Ig), 
murine IgG and human Furin (total Ig) using proprietary enzyme immunoassays. The 
testing strategy will be as described for binding anti- VWF antibodies. 
Antibody-containing samples will be identified in a screening assay followed by a 
confirmatory assay to exclude false positive results.
12.9.4.1 Anti-CHO Protein
Total Ig antibodies (IgG, IgA, IgM) against CHO protein will be analyzed. For this assay 
(ELISA), CHO protein derived from cultures of untransfected cells and propagated under 
the identical cell culture conditions used for ADVATE production will be coated onto a 
microtiter plate, then incubated with dilutions of the positive control, negative control or 
test sample. Antibodies against CHO protein that are present in the samples bind to the 
coated antigen and will be detected with a horseradish peroxidase (HRP)-coupled goat 
anti-human antibody (secondary antibody). The positive control for this assay will be a 
polyclonal goat anti-CHO protein antibody spiked into the negative control. The negative 
control for this assay is pooled normal human plasma.
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12.9.4.2 Anti-Murine IgG
A commercially available ELISA (Medac, Hamburg, Germany) will be used to detect and 
to quantify IgG antibodies originating from human plasma that are directed against 
mouse-IgG (HAMA: human anti- mouse antibodies). Microtiter plates coated with 
mouse IgG will be incubated with dilutions of the standard, the positive control, the 
negative control or the test sample. Antibodies against mouse IgG that are present in 
the samples bind to the coated antigen and form a bridge to a peroxidase coupled mouse 
IgG antibody that will be used for detection (bridging format of the ELISA assay). 
The positive control for this assay will be a polyclonal goat anti-murine IgG spiked into 
the negative control. The negative control for this assay is pooled normal human plasma.
12.9.4.3 Antibodies to Human Furin
Total Ig antibodies (IgG, IgA, IgM) against human Furin will be analyzed. For this assay 
(ELISA), recombinant human Furin will be coated onto a microtiter plate, then incubated 
with dilutions of the positive control, the negative control or test sample. Antibodies 
against human Furin that are present in the samples bind to the coated antigen and will be 
detected with a horseradish peroxidase (HRP)-coupled goat anti-human antibody 
(secondary antibody). The positive control for this assay will be a human monoclonal 
antibody specific for human Furin spiked into the negative control. The negative control 
for this assay is pooled normal human plasma.
12.9.5 Viral Serology
The following viral seromarkers will be assessed at screening:

HIV: anti-HIV 1, HIV 2 

HAV: anti-HAV (IgG and immunoglobulin M [IgM])

HBV: Hepatitis B surface antigen (HbsAg), anti-Hepatitis B (HB) core, anti-HBs

HCV: anti-HCV ELISA

Parvovirus B19: anti-B19V (IgG and IgM)
Virus serology will be established during the screening period. The relevant confirmatory 
Polymerase Chain Reaction (PCR) testing may be performed from appropriate left-over 
samples as needed. 
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12.9.6 Urinalysis (Dipstick)
The urinalysis will include assessments for erythrocytes, specific gravity, urobilinogen, 
ketones, glucose, protein, bilirubin, nitrite and pH and will be performed at the central 
laboratory.
12.9.7 Pregnancy Test
A pregnancy test for females of child-bearing potential will be performed at the local 
laboratory primarily from urine. If no urine sample is available, the pregnancy testing will 
be done from serum. The pregnancy test may need to be repeated during the course of 
study in countries where mandated by national law.
12.9.8 VWD Mutational Analysis, Multimer Analysis and Human Leukocyte 
Antigen Genotyping 
A cell pellet (buffy coat and erythrocytes) will be retained at the screening visit for VWD 
gene mutational analysis, VWF multimer analysis and HLA genotype determination if the 
information is not already available in the subject’s medical history. Results from 
multimer analysis (see Section 12.9.10.1) may contribute to VWD gene mutational 
analysis. The genetic testing will be done, when the subject consents to the genetic 
testing.
12.9.9 Blood Group Analysis
The blood group needs to be determined during the screening period. If the information is 
not already available in the subject’s medical history, it has to be determined at the local 
lab.
12.9.10 Additional Laboratory Testing in Case of Thromboembolic Events
rVWF contains ultra large molecular weight (ULMW) multimers because of a lack of 
exposure to endogenous VWF protease (a disintegrin and metalloproteinase with a 
thrombospondin type 1 motif, member 13 (ADAMTS13) during the manufacturing 
process. In vitro and in vivo cleavage of these ultralarge molecular fractions by 
ADAMTS13 and generation of characteristic satellite bands has been extensively 
demonstrated during nonclinical and clinical development. Nevertheless, the potential 
elevated risk of thrombosis and/or other thromboembolic complications due to the 
administration of ultra large molecular VWF multimers in subjects with normal levels of 
VWF cannot be completely excluded. Therefore VWF multimer analysis will not only be 
performed routinely at screening but in case of thromboembolic events both VWF 
multimer analysis as well as ADAMTS13 activity will be determined to assess any 
relatedness of these occurrences with IP treatment. 
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12.9.10.1 VWF Multimer Analysis 
The VWF multimer pattern will be assessed using low-resolution sodium dodecyl sulfate 
(SDS)–agarose gel electrophoresis. High-resolution SDS–agarose gel electrophoresis, 
with agarose concentrations 1.5%, will be used to determine the satellite band structure 
of VWF. These analyses will employ Western blot with luminescence video imaging.
12.9.10.2 ADAMTS13 Activity 
VWF73 was identified as the 73 amino acid minimal region of the VWF A2 domain 
required for ADAMTS13 cleavage. The cleavage of this substrate will be detected by a 
commercially available ELISA-based Chromogenic assay (Technoclone Austria):
Cleavage of immobilized VWF73 substrate is detected by a HRP-labeled antibody 
directed against the cleavage site of VWF73. The amount of bound antibody, which is the 
function of the ADAMTS13 cleavage is detected by a chromogenic substrate.
12.9.11 Soluble P-Selectin (sP-Selectin)
sP-selectin is a cell adhesion molecule (CAM) found in granules in endothelial cells 
(cells lining blood vessels) and activated platelets. Data for an association between the 
sP-selectin concentration, thrombotic thrombocytopenic purpura (TTP) and venous 
thromboembolism (VTE) are limited and the predictive value has not yet established. 
A commercial ELISA assay will be employed as an exploratory test. sP-selectin will be 
determined at the Screening visit and used as indicator for an increased thrombotic risk.
12.9.12 D-Dimer
D-dimer will be used as a marker for DVT and disseminated intravascular coagulation
(DIC). While a negative result practically rules out thrombosis, a positive result can 
indicate thrombosis but does not rule out other potential etiologies, including a recent 
hemorrhage. Its main use, therefore, is to exclude thromboembolic disease where the 
probability is low. D-Dimer will be measured at the Screening visit and used as indicator 
for an increased thrombotic risk.
12.9.13 Additional Laboratory Testing in Case of Severe Hypersensitivity Reactions
If a subject develops a severe hypersensitivity reaction in the course of the clinical 
study, additional blood draws for anti-VWF IgE antibody testing will be drawn. The 
presence of anti-VWF IgE will be determined by using the ImmunoCAP®, a VWF-
specific IgE blood test (Thermo Scientific). The basis of the ImmunoCAP® technology 
is a cellulose polymer as solid phase in a plastic capsule providing a large surface for 
protein binding. rVWF as antigen is covalently coupled to the cellulose polymer.
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Detection of specific anti-VWF IgE bound to the antigen will be accomplished by a 
secondary enzyme-labeled anti-human IgE antibody. Testing for binding anti-human 
VWF IgE antibodies will be done with 0.5 mL plasma. Antibody containing samples will 
be identified and quantified in a screening assay followed by a confirmatory assay to 
exclude false positive results.
12.9.14 Assessment of Laboratory Values
12.9.14.1 Assessment of Abnormal Laboratory Values 
For VWF and FVIII laboratory assessments no evaluation of clinical significance is 
necessary.
Each other laboratory value (except results to determine genetics of the underlying VWD 
disease and blood group) has to be assessed by the investigator and the assessment will be 
recorded on the eCRF. The investigator will determine for each abnormal laboratory 
value whether the value is considered clinically significant or not. For clinically 
significant values, the investigator will indicate if the value constitutes a new AE (see 
definition in Section 12.1) and record the sign, symptom, or medical diagnosis on the AE 
CRF, is a symptom or related to a previously recorded AE, is due to a pre-existing 
disease (described in Section 12.1.1.5), or is due to another issue that will be specified. If 
the abnormal value was not clinically significant, the investigator will indicate the reason, 
i.e. because it is due to a preexisting disease, due to a lab error, due to variation or due to 
another issue that will be specified. Additional tests and other evaluations required to 
establish the significance or etiology of an abnormal value, or to monitor the course of an 
AE should be obtained when clinically indicated. Any abnormal value that persists should 
be followed at the discretion of the investigator.
Any seroconversion result for human immunodeficiency virus (HIV), hepatitis A virus 
(HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis E virus (HEV), or 
parvovirus B19 (B19V) shall be re-tested.
12.10
12.10.1
 
 
 
 
 
 
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12.10.2
 
 
 
 
 
 
 
 
 
 
 
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13. STATISTICS
13.1 Sample Size and Power Calculations
The determination of the sample size for this study is not based on strict statistical 
considerations. The sample size of a subset of at least 15 subjects with severe VWD, 5 of 
whom must have Type 3 VWD, is based on the Guideline on the Clinical Investigation of 
Human Plasma Derived von Willebrand Factor Products (CPMP/BPWG/220/02).1
13.2 Datasets and Analysis Cohorts
13.2.1 Safety Analysis Set
The Safety Analysis Set will be composed of all subjects who received any amount of IP, 
rVWF:ADVATE or rVWF alone. 
13.2.2 Full Analysis Dataset
The Full Analysis Set (FAS) will be composed of all subjects with available bleeding 
data gathered during prophylaxis IP treatment.
13.2.3 Per-Protocol Analysis Set
The Per-Protocol (PP) Analysis Set will be composed of subjects who are at least 70% 
compliant regarding required prophylactic infusions. Only subjects who met all study 
entry criteria and who had no major protocol violations that might impact efficacy 
assessments will be included in the PP analysis set.
13.2.4 PK Full Analysis Set
The Pharmacokinetic Full Analysis Set (PKFAS) will be composed of all subjects who 
received the PK infusion and who provided acceptable data for PK analysis. Acceptable 
PK data will be defined in the Statistical Analysis Plan. 
13.2.5 PK Per Protocol Analysis Set 
The Pharmacokinetic Per Protocol Analysis Set (PKPPAS) is defined as a subset of the 
PKFAS. Subjects who met the following additional criteria will be included in the 
PKPPAS: had no major violation of affecting the PK period of the study as defined in the
detailed Statistical Analysis Plan.
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13.3 Handling of Missing, Unused, and Spurious Data
13.3.1 General
Statistical techniques will not be used to identify and exclude any observations as outliers 
from the analyses. If data are considered spurious, e.g. for lack of biological plausibility, 
it will be documented to include the reason for exclusion and the analyses from which the 
data were excluded.
13.3.2 Other
1.
Regarding missing data in PK records:

Body weight: If a subject’s weight is missing from the PK infusion record, the 
subject’s last recorded weight will be used to calculate the weight-adjusted 
dose.

Concentration:

Baseline concentration levels reported as below the limit of quantification 
will be considered to be 0. Missing VWF baseline concentration levels 
(VWF: RCo, VWF: AG or VWF: CB) for Type 3 subjects will be set to 0.

Time:

If start time of infusion is missing (but stop time is available) and actual 
collection time is available, then stop time of infusion will be taken for 
further calculation (i.e. time difference between actual end date/time of 
infusion and date/time blood sample drawn).

If actual collection date/time is missing and planned collection date/time is 
missing, then this PK time point will be taken out from the PK analysis 
(i.e. no data entry for this time point). 

For all other scenarios, the planned collection date/time will be taken for 
further calculation.
2.
Regarding missing data in AE records:

Handling of unknown causality assessment:

If a subject experiences an AE with a missing causality assessment, the 
relationship of the AE will be counted as “related.”
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
Handling of unknown severity grades:

If a subject experiences more than one AE categorized under the same 
preferred term, one of them is categorized as “severe” and one of them is 
categorized as “unknown”, then the maximum severity for this preferred 
term should be counted as “severe” for this subject.

If a subject experiences more than one AE categorized under the same 
preferred term, one of them is categorized as “mild” or “moderate” and 
one of them is categorized as “unknown”, then the maximum severity for 
this preferred term should be counted as “unknown” for this subject.
13.4 Methods of Analysis
The study success criteria are the objectives as stated in Section 7. “Treatment success” 
was defined as the extent of control of bleeding episodes achieved during this study.
13.4.1 Primary Outcome Measure
The statistical analysis will provide descriptive summaries.
For the number of infusions and for the total weight adjusted consumption of rVWF and 
ADVATE per month and per year during on-demand treatment, summary statistics will 
be carried out.
For the number (proportion) of subjects with reduction of ABR relative to historic ABR 
as well as for the number (proportion) of subjects with 0 bleeds, proportions and 
corresponding 95% two-sided CIs will be performed.
The annualized rate of bleeding episodes will be calculated as (Number of bleeding 
episodes/observed treatment period in days) * 365.25. 
The primary efficacy analysis will be based on the FAS. As a supportive analysis, the 
same analysis will also be carried out on the PP.
The two time periods (prior to prophylaxis treatment and while on prophylaxis) will be 
compared within each subject in terms of mean ABR using a generalized estimating 
equations model framework (with a logarithmic link function which was the default for 
the negative binomial distribution), accounting for the fixed effect of the two time 
periods. The follow-up time (in years) will be specified as an offset and an unstructured 
working correlation matrix will be used to account for the correlated data. Ratios between 
the two time period means (95% CI) will be estimated within this model by SAS 
procedure GENMOD.
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13.4.2 Secondary Outcome Measures 
13.4.2.1 Efficacy
For the number of infusions and for the total weight adjusted consumption of rVWF and 
ADVATE per month and per year during prophylactic treatment as well as during 
on-demand treatment for bleeding episodes, summary statistics will be carried out.
For the number (proportion) of subjects with reduction of ABR relative to historic ABR 
as well as for the number (proportion) of subjects with 0 bleeds, proportions and 
corresponding 95% two-sided CIs will be performed. An ABR reduction of >25% is 
considered relevant.
The cause, type, localization and severity of bleeding episodes will also be recorded and 
summarized. Bleeding episodes should be organized by where they occur in addition to 
whether they occurred spontaneously or due to a traumatic event.
The secondary efficacy analysis will be performed on the FAS only.
13.4.2.2 Efficacy of the Treatment of Bleeding Episodes
For the number of infusions of rVWF and ADVATE per bleeding episode, for the weight 
adjusted consumption of rVWF and ADVATE per bleeding event as well as for the 
overall hemostatic efficacy rating at resolution of bleed, summary statistics will be 
carried out.
The severity and localization of bleeding episodes will also be recorded and summarized.
The analysis will be performed on the FAS.
13.4.2.3 Efficacy of the Treatment of Peroperative Bleeding Management, if Surgery 
is Required
Descriptive statistics will be performed for the following secondary outcome measures -

Intraoperative actual versus predicted blood loss (assessed by the operating 
surgeon) at completion of surgery

Intraoperative hemostatic efficacy score on a scale of excellent, good, moderate 
or none (assessed by the operating surgeon) at completion of surgery

For elective surgery: an overall assessment of hemostatic efficacy 24 hours 
after the last perioperative infusion of rVWF, assessed by the Investigator

Daily intra- and postoperative weight-adjusted dose of rVWF with or without 
ADVATE through postoperative day 14
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13.4.2.4 Pharmacokinetic Analysis
All PK analyses will use the actual sampling times, not nominal times specified in the 
protocol, wherever possible. Actual sampling times will be defined as time from the start 
of infusion to the blood sample collection time. A deviation from the protocol-specified 
blood sample drawing time window will not be a reason to exclude an observation from 
the analysis. Samples with unknown actual and planned collection date/time or where the 
concentration could not be determined, or where results were biologically implausible 
will be eliminated from the analysis.
If any concentration data are considered spurious (e.g. lack of biological plausibility), the 
reason for exclusion from the analysis and the analysis from which the data point was 
excluded will be documented.
To ensure that values at baseline (pre-infusion) are not affecting the estimation of PK 
parameters, post-infusion concentration data will be adjusted for baseline as follows:
After adjustment of the post-infusion concentration data, any pre-infusion data will be set 
to 0.
CCorrected will be set to missing, if:

Samples have an unknown draw time or where the concentration could not be 
determined, or where results were deemed to be unreliable due to analytical 
issues.

Any concentration data are considered spurious (e.g. lack of biological 
plausibility).
Handling of concentrations that are below the quantification limit: 

Baseline concentration values reported as below the limit of quantification will be 
considered to be 0 (CCorrected = Concentration value)

Post-infusion concentration values reported as below the limit of quantification or 
missing repeated concentration values will be set to missing (CCorrected = 
missing)
t
Measured,
C
)
Tmax
Measured,
C
infusion
pre
Measured,
C
(1
t
Corrected,
C




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The area under the plasma concentration/time curve from time 0 to infinity (AUC0-) and 
the area under the first moment curve from time 0 to infinity (AUMC0-) will be 
calculated as the sum of AUC or AUMC from time 0 to the time of last quantifiable 
concentration plus a tail area correction calculated as Ct/z and Ct/z(t + 1/z), 
respectively, where Ct is the last quantifiable concentration, t is the time of last 
quantifiable concentration and z is the terminal or disposition rate constant.
The area under the plasma concentration/time curve from time 0 to 72 hours post-infusion 
(AUC0-72h) will be computed using the linear trapezoidal rule. For the calculation of 
AUC0-72h the levels at 72 hours will be linearly interpolated/ extrapolated from the 
2 nearest sampling time points.
Elimination phase half-life (HL) in hours will be calculated as:
/ = 	
(2)/
where the elimination rate constant (z) will be obtained by loge-linear fitting using least 
squares deviations to at least the last 3 quantifiable concentrations above pre-infusion 
level.
The Mean Residence Time (MRT) in hours will be calculated as total area under the 
moment curve divided by the total area under the curve:
MRT = ∞[ℎ ∗/]
∞[ℎ∗/]
Systemic clearance in dL/kg/h will be calculated as the dose in IU/kg divided by the 
total AUC: 
 = 
!
"#[/$]
%[ℎ∗/]
Apparent steady state volume of distribution (Vss) in dL/kg will be calculated as:
&"" = !
"#[ $
⁄
] × %[ℎ ∗/]
%

[ℎ ∗/]
The maximum concentration, Cmax, will be calculated as the maximum concentration 
post-infusion.
The time to reach the maximum concentration, Tmax, in hours was defined as the time 
to reach Cmax.
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Incremental recovery (IR) in (IU/dL)/(IU VWF:RCo/kg) will be calculated as:
) = *+,[ 
⁄
] −./01234051[/]

"# 6#7 $ 8
9 :#;ℎ< [/$]
where Cmax and Cpre-infusion are the unadjusted concentration values.
The PK parameters AUC0-72h/Dose, AUC0-∞/Dose, AUMC0-∞/Dose, MRT (mean 
residence time), CL (clearance), IR (incremental recovery), T1/2 (elimination phase half-
life), Vss (Volume of distribution at steady state), Cmax (maximum concentration) and
Tmax (time to reach the maximum concentration) will be summarized by mean, standard 
deviation and the corresponding 90% CIs, median, Q1, Q3, IQR and range.
Descriptive statistics will be used to summarize VWF:RCo levels for each nominal time 
point on the PK curve. 
PK analysis as described above will be carried out on the PKFAS as well as on the 
PKPPAS.
For all subjects in the PKFAS concentration vs. time curves will be prepared.
PK parameters will be derived using non-compartmental methods in WinNonlin.
The analysis will be performed on the FAS.
13.4.2.5 Safety
AEs that occurred during or within 24 hours after first IP infusion will be presented in 
summary tables. Summary tables shall indicate the number of subjects who experienced 
adverse events. Separate tables will be carried out for temporally associated adverse 
events; and for temporally associated or causally related adverse events. 
In addition, tables will be prepared to list each AE, the number of subjects who 
experienced an AE at least once, and the rate of subjects with AE(s). AEs will be grouped 
by system organ class. Each event will then be divided into defined severity grades (mild, 
moderate, severe). The tables will also divide the AEs into those considered related (a 
“possibly related” or a “probably related” AE will be considered as a “related AE”) to the 
treatment and those considered unrelated (an “unlikely related” or a “not related” AE will 
be considered as an “unrelated” AE). These tables will also be carried out for temporally 
associated adverse events; and for temporally associated or causally related adverse 
events. 
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All AEs; temporally associated AEs; causally related AEs (by investigator assessment); 
and temporally associated or causally related AEs will also be summarized by system 
organ class, preferred term, including the number of AEs, the number (%) of unique 
subjects, the frequency category (very common: ≥10%, common: ≥1% to <10%, 
uncommon: ≥0.1% to <1%, rare: ≥0.01% to <0.1%, very rare: <0.01%) and the number 
of IP-infusions associated with an AE.
Temporally associated AEs are defined as AEs that begin during infusion or within 
24 hours (or 1 day where time of onset is not available) after completion of infusion, 
irrespective of being related or not related to treatment.
AEs and SAEs for each subject, including the same event on several occasions, will be 
listed separately, giving both MedDRA preferred term and the original verbatim term 
used by the investigator, system organ class, severity grade, seriousness, relation to the 
treatment (by investigator assessment; for SAEs this will be by investigator and sponsor 
assessment), onset date, and stop date.
AEs that occurred before first IP infusion will be listed separately.
Incidences of thromboembolic events and hypersensitivity reactions will be tabulated and 
also listed per subject. For the development of antibodies, proportions will be carried out.
The safety analyses will be based on the safety analysis set. 
13.5 Exploratory Outcome Measures
 
 
 
 
 
 
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13.6 Planned Interim Analysis of the Study
No formal interim analysis is planned for this study. However, a descriptive summary 
report for this study is planned after all subjects have completed at least 6 months of
prophylactic treatment with rVWF.
14. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
The investigator/study site will cooperate and provide direct access to study documents 
and data, including source documentation for monitoring by the study monitor, audits by 
the sponsor or sponsor’s representatives, review by the EC, and inspections by applicable 
regulatory authorities, as described in the Clinical Trial Agreement (CTA). If contacted 
by an applicable regulatory authority, the investigator will notify the sponsor of contact, 
cooperate with the authority, provide the sponsor with copies of all documents received 
from the authority, and allow the sponsor to comment on any responses, as described in 
the CTA.
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15. QUALITY CONTROL AND QUALITY ASSURANCE
15.1 Investigator’s Responsibility
The investigator will comply with the protocol (which has been approved/given favorable 
opinion by the EC), ICH GCP, and applicable national and local regulatory requirements 
as described in the CTA. The investigator is ultimately responsible for the conduct of all 
aspects of the study at the study site and verifies by signature the integrity of all data 
transmitted to the sponsor. The term “investigator” as used in this protocol as well as in 
other study documents, refers to the investigator or authorized study personnel that the 
investigator has designated to perform certain duties. Sub-investigators or other 
authorized study personnel are eligible to sign for the investigator, except where the 
investigator’s signature is specifically required.
15.1.1 Investigator Report and Final Clinical Study Report 
The investigator, or coordinating investigator(s) for multicenter studies, will sign the 
clinical study report. The coordinating investigator will be selected before study start. 
15.2 Training
The study monitor will ensure that the investigator and study site personnel understand all 
requirements of the protocol, the investigational status of the IP, and his/her regulatory 
responsibilities as an investigator. Training may be provided at an investigator’s meeting, 
at the study site, and/or by instruction manuals. In addition, the study monitor will be 
available for consultation with the investigator and will serve as the liaison between the 
study site and the sponsor.
15.3 Monitoring
The study monitor is responsible for ensuring and verifying that each study site conducts 
the study according to the protocol, standard operating procedures other written 
instructions/agreements, ICH GCP, and applicable national and local regulatory 
guidelines/requirements. The investigator will permit the study monitor to visit the study 
site at appropriate intervals, as described in the CTA. Monitoring processes specific to the 
study will be described in the clinical monitoring plan. 
15.4 Auditing
The sponsor and/or sponsor’s representatives may conduct audits to evaluate study 
conduct and compliance with the protocol, standard operating procedures, other written 
instructions/agreements, ICH GCP, and applicable national and local regulatory 
guidelines/requirements. The investigator will permit auditors to visit the study site, as 
described in the CTA. Auditing processes specific to the study will be described in the 
audit plan.
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15.5 Non-Compliance with the Protocol
The investigator may deviate from the protocol only to eliminate an apparent immediate 
hazard to the subject. In the event(s) of an apparent immediate hazard to the subject, the 
investigator will notify the sponsor immediately by phone and confirm notification to the 
sponsor in writing as soon as possible, but within 1 calendar day after the change is 
implemented. The sponsor (Baxalta) will also ensure the responsible EC and relevant 
competent authority are notified of the urgent measures taken in such cases according to 
local regulations.
If monitoring and/or auditing identify serious and/or persistent non-compliance with the 
protocol, the sponsor may terminate the investigator’s participation. The sponsor will 
notify the EC and applicable regulatory authorities of any investigator termination.
15.6 Laboratory and Reader Standardization
A central laboratory/reader will be used for all clinical assessments except for pregnancy
testing and blood group test (refer to Section 12.9). Local laboratories are requested to 
provide their laboratory specifications of the individual tests that are also being tested 
locally.
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16. ETHICS 
16.1 Subject Privacy
The investigator will comply with applicable subject privacy regulations/guidance as 
described in the CTA.
16.2 Ethics Committee and Regulatory Authorities
Before enrollment of patients into this study, the protocol, informed consent form, any 
promotional material/advertisements, and any other written information to be provided 
will be reviewed and approved/given favorable opinion by the EC and applicable 
regulatory authorities. The IB will be provided for review. The EC’s composition or a 
statement that the EC’s composition meets applicable regulatory criteria will be 
documented. The study will commence only upon the sponsor’s receipt of 
approval/favorable opinion from the EC and, if required, upon the sponsor’s notification 
of applicable regulatory authority(ies) approval, as described in the CTA.
If the protocol or any other information given to the subject is amended, the revised 
documents will be reviewed and approved/given favorable opinion by the EC and 
applicable regulatory authorities, where applicable. The protocol amendment will only be 
implemented upon the sponsor’s receipt of approval and, if required, upon the sponsor’s 
notification of applicable regulatory authority(ies) approval.
16.3 Informed Consent
Investigators will choose patients for enrollment considering the study eligibility criteria. 
The investigator will exercise no selectivity so that no bias is introduced from this source. 
All patients and/or their legally authorized representative must sign an informed consent 
form before entering into the study according to applicable national and local regulatory 
requirements and ICH GCP. Before use, the informed consent form will be reviewed by 
the sponsor and approved by the EC and regulatory authority(ies), where applicable, (see 
Section 16.2). The informed consent form will include a comprehensive explanation of 
the proposed treatment without any exculpatory statements, in accordance with the 
elements required by ICH GCP and applicable national and local regulatory 
requirements. Patients or their legally-authorized representative(s) will be allowed 
sufficient time to consider participation in the study. By signing the informed consent 
form, patients or their legally authorized representative(s) agree that they will complete 
all evaluations required by the study, unless they withdraw voluntarily or are terminated 
from the study for any reason.
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The sponsor will provide to the investigator in written form any new information that 
significantly bears on the subjects’ risks associated with IP exposure. The informed 
consent will be updated, if necessary. This new information and/or revised informed 
consent form, which have been approved by the applicable EC and regulatory authorities, 
will be provided by the investigator to the subjects who consented to participate in the 
study 
16.4 Data Monitoring Committee
This study will be monitored by Data Monitoring Committee (DMC). The DMC is a 
group of individuals with pertinent expertise that reviews on a regular basis accumulating 
data from an ongoing clinical study. For this study, the DMC will be composed of 
recognized experts in the field of VWD clinical care and research who are not actively 
recruiting subjects, and an independent statistician. The DMC can stop a trial if it finds 
toxicities or if treatment is proven to be not beneficial. Details will be defined in the 
DMC charter. 
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17. DATA HANDLING AND RECORD KEEPING
17.1 Confidentiality Policy
The investigator will comply with the confidentiality policy as described in the CTA. 
17.2 Study Documentation and Case Report Forms
The investigator will maintain complete and accurate paper format study documentation 
in a separate file. Study documentation may include information defined as “source data” 
(see Section 8.7), records detailing the progress of the study for each subject, signed 
informed consent forms, correspondence with the EC and the study monitor/sponsor, 
enrollment and screening information, CRFs, SAERs, laboratory reports (if applicable),
and data clarifications requested by the sponsor.
The investigator will comply with the procedures for data recording and reporting. Any 
corrections to paper study documentation must be performed as follows: 1) the first entry 
will be crossed out entirely, remaining legible; and 2) each correction must be dated and 
initialed by the person correcting the entry; the use of correction fluid and erasing are 
prohibited.
The investigator is responsible for the procurement of data and for the quality of data 
recorded on the CRFs. CRFs will be provided in electronic form. 
If electronic format CRFs are provided by the sponsor, only authorized study site 
personnel will record or change data on the CRFs. If data is not entered on the CRFs 
during the study visit the data will be recorded on paper and this documentation will be 
considered source documentation. Changes to a CRF will require documentation of the 
reason for each change. An identical (electronic/paper) version of the complete set of 
CRFs for each subject will remain in the investigator file at the study site in accordance 
with the data retention policy (see Section 17.3).
The handling of data by the sponsor, including data quality assurance, will comply with 
regulatory guidelines (e.g., ICH GCP) and the standard operating procedures of the 
sponsor. Data management and control processes specific to the study will be described 
in the data management plan.
17.3 Document and Data Retention 
The investigator will retain study documentation and data (paper and electronic forms) in 
accordance with applicable regulatory requirements and the document and data retention 
policy, as described in the CTA.
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18. FINANCING AND INSURANCE
The investigator will comply with investigator financing, investigator/sponsor insurance, 
and subject compensation policies, if applicable, as described in the CTA.
19. PUBLICATION POLICY
The investigator will comply with the publication policy as described in the CTA. 
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20. SUPPLEMENTS
20.1 Study Flow Chart
Figure 1
Study Design for Baxalta Clinical Study 071301
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20.2 Schedule of Study Procedures and Assessments
Table 6
Schedule of Study Procedures and Assessments
Procedures/
Assessments
Screening Visit
Baseline Visit 
(PK-assessment visit)
Prophylaxis Initiation 
Visit
Interval/Follow-Up 
Study Visits
PK Assessment and 
Study Completion
Termination 
Visit
Pre-infusion
Infusion
Post-infusiong
1 month ± 
1 week
2 month ± 
1 week 
3 month ± 
2 weeks
6 month ± 
2 weeks 
9 month ± 
2 weeks
Pre-
infusion
Infusion
Post-
infusiong
Conducted 
at the 
96 hour 
postinfusion
PK 
Assessment
12 month± 
2 weeks
Informed Consent a
X
Eligibility Criteria
X
Medical Historyb
X
X
Medicationsc
X
X
X
X
X
X
X
X
X
X
Non-drug Therapiesc
X
X
X
X
X
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
Bleeding Episodes
X
X
X
X
X
X
X
X
X
X
Laboratories 
X
X
X
Xh
X
X
X
X
X
X
X
X
Vital Signsd
X
X
X
X
X
X
X
X
X
X
X
X
ECG
X
X
X
IP Treatmente
X
X
X
X
X
X
X
X
IP Consumption / Treatment 
Compliance 
X
X
X
X
X
Subject Diary
X
X
X
X
X
X
Xf
X
X
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Continued
a) Occurs at enrollment (before screening).
b) Including documented history of on-demand treatment for the past 12 months and a documented history, e.g., patient charts and prescription information, 
of all bleeding episodes within the past 12 months. 
c) Including all medications and non- drug therapies taken in the 2 weeks prior to study entry and all the concomitant medications and non-drug therapies 
during the course of the study.
d) Vital signs (pulse rate, respiratory rate, and blood pressure): within 30 minutes before infusion start and 30 ± 15 minutes post-infusion.
e) IP treatment after the prophylactic treatment initiation visit at the site will be continued as home-treatment if the subject qualifies; a wash-out period of at 
least 72 hours is required after the last IP infusion before the follow-up visit. IP infusion will be given at the study site after the blood sample for 
immunology testing and IR determination is drawn.
f) Can be done either at the screening or the baseline visit.
g) Time points for blood draws post infusion: 15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 
30 ± 2 hours, 48 2 hours, 72 2 hours and 96 ± 2 hours. 
h) If a subject did not undergo PK assessment, laboratory assessments will be performed at this visit.
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20.2.1 Summary Schedule of Visit Assesments for Surgical Bleeding
Table 7
Summary Schedule of Visit Assesments for Surgical Bleeding
Procedures/
Assessments
Surgical procedure
Post-Operative 
Day 7 Visit
(± 1 day)
Study Completion
Visit (14 ± 2 days 
post Surgery)
Priming Dose 
Procedures 
(12-24 hours prior 
to surgery)
Loading Dose 
Procedures 
(≤3 hours prior
to surgery)
Intraoperative
Postoperative 
(day 1 → end of 
perioperative IP 
treatment)
ECG
X
Physical examination
X
X
X
X
X
Adverse events
X
X
X
X
X
X
Laboratories
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
IP treatment: rVWF:ADVATE or 
rVWF only infusion
X
X
X
as required
X
as required
X
as required
X
as required
Concomitant medications and non-
drug therapy
X
X
X
X
X
X
X
Hemostatic efficacy assessments
X
X
X
Blood loss
X
estimated
X
actual
X
X
X
Treatment days estimate
X
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20.3 Clinical Laboratory Assessments
Table 8
Clinical Laboratory Assessments
Procedures/
Assessments
Screening Visit
Baseline Visit 
(PK-assessment visit)
Prophylaxis Initiation 
Visitk
Interval/Follow-Up 
Study Visits
PK Assessment and 
Study Completion
Termination 
Visit
Pre-infusion
Infusion
Post-infusiong
1 month ± 
1 week
2 month ± 
1 week 
3 month ± 
2 weeks
6 month ± 
2 weeks 
9 month ± 
2 weeks
Pre-
infusion
Infusion
Post-
infusiong
Conducted 
at the 
96 hour 
postinfusion 
PK 
Assessment
12 month± 
2 weeks
Hematology a
X
X
X
X
X
X
X
X
X
Xm
X
Clinical Chemistryb
X
X
X
X
X
X
X
X
X
X
X
Coagulation Panel/PK 
assessmentc
X
X
X
X
X
X
X
X
X
X
X
Immunogenicityd
X
X
Xl
X
X
X
X
X
X
X
Viral Serologye
X
Urinalysisf
X
VWD Gene Mutational 
Analysis / HLA genotype 
analysis and Analysis of 
VWF multimersg
X
sP-selectin and D-dimer
Xh
Blood Groupi 
X
Pregnancy Testj
X
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Continued
a) Hematology assessments include: complete blood count [hemoglobin, hematocrit, erythrocytes (i.e. red blood cell count), mean corpuscular volume 
(MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), leukocytes (i.e. white blood cell count)] with 
differential (i.e. basophils, eosinophils, lymphocytes, monocytes, neutrophils) and platelet counts. Hematology assessments during PK assessments will be 
determined prior IP infusion and 24 ± 2 hours, 48 ± 2 hours and 72 ± 2 hours thereafter.
b) Clinical chemistry assessments include: Sodium, potassium, chloride, glucose, creatinine, blood urea nitrogen (BUN), aspartate aminotransferase (AST), 
alanine aminotransferase (ALT) lactate dehydrogenase (LDH), alkaline phosphatase (AP), bilirubin. Clinical chemistry will be determined at baseline, 
after 24 ± 2 h, 48 ± 2 hours and 72 ± 2 hours during the PK assessments. 
c) Coagulation panel/PK assessment (also refers to IR pre/post dose assessments at each follow-up visit): INR/aPTT, VWF:RCo, VWF:Ag, VWF:CB, 
FVIII:C,; during the PK assessment at the baseline visit blood samples will be drawn 30 min prior PK infusion; once the PK infusion is completed 
15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours and 
96 ± 2 hours and VWF:RCo, VWF:CB, VWF:Ag, FVIII:C will be determined; in case of thromboembolic event VWF multimers and ADAMTS13 will be 
analyzed to judge on a possibly relatedness to UHMW fractions of the IP.
d) Immunogenicity assessment includes Neutralizing Antibodies (Ab) to FVIII – Neutralizing and Neutralizing Ab to VWF:RCo, Neutralizing Ab to 
VWF:CB, Neutralizing Ab to VWF:FVIII, Binding Ab to VWF and FVIII, Binding Ab to CHO-Protein, Binding Ab to rFurin, Binding Ab to Murine IgG; 
.CD4* In case of an SAE hypersensitivity reaction IgE antibodies to VWF will be determined. A washout period of at least 72 hours after the last IP 
infusion is required before blood samples for immunogenicity assessments can be drawn. 
e) Viral Serology Hepatitis A Antibody, Total - Hepatitis A Antibody, IgM - Hepatitis B Surface Antibody - Hepatitis B Core Ab, Total - Hepatitis B Surface 
Antigen - Hepatitis C Virus Antibody; Parvovirus B19; HIV-1/HIV-2 Antibodies
f) Urinalysis comprehends: erythrocytes, specific gravity, urobilinogen, ketones, glucose, protein, bilirubin, nitrite, and pH
g) Not required if available in the subject’s medical history; VWF multimers: additionally in case of thromboembolic events
h) At screening and in case of thromboembolic events
i) Blood group assessment major blood group (local laboratory) only if not available in the subject’s medical history
j) Serum pregnancy test (in females of child-bearing potential if no urine sample is available)
k) The 96 h post-infusion laboratory assessments coincidence with the initiation visit for prophylactic treatment. After the blood samples are drawn for 
laboratory assessment for the 96 h post infusion PK assessment, the subject receives the first IP infusion for prophylactic treatment (prophylactic treatment 
initiation visit). 
l) Only needed for subjects without PK assessment prior to their first IP infusion in this study.
m) A full PK analysis will be performed. Blood samples will be drawn within 30 minutes pre-infusion, and at 11 time points post-infusion (15 ± 5 minutes, 
30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours and 96 ± 2 hours).
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20.3.1 Laboratory Sampling for Surgical Bleeding
Table 9
Laboratory Sampling for Surgical Bleeding
Procedures/
Assessments
Surgical procedure
Post-Operative 
Day 7 Visit
(± 1 day)
Study Completion
Visit (14 ± 2 days 
post Surgery)
Priming Dose 
Procedures 
(12-24 hours prior 
to surgery)
Loading Dose 
Procedures 
(≤3 hours prior 
to surgery)
Intraoperative
Postoperative 
(day 1 → end of 
perioperative IP 
treatment)
Pregnancy Test
Hematology
X
(w/o Differential)
X
(w/o Differential)
X
(w/o Differential)
X
X
Clinical Chemistry
X
X
X
X
Coagulation panel
X
X
X
X
X
X
Pharmacokinetic Tests
VWF inhibitory and binding 
antibodies, antibodies to other 
proteins
X
X
X
if excessive or 
unexplainedbleeding
X
X
X
Viral markers
VWD Gene Mutational Analysis / 
HLA genotype analysis
Urinalysis
X
X
VWF Multimers
Anti VWF IgE antibody testing
only in case of allergic reaction/ 
anaphylaxis
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20.4 Contraceptive Methods for Female Subjects of Childbearing Potential
In this study, subjects who are women of childbearing potential must agree to utilize a 
highly effective contraceptive measure throughout the course of the study and for 30 days 
after the last administration of investigational product. In accordance with the Clinical 
Trial Facilitation Group (CTFG) recommendations related to contraception and 
pregnancy testing in clinical trials (version 2014-09-15),ii birth control methods which 
may be considered as highly effective include the following:

Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation:
oral
intravaginal
transdermal

Progestogen-only hormonal contraception associated with inhibition of ovulation:
oral
injectable
implantableiii

Intrauterine device (IUD)iii

Intrauterine hormone-releasing system (IUS) iii

Bilateral tubal occlusioniii

Vasectomised partner(s)iii

Sexual abstinence during the entire study period
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhoea method (LAM) are 
not acceptable methods of contraception. Female condom and male condom should not 
be used together.
                                                
ii Clinical Trial Facilitation Group (CTFG) recommendations related to contraception and pregnancy 
testing in clinical trials: http://www.hma.eu/fileadmin/dateien/ 
Human_Medicines/01About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf.
iii Contraception methods that are considered to have low user dependency.
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21. REFERENCES
1.
Committee for Medicinal Products for Human Use. Guideline on clinical 
investigation of human plasma derived von Willebrand factor products.:London, 
European Medicines Agency (EMA). Web Link: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/201
0/01/WC500067126.pdf
2.
Mannucci PM. Treatment of von Willebrand's Disease. N Engl J Med. 
2004;351(7):683-694.
3.
Goudemand J, Scharrer I, Berntorp E, et al. Pharmacokinetic studies on Wilfactin, a 
von Willebrand factor concentrate with a low factor VIII content treated with three 
virus-inactivations/removal methods. J Thromb Haemost. 2005;3(10):2219-2227.
4.
Abshire T. The role of prophylaxis in the management of von Willebrand disease: 
today and tomorrow. Thromb Res. 2009;124 Suppl 1:S15-S19.
5.
Nilsson IM, Blombäck M, Jorpes E, Blombäck B, Johansson SA. V. Willebrand's 
disease and its correction with human plasma fraction 1-0. Acta Med Scand. 
1957;159(3):179-188.
6.
Berntorp E, Petrini P. Long-term prophylaxis in von Willebrand disease. Blood 
Coagul Fibrinolysis. 2005;16 Suppl 1:S23-S26.
7.
Berntorp E. Prophylaxis and treatment of bleeding complications in von Willebrand 
disease type 3. Semin Thromb Hemost. 2006;32(6):621-625.
8.
Federici AB. Highly purified VWF/FVIII concentrates in the treatment and 
prophylaxis of von Willebrand disease: the PRO.WILL Study. Haemophilia. 
2007;13 Suppl 5:15-24.
9.
Halimeh S, Krümpel A, Rott H, et al. Long-term secondary prophylaxis in children, 
adolescents and young adults with von Willebrand disease. Results of a cohort 
study. Thromb Haemost. 2011;105(4):597-604.
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10.
Abshire TC, Federici AB, Alvárez MT, et al. Prophylaxis in severe forms of von 
Willebrand's disease: results from the von Willebrand Disease Prophylaxis Network 
(VWD PN). Haemophilia. 2013;19(1):76-81.
11.
Abshire T, Cox-Gill J, Kempton CL, et al. Prophylaxis escalation in severe von 
Willebrand disease: A prospective study from the von Willebrand Disease 
Prophylaxis Network. J Thromb Haemost. 2015;13(9):1585-1589.
12.
Berntorp E. Prophylaxis in von Willebrand disease. Haemophilia. 2008;14 Suppl 
5:47-53.
13.
Varadi K, Rottensteiner H, Vejda S, et al. Species-dependent variability of 
ADAMTS13-mediated proteolysis of human recombinant von Willebrand factor. J 
Thromb Haemost. 2009;7(7):1134-1142.
14.
Mannucci PM, Kempton C, Millar C, et al. Pharmacokinetics and safety of a novel 
recombinant human von Willebrand factor manufactured with a plasma-free 
method: a prospective clinical trial. Blood. 2013;122(5):648-657.
15.
Gill JC, Castaman G, Windyga J, et al. Hemostatic efficacy, safety and 
pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand 
disease. Blood. 2015;126(17):2038-2046.
16.
Committee for Medicinal Products for Human Use. Guideline on immunogenicity 
assessment of biotechnology-derived therapeutic proteins:London, European 
Medicines Agency (EMA). Web Link: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/200
9/09/WC500003946.pdf
17.
Kasper CK. Laboratory tests for factor VIII inhibitors, their variation, significance 
and interpretation. Blood Coagul Fibrinolysis. 1991;2 Suppl 1:7-10.
18.
Lillicrap D. Von Willebrand Factor. International Society for Thrombosis and 
Hemostasis (ISTH) 54th Annual Scientific and Standardization Committee 
Meeting; 2008:60-64.
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22. SUMMARY OF CHANGES
Protocol 071301: Global Amendment 3: 2017AUG 03
Replaces: Amendment 2: 2016 DEC 15
In this section, changes from the previous version of the Protocol, dated 2016 DEC 15,
are described and their rationale is given.
1.
Synopsis(Secondary objectives, Efficacy), Section 7.3, Section 8.4.2.5, 
Section 13.4.2.3
Description of Change:
The text/summary text/bullets for ‘efficacy of treatment of perioperative bleeding 
management, if surgery is required’ is added.
Purpose for Change: To provide further clarifications to the surgery arm and to 
address the possibility for subjects on year long prophy study who coud require 
surgical procedure during this time.
2.
Synopsis (Secondary Outcome Measures, Efficacy), Section 8.4.2.1
Description of Change: 
Original text:
Number (proportion) of subjects with reduction of ABR for spontaneous (not 
related to trauma) bleeding episodes during prophylaxis relative to the subjects’ 
own historical ABR during on-demand treatment
New text:
Number (proportion) of subjects with reduction of ABR for spontaneous (not 
related to trauma) bleeding episodes during prophylaxis relative to the subjects’ 
own historical ABR during on-demand treatment. An ABR reduction of >25% is 
considered relevant.
Purpose for Change: To define the threshold considered as relevant ABR reduction 
relative to subjects’ historical ABR, to improve the clarity of the protocol.
3.
Synopsis, Abbreviation list, Section 8.4.2.3, Section 10.3.6, Section 10.3.8, 
Section 12.9.1, Section 12.9.14, Section 20.3 Table 7 and Footnote “c”)
Description of Change:
The mention of the ‘Innovance VWF Ac assay’ is removed from the protocol text.
Purpose for Change: As the text related to ‘Innovance VWF Ac assay’ was not 
applicable for the study, the relevant instances are removed for further clarity.
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4.
Section 8.4.2.1
Description of Change: 
Original text:
Number of infusions and total weight adjusted consumption of rVWF and 
ADVATE per month and per year during on-demand treatment
New text:
Number of infusions and total weight adjusted consumption of rVWF and 
ADVATE per month and per year during prophylactic treatment as well as
during on-demand treatment
Purpose for Change: Calculation of consumption will be carried out on prophylaxis 
as well as for on demand treatment, so the revision done to improve the clarity of 
the protocol.
5.
Section 8.7.4.1, Section 10.3.2, Section 10.3.7, Section 12.9.1
Description of Change:
Original text:
Blood samples will be drawn within 30 minutes pre-infusion, and at 7 time points 
post-infusion (30 5 minutes, 60 5 minutes, 6 1 hours, 12 1 hours, 
24 2 hours, 48 2 hours, 72 2 hours)
New text:
Blood samples will be drawn within 30 minutes pre-infusion, and at 711 time 
points post-infusion (15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 3 ± 0.5 
hours, 6 100.5 hours, 12 100.5 hours, 24 100.5 hours, 30 ± 2 hours,
48 2 hours, 72 2 hours and 96 ± 2 hours)
Purpose for Change: Need to align with (CPMP/BPWG/220/02) to include 15 min, 
3 hr and 30 hr PK sampling timepoints.
6.
Section 8.7.4.1, Section 8.7.4.2, Section 10.3.2, Section 10.3.3, 
Section 20.2 – Footnote “h”)
Description of Change:
The text related to PK assessments in the subjects previously enrolled in rVWF 
studies is modified as applicable.
Purpose of Change:
Text modified for relevance and further clarification.
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7.
Section 8.7.4.2, Section 10.3.3, Section 10.3.7, Section 20.3 – Footnote” k”)
Description of Change:
All instances of 72 ± 2 hours PK assessment is replaced with 96 ± 2 hour PK 
assessment, when referring to the case window.
Purpose of Change:
The time point 96 ± 2 hour is the new time span for PK assessment, when referring 
to the case window.
8.
Section 8.7.4.3
Description of Change: 
Original text:
rVWF Dosing Schedule Examples: Schedules, A, B, and C
New text:
rVWF Dosing Schedule Examples: Schedules A, and B, and C
Purpose for Change: Table heading corrected to remove error.
9.
Section 8.7.4.4.2
Description of Change: 
Original text:
If an acute bleeding episode occurs, the subject will be treated with rVWF with or 
without ADVATE. In general initially, an infusion of rVWF: ADVATE at an
rVWF: ADVATE ratio of 1.3:1± 0.2 will be administered. Subsequent infusions 
may either use rVWF alone or with ADVATE, based on FVIII levels, if available.
New text:
If an acute bleeding episode occurs, the subject will be treated with rVWF with or 
without ADVATE. In general initially, an infusion of rVWF: ADVATE at an
rVWF: ADVATE ratio of 1.3:1± 0.2 will be administered. Subsequent infusions 
may either use rVWF alone or with ADVATE, based on FVIII levels, if 
availablewill be with rVWF:RCo 40 to 60 IU/kg with or without 30 to 45 IU/kg 
ADVATE (only to be administered if plasma FVIII levels fall below 30 IU/L 
during the treatment period).
Purpose for Change: To clearly define the ADVATE use, the revision of text was 
done.
10. Section 8.7.4.5
Description of Change: New section added: “Treatment of Surgical Bleeding”
Purpose for Change: Section added in order to address the possibility for subjects on 
year-long prophy study who could require surgical procedure during this time.
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11. Section 8.7.4.6
Description of Change: New section added: “Thrombosis Prophylaxis”
Purpose for Change: Section added in order to address the clarity around the 
thrombosis prophylaxis.
12. Section 10.3.4
Description of Change:
Original text: 
Treatment of bleeding episodes is described in detail in Section 8.7.4.4.
New text:
Treatment of bleeding episodes is described in detail in Section 8.7.4.4 and 
treatment of perioperative bleeding is described in detail in Section 8.7.4.5.
Purpose of Change: The reference to new section 8.7.4.5 also added for further 
clarification, to address this possibility for subjects on year-long prophy study who 
could require surgical procedure during this time.
13. Section 10.3.5
Description of Change:
The details for surgery related Perioperative visit added in new subsection.
Purpose of Change: The details for surgery related visit added for further 
clarification, to address this possibility for subjects on year-long prophy study who 
could require surgical procedure during this time.
14. Section 10.5
Description of Change:
Original text: 
Infusions performed at the study site will be recorded in the site’s source 
documents and not in the patient diary.
New text:
Infusions performed at the study site will first be recorded in the site’s source 
documents and not in the patient diary.
Purpose of Change: For further clarification, as afterwards site infusions need to be 
sent to ERT for entry.
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15. Section 10.5
Description of Change:
Original text:
Not applicable
New text:
Paper diary may be utilized in rare case where electronic diary use is not possible.
Purpose of Change: New text is added to further clarify that recruitment / retention 
materials include a paper diary in case needed, so to match to subject-facing 
material submitted.
16. Section 11.5
Description of Change:
Original text: 
Not applicable
New text:
New subsection for ‘Assessment of Efficacy for Treatment for Surgical Bleeding’ 
is added.
Purpose of Change: For further clarification, to address this possibility for subjects 
on year-long prophy study who could require surgical procedure during this time.
17. Synopsis, Section 13.4.2.1
Description of Change: 
Original text:
For the number (proportion) of subjects with reduction of ABR relative to historic 
ABR as well as for the number (proportion) of subjects with 0 bleeds, proportions 
and corresponding 95% two-sided CIs will be performed.
New text:
For the number (proportion) of subjects with reduction of ABR relative to historic 
ABR as well as for the number (proportion) of subjects with 0 bleeds, proportions 
and corresponding 95% two-sided CIs will be performed. An ABR reduction of 
>25% is considered relevant.
Purpose for Change: To define the threshold considered as relevant ABR reduction 
relative to subjects’ historical ABR, to improve the clarity of the protocol.
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18. Synopsis, Section 13.4.2.1
Description of Change: 
Original text:
For the number of infusions and for the total weight adjusted consumption of rVWF 
and ADVATE per month and per year during on-demand treatment for bleeding 
episodes, summary statistics will be carried out.
New text:
For the number of infusions and for the total weight adjusted consumption of rVWF 
and ADVATE per month and per year during prophylactic treatment as well as
during on-demand treatment for bleeding episodes, summary statistics will be 
carried out.
Purpose for Change: Calculation of consumption will be carried out on prophylaxis
as well as for on demand treatment, so the revision done to improve the clarity of 
the protocol.
19. Section 20.2 - Table 6
Description of Change: Removal of Medical History ‘X’ in PK assessment and 
study completion/pre-infusion column
Purpose of Change: To correct error on study procedure and assessment chart.
20. Section 20.2 – Table 6
Description of Change:
Original text:
Footnote g) Time points for blood draws post infusion: 30 5 minutes, 
60 5 minutes, 6 1 hours, 12 1 hours, 24 2 hours, 48 2 hours, 
72 2 hours
New text:
Footnote g) Time points for blood draws post infusion: 15 ± 5 minutes, 
30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 100.5 hours, 12 100.5 hours, 
24 100.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours and 96 ± 2 hours)
Purpose for Change: Need to align with (CPMP/BPWG/220/02) to include 15 min, 
3 hr and 30 hr PK sampling timepoints.
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21. Section 20.2.1 – Table 7
Description of Change:
The details for summary schedule of visit assessment for surgical bleeding added in 
new subsection.
Purpose of Change: The details for surgery related visit added for further 
clarification, to address this possibility for subjects on year-long prophy study who 
could require surgical procedure during this time.
22. Section 20.3 - Table 8
Description of Change:
Removal of Immunogenicity ‘X’ in baseline visit/post-infusion column
Purpose of Change: To correct error on clinical laboratory assessment chart.
23. Section 20.3 - Table 8
Description of Change: 
Removal of blood group ‘X’ from 6-month follow-up visit
Purpose of Change: To correct error on clinical laboratory assessment chart.
24. Section 20.3 - Table 8
Description of Change: 
Original text:
Footnote c) Coagulation panel/PK assessment:
New text:
Footnote c) Coagulation panel/PK assessment (also refers to IR pre/post dose 
assessments at each follow-up visit):
Purpose of Change: To clarify the information.
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25. Section 20.3– Table 8
Description of Change:
Original text:
Footnote c) once the PK infusion is completed 30 5 minutes, 60 5 minutes, 6 
1 hours, 12 1 hours, 24 2 hours, 48 2 hours, 72 2 hours
Footnote m) Blood samples will be drawn within 30 minutes pre-infusion, and at 7 
time points post-infusion (30 5 minutes, 60 5 minutes, 6 1 hours, 12 1 
hours, 24 2 hours, 48 2 hours, 72 2 hours)
New text:
Footnote c) once the PK infusion is completed 15 ± 5 minutes, 30 5 minutes, 60
5 minutes, 3 ± 0.5 hours, 6 100.5 hours, 12 100.5 hours, 24 100.5 hours, 
30 ± 2 hours, 48 2 hours, 72 2 hours and 96 ± 2 hours)
Footnote m) 
Blood samples will be drawn within 30 minutes pre-infusion, and at 711 time 
points post-infusion (15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 3 ± 0.5 
hours, 6 100.5 hours, 12 100.5 hours, 24 100.5 hours, 30 ± 2 hours,
48 2 hours, 72 2 hours and 96 ± 2 hours)
Purpose for Change: Need to align with (CPMP/BPWG/220/02) to include 15 min, 
3 hr and 30 hr PK sampling timepoints.
26. Section 20.3.1 – Table 9
Description of Change:
The details for laboratory sampling for surgical bleeding added in new subsection
Purpose of Change: The details for surgery related visit added for further 
clarification, to address this possibility for subjects on year-long prophy study who 
could require surgical procedure during this time
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INVESTIGATOR ACKNOWLEDGEMENT
RECOMBINANT VON WILLEBRAND FACTOR (rVWF)
A prospective, phase 3, open-label, international multicenter study on efficacy and 
safety of prophylaxis with rVWF in severe von Willebrand Disease
PROTOCOL IDENTIFIER: 071301
CLINICAL TRIAL PHASE 3
GLOBAL AMENDMENT 3: 2017 AUG 03
Replaces: AMENDMENT 2: 2016 DEC 15
OTHER PROTOCOL ID(s)
NCT Number: NCT02973087
EudraCT Number: 2016-001478-14
IND NUMBER: 013657
By signing below, the investigator acknowledges that he/she has read and understands 
this protocol, and will comply with the requirements for obtaining informed consent from 
all study subjects prior to initiating any protocol-specific procedures, obtaining written 
initial and ongoing EC(s) protocol review and approval, understands and abides by the 
requirements for maintenance of source documentation, and provides assurance that this 
study will be conducted according to all requirements as defined in this protocol, Clinical 
Trial Agreement, ICH GCP guidelines, and all applicable national and local regulatory 
requirements.
Signature of Principal Investigator
Date
Print Name of Principal Investigator
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CLINICAL STUDY PROTOCOL
PRODUCT: Recombinant Von Willebrand Factor (rVWF, vonicog alfa)
STUDY TITLE: A PROSPECTIVE, PHASE 3, OPEN-LABEL, INTERNATIONAL 
MULTICENTER STUDY ON EFFICACY AND SAFETY OF PROPHYLAXIS 
WITH rVWF IN SEVERE VON WILLEBRAND DISEASE
STUDY SHORT TITLE: rVWF IN PROPHYLAXIS
PROTOCOL IDENTIFIER: 071301
CLINICAL TRIAL PHASE 3
GLOBAL AMENDMENT 6: 2018 MAR 12
Replaces: 
AMENDMENT 3: 2017 AUG 03
ALL VERSIONS: 
Amendment 6: 2018 MAR 12
Local (Czech) Amendment 5: 2017 AUG 08
Local (Germany) Amendment 4: 2017 AUG 04
Amendment 3: 2017 AUG 03
Amendment 2: 2016 DEC 15
Amendment 1: 2016 APR 08
Original: 2014 FEB 09
OTHER ID(s)
NCT Number: NCT02973087
EudraCT Number: 2016-001478-14
IND NUMBER: 013657
Study Sponsor(s):
Baxalta US Inc.
300 Shire Way
Lexington, MA 02421,US
Baxalta Innovations GmbH
Industriestrasse 67
A-1221 Vienna, AUSTRIA
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1. STUDY PERSONNEL
1.1 Authorized Representative (Signatory) / Responsible Party
, MD
Global Clinical Development Operations
Baxalta Innovations GmbH
1.2 Study Organization
The name and contact information of the responsible party and individuals involved with 
the study (e.g. investigator(s), sponsor’s medical expert and study monitor, sponsor’s 
representative(s), laboratories, steering committees, and oversight committees [including 
ethics committees (ECs)], as applicable) will be maintained by the sponsor and provided 
to the investigator.
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2. SERIOUS ADVERSE EVENT REPORTING
The investigator will comply with applicable laws/requirements for reporting serious 
adverse events (SAEs) and suspected unexpected serious adverse events (SUSARs) to the 
ECs.
ALL SAEs, INCLUDING SUSARs, ARE TO BE REPORTED ON THE SERIOUS 
ADVERSE EVENT REPORT (SAER) FORM AND TRANSMITTED TO THE 
SPONSOR WITHIN 24 HOURS AFTER BECOMING AWARE OF THE EVENT.
Bleeding events that meet seriousness criteria (death, life-threatening, 
hospitalizing/prolongation of hospitalization, disability, congenital anomaly, or medically 
significant and if not urgently treated would result in one of the above) should be reported 
on the SAE eCRF and SAE Report form as an SAE.
Drug Safety contact information:
Baxalta Global Drug Safety fax number:  
OR 
email: 
For definitions and information on the assessment of these events, refer to the following:

Adverse Events (AEs), Section 12.1

SAEs, Section 12.1.1.1

SUSARs, Section 12.1.1.2

Assessment of AEs, Section 12.1.2

Safety Reporting, Section 12.1.2.3
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3. SYNOPSIS
INVESTIGATIONAL PRODUCT
Name of Investigational Product (IP)
Recombinant von Willebrand factor (rVWF, vonicog alpha)
Name(s) of Active Ingredient(s)
Recombinant von Willebrand factor (rVWF, vonicog alpha)
CLINICAL CONDITION(S)/INDICATION(S)
Subjects with severe von Willebrand disease (VWD) (baseline VWF: Ristocetin cofactor activity
(VWF:RCo) <20 IU/dL) requiring prophylactic treatment with coagulation factor replacement
PROTOCOL ID
071301
PROTOCOL TITLE
A prospective, phase 3, open-label, international multicenter 
study on efficacy and safety of prophylaxis with rVWF in severe 
von Willebrand disease
Short Title
rVWF in prophylaxis
STUDY PHASE
Phase 3
PLANNED STUDY PERIOD
Initiation
2017 OCT
Primary Completion
2019 Q4
Study Completion
2019 Q4
Duration
27 months
STUDY OBJECTIVES AND PURPOSE
Study Purpose
The purpose of this phase 3 study is to investigate the efficacy and safety, including immunogenicity, 
thrombogenicity and hypersensitivity reactions, as well as pharmacokinetics (PK),
 
and 
 of prophylactic treatment with rVWF (vonicog alfa) in adult 
subjects with severe VWD.
Primary Objective
The primary objective of this study is to prospectively evaluate the annualized bleeding rate (ABR) for
spontaneous bleeding episodes while on prophylactic treatment with rVWF (vonicog alfa) and to compare 
it to the subject’s historical ABR for spontaneous bleeding episodes. 
Secondary Objectives
Secondary Objectives are to assess

Additional efficacy of prophylactic treatment with rVWF (vonicog alfa)

Safety of rVWF (vonicog alfa), including immunogenicity, thrombogenicity and hypersensitivity

Pharmacokinetics (PK) of rVWF (vonicog alfa) and Pharmacodynamics (PD) of rVWF (vonicog alfa)
as measured in FVIII activity
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Exploratory Objectives
 
 
rk 
STUDY DESIGN
Study Type/ Classification/ Discipline
Efficacy and Safety 
Control Type
No control
Study Indication Type
Prophylaxis and treatment of bleeding episodes
Intervention model 
Single-group
Blinding/Masking
Open-label
Study Design
This is a phase 3, prospective, open-label, uncontrolled, non-
randomized, international multicenter study evaluating efficacy, 
safety, including immunogenicity, thrombogenicity and 
hypersensitivity reactions, as well as PK, 
and 
 of prophylactic treatment regimen with 
rVWF (vonicog alfa) in adult subjects with severe VWD.
Subjects transitioning from on-demand treatment (OD subjects) 
or subjects switching from prophylactic treatment with pdVWF 
(pdVWF switch subjects) will receive prophylactic treatment 
with rVWF (vonicog alfa) for a 12-month period.
Planned Duration of Subject 
Participation
Approximately 15 months 
Primary Outcome Measure 
Efficacy

Annualized bleeding rate (ABR) for spontaneous (not related to trauma) bleeding episodes during 
prophylactic treatment with rVWF (vonicog alfa)
Secondary Outcome Measures
Additional efficacy of prophylactic treatment with rVWF (vonicog alfa)

ABR percent reduction success for OD subjects defined as at least 25% reduction of ABR for
spontaneous (not related to trauma) bleeding episodes during rVWF (vonicog alfa) prophylaxis 
relative to the subject’s own historical ABR during on-demand treatment
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
ABR preservation success for pdVWF switch subjects defined as achieving an ABR for spontaneous 
bleeding episodes during rVWF (vonicog alfa) prophylaxis that is no greater than the subject’s own 
historical ABR during prophylactic treatment with pdVWF 

Categorized spontaneous ABR defined as 0, 1-2, 3-5, or >5 bleeding episodes during the 12-month 
prophylactic treatment with rVWF (vonicog alfa)

Total number of infusions and the average number of infusions per week during prophylactic 
treatment with rVWF (vonicog alfa)

Total weight adjusted consumption of rVWF (vonicog alfa) during prophylactic treatment

Spontaneous ABR by location of bleeding (Gastrointestinal [GI], epistaxis, joint bleeding, 
menorrhagia, oral and other mucosa, muscle and soft tissue, etc.) while on prophylactic treatment with 
rVWF (vonicog alfa)
Safety

Adverse events (AEs) : incidence, severity, causality

Thromboembolic events 

Hypersensitivity reactions

Development of neutralizing antibodies to VWF and FVIII 

Development of total binding antibodies to VWF and FVIII

Development of binding antibodies to Chinese hamster ovary (CHO) proteins, mouse 
immunoglobulin G (IgG) and rFurin

Clinically significant changes in vital signs and clinical laboratory parameters relative to baseline
Pharmacokinetics (PK) and Pharmacodynamics (PD)

PK parameters after a washout for on-demand subjects: incremental recovery (IR), terminal half-life
(T1/2), mean residence time (MRT), area under the concentration versus time curve from 0 to infinity 
(AUC0-), area under the concentration versus time curve from 0 to the last measurable concentration 
(AUC0-tlast), maximum concentration (Cmax), minimum time to reach the maximum concentration
(Tmax), volume of distribution at steady state (Vss) and clearance (CL) based on VWF:RCo, Von 
Willebrand factor antigen (VWF:Ag), Von Willebrand collagen binding activity (VWF:CB).

PD parameters after a washout for on-demand subjects: Cmax, Tmax, and AUC0-tlast as measured in 
FVIII activity by the 1-stage clotting assay (FVIII:C). 

PK parameters at steady state for on-demand and switch subjects: area under the concentration versus 
time curve from 0 to end of the partial dosing interval (AUC0- tau;ss), maximum concentration during 
the partial dosing interval (Cmax;ss), minimum time to reach the maximum concentration (Tmax;ss) and 
minimum concentration during the partial dosing interval (Cmin;ss) based on VWF:RCo, VWF:Ag and 
VWF:CB. PK parameters at steady state will be assessed shortly after reaching steady state for switch 
subjects and at the end of the study for on-demand as well as for switch subjects all based on the 
longer interval of the irregular dosing intervals employed.

PD parameters at steady state for on-demand and switch subjects: AUC0-tau;ss, Cmax;ss, Tmax;ss, and Cmin;ss
as measured in FVIII actvitiy by the 1-stage clotting assay (FVIII:C). PD parameters at steady state 
will be assessed shortly after reaching steady state for switch subjects and at the end of the study for 
on-demand as well as for switch subjects all based on the longer interval of the irregular dosing 
intervals employed.

Time course of FVIII clotting activity (FVIII:C) levels.
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Exploratory Outcome Measures
 
 
 
 
 
 
 
 
 
 
INVESTIGATIONAL PRODUCT(S), DOSE AND MODE OF ADMINISTRATION
Active Product
Dosage form: powder and solvent for solution for injection
Dosage frequency:
Prophylactic Treatment
Subjects transitioning from on-demand treatment will receive twice weekly
infusion with rVWF (vonicog alfa) at doses of 50 ± 10 IU/kg rVWF:RCo. 
Dosage may be individualized within this range based on:

available historical PK data

type and severity of bleeding episodes the subject has experienced in the past

monitoring of appropriate clinical and laboratory measures
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The starting dose can, after consultation with the Sponsor, be increased up to 
80 U/kg if considered necessary to assure effective prophylaxis.
Subjects switching from pdVWF prophylaxis treatment: the weekly dose (IU/kg) 
of rVWF (vonicog alfa) for each patient will be equivalent (± 10%) to the weekly
VWF dose received during prophylactic treatment with pdVWF. The weekly 
dose should be divided into 2 infusions, with a maximum of 80 IU/kg/infusion. If 
needed, based on the total weekly dose or other clinical judgements, the weekly 
dose may be given as three infusions. A once weekly dose regimen will be 
allowed after switch to rVWF (vonicog alfa) if the patient has been on a once 
weekly dose regimen with pdVWF. Dose and dose interval may, after 
consultation with the sponsor, be further individualized based on: 

available historical PK data

type and severity of bleeding episodes the subject has experienced in the past

monitoring of appropriate clinical and laboratory measures
Treatment of Bleeding Episodes:
Dosage must be individualized based on the subject’s weight, type and severity 
of bleeding episode and monitoring of appropriate clinical and laboratory 
measures. In general, an initial dose of 40-60 IU/kg VWF:RCo with or without
30-45 IU rFVIII [ADVATE, octocog alfa]/kg is recommended (rVWF:rFVIII
ratio of 1.3:1: ± 0.2). In cases of major bleeding episodes, a dose of up to 80 
IU/kg VWF:RCo may be infused. Subsequent doses, if necessary, will be 
administered with or without ADVATE (rFVIII, octocog alfa) to maintain 
VWF:RCo and FVIII levels for as long as deemed necessary by the investigator.
Mode of Administration: intravenous
SUBJECT SELECTION
Targeted Accrual
Approximately 22 adult subjects with severe VWD will be included to have 
≥8 subjects in each cohort (OD and switch). A total of at least 5 type 3 VWD 
subjects will be followed for 12 months.
Number of Groups/
Arms/ Cohorts
Single-group
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Inclusion Criteria
Subjects who meet ALL of the following criteria are eligible for this study:
1. Subject has a documented diagnosis of severe VWD (baseline VWF:RCo <20 IU/dL) with a history of 
requiring substitution therapy with von Willebrand factor concentrate to control bleeding:
a. Type 1 (VWF:RCo <20 IU/dL) or,
b. Type 2A (as verified by multimer pattern), Type 2B (as diagnosed by genotype), Type 2M or,
c. Type 3 (VWF:Ag ≤3 IU/dL).
2. Diagnosis is confirmed by genetic testing and multimer analysis, documented in patient history or at 
screening.
3. For on-demand patient group, subject currently receiving on-demand treatment for whom prophylactic 
treatment is recommended by the investigator.
4. For pdVWF switch patient group, subject has been receiving prophylactic treatment of pdVWF 
products for no less than 12 months prior to screening.
5. For on-demand patient group, subject has ≥3 documented spontaneous bleeds (not including 
menorrhagia) requiring VWF treatment during the past 12 months.
6. Availability of records to reliably evaluate type, frequency and treatment of bleeding episodes during 
at least 12 months preceding enrollment. Up to 24 months of retrospective data should be collected if 
available. Availability of dosing and factor consumption during 12 months (up to 24 months) of 
treatment prior to enrollment is required for pdVWF switch subjects and is desired (but not a 
requirement) for on-demand subjects.
7. Subject is ≥18 years old at the time of screening and has a body mass index ≥15 but <40 kg/m2.
8. If female of childbearing potential, subject presents with a negative blood/urine pregnancy test at 
screening and agrees to employ adequate birth control measures for the duration of the study.
9. Subject is willing and able to comply with the requirements of the protocol.
Exclusion Criteria
Subjects who meet ANY of the following criteria are not eligible for this study:
1. The subject has been diagnosed with Type 2N VWD, pseudo VWD, or another hereditary or acquired 
coagulation disorder other than VWD (e.g., qualitative and quantitative platelet disorders or elevated
prothrombin time (PT)/international normalized ratio [INR] 1.4).
2. The subject is currently receiving prophylactic treatment with more than 5 infusions per week.
3. The subject is currently receiving prophylactic treatment with a weekly dose exceeding 240 IU/kg.
4. The subject has a history or presence of a VWF inhibitor at screening.
5. The subject has a history or presence of a FVIII inhibitor with a titer ≥0.4 Bethesda units (BU) (by 
Nijmegen modified Bethesda assay) or ≥0.6 BU (by Bethesda assay).
6. The subject has a known hypersensitivity to any of the components of the study drugs, such as to 
mouse or hamster proteins.
7. The subject has a medical history of immunological disorders, excluding seasonal allergic 
rhinitis/conjunctivitis, mild asthma, food allergies or animal allergies.
8. The subject has a medical history of a thromboembolic event.
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9. The subject is human immunodeficiency virus (HIV) positive with an absolute Helper T cell 
(CD4) count 200/mm3.
10. The subject has been diagnosed with significant liver disease per investigator’s medical assessment of 
the subject’s current condition or medical history or as evidenced by any of the following: serum 
alanine aminotransferase (ALT) greater than 5 times the upper limit of normal; hypoalbuminemia; 
portal vein hypertension (e.g., presence of otherwise unexplained splenomegaly, history of esophageal 
varices).
11. The subject has been diagnosed with renal disease, with a serum creatinine (CR) level ≥2.5 mg/dL.
12. The subject has a platelet count <100,000/mL at screening.
13. The subject has been treated with an immunomodulatory drug, excluding topical treatment (e.g., 
ointments, nasal sprays), within 30 days prior to signing the informed consent.
14. The subject is pregnant or lactating at the time of enrollment.
15. Patient has cervical or uterine conditions causing menorrhagia or metrorrhagia (including infection, 
dysplasia).
16. The subject has participated in another clinical study involving another investigational product (IP) or 
investigational device within 30 days prior to enrollment or is scheduled to participate in another 
clinical study involving an IP or investigational device during the course of this study.
17. The subject has a progressive fatal disease and/or life expectancy of less than 15 months.
18. The subject is scheduled for a surgical intervention.
19. The subject is identified by the investigator as being unable or unwilling to cooperate with study 
procedures.
20. The subject has a mental condition rendering him/her unable to understand the nature, scope and 
possible consequences of the study and/or evidence of an uncooperative attitude.
21. The subject is in prison or compulsory detention by regulatory and/or juridical order
22. The subject is member of the study team or in a dependent relationship with one of the study team 
members which includes close relatives (i.e., children, partner/spouse, siblings and parents) as well as 
employees.
Delay criteria
1. If the subject presents with an acute bleeding episodes or acute illness (e.g., influenza, flu-like 
syndrome, allergic rhinitis/conjunctivitis, non-seasonal asthma) the screening visit will be postponed 
until the subject has recovered.
STATISTICAL ANALYSIS
Sample Size Calculation
Approximately 22 adult subjects with severe VWD will be included in the study. The aim is to have
≥8 subjects in each cohort (OD and switch). A total of at least five type 3 VWD subjects will be followed 
for 12 months. The sample size is driven by practical considerations (primarily the enrollment of a rare 
patient population) and EMA Guideline on the Clinical Investigation of Human Plasma Derived von 
Willebrand Factor Products (CPMP/BPWG/220/02).1
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Planned Statistical Analysis
The Full Analysis Set (FAS) will be composed of all subjects who receive prophylaxis IP treatment.
The Safety Analysis Set will be composed of all subjects who received any amount of IP  (rVWF, vonicog 
alpha).
The Per-Protocol (PP) Analysis Set will be composed of subjects who are at least 70% compliant regarding 
the number of scheduled prophylactic infusions. Only subjects who meet all study entry criteria and who 
have no major protocol violations that might impact primary efficacy assessments will be included in the 
PP analysis set.
The Pharmacokinetic Full Analysis Set (PKFAS) will be composed of all subjects who received the PK 
infusion and who provided acceptable data for PK and PD analysis. Acceptable PK/PD data will be defined 
in the Statistical Analysis Plan.
Primary Outcome Measure:
No formal statistical hypothesis test is planned for the analysis. Spontaneous ABR while treated with rVWF 
(vonicog alfa) for each cohort, on demand and switch subjects, will be estimated using a negative binomial 
regression. The prior ABR for each cohort will be based on historical data collected from each enrolled 
subject. The two ABRs (observed on the study and historical) will be assessed using a generalized linear 
mixed-effects model (GLMM) with the negative binomial distribution as a family and with a logarithmic 
link function (the default). The ABR ratio together with a two-sided, 95% confidence interval (CI) will be 
reported for each cohort.
The difference in on-study ABR relative to historical ABR will be summarized descriptively.
The primary efficacy analysis will be based on the FAS and will be summarized by the two cohorts: on-
demand and switch subjects. As a supportive analysis, the same analysis will also be carried out on the per-
PP analysis set.
Secondary Outcome Measures:
In general, data for  secondary efficacy analysis will be summarized by the two cohorts: on-demand and 
switch subjects and when applicable overall. Mean, standard deviation, median, range, quartiles will be 
calculated for continuous endpoints. Proportions will be calculated for categorical endpoints. Confidence 
intervals at the 95% level will be provided when appropriate.
Additional efficacy of prophylactic treatment with  rVWF (vonicog alfa):
The number  and proportion of on-demand subjects with ABR percent reduction success (i.e. ≥ 25% ) will 
be calculated together with a two-sided 95% CI for the proportion. 
The number and proportion of pdVWF switch subjects with ABR preservation success will be reported 
together with the corresponding 95% two-sided CIs for the proportion. 
The number and proportion of subjects with categorized spontaneous ABR (i.e. 0, 1-2, 3-5, more than 
5 bleeds) will be reported descriptively.
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Summary statistics for the total number of infusions, as well as average number of infusions per week will 
be provided. The total weight adjusted consumption of rVWF (vonicog alfa) during prophylactic treatment 
will be provided. If applicable, historical data on consumption of pdVWF prior to the study will be 
summarized as well.
The change in spontaneous ABR from the historical rate to that during the rVWF (vonicog alfa)
prophylaxis period will be summarized by location of bleeding (GI, epistaxis, joint bleeding, 
menorrhagia, oral and other mucosa, muscle and soft tissue, etc.).
Pharmacokinetics (PK) and Pharmacodynamics (PD):
The following PK parameters, based on the initial PK assessment after a washout for on-demand subjects, 
will be listed and summarized descriptively for VWF:RCo, VWF:Ag and VWF:CB: IR, T1/2, MRT, 
AUC0-, AUC0-tlast, Cmax, Tmax, Vss, and CL. The corresponding pharmacodynamics (PD) of rVWF 
(vonicog alfa) as measured in FVIII activity (FVIII:C), based on the initial PK assessment after a 
washout for on-demand subjects will be assessed using Cmax, Tmax, and AUC0-tlast. These PD parameters 
will be listed and summarized descriptively. 
PK parameters at steady state (AUC0-tau;ss, Cmax;ss, Tmax;ss, and Cmin;ss) for the partial dosing interval will be 
listed for on-demand subjects at the end of the study and for switch subjects shortly after reaching steady 
state and at the end of the study for VWF:RCo, VWF:Ag and VWF:CB and summarized descriptively for 
subjects with the same dosing regimens. The corresponding pharmacodynamics (PD) of rVWF (vonicog 
alfa) as measured in FVIII activity (FVIII:C) will be assessed using AUC0-tau;ss, Cmax;ss, Tmax;ss, and Cmin;ss. 
These PD parameters will be listed for on-demand subjects at the end of the study and for switch subjects 
shortly after reaching steady state and at the end of the study and will be summarized descriptively for
subjects with the same dosing regimens. 
For the on-demand subjects, the PK of VWF:RCo will be analyzed using a population PK approach to 
characterize the single and multiple dose pharmacokinetics, including associated variability, of VWF:RCo 
in the study population.
For the switch subjects, differences in AUC0-tau;ss, Cmax;ss, and Cmin;ss assessess shortly after reaching steady 
state and assessed at the end of the study will be assessed by ratio of geometric means and corresponding 
two-sided 95% confidence intervals for VWF:RCo, VWF:Ag, VWF:CB, and FVIII:C. The difference in 
Tmax;ss, between first and second pharmacokinetic assessment will be summarized by the median and range 
(minimum to maximum) for VWF:RCo, VWF:Ag,VWF:CB, and FVIII:C.
Descriptive statistics will be used to summarize VWF:RCo, VWF:Ag, VWF:CB, and FVIII:C levels for 
each nominal time point on the PK curve. For all subjects activity/concentration vs. time curves will be 
prepared.
Safety:
Safety analysis will be performed overall and by the two cohorts: on-demand and switch subjects.
Treatment-emergent AEs (TEAEs) are defined as AEs with start dates on or after the first exposure to IP. 
Summaries of AEs will be based on TEAEs unless otherwise indicated.
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Occurrence of AEs and serious AEs (SAEs) will be summarized descriptively, by system organ class and 
preferred term. The number and percentage of subjects who experienced AEs and SAEs, and the number of 
AEs and SAEs will be tabulated. In addition, the number of subjects who experienced AEs assessed as 
related to IP by the investigator, and the number of IP-related AEs will be tabulated. The number of 
patients with AEs by severity will be presented similarly.
A listing of all AEs will be presented by subject identifier, age, sex, preferred term and reported term of the 
AE, duration, severity, seriousness, action taken, outcome, causality assessment by investigator, onset date, 
stop date and medication or non-drug therapy to treat the AE. 
Temporally associated AEs are defined as AEs that begin during infusion or within 24 hours (or 1 day 
where time of onset is not available) after completion of infusion, irrespective of being related or not 
related to treatment. Temporally associated AEs will be presented in summary tables.
Adverse events of special interest (AESI), such as hypersensitivity reactions and thromboembolic events,  
will be monitored throughout the study and statistical analysis will be conducted based on the search 
criteria (eg, standardized MedDRA queries [SMQ]) determined prior to database lock, and summarized.
For immunogenicity analysis frequency counts and proportions will be calculated for subjects with the 
occurrence of neutralizing (inhibitory) antibodies to VWF and FVIII, occurrence of binding antibodies to 
VWF and FVIII, and occurrence of binding antibodies to CHO proteins, mouse immunoglobulin G (IgG) 
and rFurin.
Clinically significant changes relative to baseline in vital signs and clinical laboratory parameters 
(hematology, clinical chemistry) will be reported.
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4. TABLE OF CONTENTS
1. STUDY PERSONNEL.................................................................................................. 2
1.1 Authorized Representative (Signatory) / Responsible Party .............................. 2
1.2 Study Organization................................................................................................. 2
2. SERIOUS ADVERSE EVENT REPORTING........................................................... 3
3. SYNOPSIS..................................................................................................................... 4
4. TABLE OF CONTENTS ........................................................................................... 14
5. LIST OF ABBREVIATIONS .................................................................................... 20
6. BACKGROUND INFORMATION .......................................................................... 24
6.1 Description of Investigational Product ............................................................... 24
6.2 Clinical Condition/Indication .............................................................................. 24
6.3 The Role of Prophylaxis in the Management of VWD...................................... 25
6.4 Populations to be Studied..................................................................................... 27
6.5 Findings from Nonclinical and Clinical Studies................................................. 28
6.5.1 Findings from Nonclinical Studies ............................................................... 28
6.5.1.1 Primary Pharmacodynamics ................................................................. 28
6.5.1.2 Safety Pharmacology.............................................................................. 28
6.5.1.3 Pharmacokinetics.................................................................................... 29
6.5.1.4 Toxicology................................................................................................ 29
6.5.2 Findings from Clinical Studies ..................................................................... 30
6.5.2.1 Study 070701 ........................................................................................... 30
6.5.2.2 Study 071104 ........................................................................................... 32
6.5.2.3 Study 071001 ........................................................................................... 33
6.5.2.4 Study 071101 ........................................................................................... 35
6.5.2.5 Study 071401: Single Subject with von Willebrand Disease............... 37
6.6 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) 
to Human Subjects................................................................................................ 37
6.7 Compliance Statement.......................................................................................... 38
7. STUDY PURPOSE AND OBJECTIVES ................................................................. 39
7.1 Study Purpose ....................................................................................................... 39
7.2 Primary Objective................................................................................................. 39
7.3 Secondary Objectives ........................................................................................... 39
7.4 Exploratory Objectives......................................................................................... 39
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10.2 Subject Identification Code................................................................................ 62
10.3 Screening and Study Visits................................................................................. 62
10.3.1 Screening Visit.............................................................................................. 62
10.3.2 Baseline Visit – Initial PK Assessment (On-demand Subjects Only)...... 63
10.3.3 Prophylaxis Initiation Visit......................................................................... 64
10.3.4 Initial Steady State PK-Assessment (pdVWF switch subjects only)....... 64
10.3.5 Treatment of Bleeding Episodes................................................................. 65
10.3.6 Perioperative Visits (only applicable if surgery is needed)...................... 65
10.3.7 Follow-Up Visits (1 Month ± 1 Week, 2 Months ± 1 Week, 
3 Months ± 2 Weeks, 6 Months ± 2 Weeks, 9 Months ± 2 Weeks post 
Prophylaxis Initiation Visit) ......................................................................... 65
10.3.8 Unscheduled Visits....................................................................................... 67
10.3.9 End of Study PK Assessment and Study Termination Visit 
(12 Months ± 2 Weeks post Prophylaxis Initiation Visit) .......................... 67
10.4 Medications and Non-Drug Therapies.............................................................. 68
10.5 Subject Diary....................................................................................................... 68
10.6 Subject Completion/Discontinuation ................................................................ 69
10.7 Procedures for Monitoring Subject Compliance ............................................. 70
11. ASSESSMENT OF EFFICACY AND PHARMACOKINETICS........................ 71
11.1 Assessment of Spontaneous Bleeding Episodes/Annualized Bleed Rate........ 71
11.2 Evaluation of ABR Before rVWF Prophylaxis and ABR Under rVWF 
Prophylactic Treatment........................................................................................ 72
11.3 Number of Infusions and Total Weight Adjusted Consumption of rVWF and 
ADVATE and historical prophylaxis dosing and factor consumption during 
pdVWF prophylaxis treatment prior to enrollment.......................................... 72
11.4 Assessment of Efficacy for Treatment of Bleeding Episode ........................... 72
11.5 Assessment of Efficacy for Treatment for Surgical Bleeding......................... 73
11.6 rVWF Pharmacokinetics and Pharmacodynamics ......................................... 74
12. ASSESSMENT OF SAFETY................................................................................... 76
12.1 Adverse Events.................................................................................................... 76
12.1.1 Definitions..................................................................................................... 76
12.1.1.1 Serious Adverse Event.......................................................................... 76
12.1.1.2 Suspected Unexpected Serious Adverse Reaction (SUSAR)............. 77
12.1.1.3 Non-Serious Adverse Event ................................................................. 77
12.1.1.4 Unexpected Adverse Events................................................................. 78
12.1.1.5 Preexisting Disease................................................................................ 78
12.1.2 Assessment of Adverse Events.................................................................... 78
12.1.2.1 Severity .................................................................................................. 80
12.1.2.2 Causality................................................................................................ 80
12.1.2.3 Safety Reporting ................................................................................... 81
12.2 Urgent Safety Measures ..................................................................................... 83
12.3 Untoward Medical Occurrences........................................................................ 84
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18. FINANCING AND INSURANCE......................................................................... 111
19. PUBLICATION POLICY...................................................................................... 111
20. SUPPLEMENTS..................................................................................................... 112
20.1 Study Flow Chart.............................................................................................. 112
20.2 Schedule of Study Procedures and Assessments............................................ 113
20.2.1 Summary Schedule of Visit Assesments for Surgical Bleeding............. 117
20.3 Clinical Laboratory Assessments .................................................................... 119
20.3.1 Laboratory Sampling for Surgical Bleeding ........................................... 123
20.4 Contraceptive Methods for Female Subjects of Childbearing Potential..... 125
21. REFERENCES........................................................................................................ 126
22. SUMMARY OF CHANGES.................................................................................. 129
Tables
Table 1 rVWF (vonicog alfa) Dosing Schedule Examples: Schedules A and B............. 47
Table 2 Criteria for Escalation Specific to Each Bleeding Indication............................. 49
Table 3 rVWF:RCo Dosing Recommendations for the Treatment of Bleeding Episodes 
Due to VWD ............................................................................................................. 53
Table 4 Efficacy Rating Scale.......................................................................................... 73
Table 5 Assessment of Hemostatic Efficacy ................................................................... 74
Table 6a Schedule of Study Procedures and Assessments for On-demand Subject...... 113
Table 7 Summary Schedule of Visit Assesments for Surgical Bleeding....................... 117
Table 8a Clinical Laboratory Assessments for On-demand Subject ............................. 119
Table 9 Laboratory Samplinga for Surgical Bleeding................................................... 123
Figures
Figure 1 Study Design for Baxalta Clinical Study 071301............................................ 112
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5. LIST OF ABBREVIATIONS
Abbreviation
Definition
ABR
Annualized bleeding rate
ADAMTS13
A Disintegrin And Metalloproteinase with a Thrombospondin type 1 motif, number 13
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine aminotransferase
AP
Alkaline phosphatase
AST
Aspartate aminotransferase
AUC0-∞
Area under the plasma concentration /time curve from time 0 to infinity
AUC0-tau;ss
Area under the plasma concentration /time curve from time 0 to end of the partial 
dosing interval
AUC0-tlast
Area under the plasma concentration /time curve from 0 to the last measurable 
concentration
aPTT
Activated partial thromboplastin time
B19V
Parvovirus B19
BP
Blood pressure
BU
Bethesda Unit
BUN
Blood urea nitrogen
BW
Body weight
CAM
Cell adhesion molecule
CBC
Complete blood count
CD4
Helper T cell
CHO
Chinese hamster ovary
CI
Confidence interval
Cl
Chloride
CL
Clearance
Cmax
Maximum plasma concentration
Cmax;ss
Maximum plasma concentration during the partial dosing interval at steady state
Cmin;ss
Minimum plasma concentration during the partial dosing interval at steady state
CR
Creatinine
CTA
Clinical Trial Agreement
eCRF
Electronic case report form
DMC
Data monitoring committee
DIC
Disseminated intravascular coagulation
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Abbreviation
Definition
DVT
Deep vein thrombosis
EC
Ethics committee
ECG
Electrocardiogram 
EDC
Electronic Data Capture
EDTA
Ethylenediaminetetraacetic acid
ELISA
Enzyme-linked immunosorbent assay
FAS
Full analysis set
FVIII
Factor VIII
FVIII:C
Factor VIII clotting activity
GCP
Good Clinical Practice
GI
Gastrointestinal
Glu
Glucose
HAMA
Human anti- mouse antibodies
HAV
Hepatitis A virus
HB
Hepatitis B
HBs
Hepatitis B surface
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HEV
Hepatitis E virus
HIV
Human immunodeficiency virus 
HLA
Human leukocyte antigen
HRP
Horseradish peroxidase
IB
Investigator's brochure
ICH
International Council for Harmonisation
Ig
Immunoglobulin
INN
International Nonproprietary Name
INR
International normalized ratio
IP
Investigational product
IR
Incremental recovery
i.v.
Intravenous
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Abbreviation
Definition
K
Potassium
k.o.
Knock out
LDH
Lactate Dehydrogenase
Na
Sodium
NMC
Non-medical complaint
NOAEL
No observed adverse effect level
MRI
Magnetic resonance imaging
MRT
Mean residence time
pdVWF
Plasma derived VWF product
pdVWF/FVIII
Plasma derived VWF product containing fractions of FVIII
PBAC
Pictorial Blood Assessment Chart
PCR
Polymerase Chain Reaction
PEF
Peak expiratory flow
PK
Pharmacokinetic
PKFAS
Pharmacokinetic Full Analysis Set
PKPPAS
Pharmacokinetic Per Protocol Analysis Set
PP
Per protocol 
PT
Prothrombin time
Q1, Q3
Quartile
rFVIII
Recombinant factor VIII
rVWF
Recombinant von Willebrand factor
RBC
Red blood cell count
SAE
Serious adverse event
SAER
Serious adverse event report
SDS-PAGE
Sodium dodecyl sulfate polyacrylamide gel electrophoresis
SIC
Subject identification code
SMQ
Standardised MedDRA queries 
sP-selectin
Soluble P-selectin
SUSAR
Suspected unexpected serious adverse reaction
T1/2
Terminal phase half life
TEAE
Treatment-emergent adverse event
TIA
Transient ischemic attack
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Abbreviation
Definition
Tmax
Minimum time to reach the maximum concentration
Tmax;ss
Minimum time to reach the maximum concentration at steady state
TTP
Thrombotic thrombocytopenic purpura
ULMW
Ultra-large molecular weight 
ULN
Upper limit of normal
Vss
Volume of distribution at steady state
VTE
Venous thromboembolism 
VWD
von Willebrand disease
VWF
Von Willebrand factor
VWF:Ag
Von Willebrand factor antigen
VWF:CB
Von Willebrand Factor collagen binding
VWF:RCo
Von Willebrand factor: Ristocetin cofactor activity
WBC
White blood cell
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6. BACKGROUND INFORMATION
6.1 Description of Investigational Product
Baxalta US Inc. (hereafter referred to as Baxalta or sponsor) has developed a human 
recombinant von Willebrand Factor (rVWF, vonicog alpha), which is co-expressed with 
recombinant factor VIII (rFVIII) in a Chinese hamster ovary (CHO) cell line and
separated during the subsequent downstream process. To address concerns regarding the 
risk of transmission of blood-borne pathogens that may be introduced by human plasma, 
no exogenously added raw materials of human or animal origin are employed in the cell 
culture, purification, or formulation of the final container product. The only proteins 
present in the final container product other than rVWF (vonicog alfa) are trace quantities 
of murine immunoglobulin (IgG, from the immunoaffinity purification), host cell (i.e., 
CHO) protein, rFurin (used to further process rVWF). rVWF (vonicog alfa) is intended 
for the treatment of von Willebrand disease (VWD).
rVWF (vonicog alfa) has been developed under the Baxalta internal code BAX111 and is 
used as investigational product (IP) in this study. rVWF (vonicog alfa) may be used with 
or without ADVATE (rFVIII, octocog alfa) for the treatment of bleeding episodes (see 
Section 8.6.4.4). See Section 8.6 for further information on the IPs and their usage in this 
study. A detailed description of rVWF (vonicog alfa) is also provided in the
Investigator’s Brochure (IB).
rVWF (vonicog alfa) was granted licensure in the United States in December 2015 under 
the brand name VONVENDI for the on-demand treatment and control of bleeding 
episodes in adults diagnosed with VWD; as of the date of this protocol VONVENDI is
not yet available on the market.
6.2 Clinical Condition/Indication
Von Willebrand Factor (VWF) is a large multimeric glycoprotein with a molecular 
weight that varies from 500 to 20,000 kDa. VWF is normally found in plasma and 
produced in the alpha-granules of platelets and in endothelial cell organelles known as the 
Weibel-Palade bodies. VWF mediates platelet adhesion and aggregation at sites of 
vascular injury, one of the key functions in primary hemostasis. VWF also serves to 
stabilize coagulation factor VIII (FVIII), where FVIII is an essential cofactor of 
secondary hemostasis, which leads to fibrin clot formation.2 Qualitative and/or 
quantitative deficiencies of VWF lead to a highly variable bleeding diathesis known as 
VWD, the most common of the hereditary coagulation factor deficiencies. Penetrance of 
VWD is highly variable, with only a small fraction of mildly affected patients displaying 
clinical symptoms or a family history of a bleeding diathesis.
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The current biochemical-based classification distinguishes disorders arising from partial 
quantitative (type 1), qualitative (type 2), or virtually complete (type 3) deficiencies of 
VWF. Up to 70% of VWD patients are diagnosed with type 1 VWD, which may also be 
associated with minor functional defects in the molecule. In general, patients with type 1 
VWD display mild clinical symptoms. Approximately 20 to 30% of VWD patients are 
diagnosed with type 2 VWD. Type 2 VWD is further divided into 4 subtypes (A, B, N, 
and M), reflecting distinct classes of functional abnormalities. These defects result in 
abnormal functional and/or multimeric distribution patterns that facilitate their diagnosis. 
The bleeding diathesis is usually moderate and primarily affects the mucosal tissues. 
Type 2N VWD patients are sometimes misdiagnosed as mild hemophilia A. Finally, 
approximately 1% percent of VWD patients exhibit a total or near total absence of VWF, 
which is classified as type 3 VWD. The incidence of type 3 VWD is estimated at 
0.5-1.0 x 106. This type is also associated with a very low FVIII level (typically <5%) 
because the VWF carrier function for FVIII is lost. Replacement of VWF alone stabilizes 
endogenous FVIII, resulting in hemostatic levels within several hours post-infusion. 
Published results from studies of a plasma-derived VWF (pdVWF) concentrate 
demonstrated an increase of FVIII at an approximate rate of 5.8 1 IU dL-1 h-1.3 Type 3 
VWD patients display severe hemorrhagic symptoms with bleeding predominantly in 
mucosal tissues, muscle and joints. All VWD patients, particularly those with type 2 or 
type 3 VWD, are at an increased risk for life-threatening bleeding episodes.
6.3 The Role of Prophylaxis in the Management of VWD
The goals of long term prophylaxis in VWD are to maintain VWF and FVIII at sufficient 
levels to reduce the frequency and duration of bleeding episodes, the need for red blood 
cell transfusions, and the risk of complications, such as arthropathy.4 In contrast to 
hemophilia, routine prophylaxis is not as established in VWD, although prophylaxis for 
patients with severe VWD was in use in Sweden already during the 1950s.5 In those early 
days of VWD treatment, plasma FVIII concentrates containing VWF fractions were 
applied for replacement therapy, which then were followed by plasma derived VWF 
products containing fractions of FVIII (pdVWF/FVIII). 
A Swedish cohort including 37 patients with type 3 VWD under prophylactic median 
treatment of 11 years (range 2 to 45 years) was retrospectively analyzed.6,7 The 
doses used for prophylaxis, given once weekly for at least 45 weeks per year, were 
calculated based on 12 to 50 IU/kg body weight (BW) of FVIII clotting activity (FVIII:C)
which approximately corresponded to 24-100 IU/kg von Willebrand factor: Ristocetin 
cofactor activity (VWF:RCo) considering that mainly Haemate with a known 
VWF:RCo/FVIII:C ratio of about 2 was used. An escalation of doses from 1 to 3 dose 
levels was allowed depending on the frequency and severity of bleeding episodes. 
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The results demonstrate that under long-term prophylaxis the number of bleeds could be 
reduced dramatically. Whereas the median value for bleeds per year was about 10 before 
prophylaxis this value could be reduced to less than 1 bleed per year during prophylaxis.
The benefit of prophylaxis for such indications was retrospectively also demonstrated in a 
cohort of Italian patients including type 3, 2A, 2M and type 1 patients. Prophylaxis was 
started after severe gastrointestinal or joint bleeding episodes and completely prevented 
bleeding episodes in 8 of these 11 patients and largely reduced the need of blood 
transfusions in the remaining 3. A regimen of 40 IU rVWF:RCo/kg was applied every 
other day or twice a week. A prospective study on prophylaxis, the PRO.WILL study, has 
been initiated in Italy.8
The results of a prospective study investigating the prophylaxis in children and young 
adults showed a significantly reduced bleeding frequency and bleeding score (3 vs. 0.07; 
3 vs. 0. p<0.001) compared to the pre-prophylaxis values. The median dose was 
40 (20-47) IU/kg VWF:RCo administered mainly twice weekly in 23 patients, 3 times a 
week in 7 patients and 4 times a week in 2 children.9
The VWD Prophylaxis Network initiated the VWD International Prophylaxis (VIP) trial 
to investigate the role of prophylaxis in patients with severe VWD including Type 1, 2,
and 3. The dose of the factor replacement product was 50 IU /kgVWF:RCo. The 
frequency of the dose depended on the type of bleeding and could be increased from once 
weekly to twice weekly or 3 times per week. For the treatment of menorrhagia the dose of 
50 IU/kg VWF:RCo was given on the first day of menses for 2 cycles. The frequency 
could be increased to Day 1 and 2 for 2 cycles or to Day 1, 2, and 3 of menses.
The study contains both retrospective and prospective study components. Results from 
the retrospective study component were published, including 61 subjects on prophylactic 
regimen in the past 6 months prior to enrollment or subjects with a history of prophylaxis 
over at least 6 month.10 Differences in annualized bleeding rates (ABR) within 
individuals (during prophylaxis – before prophylaxis) were significant for those with 
primary indications of epistaxis (P = 0.0005), joint bleeding (P = 0.002) and GI bleeding 
(P = 0.001). The difference in the group whose primary indication for treatment was 
abnormally heavy bleeding at menstruation (n = 4) was not significant (P = 0.25). The 
reduction of mucosal bleeding likely not only dependents on normal circulating levels of 
active VWF, but also on the presence of discrete concentrations of normal VWF inside 
the platelets and within endothelial matrices. The low subject number (n=4) and the 
treatment scheme for menorrhagia on Days 1, 2, and 3 of menses which might represent 
rather on-demand than prophylactic treatment may also account for the outcome in this 
study.
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Results from the prospective study component were reported recently.11 Eleven subjects 
completed the study. Six subjects had type 2A, and 5 subjects had type 3 VWD. 
Six subjects presented with epistaxis, 3 with GI bleeding, and 2 with joint bleeding. 
Seven subjects had dose escalation above the first level. Among the 10 subjects with 
evaluable bleeding log data, the use of prophylaxis decreased the median ABR from 25 to 
6.1 (95% confidence interval [CI] of the rate difference: -51.6 to -1.7), and the median 
ABR was even lower (4.0; 95% CI: -57.5 to -5.3) when the subjects reached their final 
dosing level. The authors concluded that this was the first prospective study to 
demonstrate that prophylaxis with VWF concentrates is highly effective in reducing 
mucosal and joint bleeding rates in clinically severe VWD.
The results of the VIP study and previous investigations suggest that VWD patients with 
recurrent bleeding episodes and severe menorrhagia will benefit from a prophylactic 
VWF replacement therapy. There is evidence that up to 40% of patients with type 3 
VWD experience joint bleeding which can lead to hemophilic arthropathy. Other 
potential indications for prophylaxis include patients with type 2A or 2B VWD with 
recurrent gastrointestinal bleeding, menorrhagia or frequent epistaxis.4 Long-term 
prophylaxis for most patients with type 3 VWD and in some patients with type 1 or 
2 VWD, depending on the pattern of bleeding, may be the treatment option of choice.
Although the main experience with long-term prophylaxis is with secondary prophylaxis, 
primary prophylaxis starting at young age is recommended to prevent arthropathy in 
patients with severe VWD.12
However, further studies are needed to develop evidence-based guidelines for 
prophylactic treatment in VWD.
6.4 Populations to be Studied
A total of approximately 22 eligible, adult subjects with severe VWD (baseline 
VWF:RCo <20 IU/dL) are planned to be enrolled. Two cohorts of patients will be 
included: patients currently receiving on-demand VWF treatment (OD subjects) and 
patients currently on prophylactic treatment with pdVWF (pdVWF switch subjects), and 
the aim is to have ≥8 subjects in each of the 2 cohorts, with a total of at least 5 type 3 
VWD subjects followed for 12 months. Enrolled subjects (i.e., subjects who have signed 
the informed consent form) will be eligible to participate in the study if they meet all of 
the inclusion criteria (see Section 9.1) and none of the exclusion criteria (see Section 9.2).
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6.5 Findings from Nonclinical and Clinical Studies
The following summarizes the key findings from relevant nonclinical studies as well as 
from the completed clinical studies 070701 (Phase 1 pharmacokinetics [PK] and safety in 
VWD), 071001 (Phase 3 safety and efficacy in the treatment of bleeding episodes in 
VWD), 071101 (Phase 3 efficacy and safety in VWD subjects undergo elective surgical 
procedures), 071104 (Phase 1 safety and PK in hemophilia A), and 071401 (Phase 3, 
expanded access in a single subject with VWD). Potential risks and efficacy of rVWF 
(vonicog alfa):ADVATE (rFVIII, octocog alfa) are summarized in the following sections. 
For additional information on nonclinical and clinical Phase 1 results refer to the rVWF 
(vonicog alfa) IB.
6.5.1 Findings from Nonclinical Studies
6.5.1.1 Primary Pharmacodynamics
Efficacy of rVWF (vonicog alfa) combined with ADVATE (rFVIII, octocog alfa) was 
shown in VWD animal models, which have also low endogenous FVIII levels. Time to 
occlusion and stable thrombus formation was assessed in the carotid occlusion model in 
VWD mice. The results demonstrated that rVWF (vonicog alfa) in combination with 
ADVATE (rFVIII, octocog alfa) acted efficiently in a dose-dependent manner and had 
higher efficacy than rVWF (vonicog alfa) alone or plasma derived (pd)VWF. These 
results were confirmed in an additional study assessing blood loss and survival in a tail 
tip bleeding model in VWD mice. In a VWD dog, rVWF (vonicog alfa) stabilized canine 
FVIII in the circulation and significantly reduced the bleeding time.
6.5.1.2 Safety Pharmacology
The anaphylactoid and thrombogenic potential of the co-infusion of ADVATE (rFVIII, 
octocog alfa) and rVWF (vonicog alfa) and the co-infused product’s effects on blood 
pressure, cardiac and respiratory function and parameters of coagulation activation were 
investigated in 4 in vivo studies in different animal models. Safety pharmacology studies 
in rats, guinea pigs, rabbits, and dogs revealed no risks for anaphylactoid and 
thrombogenic potential of ADVATE (rFVIII, octocog alfa) in combination with rVWF 
(vonicog alfa). All observations in safety pharmacology studies are considered to lie 
within the biological variability of animal models or occurred due to known species-
specific anaphylactoid effects of excipients.
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6.5.1.3 Pharmacokinetics
Pharmacokinetic studies of both rVWF (vonicog alfa) alone and combined with human 
rFVIII (rVWF+ADVATE) were conducted in VWD mice, VWD dogs, VWD pigs, rats,
and cynomolgus monkeys. Human rVWF (vonicog alfa) stabilized the endogenous FVIII 
in VWD mice, VWD pigs, and VWD dogs. Furthermore, the hypotheses that the area 
under the curve (AUC) with rVWF alone and rVWF+ADVATE is not inferior to the 
AUC with pdVWF (Haemate P) was tested and confirmed statistically in normal rats.
The PK characteristics of ADVATE (rFVIII, octocog alfa) were not affected by co-
administration of rVWF (vonicog alfa) in cynomolgus monkeys. The PK data in the 
FVIII knock out (k.o.) mice model are inconclusive and might not be relevant for the 
clinical situation. However, a stabilizing effect of VWF on FVIII could be shown in a 
double k.o. model in a dose dependent manner.
6.5.1.4 Toxicology
Single dose toxicity studies were conducted in C57BL/6J-mice, VWD mice, rats, rabbits,
and cynomolgus monkeys. Rats, rabbits, and cynomolgus monkeys showed no signs of
toxicity. Signs of microthrombosis, an exaggerated pharmacological effect, were
observed in mice. Mice are not capable of sufficiently cleaving the rVWF (vonicog alfa)
subunit as murine disintegrin and metalloproteinase with a thrombospondin type 1 motif, 
number 13 (ADAMTS13) does not decrease the ultra-large molecular weight multimers 
of rVWF (vonicog alfa).13 The observed symptoms of microthrombosis are interpreted as 
a species-specific exaggerated pharmacological effect. Studies evaluating the safety of 
repeated administration of rVWF (vonicog alfa) with or without ADVATE (rFVIII, 
octocog alfa) (daily over 14 days) were performed in a rodent (rat) and non-rodent 
(cynomolgus monkey) species. Reversible signs of exaggerated pharmacological effects 
(regenerative anemia, thrombocytopenia, and treatment-related histopathologic changes 
in the heart, liver, and spleen) were observed in rats that were administered 1400 U 
VWF:RCo/kg /day + 1080 IU ADVATE/kg/day intravenously once daily for 14 days. 
Also, these findings are interpreted as a species-specific exaggerated pharmacological 
effect due to the low susceptibility of human rVWF (vonicog alfa) to cleavage by rodent 
ADAMTS13.13 No toxicologically relevant changes were evident for clinical 
observations, body weight, feed consumption, ophthalmology, urinalysis, coagulation,
and serum chemistry parameters, platelet aggregation, and gross pathology. rVWF 
(vonicog alfa) combined with ADVATE (rFVIII, octocog alfa) was well tolerated in 
cynomolgus monkeys after daily intravenous (i.v.) (bolus) administration of 100 U 
VWF:RCo/kg rVWF (vonicog alfa) combined with 77 IU/kg ADVATE (rFVIII, octocog 
alfa) over a period of 14 days. No adverse effects could be detected in this species. 
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There were no signs of hemolysis, thrombosis, or thrombocytopenia after repeated 
intravenous application of rVWF (vonicog alfa) with or without ADVATE (rFVIII, 
octocog alfa). Therefore, 100 U VWF:RCo/kg/day rVWF (vonicog alfa) with or without 
77 IU/kg ADVATE (rFVIII, octocog alfa) was considered the no observed adverse effect 
level (NOAEL) in this study, which was the highest dose tested. Anti-drug antibodies, 
however, were formed in both species and resulted in a significant reduction in drug 
exposure after 14 applications as compared to a single application. These antibodies 
substantially reduced the systemic exposure to the test substance as compared to a single 
dose administration. No adverse effects due to antibody formation were observed in both 
species.
rVWF (vonicog alfa) combined with ADVATE (rFVIII, octocog alfa) was well tolerated 
locally and no genotoxic potential was evident after 2 in vitro and 1 in vivo genotoxicity 
study. A study on the influence of co-administration of VWF and ADVATE (rFVIII, 
octocog alfa) on the immunogenicity of ADVATE (rFVIII, octocog alfa) in 3 different 
hemophilic mouse models (E17 hemophilic Balb/c mice, E17 hemophilic C57BL/6J 
mice, and E17 hemophilic human F8 transgenic mice) showed that rVWF (vonicog alfa)
does not negatively impact the immunogenicity of ADVATE (rFVIII, octocog alfa) in 
any of the three different hemophilic mouse models.
6.5.2 Findings from Clinical Studies
The clinical safety, efficacy and PK were assessed in 4 completed trials: one phase 1 
study (070701)) and two phase 3 studies (071001 and 071101) that enrolled patients with 
VWD; one phase 1 study (071104) that enrolled patients with hemophilia A. Details on 
study design, populations enrolled, and safety and efficacy outcomes of the phase 1
studies are presented in Section 6.5.2.1 and Section 6.5.2.2, the phase 3 study in 
Section 6.5.2.3, and the phase 3 surgery study in Section 6.5.2.4. Information on a single 
subject with VWD in Study 071401 is presented in Section 6.5.2.5.
6.5.2.1 Study 070701
Phase 1 clinical study 070701 was a multicenter, controlled, randomized, single-blind,
prospective 3-step, dose escalation study to investigate safety, tolerability, and PK of 
rVWF (vonicog alfa) combined at a fixed ratio with ADVATE (VWF:RCo/FVIII:C of 
1.3 ± 0.2:1) in adults with severe VWD.14 Subjects were enrolled in sequential cohorts in 
a dose escalating manner: Cohort 1, 2, and 3 received a single intravenous infusion of 
rVWF:ADVATE at the following doses: 2 IU/kg VWF:RCo (Cohort 1), 7.5 IU/kg 
VWF:RCo (Cohort 2), and 20 IU/kg VWF:RCo (Cohort 3). Subjects in Cohort 4 received 
a single intravenous infusion of rVWF:ADVATE and pdVWF/ADVATE at 50 IU/kg 
VWF:RCo in random order.
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The primary endpoint was the tolerability and safety after single dose injections of 
rVWF:ADVATE at 2, 7.5, 20, and 50 IU/kg VWF:RCo for up to 30 days after the last IP 
infusion. The data generated in this phase 1 study suggest that rVWF:ADVATE up to the 
highest investigated dose of 50 IU/kg VWF:RCo is well tolerated and safe in adults with 
severe VWD. No thrombogenic risk or thrombotic thrombocytopenic purpura (TTP)-like 
syndrome was observed, and no neutralizing antibodies to VWF or FVIII were identified. 
There were no deaths or other serious adverse reactions, and no infusions were 
interrupted or stopped due to an AE. Overall, the reported AE profile was similar 
between the recombinant and plasma-derived concentrates.
Secondary endpoints were the PK assessment of VWF:RCo, von Willebrand factor 
antigen (VWF:Ag) and multimeric composition of rVWF (vonicog alfa) as well as 
FVIII:C at standardized time points after single injections of rVWF:ADVATE and 
pdVWF:FVIII. 
The median VWF:RCo terminal half-life (T1/2) of rVWF (vonicog alfa) at the 50 IU/kg 
dose was 16 hours. T1/2 with pdVWF:FVIII at the same dose level appeared shorter at 
12.58 hours, however, the limits of the 90% CI were similar (11.73 to 17.7 hours vs. 
11.87 to 18.03 hours). The median T1/2 of VWF:RCo were shorter with the lower 
investigated doses: 7.13 hours and 13.23 hours with the 7.5 IU/kg and 20 IU/kg doses, 
although these data were derived from a much smaller number of subjects.
In consequence of the missing ADAMTS13 cleavage, ultra-large molecular weight 
(ULMW) multimers are contained in the rVWF (vonicog alfa) final product. The 
immediate cleavage of these ultra-large multimers by ADAMTS13 upon release into the 
circulation could be demonstrated applying sodium dodecyl sulfate polyacrylamide gel 
electrophoresis (SDS-PAGE)/Immunoblot with polyclonal anti-VWF antibodies to detect 
the resulting rVWF (vonicog alfa) subunit cleavage fragments.
Overall the data generated in this phase 1 study suggest that rVWF (vonicog 
alfa):ADVATE (rFVIII, octocog alfa) is well tolerated and safe in adults with severe 
VWD.
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6.5.2.2 Study 071104
This study was a prospective, uncontrolled, non-randomized, multicenter proof of 
concept study to assess safety and PK of the addition of rVWF (vonicog alfa) to 
ADVATE (rFVIII, octocog alfa) treatment in 12 evaluable subjects with severe 
hemophilia A. All subjects underwent 3 PK analyses: the first after infusion with 
ADVATE (rFVIII, octocog alfa) alone, the second after infusion with ADVATE (rFVIII, 
octocog alfa) plus 10 IU/kg rVWF (vonicog alfa) and the third after infusion with 
ADVATE (rFVIII, octocog alfa) plus 50 IU/kg rVWF (vonicog alfa).
The PK analysis was performed at intervals of approximately 8 to 14 days. Before each 
infusion for PK assessment, there was a wash-out period of at least 5 days and the 
subjects were not actively bleeding. 
Primary outcome measures indicate that co-administration of rVWF (vonicog alfa)
slightly sustain ADVATE activity with the highest observed ADVATE (rFVIII, octocog 
alfa) half-life of 13.74 h (CI 11.44 to 16.52) after co-infusion of 50 IU/kg ADVATE plus 
50 IU/kg rVWF:RCo.
The highest improvement in ADVATE (rFVIII, octocog alfa) circulating half-life was 
observed in subjects with VWF:Ag levels below 100% which indicates an association 
between baseline VWF:Ag levels and ADVATE (rFVIII, octocog alfa) half-life increase. 
No treatment related AEs or SAEs were reported. No subject withdrew due to an AE and 
there were no deaths. No binding antibodies to VWF, CHO, and rFurin were detectable in 
the confirmatory assay and no signs of a hypersensitivity to rVWF (vonicog alfa) or 
ADVATE (rFVIII, octocog alfa) antigen were observed. Laboratory values over time did 
not indicate any potential safety risk for hemophilia A patients treated with rVWF 
(vonicog alfa) and ADVATE (rFVIII, octocog alfa) in combination.
In summary, the data indicate that rVWF (vonicog alfa) co-administered with ADVATE 
(rFVIII, octocog alfa) up to the highest dose of 50 IU/kg VWF:RCo is well tolerated and 
safe in hemophilia A patients. 
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6.5.2.3 Study 071001
This was a phase 3, multicenter, open-label, part-randomized clinical study to assess the 
PK, safety, and efficacy of rVWF:rFVIII and rVWF in the treatment of bleeding episodes 
in adult subjects with severe type 3 and severe non-type 3 VWD.15 A total of 49 subjects 
were enrolled (signed informed consent) and screened, 18 subjects were randomized 
(randomization only applies to Arm 1[PK50 with treatment of BE] and Arm 2 [PK50
only] see below), 37 subjects were treated with IP (all study arms), and 30 subjects 
completed the study.
The study consisted of 2 parts (Part A and Part B). Part A consisted of PK assessments 
alone (Arm 2: PK50 only [without treatment of bleeding episodes]), or PK assessments 
(Arm 1: PK50 and Arm 3: PK80) plus on-demand treatment period(s) of 6 months for 
bleeding episodes, or on-demand treatment for bleeding episodes only (Arm 4). Except 
for subjects in arm 2 who completed study after second PK assessment, subjects  
receiving treatment for PK assessments and/or bleeding episodes in Part A were to be 
entered into Part B to continue on-demand treatment for bleeding episodes for 
6 additional months for a total of 12 months in the study. 
The primary outcome measure was the number of subjects with “treatment success” 
(extent of control of bleeding episodes), which was defined as a mean efficacy rating 
score of <2.5 for a subject’s IP-treated bleeding episodes during the study. The rate of 
subjects with treatment success was 100% (Clopper-Pearson exact 90% CI: 84.7 to 
100.0) for bleeds where the assessments were made prospectively and excluding GI 
bleeds. Sensitivity analyses confirmed the results of the primary analysis.
Crossover results at 50 IU/kg VWF:RCo showed that the PK profile for rVWF (vonicog 
alfa) VWF:RCo was independent of administration alone or with rFVIII (ADVATE, 
octocog alpha) (T1/2: 19.4 hours for rVWF and 16.6 hours for rVWF:rFVIII; IR: 1.8 U/dL 
per IU/kg infused for both rVWF and rVWF:rFVIII; mean residence time (MRT): 
26.7 hours for rVWF and 25.2 hours for rVWF:rFVIII). FVIII levels increased 
substantially with a median peak at 24 hours of 111.0 U/dL for rVWF:rFVIII and 
86.0 U/dL after rVWF alone, indicating that rVWF (vonicog alfa) induces a sustained 
increase in endogenous FVIII activity. The rVWF (vonicog alfa) PK profile was 
comparable at 50 IU/kg and 80 IU/kg VWF:RCo, and repeated PK at 80 IU/kg 
VWF:RCo showed close agreement between pretreatment and end-of-study results.
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Further analysis of the PK data from the 071001 study supports the initial use of 50 IU/kg 
twice weekly for prophylaxis dosing in the present study for those subjects who are 
moving from on-demand to prophylaxis. Using 50 IU/kg for PK measurements, subjects 
in the 071001 study exhibiting a T1/2 for rVWF of 14, 16, or 19 hours had rVWF plasma 
concentrations at 72 hours after administration of 2.55, 4.01, and 6.49% above baseline, 
respectively, and plasma concentrations at 96 hours after administration of 0.78, 1.40, and 
2.71% above baseline, respectively. In this context it should be noted that subjects in the 
present study who have significant spontaneous bleeding while on twice weekly
prophylaxis will have their regimen increased to 3 times per week based on clear criteria 
for different bleeding locations (for details see Section 8.6.4.3.1). Subjects in the present 
study who are switching from prophylaxis with a pdVWF product will begin on rVWF 
(vonicog alfa) using their same weekly total dose in IU/kg VWF:RCo used during their 
pdVWF prophylaxis divided into twice weekly infusions (for details see section 8.6.4.3).
A total of 125 AEs occurred in 25/37 (67.7%) subjects (62/318 infusions [19.5%]) during 
or after infusion with IP. Of these, 116/125 were non-serious (all mild or moderate; none 
were severe), and 9 SAEs were reported in 7 subjects. Of 125 total AEs, 38 were 
temporally associated with IP; 8 AEs were considered causally related to IP: 
6 non-serious related AEs (tachycardia, infusion site paraesthesia, electrocardiogram 
[ECG] t-wave inversion, dysgeusia, generalized pruritis, and hot flush) occurred in 
4 subjects, and 2 related SAEs (chest discomfort and increased heart rate) occurred in 
1 subject. No deaths occurred during this study. 
None of the subjects developed anti-VWF or anti-FVIII neutralizing antibodies and no 
binding antibodies to VWF or rFurin, or antibodies against CHO protein or anti-Murine 
IgG were observed. No clinical or subclinical signs or symptoms of a thrombogenic event 
were observed in this study. Following an initial increase in ultralarge VWF multimers 
after administration of rVWF (vonicog alfa), a notable decrease in the proportion of large 
VWF multimers occurred between 12 and 24 hours post infusion, due to degradation by 
the endogenous ADAMTS13 followed by a continued decline until the end of the 96-hour 
follow-up period. 
Overall, the data support the safe and effective use of rVWF (vonicog alfa) with or 
without rFVIII (ADVATE, octocog alpha) in the treatment of bleeds in patients with 
VWD.
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6.5.2.4 Study 071101
This was a phase 3, prospective, open-label, multicenter clinical study to evaluate 
efficacy and safety of rVWF (vonicog alfa) with or without ADVATE (rFVIII, octocog 
alfa) in elective surgical procedures in adult subjects with severe VWD. A total of 
24 subjects were enrolled (signed informed consent) and screened, 15 subjects were 
treated with rVWF (vonicog alfa), and 15 subjects completed the study. 
Eleven subjects underwent a PK assessment by infusion of 50 ± 5 IU/kg rVWF:RCo at an 
infusion rate of up to 4 mL/min. 12 to 24 hours before surgery, subjects received a dose 
of 40 to 60 IU/kg rVWF:RCo. Within 3 hours prior to surgery, the subject’s FVIII:C 
levels were assessed with a target of 30 IU/dL for minor and oral surgeries and 60 IU/dL 
for major surgeries. Within 1 hour prior to surgery, subjects received a dose of rVWF 
(vonicog alfa) with or without ADVATE (rFVIII, octocog alfa) (depending on the target 
FVIII:C levels at the 3 hour assessment). VWF and FVIII IR and T1/2 for each subject, 
when known, were used to guide the initial dose and subsequent doses.
The primary outcome measure was the overall assessment of hemostatic efficacy assessed 
by the investigator (hemophilia physician) 24 hours after last perioperative IP infusion or 
at completion of day 14 visit, whichever occurred earlier, and was summarized by the 
percentage of subjects in each efficacy category (“excellent”, “good”, “moderate” and 
“none”). Point estimate and corresponding 90% two-sided exact CI was calculated for the 
rate of subjects with an overall assessment of hemostatic efficacy. All 15 subjects treated 
with rVWF (vonicog alfa) (with or without ADVATE) for major (10), minor (4), and oral 
(1) elective surgical procedures had overall hemostatic efficacy ratings of “excellent” or 
“good”. Most (73.3%) subjects had “excellent” overall hemostatic efficacy ratings; of 
these, 7 underwent major surgery and 4 underwent minor surgery. The remaining 26.7% 
subjects had “good” overall hemostatic efficacy ratings: 3 underwent major surgery and 
1 underwent oral surgery. All 8 subjects with VWD Type 3, the subtype classified as 
absolute VWF deficiency, had overall hemostatic efficacy ratings of “excellent” (87.5%) 
or “good” (12.5%).
Intraoperative hemostatic efficacy ratings were also rated as “excellent” or “good” for all 
15 treated subjects. Most (86.7%) subjects had “excellent” intraoperative hemostatic 
efficacy ratings; of these, 8 underwent major surgery, 4 underwent minor surgery, and 
1 underwent oral surgery. Two (13.3%) subjects who underwent major surgery had 
“good” intraoperative hemostatic efficacy ratings. Intraoperative hemostatic efficacy 
was rated as “excellent” or “good” for all subjects with VWD Type 3: “excellent” for 
7 (87.5%) subjects and “good” for 1 (12.5%) subject. 
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Only 1 subject received an intraoperative dose of rVWF (18.1 IU/kg) and ADVATE 
(8.1 IU/kg). The median daily postoperative weight-adjusted dose of rVWF (vonicog 
alfa) (with or without ADVATE) was 23.5 IU/kg on postoperative Day 1 (n=3) and 
25.5 IU/kg on postoperative Day 14 (n=2). In subjects treated with rVWF:ADVATE, the 
daily postoperative weight-adjusted dose was 16.9 IU/kg rVWF and 7.6 IU/kg ADVATE 
on postoperative Day 1 (n=1) and decreased to 50.8 IU/kg rVWF and 7.6 IU/kg
ADVATE on postoperative Day 7 (n=1). For subjects treated with rVWF alone, the 
median weight-adjusted dose (Q1, Q3) of rVWF was 35.4 IU/kg on postoperative Day 1 
(n=2) and decreased to 23.7 IU/kg on postoperative Day 7 (n=4) and 25.5 IU/kg on 
postoperative Day 14 (n=2).
A total of 11 subjects were evaluated for PK in the study. As expected, postinfusion 
increases in concentrations of VWF:RCo, VWF:Ac, VWF:Ag, and VWF collagen 
binding (VWF:CB) were observed. Mean values for VWF:RCo were as follows: 
AUC0-∞/dose was 37.50 hours*IU/dL per IU/kg infused; AUC0-72h/dose was 
34.08 hours*IU/dL per IU/kg infused; T1/2 was 17.83 hours; MRT was 24.32 hours; 
CL was 0.03117 dL/hour/kg; and volume of distribution at steady state (Vss) was 
0.6837 dL/kg. Median values for VWF:RCo were as follows: AUC0-∞/dose was 
32.94 hours*IU/dL per IU/kg infused; AUC0-72h/dose was 31.70 hours*IU/dL per IU/kg 
infused; T1/2 was 14.62 hours; MRT was 21.80 hours; CL was 0.03036 dL/hour/kg; and 
Vss was 0.7078 dL/kg. The VWF:RCo activity was consistent with that previously 
observed in clinical studies 071001 and 070701.
rVWF (vonicog alfa) was safe and well tolerated in adults with severe VWD undergoing 
major, minor, and oral elective surgical procedures. Of the 12 total treatment-emergent 
AEs (TEAEs) that occurred during the study, 2 deep vein thrombosis events (1 non-
serious and 1 serious, as a part of one case) reported in one subject, who underwent total 
hip replacement surgery and who had concurrent condition of obesity, was assessed by 
the sponsor as possibly causally-related to study treatment. None of the TEAEs were 
either a severe allergic or hypersensitivity reaction or developed due to a severe allergic 
reaction. 
One subject with VWD Type 3 who had an intraoperative transfusion of packed red 
blood cells during total knee replacement surgery tested positive for binding antibodies to 
VWF on postoperative Day 7 through study completion. No subjects developed 
neutralizing antibodies to rFVIII or binding antibodies to CHO, rFurin, or murine IgG.
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In summary, the data support the safe and effective use of rVWF (vonicog alfa) with or 
without ADVATE (rFVIII, octocog alfa) in achieving intra- and post-operative 
hemostasis in adult subjects with severe VWD undergoing major, minor, and oral elective 
surgical procedures.
6.5.2.5 Study 071401: Single Subject with von Willebrand Disease
One subject who exhibited allergic reactions to currently marketed pdVWF products was 
treated in the single-subject study 071401 with rVWF (vonicog alfa) only for the bleed 
treatment of continued hematuria, and for biopsy and surgical resection of a left-kidney 
mass.
For the initial rVWF (vonicog alfa) infusion, the subject received a test dose of 5% of 
the total dose of 60 IU/kg rVWF:RCo at an infusion rate of 1 mL/min. After a 10 to 
15-minute observation period, no adverse symptoms or signs were noted and the subject 
received the remaining 95% of the total dose. The subject was monitored for any signs of 
an allergic reaction, and none were noted. Treatment with rVWF (vonicog alfa) every 
12 to 24 hours was to continue at the discretion of the investigator based on VWF levels 
and clinical symptomatology. The subject had an excellent response and recovery, which 
allowed for daily dosing of rVWF (vonicog alfa) and, within 24 hours, the subject’s 
bleeding had stopped. Daily dosing of rVWF (vonicog alfa) was maintained and the 
subject received his last dose on 
.
The subject also received rVWF (vonicog alfa) for 7 days for prophylaxis for surgery 
(surgical resection of a left-kidney mass). The subject experienced no hemorrhagic 
complications and no AEs that were considered related to the use of rVWF (vonicog 
alfa).
6.6 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) to
Human Subjects
Current treatment of VWD patients relies on desmopressin and VWF products 
manufactured from pooled human plasma. Human VWF produced by recombinant 
technology could offer a new perspective in treatment of VWD. The benefit for the 
individual subject is anticipated to be significant during this clinical study. He/she may 
benefit from a product that minimizes excessive FVIII administration and thus allowing 
individualized dosing of VWF at optimal levels. Variations in VWF multimeric 
composition may lead to variability with respect to treating or preventing bleeds in 
VWD subjects, especially mucosal bleeds which are especially problematic. rVWF 
(vonicog alfa) product manufactured by Baxalta consistently contains ULMW VWF 
multimers due to the fact that the product has not been exposed to ADAMTS13. 
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The initial presence of these ULMW VWF multimers, which are subsequently cleaved by 
the subject’s endogenous ADAMTS13, may result in improved platelet and collagen 
binding and therefore provide more predictable treatment outcomes.
By using a recombinant product, the risk of transmission of adventitious agents and other 
blood-borne pathogens associated with the use of products of human or animal origin has 
been eliminated. At this stage of product development, the key societal benefit is a better 
understanding of advanced treatment options for VWD and enhanced product 
availability.
These benefits outweigh the following identified or potential risks of rVWF (vonicog 
alfa):

allergic-type hypersensitivity reactions as with any intravenous protein product

the occurrence of thromboembolic events

the development of neutralizing antibodies to VWF
Refer to the IB for further details on benefits and risks of the IP.
6.7 Compliance Statement
This study will be conducted in accordance with this protocol, the International Council 
for Harmonisation Guideline for Good Clinical Practice E6 (ICH GCP, April 1996, with 
Addendum E6(R2) dated Nov 2016 EMA/CHMP/ICH/135/1995), Title 21 of the US 
Code of Federal Regulations (US CFR), the EU Directives 2001/20/EC and 2005/28/EC, 
the Declaration of Helsinki and applicable national and local regulatory requirements.
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7. STUDY PURPOSE AND OBJECTIVES
7.1 Study Purpose
The purpose of this phase 3 study is to investigate the efficacy and safety, including 
immunogenicity, thrombogenicity and hypersensitivity reactions, as well as 
pharmacokinetics (PK), 
and 
 
of prophylactic treatment with rVWF (vonicog alfa) in adult subjects with severe VWD.
7.2 Primary Objective
The primary objective of this study is to prospectively evaluate the ABR for spontaneous 
bleeding episodes while on prophylactic treatment with rVWF (vonicog alfa) and to 
compare it to the subject’s historical ABR for spontaneous bleeding episodes.
7.3 Secondary Objectives
Secondary Objectives are to assess:

Additional efficacy of prophylactic treatment with rVWF (vonicog alfa)

Safety of rVWF (vonicog alfa), including immunogenicity, thrombogenicity and 
hypersensitivity

Pharmacokinetics (PK) of rVWF (vonicog alfa) and pharmacodynamics (PD) of 
rVWF (vonicog alfa) as measured in FVIII activity 
7.4 Exploratory Objectives
 
 
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8. STUDY DESIGN
8.1 Overall Study Design 
This is a prospective, open label, uncontrolled, non-randomized, international, 
multicenter phase 3 study to evaluate efficacy, safety (including immunogenicity,
thrombogenicity and hypersensitivity reactions), as well as PK, 
and 
 of prophylactic treatment regimen with rVWF (vonicog alfa) in adult 
patients with severe VWD. 
Subjects transitioning from on-demand treatment (OD subjects) or subjects switching 
from prophylactic treatment with pdVWF (pdVWF switch subjects) will receive 
prophylactic treatment with rVWF (vonicog alfa) for a 12-month period. The dose will be 
50 ± 10 IU/kg rVWF twice weekly for OD subjects or will be based on their prior 
pdVWF dose for pdVWF switch subjects, and dose may be further individualized based 
on the PK data, subject’s history of bleeding episodes, and the results from clinical and 
laboratory assessments (see Section 8.6.4.3).
The overall duration of prophylactic treatment with rVWF per subject will be 12 months.
During this period any bleeding episodes requiring substitution therapy with VWF 
concentrate to control bleeding will be treated with rVWF (vonicog alfa) with or without 
ADVATE (rFVIII, octocog alfa). The dose will be according to the bleeding type and 
severity and it will be adjusted to the clinical response (see Section 8.6.4.4.2).
The overall study design is illustrated in Figure 1.
8.2 Duration of Study Period(s) and Subject Participation
The overall duration of the study is approximately 27 months from study initiation 
(i.e., first subject enrolled) to study completion (i.e., last subject last visit). The subject 
participation period is approximately 15 months from enrollment to completion (i.e, last 
study visit), unless the subject is prematurely discontinued.
8.3 Outcome Measures
8.3.1 Primary Outcome Measure
8.3.1.1 Efficacy 

Annualized bleeding rate (ABR) for spontaneous (not related to trauma) bleeding 
episodes during prophylactic treatment with rVWF (vonicog alfa)
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8.3.2 Secondary Outcome Measures
8.3.2.1 Additional efficacy of Prophylactic Treatment with rVWF (vonicog alfa)

ABR percent reduction success for OD subjects defined as at least 25% reduction 
of ABR for spontaneous (not related to trauma) bleeding episodes during rVWF 
(vonicog alfa) prophylaxis relative to the subject’s own historical ABR during on-
demand treatment

ABR preservation success for pdVWF switch subjects defined as achieving an 
ABR for spontaneous bleeding episodes during rVWF (vonicog alfa) prophylaxis 
that is no greater than the  subject’s own historical ABR during prophylactic
treatment with pdVWF

Categorized spontaneous ABR defined as 0, 1-2, 3-5, or >5 bleeding episodes
during the 12-month prophylactic treatment with rVWF (vonicog alfa)

Total number of infusions and the average number of infusions per week during 
prophylactic treatment with rVWF (vonicog alfa)

Total weight adjusted consumption of rVWF (vonicog alfa) during prophylactic 
treatment 

Spontaneous ABR by location of bleeding (GI, epistaxis, joint bleeding, 
menorrhagia, oral and other mucosa, muscle and soft tissue, etc.) while on 
prophylactic treatment with rVWF (vonicog alfa)
8.3.2.2 Safety

AEs: incidence, severity, causality

Thromboembolic events 

Hypersensitivity reactions

Development of neutralizing antibodies to VWF and FVIII

Development of total binding antibodies to VWF and FVIII

Development of binding antibodies to CHO proteins, mouse immunoglobulin G 
(IgG) and rFurin

Clinically significant changes in vital signs and clinical laboratory parameters
relative to baseline
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8.3.2.3 Pharmacokinetics (PK) and Pharmacodynamics (PD)

PK parameters after a washout for on-demand subjects: incremental recovery 
(IR), T1/2, MRT, area under the concentration versus time curve from 0 to infinity 
(AUC0-), area under the concentration versus time curve from 0 to the last 
measurable concentration (AUC0-tlast), maximum plasma concentration (Cmax), 
minimum time to reach the maximum concentration (Tmax), volume of distribution 
at steady state (Vss) and clearance (CL) based on VWF:Rco activity, VWF:Ag, 
VWF:CB activity. 

PD parameters after a washout for on-demand subjects: Cmax, Tmax, and AUC0-tlast
as measured in FVIII activity by the 1-stage clotting assay (FVIII:C). 

PK parameters at steady state for on-demand and switch subjects: area under the 
concentration versus time curve from 0 to end of the partial dosing interval 
(AUC0-tau;ss), maximum concentration during the partial dosing interval (Cmax;ss), 
minimum time to reach the maximum concentration (Tmax;ss) and minimum 
concentration during the partial dosing interval (Cmin;ss) based on VWF:RCo, 
VWF:Ag and VWF:CB. PK parameters at steady state will be assessed shortly 
after reaching steady state for switch subjects and at the end of the study for on-
demand as well as for switch subjects all based on the longer interval of the 
irregular dosing intervals employed.

PD parameters at steady state for on-demand and switch subjects: AUC0-tau;ss, 
Cmax;ss, Tmax;ss, and Cmin;ss as measured in FVIII activity by the 1-stage clotting 
assay. PD parameters at steady state will be assessed shortly after reaching steady 
state for switch subjects and at the end of the study for on-demand as well as for 
switch subjects all based on the longer interval of the irregular dosing intervals
employed.

Time course of FVIII clotting activity (FVIII:C) levels.
8.3.3 Exploratory Outcomes Measures
8.3.3.1
 
 
 
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8.3.3.2
 
 
 
 
8.3.3.3
 
8.3.3.4
 
 
8.4 Randomization and Blinding
This is a non-randomized open-label, active treatment clinical study. 
8.5 Study Stopping Criteria 
This study will be stopped if 1 or more of the following criteria are met in the absence of 
any other possible and medically plausible causal attribution (eg, underlying or 
concurrent condition, use of concomitant medication, subject’s medical history, etc):
1.
Two subjects develop a life-threatening or fatal thromboembolic event
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2.
Two subjects develop life-threatening or fatal severe hypersensitivity reactions 
(e.g., anaphylaxis)
3.
Any subject develops acute hepatic failure
4.
Two subjects develop rVWF neutralizing antibodies that are considered clinically 
significant by the investigators and are associated with significant decrease of 
efficacy or serious adverse reactions.
The study may be stopped at any time by the sponsor.
The sponsor ultimately will decide whether to terminate, temporarily halt or modify the 
study based on the data monitoring committee (DMC)’s review and recommendation on 
all relevant cases including those that meet the stopping criteria listed above.
8.6 Investigational Product(s)
8.6.1 Packaging, Labeling, and Storage
8.6.1.1 rVWF (Recombinant von Willebrand Factor, vonicog alfa)
rVWF (vonicog alfa) will be packaged in boxes with 2 glass vials, one containing the 
rVWF powder, and the second vial containing the diluent (water for injection). Further 
details are provided in the IB and Pharmacy Manual. The rVWF label will include, at a 
minimum, the actual VWF:RCo potency and the date of expiration.
rVWF (vonicog alfa) is a powder that should be stored refrigerated (2-8°C [36-46°F]) . 
Deviations from the storage condition have to be communicated and followed up with the 
sponsor. Inadequately stored product will have to be placed in quarantine and may only 
be used after written IP administration authorization by the sponsor. After removal of the 
product from the refrigerator the product must not be returned to the refrigerator. The 
reconstituted product has to be used immediately (at least within 3 hours). rVWF 
(vonicog alfa) must not be used beyond the expiration date printed on the vial label. 
Avoid freezing at all times.
8.6.1.2 rFVIII (Recombinant Factor VIII, octocog alfa /ADVATE)
ADVATE (rFVIII, octocog alfa) will be packaged in boxes with 2 glass vials, one 
containing the lyophilized rFVIII, and the second vial containing the diluent. Further 
details are provided in the IB and Pharmacy Manual. The ADVATE label will include, 
at a minimum, the actual FVIII:C potency and the date of expiration. 
ADVATE (rFVIII, octocog alfa) should be refrigerated (2-8°C [36-46°F]) in powder 
form and should not be used beyond the expiration date printed on the vial. 
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Deviations from the storage condition have to be communicated and followed up with the 
sponsor. Inadequately stored product will have to be placed in quarantine and may only 
be used after written IP administration authorization by the sponsor. After removal of the 
product from the refrigerator the product must not be returned to the refrigerator and has 
to be used immediately. Avoid freezing at all times.
8.6.2 Reconstitution
The reconstitution procedures for both rVWF (vonicog alfa) and ADVATE (rFVIII, 
octocog alfa) products are detailed in the Pharmacy Manual. 
8.6.3 Administration
Following reconstitution, rVWF (vonicog alfa) and ADVATE (rFVIII, octocog alfa) (in 
case of bleeding episode treatment) should be administered to study subjects at room 
temperature and within 3 hours of reconstitution. The reconstituted rVWF (vonicog alfa)
and ADVATE (rFVIII, octocog alfa), should be inspected for particulate matter and 
discoloration prior to administration, whenever the solution and container permit. The 
solution should be clear and colorless in appearance. If not, do not administer the product. 
Plastic syringes provided by the sponsor must be used since coagulation factors tend to 
stick to the surface of glass syringes.
Investigational product infusions should be given at a slow enough rate to ensure the 
subject’s comfort. The rate should not exceed 4 mL/minute The investigator/ subject shall 
ensure that no visible residual volume remains in the syringe(s) and that the complete 
content is administered. Upon completion of the infusion, the butterfly catheter should be 
flushed with at least 2 mL of saline solution. In case of a (central) venous access device, 
the flush should be with at least 10 mL of saline solution. The IP infusions should be 
administered over a duration of 2 to 20 minutes, depending on the volume.
Only the actual potencies of rVWF (vonicog alfa) and ADVATE (rFVIII, octocog alfa) as 
stated on the vial labels and described in the Pharmacy Manual should be used. A 
variation of up to 10% of the intended dose for prophylactic infusions and of the intended 
dose for treatment of bleeding episodes is permissible and the exact dose should be 
recorded on the Case Report Form (CRF). Using of partial vials is not allowed.
At study visits where recovery analysis is being done, vials with the same lot numbers 
should be used throughout the PK IP infusion per subject.
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For treatment of bleeding episodes, sequential administration will be done: separate 
syringes of the appropriate dose of rVWF (vonicog alfa) and ADVATE (rFVIII, octocog 
alfa) will be prepared for sequential infusion. rVWF (vonicog alfa) should be infused first 
sequentially followed preferably within 10 minutes by infusion of ADVATE (rFVIII, 
octocog alfa). Only the actual potencies of rVWF (vonicog alfa) and ADVATE (rFVIII, 
octocog alfa) as stated on the vial labels and described in the Pharmacy Manual should be 
used. 
The final dose of rVWF (vonicog alfa):ADVATE (rFVIII, octocog alfa) should be at a 
ratio of 1.3:1 ± 0.2.
8.6.4 Description of Treatment
8.6.4.1 PK-Assessment Treatment
For on-demand subjects, two PK assessments will be performed: an initial PK 
assessment after a wash-out period and a steady state PK assessments at the end of the 
study. The IP infusion for the initial PK assessment is scheduled on the baseline visit, 
which should be within 42 days after the completion of screening procedures and 
confirmation of eligibility. At the baseline visit the subjects will receive a dose of 
50 ± 5 IU/kg rVWF:RCo for PK assessment. Blood samples will be drawn within 
30 minutes pre-infusion, and at 11 time points post-infusion (15 ± 5 minutes, 
30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 
24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours and 96 ± 2 hours). A washout 
period of at least 5 days is required prior to infusion of rVWF (vonicog alpha) for PK 
assessment. The 2nd PK assessment for on-demand subjects will be performed at steady 
state at the end of the study(see Section 11.6). Subjects previously enrolled in rVWF 
studies 070701, 071001 or 071101 and having previously undergone PK assessments in 
these studies are required to repeat the PK assessment due to different dose and time 
points used in these former studies.
For pdVWF switch subjects, two steady state PK assessments will be performed. 
The 1st PK will be assessed shortly after reaching steady state, which is expected to be 
11 days after the 1st prophylactic dose for majority of the subjects, around the 
prophylactic dose #5-6. The 2nd PK will be at the end of the study. For steady state PK, 
blood samples will be drawn within 30 minutes pre-infusion, and at 11 time points post-
infusion (15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 
12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours and 96 ± 2 hours) 
as long as it won’t interfere with subject’s the normal dosing schedule, otherwise the 
96 hr sampling can be omitted (see Section 11.6). Final sample for PK analysis should be 
taken before next dose is administered.
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8.6.4.2 Prophylaxis Initiation Treatment 
The rVWF (vonicog alfa) prophylaxis initiation treatment visit will coincide with the 
96 2 h initial PK assessment for on-demand subjects. For pdVWF switch subjects, the 
rVWF (vonicog alfa) prophylaxis initiation treatment visit should occur within 42 days 
after the completion of screening procedures and confirmation of eligibility. At this visit 
subjects will receive their prophylaxis initiation dose. The prophylaxis doses are 
described in Section 8.6.4.3.
The subject will be trained on IP reconstitution and administration and may then qualify
for home treatment (see Section 8.6.4.3.2). Refer toTable 6 (a/b) for study procedures and
Table 8(a/b) for clinical laboratory assessments.
8.6.4.3 Prophylaxis Treatment
For on-demand subjects, the standard prophylactic dose is 50 ± 10 IU/kg rVWF:RCo, 
which may be increased up to 80 IU/kg. All on-demand subjects will initially receive 
rVWF (vonicog alfa) twice per week (Table 1, Schedule A). Examples of all dosing 
schedules are provided in Table 1.
For pdVWF switch subjects, the weekly dose (IU/kg) of IP for each patient will be 
equivalent (± 10%) to the weekly VWF dose received during prophylactic treatment with 
pdVWF. The weekly dose of IP should be divided into 2 infusions (Table 1, Schedule A), 
with a maximum of 80 IU/kg/infusion. If needed, based on the total weekly dose or other 
clinical judgements, the weekly dose may be given as three infusions (Table 1, 
Schedule B). A once weekly dose regimen will be allowed after switch to rVWF 
(vonicog alfa) only if the patient has been on a once weekly dose regimen with pdVWF.
Table 1
rVWF (vonicog alfa) Dosing Schedule Examples: Schedules A and B
Example
M
T
W
Th
F
Sat
Sun
M
T
W
Th
F
Sat
Sun
Schedule A
X
X
X
X
Schedule B
X
X
X
X
X
X
The prophylaxis dose may be further individualized within the range based on:

available historical PK data

type and severity of bleeding episodes the subject has experienced in the past and

monitoring of appropriate clinical and laboratory measures
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The individualized prophylaxic dose assignment will have to be agreed with the sponsor 
in advance, and the rationale should be well documented.
8.6.4.3.1 Adjustment of Dose or Dose Interval
In general, the dose and/or dose interval for each subject should not be changed unless 
prompted by clear medical needs. Dose and frequency adjustments should be agreed with 
the sponsor in advance unless it constitutes an urgent safety measure. The rationale for 
dosing adjustments needs to be documented in the subject’s medical record.
For both OD and switch patients, dose escalations (not exceeding the upper dose limit of 
80 IU/kg rVWF:RCo) and increase of dose frequency will only be allowed in case of 
insufficient therapeutic response with breakthrough bleeding episodes. The criteria for 
dose and/or frequency escalation are specific to each bleeding indication but, overall, 
involve 1 significant breakthrough bleeding episode despite the subject being compliant 
with scheduled prophylaxis treatment. For switch patients  who require a dose escalation 
due to a breakthrough bleed, the frequency should be kept the same but the dose 
(IU VWF:RCo per infusion) should be increased up to 80 IU VWF:RCo. Following that, 
increases in frequency may be considered upon consultation with the Sponsor. For on 
demand subjects who require a dose escalation, at the discretion of the PI upon 
consultation with the Sponsor, the frequency may be kept the same but the dose 
(IU VWF:RCo per infusion) should be increased up to 80 IU VWF:RCo. If this proves to 
be insufficient, then the dosing frequency may be increased in these subjects. Table 2
presents the criteria for dosing escalation per each bleeding indication taken 50 ± 10 IU 
VWF:RCo/kg twice weekly dose as an example of subject’s assigned starting dose. The 
criteria are applicable for both OD and switch subjects who were initially assigned to 
twice weekly dosing. Subjects entering the study will begin prophylaxis treatment 
according to Schedule A (Table 1) and will remain at this dose and frequency until 
meeting the criteria for escalation to the next higher schedule: for example, from 
2 infusions of 50 ± 10 IU VWF:RCo/kg/week to 3 infusions of 50 ± 10 IU 
VWF:RCo/kg/week (Schedule B) to achieve an adequate therapeutic response. If a 
subject started with a weekly dose (possible for switch subjects), similar criteria would 
apply except that the subject will be excalated to twice weekly dosing if frequency 
change is necessary.
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Table 2
Criteria for Escalation Specific to Each Bleeding Indication
Schedule A
Schedule B
Joint bleeding
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) twice per week. In the event a 
spontaneous joint bleeding episode occurs 
while on this regimen, the subject will escalate 
to up to 80 IU/kg twice per week or, if 
necessary, to Schedule B following its 
resolution
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week.
GI bleeding
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) twice per week. In the event a 
severe GI bleeding episode, i.e., requiring red 
blood cell transfusion, occurs while on this 
regimen, the subject will escalate to up to 
80 IU/kg twice per week or, if necessary, to 
Schedule B following its resolution
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week.
Menorrhagia
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) on days 1 and 2 of menses for 
2 cycles. Menstrual flow will be monitored by 
the PBAC score. If the average pictorial chart 
score is > 185, then the subject will escalate to
up to 80 IU/kg or, if necessary, to Schedule B
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) on days 1, 2, 
and 3 of menses. Menstrual flow 
will be monitored by the PBAC 
score.
Epistaxis
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) twice per week. The subject will 
escalate to up to 80 IU/kg twice per week or, if 
necessary, to Schedule B in the event of 
1 occurrence of breakthrough bleeding 
requiring intervention such as iron 
replacement therapy, transfusion, packing, 
hospitalization; or 2 bleeding events that 
require treatment with factor replacement
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week. 
Oral and Other 
Mucosa
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) twice per week. The subject will 
escalate to up to 80 IU/kg twice per week or, if 
necessary, to Schedule B in the event of 
1 occurrence of breakthrough bleeding 
requiring intervention such as iron 
replacement therapy, transfusion, packing, 
hospitalization; or 2 bleeding events that 
require treatment with factor replacement.
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week.
Muscle and Soft 
Tissue
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) twice per week. In the event a 
spontaneous bleeding episode occurs while on 
this schedule, the subject will escalate to up to 
80 IU/kg twice per week or, if necessary, to 
Schedule B following its resolution.
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week.
Abbreviations:  GI: gastrointestinal; PBAC: Pictorial Blood Assessment Chart.
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If a subject does not adequately respond to rVWF (vonicog alfa) therapy, he/she will be 
evaluated for the presence of neutralizing and total binding anti-VWF antibodies (see 
Section 12.9.3.2).
If a subject experiences a bleed while receiving rVWF (vonicog alfa) three times per 
week, the investigator should treat the bleed with rVWF (vonicog alfa) at doses up to 
80 IU VWF:RCo/kg at a frequency determined by the investigator until the bleed 
resolves. Upon resolution of the bleeding event, the subject will return to their assigned 
prophylaxis regimen. 
It is essential for the success of this study that the subjects adhere to treatment regimens. 
Therefore, procedures for monitoring subject’s compliance are implemented (see 
Section 10.7).
If 1 infusion of IP is missed, the subject may administer the IP as soon as possible. The 
subject should adhere to their treatment scheme ensuring a minimum interval of 12 hours 
between this and the previous IP infusion. For example, a subject routinely infuses IP on 
Monday and Thursday, he/she misses the Monday time point and therefore may infuse 
the IP on the next day (Tuesday) and thereafter proceed with infusing the IP on Thursday
(considering a minimum 12 hours between the infusions) and return to the initial
schedule.
If more than 30% of infusions of IP are missed within the visit interval of 3 months the 
subject will be discontinued from the study (see Section 9.4).
8.6.4.3.2 General Instructions for Home Treatment for Prophylaxis
At the discretion of the investigator, a subject may be considered suitable for home 
treatment only after the subject has received at least 1 infusion of IP in the clinic, either 
during planned prophylactic IP exposure or during the treatment of bleeding episodes, 
and meets the following additional criteria:
1.
Fully understands the concept of a clinical study and related documentation 
(documented training of at least 30 minutes), 
2.
Has a history of previous experience with home treatment including 
self-administration and treatment with VWF containing concentrates, 
3.
Has adequate time for initial training of the study drug preparation (preparation, 
mixing and infusion of the IP(s) (documented training of at least 30 minutes).
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This applies both to subjects who were on prior on-demand treatment and to subjects 
switching form prophylaxis with pdVWF. In the event a healthcare professional is 
required to administer IP, he/she must be trained and qualified by the investigator on the 
above procedures prior to the decision for home treatment. A Subject Guideline detailing 
all instructions and information listed above will be provided to each subject.
8.6.4.4 Treatment of Bleeding Episodes
8.6.4.4.1 General Instructions for Home Treatment of Bleeding Episodes
If a subject experiences a bleeding episode, he/she should contact the study site 
immediately and the site investigator should provide instructions on the treatment 
regimen. If the subject initiates the treatment at home, he/she should at least follow up 
with the study site if a visit is needed as per the standard of care at the center.
In the event a healthcare professional is required to administer treatment at the subject’s 
home, he/she must be trained and qualified by the site investigator on the above 
procedures prior to the decision for home treatment. Once a subject has received 
1 infusion of rVWF (vonicog alfa) in the clinic (either during planned IP exposure or 
during the treatment of a bleeding episode) and meets the criteria for home treatment, the 
treatment of bleeding episodes with IP can be conducted at home (see Section 8.6.4.3.2).
If a subject is not qualified for home treatment, rVWF (vonicog alfa) infusions must be 
administered at the study site.
If a subject experiences a bleeding episode that requires treatment between the screening 
and the prophylaxis initiation visit, the subject will be treated with IP (rVWF with or 
without ADVATE). Treatment with IP must occur at the study site unless the subject has 
previously qualified for home treatment with rVWF (vonicog alfa). If rVWF (vonicog 
alfa) treatment is not feasible, the subject may use his/her standard of care, such as
commercial pdVWF/FVIII products. In any case a washout period of at least 5 days is 
required prior to rVWF (vonicog alfa) PK infusion at the initial PK assessment visit for 
on-demand subjects.
If a subject experiences a bleeding episode requiring treatment during the PK assessment, 
rVWF (vonicog alfa) should be used to treat the bleed. Blood draws for PK assessment 
will be stopped and the PK assessments will be repeated once the bleed has resolved and 
the subject is free of any symptoms related with the bleeding episode. Dose and 
frequency of rVWF (vonicog alfa) infusions or any other replacement therapy to stop the 
bleed should be recorded in the electronic Case Report Form (eCRF), and the reason for 
the use of any non-IP product or therapy should be documented.
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8.6.4.4.2 Dosing Recommendations for Treatment of Bleeding Episodes 
If an acute bleeding episode occurs, the subject will be treated with rVWF (vonicog alfa)
with or without ADVATE (rFVIII, octocog alfa). It is the sponsor’s opinion that, in many 
cases, treatment with ADVATE (rFVIII, octocog alfa) may not be necessary, since rVWF 
(vonicog alfa) prophylaxis will serve to increase endogenous FVIII levels. However, if 
endogenous FVIII is below 30-40 % or is unknown and cannot be estimated from the 
subject’s PK study, an infusion of rVWF: ADVATE at an rVWF: ADVATE ratio of 
1.3:1± 0.2 should be administered initially. Subsequent infusions should be with 
rVWF:RCo 40 to 60 IU/kg with or, in  many cases,without 30 to 45 IU/kg ADVATE 
(only to be administered if plasma FVIII levels fall below 30 IU/L during the treatment 
period). Dosing may be adjusted downward or upward up to 80 IU/kg rVWF at the 
treating physician’s discretion based upon the subject’s prior history, PK and other 
factors.
If FVIII levels are not available, dosing is at the discretion of the investigator based upon 
the individual subject’s PK data. Using ADVATE (rFVIII, octocog alfa) in addition to 
rVWF (vonicog alfa) in subsequent doses carries the risk of an excessive rise in FVIII:C. 
Therefore, reduced doses of ADVATE (rFVIII, octocog alfa) and/or prolongation of the 
dose interval should be considered.
The following is general guidance and the sponsor’s suggestion for treatment of 
breakthrough bleeds, however each PI will determine the treatment based on the local 
acceptable practice how to monitor and adjust treatment for a bleeding episode. An effort 
should be made to discuss with the sponsor (or sponsor’s delegate) the treatment strategy.
In general the aim of the initial dose should be full replacement of VWF with VWF:RCo 
levels of >0.6 IU/ml (60%) and FVIII:C of >0.4 IU/mL (40%). In major bleeding 
episodes, subsequent doses should keep the trough level of VWF:RCo >50% for 3 days 
and then as deemed necessary by the investigator for subsequent days. In moderate 
bleeding episodes, the dose and trough level may be reduced to >30% for as long as 
deemed necessary by the investigator. Treatment for minor bleeding episodes will 
generally consist of only 1 or 2 doses of rVWF (vonicog alfa) IP. 
If the VWF:RCo level is above 150%, a planned treatment should be delayed by at least 
12 hours; if the VWF:RCo level is above 200%, a planned treatment should be delayed 
by at least 24 hours. In either case, a lower subsequent dose (e.g., 20 IU/kg VWF:RCo) 
may be appropriate.
Dosing recommendations are listed in Table 3.
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Dosage must be individualized based on the subject’s weight, VWD type, and the 
severity of the bleeding episode, as well as on monitoring of appropriate clinical and 
laboratory measures. In the phase 1 study 070701, 1.0 IU/kg VWF:RCo raised the 
circulating level of VWF:RCo by 0.017 IU/mL (1.7 %). In the same study, the observed 
mean half-life for rVWF (vonicog alfa) was 19.3 hours, with a standard deviation of 
10.9 hours.
Table 3
rVWF:RCo Dosing Recommendations for the Treatment of Bleeding Episodes Due to VWD
Classification of 
VWD
Hemorrhage
Dosage (IU VWF:RCo/kg BW)
Type 1 
Severe (Baseline 
VWF:RCo activity 
typically <20%) 
Minor (e.g., epistaxis, oral 
bleeding, menorrhagiaa) 
40 to 50 IU/kg (1 or 2 doses)
Major (e.g., severe or 
refractory epistaxis, 
menorrhagia*, GI bleeding, 
CNS trauma, hemarthrosis, 
or traumatic hemorrhage)
Initial dose 50 to 75 IU/kg, then 40 to 60 IU/kg 
every 8 to 12 hours for 3 days to keep the trough 
level of VWF:RCo >50%; then 40 to 60 IU/kg daily 
for a total of up to 7 days of treatment
Type 2 (all variants) 
and Type 3 
Minor (clinical indications 
above) 
40 to 50 IU/kg (1 or 2 doses)
Major (clinical indications 
above)
Initial dose of 60 to 80 IU/kg, then 40 to 60 IU/kg 
every 8 to 12 hours for 3 days to keep the trough 
level of VWF:RCo >50%; then 40 to 60 IU/kg daily 
for a total of up to 7 days of treatment
a Menorrhagia is defined as excessive bleeding during menstruation. A diagnosis of menorrhagia will be 
defined by a prospectively completed Pictorial Blood Assessment Chart (PBAC) score >185 and normal 
cervical cytology or requiring use of a VWF-containing concentrate for treatment of excessive 
menstrual bleeding for at least one menstrual cycle during the prior year.
Variances of up to 10% in dosing are permissible during treatment of bleeding episodes, 
but rounding to the nearest vial size should be avoided.
Subjects with non-neutralizing binding anti-VWF antibodies should initially be treated 
with a dose known to be efficacious based on the subject’s medical treatment history
which may differ from the recommendations provided in Table 3. Subjects should be 
monitored for lack of efficacy as well as for FVIII (mandatory), VWF:RCo (mandatory), 
and VWF:Ag (optional where testing is not available) levels after 3 to 6 hours. Re-dosing 
with rVWF (vonicog alfa) in combination with ADVATE (rFVIII, octocog alfa) using the 
same (initial) dose and adaptation of the dosing frequency should be considered until 
cessation of the bleed, if the FVIII and/or VWF:RCo levels drop below 30%-50% 
depending on bleeding severity.
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The number of subsequent infusions and the dosage levels prescribed will be determined 
by the investigator on the basis of the clinical severity, response to current therapy, 
available laboratory data, and the subject’s historical treatment for similar bleeding 
episodes.
8.6.4.5 Treatment of Surgical Bleeding
Subjects enrolled in this study who require surgery or dental procedures will be treated 
with IP to manage their surgical bleeding then afterwards will resume their prophylactic 
rVWF (vonicog alfa) treatment schedule. Subjects who at time of screening have an 
already scheduled surgical intervention are not eligible for participation in the study.
8.6.4.5.1 Major, Minor and Oral Surgery Definition
The following definitions and criteria are used to serve as a guidance for major, minor 
and oral surgery.
Major surgeries generally refer to major orthopedic surgery (e.g., joint replacement, 
arthroscopic or open synovectomy, arthrodesis, hardware removals like plates or 
intramedullary nails, etc.), major abdominal surgery (e.g. open or laparoscopic 
hernioplasty, cholecystectomy, colon or small bowel resection, etc.), major gynecological 
surgery (e.g. open or laparoscopic myomectomy, hysterectomy, removal of 
endometriosis, polyps, cysts, adhesiolysis, etc.), major head and neck surgery (e.g.: 
tonsillectomy, adenoidectomy, rhinoplasty, lymphadenectomy, thyroidectomy, 
parotidectomy. etc.), any intracranial , cardiovascular or spinal surgery and any other 
surgery which has a significant risk of large volume blood loss or blood loss into a 
confined anatomical space. Extraction of impacted third molars is generally also 
considered major surgery due to the expected difficulty of surgery and the expected blood 
loss.
Minor surgeries generally refer to interventions such as placement of intravenous access 
devices, removal of small skin lesions, arthroscopy, gastroscopy, colonoscopy or 
conisation.
Oral surgeries comprise extractions of fewer than three teeth, if the teeth are non-molars 
and have no bony involvement.
A summary schedule of visit assessments and laboratory sampling is included in 
Supplement tables in Section 20.2.1 and Section 20.3.1.
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8.6.4.5.2 Preoperative Priming Dose
12- 24 hours prior to surgery, a priming dose with rVWF (vonicog alfa), using the rVWF
IR and T1/2 for this subject , will be infused to allow the endogenous FVIII levels to raise 
to at least 30 IU/dL (minor, oral surgery), or 60 IU/dL (major surgery) at the time of the 
loading dose of rVWF (vonicog alfa) is infused.
As a general guidance a priming dose of 40-60 IU/kg rVWF:RCo will be administered. If
not assessed prior to the preoperative priming dose, a IR recovery may be calculated for
subjects undergoing minor and oral surgery.
8.6.4.5.3 Preoperative Loading Dose
An rVWF (vonicog alfa) loading dose should be administed within 3 hours before 
surgery. VWF and FVIII levels should be assessed within 3 hours prior to surgery 
initiation and results must be available prior to administering the loading dose. If FVIII 
levels prior to loading dose administration are not at least 30 IU/dL (minor, oral surgery), 
or 60 IU/dL (major surgery) ADVATE (rFVIII, octocog alfa) will be administered in 
addition to rVWF (vonicog alfa) in order to raise FVIII:C levels to recommended levels.
The preoperative loading dose will be calculated as the difference in the target peak and 
baseline plasma VWF:RCo levels divided by the IR (ΔVWF:RCo x BW (kg) /IR). The 
PK results will be provided prior to the planned surgery. If the IR is not available, assume 
an IR of 1.7 IU/dL per IU/kg and calculate the initial dose as follows: (100 – baseline 
plasma VWF:RCo) x BW (kg) / 1.7. For minor and oral surgery, the IR from the 
Preoperative Priming Dose visit will be used to guide dosing and the target peak is 
50-60 IU/dL VWF:RCo and 40-50 IU/dL FVIII. For major surgery, the target peak is 
100IU/dL VWF:RCo and 80-100 IU/dL FVIII.
The surgery may only start after normalization of the activated partial 
thromboplastin time (aPTT).
8.6.4.5.4 Intra- and Postoperative (maintenance) Dosing
After the preoperative loading dose(s), subjects who have not achieved the desired 
postinfusion recovery will continue to receive rVWF (vonicog alfa) with or without 
ADVATE (rFVIII, octocog alfa) as a bolus infusion, depending on VWF and FVIII 
levels. The peri- and post-operative substitution regimen will be individualized according 
to the PK results, intensity and duration of the hemostatic challenge, and the institution’s 
standard of care.
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Subjects undergoing minor surgery will be infused with rVWF (vonicog alfa) every 
12-24 hours or every other day, targerting >30IU/dL (rVWF and FVIII) for at least the 
first 48 hours.
Subjects undergoing oral surgery will be infused with rVWF (vonicog alfa) at least once 
within the first 8-12 hours, targeting >30 IU/dL (rVWF and FVIII).
Subjects undergoing major surgery will be infused with rVWF (vonicog alfa) every 
12-24 hours for at least the first 72 hours post-surgery, targeting a VWF:RCo and 
FVIII:C trough plasma level >50 IU/dL, followed by further treatment post-72 hours for 
as long as deemed necessary by the Investigator, targeting a VWF:RCo and FVIII:C 
trough plasma level of >30 IU/dL.
Dose modifications based on pre-infusion VWF/FVIII levels will be performed as 
needed. For subsequent infusions post surgery, in case pre-infusion levels are not 
available prior to the consecutive infusion in a timely manner, pre-infusion levels from 
the previous dose may be used by the investigator for dosing guidance.
Peak plasma level guidance is matching to Section 8.6.4.4.2
A schedule of all perioperative visit assessments and laboratory sampling can be found in 
supplement tables in Section 20.2.1 and Section 20.3.1.
8.6.4.6 Thrombosis Prophylaxis
Thromboembolic events have been reported in patients who have VWD, especially in the 
setting of known risk factors for thrombosis including low ADAMTS13 levels. 
Therefore, subjects who are at risk for developing thromboembolic events should be 
monitored for early signs of thrombosis, and prophylaxis measures against 
thromboembolism should be instituted according to current recommendations and 
standard of care. For all subjects who are VWD patients and are receiving VWF 
concentrate, attention should be given to avoid exceeding maximal recommended plasma 
activity levels of VWF:RCo (250 IU/dL) and FVIII (250 IU/dL).
Anticoagulation measures, such as heparin, are acceptable and should follow study site 
standards. The investigator will record the use and reasons for such measures/agents on 
the appropriate CRF.
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8.6.5 Investigational Product Accountability
The investigator will ensure that the IP(s) is stored as specified in the Pharmacy Manual
and that the storage area is secured, with access limited to authorized study personnel. All 
temperature excursions at the subject’s home need to be monitored by the site (please 
refer to the pharmacy manual). The investigator will maintain records that the IP(s) was
received, including the date received, drug identity code, date of manufacture or 
expiration date, amount received and disposition. The IP(s) must be dispensed only at the 
study site or other suitable location (e.g., infusion center; home, as applicable per study 
design), as specified in the protocol (see Section 10). Records will be maintained that 
includes the subject identification code (SIC), dispensation date, and amount dispensed. 
All remaining partially used and/or unused IP(s) will be returned to the sponsor or 
sponsor’s representative after study completion/termination, or destroyed with the 
permission of the sponsor in accordance with applicable laws and study site procedures. 
If IP(s) is to be destroyed, the investigator will provide documentation in accordance with 
sponsor’s specifications.
8.7 Source Data
Per ICH E6(R2) on GCP, source data are defined as all information in original records 
and certified copies of original records of clinical findings, observations, or other 
activities in a clinical trial that are necessary for the reconstruction and evaluation of the 
trial. Source data are contained in source documents (original records or certified copies). 
These may be in paper and/or electronic format. Source documents for this study
comprise the following: hospital records, medical records, clinical and office charts, 
laboratory notes, memoranda, subjects' diaries or evaluation checklists, outcomes 
reported by subjects, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate copies, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, 
and records kept at the pharmacy, at the laboratories and at medico-technical departments 
involved in the clinical study.
No data will be entered directly onto the CRF.
For additional information on study documentation and CRFs refer to Section 17.2. The 
use of subject diaries is described in Section 10.5.
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9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION
9.1 Inclusion Criteria
Subjects who meet ALL of the following criteria are eligible for this study:
1.
Subject has a documented diagnosis of severe VWD (baseline VWF:RCo 
<20 IU/dL) with a history of requiring substitution therapy with von Willebrand 
factor concentrate to control bleeding
a. Type 1 (VWF:RCo <20 IU/dL) or,
b. Type 2A (as verified by multimer pattern), Type 2B (as diagnosed by 
genotype), Type 2M or,
c. Type 3 (VWF:Ag ≤3 IU/dL).
2.
Diagnosis is confirmed by genetic testing and multimer analysis, documented in 
patient history or at screening.
3.
For on-demand patient group, subject currently receiving on-demand treatment for 
whom prophylactic treatment is recommended by the investigator.
4.
For pdVWF switch patient group, subject has been receiving prophylactic 
treatmentof pdVWF products for no less than 12 months prior to screening.
5.
For on-demand patient group, subject has ≥3 documented spontaneous bleeds (not 
including menorrhagia) requiring VWF treatment during the past 12 months.
6.
Availability of records to reliably evaluate type, frequency and treatment of 
bleeding episodes during at least 12 months preceding enrollment. Up to 
24 months retrospective data should be collected if available. Availability of 
dosing and factor consumption during 12 months (up to 24 months) of treatment 
prior to enrollment is required for pdVWF switch subjects and is desired (but not 
a requirement) for on-demand subjects.
7.
Subject is ≥18 years old at the time of screening and has a body mass index 
≥15 but <40 kg/m2.
8.
If female of childbearing potential, subject presents with a negative blood/urine 
pregnancy test at screening and agrees to employ adequate birth control measures 
for the duration of the study.i
9.
Subject is willing and able to comply with the requirements of the protocol.
                                                
i Refer to Section 20.4 for a list of adequate contraceptive methods for females of childbearing potential.
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9.2 Exclusion Criteria
Subjects who meet ANY of the following criteria are not eligible for this study:
1.
The subject has been diagnosed with Type 2N VWD, pseudo VWD, or another 
hereditary or acquired coagulation disorder other than VWD (eg qualitative and 
quantitative platelet disorders or prothrombin time (PT)/international normalized 
ratio [INR] 1.4).
2.
The subject is currently receiving prophylactic treatment with more than 
5 infusions per week.
3.
The subject is currently receiving prophylactic treatment with a weekly dose 
exceeding 240 IU/kg.
4.
The subject has a history or presence of a VWF inhibitor at screening.
5.
The subject has a history or presence of a FVIII inhibitor with a titer 
≥0.4 Bethesda units (BU) (by Nijmegen modified Bethesda assay) or ≥0.6 BU
(by Bethesda assay).
6.
The subject has a known hypersensitivity to any of the components of the study 
drugs, such as to mouse or hamster proteins.
7.
The subject has a medical history of immunological disorders, excluding seasonal 
allergic rhinitis/conjunctivitis, mild asthma, food allergies or animal allergies.
8.
The subject has a medical history of a thromboembolic event.
9.
The subject is human immunodeficiency virus (HIV) positive with an absolute 
Helper T cell (CD4) count 200/mm3.
10. The subject has been diagnosed with significant liver disease per investigator’s 
medical assessment of the subject’s current condition or medical history or as 
evidenced by any of the following: serum alanine aminotransferase (ALT) greater 
than 5 times the upper limit of normal; hypoalbuminemia; portal vein 
hypertension (e.g., presence of otherwise unexplained splenomegaly, history of 
esophageal varices).
11. The subject has been diagnosed with renal disease, with a serum creatinine (CR)
level ≥2.5 mg/dL.
12. The subject has a platelet count <100,000/mL at screening.
13. The subject has been treated with an immunomodulatory drug, excluding topical 
treatment (e.g., ointments, nasal sprays), within 30 days prior to signing the 
informed consent.
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14. The subject is pregnant or lactating at the time of enrollment.
15. Patient has cervical or uterine conditions causing menorrhagia or metrorrhagia 
(including infection, dysplasia).
16. The subject has participated in another clinical study involving another IP or 
investigational device within 30 days prior to enrollment or is scheduled to 
participate in another clinical study involving an IP or investigational device 
during the course of this study.
17. The subject has a progressive fatal disease and/or life expectancy of less than 
15 months.
18. The subject is scheduled for a surgical intervention.
19. The subject is identified by the investigator as being unable or unwilling to 
cooperate with study procedures.
20. The subject has a mental condition rendering him/her unable to understand the 
nature, scope and possible consequences of the study and/or evidence of an 
uncooperative attitude.
21. The subject is in prison or compulsory detention by regulatory and/or juridical 
order.
22. The subject is member of the study team or in a dependent relationship with one 
of the study team members which includes close relatives (i.e., children, 
partner/spouse, siblings and parents) as well as employees.
9.3 Delay Criteria
1.
If the subject has an acute bleeding episode or presents with an acute illness 
(e.g., influenza, flu-like syndrome, allergic rhinitis/conjunctivitis, non-seasonal 
asthma) the screening visit will be postponed until the subject has recovered.
9.4 Withdrawal and Discontinuation
Any subject may voluntarily withdraw (i.e., reduce the degree of participation in the 
study) consent for continued participation and data collection. The reason for withdrawal 
will be recorded on the End of Study CRF. Assessments to be performed at the 
termination visit (including cases of withdrawal or discontinuation) are described in 
Section 10.6 and Section 20.2. 
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Discontinuation (i.e., complete withdrawal from study participation) may be due to 
dropout (i.e., active discontinuation by subject) or loss to follow-up (i.e., discontinuation 
by subject without notice or action). Additionally, the investigator and sponsor have the 
discretion to discontinue any subject from the study if, in their judgment, continued 
participation would pose an unacceptable risk for the subject.
Subjects also will be withdrawn from treatment or discontinued from further study 
participation for the following reasons:
1.
The subject is scheduled for an extended treatment period 3 months with 
non-topical immunomodulating drugs other than anti-retroviral chemotherapy 
(e.g., -interferon, corticosteroid agents [equivalent to hydrocortisone greater than 
10 mg/day]) during the course of the study.
2.
Subjects with chronic hepatitis B or C develop ALT/AST levels exceeding 5 times 
the ULN for 1 month.
3.
Subjects who experience severe hypersensitivity reactions, e.g., anaphylaxis upon 
exposure to rVWF (vonicog alfa).
4.
Subjects who develop a neutralizing inhibitor to rVWF (vonicog alfa) and/or 
ADVATE (rFVIII, octocog alfa) (biological assays) that results in significant 
clinical effect, including but not limited to increasing the weekly dose of rVWF 
by > 50%.
5.
Subjects who demonstrate clinical signs of thromboembolic events.
6.
The subject becomes pregnant. IP exposure will be discontinued. Attempts will be 
made to follow the subject through completion of the pregnancy and up to 1 year 
post delivery, if feasible. The investigator will record a narrative description of 
the course of the pregnancy and its outcome. 
7.
The subject begins lactating. IP exposure will be discontinued. The investigator 
will record a narrative description of the course of the baby’s development. 
8.
The subject is not compliant with the prophylactic treatment regimen and does not 
adhere to the frequency of IP administration. Once >30% of infusions are missed 
within a visit interval (3 months), the subject will be discontinued from further 
participation in the study. 
9.
The subject repeatedly uses other VWF products for prophylaxis or for the 
treatment of bleeding episodes in the absence of an acceptable justification to the 
sponsor. 
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10. STUDY PROCEDURES
10.1 Informed Consent and Enrollment
Any patient who provides informed consent (i.e., signs and dates the informed consent 
form) is considered a subject enrolled in the study.
10.2 Subject Identification Code
The following series of numbers will comprise the SIC: protocol identifier (e.g., 071301) 
to be provided by the sponsor, 2- or 3-digit number study site number (e.g., 02) to be 
provided by the sponsor, and 3- or 4-digit subject number (e.g., 0003) reflecting the order 
of enrollment (i.e., signing the informed consent form). For example, the third subject 
who signed an informed consent form at study site 02 will be identified as Subject 
071301-020003. All study documents (e.g., CRFs, clinical documentation, sample 
containers, drug accountability logs, etc.) will be identified with the SIC. Additionally, a 
uniquely coded SIC(s) is permitted as long as it does not contain a combination of 
information that allows identification of a subject (e.g., collection of a subject’s initials 
and birth date would not be permitted), in compliance with laws governing data privacy.
10.3 Screening and Study Visits
The study site is responsible for maintaining a screening log that includes all subjects 
who provided informed consent. The log also will serve to document the reason for 
screening failure. All screening data will be collected and reported in CRF, regardless of 
screening outcome. If a subject is re-screened, the End of Study CRF should be 
completed, and a new ICF, new SIC and new CRF are required for that subject.
The overall study design is illustrated in the Figure 1. Details on the procedures to be 
performed at each study visit, including screening, are provided in Supplement 20.2
„Schedule of Study Procedures and Assessments“ and Supplement 20.3 „Clinical 
Laboratory Assessments“.
10.3.1 Screening Visit
Written informed consent must be obtained from each subject before any study 
related procedures are performed. To initiate screening procedures, at least 72 hours 
must have elapsed since the last VWF administration for on-demand subjects and the 
subject must not be actively bleeding at the time of screening. For switch subjects, the 
usual interval between their pdVWF prophy infusions must have elapsed since the last 
VWF administration and the subject must not be actively bleeding at the time of 
screening. Multimer analysis and VWD gene mutation analysis should be performed 
at screening if not available in the subject’s medical history.
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The screening visit will be delayed if the subjects presents with an acute bleeding 
episodes or acute illness (e.g., influenza, flu-like symptoms, inflammatory diseases) until 
the event has resolved. All screening procedures and confirmation of eligibility shall take 
place within 42 days prior to the first infusion of IP. If the IP is not infused within 
42 days, all screening assessments except blood group, human leukocyte antigen (HLA), 
genetics, multimeric pattern and 
, must be repeated to reconfirm eligibility. Refer 
to Supplement 20.2 and Supplement 20.3. Upon completion of screening procedures, 
subject eligibility will be confirmed by the sponsor on a subject eligibility form before 
additional study procedures are undertaken. The subject will maintain a diary that will 
include infusion logs (see Section 10.5). The allocation of IP will be initiated after the 
subject has qualified for home treatment (see Section 8.6.4.3.2).
In the event of a subject experiencing a bleeding episode that requires treatment between 
the screening visit and the subsequent visit (i.e. initial PK assessment visit for on-demand 
subjects or prophylaxis initiation visit for switch subjects), the subject will be treated with
rVWF (vonicog alfa). If rVWF (vonicog alfa) is not available for any reason, e.g., subject 
not yet trained on IP administration, study site visit for IP administration not feasible, 
etc., the subject may use his/her standard of care, such as commercial pdVWF/FVIII 
products, and the reason for the use of non-IP products should be clearly documented.
10.3.2 Baseline Visit – Initial PK Assessment (On-demand Subjects Only)
After screening and confirmation of eligibility on-demand subjects will undergo an initial
PK assessment. Subjects will receive a dose of 50 ± 5 IU/kg rVWF:RCo to determine 
VWF and FVIII levels. Blood samples will be drawn within 30 minutes pre-infusion, and 
at 11 time points post-infusion (15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 
3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 
72 2 hours and 96 ± 2 hours). See Section 20.2 and Section 20.3. IP infusion vials from 
the same lot number should be used for all PK-assessments per subject. Samples for 
measurement of FVIII and VWF activity taken through to 6 hours post-infusion will be
obtained from an extremity different from that used for the infusion of IP. Where needed, 
the phlebotomy site will be kept patent via an infusion of normal saline. In this event, at 
least 5 mL of blood will be collected and discarded before collection of the next test 
sample into a fresh syringe.
If the subject has a central venous catheter, the central line should be used to administer 
the infusion and a peripheral venipuncture should be used to collect the blood samples. 
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In the event that a blood sample must be drawn through the central line used for 
administration of IP, the line must first be flushed with at least 10 mL normal saline or 
other suitable catheter flush solution that does not contain anticoagulant. At least 5 mL of 
whole blood must be collected and discarded prior to obtaining the sample. 
If a subject experiences a bleeding episode during the PK assessment no subsequent 
blood sample will be drawn in that specific PK period. The guidance provided in 
Section 8.6.4.4 has to be followed for the treatment of the bleeding episode. The subject 
once recovered is eligible to repeat the PK assessment. 
For pdVWF switch subjects, PK profile will not be assessed until reaching steady state 
after initiation of prophylaxis (see Section 10.3.4).
10.3.3 Prophylaxis Initiation Visit
The prophylaxis initiation visit will occur after the blood sample for the 96 hour PK 
assessment is drawn for on-demand subjects or within 42 days after screening and 
confirmation of eligibility for pdVWF switch subjects. The subject will receive the first 
rVWF (vonicog alfa) prophylactic dose of rVWF: RCo. Details on dose are provided in 
Section 8.6.4.3. 
Procedures and assessments at this visit include (but are not limited to): AEs, bleeding 
episodes, medications taken, and non-drug therapies. Within 2 hours prior the IP infusion, 
a physical examination will be performed. Vital signs will be assessed within 30 minutes 
prior to IP rVWF (vonicog alfa) infusion and 30 minutes ± 15 minutes after IP infusion.
Further details are provided in Supplement 20.2 and Supplement 20.3.
10.3.4 Initial Steady State PK-Assessment (pdVWF switch subjects only)
For pdVWF switch subjects, a full PK profile will be assessed at steady state conditions 
on two occasions. The initial PK assessment will be performed shortly after reaching 
steady state after starting prophylaxis dosing, which is suggested after 11 days post the 
1st, around prophylaxis dose #5-6. The 2nd PK assessment at steady state will be 
performed at the end of the study.
Blood samples will be drawn within 30 minutes pre-infusion, and at 11 time points 
post-infusion (15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 
6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours 
and 96 ± 2 hours). In case the dosing schedule does not permit the 96 hr sampling, 
this sampling time point can be omitted (See Section 11.6). IP infusion vials from 
the same lot number should be used for all PK-assessments per subject. 
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Samples for measurement of FVIII and VWF activity taken through to 6 hours post-
infusion will be obtained from an extremity different from that used for the infusion of 
IP. Where needed, the phlebotomy site will be kept patent via an infusion of normal 
saline. In this event, at least 5 mL of blood will be collected and discarded before 
collection of the next test sample into a fresh syringe.
If the subject has a central venous catheter, the central line should be used to administer 
the infusion and a peripheral venipuncture should be used to collect the blood samples. 
In the event that a blood sample must be drawn through the central line used for 
administration of IP, the line must first be flushed with at least 10 mL normal saline or 
other suitable catheter flush solution that does not contain anticoagulant. At least 5 mL of 
whole blood must be collected and discarded prior to obtaining the sample. 
If a subject experiences a bleeding episode during the PK assessment no subsequent 
blood sample will be drawn in that specific PK period. The guidance provided in 
Section 8.6.4.4 has to be followed for the treatment of the bleeding episode. The subject 
once recovered is eligible to repeat the PK assessment. In case of surgery or bleeding, the 
PK assessment should be performed after 11 days after 1st prophylactic dose after re-start 
of prophylactic regimen. See section 11.6 for more details.
10.3.5 Treatment of Bleeding Episodes
Treatment of bleeding episodes is described in detail in Section 8.6.4.4 and treatment of 
perioperative bleeding is described in detail in Section 8.6.4.5.
10.3.6 Perioperative Visits (only applicable if surgery is needed)
The perioperative visits from priming dose through postoperative day 14 will be required 
to check daily intra- and postoperative weight-adjusted dose of rVWF (vonicog alfa) with 
or without ADVATE (rFVIII, octocog alfa). Details on the procedures and assessments 
performed at each visit can be found in supplement tables in Section 20.2.1 and 
Section 20.3.1.
10.3.7 Follow-Up Visits (1 Month ± 1 Week, 2 Months ± 1 Week, 
3 Months ± 2 Weeks, 6 Months ± 2 Weeks, 9 Months ± 2 Weeks post 
Prophylaxis Initiation Visit)
Visits will be performed after the prophylaxis initiation visit at 1 month ± 1 week, 
2 months ± 1 week, and 3 months ± 2 weeks and thereafter every three months
± 2 weeks. Additional visits may occur if clinically indicated (see Section 10.3.8).
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When possible, site visits should be scheduled on days when the subject is expected to 
infuse rVWF (vonicog alfa). Within 2 hours prior to the rVWF (vonicog alfa) IP infusion,
a physical examination will be performed. Vital signs will be assessed within 30 minutes 
prior to IP infusion and 30 minutes ± 15 minutes after IP infusion. Incremental recovery 
(IR) will be determined at each follow-up visit based on VWF:RCo activity assessed 
prior to and after IP infusion.
The blood sample for IR analysis will be drawn within 30 minutes prior to IP infusion 
and 30 minutes ± 5 minutes after IP infusion. rVWF (vonicog alfa) will be infused at the 
regular prophylactic dose. For each subject’s recovery analysis IP infusion, vials from the 
same lot number should be used. 
Testing for VWF:RCo VWF:CB, rVWF:Ag, and FVIII:C level will be performed using 
the blood sample obtained before and after IP infusion. 
The blood sample prior to IP infusion will also be used for the assessment of neutralizing
and binding antibodies, clinical chemistry and hematology. For on-demand subjects, a
washout period of at least 72 hours after the last infusion applies before the blood draw 
for the immunogenicity assays. For switch subjects, the wash out period may be reduced 
to the time interval between their pdVWF prophy infusions Bleeding episodes and the 
hemostatic efficacy will be evaluated based on the review of the patient diary. See
Section 20.2 and Section 20.3. The evaluation of IP consumption and treatment 
compliance will be performed based on subject’s diary entries. If a subject is not 
compliant with the prophylactic treatment regimen and does not adhere to the required 
frequency of administration of IP infusions (>30% of infusions were missed within a visit 
interval [3 months]) the subject will be withdrawn from the study.
At the 6 months ± 2 week visit an ECG will be performed and 
data will be 
collected. 
For the hemostatic efficacy assessment the following information will be recorded by the 
subject in the patient diary: bleeding location, type, severity, onset and resolution date 
and time, infusion date and time, clinical efficacy according to the rating scale. If at any 
time during the study a subject’s bleeding episode does not adequately respond to rVWF 
(vonicog alfa) therapy, he/she will be evaluated for the presence of neutralizing and total 
binding antibodies. Refer to Section 12.9.3.2.
Further guidance on completing the subject’s diary will be provided to the subjects during 
training for home treatment (see Section 8.6.4.3.2).
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10.3.8 Unscheduled Visits
For any unscheduled visit (except for collection of IP) a clinical assessment will be 
performed as per the scheduled follow-up visits with the exception of 
, ECG, and 
IR determination (refer to Supplement 20.2 and Supplement 20.3).
Subjects who have more than one bleeding episode in 3 months, or an increased 
frequency of bleeding, should go to the study site for an unscheduled visit.
Follow-up visits after the subject has experienced a bleed may be requested by the 
investigator. Additional assessments may be required which are at the discretion of the 
investigator. 
10.3.9 End of Study PK Assessment and Study Termination Visit
(12 Months ± 2 Weeks post Prophylaxis Initiation Visit)
At the 12 month ± 2 week visit, a full PK analysis at steady state will be performed for 
both cohorts: on-demand and switch subjects. Blood samples will be drawn within 
30 minutes pre-infusion, and at 11 time points post-infusion (15 ± 5 minutes, 
30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 
24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours and 96 ± 2 hours) unless dosing 
schedule does not permit, in which case the 96 hr sampling can be omitted. If a subject 
experiences a bleeding episode during the PK assessment no subsequent blood sample 
will be drawn in that specific PK period. The guidance provided in Section 8.6.4.4 has to 
be followed for the treatment of the bleeding episode. The subject once recovered is 
eligible to repeat the PK assessment and the PK assessment should be performed after 
11 days after 1st prophylactic dose after re-start of prophylactic regimen. See section 11.6
for more details.
Refer to Supplement 20.2 and Supplement 20.3 for the other assessments to be performed 
at the PK assessment and study completion visits.
For on-demand subjects, a washout period of at least 72 hours is required between the PK
infusion and the study termination visit (at the time of the 96 hour postinfusion PK 
assessment). For switch subjects,  the wash out period may be reduced to the time interval 
between their rVWF (vonicog alfa) prophy infusions.Refer to Supplement 20.2 and 
Supplement 20.3 for the list of assessments to be performed at the termination visit.
Subjects will be offered the option to continue to receive rVWF (vonicog alfa) in a 
long-term continuation study.
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10.4 Medications and Non-Drug Therapies 
The following medications and non-drug therapies are not permitted within 30 days 
before study entry and during the course of the study:
Medications:

Immunomodulating drugs other than anti-retroviral chemotherapy (e.g.,
-interferon, or corticosteroid agents at a dose equivalent to hydrocortisone 
greater than 10 mg/day) and an extended treatment period 3 months.

Another investigational and/or interventional study drug (except rVWF and FVIII 
administered under the surgery protocol).
A subject who has taken any of these medications or received any of these non-drug 
therapies during the study will be withdrawn from the study. 
The following medications are permitted during the course of the study:

Antifibrinolytics (e.g., tranexamic acid, -amino caproic acid) or topical
hemostats as needed, according to each institution’s standard of care. These may 
be used, in accordance with local standard clinical practice, as the initial or only 
treatment for minor and moderate bleeding events. However, if the bleeding has 
not stopped within 24 hour following administration of this non-VWF treatment, 
infusion(s) with rVWF (vonicog alfa) should be started per protocol

Emergent use of a VWF concentrate other than rVWF (vonicog alfa) may be 
permissible under certain circumstances (see Section 8.6.4.4.1)
Details of all adjunctive hemostatic medication used, including dose and reason for use, 
must be recorded in the eCRF.
10.5 Subject Diary
1.
An electronic subject diary will be provided to each subject at the screening visit 
to record the following information:

IP infusions to include date, start and stop times of the infusion, number of 
vials utilized, and infusion volume for prophylactic treatment or treatment of 
spontaneous and traumatic bleeding episodes 
2.
Details of bleeding episodes (site, type, severity and date/time of bleeding) and 
response to treatment as described in Section 8.6.4.4
3.
Subjective hemostatic efficacy assessments
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4.
Untoward events/unwanted experiences
5.
Concomitant medications (including immunizations) and non-drug therapies
6.
Patient Reported Outcomes (PROs)
Subjects and/or their legally authorized representatives will be trained on use of the diary. 
The diary will be provided in electronic format and remain with the subject for the 
duration of the study. The investigator will review the diary for completeness and request 
missing information periodically and in a timely manner. The investigator will 
record/capture any unwanted experience reported by the subject which may qualify as an 
AE on the AE eCRF.
Infusions performed at the study site will first be recorded in the site’s source documents 
and not in the patient diary.
Subject entries in the diary will serve as source records. During study participation the 
investigator has access to the database holding the subject diary data. After study closure, 
the investigator will receive the diary records for their subjects, including audit trail 
records, in PDF format. The data will be transmitted to the CRF by a validated transfer. 
Paper diary may be utilized in rare case where electronic diary use is not possible.
10.6 Subject Completion/Discontinuation
A subject is considered to have completed the study when he/she ceases active 
participation in the study because the subject has, or is presumed to have completed all 
study procedures according with the protocol (with or without protocol deviations).
Reasons for completion/discontinuation will be reported on the 
Completion/Discontinuation CRF, including: completed, screen failure, AE (e.g., death), 
discontinuation by subject (e.g., lost to follow-up [defined as 3 documented unsuccessful 
attempts to contact the subject], dropout), physician decision (e.g., pregnancy, 
progressive disease, non-compliance with IP/protocol violation(s), recovery), study 
terminated by sponsor, or other (reason to be specified by the investigator, e.g., technical 
problems). Regardless of the reason, all data available for the subject up to the time of 
completion/discontinuation should be recorded on the appropriate CRF. 
Every effort will be made to have discontinued subjects complete the study 
termination visit. If the termination visit is done as an additional, unscheduled 
visit, the assessment results shall be recorded with the termination visit.
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If a subject terminates participation in the study and does not return for termination visit, 
his/her last recorded assessments shall remain with the last visit. The reason for 
discontinuation will be recorded, and the data collected up to the time of discontinuation 
will be used in the analysis and included in the clinical study report. If additional 
assessments are required, the assessments shall be recorded separately. Assessments to be 
performed at the termination visit (including in cases of withdraw or discontinuation) can 
be found in Supplement 20.2 Schedule of Study Procedures and Assessments and 
Supplement 20.3 Clinical Laboratory Assessments.
In the event of subject discontinuation due to an AE, clinical and/or laboratory 
investigations that are beyond the scope of the required study observations/assessments 
may be performed as part of the evaluation of the event. These investigations will take
place under the direction of the investigator in consultation with the sponsor, and the 
details of the outcome may be reported to the appropriate regulatory authorities by the 
sponsor. 
10.7 Procedures for Monitoring Subject Compliance
Subject compliance with the procedures of this study (treatment regimens and study 
visits) will be monitored by the investigator or/a licensed healthcare professional at the 
study site.
During the regular scheduled follow-up visits a direct review of the subject’s source data 
(e-diaries) will be performed at the sites and evaluated against the protocol requirements. 
In addition drug accountability will be evaluated at each follow-up study visit and the 
study termination visit by comparing the infusions recorded in the subject diary with
empty vials returned by each subject to the study site, and the study site’s dispensing 
record. Protocol deviations will be noted in the final report. 
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11. ASSESSMENT OF EFFICACY AND PHARMACOKINETICS
11.1 Assessment of Spontaneous Bleeding Episodes/Annualized Bleed Rate 
The annualized bleed rate (ABR) will be assessed based upon each individual 
spontaneous bleed, requiring coagulation factor replacement therapy, i.e., rVWF 
(vonicog alfa) treatment. The following details on bleeding episodes will be recorded by 
the subject in the electronic diary (for home treatment), the subject’s healthcare provider 
in the site’s source documents (for treatments away from the primary investigative site), 
or by authorized, qualified personnel at the participating site in the subject’s medical 
records (for hospital-based treatment):

Location of bleed; i.e., joint, menorrhagia, epistaxis, gastrointestinal, soft tissue, 
muscle, body cavity, intracranial, etc.

Type of bleed; i.e., spontaneous, traumatic, unknown

Severity of bleed; i.e., minor, moderate, and major (see Table 3)

Date and time of onset of bleed

Date and time of each infusion of rVWF (vonicog alfa) or rVWF (vonicog alfa)-
ADVATE (rFVIII, octocog alfa) used to treat a bleeding episode

Date and time of resolution of the bleeding episode
Study site personnel are qualified after they have undergone training during the 
qualification of the site.
All types of bleeds, including traumatic bleeds, will be recorded. Bleeding episodes 
should be organized by where they occur in addition to whether they occurred 
spontaneously or due to a traumatic event.
Bleeds occurring at the same anatomical location (e.g., right knee) with the same etiology 
(i.e., spontaneous versus injury) within 24 hours after onset of the first bleed will be 
considered a single bleed. Bleeding occurring at multiple locations related to the same 
injury (e.g., knee and ankle bleeds following a fall) will be counted as a single bleeding 
episode.
All efforts should be made to use rVWF (vonicog alfa) for treatment of bleeding 
episodes. If needed, the use of a VWF concentrate other than IP for the treatment of 
bleeding episodes will not disqualify the subject from further participation in the study.
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11.2 Evaluation of ABR Before rVWF Prophylaxis and ABR Under rVWF
Prophylactic Treatment
At screening, the subject’s medical history will be recorded, including the number and 
location of all spontaneous and traumatic bleeding episodes within the past 12 months (up
to 24 months if available). The maximum interval of bleed-free periods as well as trauma
induced bleeding episodes will also be recorded (prospectively and retrospectively).
11.3 Number of Infusions and Total Weight Adjusted Consumption of rVWF and 
ADVATE and historical prophylaxis dosing and factor consumption during 
pdVWF prophylaxis treatment prior to enrollment
The number of rVWF (vonicog alfa) and ADVATE (rFVIII, octocog alfa) (in case of 
bleeding episode treatment) infusions will be logged in the subject diary. Based on these 
entries the weight adjusted consumption will be calculated. 
At the screening, historical pdVWF dosage and dosing frequency during 12 and up to 
24 months of pdVWF prophylactic treatment prior to enrollment will be recorded for the 
pdVWF switch subjects in order to calculate the consumption of pdVWF.
11.4 Assessment of Efficacy for Treatment of Bleeding Episode
Investigators will be asked to assess and record hemostatic efficacy after resolution of 
each bleeding episode using the 4-scale rating system outlined in Table 4. 
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Table 4
Efficacy Rating Scale
Rating
Efficacy Rating Criterion
Minor and Moderate Bleeding Events
Major Bleeding Events
Excellent (=1)
Actual number of infusions ≤ estimated 
number of infusions required to treat that 
bleeding episode
No additional VWF containing 
coagulation factor containing product 
required
Actual number of infusions ≤ estimated 
number of infusions required to treat that 
bleeding episode
No additional VWF containing coagulation 
factor containing product required
Good (=2)
1-2 infusions greater than estimated 
required to control that bleeding episode
No additional VWF containing 
coagulation factor containing product 
required
< 1.5 x infusions greater than estimated 
required to control that bleeding episode
No additional VWF containing coagulation 
factor containing product required
Moderate (=3)
3 or more infusions greater than estimated 
required to control that bleeding episode
No additional VWF containing 
coagulation factor containing product 
required
≥1.5 x infusions greater than estimated 
required to control that bleeding episode
No additional VWF containing coagulation 
factor containing product required
None (=4)
Severe uncontrolled bleeding or intensity 
of bleeding not changed
Additional VWF containing coagulation 
factor containing product required
Severe uncontrolled bleeding or intensity 
of bleeding not changed
Additional VWF containing coagulation 
factor containing product required
11.5 Assessment of Efficacy for Treatment for Surgical Bleeding
For those undergoing surgery, the operating surgeon will be asked to assess and record 
actual versus predicated blood loss and intraoperative hemostatic efficacy immediately 
after surgery. 
The investigator will be asked to assess and record an overall assessment of hemostatic 
efficacy 24 hours after the last perioperative rVWF (vonicog alfa) infusion or at day 14 
post-operation, whichever occurs first, using the 4-scale rating system described in 
Table 5.
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Table 5
Assessment of Hemostatic Efficacy
Rating
Overall Assessment of Hemostatic Efficacy 24 Hours After the Last Perioperative
rVWF Infusion
Excellent (1)
Intra- and post-operative hemostasis achieved with rVWF (vonicog alfa) with or without 
ADVATE (rFVIII, octocog alfa) was as good or better than that expected for the type of 
surgical procedure performed in a hemostatically normal subject
Good (2)
Intra- and post-operative hemostasis achieved with rVWF (vonicog alfa) with or without 
ADVATE (rFVIII, octocog alfa) was probably as good as that expected for the type of 
surgical procedure performed in a hemostatically normal subject
Moderate (3)
Intra- and post-operative hemostasis with rVWF (vonicog alfa) with or without ADVATE 
(rFVIII, octocog alfa) was clearly less than optimal for the type of procedure performed but 
was maintained without the need to change the rVWF (vonicog alfa) concentrate
None (4)
Subject experienced uncontrolled bleeding that was the result of inadequate therapeutic 
response despite proper dosing, necessitating a change of rVWF (vonicog alfa) concentrate
11.6 rVWF Pharmacokinetics and Pharmacodynamics 
PK will be assessed twice for all subjects.
For on-demand subjects, an initial PK assessment using a dose of 50 IU ± 5 IU/kg 
rVWF:RCo will be performed at the baseline visit, and a washout period of at least 
5 days is required before the infusion of rVWF (vonicog alfa) for PK assessment can 
be administered. At the 12 month ± 2 week visit, a steady state PK analysis will be 
performed based on the longer interval of the irregular dosing intervals employed. For 
both assessments, blood samples will be drawn within 30 minutes pre-infusion, and at 
11 time points post-infusion (15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 
3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 
72 2 hours and 96 ± 2 hours). VWF activity will be determined using the VWF:RCo, 
VWF:CB and the VWF: Ag assay. Endogenous FVIII activity will be measured using the 
1-stage clotting assay to assess the pharmacodynamics of rVWF (vonicog alfa). 
For pdVWF switch subjects, the initial PK assessment using the subject’s individualized 
dose will be performed shortly after reaching steady state, which is estimated to be 
reached for the majority of subjects after  approximately 11 days from the 1st prophylactic 
dose. To fit any logistical requirements, samples for PK analysis can be taken after 
prophylaxis dose #5-6, and whenever possible, sample collections should be during the 
longer partial interval of the alternating irregular dosing intervals. For example, if a 
subject follows a dosing regimen as follows:
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Date
Weekday
Dose number
Interval
Time from 1st dose in hours
8.1.18 8:00
Monday
1
0
0
12.1.18 8:00
Friday
2
4
96
15.1.18 8:00
Monday
3
3
168
19.1.18 8:00
Friday
4
4
264
22.1.18 8:00
Monday
5
3
336
26.1.18 8:00
Friday
6
4
432
After reaching the steady state, the PK assessment can be done at dose 5 to allow the 96h 
post-infusion sampling, before the next scheduled dose (for patients on a twice per week 
dosing schedule). A similar 2nd full PK profile will be assessed at the end of the study, i.e. 
12 month ± 2 week visit with a PK infusion at the same dosing partial interval (96h 
interval in this case). Blood samples will be drawn within 30 minutes pre-infusion, 
and at 11 time points post-infusion (15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 
3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 
72 2 hours, and 96 ± 2 hours). If the dosing interval for a certain switch subject 
wouldn’t allow for the full 11 post-infusion timepoints sample collection, the 96-hour 
sampling timepoint can be omitted, but it is critical that the assessments are at the same 
partial interval, thereby same number of sampling timepoints, for the 1st and 2nd PK for an 
individual switch subject.
If a subject experiences a bleeding episode during the PK assessment no subsequent 
blood sample will be drawn in that specific PK period. The guidance provided in 
Section 8.6.4.4 has to be followed for the treatment of the bleeding episode. The subject 
once recovered is eligible to repeat the PK assessment. In case of surgery or bleeding, the 
PK assessment should be performed after 11 days after 1st prophylactic dose after restart 
of prophylactic regimen.
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12. ASSESSMENT OF SAFETY
12.1 Adverse Events
12.1.1 Definitions
An AE is defined as any untoward medical occurrence in a subject administered IP that 
does not necessarily have a causal relationship with the treatment. An AE can therefore 
be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom
(e.g., rash, pain, discomfort, fever, dizziness, etc.), disease (e.g., peritonitis, bacteremia, 
etc.), or outcome of death temporally associated with the use of an IP, whether or not 
considered causally related to the IP.
12.1.1.1 Serious Adverse Event
An SAE is defined as an untoward medical occurrence that, at any dose, meets one or 
more of the following criteria:

Outcome is fatal/results in death (including fetal death)

Is life-threatening – defined as an event in which the subject was, in the judgment 
of the investigator, at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death had it been more severe.

Requires inpatient hospitalization or results in prolongation of an existing 
hospitalization – inpatient hospitalization refers to any inpatient admission, 
regardless of length of stay.

Results in persistent or significant disability/incapacity (i.e., a substantial 
disruption of a person’s ability to conduct normal life functions)

Is a congenital anomaly/birth defect

Is a medically important event – a medical event that may not be immediately 
life-threatening or result in death or require hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the definitions above. Examples of such events are (including 
but not limited to): 

Intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias, or convulsions that do not result in 
hospitalization, or development of drug dependence or drug abuse 

Reviewed and confirmed seroconversion for HIV, hepatitis A virus (HAV), 
hepatitis B virus (HBV), hepatitis C virus
(HCV), hepatitis E virus (HEV), or parvovirus B19 (B19V)
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
Development of clinically significant neutralizing VWF antibodies

Development of neutralizing antibodies to FVIII (titer ≥0.4 BU [by 
Nijmegen- modified Bethesda assay] or ≥0.6 BU [by Bethesda assay])

Thromboembolic events (e.g., myocardial infarction, stroke, transient 
ischemic attack [TIA], deep vein thrombosis [DVT] or pulmonary 
embolism)

Hypersensitivity reactions (e.g., anaphylaxis [for definition, refer to 
Section 12.6.2] and other immediate and delayed hypersensitivity reactions 
which may manifest with urticarial rash, pruritus, flushing, angioedema of 
the face, extremities, or laryngeal tissues [leading to throat tightness with 
stridor], wheezing, gastrointestinal symptoms, and/or hypotension)
Uncomplicated pregnancies, following maternal or paternal exposure to IP are not 
considered an AE/SAE; however, any pregnancy complication or pregnancy termination 
by therapeutic, elective, or spontaneous abortion shall be considered an SAE and should 
be reported per SAE reporting guidelines provided in Section 12.1.2.3 (Safety Reporting).
12.1.1.2 Suspected Unexpected Serious Adverse Reaction (SUSAR)
Any suspected adverse reaction to study treatment that is both serious and unexpected is 
considered a SUSAR. 
The event(s) must meet all of the following:

Suspected adverse reaction (which implies that there is reasonable evidence 
indicating a causal relationship between the event and the study treatment),

Unexpected (per Reference Safety Information (RSI)/IB), and

Serious
Once determined to meet the criteria for a SUSAR, the sponsor will ensure expedited 
SUSAR reporting is completed in line with the regulatory requirements in participating 
countries as outlined in the Safety Management Plan.
12.1.1.3 Non-Serious Adverse Event
A non-serious AE is an AE that does not meet any of the seriousness criteria (death, 
life-threatening, hospitalizing/prolongation of hospitalization, disability, congenital 
anomaly, or medically significant and if not urgently treated would result in one of the 
above) listed in section 12.1.1.1.
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12.1.1.4 Unexpected Adverse Events
An unexpected adverse event is an AE whose nature, severity, specificity, or outcome is 
not consistent with the term, representation, or description used in the Reference Safety 
Information (e.g., IB, PI [prescribing information]). “Unexpected” also refers to the AEs
that are mentioned in the IB as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring 
with the particular drug under investigation.
12.1.1.5 Preexisting Disease
Preexisting diseases that are present before entry in to the study are described in the 
medical history, and those that manifest with the same severity, frequency, or duration 
after IP exposure will not be recorded as AEs. However, when there is an increase in the 
severity, duration, or frequency of a preexisting disease, the event must be described as 
“worsening” of the pre-existing condition on the AE CRF.
12.1.2 Assessment of Adverse Events
For the purposes of this study, the following will not be considered as AEs and will not 
be included in the analysis of AEs.

Bleeding episodes are part of the underlying disease and therefore are not AEs; 
they will be evaluated in the context of efficacy.

For non-serious bleeding episodes caused by an injury, the injury would not 
be reported as an AE, unless it resulted in a medical finding other than a 
bleeding episode (e.g., abrasion of skin). Therefore, any VWD-related 
bleeding event (e.g., epistaxis, gastrointestinal bleeding, musculo-skeletal 
bleeding, menorrhagia) that is non-serious will not be reported as an AE. 
However, the investigator may decide that the event is an AE if the event also 
would have occurred in a healthy individual under the same circumstances.

For serious bleeding episodes (bleeding SAEs): Bleeding events that meet 
seriousness criteria (death, life-threatening, hospitalizing/prolongation of 
hospitalization, disability, congenital anomaly, or medically significant and if 
not urgently treated would result in one of the above) should be captured on 
the SAE eCRF and reported as an SAE to the Sponsor or designee (e.g., 
CRO) on an SAE Report form as described in Section 12.1.2.3 (Safety 
Reporting).

Seroconversion after documented HAV/HBV vaccination prior to or during the 
study period.
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Each AE from the first IP exposure to the study completion date will be described on the 
AE CRF using the term representing medical diagnosis (preferred), or, if no diagnosis 
could be established at the time of reporting the AE, a symptom or sign, in standard 
medical terminology in order to avoid the use of vague, ambiguous, or colloquial 
verbatim expressions (see definition in Section 12.1). Each AE will be evaluated by the 
investigator for:

Seriousness as defined in Section 12.1.1.1

Severity as defined in Section 12.1.2.1

Causal relationship to IP exposure or study procedure as defined in 
Section 12.1.2.2
For each AE, the outcome (i.e., recovering/resolving, recovered/resolved, 
recovered/resolved with sequelae, not recovered/not resolved, fatal, unknown) and if 
applicable, action taken with regards to the study treatment (i.e., dose increased, dose not 
changed, dose reduced, drug interrupted, drug withdrawn, not applicable, or unknown) 
will also be recorded on the AE CRF. Recovering/resolving AEs will be followed until 
resolution or until the subject’s condition returns to the level at the baseline for pre-
existing conditions.
If the severity rating for an ongoing AE changes before the event resolves, the original 
AE report will be revised (i.e., the event will not be reported as separate AE). During the 
course of any AE, the highest severity rating will be reported.
Deviations from the protocol-specified dosage (including underdosing /overdosing
[<20 IU/kg rVWF:RCo or >100 rVWF:RCo], abuse, and withdrawal, treatment errors 
(including incorrect route of administration, use of an incorrect product, and deviations 
from the protocol-defined dosing schedule), failures of expected pharmacological actions, 
and unexpected therapeutic or clinical benefits will be followed with regard to occurrence 
of AEs, lack of efficacy, and/or other observations because these events may be 
reportable to regulatory authorities. 
Any pregnancy that occurs after administration of IP will be reported on a Pregnancy 
Form and followed-up at 1 year post-delivery, if feasible. 
If an investigator becomes aware of an SAE occurring in a subject after study completion, 
the SAE must be reported on the SAE Form within 24 hours after awareness: no 
additional reporting on CRFs is necessary.
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12.1.2.1 Severity
The investigator will assess the severity of each AE using his/her clinical expertise and 
judgment based on the most appropriate description below:

Mild
The AE is a transient discomfort and does not interfere in a significant manner 
with the subject’s normal functioning level.
The AE resolves spontaneously or may require minimal therapeutic 
intervention.

Moderate
The AE produces limited impairment of function and may require therapeutic 
intervention.
The AE produces no sequela/sequelae.

Severe
The AE results in a marked impairment of function and may lead to temporary 
inability to resume usual life pattern.
The AE produces sequela/sequelae, which require (prolonged) therapeutic 
intervention.
These severity definitions will also be used to assess the severity of an AE with a study-
related procedure(s), if necessary.
12.1.2.2 Causality
Causality is a determination of whether there is a reasonable possibility that the IP is 
etiologically related to/associated with the AE. Causality assessment includes, e.g., 
assessment of temporal relationships, dechallenge/rechallenge information, association 
(or lack of association) with underlying disease, presence (or absence) of a more likely 
cause, and physiological plausibility. For each AE, the investigator will assess the causal 
relationship between the IP and the AE using his/her clinical expertise and judgment 
according to the following most appropriate algorithm for the circumstances of the AE:

Not related (both circumstances must be met)
Is due to underlying or concurrent illness, complications, concurrent 
treatments, or effects of concurrent drugs
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Is not associated with the IP (i.e., does not follow a reasonable temporal 
relationship to the administration of IP, is not biologically plausible per 
mechanism of action of the IP, or has a much more likely alternative etiology). 

Unlikely related (either 1 or both circumstances are met)
Has little or no temporal relationship to the IP 
A more likely alternative etiology exists

Possibly related (both circumstances must be met)
Follows a reasonable temporal relationship to the administration of IP
An alternative etiology is equally or less likely compared to the potential 
relationship to the IP

Probably related (both circumstances must be met)
Follows a strong temporal relationship to the administration of IP, which may 
include but is not limited to the following: 
o
Reappearance of a similar reaction upon re-administration (positive re-
challenge)
o
Positive results in a drug sensitivity test (skin test, etc.)
o
Toxic level of the IP as evidenced by measurement of the IP 
concentrations in the blood or other bodily fluid
Another etiology is unlikely or significantly less likely
For events assessed as not related or unlikely related and occurring within 5 days after IP 
infusion, the investigator shall provide the alternative etiology. These causality 
definitions will also be used to assess the relationship of an AE with a study-related 
procedure(s), if necessary.
12.1.2.3 Safety Reporting
AEs and SAEs will be assessed at all study visits as outlined in the Schedule of Study 
Procedures and Assessments (see Section 20.2) and Section 12.1.2.
Adverse Events and SAEs are to be recorded on the AE page of the eCRF. Each event 
should be recorded separately.
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Any SAE, including death due to any cause, which occurs during this study, whether or 
not related to the IP, must be reported immediately (within 24 hours of the study center’s 
first knowledge of the event). All SAEs must be reported in English via the Electronic 
Data Capture (EDC) system by completing the relevant eCRF page(s) and also by SAE 
Report Form via fax/email to Sponsor’s Global Drug Safety (Baxalta GDS) department 
within 24 hours of becoming aware of the event for SAEs (for contacts, instructions, and
additional details, refer to the SAER form).
Within 24 hours of site awareness of a SAE (or Pregnancy) study sites will complete and 
send all SAE (or Pregnancy) reports to a dedicated:
Baxalta Global Drug Safety fax number:  
OR 
email:
The responsible Site Monitor will review the SAE (or Pregnancy) Reports for 
completeness, will reconcile the reports against the EDC database, and will follow-up 
with sites to obtain missing information and/or information requiring clarification. Any 
SAE associated with a pregnancy must be reported on the SAER Form.
For Follow-up Reports, the site shall use a new SAER form (marked as Follow-up) and 
the new information should be entered together with a brief narrative identifying the 
updated data. 
An SAER should include the following minimum information:
1.
Protocol Number (on all pages)
2.
Subject identification number (on all pages) and demographics (gender, age at 
onset of event and/or date of birth)
3.
Investigational product and treatment regimen (including date of the first dose of 
IP, date of the last dose of IP prior to the onset of the SAE)
4.
Medical Term for Event (Diagnosis preferably) 
5.
Description of the SAE, including:

Date of onset

Causal relationship assessment by the Investigator
6.
Seriousness criteria (e.g., death, life-threatening, hospitalization, medically 
significant, or other criterion)
7.
Name, address, fax number, email, and telephone number of the 
reporter/Investigator
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Post-trial SAE Reporting: In compliance to EudraLex Volume 10 (Clinical trials 
guidelines, Chapter II: Safety Reporting from the European Commission), which 
references an EMA guidance (ICH Topic E 2 A - Clinical Safety Data Management: 
Definitions and Standards for Expedited Reporting), clinical sites/the investigator should 
report to the Sponsor SAEs after a subject´s study completion. Study sites will be 
provided a Post-Trial SAER form to complete and report these post-study SAEs to the 
Sponsor within the 24 hours of their awareness. Site Monitor will instruct the site that any 
such Post-Trial SAEs should be reported on the study-specific Post-Trial SAER form 
if/when the site becomes aware of it. Such information will not be actively monitored by 
the sponsor after completion of the study.
These events shall be reported to Baxalta GDS who will process them in the same way as 
SAEs occurring during the study. Post-Trial SAEs do not need to be captured in the study 
EDC database if it is already locked. Irrespective if captured in the EDC database or not, 
such Post-Trial SAEs will become part of the GDS database. The monitor should remind 
the clinical site about the post-trial SAE reporting requirements during interim 
monitoring visits, upon each subject’s study completion as well as during the close-out 
visit.
12.2 Urgent Safety Measures
An urgent safety measure is an immediate action taken, which is not defined by the 
protocol, in order to protect subjects participating in a clinical trial from immediate harm. 
Urgent safety measures may be taken by the sponsor or clinical investigator, and may 
include any of the following: 

Immediate change in study design or study procedures

Temporary or permanent halt of the clinical trial 

Any other immediate action taken in order to protect clinical trial participants 
from immediate hazard to their health and safety
The investigator may take appropriate urgent safety measures in order to protect subjects 
against any immediate hazard to their health or safety. The measures should be taken 
immediately and may be taken without prior authorization from the sponsor. 
In the event(s) of an apparent immediate hazard to the subject, the investigator will notify 
the sponsor immediately by phone and confirm notification to the sponsor in writing as 
soon as possible, but within 1 calendar day after the change is implemented. The sponsor 
will also ensure the responsible ethics committees (ECs) and relevant competent 
authority(s) are notified of the urgent measures taken in such cases according to local 
regulations.
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12.3 Untoward Medical Occurrences
Untoward medical occurrences occurring before the first exposure to IP are not 
considered AEs (according to the definition of AE, see Section 12.1.1). However, each 
serious untoward medical occurrence experienced before the first IP exposure (i.e., from 
the time of signed informed consent up to but not including the first IP exposure) will be 
described on the SAER. These events will not be considered as SAEs and will not be 
included in the analysis of SAEs. 
12.4 Non-Medical Complaints
A non-medical complaint (NMC) is any alleged product deficiency that relates to 
identity, quality, durability, reliability, safety and performance of the product but did not 
result in an AE. NMCs include but are not limited to the following:

A failure of a product to exhibit its expected pharmacological activity and/or 
design function, e.g. reconstitution difficulty

Missing components

Damage to the product or unit carton

A mislabeled product (e.g., potential counterfeiting/tampering)

A bacteriological, chemical, or physical change or deterioration of the product 
causing it to malfunction or to present a hazard or fail to meet label claims
Any NMCs of the product will be documented on an NMC form and reported to the 
sponsor within 1 business day. If requested, defective product(s) will be returned to the 
sponsor for inspection and analysis according to procedures.
12.5 Medical, Medication, and Non-Drug Therapy History
At screening, the subject’s medical history will be described for the following body 
systems including severity (defined in Section 12.1.2.1) or surgery and start and end 
dates, if known: eyes, ears, nose, and throat; respiratory; cardiovascular; gastrointestinal; 
musculoskeletal; neurological; endocrine; hematopoietic/lymphatic; dermatological; and 
genitourinary. The subject’s medical history will also include documented history of 
on-demand or pdVWF prophylaxis treatment for at least the past 12 months and a 
documented history, e.g., patient charts and prescription information, of all bleeding 
episodes within the past 12 months (up to 24 months if available).
All medications taken and non-drug therapies received in the 2 weeks prior to study entry 
and all concomitant medications and non-drug therapies during study will be recorded on 
the CRFs.
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Data on medical history, drug and non-drug therapy history of those subjects who 
transition from surgery rVWF (vonicog alfa) study will be used from the eCRF of the 
main studies, will be updated, if applicable, and transcribed into the respective eCRF of 
the prophy study. 
12.6 Physical Examinations
At screening and subsequent study visits (as described in Section 10.3), a physical 
examination will be performed on the following body systems: general appearance, head 
and neck, eyes and ears, nose and throat, chest, lungs, heart, abdomen, extremities and 
joints, lymph nodes, skin, and neurological. At screening, if an abnormal condition is 
detected, the condition will be described on the medical history CRF. At study visits, if a 
new abnormal or worsened abnormal pre-existing condition is detected, the condition will 
be described on the AE CRF. If the abnormal value was not deemed an AE because it 
was due to an error, due to a preexisting disease (described in Section 12.1.1.5), not 
clinically significant, a symptom of a new/worsened condition already recorded as an AE, 
or due to another issue that will be specified, the investigator will record the justification 
on the source record.
12.6.1 Thromboembolic Events
There is a risk of occurrence of thrombotic events, particularly in patients with known 
clinical or laboratory risk factors for thrombosis including low ADAMTS13 levels.  
Therefore, patients at risk must be monitored for early signs of thrombosis during the 
study and prophylaxis measures against thromboembolism should be instituted according 
to current recommendations and standard of care. Additional diagnostic procedures are 
required according to each institution’s standard of care which may consist of, but are not 
limited to the following:

For DVT: Magnetic Resonance Imaging (MRI), compression ultrasound or 
impedance plethysmography.

For pulmonary embolism: ECG, chest radiography, perfusion/scintiscan or MRI. 

For myocardial infarction: ECG, cardiac enzymes, echocardiography

For stroke: diffusion-weighted magnetic resonance imaging or computed 
tomography, ABCD scoring, carotid imaging 
Results of diagnostic procedures may be forwarded to the sponsor to be reviewed by an 
independent external expert panel, such as the DMC, if applicable.
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12.6.2 Anaphylaxis
The diagnosis of anaphylaxis is highly likely when any of the following 3 criteria are 
fulfilled:
1.
Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue or both (e.g, generalized urticaria, pruritus or flushing, swollen 
lips-tongue-uvula) and at least one of the following:
a. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced peak expiratory flow [PEF], hypoxemia)
b. Reduced blood pressure (BP) or associated symptoms of end-organ 
dysfunction (e.g., hypotonia [collapse], syncope, incontinence)
2.
Two or more of the following that occur rapidly after exposure to a likely allergen 
for that patient (minutes to several hours):
a. Involvement of the skin or mucosal tissue (e.g., generalized urticaria, pruritus 
or flushing, swollen lips-tongue-uvula)
b. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced PEF, hypoxemia)
c. Reduced BP or associated symptoms (hypotonia [collapse], syncope, 
incontinence)
d. Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)
3.
Reduced BP after exposure to a known allergen for that patient (minutes to 
several hours):
a. Infants and children: low systolic BP (age specific) or greater than 30% 
decrease in systolic BP
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from 
that person’s baseline BP
If a subject develops anaphylaxis in the course of the clinical study, this needs to be 
reported as SAE (Section 12.1.1.1). Additional blood will be drawn for Anti-VWF IgE 
antibody testing (Section 12.9.13).
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12.7 Vital Signs
Vital signs will be assessed pre- and post-infusion at each visit, if not stated otherwise:

Height (cm) (Screening only) and weight (kg) (pre-infusion only)

Blood pressure: Systolic/diastolic blood pressure (mmHg) baseline measurements 
will be measured after a 10-minute rest in the supine/semi-recumbent position.

Pulse rate: Pulse rate (beats/min) will be measured at the distal radial arteries 
under the same conditions as above.

Respiratory rate: Respiratory rate (breaths/min) will be measured over a period of 
1 minute under the same conditions as above.

Temperature: Body temperature (oC or oF) may be determined by oral, rectal, 
axillary, or tympanic measurement at the discretion of the investigator. However, 
the same method should be used for all measurements in 1 subject.
Vital signs (pulse rate, respiratory rate, and blood pressure) should be recorded within 
30 min before and after IP administration. The assessment of vital signs per planned 
study visit is outlined in Supplement 20.2.
Vital sign values are to be recorded on the physical examination eCRF. For each vital 
sign value, the investigator will determine whether the value is considered an AE (see 
definition in Section 12.1). If assessed as an AE, the medical diagnosis (preferably), 
symptom, or sign, will be recorded on the AE eCRF. Additional tests and other 
evaluations required to establish the significance or etiology of an abnormal result, or to 
monitor the course of an AE, should be obtained when clinically indicated. Any abnormal 
value that persists should be followed at the discretion of the investigator.
12.8 Electrocardiogram 
A standard 12-lead ECG at rest will be performed at screening, at the 6 month follow-up 
visit and at the study termination visit and evaluated for medical significance by the 
investigator.
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12.9 Clinical Laboratory Parameters
Refer to the Laboratory Manual for information on collection and processing of samples.
In general all laboratory tests will be performed at central laboratories, except the 
pregnancy and blood group test which will be performed at the local laboratory. In 
addition, relevant critical safety laboratory tests for complete blood count (CBC), serum 
chemistry and/or coagulation parameters such as VWF and FVIII activity may also be 
performed in the local laboratory to ensure that results will be available immediately to 
the investigator. In principle, results from the central laboratory will be used for data 
analysis purposes. The assays performed in the central laboratories are specified in the 
Laboratory Manual. The investigator will supply the sponsor with a list of the normal 
ranges and units of measurement for the laboratory variables to be determined at the site. 
Laboratory values such as antibodies to other proteins are not required immediately and 
will be assessed later during the course of the study. 
Any abnormal laboratory value that is considered clinically significant by the investigator 
based on a local laboratory test result (reference range and the units to be provided) 
should be confirmed by a central laboratory test result for which the sample is 
drawn/collected within 24 hours of the abnormal finding by the local laboratory.
12.9.1 rVWF Pharmacokinetics and Pharmacodynamics
Details on pharmacokinetic and pharmacodynamics assessments are provided in 
Section 11.6.
12.9.2 Hematology and Clinical Chemistry
The hematology panel will consist of CBC [hemoglobin, hematocrit, erythrocytes (ie, red 
blood cell count [RBC]; mean corpuscular volume [MCV], mean corpuscular hemoglobin 
(MCH), mean corpuscular hemoglobin concentration [MCHC]), and leukocytes (i.e., 
white blood cell count [WBC])] with differential (i.e., basophils, eosinophils, 
lymphocytes, monocytes, neutrophils) and platelet counts.
The clinical chemistry panel will consist of sodium (Na), potassium (K), chloride (Cl), 
ALT, lactate dehydrogenase (LDH), aspartate aminotransferase (AST), bilirubin, alkaline 
phosphatase (AP), blood urea nitrogen (BUN), CR, and glucose (Glu).
Blood will be obtained for assessment of hematology and clinical chemistry parameters 
at screening, during PK-assessment prior to rVWF (vonicog alfa) IP infusion, after 
24 ± 2 hours, 48 ± 2 hours and 72 ± 2 hours post rVWF (vonicog alfa) IP infusion, at all 
follow-up visits as per schedule (refer to Supplement 20.3 Clinical Laboratory 
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Assessments), i.e., 4 weeks ± 1 week, 8 weeks ± 1 week and every 3 months ± 2 weeks, 
and at study completion. Hematology and clinical chemistry assessments will be 
performed on Ethylenediaminetetraacetic acid (EDTA)-anticoagulated whole blood and 
serum, respectively, at the central laboratory.
12.9.3 Immunology
12.9.3.1 Antibodies to VWF and FVIII
All subjects will be tested for binding and neutralizing antibodies to VWF and FVIII at 
screening, at initial PK assessment, at each of the scheduled follow-up visits and at the 
study completion visit. Testing will be done prior to IP infusion and with at least a 
72 hour wash out period since the last IP infusion. If there is any suspicion of inhibitor 
development (e.g. excessive bleeding) binding and neutralizing antibodies to VWF and 
FVIII may be tested at the discretion of the investigator. 
12.9.3.2 Neutralizing and Total Binding Anti-VWF Antibodies
The assays to establish the presence of neutralizing and total binding anti-VWF 
antibodies have been established in the absence of international standards and with only 
limited numbers of positive controls. Therefore, caution is advised in interpreting positive 
results. In particular, any clinical association, changes in the natural history of the 
disease, effect of therapy, etc. needs to be taken into account for final judgment. 
The sponsor’s Medical Director should be consulted for additional advice. As part of the 
AE follow-up, any sample testing positive needs to be confirmed after 2-4 weeks for 
central laboratory testing. Only confirmed neutralizing anti -VWF antibodies are 
considered inhibitors (see Section 12.9.3.4). These subjects need to be closely monitored 
and therapy adjusted accordingly. 
12.9.3.3 Binding antibodies to VWF 
The presence of total binding anti-VWF antibodies will be determined by an enzyme-
linked immunosorbent assay (ELISA) employing polyclonal anti-human Immunoglobulin
(Ig) antibodies (IgG, IgM and IgA). For this assay (ELISA), recombinant human VWF 
will be coated onto a microtiter plate, then incubated with dilutions of the positive 
control, the negative control or test sample. Antibodies against human VWF that are 
present in the samples bind to the coated antigen and will be detected with a horseradish 
peroxidase (HRP)-coupled goat anti-human antibody (secondary antibody). The positive 
control for this assay will be a human monoclonal antibody specific for human VWF 
spiked into the negative control. The negative control for this assay is pooled normal 
human plasma.
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Plasma samples are analyzed for binding antibodies against the specific antigen in two 
steps. First, the sample is screened for antibodies and the titer of binding antibodies is 
determined. Second, the specificity of positive antibody results is confirmed.16
In brief, all samples are serially diluted (initial dilution 1:20 and further diluted 1:2).
The titer endpoint, defined as the highest dilution that still gives a positive signal above 
cut off level, is determined in two independent duplicates. The cut off level is established 
based on background signal level of healthy plasma donors (n=160) and set to include 5% 
false positives to be as sensitive as possible (95% percentile). The ELISA assay is 
validated allowing an assay variability of ± 1 titer step. Therefore, differences ≤ 2 titers 
steps may be due to variability of the ELISA assay. Specificity has to be confirmed in a 
competition assay when a sample has a titer of 1:80 or higher in the screening assay. 
Based on the validation criteria samples tested in the screening assay at 1:20 or 1:40 
cannot be confirmed in the competition assay. A positive screening value is confirmed if 
the difference between the titers determined for the subject sample (re-screen) and for the 
subject sample with pre-incubation (confirmation sample) is > 2 titer steps. Antibody 
titers of subject samples will only be reported as positive, if the results of the screening 
and confirmatory analysis fulfill these acceptance criteria. The titer to be reported is 
always the one determined in the original screening procedure (independent of the result 
of the re-screening in the confirmation procedure). 
A more detailed test procedure will be supplied upon request or pro-actively if a sample 
tests positive. A treatment related increase of the binding anti-VWF antibodies is 
expected, if the titer increases by more than 2 titration steps. These subjects need to be 
closely monitored and therapy adjusted accordingly.
12.9.3.4 Neutralizing Antibodies to VWF
Three functional VWF assays, VWF:CB, VWF:RCo and VWF:FVIIIB assays, will be 
used to test for the presence of neutralizing anti-VWF antibodies. Neutralizing antibodies 
to VWF:RCo, VWF:CB and VWF:FVIIIB activities will be measured by assays based on 
the Bethesda assay established for quantitative analysis of FVIII inhibitors (Nijmegen 
modification of the Bethesda assay).17 The amount of inhibitor is expressed as BU per 
mL. One BU is thereby defined as the amount of inhibitor that decreases the measured 
activity in the assays to 50% of that of the negative control samples. The assays were 
validated using human plasma samples from two type 3 VWD patients with low 
(1-2 BU/mL) and high (~10 BU/mL) titer inhibitors and plasma samples from 
non-human primates immunized with human rVWF (vonicog alfa) (>100 BU/mL).
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If a subject has a measurable baseline level of VWF activity in the respective assay, it is 
taken into account in the calculation of the residual activity. However, if baseline levels 
are too high (>15% VWF:RCo), inhibitors may not be reliably detected.
To exclude false positive results, the detection limit for anti-VWF inhibitors was set to 
1 BU/ml for all 3 assays. The rationale for this cut-off value is the relatively high CI of 
the underlying assays, making determinations at the end of the evaluation range of the 
Bethesda reference curve uncertain.18 A more detailed test procedure may be requested to 
further characterize the anti-VWF inhibitors, if detected.
Only confirmed positive anti-VWF inhibitor test result will be reported and will be
considered as a medically significant SAE.
12.9.3.5 Binding Antibodies to FVIII
Binding antibodies against FVIII will be analyzed using a proprietary enzyme 
immunoassay. The testing strategy will be as described for binding anti-VWF antibodies. 
Antibody-containing samples will be identified in a screening assay followed by a 
confirmatory assay to exclude false positive results.
12.9.3.6 Neutralizing Antibodies (Inhibitors) to FVIII 
Neutralizing antibodies (inhibitors) to FVIII will be assessed by the Nijmegen 
modification of the Bethesda assay in a central laboratory. To verify a FVIII inhibitor, 
additional testing (such as tests for Lupus anticoagulants) may be initiated. Positive FVIII 
inhibitor tests will be defined as ≥0.4 BU by the Nijmegen-modified Bethesda assay that 
is confirmed by a second test performed on an independent sample obtained 2-4 weeks 
following the first test. Only confirmed positive FVIII inhibitor test result will be 
reported.
12.9.4 Antibodies to Other Proteins
Plasma will be assayed for the presence of antibodies against CHO protein (total Ig), 
murine IgG and human Furin (total Ig) using proprietary enzyme immunoassays. The 
testing strategy will be as described for binding anti- VWF antibodies. 
Antibody-containing samples will be identified in a screening assay followed by a 
confirmatory assay to exclude false positive results.
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12.9.4.1 Anti-CHO Protein
Total Ig antibodies (IgG, IgA, IgM) against CHO protein will be analyzed. For this assay 
(ELISA), CHO protein derived from cultures of untransfected cells and propagated under 
the identical cell culture conditions used for ADVATE (rFVIII, octocog alfa) production 
will be coated onto a microtiter plate, then incubated with dilutions of the positive 
control, negative control or test sample. Antibodies against CHO protein that are present 
in the samples bind to the coated antigen and will be detected with a HRP-coupled goat 
anti-human antibody (secondary antibody). The positive control for this assay will be a 
polyclonal goat anti-CHO protein antibody spiked into the negative control. The negative 
control for this assay is pooled normal human plasma.
12.9.4.2 Anti-Murine IgG
A commercially available ELISA (Medac, Hamburg, Germany) will be used to detect and 
to quantify IgG antibodies originating from human plasma that are directed against 
mouse-IgG (HAMA: human anti- mouse antibodies). Microtiter plates coated with 
mouse IgG will be incubated with dilutions of the standard, the positive control, the 
negative control or the test sample. Antibodies against mouse IgG that are present in 
the samples bind to the coated antigen and form a bridge to a peroxidase coupled mouse 
IgG antibody that will be used for detection (bridging format of the ELISA assay). 
The positive control for this assay will be a polyclonal goat anti-murine IgG spiked into 
the negative control. The negative control for this assay is pooled normal human plasma.
12.9.4.3 Antibodies to Human Furin
Total Ig antibodies (IgG, IgA, IgM) against human Furin will be analyzed. For this assay 
(ELISA), recombinant human Furin will be coated onto a microtiter plate, then incubated 
with dilutions of the positive control, the negative control or test sample. Antibodies 
against human Furin that are present in the samples bind to the coated antigen and will be 
detected with a HRP-coupled goat anti-human antibody (secondary antibody). The 
positive control for this assay will be a human monoclonal antibody specific for human 
Furin spiked into the negative control. The negative control for this assay is pooled 
normal human plasma.
12.9.5 Viral Serology
The following viral seromarkers will be assessed at screening:

HIV: anti-HIV 1, HIV 2 

HAV: anti-HAV (IgG and immunoglobulin M [IgM])

HBV: Hepatitis B surface antigen (HbsAg), anti-Hepatitis B (HB) core, anti-HBs
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
HCV: anti-HCV ELISA

Parvovirus B19: anti-B19V (IgG and IgM)
Virus serology will be established during the screening period. The relevant confirmatory 
Polymerase Chain Reaction (PCR) testing may be performed from appropriate left-over 
samples as needed. 
12.9.6 Urinalysis (Dipstick)
The urinalysis will include assessments for erythrocytes, specific gravity, urobilinogen, 
ketones, glucose, protein, bilirubin, nitrite and pH and will be performed at the central 
laboratory.
12.9.7 Pregnancy Test
A pregnancy test for females of child-bearing potential will be performed at the local 
laboratory primarily from urine. If no urine sample is available, the pregnancy testing will 
be done from serum. The pregnancy test may need to be repeated during the course of 
study in countries where mandated by national law.
12.9.8 VWD Mutational Analysis, Multimer Analysis and Human Leukocyte 
Antigen Genotyping 
A cell pellet (buffy coat and erythrocytes) will be retained at the screening visit for VWD 
gene mutational analysis, VWF multimer analysis and HLA genotype determination if the 
information is not already available in the subject’s medical history. Results from 
multimer analysis (see Section 12.9.10.1) may contribute to VWD gene mutational 
analysis. The genetic testing will be done, when the subject consents to the genetic 
testing.
12.9.9 Blood Group Analysis
The blood group needs to be determined during the screening period. If the information is 
not already available in the subject’s medical history, it has to be determined at the local 
lab.
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12.9.10 Additional Laboratory Testing in Case of Thromboembolic Events
rVWF (vonicog alfa) contains ULMW multimers because of a lack of exposure to 
endogenous VWF protease (a disintegrin and metalloproteinase with a thrombospondin 
type 1 motif, member 13 (ADAMTS13) during the manufacturing process. In vitro and in 
vivo cleavage of these ultralarge molecular fractions by ADAMTS13 and generation of 
characteristic satellite bands has been extensively demonstrated during nonclinical and 
clinical development. Nevertheless, the potential elevated risk of thrombosis and/or other 
thromboembolic complications due to the administration of ultra large molecular VWF 
multimers in subjects with normal levels of VWF cannot be completely excluded. 
Therefore VWF multimer analysis will not only be performed routinely at screening but 
in case of thromboembolic events, both VWF multimer analysis as well as ADAMTS13 
activity will be determined to assess any relatedness of these occurrences with IP 
treatment. 
12.9.10.1 VWF Multimer Analysis 
The VWF multimer pattern will be assessed using low-resolution sodium dodecyl sulfate 
(SDS)–agarose gel electrophoresis. High-resolution SDS–agarose gel electrophoresis, 
with agarose concentrations 1.5%, will be used to determine the satellite band structure 
of VWF. These analyses will employ Western blot with luminescence video imaging.
12.9.10.2 ADAMTS13 Activity 
VWF73 was identified as the 73 amino acid minimal region of the VWF A2 domain 
required for ADAMTS13 cleavage. The cleavage of this substrate will be detected by a 
commercially available ELISA-based Chromogenic assay (Technoclone Austria):
Cleavage of immobilized VWF73 substrate is detected by a HRP-labeled antibody 
directed against the cleavage site of VWF73. The amount of bound antibody, which is the 
function of the ADAMTS13 cleavage is detected by a chromogenic substrate.
12.9.11 Soluble P-Selectin (sP-Selectin)
sP-selectin is a cell adhesion molecule (CAM) found in granules in endothelial cells 
(cells lining blood vessels) and activated platelets. Data for an association between the 
sP-selectin concentration, TTP and venous thromboembolism (VTE) are limited and the 
predictive value has not yet established. A commercial ELISA assay will be employed as 
an exploratory test. sP-selectin will be determined at the Screening visit and used as 
indicator for an increased thrombotic risk.
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12.9.12 D-Dimer
D-dimer will be used as a marker for DVT and disseminated intravascular coagulation
(DIC). While a negative result practically rules out thrombosis, a positive result can 
indicate thrombosis but does not rule out other potential etiologies, including a recent 
hemorrhage. Its main use, therefore, is to exclude thromboembolic disease where the 
probability is low. D-Dimer will be measured at the Screening visit and used as indicator 
for an increased thrombotic risk.
12.9.13 Additional Laboratory Testing in Case of Severe Hypersensitivity Reactions
If a subject develops a severe hypersensitivity reaction in the course of the clinical 
study, additional blood will be drawn for anti-VWF IgE antibody testing. The presence of 
anti-VWF IgE will be determined by using the ImmunoCAP®, a VWF-specific IgE 
blood test (Thermo Scientific). The basis of the ImmunoCAP® technology is a cellulose 
polymer as solid phase in a plastic capsule providing a large surface for protein binding. 
rVWF (vonicog alfa) as antigen is covalently coupled to the cellulose polymer. 
Detection of specific anti-VWF IgE bound to the antigen will be accomplished by a 
secondary enzyme-labeled anti-human IgE antibody. Testing for binding anti-human 
VWF IgE antibodies will be done with 0.5 mL plasma. Antibody containing samples will 
be identified and quantified in a screening assay followed by a confirmatory assay to 
exclude false positive results.
12.9.14 Assessment of Laboratory Values
12.9.14.1 Assessment of Abnormal Laboratory Values 
For VWF and FVIII laboratory assessments no evaluation of clinical significance is 
necessary.
Each other laboratory value (except results to determine genetics of the underlying VWD 
disease and blood group) has to be assessed by the investigator and the assessment will be 
recorded on the eCRF. The investigator will determine for each abnormal laboratory 
value whether the value is considered clinically significant or not and provide the 
reference range including the units. For clinically significant values, the investigator will 
indicate if the value constitutes a new AE (see definition in Section 12.1) and record the 
sign, symptom, or medical diagnosis on the AE CRF, is a symptom or related to a 
previously recorded AE, is due to a pre-existing disease (described in Section 12.1.1.5), 
or is due to another issue that will be specified. If the abnormal value was not clinically 
significant, the investigator will indicate the reason, i.e. because it is due to a preexisting 
disease, due to a lab error, due to variation or due to another issue that will be specified. 
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13. STATISTICS
13.1 Sample Size and Power Calculations
Approximately 22 adult subjects with severe VWD (baseline VWF:RCo <20 IU/dL) will 
be included in the study. The aim is to have at least 8 subjects in each cohort (OD and 
switch). A total of at least 5 type 3 VWD subjects will be followed for 12 months. The
sample size is driven by practical considerations (primarily the enrollment of a rare 
patient population) and EMA Guideline on the Clinical Investigation of Human Plasma 
Derived von Willebrand Factor Products (CPMP/BPWG/220/02).1
13.2 Datasets and Analysis Cohorts
13.2.1 Safety Analysis Set
The Safety Analysis Set will be composed of all subjects who received any amount of IP 
(rVWF, vonicog alpha). 
13.2.2 Full Analysis Dataset
The Full Analysis Set (FAS) will be composed of all subjects who receive prophylaxis IP 
treatment.
13.2.3 Per-Protocol Analysis Set
The Per-Protocol (PP) Analysis Set will be composed of subjects who are at least 70% 
compliant regarding the number of scheduled prophylactic infusions (as measured by the 
ratio of actual number of infusions to planned number of infusions). Only subjects who 
met all study entry criteria and who had no major protocol violations that might impact 
primary efficacy assessments will be included in the PP analysis set.
13.2.4 PK Full Analysis Set
The Pharmacokinetic Full Analysis Set (PKFAS) will be composed of all subjects who 
received the PK infusion and who provided acceptable data for PK and PD analysis. 
Acceptable PK/PD data will be defined in the Statistical Analysis Plan. 
13.2.5 PK Per Protocol Analysis Set 
The Pharmacokinetic Per Protocol Analysis Set (PKPPAS) is defined as a subset of the 
PKFAS. Subjects who met the following additional criteria will be included in the 
PKPPAS: had no major violation of affecting the PK period of the study as defined in the
detailed Statistical Analysis Plan.
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13.3 Handling of Missing, Unused, and Spurious Data
13.3.1 General
Statistical techniques will not be used to identify and exclude any observations as outliers 
from the analyses. If data are considered spurious, e.g. for lack of biological plausibility, 
it will be documented to include the reason for exclusion and the analyses from which the 
data were excluded.
13.3.2 Other
1.
Regarding missing data in PK records:

Body weight: If a subject’s weight is missing from the PK infusion record, the 
subject’s last recorded weight will be used to calculate the weight-adjusted 
dose.

Concentration:

Baseline concentration levels reported as below the limit of quantification 
will be considered to be 0. Missing VWF baseline concentration levels 
(VWF: RCo, VWF: AG or VWF: CB) for Type 3 subjects will be set to 0.

Time:

If start time of infusion is missing (but stop time is available) and actual 
collection time is available, then stop time of infusion will be taken for 
further calculation (i.e. time difference between actual end date/time of 
infusion and date/time blood sample drawn).

If actual collection date/time is missing and planned collection date/time is 
missing, then this PK time point will be taken out from the PK analysis 
(i.e. no data entry for this time point). 

For all other scenarios, the planned collection date/time will be taken for 
further calculation.
2.
Regarding missing data in AE records:

Handling of unknown causality assessment:

If a subject experiences an AE with a missing causality assessment, the 
relationship of the AE will be counted as “related.”
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
Handling of unknown severity grades:

If a subject experiences more than one AE categorized under the same 
preferred term, one of them is categorized as “severe” and one of them is 
categorized as “unknown”, then the maximum severity for this preferred 
term should be counted as “severe” for this subject.

If a subject experiences more than one AE categorized under the same 
preferred term, one of them is categorized as “mild” or “moderate” and 
one of them is categorized as “unknown”, then the maximum severity for 
this preferred term should be counted as “unknown” for this subject.
13.4 Methods of Analysis
The study success criteria are the objectives as stated in Section 7. “Treatment success” 
was defined as the extent of control of bleeding episodes achieved during this study.
13.4.1 Primary Outcome Measure
The primary outcome measure is ABR for spontaneous (not related to trauma) bleeding 
episodes during prophylactic treatment with rVWF (vonicog alfa). No formal statistical 
hypothesis test is planned for the analysis. The primary efficacy analysis will be based on 
the FAS and will be summarized by the two cohorts: on-demand and switch subjects. As 
a supportive analysis, the same analysis will also be carried out on the PP analysis set.
The spontaneous ABR while treated with rVWF (vonicog alfa) for each cohort will be 
estimated using a negative binomial regression. The prior ABR will be based on 
historical data collected from each enrolled subject. 
The two ABRs (prior to prophylaxis treatment and while on prophylaxis) for each cohort 
will be compared within each subject using a generalized linear mixed-effects model 
(GLMM) (with a logarithmic link function, the default for the negative binomial 
distribution), accounting for the fixed effect of the two treatments. The follow-up time 
(in years) will be specified as an offset. The ratio of ABR while in the study to historical
ABR will be estimated and reported together with the 95% confidence interval for each 
of the two cohorts.
The difference in on-study ABR relative to historical ABR will be also summarized 
descriptively.
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13.4.2 Secondary Outcome Measures 
In general, data for  secondary efficacy analysis will be summarized by the two cohorts: 
on-demand and switch subjects and when applicable overall.  Mean, standard deviation, 
median, range, quartiles will be calculated for continuous endpoints.  Proportions, will be 
calculated for categorical endpoints. Confidence intervals at the two-sided 95% level will 
be provided when appropriate.
13.4.2.1 Additional Efficacy of Prophylaxis Treatment with rVWF
The number  and proportion of on-demand subjects with ABR percent reduction success 
(i.e.≥ 25%) will be calculated together with a two-sided, 95% CI for the proportion.
The number  and proportion of pdVWF switch subjects ABR preservation success will be 
reported together with the corresponding 95% two-sided CIs for the proportion.
The number and proportion of subjects with categorized spontaneous ABR 
(i.e. 0, 1-2, 3-5, more than 5 bleeds) will be reported descriptively.
Summary statistics for the total number of infusions, as well as average number of 
infusions per week will be provided. The total weight adjusted consumption of rVWF 
(vonicog alfa) during prophylactic treatment will be provided. If applicable, historical 
data on consumption of pdVWF prior to the study will be summarized as well.
The change in spontaneous ABR from the historical rate to that during the rVWF 
(vonicog alfa) prophylaxis period will be summarized by location of bleeding 
(GI, epistaxis, joint bleeding, menorrhagia, oral and other mucosa, muscle and soft 
tissue, etc.).
13.4.2.2 Pharmacokinetic and Pharmacodynamic Analysis
All PK and PD analyses will use the actual sampling times, not nominal times specified 
in the protocol, wherever possible. Actual sampling times will be defined as time from 
the start of infusion to the blood sample collection time. A deviation from the protocol-
specified blood sample drawing time window will not be a reason to exclude an 
observation from the analysis. Samples with unknown actual and planned collection 
date/time or where the concentration could not be determined, or where results were 
biologically implausible will be eliminated from the analysis.
If any concentration data are considered spurious (e.g. lack of biological plausibility), the 
reason for exclusion from the analysis and the analysis from which the data point was 
excluded will be documented.
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Details of calculation of PK and PD parameters and corresponding analysis will be given 
in the statistical analysis plan. 
The following PK parameters, based on the initial PK assessment after a washout for on-
demand subjects, will be listed and summarized descriptively for VWF:RCo, VWF:Ag 
and VWF:CB: IR, T1/2, MRT, AUC0-, AUC0-tlast, Cmax, Tmax, Vss, and CL. The 
corresponding pharmacodynamics (PD) of rVWF (vonicog alfa) as measured in FVIII 
activity, based on the initial PK assessment after a washout for on-demand subjects will 
be assessed using Cmax, Tmax, and AUC0-tlast. These PD parameters will be listed and 
summarized descriptively. PK parameters at steady state (AUC0-tau;ss, Cmax;ss, Tmax;ss, and 
Cmin;ss) for the partial dosing interval will be listed for on-demand subjects at the end of 
the study and for switch subjects shortly after reaching steady state and at the end of the 
study for VWF:RCo, VWF:Ag and VWF:CB and summarized descriptively for subjects 
with the same dosing regimens. The corresponding pharmacodynamics (PD) of rVWF 
(vonicog alfa) as measured in FVIII activity will be assessed using AUC0-tau;ss, Cmax;ss, 
Tmax;ss, and Cmin;ss. These PD parameters will be listed for on-demand subjects at the end 
of the study and for switch subjects shortly after reaching steady state and at the end of 
the study and will be summarized descriptively for subjects with the same dosing 
regimens.
For the on-demand subjects, the PK of VWF:RCo will be analyzed using a population PK 
approach to characterize the single and multiple dose pharmacokinetics, including 
associated variability assessed at after washout and at end of study, respectively. The 
population PK analysis will be performed in a stepwise manner as outlined below.
1.
Exploratory graphical analysis of VWF:RCo versus time data for identification of 
potential outliers and to inform the pharmacometric analysis.
2.
Population PK model development for rVWF (vonicog alfa):
a.
Evaluate alternative structural and stochastic models to describe the typical 
and individual rVWF (vonicog alfa) profiles.
b.
Investigate and characterize the potential for a time dependency in CL of 
rVWF (vonicog alfa). 
c.
Evaluate, and if necessary refine, the candidate final model
Details of this Population PK analysis will be given in a separate Population PK analysis 
plan.
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For the switch subjects, differences in AUC0-tau;ss, Cmax;ss, and Cmin;ss assessess shortly 
after reaching steady state and assessed at the end of the study will be assessed by the 
ratio of geometric means and corresponding two-sided 95% confidence intervals for 
VWF:RCo, VWF:Ag,VWF:CB, and FVIII:C. These analyses will be performed using a 
linear mixed effects model with PK assessment (i.e. factor of two levels relating to the 
PK assessment shortly after reaching steady state and the PK assessment at end of study, 
respectively) as a fixed effect and subject as a random effect based on log-transformed 
PK parameters. The difference in Tmax;ss, between first and second pharmacokinetic 
assessment will be summarized by the median and range (minimum to maximum) for 
VWF:RCo, VWF:Ag,VWF:CB, and FVIII:C.
Descriptive statistics will be used to summarize VWF:RCo, VWF:AG and VWF:CB and 
FVIII:C levels for each nominal time point on the PK curve.
For all subjects in the PKFAS activity/concentration vs. time curves will be prepared.
Formulas for PK parameters IR, T1/2, MRT, AUC0-, AUC0-tlast, Cmax, Tmax, Vss, and CL, 
AUC0-tau;ss, Cmax;ss, Tmax;ss ,and Cmin;ss will be given in the statistical analysis plan and will 
be derived using non-compartmental methods in WinNonlin. Analysis of these 
parameters will be carried out on the PKFAS as well as on the PKPPAS.
13.4.2.3 Safety
Safety analysis will be performed overall and by the two cohorts: on-demand and switch 
subjects.
TEAEs are defined as AEs with start dates on or after the first exposure to IP. Summaries 
of AEs will be based on TEAEs unless otherwise indicated.
Occurrence of AEs and SAEs will be summarized descriptively, by system organ class 
and preferred term. The number and percentage of subjects who experienced AEs and 
SAEs, and the number of AEs and SAEs will be tabulated. In addition, the number of 
subjects who experienced AEs assessed as related to IP by the investigator, and the 
number of IP-related AEs will be tabulated. The number of patients with AEs by severity 
will be presented similarly.
A listing of all AEs will be presented by subject identifier, age, sex, preferred term and 
reported term of the AE, duration, severity, seriousness, action taken, outcome, causality 
assessment by investigator, onset date, stop date and medication or non-drug therapy to 
treat the AE.
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Temporally associated AEs are defined as AEs that begin during infusion or within
24 hours (or 1 day where time of onset is not available) after completion of infusion, 
irrespective of being related or not related to treatment. Temporally associated AEs will 
be presented in summary tables. 
AEs that occurred before first IP infusion will be listed separately.
Adverse events of special interest (AESI), such as hypersensitivity reactions and 
thromboembolic events,  will be monitored throughout the study and statistical analysis 
will be conducted based on the search criteria (eg, standardised MedDRA queries [SMQ]) 
determined prior to database lock, and summarized.
For immunogenicity, frequency counts and percentages will be calculated for the 
occurrence of neutralizing (inhibitory) antibodies to VWF and FVIII, occurrence of 
binding antibodies to VWF and FVIII, and occurrence of binding antibodies to CHO 
proteins, mouse immunoglobulin G (IgG) and rFurin. Clinically significant changes 
relative to baseline in vital signs and clinical laboratory parameters (hematology, clinical 
chemistry) will be reported.
13.4.3 Exploratory Outcome Measures
 
13.4.3.1
 
 
 
 
13.4.3.2
 
 
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13.4.3.3
 
 
 
13.4.3.4
 
 
 
 
 
13.5 Planned Interim Analysis of the Study
No formal interim analysis is planned for this study. 
14. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
The investigator/study site will cooperate and provide direct access to study documents 
and data, including source documentation for monitoring by the study monitor, audits by 
the sponsor or sponsor’s representatives, review by the EC, and inspections by applicable 
regulatory authorities, as described in the Clinical Trial Agreement (CTA). If contacted 
by an applicable regulatory authority, the investigator will notify the sponsor of contact, 
cooperate with the authority, provide the sponsor with copies of all documents received 
from the authority, and allow the sponsor to comment on any responses, as described in 
the CTA.
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15. QUALITY CONTROL AND QUALITY ASSURANCE
15.1 Investigator’s Responsibility
The investigator will comply with the protocol (which has been approved/given favorable 
opinion by the EC), ICH GCP, and applicable national and local regulatory requirements 
as described in the CTA. The investigator is ultimately responsible for the conduct of all 
aspects of the study at the study site and verifies by signature the integrity of all data 
transmitted to the sponsor. The term “investigator” as used in this protocol as well as in 
other study documents, refers to the investigator or authorized study personnel that the 
investigator has designated to perform certain duties. Sub-investigators or other 
authorized study personnel are eligible to sign for the investigator, except where the
investigator’s signature is specifically required.
15.1.1 Investigator Report and Final Clinical Study Report 
The investigator, or coordinating investigator(s) for multicenter studies, will sign the 
clinical study report. The coordinating investigator will be selected before study start. 
15.2 Training
The study monitor will ensure that the investigator and study site personnel understand all 
requirements of the protocol, the investigational status of the IP, and his/her regulatory 
responsibilities as an investigator. Training may be provided at an investigator’s meeting, 
at the study site, and/or by instruction manuals. In addition, the study monitor will be 
available for consultation with the investigator and will serve as the liaison between the 
study site and the sponsor.
15.3 Monitoring
The study monitor is responsible for ensuring and verifying that each study site conducts 
the study according to the protocol, standard operating procedures other written 
instructions/agreements, ICH GCP, and applicable national and local regulatory 
guidelines/requirements. The investigator will permit the study monitor to visit the study 
site at appropriate intervals, as described in the CTA. Monitoring processes specific to the 
study will be described in the clinical monitoring plan. 
15.4 Auditing
The sponsor and/or sponsor’s representatives may conduct audits to evaluate study 
conduct and compliance with the protocol, standard operating procedures, other written 
instructions/agreements, ICH GCP, and applicable national and local regulatory 
guidelines/requirements. The investigator will permit auditors to visit the study site, as 
described in the CTA. Auditing processes specific to the study will be described in the 
audit plan.
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15.5 Non-Compliance with the Protocol
The investigator may deviate from the protocol only to eliminate an apparent immediate 
hazard to the subject. In the event(s) of an apparent immediate hazard to the subject, the 
investigator will notify the sponsor immediately by phone and confirm notification to the 
sponsor in writing as soon as possible, but within 1 calendar day after the change is 
implemented. Also, the investigator will notify the sponsor immediately by phone and 
confirm notification to the sponsor in writing whenever pdVWF is used instead of rVWF 
(vonicog alfa). The reason for this use must also be provided to the sponsor.The sponsor 
(Baxalta) will also ensure the responsible EC and relevant competent authority are 
notified of the urgent measures taken in such cases according to local regulations.
If monitoring and/or auditing identify serious and/or persistent non-compliance with the 
protocol, the sponsor may terminate the investigator’s participation. The sponsor will 
notify the EC and applicable regulatory authorities of any investigator termination.
15.6 Laboratory and Reader Standardization
A central laboratory/reader will be used for all clinical assessments except for pregnancy
testing and blood group test (refer to Section 12.9). Local laboratories are requested to 
provide their laboratory specifications of the individual tests that are also being tested 
locally.
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16. ETHICS 
16.1 Subject Privacy
The investigator will comply with applicable subject privacy regulations/guidance as 
described in the CTA.
16.2 Ethics Committee and Regulatory Authorities
Before enrollment of patients into this study, the protocol, informed consent form, any 
promotional material/advertisements, and any other written information to be provided 
will be reviewed and approved/given favorable opinion by the EC and applicable 
regulatory authorities. The IB will be provided for review. The EC’s composition or a 
statement that the EC’s composition meets applicable regulatory criteria will be 
documented. The study will commence only upon the sponsor’s receipt of 
approval/favorable opinion from the EC and, if required, upon the sponsor’s notification 
of applicable regulatory authority(ies) approval, as described in the CTA.
If the protocol or any other information given to the subject is amended, the revised 
documents will be reviewed and approved/given favorable opinion by the EC and 
applicable regulatory authorities, where applicable. The protocol amendment will only be 
implemented upon the sponsor’s receipt of approval and, if required, upon the sponsor’s 
notification of applicable regulatory authority(ies) approval.
16.3 Informed Consent
Investigators will choose patients for enrollment considering the study eligibility criteria. 
The investigator will exercise no selectivity so that no bias is introduced from this source. 
All patients and/or their legally authorized representative must sign an informed consent 
form before entering into the study according to applicable national and local regulatory 
requirements and ICH GCP. Before use, the informed consent form will be reviewed by 
the sponsor and approved by the EC and regulatory authority(ies), where applicable, (see 
Section 16.2). The informed consent form will include a comprehensive explanation of 
the proposed treatment without any exculpatory statements, in accordance with the 
elements required by ICH GCP and applicable national and local regulatory 
requirements. Patients or their legally-authorized representative(s) will be allowed 
sufficient time to consider participation in the study. By signing the informed consent 
form, patients or their legally authorized representative(s) agree that they will complete 
all evaluations required by the study, unless they withdraw voluntarily or are terminated 
from the study for any reason.
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The sponsor will provide to the investigator in written form any new information that 
significantly bears on the subjects’ risks associated with IP exposure. The informed 
consent will be updated, if necessary. This new information and/or revised informed 
consent form, which have been approved by the applicable EC and regulatory authorities, 
will be provided by the investigator to the subjects who consented to participate in the 
study 
16.4 Data Monitoring Committee
This study will be monitored by aDMC. The DMC is a group of individuals with 
pertinent expertise that reviews on a regular basis accumulating data from an ongoing 
clinical study. For this study, the DMC will be composed of recognized experts in the 
field of VWD clinical care and research who are not actively recruiting subjects, and an 
independent statistician. The DMC can stop a trial if it finds toxicities or if treatment is 
proven to be not beneficial. Details will be defined in the DMC charter.
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17. DATA HANDLING AND RECORD KEEPING
17.1 Confidentiality Policy
The investigator will comply with the confidentiality policy as described in the CTA.
17.2 Study Documentation and Case Report Forms
The investigator will maintain complete and accurate paper format study documentation 
in a separate file. Study documentation may include information defined as “source data” 
(see Section 8.7), records detailing the progress of the study for each subject, signed 
informed consent forms, correspondence with the EC and the study monitor/sponsor, 
enrollment and screening information, CRFs, SAERs, laboratory reports (if applicable),
and data clarifications requested by the sponsor.
The investigator will comply with the procedures for data recording and reporting. Any 
corrections to paper study documentation must be performed as follows: 1) the first entry 
will be crossed out entirely, remaining legible; and 2) each correction must be dated and 
initialed by the person correcting the entry; the use of correction fluid and erasing are 
prohibited.
The investigator is responsible for the procurement of data and for the quality of data 
recorded on the CRFs. CRFs will be provided in electronic form. 
If electronic format CRFs are provided by the sponsor, only authorized study site 
personnel will record or change data on the CRFs. If data is not entered on the CRFs 
during the study visit the data will be recorded on paper and this documentation will be 
considered source documentation. Changes to a CRF will require documentation of the 
reason for each change. An identical (electronic/paper) version of the complete set of 
CRFs for each subject will remain in the investigator file at the study site in accordance 
with the data retention policy (see Section 17.3).
The handling of data by the sponsor, including data quality assurance, will comply with 
regulatory guidelines (e.g., ICH GCP) and the standard operating procedures of the 
sponsor. Data management and control processes specific to the study will be described 
in the data management plan.
17.3 Document and Data Retention 
The investigator will retain study documentation and data (paper and electronic forms) in 
accordance with applicable regulatory requirements and the document and data retention 
policy, as described in the CTA.
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18. FINANCING AND INSURANCE
The investigator will comply with investigator financing, investigator/sponsor insurance, 
and subject compensation policies, if applicable, as described in the CTA.
19. PUBLICATION POLICY
The investigator will comply with the publication policy as described in the CTA. 
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20. SUPPLEMENTS
20.1 Study Flow Chart
Figure 1
Study Design for Baxalta Clinical Study 071301
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20.2 Schedule of Study Procedures and Assessments
Table 6a
Schedule of Study Procedures and Assessments for On-demand Subject
Procedures/
Assessments
Screening Visit
Baseline Visit 
(PK-assessment visit)
Prophylaxis 
Initiation Visit
Interval/Follow-Up 
Study Visits
PK Assessment at 
Study Completion
Termination 
Visit
Pre-
infusiong
Infusion
Post-
infusiong
1 month ± 
1 week
2 month ± 
1 week 
3 month ± 
2 weeks
6 month ± 
2 weeks 
9 month ± 
2 weeks
Pre-
infusiong
Infusion
Post-
infusiong
Conducted at 
the 96 hour 
postinfusion 
PK 
Assessment
12 month ± 2 weeks
Informed Consent a
X
Eligibility Criteria
X
Medical Historyb
X
Concomitant Medicationsc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Non-drug Therapiesc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
Bleeding Episodes and 
Treatment and Hemostatic 
Efficacy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratories 
X
X
X
Xh
X
X
X
X
X
X
X
X
Vital Signsd
X
X
X
X
X
X
X
X
X
X
X
X
ECG
X
X
X
IP Treatmente
X
X
X
X
X
X
X
X
IP Consumption / Treatment 
Compliance 
X
X
X
X
X
Subject Diary
X
X
X
X
X
X
Xf
X
X
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Continued
a) Occurs at enrollment (before screening).
b) Including documented history of on-demand treatment for the past 12 months (up to 24 months if available) and a documented history, e.g., patient charts 
and prescription information, of all bleeding episodes within the past 12 (up to 24) months. 
c) Including all medications and non- drug therapies taken in the 2 weeks prior to study entry and all the concomitant medications and non-drug therapies 
during the course of the study.
d) Vital signs: height, weight, body temperature, pulse rate, respiratory rate, and blood pressure. Height is only required at the screening visit. The time points 
for pre- and post-infusion measurements are (weight is measured pre-infusion only): within 30 minutes before infusion start and 30 ± 15 minutes post-
infusion.
e) IP treatment after the prophylactic treatment initiation visit at the site will be continued as home-treatment if the subject qualifies; a wash-out period of at 
least 72 hours is required after the last IP infusion before the follow-up visit. IP infusion will be given at the study site after the blood sample for 
immunology testing and IR determination is drawn.
f) Can be done either at the screening or the baseline visit.
g) Time points for PK blood draws: within 30 minutes pre-infusion, and at 11 time points post-infusion: 15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 
3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours and 96 ± 2 hours (the 96 hr sampling can be omitted 
if not allowed by the dosing interval).
h) If a subject did not undergo PK assessment, laboratory assessments will be performed at this visit.
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Table 6b
Schedule of Study Procedures and Assessments for pdVWF Switch Subject
Procedures/
Assessments
Screening Visit
Prophylaxis Initiation 
Visit
PK Assessment
(at prophylaxis dose #5-6)
Interval/Follow-Up 
Study Visits
PK Assessment at 
Study Completion
Termination 
Visit
Pre-infusiong
Infusion
Post-infusiong
1 month ± 
1 week
2 month ± 
1 week 
3 month ± 
2 weeks
6 month ± 
2 weeks 
9 month ± 
2 weeks
Pre-
infusiong
Infusion
Post-
infusiong
Conducted at 
the 96 hour 
postinfusion 
PK 
Assessment
12 month± 2 weeks
Informed Consent a
X
Eligibility Criteria
X
Medical Historyb
X
Concomitant Medicationsc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Non-drug Therapiesc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
Bleeding Episodes and 
Treatment and Hemostatic 
Efficacy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratories 
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signsd
X
X
X
X
X
X
X
X
X
X
X
X
ECG
X
X
X
IP Treatmente
X
X
X
X
X
X
X
X
IP Consumption / Treatment 
Compliance 
X
X
X
X
X
Subject Diary
X
X
X
X
X
X
Xf
X
X
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Continued
a) Occurs at enrollment (before screening).
b) Including documented history of prophylaxis treatment for the past 12 months (up to 24 months if available) and a documented history, e.g., patient charts 
and prescription information, of all bleeding episodes within the past 12 (up to 24) months. 
c) Including all medications and non- drug therapies taken in the 2 weeks prior to study entry and all the concomitant medications and non-drug therapies 
during the course of the study.
d) Vital signs: height, weight, body temperature, pulse rate, respiratory rate, and blood pressure. Height is only required at the screening visit. The time 
points for pre- and post-infusion measurements are (weight is measured pre-infusion only): within 30 minutes before infusion start and 30 ± 15 minutes
post-infusion.
e) IP treatment after the prophylactic treatment initiation visit at the site will be continued as home-treatment if the subject qualifies; a wash-out period of at 
least 72 hours is required after the last IP infusion before the follow-up visit. IP infusion will be given at the study site after the blood sample for 
immunology testing and IR determination is drawn.
f) Can be done either at the screening or the prophylaxis initiation visit.
g) Time points for PK blood draws: within 30 minutes pre-infusion, and at 11 time points post infusion: 15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 
3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours and 96 ± 2 hours ( the 96 hr sampling can be 
omitted if not allowed by the dosing interval).
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20.2.1 Summary Schedule of Visit Assesments for Surgical Bleeding
Table 7
Summary Schedule of Visit Assesments for Surgical Bleeding
Procedures/
Assessments
Surgical procedure
Post-Operative 
Day 7 Visit
(± 1 day)
Post-Operative 
Day 14 Visit
(± 2 day)
Priming Dose 
Procedures 
(12-24 hours prior 
to surgery)
Loading Dose 
Procedures 
(≤3 hours prior
to surgery)
Intraoperative
Postoperative 
(day 1 → end of 
perioperative IP 
treatment)a
ECG
X
Physical examinationb
X
X
X
X
X
Adverse events
X
X
X
X
X
X
Laboratoriesc
X
X
X
X
X
X
Vital signsd
X
X
X
X
X
X
IP treatment: rVWF (vonicog 
alfa):ADVATE (rFVIII, octocog 
alfa) or rVWF (vonicog alfa) only 
infusion
X
X
X
as required
X
as required
X
as required
X
as required
Concomitant medications and non-
drug therapy
X
X
X
X
X
X
X
Hemostatic efficacy assessmentse
X
X
X
X
Blood loss
X
estimated
X
actual
X
Xf
Xf
Treatment days estimate
X
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Continued 
a) The assessments will be performed daily until perioperative IP treatment end (potentially multi-visits)
b) Physical Examination: within 2 hours prior to IP infusion start
c) For laboratory assessments, see Table 9
d) Vital signs: within 30 minutes before infusion start and 30 ± 15 minutes post-infusion
e) Completed immediately postsurgery by the operating surgeon 24 hours post last IP infusion or at Day 14 visit (whichever occurs first) by the investigator
f) In case bleeding still ongoing
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20.3 Clinical Laboratory Assessments
Table 8a
Clinical Laboratory Assessments for On-demand Subject
Procedures/
Assessments
Screening Visit
Baseline Visit 
(PK-assessment visit)
Prophylaxis Initiation 
Visitk
Interval/Follow-Up 
Study Visits
PK Assessmentm at 
Study Completion
Termination 
Visit
Pre-infusion
Infusion
Post-infusion
1 month ± 
1 week
2 month ± 
1 week 
3 month ± 
2 weeks
6 month ± 
2 weeks 
9 month ± 
2 weeks
Pre-
infusion
Infusion
Post-
infusion
Conducted 
at the 
96 hour 
postinfusion 
PK 
Assessment
12 month± 
2 weeks
Hematology a
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Chemistryb
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation Panel/ PK 
assessmentc
X
X
X
X
X
X
X
X
X
X
X
Immunogenicityd
X
X
Xl
X
X
X
X
X
X
X
Viral Serologye
X
Urinalysisf
X
VWD Gene Mutational 
Analysis / HLA genotype 
analysis and Analysis of 
VWF multimersg
X
sP-selectin and D-dimer
Xh
Blood Groupi 
X
Pregnancy Testj
X
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Continued
a) Hematology assessments include: complete blood count [hemoglobin, hematocrit, erythrocytes (i.e. red blood cell count), mean corpuscular volume 
(MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), leukocytes (i.e. white blood cell count)] with 
differential (i.e. basophils, eosinophils, lymphocytes, monocytes, neutrophils) and platelet counts. Hematology assessments during PK assessments will be 
determined prior to IP infusion and 24 ± 2 hours, 48 ± 2 hours and 72 ± 2 hours thereafter. For other IP-associated visits, samplings are within 60 minutes 
pre-infusion.
b) Clinical chemistry assessments include: Sodium, potassium, chloride, glucose, creatinine, blood urea nitrogen (BUN), aspartate aminotransferase (AST), 
alanine aminotransferase (ALT) lactate dehydrogenase (LDH), alkaline phosphatase (AP), bilirubin. Clinical chemistry will be determined prior to IP 
infusion and after 24 ± 2 h, 48 ± 2 hours and 72 ± 2 hours during the PK assessments. For other IP-associated visits, samplings are within 60 minutes pre-
infusion.
c) Coagulation panel/PK assessment (also refers to IR pre/post dose assessments at prophy initiation visit and each follow-up visit): PT, INR and aPTT (only 
for screening), VWF:RCo, VWF:Ag, VWF:CB, FVIII:C,; during the PK assessment at the baseline visit blood samples will be drawn 30 min prior PK 
infusion; once the PK infusion is completed 15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 
30 ± 2 hours, 48 2 hours, 72 2 hours and 96 ± 2 hours and VWF:RCo, VWF:CB, VWF:Ag, FVIII:C will be determined; for follow-up visits, IR 
samples will be drawn within 30 minutes pre-infusion and 30 5 minutes post-infusion. During screening and in case of thromboembolic event VWF 
multimers and ADAMTS13 will be analyzed to judge on a possibly relatedness to UHMW fractions of the IP.
d) Immunogenicity assessment includes Neutralizing Antibodies (Ab) to FVIII –Neutralizing Ab to VWF:RCo, Neutralizing Ab to VWF:CB, Neutralizing 
Ab to VWF:FVIII, Binding Ab to VWF and FVIII, Binding Ab to CHO-Protein, Binding Ab to rFurin, Binding Ab to Murine IgG . In case of an SAE 
hypersensitivity reaction IgE antibodies to VWF will be determined. For on-demand subjects, a washout period of at least 72 hours after the last IP 
infusion is required before blood samples for immunogenicity assessments can be drawn. 
e) Viral Serology Hepatitis A Antibody, Total - Hepatitis A Antibody, IgM - Hepatitis B Surface Antibody - Hepatitis B Core Ab, Total - Hepatitis B Surface 
Antigen - Hepatitis C Virus Antibody; Parvovirus B19; HIV-1/HIV-2 Antibodies 
f) Urinalysis comprehends: erythrocytes, specific gravity, urobilinogen, ketones, glucose, protein, bilirubin, nitrite, and pH
g) Not required if available in the subject’s medical history; VWF multimers: additionally in case of thromboembolic events
h) At screening and in case of thromboembolic events
i) Blood group assessment major blood group (local laboratory) only if not available in the subject’s medical history
j) Serum pregnancy test (in females of child-bearing potential if no urine sample is available)
k) The last post-infusion laboratory assessments coincidence with the initiation visit for prophylactic treatment. After the blood samples are drawn for 
laboratory assessment for the 96 h post infusion PK assessment, the subject receives the first IP infusion for prophylactic treatment (prophylactic treatment 
initiation visit). 
l) Only needed for subjects without PK assessment prior to their first IP infusion in this study.
m) A steady state full PK analysis will be performed at the end of the study. Blood samples will be drawn within 30 minutes pre-infusion, and at 11 time points 
post-infusion (15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 
72 2 hours and 96 ± 2 hours), the 96 hr sampling can be omitted if not allowed by the dosinig interval.
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Table 8b
Clinical Laboratory Assessments for pdVWF Switch Subject
Procedures/
Assessments
Screening Visit
Prophylaxis Initiation Visit
PK Assessmentk
(at prophylaxis dose #5-6)
Interval/Follow-Up 
Study Visits
PK Assessmentk at 
Study Completion
Termination 
Visit
Pre-infusion
Infusion
Post-infusion
1 month ± 1 week
2 month ± 1 week 
3 month ± 2 weeks
6 month ± 2 weeks 
9 month ± 2 weeks
Pre-
infusion
Infusion
Post-
infusion
Conducted at 
the 96 hour 
postinfusion 
PK 
Assessment
12 month± 
2 weeks
Hematology a
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Chemistryb
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation Panel/PK 
assessmentc
X
X
X
X
X
X
X
X
X
X
X
Immunogenicityd
X
X
X
X
X
X
X
X
X
Viral Serologye
X
Urinalysisf
X
VWD Gene Mutational 
Analysis / HLA 
genotype analysis and 
Analysis of VWF 
multimersg
X
sP-selectin and D-dimer
Xh
Blood Groupi 
X
Pregnancy Testj
X
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Continued
a) Hematology assessments include: complete blood count [hemoglobin, hematocrit, erythrocytes (i.e. red blood cell count), mean corpuscular volume 
(MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), leukocytes (i.e. white blood cell count)] with 
differential (i.e. basophils, eosinophils, lymphocytes, monocytes, neutrophils) and platelet counts. Hematology assessments during PK assessments will be 
determined prior to IP infusion and 24 ± 2 hours, 48 ± 2 hours and 72 ± 2 hours thereafter. For other IP-associated visits, samplings are within 60 minutes 
pre-infusion.
b) Clinical chemistry assessments include: Sodium, potassium, chloride, glucose, creatinine, blood urea nitrogen (BUN), aspartate aminotransferase (AST), 
alanine aminotransferase (ALT) lactate dehydrogenase (LDH), alkaline phosphatase (AP), bilirubin. Clinical chemistry will be determined prior to IP 
infusion and after 24 ± 2 h, 48 ± 2 hours and 72 ± 2 hours during the PK assessments. For other IP-associated visits, samplings are within 60 minutes pre-
infusion.
c) Coagulation panel/PK assessment (also refers to IR pre/post dose assessments at prophy initiation visit and each follow-up visit): PT, INR and aPTT (only 
for screening), VWF:RCo, VWF:Ag, VWF:CB, FVIII:C,; during the PK assessment blood samples will be drawn 30 min prior PK infusion; once the PK
infusion is completed 15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 
48 2 hours, 72 2 hours and 96 ± 2 hours and VWF:RCo, VWF:CB, VWF:Ag, FVIII:C will be determined; for follow-up visits, IR samples will be 
drawn within 30 minutes pre-infusion and 30 5 minutes post-infusion. During screening and in case of thromboembolic event VWF multimers and 
ADAMTS13 will be analyzed to judge on a possibly relatedness to UHMW fractions of the IP.
d) Immunogenicity assessment includes Neutralizing Antibodies (Ab) to FVIII –Neutralizing Ab to VWF:RCo, Neutralizing Ab to VWF:CB, Neutralizing 
Ab to VWF:FVIII, Binding Ab to VWF and FVIII, Binding Ab to CHO-Protein, Binding Ab to rFurin, Binding Ab to Murine IgG. In case of an SAE 
hypersensitivity reaction IgE antibodies to VWF will be determined. For switch subjects, the wash out period may be reduced to the time interval between 
their pdVWF prophy infusions.
e) Viral Serology Hepatitis A Antibody, Total - Hepatitis A Antibody, IgM - Hepatitis B Surface Antibody - Hepatitis B Core Ab, Total - Hepatitis B Surface 
Antigen - Hepatitis C Virus Antibody; Parvovirus B19; HIV-1/HIV-2 Antibodies
f) Urinalysis comprehends: erythrocytes, specific gravity, urobilinogen, ketones, glucose, protein, bilirubin, nitrite, and pH
g) Not required if available in the subject’s medical history; VWF multimers: additionally in case of thromboembolic events
h) At screening and in case of thromboembolic events
i) Blood group assessment major blood group (local laboratory) only if not available in the subject’s medical history
j) Serum pregnancy test (in females of child-bearing potential if no urine sample is available)
k) A full steady state PK analysis will be performed. Blood samples will be drawn within 30 minutes pre-infusion, and at 11 time points post-infusion
(15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours 
and 96 ± 2 hours) , the 96 hr sampling can be omitted if not allowed by the dosinig interval.
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20.3.1 Laboratory Sampling for Surgical Bleeding
Table 9
Laboratory Samplinga for Surgical Bleeding
Procedures/
Assessments
Surgical procedure
Post-Operative 
Day 7 Visit
(± 1 day)
Post-Operative 
Day 14 Visit
(± 2 day)
Priming Dose 
Procedures 
(12-24 hours prior 
to surgery)
Loading Dose 
Procedures 
(≤3 hours prior 
to surgery)
Intraoperative
Postoperative
(day 1 → end of 
perioperative IP 
treatment)b
Hematologyc
X
(w/o Differential)
Xd
(w/o Differential)
X
(w/o Differential)
X
X
Clinical Chemistrye
X
Xd
X
X
Coagulation panelf
X
X
X
X
X
X
VWF inhibitory and binding 
antibodies, antibodies to other 
proteinsg
X
X
X
if excessive or 
unexplainedbleeding
X
X
X
Urinalysish
X
X
VWF Multimersi
Anti VWF IgE antibody testing
only in case of allergic reaction/ 
anaphylaxis
Continued on next page
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Continued
a) Blood draws are within 3 hrs  prior to infusion start, expect that for the priming dose blood draw is within 30 minutes prior to infusion start. For 
coagulation panel, an additional 30 ± 5 minutes post-infusion blood draw is needed.
b) The assessments will be performed daily until perioperative IP treatment end (potentially multi-visits)
c) Hematology assessments include: complete blood count [hemoglobin, hematocrit, erythrocytes (i.e. red blood cell count), mean corpuscular volume 
(MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), leukocytes (i.e. white blood cell count)] with 
differential (i.e. basophils, eosinophils, lymphocytes, monocytes, neutrophils) and platelet counts. 
d) Not required if sample already drawn at the time of the priming dose
e) Clinical chemistry assessments include: Sodium, potassium, chloride, glucose, creatinine, blood urea nitrogen (BUN), aspartate aminotransferase (AST), 
alanine aminotransferase (ALT) lactate dehydrogenase (LDH), alkaline phosphatase (AP), bilirubin. 
f) Coagulation panel: VWF:RCo, VWF:Ag, FVIII:C PT INR and aPTT; in additiona to pre-infusion, 30 ± 5 minutes post infusion blood draw is needed. 
g) Immunogenicity assessment includes Neutralizing Antibodies (Ab) to FVIII – Neutralizing and Neutralizing Ab to VWF:RCo, Neutralizing Ab to 
VWF:CB, Neutralizing Ab to VWF:FVIII, Binding Ab to VWF and FVIII, Binding Ab to CHO-Protein, Binding Ab to rFurin, Binding Ab to Murine IgG.
In case of an SAE hypersensitivity reaction IgE antibodies to VWF will be determined.
h) Urinalysis comprehends: erythrocytes, specific gravity, urobilinogen, ketones, glucose, protein, bilirubin, nitrite, and pH
i) VWD multimers and ADAMTS13 during the study only in case of thrombotic events
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20.4 Contraceptive Methods for Female Subjects of Childbearing Potential
In this study, subjects who are women of childbearing potential must agree to utilize a 
highly effective contraceptive measure throughout the course of the study and for 30 days 
after the last administration ofIP. In accordance with the Clinical Trial Facilitation Group 
(CTFG) recommendations related to contraception and pregnancy testing in clinical trials 
(version 2014-09-15)ii, birth control methods which may be considered as highly 
effective include the following:

Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation:

oral

intravaginal

transdermal

Progestogen-only hormonal contraception associated with inhibition of ovulation:

oral

injectable

implantableiii

Intrauterine device (IUD)iii

Intrauterine hormone-releasing system (IUS) iii

Bilateral tubal occlusioniii

Vasectomised partner(s)iii

Sexual abstinence during the entire study period
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhoea method (LAM) are 
not acceptable methods of contraception. Female condom and male condom should not 
be used together.
                                                
ii Clinical Trial Facilitation Group (CTFG) recommendations related to contraception and pregnancy 
testing in clinical trials: http://www.hma.eu/fileadmin/dateien/ 
Human_Medicines/01About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf.
iii Contraception methods that are considered to have low user dependency.
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21. REFERENCES
1.
Committee for Medicinal Products for Human Use. Guideline on clinical 
investigation of human plasma derived von Willebrand factor products. 
CPMP/BPWG/220/02, 12. 11-17-2005:London, European Medicines Agency 
(EMA). Web Link: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/201
0/01/WC500067126.pdf
2.
Mannucci PM. Treatment of von Willebrand's Disease. N Engl J Med. 
2004;351(7):683-694.
3.
Goudemand J, Scharrer I, Berntorp E, et al. Pharmacokinetic studies on Wilfactin, a 
von Willebrand factor concentrate with a low factor VIII content treated with three 
virus-inactivations/removal methods. J Thromb Haemost. 2005;3(10):2219-2227.
4.
Abshire T. The role of prophylaxis in the management of von Willebrand disease: 
today and tomorrow. Thromb Res. 2009;124 Suppl 1:S15-S19.
5.
Nilsson IM, Blombäck M, Jorpes E, Blombäck B, Johansson SA. V. Willebrand's 
disease and its correction with human plasma fraction 1-0. Acta Med Scand. 
1957;159(3):179-188.
6.
Berntorp E, Petrini P. Long-term prophylaxis in von Willebrand disease. Blood 
Coagul Fibrinolysis. 2005;16 Suppl 1:S23-S26.
7.
Berntorp E. Prophylaxis and treatment of bleeding complications in von Willebrand 
disease type 3. Semin Thromb Hemost. 2006;32(6):621-625.
8.
Federici AB. Highly purified VWF/FVIII concentrates in the treatment and 
prophylaxis of von Willebrand disease: the PRO.WILL Study. Haemophilia. 
2007;13 Suppl 5:15-24.
For non-commercial use only

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9.
Halimeh S, Krümpel A, Rott H, et al. Long-term secondary prophylaxis in children, 
adolescents and young adults with von Willebrand disease. Results of a cohort 
study. Thromb Haemost. 2011;105(4):597-604.
10.
Abshire TC, Federici AB, Alvárez MT, et al. Prophylaxis in severe forms of von 
Willebrand's disease: results from the von Willebrand Disease Prophylaxis Network 
(VWD PN). Haemophilia. 2013;19(1):76-81.
11.
Abshire T, Cox-Gill J, Kempton CL, et al. Prophylaxis escalation in severe von 
Willebrand disease: A prospective study from the von Willebrand Disease 
Prophylaxis Network. J Thromb Haemost. 2015;13(9):1585-1589.
12.
Berntorp E. Prophylaxis in von Willebrand disease. Haemophilia. 2008;14 Suppl 
5:47-53.
13.
Varadi K, Rottensteiner H, Vejda S, et al. Species-dependent variability of 
ADAMTS13-mediated proteolysis of human recombinant von Willebrand factor. J 
Thromb Haemost. 2009;7(7):1134-1142.
14.
Mannucci PM, Kempton C, Millar C, et al. Pharmacokinetics and safety of a novel 
recombinant human von Willebrand factor manufactured with a plasma-free 
method: a prospective clinical trial. Blood. 2013;122(5):648-657.
15.
Gill JC, Castaman G, Windyga J, et al. Hemostatic efficacy, safety and 
pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand 
disease. Blood. 2015;126(17):2038-2046.
For non-commercial use only

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16.
Committee for Medicinal Products for Human Use. Guideline on immunogenicity 
assessment of biotechnology-derived therapeutic proteins. 
CHMP/BMWP/14327/2006, 18. 12-13-2007:London, European Medicines Agency 
(EMA),. Web Link: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/200
9/09/WC500003946.pdf
17.
Kasper CK. Laboratory tests for factor VIII inhibitors, their variation, significance 
and interpretation. Blood Coagul Fibrinolysis. 1991;2 Suppl 1:7-10.
18.
Lillicrap D. Von Willebrand Factor. International Society for Thrombosis and 
Hemostasis (ISTH) 54th Annual Scientific and Standardization Committee 
Meeting:2008:60-64. Web Link: 
http://c.ymcdn.com/sites/www.isth.org/resource/resmgr/yearly_subcommittee_min
utes/2008minutes.pdf?hhSearchTerms=lillicrap+and+2008
19.
 
20.
 
21.
 
 
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22. SUMMARY OF CHANGES
Protocol 071301: Global Amendment 6: 2018 MAR 12
Replaces: Amendment 3: 2017 AUG 03
In this section, changes from the previous version of the Protocol, dated 2017 AUG 03, 
are described and their rationale is given.
1.
Throughout the document
Description of Change:
Minor grammatical and/or administrative changes and/or rewording have been 
made.
Purpose for Change: To improve the readability and/or clarity of the protocol.
2.
Throughout the document
Description of Change:
INN was added to rVWF and ADVATE by changing rVWF to rVWF (vonicog 
alfa) and changing ADVATE to ADVATE (rFVIII, octocog alfa).
Purpose for Change: To add INN.
3.
Section 2, Section 12.1.2
Description of Change:
Bleeding events that meet seriousness criteria should be reported on both SAE 
eCRF and SAE report form. Section 12.1.2.3 was added as a reference for SAE 
assessment.
Purpose for Change: To provide further clarifications on SAE reporting.
4.
Synopsis (Clinical condition(s)/indication(s)), Section 6.4, Section 13.1
Description of Change: 
Original text:
Subjects with severe von Willebrand disease (VWD) requiring prophylactic 
treatment with coagulation factor replacement.
New text:
Subjects with severe von Willebrand disease (VWD) (baseline VWF:RCo 
<20 IU/dL) requiring prophylactic treatment with coagulation factor replacement.
Purpose for Change: To add definition of severe VWD.
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5.
Synopsis (Planned study period), Section 8.2
Description of Change:
The initiation/completion and duration of the study were updated per the new 
timeline.
Purpose for Change: To reflect the new study timeline.
6.
Synopsis (Study purpose, Study design), Section 7.1, Section 8.1
Description of Change:
Hypersensitivity was added for safety evaluation; PK and pharmacoecnomics 
evaluation was added.
Purpose for Change: To provide further clarifications to the purpose of the study.
7.
Synopsis (Primary objective), Section 7.2
Description of Change:
Original text:
The primary objective of this study is to prospectively evaluate the annualized 
bleeding rate (ABR) for spontaneous bleeding episodes while on prophylactic 
treatment with rVWF and to compare it to the subject’s historical ABR for 
spontaneous bleeding episodes during on-demand treatment.
New text:
The primary objective of this study is to prospectively evaluate the annualized 
bleeding rate (ABR) for spontaneous bleeding episodes while on prophylactic 
treatment with rVWF and to compare it to the subject’s historical ABR for 
spontaneous bleeding episodes. 
Purpose for Change: To remove wording to accommodate pdVWF switch subject 
cohort, which is a new study cohort added in this amendment.
8.
Synopsis (Secondary objectives), Section 7.3
Description of Change: 
 
. Additional wording was added to clarify the objectives.
Purpose for Change: Remove some of the objectives (
 
) and add clarification.
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9.
Synopsis (Exploratory objectives, Exploratory outcome measures), 
Section 7.4, Section 8.3.3
Description of Change: 
  
 
 and additional wording was added to clarify the assessments.
Purpose for Change: Clarification and adding additional objectives/assessments.
10.
Synopsis (Study Design), Section 8.1
Description of Change: 
Additional details about the study design were added for on-demand and the 
switch cohort.
Purpose for Change: To provide further clarification and to add study design for 
the switch cohort.
11.
Synopsis (Primary outcome measure), Section 8.3.1
Description of Change: 
Original text:
Prospectively recorded ABR for spontaneous (not related to trauma) bleeding 
episodes during prophylactic treatment with rVWF and the subjects’ historical 
ABR for spontaneous bleeding episodes during on-demand treatment.
New text:
Annualized bleeding rate (ABR) for spontaneous (not related to trauma) 
bleeding episodes during prophylactic treatment with rVWF (vonicog alfa).
Purpose for Change: To remove the unnecessary text.
12.
Synopsis (Secondary outcome measures), Section 8.3.2
Description of Change:
Rewording some of the exisiting secondary outcome measures (efficacy and 
safety) to provide clarification. New efficacy outcome measures were added to 
further access the efficacy of prophylaxis for switch subjects. Clinically 
significant changes in vital signs and clinical laboratory parameters were added as 
one additional safety measure. New steady-state PK parameters were added. PD 
parameters were added. 
 
.
Purpose for Change: To provide further clarifications and to add new outcome 
measures for switch subjects. And to remove some of the outcome measures 
(
)
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13.
Synopsis (Investigational product(s), dose and mode of administration)
Description of Change: 
Prophylaxis dosing guidelines were added for the pdVWF switch subjects.
Purpose for Change: To add dosing guide for the switch subjects.
14.
Synopsis (Targeted accrual, sample size calculation), Section 6.4, Section 13.1
Description of Change:
Sample size was increased and targeted accrual of each cohort was added and a 
followup period of 12 months was added.
Purpose for Change: To update the sample to reflect the adding of switch cohort.
15.
Synopsis (Inclusion criteria, Exclusion criteria), Section 9.1, Section 9.2
Description of Change: 
Criteria for the switch subjects were added.
Criteria added to clarify no pre-planned surgery is allowed.
Purpose for Change: To update for the eligibility of switch subjects and to add 
some clarity.
16.
Synopsis (Planned statistical analysis), Section 13.4
Description of Change: 
Changes were made throughout the section according to the updated outcome 
measures. Remove the planned analysis of exploratory outcome measure from 
synopsis to avoid redundance
Purpose for Change: To better test the updated outcome measures.
17.
Section 5
Description of Change: 
New abbreviations were added.
Purpose for Change: Clarification.
18.
Section 6.5, Section 6.5.2, Section 6.5.2.4, Section 6.5.2.5
Description of Change: 
Summary of recently completed clinical study 071101 was added as section 
6.5.2.4, the summary of 071401 was moved to section 6.5.2.5 .
Purpose for Change: To provide clinical study summary for study 071101.
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19.
Section 6.5.2.3
Description of Change: 
To add wording about the basis of the dosing for the current study.
Purpose for Change: To provide clarification.
20.
Section 6.6
Description of Change: 
Original text:
He/she may benefit from a product that minimizes excessive FVIII administration.
New text:
He/she may benefit from a product that minimizes excessive FVIII administration 
and thus allowing individualized dosing of VWF at optimal levels. 
Original text:
By using a recombinant product, the risk of contamination with blood derived 
viruses or variant Creutzfeldt-Jakob Disease associated with the use of 
products of human or animal origin has been virtually eliminated.
New text:
By using a recombinant product, the risk of transmission of adventitious agents 
and other blood-borne pathogens associated with the use of products of human 
or animal origin has been eliminated.
Purpose for Change: To provide accuracy and clarification.
21.
Section 6.6
Description of Change: 
Original text:
These benefits outweigh the following potential risks of rVWF.
New text:
These benefits outweigh the following identified or potential risks of rVWF
Purpose for Change: To provide accuracy since Thromboembolic events has been 
upgraded to identified risk.
22.
Section 8.5
Description of Change: 
Updates were made based on safety considerations.
Purpose for Change: To avoid unnecessary study stop.
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23.
Section 8.6.3
Description of Change: 
Wording was added to clarify that partial vials are not allowed to use.
Wording about mixing of two products was removed as it is not allowed any 
more.
Purpose for Change: To provide clarification on IP administration.
24.
Section 8.6.4.1
Description of Change: 
Details about PK assessment IP treatment were added for both on-demand and 
switch cohorts.
Purpose for Change: To provide more details and clarifications.
25.
Section 8.6.4.2
Description of Change:
Prophylaxis initiation treatment was updated to be also applicable to the switch 
subjects and the dosing details were removed from this section (moved to 
Section 8.6.4.3).
Purpose for Change: To provide details to accommodate newly added switch 
cohort.
26.
Section 8.6.4.3, Section 8.6.4.3.1, Section 8.6.4.3.2
Description of Change:
Detailed instructions of prophylaxis dosing and dosing adjustment were added to 
this section for both on-demand and pdVWF switch subjects. Home treatment 
rules were also made applicable to switch subjects, and made correction that the 
investigator is responsible for the home treatment procedures.
Purpose for Change: To provide details and clarifications to accommodate newly 
added switch cohort.
27.
Section 8.6.4.4.1, Section 10.3.1
Description of Change:
Added the requirement of documentation the reason for the use of any non-IP
product or therapy.
Purpose for Change: To ensure proper documentation of non-IP product use.
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28.
Section 8.6.4.4.2
Description of Change: 
Added the wording about dose adjustment and the optional use of ADVATE.
Purpose for Change: To provide further clarification.
29.
Section 8.6.4.5
Description of Change: 
Sentence was added to clarify no pre-planned surgery is allowed.
Purpose for Change: To add some clarity.
30.
Section 8.6.4.5.2
Description of Change:
Added description of priming dose for surgery.
Purpose for Change: To provide further clarification.
31.
Section 8.6.4.5.3
Description of Change:
Added description of loading dose for surgery.
Purpose for Change: To provide further clarification.
32.
Section 8.6.4.6, Section 12.6.1
Description of Change:
Added the details about prophylaxis measures against thromboembolism.
Purpose for Change: To ensure safety monitoring of thromboembolic events.
33.
Section 8.6.5
Description of Change:
Added the wording about the requirement to monitor temperature excursions at 
the subject’s home.
Purpose for Change: To ensure IP is stored as specified in the Pharmacy Manual.
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34.
Section 9.4
Description of Change: 
Original text:
Subjects who develop a neutralizing inhibitor to rVWF and/or ADVATE 
(biological assays). 
New text:
Subjects who develop a neutralizing inhibitor to rVWF and/or ADVATE 
(biological assays) that results in significant clinical effect, including but not 
limited to increasing the weekly dose of rVWF by > 50%.
Purpose for Change: To provide more clarifications.
35.
Section 9.4
Description of Change:
One more discontinuation criteria was added.
Purpose for Change: To avoid the continue of non-compliance subjects.
36.
Section 10.3.1
Description of Change:
Added the wording to clarify the wash-out period of the screening visit and the 
timing of the subsequent visit for switch subjects.
Purpose for Change: To clarify for switch subjects.
37.
Section 10.3.2
Description of Change: 
Wording was added to specify this visit only applicable to on-demand cohort.
Purpose for Change: To provide clarification.
38.
Section 10.3.3
Description of Change: 
Wording was added to specify the timing of this visit for the switch cohort.
Purpose for Change: To provide clarification.
39.
Section 10.3.4
Description of Change:
The initial steady-state PK assessment that only applicable to the switch subjects 
was specified in this section.
Purpose for Change: To accommodate PK assessment of switch subjects.
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40.
Section 10.3.5, Section 10.3.6, Section 10.3.7, Section 10.3.8, Section 10.3.9
Description of Change: 
The original sections from 10.3.4 – 10.3.8 became 10.3.5 – 10.3.9 due to the 
insertion of new section 10.3.4.
Purpose for Change: To accommodate the insertion of new Section 10.3.4.
41.
Section 10.3.7
Description of Change: 
The value of prophylaxis dose was removed since it was not correct for switch 
patients. The different wash-out period for switch subjects was specified.
Purpose for Change: To make corrections and to make clarifications for switch 
subjects.
42.
Section 10.3.9
Description of Change:
Wording was added to clarify that the EOS PK assessment also applicabe for 
switch subjects and the wash-out requirement for switch subjects was added. The 
details about PK parameters were removed (specified in other sections).
Purpose for Change: To provide clarifications for switch subjects.
43.
Section 10.4
Description of Change: 
Added more clarification about the use of Antifibrinolytics.
Purpose for Change: To provide further clarifications.
44.
Section 10.5
Description of Change:
Added more details about what would be recorded in the diary.
Purpose for Change: To provide further clarifications.
45.
Section 11.2, Section 12.5
Description of Change:
Specified the need of location for historical bleeds records. Clarified that it is 
good to have upto 24 months of historical records if available.
Purpose for Change: To provide further clarifications.
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46.
Section 11.3
Description of Change:
Added more details about what would be needed for switch subjects as the 
historical factor dosing and consumption records.
Purpose for Change: To provide further clarifications.
47.
Section 11.5
Description of Change:
Clarify the assessment of overall assessment of hemostatic efficacy.
Purpose for Change: To provide clarifications.
48.
Section 11.6
Description of Change:
Section title was updated to add PD assessment.
PK/PD assessment details including schedule, dosing, parameters, etc.
Purpose for Change: To provide instruction/protocol for PK/PD assessment.
49.
Section 12.1.1.1
Description of Change: 
More details about hypersensitivity reactions were specified. SAE reporting 
reference was added. 
Purpose for Change: To provide further clarification.
50.
Section 12.1.1.2
Description of Change:
More clarifications about SUSAR were added. 
Purpose for Change: To provide further clarification.
51.
Section 12.1.1.3
Description of Change: 
More details about criteria of serious AE were added. 
Purpose for Change: To provide further clarification.
52.
Section 12.1.2
Description of Change: 
Some wording of clarification was added for assessment of AE. 
Purpose for Change: To provide further clarification.
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53.
Section 12.1.2.2
Description of Change: 
Original text:
Is not associated with the IP (i.e., does not follow a reasonable temporal 
relationship to the administration of IP or has a much more likely alternative 
etiology).
New text:
Is not associated with the IP (i.e., does not follow a reasonable temporal 
relationship to the administration of IP, is not biologically plausible per 
mechanism of action of the IP, or has a much more likely alternative etiology).
Purpose for Change: To provide more clarifications.
54.
Section 12.1.2.3
Description of Change: 
More details about hypersensitivity reactions were specified. SAE reporting 
reference was added. 
Purpose for Change: To provide further clarification.
55.
Section 12.7
Description of Change: 
Added clarification that height is only assessed on screening visit. 
Purpose for Change: To provide further clarification.
56.
Section 12.9, Section 12.9.14.1
Description of Change: 
“Abnormal laboratory values deemed clinically significant by the investigator are 
to be recorded as AEs (see Section 12.1.2).” was removed due to inaccuracy.
New Text added: “Any abnormal laboratory value that is considered clinically 
significant by the investigator based on a local laboratory test result (reference 
range and the units to be provided) should be confirmed by a central laboratory 
test result for which the sample is drawn/collected within 24 hours of the 
abnormal finding by the local laboratory”. 
Purpose for Change: To provide accuracy and further clarification.
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57.
Section 12.9.1
Description of Change: 
Section title was updated to add PD assessment.
Text was removed, and refered to Section 11.6. 
Purpose for Change: To avoid duplicated text.
58.
Section 12.9.3.4
Description of Change: 
Wording added to specify that only confirmed positive anti-VWF inhibitor test 
result will be reported and will be considered as a medically significant SAE. 
Purpose for Change: To clarify.
59.
Section 12.10.2
Description of Change:
 
 
Purpose for Change: 
60.
Section 13.2.2
Description of Change: 
Original text:
The Full Analysis Set (FAS) will be composed of all subjects with available 
bleeding data gathered during prophylaxis IP treatment.
New text:
The Full Analysis Set (FAS) will be composed of all subjects who receive
prophylaxis IP treatment.
Purpose for Change: To re-define FAS.
61.
Section 13.2.3
Description of Change: 
Details were added on how to measure the compliance. 
Purpose for Change: To add clarifications.
62.
Section 13.2.4
Description of Change: 
Wording added to clarify PK analysis set is also for PD analysis. 
Purpose for Change: To add clarifications.
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63.
Section 13.4.2.2, Section 13.4.2.3 
Description of Change:
 
 
 
 
Purpose for Change: 
 
64.
Section 13.4.3.1, Section 13.4.3.2, Section 13.4.3.3 and Section 13.4.3.4
Description of Change: 
 
 
 
 
Purpose for Change: 
 
65.
Section 13.5
Description of Change:
Removed the interim analysis 
Purpose for Change: No interim analysis is planned.
66.
Section 15.5
Description of Change:
Additional instruction was provided to ensure the compliance by adding the text 
“Also, the investigator will notify the sponsor immediately by phone and confirm 
notification to the sponsor in writing whenever pdVWF is used instead of rVWF. 
The reason for this use must also be provided to the sponsor”.
Purpose for Change: To ensure compliance.
67.
Section 20.1
Description of Change: 
The study flow chart was updated to reflect the addition of switch cohort and to 
illustrate the study design for this new cohort.
Purpose for Change: To update the study design.
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68.
Section 20.2, Section 20.2.1
Description of Change:
Some clarifications were made to the tables and the footnotes, the original table 6 
was changed to 6a and specified just for on-demand subjects, table 6b that is for 
switch subjects was added. 
Purpose for Change: To provide schedule for the switch subjects and to provide 
clarifications for surgery procedure schedule.
69.
Section 20.3, Section 20.3.1
Description of Change: 
Some clarifications were made to the tables and the footnotes, the original table 8 
was changed to 8a and specified just for on-demand subjects, table 8b that is for 
switch subjects was added. 
Purpose for Change: To provide schedule for the switch subjects and to provide 
clarifications for surgery lab assessments.
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INVESTIGATOR ACKNOWLEDGEMENT
RECOMBINANT VON WILLEBRAND FACTOR (rVWF)
A prospective, phase 3, open-label, international multicenter study on efficacy and 
safety of prophylaxis with rVWF in severe von Willebrand Disease
PROTOCOL IDENTIFIER: 071301
CLINICAL TRIAL PHASE 3
GLOBAL AMENDMENT 6: 2018 MAR 12
Replaces: AMENDMENT 3: 2017 AUG 03
OTHER PROTOCOL ID(s)
NCT Number: NCT02973087
EudraCT Number: 2016-001478-14
IND NUMBER: 013657
By signing below, the investigator acknowledges that he/she has read and understands 
this protocol, and will comply with the requirements for obtaining informed consent from 
all study subjects prior to initiating any protocol-specific procedures, obtaining written 
initial and ongoing EC(s) protocol review and approval, understands and abides by the 
requirements for maintenance of source documentation, and provides assurance that this 
study will be conducted according to all requirements as defined in this protocol, Clinical 
Trial Agreement, ICH GCP guidelines, and all applicable national and local regulatory 
requirements.
Signature of Principal Investigator
Date
Print Name of Principal Investigator
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CLINICAL STUDY PROTOCOL
PRODUCT: Recombinant Von Willebrand Factor (rVWF, vonicog alfa)
STUDY TITLE: A PROSPECTIVE, PHASE 3, OPEN-LABEL, 
INTERNATIONAL MULTICENTER STUDY ON EFFICACY AND SAFETY OF 
PROPHYLAXIS WITH rVWF IN SEVERE VON WILLEBRAND DISEASE
STUDY SHORT TITLE: rVWF IN PROPHYLAXIS
PROTOCOL IDENTIFIER: 071301
CLINICAL TRIAL PHASE 3
LOCAL AMENDMENT 7 (GERMANY): 2018 MAY 18
Replaces: 
LOCAL AMENDMENT 4 (GERMANY): 2017 AUG 04
ALL VERSIONS: 
Local (Germany) Amendment 7: 2018 MAY 18
Amendment 6: 2018 MAR 12
Local (Czech Republic) Amendment 5: 2017 AUG 08
Local (Germany) Amendment 4: 2017 AUG 04
Amendment 3: 2017 AUG 03
Amendment 2: 2016 DEC 15
Amendment 1: 2016 APR 08
Original: 2014 FEB 19
OTHER ID(s)
NCT Number: NCT02973087
EudraCT Number: 2016-001478-14
IND NUMBER: 013657
Study Sponsor(s):
Baxalta US Inc.
300 Shire Way
Lexington, MA 02421,
UNITED STATES
Baxalta Innovations GmbH
Industriestrasse 67
A-1221 Vienna, 
AUSTRIA
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1. STUDY PERSONNEL
1.1 Authorized Representative (Signatory) / Responsible Party
, MD
Global Clinical Development Operations
Baxalta Innovations GmbH
1.2 Study Organization
The name and contact information of the responsible party and individuals involved with 
the study (e.g. investigator(s), sponsor’s medical expert and study monitor, sponsor’s 
representative(s), laboratories, steering committees, and oversight committees [including 
ethics committees (ECs)], as applicable) will be maintained by the sponsor and provided 
to the investigator.
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2. SERIOUS ADVERSE EVENT REPORTING
The investigator will comply with applicable laws/requirements for reporting serious 
adverse events (SAEs) and suspected unexpected serious adverse events (SUSARs) to the 
ECs.
ALL SAEs, INCLUDING SUSARs, ARE TO BE REPORTED ON THE SERIOUS 
ADVERSE EVENT REPORT (SAER) FORM AND TRANSMITTED TO THE 
SPONSOR WITHIN 24 HOURS AFTER BECOMING AWARE OF THE EVENT.
Bleeding events that meet seriousness criteria (death, life-threatening, 
hospitalizing/prolongation of hospitalization, disability, congenital anomaly, or medically 
significant and if not urgently treated would result in one of the above) should be 
reported on the SAE eCRF and SAE Report form as an SAE.
Drug Safety contact information:
Baxalta Global Drug Safety fax number:  
OR 
email: 
For definitions and information on the assessment of these events, refer to the following:

Adverse Events (AEs), Section 12.1

SAEs, Section 12.1.1.1

SUSARs, Section 12.1.1.2

Assessment of AEs, Section 12.1.2

Safety Reporting, Section 12.1.2.3
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3. SYNOPSIS
INVESTIGATIONAL PRODUCT
Name of Investigational Product (IP)
Recombinant von Willebrand factor (rVWF, vonicog alpha)
Name(s) of Active Ingredient(s)
Recombinant von Willebrand factor (rVWF, vonicog alpha)
CLINICAL CONDITION(S)/INDICATION(S)
Subjects with severe von Willebrand disease (VWD) (baseline VWF: Ristocetin cofactor activity
(VWF:RCo) <20 IU/dL) requiring prophylactic treatment with coagulation factor replacement
PROTOCOL ID
071301
PROTOCOL TITLE
A prospective, phase 3, open-label, international multicenter 
study on efficacy and safety of prophylaxis with rVWF in 
severe von Willebrand disease
Short Title
rVWF in prophylaxis
STUDY PHASE
Phase 3
PLANNED STUDY PERIOD
Initiation
2017 OCT
Primary Completion
2019 Q4
Study Completion
2019 Q4
Duration
27 months
STUDY OBJECTIVES AND PURPOSE
Study Purpose
The purpose of this phase 3 study is to investigate the efficacy and safety, including immunogenicity, 
thrombogenicity and hypersensitivity reactions, as well as pharmacokinetics (PK),
 
and 
 of prophylactic treatment with rVWF (vonicog alfa) in adult 
subjects with severe VWD.
Primary Objective
The primary objective of this study is to prospectively evaluate the annualized bleeding rate (ABR) for
spontaneous bleeding episodes while on prophylactic treatment with rVWF (vonicog alfa) and to compare 
it to the subject’s historical ABR for spontaneous bleeding episodes. 
Secondary Objectives
Secondary Objectives are to assess

Additional efficacy of prophylactic treatment with rVWF (vonicog alfa)

Safety of rVWF (vonicog alfa), including immunogenicity, thrombogenicity and hypersensitivity

Pharmacokinetics (PK) of rVWF (vonicog alfa) and Pharmacodynamics (PD) of rVWF (vonicog alfa)
as measured in FVIII activity
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Exploratory Objectives
 
 
 
STUDY DESIGN
Study Type/ Classification/ Discipline
Efficacy and Safety 
Control Type
No control
Study Indication Type
Prophylaxis and treatment of bleeding episodes
Intervention model 
Single-group
Blinding/Masking
Open-label
Study Design
This is a phase 3, prospective, open-label, uncontrolled, non-
randomized, international multicenter study evaluating efficacy, 
safety, including immunogenicity, thrombogenicity and 
hypersensitivity reactions, as well as PK, 
and 
 of prophylactic treatment regimen with 
rVWF (vonicog alfa) in adult subjects with severe VWD.
Subjects transitioning from on-demand treatment (OD subjects) 
or subjects switching from prophylactic treatment with pdVWF
(pdVWF switch subjects) will receive prophylactic treatment 
with rVWF (vonicog alfa) for a 12-month period.
Planned Duration of Subject 
Participation
Approximately 15 months 
Primary Outcome Measure 
Efficacy

Annualized bleeding rate (ABR) for spontaneous (not related to trauma) bleeding episodes during 
prophylactic treatment with rVWF (vonicog alfa)
Secondary Outcome Measures
Additional efficacy of prophylactic treatment with rVWF (vonicog alfa)

ABR percent reduction success for OD subjects defined as at least 25% reduction of ABR for
spontaneous (not related to trauma) bleeding episodes during rVWF (vonicog alfa) prophylaxis 
relative to the subject’s own historical ABR during on-demand treatment
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
ABR preservation success for pdVWF switch subjects defined as achieving an ABR for spontaneous 
bleeding episodes during rVWF (vonicog alfa) prophylaxis that is no greater than the subject’s own 
historical ABR during prophylactic treatment with pdVWF 

Categorized spontaneous ABR defined as 0, 1-2, 3-5, or >5 bleeding episodes during the 12-month 
prophylactic treatment with rVWF (vonicog alfa)

Total number of infusions and the average number of infusions per week during prophylactic 
treatment with rVWF (vonicog alfa)

Total weight adjusted consumption of rVWF (vonicog alfa) during prophylactic treatment

Spontaneous ABR by location of bleeding (Gastrointestinal [GI], epistaxis, joint bleeding, 
menorrhagia, oral and other mucosa, muscle and soft tissue, etc.) while on prophylactic treatment with 
rVWF (vonicog alfa)
Safety

Adverse events (AEs) : incidence, severity, causality

Thromboembolic events 

Hypersensitivity reactions

Development of neutralizing antibodies to VWF and FVIII 

Development of total binding antibodies to VWF and FVIII

Development of binding antibodies to Chinese hamster ovary (CHO) proteins, mouse 
immunoglobulin G (IgG) and rFurin

Clinically significant changes in vital signs and clinical laboratory parameters relative to baseline
Pharmacokinetics (PK) and Pharmacodynamics (PD)

PK parameters after a washout for on-demand subjects: incremental recovery (IR), terminal half-life
(T1/2), mean residence time (MRT), area under the concentration versus time curve from 0 to infinity 
(AUC0-), area under the concentration versus time curve from 0 to the last measurable concentration 
(AUC0-tlast), maximum concentration (Cmax), minimum time to reach the maximum concentration
(Tmax), volume of distribution at steady state (Vss) and clearance (CL) based on VWF:RCo, Von 
Willebrand factor antigen (VWF:Ag), Von Willebrand collagen binding activity (VWF:CB).

PD parameters after a washout for on-demand subjects: Cmax, Tmax, and AUC0-tlast as measured in 
FVIII activity by the 1-stage clotting assay (FVIII:C). 

PK parameters at steady state for on-demand and switch subjects: area under the concentration versus 
time curve from 0 to end of the partial dosing interval (AUC0- tau;ss), maximum concentration during 
the partial dosing interval (Cmax;ss), minimum time to reach the maximum concentration (Tmax;ss) and 
minimum concentration during the partial dosing interval (Cmin;ss) based on VWF:RCo, VWF:Ag and 
VWF:CB. PK parameters at steady state will be assessed shortly after reaching steady state for switch 
subjects and at the end of the study for on-demand as well as for switch subjects all based on the 
longer interval of the irregular dosing intervals employed.

PD parameters at steady state for on-demand and switch subjects: AUC0-tau;ss, Cmax;ss, Tmax;ss, and 
Cmin;ss as measured in FVIII actvitiy by the 1-stage clotting assay (FVIII:C). PD parameters at steady 
state will be assessed shortly after reaching steady state for switch subjects and at the end of the study 
for on-demand as well as for switch subjects all based on the longer interval of the irregular dosing 
intervals employed.

Time course of FVIII clotting activity (FVIII:C) levels.
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Exploratory Outcome Measures
 
 
 
 
 
 
 
 
 
 
INVESTIGATIONAL PRODUCT(S), DOSE AND MODE OF ADMINISTRATION
Active Product
Dosage form: powder and solvent for solution for injection
Dosage frequency:
Prophylactic Treatment
Subjects transitioning from on-demand treatment will receive twice weekly
infusion with rVWF (vonicog alfa) at doses of 50 ± 10 IU/kg rVWF:RCo. 
Dosage may be individualized within this range based on:

available historical PK data

type and severity of bleeding episodes the subject has experienced in the past

monitoring of appropriate clinical and laboratory measures
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The starting dose can, after consultation with the Sponsor, be increased up to 
80 U/kg if considered necessary to assure effective prophylaxis.
Subjects switching from pdVWF prophylaxis treatment: the weekly dose (IU/kg) 
of rVWF (vonicog alfa) for each patient will be equivalent (± 10%) to the weekly 
VWF dose received during prophylactic treatment with pdVWF. The weekly 
dose should be divided into 2 infusions, with a maximum of 80 IU/kg/infusion. If 
needed, based on the total weekly dose or other clinical judgements, the weekly 
dose may be given as three infusions. A once weekly dose regimen will be 
allowed after switch to rVWF (vonicog alfa) if the patient has been on a once 
weekly dose regimen with pdVWF. Dose and dose interval may, after 
consultation with the sponsor, be further individualized based on: 

available historical PK data

type and severity of bleeding episodes the subject has experienced in the past

monitoring of appropriate clinical and laboratory measures
Treatment of Bleeding Episodes:
Dosage must be individualized based on the subject’s weight, type and severity 
of bleeding episode and monitoring of appropriate clinical and laboratory 
measures. In general, an initial dose of 40-60 IU/kg VWF:RCo with or without
30-45 IU rFVIII [ADVATE, octocog alfa]/kg is recommended (rVWF:rFVIII 
ratio of 1.3:1: ± 0.2). In cases of major bleeding episodes, a dose of up to 80 
IU/kg VWF:RCo may be infused. Subsequent doses, if necessary, will be 
administered with or without ADVATE (rFVIII, octocog alfa) to maintain 
VWF:RCo and FVIII levels for as long as deemed necessary by the investigator.
Mode of Administration: intravenous
SUBJECT SELECTION
Targeted Accrual
Approximately 22 adult subjects with severe VWD will be included to have 
≥8 subjects in each cohort (OD and switch). A total of at least 5 type 3 VWD 
subjects will be followed for 12 months.
Number of Groups/
Arms/ Cohorts
Single-group
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Inclusion Criteria
Subjects who meet ALL of the following criteria are eligible for this study:
1. Subject has a documented diagnosis of severe VWD (baseline VWF:RCo <20 IU/dL) with a history 
of requiring substitution therapy with von Willebrand factor concentrate to control bleeding:
a. Type 1 (VWF:RCo <20 IU/dL) or,
b. Type 2A (as verified by multimer pattern), Type 2B (as diagnosed by genotype), Type 2M or,
c. Type 3 (VWF:Ag ≤3 IU/dL).
2. Diagnosis is confirmed by genetic testing and multimer analysis, documented in patient history or at 
screening.
3. For on-demand patient group, subject currently receiving on-demand treatment for whom prophylactic 
treatment is recommended by the investigator.
4. For pdVWF switch patient group, subject has been receiving prophylactic treatment of pdVWF 
products for no less than 12 months prior to screening.
5. For on-demand patient group, subject has ≥3 documented spontaneous bleeds (not including 
menorrhagia) requiring VWF treatment during the past 12 months.
6. Availability of records to reliably evaluate type, frequency and treatment of bleeding episodes during 
at least 12 months preceding enrollment. Up to 24 months of retrospective data should be collected if 
available. Availability of dosing and factor consumption during 12 months (up to 24 months) of 
treatment prior to enrollment is required for pdVWF switch subjects and is desired (but not a 
requirement) for on-demand subjects.
7. Subject is ≥18 years old at the time of screening and has a body mass index ≥18 but ≤30 kg/m2.
8. If female of childbearing potential, subject presents with a negative blood/urine pregnancy test at 
screening and agrees to employ adequate birth control measures for the duration of the study.
9. Subject is willing and able to comply with the requirements of the protocol.
Exclusion Criteria
Subjects who meet ANY of the following criteria are not eligible for this study:
1. The subject has been diagnosed with Type 2N VWD, pseudo VWD, or another hereditary or acquired 
coagulation disorder other than VWD (e.g., qualitative and quantitative platelet disorders or elevated
prothrombin time (PT)/international normalized ratio [INR] 1.4).
2. The subject is currently receiving prophylactic treatment with more than 5 infusions per week.
3. The subject is currently receiving prophylactic treatment with a weekly dose exceeding 240 IU/kg.
4. The subject has a history or presence of a VWF inhibitor at screening.
5. The subject has a history or presence of a FVIII inhibitor with a titer ≥0.4 Bethesda units (BU) (by 
Nijmegen modified Bethesda assay) or ≥0.6 BU (by Bethesda assay).
6. The subject has a known hypersensitivity to any of the components of the study drugs, such as to 
mouse or hamster proteins.
7. The subject has a medical history of immunological disorders, excluding seasonal allergic 
rhinitis/conjunctivitis, mild asthma, food allergies or animal allergies.
8. The subject has a medical history of a thromboembolic event.
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9. The subject is human immunodeficiency virus (HIV) positive with an absolute Helper T cell 
(CD4) count 200/mm3.
10. The subject has been diagnosed with significant liver disease per investigator’s medical assessment of 
the subject’s current condition or medical history or as evidenced by any of the following: serum 
alanine aminotransferase (ALT) greater than 5 times the upper limit of normal; hypoalbuminemia; 
portal vein hypertension (e.g., presence of otherwise unexplained splenomegaly, history of esophageal 
varices).
11. The subject has been diagnosed with renal disease, with a serum creatinine (CR) level ≥2.5 mg/dL.
12. The subject has a platelet count <100,000/mL at screening.
13. The subject has been treated with an immunomodulatory drug, excluding topical treatment (e.g., 
ointments, nasal sprays), within 30 days prior to signing the informed consent.
14. The subject is pregnant or lactating at the time of enrollment.
15. Patient has cervical or uterine conditions causing menorrhagia or metrorrhagia (including infection, 
dysplasia).
16. The subject has participated in another clinical study involving another investigational product (IP) or 
investigational device within 30 days prior to enrollment or is scheduled to participate in another 
clinical study involving an IP or investigational device during the course of this study.
17. The subject has a progressive fatal disease and/or life expectancy of less than 15 months.
18. The subject is scheduled for a surgical intervention.
19. The subject is identified by the investigator as being unable or unwilling to cooperate with study 
procedures.
20. The subject has a mental condition rendering him/her unable to understand the nature, scope and 
possible consequences of the study and/or evidence of an uncooperative attitude.
21. The subject is in prison or compulsory detention by regulatory and/or juridical order
22. The subject is member of the study team or in a dependent relationship with one of the study team 
members which includes close relatives (i.e., children, partner/spouse, siblings and parents) as well as 
employees.
Delay criteria
1. If the subject presents with an acute bleeding episodes or acute illness (e.g., influenza, flu-like 
syndrome, allergic rhinitis/conjunctivitis, non-seasonal asthma) the screening visit will be postponed 
until the subject has recovered.
STATISTICAL ANALYSIS
Sample Size Calculation
Approximately 22 adult subjects with severe VWD will be included in the study. The aim is to have
≥8 subjects in each cohort (OD and switch). A total of at least five type 3 VWD subjects will be followed 
for 12 months. The sample size is driven by practical considerations (primarily the enrollment of a rare 
patient population) and EMA Guideline on the Clinical Investigation of Human Plasma Derived von 
Willebrand Factor Products (CPMP/BPWG/220/02).1
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Planned Statistical Analysis
The Full Analysis Set (FAS) will be composed of all subjects who receive prophylaxis IP treatment.
The Safety Analysis Set will be composed of all subjects who received any amount of IP  (rVWF, vonicog 
alpha).
The Per-Protocol (PP) Analysis Set will be composed of subjects who are at least 70% compliant regarding 
the number of scheduled prophylactic infusions. Only subjects who meet all study entry criteria and who 
have no major protocol violations that might impact primary efficacy assessments will be included in the 
PP analysis set.
The Pharmacokinetic Full Analysis Set (PKFAS) will be composed of all subjects who received the PK 
infusion and who provided acceptable data for PK and PD analysis. Acceptable PK/PD data will be defined 
in the Statistical Analysis Plan.
Primary Outcome Measure:
No formal statistical hypothesis test is planned for the analysis. Spontaneous ABR while treated with 
rVWF (vonicog alfa) for each cohort, on demand and switch subjects, will be estimated using a negative 
binomial regression. The prior ABR for each cohort will be based on historical data collected from each 
enrolled subject. The two ABRs (observed on the study and historical) will be assessed using a generalized 
linear mixed-effects model (GLMM) with the negative binomial distribution as a family and with a 
logarithmic link function (the default). The ABR ratio together with a two-sided, 95% confidence interval 
(CI) will be reported for each cohort.
The difference in on-study ABR relative to historical ABR will be summarized descriptively.
The primary efficacy analysis will be based on the FAS and will be summarized by the two cohorts: on-
demand and switch subjects. As a supportive analysis, the same analysis will also be carried out on the PP
analysis set.
Secondary Outcome Measures:
In general, data for  secondary efficacy analysis will be summarized by the two cohorts: on-demand and 
switch subjects and when applicable overall. Mean, standard deviation, median, range, quartiles will be 
calculated for continuous endpoints. Proportions will be calculated for categorical endpoints. Confidence 
intervals at the 95% level will be provided when appropriate.
Additional efficacy of prophylactic treatment with  rVWF (vonicog alfa):
The number  and proportion of on-demand subjects with ABR percent reduction success (i.e. ≥ 25% ) will 
be calculated together with a two-sided 95% CI for the proportion. 
The number and proportion of pdVWF switch subjects with ABR preservation success will be reported 
together with the corresponding 95% two-sided CIs for the proportion. 
The number and proportion of subjects with categorized spontaneous ABR (i.e. 0, 1-2, 3-5, more than 
5 bleeds) will be reported descriptively.
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Summary statistics for the total number of infusions, as well as average number of infusions per week will 
be provided. The total weight adjusted consumption of rVWF (vonicog alfa) during prophylactic treatment 
will be provided. If applicable, historical data on consumption of pdVWF prior to the study will be 
summarized as well.
The change in spontaneous ABR from the historical rate to that during the rVWF (vonicog alfa) prophylaxis 
period will be summarized by location of bleeding (GI, epistaxis, joint bleeding, menorrhagia, oral and other 
mucosa, muscle and soft tissue, etc.).
Pharmacokinetics (PK) and Pharmacodynamics (PD):
The following PK parameters, based on the initial PK assessment after a washout for on-demand subjects, 
will be listed and summarized descriptively for VWF:RCo, VWF:Ag and VWF:CB: IR, T1/2, MRT, 
AUC0-, AUC0-tlast, Cmax, Tmax, Vss, and CL. The corresponding pharmacodynamics (PD) of rVWF 
(vonicog alfa) as measured in FVIII activity (FVIII:C), based on the initial PK assessment after a 
washout for on-demand subjects will be assessed using Cmax, Tmax, and AUC0-tlast. These PD parameters 
will be listed and summarized descriptively. 
PK parameters at steady state (AUC0-tau;ss, Cmax;ss, Tmax;ss, and Cmin;ss) for the partial dosing interval will be 
listed for on-demand subjects at the end of the study and for switch subjects shortly after reaching steady 
state and at the end of the study for VWF:RCo, VWF:Ag and VWF:CB and summarized descriptively for 
subjects with the same dosing regimens. The corresponding pharmacodynamics (PD) of rVWF (vonicog 
alfa) as measured in FVIII activity (FVIII:C) will be assessed using AUC0-tau;ss, Cmax;ss, Tmax;ss, and Cmin;ss. 
These PD parameters will be listed for on-demand subjects at the end of the study and for switch subjects 
shortly after reaching steady state and at the end of the study and will be summarized descriptively for
subjects with the same dosing regimens. 
For the on-demand subjects, the PK of VWF:RCo will be analyzed using a population PK approach to 
characterize the single and multiple dose pharmacokinetics, including associated variability, of VWF:RCo 
in the study population.
For the switch subjects, differences in AUC0-tau;ss, Cmax;ss, and Cmin;ss assessess shortly after reaching steady 
state and assessed at the end of the study will be assessed by ratio of geometric means and corresponding 
two-sided 95% confidence intervals for VWF:RCo, VWF:Ag, VWF:CB, and FVIII:C. The difference in 
Tmax;ss, between first and second pharmacokinetic assessment will be summarized by the median and range 
(minimum to maximum) for VWF:RCo, VWF:Ag,VWF:CB, and FVIII:C.
Descriptive statistics will be used to summarize VWF:RCo, VWF:Ag, VWF:CB, and FVIII:C levels for
each nominal time point on the PK curve. For all subjects activity/concentration vs. time curves will be 
prepared.
Safety:
Safety analysis will be performed overall and by the two cohorts: on-demand and switch subjects.
Treatment-emergent AEs (TEAEs) are defined as AEs with start dates on or after the first exposure to IP. 
Summaries of AEs will be based on TEAEs unless otherwise indicated.
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Occurrence of AEs and serious AEs (SAEs) will be summarized descriptively, by system organ class and 
preferred term. The number and percentage of subjects who experienced AEs and SAEs, and the number of 
AEs and SAEs will be tabulated. In addition, the number of subjects who experienced AEs assessed as 
related to IP by the investigator, and the number of IP-related AEs will be tabulated. The number of 
patients with AEs by severity will be presented similarly.
A listing of all AEs will be presented by subject identifier, age, sex, preferred term and reported term of the 
AE, duration, severity, seriousness, action taken, outcome, causality assessment by investigator, onset date, 
stop date and medication or non-drug therapy to treat the AE. 
Temporally associated AEs are defined as AEs that begin during infusion or within 24 hours (or 1 day 
where time of onset is not available) after completion of infusion, irrespective of being related or not 
related to treatment. Temporally associated AEs will be presented in summary tables.
Adverse events of special interest (AESI), such as hypersensitivity reactions and thromboembolic events,  
will be monitored throughout the study and statistical analysis will be conducted based on the search 
criteria (eg, standardized MedDRA queries [SMQ]) determined prior to database lock, and summarized.
For immunogenicity analysis frequency counts and proportions will be calculated for subjects with the 
occurrence of neutralizing (inhibitory) antibodies to VWF and FVIII, occurrence of binding antibodies to 
VWF and FVIII, and occurrence of binding antibodies to CHO proteins, mouse immunoglobulin G (IgG) 
and rFurin.
Clinically significant changes relative to baseline in vital signs and clinical laboratory parameters 
(hematology, clinical chemistry) will be reported.
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4. TABLE OF CONTENTS
1. STUDY PERSONNEL ................................................................................................. 2
1.1 Authorized Representative (Signatory) / Responsible Party .............................. 2
1.2 Study Organization................................................................................................. 2
2. SERIOUS ADVERSE EVENT REPORTING........................................................... 3
3. SYNOPSIS..................................................................................................................... 4
4. TABLE OF CONTENTS ........................................................................................... 14
5. LIST OF ABBREVIATIONS .................................................................................... 20
6. BACKGROUND INFORMATION .......................................................................... 24
6.1 Description of Investigational Product ............................................................... 24
6.2 Clinical Condition/Indication .............................................................................. 24
6.3 The Role of Prophylaxis in the Management of VWD...................................... 25
6.4 Populations to be Studied..................................................................................... 27
6.5 Findings from Nonclinical and Clinical Studies................................................. 28
6.5.1 Findings from Nonclinical Studies ............................................................... 28
6.5.1.1 Primary Pharmacodynamics................................................................. 28
6.5.1.2 Safety Pharmacology.............................................................................. 28
6.5.1.3 Pharmacokinetics.................................................................................... 29
6.5.1.4 Toxicology................................................................................................ 29
6.5.2 Findings from Clinical Studies ..................................................................... 30
6.5.2.1 Study 070701 ........................................................................................... 30
6.5.2.2 Study 071104 ........................................................................................... 32
6.5.2.3 Study 071001 ........................................................................................... 33
6.5.2.4 Study 071101 ........................................................................................... 35
6.5.2.5 Study 071401: Single Subject with von Willebrand Disease............... 37
6.6 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) 
to Human Subjects................................................................................................ 37
6.7 Compliance Statement.......................................................................................... 38
7. STUDY PURPOSE AND OBJECTIVES ................................................................. 39
7.1 Study Purpose ....................................................................................................... 39
7.2 Primary Objective................................................................................................. 39
7.3 Secondary Objectives ........................................................................................... 39
7.4 Exploratory Objectives......................................................................................... 39
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10.2 Subject Identification Code................................................................................ 62
10.3 Screening and Study Visits................................................................................. 62
10.3.1 Screening Visit ............................................................................................. 62
10.3.2 Baseline Visit – Initial PK Assessment (On-demand Subjects Only)...... 63
10.3.3 Prophylaxis Initiation Visit......................................................................... 64
10.3.4 Initial Steady State PK-Assessment (pdVWF switch subjects only)....... 64
10.3.5 Treatment of Bleeding Episodes................................................................. 65
10.3.6 Perioperative Visits (only applicable if surgery is needed)...................... 65
10.3.7 Follow-Up Visits (1 Month ± 1 Week, 2 Months ± 1 Week, 
3 Months ± 2 Weeks, 6 Months ± 2 Weeks, 9 Months ± 2 Weeks post 
Prophylaxis Initiation Visit) ......................................................................... 66
10.3.8 Unscheduled Visits....................................................................................... 67
10.3.9 End of Study PK Assessment and Study Termination Visit 
(12 Months ± 2 Weeks post Prophylaxis Initiation Visit).......................... 67
10.4 Medications and Non-Drug Therapies.............................................................. 68
10.5 Subject Diary....................................................................................................... 69
10.6 Subject Completion/Discontinuation ................................................................ 69
10.7 Procedures for Monitoring Subject Compliance............................................. 70
11. ASSESSMENT OF EFFICACY AND PHARMACOKINETICS........................ 71
11.1 Assessment of Spontaneous Bleeding Episodes/Annualized Bleed Rate........ 71
11.2 Evaluation of ABR Before rVWF Prophylaxis and ABR Under rVWF 
Prophylactic Treatment ....................................................................................... 72
11.3 Number of Infusions and Total Weight Adjusted Consumption of rVWF and 
ADVATE and historical prophylaxis dosing and factor consumption during 
pdVWF prophylaxis treatment prior to enrollment.......................................... 72
11.4 Assessment of Efficacy for Treatment of Bleeding Episode ........................... 72
11.5 Assessment of Efficacy for Treatment for Surgical Bleeding......................... 73
11.6 rVWF Pharmacokinetics and Pharmacodynamics ......................................... 74
12. ASSESSMENT OF SAFETY................................................................................... 76
12.1 Adverse Events.................................................................................................... 76
12.1.1 Definitions..................................................................................................... 76
12.1.1.1 Serious Adverse Event.......................................................................... 76
12.1.1.2 Suspected Unexpected Serious Adverse Reaction (SUSAR)............. 77
12.1.1.3 Non-Serious Adverse Event ................................................................. 77
12.1.1.4 Unexpected Adverse Events................................................................. 78
12.1.1.5 Preexisting Disease ............................................................................... 78
12.1.2 Assessment of Adverse Events.................................................................... 78
12.1.2.1 Severity .................................................................................................. 80
12.1.2.2 Causality................................................................................................ 80
12.1.2.3 Safety Reporting ................................................................................... 81
12.2 Urgent Safety Measures ..................................................................................... 83
12.3 Untoward Medical Occurrences........................................................................ 84
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18. FINANCING AND INSURANCE......................................................................... 110
19. PUBLICATION POLICY...................................................................................... 110
20. SUPPLEMENTS..................................................................................................... 111
20.1 Study Flow Chart.............................................................................................. 111
20.2 Schedule of Study Procedures and Assessments............................................ 112
20.2.1 Summary Schedule of Visit Assesments for Surgical Bleeding............. 116
20.3 Clinical Laboratory Assessments .................................................................... 118
20.3.1 Laboratory Sampling for Surgical Bleeding ........................................... 122
20.4 Contraceptive Methods for Female Subjects of Childbearing Potential..... 124
21. REFERENCES........................................................................................................ 125
22. SUMMARY OF CHANGES.................................................................................. 128
INVESTIGATOR ACKNOWLEDGEMENT............................................................ 142
Tables
Table 1 rVWF (vonicog alfa) Dosing Schedule Examples: Schedules A and B............. 47
Table 2 Criteria for Escalation Specific to Each Bleeding Indication............................. 49
Table 3 rVWF:RCo Dosing Recommendations for the Treatment of Bleeding Episodes 
Due to VWD ............................................................................................................. 53
Table 4 Efficacy Rating Scale.......................................................................................... 73
Table 5 Assessment of Hemostatic Efficacy ................................................................... 74
Table 6a Schedule of Study Procedures and Assessments for On-demand Subject...... 112
Table 6b Schedule of Study Procedures and Assessments for pdVWF Switch Subject 114
Table 7 Summary Schedule of Visit Assesments for Surgical Bleeding....................... 116
Table 8a Clinical Laboratory Assessments for On-demand Subject ............................. 118
Table 8b Clinical Laboratory Assessments for pdVWF Switch Subject
120
Table 9 Laboratory Samplinga for Surgical Bleeding.................................................... 122
Figures
Figure 1 Study Design for Baxalta Clinical Study 071301............................................ 111
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5. LIST OF ABBREVIATIONS
Abbreviation
Definition
ABR
Annualized bleeding rate
ADAMTS13
A Disintegrin And Metalloproteinase with a Thrombospondin type 1 motif, number 13
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine aminotransferase
AP
Alkaline phosphatase
AST
Aspartate aminotransferase
AUC0-∞
Area under the plasma concentration /time curve from time 0 to infinity
AUC0-tau;ss
Area under the plasma concentration /time curve from time 0 to end of the partial 
dosing interval
AUC0-tlast
Area under the plasma concentration /time curve from 0 to the last measurable 
concentration
aPTT
Activated partial thromboplastin time
B19V
Parvovirus B19
BP
Blood pressure
BU
Bethesda Unit
BUN
Blood urea nitrogen
BW
Body weight
CAM
Cell adhesion molecule
CBC
Complete blood count
CD4
Helper T cell
CHO
Chinese hamster ovary
CI
Confidence interval
Cl
Chloride
CL
Clearance
Cmax
Maximum plasma concentration
Cmax;ss
Maximum plasma concentration during the partial dosing interval at steady state
Cmin;ss
Minimum plasma concentration during the partial dosing interval at steady state
CR
Creatinine
CTA
Clinical Trial Agreement
eCRF
Electronic case report form
DMC
Data monitoring committee
DIC
Disseminated intravascular coagulation
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Abbreviation
Definition
DVT
Deep vein thrombosis
EC
Ethics committee
ECG
Electrocardiogram 
EDC
Electronic Data Capture
EDTA
Ethylenediaminetetraacetic acid
ELISA
Enzyme-linked immunosorbent assay
FAS
Full analysis set
FVIII
Factor VIII
FVIII:C
Factor VIII clotting activity
GCP
Good Clinical Practice
GI
Gastrointestinal
Glu
Glucose
HAMA
Human anti- mouse antibodies
HAV
Hepatitis A virus
HB
Hepatitis B
HBs
Hepatitis B surface
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HEV
Hepatitis E virus
HIV
Human immunodeficiency virus 
HLA
Human leukocyte antigen
HRP
Horseradish peroxidase
IB
Investigator's brochure
ICH
International Council for Harmonisation
Ig
Immunoglobulin
INN
International Nonproprietary Name
INR
International normalized ratio
IP
Investigational product
IR
Incremental recovery
i.v.
Intravenous
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Abbreviation
Definition
K
Potassium
k.o.
Knock out
LDH
Lactate Dehydrogenase
Na
Sodium
NMC
Non-medical complaint
NOAEL
No observed adverse effect level
MRI
Magnetic resonance imaging
MRT
Mean residence time
pdVWF
Plasma derived VWF product
pdVWF/FVIII
Plasma derived VWF product containing fractions of FVIII
PBAC
Pictorial Blood Assessment Chart
PCR
Polymerase Chain Reaction
PEF
Peak expiratory flow
PK
Pharmacokinetic
PKFAS
Pharmacokinetic Full Analysis Set
PKPPAS
Pharmacokinetic Per Protocol Analysis Set
PP
Per protocol 
PT
Prothrombin time
Q1, Q3
Quartile
rFVIII
Recombinant factor VIII
rVWF
Recombinant von Willebrand factor
RBC
Red blood cell count
SAE
Serious adverse event
SAER
Serious adverse event report
SDS-PAGE
Sodium dodecyl sulfate polyacrylamide gel electrophoresis
SIC
Subject identification code
SMQ
Standardised MedDRA queries 
sP-selectin
Soluble P-selectin
SUSAR
Suspected unexpected serious adverse reaction
T1/2
Terminal phase half life
TEAE
Treatment-emergent adverse event
TIA
Transient ischemic attack
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Abbreviation
Definition
Tmax
Minimum time to reach the maximum concentration
Tmax;ss
Minimum time to reach the maximum concentration at steady state
TTP
Thrombotic thrombocytopenic purpura
ULMW
Ultra-large molecular weight 
ULN
Upper limit of normal
Vss
Volume of distribution at steady state
VTE
Venous thromboembolism 
VWD
von Willebrand disease
VWF
Von Willebrand factor
VWF:Ag
Von Willebrand factor antigen
VWF:CB
Von Willebrand Factor collagen binding
VWF:RCo
Von Willebrand factor: Ristocetin cofactor activity
WBC
White blood cell
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6. BACKGROUND INFORMATION
6.1 Description of Investigational Product
Baxalta US Inc. (hereafter referred to as Baxalta or sponsor) has developed a human 
recombinant von Willebrand Factor (rVWF, vonicog alfa), which is co-expressed with 
recombinant factor VIII (rFVIII) in a Chinese hamster ovary (CHO) cell line and
separated during the subsequent downstream process. To address concerns regarding the 
risk of transmission of blood-borne pathogens that may be introduced by human plasma, 
no exogenously added raw materials of human or animal origin are employed in the cell 
culture, purification, or formulation of the final container product. The only proteins 
present in the final container product other than rVWF (vonicog alfa) are trace quantities 
of murine immunoglobulin (IgG, from the immunoaffinity purification), host cell (i.e., 
CHO) protein, rFurin (used to further process rVWF). rVWF (vonicog alfa) is intended 
for the treatment of von Willebrand disease (VWD).
rVWF (vonicog alfa) has been developed under the Baxalta internal code BAX111 and is 
used as investigational product (IP) in this study. rVWF (vonicog alfa) may be used with 
or without ADVATE (rFVIII, octocog alfa) for the treatment of bleeding episodes (see 
Section 8.6.4.4). See Section 8.6 for further information on the IPs and their usage in this 
study. A detailed description of rVWF (vonicog alfa) is also provided in the
Investigator’s Brochure (IB).
rVWF (vonicog alfa) was granted licensure in the United States in December 2015 under 
the brand name VONVENDI for the on-demand treatment and control of bleeding 
episodes in adults diagnosed with VWD; as of the date of this protocol VONVENDI is
not yet available on the market.
6.2 Clinical Condition/Indication
Von Willebrand Factor (VWF) is a large multimeric glycoprotein with a molecular 
weight that varies from 500 to 20,000 kDa. VWF is normally found in plasma and 
produced in the alpha-granules of platelets and in endothelial cell organelles known as 
the Weibel-Palade bodies. VWF mediates platelet adhesion and aggregation at sites of 
vascular injury, one of the key functions in primary hemostasis. VWF also serves to 
stabilize coagulation factor VIII (FVIII), where FVIII is an essential cofactor of 
secondary hemostasis, which leads to fibrin clot formation.2 Qualitative and/or 
quantitative deficiencies of VWF lead to a highly variable bleeding diathesis known as 
VWD, the most common of the hereditary coagulation factor deficiencies. Penetrance 
of VWD is highly variable, with only a small fraction of mildly affected patients 
displaying clinical symptoms or a family history of a bleeding diathesis.
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The current biochemical-based classification distinguishes disorders arising from partial 
quantitative (type 1), qualitative (type 2), or virtually complete (type 3) deficiencies of 
VWF. Up to 70% of VWD patients are diagnosed with type 1 VWD, which may also be 
associated with minor functional defects in the molecule. In general, patients with type 1 
VWD display mild clinical symptoms. Approximately 20 to 30% of VWD patients are 
diagnosed with type 2 VWD. Type 2 VWD is further divided into 4 subtypes (A, B, N, 
and M), reflecting distinct classes of functional abnormalities. These defects result in 
abnormal functional and/or multimeric distribution patterns that facilitate their diagnosis. 
The bleeding diathesis is usually moderate and primarily affects the mucosal tissues. 
Type 2N VWD patients are sometimes misdiagnosed as mild hemophilia A. Finally, 
approximately 1% percent of VWD patients exhibit a total or near total absence of VWF, 
which is classified as type 3 VWD. The incidence of type 3 VWD is estimated at 
0.5-1.0 x 106. This type is also associated with a very low FVIII level (typically <5%) 
because the VWF carrier function for FVIII is lost. Replacement of VWF alone stabilizes 
endogenous FVIII, resulting in hemostatic levels within several hours post-infusion. 
Published results from studies of a plasma-derived VWF (pdVWF) concentrate 
demonstrated an increase of FVIII at an approximate rate of 5.8 1 IU dL-1 h-1.3 Type 3 
VWD patients display severe hemorrhagic symptoms with bleeding predominantly in 
mucosal tissues, muscle and joints. All VWD patients, particularly those with type 2 or
type 3 VWD, are at an increased risk for life-threatening bleeding episodes.
6.3 The Role of Prophylaxis in the Management of VWD
The goals of long term prophylaxis in VWD are to maintain VWF and FVIII at sufficient 
levels to reduce the frequency and duration of bleeding episodes, the need for red blood 
cell transfusions, and the risk of complications, such as arthropathy.4 In contrast to 
hemophilia, routine prophylaxis is not as established in VWD, although prophylaxis for 
patients with severe VWD was in use in Sweden already during the 1950s.5 In those early 
days of VWD treatment, plasma FVIII concentrates containing VWF fractions were 
applied for replacement therapy, which then were followed by plasma derived VWF 
products containing fractions of FVIII (pdVWF/FVIII). 
A Swedish cohort including 37 patients with type 3 VWD under prophylactic median 
treatment of 11 years (range 2 to 45 years) was retrospectively analyzed.6,7 The 
doses used for prophylaxis, given once weekly for at least 45 weeks per year, were 
calculated based on 12 to 50 IU/kg body weight (BW) of FVIII clotting activity (FVIII:C)
which approximately corresponded to 24-100 IU/kg von Willebrand factor: Ristocetin 
cofactor activity (VWF:RCo) considering that mainly Haemate with a known 
VWF:RCo/FVIII:C ratio of about 2 was used. An escalation of doses from 1 to 3 dose 
levels was allowed depending on the frequency and severity of bleeding episodes. 
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The results demonstrate that under long-term prophylaxis the number of bleeds could be 
reduced dramatically. Whereas the median value for bleeds per year was about 10 before 
prophylaxis this value could be reduced to less than 1 bleed per year during prophylaxis.
The benefit of prophylaxis for such indications was retrospectively also demonstrated in a 
cohort of Italian patients including type 3, 2A, 2M and type 1 patients. Prophylaxis was 
started after severe gastrointestinal or joint bleeding episodes and completely prevented 
bleeding episodes in 8 of these 11 patients and largely reduced the need of blood 
transfusions in the remaining 3. A regimen of 40 IU rVWF:RCo/kg was applied every 
other day or twice a week. A prospective study on prophylaxis, the PRO.WILL study, has 
been initiated in Italy.8
The results of a prospective study investigating the prophylaxis in children and young 
adults showed a significantly reduced bleeding frequency and bleeding score (3 vs. 0.07; 
3 vs. 0. p<0.001) compared to the pre-prophylaxis values. The median dose was 
40 (20-47) IU/kg VWF:RCo administered mainly twice weekly in 23 patients, 3 times a 
week in 7 patients and 4 times a week in 2 children.9
The VWD Prophylaxis Network initiated the VWD International Prophylaxis (VIP) trial 
to investigate the role of prophylaxis in patients with severe VWD including Type 1, 2,
and 3. The dose of the factor replacement product was 50 IU /kgVWF:RCo. The 
frequency of the dose depended on the type of bleeding and could be increased from once 
weekly to twice weekly or 3 times per week. For the treatment of menorrhagia the dose 
of 50 IU/kg VWF:RCo was given on the first day of menses for 2 cycles. The frequency 
could be increased to Day 1 and 2 for 2 cycles or to Day 1, 2, and 3 of menses.
The study contains both retrospective and prospective study components. Results from 
the retrospective study component were published, including 61 subjects on prophylactic 
regimen in the past 6 months prior to enrollment or subjects with a history of prophylaxis 
over at least 6 month.10 Differences in annualized bleeding rates (ABR) within 
individuals (during prophylaxis – before prophylaxis) were significant for those with 
primary indications of epistaxis (P = 0.0005), joint bleeding (P = 0.002) and GI bleeding 
(P = 0.001). The difference in the group whose primary indication for treatment was 
abnormally heavy bleeding at menstruation (n = 4) was not significant (P = 0.25). The 
reduction of mucosal bleeding likely not only dependents on normal circulating levels of 
active VWF, but also on the presence of discrete concentrations of normal VWF inside 
the platelets and within endothelial matrices. The low subject number (n=4) and the 
treatment scheme for menorrhagia on Days 1, 2, and 3 of menses which might represent 
rather on-demand than prophylactic treatment may also account for the outcome in this 
study.
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Results from the prospective study component were reported recently.11 Eleven subjects 
completed the study. Six subjects had type 2A, and 5 subjects had type 3 VWD. 
Six subjects presented with epistaxis, 3 with GI bleeding, and 2 with joint bleeding. 
Seven subjects had dose escalation above the first level. Among the 10 subjects with 
evaluable bleeding log data, the use of prophylaxis decreased the median ABR from 25 to 
6.1 (95% confidence interval [CI] of the rate difference: -51.6 to -1.7), and the median 
ABR was even lower (4.0; 95% CI: -57.5 to -5.3) when the subjects reached their final 
dosing level. The authors concluded that this was the first prospective study to 
demonstrate that prophylaxis with VWF concentrates is highly effective in reducing 
mucosal and joint bleeding rates in clinically severe VWD.
The results of the VIP study and previous investigations suggest that VWD patients with 
recurrent bleeding episodes and severe menorrhagia will benefit from a prophylactic 
VWF replacement therapy. There is evidence that up to 40% of patients with type 3 
VWD experience joint bleeding which can lead to hemophilic arthropathy. Other 
potential indications for prophylaxis include patients with type 2A or 2B VWD with 
recurrent gastrointestinal bleeding, menorrhagia or frequent epistaxis.4 Long-term 
prophylaxis for most patients with type 3 VWD and in some patients with type 1 or 
2 VWD, depending on the pattern of bleeding, may be the treatment option of choice.
Although the main experience with long-term prophylaxis is with secondary prophylaxis, 
primary prophylaxis starting at young age is recommended to prevent arthropathy in 
patients with severe VWD.12
However, further studies are needed to develop evidence-based guidelines for 
prophylactic treatment in VWD.
6.4 Populations to be Studied
A total of approximately 22 eligible, adult subjects with severe VWD (baseline 
VWF:RCo <20 IU/dL) are planned to be enrolled. Two cohorts of patients will be 
included: patients currently receiving on-demand VWF treatment (OD subjects) and 
patients currently on prophylactic treatment with pdVWF (pdVWF switch subjects), and 
the aim is to have ≥8 subjects in each of the 2 cohorts, with a total of at least 5 type 3 
VWD subjects followed for 12 months. Enrolled subjects (i.e., subjects who have signed 
the informed consent form) will be eligible to participate in the study if they meet all of 
the inclusion criteria (see Section 9.1) and none of the exclusion criteria (see Section 9.2).
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6.5 Findings from Nonclinical and Clinical Studies
The following summarizes the key findings from relevant nonclinical studies as well as 
from the completed clinical studies 070701 (Phase 1 pharmacokinetics [PK] and safety in 
VWD), 071001 (Phase 3 safety and efficacy in the treatment of bleeding episodes in 
VWD), 071101 (Phase 3 efficacy and safety in VWD subjects undergo elective surgical 
procedures), 071104 (Phase 1 safety and PK in hemophilia A), and 071401 (Phase 3, 
expanded access in a single subject with VWD). Potential risks and efficacy of rVWF 
(vonicog alfa):ADVATE (rFVIII, octocog alfa) are summarized in the following sections. 
For additional information on nonclinical and clinical Phase 1 results refer to the rVWF 
(vonicog alfa) IB.
6.5.1 Findings from Nonclinical Studies
6.5.1.1 Primary Pharmacodynamics
Efficacy of rVWF (vonicog alfa) combined with ADVATE (rFVIII, octocog alfa) was 
shown in VWD animal models, which have also low endogenous FVIII levels. Time to 
occlusion and stable thrombus formation was assessed in the carotid occlusion model in 
VWD mice. The results demonstrated that rVWF (vonicog alfa) in combination with 
ADVATE (rFVIII, octocog alfa) acted efficiently in a dose-dependent manner and had 
higher efficacy than rVWF (vonicog alfa) alone or plasma derived (pd)VWF. These 
results were confirmed in an additional study assessing blood loss and survival in a tail 
tip bleeding model in VWD mice. In a VWD dog, rVWF (vonicog alfa) stabilized canine 
FVIII in the circulation and significantly reduced the bleeding time.
6.5.1.2 Safety Pharmacology
The anaphylactoid and thrombogenic potential of the co-infusion of ADVATE (rFVIII, 
octocog alfa) and rVWF (vonicog alfa) and the co-infused product’s effects on blood 
pressure, cardiac and respiratory function and parameters of coagulation activation were 
investigated in 4 in vivo studies in different animal models. Safety pharmacology studies 
in rats, guinea pigs, rabbits, and dogs revealed no risks for anaphylactoid and 
thrombogenic potential of ADVATE (rFVIII, octocog alfa) in combination with rVWF 
(vonicog alfa). All observations in safety pharmacology studies are considered to lie 
within the biological variability of animal models or occurred due to known species-
specific anaphylactoid effects of excipients.
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6.5.1.3 Pharmacokinetics
Pharmacokinetic studies of both rVWF (vonicog alfa) alone and combined with human 
rFVIII (rVWF+ADVATE) were conducted in VWD mice, VWD dogs, VWD pigs, rats,
and cynomolgus monkeys. Human rVWF (vonicog alfa) stabilized the endogenous FVIII 
in VWD mice, VWD pigs, and VWD dogs. Furthermore, the hypotheses that the area 
under the curve (AUC) with rVWF alone and rVWF+ADVATE is not inferior to the 
AUC with pdVWF (Haemate P) was tested and confirmed statistically in normal rats.
The PK characteristics of ADVATE (rFVIII, octocog alfa) were not affected by co-
administration of rVWF (vonicog alfa) in cynomolgus monkeys. The PK data in the 
FVIII knock out (k.o.) mice model are inconclusive and might not be relevant for the 
clinical situation. However, a stabilizing effect of VWF on FVIII could be shown in a 
double k.o. model in a dose dependent manner.
6.5.1.4 Toxicology
Single dose toxicity studies were conducted in C57BL/6J-mice, VWD mice, rats, rabbits,
and cynomolgus monkeys. Rats, rabbits, and cynomolgus monkeys showed no signs of
toxicity. Signs of microthrombosis, an exaggerated pharmacological effect, were
observed in mice. Mice are not capable of sufficiently cleaving the rVWF (vonicog alfa)
subunit as murine disintegrin and metalloproteinase with a thrombospondin type 1 motif, 
number 13 (ADAMTS13) does not decrease the ultra-large molecular weight multimers 
of rVWF (vonicog alfa).13 The observed symptoms of microthrombosis are interpreted as 
a species-specific exaggerated pharmacological effect. Studies evaluating the safety of 
repeated administration of rVWF (vonicog alfa) with or without ADVATE (rFVIII, 
octocog alfa) (daily over 14 days) were performed in a rodent (rat) and non-rodent 
(cynomolgus monkey) species. Reversible signs of exaggerated pharmacological effects 
(regenerative anemia, thrombocytopenia, and treatment-related histopathologic changes 
in the heart, liver, and spleen) were observed in rats that were administered 1400 U 
VWF:RCo/kg /day + 1080 IU ADVATE/kg/day intravenously once daily for 14 days. 
Also, these findings are interpreted as a species-specific exaggerated pharmacological 
effect due to the low susceptibility of human rVWF (vonicog alfa) to cleavage by rodent 
ADAMTS13.13 No toxicologically relevant changes were evident for clinical 
observations, body weight, feed consumption, ophthalmology, urinalysis, coagulation,
and serum chemistry parameters, platelet aggregation, and gross pathology. rVWF 
(vonicog alfa) combined with ADVATE (rFVIII, octocog alfa) was well tolerated in 
cynomolgus monkeys after daily intravenous (i.v.) (bolus) administration of 100 U 
VWF:RCo/kg rVWF (vonicog alfa) combined with 77 IU/kg ADVATE (rFVIII, octocog 
alfa) over a period of 14 days. No adverse effects could be detected in this species. 
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There were no signs of hemolysis, thrombosis, or thrombocytopenia after repeated 
intravenous application of rVWF (vonicog alfa) with or without ADVATE (rFVIII, 
octocog alfa). Therefore, 100 U VWF:RCo/kg/day rVWF (vonicog alfa) with or without 
77 IU/kg ADVATE (rFVIII, octocog alfa) was considered the no observed adverse effect 
level (NOAEL) in this study, which was the highest dose tested. Anti-drug antibodies, 
however, were formed in both species and resulted in a significant reduction in drug 
exposure after 14 applications as compared to a single application. These antibodies 
substantially reduced the systemic exposure to the test substance as compared to a single 
dose administration. No adverse effects due to antibody formation were observed in both 
species.
rVWF (vonicog alfa) combined with ADVATE (rFVIII, octocog alfa) was well tolerated 
locally and no genotoxic potential was evident after 2 in vitro and 1 in vivo genotoxicity 
study. A study on the influence of co-administration of VWF and ADVATE (rFVIII, 
octocog alfa) on the immunogenicity of ADVATE (rFVIII, octocog alfa) in 3 different 
hemophilic mouse models (E17 hemophilic Balb/c mice, E17 hemophilic C57BL/6J 
mice, and E17 hemophilic human F8 transgenic mice) showed that rVWF (vonicog alfa)
does not negatively impact the immunogenicity of ADVATE (rFVIII, octocog alfa) in 
any of the three different hemophilic mouse models.
6.5.2 Findings from Clinical Studies
Details on study design, populations enrolled, and safety and efficacy outcomes of the 
phase 1 studies are presented in Section 6.5.2.1 and Section 6.5.2.2, the phase 3 study in 
Section 6.5.2.3, and the phase 3 surgery study in Section 6.5.2.4. Information on a single 
subject with VWD in Study 071401 is presented in Section 6.5.2.5.
6.5.2.1 Study 070701
Phase 1 clinical study 070701 was a multicenter, controlled, randomized, single-blind,
prospective 3-step, dose escalation study to investigate safety, tolerability, and PK of 
rVWF (vonicog alfa) combined at a fixed ratio with ADVATE (VWF:RCo/FVIII:C of 
1.3 ± 0.2:1) in adults with severe VWD.14 Subjects were enrolled in sequential cohorts in 
a dose escalating manner: Cohort 1, 2, and 3 received a single intravenous infusion of 
rVWF:ADVATE at the following doses: 2 IU/kg VWF:RCo (Cohort 1), 7.5 IU/kg 
VWF:RCo (Cohort 2), and 20 IU/kg VWF:RCo (Cohort 3). Subjects in Cohort 4 received 
a single intravenous infusion of rVWF:ADVATE and pdVWF/ADVATE at 50 IU/kg 
VWF:RCo in random order.
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The primary endpoint was the tolerability and safety after single dose injections of 
rVWF:ADVATE at 2, 7.5, 20, and 50 IU/kg VWF:RCo for up to 30 days after the last IP 
infusion. The data generated in this phase 1 study suggest that rVWF:ADVATE up to the 
highest investigated dose of 50 IU/kg VWF:RCo is well tolerated and safe in adults with 
severe VWD. No thrombogenic risk or thrombotic thrombocytopenic purpura (TTP)-like 
syndrome was observed, and no neutralizing antibodies to VWF or FVIII were identified. 
There were no deaths or other serious adverse reactions, and no infusions were 
interrupted or stopped due to an AE. Overall, the reported AE profile was similar 
between the recombinant and plasma-derived concentrates.
Secondary endpoints were the PK assessment of VWF:RCo, von Willebrand factor 
antigen (VWF:Ag) and multimeric composition of rVWF (vonicog alfa) as well as 
FVIII:C at standardized time points after single injections of rVWF:ADVATE and 
pdVWF:FVIII. 
The median VWF:RCo terminal half-life (T1/2) of rVWF (vonicog alfa) at the 50 IU/kg 
dose was 16 hours. T1/2 with pdVWF:FVIII at the same dose level appeared shorter at 
12.58 hours, however, the limits of the 90% CI were similar (11.73 to 17.7 hours vs. 
11.87 to 18.03 hours). The median T1/2 of VWF:RCo were shorter with the lower 
investigated doses: 7.13 hours and 13.23 hours with the 7.5 IU/kg and 20 IU/kg doses, 
although these data were derived from a much smaller number of subjects.
In consequence of the missing ADAMTS13 cleavage, ultra-large molecular weight 
(ULMW) multimers are contained in the rVWF (vonicog alfa) final product. The 
immediate cleavage of these ultra-large multimers by ADAMTS13 upon release into the 
circulation could be demonstrated applying sodium dodecyl sulfate polyacrylamide gel 
electrophoresis (SDS-PAGE)/Immunoblot with polyclonal anti-VWF antibodies to detect 
the resulting rVWF (vonicog alfa) subunit cleavage fragments.
Overall the data generated in this phase 1 study suggest that rVWF (vonicog 
alfa):ADVATE (rFVIII, octocog alfa) is well tolerated and safe in adults with severe 
VWD.
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6.5.2.2 Study 071104
This study was a prospective, uncontrolled, non-randomized, multicenter proof of 
concept study to assess safety and PK of the addition of rVWF (vonicog alfa) to 
ADVATE (rFVIII, octocog alfa) treatment in 12 evaluable subjects with severe 
hemophilia A. All subjects underwent 3 PK analyses: the first after infusion with 
ADVATE (rFVIII, octocog alfa) alone, the second after infusion with ADVATE (rFVIII, 
octocog alfa) plus 10 IU/kg rVWF (vonicog alfa) and the third after infusion with 
ADVATE (rFVIII, octocog alfa) plus 50 IU/kg rVWF (vonicog alfa).
The PK analysis was performed at intervals of approximately 8 to 14 days. Before each 
infusion for PK assessment, there was a wash-out period of at least 5 days and the 
subjects were not actively bleeding. 
Primary outcome measures indicate that co-administration of rVWF (vonicog alfa)
slightly sustain ADVATE activity with the highest observed ADVATE (rFVIII, octocog 
alfa) half-life of 13.74 h (CI 11.44 to 16.52) after co-infusion of 50 IU/kg ADVATE plus 
50 IU/kg rVWF:RCo.
The highest improvement in ADVATE (rFVIII, octocog alfa) circulating half-life was 
observed in subjects with VWF:Ag levels below 100% which indicates an association 
between baseline VWF:Ag levels and ADVATE (rFVIII, octocog alfa) half-life increase. 
No treatment related AEs or SAEs were reported. No subject withdrew due to an AE and 
there were no deaths. No binding antibodies to VWF, CHO, and rFurin were detectable in 
the confirmatory assay and no signs of a hypersensitivity to rVWF (vonicog alfa) or 
ADVATE (rFVIII, octocog alfa) antigen were observed. Laboratory values over time did 
not indicate any potential safety risk for hemophilia A patients treated with rVWF 
(vonicog alfa) and ADVATE (rFVIII, octocog alfa) in combination.
In summary, the data indicate that rVWF (vonicog alfa) co-administered with ADVATE 
(rFVIII, octocog alfa) up to the highest dose of 50 IU/kg VWF:RCo is well tolerated and 
safe in hemophilia A patients. 
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6.5.2.3 Study 071001
This was a phase 3, multicenter, open-label, part-randomized clinical study to assess the 
PK, safety, and efficacy of rVWF:rFVIII and rVWF in the treatment of bleeding episodes 
in adult subjects with severe type 3 and severe non-type 3 VWD.15 A total of 49 subjects 
were enrolled (signed informed consent) and screened, 18 subjects were randomized 
(randomization only applies to Arm 1[PK50 with treatment of BE] and Arm 2 [PK50
only] see below), 37 subjects were treated with IP (all study arms), and 30 subjects 
completed the study.
The study consisted of 2 parts (Part A and Part B). Part A consisted of PK assessments 
alone (Arm 2: PK50 only [without treatment of bleeding episodes]), or PK assessments 
(Arm 1: PK50 and Arm 3: PK80) plus on-demand treatment period(s) of 6 months for 
bleeding episodes, or on-demand treatment for bleeding episodes only (Arm 4). Except 
for subjects in arm 2 who completed study after second PK assessment, subjects  
receiving treatment for PK assessments and/or bleeding episodes in Part A were to be 
entered into Part B to continue on-demand treatment for bleeding episodes for 
6 additional months for a total of 12 months in the study. 
The primary outcome measure was the number of subjects with “treatment success” 
(extent of control of bleeding episodes), which was defined as a mean efficacy rating 
score of <2.5 for a subject’s IP-treated bleeding episodes during the study. The rate of 
subjects with treatment success was 100% (Clopper-Pearson exact 90% CI: 84.7 to 
100.0) for bleeds where the assessments were made prospectively and excluding GI 
bleeds. Sensitivity analyses confirmed the results of the primary analysis.
Crossover results at 50 IU/kg VWF:RCo showed that the PK profile for rVWF (vonicog 
alfa) VWF:RCo was independent of administration alone or with rFVIII (ADVATE, 
octocog alpha) (T1/2: 19.4 hours for rVWF and 16.6 hours for rVWF:rFVIII; IR: 1.8 U/dL 
per IU/kg infused for both rVWF and rVWF:rFVIII; mean residence time (MRT): 
26.7 hours for rVWF and 25.2 hours for rVWF:rFVIII). FVIII levels increased 
substantially with a median peak at 24 hours of 111.0 U/dL for rVWF:rFVIII and 
86.0 U/dL after rVWF alone, indicating that rVWF (vonicog alfa) induces a sustained 
increase in endogenous FVIII activity. The rVWF (vonicog alfa) PK profile was 
comparable at 50 IU/kg and 80 IU/kg VWF:RCo, and repeated PK at 80 IU/kg 
VWF:RCo showed close agreement between pretreatment and end-of-study results.
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Further analysis of the PK data from the 071001 study supports the initial use of 50 IU/kg 
twice weekly for prophylaxis dosing in the present study for those subjects who are 
moving from on-demand to prophylaxis. Using 50 IU/kg for PK measurements, subjects 
in the 071001 study exhibiting a T1/2 for rVWF of 14, 16, or 19 hours had rVWF plasma 
concentrations at 72 hours after administration of 2.55, 4.01, and 6.49% above baseline, 
respectively, and plasma concentrations at 96 hours after administration of 0.78, 1.40,
and 2.71% above baseline, respectively. In this context it should be noted that subjects in 
the present study who have significant spontaneous bleeding while on twice weekly
prophylaxis will have their regimen increased to 3 times per week based on clear criteria 
for different bleeding locations (for details see Section 8.6.4.3.1). Subjects in the present 
study who are switching from prophylaxis with a pdVWF product will begin on rVWF 
(vonicog alfa) using their same weekly total dose in IU/kg VWF:RCo used during their 
pdVWF prophylaxis divided into twice weekly infusions (for details see Section 8.6.4.3).
A total of 125 AEs occurred in 25/37 (67.7%) subjects (62/318 infusions [19.5%]) during 
or after infusion with IP. Of these, 116/125 were non-serious (all mild or moderate; none 
were severe), and 9 SAEs were reported in 7 subjects. Of 125 total AEs, 38 were 
temporally associated with IP; 8 AEs were considered causally related to IP: 
6 non-serious related AEs (tachycardia, infusion site paraesthesia, electrocardiogram 
[ECG] t-wave inversion, dysgeusia, generalized pruritis, and hot flush) occurred in 
4 subjects, and 2 related SAEs (chest discomfort and increased heart rate) occurred in 
1 subject. No deaths occurred during this study. 
None of the subjects developed anti-VWF or anti-FVIII neutralizing antibodies and no 
binding antibodies to VWF or rFurin, or antibodies against CHO protein or anti-Murine 
IgG were observed. No clinical or subclinical signs or symptoms of a thrombogenic event 
were observed in this study. Following an initial increase in ultralarge VWF multimers 
after administration of rVWF (vonicog alfa), a notable decrease in the proportion of large 
VWF multimers occurred between 12 and 24 hours post infusion, due to degradation by 
the endogenous ADAMTS13 followed by a continued decline until the end of the 96-
hour follow-up period.
Overall, the data support the safe and effective use of rVWF (vonicog alfa) with or 
without rFVIII (ADVATE, octocog alpha) in the treatment of bleeds in patients with 
VWD.
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6.5.2.4 Study 071101
This was a phase 3, prospective, open-label, multicenter clinical study to evaluate 
efficacy and safety of rVWF (vonicog alfa) with or without ADVATE (rFVIII, octocog 
alfa) in elective surgical procedures in adult subjects with severe VWD. A total of 
24 subjects were enrolled (signed informed consent) and screened, 15 subjects were 
treated with rVWF (vonicog alfa), and 15 subjects completed the study. 
Eleven subjects underwent a PK assessment by infusion of 50 ± 5 IU/kg rVWF:RCo at an 
infusion rate of up to 4 mL/min. 12 to 24 hours before surgery, subjects received a dose 
of 40 to 60 IU/kg rVWF:RCo. Within 3 hours prior to surgery, the subject’s FVIII:C 
levels were assessed with a target of 30 IU/dL for minor and oral surgeries and 60 IU/dL 
for major surgeries. Within 1 hour prior to surgery, subjects received a dose of rVWF 
(vonicog alfa) with or without ADVATE (rFVIII, octocog alfa) (depending on the target 
FVIII:C levels at the 3 hour assessment). VWF and FVIII IR and T1/2 for each subject, 
when known, were used to guide the initial dose and subsequent doses.
The primary outcome measure was the overall assessment of hemostatic efficacy 
assessed by the investigator (hemophilia physician) 24 hours after last perioperative IP 
infusion or at completion of day 14 visit, whichever occurred earlier, and was 
summarized by the percentage of subjects in each efficacy category (“excellent”, “good”, 
“moderate” and “none”). Point estimate and corresponding 90% two-sided exact CI was 
calculated for the rate of subjects with an overall assessment of hemostatic efficacy. All 
15 subjects treated with rVWF (vonicog alfa) (with or without ADVATE) for major (10), 
minor (4), and oral (1) elective surgical procedures had overall hemostatic efficacy 
ratings of “excellent” or “good”. Most (73.3%) subjects had “excellent” overall 
hemostatic efficacy ratings; of these, 7 underwent major surgery and 4 underwent minor 
surgery. The remaining 26.7% subjects had “good” overall hemostatic efficacy ratings: 
3 underwent major surgery and 1 underwent oral surgery. All 8 subjects with VWD 
Type 3, the subtype classified as absolute VWF deficiency, had overall hemostatic 
efficacy ratings of “excellent” (87.5%) or “good” (12.5%).
Intraoperative hemostatic efficacy ratings were also rated as “excellent” or “good” for all 
15 treated subjects. Most (86.7%) subjects had “excellent” intraoperative hemostatic 
efficacy ratings; of these, 8 underwent major surgery, 4 underwent minor surgery, and 
1 underwent oral surgery. Two (13.3%) subjects who underwent major surgery had 
“good” intraoperative hemostatic efficacy ratings. Intraoperative hemostatic efficacy 
was rated as “excellent” or “good” for all subjects with VWD Type 3: “excellent” for 
7 (87.5%) subjects and “good” for 1 (12.5%) subject. 
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Only 1 subject received an intraoperative dose of rVWF (18.1 IU/kg) and ADVATE 
(8.1 IU/kg). The median daily postoperative weight-adjusted dose of rVWF (vonicog 
alfa) (with or without ADVATE) was 23.5 IU/kg on postoperative Day 1 (n=3) and 
25.5 IU/kg on postoperative Day 14 (n=2). In subjects treated with rVWF:ADVATE, the 
daily postoperative weight-adjusted dose was 16.9 IU/kg rVWF and 7.6 IU/kg ADVATE 
on postoperative Day 1 (n=1) and decreased to 50.8 IU/kg rVWF and 7.6 IU/kg
ADVATE on postoperative Day 7 (n=1). For subjects treated with rVWF alone, the 
median weight-adjusted dose (Q1, Q3) of rVWF was 35.4 IU/kg on postoperative Day 1 
(n=2) and decreased to 23.7 IU/kg on postoperative Day 7 (n=4) and 25.5 IU/kg on 
postoperative Day 14 (n=2).
A total of 11 subjects were evaluated for PK in the study. As expected, postinfusion 
increases in concentrations of VWF:RCo, VWF:Ac, VWF:Ag, and VWF collagen 
binding (VWF:CB) were observed. Mean values for VWF:RCo were as follows: 
AUC0-∞/dose was 37.50 hours*IU/dL per IU/kg infused; AUC0-72h/dose was 
34.08 hours*IU/dL per IU/kg infused; T1/2 was 17.83 hours; MRT was 24.32 hours; 
CL was 0.03117 dL/hour/kg; and volume of distribution at steady state (Vss) was 
0.6837 dL/kg. Median values for VWF:RCo were as follows: AUC0-∞/dose was 
32.94 hours*IU/dL per IU/kg infused; AUC0-72h/dose was 31.70 hours*IU/dL per IU/kg 
infused; T1/2 was 14.62 hours; MRT was 21.80 hours; CL was 0.03036 dL/hour/kg; and 
Vss was 0.7078 dL/kg. The VWF:RCo activity was consistent with that previously 
observed in clinical studies 071001 and 070701.
rVWF (vonicog alfa) was safe and well tolerated in adults with severe VWD undergoing 
major, minor, and oral elective surgical procedures. Of the 12 total treatment-emergent 
AEs (TEAEs) that occurred during the study, 2 deep vein thrombosis events (1 non-
serious and 1 serious, as a part of one case) reported in one subject, who underwent total 
hip replacement surgery and who had concurrent condition of obesity, was assessed by 
the sponsor as possibly causally-related to study treatment. None of the TEAEs were 
either a severe allergic or hypersensitivity reaction or developed due to a severe allergic 
reaction. 
One subject with VWD Type 3 who had an intraoperative transfusion of packed red 
blood cells during total knee replacement surgery tested positive for binding antibodies to 
VWF on postoperative Day 7 through study completion. No subjects developed 
neutralizing antibodies to rFVIII or binding antibodies to CHO, rFurin, or murine IgG.
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In summary, the data support the safe and effective use of rVWF (vonicog alfa) with or 
without ADVATE (rFVIII, octocog alfa) in achieving intra- and post-operative 
hemostasis in adult subjects with severe VWD undergoing major, minor, and oral elective 
surgical procedures.
6.5.2.5 Study 071401: Single Subject with von Willebrand Disease
One subject who exhibited allergic reactions to currently marketed pdVWF products was 
treated in the single-subject study 071401 with rVWF (vonicog alfa) only for the bleed 
treatment of continued hematuria, and for biopsy and surgical resection of a left-kidney 
mass.
For the initial rVWF (vonicog alfa) infusion, the subject received a test dose of 5% of 
the total dose of 60 IU/kg rVWF:RCo at an infusion rate of 1 mL/min. After a 10 to 
15-minute observation period, no adverse symptoms or signs were noted and the subject 
received the remaining 95% of the total dose. The subject was monitored for any signs of 
an allergic reaction, and none were noted. Treatment with rVWF (vonicog alfa) every 
12 to 24 hours was to continue at the discretion of the investigator based on VWF levels 
and clinical symptomatology. The subject had an excellent response and recovery, which 
allowed for daily dosing of rVWF (vonicog alfa) and, within 24 hours, the subject’s 
bleeding had stopped. Daily dosing of rVWF (vonicog alfa) was maintained and the 
subject received his last dose on 
.
The subject also received rVWF (vonicog alfa) for 7 days for prophylaxis for surgery 
(surgical resection of a left-kidney mass). The subject experienced no hemorrhagic 
complications and no AEs that were considered related to the use of rVWF 
(vonicog alfa).
6.6 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) to
Human Subjects
Current treatment of VWD patients relies on desmopressin and VWF products 
manufactured from pooled human plasma. Human VWF produced by recombinant 
technology could offer a new perspective in treatment of VWD. The benefit for the 
individual subject is anticipated to be significant during this clinical study. He/she may 
benefit from a product that minimizes excessive FVIII administration and thus allowing 
individualized dosing of VWF at optimal levels. Variations in VWF multimeric 
composition may lead to variability with respect to treating or preventing bleeds in 
VWD subjects, especially mucosal bleeds which are especially problematic. rVWF 
(vonicog alfa) product manufactured by Baxalta consistently contains ULMW VWF 
multimers due to the fact that the product has not been exposed to ADAMTS13. 
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The initial presence of these ULMW VWF multimers, which are subsequently cleaved by 
the subject’s endogenous ADAMTS13, may result in improved platelet and collagen 
binding and therefore provide more predictable treatment outcomes.
By using a recombinant product, the risk of transmission of adventitious agents and other 
blood-borne pathogens associated with the use of products of human or animal origin has 
been eliminated. At this stage of product development, the key societal benefit is a better 
understanding of advanced treatment options for VWD and enhanced product 
availability.
These benefits outweigh the following identified or potential risks of rVWF (vonicog 
alfa):

allergic-type hypersensitivity reactions as with any intravenous protein product

the occurrence of thromboembolic events

the development of neutralizing antibodies to VWF
Refer to the IB for further details on benefits and risks of the IP.
6.7 Compliance Statement
This study will be conducted in accordance with this protocol, the International Council 
for Harmonisation Guideline for Good Clinical Practice E6 (ICH GCP, April 1996, with 
Addendum E6(R2) dated Nov 2016 EMA/CHMP/ICH/135/1995), Title 21 of the US 
Code of Federal Regulations (US CFR), the EU Directives 2001/20/EC and 2005/28/EC, 
the Declaration of Helsinki and applicable national and local regulatory requirements.
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7. STUDY PURPOSE AND OBJECTIVES
7.1 Study Purpose
The purpose of this phase 3 study is to investigate the efficacy and safety, including 
immunogenicity, thrombogenicity and hypersensitivity reactions, as well as 
pharmacokinetics (PK), 
and 
 
of prophylactic treatment with rVWF (vonicog alfa) in adult subjects with severe VWD.
7.2 Primary Objective
The primary objective of this study is to prospectively evaluate the ABR for spontaneous 
bleeding episodes while on prophylactic treatment with rVWF (vonicog alfa) and to 
compare it to the subject’s historical ABR for spontaneous bleeding episodes.
7.3 Secondary Objectives
Secondary Objectives are to assess:

Additional efficacy of prophylactic treatment with rVWF (vonicog alfa)

Safety of rVWF (vonicog alfa), including immunogenicity, thrombogenicity and 
hypersensitivity

Pharmacokinetics (PK) of rVWF (vonicog alfa) and pharmacodynamics (PD) of 
rVWF (vonicog alfa) as measured in FVIII activity 
7.4 Exploratory Objectives
 
 
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8. STUDY DESIGN
8.1 Overall Study Design
This is a prospective, open label, uncontrolled, non-randomized, international, 
multicenter phase 3 study to evaluate efficacy, safety (including immunogenicity,
thrombogenicity and hypersensitivity reactions), as well as PK, 
and 
 of prophylactic treatment regimen with rVWF (vonicog alfa) in adult 
patients with severe VWD. 
Subjects transitioning from on-demand treatment (OD subjects) or subjects switching 
from prophylactic treatment with pdVWF (pdVWF switch subjects) will receive 
prophylactic treatment with rVWF (vonicog alfa) for a 12-month period. The dose will be 
50 ± 10 IU/kg rVWF twice weekly for OD subjects or will be based on their prior 
pdVWF dose for pdVWF switch subjects, and dose may be further individualized based 
on the PK data, subject’s history of bleeding episodes, and the results from clinical and 
laboratory assessments (see Section 8.6.4.3).
The overall duration of prophylactic treatment with rVWF per subject will be 12 months.
During this period any bleeding episodes requiring substitution therapy with VWF 
concentrate to control bleeding will be treated with rVWF (vonicog alfa) with or without 
ADVATE (rFVIII, octocog alfa). The dose will be according to the bleeding type and 
severity and it will be adjusted to the clinical response (see Section 8.6.4.4.2).
The overall study design is illustrated in Figure 1.
8.2 Duration of Study Period(s) and Subject Participation
The overall duration of the study is approximately 27 months from study initiation 
(i.e., first subject enrolled) to study completion (i.e., last subject last visit). The subject 
participation period is approximately 15 months from enrollment to completion (i.e, last 
study visit), unless the subject is prematurely discontinued.
8.3 Outcome Measures
8.3.1 Primary Outcome Measure
8.3.1.1 Efficacy 

Annualized bleeding rate (ABR) for spontaneous (not related to trauma) bleeding 
episodes during prophylactic treatment with rVWF (vonicog alfa)
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8.3.2 Secondary Outcome Measures
8.3.2.1 Additional efficacy of Prophylactic Treatment with rVWF (vonicog alfa)

ABR percent reduction success for OD subjects defined as at least 25% reduction 
of ABR for spontaneous (not related to trauma) bleeding episodes during rVWF 
(vonicog alfa) prophylaxis relative to the subject’s own historical ABR during on-
demand treatment

ABR preservation success for pdVWF switch subjects defined as achieving an 
ABR for spontaneous bleeding episodes during rVWF (vonicog alfa) prophylaxis 
that is no greater than the  subject’s own historical ABR during prophylactic
treatment with pdVWF

Categorized spontaneous ABR defined as 0, 1-2, 3-5, or >5 bleeding episodes
during the 12-month prophylactic treatment with rVWF (vonicog alfa)

Total number of infusions and the average number of infusions per week during 
prophylactic treatment with rVWF (vonicog alfa)

Total weight adjusted consumption of rVWF (vonicog alfa) during prophylactic 
treatment 

Spontaneous ABR by location of bleeding (GI, epistaxis, joint bleeding, 
menorrhagia, oral and other mucosa, muscle and soft tissue, etc.) while on 
prophylactic treatment with rVWF (vonicog alfa)
8.3.2.2 Safety

AEs: incidence, severity, causality

Thromboembolic events 

Hypersensitivity reactions

Development of neutralizing antibodies to VWF and FVIII

Development of total binding antibodies to VWF and FVIII

Development of binding antibodies to CHO proteins, mouse immunoglobulin G 
(IgG) and rFurin

Clinically significant changes in vital signs and clinical laboratory parameters
relative to baseline
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8.3.2.3 Pharmacokinetics (PK) and Pharmacodynamics (PD)

PK parameters after a washout for on-demand subjects: incremental recovery 
(IR), T1/2, MRT, area under the concentration versus time curve from 0 to infinity 
(AUC0-), area under the concentration versus time curve from 0 to the last 
measurable concentration (AUC0-tlast), maximum plasma concentration (Cmax), 
minimum time to reach the maximum concentration (Tmax), volume of distribution 
at steady state (Vss) and clearance (CL) based on VWF:Rco activity, VWF:Ag, 
VWF:CB activity. 

PD parameters after a washout for on-demand subjects: Cmax, Tmax, and AUC0-tlast
as measured in FVIII activity by the 1-stage clotting assay (FVIII:C). 

PK parameters at steady state for on-demand and switch subjects: area under the 
concentration versus time curve from 0 to end of the partial dosing interval 
(AUC0-tau;ss), maximum concentration during the partial dosing interval (Cmax;ss), 
minimum time to reach the maximum concentration (Tmax;ss) and minimum 
concentration during the partial dosing interval (Cmin;ss) based on VWF:RCo, 
VWF:Ag and VWF:CB. PK parameters at steady state will be assessed shortly 
after reaching steady state for switch subjects and at the end of the study for on-
demand as well as for switch subjects all based on the longer interval of the 
irregular dosing intervals employed.

PD parameters at steady state for on-demand and switch subjects: AUC0-tau;ss, 
Cmax;ss, Tmax;ss, and Cmin;ss as measured in FVIII activity by the 1-stage clotting 
assay. PD parameters at steady state will be assessed shortly after reaching steady 
state for switch subjects and at the end of the study for on-demand as well as for 
switch subjects all based on the longer interval of the irregular dosing intervals 
employed.

Time course of FVIII clotting activity (FVIII:C) levels.
8.3.3 Exploratory Outcomes Measures
8.3.3.1
 
 
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8.3.3.2
 
 
 
 
 
8.3.3.3
 
8.3.3.4
 
 
8.4 Randomization and Blinding
This is a non-randomized open-label, active treatment clinical study. 
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8.5 Study Stopping Criteria 
This study will be stopped if 1 or more of the following criteria are met in the absence of 
any other possible and medically plausible causal attribution (eg, underlying or 
concurrent condition, use of concomitant medication, subject’s medical history, etc):
1.
Two subjects develop a life-threatening or fatal thromboembolic event
2.
Two subjects develop life-threatening or fatal severe hypersensitivity reactions 
(e.g., anaphylaxis)
3.
Any subject develops acute hepatic failure
4.
Two subjects develop rVWF neutralizing antibodies that are considered clinically 
significant by the investigators and are associated with significant decrease of 
efficacy or serious adverse reactions.
The study may be stopped at any time by the sponsor.
The sponsor ultimately will decide whether to terminate, temporarily halt or modify the 
study based on the data monitoring committee (DMC)’s review and recommendation on 
all relevant cases including those that meet the stopping criteria listed above.
8.6 Investigational Product(s)
8.6.1 Packaging, Labeling, and Storage
8.6.1.1 rVWF (Recombinant von Willebrand Factor, vonicog alfa)
rVWF (vonicog alfa) will be packaged in boxes with 2 glass vials, one containing the 
rVWF powder, and the second vial containing the diluent (water for injection). Further 
details are provided in the IB and Pharmacy Manual. The rVWF label will include, at a 
minimum, the actual VWF:RCo potency and the date of expiration.
rVWF (vonicog alfa) is a powder that should be stored refrigerated (2-8°C [36-46°F]) . 
Deviations from the storage condition have to be communicated and followed up with the 
sponsor. Inadequately stored product will have to be placed in quarantine and may only 
be used after written IP administration authorization by the sponsor. After removal of the 
product from the refrigerator the product must not be returned to the refrigerator. The 
reconstituted product has to be used immediately (at least within 3 hours). rVWF 
(vonicog alfa) must not be used beyond the expiration date printed on the vial label. 
Avoid freezing at all times.
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8.6.1.2 rFVIII (Recombinant Factor VIII, octocog alfa /ADVATE)
ADVATE (rFVIII, octocog alfa) will be packaged in boxes with 2 glass vials, one 
containing the lyophilized rFVIII, and the second vial containing the diluent. Further 
details are provided in the IB and Pharmacy Manual. The ADVATE label will include, 
at a minimum, the actual FVIII:C potency and the date of expiration. 
ADVATE (rFVIII, octocog alfa) should be refrigerated (2-8°C [36-46°F]) in powder 
form and should not be used beyond the expiration date printed on the vial. 
Deviations from the storage condition have to be communicated and followed up with the 
sponsor. Inadequately stored product will have to be placed in quarantine and may only 
be used after written IP administration authorization by the sponsor. After removal of the 
product from the refrigerator the product must not be returned to the refrigerator and has 
to be used immediately. Avoid freezing at all times.
8.6.2 Reconstitution
The reconstitution procedures for both rVWF (vonicog alfa) and ADVATE (rFVIII, 
octocog alfa) products are detailed in the Pharmacy Manual. 
8.6.3 Administration
Following reconstitution, rVWF (vonicog alfa) and ADVATE (rFVIII, octocog alfa) (in 
case of bleeding episode treatment) should be administered to study subjects at room 
temperature and within 3 hours of reconstitution. The reconstituted rVWF (vonicog alfa)
and ADVATE (rFVIII, octocog alfa), should be inspected for particulate matter and 
discoloration prior to administration, whenever the solution and container permit. The 
solution should be clear and colorless in appearance. If not, do not administer the 
product. Plastic syringes provided by the sponsor must be used since coagulation factors 
tend to stick to the surface of glass syringes.
Investigational product infusions should be given at a slow enough rate to ensure the 
subject’s comfort. The rate should not exceed 4 mL/minute The investigator/ subject shall 
ensure that no visible residual volume remains in the syringe(s) and that the complete 
content is administered. Upon completion of the infusion, the butterfly catheter should be 
flushed with at least 2 mL of saline solution. In case of a (central) venous access device, 
the flush should be with at least 10 mL of saline solution. The IP infusions should be 
administered over a duration of 2 to 20 minutes, depending on the volume.
Only the actual potencies of rVWF (vonicog alfa) and ADVATE (rFVIII, octocog alfa)
as stated on the vial labels and described in the Pharmacy Manual should be used. 
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A variation of up to 10% of the intended dose for prophylactic infusions and of the 
intended dose for treatment of bleeding episodes is permissible and the exact dose should 
be recorded on the Case Report Form (CRF). Using of partial vials is not allowed.
At study visits where recovery analysis is being done, vials with the same lot numbers 
should be used throughout the PK IP infusion per subject.
For treatment of bleeding episodes, sequential administration will be done: separate 
syringes of the appropriate dose of rVWF (vonicog alfa) and ADVATE (rFVIII, octocog 
alfa) will be prepared for sequential infusion. rVWF (vonicog alfa) should be infused first 
sequentially followed preferably within 10 minutes by infusion of ADVATE (rFVIII, 
octocog alfa). Only the actual potencies of rVWF (vonicog alfa) and ADVATE (rFVIII, 
octocog alfa) as stated on the vial labels and described in the Pharmacy Manual should be 
used. 
The final dose of rVWF (vonicog alfa):ADVATE (rFVIII, octocog alfa) should be at a 
ratio of 1.3:1 ± 0.2.
8.6.4 Description of Treatment
8.6.4.1 PK-Assessment Treatment
For on-demand subjects, two PK assessments will be performed: an initial PK 
assessment after a follow up visit and a steady state PK assessments at the end of the 
study. The IP infusion for the initial PK assessment is scheduled on the baseline visit, 
which should be within 42 days after the completion of screening procedures and 
confirmation of eligibility. At the baseline visit the subjects will receive a dose of 
50 ± 5 IU/kg rVWF:RCo for PK assessment. Blood samples will be drawn within 
30 minutes pre-infusion, and at 11 time points post-infusion (15 ± 5 minutes, 
30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 
24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours and 96 ± 2 hours). A washout 
period of at least 5 days is required prior to infusion of rVWF (vonicog alpha) for PK 
assessment. The 2nd PK assessment for on-demand subjects will be performed at steady 
state at the end of the study(see Section 11.6). Subjects previously enrolled in rVWF 
studies 070701, 071001 or 071101 and having previously undergone PK assessments in 
these studies are required to repeat the PK assessment due to different dose and time 
points used in these former studies.
For pdVWF switch subjects, two steady state PK assessments will be performed. 
The 1st PK will be assessed shortly after reaching steady state, which is expected to be 
11 days after the 1st prophylactic dose for majority of the subjects, around the 
prophylactic dose #5-6. The 2nd PK will be at the end of the study.
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For steady state PK, blood samples will be drawn within 30 minutes pre-infusion, 
and at 11 time points post-infusion (15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 
3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 
72 2 hours and 96 ± 2 hours) as long as it won’t interfere with subject’s the normal 
dosing schedule, otherwise the 96 hr sampling can be omitted (see Section 11.6). Final 
sample for PK analysis should be taken before next dose is administered.
8.6.4.2 Prophylaxis Initiation Treatment 
The rVWF (vonicog alfa) prophylaxis initiation treatment visit will coincide with the 
96 2 h initial PK assessment for on-demand subjects. For pdVWF switch subjects, the 
rVWF (vonicog alfa) prophylaxis initiation treatment visit should occur within 42 days 
after the completion of screening procedures and confirmation of eligibility. At this visit 
subjects will receive their prophylaxis initiation dose. The prophylaxis doses are 
described in Section 8.6.4.3.
The subject will be trained on IP reconstitution and administration and may then qualify
for home treatment (see Section 8.6.4.3.2). Refer toTable 6 (a/b) for study procedures and
Table 8 (a/b) for clinical laboratory assessments.
8.6.4.3 Prophylaxis Treatment
For on-demand subjects, the standard prophylactic dose is 50 ± 10 IU/kg rVWF:RCo, 
which may be increased up to 80 IU/kg. All on-demand subjects will initially receive 
rVWF (vonicog alfa) twice per week (Table 1, Schedule A). Examples of all dosing 
schedules are provided in Table 1.
For pdVWF switch subjects, the weekly dose (IU/kg) of IP for each patient will be 
equivalent (± 10%) to the weekly VWF dose received during prophylactic treatment with 
pdVWF. The weekly dose of IP should be divided into 2 infusions (Table 1, Schedule A), 
with a maximum of 80 IU/kg/infusion. If needed, based on the total weekly dose or other 
clinical judgements, the weekly dose may be given as three infusions (Table 1, 
Schedule B). A once weekly dose regimen will be allowed after switch to rVWF 
(vonicog alfa) only if the patient has been on a once weekly dose regimen with pdVWF.
Table 1
rVWF (vonicog alfa) Dosing Schedule Examples: Schedules A and B
Example
M
T
W
Th
F
Sat
Sun
M
T
W
Th
F
Sat
Sun
Schedule A
X
X
X
X
Schedule B
X
X
X
X
X
X
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The prophylaxis dose may be further individualized within the range based on:

available historical PK data

type and severity of bleeding episodes the subject has experienced in the past and

monitoring of appropriate clinical and laboratory measures
The individualized prophylaxic dose assignment will have to be agreed with the sponsor 
in advance, and the rationale should be well documented.
8.6.4.3.1 Adjustment of Dose or Dose Interval
In general, the dose and/or dose interval for each subject should not be changed unless 
prompted by clear medical needs. Dose and frequency adjustments should be agreed with 
the sponsor in advance unless it constitutes an urgent safety measure. The rationale for 
dosing adjustments needs to be documented in the subject’s medical record.
For both OD and switch patients, dose escalations (not exceeding the upper dose limit of 
80 IU/kg rVWF:RCo) and increase of dose frequency will only be allowed in case of 
insufficient therapeutic response with breakthrough bleeding episodes. The criteria for 
dose and/or frequency escalation are specific to each bleeding indication but, overall, 
involve 1 significant breakthrough bleeding episode despite the subject being compliant 
with scheduled prophylaxis treatment. For switch patients  who require a dose escalation 
due to a breakthrough bleed, the frequency should be kept the same but the dose 
(IU VWF:RCo per infusion) should be increased up to 80 IU VWF:RCo. Following that, 
increases in frequency may be considered upon consultation with the Sponsor. For on 
demand subjects who require a dose escalation, at the discretion of the PI upon 
consultation with the Sponsor, the frequency may be kept the same but the dose 
(IU VWF:RCo per infusion) should be increased up to 80 IU VWF:RCo. If this proves to 
be insufficient, then the dosing frequency may be increased in these subjects. Table 2
presents the criteria for dosing escalation per each bleeding indication taken 50 ± 10 IU 
VWF:RCo/kg twice weekly dose as an example of subject’s assigned starting dose. The 
criteria are applicable for both OD and switch subjects who were initially assigned to 
twice weekly dosing. Subjects entering the study will begin prophylaxis treatment 
according to Schedule A (Table 1) and will remain at this dose and frequency until 
meeting the criteria for escalation to the next higher schedule: for example, from 
2 infusions of 50 ± 10 IU VWF:RCo/kg/week to 3 infusions of 50 ± 10 IU 
VWF:RCo/kg/week (Schedule B) to achieve an adequate therapeutic response. If a 
subject started with a weekly dose (possible for switch subjects), similar criteria would 
apply except that the subject will be excalated to twice weekly dosing if frequency 
change is necessary.
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Table 2
Criteria for Escalation Specific to Each Bleeding Indication
Schedule A
Schedule B
Joint bleeding
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) twice per week. In the event a 
spontaneous joint bleeding episode occurs 
while on this regimen, the subject will 
escalate to up to 80 IU/kg twice per week or, 
if necessary, to Schedule B following its 
resolution
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week.
GI bleeding
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) twice per week. In the event a 
severe GI bleeding episode, i.e., requiring red 
blood cell transfusion, occurs while on this 
regimen, the subject will escalate to up to 
80 IU/kg twice per week or, if necessary, to 
Schedule B following its resolution
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week.
Menorrhagia
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) on days 1 and 2 of menses for 
2 cycles. Menstrual flow will be monitored by 
the PBAC score. If the average pictorial chart 
score is > 185, then the subject will escalate to
up to 80 IU/kg or, if necessary, to Schedule B
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) on days 1, 2, 
and 3 of menses. Menstrual flow 
will be monitored by the PBAC 
score.
Epistaxis
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) twice per week. The subject will 
escalate to up to 80 IU/kg twice per week or, 
if necessary, to Schedule B in the event of 
1 occurrence of breakthrough bleeding 
requiring intervention such as iron 
replacement therapy, transfusion, packing, 
hospitalization; or 2 bleeding events that 
require treatment with factor replacement
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week. 
Oral and Other 
Mucosa
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) twice per week. The subject will 
escalate to up to 80 IU/kg twice per week or, 
if necessary, to Schedule B in the event of 
1 occurrence of breakthrough bleeding 
requiring intervention such as iron 
replacement therapy, transfusion, packing, 
hospitalization; or 2 bleeding events that 
require treatment with factor replacement.
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week.
Muscle and Soft 
Tissue
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) twice per week. In the event a 
spontaneous bleeding episode occurs while on 
this schedule, the subject will escalate to up to 
80 IU/kg twice per week or, if necessary, to 
Schedule B following its resolution.
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week.
Abbreviations:  GI: gastrointestinal; PBAC: Pictorial Blood Assessment Chart.
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If a subject does not adequately respond to rVWF (vonicog alfa) therapy, he/she will be 
evaluated for the presence of neutralizing and total binding anti-VWF antibodies (see 
Section 12.9.3.2).
If a subject experiences a bleed while receiving rVWF (vonicog alfa) three times per 
week, the investigator should treat the bleed with rVWF (vonicog alfa) at doses up to 
80 IU VWF:RCo/kg at a frequency determined by the investigator until the bleed 
resolves. Upon resolution of the bleeding event, the subject will return to their assigned 
prophylaxis regimen. 
It is essential for the success of this study that the subjects adhere to treatment regimens. 
Therefore, procedures for monitoring subject’s compliance are implemented (see 
Section 10.7).
If 1 infusion of IP is missed, the subject may administer the IP as soon as possible. The 
subject should adhere to their treatment scheme ensuring a minimum interval of 12 hours 
between this and the previous IP infusion. For example, a subject routinely infuses IP on 
Monday and Thursday, he/she misses the Monday time point and therefore may infuse 
the IP on the next day (Tuesday) and thereafter proceed with infusing the IP on Thursday
(considering a minimum 12 hours between the infusions) and return to the initial
schedule.
If more than 30% of infusions of IP are missed within the visit interval of 3 months the 
subject will be discontinued from the study (see Section 9.4).
8.6.4.3.2 General Instructions for Home Treatment for Prophylaxis
At the discretion of the investigator, a subject may be considered suitable for home 
treatment only after the subject has received at least 1 infusion of IP in the clinic, either 
during planned prophylactic IP exposure or during the treatment of bleeding episodes, 
and meets the following additional criteria:
1.
Fully understands the concept of a clinical study and related documentation 
(documented training of at least 30 minutes), 
2.
Has a history of previous experience with home treatment including 
self-administration and treatment with VWF containing concentrates, 
3.
Has adequate time for initial training of the study drug preparation (preparation, 
mixing and infusion of the IP(s) (documented training of at least 30 minutes).
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This applies both to subjects who were on prior on-demand treatment and to subjects 
switching form prophylaxis with pdVWF. In the event a healthcare professional is 
required to administer IP, he/she must be trained and qualified by the investigator on the 
above procedures prior to the decision for home treatment. A Subject Guideline detailing 
all instructions and information listed above will be provided to each subject.
8.6.4.4 Treatment of Bleeding Episodes
8.6.4.4.1 General Instructions for Home Treatment of Bleeding Episodes
If a subject experiences a bleeding episode, he/she should contact the study site 
immediately and the site investigator should provide instructions on the treatment
regimen. If the subject initiates the treatment at home, he/she should at least follow up 
with the study site if a visit is needed as per the standard of care at the center.
In the event a healthcare professional is required to administer treatment at the subject’s 
home, he/she must be trained and qualified by the site investigator on the above 
procedures prior to the decision for home treatment. Once a subject has received 
1 infusion of rVWF (vonicog alfa) in the clinic (either during planned IP exposure or 
during the treatment of a bleeding episode) and meets the criteria for home treatment, the 
treatment of bleeding episodes with IP can be conducted at home (see Section 8.6.4.3.2).
If a subject is not qualified for home treatment, rVWF (vonicog alfa) infusions must be 
administered at the study site.
If a subject experiences a bleeding episode that requires treatment between the screening 
and the prophylaxis initiation visit, the subject will be treated with IP (rVWF with or 
without ADVATE). Treatment with IP must occur at the study site unless the subject has 
previously qualified for home treatment with rVWF (vonicog alfa). If rVWF (vonicog 
alfa) treatment is not feasible, the subject may use his/her standard of care, such as
commercial pdVWF/FVIII products. In any case a washout period of at least 5 days is 
required prior to rVWF (vonicog alfa) PK infusion at the initial PK assessment visit for 
on-demand subjects.
If a subject experiences a bleeding episode requiring treatment during the PK assessment, 
rVWF (vonicog alfa) should be used to treat the bleed. Blood draws for PK assessment 
will be stopped and the PK assessments will be repeated once the bleed has resolved and 
the subject is free of any symptoms related with the bleeding episode. Dose and 
frequency of rVWF (vonicog alfa) infusions or any other replacement therapy to stop the 
bleed should be recorded in the electronic Case Report Form (eCRF), and the reason for 
the use of any non-IP product or therapy should be documented.
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8.6.4.4.2 Dosing Recommendations for Treatment of Bleeding Episodes 
If an acute bleeding episode occurs, the subject will be treated with rVWF (vonicog alfa)
with or without ADVATE (rFVIII, octocog alfa). It is the sponsor’s opinion that, in many 
cases, treatment with ADVATE (rFVIII, octocog alfa) may not be necessary, since rVWF 
(vonicog alfa) prophylaxis will serve to increase endogenous FVIII levels. However, if 
endogenous FVIII is below 30-40 % or is unknown and cannot be estimated from the 
subject’s PK study, an infusion of rVWF: ADVATE at an rVWF: ADVATE ratio of 
1.3:1± 0.2 should be administered initially. Subsequent infusions should be with 
rVWF:RCo 40 to 60 IU/kg with or, in  many cases,without 30 to 45 IU/kg ADVATE 
(only to be administered if plasma FVIII levels fall below 30 IU/L during the treatment 
period). Dosing may be adjusted downward or upward up to 80 IU/kg rVWF at the 
treating physician’s discretion based upon the subject’s prior history, PK and other 
factors.
If FVIII levels are not available, dosing is at the discretion of the investigator based upon 
the individual subject’s PK data. Using ADVATE (rFVIII, octocog alfa) in addition to 
rVWF (vonicog alfa) in subsequent doses carries the risk of an excessive rise in FVIII:C. 
Therefore, reduced doses of ADVATE (rFVIII, octocog alfa) and/or prolongation of the 
dose interval should be considered.
The following is general guidance and the sponsor’s suggestion for treatment of 
breakthrough bleeds, however each PI will determine the treatment based on the local 
acceptable practice how to monitor and adjust treatment for a bleeding episode. An effort 
should be made to discuss with the sponsor (or sponsor’s delegate) the treatment strategy.
In general the aim of the initial dose should be full replacement of VWF with VWF:RCo 
levels of >0.6 IU/ml (60%) and FVIII:C of >0.4 IU/mL (40%). In major bleeding 
episodes, subsequent doses should keep the trough level of VWF:RCo >50% for 3 days 
and then as deemed necessary by the investigator for subsequent days. In moderate 
bleeding episodes, the dose and trough level may be reduced to >30% for as long as 
deemed necessary by the investigator. Treatment for minor bleeding episodes will 
generally consist of only 1 or 2 doses of rVWF (vonicog alfa) IP. 
If the VWF:RCo level is above 150%, a planned treatment should be delayed by at least 
12 hours; if the VWF:RCo level is above 200%, a planned treatment should be delayed 
by at least 24 hours. In either case, a lower subsequent dose (e.g., 20 IU/kg VWF:RCo) 
may be appropriate.
Dosing recommendations are listed in Table 3.
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Dosage must be individualized based on the subject’s weight, VWD type, and the 
severity of the bleeding episode, as well as on monitoring of appropriate clinical and 
laboratory measures. In the phase 1 study 070701, 1.0 IU/kg VWF:RCo raised the 
circulating level of VWF:RCo by 0.017 IU/mL (1.7 %). In the same study, the observed 
mean half-life for rVWF (vonicog alfa) was 19.3 hours, with a standard deviation of 
10.9 hours.
Table 3
rVWF:RCo Dosing Recommendations for the Treatment of Bleeding Episodes Due to VWD
Classification of 
VWD
Hemorrhage
Dosage (IU VWF:RCo/kg BW)
Type 1 
Severe (Baseline 
VWF:RCo activity 
typically <20%) 
Minor (e.g., epistaxis, oral 
bleeding, menorrhagiaa) 
40 to 50 IU/kg (1 or 2 doses)
Major (e.g., severe or 
refractory epistaxis, 
menorrhagia*, GI bleeding, 
CNS trauma, hemarthrosis, 
or traumatic hemorrhage)
Initial dose 50 to 75 IU/kg, then 40 to 60 IU/kg 
every 8 to 12 hours for 3 days to keep the trough 
level of VWF:RCo >50%; then 40 to 60 IU/kg daily 
for a total of up to 7 days of treatment
Type 2 (all variants) 
and Type 3 
Minor (clinical indications 
above) 
40 to 50 IU/kg (1 or 2 doses)
Major (clinical indications 
above)
Initial dose of 60 to 80 IU/kg, then 40 to 60 IU/kg 
every 8 to 12 hours for 3 days to keep the trough 
level of VWF:RCo >50%; then 40 to 60 IU/kg daily 
for a total of up to 7 days of treatment
a
Menorrhagia is defined as excessive bleeding during menstruation. A diagnosis of menorrhagia will be 
defined by a prospectively completed Pictorial Blood Assessment Chart (PBAC) score >185 and normal 
cervical cytology or requiring use of a VWF-containing concentrate for treatment of excessive menstrual 
bleeding for at least one menstrual cycle during the prior year.
Variances of up to 10% in dosing are permissible during treatment of bleeding episodes,
but rounding to the nearest vial size should be avoided.
Subjects with non-neutralizing binding anti-VWF antibodies should initially be treated 
with a dose known to be efficacious based on the subject’s medical treatment history
which may differ from the recommendations provided in Table 3. Subjects should be 
monitored for lack of efficacy as well as for FVIII (mandatory), VWF:RCo (mandatory), 
and VWF:Ag (optional where testing is not available) levels after 3 to 6 hours. Re-dosing 
with rVWF (vonicog alfa) in combination with ADVATE (rFVIII, octocog alfa) using the 
same (initial) dose and adaptation of the dosing frequency should be considered until 
cessation of the bleed, if the FVIII and/or VWF:RCo levels drop below 30%-50% 
depending on bleeding severity.
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The number of subsequent infusions and the dosage levels prescribed will be determined 
by the investigator on the basis of the clinical severity, response to current therapy, 
available laboratory data, and the subject’s historical treatment for similar bleeding 
episodes.
8.6.4.5 Treatment of Surgical Bleeding
Subjects enrolled in this study who require surgery or dental procedures will be treated 
with IP to manage their surgical bleeding then afterwards will resume their prophylactic 
rVWF (vonicog alfa) treatment schedule. Subjects who at time of screening have an 
already scheduled surgical intervention are not eligible for participation in the study.
8.6.4.5.1 Major, Minor and Oral Surgery Definition
The following definitions and criteria are used to serve as a guidance for major, minor 
and oral surgery.
Major surgeries generally refer to major orthopedic surgery (e.g., joint replacement, 
arthroscopic or open synovectomy, arthrodesis, hardware removals like plates or 
intramedullary nails, etc.), major abdominal surgery (e.g. open or laparoscopic 
hernioplasty, cholecystectomy, colon or small bowel resection, etc.), major gynecological 
surgery (e.g. open or laparoscopic myomectomy, hysterectomy, removal of 
endometriosis, polyps, cysts, adhesiolysis, etc.), major head and neck surgery (e.g.: 
tonsillectomy, adenoidectomy, rhinoplasty, lymphadenectomy, thyroidectomy, 
parotidectomy. etc.), any intracranial , cardiovascular or spinal surgery and any other 
surgery which has a significant risk of large volume blood loss or blood loss into a 
confined anatomical space. Extraction of impacted third molars is generally also 
considered major surgery due to the expected difficulty of surgery and the expected blood 
loss.
Minor surgeries generally refer to interventions such as placement of intravenous access 
devices, removal of small skin lesions, arthroscopy, gastroscopy, colonoscopy or 
conisation.
Oral surgeries comprise extractions of fewer than three teeth, if the teeth are non-molars 
and have no bony involvement.
A summary schedule of visit assessments and laboratory sampling is included in 
Supplement tables in Section 20.2.1 and Section 20.3.1.
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8.6.4.5.2 Preoperative Priming Dose
12- 24 hours prior to surgery, a priming dose with rVWF (vonicog alfa), using the rVWF
IR and T1/2 for this subject , will be infused to allow the endogenous FVIII levels to raise 
to at least 30 IU/dL (minor, oral surgery), or 60 IU/dL (major surgery) at the time of the 
loading dose of rVWF (vonicog alfa) is infused.
As a general guidance a priming dose of 40-60 IU/kg rVWF:RCo will be administered. If
not assessed prior to the preoperative priming dose, a IR recovery may be calculated for
subjects undergoing minor and oral surgery.
8.6.4.5.3 Preoperative Loading Dose
An rVWF (vonicog alfa) loading dose should be administed within 3 hours before 
surgery. VWF and FVIII levels should be assessed within 3 hours prior to surgery 
initiation and results must be available prior to administering the loading dose. If FVIII 
levels prior to loading dose administration are not at least 30 IU/dL (minor, oral surgery), 
or 60 IU/dL (major surgery) ADVATE (rFVIII, octocog alfa) will be administered in 
addition to rVWF (vonicog alfa) in order to raise FVIII:C levels to recommended levels.
The preoperative loading dose will be calculated as the difference in the target peak and 
baseline plasma VWF:RCo levels divided by the IR (ΔVWF:RCo x BW (kg) /IR). The 
PK results will be provided prior to the planned surgery. If the IR is not available, assume 
an IR of 1.7 IU/dL per IU/kg and calculate the initial dose as follows: (100 – baseline 
plasma VWF:RCo) x BW (kg) / 1.7. For minor and oral surgery, the IR from the 
Preoperative Priming Dose visit will be used to guide dosing and the target peak is 
50-60 IU/dL VWF:RCo and 40-50 IU/dL FVIII. For major surgery, the target peak is 
100IU/dL VWF:RCo and 80-100 IU/dL FVIII.
The surgery may only start after normalization of the activated partial 
thromboplastin time (aPTT).
8.6.4.5.4 Intra- and Postoperative (maintenance) Dosing
After the preoperative loading dose(s), subjects who have not achieved the desired 
postinfusion recovery will continue to receive rVWF (vonicog alfa) with or without 
ADVATE (rFVIII, octocog alfa) as a bolus infusion, depending on VWF and FVIII 
levels. The peri- and post-operative substitution regimen will be individualized according 
to the PK results, intensity and duration of the hemostatic challenge, and the institution’s 
standard of care.
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Subjects undergoing minor surgery will be infused with rVWF (vonicog alfa) every 
12-24 hours or every other day, targerting ≥30IU/dL (rVWF and FVIII) for at least the 
first 48 hours.
Subjects undergoing oral surgery will be infused with rVWF (vonicog alfa) at least once 
within the first 8-12 hours, targeting ≥30 IU/dL (rVWF and FVIII).
Subjects undergoing major surgery will be infused with rVWF (vonicog alfa) every 
12-24 hours for at least the first 72 hours post-surgery, targeting a VWF:RCo and 
FVIII:C trough plasma level >50 IU/dL, followed by further treatment post-72 hours for 
as long as deemed necessary by the Investigator, targeting a VWF:RCo and FVIII:C 
trough plasma level of ≥30 IU/dL.
Dose modifications based on pre-infusion VWF/FVIII levels will be performed as 
needed. For subsequent infusions post surgery, in case pre-infusion levels are not 
available prior to the consecutive infusion in a timely manner, pre-infusion levels from 
the previous dose may be used by the investigator for dosing guidance.
Peak plasma level guidance is matching to Section 8.6.4.4.2
A schedule of all perioperative visit assessments and laboratory sampling can be found in 
supplement tables in Section 20.2.1 and Section 20.3.1.
8.6.4.6 Thrombosis Prophylaxis
Thromboembolic events have been reported in patients who have VWD, especially in the 
setting of known risk factors for thrombosis including low ADAMTS13 levels. 
Therefore, subjects who are at risk for developing thromboembolic events should be 
monitored for early signs of thrombosis, and prophylaxis measures against 
thromboembolism should be instituted according to current recommendations and 
standard of care. For all subjects who are VWD patients and are receiving VWF 
concentrate, attention should be given to avoid exceeding maximal recommended plasma 
activity levels of VWF:RCo (250 IU/dL) and FVIII (250 IU/dL).
Anticoagulation measures, such as heparin, are acceptable and should follow study site 
standards. The investigator will record the use and reasons for such measures/agents on 
the appropriate CRF.
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8.6.5 Investigational Product Accountability
The investigator will ensure that the IP(s) is stored as specified in the Pharmacy Manual
and that the storage area is secured, with access limited to authorized study personnel. All 
temperature excursions at the subject’s home need to be monitored by the site (please 
refer to the pharmacy manual). The investigator will maintain records that the IP(s) was
received, including the date received, drug identity code, date of manufacture or 
expiration date, amount received and disposition. The IP(s) must be dispensed only at the 
study site or other suitable location (e.g., infusion center; home, as applicable per study 
design), as specified in the protocol (see Section 10). Records will be maintained that 
includes the subject identification code (SIC), dispensation date, and amount dispensed. 
All remaining partially used and/or unused IP(s) will be returned to the sponsor or 
sponsor’s representative after study completion/termination, or destroyed with the 
permission of the sponsor in accordance with applicable laws and study site procedures. 
If IP(s) is to be destroyed, the investigator will provide documentation in accordance with 
sponsor’s specifications.
8.7 Source Data
Per ICH E6(R2) on GCP, source data are defined as all information in original records 
and certified copies of original records of clinical findings, observations, or other 
activities in a clinical trial that are necessary for the reconstruction and evaluation of the 
trial. Source data are contained in source documents (original records or certified copies). 
These may be in paper and/or electronic format. Source documents for this study
comprise the following: hospital records, medical records, clinical and office charts, 
laboratory notes, memoranda, subjects' diaries or evaluation checklists, outcomes 
reported by subjects, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate copies, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, 
and records kept at the pharmacy, at the laboratories and at medico-technical departments 
involved in the clinical study.
No data will be entered directly onto the CRF.
For additional information on study documentation and CRFs refer to Section 17.2. The 
use of subject diaries is described in Section 10.5.
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9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION
9.1 Inclusion Criteria
Subjects who meet ALL of the following criteria are eligible for this study:
1.
Subject has a documented diagnosis of severe VWD (baseline VWF:RCo 
<20 IU/dL) with a history of requiring substitution therapy with von Willebrand 
factor concentrate to control bleeding
a. Type 1 (VWF:RCo <20 IU/dL) or,
b. Type 2A (as verified by multimer pattern), Type 2B (as diagnosed by 
genotype), Type 2M or,
c. Type 3 (VWF:Ag ≤3 IU/dL).
2.
Diagnosis is confirmed by genetic testing and multimer analysis, documented in 
patient history or at screening.
3.
For on-demand patient group, subject currently receiving on-demand treatment for 
whom prophylactic treatment is recommended by the investigator.
4.
For pdVWF switch patient group, subject has been receiving prophylactic 
treatmentof pdVWF products for no less than 12 months prior to screening.
5.
For on-demand patient group, subject has ≥3 documented spontaneous bleeds (not 
including menorrhagia) requiring VWF treatment during the past 12 months.
6.
Availability of records to reliably evaluate type, frequency and treatment of 
bleeding episodes during at least 12 months preceding enrollment. Up to 
24 months retrospective data should be collected if available. Availability of 
dosing and factor consumption during 12 months (up to 24 months) of treatment 
prior to enrollment is required for pdVWF switch subjects and is desired (but not 
a requirement) for on-demand subjects.
7.
Subject is ≥18 years old at the time of screening and has a body mass index 
≥18 but ≤30 kg/m2.
8.
If female of childbearing potential, subject presents with a negative blood/urine 
pregnancy test at screening and agrees to employ adequate birth control measures 
for the duration of the study.i
9.
Subject is willing and able to comply with the requirements of the protocol.
                                                
i Refer to Section 20.4 for a list of adequate contraceptive methods for females of childbearing potential.
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9.2 Exclusion Criteria
Subjects who meet ANY of the following criteria are not eligible for this study:
1.
The subject has been diagnosed with Type 2N VWD, pseudo VWD, or another 
hereditary or acquired coagulation disorder other than VWD (eg qualitative and 
quantitative platelet disorders or prothrombin time (PT)/international normalized 
ratio [INR] 1.4).
2.
The subject is currently receiving prophylactic treatment with more than 
5 infusions per week.
3.
The subject is currently receiving prophylactic treatment with a weekly dose 
exceeding 240 IU/kg.
4.
The subject has a history or presence of a VWF inhibitor at screening.
5.
The subject has a history or presence of a FVIII inhibitor with a titer 
≥0.4 Bethesda units (BU) (by Nijmegen modified Bethesda assay) or ≥0.6 BU
(by Bethesda assay).
6.
The subject has a known hypersensitivity to any of the components of the study 
drugs, such as to mouse or hamster proteins.
7.
The subject has a medical history of immunological disorders, excluding seasonal 
allergic rhinitis/conjunctivitis, mild asthma, food allergies or animal allergies.
8.
The subject has a medical history of a thromboembolic event.
9.
The subject is human immunodeficiency virus (HIV) positive with an absolute 
Helper T cell (CD4) count 200/mm3.
10. The subject has been diagnosed with significant liver disease per investigator’s 
medical assessment of the subject’s current condition or medical history or as 
evidenced by any of the following: serum alanine aminotransferase (ALT) greater 
than 5 times the upper limit of normal; hypoalbuminemia; portal vein 
hypertension (e.g., presence of otherwise unexplained splenomegaly, history of 
esophageal varices).
11. The subject has been diagnosed with renal disease, with a serum creatinine (CR)
level ≥2.5 mg/dL.
12. The subject has a platelet count <100,000/mL at screening.
13. The subject has been treated with an immunomodulatory drug, excluding topical 
treatment (e.g., ointments, nasal sprays), within 30 days prior to signing the 
informed consent.
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14. The subject is pregnant or lactating at the time of enrollment.
15. Patient has cervical or uterine conditions causing menorrhagia or metrorrhagia 
(including infection, dysplasia).
16. The subject has participated in another clinical study involving another IP or 
investigational device within 30 days prior to enrollment or is scheduled to 
participate in another clinical study involving an IP or investigational device 
during the course of this study.
17. The subject has a progressive fatal disease and/or life expectancy of less than 
15 months.
18. The subject is scheduled for a surgical intervention.
19. The subject is identified by the investigator as being unable or unwilling to 
cooperate with study procedures.
20. The subject has a mental condition rendering him/her unable to understand the 
nature, scope and possible consequences of the study and/or evidence of an 
uncooperative attitude.
21. The subject is in prison or compulsory detention by regulatory and/or juridical 
order.
22. The subject is member of the study team or in a dependent relationship with one 
of the study team members which includes close relatives (i.e., children, 
partner/spouse, siblings and parents) as well as employees.
9.3 Delay Criteria
1.
If the subject has an acute bleeding episode or presents with an acute illness 
(e.g., influenza, flu-like syndrome, allergic rhinitis/conjunctivitis, non-seasonal 
asthma) the screening visit will be postponed until the subject has recovered.
9.4 Withdrawal and Discontinuation
Any subject may voluntarily withdraw (i.e., reduce the degree of participation in the 
study) consent for continued participation and data collection. The reason for withdrawal 
will be recorded on the End of Study CRF. Assessments to be performed at the 
termination visit (including cases of withdrawal or discontinuation) are described in 
Section 10.6 and Section 20.2. 
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Discontinuation (i.e., complete withdrawal from study participation) may be due to 
dropout (i.e., active discontinuation by subject) or loss to follow-up (i.e., discontinuation 
by subject without notice or action). Additionally, the investigator and sponsor have the 
discretion to discontinue any subject from the study if, in their judgment, continued 
participation would pose an unacceptable risk for the subject.
Subjects also will be withdrawn from treatment or discontinued from further study 
participation for the following reasons:
1.
The subject is scheduled for an extended treatment period 3 months with 
non-topical immunomodulating drugs other than anti-retroviral chemotherapy 
(e.g., -interferon, corticosteroid agents [equivalent to hydrocortisone greater 
than 10 mg/day]) during the course of the study.
2.
Subjects with chronic hepatitis B or C develop ALT/AST levels exceeding 
5 times the ULN for 1 month.
3.
Subjects who experience severe hypersensitivity reactions, e.g., anaphylaxis upon 
exposure to rVWF (vonicog alfa).
4.
Subjects who develop a neutralizing inhibitor to rVWF (vonicog alfa) and/or 
ADVATE (rFVIII, octocog alfa) (biological assays) that results in significant 
clinical effect, including but not limited to increasing the weekly dose of rVWF 
by ≥50%.
5.
Subjects who demonstrate clinical signs of thromboembolic events.
6.
The subject becomes pregnant. IP exposure will be discontinued. Attempts will be 
made to follow the subject through completion of the pregnancy and up to 1 year 
post delivery, if feasible. The investigator will record a narrative description of 
the course of the pregnancy and its outcome. 
7.
The subject begins lactating. IP exposure will be discontinued. The investigator 
will record a narrative description of the course of the baby’s development. 
8.
The subject is not compliant with the prophylactic treatment regimen and does not 
adhere to the frequency of IP administration. Once >30% of infusions are missed 
within a visit interval (3 months), the subject will be discontinued from further 
participation in the study. 
9.
The subject repeatedly uses other VWF products for prophylaxis or for the 
treatment of bleeding episodes in the absence of an acceptable justification to the 
sponsor. 
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10. STUDY PROCEDURES
10.1 Informed Consent and Enrollment
Any patient who provides informed consent (i.e., signs and dates the informed consent 
form) is considered a subject enrolled in the study.
10.2 Subject Identification Code
The following series of numbers will comprise the SIC: protocol identifier (e.g., 071301) 
to be provided by the sponsor, 2- or 3-digit number study site number (e.g., 02) to be 
provided by the sponsor, and 3- or 4-digit subject number (e.g., 0003) reflecting the order 
of enrollment (i.e., signing the informed consent form). For example, the third subject 
who signed an informed consent form at study site 02 will be identified as Subject 
071301-020003. All study documents (e.g., CRFs, clinical documentation, sample 
containers, drug accountability logs, etc.) will be identified with the SIC. Additionally, a 
uniquely coded SIC(s) is permitted as long as it does not contain a combination of 
information that allows identification of a subject (e.g., collection of a subject’s initials 
and birth date would not be permitted), in compliance with laws governing data privacy.
10.3 Screening and Study Visits
The study site is responsible for maintaining a screening log that includes all subjects 
who provided informed consent. The log also will serve to document the reason for 
screening failure. All screening data will be collected and reported in CRF, regardless of 
screening outcome. If a subject is re-screened, the End of Study CRF should be 
completed, and a new ICF, new SIC and new CRF are required for that subject.
The overall study design is illustrated in the Figure 1. Details on the procedures to be 
performed at each study visit, including screening, are provided in Supplement 20.2
“Schedule of Study Procedures and Assessments” and Supplement 20.3 “Clinical 
Laboratory Assessments”.
10.3.1 Screening Visit
Written informed consent must be obtained from each subject before any study 
related procedures are performed. During the screening, site staff would be required to 
collect all details including date, location, type, severity and treatment received for all 
spontaneous and traumatic bleeding episodes occurring within the past 12 months. The 
maximum interval of bleed-free periods as well as trauma-induced bleeding episodes will 
also be recorded (prospectively and retrospectively). Study site personnel would be 
trained and qualified about which information should be obtained from diary, chart 
and pharmacy records, along with any other applicable site source documentation.
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To initiate screening procedures, at least 72 hours must have elapsed since the last VWF 
administration for on-demand subjects and the subject must not be actively bleeding at 
the time of screening. For switch subjects, the usual interval between their pdVWF 
prophy infusions must have elapsed since the last VWF administration and the subject 
must not be actively bleeding at the time of screening. Multimer analysis and VWD gene 
mutation analysis should be performed at screening if not available in the subject’s 
medical history.
The screening visit will be delayed if the subjects presents with an acute bleeding 
episodes or acute illness (e.g., influenza, flu-like symptoms, inflammatory diseases) until 
the event has resolved. All screening procedures and confirmation of eligibility shall take 
place within 42 days prior to the first infusion of IP. If the IP is not infused within 
42 days, all screening assessments except blood group, human leukocyte antigen (HLA), 
genetics, multimeric pattern and 
, must be repeated to reconfirm eligibility. Refer 
to Supplement 20.2 and Supplement 20.3. Upon completion of screening procedures, 
subject eligibility will be confirmed by the sponsor on a subject eligibility form before 
additional study procedures are undertaken. The subject will maintain a diary that will 
include infusion logs (see Section 10.5). The allocation of IP will be initiated after the 
subject has qualified for home treatment (see Section 8.6.4.3.2).
In the event of a subject experiencing a bleeding episode that requires treatment between 
the screening visit and the subsequent visit (i.e. initial PK assessment visit for on-demand 
subjects or prophylaxis initiation visit for switch subjects), the subject will be treated with
rVWF (vonicog alfa). If rVWF (vonicog alfa) is not available for any reason, e.g., subject 
not yet trained on IP administration, study site visit for IP administration not feasible, 
etc., the subject may use his/her standard of care, such as commercial pdVWF/FVIII 
products, and the reason for the use of non-IP products should be clearly documented.
10.3.2 Baseline Visit – Initial PK Assessment (On-demand Subjects Only)
After screening and confirmation of eligibility on-demand subjects will undergo an initial
PK assessment. Subjects will receive a dose of 50 ± 5 IU/kg rVWF:RCo to determine 
VWF and FVIII levels. Blood samples will be drawn within 30 minutes pre-infusion, 
and at 11 time points post-infusion (15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 
3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 
72 2 hours and 96 ± 2 hours). See Section 20.2 and Section 20.3. IP infusion vials 
from the same lot number should be used for all PK-assessments per subject. Samples 
for measurement of FVIII and VWF activity taken through to 6 hours post-infusion 
will be obtained from an extremity different from that used for the infusion of IP. 
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Where needed, the phlebotomy site will be kept patent via an infusion of normal saline. 
In this event, at least 5 mL of blood will be collected and discarded before collection of 
the next test sample into a fresh syringe.
If the subject has a central venous catheter, the central line should be used to administer 
the infusion and a peripheral venipuncture should be used to collect the blood samples. 
In the event that a blood sample must be drawn through the central line used for 
administration of IP, the line must first be flushed with at least 10 mL normal saline or 
other suitable catheter flush solution that does not contain anticoagulant. At least 5 mL of 
whole blood must be collected and discarded prior to obtaining the sample. 
If a subject experiences a bleeding episode during the PK assessment no subsequent 
blood sample will be drawn in that specific PK period. The guidance provided in 
Section 8.6.4.4 has to be followed for the treatment of the bleeding episode. The subject 
once recovered is eligible to repeat the PK assessment.
For pdVWF switch subjects, PK profile will not be assessed until reaching steady state 
after initiation of prophylaxis (see Section 10.3.4).
10.3.3 Prophylaxis Initiation Visit
The prophylaxis initiation visit will occur after the blood sample for the 96 hour PK 
assessment is drawn for on-demand subjects or within 42 days after screening and 
confirmation of eligibility for pdVWF switch subjects. The subject will receive the first 
rVWF (vonicog alfa) prophylactic dose of rVWF: RCo. Details on dose are provided in 
Section 8.6.4.3. 
Procedures and assessments at this visit include (but are not limited to): AEs, bleeding 
episodes, medications taken, and non-drug therapies. Within 2 hours prior the IP infusion, 
a physical examination will be performed. Vital signs will be assessed within 30 minutes 
prior to IP rVWF (vonicog alfa) infusion and 30 minutes ± 15 minutes after IP infusion.
Further details are provided in Supplement 20.2 and Supplement 20.3.
10.3.4 Initial Steady State PK-Assessment (pdVWF switch subjects only)
For pdVWF switch subjects, a full PK profile will be assessed at steady state conditions 
on two occasions. The initial PK assessment will be performed shortly after reaching 
steady state after starting prophylaxis dosing, which is suggested after 11 days post the 
1st, around prophylaxis dose #5-6. The 2nd PK assessment at steady state will be 
performed at the end of the study.
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Blood samples will be drawn within 30 minutes pre-infusion, and at 11 time points 
post-infusion (15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 
6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours 
and 96 ± 2 hours). In case the dosing schedule does not permit the 96 hr sampling, 
this sampling time point can be omitted (See Section 11.6). IP infusion vials from 
the same lot number should be used for all PK-assessments per subject. 
Samples for measurement of FVIII and VWF activity taken through to 6 hours post-
infusion will be obtained from an extremity different from that used for the infusion of 
IP. Where needed, the phlebotomy site will be kept patent via an infusion of normal 
saline. In this event, at least 5 mL of blood will be collected and discarded before 
collection of the next test sample into a fresh syringe.
If the subject has a central venous catheter, the central line should be used to administer 
the infusion and a peripheral venipuncture should be used to collect the blood samples. 
In the event that a blood sample must be drawn through the central line used for 
administration of IP, the line must first be flushed with at least 10 mL normal saline or 
other suitable catheter flush solution that does not contain anticoagulant. At least 5 mL of 
whole blood must be collected and discarded prior to obtaining the sample. 
If a subject experiences a bleeding episode during the PK assessment no subsequent 
blood sample will be drawn in that specific PK period. The guidance provided in 
Section 8.6.4.4 has to be followed for the treatment of the bleeding episode. The subject 
once recovered is eligible to repeat the PK assessment. In case of surgery or bleeding, the 
PK assessment should be performed after 11 days after 1st prophylactic dose after re-start 
of prophylactic regimen. See Section 11.6 for more details.
10.3.5 Treatment of Bleeding Episodes
Treatment of bleeding episodes is described in detail in Section 8.6.4.4 and treatment of 
perioperative bleeding is described in detail in Section 8.6.4.5.
10.3.6 Perioperative Visits (only applicable if surgery is needed)
The perioperative visits from priming dose through postoperative day 14 will be required 
to check daily intra- and postoperative weight-adjusted dose of rVWF (vonicog alfa) with 
or without ADVATE (rFVIII, octocog alfa). Details on the procedures and assessments 
performed at each visit can be found in supplement tables in Section 20.2.1 and 
Section 20.3.1.
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10.3.7 Follow-Up Visits (1 Month ± 1 Week, 2 Months ± 1 Week, 
3 Months ± 2 Weeks, 6 Months ± 2 Weeks, 9 Months ± 2 Weeks post 
Prophylaxis Initiation Visit)
Visits will be performed after the prophylaxis initiation visit at 1 month ± 1 week, 
2 months ± 1 week, and 3 months ± 2 weeks and thereafter every three months
± 2 weeks. Additional visits may occur if clinically indicated (see Section 10.3.8).
When possible, site visits should be scheduled on days when the subject is expected to 
infuse rVWF (vonicog alfa). Within 2 hours prior to the rVWF (vonicog alfa) IP infusion,
a physical examination will be performed. Vital signs will be assessed within 30 minutes 
prior to IP infusion and 30 minutes ± 15 minutes after IP infusion. Incremental recovery 
(IR) will be determined at each follow-up visit based on VWF:RCo activity assessed 
prior to and after IP infusion.
The blood sample for IR analysis will be drawn within 30 minutes prior to IP infusion 
and 30 minutes ± 5 minutes after IP infusion. rVWF (vonicog alfa) will be infused at the 
regular prophylactic dose. For each subject’s recovery analysis IP infusion, vials from the 
same lot number should be used. 
Testing for VWF:RCo VWF:CB, rVWF:Ag, and FVIII:C level will be performed using 
the blood sample obtained before and after IP infusion. 
The blood sample prior to IP infusion will also be used for the assessment of neutralizing
and binding antibodies, clinical chemistry and hematology. For on-demand subjects, a
washout period of at least 72 hours after the last infusion applies before the blood draw 
for the immunogenicity assays. For switch subjects, the wash out period may be reduced 
to the time interval between their pdVWF prophy infusions Bleeding episodes and the 
hemostatic efficacy will be evaluated based on the review of the patient diary. See
Section 20.2 and Section 20.3. The evaluation of IP consumption and treatment 
compliance will be performed based on subject’s diary entries. If a subject is not 
compliant with the prophylactic treatment regimen and does not adhere to the required 
frequency of administration of IP infusions (>30% of infusions were missed within a visit 
interval [3 months]) the subject will be withdrawn from the study.
At the 6 months ± 2 week visit an ECG will be performed and 
data will be 
collected.
For the hemostatic efficacy assessment the following information will be recorded by 
the subject in the patient diary: bleeding location, type, severity, onset and resolution 
date and time, infusion date and time, clinical efficacy according to the rating scale. 
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If at any time during the study a subject’s bleeding episode does not adequately respond 
to rVWF (vonicog alfa) therapy, he/she will be evaluated for the presence of neutralizing
and total binding antibodies. Refer to Section 12.9.3.2.
Further guidance on completing the subject’s diary will be provided to the subjects 
during training for home treatment (see Section 8.6.4.3.2).
10.3.8 Unscheduled Visits
For any unscheduled visit (except for collection of IP) a clinical assessment will be 
performed as per the scheduled follow-up visits with the exception of 
, ECG, and 
IR determination (refer to Supplement 20.2 and Supplement 20.3).
Subjects who have more than one bleeding episode in 3 months, or an increased 
frequency of bleeding, should go to the study site for an unscheduled visit.
Follow-up visits after the subject has experienced a bleed may be requested by the 
investigator. Additional assessments may be required which are at the discretion of the 
investigator. 
10.3.9 End of Study PK Assessment and Study Termination Visit
(12 Months ± 2 Weeks post Prophylaxis Initiation Visit)
At the 12 month ± 2 week visit, a full PK analysis at steady state will be performed for 
both cohorts: on-demand and switch subjects. Blood samples will be drawn within 
30 minutes pre-infusion, and at 11 time points post-infusion (15 ± 5 minutes, 
30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 
24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours and 96 ± 2 hours) unless dosing 
schedule does not permit, in which case the 96 hr sampling can be omitted. If a subject 
experiences a bleeding episode during the PK assessment no subsequent blood sample 
will be drawn in that specific PK period. The guidance provided in Section 8.6.4.4 has to 
be followed for the treatment of the bleeding episode. The subject once recovered is 
eligible to repeat the PK assessment and the PK assessment should be performed after 
11 days after 1st prophylactic dose after re-start of prophylactic regimen. See 
Section 11.6 for more details.
Refer to Supplement 20.2 and Supplement 20.3 for the other assessments to be performed 
at the PK assessment and study completion visits.
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For on-demand subjects, a washout period of at least 72 hours is required between the PK
infusion and the study termination visit (at the time of the 96 hour postinfusion PK 
assessment). For switch subjects, the wash out period may be reduced to the time interval 
between their rVWF (vonicog alfa) prophy infusions.Refer to Supplement 20.2 and 
Supplement 20.3 for the list of assessments to be performed at the termination visit.
Subjects will be offered the option to continue to receive rVWF (vonicog alfa) in a 
long-term continuation study.
10.4 Medications and Non-Drug Therapies 
The following medications and non-drug therapies are not permitted within 30 days 
before study entry and during the course of the study:
Medications:

Immunomodulating drugs other than anti-retroviral chemotherapy (e.g.,
-interferon, or corticosteroid agents at a dose equivalent to hydrocortisone 
greater than 10 mg/day) and an extended treatment period 3 months.

Another investigational and/or interventional study drug (except rVWF and FVIII 
administered under the surgery protocol).
A subject who has taken any of these medications or received any of these non-drug 
therapies during the study will be withdrawn from the study. 
The following medications are permitted during the course of the study:

Antifibrinolytics (e.g., tranexamic acid, -amino caproic acid) or topical
hemostats as needed, according to each institution’s standard of care. These may 
be used, in accordance with local standard clinical practice, as the initial or only 
treatment for minor and moderate bleeding events. However, if the bleeding has 
not stopped within 24 hour following administration of this non-VWF treatment, 
infusion(s) with rVWF (vonicog alfa) should be started per protocol

Emergent use of a VWF concentrate other than rVWF (vonicog alfa) may be 
permissible under certain circumstances (see Section 8.6.4.4.1)
Details of all adjunctive hemostatic medication used, including dose and reason for use, 
must be recorded in the eCRF.
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10.5 Subject Diary
1.
An electronic subject diary will be provided to each subject at the screening visit 
to record the following information:

IP infusions to include date, start and stop times of the infusion, number of 
vials utilized, and infusion volume for prophylactic treatment or treatment of 
spontaneous and traumatic bleeding episodes 
2.
Details of bleeding episodes (site, type, severity and date/time of bleeding) and 
response to treatment as described in Section 8.6.4.4
3.
Subjective hemostatic efficacy assessments
4.
Untoward events/unwanted experiences
5.
Concomitant medications (including immunizations) and non-drug therapies
6.
Patient Reported Outcomes (PROs)
Subjects and/or their legally authorized representatives will be trained on use of the diary. 
The diary will be provided in electronic format and remain with the subject for the 
duration of the study. The investigator will review the diary for completeness and request 
missing information periodically and in a timely manner. The investigator will 
record/capture any unwanted experience reported by the subject which may qualify as an 
AE on the AE eCRF.
Infusions performed at the study site will first be recorded in the site’s source documents 
and not in the patient diary.
Subject entries in the diary will serve as source records. During study participation the 
investigator has access to the database holding the subject diary data. After study closure, 
the investigator will receive the diary records for their subjects, including audit trail 
records, in PDF format. The data will be transmitted to the CRF by a validated transfer. 
Paper diary may be utilized in rare case where electronic diary use is not possible.
10.6 Subject Completion/Discontinuation
A subject is considered to have completed the study when he/she ceases active 
participation in the study because the subject has, or is presumed to have completed all 
study procedures according with the protocol (with or without protocol deviations).
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Reasons for completion/discontinuation will be reported on the 
Completion/Discontinuation CRF, including: completed, screen failure, AE (e.g., death), 
discontinuation by subject (e.g., lost to follow-up [defined as 3 documented unsuccessful 
attempts to contact the subject], dropout), physician decision (e.g., pregnancy, 
progressive disease, non-compliance with IP/protocol violation(s), recovery), study 
terminated by sponsor, or other (reason to be specified by the investigator, e.g., technical 
problems). Regardless of the reason, all data available for the subject up to the time of 
completion/discontinuation should be recorded on the appropriate CRF. 
Every effort will be made to have discontinued subjects complete the study 
termination visit. If the termination visit is done as an additional, unscheduled 
visit, the assessment results shall be recorded with the termination visit.
If a subject terminates participation in the study and does not return for termination visit, 
his/her last recorded assessments shall remain with the last visit. The reason for 
discontinuation will be recorded, and the data collected up to the time of discontinuation 
will be used in the analysis and included in the clinical study report. If additional 
assessments are required, the assessments shall be recorded separately. Assessments to be 
performed at the termination visit (including in cases of withdraw or discontinuation) can 
be found in Supplement 20.2 Schedule of Study Procedures and Assessments and 
Supplement 20.3 Clinical Laboratory Assessments.
In the event of subject discontinuation due to an AE, clinical and/or laboratory 
investigations that are beyond the scope of the required study observations/assessments 
may be performed as part of the evaluation of the event. These investigations will take
place under the direction of the investigator in consultation with the sponsor, and the 
details of the outcome may be reported to the appropriate regulatory authorities by the 
sponsor. 
10.7 Procedures for Monitoring Subject Compliance
Subject compliance with the procedures of this study (treatment regimens and study 
visits) will be monitored by the investigator or/a licensed healthcare professional at the 
study site.
During the regular scheduled follow-up visits a direct review of the subject’s source data 
(e-diaries) will be performed at the sites and evaluated against the protocol requirements. 
In addition drug accountability will be evaluated at each follow-up study visit and the 
study termination visit by comparing the infusions recorded in the subject diary with
empty vials returned by each subject to the study site, and the study site’s dispensing 
record. Protocol deviations will be noted in the final report.
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11. ASSESSMENT OF EFFICACY AND PHARMACOKINETICS
11.1 Assessment of Spontaneous Bleeding Episodes/Annualized Bleed Rate 
The annualized bleed rate (ABR) will be assessed based upon each individual 
spontaneous bleed, requiring coagulation factor replacement therapy, i.e., rVWF 
(vonicog alfa) treatment. The following details on bleeding episodes will be recorded by 
the subject in the electronic diary (for home treatment), the subject’s healthcare provider 
in the site’s source documents (for treatments away from the primary investigative site), 
or by authorized, qualified personnel at the participating site in the subject’s medical 
records (for hospital-based treatment):

Location of bleed; i.e., joint, menorrhagia, epistaxis, gastrointestinal, soft tissue, 
muscle, body cavity, intracranial, etc.

Type of bleed; i.e., spontaneous, traumatic, unknown

Severity of bleed; i.e., minor, moderate, and major (see Table 3)

Date and time of onset of bleed

Date and time of each infusion of rVWF (vonicog alfa) or rVWF (vonicog alfa)-
ADVATE (rFVIII, octocog alfa) used to treat a bleeding episode

Date and time of resolution of the bleeding episode
Study site personnel are qualified after they have undergone training during the 
qualification of the site.
All types of bleeds, including traumatic bleeds, will be recorded. Bleeding episodes 
should be organized by where they occur in addition to whether they occurred 
spontaneously or due to a traumatic event.
Bleeds occurring at the same anatomical location (e.g., right knee) with the same etiology 
(i.e., spontaneous versus injury) within 24 hours after onset of the first bleed will be 
considered a single bleed. Bleeding occurring at multiple locations related to the same 
injury (e.g., knee and ankle bleeds following a fall) will be counted as a single bleeding 
episode.
All efforts should be made to use rVWF (vonicog alfa) for treatment of bleeding 
episodes. If needed, the use of a VWF concentrate other than IP for the treatment of 
bleeding episodes will not disqualify the subject from further participation in the study.
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11.2 Evaluation of ABR Before rVWF Prophylaxis and ABR Under rVWF
Prophylactic Treatment
At screening, the subject’s medical history will be recorded, including the number and 
location of all spontaneous and traumatic bleeding episodes within the past 12 months
(up to 24 months if available). The maximum interval of bleed-free periods as well as 
trauma induced bleeding episodes will also be recorded (prospectively and 
retrospectively).
11.3 Number of Infusions and Total Weight Adjusted Consumption of rVWF and 
ADVATE and historical prophylaxis dosing and factor consumption during 
pdVWF prophylaxis treatment prior to enrollment
The number of rVWF (vonicog alfa) and ADVATE (rFVIII, octocog alfa) (in case of 
bleeding episode treatment) infusions will be logged in the subject diary. Based on these 
entries the weight adjusted consumption will be calculated. 
At the screening, historical pdVWF dosage and dosing frequency during 12 and up to 
24 months of pdVWF prophylactic treatment prior to enrollment will be recorded for the 
pdVWF switch subjects in order to calculate the consumption of pdVWF.
11.4 Assessment of Efficacy for Treatment of Bleeding Episode
Investigators will be asked to assess and record hemostatic efficacy after resolution of 
each bleeding episode using the 4-scale rating system outlined in Table 4. 
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Table 4
Efficacy Rating Scale
Rating
Efficacy Rating Criterion
Minor and Moderate Bleeding Events
Major Bleeding Events
Excellent (=1)
Actual number of infusions ≤ estimated 
number of infusions required to treat that 
bleeding episode
No additional VWF containing coagulation 
factor containing product required
Actual number of infusions ≤ estimated 
number of infusions required to treat that 
bleeding episode
No additional VWF containing 
coagulation factor containing product 
required
Good (=2)
1-2 infusions greater than estimated 
required to control that bleeding episode
No additional VWF containing coagulation 
factor containing product required
< 1.5 x infusions greater than estimated 
required to control that bleeding episode
No additional VWF containing 
coagulation factor containing product 
required
Moderate (=3)
3 or more infusions greater than estimated 
required to control that bleeding episode
No additional VWF containing coagulation 
factor containing product required
≥1.5 x infusions greater than estimated 
required to control that bleeding episode
No additional VWF containing 
coagulation factor containing product 
required
None (=4)
Severe uncontrolled bleeding or intensity of 
bleeding not changed
Additional VWF containing coagulation 
factor containing product required
Severe uncontrolled bleeding or intensity 
of bleeding not changed
Additional VWF containing coagulation 
factor containing product required
11.5 Assessment of Efficacy for Treatment for Surgical Bleeding
For those undergoing surgery, the operating surgeon will be asked to assess and record 
actual versus predicated blood loss and intraoperative hemostatic efficacy immediately 
after surgery.
The investigator will be asked to assess and record an overall assessment of hemostatic 
efficacy 24 hours after the last perioperative rVWF (vonicog alfa) infusion or at day 
14 post-operation, whichever occurs first, using the 4-scale rating system described in 
Table 5.
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Table 5
Assessment of Hemostatic Efficacy
Rating
Overall Assessment of Hemostatic Efficacy 24 Hours After the Last Perioperative
rVWF Infusion
Excellent (1)
Intra- and post-operative hemostasis achieved with rVWF (vonicog alfa) with or without 
ADVATE (rFVIII, octocog alfa) was as good or better than that expected for the type of 
surgical procedure performed in a hemostatically normal subject
Good (2)
Intra- and post-operative hemostasis achieved with rVWF (vonicog alfa) with or without 
ADVATE (rFVIII, octocog alfa) was probably as good as that expected for the type of 
surgical procedure performed in a hemostatically normal subject
Moderate (3)
Intra- and post-operative hemostasis with rVWF (vonicog alfa) with or without ADVATE 
(rFVIII, octocog alfa) was clearly less than optimal for the type of procedure performed 
but was maintained without the need to change the rVWF (vonicog alfa) concentrate
None (4)
Subject experienced uncontrolled bleeding that was the result of inadequate therapeutic 
response despite proper dosing, necessitating a change of rVWF (vonicog alfa) concentrate
11.6 rVWF Pharmacokinetics and Pharmacodynamics 
PK will be assessed twice for all subjects.
For on-demand subjects, an initial PK assessment using a dose of 50 IU ± 5 IU/kg 
rVWF:RCo will be performed at the baseline visit, and a washout period of at least 
5 days is required before the infusion of rVWF (vonicog alfa) for PK assessment can 
be administered. At the 12 month ± 2 week visit, a steady state PK analysis will be 
performed based on the longer interval of the irregular dosing intervals employed. For 
both assessments, blood samples will be drawn within 30 minutes pre-infusion, and at 
11 time points post-infusion (15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 
3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 
72 2 hours and 96 ± 2 hours). VWF activity will be determined using the VWF:RCo, 
VWF:CB and the VWF: Ag assay. Endogenous FVIII activity will be measured using the 
1-stage clotting assay to assess the pharmacodynamics of rVWF (vonicog alfa). 
For pdVWF switch subjects, the initial PK assessment using the subject’s individualized 
dose will be performed shortly after reaching steady state, which is estimated to be 
reached for the majority of subjects after  approximately 11 days from the 1st prophylactic 
dose. To fit any logistical requirements, samples for PK analysis can be taken after 
prophylaxis dose #5-6, and whenever possible, sample collections should be during the 
longer partial interval of the alternating irregular dosing intervals. For example, if a 
subject follows a dosing regimen as follows:
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Date
Weekday
Dose number
Interval
Time from 1st dose in hours
8.1.18 8:00
Monday
1
0
0
12.1.18 8:00
Friday
2
4
96
15.1.18 8:00
Monday
3
3
168
19.1.18 8:00
Friday
4
4
264
22.1.18 8:00
Monday
5
3
336
26.1.18 8:00
Friday
6
4
432
After reaching the steady state, the PK assessment can be done at dose 5 to allow the 96h 
post-infusion sampling, before the next scheduled dose (for patients on a twice per week 
dosing schedule). A similar 2nd full PK profile will be assessed at the end of the study, i.e. 
12 month ± 2 week visit with a PK infusion at the same dosing partial interval (96h 
interval in this case). Blood samples will be drawn within 30 minutes pre-infusion, 
and at 11 time points post-infusion (15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 
3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 
72 2 hours, and 96 ± 2 hours). If the dosing interval for a certain switch subject 
wouldn’t allow for the full 11 post-infusion timepoints sample collection, the 96-hour 
sampling timepoint can be omitted, but it is critical that the assessments are at the same 
partial interval, thereby same number of sampling timepoints, for the 1st and 2nd PK for 
an individual switch subject.
If a subject experiences a bleeding episode during the PK assessment no subsequent 
blood sample will be drawn in that specific PK period. The guidance provided in
Section 8.6.4.4 has to be followed for the treatment of the bleeding episode. The subject 
once recovered is eligible to repeat the PK assessment. In case of surgery or bleeding, the 
PK assessment should be performed after 11 days after 1st prophylactic dose after restart 
of prophylactic regimen.
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12. ASSESSMENT OF SAFETY
12.1 Adverse Events
12.1.1 Definitions
An AE is defined as any untoward medical occurrence in a subject administered IP that 
does not necessarily have a causal relationship with the treatment. An AE can therefore 
be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom
(e.g., rash, pain, discomfort, fever, dizziness, etc.), disease (e.g., peritonitis, bacteremia, 
etc.), or outcome of death temporally associated with the use of an IP, whether or not 
considered causally related to the IP.
12.1.1.1 Serious Adverse Event
An SAE is defined as an untoward medical occurrence that, at any dose, meets one or 
more of the following criteria:

Outcome is fatal/results in death (including fetal death)

Is life-threatening – defined as an event in which the subject was, in the judgment 
of the investigator, at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death had it been more severe.

Requires inpatient hospitalization or results in prolongation of an existing 
hospitalization – inpatient hospitalization refers to any inpatient admission, 
regardless of length of stay.

Results in persistent or significant disability/incapacity (i.e., a substantial 
disruption of a person’s ability to conduct normal life functions)

Is a congenital anomaly/birth defect

Is a medically important event – a medical event that may not be immediately 
life-threatening or result in death or require hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the definitions above. Examples of such events are (including 
but not limited to): 

Intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias, or convulsions that do not result in 
hospitalization, or development of drug dependence or drug abuse 

Reviewed and confirmed seroconversion for HIV, hepatitis A virus (HAV), 
hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis E virus (HEV), 
or parvovirus B19 (B19V)
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
Development of clinically significant neutralizing VWF antibodies

Development of neutralizing antibodies to FVIII (titer ≥0.4 BU [by 
Nijmegen- modified Bethesda assay] or ≥0.6 BU [by Bethesda assay])

Thromboembolic events (e.g., myocardial infarction, stroke, transient 
ischemic attack [TIA], deep vein thrombosis [DVT] or pulmonary 
embolism)

Hypersensitivity reactions (e.g., anaphylaxis [for definition, refer to 
Section 12.6.2] and other immediate and delayed hypersensitivity reactions 
which may manifest with urticarial rash, pruritus, flushing, angioedema of 
the face, extremities, or laryngeal tissues [leading to throat tightness with 
stridor], wheezing, gastrointestinal symptoms, and/or hypotension)
Uncomplicated pregnancies, following maternal or paternal exposure to IP are not 
considered an AE/SAE; however, any pregnancy complication or pregnancy termination 
by therapeutic, elective, or spontaneous abortion shall be considered an SAE and should 
be reported per SAE reporting guidelines provided in Section 12.1.2.3 (Safety 
Reporting).
12.1.1.2 Suspected Unexpected Serious Adverse Reaction (SUSAR)
Any suspected adverse reaction to study treatment that is both serious and unexpected is 
considered a SUSAR. 
The event(s) must meet all of the following:

Suspected adverse reaction (which implies that there is reasonable evidence 
indicating a causal relationship between the event and the study treatment),

Unexpected (per Reference Safety Information (RSI)/IB), and

Serious
Once determined to meet the criteria for a SUSAR, the sponsor will ensure expedited 
SUSAR reporting is completed in line with the regulatory requirements in participating 
countries as outlined in the Safety Management Plan.
12.1.1.3 Non-Serious Adverse Event
A non-serious AE is an AE that does not meet any of the seriousness criteria (death, 
life-threatening, hospitalizing/prolongation of hospitalization, disability, congenital 
anomaly, or medically significant and if not urgently treated would result in one of the 
above) listed in Section 12.1.1.1.
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12.1.1.4 Unexpected Adverse Events
An unexpected adverse event is an AE whose nature, severity, specificity, or outcome is 
not consistent with the term, representation, or description used in the Reference Safety 
Information (e.g., IB, PI [prescribing information]). “Unexpected” also refers to the AEs
that are mentioned in the IB as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring 
with the particular drug under investigation.
12.1.1.5 Preexisting Disease
Preexisting diseases that are present before entry in to the study are described in the 
medical history, and those that manifest with the same severity, frequency, or duration 
after IP exposure will not be recorded as AEs. However, when there is an increase in the 
severity, duration, or frequency of a preexisting disease, the event must be described as 
“worsening” of the pre-existing condition on the AE CRF.
12.1.2 Assessment of Adverse Events
For the purposes of this study, the following will not be considered as AEs and will not 
be included in the analysis of AEs.

Bleeding episodes are part of the underlying disease and therefore are not AEs; 
they will be evaluated in the context of efficacy.

For non-serious bleeding episodes caused by an injury, the injury would not 
be reported as an AE, unless it resulted in a medical finding other than a 
bleeding episode (e.g., abrasion of skin). Therefore, any VWD-related 
bleeding event (e.g., epistaxis, gastrointestinal bleeding, musculo-skeletal 
bleeding, menorrhagia) that is non-serious will not be reported as an AE. 
However, the investigator may decide that the event is an AE if the event also 
would have occurred in a healthy individual under the same circumstances.

For serious bleeding episodes (bleeding SAEs): Bleeding events that meet 
seriousness criteria (death, life-threatening, hospitalizing/prolongation of 
hospitalization, disability, congenital anomaly, or medically significant and if 
not urgently treated would result in one of the above) should be captured on 
the SAE eCRF and reported as an SAE to the Sponsor or designee (e.g., 
CRO) on an SAE Report form as described in Section 12.1.2.3 (Safety 
Reporting).

Seroconversion after documented HAV/HBV vaccination prior to or during the 
study period.
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Each AE from the first IP exposure to the study completion date will be described on the 
AE CRF using the term representing medical diagnosis (preferred), or, if no diagnosis 
could be established at the time of reporting the AE, a symptom or sign, in standard 
medical terminology in order to avoid the use of vague, ambiguous, or colloquial 
verbatim expressions (see definition in Section 12.1). Each AE will be evaluated by the 
investigator for:

Seriousness as defined in Section 12.1.1.1

Severity as defined in Section 12.1.2.1

Causal relationship to IP exposure or study procedure as defined in 
Section 12.1.2.2
For each AE, the outcome (i.e., recovering/resolving, recovered/resolved, 
recovered/resolved with sequelae, not recovered/not resolved, fatal, unknown) and if 
applicable, action taken with regards to the study treatment (i.e., dose increased, dose not 
changed, dose reduced, drug interrupted, drug withdrawn, not applicable, or unknown) 
will also be recorded on the AE CRF. Recovering/resolving AEs will be followed until 
resolution or until the subject’s condition returns to the level at the baseline for pre-
existing conditions.
If the severity rating for an ongoing AE changes before the event resolves, the original 
AE report will be revised (i.e., the event will not be reported as separate AE). During the 
course of any AE, the highest severity rating will be reported.
Deviations from the protocol-specified dosage (including underdosing /overdosing
[<20 IU/kg rVWF:RCo or >100 rVWF:RCo], abuse, and withdrawal, treatment errors 
(including incorrect route of administration, use of an incorrect product, and deviations 
from the protocol-defined dosing schedule), failures of expected pharmacological actions, 
and unexpected therapeutic or clinical benefits will be followed with regard to occurrence 
of AEs, lack of efficacy, and/or other observations because these events may be 
reportable to regulatory authorities. 
Any pregnancy that occurs after administration of IP will be reported on a Pregnancy 
Form and followed-up at 1 year post-delivery, if feasible. 
If an investigator becomes aware of an SAE occurring in a subject after study 
completion, the SAE must be reported on the SAE Form within 24 hours after awareness: 
no additional reporting on CRFs is necessary.
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12.1.2.1 Severity
The investigator will assess the severity of each AE using his/her clinical expertise and 
judgment based on the most appropriate description below:

Mild
The AE is a transient discomfort and does not interfere in a significant manner 
with the subject’s normal functioning level.
The AE resolves spontaneously or may require minimal therapeutic 
intervention.

Moderate
The AE produces limited impairment of function and may require therapeutic 
intervention.
The AE produces no sequela/sequelae.

Severe
The AE results in a marked impairment of function and may lead to temporary 
inability to resume usual life pattern.
The AE produces sequela/sequelae, which require (prolonged) therapeutic 
intervention.
These severity definitions will also be used to assess the severity of an AE with a study-
related procedure(s), if necessary.
12.1.2.2 Causality
Causality is a determination of whether there is a reasonable possibility that the IP is 
etiologically related to/associated with the AE. Causality assessment includes, e.g., 
assessment of temporal relationships, dechallenge/rechallenge information, association 
(or lack of association) with underlying disease, presence (or absence) of a more likely 
cause, and physiological plausibility. For each AE, the investigator will assess the causal 
relationship between the IP and the AE using his/her clinical expertise and judgment 
according to the following most appropriate algorithm for the circumstances of the AE:

Not related (both circumstances must be met)
Is due to underlying or concurrent illness, complications, concurrent 
treatments, or effects of concurrent drugs
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Is not associated with the IP (i.e., does not follow a reasonable temporal 
relationship to the administration of IP, is not biologically plausible per 
mechanism of action of the IP, or has a much more likely alternative
etiology).

Unlikely related (either 1 or both circumstances are met)
Has little or no temporal relationship to the IP 
A more likely alternative etiology exists

Possibly related (both circumstances must be met)
Follows a reasonable temporal relationship to the administration of IP
An alternative etiology is equally or less likely compared to the potential 
relationship to the IP

Probably related (both circumstances must be met)
Follows a strong temporal relationship to the administration of IP, which may 
include but is not limited to the following: 
o
Reappearance of a similar reaction upon re-administration (positive re-
challenge)
o
Positive results in a drug sensitivity test (skin test, etc.)
o
Toxic level of the IP as evidenced by measurement of the IP 
concentrations in the blood or other bodily fluid
Another etiology is unlikely or significantly less likely
For events assessed as not related or unlikely related and occurring within 5 days after IP 
infusion, the investigator shall provide the alternative etiology. These causality 
definitions will also be used to assess the relationship of an AE with a study-related 
procedure(s), if necessary.
12.1.2.3 Safety Reporting
AEs and SAEs will be assessed at all study visits as outlined in the Schedule of Study 
Procedures and Assessments (see Section 20.2) and Section 12.1.2.
Adverse Events and SAEs are to be recorded on the AE page of the eCRF. Each event 
should be recorded separately.
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Any SAE, including death due to any cause, which occurs during this study, whether or 
not related to the IP, must be reported immediately (within 24 hours of the study center’s 
first knowledge of the event). All SAEs must be reported in English via the Electronic 
Data Capture (EDC) system by completing the relevant eCRF page(s) and also by SAE 
Report Form via fax/email to Sponsor’s Global Drug Safety (Baxalta GDS) department 
within 24 hours of becoming aware of the event for SAEs (for contacts, instructions, and
additional details, refer to the SAER form).
Within 24 hours of site awareness of a SAE (or Pregnancy) study sites will complete and 
send all SAE (or Pregnancy) reports to a dedicated:
Baxalta Global Drug Safety fax number:  
OR 
email:
The responsible Site Monitor will review the SAE (or Pregnancy) Reports for 
completeness, will reconcile the reports against the EDC database, and will follow-up 
with sites to obtain missing information and/or information requiring clarification. Any 
SAE associated with a pregnancy must be reported on the SAER Form.
For Follow-up Reports, the site shall use a new SAER form (marked as Follow-up) and 
the new information should be entered together with a brief narrative identifying the 
updated data. 
An SAER should include the following minimum information:
1.
Protocol Number (on all pages)
2.
Subject identification number (on all pages) and demographics (gender, age at 
onset of event and/or date of birth)
3.
Investigational product and treatment regimen (including date of the first dose of 
IP, date of the last dose of IP prior to the onset of the SAE)
4.
Medical Term for Event (Diagnosis preferably) 
5.
Description of the SAE, including:

Date of onset

Causal relationship assessment by the Investigator
6.
Seriousness criteria (e.g., death, life-threatening, hospitalization, medically 
significant, or other criterion)
7.
Name, address, fax number, email, and telephone number of the 
reporter/Investigator
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Post-trial SAE Reporting: In compliance to EudraLex Volume 10 (Clinical trials 
guidelines, Chapter II: Safety Reporting from the European Commission), which 
references an EMA guidance (ICH Topic E 2 A - Clinical Safety Data Management: 
Definitions and Standards for Expedited Reporting), clinical sites/the investigator should 
report to the Sponsor SAEs after a subject´s study completion. Study sites will be 
provided a Post-Trial SAER form to complete and report these post-study SAEs to the 
Sponsor within the 24 hours of their awareness. Site Monitor will instruct the site that any 
such Post-Trial SAEs should be reported on the study-specific Post-Trial SAER form 
if/when the site becomes aware of it. Such information will not be actively monitored by 
the sponsor after completion of the study.
These events shall be reported to Baxalta GDS who will process them in the same way as 
SAEs occurring during the study. Post-Trial SAEs do not need to be captured in the study 
EDC database if it is already locked. Irrespective if captured in the EDC database or not, 
such Post-Trial SAEs will become part of the GDS database. The monitor should remind 
the clinical site about the post-trial SAE reporting requirements during interim 
monitoring visits, upon each subject’s study completion as well as during the close-out 
visit.
12.2 Urgent Safety Measures
An urgent safety measure is an immediate action taken, which is not defined by the 
protocol, in order to protect subjects participating in a clinical trial from immediate harm. 
Urgent safety measures may be taken by the sponsor or clinical investigator, and may 
include any of the following: 

Immediate change in study design or study procedures

Temporary or permanent halt of the clinical trial 

Any other immediate action taken in order to protect clinical trial participants 
from immediate hazard to their health and safety
The investigator may take appropriate urgent safety measures in order to protect subjects 
against any immediate hazard to their health or safety. The measures should be taken 
immediately and may be taken without prior authorization from the sponsor. 
In the event(s) of an apparent immediate hazard to the subject, the investigator will notify 
the sponsor immediately by phone and confirm notification to the sponsor in writing as 
soon as possible, but within 1 calendar day after the change is implemented. The sponsor 
will also ensure the responsible ethics committees (ECs) and relevant competent 
authority(s) are notified of the urgent measures taken in such cases according to local 
regulations.
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12.3 Untoward Medical Occurrences
Untoward medical occurrences occurring before the first exposure to IP are not 
considered AEs (according to the definition of AE, see Section 12.1.1). However, each 
serious untoward medical occurrence experienced before the first IP exposure (i.e., from 
the time of signed informed consent up to but not including the first IP exposure) will be 
described on the SAER. These events will not be considered as SAEs and will not be 
included in the analysis of SAEs. 
12.4 Non-Medical Complaints
A non-medical complaint (NMC) is any alleged product deficiency that relates to 
identity, quality, durability, reliability, safety and performance of the product but did not 
result in an AE. NMCs include but are not limited to the following:

A failure of a product to exhibit its expected pharmacological activity and/or 
design function, e.g. reconstitution difficulty

Missing components

Damage to the product or unit carton

A mislabeled product (e.g., potential counterfeiting/tampering)

A bacteriological, chemical, or physical change or deterioration of the product 
causing it to malfunction or to present a hazard or fail to meet label claims
Any NMCs of the product will be documented on an NMC form and reported to the
sponsor within 1 business day. If requested, defective product(s) will be returned to the 
sponsor for inspection and analysis according to procedures.
12.5 Medical, Medication, and Non-Drug Therapy History
At screening, the subject’s medical history will be described for the following body 
systems including severity (defined in Section 12.1.2.1) or surgery and start and end 
dates, if known: eyes, ears, nose, and throat; respiratory; cardiovascular; gastrointestinal; 
musculoskeletal; neurological; endocrine; hematopoietic/lymphatic; dermatological; and 
genitourinary. The subject’s medical history will also include documented history of 
on-demand or pdVWF prophylaxis treatment for at least the past 12 months and a 
documented history, e.g., patient charts and prescription information, of all bleeding 
episodes within the past 12 months (up to 24 months if available).
All medications taken and non-drug therapies received in the 2 weeks prior to study entry 
and all concomitant medications and non-drug therapies during study will be recorded on 
the CRFs.
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Data on medical history, drug and non-drug therapy history of those subjects who 
transition from surgery rVWF (vonicog alfa) study will be used from the eCRF of the 
main studies, will be updated, if applicable, and transcribed into the respective eCRF of 
the prophy study. 
12.6 Physical Examinations
At screening and subsequent study visits (as described in Section 10.3), a physical 
examination will be performed on the following body systems: general appearance, head 
and neck, eyes and ears, nose and throat, chest, lungs, heart, abdomen, extremities and 
joints, lymph nodes, skin, and neurological. At screening, if an abnormal condition is 
detected, the condition will be described on the medical history CRF. At study visits, if a 
new abnormal or worsened abnormal pre-existing condition is detected, the condition will 
be described on the AE CRF. If the abnormal value was not deemed an AE because it 
was due to an error, due to a preexisting disease (described in Section 12.1.1.5), not 
clinically significant, a symptom of a new/worsened condition already recorded as an AE, 
or due to another issue that will be specified, the investigator will record the justification 
on the source record.
12.6.1 Thromboembolic Events
There is a risk of occurrence of thrombotic events, particularly in patients with known 
clinical or laboratory risk factors for thrombosis including low ADAMTS13 levels.  
Therefore, patients at risk must be monitored for early signs of thrombosis during the 
study and prophylaxis measures against thromboembolism should be instituted according 
to current recommendations and standard of care. Additional diagnostic procedures are 
required according to each institution’s standard of care which may consist of, but are not 
limited to the following:

For DVT: Magnetic Resonance Imaging (MRI), compression ultrasound or 
impedance plethysmography.

For pulmonary embolism: ECG, chest radiography, perfusion/scintiscan or MRI. 

For myocardial infarction: ECG, cardiac enzymes, echocardiography

For stroke: diffusion-weighted magnetic resonance imaging or computed 
tomography, ABCD scoring, carotid imaging 
Results of diagnostic procedures may be forwarded to the sponsor to be reviewed by an 
independent external expert panel, such as the DMC, if applicable.
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12.6.2 Anaphylaxis
The diagnosis of anaphylaxis is highly likely when any of the following 3 criteria are 
fulfilled:
1.
Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue or both (e.g, generalized urticaria, pruritus or flushing, swollen 
lips-tongue-uvula) and at least one of the following:
a. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced peak expiratory flow [PEF], hypoxemia)
b. Reduced blood pressure (BP) or associated symptoms of end-organ 
dysfunction (e.g., hypotonia [collapse], syncope, incontinence)
2.
Two or more of the following that occur rapidly after exposure to a likely allergen 
for that patient (minutes to several hours):
a. Involvement of the skin or mucosal tissue (e.g., generalized urticaria, pruritus 
or flushing, swollen lips-tongue-uvula)
b. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced PEF, hypoxemia)
c. Reduced BP or associated symptoms (hypotonia [collapse], syncope, 
incontinence)
d. Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)
3.
Reduced BP after exposure to a known allergen for that patient (minutes to 
several hours):
a. Infants and children: low systolic BP (age specific) or greater than 30% 
decrease in systolic BP
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from 
that person’s baseline BP
If a subject develops anaphylaxis in the course of the clinical study, this needs to be 
reported as SAE (Section 12.1.1.1). Additional blood will be drawn for Anti-VWF IgE 
antibody testing (Section 12.9.13).
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12.7 Vital Signs
Vital signs will be assessed pre- and post-infusion at each visit, if not stated otherwise:

Height (cm) (Screening only) and weight (kg) (pre-infusion only)

Blood pressure: Systolic/diastolic blood pressure (mmHg) baseline measurements 
will be measured after a 10-minute rest in the supine/semi-recumbent position.

Pulse rate: Pulse rate (beats/min) will be measured at the distal radial arteries 
under the same conditions as above.

Respiratory rate: Respiratory rate (breaths/min) will be measured over a period of 
1 minute under the same conditions as above.

Temperature: Body temperature (oC or oF) may be determined by oral, rectal, 
axillary, or tympanic measurement at the discretion of the investigator. However, 
the same method should be used for all measurements in 1 subject.
Vital signs (pulse rate, respiratory rate, and blood pressure) should be recorded within 
30 min before and after IP administration. The assessment of vital signs per planned 
study visit is outlined in Supplement 20.2.
Vital sign values are to be recorded on the physical examination eCRF. For each vital 
sign value, the investigator will determine whether the value is considered an AE (see 
definition in Section 12.1). If assessed as an AE, the medical diagnosis (preferably), 
symptom, or sign, will be recorded on the AE eCRF. Additional tests and other
evaluations required to establish the significance or etiology of an abnormal result, or to 
monitor the course of an AE, should be obtained when clinically indicated. Any abnormal 
value that persists should be followed at the discretion of the investigator.
12.8 Electrocardiogram
A standard 12-lead ECG at rest will be performed at screening, at the 6 month follow-up 
visit and at the study termination visit and evaluated for medical significance by the 
investigator.
12.9 Clinical Laboratory Parameters
Refer to the Laboratory Manual for information on collection and processing of samples.
In general all laboratory tests will be performed at central laboratories, except the 
pregnancy and blood group test which will be performed at the local laboratory.
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In addition, relevant critical safety laboratory tests for complete blood count (CBC), 
serum chemistry and/or coagulation parameters such as VWF and FVIII activity may also 
be performed in the local laboratory to ensure that results will be available immediately 
to the investigator. In principle, results from the central laboratory will be used for data 
analysis purposes. The assays performed in the central laboratories are specified in the 
Laboratory Manual. The investigator will supply the sponsor with a list of the normal 
ranges and units of measurement for the laboratory variables to be determined at the site. 
Laboratory values such as antibodies to other proteins are not required immediately and 
will be assessed later during the course of the study. 
Any abnormal laboratory value that is considered clinically significant by the investigator 
based on a local laboratory test result (reference range and the units to be provided) 
should be confirmed by a central laboratory test result for which the sample is 
drawn/collected within 24 hours of the abnormal finding by the local laboratory.
12.9.1 rVWF Pharmacokinetics and Pharmacodynamics
Details on pharmacokinetic and pharmacodynamics assessments are provided in 
Section 11.6.
12.9.2 Hematology and Clinical Chemistry
The hematology panel will consist of CBC [hemoglobin, hematocrit, erythrocytes (ie, red 
blood cell count [RBC]; mean corpuscular volume [MCV], mean corpuscular 
hemoglobin (MCH), mean corpuscular hemoglobin concentration [MCHC]), and 
leukocytes (i.e., white blood cell count [WBC])] with differential (i.e., basophils, 
eosinophils, lymphocytes, monocytes, neutrophils) and platelet counts.
The clinical chemistry panel will consist of sodium (Na), potassium (K), chloride (Cl), 
ALT, lactate dehydrogenase (LDH), aspartate aminotransferase (AST), bilirubin, alkaline 
phosphatase (AP), blood urea nitrogen (BUN), CR, and glucose (Glu).
Blood will be obtained for assessment of hematology and clinical chemistry parameters 
at screening, during PK-assessment prior to rVWF (vonicog alfa) IP infusion, after 
24 ± 2 hours, 48 ± 2 hours and 72 ± 2 hours post rVWF (vonicog alfa) IP infusion, at all 
follow-up visits as per schedule (refer to Supplement 20.3 Clinical Laboratory 
Assessments), i.e., 4 weeks ± 1 week, 8 weeks ± 1 week and every 3 months ± 2 weeks, 
and at study completion. Hematology and clinical chemistry assessments will be 
performed on Ethylenediaminetetraacetic acid (EDTA)-anticoagulated whole blood and 
serum, respectively, at the central laboratory.
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12.9.3 Immunology
12.9.3.1 Antibodies to VWF and FVIII
All subjects will be tested for binding and neutralizing antibodies to VWF and FVIII at 
screening, at initial PK assessment, at each of the scheduled follow-up visits and at the 
study completion visit. Testing will be done prior to IP infusion and with at least a 
72 hour wash out period since the last IP infusion. If there is any suspicion of inhibitor 
development (e.g. excessive bleeding) binding and neutralizing antibodies to VWF and 
FVIII may be tested at the discretion of the investigator. 
12.9.3.2 Neutralizing and Total Binding Anti-VWF Antibodies
The assays to establish the presence of neutralizing and total binding anti-VWF 
antibodies have been established in the absence of international standards and with only 
limited numbers of positive controls. Therefore, caution is advised in interpreting positive 
results. In particular, any clinical association, changes in the natural history of the 
disease, effect of therapy, etc. needs to be taken into account for final judgment. 
The sponsor’s Medical Director should be consulted for additional advice. As part of the 
AE follow-up, any sample testing positive needs to be confirmed after 2-4 weeks for 
central laboratory testing. Only confirmed neutralizing anti -VWF antibodies are 
considered inhibitors (see Section 12.9.3.4). These subjects need to be closely monitored 
and therapy adjusted accordingly.
12.9.3.3 Binding antibodies to VWF 
The presence of total binding anti-VWF antibodies will be determined by an enzyme-
linked immunosorbent assay (ELISA) employing polyclonal anti-human Immunoglobulin
(Ig) antibodies (IgG, IgM and IgA). For this assay (ELISA), recombinant human VWF 
will be coated onto a microtiter plate, then incubated with dilutions of the positive 
control, the negative control or test sample. Antibodies against human VWF that are 
present in the samples bind to the coated antigen and will be detected with a horseradish 
peroxidase (HRP)-coupled goat anti-human antibody (secondary antibody). The positive 
control for this assay will be a human monoclonal antibody specific for human VWF 
spiked into the negative control. The negative control for this assay is pooled normal 
human plasma.
Plasma samples are analyzed for binding antibodies against the specific antigen in two 
steps. First, the sample is screened for antibodies and the titer of binding antibodies is 
determined. Second, the specificity of positive antibody results is confirmed.16
In brief, all samples are serially diluted (initial dilution 1:20 and further diluted 1:2).
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The titer endpoint, defined as the highest dilution that still gives a positive signal above 
cut off level, is determined in two independent duplicates. The cut off level is established 
based on background signal level of healthy plasma donors (n=160) and set to include 5% 
false positives to be as sensitive as possible (95% percentile). The ELISA assay is 
validated allowing an assay variability of ± 1 titer step. Therefore, differences ≤ 2 titers 
steps may be due to variability of the ELISA assay. Specificity has to be confirmed in a 
competition assay when a sample has a titer of 1:80 or higher in the screening assay. 
Based on the validation criteria samples tested in the screening assay at 1:20 or 1:40 
cannot be confirmed in the competition assay. A positive screening value is confirmed if 
the difference between the titers determined for the subject sample (re-screen) and for the 
subject sample with pre-incubation (confirmation sample) is > 2 titer steps. Antibody 
titers of subject samples will only be reported as positive, if the results of the screening 
and confirmatory analysis fulfill these acceptance criteria. The titer to be reported is 
always the one determined in the original screening procedure (independent of the result 
of the re-screening in the confirmation procedure). 
A more detailed test procedure will be supplied upon request or pro-actively if a sample 
tests positive. A treatment related increase of the binding anti-VWF antibodies is 
expected, if the titer increases by more than 2 titration steps. These subjects need to be 
closely monitored and therapy adjusted accordingly.
12.9.3.4 Neutralizing Antibodies to VWF
Three functional VWF assays, VWF:CB, VWF:RCo and VWF:FVIIIB assays, will be 
used to test for the presence of neutralizing anti-VWF antibodies. Neutralizing antibodies 
to VWF:RCo, VWF:CB and VWF:FVIIIB activities will be measured by assays based on 
the Bethesda assay established for quantitative analysis of FVIII inhibitors (Nijmegen 
modification of the Bethesda assay).17 The amount of inhibitor is expressed as BU per 
mL. One BU is thereby defined as the amount of inhibitor that decreases the measured 
activity in the assays to 50% of that of the negative control samples. The assays were 
validated using human plasma samples from two type 3 VWD patients with low 
(1-2 BU/mL) and high (~10 BU/mL) titer inhibitors and plasma samples from 
non-human primates immunized with human rVWF (vonicog alfa) (>100 BU/mL).
If a subject has a measurable baseline level of VWF activity in the respective assay, it is 
taken into account in the calculation of the residual activity. However, if baseline levels 
are too high (>15% VWF:RCo), inhibitors may not be reliably detected.
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To exclude false positive results, the detection limit for anti-VWF inhibitors was set to 
1 BU/ml for all 3 assays. The rationale for this cut-off value is the relatively high CI of 
the underlying assays, making determinations at the end of the evaluation range of the 
Bethesda reference curve uncertain.18 A more detailed test procedure may be requested to 
further characterize the anti-VWF inhibitors, if detected.
Only confirmed positive anti-VWF inhibitor test result will be reported and will be
considered as a medically significant SAE.
12.9.3.5 Binding Antibodies to FVIII
Binding antibodies against FVIII will be analyzed using a proprietary enzyme 
immunoassay. The testing strategy will be as described for binding anti-VWF antibodies. 
Antibody-containing samples will be identified in a screening assay followed by a 
confirmatory assay to exclude false positive results.
12.9.3.6 Neutralizing Antibodies (Inhibitors) to FVIII 
Neutralizing antibodies (inhibitors) to FVIII will be assessed by the Nijmegen 
modification of the Bethesda assay in a central laboratory. To verify a FVIII inhibitor, 
additional testing (such as tests for Lupus anticoagulants) may be initiated. Positive FVIII 
inhibitor tests will be defined as ≥0.4 BU by the Nijmegen-modified Bethesda assay that 
is confirmed by a second test performed on an independent sample obtained 2-4 weeks 
following the first test. Only confirmed positive FVIII inhibitor test result will be 
reported.
12.9.4 Antibodies to Other Proteins
Plasma will be assayed for the presence of antibodies against CHO protein (total Ig), 
murine IgG and human Furin (total Ig) using proprietary enzyme immunoassays. The 
testing strategy will be as described for binding anti- VWF antibodies. 
Antibody-containing samples will be identified in a screening assay followed by a 
confirmatory assay to exclude false positive results.
12.9.4.1 Anti-CHO Protein
Total Ig antibodies (IgG, IgA, IgM) against CHO protein will be analyzed. For this 
assay (ELISA), CHO protein derived from cultures of untransfected cells and 
propagated under the identical cell culture conditions used for ADVATE (rFVIII, 
octocog alfa) production will be coated onto a microtiter plate, then incubated with 
dilutions of the positive control, negative control or test sample. Antibodies against 
CHO protein that are present in the samples bind to the coated antigen and will be 
detected with a HRP-coupled goat anti-human antibody (secondary antibody). 
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The positive control for this assay will be a polyclonal goat anti-CHO protein antibody 
spiked into the negative control. The negative control for this assay is pooled normal 
human plasma.
12.9.4.2 Anti-Murine IgG
A commercially available ELISA (Medac, Hamburg, Germany) will be used to detect and 
to quantify IgG antibodies originating from human plasma that are directed against 
mouse-IgG (HAMA: human anti- mouse antibodies). Microtiter plates coated with 
mouse IgG will be incubated with dilutions of the standard, the positive control, the 
negative control or the test sample. Antibodies against mouse IgG that are present in 
the samples bind to the coated antigen and form a bridge to a peroxidase coupled mouse 
IgG antibody that will be used for detection (bridging format of the ELISA assay). 
The positive control for this assay will be a polyclonal goat anti-murine IgG spiked into 
the negative control. The negative control for this assay is pooled normal human plasma.
12.9.4.3 Antibodies to Human Furin
Total Ig antibodies (IgG, IgA, IgM) against human Furin will be analyzed. For this assay 
(ELISA), recombinant human Furin will be coated onto a microtiter plate, then incubated 
with dilutions of the positive control, the negative control or test sample. Antibodies 
against human Furin that are present in the samples bind to the coated antigen and will be 
detected with a HRP-coupled goat anti-human antibody (secondary antibody). The 
positive control for this assay will be a human monoclonal antibody specific for human 
Furin spiked into the negative control. The negative control for this assay is pooled 
normal human plasma.
12.9.5 Viral Serology
The following viral seromarkers will be assessed at screening:

HIV: anti-HIV 1, HIV 2 

HAV: anti-HAV (IgG and immunoglobulin M [IgM])

HBV: Hepatitis B surface antigen (HbsAg), anti-Hepatitis B (HB) core, anti-HBs

HCV: anti-HCV ELISA

Parvovirus B19: anti-B19V (IgG and IgM)
Virus serology will be established during the screening period. The relevant confirmatory 
Polymerase Chain Reaction (PCR) testing may be performed from appropriate left-over 
samples as needed.
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12.9.6 Urinalysis (Dipstick)
The urinalysis will include assessments for erythrocytes, specific gravity, urobilinogen, 
ketones, glucose, protein, bilirubin, nitrite and pH and will be performed at the central 
laboratory.
12.9.7 Pregnancy Test
A pregnancy test for females of child-bearing potential will be performed at the local 
laboratory primarily from urine. If no urine sample is available, the pregnancy testing 
will be done from serum. The pregnancy test may need to be repeated during the course 
of study in countries where mandated by national law.
12.9.8 VWD Mutational Analysis, Multimer Analysis and Human Leukocyte 
Antigen Genotyping 
A cell pellet (buffy coat and erythrocytes) will be retained at the screening visit for VWD 
gene mutational analysis, VWF multimer analysis and HLA genotype determination if 
the information is not already available in the subject’s medical history. Results from 
multimer analysis (see Section 12.9.10.1) may contribute to VWD gene mutational 
analysis. The genetic testing will be done, when the subject consents to the genetic 
testing.
12.9.9 Blood Group Analysis
The blood group needs to be determined during the screening period. If the information is 
not already available in the subject’s medical history, it has to be determined at the local 
lab.
12.9.10 Additional Laboratory Testing in Case of Thromboembolic Events
rVWF (vonicog alfa) contains ULMW multimers because of a lack of exposure to 
endogenous VWF protease (a disintegrin and metalloproteinase with a thrombospondin 
type 1 motif, member 13 (ADAMTS13) during the manufacturing process. In vitro and in 
vivo cleavage of these ultralarge molecular fractions by ADAMTS13 and generation of 
characteristic satellite bands has been extensively demonstrated during nonclinical and 
clinical development. Nevertheless, the potential elevated risk of thrombosis and/or other 
thromboembolic complications due to the administration of ultra large molecular VWF 
multimers in subjects with normal levels of VWF cannot be completely excluded. 
Therefore VWF multimer analysis will not only be performed routinely at screening but 
in case of thromboembolic events, both VWF multimer analysis as well as ADAMTS13 
activity will be determined to assess any relatedness of these occurrences with IP 
treatment.
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12.9.10.1 VWF Multimer Analysis 
The VWF multimer pattern will be assessed using low-resolution sodium dodecyl sulfate 
(SDS)–agarose gel electrophoresis. High-resolution SDS–agarose gel electrophoresis, 
with agarose concentrations 1.5%, will be used to determine the satellite band structure 
of VWF. These analyses will employ Western blot with luminescence video imaging.
12.9.10.2 ADAMTS13 Activity 
VWF73 was identified as the 73 amino acid minimal region of the VWF A2 domain 
required for ADAMTS13 cleavage. The cleavage of this substrate will be detected by a 
commercially available ELISA-based Chromogenic assay (Technoclone Austria):
Cleavage of immobilized VWF73 substrate is detected by a HRP-labeled antibody 
directed against the cleavage site of VWF73. The amount of bound antibody, which is the 
function of the ADAMTS13 cleavage is detected by a chromogenic substrate.
12.9.11 Soluble P-Selectin (sP-Selectin)
sP-selectin is a cell adhesion molecule (CAM) found in granules in endothelial cells 
(cells lining blood vessels) and activated platelets. Data for an association between the 
sP-selectin concentration, TTP and venous thromboembolism (VTE) are limited and the 
predictive value has not yet established. A commercial ELISA assay will be employed as 
an exploratory test. sP-selectin will be determined at the Screening visit and used as 
indicator for an increased thrombotic risk.
12.9.12 D-Dimer
D-dimer will be used as a marker for DVT and disseminated intravascular coagulation
(DIC). While a negative result practically rules out thrombosis, a positive result can 
indicate thrombosis but does not rule out other potential etiologies, including a recent 
hemorrhage. Its main use, therefore, is to exclude thromboembolic disease where the 
probability is low. D-Dimer will be measured at the Screening visit and used as indicator 
for an increased thrombotic risk.
12.9.13 Additional Laboratory Testing in Case of Severe Hypersensitivity Reactions
If a subject develops a severe hypersensitivity reaction in the course of the clinical 
study, additional blood will be drawn for anti-VWF IgE antibody testing. The presence of 
anti-VWF IgE will be determined by using the ImmunoCAP®, a VWF-specific IgE 
blood test (Thermo Scientific). The basis of the ImmunoCAP® technology is a cellulose 
polymer as solid phase in a plastic capsule providing a large surface for protein binding. 
rVWF (vonicog alfa) as antigen is covalently coupled to the cellulose polymer.
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Detection of specific anti-VWF IgE bound to the antigen will be accomplished by a 
secondary enzyme-labeled anti-human IgE antibody. Testing for binding anti-human 
VWF IgE antibodies will be done with 0.5 mL plasma. Antibody containing samples will 
be identified and quantified in a screening assay followed by a confirmatory assay to 
exclude false positive results.
12.9.14 Assessment of Laboratory Values
12.9.14.1 Assessment of Abnormal Laboratory Values 
For VWF and FVIII laboratory assessments no evaluation of clinical significance is 
necessary.
Each other laboratory value (except results to determine genetics of the underlying VWD 
disease and blood group) has to be assessed by the investigator and the assessment will
be recorded on the eCRF. The investigator will determine for each abnormal laboratory 
value whether the value is considered clinically significant or not and provide the 
reference range including the units. For clinically significant values, the investigator will 
indicate if the value constitutes a new AE (see definition in Section 12.1) and record the 
sign, symptom, or medical diagnosis on the AE CRF, is a symptom or related to a 
previously recorded AE, is due to a pre-existing disease (described in Section 12.1.1.5), 
or is due to another issue that will be specified. If the abnormal value was not clinically 
significant, the investigator will indicate the reason, i.e. because it is due to a preexisting 
disease, due to a lab error, due to variation or due to another issue that will be specified. 
Additional tests and other evaluations required to establish the significance or etiology of 
an abnormal value, or to monitor the course of an AE should be obtained when clinically 
indicated. Any abnormal value that persists should be followed at the discretion of the 
investigator. Any abnormal laboratory value that is considered clinically significant by 
the investigator based on a local laboratory test result (reference range and the units to be 
provided) should be confirmed by a central laboratory test result for which the sample is 
drawn/collected within 24 hours of the abnormal finding by the local laboratory.
Any seroconversion result for HIV, HAV, hepatitis B virus (HBV), HCV, HEV, or B19V
shall be re-tested.
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12.10
12.10.1
 
 
 
 
 
 
 
 
 
 
 
12.10.2
 
 
 
 
 
 
 
 
 
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13. STATISTICS
13.1 Sample Size and Power Calculations
Approximately 22 adult subjects with severe VWD (baseline VWF:RCo <20 IU/dL) will 
be included in the study. The aim is to have at least 8 subjects in each cohort (OD and 
switch). A total of at least 5 type 3 VWD subjects will be followed for 12 months. The 
sample size is driven by practical considerations (primarily the enrollment of a rare 
patient population) and EMA Guideline on the Clinical Investigation of Human Plasma 
Derived von Willebrand Factor Products (CPMP/BPWG/220/02).1
13.2 Datasets and Analysis Cohorts
13.2.1 Safety Analysis Set
The Safety Analysis Set will be composed of all subjects who received any amount of IP 
(rVWF, vonicog alpha). 
13.2.2 Full Analysis Dataset
The Full Analysis Set (FAS) will be composed of all subjects who receive prophylaxis IP 
treatment.
13.2.3 Per-Protocol Analysis Set
The Per-Protocol (PP) Analysis Set will be composed of subjects who are at least 70% 
compliant regarding the number of scheduled prophylactic infusions (as measured by the 
ratio of actual number of infusions to planned number of infusions). Only subjects who 
met all study entry criteria and who had no major protocol violations that might impact 
primary efficacy assessments will be included in the PP analysis set.
13.2.4 PK Full Analysis Set
The Pharmacokinetic Full Analysis Set (PKFAS) will be composed of all subjects who 
received the PK infusion and who provided acceptable data for PK and PD analysis. 
Acceptable PK/PD data will be defined in the Statistical Analysis Plan. 
13.2.5 PK Per Protocol Analysis Set 
The Pharmacokinetic Per Protocol Analysis Set (PKPPAS) is defined as a subset of the 
PKFAS. Subjects who met the following additional criteria will be included in the 
PKPPAS: had no major violation of affecting the PK period of the study as defined in the
detailed Statistical Analysis Plan.
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13.3 Handling of Missing, Unused, and Spurious Data
13.3.1 General
Statistical techniques will not be used to identify and exclude any observations as outliers 
from the analyses. If data are considered spurious, e.g. for lack of biological plausibility, 
it will be documented to include the reason for exclusion and the analyses from which the 
data were excluded.
13.3.2 Other
1.
Regarding missing data in PK records:

Body weight: If a subject’s weight is missing from the PK infusion record, the 
subject’s last recorded weight will be used to calculate the weight-adjusted 
dose.

Concentration:

Baseline concentration levels reported as below the limit of quantification 
will be considered to be 0. Missing VWF baseline concentration levels 
(VWF: RCo, VWF: AG or VWF: CB) for Type 3 subjects will be set to 0.

Time:

If start time of infusion is missing (but stop time is available) and actual 
collection time is available, then stop time of infusion will be taken for 
further calculation (i.e. time difference between actual end date/time of 
infusion and date/time blood sample drawn).

If actual collection date/time is missing and planned collection date/time is 
missing, then this PK time point will be taken out from the PK analysis 
(i.e. no data entry for this time point). 

For all other scenarios, the planned collection date/time will be taken for 
further calculation.
2.
Regarding missing data in AE records:

Handling of unknown causality assessment:

If a subject experiences an AE with a missing causality assessment, the 
relationship of the AE will be counted as “related.”
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
Handling of unknown severity grades:

If a subject experiences more than one AE categorized under the same 
preferred term, one of them is categorized as “severe” and one of them is 
categorized as “unknown”, then the maximum severity for this preferred 
term should be counted as “severe” for this subject.

If a subject experiences more than one AE categorized under the same 
preferred term, one of them is categorized as “mild” or “moderate” and 
one of them is categorized as “unknown”, then the maximum severity for 
this preferred term should be counted as “unknown” for this subject.
13.4 Methods of Analysis
The study success criteria are the objectives as stated in Section 7. “Treatment success” 
was defined as the extent of control of bleeding episodes achieved during this study.
13.4.1 Primary Outcome Measure
The primary outcome measure is ABR for spontaneous (not related to trauma) bleeding 
episodes during prophylactic treatment with rVWF (vonicog alfa). No formal statistical 
hypothesis test is planned for the analysis. The primary efficacy analysis will be based on 
the FAS and will be summarized by the two cohorts: on-demand and switch subjects. As 
a supportive analysis, the same analysis will also be carried out on the PP analysis set.
The spontaneous ABR while treated with rVWF (vonicog alfa) for each cohort will be 
estimated using a negative binomial regression. The prior ABR will be based on 
historical data collected from each enrolled subject. 
The two ABRs (prior to prophylaxis treatment and while on prophylaxis) for each cohort 
will be compared within each subject using a generalized linear mixed-effects model 
(GLMM) (with a logarithmic link function, the default for the negative binomial 
distribution), accounting for the fixed effect of the two treatments. The follow-up time 
(in years) will be specified as an offset. The ratio of ABR while in the study to historical
ABR will be estimated and reported together with the 95% confidence interval for each 
of the two cohorts.
The difference in on-study ABR relative to historical ABR will be also summarized 
descriptively.
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13.4.2 Secondary Outcome Measures 
In general, data for  secondary efficacy analysis will be summarized by the two cohorts: 
on-demand and switch subjects and when applicable overall.  Mean, standard deviation, 
median, range, quartiles will be calculated for continuous endpoints.  Proportions, will be 
calculated for categorical endpoints. Confidence intervals at the two-sided 95% level will 
be provided when appropriate.
13.4.2.1 Additional Efficacy of Prophylaxis Treatment with rVWF
The number  and proportion of on-demand subjects with ABR percent reduction success 
(i.e.≥ 25%) will be calculated together with a two-sided, 95% CI for the proportion.
The number and proportion of pdVWF switch subjects ABR preservation success will be 
reported together with the corresponding 95% two-sided CIs for the proportion.
The number and proportion of subjects with categorized spontaneous ABR 
(i.e. 0, 1-2, 3-5, more than 5 bleeds) will be reported descriptively.
Summary statistics for the total number of infusions, as well as average number of 
infusions per week will be provided. The total weight adjusted consumption of rVWF 
(vonicog alfa) during prophylactic treatment will be provided. If applicable, historical 
data on consumption of pdVWF prior to the study will be summarized as well.
The change in spontaneous ABR from the historical rate to that during the rVWF 
(vonicog alfa) prophylaxis period will be summarized by location of bleeding 
(GI, epistaxis, joint bleeding, menorrhagia, oral and other mucosa, muscle and soft 
tissue, etc.).
13.4.2.2 Pharmacokinetic and Pharmacodynamic Analysis
All PK and PD analyses will use the actual sampling times, not nominal times specified 
in the protocol, wherever possible. Actual sampling times will be defined as time from 
the start of infusion to the blood sample collection time. A deviation from the protocol-
specified blood sample drawing time window will not be a reason to exclude an 
observation from the analysis. Samples with unknown actual and planned collection 
date/time or where the concentration could not be determined, or where results were 
biologically implausible will be eliminated from the analysis.
If any concentration data are considered spurious (e.g. lack of biological plausibility), the 
reason for exclusion from the analysis and the analysis from which the data point was 
excluded will be documented.
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Details of calculation of PK and PD parameters and corresponding analysis will be given 
in the statistical analysis plan. 
The following PK parameters, based on the initial PK assessment after a washout for on-
demand subjects, will be listed and summarized descriptively for VWF:RCo, VWF:Ag 
and VWF:CB: IR, T1/2, MRT, AUC0-, AUC0-tlast, Cmax, Tmax, Vss, and CL. The 
corresponding pharmacodynamics (PD) of rVWF (vonicog alfa) as measured in FVIII 
activity, based on the initial PK assessment after a washout for on-demand subjects will 
be assessed using Cmax, Tmax, and AUC0-tlast. These PD parameters will be listed and 
summarized descriptively. PK parameters at steady state (AUC0-tau;ss, Cmax;ss, Tmax;ss, and 
Cmin;ss) for the partial dosing interval will be listed for on-demand subjects at the end of 
the study and for switch subjects shortly after reaching steady state and at the end of the 
study for VWF:RCo, VWF:Ag and VWF:CB and summarized descriptively for subjects 
with the same dosing regimens. The corresponding pharmacodynamics (PD) of rVWF 
(vonicog alfa) as measured in FVIII activity will be assessed using AUC0-tau;ss, Cmax;ss, 
Tmax;ss, and Cmin;ss. These PD parameters will be listed for on-demand subjects at the end 
of the study and for switch subjects shortly after reaching steady state and at the end of 
the study and will be summarized descriptively for subjects with the same dosing 
regimens.
For the on-demand subjects, the PK of VWF:RCo will be analyzed using a population PK 
approach to characterize the single and multiple dose pharmacokinetics, including 
associated variability assessed at after washout and at end of study, respectively. The 
population PK analysis will be performed in a stepwise manner as outlined below.
1.
Exploratory graphical analysis of VWF:RCo versus time data for identification of 
potential outliers and to inform the pharmacometric analysis.
2.
Population PK model development for rVWF (vonicog alfa):
a.
Evaluate alternative structural and stochastic models to describe the typical 
and individual rVWF (vonicog alfa) profiles.
b.
Investigate and characterize the potential for a time dependency in CL of 
rVWF (vonicog alfa). 
c.
Evaluate, and if necessary refine, the candidate final model
Details of this Population PK analysis will be given in a separate Population PK analysis 
plan.
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For the switch subjects, differences in AUC0-tau;ss, Cmax;ss, and Cmin;ss assessess shortly 
after reaching steady state and assessed at the end of the study will be assessed by the 
ratio of geometric means and corresponding two-sided 95% confidence intervals for 
VWF:RCo, VWF:Ag,VWF:CB, and FVIII:C. These analyses will be performed using a 
linear mixed effects model with PK assessment (i.e. factor of two levels relating to the 
PK assessment shortly after reaching steady state and the PK assessment at end of study, 
respectively) as a fixed effect and subject as a random effect based on log-transformed 
PK parameters. The difference in Tmax;ss, between first and second pharmacokinetic 
assessment will be summarized by the median and range (minimum to maximum) for 
VWF:RCo, VWF:Ag,VWF:CB, and FVIII:C.
Descriptive statistics will be used to summarize VWF:RCo, VWF:AG and VWF:CB and 
FVIII:C levels for each nominal time point on the PK curve.
For all subjects in the PKFAS activity/concentration vs. time curves will be prepared.
Formulas for PK parameters IR, T1/2, MRT, AUC0-, AUC0-tlast, Cmax, Tmax, Vss, and CL, 
AUC0-tau;ss, Cmax;ss, Tmax;ss ,and Cmin;ss will be given in the statistical analysis plan and will 
be derived using non-compartmental methods in WinNonlin. Analysis of these 
parameters will be carried out on the PKFAS as well as on the PKPPAS.
13.4.2.3 Safety
Safety analysis will be performed overall and by the two cohorts: on-demand and switch 
subjects.
TEAEs are defined as AEs with start dates on or after the first exposure to IP. Summaries 
of AEs will be based on TEAEs unless otherwise indicated.
Occurrence of AEs and SAEs will be summarized descriptively, by system organ class 
and preferred term. The number and percentage of subjects who experienced AEs and 
SAEs, and the number of AEs and SAEs will be tabulated. In addition, the number of 
subjects who experienced AEs assessed as related to IP by the investigator, and the 
number of IP-related AEs will be tabulated. The number of patients with AEs by severity 
will be presented similarly.
A listing of all AEs will be presented by subject identifier, age, sex, preferred term and 
reported term of the AE, duration, severity, seriousness, action taken, outcome, causality 
assessment by investigator, onset date, stop date and medication or non-drug therapy to 
treat the AE.
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Temporally associated AEs are defined as AEs that begin during infusion or within 
24 hours (or 1 day where time of onset is not available) after completion of infusion, 
irrespective of being related or not related to treatment. Temporally associated AEs will 
be presented in summary tables. 
AEs that occurred before first IP infusion will be listed separately.
Adverse events of special interest (AESI), such as hypersensitivity reactions and 
thromboembolic events,  will be monitored throughout the study and statistical analysis 
will be conducted based on the search criteria (eg, standardised MedDRA queries 
[SMQ]) determined prior to database lock, and summarized.
For immunogenicity, frequency counts and percentages will be calculated for the 
occurrence of neutralizing (inhibitory) antibodies to VWF and FVIII, occurrence of 
binding antibodies to VWF and FVIII, and occurrence of binding antibodies to CHO 
proteins, mouse immunoglobulin G (IgG) and rFurin. Clinically significant changes 
relative to baseline in vital signs and clinical laboratory parameters (hematology, clinical 
chemistry) will be reported.
13.4.3 Exploratory Outcome Measures
 
13.4.3.1
 
 
 
 
13.4.3.2
 
 
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13.4.3.3
 
 
 
13.4.3.4
 
 
 
 
 
13.5 Planned Interim Analysis of the Study
No formal interim analysis is planned for this study. 
14. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
The investigator/study site will cooperate and provide direct access to study documents 
and data, including source documentation for monitoring by the study monitor, audits by 
the sponsor or sponsor’s representatives, review by the EC, and inspections by applicable 
regulatory authorities, as described in the Clinical Trial Agreement (CTA). If contacted 
by an applicable regulatory authority, the investigator will notify the sponsor of contact, 
cooperate with the authority, provide the sponsor with copies of all documents received 
from the authority, and allow the sponsor to comment on any responses, as described in 
the CTA.
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15. QUALITY CONTROL AND QUALITY ASSURANCE
15.1 Investigator’s Responsibility
The investigator will comply with the protocol (which has been approved/given favorable 
opinion by the EC), ICH GCP, and applicable national and local regulatory requirements 
as described in the CTA. The investigator is ultimately responsible for the conduct of all 
aspects of the study at the study site and verifies by signature the integrity of all data 
transmitted to the sponsor. The term “investigator” as used in this protocol as well as in 
other study documents, refers to the investigator or authorized study personnel that the 
investigator has designated to perform certain duties. Sub-investigators or other 
authorized study personnel are eligible to sign for the investigator, except where the 
investigator’s signature is specifically required.
15.1.1 Investigator Report and Final Clinical Study Report 
The investigator, or coordinating investigator(s) for multicenter studies, will sign the 
clinical study report. The coordinating investigator will be selected before study start. 
15.2 Training
The study monitor will ensure that the investigator and study site personnel understand 
all requirements of the protocol, the investigational status of the IP, and his/her regulatory 
responsibilities as an investigator. Training may be provided at an investigator’s meeting, 
at the study site, and/or by instruction manuals. In addition, the study monitor will be 
available for consultation with the investigator and will serve as the liaison between the 
study site and the sponsor.
15.3 Monitoring
The study monitor is responsible for ensuring and verifying that each study site conducts 
the study according to the protocol, standard operating procedures other written 
instructions/agreements, ICH GCP, and applicable national and local regulatory 
guidelines/requirements. The investigator will permit the study monitor to visit the study 
site at appropriate intervals, as described in the CTA. Monitoring processes specific to 
the study will be described in the clinical monitoring plan. 
15.4 Auditing
The sponsor and/or sponsor’s representatives may conduct audits to evaluate study 
conduct and compliance with the protocol, standard operating procedures, other written 
instructions/agreements, ICH GCP, and applicable national and local regulatory 
guidelines/requirements. The investigator will permit auditors to visit the study site, as 
described in the CTA. Auditing processes specific to the study will be described in the 
audit plan.
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15.5 Non-Compliance with the Protocol
The investigator may deviate from the protocol only to eliminate an apparent immediate 
hazard to the subject. In the event(s) of an apparent immediate hazard to the subject, the 
investigator will notify the sponsor immediately by phone and confirm notification to the 
sponsor in writing as soon as possible, but within 1 calendar day after the change is 
implemented. Also, the investigator will notify the sponsor immediately by phone and 
confirm notification to the sponsor in writing whenever pdVWF is used instead of rVWF 
(vonicog alfa). The reason for this use must also be provided to the sponsor. The sponsor 
(Baxalta) will also ensure the responsible EC and relevant competent authority are 
notified of the urgent measures taken in such cases according to local regulations.
If monitoring and/or auditing identify serious and/or persistent non-compliance with the 
protocol, the sponsor may terminate the investigator’s participation. The sponsor will 
notify the EC and applicable regulatory authorities of any investigator termination.
15.6 Laboratory and Reader Standardization
A central laboratory/reader will be used for all clinical assessments except for pregnancy
testing and blood group test (refer to Section 12.9). Local laboratories are requested to 
provide their laboratory specifications of the individual tests that are also being tested 
locally.
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16. ETHICS
16.1 Subject Privacy
The investigator will comply with applicable subject privacy regulations/guidance as 
described in the CTA.
16.2 Ethics Committee and Regulatory Authorities
Before enrollment of patients into this study, the protocol, informed consent form, any 
promotional material/advertisements, and any other written information to be provided 
will be reviewed and approved/given favorable opinion by the EC and applicable 
regulatory authorities. The IB will be provided for review. The EC’s composition or a 
statement that the EC’s composition meets applicable regulatory criteria will be 
documented. The study will commence only upon the sponsor’s receipt of 
approval/favorable opinion from the EC and, if required, upon the sponsor’s notification 
of applicable regulatory authority(ies) approval, as described in the CTA.
If the protocol or any other information given to the subject is amended, the revised 
documents will be reviewed and approved/given favorable opinion by the EC and 
applicable regulatory authorities, where applicable. The protocol amendment will only be 
implemented upon the sponsor’s receipt of approval and, if required, upon the sponsor’s 
notification of applicable regulatory authority(ies) approval.
16.3 Informed Consent
Investigators will choose patients for enrollment considering the study eligibility criteria. 
The investigator will exercise no selectivity so that no bias is introduced from this source.
All patients and/or their legally authorized representative must sign an informed consent 
form before entering into the study according to applicable national and local regulatory 
requirements and ICH GCP. Before use, the informed consent form will be reviewed by 
the sponsor and approved by the EC and regulatory authority(ies), where applicable, (see 
Section 16.2). The informed consent form will include a comprehensive explanation of 
the proposed treatment without any exculpatory statements, in accordance with the 
elements required by ICH GCP and applicable national and local regulatory 
requirements. Patients or their legally-authorized representative(s) will be allowed 
sufficient time to consider participation in the study. By signing the informed consent 
form, patients or their legally authorized representative(s) agree that they will complete 
all evaluations required by the study, unless they withdraw voluntarily or are terminated 
from the study for any reason.
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The sponsor will provide to the investigator in written form any new information that 
significantly bears on the subjects’ risks associated with IP exposure. The informed 
consent will be updated, if necessary. This new information and/or revised informed 
consent form, which have been approved by the applicable EC and regulatory authorities, 
will be provided by the investigator to the subjects who consented to participate in the 
study 
16.4 Data Monitoring Committee
This study will be monitored by aDMC. The DMC is a group of individuals with 
pertinent expertise that reviews on a regular basis accumulating data from an ongoing 
clinical study. For this study, the DMC will be composed of recognized experts in the 
field of VWD clinical care and research who are not actively recruiting subjects, and an 
independent statistician. The DMC can stop a trial if it finds toxicities or if treatment is 
proven to be not beneficial. Details will be defined in the DMC charter.
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17. DATA HANDLING AND RECORD KEEPING
17.1 Confidentiality Policy
The investigator will comply with the confidentiality policy as described in the CTA.
17.2 Study Documentation and Case Report Forms
The investigator will maintain complete and accurate paper format study documentation 
in a separate file. Study documentation may include information defined as “source data” 
(see Section 8.7), records detailing the progress of the study for each subject, signed 
informed consent forms, correspondence with the EC and the study monitor/sponsor, 
enrollment and screening information, CRFs, SAERs, laboratory reports (if applicable),
and data clarifications requested by the sponsor.
The investigator will comply with the procedures for data recording and reporting. Any 
corrections to paper study documentation must be performed as follows: 1) the first entry 
will be crossed out entirely, remaining legible; and 2) each correction must be dated and 
initialed by the person correcting the entry; the use of correction fluid and erasing are 
prohibited.
The investigator is responsible for the procurement of data and for the quality of data 
recorded on the CRFs. CRFs will be provided in electronic form. 
If electronic format CRFs are provided by the sponsor, only authorized study site 
personnel will record or change data on the CRFs. If data is not entered on the CRFs 
during the study visit the data will be recorded on paper and this documentation will be 
considered source documentation. Changes to a CRF will require documentation of the 
reason for each change. An identical (electronic/paper) version of the complete set of 
CRFs for each subject will remain in the investigator file at the study site in accordance 
with the data retention policy (see Section 17.3).
The handling of data by the sponsor, including data quality assurance, will comply with 
regulatory guidelines (e.g., ICH GCP) and the standard operating procedures of the 
sponsor. Data management and control processes specific to the study will be described 
in the data management plan.
17.3 Document and Data Retention 
The investigator will retain study documentation and data (paper and electronic forms) in 
accordance with applicable regulatory requirements and the document and data retention 
policy, as described in the CTA.
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18. FINANCING AND INSURANCE
The investigator will comply with investigator financing, investigator/sponsor insurance, 
and subject compensation policies, if applicable, as described in the CTA.
19. PUBLICATION POLICY
The investigator will comply with the publication policy as described in the CTA. 
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20. SUPPLEMENTS
20.1 Study Flow Chart
Figure 1
Study Design for Baxalta Clinical Study 071301
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20.2 Schedule of Study Procedures and Assessments
Table 6a
Schedule of Study Procedures and Assessments for On-demand Subject
Procedures/
Assessments
Screening Visit
Baseline Visit 
(PK-assessment visit)
Prophylaxis 
Initiation Visit
Interval/Follow-Up 
Study Visits
PK Assessment at 
Study Completion
Termination 
Visit
Pre-
infusiong
Infusion
Post-
infusiong
1 month ± 
1 week
2 month ± 
1 week 
3 month ± 
2 weeks
6 month ± 
2 weeks 
9 month ± 
2 weeks
Pre-
infusiong
Infusion
Post-
infusiong
Conducted at 
the 96 hour 
postinfusion 
PK 
Assessment
12 month ± 2 weeks
Informed Consent a
X
Eligibility Criteria
X
Medical Historyb
X
Concomitant Medicationsc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Non-drug Therapiesc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
Bleeding Episodes and 
Treatment and Hemostatic 
Efficacy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratories 
X
X
X
Xh
X
X
X
X
X
X
X
X
Vital Signsd
X
X
X
X
X
X
X
X
X
X
X
X
ECG
X
X
X
IP Treatmente
X
X
X
X
X
X
X
X
IP Consumption / Treatment 
Compliance 
X
X
X
X
X
Subject Diary
X
X
X
X
X
X
Xf
X
X
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Continued
a Occurs at enrollment (before screening).
b Including documented history of on-demand treatment for the past 12 months (up to 24 months if available) and a documented history, e.g., patient charts 
and prescription information, of all bleeding episodes within the past 12 (up to 24) months. 
c Including all medications and non- drug therapies taken in the 2 weeks prior to study entry and all the concomitant medications and non-drug therapies 
during the course of the study.
d Vital signs: height, weight, body temperature, pulse rate, respiratory rate, and blood pressure. Height is only required at the screening visit. The time points 
for pre- and post-infusion measurements are (weight is measured pre-infusion only): within 30 minutes before infusion start and 30 ± 15 minutes post-
infusion.
e IP treatment after the prophylactic treatment initiation visit at the site will be continued as home-treatment if the subject qualifies; a wash-out period of at 
least 72 hours is required after the last IP infusion before the follow-up visit. IP infusion will be given at the study site after the blood sample for 
immunology testing and IR determination is drawn.
f Can be done either at the screening or the baseline visit.
g Time points for PK blood draws: within 30 minutes pre-infusion, and at 11 time points post-infusion: 15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 
3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours and 96 ± 2 hours (the 96 hr sampling can be omitted 
if not allowed by the dosing interval).
h If a subject did not undergo PK assessment, laboratory assessments will be performed at this visit.
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Table 6b
Schedule of Study Procedures and Assessments for pdVWF Switch Subject
Procedures/
Assessments
Screening Visit
Prophylaxis Initiation 
Visit
PK Assessment
(at prophylaxis dose #5-6)
Interval/Follow-Up 
Study Visits
PK Assessment at 
Study Completion
Termination 
Visit
Pre-infusiong
Infusion
Post-infusiong
1 month ± 
1 week
2 month ± 
1 week 
3 month ± 
2 weeks
6 month ± 
2 weeks 
9 month ± 
2 weeks
Pre-
infusiong
Infusion
Post-
infusiong
Conducted at 
the 96 hour 
postinfusion 
PK 
Assessment
12 month± 2 weeks
Informed Consent a
X
Eligibility Criteria
X
Medical Historyb
X
Concomitant Medicationsc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Non-drug Therapiesc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
Bleeding Episodes and 
Treatment and Hemostatic 
Efficacy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratories 
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signsd
X
X
X
X
X
X
X
X
X
X
X
X
ECG
X
X
X
IP Treatmente
X
X
X
X
X
X
X
X
IP Consumption / Treatment 
Compliance 
X
X
X
X
X
Subject Diary
X
X
X
X
X
X
Xf
X
X
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Continued
a Occurs at enrollment (before screening).
b Including documented history of prophylaxis treatment for the past 12 months (up to 24 months if available) and a documented history, e.g., patient charts 
and prescription information, of all bleeding episodes within the past 12 (up to 24) months. 
c Including all medications and non- drug therapies taken in the 2 weeks prior to study entry and all the concomitant medications and non-drug therapies 
during the course of the study.
d Vital signs: height, weight, body temperature, pulse rate, respiratory rate, and blood pressure. Height is only required at the screening visit. The time 
points for pre- and post-infusion measurements are (weight is measured pre-infusion only): within 30 minutes before infusion start and 30 ± 15 minutes
post-infusion.
e IP treatment after the prophylactic treatment initiation visit at the site will be continued as home-treatment if the subject qualifies; a wash-out period of at 
least 72 hours is required after the last IP infusion before the follow-up visit. IP infusion will be given at the study site after the blood sample for 
immunology testing and IR determination is drawn.
f Can be done either at the screening or the prophylaxis initiation visit.
g Time points for PK blood draws: within 30 minutes pre-infusion, and at 11 time points post infusion: 15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 
3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours and 96 ± 2 hours ( the 96 hr sampling can be 
omitted if not allowed by the dosing interval).
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20.2.1 Summary Schedule of Visit Assesments for Surgical Bleeding
Table 7
Summary Schedule of Visit Assesments for Surgical Bleeding
Procedures/
Assessments
Surgical procedure
Post-Operative 
Day 7 Visit
(± 1 day)
Post-Operative 
Day 14 Visit
(± 2 day)
Priming Dose 
Procedures 
(12-24 hours prior 
to surgery)
Loading Dose 
Procedures 
(≤3 hours prior
to surgery)
Intraoperative
Postoperative 
(day 1 → end of 
perioperative IP 
treatment)a
ECG
X
Physical examinationb
X
X
X
X
X
Adverse events
X
X
X
X
X
X
Laboratoriesc
X
X
X
X
X
X
Vital signsd
X
X
X
X
X
X
IP treatment: rVWF (vonicog 
alfa):ADVATE (rFVIII, octocog 
alfa) or rVWF (vonicog alfa) only 
infusion
X
X
X
as required
X
as required
X
as required
X
as required
Concomitant medications and non-
drug therapy
X
X
X
X
X
X
X
Hemostatic efficacy assessmentse
X
X
X
X
Blood loss
X
estimated
X
actual
X
Xf
Xf
Treatment days estimate
X
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Continued 
a The assessments will be performed daily until perioperative IP treatment end (potentially multi-visits)
b Physical Examination: within 2 hours prior to IP infusion start
c For laboratory assessments, see Table 9
d Vital signs: within 30 minutes before infusion start and 30 ± 15 minutes post-infusion
e Completed immediately postsurgery by the operating surgeon 24 hours post last IP infusion or at Day 14 visit (whichever occurs first) by the investigator
f In case bleeding still ongoing
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20.3 Clinical Laboratory Assessments
Table 8a
Clinical Laboratory Assessments for On-demand Subject
Procedures/
Assessments
Screening Visit
Baseline Visit 
(PK-assessment visit)
Prophylaxis Initiation 
Visitk
Interval/Follow-Up 
Study Visits
PK Assessmentm at 
Study Completion
Termination 
Visit
Pre-infusion
Infusion
Post-infusion
1 month ± 
1 week
2 month ± 
1 week 
3 month ± 
2 weeks
6 month ± 
2 weeks 
9 month ± 
2 weeks
Pre-
infusion
Infusion
Post-
infusion
Conducted 
at the 
96 hour 
postinfusion 
PK 
Assessment
12 month± 
2 weeks
Hematology a
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Chemistryb
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation Panel/ PK 
assessmentc
X
X
X
X
X
X
X
X
X
X
X
Immunogenicityd
X
X
Xl
X
X
X
X
X
X
X
Viral Serologye
X
Urinalysisf
X
VWD Gene Mutational 
Analysis / HLA genotype 
analysis and Analysis of 
VWF multimersg
X
sP-selectin and D-dimer
Xh
Blood Groupi 
X
Pregnancy Testj
X
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Continued
a Hematology assessments include: complete blood count [hemoglobin, hematocrit, erythrocytes (i.e. red blood cell count), mean corpuscular volume 
(MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), leukocytes (i.e. white blood cell count)] with 
differential (i.e. basophils, eosinophils, lymphocytes, monocytes, neutrophils) and platelet counts. Hematology assessments during PK assessments will be 
determined prior to IP infusion and 24 ± 2 hours, 48 ± 2 hours and 72 ± 2 hours thereafter. For other IP-associated visits, samplings are within 60 minutes 
pre-infusion.
b Clinical chemistry assessments include: Sodium, potassium, chloride, glucose, creatinine, blood urea nitrogen (BUN), aspartate aminotransferase (AST), 
alanine aminotransferase (ALT) lactate dehydrogenase (LDH), alkaline phosphatase (AP), bilirubin. Clinical chemistry will be determined prior to IP 
infusion and after 24 ± 2 h, 48 ± 2 hours and 72 ± 2 hours during the PK assessments. For other IP-associated visits, samplings are within 60 minutes pre-
infusion.
c Coagulation panel/PK assessment (also refers to IR pre/post dose assessments at prophy initiation visit and each follow-up visit): PT, INR and aPTT (only 
for screening), VWF:RCo, VWF:Ag, VWF:CB, FVIII:C,; during the PK assessment at the baseline visit blood samples will be drawn 30 min prior PK 
infusion; once the PK infusion is completed 15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 
30 ± 2 hours, 48 2 hours, 72 2 hours and 96 ± 2 hours and VWF:RCo, VWF:CB, VWF:Ag, FVIII:C will be determined; for follow-up visits, IR 
samples will be drawn within 30 minutes pre-infusion and 30 5 minutes post-infusion. During screening and in case of thromboembolic event VWF 
multimers and ADAMTS13 will be analyzed to judge on a possibly relatedness to UHMW fractions of the IP.
d Immunogenicity assessment includes Neutralizing Antibodies (Ab) to FVIII –Neutralizing Ab to VWF:RCo, Neutralizing Ab to VWF:CB, Neutralizing Ab 
to VWF:FVIII, Binding Ab to VWF and FVIII, Binding Ab to CHO-Protein, Binding Ab to rFurin, Binding Ab to Murine IgG . In case of an SAE 
hypersensitivity reaction IgE antibodies to VWF will be determined. For on-demand subjects, a washout period of at least 72 hours after the last IP 
infusion is required before blood samples for immunogenicity assessments can be drawn. 
e Viral Serology Hepatitis A Antibody, Total - Hepatitis A Antibody, IgM - Hepatitis B Surface Antibody - Hepatitis B Core Ab, Total - Hepatitis B Surface 
Antigen - Hepatitis C Virus Antibody; Parvovirus B19; HIV-1/HIV-2 Antibodies 
f Urinalysis comprehends: erythrocytes, specific gravity, urobilinogen, ketones, glucose, protein, bilirubin, nitrite, and pH
g Not required if available in the subject’s medical history; VWF multimers: additionally in case of thromboembolic events
h At screening and in case of thromboembolic events
i Blood group assessment major blood group (local laboratory) only if not available in the subject’s medical history
j Serum pregnancy test (in females of child-bearing potential if no urine sample is available)
k The last post-infusion laboratory assessments coincide with the initiation visit for prophylactic treatment. After the blood samples are drawn for laboratory 
assessment for the 96 h post infusion PK assessment, the subject receives the first IP infusion for prophylactic treatment (prophylactic treatment initiation 
visit). 
l Only needed for subjects without PK assessment prior to their first IP infusion in this study.
m A steady state full PK analysis will be performed at the end of the study. Blood samples will be drawn within 30 minutes pre-infusion, and at 11 time points 
post-infusion (15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 
72 2 hours and 96 ± 2 hours), the 96 hr sampling can be omitted if not allowed by the dosinig interval.
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Table 8b
Clinical Laboratory Assessments for pdVWF Switch Subject
Procedures/
Assessments
Screening Visit
Prophylaxis Initiation Visit
PK Assessmentk
(at prophylaxis dose #5-6)
Interval/Follow-Up 
Study Visits
PK Assessmentk at 
Study Completion
Termination 
Visit
Pre-infusion
Infusion
Post-infusion
1 month ± 1 week
2 month ± 1 week 
3 month ± 2 weeks
6 month ± 2 weeks 
9 month ± 2 weeks
Pre-
infusion
Infusion
Post-
infusion
Conducted at 
the 96 hour 
postinfusion 
PK 
Assessment
12 month± 
2 weeks
Hematology a
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Chemistryb
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation Panel/PK 
assessmentc
X
X
X
X
X
X
X
X
X
X
X
Immunogenicityd
X
X
X
X
X
X
X
X
X
X
Viral Serologye
X
Urinalysisf
X
VWD Gene Mutational 
Analysis / HLA 
genotype analysis and 
Analysis of VWF 
multimersg
X
sP-selectin and D-dimer
Xh
Blood Groupi 
X
Pregnancy Testj
X
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Continued
a Hematology assessments include: complete blood count [hemoglobin, hematocrit, erythrocytes (i.e. red blood cell count), mean corpuscular volume 
(MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), leukocytes (i.e. white blood cell count)] with 
differential (i.e. basophils, eosinophils, lymphocytes, monocytes, neutrophils) and platelet counts. Hematology assessments during PK assessments will be 
determined prior to IP infusion and 24 ± 2 hours, 48 ± 2 hours and 72 ± 2 hours thereafter. For other IP-associated visits, samplings are within 60 minutes 
pre-infusion.
b Clinical chemistry assessments include: Sodium, potassium, chloride, glucose, creatinine, blood urea nitrogen (BUN), aspartate aminotransferase (AST), 
alanine aminotransferase (ALT) lactate dehydrogenase (LDH), alkaline phosphatase (AP), bilirubin. Clinical chemistry will be determined prior to IP 
infusion and after 24 ± 2 h, 48 ± 2 hours and 72 ± 2 hours during the PK assessments. For other IP-associated visits, samplings are within 60 minutes pre-
infusion.
c Coagulation panel/PK assessment (also refers to IR pre/post dose assessments at prophy initiation visit and each follow-up visit): PT, INR and aPTT (only 
for screening), VWF:RCo, VWF:Ag, VWF:CB, FVIII:C,; during the PK assessment blood samples will be drawn 30 min prior PK infusion; once the PK
infusion is completed 15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 
48 2 hours, 72 2 hours and 96 ± 2 hours and VWF:RCo, VWF:CB, VWF:Ag, FVIII:C will be determined; for follow-up visits, IR samples will be 
drawn within 30 minutes pre-infusion and 30 5 minutes post-infusion. During screening and in case of thromboembolic event VWF multimers and 
ADAMTS13 will be analyzed to judge on a possibly relatedness to UHMW fractions of the IP.
d Immunogenicity assessment includes Neutralizing Antibodies (Ab) to FVIII –Neutralizing Ab to VWF:RCo, Neutralizing Ab to VWF:CB, Neutralizing Ab 
to VWF:FVIII, Binding Ab to VWF and FVIII, Binding Ab to CHO-Protein, Binding Ab to rFurin, Binding Ab to Murine IgG. In case of an SAE 
hypersensitivity reaction IgE antibodies to VWF will be determined. For switch subjects, the wash out period may be reduced to the time interval between 
their pdVWF prophy infusions.
e Viral Serology Hepatitis A Antibody, Total - Hepatitis A Antibody, IgM - Hepatitis B Surface Antibody - Hepatitis B Core Ab, Total - Hepatitis B Surface 
Antigen - Hepatitis C Virus Antibody; Parvovirus B19; HIV-1/HIV-2 Antibodies
f Urinalysis comprehends: erythrocytes, specific gravity, urobilinogen, ketones, glucose, protein, bilirubin, nitrite, and pH
g Not required if available in the subject’s medical history; VWF multimers: additionally in case of thromboembolic events
h At screening and in case of thromboembolic events
i Blood group assessment major blood group (local laboratory) only if not available in the subject’s medical history
j Serum pregnancy test (in females of child-bearing potential if no urine sample is available)
k A full steady state PK analysis will be performed. Blood samples will be drawn within 30 minutes pre-infusion, and at 11 time points post-infusion
(15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours 
and 96 ± 2 hours) , the 96 hr sampling can be omitted if not allowed by the dosinig interval.
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20.3.1 Laboratory Sampling for Surgical Bleeding
Table 9
Laboratory Samplinga for Surgical Bleeding
Procedures/
Assessments
Surgical procedure
Post-Operative 
Day 7 Visit
(± 1 day)
Post-Operative 
Day 14 Visit
(± 2 day)
Priming Dose 
Procedures 
(12-24 hours prior 
to surgery)
Loading Dose 
Procedures 
(≤3 hours prior 
to surgery)
Intraoperative
Postoperative 
(day 1 → end of 
perioperative IP 
treatment)b
Hematologyc
X
(w/o Differential)
Xd
(w/o 
Differential)
X
(w/o Differential)
X
X
Clinical Chemistrye
X
Xd
X
X
Coagulation panelf
X
X
X
X
X
X
VWF inhibitory and binding 
antibodies, antibodies to other 
proteinsg
X
X
X
if excessive or 
unexplainedbleeding
X
X
X
Urinalysish
X
X
VWF Multimersi
Anti VWF IgE antibody testing
only in case of allergic reaction/ 
anaphylaxis
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Continued
a Blood draws are within 3 hrs  prior to infusion start, expect that for the priming dose blood draw is within 30 minutes prior to infusion start. For 
coagulation panel, an additional 30 ± 5 minutes post-infusion blood draw is needed.
b The assessments will be performed daily until perioperative IP treatment end (potentially multi-visits)
c Hematology assessments include: complete blood count [hemoglobin, hematocrit, erythrocytes (i.e. red blood cell count), mean corpuscular volume 
(MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), leukocytes (i.e. white blood cell count)] with 
differential (i.e. basophils, eosinophils, lymphocytes, monocytes, neutrophils) and platelet counts. 
d Not required if sample already drawn at the time of the priming dose
e Clinical chemistry assessments include: Sodium, potassium, chloride, glucose, creatinine, blood urea nitrogen (BUN), aspartate aminotransferase (AST), 
alanine aminotransferase (ALT) lactate dehydrogenase (LDH), alkaline phosphatase (AP), bilirubin. 
f Coagulation panel: VWF:RCo, VWF:Ag, FVIII:C PT INR and aPTT; in additiona to pre-infusion, 30 ± 5 minutes post infusion blood draw is needed. 
g Immunogenicity assessment includes Neutralizing Antibodies (Ab) to FVIII – Neutralizing and Neutralizing Ab to VWF:RCo, Neutralizing Ab to 
VWF:CB, Neutralizing Ab to VWF:FVIII, Binding Ab to VWF and FVIII, Binding Ab to CHO-Protein, Binding Ab to rFurin, Binding Ab to Murine IgG.
In case of an SAE hypersensitivity reaction IgE antibodies to VWF will be determined.
h Urinalysis comprehends: erythrocytes, specific gravity, urobilinogen, ketones, glucose, protein, bilirubin, nitrite, and pH
i VWD multimers and ADAMTS13 during the study only in case of thrombotic events
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20.4 Contraceptive Methods for Female Subjects of Childbearing Potential
In this study, subjects who are women of childbearing potential must agree to utilize a 
highly effective contraceptive measure throughout the course of the study and for 30 days 
after the last administration ofIP. In accordance with the Clinical Trial Facilitation Group 
(CTFG) recommendations related to contraception and pregnancy testing in clinical trials 
(version 2014-09-15)ii, birth control methods which may be considered as highly 
effective include the following:

Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation:

oral

intravaginal

transdermal

Progestogen-only hormonal contraception associated with inhibition of ovulation:

oral

injectable

implantableiii

Intrauterine device (IUD)iii

Intrauterine hormone-releasing system (IUS) iii

Bilateral tubal occlusioniii

Vasectomised partner(s)iii

Sexual abstinence during the entire study period
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhoea method (LAM) are 
not acceptable methods of contraception. Female condom and male condom should not 
be used together.
                                                
ii Clinical Trial Facilitation Group (CTFG) recommendations related to contraception and pregnancy 
testing in clinical trials: http://www.hma.eu/fileadmin/dateien/ 
Human_Medicines/01About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf.
iii Contraception methods that are considered to have low user dependency.
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21. REFERENCES
1.
Committee for Medicinal Products for Human Use. Guideline on clinical 
investigation of human plasma derived von Willebrand factor products. 
CPMP/BPWG/220/02, 12. 11-17-2005:London, European Medicines Agency 
(EMA). Web Link: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/201
0/01/WC500067126.pdf
2.
Mannucci PM. Treatment of von Willebrand's Disease. N Engl J Med. 
2004;351(7):683-694.
3.
Goudemand J, Scharrer I, Berntorp E, et al. Pharmacokinetic studies on Wilfactin, a 
von Willebrand factor concentrate with a low factor VIII content treated with three 
virus-inactivations/removal methods. J Thromb Haemost. 2005;3(10):2219-2227.
4.
Abshire T. The role of prophylaxis in the management of von Willebrand disease: 
today and tomorrow. Thromb Res. 2009;124 Suppl 1:S15-S19.
5.
Nilsson IM, Blombäck M, Jorpes E, Blombäck B, Johansson SA. V. Willebrand's 
disease and its correction with human plasma fraction 1-0. Acta Med Scand. 
1957;159(3):179-188.
6.
Berntorp E, Petrini P. Long-term prophylaxis in von Willebrand disease. Blood 
Coagul Fibrinolysis. 2005;16 Suppl 1:S23-S26.
7.
Berntorp E. Prophylaxis and treatment of bleeding complications in von Willebrand 
disease type 3. Semin Thromb Hemost. 2006;32(6):621-625.
8.
Federici AB. Highly purified VWF/FVIII concentrates in the treatment and 
prophylaxis of von Willebrand disease: the PRO.WILL Study. Haemophilia. 
2007;13 Suppl 5:15-24.
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9.
Halimeh S, Krümpel A, Rott H, et al. Long-term secondary prophylaxis in children, 
adolescents and young adults with von Willebrand disease. Results of a cohort 
study. Thromb Haemost. 2011;105(4):597-604.
10.
Abshire TC, Federici AB, Alvárez MT, et al. Prophylaxis in severe forms of von 
Willebrand's disease: results from the von Willebrand Disease Prophylaxis 
Network (VWD PN). Haemophilia. 2013;19(1):76-81.
11.
Abshire T, Cox-Gill J, Kempton CL, et al. Prophylaxis escalation in severe von 
Willebrand disease: A prospective study from the von Willebrand Disease 
Prophylaxis Network. J Thromb Haemost. 2015;13(9):1585-1589.
12.
Berntorp E. Prophylaxis in von Willebrand disease. Haemophilia. 2008;14 Suppl 
5:47-53.
13.
Varadi K, Rottensteiner H, Vejda S, et al. Species-dependent variability of 
ADAMTS13-mediated proteolysis of human recombinant von Willebrand factor. J 
Thromb Haemost. 2009;7(7):1134-1142.
14.
Mannucci PM, Kempton C, Millar C, et al. Pharmacokinetics and safety of a novel 
recombinant human von Willebrand factor manufactured with a plasma-free 
method: a prospective clinical trial. Blood. 2013;122(5):648-657.
15.
Gill JC, Castaman G, Windyga J, et al. Hemostatic efficacy, safety and 
pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand 
disease. Blood. 2015;126(17):2038-2046.
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16.
Committee for Medicinal Products for Human Use. Guideline on immunogenicity 
assessment of biotechnology-derived therapeutic proteins. 
CHMP/BMWP/14327/2006, 18. 12-13-2007:London, European Medicines Agency 
(EMA),. Web Link: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/200
9/09/WC500003946.pdf
17.
Kasper CK. Laboratory tests for factor VIII inhibitors, their variation, significance 
and interpretation. Blood Coagul Fibrinolysis. 1991;2 Suppl 1:7-10.
18.
Lillicrap D. Von Willebrand Factor. International Society for Thrombosis and 
Hemostasis (ISTH), 54th Annual Scientific and Standardization Committee 
Meeting - Scientific Subcommittee Minutes:2008:60-64. Web Link: 
http://c.ymcdn.com/sites/www.isth.org/resource/resmgr/yearly_subcommittee_min
utes/2008minutes.pdf?hhSearchTerms=lillicrap+and+2008
19.
 
20.
 
21.
 
 
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22. SUMMARY OF CHANGES
Protocol 071301: Local Amendment 7 (Germany): 2018 MAY 18
Replaces: Local Amendment 4 (Germany): 2017 AUG 04
In this section, changes from the previous local version of the protocol, dated 
2017 AUG 04, are described and their rationale is given.
1.
Throughout the document
Description of Change:
Minor grammatical and/or administrative changes and/or rewording have been 
made.
Purpose for Change: To improve the readability and/or clarity of the protocol.
2.
Throughout the document
Description of Change:
INN was added to rVWF and ADVATE by changing rVWF to rVWF (vonicog 
alfa) and changing ADVATE to ADVATE (rFVIII, octocog alfa).
Purpose for Change: To add INN.
3.
Section 2, Section 12.1.2
Description of Change:
Bleeding events that meet seriousness criteria should be reported on both SAE 
eCRF and SAE report form. Section 12.1.2.3 was added as a reference for SAE 
assessment.
Purpose for Change: To provide further clarifications on SAE reporting.
4.
Synopsis (Clinical condition(s)/indication(s)), Section 6.4, Section 13.1
Description of Change: 
Original text:
Subjects with severe von Willebrand disease (VWD) requiring prophylactic 
treatment with coagulation factor replacement.
New text:
Subjects with severe von Willebrand disease (VWD) (baseline VWF:RCo 
<20 IU/dL) requiring prophylactic treatment with coagulation factor replacement.
Purpose for Change: To add definition of severe VWD.
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5.
Synopsis (Planned study period), Section 8.2
Description of Change:
The initiation/completion and duration of the study were updated per the new 
timeline.
Purpose for Change: To reflect the new study timeline.
6.
Synopsis (Study purpose, Study design), Section 7.1, Section 8.1
Description of Change:
Hypersensitivity was added for safety evaluation; PK and pharmacoecnomics 
evaluation was added.
Purpose for Change: To provide further clarifications to the purpose of the study.
7.
Synopsis (Primary objective), Section 7.2
Description of Change:
Original text:
The primary objective of this study is to prospectively evaluate the annualized 
bleeding rate (ABR) for spontaneous bleeding episodes while on prophylactic 
treatment with rVWF and to compare it to the subject’s historical ABR for 
spontaneous bleeding episodes during on-demand treatment.
New text:
The primary objective of this study is to prospectively evaluate the annualized 
bleeding rate (ABR) for spontaneous bleeding episodes while on prophylactic 
treatment with rVWF and to compare it to the subject’s historical ABR for 
spontaneous bleeding episodes. 
Purpose for Change: To remove wording to accommodate pdVWF switch subject 
cohort, which is a new study cohort added in this amendment.
8.
Synopsis (Secondary objectives), Section 7.3
Description of Change: 
 
. Additional wording was added to clarify the objectives.
Purpose for Change: Remove some of the objectives (
 
) and add clarification.
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9.
Synopsis (Exploratory objectives, Exploratory outcome measures), 
Section 7.4, Section 8.3.3
Description of Change: 
  
 
 and additional wording was added to clarify the assessments.
Purpose for Change: Clarification and adding additional objectives/assessments.
10.
Synopsis (Study Design), Section 8.1
Description of Change: 
Additional details about the study design were added for on-demand and the 
switch cohort.
Purpose for Change: To provide further clarification and to add study design for 
the switch cohort.
11.
Synopsis (Primary outcome measure), Section 8.3.1
Description of Change: 
Original text:
Prospectively recorded ABR for spontaneous (not related to trauma) bleeding 
episodes during prophylactic treatment with rVWF and the subjects’ historical 
ABR for spontaneous bleeding episodes during on-demand treatment.
New text:
Annualized bleeding rate (ABR) for spontaneous (not related to trauma) 
bleeding episodes during prophylactic treatment with rVWF (vonicog alfa).
Purpose for Change: To remove the unnecessary text.
12.
Synopsis (Secondary outcome measures), Section 8.3.2
Description of Change:
Rewording some of the exisiting secondary outcome measures (efficacy and 
safety) to provide clarification. New efficacy outcome measures were added to 
further access the efficacy of prophylaxis for switch subjects. Clinically 
significant changes in vital signs and clinical laboratory parameters were added as 
one additional safety measure. New steady-state PK parameters were added. PD 
parameters were added. 
 
Purpose for Change: To provide further clarifications and to add new outcome 
measures for switch subjects. And to remove some of the outcome measures 
(
)
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13.
Synopsis (Investigational product(s), dose and mode of administration)
Description of Change: 
Prophylaxis dosing guidelines were added for the pdVWF switch subjects.
Purpose for Change: To add dosing guide for the switch subjects.
14.
Synopsis (Targeted accrual, sample size calculation), Section 6.4, Section 13.1
Description of Change:
Sample size was increased and targeted accrual of each cohort was added and a 
followup period of 12 months was added.
Purpose for Change: To update the sample to reflect the adding of switch cohort.
15.
Synopsis (Inclusion criteria, Exclusion criteria), Section 9.1, Section 9.2
Description of Change: 
Criteria for the switch subjects were added.
Criteria added to clarify no pre-planned surgery is allowed.
Purpose for Change: To update for the eligibility of switch subjects and to add 
some clarity.
16.
Synopsis (Inclusion Criteria), Section 9.1
Description of Change:
Original text:
Subject is ≥18 years old at the time of screening and has a body mass index 
≥18 but <30 kg/m2.
New text:
Subject is ≥18 years old at the time of screening and has a body mass index 
≥18 but <30≤30 kg/m2.
PurposeforChange: To update the BMI value from “18 - <30” to “18-≤30” range, 
in response to query received from regulatory authority in Germany only.
17.
Synopsis (Planned statistical analysis), Section 13.4
Description of Change: 
Changes were made throughout the section according to the updated outcome 
measures. Remove the planned analysis of exploratory outcome measure from 
synopsis to avoid redundance
Purpose for Change: To better test the updated outcome measures.
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18.
Section 5
Description of Change: 
New abbreviations were added.
Purpose for Change: Clarification.
19.
Section 6.5, Section 6.5.2, Section 6.5.2.4, Section 6.5.2.5
Description of Change: 
Summary of recently completed clinical study 071101 was added as 
Section 6.5.2.4, the summary of 071401 was moved to Section 6.5.2.5.
Purpose for Change: To provide clinical study summary for study 071101.
20.
Section 6.5.2.3
Description of Change: 
To add wording about the basis of the dosing for the current study.
Purpose for Change: To provide clarification.
21.
Section 6.6
Description of Change: 
Original text:
He/she may benefit from a product that minimizes excessive FVIII administration.
New text:
He/she may benefit from a product that minimizes excessive FVIII administration 
and thus allowing individualized dosing of VWF at optimal levels. 
Original text:
By using a recombinant product, the risk of contamination with blood derived 
viruses or variant Creutzfeldt-Jakob Disease associated with the use of 
products of human or animal origin has been virtually eliminated.
New text:
By using a recombinant product, the risk of transmission of adventitious agents 
and other blood-borne pathogens associated with the use of products of human 
or animal origin has been eliminated.
Purpose for Change: To provide accuracy and clarification.
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22.
Section 6.6
Description of Change: 
Original text:
These benefits outweigh the following potential risks of rVWF.
New text:
These benefits outweigh the following identified or potential risks of rVWF
Purpose for Change: To provide accuracy since thromboembolic events has been 
upgraded to identified risk.
23.
Section 8.5
Description of Change: 
Updates were made based on safety considerations.
Purpose for Change: To avoid unnecessary study stop.
24.
Section 8.6.3
Description of Change: 
Wording was added to clarify that partial vials are not allowed to use. 
Wording about mixing of two products was removed as it is not allowed any
more.
Purpose for Change: To provide clarification on IP administration.
25.
Section 8.6.4.1
Description of Change: 
Details about PK assessment IP treatment were added for both on-demand and 
switch cohorts.
Purpose for Change: To provide more details and clarifications.
26.
Section 8.6.4.2
Description of Change:
Prophylaxis initiation treatment was updated to be also applicable to the switch 
subjects and the dosing details were removed from this section (moved to 
Section 8.6.4.3).
Purpose for Change: To provide details to accommodate newly added switch 
cohort.
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27.
Section 8.6.4.3, Section 8.6.4.3.1, Section 8.6.4.3.2
Description of Change:
Detailed instructions of prophylaxis dosing and dosing adjustment were added to 
this section for both on-demand and pdVWF switch subjects. Home treatment 
rules were also made applicable to switch subjects, and made correction that the 
investigator is responsible for the home treatment procedures.
Purpose for Change: To provide details and clarifications to accommodate newly 
added switch cohort.
28.
Section 8.6.4.4.1, Section 10.3.1
Description of Change:
Added the requirement of documentation the reason for the use of any non-IP 
product or therapy.
Purpose for Change: To ensure proper documentation of non-IP product use.
29.
Section 8.6.4.4.2
Description of Change: 
Added the wording about dose adjustment and the optional use of ADVATE.
Purpose for Change: To provide further clarification.
30.
Section 8.6.4.5
Description of Change: 
Sentence was added to clarify no pre-planned surgery is allowed.
Purpose for Change: To add some clarity.
31.
Section 8.6.4.5.2
Description of Change:
Added description of priming dose for surgery.
Purpose for Change: To provide further clarification.
32.
Section 8.6.4.5.3
Description of Change:
Added description of loading dose for surgery.
Purpose for Change: To provide further clarification.
33.
Section 8.6.4.6, Section 12.6.1
Description of Change:
Added the details about prophylaxis measures against thromboembolism.
Purpose for Change: To ensure safety monitoring of thromboembolic events.
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34.
Section 8.6.5
Description of Change:
Added the wording about the requirement to monitor temperature excursions at 
the subject’s home.
Purpose for Change: To ensure IP is stored as specified in the Pharmacy Manual.
35.
Section 9.4
Description of Change: 
Original text:
Subjects who develop a neutralizing inhibitor to rVWF and/or ADVATE 
(biological assays). 
New text:
Subjects who develop a neutralizing inhibitor to rVWF and/or ADVATE 
(biological assays) that results in significant clinical effect, including but not 
limited to increasing the weekly dose of rVWF by ≥50%.
Purpose for Change: To provide more clarifications.
36.
Section 9.4
Description of Change:
One more discontinuation criteria was added.
Purpose for Change: To avoid the continue of non-compliance subjects.
37.
Section 10.3.1
Description of Change:
Added the wording to clarify the wash-out period of the screening visit and the 
timing of the subsequent visit for switch subjects.
Purpose for Change: To clarify for switch subjects.
38.
Section 10.3.2
Description of Change: 
Wording was added to specify this visit only applicable to on-demand cohort.
Purpose for Change: To provide clarification.
39.
Section 10.3.3
Description of Change: 
Wording was added to specify the timing of this visit for the switch cohort.
Purpose for Change: To provide clarification.
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40.
Section 10.3.4
Description of Change:
The initial steady-state PK assessment that only applicable to the switch subjects 
was specified in this section.
Purpose for Change: To accommodate PK assessment of switch subjects.
41.
Section 10.3.5, Section 10.3.6, Section 10.3.7, Section 10.3.8, Section 10.3.9
Description of Change: 
The original sections from 10.3.4 – 10.3.8 became 10.3.5 – 10.3.9 due to the 
insertion of new Section 10.3.4.
Purpose for Change: To accommodate the insertion of new Section 10.3.4.
42.
Section 10.3.7
Description of Change: 
The value of prophylaxis dose was removed since it was not correct for switch 
patients. The different wash-out period for switch subjects was specified.
Purpose for Change: To make corrections and to make clarifications for switch 
subjects.
43.
Section 10.3.9
Description of Change:
Wording was added to clarify that the EOS PK assessment also applicabe for 
switch subjects and the wash-out requirement for switch subjects was added. 
The details about PK parameters were removed (specified in other sections).
Purpose for Change: To provide clarifications for switch subjects.
44.
Section 10.4
Description of Change: 
Added more clarification about the use of Antifibrinolytics.
Purpose for Change: To provide further clarifications.
45.
Section 10.5
Description of Change:
Added more details about what would be recorded in the diary.
Purpose for Change: To provide further clarifications.
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46.
Section 11.2, Section 12.5
Description of Change:
Specified the need of location for historical bleeds records. Clarified that it is 
good to have upto 24 months of historical records if available.
Purpose for Change: To provide further clarifications.
47.
Section 11.3
Description of Change:
Added more details about what would be needed for switch subjects as the 
historical factor dosing and consumption records.
Purpose for Change: To provide further clarifications.
48.
Section 11.5
Description of Change:
Clarify the assessment of overall assessment of hemostatic efficacy.
Purpose for Change: To provide clarifications.
49.
Section 11.6
Description of Change:
Section title was updated to add PD assessment.
PK/PD assessment details including schedule, dosing, parameters, etc.
Purpose for Change: To provide instruction/protocol for PK/PD assessment.
50.
Section 12.1.1.1
Description of Change: 
More details about hypersensitivity reactions were specified. SAE reporting 
reference was added. 
Purpose for Change: To provide further clarification.
51.
Section 12.1.1.2
Description of Change:
More clarifications about SUSAR were added. 
Purpose for Change: To provide further clarification.
52.
Section 12.1.1.3
Description of Change: 
More details about criteria of serious AE were added. 
Purpose for Change: To provide further clarification.
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53.
Section 12.1.2
Description of Change: 
Some wording of clarification was added for assessment of AE. 
Purpose for Change: To provide further clarification.
54.
Section 12.1.2.2
Description of Change: 
Original text:
Is not associated with the IP (i.e., does not follow a reasonable temporal 
relationship to the administration of IP or has a much more likely alternative 
etiology).
New text:
Is not associated with the IP (i.e., does not follow a reasonable temporal 
relationship to the administration of IP, is not biologically plausible per 
mechanism of action of the IP, or has a much more likely alternative etiology).
Purpose for Change: To provide more clarifications.
55.
Section 12.1.2.3
Description of Change: 
More details about hypersensitivity reactions were specified. SAE reporting 
reference was added. 
Purpose for Change: To provide further clarification.
56.
Section 12.7
Description of Change: 
Added clarification that height is only assessed on screening visit. 
Purpose for Change: To provide further clarification.
57.
Section 12.9, Section 12.9.14.1
Description of Change: 
“Abnormal laboratory values deemed clinically significant by the investigator are 
to be recorded as AEs (see Section 12.1.2).” was removed due to inaccuracy.
New Text added: “Any abnormal laboratory value that is considered clinically 
significant by the investigator based on a local laboratory test result (reference 
range and the units to be provided) should be confirmed by a central laboratory 
test result for which the sample is drawn/collected within 24 hours of the 
abnormal finding by the local laboratory”. 
Purpose for Change: To provide accuracy and further clarification.
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58.
Section 12.9.1
Description of Change: 
Section title was updated to add PD assessment.
Text was removed, and refered to Section 11.6. 
Purpose for Change: To avoid duplicated text.
59.
Section 12.9.3.4
Description of Change: 
Wording added to specify that only confirmed positive anti-VWF inhibitor test 
result will be reported and will be considered as a medically significant SAE. 
Purpose for Change: To clarify.
60.
Section 12.10.2
Description of Change:
 
 
Purpose for Change: 
61.
Section 13.2.2
Description of Change: 
Original text:
The Full Analysis Set (FAS) will be composed of all subjects with available 
bleeding data gathered during prophylaxis IP treatment.
New text:
The Full Analysis Set (FAS) will be composed of all subjects who receive
prophylaxis IP treatment.
Purpose for Change: To re-define FAS.
62.
Section 13.2.3
Description of Change: 
Details were added on how to measure the compliance. 
Purpose for Change: To add clarifications.
63.
Section 13.2.4
Description of Change: 
Wording added to clarify PK analysis set is also for PD analysis. 
Purpose for Change: To add clarifications.
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64.
Section 13.4.2.2, Section 13.4.2.3 
Description of Change:
 
 
 
 
Purpose for Change: 
 
65.
Section 13.4.3.1, Section 13.4.3.2, Section 13.4.3.3 and Section 13.4.3.4
Description of Change: 
 
 
 
 
Purpose for Change: 
 
66.
Section 13.5
Description of Change:
Removed the interim analysis 
Purpose for Change: No interim analysis is planned.
67.
Section 15.5
Description of Change:
Additional instruction was provided to ensure the compliance by adding the text 
“Also, the investigator will notify the sponsor immediately by phone and confirm 
notification to the sponsor in writing whenever pdVWF is used instead of rVWF. 
The reason for this use must also be provided to the sponsor”.
Purpose for Change: To ensure compliance.
68.
Section 20.1
Description of Change:
The study flow chart was updated to reflect the addition of switch cohort and to 
illustrate the study design for this new cohort.
Purpose for Change: To update the study design.
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69. Section 20.2, Section 20.2.1
Description of Change:
Some clarifications were made to the tables and the footnotes, the original 
Table 6 was changed to 6a and specified just for on-demand subjects, Table 6b 
that is for switch subjects was added. 
Purpose for Change: To provide schedule for the switch subjects and to provide 
clarifications for surgery procedure schedule.
70. Section 20.3, Section 20.3.1
Description of Change: 
Some clarifications were made to the tables and the footnotes, the original 
Table 8 was changed to 8a and specified just for on-demand subjects, Table 8b 
that is for switch subjects was added. 
Purpose for Change: To provide schedule for the switch subjects and to provide 
clarifications for surgery lab assessments.
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INVESTIGATOR ACKNOWLEDGEMENT
RECOMBINANT VON WILLEBRAND FACTOR (rVWF)
A prospective, phase 3, open-label, international multicenter study on efficacy and 
safety of prophylaxis with rVWF in severe von Willebrand Disease
PROTOCOL IDENTIFIER: 071301
CLINICAL TRIAL PHASE 3
LOCAL AMENDMENT 7 (GERMANY): 2018 MAY 18
Replaces: LOCAL AMENDMENT 4 (GERMANY): 2017 AUG 04
OTHER PROTOCOL ID(s)
NCT Number: NCT02973087
EudraCT Number: 2016-001478-14
IND NUMBER: 013657
By signing below, the investigator acknowledges that he/she has read and understands 
this protocol, and will comply with the requirements for obtaining informed consent from 
all study subjects prior to initiating any protocol-specific procedures, obtaining written 
initial and ongoing EC(s) protocol review and approval, understands and abides by the 
requirements for maintenance of source documentation, and provides assurance that this 
study will be conducted according to all requirements as defined in this protocol, Clinical 
Trial Agreement, ICH GCP guidelines, and all applicable national and local regulatory 
requirements.
Signature of Principal Investigator
Date
Print Name of Principal Investigator
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CLINICAL STUDY PROTOCOL
PRODUCT: Recombinant Von Willebrand Factor (rVWF, vonicog alfa)
STUDY TITLE: A PROSPECTIVE, PHASE 3, OPEN-LABEL, 
INTERNATIONAL MULTICENTER STUDY ON EFFICACY AND SAFETY OF 
PROPHYLAXIS WITH rVWF IN SEVERE VON WILLEBRAND DISEASE
STUDY SHORT TITLE: rVWF IN PROPHYLAXIS
PROTOCOL IDENTIFIER: 071301
CLINICAL TRIAL PHASE 3
LOCAL AMENDMENT 8 (CZECH REPUBLIC): 2018 MAY 18
Replaces: 
LOCAL AMENDMENT 5 (Czech Republic): 2017 AUG 08
ALL VERSIONS: 
Local (Czech Republic) Amendment 8: 2018 MAY 18
Local (Germany) Amendment 7: 2018 MAY 18
Amendment 6: 2018 MAR 12
Local (Czech Republic) Amendment 5: 2017 AUG 08
Local (Germany) Amendment 4: 2017 AUG 04
Amendment 3: 2017 AUG 03
Amendment 2: 2016 DEC 15
Amendment 1: 2016 APR 08
Original: 2014 FEB 19
OTHER ID(s)
NCT Number: NCT02973087
EudraCT Number: 2016-001478-14
IND NUMBER: 013657
Study Sponsor(s):
Baxalta US Inc.
300 Shire Way
Lexington, MA 02421,
UNITED STATES
Baxalta Innovations GmbH
Industriestrasse 67
A-1221 Vienna, 
AUSTRIA
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1. STUDY PERSONNEL
1.1 Authorized Representative (Signatory) / Responsible Party
, MD
Global Clinical Development Operations
Baxalta Innovations GmbH
1.2 Study Organization
The name and contact information of the responsible party and individuals involved with 
the study (e.g. investigator(s), sponsor’s medical expert and study monitor, sponsor’s 
representative(s), laboratories, steering committees, and oversight committees [including 
ethics committees (ECs)], as applicable) will be maintained by the sponsor and provided 
to the investigator.
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2. SERIOUS ADVERSE EVENT REPORTING
The investigator will comply with applicable laws/requirements for reporting serious 
adverse events (SAEs) and suspected unexpected serious adverse events (SUSARs) to the 
ECs.
ALL SAEs, INCLUDING SUSARs, ARE TO BE REPORTED ON THE SERIOUS 
ADVERSE EVENT REPORT (SAER) FORM AND TRANSMITTED TO THE 
SPONSOR WITHIN 24 HOURS AFTER BECOMING AWARE OF THE EVENT.
Bleeding events that meet seriousness criteria (death, life-threatening, 
hospitalizing/prolongation of hospitalization, disability, congenital anomaly, or medically 
significant and if not urgently treated would result in one of the above) should be 
reported on the SAE eCRF and SAE Report form as an SAE.
Drug Safety contact information:
Baxalta Global Drug Safety fax number:  
OR 
email: 
For definitions and information on the assessment of these events, refer to the following:

Adverse Events (AEs), Section 12.1

SAEs, Section 12.1.1.1

SUSARs, Section 12.1.1.2

Assessment of AEs, Section 12.1.2

Safety Reporting, Section 12.1.2.3
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3. SYNOPSIS
INVESTIGATIONAL PRODUCT
Name of Investigational Product (IP)
Recombinant von Willebrand factor (rVWF, vonicog alpha)
Name(s) of Active Ingredient(s)
Recombinant von Willebrand factor (rVWF, vonicog alpha)
CLINICAL CONDITION(S)/INDICATION(S)
Subjects with severe von Willebrand disease (VWD) (baseline VWF: Ristocetin cofactor activity
(VWF:RCo) <20 IU/dL) requiring prophylactic treatment with coagulation factor replacement
PROTOCOL ID
071301
PROTOCOL TITLE
A prospective, phase 3, open-label, international multicenter 
study on efficacy and safety of prophylaxis with rVWF in severe 
von Willebrand disease
Short Title
rVWF in prophylaxis
STUDY PHASE
Phase 3
PLANNED STUDY PERIOD
Initiation
2017 OCT
Primary Completion
2019 Q4
Study Completion
2019 Q4
Duration
27 months
STUDY OBJECTIVES AND PURPOSE
Study Purpose
The purpose of this phase 3 study is to investigate the efficacy and safety, including immunogenicity, 
thrombogenicity and hypersensitivity reactions, as well as pharmacokinetics (PK),
 
and 
 of prophylactic treatment with rVWF (vonicog alfa) in adult 
subjects with severe VWD.
Primary Objective
The primary objective of this study is to prospectively evaluate the annualized bleeding rate (ABR) for
spontaneous bleeding episodes while on prophylactic treatment with rVWF (vonicog alfa) and to compare 
it to the subject’s historical ABR for spontaneous bleeding episodes. 
Secondary Objectives
Secondary Objectives are to assess

Additional efficacy of prophylactic treatment with rVWF (vonicog alfa)

Safety of rVWF (vonicog alfa), including immunogenicity, thrombogenicity and hypersensitivity

Pharmacokinetics (PK) of rVWF (vonicog alfa) and Pharmacodynamics (PD) of rVWF (vonicog alfa)
as measured in FVIII activity
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Exploratory Objectives
 
 
 
STUDY DESIGN
Study Type/ Classification/ Discipline
Efficacy and Safety 
Control Type
No control
Study Indication Type
Prophylaxis and treatment of bleeding episodes
Intervention model 
Single-group
Blinding/Masking
Open-label
Study Design
This is a phase 3, prospective, open-label, uncontrolled, non-
randomized, international multicenter study evaluating efficacy, 
safety, including immunogenicity, thrombogenicity and 
hypersensitivity reactions, as well as PK, 
and 
 of prophylactic treatment regimen with 
rVWF (vonicog alfa) in adult subjects with severe VWD.
Subjects transitioning from on-demand treatment (OD subjects) 
or subjects switching from prophylactic treatment with pdVWF 
(pdVWF switch subjects) will receive prophylactic treatment 
with rVWF (vonicog alfa) for a 12-month period.
Planned Duration of Subject 
Participation
Approximately 15 months 
Primary Outcome Measure 
Efficacy

Annualized bleeding rate (ABR) for spontaneous (not related to trauma) bleeding episodes during 
prophylactic treatment with rVWF (vonicog alfa)
Secondary Outcome Measures
Additional efficacy of prophylactic treatment with rVWF (vonicog alfa)

ABR percent reduction success for OD subjects defined as at least 25% reduction of ABR for
spontaneous (not related to trauma) bleeding episodes during rVWF (vonicog alfa) prophylaxis 
relative to the subject’s own historical ABR during on-demand treatment
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
ABR preservation success for pdVWF switch subjects defined as achieving an ABR for spontaneous 
bleeding episodes during rVWF (vonicog alfa) prophylaxis that is no greater than the subject’s own 
historical ABR during prophylactic treatment with pdVWF 

Categorized spontaneous ABR defined as 0, 1-2, 3-5, or >5 bleeding episodes during the 12-month 
prophylactic treatment with rVWF (vonicog alfa)

Total number of infusions and the average number of infusions per week during prophylactic 
treatment with rVWF (vonicog alfa)

Total weight adjusted consumption of rVWF (vonicog alfa) during prophylactic treatment

Spontaneous ABR by location of bleeding (Gastrointestinal [GI], epistaxis, joint bleeding, 
menorrhagia, oral and other mucosa, muscle and soft tissue, etc.) while on prophylactic treatment with 
rVWF (vonicog alfa)
Safety

Adverse events (AEs) : incidence, severity, causality

Thromboembolic events 

Hypersensitivity reactions

Development of neutralizing antibodies to VWF and FVIII 

Development of total binding antibodies to VWF and FVIII

Development of binding antibodies to Chinese hamster ovary (CHO) proteins, mouse 
immunoglobulin G (IgG) and rFurin

Clinically significant changes in vital signs and clinical laboratory parameters relative to baseline
Pharmacokinetics (PK) and Pharmacodynamics (PD)

PK parameters after a washout for on-demand subjects: incremental recovery (IR), terminal half-life
(T1/2), mean residence time (MRT), area under the concentration versus time curve from 0 to infinity 
(AUC0-), area under the concentration versus time curve from 0 to the last measurable concentration 
(AUC0-tlast), maximum concentration (Cmax), minimum time to reach the maximum concentration
(Tmax), volume of distribution at steady state (Vss) and clearance (CL) based on VWF:RCo, Von 
Willebrand factor antigen (VWF:Ag), Von Willebrand collagen binding activity (VWF:CB).

PD parameters after a washout for on-demand subjects: Cmax, Tmax, and AUC0-tlast as measured in 
FVIII activity by the 1-stage clotting assay (FVIII:C). 

PK parameters at steady state for on-demand and switch subjects: area under the concentration versus 
time curve from 0 to end of the partial dosing interval (AUC0- tau;ss), maximum concentration during 
the partial dosing interval (Cmax;ss), minimum time to reach the maximum concentration (Tmax;ss) and 
minimum concentration during the partial dosing interval (Cmin;ss) based on VWF:RCo, VWF:Ag and 
VWF:CB. PK parameters at steady state will be assessed shortly after reaching steady state for switch 
subjects and at the end of the study for on-demand as well as for switch subjects all based on the 
longer interval of the irregular dosing intervals employed.

PD parameters at steady state for on-demand and switch subjects: AUC0-tau;ss, Cmax;ss, Tmax;ss, and 
Cmin;ss as measured in FVIII actvitiy by the 1-stage clotting assay (FVIII:C). PD parameters at steady 
state will be assessed shortly after reaching steady state for switch subjects and at the end of the study 
for on-demand as well as for switch subjects all based on the longer interval of the irregular dosing 
intervals employed.

Time course of FVIII clotting activity (FVIII:C) levels.
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Exploratory Outcome Measures
 
 
 
 
 
 
 
 
 
 
INVESTIGATIONAL PRODUCT(S), DOSE AND MODE OF ADMINISTRATION
Active Product
Dosage form: powder and solvent for solution for injection
Dosage frequency:
Prophylactic Treatment
Subjects transitioning from on-demand treatment will receive twice weekly
infusion with rVWF (vonicog alfa) at doses of 50 ± 10 IU/kg rVWF:RCo. Dosage 
may be individualized within this range based on:

available historical PK data

type and severity of bleeding episodes the subject has experienced in the past

monitoring of appropriate clinical and laboratory measures
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The starting dose can, after consultation with the Sponsor, be increased up to 
80 U/kg if considered necessary to assure effective prophylaxis.
Subjects switching from pdVWF prophylaxis treatment: the weekly dose (IU/kg) 
of rVWF (vonicog alfa) for each patient will be equivalent (± 10%) to the weekly 
VWF dose received during prophylactic treatment with pdVWF. The weekly dose 
should be divided into 2 infusions, with a maximum of 80 IU/kg/infusion. If 
needed, based on the total weekly dose or other clinical judgements, the weekly 
dose may be given as three infusions. A once weekly dose regimen will be 
allowed after switch to rVWF (vonicog alfa) if the patient has been on a once 
weekly dose regimen with pdVWF. Dose and dose interval may, after 
consultation with the sponsor, be further individualized based on: 

available historical PK data

type and severity of bleeding episodes the subject has experienced in the past

monitoring of appropriate clinical and laboratory measures
Treatment of Bleeding Episodes:
Dosage must be individualized based on the subject’s weight, type and severity of 
bleeding episode and monitoring of appropriate clinical and laboratory measures. 
In general, an initial dose of 40-60 IU/kg VWF:RCo with or without 30-45 IU 
rFVIII [ADVATE, octocog alfa]/kg is recommended (rVWF:rFVIII ratio of 1.3:1: 
± 0.2). In cases of major bleeding episodes, a dose of up to 80 IU/kg VWF:RCo 
may be infused. Subsequent doses, if necessary, will be administered with or 
without ADVATE (rFVIII, octocog alfa) to maintain VWF:RCo and FVIII levels 
for as long as deemed necessary by the investigator.
Mode of Administration: intravenous
SUBJECT SELECTION
Targeted Accrual
Approximately 22 adult subjects with severe VWD will be included to have 
≥8 subjects in each cohort (OD and switch). A total of at least 5 type 3 VWD 
subjects will be followed for 12 months.
Number of Groups/
Arms/ Cohorts
Single-group
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Inclusion Criteria
Subjects who meet ALL of the following criteria are eligible for this study:
1. Subject has a documented diagnosis of severe VWD (baseline VWF:RCo <20 IU/dL) with a history 
of requiring substitution therapy with von Willebrand factor concentrate to control bleeding:
a. Type 1 (VWF:RCo <20 IU/dL) or,
b. Type 2A (as verified by multimer pattern), Type 2B (as diagnosed by genotype), Type 2M or,
c. Type 3 (VWF:Ag ≤3 IU/dL).
2. Diagnosis is confirmed by genetic testing and multimer analysis, documented in patient history or at 
screening.
3. For on-demand patient group, subject currently receiving on-demand treatment for whom prophylactic 
treatment is recommended by the investigator.
4. For pdVWF switch patient group, subject has been receiving prophylactic treatment of pdVWF 
products for no less than 12 months prior to screening.
5. For on-demand patient group, subject has ≥3 documented spontaneous bleeds (not including 
menorrhagia) requiring VWF treatment during the past 12 months.
6. Availability of records to reliably evaluate type, frequency and treatment of bleeding episodes during 
at least 12 months preceding enrollment. Up to 24 months of retrospective data should be collected if 
available. Availability of dosing and factor consumption during 12 months (up to 24 months) of 
treatment prior to enrollment is required for pdVWF switch subjects and is desired (but not a 
requirement) for on-demand subjects.
7. Subject is ≥18 years old at the time of screening and has a body mass index ≥17.5 but <40 kg/m2.
8. If female of childbearing potential, subject presents with a negative blood/urine pregnancy test at 
screening and agrees to employ adequate birth control measures for the duration of the study.
9. Subject is willing and able to comply with the requirements of the protocol.
Exclusion Criteria
Subjects who meet ANY of the following criteria are not eligible for this study:
1. The subject has been diagnosed with Type 2N VWD, pseudo VWD, or another hereditary or acquired 
coagulation disorder other than VWD (e.g., qualitative and quantitative platelet disorders or elevated
prothrombin time (PT)/international normalized ratio [INR] 1.4).
2. The subject is currently receiving prophylactic treatment with more than 5 infusions per week.
3. The subject is currently receiving prophylactic treatment with a weekly dose exceeding 240 IU/kg.
4. The subject has a history or presence of a VWF inhibitor at screening.
5. The subject has a history or presence of a FVIII inhibitor with a titer ≥0.4 Bethesda units (BU) (by 
Nijmegen modified Bethesda assay) or ≥0.6 BU (by Bethesda assay).
6. The subject has a known hypersensitivity to any of the components of the study drugs, such as to 
mouse or hamster proteins.
7. The subject has a medical history of immunological disorders, excluding seasonal allergic 
rhinitis/conjunctivitis, mild asthma, food allergies or animal allergies.
8. The subject has a medical history of a thromboembolic event.
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9. The subject is human immunodeficiency virus (HIV) positive with an absolute Helper T cell 
(CD4) count 200/mm3.
10. The subject has been diagnosed with significant liver disease per investigator’s medical assessment of 
the subject’s current condition or medical history or as evidenced by any of the following: serum 
alanine aminotransferase (ALT) greater than 5 times the upper limit of normal; hypoalbuminemia; 
portal vein hypertension (e.g., presence of otherwise unexplained splenomegaly, history of esophageal 
varices).
11. The subject has been diagnosed with renal disease, with a serum creatinine (CR) level ≥2.5 mg/dL.
12. The subject has a platelet count <100,000/mL at screening.
13. The subject has been treated with an immunomodulatory drug, excluding topical treatment (e.g., 
ointments, nasal sprays), within 30 days prior to signing the informed consent.
14. The subject is pregnant or lactating at the time of enrollment.
15. Patient has cervical or uterine conditions causing menorrhagia or metrorrhagia (including infection, 
dysplasia).
16. The subject has participated in another clinical study involving another investigational product (IP) or 
investigational device within 30 days prior to enrollment or is scheduled to participate in another 
clinical study involving an IP or investigational device during the course of this study.
17. The subject has a progressive fatal disease and/or life expectancy of less than 15 months.
18. The subject is scheduled for a surgical intervention.
19. The subject is identified by the investigator as being unable or unwilling to cooperate with study 
procedures.
20. The subject has a mental condition rendering him/her unable to understand the nature, scope and 
possible consequences of the study and/or evidence of an uncooperative attitude.
21. The subject is in prison or compulsory detention by regulatory and/or juridical order
22. The subject is member of the study team or in a dependent relationship with one of the study team 
members which includes close relatives (i.e., children, partner/spouse, siblings and parents) as well as 
employees.
Delay criteria
1. If the subject presents with an acute bleeding episodes or acute illness (e.g., influenza, flu-like 
syndrome, allergic rhinitis/conjunctivitis, non-seasonal asthma) the screening visit will be postponed 
until the subject has recovered.
STATISTICAL ANALYSIS
Sample Size Calculation
Approximately 22 adult subjects with severe VWD will be included in the study. The aim is to have
≥8 subjects in each cohort (OD and switch). A total of at least five type 3 VWD subjects will be followed 
for 12 months. The sample size is driven by practical considerations (primarily the enrollment of a rare 
patient population) and EMA Guideline on the Clinical Investigation of Human Plasma Derived von 
Willebrand Factor Products (CPMP/BPWG/220/02).1
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Planned Statistical Analysis
The Full Analysis Set (FAS) will be composed of all subjects who receive prophylaxis IP treatment.
The Safety Analysis Set will be composed of all subjects who received any amount of IP  (rVWF, vonicog 
alpha).
The Per-Protocol (PP) Analysis Set will be composed of subjects who are at least 70% compliant regarding 
the number of scheduled prophylactic infusions. Only subjects who meet all study entry criteria and who 
have no major protocol violations that might impact primary efficacy assessments will be included in the 
PP analysis set.
The Pharmacokinetic Full Analysis Set (PKFAS) will be composed of all subjects who received the PK 
infusion and who provided acceptable data for PK and PD analysis. Acceptable PK/PD data will be defined 
in the Statistical Analysis Plan.
Primary Outcome Measure:
No formal statistical hypothesis test is planned for the analysis. Spontaneous ABR while treated with 
rVWF (vonicog alfa) for each cohort, on demand and switch subjects, will be estimated using a negative 
binomial regression. The prior ABR for each cohort will be based on historical data collected from each 
enrolled subject. The two ABRs (observed on the study and historical) will be assessed using a generalized 
linear mixed-effects model (GLMM) with the negative binomial distribution as a family and with a 
logarithmic link function (the default). The ABR ratio together with a two-sided, 95% confidence interval 
(CI) will be reported for each cohort.
The difference in on-study ABR relative to historical ABR will be summarized descriptively.
The primary efficacy analysis will be based on the FAS and will be summarized by the two cohorts: on-
demand and switch subjects. As a supportive analysis, the same analysis will also be carried out on the PP
analysis set.
Secondary Outcome Measures:
In general, data for  secondary efficacy analysis will be summarized by the two cohorts: on-demand and 
switch subjects and when applicable overall. Mean, standard deviation, median, range, quartiles will be 
calculated for continuous endpoints. Proportions will be calculated for categorical endpoints. Confidence 
intervals at the 95% level will be provided when appropriate.
Additional efficacy of prophylactic treatment with  rVWF (vonicog alfa):
The number  and proportion of on-demand subjects with ABR percent reduction success (i.e. ≥ 25% ) will 
be calculated together with a two-sided 95% CI for the proportion. 
The number and proportion of pdVWF switch subjects with ABR preservation success will be reported 
together with the corresponding 95% two-sided CIs for the proportion. 
The number and proportion of subjects with categorized spontaneous ABR (i.e. 0, 1-2, 3-5, more than 
5 bleeds) will be reported descriptively.
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Summary statistics for the total number of infusions, as well as average number of infusions per week will 
be provided. The total weight adjusted consumption of rVWF (vonicog alfa) during prophylactic treatment 
will be provided. If applicable, historical data on consumption of pdVWF prior to the study will be 
summarized as well.
The change in spontaneous ABR from the historical rate to that during the rVWF (vonicog alfa)
prophylaxis period will be summarized by location of bleeding (GI, epistaxis, joint bleeding, 
menorrhagia, oral and other mucosa, muscle and soft tissue, etc.).
Pharmacokinetics (PK) and Pharmacodynamics (PD):
The following PK parameters, based on the initial PK assessment after a washout for on-demand subjects, 
will be listed and summarized descriptively for VWF:RCo, VWF:Ag and VWF:CB: IR, T1/2, MRT, 
AUC0-, AUC0-tlast, Cmax, Tmax, Vss, and CL. The corresponding pharmacodynamics (PD) of rVWF 
(vonicog alfa) as measured in FVIII activity (FVIII:C), based on the initial PK assessment after a 
washout for on-demand subjects will be assessed using Cmax, Tmax, and AUC0-tlast. These PD parameters 
will be listed and summarized descriptively. 
PK parameters at steady state (AUC0-tau;ss, Cmax;ss, Tmax;ss, and Cmin;ss) for the partial dosing interval will be 
listed for on-demand subjects at the end of the study and for switch subjects shortly after reaching steady 
state and at the end of the study for VWF:RCo, VWF:Ag and VWF:CB and summarized descriptively for 
subjects with the same dosing regimens. The corresponding pharmacodynamics (PD) of rVWF (vonicog 
alfa) as measured in FVIII activity (FVIII:C) will be assessed using AUC0-tau;ss, Cmax;ss, Tmax;ss, and Cmin;ss. 
These PD parameters will be listed for on-demand subjects at the end of the study and for switch subjects 
shortly after reaching steady state and at the end of the study and will be summarized descriptively for
subjects with the same dosing regimens. 
For the on-demand subjects, the PK of VWF:RCo will be analyzed using a population PK approach to 
characterize the single and multiple dose pharmacokinetics, including associated variability, of VWF:RCo 
in the study population.
For the switch subjects, differences in AUC0-tau;ss, Cmax;ss, and Cmin;ss assessess shortly after reaching steady 
state and assessed at the end of the study will be assessed by ratio of geometric means and corresponding 
two-sided 95% confidence intervals for VWF:RCo, VWF:Ag, VWF:CB, and FVIII:C. The difference in 
Tmax;ss, between first and second pharmacokinetic assessment will be summarized by the median and range 
(minimum to maximum) for VWF:RCo, VWF:Ag,VWF:CB, and FVIII:C.
Descriptive statistics will be used to summarize VWF:RCo, VWF:Ag, VWF:CB, and FVIII:C levels for 
each nominal time point on the PK curve. For all subjects activity/concentration vs. time curves will be 
prepared.
Safety:
Safety analysis will be performed overall and by the two cohorts: on-demand and switch subjects.
Treatment-emergent AEs (TEAEs) are defined as AEs with start dates on or after the first exposure to IP. 
Summaries of AEs will be based on TEAEs unless otherwise indicated.
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Occurrence of AEs and serious AEs (SAEs) will be summarized descriptively, by system organ class and 
preferred term. The number and percentage of subjects who experienced AEs and SAEs, and the number of 
AEs and SAEs will be tabulated. In addition, the number of subjects who experienced AEs assessed as 
related to IP by the investigator, and the number of IP-related AEs will be tabulated. The number of 
patients with AEs by severity will be presented similarly.
A listing of all AEs will be presented by subject identifier, age, sex, preferred term and reported term of the 
AE, duration, severity, seriousness, action taken, outcome, causality assessment by investigator, onset date, 
stop date and medication or non-drug therapy to treat the AE. 
Temporally associated AEs are defined as AEs that begin during infusion or within 24 hours (or 1 day 
where time of onset is not available) after completion of infusion, irrespective of being related or not 
related to treatment. Temporally associated AEs will be presented in summary tables.
Adverse events of special interest (AESI), such as hypersensitivity reactions and thromboembolic events,  
will be monitored throughout the study and statistical analysis will be conducted based on the search 
criteria (eg, standardized MedDRA queries [SMQ]) determined prior to database lock, and summarized.
For immunogenicity analysis frequency counts and proportions will be calculated for subjects with the 
occurrence of neutralizing (inhibitory) antibodies to VWF and FVIII, occurrence of binding antibodies to 
VWF and FVIII, and occurrence of binding antibodies to CHO proteins, mouse immunoglobulin G (IgG) 
and rFurin.
Clinically significant changes relative to baseline in vital signs and clinical laboratory parameters 
(hematology, clinical chemistry) will be reported.
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4. TABLE OF CONTENTS
1. STUDY PERSONNEL ................................................................................................. 2
1.1 Authorized Representative (Signatory) / Responsible Party .............................. 2
1.2 Study Organization................................................................................................. 2
2. SERIOUS ADVERSE EVENT REPORTING........................................................... 3
3. SYNOPSIS..................................................................................................................... 4
4. TABLE OF CONTENTS ........................................................................................... 14
5. LIST OF ABBREVIATIONS .................................................................................... 20
6. BACKGROUND INFORMATION .......................................................................... 24
6.1 Description of Investigational Product ............................................................... 24
6.2 Clinical Condition/Indication .............................................................................. 24
6.3 The Role of Prophylaxis in the Management of VWD...................................... 25
6.4 Populations to be Studied..................................................................................... 27
6.5 Findings from Nonclinical and Clinical Studies................................................. 28
6.5.1 Findings from Nonclinical Studies ............................................................... 28
6.5.1.1 Primary Pharmacodynamics................................................................. 28
6.5.1.2 Safety Pharmacology.............................................................................. 28
6.5.1.3 Pharmacokinetics.................................................................................... 29
6.5.1.4 Toxicology................................................................................................ 29
6.5.2 Findings from Clinical Studies ..................................................................... 30
6.5.2.1 Study 070701 ........................................................................................... 30
6.5.2.2 Study 071104 ........................................................................................... 32
6.5.2.3 Study 071001 ........................................................................................... 33
6.5.2.4 Study 071101 ........................................................................................... 35
6.5.2.5 Study 071401: Single Subject with von Willebrand Disease............... 37
6.6 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) 
to Human Subjects................................................................................................ 37
6.7 Compliance Statement.......................................................................................... 38
7. STUDY PURPOSE AND OBJECTIVES ................................................................. 39
7.1 Study Purpose ....................................................................................................... 39
7.2 Primary Objective................................................................................................. 39
7.3 Secondary Objectives ........................................................................................... 39
7.4 Exploratory Objectives......................................................................................... 39
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10.2 Subject Identification Code................................................................................ 62
10.3 Screening and Study Visits................................................................................. 62
10.3.1 Screening Visit ............................................................................................. 62
10.3.2 Baseline Visit – Initial PK Assessment (On-demand Subjects Only)...... 63
10.3.3 Prophylaxis Initiation Visit......................................................................... 64
10.3.4 Initial Steady State PK-Assessment (pdVWF switch subjects only)....... 64
10.3.5 Treatment of Bleeding Episodes................................................................. 65
10.3.6 Perioperative Visits (only applicable if surgery is needed)...................... 65
10.3.7 Follow-Up Visits (1 Month ± 1 Week, 2 Months ± 1 Week, 
3 Months ± 2 Weeks, 6 Months ± 2 Weeks, 9 Months ± 2 Weeks post 
Prophylaxis Initiation Visit) ......................................................................... 65
10.3.8 Unscheduled Visits....................................................................................... 67
10.3.9 End of Study PK Assessment and Study Termination Visit 
(12 Months ± 2 Weeks post Prophylaxis Initiation Visit).......................... 67
10.4 Medications and Non-Drug Therapies.............................................................. 68
10.5 Subject Diary....................................................................................................... 68
10.6 Subject Completion/Discontinuation ................................................................ 69
10.7 Procedures for Monitoring Subject Compliance............................................. 70
11. ASSESSMENT OF EFFICACY AND PHARMACOKINETICS........................ 71
11.1 Assessment of Spontaneous Bleeding Episodes/Annualized Bleed Rate........ 71
11.2 Evaluation of ABR Before rVWF Prophylaxis and ABR Under rVWF 
Prophylactic Treatment ....................................................................................... 72
11.3 Number of Infusions and Total Weight Adjusted Consumption of rVWF and 
ADVATE and historical prophylaxis dosing and factor consumption during 
pdVWF prophylaxis treatment prior to enrollment.......................................... 72
11.4 Assessment of Efficacy for Treatment of Bleeding Episode ........................... 72
11.5 Assessment of Efficacy for Treatment for Surgical Bleeding......................... 73
11.6 rVWF Pharmacokinetics and Pharmacodynamics ......................................... 74
12. ASSESSMENT OF SAFETY................................................................................... 76
12.1 Adverse Events.................................................................................................... 76
12.1.1 Definitions..................................................................................................... 76
12.1.1.1 Serious Adverse Event.......................................................................... 76
12.1.1.2 Suspected Unexpected Serious Adverse Reaction (SUSAR)............. 77
12.1.1.3 Non-Serious Adverse Event ................................................................. 78
12.1.1.4 Unexpected Adverse Events................................................................. 78
12.1.1.5 Preexisting Disease ............................................................................... 78
12.1.2 Assessment of Adverse Events.................................................................... 78
12.1.2.1 Severity .................................................................................................. 80
12.1.2.2 Causality................................................................................................ 81
12.1.2.3 Safety Reporting ................................................................................... 82
12.2 Urgent Safety Measures ..................................................................................... 84
12.3 Untoward Medical Occurrences........................................................................ 84
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18. FINANCING AND INSURANCE......................................................................... 111
19. PUBLICATION POLICY...................................................................................... 111
20. SUPPLEMENTS..................................................................................................... 112
20.1 Study Flow Chart.............................................................................................. 112
20.2 Schedule of Study Procedures and Assessments............................................ 113
20.2.1 Summary Schedule of Visit Assesments for Surgical Bleeding............. 117
20.3 Clinical Laboratory Assessments .................................................................... 119
20.3.1 Laboratory Sampling for Surgical Bleeding ........................................... 123
20.4 Contraceptive Methods for Female Subjects of Childbearing Potential..... 125
21. REFERENCES........................................................................................................ 126
22. SUMMARY OF CHANGES.................................................................................. 129
INVESTIGATOR ACKNOWLEDGEMENT............................................................ 143
Tables
Table 1 rVWF (vonicog alfa) Dosing Schedule Examples: Schedules A and B............. 47
Table 2 Criteria for Escalation Specific to Each Bleeding Indication............................. 49
Table 3 rVWF:RCo Dosing Recommendations for the Treatment of Bleeding Episodes 
Due to VWD ............................................................................................................. 53
Table 4 Efficacy Rating Scale.......................................................................................... 73
Table 5 Assessment of Hemostatic Efficacy ................................................................... 74
Table 6a Schedule of Study Procedures and Assessments for On-demand Subject...... 113
Table 6b Schedule of Study Procedures and Assessments for pdVWF Switch Subject 115
Table 7 Summary Schedule of Visit Assesments for Surgical Bleeding....................... 117
Table 8a Clinical Laboratory Assessments for On-demand Subject ............................. 119
Table 8b Clinical Laboratory Assessments for pdVWF Switch Subject
121
Table 9 Laboratory Samplinga for Surgical Bleeding.................................................... 123
Figures
Figure 1 Study Design for Baxalta Clinical Study 071301............................................ 112
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5. LIST OF ABBREVIATIONS
Abbreviation
Definition
ABR
Annualized bleeding rate
ADAMTS13
A Disintegrin And Metalloproteinase with a Thrombospondin type 1 motif, number 13
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine aminotransferase
AP
Alkaline phosphatase
AST
Aspartate aminotransferase
AUC0-∞
Area under the plasma concentration /time curve from time 0 to infinity
AUC0-tau;ss
Area under the plasma concentration /time curve from time 0 to end of the partial 
dosing interval
AUC0-tlast
Area under the plasma concentration /time curve from 0 to the last measurable 
concentration
aPTT
Activated partial thromboplastin time
B19V
Parvovirus B19
BP
Blood pressure
BU
Bethesda Unit
BUN
Blood urea nitrogen
BW
Body weight
CAM
Cell adhesion molecule
CBC
Complete blood count
CD4
Helper T cell
CHO
Chinese hamster ovary
CI
Confidence interval
Cl
Chloride
CL
Clearance
Cmax
Maximum plasma concentration
Cmax;ss
Maximum plasma concentration during the partial dosing interval at steady state
Cmin;ss
Minimum plasma concentration during the partial dosing interval at steady state
CR
Creatinine
CTA
Clinical Trial Agreement
eCRF
Electronic case report form
DMC
Data monitoring committee
DIC
Disseminated intravascular coagulation
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Abbreviation
Definition
DVT
Deep vein thrombosis
EC
Ethics committee
ECG
Electrocardiogram 
EDC
Electronic Data Capture
EDTA
Ethylenediaminetetraacetic acid
ELISA
Enzyme-linked immunosorbent assay
FAS
Full analysis set
FVIII
Factor VIII
FVIII:C
Factor VIII clotting activity
GCP
Good Clinical Practice
GI
Gastrointestinal
Glu
Glucose
HAMA
Human anti- mouse antibodies
HAV
Hepatitis A virus
HB
Hepatitis B
HBs
Hepatitis B surface
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HEV
Hepatitis E virus
HIV
Human immunodeficiency virus 
HLA
Human leukocyte antigen
HRP
Horseradish peroxidase
IB
Investigator's brochure
ICH
International Council for Harmonisation
Ig
Immunoglobulin
INN
International Nonproprietary Name
INR
International normalized ratio
IP
Investigational product
IR
Incremental recovery
i.v.
Intravenous
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Abbreviation
Definition
K
Potassium
k.o.
Knock out
LDH
Lactate Dehydrogenase
Na
Sodium
NMC
Non-medical complaint
NOAEL
No observed adverse effect level
MRI
Magnetic resonance imaging
MRT
Mean residence time
pdVWF
Plasma derived VWF product
pdVWF/FVIII
Plasma derived VWF product containing fractions of FVIII
PBAC
Pictorial Blood Assessment Chart
PCR
Polymerase Chain Reaction
PEF
Peak expiratory flow
PK
Pharmacokinetic
PKFAS
Pharmacokinetic Full Analysis Set
PKPPAS
Pharmacokinetic Per Protocol Analysis Set
PP
Per protocol 
PT
Prothrombin time
Q1, Q3
Quartile
rFVIII
Recombinant factor VIII
rVWF
Recombinant von Willebrand factor
RBC
Red blood cell count
SAE
Serious adverse event
SAER
Serious adverse event report
SDS-PAGE
Sodium dodecyl sulfate polyacrylamide gel electrophoresis
SIC
Subject identification code
SMQ
Standardised MedDRA queries 
sP-selectin
Soluble P-selectin
SUSAR
Suspected unexpected serious adverse reaction
T1/2
Terminal phase half life
TEAE
Treatment-emergent adverse event
TIA
Transient ischemic attack
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Abbreviation
Definition
Tmax
Minimum time to reach the maximum concentration
Tmax;ss
Minimum time to reach the maximum concentration at steady state
TTP
Thrombotic thrombocytopenic purpura
ULMW
Ultra-large molecular weight 
ULN
Upper limit of normal
Vss
Volume of distribution at steady state
VTE
Venous thromboembolism 
VWD
von Willebrand disease
VWF
Von Willebrand factor
VWF:Ag
Von Willebrand factor antigen
VWF:CB
Von Willebrand Factor collagen binding
VWF:RCo
Von Willebrand factor: Ristocetin cofactor activity
WBC
White blood cell
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6. BACKGROUND INFORMATION
6.1 Description of Investigational Product
Baxalta US Inc. (hereafter referred to as Baxalta or sponsor) has developed a human 
recombinant von Willebrand Factor (rVWF, vonicog alfa), which is co-expressed with 
recombinant factor VIII (rFVIII) in a Chinese hamster ovary (CHO) cell line and
separated during the subsequent downstream process. To address concerns regarding the 
risk of transmission of blood-borne pathogens that may be introduced by human plasma, 
no exogenously added raw materials of human or animal origin are employed in the cell 
culture, purification, or formulation of the final container product. The only proteins 
present in the final container product other than rVWF (vonicog alfa) are trace quantities 
of murine immunoglobulin (IgG, from the immunoaffinity purification), host cell (i.e., 
CHO) protein, rFurin (used to further process rVWF). rVWF (vonicog alfa) is intended 
for the treatment of von Willebrand disease (VWD).
rVWF (vonicog alfa) has been developed under the Baxalta internal code BAX111 and is 
used as investigational product (IP) in this study. rVWF (vonicog alfa) may be used with 
or without ADVATE (rFVIII, octocog alfa) for the treatment of bleeding episodes (see 
Section 8.6.4.4). See Section 8.6 for further information on the IPs and their usage in this 
study. A detailed description of rVWF (vonicog alfa) is also provided in the
Investigator’s Brochure (IB).
rVWF (vonicog alfa) was granted licensure in the United States in December 2015 under 
the brand name VONVENDI for the on-demand treatment and control of bleeding 
episodes in adults diagnosed with VWD; as of the date of this protocol VONVENDI is
not yet available on the market.
6.2 Clinical Condition/Indication
Von Willebrand Factor (VWF) is a large multimeric glycoprotein with a molecular 
weight that varies from 500 to 20,000 kDa. VWF is normally found in plasma and 
produced in the alpha-granules of platelets and in endothelial cell organelles known as 
the Weibel-Palade bodies. VWF mediates platelet adhesion and aggregation at sites of 
vascular injury, one of the key functions in primary hemostasis. VWF also serves to 
stabilize coagulation factor VIII (FVIII), where FVIII is an essential cofactor of 
secondary hemostasis, which leads to fibrin clot formation.2 Qualitative and/or 
quantitative deficiencies of VWF lead to a highly variable bleeding diathesis known as 
VWD, the most common of the hereditary coagulation factor deficiencies. Penetrance of 
VWD is highly variable, with only a small fraction of mildly affected patients displaying 
clinical symptoms or a family history of a bleeding diathesis.
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The current biochemical-based classification distinguishes disorders arising from partial 
quantitative (type 1), qualitative (type 2), or virtually complete (type 3) deficiencies of 
VWF. Up to 70% of VWD patients are diagnosed with type 1 VWD, which may also be 
associated with minor functional defects in the molecule. In general, patients with type 1 
VWD display mild clinical symptoms. Approximately 20 to 30% of VWD patients are 
diagnosed with type 2 VWD. Type 2 VWD is further divided into 4 subtypes (A, B, N, 
and M), reflecting distinct classes of functional abnormalities. These defects result in 
abnormal functional and/or multimeric distribution patterns that facilitate their diagnosis. 
The bleeding diathesis is usually moderate and primarily affects the mucosal tissues. 
Type 2N VWD patients are sometimes misdiagnosed as mild hemophilia A. Finally, 
approximately 1% percent of VWD patients exhibit a total or near total absence of VWF, 
which is classified as type 3 VWD. The incidence of type 3 VWD is estimated at 
0.5-1.0 x 106. This type is also associated with a very low FVIII level (typically <5%) 
because the VWF carrier function for FVIII is lost. Replacement of VWF alone stabilizes 
endogenous FVIII, resulting in hemostatic levels within several hours post-infusion. 
Published results from studies of a plasma-derived VWF (pdVWF) concentrate 
demonstrated an increase of FVIII at an approximate rate of 5.8 1 IU dL-1 h-1.3 Type 3 
VWD patients display severe hemorrhagic symptoms with bleeding predominantly in 
mucosal tissues, muscle and joints. All VWD patients, particularly those with type 2 or 
type 3 VWD, are at an increased risk for life-threatening bleeding episodes.
6.3 The Role of Prophylaxis in the Management of VWD
The goals of long term prophylaxis in VWD are to maintain VWF and FVIII at sufficient 
levels to reduce the frequency and duration of bleeding episodes, the need for red blood 
cell transfusions, and the risk of complications, such as arthropathy.4 In contrast to 
hemophilia, routine prophylaxis is not as established in VWD, although prophylaxis for 
patients with severe VWD was in use in Sweden already during the 1950s.5 In those early 
days of VWD treatment, plasma FVIII concentrates containing VWF fractions were 
applied for replacement therapy, which then were followed by plasma derived VWF 
products containing fractions of FVIII (pdVWF/FVIII). 
A Swedish cohort including 37 patients with type 3 VWD under prophylactic median 
treatment of 11 years (range 2 to 45 years) was retrospectively analyzed.6,7 The 
doses used for prophylaxis, given once weekly for at least 45 weeks per year, were 
calculated based on 12 to 50 IU/kg body weight (BW) of FVIII clotting activity (FVIII:C)
which approximately corresponded to 24-100 IU/kg von Willebrand factor: Ristocetin 
cofactor activity (VWF:RCo) considering that mainly Haemate with a known 
VWF:RCo/FVIII:C ratio of about 2 was used. An escalation of doses from 1 to 3 dose 
levels was allowed depending on the frequency and severity of bleeding episodes. 
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The results demonstrate that under long-term prophylaxis the number of bleeds could be 
reduced dramatically. Whereas the median value for bleeds per year was about 10 before 
prophylaxis this value could be reduced to less than 1 bleed per year during prophylaxis.
The benefit of prophylaxis for such indications was retrospectively also demonstrated in a 
cohort of Italian patients including type 3, 2A, 2M and type 1 patients. Prophylaxis was 
started after severe gastrointestinal or joint bleeding episodes and completely prevented 
bleeding episodes in 8 of these 11 patients and largely reduced the need of blood 
transfusions in the remaining 3. A regimen of 40 IU rVWF:RCo/kg was applied every 
other day or twice a week. A prospective study on prophylaxis, the PRO.WILL study, has 
been initiated in Italy.8
The results of a prospective study investigating the prophylaxis in children and young 
adults showed a significantly reduced bleeding frequency and bleeding score (3 vs. 0.07; 
3 vs. 0. p<0.001) compared to the pre-prophylaxis values. The median dose was 
40 (20-47) IU/kg VWF:RCo administered mainly twice weekly in 23 patients, 3 times a 
week in 7 patients and 4 times a week in 2 children.9
The VWD Prophylaxis Network initiated the VWD International Prophylaxis (VIP) trial 
to investigate the role of prophylaxis in patients with severe VWD including Type 1, 2,
and 3. The dose of the factor replacement product was 50 IU /kgVWF:RCo. The 
frequency of the dose depended on the type of bleeding and could be increased from once 
weekly to twice weekly or 3 times per week. For the treatment of menorrhagia the dose 
of 50 IU/kg VWF:RCo was given on the first day of menses for 2 cycles. The frequency 
could be increased to Day 1 and 2 for 2 cycles or to Day 1, 2, and 3 of menses.
The study contains both retrospective and prospective study components. Results from 
the retrospective study component were published, including 61 subjects on prophylactic 
regimen in the past 6 months prior to enrollment or subjects with a history of prophylaxis 
over at least 6 month.10 Differences in annualized bleeding rates (ABR) within 
individuals (during prophylaxis – before prophylaxis) were significant for those with 
primary indications of epistaxis (P = 0.0005), joint bleeding (P = 0.002) and GI bleeding 
(P = 0.001). The difference in the group whose primary indication for treatment was 
abnormally heavy bleeding at menstruation (n = 4) was not significant (P = 0.25). The 
reduction of mucosal bleeding likely not only dependents on normal circulating levels of 
active VWF, but also on the presence of discrete concentrations of normal VWF inside 
the platelets and within endothelial matrices. The low subject number (n=4) and the 
treatment scheme for menorrhagia on Days 1, 2, and 3 of menses which might represent 
rather on-demand than prophylactic treatment may also account for the outcome in this 
study.
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Results from the prospective study component were reported recently.11 Eleven subjects 
completed the study. Six subjects had type 2A, and 5 subjects had type 3 VWD. 
Six subjects presented with epistaxis, 3 with GI bleeding, and 2 with joint bleeding. 
Seven subjects had dose escalation above the first level. Among the 10 subjects with 
evaluable bleeding log data, the use of prophylaxis decreased the median ABR from 25 to 
6.1 (95% confidence interval [CI] of the rate difference: -51.6 to -1.7), and the median 
ABR was even lower (4.0; 95% CI: -57.5 to -5.3) when the subjects reached their final 
dosing level. The authors concluded that this was the first prospective study to 
demonstrate that prophylaxis with VWF concentrates is highly effective in reducing 
mucosal and joint bleeding rates in clinically severe VWD.
The results of the VIP study and previous investigations suggest that VWD patients with 
recurrent bleeding episodes and severe menorrhagia will benefit from a prophylactic 
VWF replacement therapy. There is evidence that up to 40% of patients with type 3 
VWD experience joint bleeding which can lead to hemophilic arthropathy. Other 
potential indications for prophylaxis include patients with type 2A or 2B VWD with 
recurrent gastrointestinal bleeding, menorrhagia or frequent epistaxis.4 Long-term 
prophylaxis for most patients with type 3 VWD and in some patients with type 1 or 
2 VWD, depending on the pattern of bleeding, may be the treatment option of choice.
Although the main experience with long-term prophylaxis is with secondary prophylaxis, 
primary prophylaxis starting at young age is recommended to prevent arthropathy in 
patients with severe VWD.12
However, further studies are needed to develop evidence-based guidelines for 
prophylactic treatment in VWD.
6.4 Populations to be Studied
A total of approximately 22 eligible, adult subjects with severe VWD (baseline 
VWF:RCo <20 IU/dL) are planned to be enrolled. Two cohorts of patients will be 
included: patients currently receiving on-demand VWF treatment (OD subjects) and 
patients currently on prophylactic treatment with pdVWF (pdVWF switch subjects), and 
the aim is to have ≥8 subjects in each of the 2 cohorts, with a total of at least 5 type 3 
VWD subjects followed for 12 months. Enrolled subjects (i.e., subjects who have signed 
the informed consent form) will be eligible to participate in the study if they meet all of 
the inclusion criteria (see Section 9.1) and none of the exclusion criteria (see Section 9.2).
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6.5 Findings from Nonclinical and Clinical Studies
The following summarizes the key findings from relevant nonclinical studies as well as 
from the completed clinical studies 070701 (Phase 1 pharmacokinetics [PK] and safety in 
VWD), 071001 (Phase 3 safety and efficacy in the treatment of bleeding episodes in 
VWD), 071101 (Phase 3 efficacy and safety in VWD subjects undergo elective surgical 
procedures), 071104 (Phase 1 safety and PK in hemophilia A), and 071401 (Phase 3, 
expanded access in a single subject with VWD). Potential risks and efficacy of rVWF 
(vonicog alfa):ADVATE (rFVIII, octocog alfa) are summarized in the following sections. 
For additional information on nonclinical and clinical Phase 1 results refer to the rVWF 
(vonicog alfa) IB.
6.5.1 Findings from Nonclinical Studies
6.5.1.1 Primary Pharmacodynamics
Efficacy of rVWF (vonicog alfa) combined with ADVATE (rFVIII, octocog alfa) was 
shown in VWD animal models, which have also low endogenous FVIII levels. Time to 
occlusion and stable thrombus formation was assessed in the carotid occlusion model in 
VWD mice. The results demonstrated that rVWF (vonicog alfa) in combination with 
ADVATE (rFVIII, octocog alfa) acted efficiently in a dose-dependent manner and had 
higher efficacy than rVWF (vonicog alfa) alone or plasma derived (pd)VWF. These 
results were confirmed in an additional study assessing blood loss and survival in a tail 
tip bleeding model in VWD mice. In a VWD dog, rVWF (vonicog alfa) stabilized canine 
FVIII in the circulation and significantly reduced the bleeding time.
6.5.1.2 Safety Pharmacology
The anaphylactoid and thrombogenic potential of the co-infusion of ADVATE (rFVIII, 
octocog alfa) and rVWF (vonicog alfa) and the co-infused product’s effects on blood 
pressure, cardiac and respiratory function and parameters of coagulation activation were 
investigated in 4 in vivo studies in different animal models. Safety pharmacology studies 
in rats, guinea pigs, rabbits, and dogs revealed no risks for anaphylactoid and 
thrombogenic potential of ADVATE (rFVIII, octocog alfa) in combination with rVWF 
(vonicog alfa). All observations in safety pharmacology studies are considered to lie 
within the biological variability of animal models or occurred due to known species-
specific anaphylactoid effects of excipients.
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6.5.1.3 Pharmacokinetics
Pharmacokinetic studies of both rVWF (vonicog alfa) alone and combined with human 
rFVIII (rVWF+ADVATE) were conducted in VWD mice, VWD dogs, VWD pigs, rats,
and cynomolgus monkeys. Human rVWF (vonicog alfa) stabilized the endogenous FVIII 
in VWD mice, VWD pigs, and VWD dogs. Furthermore, the hypotheses that the area 
under the curve (AUC) with rVWF alone and rVWF+ADVATE is not inferior to the 
AUC with pdVWF (Haemate P) was tested and confirmed statistically in normal rats.
The PK characteristics of ADVATE (rFVIII, octocog alfa) were not affected by co-
administration of rVWF (vonicog alfa) in cynomolgus monkeys. The PK data in the 
FVIII knock out (k.o.) mice model are inconclusive and might not be relevant for the 
clinical situation. However, a stabilizing effect of VWF on FVIII could be shown in a 
double k.o. model in a dose dependent manner.
6.5.1.4 Toxicology
Single dose toxicity studies were conducted in C57BL/6J-mice, VWD mice, rats, rabbits,
and cynomolgus monkeys. Rats, rabbits, and cynomolgus monkeys showed no signs of
toxicity. Signs of microthrombosis, an exaggerated pharmacological effect, were
observed in mice. Mice are not capable of sufficiently cleaving the rVWF (vonicog alfa)
subunit as murine disintegrin and metalloproteinase with a thrombospondin type 1 motif, 
number 13 (ADAMTS13) does not decrease the ultra-large molecular weight multimers 
of rVWF (vonicog alfa).13 The observed symptoms of microthrombosis are interpreted as 
a species-specific exaggerated pharmacological effect. Studies evaluating the safety of 
repeated administration of rVWF (vonicog alfa) with or without ADVATE (rFVIII, 
octocog alfa) (daily over 14 days) were performed in a rodent (rat) and non-rodent 
(cynomolgus monkey) species. Reversible signs of exaggerated pharmacological effects 
(regenerative anemia, thrombocytopenia, and treatment-related histopathologic changes 
in the heart, liver, and spleen) were observed in rats that were administered 1400 U 
VWF:RCo/kg /day + 1080 IU ADVATE/kg/day intravenously once daily for 14 days. 
Also, these findings are interpreted as a species-specific exaggerated pharmacological 
effect due to the low susceptibility of human rVWF (vonicog alfa) to cleavage by rodent 
ADAMTS13.13 No toxicologically relevant changes were evident for clinical 
observations, body weight, feed consumption, ophthalmology, urinalysis, coagulation,
and serum chemistry parameters, platelet aggregation, and gross pathology. rVWF 
(vonicog alfa) combined with ADVATE (rFVIII, octocog alfa) was well tolerated in 
cynomolgus monkeys after daily intravenous (i.v.) (bolus) administration of 100 U 
VWF:RCo/kg rVWF (vonicog alfa) combined with 77 IU/kg ADVATE (rFVIII, octocog 
alfa) over a period of 14 days. No adverse effects could be detected in this species.
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There were no signs of hemolysis, thrombosis, or thrombocytopenia after repeated 
intravenous application of rVWF (vonicog alfa) with or without ADVATE (rFVIII, 
octocog alfa). Therefore, 100 U VWF:RCo/kg/day rVWF (vonicog alfa) with or without 
77 IU/kg ADVATE (rFVIII, octocog alfa) was considered the no observed adverse effect 
level (NOAEL) in this study, which was the highest dose tested. Anti-drug antibodies, 
however, were formed in both species and resulted in a significant reduction in drug 
exposure after 14 applications as compared to a single application. These antibodies 
substantially reduced the systemic exposure to the test substance as compared to a single 
dose administration. No adverse effects due to antibody formation were observed in both 
species.
rVWF (vonicog alfa) combined with ADVATE (rFVIII, octocog alfa) was well tolerated 
locally and no genotoxic potential was evident after 2 in vitro and 1 in vivo genotoxicity 
study. A study on the influence of co-administration of VWF and ADVATE (rFVIII, 
octocog alfa) on the immunogenicity of ADVATE (rFVIII, octocog alfa) in 3 different 
hemophilic mouse models (E17 hemophilic Balb/c mice, E17 hemophilic C57BL/6J 
mice, and E17 hemophilic human F8 transgenic mice) showed that rVWF (vonicog alfa)
does not negatively impact the immunogenicity of ADVATE (rFVIII, octocog alfa) in 
any of the three different hemophilic mouse models.
6.5.2 Findings from Clinical Studies
Details on study design, populations enrolled, and safety and efficacy outcomes of the 
phase 1 studies are presented in Section 6.5.2.1 and Section 6.5.2.2, the phase 3 study in 
Section 6.5.2.3, and the phase 3 surgery study in Section 6.5.2.4. Information on a single 
subject with VWD in Study 071401 is presented in Section 6.5.2.5.
6.5.2.1 Study 070701
Phase 1 clinical study 070701 was a multicenter, controlled, randomized, single-blind,
prospective 3-step, dose escalation study to investigate safety, tolerability, and PK of 
rVWF (vonicog alfa) combined at a fixed ratio with ADVATE (VWF:RCo/FVIII:C of 
1.3 ± 0.2:1) in adults with severe VWD.14 Subjects were enrolled in sequential cohorts in 
a dose escalating manner: Cohort 1, 2, and 3 received a single intravenous infusion of 
rVWF:ADVATE at the following doses: 2 IU/kg VWF:RCo (Cohort 1), 7.5 IU/kg 
VWF:RCo (Cohort 2), and 20 IU/kg VWF:RCo (Cohort 3). Subjects in Cohort 4 received 
a single intravenous infusion of rVWF:ADVATE and pdVWF/ADVATE at 50 IU/kg 
VWF:RCo in random order.
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The primary endpoint was the tolerability and safety after single dose injections of 
rVWF:ADVATE at 2, 7.5, 20, and 50 IU/kg VWF:RCo for up to 30 days after the last IP 
infusion. The data generated in this phase 1 study suggest that rVWF:ADVATE up to the 
highest investigated dose of 50 IU/kg VWF:RCo is well tolerated and safe in adults with 
severe VWD. No thrombogenic risk or thrombotic thrombocytopenic purpura (TTP)-like 
syndrome was observed, and no neutralizing antibodies to VWF or FVIII were identified. 
There were no deaths or other serious adverse reactions, and no infusions were 
interrupted or stopped due to an AE. Overall, the reported AE profile was similar 
between the recombinant and plasma-derived concentrates.
Secondary endpoints were the PK assessment of VWF:RCo, von Willebrand factor 
antigen (VWF:Ag) and multimeric composition of rVWF (vonicog alfa) as well as 
FVIII:C at standardized time points after single injections of rVWF:ADVATE and 
pdVWF:FVIII. 
The median VWF:RCo terminal half-life (T1/2) of rVWF (vonicog alfa) at the 50 IU/kg 
dose was 16 hours. T1/2 with pdVWF:FVIII at the same dose level appeared shorter at 
12.58 hours, however, the limits of the 90% CI were similar (11.73 to 17.7 hours vs. 
11.87 to 18.03 hours). The median T1/2 of VWF:RCo were shorter with the lower 
investigated doses: 7.13 hours and 13.23 hours with the 7.5 IU/kg and 20 IU/kg doses, 
although these data were derived from a much smaller number of subjects.
In consequence of the missing ADAMTS13 cleavage, ultra-large molecular weight 
(ULMW) multimers are contained in the rVWF (vonicog alfa) final product. The 
immediate cleavage of these ultra-large multimers by ADAMTS13 upon release into the 
circulation could be demonstrated applying sodium dodecyl sulfate polyacrylamide gel 
electrophoresis (SDS-PAGE)/Immunoblot with polyclonal anti-VWF antibodies to detect 
the resulting rVWF (vonicog alfa) subunit cleavage fragments.
Overall the data generated in this phase 1 study suggest that rVWF (vonicog 
alfa):ADVATE (rFVIII, octocog alfa) is well tolerated and safe in adults with severe 
VWD.
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6.5.2.2 Study 071104
This study was a prospective, uncontrolled, non-randomized, multicenter proof of 
concept study to assess safety and PK of the addition of rVWF (vonicog alfa) to 
ADVATE (rFVIII, octocog alfa) treatment in 12 evaluable subjects with severe 
hemophilia A. All subjects underwent 3 PK analyses: the first after infusion with 
ADVATE (rFVIII, octocog alfa) alone, the second after infusion with ADVATE (rFVIII, 
octocog alfa) plus 10 IU/kg rVWF (vonicog alfa) and the third after infusion with 
ADVATE (rFVIII, octocog alfa) plus 50 IU/kg rVWF (vonicog alfa).
The PK analysis was performed at intervals of approximately 8 to 14 days. Before each 
infusion for PK assessment, there was a wash-out period of at least 5 days and the 
subjects were not actively bleeding. 
Primary outcome measures indicate that co-administration of rVWF (vonicog alfa)
slightly sustain ADVATE activity with the highest observed ADVATE (rFVIII, octocog 
alfa) half-life of 13.74 h (CI 11.44 to 16.52) after co-infusion of 50 IU/kg ADVATE plus 
50 IU/kg rVWF:RCo.
The highest improvement in ADVATE (rFVIII, octocog alfa) circulating half-life was 
observed in subjects with VWF:Ag levels below 100% which indicates an association 
between baseline VWF:Ag levels and ADVATE (rFVIII, octocog alfa) half-life increase. 
No treatment related AEs or SAEs were reported. No subject withdrew due to an AE and 
there were no deaths. No binding antibodies to VWF, CHO, and rFurin were detectable in 
the confirmatory assay and no signs of a hypersensitivity to rVWF (vonicog alfa) or
ADVATE (rFVIII, octocog alfa) antigen were observed. Laboratory values over time did 
not indicate any potential safety risk for hemophilia A patients treated with rVWF 
(vonicog alfa) and ADVATE (rFVIII, octocog alfa) in combination.
In summary, the data indicate that rVWF (vonicog alfa) co-administered with ADVATE 
(rFVIII, octocog alfa) up to the highest dose of 50 IU/kg VWF:RCo is well tolerated and 
safe in hemophilia A patients.
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6.5.2.3 Study 071001
This was a phase 3, multicenter, open-label, part-randomized clinical study to assess the 
PK, safety, and efficacy of rVWF:rFVIII and rVWF in the treatment of bleeding episodes 
in adult subjects with severe type 3 and severe non-type 3 VWD.15 A total of 49 subjects 
were enrolled (signed informed consent) and screened, 18 subjects were randomized 
(randomization only applies to Arm 1[PK50 with treatment of BE] and Arm 2 [PK50
only] see below), 37 subjects were treated with IP (all study arms), and 30 subjects 
completed the study.
The study consisted of 2 parts (Part A and Part B). Part A consisted of PK assessments 
alone (Arm 2: PK50 only [without treatment of bleeding episodes]), or PK assessments 
(Arm 1: PK50 and Arm 3: PK80) plus on-demand treatment period(s) of 6 months for 
bleeding episodes, or on-demand treatment for bleeding episodes only (Arm 4). Except 
for subjects in arm 2 who completed study after second PK assessment, subjects  
receiving treatment for PK assessments and/or bleeding episodes in Part A were to be 
entered into Part B to continue on-demand treatment for bleeding episodes for 
6 additional months for a total of 12 months in the study. 
The primary outcome measure was the number of subjects with “treatment success” 
(extent of control of bleeding episodes), which was defined as a mean efficacy rating 
score of <2.5 for a subject’s IP-treated bleeding episodes during the study. The rate of 
subjects with treatment success was 100% (Clopper-Pearson exact 90% CI: 84.7 to 
100.0) for bleeds where the assessments were made prospectively and excluding GI 
bleeds. Sensitivity analyses confirmed the results of the primary analysis.
Crossover results at 50 IU/kg VWF:RCo showed that the PK profile for rVWF (vonicog 
alfa) VWF:RCo was independent of administration alone or with rFVIII (ADVATE, 
octocog alpha) (T1/2: 19.4 hours for rVWF and 16.6 hours for rVWF:rFVIII; IR: 1.8 U/dL 
per IU/kg infused for both rVWF and rVWF:rFVIII; mean residence time (MRT): 
26.7 hours for rVWF and 25.2 hours for rVWF:rFVIII). FVIII levels increased 
substantially with a median peak at 24 hours of 111.0 U/dL for rVWF:rFVIII and 
86.0 U/dL after rVWF alone, indicating that rVWF (vonicog alfa) induces a sustained 
increase in endogenous FVIII activity. The rVWF (vonicog alfa) PK profile was 
comparable at 50 IU/kg and 80 IU/kg VWF:RCo, and repeated PK at 80 IU/kg 
VWF:RCo showed close agreement between pretreatment and end-of-study results.
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Further analysis of the PK data from the 071001 study supports the initial use of 50 IU/kg 
twice weekly for prophylaxis dosing in the present study for those subjects who are 
moving from on-demand to prophylaxis. Using 50 IU/kg for PK measurements, subjects 
in the 071001 study exhibiting a T1/2 for rVWF of 14, 16, or 19 hours had rVWF plasma 
concentrations at 72 hours after administration of 2.55, 4.01, and 6.49% above baseline, 
respectively, and plasma concentrations at 96 hours after administration of 0.78, 1.40,
and 2.71% above baseline, respectively. In this context it should be noted that subjects in 
the present study who have significant spontaneous bleeding while on twice weekly
prophylaxis will have their regimen increased to 3 times per week based on clear criteria 
for different bleeding locations (for details see Section 8.6.4.3.1). Subjects in the present 
study who are switching from prophylaxis with a pdVWF product will begin on rVWF 
(vonicog alfa) using their same weekly total dose in IU/kg VWF:RCo used during their 
pdVWF prophylaxis divided into twice weekly infusions (for details see Section 8.6.4.3).
A total of 125 AEs occurred in 25/37 (67.7%) subjects (62/318 infusions [19.5%]) during 
or after infusion with IP. Of these, 116/125 were non-serious (all mild or moderate; none 
were severe), and 9 SAEs were reported in 7 subjects. Of 125 total AEs, 38 were 
temporally associated with IP; 8 AEs were considered causally related to IP: 
6 non-serious related AEs (tachycardia, infusion site paraesthesia, electrocardiogram 
[ECG] t-wave inversion, dysgeusia, generalized pruritis, and hot flush) occurred in 
4 subjects, and 2 related SAEs (chest discomfort and increased heart rate) occurred in 
1 subject. No deaths occurred during this study.
None of the subjects developed anti-VWF or anti-FVIII neutralizing antibodies and no 
binding antibodies to VWF or rFurin, or antibodies against CHO protein or anti-Murine 
IgG were observed. No clinical or subclinical signs or symptoms of a thrombogenic event 
were observed in this study. Following an initial increase in ultralarge VWF multimers 
after administration of rVWF (vonicog alfa), a notable decrease in the proportion of large 
VWF multimers occurred between 12 and 24 hours post infusion, due to degradation by 
the endogenous ADAMTS13 followed by a continued decline until the end of the 96-
hour follow-up period. 
Overall, the data support the safe and effective use of rVWF (vonicog alfa) with or 
without rFVIII (ADVATE, octocog alpha) in the treatment of bleeds in patients with 
VWD.
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6.5.2.4 Study 071101
This was a phase 3, prospective, open-label, multicenter clinical study to evaluate 
efficacy and safety of rVWF (vonicog alfa) with or without ADVATE (rFVIII, octocog 
alfa) in elective surgical procedures in adult subjects with severe VWD. A total of 
24 subjects were enrolled (signed informed consent) and screened, 15 subjects were 
treated with rVWF (vonicog alfa), and 15 subjects completed the study. 
Eleven subjects underwent a PK assessment by infusion of 50 ± 5 IU/kg rVWF:RCo at an 
infusion rate of up to 4 mL/min. 12 to 24 hours before surgery, subjects received a dose 
of 40 to 60 IU/kg rVWF:RCo. Within 3 hours prior to surgery, the subject’s FVIII:C 
levels were assessed with a target of 30 IU/dL for minor and oral surgeries and 60 IU/dL 
for major surgeries. Within 1 hour prior to surgery, subjects received a dose of rVWF 
(vonicog alfa) with or without ADVATE (rFVIII, octocog alfa) (depending on the target 
FVIII:C levels at the 3 hour assessment). VWF and FVIII IR and T1/2 for each subject, 
when known, were used to guide the initial dose and subsequent doses.
The primary outcome measure was the overall assessment of hemostatic efficacy 
assessed by the investigator (hemophilia physician) 24 hours after last perioperative IP 
infusion or at completion of day 14 visit, whichever occurred earlier, and was 
summarized by the percentage of subjects in each efficacy category (“excellent”, “good”, 
“moderate” and “none”). Point estimate and corresponding 90% two-sided exact CI was 
calculated for the rate of subjects with an overall assessment of hemostatic efficacy. All 
15 subjects treated with rVWF (vonicog alfa) (with or without ADVATE) for major (10), 
minor (4), and oral (1) elective surgical procedures had overall hemostatic efficacy 
ratings of “excellent” or “good”. Most (73.3%) subjects had “excellent” overall 
hemostatic efficacy ratings; of these, 7 underwent major surgery and 4 underwent minor 
surgery. The remaining 26.7% subjects had “good” overall hemostatic efficacy ratings: 
3 underwent major surgery and 1 underwent oral surgery. All 8 subjects with VWD 
Type 3, the subtype classified as absolute VWF deficiency, had overall hemostatic 
efficacy ratings of “excellent” (87.5%) or “good” (12.5%).
Intraoperative hemostatic efficacy ratings were also rated as “excellent” or “good” for all 
15 treated subjects. Most (86.7%) subjects had “excellent” intraoperative hemostatic 
efficacy ratings; of these, 8 underwent major surgery, 4 underwent minor surgery, and 
1 underwent oral surgery. Two (13.3%) subjects who underwent major surgery had 
“good” intraoperative hemostatic efficacy ratings. Intraoperative hemostatic efficacy 
was rated as “excellent” or “good” for all subjects with VWD Type 3: “excellent” for 
7 (87.5%) subjects and “good” for 1 (12.5%) subject. 
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Only 1 subject received an intraoperative dose of rVWF (18.1 IU/kg) and ADVATE 
(8.1 IU/kg). The median daily postoperative weight-adjusted dose of rVWF (vonicog 
alfa) (with or without ADVATE) was 23.5 IU/kg on postoperative Day 1 (n=3) and 
25.5 IU/kg on postoperative Day 14 (n=2). In subjects treated with rVWF:ADVATE, the 
daily postoperative weight-adjusted dose was 16.9 IU/kg rVWF and 7.6 IU/kg ADVATE 
on postoperative Day 1 (n=1) and decreased to 50.8 IU/kg rVWF and 7.6 IU/kg
ADVATE on postoperative Day 7 (n=1). For subjects treated with rVWF alone, the 
median weight-adjusted dose (Q1, Q3) of rVWF was 35.4 IU/kg on postoperative Day 1 
(n=2) and decreased to 23.7 IU/kg on postoperative Day 7 (n=4) and 25.5 IU/kg on 
postoperative Day 14 (n=2).
A total of 11 subjects were evaluated for PK in the study. As expected, postinfusion 
increases in concentrations of VWF:RCo, VWF:Ac, VWF:Ag, and VWF collagen 
binding (VWF:CB) were observed. Mean values for VWF:RCo were as follows: 
AUC0-∞/dose was 37.50 hours*IU/dL per IU/kg infused; AUC0-72h/dose was 
34.08 hours*IU/dL per IU/kg infused; T1/2 was 17.83 hours; MRT was 24.32 hours; 
CL was 0.03117 dL/hour/kg; and volume of distribution at steady state (Vss) was 
0.6837 dL/kg. Median values for VWF:RCo were as follows: AUC0-∞/dose was 
32.94 hours*IU/dL per IU/kg infused; AUC0-72h/dose was 31.70 hours*IU/dL per IU/kg 
infused; T1/2 was 14.62 hours; MRT was 21.80 hours; CL was 0.03036 dL/hour/kg; and 
Vss was 0.7078 dL/kg. The VWF:RCo activity was consistent with that previously 
observed in clinical studies 071001 and 070701.
rVWF (vonicog alfa) was safe and well tolerated in adults with severe VWD undergoing 
major, minor, and oral elective surgical procedures. Of the 12 total treatment-emergent 
AEs (TEAEs) that occurred during the study, 2 deep vein thrombosis events (1 non-
serious and 1 serious, as a part of one case) reported in one subject, who underwent total 
hip replacement surgery and who had concurrent condition of obesity, was assessed by 
the sponsor as possibly causally-related to study treatment. None of the TEAEs were 
either a severe allergic or hypersensitivity reaction or developed due to a severe allergic 
reaction. 
One subject with VWD Type 3 who had an intraoperative transfusion of packed red 
blood cells during total knee replacement surgery tested positive for binding antibodies to 
VWF on postoperative Day 7 through study completion. No subjects developed 
neutralizing antibodies to rFVIII or binding antibodies to CHO, rFurin, or murine IgG.
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In summary, the data support the safe and effective use of rVWF (vonicog alfa) with or 
without ADVATE (rFVIII, octocog alfa) in achieving intra- and post-operative 
hemostasis in adult subjects with severe VWD undergoing major, minor, and oral elective 
surgical procedures.
6.5.2.5 Study 071401: Single Subject with von Willebrand Disease
One subject who exhibited allergic reactions to currently marketed pdVWF products was 
treated in the single-subject study 071401 with rVWF (vonicog alfa) only for the bleed 
treatment of continued hematuria, and for biopsy and surgical resection of a left-kidney 
mass.
For the initial rVWF (vonicog alfa) infusion, the subject received a test dose of 5% of 
the total dose of 60 IU/kg rVWF:RCo at an infusion rate of 1 mL/min. After a 10 to
15-minute observation period, no adverse symptoms or signs were noted and the subject 
received the remaining 95% of the total dose. The subject was monitored for any signs of 
an allergic reaction, and none were noted. Treatment with rVWF (vonicog alfa) every 
12 to 24 hours was to continue at the discretion of the investigator based on VWF levels 
and clinical symptomatology. The subject had an excellent response and recovery, which 
allowed for daily dosing of rVWF (vonicog alfa) and, within 24 hours, the subject’s 
bleeding had stopped. Daily dosing of rVWF (vonicog alfa) was maintained and the 
subject received his last dose on 
.
The subject also received rVWF (vonicog alfa) for 7 days for prophylaxis for surgery 
(surgical resection of a left-kidney mass). The subject experienced no hemorrhagic 
complications and no AEs that were considered related to the use of rVWF (vonicog 
alfa).
6.6 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) to
Human Subjects
Current treatment of VWD patients relies on desmopressin and VWF products 
manufactured from pooled human plasma. Human VWF produced by recombinant 
technology could offer a new perspective in treatment of VWD. The benefit for the 
individual subject is anticipated to be significant during this clinical study. He/she may 
benefit from a product that minimizes excessive FVIII administration and thus allowing 
individualized dosing of VWF at optimal levels. Variations in VWF multimeric 
composition may lead to variability with respect to treating or preventing bleeds in 
VWD subjects, especially mucosal bleeds which are especially problematic. rVWF 
(vonicog alfa) product manufactured by Baxalta consistently contains ULMW VWF 
multimers due to the fact that the product has not been exposed to ADAMTS13. 
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The initial presence of these ULMW VWF multimers, which are subsequently cleaved by 
the subject’s endogenous ADAMTS13, may result in improved platelet and collagen 
binding and therefore provide more predictable treatment outcomes.
By using a recombinant product, the risk of transmission of adventitious agents and other 
blood-borne pathogens associated with the use of products of human or animal origin has 
been eliminated. At this stage of product development, the key societal benefit is a better 
understanding of advanced treatment options for VWD and enhanced product 
availability.
These benefits outweigh the following identified or potential risks of rVWF (vonicog 
alfa):

allergic-type hypersensitivity reactions as with any intravenous protein product

the occurrence of thromboembolic events

the development of neutralizing antibodies to VWF
Refer to the IB for further details on benefits and risks of the IP.
6.7 Compliance Statement
This study will be conducted in accordance with this protocol, the International Council 
for Harmonisation Guideline for Good Clinical Practice E6 (ICH GCP, April 1996, with 
Addendum E6(R2) dated Nov 2016 EMA/CHMP/ICH/135/1995), Title 21 of the US 
Code of Federal Regulations (US CFR), the EU Directives 2001/20/EC and 2005/28/EC, 
the Declaration of Helsinki and applicable national and local regulatory requirements.
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7. STUDY PURPOSE AND OBJECTIVES
7.1 Study Purpose
The purpose of this phase 3 study is to investigate the efficacy and safety, including 
immunogenicity, thrombogenicity and hypersensitivity reactions, as well as 
pharmacokinetics (PK), 
and 
 
of prophylactic treatment with rVWF (vonicog alfa) in adult subjects with severe VWD.
7.2 Primary Objective
The primary objective of this study is to prospectively evaluate the ABR for spontaneous 
bleeding episodes while on prophylactic treatment with rVWF (vonicog alfa) and to 
compare it to the subject’s historical ABR for spontaneous bleeding episodes.
7.3 Secondary Objectives
Secondary Objectives are to assess:

Additional efficacy of prophylactic treatment with rVWF (vonicog alfa)

Safety of rVWF (vonicog alfa), including immunogenicity, thrombogenicity and 
hypersensitivity

Pharmacokinetics (PK) of rVWF (vonicog alfa) and pharmacodynamics (PD) of 
rVWF (vonicog alfa) as measured in FVIII activity 
7.4 Exploratory Objectives
 
 
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8. STUDY DESIGN
8.1 Overall Study Design 
This is a prospective, open label, uncontrolled, non-randomized, international, 
multicenter phase 3 study to evaluate efficacy, safety (including immunogenicity,
thrombogenicity and hypersensitivity reactions), as well as PK, 
and 
 of prophylactic treatment regimen with rVWF (vonicog alfa) in adult 
patients with severe VWD. 
Subjects transitioning from on-demand treatment (OD subjects) or subjects switching 
from prophylactic treatment with pdVWF (pdVWF switch subjects) will receive 
prophylactic treatment with rVWF (vonicog alfa) for a 12-month period. The dose will be 
50 ± 10 IU/kg rVWF twice weekly for OD subjects or will be based on their prior 
pdVWF dose for pdVWF switch subjects, and dose may be further individualized based 
on the PK data, subject’s history of bleeding episodes, and the results from clinical and 
laboratory assessments (see Section 8.6.4.3).
The overall duration of prophylactic treatment with rVWF per subject will be 12 months.
During this period any bleeding episodes requiring substitution therapy with VWF 
concentrate to control bleeding will be treated with rVWF (vonicog alfa) with or without 
ADVATE (rFVIII, octocog alfa). The dose will be according to the bleeding type and 
severity and it will be adjusted to the clinical response (see Section 8.6.4.4.2).
The overall study design is illustrated in Figure 1.
8.2 Duration of Study Period(s) and Subject Participation
The overall duration of the study is approximately 27 months from study initiation 
(i.e., first subject enrolled) to study completion (i.e., last subject last visit). The subject 
participation period is approximately 15 months from enrollment to completion (i.e, last 
study visit), unless the subject is prematurely discontinued.
8.3 Outcome Measures
8.3.1 Primary Outcome Measure
8.3.1.1 Efficacy 

Annualized bleeding rate (ABR) for spontaneous (not related to trauma) bleeding 
episodes during prophylactic treatment with rVWF (vonicog alfa)
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8.3.2 Secondary Outcome Measures
8.3.2.1 Additional efficacy of Prophylactic Treatment with rVWF (vonicog alfa)

ABR percent reduction success for OD subjects defined as at least 25% reduction 
of ABR for spontaneous (not related to trauma) bleeding episodes during rVWF 
(vonicog alfa) prophylaxis relative to the subject’s own historical ABR during
on-demand treatment

ABR preservation success for pdVWF switch subjects defined as achieving an 
ABR for spontaneous bleeding episodes during rVWF (vonicog alfa) prophylaxis 
that is no greater than the  subject’s own historical ABR during prophylactic
treatment with pdVWF

Categorized spontaneous ABR defined as 0, 1-2, 3-5, or >5 bleeding episodes
during the 12-month prophylactic treatment with rVWF (vonicog alfa)

Total number of infusions and the average number of infusions per week during 
prophylactic treatment with rVWF (vonicog alfa)

Total weight adjusted consumption of rVWF (vonicog alfa) during prophylactic 
treatment 

Spontaneous ABR by location of bleeding (GI, epistaxis, joint bleeding, 
menorrhagia, oral and other mucosa, muscle and soft tissue, etc.) while on 
prophylactic treatment with rVWF (vonicog alfa)
8.3.2.2 Safety

AEs: incidence, severity, causality

Thromboembolic events 

Hypersensitivity reactions

Development of neutralizing antibodies to VWF and FVIII

Development of total binding antibodies to VWF and FVIII

Development of binding antibodies to CHO proteins, mouse immunoglobulin G 
(IgG) and rFurin

Clinically significant changes in vital signs and clinical laboratory parameters
relative to baseline
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8.3.2.3 Pharmacokinetics (PK) and Pharmacodynamics (PD)

PK parameters after a washout for on-demand subjects: incremental recovery 
(IR), T1/2, MRT, area under the concentration versus time curve from 0 to infinity 
(AUC0-), area under the concentration versus time curve from 0 to the last 
measurable concentration (AUC0-tlast), maximum plasma concentration (Cmax), 
minimum time to reach the maximum concentration (Tmax), volume of 
distribution at steady state (Vss) and clearance (CL) based on VWF:Rco activity, 
VWF:Ag, VWF:CB activity. 

PD parameters after a washout for on-demand subjects: Cmax, Tmax, and AUC0-tlast
as measured in FVIII activity by the 1-stage clotting assay (FVIII:C). 

PK parameters at steady state for on-demand and switch subjects: area under the 
concentration versus time curve from 0 to end of the partial dosing interval 
(AUC0-tau;ss), maximum concentration during the partial dosing interval (Cmax;ss), 
minimum time to reach the maximum concentration (Tmax;ss) and minimum 
concentration during the partial dosing interval (Cmin;ss) based on VWF:RCo, 
VWF:Ag and VWF:CB. PK parameters at steady state will be assessed shortly 
after reaching steady state for switch subjects and at the end of the study for on-
demand as well as for switch subjects all based on the longer interval of the 
irregular dosing intervals employed.

PD parameters at steady state for on-demand and switch subjects: AUC0-tau;ss, 
Cmax;ss, Tmax;ss, and Cmin;ss as measured in FVIII activity by the 1-stage clotting 
assay. PD parameters at steady state will be assessed shortly after reaching 
steady state for switch subjects and at the end of the study for on-demand as well 
as for switch subjects all based on the longer interval of the irregular dosing 
intervals employed.

Time course of FVIII clotting activity (FVIII:C) levels.
8.3.3 Exploratory Outcomes Measures
8.3.3.1
 
 
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8.3.3.2
 
 
 
 
 
8.3.3.3
 
8.3.3.4
 
 
8.4 Randomization and Blinding
This is a non-randomized open-label, active treatment clinical study. 
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8.5 Study Stopping Criteria 
This study will be stopped if 1 or more of the following criteria are met in the absence of 
any other possible and medically plausible causal attribution (eg, underlying or 
concurrent condition, use of concomitant medication, subject’s medical history, etc):
1.
Two subjects develop a life-threatening or fatal thromboembolic event
2.
Two subjects develop life-threatening or fatal severe hypersensitivity reactions 
(e.g., anaphylaxis)
3.
Any subject develops acute hepatic failure
4.
Two subjects develop rVWF neutralizing antibodies that are considered clinically 
significant by the investigators and are associated with significant decrease of 
efficacy or serious adverse reactions.
The study may be stopped at any time by the sponsor.
The sponsor ultimately will decide whether to terminate, temporarily halt or modify the 
study based on the data monitoring committee (DMC)’s review and recommendation on 
all relevant cases including those that meet the stopping criteria listed above.
8.6 Investigational Product(s)
8.6.1 Packaging, Labeling, and Storage
8.6.1.1 rVWF (Recombinant von Willebrand Factor, vonicog alfa)
rVWF (vonicog alfa) will be packaged in boxes with 2 glass vials, one containing the 
rVWF powder, and the second vial containing the diluent (water for injection). Further 
details are provided in the IB and Pharmacy Manual. The rVWF label will include, at a 
minimum, the actual VWF:RCo potency and the date of expiration.
rVWF (vonicog alfa) is a powder that should be stored refrigerated (2-8°C [36-46°F]) . 
Deviations from the storage condition have to be communicated and followed up with the 
sponsor. Inadequately stored product will have to be placed in quarantine and may only 
be used after written IP administration authorization by the sponsor. After removal of the 
product from the refrigerator the product must not be returned to the refrigerator. The 
reconstituted product has to be used immediately (at least within 3 hours). rVWF 
(vonicog alfa) must not be used beyond the expiration date printed on the vial label. 
Avoid freezing at all times.
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8.6.1.2 rFVIII (Recombinant Factor VIII, octocog alfa /ADVATE)
ADVATE (rFVIII, octocog alfa) will be packaged in boxes with 2 glass vials, one 
containing the lyophilized rFVIII, and the second vial containing the diluent. Further 
details are provided in the IB and Pharmacy Manual. The ADVATE label will include, 
at a minimum, the actual FVIII:C potency and the date of expiration.
ADVATE (rFVIII, octocog alfa) should be refrigerated (2-8°C [36-46°F]) in powder 
form and should not be used beyond the expiration date printed on the vial. 
Deviations from the storage condition have to be communicated and followed up with the 
sponsor. Inadequately stored product will have to be placed in quarantine and may only 
be used after written IP administration authorization by the sponsor. After removal of the 
product from the refrigerator the product must not be returned to the refrigerator and has 
to be used immediately. Avoid freezing at all times.
8.6.2 Reconstitution
The reconstitution procedures for both rVWF (vonicog alfa) and ADVATE (rFVIII, 
octocog alfa) products are detailed in the Pharmacy Manual. 
8.6.3 Administration
Following reconstitution, rVWF (vonicog alfa) and ADVATE (rFVIII, octocog alfa) (in 
case of bleeding episode treatment) should be administered to study subjects at room 
temperature and within 3 hours of reconstitution. The reconstituted rVWF (vonicog alfa)
and ADVATE (rFVIII, octocog alfa), should be inspected for particulate matter and 
discoloration prior to administration, whenever the solution and container permit. The 
solution should be clear and colorless in appearance. If not, do not administer the 
product. Plastic syringes provided by the sponsor must be used since coagulation factors 
tend to stick to the surface of glass syringes.
Investigational product infusions should be given at a slow enough rate to ensure the 
subject’s comfort. The rate should not exceed 4 mL/minute The investigator/ subject shall 
ensure that no visible residual volume remains in the syringe(s) and that the complete 
content is administered. Upon completion of the infusion, the butterfly catheter should be 
flushed with at least 2 mL of saline solution. In case of a (central) venous access device, 
the flush should be with at least 10 mL of saline solution. The IP infusions should be 
administered over a duration of 2 to 20 minutes, depending on the volume.
Only the actual potencies of rVWF (vonicog alfa) and ADVATE (rFVIII, octocog alfa)
as stated on the vial labels and described in the Pharmacy Manual should be used.
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A variation of up to 10% of the intended dose for prophylactic infusions and of the 
intended dose for treatment of bleeding episodes is permissible and the exact dose should 
be recorded on the Case Report Form (CRF). Using of partial vials is not allowed.
At study visits where recovery analysis is being done, vials with the same lot numbers 
should be used throughout the PK IP infusion per subject.
For treatment of bleeding episodes, sequential administration will be done: separate 
syringes of the appropriate dose of rVWF (vonicog alfa) and ADVATE (rFVIII, octocog 
alfa) will be prepared for sequential infusion. rVWF (vonicog alfa) should be infused first 
sequentially followed preferably within 10 minutes by infusion of ADVATE (rFVIII, 
octocog alfa). Only the actual potencies of rVWF (vonicog alfa) and ADVATE (rFVIII, 
octocog alfa) as stated on the vial labels and described in the Pharmacy Manual should be 
used. 
The final dose of rVWF (vonicog alfa):ADVATE (rFVIII, octocog alfa) should be at a 
ratio of 1.3:1 ± 0.2.
8.6.4 Description of Treatment
8.6.4.1 PK-Assessment Treatment
For on-demand subjects, two PK assessments will be performed: an initial PK 
assessment after a wash-out period and a steady state PK assessments at the end of the 
study. The IP infusion for the initial PK assessment is scheduled on the baseline visit, 
which should be within 42 days after the completion of screening procedures and 
confirmation of eligibility. At the baseline visit the subjects will receive a dose of 
50 ± 5 IU/kg rVWF:RCo for PK assessment. Blood samples will be drawn within 
30 minutes pre-infusion, and at 11 time points post-infusion (15 ± 5 minutes, 
30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 
24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours and 96 ± 2 hours). A washout 
period of at least 5 days is required prior to infusion of rVWF (vonicog alpha) for PK 
assessment. The 2nd PK assessment for on-demand subjects will be performed at steady 
state at the end of the study (see Section 11.6). Subjects previously enrolled in rVWF 
studies 070701, 071001 or 071101 and having previously undergone PK assessments in 
these studies are required to repeat the PK assessment due to different dose and time 
points used in these former studies.
For pdVWF switch subjects, two steady state PK assessments will be performed. 
The 1st PK will be assessed shortly after reaching steady state, which is expected to 
be 11 days after the 1st prophylactic dose for majority of the subjects, around 
the prophylactic dose #5-6. The 2nd PK will be at the end of the study.
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For steady state PK, blood samples will be drawn within 30 minutes pre-infusion, and 
at 11 time points post-infusion (15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 
3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 
72 2 hours and 96 ± 2 hours) as long as it won’t interfere with subject’s the normal 
dosing schedule, otherwise the 96 hr sampling can be omitted (see Section 11.6). Final 
sample for PK analysis should be taken before next dose is administered.
8.6.4.2 Prophylaxis Initiation Treatment 
The rVWF (vonicog alfa) prophylaxis initiation treatment visit will coincide with the 
96 2 h initial PK assessment for on-demand subjects. For pdVWF switch subjects, the 
rVWF (vonicog alfa) prophylaxis initiation treatment visit should occur within 42 days 
after the completion of screening procedures and confirmation of eligibility. At this visit 
subjects will receive their prophylaxis initiation dose. The prophylaxis doses are 
described in Section 8.6.4.3.
The subject will be trained on IP reconstitution and administration and may then qualify
for home treatment (see Section 8.6.4.3.2). Refer toTable 6 (a/b) for study procedures and
Table 8 (a/b) for clinical laboratory assessments.
8.6.4.3 Prophylaxis Treatment
For on-demand subjects, the standard prophylactic dose is 50 ± 10 IU/kg rVWF:RCo, 
which may be increased up to 80 IU/kg. All on-demand subjects will initially receive 
rVWF (vonicog alfa) twice per week (Table 1, Schedule A). Examples of all dosing 
schedules are provided in Table 1.
For pdVWF switch subjects, the weekly dose (IU/kg) of IP for each patient will be 
equivalent (± 10%) to the weekly VWF dose received during prophylactic treatment with 
pdVWF. The weekly dose of IP should be divided into 2 infusions (Table 1, Schedule A), 
with a maximum of 80 IU/kg/infusion. If needed, based on the total weekly dose or other 
clinical judgements, the weekly dose may be given as three infusions (Table 1, 
Schedule B). A once weekly dose regimen will be allowed after switch to rVWF 
(vonicog alfa) only if the patient has been on a once weekly dose regimen with pdVWF.
Table 1
rVWF (vonicog alfa) Dosing Schedule Examples: Schedules A and B
Example
M
T
W
Th
F
Sat
Sun
M
T
W
Th
F
Sat
Sun
Schedule A
X
X
X
X
Schedule B
X
X
X
X
X
X
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The prophylaxis dose may be further individualized within the range based on:

available historical PK data

type and severity of bleeding episodes the subject has experienced in the past and

monitoring of appropriate clinical and laboratory measures
The individualized prophylaxic dose assignment will have to be agreed with the sponsor 
in advance, and the rationale should be well documented.
8.6.4.3.1 Adjustment of Dose or Dose Interval
In general, the dose and/or dose interval for each subject should not be changed unless 
prompted by clear medical needs. Dose and frequency adjustments should be agreed with 
the sponsor in advance unless it constitutes an urgent safety measure. The rationale for 
dosing adjustments needs to be documented in the subject’s medical record.
For both OD and switch patients, dose escalations (not exceeding the upper dose limit of 
80 IU/kg rVWF:RCo) and increase of dose frequency will only be allowed in case of 
insufficient therapeutic response with breakthrough bleeding episodes. The criteria for 
dose and/or frequency escalation are specific to each bleeding indication but, overall, 
involve 1 significant breakthrough bleeding episode despite the subject being compliant 
with scheduled prophylaxis treatment. For switch patients  who require a dose escalation 
due to a breakthrough bleed, the frequency should be kept the same but the dose 
(IU VWF:RCo per infusion) should be increased up to 80 IU VWF:RCo. Following that, 
increases in frequency may be considered upon consultation with the Sponsor. For on 
demand subjects who require a dose escalation, at the discretion of the PI upon 
consultation with the Sponsor, the frequency may be kept the same but the dose 
(IU VWF:RCo per infusion) should be increased up to 80 IU VWF:RCo. If this proves to 
be insufficient, then the dosing frequency may be increased in these subjects. Table 2
presents the criteria for dosing escalation per each bleeding indication taken 50 ± 10 IU 
VWF:RCo/kg twice weekly dose as an example of subject’s assigned starting dose. The 
criteria are applicable for both OD and switch subjects who were initially assigned to 
twice weekly dosing. Subjects entering the study will begin prophylaxis treatment 
according to Schedule A (Table 1) and will remain at this dose and frequency until 
meeting the criteria for escalation to the next higher schedule: for example, from 
2 infusions of 50 ± 10 IU VWF:RCo/kg/week to 3 infusions of 50 ± 10 IU 
VWF:RCo/kg/week (Schedule B) to achieve an adequate therapeutic response. If a 
subject started with a weekly dose (possible for switch subjects), similar criteria would 
apply except that the subject will be excalated to twice weekly dosing if frequency 
change is necessary.
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Table 2
Criteria for Escalation Specific to Each Bleeding Indication
Schedule A
Schedule B
Joint bleeding
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) twice per week. In the event a 
spontaneous joint bleeding episode occurs 
while on this regimen, the subject will escalate 
to up to 80 IU/kg twice per week or, if 
necessary, to Schedule B following its 
resolution
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week.
GI bleeding
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) twice per week. In the event a 
severe GI bleeding episode, i.e., requiring red 
blood cell transfusion, occurs while on this 
regimen, the subject will escalate to up to 
80 IU/kg twice per week or, if necessary, to 
Schedule B following its resolution
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week.
Menorrhagia
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) on days 1 and 2 of menses for 
2 cycles. Menstrual flow will be monitored by 
the PBAC score. If the average pictorial chart 
score is > 185, then the subject will escalate to
up to 80 IU/kg or, if necessary, to Schedule B
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) on days 1, 2, 
and 3 of menses. Menstrual flow 
will be monitored by the PBAC 
score.
Epistaxis
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) twice per week. The subject will 
escalate to up to 80 IU/kg twice per week or, if 
necessary, to Schedule B in the event of 
1 occurrence of breakthrough bleeding 
requiring intervention such as iron 
replacement therapy, transfusion, packing, 
hospitalization; or 2 bleeding events that 
require treatment with factor replacement
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week. 
Oral and Other 
Mucosa
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) twice per week. The subject will 
escalate to up to 80 IU/kg twice per week or, if 
necessary, to Schedule B in the event of 
1 occurrence of breakthrough bleeding 
requiring intervention such as iron 
replacement therapy, transfusion, packing, 
hospitalization; or 2 bleeding events that 
require treatment with factor replacement.
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week.
Muscle and Soft 
Tissue
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) twice per week. In the event a 
spontaneous bleeding episode occurs while on 
this schedule, the subject will escalate to up to 
80 IU/kg twice per week or, if necessary, to 
Schedule B following its resolution.
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week.
Abbreviations:  GI: gastrointestinal; PBAC: Pictorial Blood Assessment Chart.
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If a subject does not adequately respond to rVWF (vonicog alfa) therapy, he/she will be 
evaluated for the presence of neutralizing and total binding anti-VWF antibodies (see 
Section 12.9.3.2).
If a subject experiences a bleed while receiving rVWF (vonicog alfa) three times per 
week, the investigator should treat the bleed with rVWF (vonicog alfa) at doses up to 
80 IU VWF:RCo/kg at a frequency determined by the investigator until the bleed 
resolves. Upon resolution of the bleeding event, the subject will return to their assigned 
prophylaxis regimen. 
It is essential for the success of this study that the subjects adhere to treatment regimens. 
Therefore, procedures for monitoring subject’s compliance are implemented (see 
Section 10.7).
If 1 infusion of IP is missed, the subject may administer the IP as soon as possible. The 
subject should adhere to their treatment scheme ensuring a minimum interval of 12 hours 
between this and the previous IP infusion. For example, a subject routinely infuses IP on 
Monday and Thursday, he/she misses the Monday time point and therefore may infuse 
the IP on the next day (Tuesday) and thereafter proceed with infusing the IP on Thursday
(considering a minimum 12 hours between the infusions) and return to the initial
schedule.
If more than 30% of infusions of IP are missed within the visit interval of 3 months the 
subject will be discontinued from the study (see Section 9.4).
8.6.4.3.2 General Instructions for Home Treatment for Prophylaxis
At the discretion of the investigator, a subject may be considered suitable for home 
treatment only after the subject has received at least 1 infusion of IP in the clinic, either 
during planned prophylactic IP exposure or during the treatment of bleeding episodes, 
and meets the following additional criteria:
1.
Fully understands the concept of a clinical study and related documentation 
(documented training of at least 30 minutes), 
2.
Has a history of previous experience with home treatment including 
self-administration and treatment with VWF containing concentrates, 
3.
Has adequate time for initial training of the study drug preparation (preparation, 
mixing and infusion of the IP(s) (documented training of at least 30 minutes).
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This applies both to subjects who were on prior on-demand treatment and to subjects 
switching form prophylaxis with pdVWF. In the event a healthcare professional is 
required to administer IP, he/she must be trained and qualified by the investigator on the 
above procedures prior to the decision for home treatment. A Subject Guideline detailing 
all instructions and information listed above will be provided to each subject.
8.6.4.4 Treatment of Bleeding Episodes
8.6.4.4.1 General Instructions for Home Treatment of Bleeding Episodes
If a subject experiences a bleeding episode, he/she should contact the study site 
immediately and the site investigator should provide instructions on the treatment 
regimen. If the subject initiates the treatment at home, he/she should at least follow up 
with the study site if a visit is needed as per the standard of care at the center.
In the event a healthcare professional is required to administer treatment at the subject’s 
home, he/she must be trained and qualified by the site investigator on the above 
procedures prior to the decision for home treatment. Once a subject has received 
1 infusion of rVWF (vonicog alfa) in the clinic (either during planned IP exposure or 
during the treatment of a bleeding episode) and meets the criteria for home treatment, the 
treatment of bleeding episodes with IP can be conducted at home (see Section 8.6.4.3.2).
If a subject is not qualified for home treatment, rVWF (vonicog alfa) infusions must be 
administered at the study site.
If a subject experiences a bleeding episode that requires treatment between the screening 
and the prophylaxis initiation visit, the subject will be treated with IP (rVWF with or 
without ADVATE). Treatment with IP must occur at the study site unless the subject has 
previously qualified for home treatment with rVWF (vonicog alfa). If rVWF (vonicog 
alfa) treatment is not feasible, the subject may use his/her standard of care, such as
commercial pdVWF/FVIII products. In any case a washout period of at least 5 days is 
required prior to rVWF (vonicog alfa) PK infusion at the initial PK assessment visit for 
on-demand subjects.
If a subject experiences a bleeding episode requiring treatment during the PK assessment, 
rVWF (vonicog alfa) should be used to treat the bleed. Blood draws for PK assessment 
will be stopped and the PK assessments will be repeated once the bleed has resolved and 
the subject is free of any symptoms related with the bleeding episode. Dose and 
frequency of rVWF (vonicog alfa) infusions or any other replacement therapy to stop the 
bleed should be recorded in the electronic Case Report Form (eCRF), and the reason for 
the use of any non-IP product or therapy should be documented.
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8.6.4.4.2 Dosing Recommendations for Treatment of Bleeding Episodes 
If an acute bleeding episode occurs, the subject will be treated with rVWF (vonicog alfa)
with or without ADVATE (rFVIII, octocog alfa). It is the sponsor’s opinion that, in many 
cases, treatment with ADVATE (rFVIII, octocog alfa) may not be necessary, since rVWF 
(vonicog alfa) prophylaxis will serve to increase endogenous FVIII levels. However, if 
endogenous FVIII is below 30-40 % or is unknown and cannot be estimated from the 
subject’s PK study, an infusion of rVWF: ADVATE at an rVWF: ADVATE ratio of 
1.3:1± 0.2 should be administered initially. Subsequent infusions should be with 
rVWF:RCo 40 to 60 IU/kg with or, in  many cases,without 30 to 45 IU/kg ADVATE 
(only to be administered if plasma FVIII levels fall below 30 IU/L during the treatment 
period). Dosing may be adjusted downward or upward up to 80 IU/kg rVWF at the 
treating physician’s discretion based upon the subject’s prior history, PK and other 
factors.
If FVIII levels are not available, dosing is at the discretion of the investigator based upon 
the individual subject’s PK data. Using ADVATE (rFVIII, octocog alfa) in addition to 
rVWF (vonicog alfa) in subsequent doses carries the risk of an excessive rise in FVIII:C. 
Therefore, reduced doses of ADVATE (rFVIII, octocog alfa) and/or prolongation of the 
dose interval should be considered.
The following is general guidance and the sponsor’s suggestion for treatment of 
breakthrough bleeds, however each PI will determine the treatment based on the local 
acceptable practice how to monitor and adjust treatment for a bleeding episode. An effort 
should be made to discuss with the sponsor (or sponsor’s delegate) the treatment strategy.
In general the aim of the initial dose should be full replacement of VWF with VWF:RCo 
levels of >0.6 IU/ml (60%) and FVIII:C of >0.4 IU/mL (40%). In major bleeding 
episodes, subsequent doses should keep the trough level of VWF:RCo >50% for 3 days 
and then as deemed necessary by the investigator for subsequent days. In moderate 
bleeding episodes, the dose and trough level may be reduced to >30% for as long as 
deemed necessary by the investigator. Treatment for minor bleeding episodes will 
generally consist of only 1 or 2 doses of rVWF (vonicog alfa) IP. 
If the VWF:RCo level is above 150%, a planned treatment should be delayed by at least 
12 hours; if the VWF:RCo level is above 200%, a planned treatment should be delayed 
by at least 24 hours. In either case, a lower subsequent dose (e.g., 20 IU/kg VWF:RCo) 
may be appropriate.
Dosing recommendations are listed in Table 3.
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Dosage must be individualized based on the subject’s weight, VWD type, and the 
severity of the bleeding episode, as well as on monitoring of appropriate clinical and 
laboratory measures. In the phase 1 study 070701, 1.0 IU/kg VWF:RCo raised the 
circulating level of VWF:RCo by 0.017 IU/mL (1.7 %). In the same study, the observed 
mean half-life for rVWF (vonicog alfa) was 19.3 hours, with a standard deviation of 
10.9 hours.
Table 3
rVWF:RCo Dosing Recommendations for the Treatment of Bleeding Episodes Due to VWD
Classification of 
VWD
Hemorrhage
Dosage (IU VWF:RCo/kg BW)
Type 1 
Severe (Baseline 
VWF:RCo activity 
typically <20%) 
Minor (e.g., epistaxis, oral 
bleeding, menorrhagiaa) 
40 to 50 IU/kg (1 or 2 doses)
Major (e.g., severe or 
refractory epistaxis, 
menorrhagia*, GI bleeding, 
CNS trauma, hemarthrosis, 
or traumatic hemorrhage)
Initial dose 50 to 75 IU/kg, then 40 to 60 IU/kg 
every 8 to 12 hours for 3 days to keep the trough 
level of VWF:RCo >50%; then 40 to 60 IU/kg daily 
for a total of up to 7 days of treatment
Type 2 (all variants) 
and Type 3 
Minor (clinical indications 
above) 
40 to 50 IU/kg (1 or 2 doses)
Major (clinical indications 
above)
Initial dose of 60 to 80 IU/kg, then 40 to 60 IU/kg 
every 8 to 12 hours for 3 days to keep the trough 
level of VWF:RCo >50%; then 40 to 60 IU/kg daily 
for a total of up to 7 days of treatment
a Menorrhagia is defined as excessive bleeding during menstruation. A diagnosis of menorrhagia will be 
defined by a prospectively completed Pictorial Blood Assessment Chart (PBAC) score >185 and normal 
cervical cytology or requiring use of a VWF-containing concentrate for treatment of excessive menstrual 
bleeding for at least one menstrual cycle during the prior year.
Variances of up to 10% in dosing are permissible during treatment of bleeding episodes, 
but rounding to the nearest vial size should be avoided.
Subjects with non-neutralizing binding anti-VWF antibodies should initially be treated 
with a dose known to be efficacious based on the subject’s medical treatment history
which may differ from the recommendations provided in Table 3. Subjects should be 
monitored for lack of efficacy as well as for FVIII (mandatory), VWF:RCo (mandatory), 
and VWF:Ag (optional where testing is not available) levels after 3 to 6 hours. Re-dosing 
with rVWF (vonicog alfa) in combination with ADVATE (rFVIII, octocog alfa) using the 
same (initial) dose and adaptation of the dosing frequency should be considered until 
cessation of the bleed, if the FVIII and/or VWF:RCo levels drop below 30%-50% 
depending on bleeding severity.
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The number of subsequent infusions and the dosage levels prescribed will be determined 
by the investigator on the basis of the clinical severity, response to current therapy, 
available laboratory data, and the subject’s historical treatment for similar bleeding 
episodes.
8.6.4.5 Treatment of Surgical Bleeding
Subjects enrolled in this study who require surgery or dental procedures will be treated 
with IP to manage their surgical bleeding then afterwards will resume their prophylactic 
rVWF (vonicog alfa) treatment schedule. Subjects who at time of screening have an 
already scheduled surgical intervention are not eligible for participation in the study.
8.6.4.5.1 Major, Minor and Oral Surgery Definition
The following definitions and criteria are used to serve as a guidance for major, minor 
and oral surgery.
Major surgeries generally refer to major orthopedic surgery (e.g., joint replacement, 
arthroscopic or open synovectomy, arthrodesis, hardware removals like plates or 
intramedullary nails, etc.), major abdominal surgery (e.g. open or laparoscopic 
hernioplasty, cholecystectomy, colon or small bowel resection, etc.), major gynecological 
surgery (e.g. open or laparoscopic myomectomy, hysterectomy, removal of 
endometriosis, polyps, cysts, adhesiolysis, etc.), major head and neck surgery (e.g.: 
tonsillectomy, adenoidectomy, rhinoplasty, lymphadenectomy, thyroidectomy, 
parotidectomy. etc.), any intracranial , cardiovascular or spinal surgery and any other 
surgery which has a significant risk of large volume blood loss or blood loss into a 
confined anatomical space. Extraction of impacted third molars is generally also 
considered major surgery due to the expected difficulty of surgery and the expected blood 
loss.
Minor surgeries generally refer to interventions such as placement of intravenous access 
devices, removal of small skin lesions, arthroscopy, gastroscopy, colonoscopy or 
conisation.
Oral surgeries comprise extractions of fewer than three teeth, if the teeth are non-molars 
and have no bony involvement.
A summary schedule of visit assessments and laboratory sampling is included in 
Supplement tables in Section 20.2.1 and Section 20.3.1.
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8.6.4.5.2 Preoperative Priming Dose
12- 24 hours prior to surgery, a priming dose with rVWF (vonicog alfa), using the rVWF
IR and T1/2 for this subject , will be infused to allow the endogenous FVIII levels to raise 
to at least 30 IU/dL (minor, oral surgery), or 60 IU/dL (major surgery) at the time of the 
loading dose of rVWF (vonicog alfa) is infused.
As a general guidance a priming dose of 40-60 IU/kg rVWF:RCo will be administered. If 
not assessed prior to the preoperative priming dose, a IR recovery may be calculated for 
subjects undergoing minor and oral surgery.
8.6.4.5.3 Preoperative Loading Dose
An rVWF (vonicog alfa) loading dose should be administed within 3 hours before 
surgery. VWF and FVIII levels should be assessed within 3 hours prior to surgery 
initiation and results must be available prior to administering the loading dose. If FVIII 
levels prior to loading dose administration are not at least 30 IU/dL (minor, oral surgery), 
or 60 IU/dL (major surgery) ADVATE (rFVIII, octocog alfa) will be administered in 
addition to rVWF (vonicog alfa) in order to raise FVIII:C levels to recommended levels.
The preoperative loading dose will be calculated as the difference in the target peak and 
baseline plasma VWF:RCo levels divided by the IR (ΔVWF:RCo x BW (kg) /IR). The 
PK results will be provided prior to the planned surgery. If the IR is not available, assume 
an IR of 1.7 IU/dL per IU/kg and calculate the initial dose as follows: (100 – baseline 
plasma VWF:RCo) x BW (kg) / 1.7. For minor and oral surgery, the IR from the 
Preoperative Priming Dose visit will be used to guide dosing and the target peak is 
50-60 IU/dL VWF:RCo and 40-50 IU/dL FVIII. For major surgery, the target peak is 
100IU/dL VWF:RCo and 80-100 IU/dL FVIII.
The surgery may only start after normalization of the activated partial 
thromboplastin time (aPTT).
8.6.4.5.4 Intra- and Postoperative (maintenance) Dosing
After the preoperative loading dose(s), subjects who have not achieved the desired 
postinfusion recovery will continue to receive rVWF (vonicog alfa) with or without 
ADVATE (rFVIII, octocog alfa) as a bolus infusion, depending on VWF and FVIII 
levels. The peri- and post-operative substitution regimen will be individualized according 
to the PK results, intensity and duration of the hemostatic challenge, and the institution’s 
standard of care.
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Subjects undergoing minor surgery will be infused with rVWF (vonicog alfa) every 
12-24 hours or every other day, targerting ≥30IU/dL (rVWF and FVIII) for at least the 
first 48 hours.
Subjects undergoing oral surgery will be infused with rVWF (vonicog alfa) at least once 
within the first 8-12 hours, targeting ≥30 IU/dL (rVWF and FVIII).
Subjects undergoing major surgery will be infused with rVWF (vonicog alfa) every 
12-24 hours for at least the first 72 hours post-surgery, targeting a VWF:RCo and 
FVIII:C trough plasma level >50 IU/dL, followed by further treatment post-72 hours for 
as long as deemed necessary by the Investigator, targeting a VWF:RCo and FVIII:C 
trough plasma level of ≥30 IU/dL.
Dose modifications based on pre-infusion VWF/FVIII levels will be performed as 
needed. For subsequent infusions post surgery, in case pre-infusion levels are not 
available prior to the consecutive infusion in a timely manner, pre-infusion levels from 
the previous dose may be used by the investigator for dosing guidance.
Peak plasma level guidance is matching to Section 8.6.4.4.2
A schedule of all perioperative visit assessments and laboratory sampling can be found in 
Supplement tables in Section 20.2.1 and Section 20.3.1.
8.6.4.6 Thrombosis Prophylaxis
Thromboembolic events have been reported in patients who have VWD, especially in the 
setting of known risk factors for thrombosis including low ADAMTS13 levels. 
Therefore, subjects who are at risk for developing thromboembolic events should be 
monitored for early signs of thrombosis, and prophylaxis measures against
thromboembolism should be instituted according to current recommendations and 
standard of care. For all subjects who are VWD patients and are receiving VWF 
concentrate, attention should be given to avoid exceeding maximal recommended plasma 
activity levels of VWF:RCo (250 IU/dL) and FVIII (250 IU/dL).
Anticoagulation measures, such as heparin, are acceptable and should follow study site 
standards. The investigator will record the use and reasons for such measures/agents on 
the appropriate CRF.
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8.6.5 Investigational Product Accountability
The investigator will ensure that the IP(s) is stored as specified in the Pharmacy Manual
and that the storage area is secured, with access limited to authorized study personnel. All 
temperature excursions at the subject’s home need to be monitored by the site (please 
refer to the pharmacy manual). The investigator will maintain records that the IP(s) was
received, including the date received, drug identity code, date of manufacture or 
expiration date, amount received and disposition. The IP(s) must be dispensed only at the 
study site or other suitable location (e.g., infusion center; home, as applicable per study 
design), as specified in the protocol (see Section 10). Records will be maintained that 
includes the subject identification code (SIC), dispensation date, and amount dispensed. 
All remaining partially used and/or unused IP(s) will be returned to the sponsor or 
sponsor’s representative after study completion/termination, or destroyed with the 
permission of the sponsor in accordance with applicable laws and study site procedures. 
If IP(s) is to be destroyed, the investigator will provide documentation in accordance with 
sponsor’s specifications.
8.7 Source Data
Per ICH E6(R2) on GCP, source data are defined as all information in original records 
and certified copies of original records of clinical findings, observations, or other 
activities in a clinical trial that are necessary for the reconstruction and evaluation of the 
trial. Source data are contained in source documents (original records or certified copies). 
These may be in paper and/or electronic format. Source documents for this study
comprise the following: hospital records, medical records, clinical and office charts, 
laboratory notes, memoranda, subjects' diaries or evaluation checklists, outcomes 
reported by subjects, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate copies, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, 
and records kept at the pharmacy, at the laboratories and at medico-technical departments 
involved in the clinical study.
No data will be entered directly onto the CRF.
For additional information on study documentation and CRFs refer to Section 17.2. The 
use of subject diaries is described in Section 10.5.
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9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION
9.1 Inclusion Criteria
Subjects who meet ALL of the following criteria are eligible for this study:
1.
Subject has a documented diagnosis of severe VWD (baseline VWF:RCo 
<20 IU/dL) with a history of requiring substitution therapy with von Willebrand 
factor concentrate to control bleeding
a.
Type 1 (VWF:RCo <20 IU/dL) or,
b. Type 2A (as verified by multimer pattern), Type 2B (as diagnosed by 
genotype), Type 2M or,
c.
Type 3 (VWF:Ag ≤3 IU/dL).
2.
Diagnosis is confirmed by genetic testing and multimer analysis, documented in 
patient history or at screening.
3.
For on-demand patient group, subject currently receiving on-demand treatment for 
whom prophylactic treatment is recommended by the investigator.
4.
For pdVWF switch patient group, subject has been receiving prophylactic 
treatment of pdVWF products for no less than 12 months prior to screening.
5.
For on-demand patient group, subject has ≥3 documented spontaneous bleeds (not 
including menorrhagia) requiring VWF treatment during the past 12 months.
6.
Availability of records to reliably evaluate type, frequency and treatment of 
bleeding episodes during at least 12 months preceding enrollment. Up to 
24 months retrospective data should be collected if available. Availability of 
dosing and factor consumption during 12 months (up to 24 months) of treatment 
prior to enrollment is required for pdVWF switch subjects and is desired (but not 
a requirement) for on-demand subjects.
7.
Subject is ≥18 years old at the time of screening and has a body mass index ≥17.5 
but <40 kg/m2.
8.
If female of childbearing potential, subject presents with a negative blood/urine 
pregnancy test at screening and agrees to employ adequate birth control measures 
for the duration of the study.i
9.
Subject is willing and able to comply with the requirements of the protocol.
                                                
i Refer to Section 20.4 for a list of adequate contraceptive methods for females of childbearing potential.
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9.2 Exclusion Criteria
Subjects who meet ANY of the following criteria are not eligible for this study:
1.
The subject has been diagnosed with Type 2N VWD, pseudo VWD, or another 
hereditary or acquired coagulation disorder other than VWD (eg qualitative and 
quantitative platelet disorders or prothrombin time (PT)/international normalized 
ratio [INR] 1.4).
2.
The subject is currently receiving prophylactic treatment with more than 
5 infusions per week.
3.
The subject is currently receiving prophylactic treatment with a weekly dose 
exceeding 240 IU/kg.
4.
The subject has a history or presence of a VWF inhibitor at screening.
5.
The subject has a history or presence of a FVIII inhibitor with a titer 
≥0.4 Bethesda units (BU) (by Nijmegen modified Bethesda assay) or ≥0.6 BU
(by Bethesda assay).
6.
The subject has a known hypersensitivity to any of the components of the study 
drugs, such as to mouse or hamster proteins.
7.
The subject has a medical history of immunological disorders, excluding seasonal 
allergic rhinitis/conjunctivitis, mild asthma, food allergies or animal allergies.
8.
The subject has a medical history of a thromboembolic event.
9.
The subject is human immunodeficiency virus (HIV) positive with an absolute 
Helper T cell (CD4) count 200/mm3.
10. The subject has been diagnosed with significant liver disease per investigator’s 
medical assessment of the subject’s current condition or medical history or as 
evidenced by any of the following: serum alanine aminotransferase (ALT) greater 
than 5 times the upper limit of normal; hypoalbuminemia; portal vein 
hypertension (e.g., presence of otherwise unexplained splenomegaly, history of 
esophageal varices).
11. The subject has been diagnosed with renal disease, with a serum creatinine (CR)
level ≥2.5 mg/dL.
12. The subject has a platelet count <100,000/mL at screening.
13. The subject has been treated with an immunomodulatory drug, excluding topical 
treatment (e.g., ointments, nasal sprays), within 30 days prior to signing the 
informed consent.
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14. The subject is pregnant or lactating at the time of enrollment.
15. Patient has cervical or uterine conditions causing menorrhagia or metrorrhagia 
(including infection, dysplasia).
16. The subject has participated in another clinical study involving another IP or 
investigational device within 30 days prior to enrollment or is scheduled to 
participate in another clinical study involving an IP or investigational device 
during the course of this study.
17. The subject has a progressive fatal disease and/or life expectancy of less than 
15 months.
18. The subject is scheduled for a surgical intervention.
19. The subject is identified by the investigator as being unable or unwilling to 
cooperate with study procedures.
20. The subject has a mental condition rendering him/her unable to understand the 
nature, scope and possible consequences of the study and/or evidence of an 
uncooperative attitude.
21. The subject is in prison or compulsory detention by regulatory and/or juridical 
order.
22. The subject is member of the study team or in a dependent relationship with one 
of the study team members which includes close relatives (i.e., children, 
partner/spouse, siblings and parents) as well as employees.
9.3 Delay Criteria
1.
If the subject has an acute bleeding episode or presents with an acute illness 
(e.g., influenza, flu-like syndrome, allergic rhinitis/conjunctivitis, non-seasonal 
asthma) the screening visit will be postponed until the subject has recovered.
9.4 Withdrawal and Discontinuation
Any subject may voluntarily withdraw (i.e., reduce the degree of participation in the 
study) consent for continued participation and data collection. The reason for withdrawal 
will be recorded on the End of Study CRF. Assessments to be performed at the 
termination visit (including cases of withdrawal or discontinuation) are described in 
Section 10.6 and Section 20.2. 
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Discontinuation (i.e., complete withdrawal from study participation) may be due to 
dropout (i.e., active discontinuation by subject) or loss to follow-up (i.e., discontinuation 
by subject without notice or action). Additionally, the investigator and sponsor have the 
discretion to discontinue any subject from the study if, in their judgment, continued 
participation would pose an unacceptable risk for the subject.
Subjects also will be withdrawn from treatment or discontinued from further study 
participation for the following reasons:
1.
The subject is scheduled for an extended treatment period 3 months with 
non-topical immunomodulating drugs other than anti-retroviral chemotherapy 
(e.g., -interferon, corticosteroid agents [equivalent to hydrocortisone greater 
than 10 mg/day]) during the course of the study.
2.
Subjects with chronic hepatitis B or C develop ALT/AST levels exceeding 
5 times the ULN for 1 month.
3.
Subjects who experience severe hypersensitivity reactions, e.g., anaphylaxis upon 
exposure to rVWF (vonicog alfa).
4.
Subjects who develop a neutralizing inhibitor to rVWF (vonicog alfa) and/or 
ADVATE (rFVIII, octocog alfa) (biological assays) that results in significant 
clinical effect, including but not limited to increasing the weekly dose of rVWF 
by ≥50%.
5.
Subjects who demonstrate clinical signs of thromboembolic events.
6.
The subject becomes pregnant. IP exposure will be discontinued. Attempts will be 
made to follow the subject through completion of the pregnancy and up to 1 year 
post delivery, if feasible. The investigator will record a narrative description of 
the course of the pregnancy and its outcome. 
7.
The subject begins lactating. IP exposure will be discontinued. The investigator 
will record a narrative description of the course of the baby’s development. 
8.
The subject is not compliant with the prophylactic treatment regimen and does not 
adhere to the frequency of IP administration. Once >30% of infusions are missed 
within a visit interval (3 months), the subject will be discontinued from further 
participation in the study. 
9.
The subject repeatedly uses other VWF products for prophylaxis or for the 
treatment of bleeding episodes in the absence of an acceptable justification to the 
sponsor. 
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10. STUDY PROCEDURES
10.1 Informed Consent and Enrollment
Any patient who provides informed consent (i.e., signs and dates the informed consent 
form) is considered a subject enrolled in the study.
10.2 Subject Identification Code
The following series of numbers will comprise the SIC: protocol identifier (e.g., 071301) 
to be provided by the sponsor, 2- or 3-digit number study site number (e.g., 02) to be 
provided by the sponsor, and 3- or 4-digit subject number (e.g., 0003) reflecting the order 
of enrollment (i.e., signing the informed consent form). For example, the third subject 
who signed an informed consent form at study site 02 will be identified as Subject 
071301-020003. All study documents (e.g., CRFs, clinical documentation, sample 
containers, drug accountability logs, etc.) will be identified with the SIC. Additionally, a 
uniquely coded SIC(s) is permitted as long as it does not contain a combination of 
information that allows identification of a subject (e.g., collection of a subject’s initials 
and birth date would not be permitted), in compliance with laws governing data privacy.
10.3 Screening and Study Visits
The study site is responsible for maintaining a screening log that includes all subjects 
who provided informed consent. The log also will serve to document the reason for 
screening failure. All screening data will be collected and reported in CRF, regardless of 
screening outcome. If a subject is re-screened, the End of Study CRF should be 
completed, and a new ICF, new SIC and new CRF are required for that subject.
The overall study design is illustrated in the Figure 1. Details on the procedures to be 
performed at each study visit, including screening, are provided in Supplement 20.2
“Schedule of Study Procedures and Assessments” and Supplement 20.3 “Clinical 
Laboratory Assessments”.
10.3.1 Screening Visit
Written informed consent must be obtained from each subject before any study 
related procedures are performed. To initiate screening procedures, at least 72 hours 
must have elapsed since the last VWF administration for on-demand subjects and the 
subject must not be actively bleeding at the time of screening. For switch subjects, the 
usual interval between their pdVWF prophy infusions must have elapsed since the last 
VWF administration and the subject must not be actively bleeding at the time of 
screening. Multimer analysis and VWD gene mutation analysis should be performed 
at screening if not available in the subject’s medical history.
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The screening visit will be delayed if the subjects presents with an acute bleeding 
episodes or acute illness (e.g., influenza, flu-like symptoms, inflammatory diseases) until 
the event has resolved. All screening procedures and confirmation of eligibility shall take 
place within 42 days prior to the first infusion of IP. If the IP is not infused within 
42 days, all screening assessments except blood group, human leukocyte antigen (HLA), 
genetics, multimeric pattern and 
, must be repeated to reconfirm eligibility. Refer 
to Supplement 20.2 and Supplement 20.3. Upon completion of screening procedures, 
subject eligibility will be confirmed by the sponsor on a subject eligibility form before 
additional study procedures are undertaken. The subject will maintain a diary that will 
include infusion logs (see Section 10.5). The allocation of IP will be initiated after the 
subject has qualified for home treatment (see Section 8.6.4.3.2).
In the event of a subject experiencing a bleeding episode that requires treatment between 
the screening visit and the subsequent visit (i.e. initial PK assessment visit for on-demand 
subjects or prophylaxis initiation visit for switch subjects), the subject will be treated with
rVWF (vonicog alfa). If rVWF (vonicog alfa) is not available for any reason, e.g., subject 
not yet trained on IP administration, study site visit for IP administration not feasible, 
etc., the subject may use his/her standard of care, such as commercial pdVWF/FVIII 
products, and the reason for the use of non-IP products should be clearly documented.
10.3.2 Baseline Visit – Initial PK Assessment (On-demand Subjects Only)
After screening and confirmation of eligibility on-demand subjects will undergo an initial
PK assessment. Subjects will receive a dose of 50 ± 5 IU/kg rVWF:RCo to determine 
VWF and FVIII levels. Blood samples will be drawn within 30 minutes pre-infusion, and 
at 11 time points post-infusion (15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 
3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 
72 2 hours and 96 ± 2 hours). See Section 20.2 and Section 20.3. IP infusion vials from 
the same lot number should be used for all PK-assessments per subject. Samples for 
measurement of FVIII and VWF activity taken through to 6 hours post-infusion will be 
obtained from an extremity different from that used for the infusion of IP. Where needed, 
the phlebotomy site will be kept patent via an infusion of normal saline. In this event, at 
least 5 mL of blood will be collected and discarded before collection of the next test 
sample into a fresh syringe.
If the subject has a central venous catheter, the central line should be used to administer 
the infusion and a peripheral venipuncture should be used to collect the blood samples.
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In the event that a blood sample must be drawn through the central line used for 
administration of IP, the line must first be flushed with at least 10 mL normal saline or 
other suitable catheter flush solution that does not contain anticoagulant. At least 5 mL of 
whole blood must be collected and discarded prior to obtaining the sample. 
If a subject experiences a bleeding episode during the PK assessment no subsequent 
blood sample will be drawn in that specific PK period. The guidance provided in 
Section 8.6.4.4 has to be followed for the treatment of the bleeding episode. The subject 
once recovered is eligible to repeat the PK assessment. 
For pdVWF switch subjects, PK profile will not be assessed until reaching steady state 
after initiation of prophylaxis (see Section 10.3.4).
10.3.3 Prophylaxis Initiation Visit
The prophylaxis initiation visit will occur after the blood sample for the 96 hour PK 
assessment is drawn for on-demand subjects or within 42 days after screening and 
confirmation of eligibility for pdVWF switch subjects. The subject will receive the first 
rVWF (vonicog alfa) prophylactic dose of rVWF: RCo. Details on dose are provided in 
Section 8.6.4.3. 
Procedures and assessments at this visit include (but are not limited to): AEs, bleeding 
episodes, medications taken, and non-drug therapies. Within 2 hours prior the IP infusion, 
a physical examination will be performed. Vital signs will be assessed within 30 minutes 
prior to IP rVWF (vonicog alfa) infusion and 30 minutes ± 15 minutes after IP infusion.
Further details are provided in Supplement 20.2 and Supplement 20.3.
10.3.4 Initial Steady State PK-Assessment (pdVWF switch subjects only)
For pdVWF switch subjects, a full PK profile will be assessed at steady state conditions 
on two occasions. The initial PK assessment will be performed shortly after reaching 
steady state after starting prophylaxis dosing, which is suggested after 11 days post the 
1st, around prophylaxis dose #5-6. The 2nd PK assessment at steady state will be 
performed at the end of the study.
Blood samples will be drawn within 30 minutes pre-infusion, and at 11 time points 
post-infusion (15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 
6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours 
and 96 ± 2 hours). In case the dosing schedule does not permit the 96 hr sampling, 
this sampling time point can be omitted (See Section 11.6). IP infusion vials from 
the same lot number should be used for all PK-assessments per subject. 
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Samples for measurement of FVIII and VWF activity taken through to 6 hours post-
infusion will be obtained from an extremity different from that used for the infusion of 
IP. Where needed, the phlebotomy site will be kept patent via an infusion of normal 
saline. In this event, at least 5 mL of blood will be collected and discarded before 
collection of the next test sample into a fresh syringe.
If the subject has a central venous catheter, the central line should be used to administer 
the infusion and a peripheral venipuncture should be used to collect the blood samples. 
In the event that a blood sample must be drawn through the central line used for 
administration of IP, the line must first be flushed with at least 10 mL normal saline or 
other suitable catheter flush solution that does not contain anticoagulant. At least 5 mL of 
whole blood must be collected and discarded prior to obtaining the sample. 
If a subject experiences a bleeding episode during the PK assessment no subsequent 
blood sample will be drawn in that specific PK period. The guidance provided in 
Section 8.6.4.4 has to be followed for the treatment of the bleeding episode. The subject 
once recovered is eligible to repeat the PK assessment. In case of surgery or bleeding, the 
PK assessment should be performed after 11 days after 1st prophylactic dose after re-start
of prophylactic regimen. See section 11.6 for more details.
10.3.5 Treatment of Bleeding Episodes
Treatment of bleeding episodes is described in detail in Section 8.6.4.4 and treatment of 
perioperative bleeding is described in detail in Section 8.6.4.5.
10.3.6 Perioperative Visits (only applicable if surgery is needed)
The perioperative visits from priming dose through postoperative day 14 will be required 
to check daily intra- and postoperative weight-adjusted dose of rVWF (vonicog alfa) with 
or without ADVATE (rFVIII, octocog alfa). Details on the procedures and assessments 
performed at each visit can be found in Supplement tables in Section 20.2.1 and 
Section 20.3.1.
10.3.7 Follow-Up Visits (1 Month ± 1 Week, 2 Months ± 1 Week, 
3 Months ± 2 Weeks, 6 Months ± 2 Weeks, 9 Months ± 2 Weeks post 
Prophylaxis Initiation Visit)
Visits will be performed after the prophylaxis initiation visit at 1 month ± 1 week, 
2 months ± 1 week, and 3 months ± 2 weeks and thereafter every three months
± 2 weeks. Additional visits may occur if clinically indicated (see Section 10.3.8).
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When possible, site visits should be scheduled on days when the subject is expected to 
infuse rVWF (vonicog alfa). Within 2 hours prior to the rVWF (vonicog alfa) IP infusion,
a physical examination will be performed. Vital signs will be assessed within 30 minutes 
prior to IP infusion and 30 minutes ± 15 minutes after IP infusion. Incremental recovery 
(IR) will be determined at each follow-up visit based on VWF:RCo activity assessed 
prior to and after IP infusion.
The blood sample for IR analysis will be drawn within 30 minutes prior to IP infusion 
and 30 minutes ± 5 minutes after IP infusion. rVWF (vonicog alfa) will be infused at the 
regular prophylactic dose. For each subject’s recovery analysis IP infusion, vials from the 
same lot number should be used. 
Testing for VWF:RCo VWF:CB, rVWF:Ag, and FVIII:C level will be performed using 
the blood sample obtained before and after IP infusion. 
The blood sample prior to IP infusion will also be used for the assessment of neutralizing
and binding antibodies, clinical chemistry and hematology. For on-demand subjects, a
washout period of at least 72 hours after the last infusion applies before the blood draw 
for the immunogenicity assays. For switch subjects, the wash out period may be reduced 
to the time interval between their pdVWF prophy infusions Bleeding episodes and the 
hemostatic efficacy will be evaluated based on the review of the patient diary. See
Section 20.2 and Section 20.3. The evaluation of IP consumption and treatment 
compliance will be performed based on subject’s diary entries. If a subject is not 
compliant with the prophylactic treatment regimen and does not adhere to the required 
frequency of administration of IP infusions (>30% of infusions were missed within a visit 
interval [3 months]) the subject will be withdrawn from the study.
At the 6 months ± 2 week visit an ECG will be performed and 
data will be 
collected. 
For the hemostatic efficacy assessment the following information will be recorded by the 
subject in the patient diary: bleeding location, type, severity, onset and resolution date 
and time, infusion date and time, clinical efficacy according to the rating scale. If at any 
time during the study a subject’s bleeding episode does not adequately respond to rVWF 
(vonicog alfa) therapy, he/she will be evaluated for the presence of neutralizing and total 
binding antibodies. Refer to Section 12.9.3.2.
Further guidance on completing the subject’s diary will be provided to the subjects 
during training for home treatment (see Section 8.6.4.3.2).
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10.3.8 Unscheduled Visits
For any unscheduled visit (except for collection of IP) a clinical assessment will be 
performed as per the scheduled follow-up visits with the exception of 
, ECG, and 
IR determination (refer to Supplement 20.2 and Supplement 20.3).
Subjects who have more than one bleeding episode in 3 months, or an increased 
frequency of bleeding, should go to the study site for an unscheduled visit.
Follow-up visits after the subject has experienced a bleed may be requested by the 
investigator. Additional assessments may be required which are at the discretion of the 
investigator. 
10.3.9 End of Study PK Assessment and Study Termination Visit
(12 Months ± 2 Weeks post Prophylaxis Initiation Visit)
At the 12 month ± 2 week visit, a full PK analysis at steady state will be performed for 
both cohorts: on-demand and switch subjects. Blood samples will be drawn within 
30 minutes pre-infusion, and at 11 time points post-infusion (15 ± 5 minutes, 
30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 
24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours and 96 ± 2 hours) unless dosing 
schedule does not permit, in which case the 96 hr sampling can be omitted. If a subject 
experiences a bleeding episode during the PK assessment no subsequent blood sample 
will be drawn in that specific PK period. The guidance provided in Section 8.6.4.4 has to 
be followed for the treatment of the bleeding episode. The subject once recovered is 
eligible to repeat the PK assessment and the PK assessment should be performed after 
11 days after 1st prophylactic dose after re-start of prophylactic regimen. See 
Section 11.6 for more details.
Refer to Supplement 20.2 and Supplement 20.3 for the other assessments to be performed 
at the PK assessment and study completion visits.
For on-demand subjects, a washout period of at least 72 hours is required between the PK
infusion and the study termination visit (at the time of the 96 hour postinfusion PK 
assessment). For switch subjects,  the wash out period may be reduced to the time 
interval between their rVWF (vonicog alfa) prophy infusions.Refer to Supplement 20.2
and Supplement 20.3 for the list of assessments to be performed at the termination visit.
Subjects will be offered the option to continue to receive rVWF (vonicog alfa) in a 
long-term continuation study.
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10.4 Medications and Non-Drug Therapies 
The following medications and non-drug therapies are not permitted within 30 days 
before study entry and during the course of the study:
Medications:

Immunomodulating drugs other than anti-retroviral chemotherapy (e.g.,
-interferon, or corticosteroid agents at a dose equivalent to hydrocortisone 
greater than 10 mg/day) and an extended treatment period 3 months.

Another investigational and/or interventional study drug (except rVWF and FVIII 
administered under the surgery protocol).
A subject who has taken any of these medications or received any of these non-drug 
therapies during the study will be withdrawn from the study. 
The following medications are permitted during the course of the study:

Antifibrinolytics (e.g., tranexamic acid, -amino caproic acid) or topical
hemostats as needed, according to each institution’s standard of care. These may 
be used, in accordance with local standard clinical practice, as the initial or only 
treatment for minor and moderate bleeding events. However, if the bleeding has 
not stopped within 24 hour following administration of this non-VWF treatment, 
infusion(s) with rVWF (vonicog alfa) should be started per protocol

Emergent use of a VWF concentrate other than rVWF (vonicog alfa) may be 
permissible under certain circumstances (see Section 8.6.4.4.1)
Details of all adjunctive hemostatic medication used, including dose and reason for use, 
must be recorded in the eCRF.
10.5 Subject Diary
1.
An electronic subject diary will be provided to each subject at the screening visit 
to record the following information:

IP infusions to include date, start and stop times of the infusion, number of 
vials utilized, and infusion volume for prophylactic treatment or treatment of 
spontaneous and traumatic bleeding episodes 
2.
Details of bleeding episodes (site, type, severity and date/time of bleeding) and 
response to treatment as described in Section 8.6.4.4
3.
Subjective hemostatic efficacy assessments
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4.
Untoward events/unwanted experiences
5.
Concomitant medications (including immunizations) and non-drug therapies
6.
Patient Reported Outcomes (PROs)
Subjects and/or their legally authorized representatives will be trained on use of the diary. 
The diary will be provided in electronic format and remain with the subject for the 
duration of the study. The investigator will review the diary for completeness and request 
missing information periodically and in a timely manner. The investigator will 
record/capture any unwanted experience reported by the subject which may qualify as an 
AE on the AE eCRF.
Infusions performed at the study site will first be recorded in the site’s source documents 
and not in the patient diary.
Subject entries in the diary will serve as source records. During study participation the 
investigator has access to the database holding the subject diary data. After study closure,
the investigator will receive the diary records for their subjects, including audit trail 
records, in PDF format. The data will be transmitted to the CRF by a validated transfer.
Paper diary may be utilized in rare case where electronic diary use is not possible.
10.6 Subject Completion/Discontinuation
A subject is considered to have completed the study when he/she ceases active 
participation in the study because the subject has, or is presumed to have completed all 
study procedures according with the protocol (with or without protocol deviations).
Reasons for completion/discontinuation will be reported on the 
Completion/Discontinuation CRF, including: completed, screen failure, AE (e.g., death), 
discontinuation by subject (e.g., lost to follow-up [defined as 3 documented unsuccessful 
attempts to contact the subject], dropout), physician decision (e.g., pregnancy, 
progressive disease, non-compliance with IP/protocol violation(s), recovery), study 
terminated by sponsor, or other (reason to be specified by the investigator, e.g., technical 
problems). Regardless of the reason, all data available for the subject up to the time of 
completion/discontinuation should be recorded on the appropriate CRF. 
Every effort will be made to have discontinued subjects complete the study 
termination visit. If the termination visit is done as an additional, unscheduled 
visit, the assessment results shall be recorded with the termination visit.
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If a subject terminates participation in the study and does not return for termination visit, 
his/her last recorded assessments shall remain with the last visit. The reason for 
discontinuation will be recorded, and the data collected up to the time of discontinuation 
will be used in the analysis and included in the clinical study report. If additional 
assessments are required, the assessments shall be recorded separately. Assessments to be 
performed at the termination visit (including in cases of withdraw or discontinuation) can 
be found in Supplement 20.2 Schedule of Study Procedures and Assessments and 
Supplement 20.3 Clinical Laboratory Assessments.
In the event of subject discontinuation due to an AE, clinical and/or laboratory 
investigations that are beyond the scope of the required study observations/assessments 
may be performed as part of the evaluation of the event. These investigations will take 
place under the direction of the investigator in consultation with the sponsor, and the 
details of the outcome may be reported to the appropriate regulatory authorities by the 
sponsor.
10.7 Procedures for Monitoring Subject Compliance
Subject compliance with the procedures of this study (treatment regimens and study 
visits) will be monitored by the investigator or/a licensed healthcare professional at the 
study site.
During the regular scheduled follow-up visits a direct review of the subject’s source data 
(e-diaries) will be performed at the sites and evaluated against the protocol requirements. 
In addition drug accountability will be evaluated at each follow-up study visit and the 
study termination visit by comparing the infusions recorded in the subject diary with
empty vials returned by each subject to the study site, and the study site’s dispensing 
record. Protocol deviations will be noted in the final report. 
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11. ASSESSMENT OF EFFICACY AND PHARMACOKINETICS
11.1 Assessment of Spontaneous Bleeding Episodes/Annualized Bleed Rate 
The annualized bleed rate (ABR) will be assessed based upon each individual 
spontaneous bleed, requiring coagulation factor replacement therapy, i.e., rVWF 
(vonicog alfa) treatment. The following details on bleeding episodes will be recorded by 
the subject in the electronic diary (for home treatment), the subject’s healthcare provider 
in the site’s source documents (for treatments away from the primary investigative site), 
or by authorized, qualified personnel at the participating site in the subject’s medical 
records (for hospital-based treatment):

Location of bleed; i.e., joint, menorrhagia, epistaxis, gastrointestinal, soft tissue, 
muscle, body cavity, intracranial, etc.

Type of bleed; i.e., spontaneous, traumatic, unknown

Severity of bleed; i.e., minor, moderate, and major (see Table 3)

Date and time of onset of bleed

Date and time of each infusion of rVWF (vonicog alfa) or rVWF (vonicog alfa)-
ADVATE (rFVIII, octocog alfa) used to treat a bleeding episode

Date and time of resolution of the bleeding episode
Study site personnel are qualified after they have undergone training during the 
qualification of the site.
All types of bleeds, including traumatic bleeds, will be recorded. Bleeding episodes 
should be organized by where they occur in addition to whether they occurred 
spontaneously or due to a traumatic event.
Bleeds occurring at the same anatomical location (e.g., right knee) with the same etiology 
(i.e., spontaneous versus injury) within 24 hours after onset of the first bleed will be 
considered a single bleed. Bleeding occurring at multiple locations related to the same 
injury (e.g., knee and ankle bleeds following a fall) will be counted as a single bleeding 
episode.
All efforts should be made to use rVWF (vonicog alfa) for treatment of bleeding 
episodes. If needed, the use of a VWF concentrate other than IP for the treatment of 
bleeding episodes will not disqualify the subject from further participation in the study.
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11.2 Evaluation of ABR Before rVWF Prophylaxis and ABR Under rVWF
Prophylactic Treatment
At screening, the subject’s medical history will be recorded, including the number and 
location of all spontaneous and traumatic bleeding episodes within the past 12 months
(up to 24 months if available). The maximum interval of bleed-free periods as well as 
trauma induced bleeding episodes will also be recorded (prospectively and 
retrospectively).
11.3 Number of Infusions and Total Weight Adjusted Consumption of rVWF and 
ADVATE and historical prophylaxis dosing and factor consumption during 
pdVWF prophylaxis treatment prior to enrollment
The number of rVWF (vonicog alfa) and ADVATE (rFVIII, octocog alfa) (in case of 
bleeding episode treatment) infusions will be logged in the subject diary. Based on these 
entries the weight adjusted consumption will be calculated. 
At the screening, historical pdVWF dosage and dosing frequency during 12 and up to 
24 months of pdVWF prophylactic treatment prior to enrollment will be recorded for the 
pdVWF switch subjects in order to calculate the consumption of pdVWF.
11.4 Assessment of Efficacy for Treatment of Bleeding Episode
Investigators will be asked to assess and record hemostatic efficacy after resolution of 
each bleeding episode using the 4-scale rating system outlined in Table 4. 
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Table 4
Efficacy Rating Scale
Rating
Efficacy Rating Criterion
Minor and Moderate Bleeding Events
Major Bleeding Events
Excellent (=1)
Actual number of infusions ≤ estimated 
number of infusions required to treat that 
bleeding episode
No additional VWF containing coagulation 
factor containing product required
Actual number of infusions ≤ estimated 
number of infusions required to treat that 
bleeding episode
No additional VWF containing coagulation 
factor containing product required
Good (=2)
1-2 infusions greater than estimated 
required to control that bleeding episode
No additional VWF containing coagulation 
factor containing product required
< 1.5 x infusions greater than estimated 
required to control that bleeding episode
No additional VWF containing coagulation 
factor containing product required
Moderate (=3)
3 or more infusions greater than estimated 
required to control that bleeding episode
No additional VWF containing coagulation 
factor containing product required
≥1.5 x infusions greater than estimated 
required to control that bleeding episode
No additional VWF containing coagulation 
factor containing product required
None (=4)
Severe uncontrolled bleeding or intensity 
of bleeding not changed
Additional VWF containing coagulation 
factor containing product required
Severe uncontrolled bleeding or intensity of 
bleeding not changed
Additional VWF containing coagulation 
factor containing product required
11.5 Assessment of Efficacy for Treatment for Surgical Bleeding
For those undergoing surgery, the operating surgeon will be asked to assess and record 
actual versus predicated blood loss and intraoperative hemostatic efficacy immediately 
after surgery. 
The investigator will be asked to assess and record an overall assessment of hemostatic 
efficacy 24 hours after the last perioperative rVWF (vonicog alfa) infusion or at day 
14 post-operation, whichever occurs first, using the 4-scale rating system described in 
Table 5.
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Table 5
Assessment of Hemostatic Efficacy
Rating
Overall Assessment of Hemostatic Efficacy 24 Hours After the Last Perioperative
rVWF Infusion
Excellent (1)
Intra- and post-operative hemostasis achieved with rVWF (vonicog alfa) with or without 
ADVATE (rFVIII, octocog alfa) was as good or better than that expected for the type of 
surgical procedure performed in a hemostatically normal subject
Good (2)
Intra- and post-operative hemostasis achieved with rVWF (vonicog alfa) with or without 
ADVATE (rFVIII, octocog alfa) was probably as good as that expected for the type of 
surgical procedure performed in a hemostatically normal subject
Moderate (3)
Intra- and post-operative hemostasis with rVWF (vonicog alfa) with or without ADVATE 
(rFVIII, octocog alfa) was clearly less than optimal for the type of procedure performed 
but was maintained without the need to change the rVWF (vonicog alfa) concentrate
None (4)
Subject experienced uncontrolled bleeding that was the result of inadequate therapeutic 
response despite proper dosing, necessitating a change of rVWF (vonicog alfa) concentrate
11.6 rVWF Pharmacokinetics and Pharmacodynamics 
PK will be assessed twice for all subjects.
For on-demand subjects, an initial PK assessment using a dose of 50 IU ± 5 IU/kg 
rVWF:RCo will be performed at the baseline visit, and a washout period of at least 
5 days is required before the infusion of rVWF (vonicog alfa) for PK assessment can 
be administered. At the 12 month ± 2 week visit, a steady state PK analysis will be 
performed based on the longer interval of the irregular dosing intervals employed. For 
both assessments, blood samples will be drawn within 30 minutes pre-infusion, and at 
11 time points post-infusion (15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 
3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 
72 2 hours and 96 ± 2 hours). VWF activity will be determined using the VWF:RCo, 
VWF:CB and the VWF: Ag assay. Endogenous FVIII activity will be measured using the 
1-stage clotting assay to assess the pharmacodynamics of rVWF (vonicog alfa).
For pdVWF switch subjects, the initial PK assessment using the subject’s individualized 
dose will be performed shortly after reaching steady state, which is estimated to be 
reached for the majority of subjects after  approximately 11 days from the 1st prophylactic 
dose. To fit any logistical requirements, samples for PK analysis can be taken after 
prophylaxis dose #5-6, and whenever possible, sample collections should be during the 
longer partial interval of the alternating irregular dosing intervals. For example, if a 
subject follows a dosing regimen as follows:
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Date
Weekday
Dose number
Interval
Time from 1st dose in hours
8.1.18 8:00
Monday
1
0
0
12.1.18 8:00
Friday
2
4
96
15.1.18 8:00
Monday
3
3
168
19.1.18 8:00
Friday
4
4
264
22.1.18 8:00
Monday
5
3
336
26.1.18 8:00
Friday
6
4
432
After reaching the steady state, the PK assessment can be done at dose 5 to allow the 96h 
post-infusion sampling, before the next scheduled dose (for patients on a twice per week 
dosing schedule). A similar 2nd full PK profile will be assessed at the end of the study, i.e. 
12 month ± 2 week visit with a PK infusion at the same dosing partial interval (96h 
interval in this case). Blood samples will be drawn within 30 minutes pre-infusion, 
and at 11 time points post-infusion (15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 
3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 
72 2 hours, and 96 ± 2 hours). If the dosing interval for a certain switch subject 
wouldn’t allow for the full 11 post-infusion timepoints sample collection, the 96-hour 
sampling timepoint can be omitted, but it is critical that the assessments are at the same 
partial interval, thereby same number of sampling timepoints, for the 1st and 2nd PK for 
an individual switch subject.
If a subject experiences a bleeding episode during the PK assessment no subsequent 
blood sample will be drawn in that specific PK period. The guidance provided in 
Section 8.6.4.4 has to be followed for the treatment of the bleeding episode. The subject 
once recovered is eligible to repeat the PK assessment. In case of surgery or bleeding, the 
PK assessment should be performed after 11 days after 1st prophylactic dose after restart 
of prophylactic regimen.
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12. ASSESSMENT OF SAFETY
12.1 Adverse Events
12.1.1 Definitions
An AE is defined as any untoward medical occurrence in a subject administered IP that 
does not necessarily have a causal relationship with the treatment. An AE can therefore 
be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom
(e.g., rash, pain, discomfort, fever, dizziness, etc.), disease (e.g., peritonitis, bacteremia, 
etc.), or outcome of death temporally associated with the use of an IP, whether or not 
considered causally related to the IP.
12.1.1.1 Serious Adverse Event
An SAE is defined as an untoward medical occurrence that, at any dose, meets one or 
more of the following criteria:

Outcome is fatal/results in death (including fetal death)

Is life-threatening – defined as an event in which the subject was, in the 
judgment of the investigator, at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death had it been more 
severe.

Requires inpatient hospitalization or results in prolongation of an existing 
hospitalization – inpatient hospitalization refers to any inpatient admission, 
regardless of length of stay.

Results in persistent or significant disability/incapacity (i.e., a substantial 
disruption of a person’s ability to conduct normal life functions)

Is a congenital anomaly/birth defect

Is a medically important event – a medical event that may not be immediately 
life-threatening or result in death or require hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the definitions above. Examples of such events are
(including but not limited to): 

Intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias, or convulsions that do not result in 
hospitalization, or development of drug dependence or drug abuse 
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
Reviewed and confirmed seroconversion for HIV, hepatitis A virus (HAV), 
hepatitis B virus (HBV), hepatitis C virus
(HCV), hepatitis E virus (HEV), or parvovirus B19 (B19V)

Development of clinically significant neutralizing VWF antibodies

Development of neutralizing antibodies to FVIII (titer ≥0.4 BU [by 
Nijmegen- modified Bethesda assay] or ≥0.6 BU [by Bethesda assay])

Thromboembolic events (e.g., myocardial infarction, stroke, transient 
ischemic attack [TIA], deep vein thrombosis [DVT] or pulmonary 
embolism)

Hypersensitivity reactions (e.g., anaphylaxis [for definition, refer to 
Section 12.6.2] and other immediate and delayed hypersensitivity reactions 
which may manifest with urticarial rash, pruritus, flushing, angioedema of 
the face, extremities, or laryngeal tissues [leading to throat tightness with 
stridor], wheezing, gastrointestinal symptoms, and/or hypotension)
Uncomplicated pregnancies, following maternal or paternal exposure to IP are not 
considered an AE/SAE; however, any pregnancy complication or pregnancy termination 
by therapeutic, elective, or spontaneous abortion shall be considered an SAE and should 
be reported per SAE reporting guidelines provided in Section 12.1.2.3 (Safety 
Reporting).
12.1.1.2 Suspected Unexpected Serious Adverse Reaction (SUSAR)
Any suspected adverse reaction to study treatment that is both serious and unexpected is 
considered a SUSAR. 
The event(s) must meet all of the following:

Suspected adverse reaction (which implies that there is reasonable evidence 
indicating a causal relationship between the event and the study treatment),

Unexpected (per Reference Safety Information (RSI)/IB), and

Serious
Once determined to meet the criteria for a SUSAR, the sponsor will ensure expedited 
SUSAR reporting is completed in line with the regulatory requirements in participating 
countries as outlined in the Safety Management Plan.
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12.1.1.3 Non-Serious Adverse Event
A non-serious AE is an AE that does not meet any of the seriousness criteria (death, 
life-threatening, hospitalizing/prolongation of hospitalization, disability, congenital 
anomaly, or medically significant and if not urgently treated would result in one of the 
above) listed in Section 12.1.1.1.
12.1.1.4 Unexpected Adverse Events
An unexpected adverse event is an AE whose nature, severity, specificity, or outcome is 
not consistent with the term, representation, or description used in the Reference Safety 
Information (e.g., IB, PI [prescribing information]). “Unexpected” also refers to the AEs
that are mentioned in the IB as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring 
with the particular drug under investigation.
12.1.1.5 Preexisting Disease
Preexisting diseases that are present before entry in to the study are described in the 
medical history, and those that manifest with the same severity, frequency, or duration 
after IP exposure will not be recorded as AEs. However, when there is an increase in the 
severity, duration, or frequency of a preexisting disease, the event must be described as 
“worsening” of the pre-existing condition on the AE CRF.
12.1.2 Assessment of Adverse Events
For the purposes of this study, the following will not be considered as AEs and will not 
be included in the analysis of AEs.

Bleeding episodes are part of the underlying disease and therefore are not AEs; 
they will be evaluated in the context of efficacy.

For non-serious bleeding episodes caused by an injury, the injury would not 
be reported as an AE, unless it resulted in a medical finding other than a 
bleeding episode (e.g., abrasion of skin). Therefore, any VWD-related 
bleeding event (e.g., epistaxis, gastrointestinal bleeding, musculo-skeletal 
bleeding, menorrhagia) that is non-serious will not be reported as an AE. 
However, the investigator may decide that the event is an AE if the event also 
would have occurred in a healthy individual under the same circumstances.
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
For serious bleeding episodes (bleeding SAEs): Bleeding events that meet 
seriousness criteria (death, life-threatening, hospitalizing/prolongation of 
hospitalization, disability, congenital anomaly, or medically significant and if 
not urgently treated would result in one of the above) should be captured on 
the SAE eCRF and reported as an SAE to the Sponsor or designee (e.g., 
CRO) on an SAE Report form as described in Section 12.1.2.3 (Safety 
Reporting).

Seroconversion after documented HAV/HBV vaccination prior to or during the 
study period.
Each AE from the first IP exposure to the study completion date will be described on the 
AE CRF using the term representing medical diagnosis (preferred), or, if no diagnosis 
could be established at the time of reporting the AE, a symptom or sign, in standard 
medical terminology in order to avoid the use of vague, ambiguous, or colloquial 
verbatim expressions (see definition in Section 12.1). Each AE will be evaluated by the 
investigator for:

Seriousness as defined in Section 12.1.1.1

Severity as defined in Section 12.1.2.1

Causal relationship to IP exposure or study procedure as defined in 
Section 12.1.2.2
For each AE, the outcome (i.e., recovering/resolving, recovered/resolved, 
recovered/resolved with sequelae, not recovered/not resolved, fatal, unknown) and if 
applicable, action taken with regards to the study treatment (i.e., dose increased, dose not 
changed, dose reduced, drug interrupted, drug withdrawn, not applicable, or unknown) 
will also be recorded on the AE CRF. Recovering/resolving AEs will be followed until 
resolution or until the subject’s condition returns to the level at the baseline for pre-
existing conditions.
If the severity rating for an ongoing AE changes before the event resolves, the original 
AE report will be revised (i.e., the event will not be reported as separate AE). During the 
course of any AE, the highest severity rating will be reported.
Deviations from the protocol-specified dosage (including underdosing /overdosing
[<20 IU/kg rVWF:RCo or >100 rVWF:RCo], abuse, and withdrawal, treatment errors 
(including incorrect route of administration, use of an incorrect product, and deviations 
from the protocol-defined dosing schedule), failures of expected pharmacological actions, 
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and unexpected therapeutic or clinical benefits will be followed with regard to occurrence 
of AEs, lack of efficacy, and/or other observations because these events may be 
reportable to regulatory authorities.
Any pregnancy that occurs after administration of IP will be reported on a Pregnancy 
Form and followed-up at 1 year post-delivery, if feasible. 
If an investigator becomes aware of an SAE occurring in a subject after study 
completion, the SAE must be reported on the SAE Form within 24 hours after awareness: 
no additional reporting on CRFs is necessary.
12.1.2.1 Severity
The investigator will assess the severity of each AE using his/her clinical expertise and 
judgment based on the most appropriate description below:

Mild
The AE is a transient discomfort and does not interfere in a significant manner 
with the subject’s normal functioning level.
The AE resolves spontaneously or may require minimal therapeutic 
intervention.

Moderate
The AE produces limited impairment of function and may require therapeutic 
intervention.
The AE produces no sequela/sequelae.

Severe
The AE results in a marked impairment of function and may lead to temporary 
inability to resume usual life pattern.
The AE produces sequela/sequelae, which require (prolonged) therapeutic 
intervention.
These severity definitions will also be used to assess the severity of an AE with a study-
related procedure(s), if necessary.
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12.1.2.2 Causality
Causality is a determination of whether there is a reasonable possibility that the IP is 
etiologically related to/associated with the AE. Causality assessment includes, e.g., 
assessment of temporal relationships, dechallenge/rechallenge information, association 
(or lack of association) with underlying disease, presence (or absence) of a more likely 
cause, and physiological plausibility. For each AE, the investigator will assess the causal 
relationship between the IP and the AE using his/her clinical expertise and judgment 
according to the following most appropriate algorithm for the circumstances of the AE:

Not related (both circumstances must be met)
Is due to underlying or concurrent illness, complications, concurrent 
treatments, or effects of concurrent drugs
Is not associated with the IP (i.e., does not follow a reasonable temporal 
relationship to the administration of IP, is not biologically plausible per 
mechanism of action of the IP, or has a much more likely alternative 
etiology). 

Unlikely related (either 1 or both circumstances are met)
Has little or no temporal relationship to the IP 
A more likely alternative etiology exists

Possibly related (both circumstances must be met)
Follows a reasonable temporal relationship to the administration of IP
An alternative etiology is equally or less likely compared to the potential 
relationship to the IP

Probably related (both circumstances must be met)
Follows a strong temporal relationship to the administration of IP, which may 
include but is not limited to the following: 
o
Reappearance of a similar reaction upon re-administration (positive re-
challenge)
o
Positive results in a drug sensitivity test (skin test, etc.)
o
Toxic level of the IP as evidenced by measurement of the IP 
concentrations in the blood or other bodily fluid
Another etiology is unlikely or significantly less likely
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For events assessed as not related or unlikely related and occurring within 5 days after IP 
infusion, the investigator shall provide the alternative etiology. These causality 
definitions will also be used to assess the relationship of an AE with a study-related 
procedure(s), if necessary.
12.1.2.3 Safety Reporting
AEs and SAEs will be assessed at all study visits as outlined in the Schedule of Study 
Procedures and Assessments (see Section 20.2) and Section 12.1.2.
Adverse Events and SAEs are to be recorded on the AE page of the eCRF. Each event 
should be recorded separately.
Any SAE, including death due to any cause, which occurs during this study, whether or 
not related to the IP, must be reported immediately (within 24 hours of the study center’s 
first knowledge of the event). All SAEs must be reported in English via the Electronic 
Data Capture (EDC) system by completing the relevant eCRF page(s) and also by SAE 
Report Form via fax/email to Sponsor’s Global Drug Safety (Baxalta GDS) department 
within 24 hours of becoming aware of the event for SAEs (for contacts, instructions, and
additional details, refer to the SAER form).
Within 24 hours of site awareness of a SAE (or Pregnancy) study sites will complete and 
send all SAE (or Pregnancy) reports to a dedicated:
Baxalta Global Drug Safety fax number:  
OR 
email:
The responsible Site Monitor will review the SAE (or Pregnancy) Reports for 
completeness, will reconcile the reports against the EDC database, and will follow-up 
with sites to obtain missing information and/or information requiring clarification. Any 
SAE associated with a pregnancy must be reported on the SAER Form.
For Follow-up Reports, the site shall use a new SAER form (marked as Follow-up) and 
the new information should be entered together with a brief narrative identifying the 
updated data. 
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An SAER should include the following minimum information:
1.
Protocol Number (on all pages)
2.
Subject identification number (on all pages) and demographics (gender, age at 
onset of event and/or date of birth)
3.
Investigational product and treatment regimen (including date of the first dose of 
IP, date of the last dose of IP prior to the onset of the SAE)
4.
Medical Term for Event (Diagnosis preferably) 
5.
Description of the SAE, including:

Date of onset

Causal relationship assessment by the Investigator
6.
Seriousness criteria (e.g., death, life-threatening, hospitalization, medically 
significant, or other criterion)
7.
Name, address, fax number, email, and telephone number of the 
reporter/Investigator
Post-trial SAE Reporting: In compliance to EudraLex Volume 10 (Clinical trials 
guidelines, Chapter II: Safety Reporting from the European Commission), which 
references an EMA guidance (ICH Topic E 2 A - Clinical Safety Data Management: 
Definitions and Standards for Expedited Reporting), clinical sites/the investigator should 
report to the Sponsor SAEs after a subject´s study completion. Study sites will be 
provided a Post-Trial SAER form to complete and report these post-study SAEs to the 
Sponsor within the 24 hours of their awareness. Site Monitor will instruct the site that any 
such Post-Trial SAEs should be reported on the study-specific Post-Trial SAER form 
if/when the site becomes aware of it. Such information will not be actively monitored by 
the sponsor after completion of the study.
These events shall be reported to Baxalta GDS who will process them in the same way as 
SAEs occurring during the study. Post-Trial SAEs do not need to be captured in the study 
EDC database if it is already locked. Irrespective if captured in the EDC database or not, 
such Post-Trial SAEs will become part of the GDS database. The monitor should remind 
the clinical site about the post-trial SAE reporting requirements during interim 
monitoring visits, upon each subject’s study completion as well as during the close-out 
visit.
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12.2 Urgent Safety Measures
An urgent safety measure is an immediate action taken, which is not defined by the 
protocol, in order to protect subjects participating in a clinical trial from immediate harm. 
Urgent safety measures may be taken by the sponsor or clinical investigator, and may 
include any of the following: 

Immediate change in study design or study procedures

Temporary or permanent halt of the clinical trial 

Any other immediate action taken in order to protect clinical trial participants 
from immediate hazard to their health and safety
The investigator may take appropriate urgent safety measures in order to protect subjects 
against any immediate hazard to their health or safety. The measures should be taken 
immediately and may be taken without prior authorization from the sponsor. 
In the event(s) of an apparent immediate hazard to the subject, the investigator will notify 
the sponsor immediately by phone and confirm notification to the sponsor in writing as 
soon as possible, but within 1 calendar day after the change is implemented. The sponsor 
will also ensure the responsible ethics committees (ECs) and relevant competent 
authority(s) are notified of the urgent measures taken in such cases according to local 
regulations.
12.3 Untoward Medical Occurrences
Untoward medical occurrences occurring before the first exposure to IP are not 
considered AEs (according to the definition of AE, see Section 12.1.1). However, each 
serious untoward medical occurrence experienced before the first IP exposure (i.e., from 
the time of signed informed consent up to but not including the first IP exposure) will be 
described on the SAER. These events will not be considered as SAEs and will not be 
included in the analysis of SAEs. 
12.4 Non-Medical Complaints
A non-medical complaint (NMC) is any alleged product deficiency that relates to 
identity, quality, durability, reliability, safety and performance of the product but did not 
result in an AE. NMCs include but are not limited to the following:

A failure of a product to exhibit its expected pharmacological activity and/or 
design function, e.g. reconstitution difficulty

Missing components

Damage to the product or unit carton
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
A mislabeled product (e.g., potential counterfeiting/tampering)

A bacteriological, chemical, or physical change or deterioration of the product 
causing it to malfunction or to present a hazard or fail to meet label claims
Any NMCs of the product will be documented on an NMC form and reported to the
sponsor within 1 business day. If requested, defective product(s) will be returned to the 
sponsor for inspection and analysis according to procedures.
12.5 Medical, Medication, and Non-Drug Therapy History
At screening, the subject’s medical history will be described for the following body 
systems including severity (defined in Section 12.1.2.1) or surgery and start and end 
dates, if known: eyes, ears, nose, and throat; respiratory; cardiovascular; gastrointestinal; 
musculoskeletal; neurological; endocrine; hematopoietic/lymphatic; dermatological; and 
genitourinary. The subject’s medical history will also include documented history of 
on-demand or pdVWF prophylaxis treatment for at least the past 12 months and a 
documented history, e.g., patient charts and prescription information, of all bleeding 
episodes within the past 12 months (up to 24 months if available).
All medications taken and non-drug therapies received in the 2 weeks prior to study entry 
and all concomitant medications and non-drug therapies during study will be recorded on 
the CRFs.
Data on medical history, drug and non-drug therapy history of those subjects who 
transition from surgery rVWF (vonicog alfa) study will be used from the eCRF of the 
main studies, will be updated, if applicable, and transcribed into the respective eCRF of 
the prophy study. 
12.6 Physical Examinations
At screening and subsequent study visits (as described in Section 10.3), a physical 
examination will be performed on the following body systems: general appearance, head 
and neck, eyes and ears, nose and throat, chest, lungs, heart, abdomen, extremities and 
joints, lymph nodes, skin, and neurological. At screening, if an abnormal condition is 
detected, the condition will be described on the medical history CRF. At study visits, if a 
new abnormal or worsened abnormal pre-existing condition is detected, the condition will 
be described on the AE CRF. If the abnormal value was not deemed an AE because it 
was due to an error, due to a preexisting disease (described in Section 12.1.1.5), not 
clinically significant, a symptom of a new/worsened condition already recorded as an AE, 
or due to another issue that will be specified, the investigator will record the justification 
on the source record.
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12.6.1 Thromboembolic Events
There is a risk of occurrence of thrombotic events, particularly in patients with known 
clinical or laboratory risk factors for thrombosis including low ADAMTS13 levels.  
Therefore, patients at risk must be monitored for early signs of thrombosis during the 
study and prophylaxis measures against thromboembolism should be instituted according 
to current recommendations and standard of care. Additional diagnostic procedures are 
required according to each institution’s standard of care which may consist of, but are not 
limited to the following:

For DVT: Magnetic Resonance Imaging (MRI), compression ultrasound or 
impedance plethysmography.

For pulmonary embolism: ECG, chest radiography, perfusion/scintiscan or MRI. 

For myocardial infarction: ECG, cardiac enzymes, echocardiography

For stroke: diffusion-weighted magnetic resonance imaging or computed 
tomography, ABCD scoring, carotid imaging 
Results of diagnostic procedures may be forwarded to the sponsor to be reviewed by an 
independent external expert panel, such as the DMC, if applicable.
12.6.2 Anaphylaxis
The diagnosis of anaphylaxis is highly likely when any of the following 3 criteria are 
fulfilled:
1.
Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue or both (e.g, generalized urticaria, pruritus or flushing, swollen 
lips-tongue-uvula) and at least one of the following:
a.
Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced peak expiratory flow [PEF], hypoxemia)
b.
Reduced blood pressure (BP) or associated symptoms of end-organ 
dysfunction (e.g., hypotonia [collapse], syncope, incontinence)
2.
Two or more of the following that occur rapidly after exposure to a likely allergen 
for that patient (minutes to several hours):
a.
Involvement of the skin or mucosal tissue (e.g., generalized urticaria, 
pruritus or flushing, swollen lips-tongue-uvula)
b.
Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced PEF, hypoxemia)
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c.
Reduced BP or associated symptoms (hypotonia [collapse], syncope, 
incontinence)
d.
Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, 
vomiting)
3.
Reduced BP after exposure to a known allergen for that patient (minutes to 
several hours):
a.
Infants and children: low systolic BP (age specific) or greater than 30% 
decrease in systolic BP
b.
Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease 
from that person’s baseline BP
If a subject develops anaphylaxis in the course of the clinical study, this needs to be 
reported as SAE (Section 12.1.1.1). Additional blood will be drawn for Anti-VWF IgE 
antibody testing (Section 12.9.13).
12.7 Vital Signs
Vital signs will be assessed pre- and post-infusion at each visit, if not stated otherwise:

Height (cm) (Screening only) and weight (kg) (pre-infusion only)

Blood pressure: Systolic/diastolic blood pressure (mmHg) baseline 
measurements will be measured after a 10-minute rest in the supine/semi-
recumbent position.

Pulse rate: Pulse rate (beats/min) will be measured at the distal radial arteries 
under the same conditions as above.

Respiratory rate: Respiratory rate (breaths/min) will be measured over a period 
of 1 minute under the same conditions as above.

Temperature: Body temperature (°C or °F) may be determined by oral, rectal, 
axillary, or tympanic measurement at the discretion of the investigator. However, 
the same method should be used for all measurements in 1 subject.
Vital signs (pulse rate, respiratory rate, and blood pressure) should be recorded within 
30 min before and after IP administration. The assessment of vital signs per planned 
study visit is outlined in Supplement 20.2.
Vital sign values are to be recorded on the physical examination eCRF. For each 
vital sign value, the investigator will determine whether the value is considered an 
AE (see definition in Section 12.1). If assessed as an AE, the medical diagnosis 
(preferably), symptom, or sign, will be recorded on the AE eCRF. 
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Additional tests and other evaluations required to establish the significance or etiology of 
an abnormal result, or to monitor the course of an AE, should be obtained when clinically 
indicated. Any abnormal value that persists should be followed at the discretion of the 
investigator.
12.8 Electrocardiogram
A standard 12-lead ECG at rest will be performed at screening, at the 6 month follow-up 
visit and at the study termination visit and evaluated for medical significance by the 
investigator.
12.9 Clinical Laboratory Parameters
Refer to the Laboratory Manual for information on collection and processing of samples.
In general all laboratory tests will be performed at central laboratories, except the 
pregnancy and blood group test which will be performed at the local laboratory. In 
addition, relevant critical safety laboratory tests for complete blood count (CBC), serum 
chemistry and/or coagulation parameters such as VWF and FVIII activity may also be 
performed in the local laboratory to ensure that results will be available immediately to 
the investigator. In principle, results from the central laboratory will be used for data 
analysis purposes. The assays performed in the central laboratories are specified in the 
Laboratory Manual. The investigator will supply the sponsor with a list of the normal 
ranges and units of measurement for the laboratory variables to be determined at the site. 
Laboratory values such as antibodies to other proteins are not required immediately and 
will be assessed later during the course of the study. 
Any abnormal laboratory value that is considered clinically significant by the investigator 
based on a local laboratory test result (reference range and the units to be provided) 
should be confirmed by a central laboratory test result for which the sample is 
drawn/collected within 24 hours of the abnormal finding by the local laboratory.
12.9.1 rVWF Pharmacokinetics and Pharmacodynamics
Details on pharmacokinetic and pharmacodynamics assessments are provided in 
Section 11.6.
12.9.2 Hematology and Clinical Chemistry
The hematology panel will consist of CBC [hemoglobin, hematocrit, erythrocytes (ie, red 
blood cell count [RBC]; mean corpuscular volume [MCV], mean corpuscular 
hemoglobin (MCH), mean corpuscular hemoglobin concentration [MCHC]), and 
leukocytes (i.e., white blood cell count [WBC])] with differential (i.e., basophils, 
eosinophils, lymphocytes, monocytes, neutrophils) and platelet counts.
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The clinical chemistry panel will consist of sodium (Na), potassium (K), chloride (Cl), 
ALT, lactate dehydrogenase (LDH), aspartate aminotransferase (AST), bilirubin, alkaline 
phosphatase (AP), blood urea nitrogen (BUN), CR, and glucose (Glu).
Blood will be obtained for assessment of hematology and clinical chemistry parameters 
at screening, during PK-assessment prior to rVWF (vonicog alfa) IP infusion, after 
24 ± 2 hours, 48 ± 2 hours and 72 ± 2 hours post rVWF (vonicog alfa) IP infusion, at all 
follow-up visits as per schedule (refer to Supplement 20.3 Clinical Laboratory 
Assessments), i.e., 4 weeks ± 1 week, 8 weeks ± 1 week and every 3 months ± 2 weeks, 
and at study completion. Hematology and clinical chemistry assessments will be 
performed on Ethylenediaminetetraacetic acid (EDTA)-anticoagulated whole blood and 
serum, respectively, at the central laboratory.
12.9.3 Immunology
12.9.3.1 Antibodies to VWF and FVIII
All subjects will be tested for binding and neutralizing antibodies to VWF and FVIII at 
screening, at initial PK assessment, at each of the scheduled follow-up visits and at the 
study completion visit. Testing will be done prior to IP infusion and with at least a 
72 hour wash out period since the last IP infusion. If there is any suspicion of inhibitor 
development (e.g. excessive bleeding) binding and neutralizing antibodies to VWF and 
FVIII may be tested at the discretion of the investigator. 
12.9.3.2 Neutralizing and Total Binding Anti-VWF Antibodies
The assays to establish the presence of neutralizing and total binding anti-VWF 
antibodies have been established in the absence of international standards and with only 
limited numbers of positive controls. Therefore, caution is advised in interpreting positive 
results. In particular, any clinical association, changes in the natural history of the 
disease, effect of therapy, etc. needs to be taken into account for final judgment. 
The sponsor’s Medical Director should be consulted for additional advice. As part of the 
AE follow-up, any sample testing positive needs to be confirmed after 2-4 weeks for 
central laboratory testing. Only confirmed neutralizing anti -VWF antibodies are 
considered inhibitors (see Section 12.9.3.4). These subjects need to be closely monitored 
and therapy adjusted accordingly. 
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12.9.3.3 Binding antibodies to VWF 
The presence of total binding anti-VWF antibodies will be determined by an enzyme-
linked immunosorbent assay (ELISA) employing polyclonal anti-human Immunoglobulin
(Ig) antibodies (IgG, IgM and IgA). For this assay (ELISA), recombinant human VWF 
will be coated onto a microtiter plate, then incubated with dilutions of the positive 
control, the negative control or test sample. Antibodies against human VWF that are 
present in the samples bind to the coated antigen and will be detected with a horseradish 
peroxidase (HRP)-coupled goat anti-human antibody (secondary antibody). The positive 
control for this assay will be a human monoclonal antibody specific for human VWF 
spiked into the negative control. The negative control for this assay is pooled normal 
human plasma.
Plasma samples are analyzed for binding antibodies against the specific antigen in two 
steps. First, the sample is screened for antibodies and the titer of binding antibodies is 
determined. Second, the specificity of positive antibody results is confirmed.16
In brief, all samples are serially diluted (initial dilution 1:20 and further diluted 1:2).
The titer endpoint, defined as the highest dilution that still gives a positive signal above 
cut off level, is determined in two independent duplicates. The cut off level is established 
based on background signal level of healthy plasma donors (n=160) and set to include 5% 
false positives to be as sensitive as possible (95% percentile). The ELISA assay is 
validated allowing an assay variability of ± 1 titer step. Therefore, differences ≤ 2 titers 
steps may be due to variability of the ELISA assay. Specificity has to be confirmed in a 
competition assay when a sample has a titer of 1:80 or higher in the screening assay. 
Based on the validation criteria samples tested in the screening assay at 1:20 or 1:40 
cannot be confirmed in the competition assay. A positive screening value is confirmed if 
the difference between the titers determined for the subject sample (re-screen) and for the 
subject sample with pre-incubation (confirmation sample) is > 2 titer steps. Antibody 
titers of subject samples will only be reported as positive, if the results of the screening 
and confirmatory analysis fulfill these acceptance criteria. The titer to be reported is 
always the one determined in the original screening procedure (independent of the result 
of the re-screening in the confirmation procedure).
A more detailed test procedure will be supplied upon request or pro-actively if a sample 
tests positive. A treatment related increase of the binding anti-VWF antibodies is 
expected, if the titer increases by more than 2 titration steps. These subjects need to be 
closely monitored and therapy adjusted accordingly.
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12.9.3.4 Neutralizing Antibodies to VWF
Three functional VWF assays, VWF:CB, VWF:RCo and VWF:FVIIIB assays, will be 
used to test for the presence of neutralizing anti-VWF antibodies. Neutralizing antibodies 
to VWF:RCo, VWF:CB and VWF:FVIIIB activities will be measured by assays based on 
the Bethesda assay established for quantitative analysis of FVIII inhibitors (Nijmegen 
modification of the Bethesda assay).17 The amount of inhibitor is expressed as BU per 
mL. One BU is thereby defined as the amount of inhibitor that decreases the measured 
activity in the assays to 50% of that of the negative control samples. The assays were 
validated using human plasma samples from two type 3 VWD patients with low 
(1-2 BU/mL) and high (~10 BU/mL) titer inhibitors and plasma samples from 
non-human primates immunized with human rVWF (vonicog alfa) (>100 BU/mL).
If a subject has a measurable baseline level of VWF activity in the respective assay, it is 
taken into account in the calculation of the residual activity. However, if baseline levels 
are too high (>15% VWF:RCo), inhibitors may not be reliably detected.
To exclude false positive results, the detection limit for anti-VWF inhibitors was set to 
1 BU/ml for all 3 assays. The rationale for this cut-off value is the relatively high CI of 
the underlying assays, making determinations at the end of the evaluation range of the 
Bethesda reference curve uncertain.18 A more detailed test procedure may be requested to 
further characterize the anti-VWF inhibitors, if detected.
Only confirmed positive anti-VWF inhibitor test result will be reported and will be
considered as a medically significant SAE.
12.9.3.5 Binding Antibodies to FVIII
Binding antibodies against FVIII will be analyzed using a proprietary enzyme 
immunoassay. The testing strategy will be as described for binding anti-VWF antibodies. 
Antibody-containing samples will be identified in a screening assay followed by a 
confirmatory assay to exclude false positive results.
12.9.3.6 Neutralizing Antibodies (Inhibitors) to FVIII 
Neutralizing antibodies (inhibitors) to FVIII will be assessed by the Nijmegen 
modification of the Bethesda assay in a central laboratory. To verify a FVIII inhibitor, 
additional testing (such as tests for Lupus anticoagulants) may be initiated. Positive FVIII 
inhibitor tests will be defined as ≥0.4 BU by the Nijmegen-modified Bethesda assay that 
is confirmed by a second test performed on an independent sample obtained 2-4 weeks 
following the first test. Only confirmed positive FVIII inhibitor test result will be 
reported.
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12.9.4 Antibodies to Other Proteins
Plasma will be assayed for the presence of antibodies against CHO protein (total Ig), 
murine IgG and human Furin (total Ig) using proprietary enzyme immunoassays. The 
testing strategy will be as described for binding anti- VWF antibodies. 
Antibody-containing samples will be identified in a screening assay followed by a 
confirmatory assay to exclude false positive results.
12.9.4.1 Anti-CHO Protein
Total Ig antibodies (IgG, IgA, IgM) against CHO protein will be analyzed. For this assay 
(ELISA), CHO protein derived from cultures of untransfected cells and propagated under 
the identical cell culture conditions used for ADVATE (rFVIII, octocog alfa) production 
will be coated onto a microtiter plate, then incubated with dilutions of the positive 
control, negative control or test sample. Antibodies against CHO protein that are present 
in the samples bind to the coated antigen and will be detected with a HRP-coupled goat 
anti-human antibody (secondary antibody). The positive control for this assay will be a 
polyclonal goat anti-CHO protein antibody spiked into the negative control. The negative 
control for this assay is pooled normal human plasma.
12.9.4.2 Anti-Murine IgG
A commercially available ELISA (Medac, Hamburg, Germany) will be used to detect and 
to quantify IgG antibodies originating from human plasma that are directed against 
mouse-IgG (HAMA: human anti- mouse antibodies). Microtiter plates coated with 
mouse IgG will be incubated with dilutions of the standard, the positive control, the 
negative control or the test sample. Antibodies against mouse IgG that are present in 
the samples bind to the coated antigen and form a bridge to a peroxidase coupled mouse 
IgG antibody that will be used for detection (bridging format of the ELISA assay). 
The positive control for this assay will be a polyclonal goat anti-murine IgG spiked into 
the negative control. The negative control for this assay is pooled normal human plasma.
12.9.4.3 Antibodies to Human Furin
Total Ig antibodies (IgG, IgA, IgM) against human Furin will be analyzed. For this assay 
(ELISA), recombinant human Furin will be coated onto a microtiter plate, then incubated 
with dilutions of the positive control, the negative control or test sample. Antibodies 
against human Furin that are present in the samples bind to the coated antigen and will be 
detected with a HRP-coupled goat anti-human antibody (secondary antibody). The 
positive control for this assay will be a human monoclonal antibody specific for human 
Furin spiked into the negative control. The negative control for this assay is pooled 
normal human plasma.
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12.9.5 Viral Serology
The following viral seromarkers will be assessed at screening:

HIV: anti-HIV 1, HIV 2 

HAV: anti-HAV (IgG and immunoglobulin M [IgM])

HBV: Hepatitis B surface antigen (HbsAg), anti-Hepatitis B (HB) core, anti-HBs

HCV: anti-HCV ELISA

Parvovirus B19: anti-B19V (IgG and IgM)
Virus serology will be established during the screening period. The relevant confirmatory 
Polymerase Chain Reaction (PCR) testing may be performed from appropriate left-over 
samples as needed. 
12.9.6 Urinalysis (Dipstick)
The urinalysis will include assessments for erythrocytes, specific gravity, urobilinogen, 
ketones, glucose, protein, bilirubin, nitrite and pH and will be performed at the central 
laboratory.
12.9.7 Pregnancy Test
A pregnancy test for females of child-bearing potential will be performed at the local 
laboratory primarily from urine. If no urine sample is available, the pregnancy testing 
will be done from serum. The pregnancy test may need to be repeated during the course 
of study in countries where mandated by national law.
12.9.8 VWD Mutational Analysis, Multimer Analysis and Human Leukocyte 
Antigen Genotyping 
A cell pellet (buffy coat and erythrocytes) will be retained at the screening visit for VWD 
gene mutational analysis, VWF multimer analysis and HLA genotype determination if 
the information is not already available in the subject’s medical history. Results from 
multimer analysis (see Section 12.9.10.1) may contribute to VWD gene mutational 
analysis. The genetic testing will be done, when the subject consents to the genetic 
testing.
12.9.9 Blood Group Analysis
The blood group needs to be determined during the screening period. If the information is 
not already available in the subject’s medical history, it has to be determined at the local 
lab.
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12.9.10 Additional Laboratory Testing in Case of Thromboembolic Events
rVWF (vonicog alfa) contains ULMW multimers because of a lack of exposure to 
endogenous VWF protease (a disintegrin and metalloproteinase with a thrombospondin 
type 1 motif, member 13 (ADAMTS13) during the manufacturing process. In vitro and in 
vivo cleavage of these ultralarge molecular fractions by ADAMTS13 and generation of 
characteristic satellite bands has been extensively demonstrated during nonclinical and 
clinical development. Nevertheless, the potential elevated risk of thrombosis and/or other 
thromboembolic complications due to the administration of ultra large molecular VWF 
multimers in subjects with normal levels of VWF cannot be completely excluded. 
Therefore VWF multimer analysis will not only be performed routinely at screening but 
in case of thromboembolic events, both VWF multimer analysis as well as ADAMTS13 
activity will be determined to assess any relatedness of these occurrences with IP 
treatment. 
12.9.10.1 VWF Multimer Analysis 
The VWF multimer pattern will be assessed using low-resolution sodium dodecyl sulfate 
(SDS)–agarose gel electrophoresis. High-resolution SDS–agarose gel electrophoresis, 
with agarose concentrations 1.5%, will be used to determine the satellite band structure 
of VWF. These analyses will employ Western blot with luminescence video imaging.
12.9.10.2 ADAMTS13 Activity 
VWF73 was identified as the 73 amino acid minimal region of the VWF A2 domain 
required for ADAMTS13 cleavage. The cleavage of this substrate will be detected by a 
commercially available ELISA-based Chromogenic assay (Technoclone Austria):
Cleavage of immobilized VWF73 substrate is detected by a HRP-labeled antibody 
directed against the cleavage site of VWF73. The amount of bound antibody, which is the 
function of the ADAMTS13 cleavage is detected by a chromogenic substrate.
12.9.11 Soluble P-Selectin (sP-Selectin)
sP-selectin is a cell adhesion molecule (CAM) found in granules in endothelial cells 
(cells lining blood vessels) and activated platelets. Data for an association between the 
sP-selectin concentration, TTP and venous thromboembolism (VTE) are limited and the 
predictive value has not yet established. A commercial ELISA assay will be employed as 
an exploratory test. sP-selectin will be determined at the Screening visit and used as 
indicator for an increased thrombotic risk.
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12.9.12 D-Dimer
D-dimer will be used as a marker for DVT and disseminated intravascular coagulation
(DIC). While a negative result practically rules out thrombosis, a positive result can 
indicate thrombosis but does not rule out other potential etiologies, including a recent 
hemorrhage. Its main use, therefore, is to exclude thromboembolic disease where the 
probability is low. D-Dimer will be measured at the Screening visit and used as indicator 
for an increased thrombotic risk.
12.9.13 Additional Laboratory Testing in Case of Severe Hypersensitivity Reactions
If a subject develops a severe hypersensitivity reaction in the course of the clinical 
study, additional blood will be drawn for anti-VWF IgE antibody testing. The presence of 
anti-VWF IgE will be determined by using the ImmunoCAP®, a VWF-specific IgE 
blood test (Thermo Scientific). The basis of the ImmunoCAP® technology is a cellulose 
polymer as solid phase in a plastic capsule providing a large surface for protein binding. 
rVWF (vonicog alfa) as antigen is covalently coupled to the cellulose polymer. 
Detection of specific anti-VWF IgE bound to the antigen will be accomplished by a 
secondary enzyme-labeled anti-human IgE antibody. Testing for binding anti-human 
VWF IgE antibodies will be done with 0.5 mL plasma. Antibody containing samples will 
be identified and quantified in a screening assay followed by a confirmatory assay to 
exclude false positive results.
12.9.14 Assessment of Laboratory Values
12.9.14.1 Assessment of Abnormal Laboratory Values 
For VWF and FVIII laboratory assessments no evaluation of clinical significance is 
necessary.
Each other laboratory value (except results to determine genetics of the underlying VWD 
disease and blood group) has to be assessed by the investigator and the assessment will
be recorded on the eCRF. The investigator will determine for each abnormal laboratory 
value whether the value is considered clinically significant or not and provide the 
reference range including the units. For clinically significant values, the investigator will 
indicate if the value constitutes a new AE (see definition in Section 12.1) and record the 
sign, symptom, or medical diagnosis on the AE CRF, is a symptom or related to a 
previously recorded AE, is due to a pre-existing disease (described in Section 12.1.1.5), 
or is due to another issue that will be specified. If the abnormal value was not clinically 
significant, the investigator will indicate the reason, i.e. because it is due to a preexisting 
disease, due to a lab error, due to variation or due to another issue that will be specified. 
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Additional tests and other evaluations required to establish the significance or etiology of 
an abnormal value, or to monitor the course of an AE should be obtained when clinically 
indicated. Any abnormal value that persists should be followed at the discretion of the 
investigator. Any abnormal laboratory value that is considered clinically significant by 
the investigator based on a local laboratory test result (reference range and the units to be 
provided) should be confirmed by a central laboratory test result for which the sample is 
drawn/collected within 24 hours of the abnormal finding by the local laboratory.
Any seroconversion result for HIV, HAV, hepatitis B virus (HBV), HCV, HEV, or B19V
shall be re-tested.
12.10
12.10.1
 
 
 
 
 
 
 
 
 
 
 
12.10.2
 
 
 
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13. STATISTICS
13.1 Sample Size and Power Calculations
Approximately 22 adult subjects with severe VWD (baseline VWF:RCo <20 IU/dL) will 
be included in the study. The aim is to have at least 8 subjects in each cohort (OD and 
switch). A total of at least 5 type 3 VWD subjects will be followed for 12 months. The 
sample size is driven by practical considerations (primarily the enrollment of a rare 
patient population) and EMA Guideline on the Clinical Investigation of Human Plasma 
Derived von Willebrand Factor Products (CPMP/BPWG/220/02).1
13.2 Datasets and Analysis Cohorts
13.2.1 Safety Analysis Set
The Safety Analysis Set will be composed of all subjects who received any amount of IP 
(rVWF, vonicog alpha). 
13.2.2 Full Analysis Dataset
The Full Analysis Set (FAS) will be composed of all subjects who receive prophylaxis IP 
treatment.
13.2.3 Per-Protocol Analysis Set
The Per-Protocol (PP) Analysis Set will be composed of subjects who are at least 70% 
compliant regarding the number of scheduled prophylactic infusions (as measured by the 
ratio of actual number of infusions to planned number of infusions). Only subjects who 
met all study entry criteria and who had no major protocol violations that might impact 
primary efficacy assessments will be included in the PP analysis set.
13.2.4 PK Full Analysis Set
The Pharmacokinetic Full Analysis Set (PKFAS) will be composed of all subjects who 
received the PK infusion and who provided acceptable data for PK and PD analysis. 
Acceptable PK/PD data will be defined in the Statistical Analysis Plan. 
13.2.5 PK Per Protocol Analysis Set 
The Pharmacokinetic Per Protocol Analysis Set (PKPPAS) is defined as a subset of the 
PKFAS. Subjects who met the following additional criteria will be included in the 
PKPPAS: had no major violation of affecting the PK period of the study as defined in the
detailed Statistical Analysis Plan.
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13.3 Handling of Missing, Unused, and Spurious Data
13.3.1 General
Statistical techniques will not be used to identify and exclude any observations as outliers 
from the analyses. If data are considered spurious, e.g. for lack of biological plausibility, 
it will be documented to include the reason for exclusion and the analyses from which the 
data were excluded.
13.3.2 Other
1.
Regarding missing data in PK records:

Body weight: If a subject’s weight is missing from the PK infusion record, the 
subject’s last recorded weight will be used to calculate the weight-adjusted 
dose.

Concentration:

Baseline concentration levels reported as below the limit of quantification 
will be considered to be 0. Missing VWF baseline concentration levels 
(VWF: RCo, VWF: AG or VWF: CB) for Type 3 subjects will be set to 0.

Time:

If start time of infusion is missing (but stop time is available) and actual 
collection time is available, then stop time of infusion will be taken for 
further calculation (i.e. time difference between actual end date/time of 
infusion and date/time blood sample drawn).

If actual collection date/time is missing and planned collection date/time is 
missing, then this PK time point will be taken out from the PK analysis 
(i.e. no data entry for this time point). 

For all other scenarios, the planned collection date/time will be taken for 
further calculation.
2.
Regarding missing data in AE records:

Handling of unknown causality assessment:

If a subject experiences an AE with a missing causality assessment, the 
relationship of the AE will be counted as “related.”
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
Handling of unknown severity grades:

If a subject experiences more than one AE categorized under the same 
preferred term, one of them is categorized as “severe” and one of them is 
categorized as “unknown”, then the maximum severity for this preferred 
term should be counted as “severe” for this subject.

If a subject experiences more than one AE categorized under the same 
preferred term, one of them is categorized as “mild” or “moderate” and 
one of them is categorized as “unknown”, then the maximum severity for 
this preferred term should be counted as “unknown” for this subject.
13.4 Methods of Analysis
The study success criteria are the objectives as stated in Section 7. “Treatment success” 
was defined as the extent of control of bleeding episodes achieved during this study.
13.4.1 Primary Outcome Measure
The primary outcome measure is ABR for spontaneous (not related to trauma) bleeding 
episodes during prophylactic treatment with rVWF (vonicog alfa). No formal statistical 
hypothesis test is planned for the analysis. The primary efficacy analysis will be based on 
the FAS and will be summarized by the two cohorts: on-demand and switch subjects. As 
a supportive analysis, the same analysis will also be carried out on the PP analysis set.
The spontaneous ABR while treated with rVWF (vonicog alfa) for each cohort will be 
estimated using a negative binomial regression. The prior ABR will be based on 
historical data collected from each enrolled subject. 
The two ABRs (prior to prophylaxis treatment and while on prophylaxis) for each cohort 
will be compared within each subject using a generalized linear mixed-effects model 
(GLMM) (with a logarithmic link function, the default for the negative binomial 
distribution), accounting for the fixed effect of the two treatments. The follow-up time 
(in years) will be specified as an offset. The ratio of ABR while in the study to historical
ABR will be estimated and reported together with the 95% confidence interval for each 
of the two cohorts.
The difference in on-study ABR relative to historical ABR will be also summarized 
descriptively.
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13.4.2 Secondary Outcome Measures 
In general, data for  secondary efficacy analysis will be summarized by the two cohorts: 
on-demand and switch subjects and when applicable overall.  Mean, standard deviation, 
median, range, quartiles will be calculated for continuous endpoints.  Proportions, will be 
calculated for categorical endpoints. Confidence intervals at the two-sided 95% level will 
be provided when appropriate.
13.4.2.1 Additional Efficacy of Prophylaxis Treatment with rVWF
The number  and proportion of on-demand subjects with ABR percent reduction success 
(i.e.≥ 25%) will be calculated together with a two-sided, 95% CI for the proportion.
The number  and proportion of pdVWF switch subjects ABR preservation success will be 
reported together with the corresponding 95% two-sided CIs for the proportion.
The number and proportion of subjects with categorized spontaneous ABR 
(i.e. 0, 1-2, 3-5, more than 5 bleeds) will be reported descriptively.
Summary statistics for the total number of infusions, as well as average number of 
infusions per week will be provided. The total weight adjusted consumption of rVWF 
(vonicog alfa) during prophylactic treatment will be provided. If applicable, historical 
data on consumption of pdVWF prior to the study will be summarized as well.
The change in spontaneous ABR from the historical rate to that during the rVWF 
(vonicog alfa) prophylaxis period will be summarized by location of bleeding 
(GI, epistaxis, joint bleeding, menorrhagia, oral and other mucosa, muscle and soft 
tissue, etc.).
13.4.2.2 Pharmacokinetic and Pharmacodynamic Analysis
All PK and PD analyses will use the actual sampling times, not nominal times specified 
in the protocol, wherever possible. Actual sampling times will be defined as time from 
the start of infusion to the blood sample collection time. A deviation from the protocol-
specified blood sample drawing time window will not be a reason to exclude an 
observation from the analysis. Samples with unknown actual and planned collection 
date/time or where the concentration could not be determined, or where results were 
biologically implausible will be eliminated from the analysis.
If any concentration data are considered spurious (e.g. lack of biological plausibility), the 
reason for exclusion from the analysis and the analysis from which the data point was 
excluded will be documented.
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Details of calculation of PK and PD parameters and corresponding analysis will be given 
in the statistical analysis plan. 
The following PK parameters, based on the initial PK assessment after a washout for on-
demand subjects, will be listed and summarized descriptively for VWF:RCo, VWF:Ag 
and VWF:CB: IR, T1/2, MRT, AUC0-, AUC0-tlast, Cmax, Tmax, Vss, and CL. The 
corresponding pharmacodynamics (PD) of rVWF (vonicog alfa) as measured in FVIII 
activity, based on the initial PK assessment after a washout for on-demand subjects will 
be assessed using Cmax, Tmax, and AUC0-tlast. These PD parameters will be listed and 
summarized descriptively. PK parameters at steady state (AUC0-tau;ss, Cmax;ss, Tmax;ss, and 
Cmin;ss) for the partial dosing interval will be listed for on-demand subjects at the end of 
the study and for switch subjects shortly after reaching steady state and at the end of the 
study for VWF:RCo, VWF:Ag and VWF:CB and summarized descriptively for subjects 
with the same dosing regimens. The corresponding pharmacodynamics (PD) of rVWF 
(vonicog alfa) as measured in FVIII activity will be assessed using AUC0-tau;ss, Cmax;ss, 
Tmax;ss, and Cmin;ss. These PD parameters will be listed for on-demand subjects at the end 
of the study and for switch subjects shortly after reaching steady state and at the end of 
the study and will be summarized descriptively for subjects with the same dosing 
regimens.
For the on-demand subjects, the PK of VWF:RCo will be analyzed using a population PK 
approach to characterize the single and multiple dose pharmacokinetics, including 
associated variability assessed at after washout and at end of study, respectively. The 
population PK analysis will be performed in a stepwise manner as outlined below.
1.
Exploratory graphical analysis of VWF:RCo versus time data for identification of 
potential outliers and to inform the pharmacometric analysis.
2.
Population PK model development for rVWF (vonicog alfa):
a.
Evaluate alternative structural and stochastic models to describe the typical 
and individual rVWF (vonicog alfa) profiles.
b. Investigate and characterize the potential for a time dependency in CL of 
rVWF (vonicog alfa). 
c.
Evaluate, and if necessary refine, the candidate final model
Details of this Population PK analysis will be given in a separate Population PK analysis 
plan.
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For the switch subjects, differences in AUC0-tau;ss, Cmax;ss, and Cmin;ss assessess shortly 
after reaching steady state and assessed at the end of the study will be assessed by the 
ratio of geometric means and corresponding two-sided 95% confidence intervals for 
VWF:RCo, VWF:Ag,VWF:CB, and FVIII:C. These analyses will be performed using a 
linear mixed effects model with PK assessment (i.e. factor of two levels relating to the 
PK assessment shortly after reaching steady state and the PK assessment at end of study, 
respectively) as a fixed effect and subject as a random effect based on log-transformed 
PK parameters. The difference in Tmax;ss, between first and second pharmacokinetic 
assessment will be summarized by the median and range (minimum to maximum) for 
VWF:RCo, VWF:Ag,VWF:CB, and FVIII:C.
Descriptive statistics will be used to summarize VWF:RCo, VWF:AG and VWF:CB and 
FVIII:C levels for each nominal time point on the PK curve.
For all subjects in the PKFAS activity/concentration vs. time curves will be prepared.
Formulas for PK parameters IR, T1/2, MRT, AUC0-, AUC0-tlast, Cmax, Tmax, Vss, and CL, 
AUC0-tau;ss, Cmax;ss, Tmax;ss ,and Cmin;ss will be given in the statistical analysis plan and will 
be derived using non-compartmental methods in WinNonlin. Analysis of these 
parameters will be carried out on the PKFAS as well as on the PKPPAS.
13.4.2.3 Safety
Safety analysis will be performed overall and by the two cohorts: on-demand and switch 
subjects.
TEAEs are defined as AEs with start dates on or after the first exposure to IP. Summaries 
of AEs will be based on TEAEs unless otherwise indicated.
Occurrence of AEs and SAEs will be summarized descriptively, by system organ class 
and preferred term. The number and percentage of subjects who experienced AEs and 
SAEs, and the number of AEs and SAEs will be tabulated. In addition, the number of 
subjects who experienced AEs assessed as related to IP by the investigator, and the 
number of IP-related AEs will be tabulated. The number of patients with AEs by severity 
will be presented similarly.
A listing of all AEs will be presented by subject identifier, age, sex, preferred term and 
reported term of the AE, duration, severity, seriousness, action taken, outcome, causality 
assessment by investigator, onset date, stop date and medication or non-drug therapy to 
treat the AE.
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Temporally associated AEs are defined as AEs that begin during infusion or within 
24 hours (or 1 day where time of onset is not available) after completion of infusion, 
irrespective of being related or not related to treatment. Temporally associated AEs will 
be presented in summary tables. 
AEs that occurred before first IP infusion will be listed separately.
Adverse events of special interest (AESI), such as hypersensitivity reactions and 
thromboembolic events,  will be monitored throughout the study and statistical analysis 
will be conducted based on the search criteria (eg, standardised MedDRA queries 
[SMQ]) determined prior to database lock, and summarized.
For immunogenicity, frequency counts and percentages will be calculated for the 
occurrence of neutralizing (inhibitory) antibodies to VWF and FVIII, occurrence of 
binding antibodies to VWF and FVIII, and occurrence of binding antibodies to CHO 
proteins, mouse immunoglobulin G (IgG) and rFurin. Clinically significant changes 
relative to baseline in vital signs and clinical laboratory parameters (hematology, clinical 
chemistry) will be reported.
13.4.3 Exploratory Outcome Measures
 
13.4.3.1
 
 
 
 
13.4.3.2
 
 
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13.4.3.3
 
 
 
13.4.3.4
 
 
 
 
13.5 Planned Interim Analysis of the Study
No formal interim analysis is planned for this study. 
14. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
The investigator/study site will cooperate and provide direct access to study documents 
and data, including source documentation for monitoring by the study monitor, audits by 
the sponsor or sponsor’s representatives, review by the EC, and inspections by applicable 
regulatory authorities, as described in the Clinical Trial Agreement (CTA). If contacted 
by an applicable regulatory authority, the investigator will notify the sponsor of contact, 
cooperate with the authority, provide the sponsor with copies of all documents received 
from the authority, and allow the sponsor to comment on any responses, as described in 
the CTA.
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15. QUALITY CONTROL AND QUALITY ASSURANCE
15.1 Investigator’s Responsibility
The investigator will comply with the protocol (which has been approved/given favorable 
opinion by the EC), ICH GCP, and applicable national and local regulatory requirements 
as described in the CTA. The investigator is ultimately responsible for the conduct of all 
aspects of the study at the study site and verifies by signature the integrity of all data 
transmitted to the sponsor. The term “investigator” as used in this protocol as well as in 
other study documents, refers to the investigator or authorized study personnel that the 
investigator has designated to perform certain duties. Sub-investigators or other 
authorized study personnel are eligible to sign for the investigator, except where the 
investigator’s signature is specifically required.
15.1.1 Investigator Report and Final Clinical Study Report 
The investigator, or coordinating investigator(s) for multicenter studies, will sign the 
clinical study report. The coordinating investigator will be selected before study start. 
15.2 Training
The study monitor will ensure that the investigator and study site personnel understand 
all requirements of the protocol, the investigational status of the IP, and his/her regulatory 
responsibilities as an investigator. Training may be provided at an investigator’s meeting, 
at the study site, and/or by instruction manuals. In addition, the study monitor will be 
available for consultation with the investigator and will serve as the liaison between the 
study site and the sponsor.
15.3 Monitoring
The study monitor is responsible for ensuring and verifying that each study site conducts 
the study according to the protocol, standard operating procedures other written 
instructions/agreements, ICH GCP, and applicable national and local regulatory 
guidelines/requirements. The investigator will permit the study monitor to visit the study 
site at appropriate intervals, as described in the CTA. Monitoring processes specific to 
the study will be described in the clinical monitoring plan. 
15.4 Auditing
The sponsor and/or sponsor’s representatives may conduct audits to evaluate study 
conduct and compliance with the protocol, standard operating procedures, other written 
instructions/agreements, ICH GCP, and applicable national and local regulatory 
guidelines/requirements. The investigator will permit auditors to visit the study site, as 
described in the CTA. Auditing processes specific to the study will be described in the 
audit plan.
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15.5 Non-Compliance with the Protocol
The investigator may deviate from the protocol only to eliminate an apparent immediate 
hazard to the subject. In the event(s) of an apparent immediate hazard to the subject, the 
investigator will notify the sponsor immediately by phone and confirm notification to the 
sponsor in writing as soon as possible, but within 1 calendar day after the change is 
implemented. Also, the investigator will notify the sponsor immediately by phone and 
confirm notification to the sponsor in writing whenever pdVWF is used instead of rVWF 
(vonicog alfa). The reason for this use must also be provided to the sponsor. The sponsor 
(Baxalta) will also ensure the responsible EC and relevant competent authority are 
notified of the urgent measures taken in such cases according to local regulations.
If monitoring and/or auditing identify serious and/or persistent non-compliance with the 
protocol, the sponsor may terminate the investigator’s participation. The sponsor will 
notify the EC and applicable regulatory authorities of any investigator termination.
15.6 Laboratory and Reader Standardization
A central laboratory/reader will be used for all clinical assessments except for pregnancy
testing and blood group test (refer to Section 12.9). Local laboratories are requested to 
provide their laboratory specifications of the individual tests that are also being tested 
locally.
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16. ETHICS
16.1 Subject Privacy
The investigator will comply with applicable subject privacy regulations/guidance as 
described in the CTA.
16.2 Ethics Committee and Regulatory Authorities
Before enrollment of patients into this study, the protocol, informed consent form, any 
promotional material/advertisements, and any other written information to be provided 
will be reviewed and approved/given favorable opinion by the EC and applicable 
regulatory authorities. The IB will be provided for review. The EC’s composition or a 
statement that the EC’s composition meets applicable regulatory criteria will be 
documented. The study will commence only upon the sponsor’s receipt of 
approval/favorable opinion from the EC and, if required, upon the sponsor’s notification 
of applicable regulatory authority(ies) approval, as described in the CTA.
If the protocol or any other information given to the subject is amended, the revised 
documents will be reviewed and approved/given favorable opinion by the EC and 
applicable regulatory authorities, where applicable. The protocol amendment will only be 
implemented upon the sponsor’s receipt of approval and, if required, upon the sponsor’s 
notification of applicable regulatory authority(ies) approval.
16.3 Informed Consent
Investigators will choose patients for enrollment considering the study eligibility criteria. 
The investigator will exercise no selectivity so that no bias is introduced from this source. 
All patients and/or their legally authorized representative must sign an informed consent 
form before entering into the study according to applicable national and local regulatory 
requirements and ICH GCP. Before use, the informed consent form will be reviewed by 
the sponsor and approved by the EC and regulatory authority(ies), where applicable, (see 
Section 16.2). The informed consent form will include a comprehensive explanation of 
the proposed treatment without any exculpatory statements, in accordance with the 
elements required by ICH GCP and applicable national and local regulatory 
requirements. Patients or their legally-authorized representative(s) will be allowed 
sufficient time to consider participation in the study. By signing the informed consent 
form, patients or their legally authorized representative(s) agree that they will complete 
all evaluations required by the study, unless they withdraw voluntarily or are terminated 
from the study for any reason.
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The sponsor will provide to the investigator in written form any new information that 
significantly bears on the subjects’ risks associated with IP exposure. The informed 
consent will be updated, if necessary. This new information and/or revised informed 
consent form, which have been approved by the applicable EC and regulatory authorities, 
will be provided by the investigator to the subjects who consented to participate in the 
study 
16.4 Data Monitoring Committee
This study will be monitored by aDMC. The DMC is a group of individuals with 
pertinent expertise that reviews on a regular basis accumulating data from an ongoing 
clinical study. For this study, the DMC will be composed of recognized experts in the 
field of VWD clinical care and research who are not actively recruiting subjects, and an 
independent statistician. The DMC can stop a trial if it finds toxicities or if treatment is 
proven to be not beneficial. Details will be defined in the DMC charter.
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17. DATA HANDLING AND RECORD KEEPING
17.1 Confidentiality Policy
The investigator will comply with the confidentiality policy as described in the CTA.
17.2 Study Documentation and Case Report Forms
The investigator will maintain complete and accurate paper format study documentation 
in a separate file. Study documentation may include information defined as “source data” 
(see Section 8.7), records detailing the progress of the study for each subject, signed 
informed consent forms, correspondence with the EC and the study monitor/sponsor, 
enrollment and screening information, CRFs, SAERs, laboratory reports (if applicable),
and data clarifications requested by the sponsor.
The investigator will comply with the procedures for data recording and reporting. Any 
corrections to paper study documentation must be performed as follows: 1) the first entry 
will be crossed out entirely, remaining legible; and 2) each correction must be dated and 
initialed by the person correcting the entry; the use of correction fluid and erasing are 
prohibited.
The investigator is responsible for the procurement of data and for the quality of data 
recorded on the CRFs. CRFs will be provided in electronic form. 
If electronic format CRFs are provided by the sponsor, only authorized study site 
personnel will record or change data on the CRFs. If data is not entered on the CRFs 
during the study visit the data will be recorded on paper and this documentation will be 
considered source documentation. Changes to a CRF will require documentation of the 
reason for each change. An identical (electronic/paper) version of the complete set of 
CRFs for each subject will remain in the investigator file at the study site in accordance 
with the data retention policy (see Section 17.3).
The handling of data by the sponsor, including data quality assurance, will comply with 
regulatory guidelines (e.g., ICH GCP) and the standard operating procedures of the 
sponsor. Data management and control processes specific to the study will be described 
in the data management plan.
17.3 Document and Data Retention 
The investigator will retain study documentation and data (paper and electronic forms) in 
accordance with applicable regulatory requirements and the document and data retention 
policy, as described in the CTA.
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18. FINANCING AND INSURANCE
The investigator will comply with investigator financing, investigator/sponsor insurance, 
and subject compensation policies, if applicable, as described in the CTA.
19. PUBLICATION POLICY
The investigator will comply with the publication policy as described in the CTA. 
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20. SUPPLEMENTS
20.1 Study Flow Chart
Figure 1
Study Design for Baxalta Clinical Study 071301
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20.2 Schedule of Study Procedures and Assessments
Table 6a
Schedule of Study Procedures and Assessments for On-demand Subject
Procedures/
Assessments
Screening Visit
Baseline Visit 
(PK-assessment visit)
Prophylaxis 
Initiation Visit
Interval/Follow-Up 
Study Visits
PK Assessment at 
Study Completion
Termination 
Visit
Pre-
infusiong
Infusion
Post-
infusiong
1 month ± 
1 week
2 month ± 
1 week 
3 month ± 
2 weeks
6 month ± 
2 weeks 
9 month ± 
2 weeks
Pre-
infusiong
Infusion
Post-
infusiong
Conducted at 
the 96 hour 
postinfusion 
PK 
Assessment
12 month ± 2 weeks
Informed Consenta
X
Eligibility Criteria
X
Medical Historyb
X
Concomitant Medicationsc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Non-drug Therapiesc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
Bleeding Episodes and 
Treatment and Hemostatic 
Efficacy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratories 
X
X
X
Xh
X
X
X
X
X
X
X
X
Vital Signsd
X
X
X
X
X
X
X
X
X
X
X
X
ECG
X
X
X
IP Treatmente
X
X
X
X
X
X
X
X
IP Consumption / Treatment 
Compliance 
X
X
X
X
X
Subject Diary
X
X
X
X
X
X
Xf
X
X
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Continued
a Occurs at enrollment (before screening).
b Including documented history of on-demand treatment for the past 12 months (up to 24 months if available) and a documented history, e.g., patient charts 
and prescription information, of all bleeding episodes within the past 12 (up to 24) months. 
c Including all medications and non- drug therapies taken in the 2 weeks prior to study entry and all the concomitant medications and non-drug therapies 
during the course of the study.
d Vital signs: height, weight, body temperature, pulse rate, respiratory rate, and blood pressure. Height is only required at the screening visit. The time 
points for pre- and post-infusion measurements are (weight is measured pre-infusion only): within 30 minutes before infusion start and 30 ± 15 minutes 
post-infusion.
e IP treatment after the prophylactic treatment initiation visit at the site will be continued as home-treatment if the subject qualifies; a wash-out period of at 
least 72 hours is required after the last IP infusion before the follow-up visit. IP infusion will be given at the study site after the blood sample for 
immunology testing and IR determination is drawn.
f Can be done either at the screening or the baseline visit.
g Time points for PK blood draws: within 30 minutes pre-infusion, and at 11 time points post-infusion: 15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 
3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours and 96 ± 2 hours (the 96 hr sampling can be omitted 
if not allowed by the dosing interval).
h If a subject did not undergo PK assessment, laboratory assessments will be performed at this visit.
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Table 6b
Schedule of Study Procedures and Assessments for pdVWF Switch Subject
Procedures/
Assessments
Screening Visit
Prophylaxis Initiation 
Visit
PK Assessment
(at prophylaxis dose #5-6)
Interval/Follow-Up 
Study Visits
PK Assessment at 
Study Completion
Termination 
Visit
Pre-infusiong
Infusion
Post-infusiong
1 month ± 
1 week
2 month ± 
1 week 
3 month ± 
2 weeks
6 month ± 
2 weeks 
9 month ± 
2 weeks
Pre-
infusiong
Infusion
Post-
infusiong
Conducted at 
the 96 hour 
postinfusion 
PK 
Assessment
12 month± 2 weeks
Informed Consenta
X
Eligibility Criteria
X
Medical Historyb
X
Concomitant Medicationsc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Non-drug Therapiesc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
Bleeding Episodes and 
Treatment and Hemostatic 
Efficacy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratories 
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signsd
X
X
X
X
X
X
X
X
X
X
X
X
ECG
X
X
X
IP Treatmente
X
X
X
X
X
X
X
X
IP Consumption / Treatment 
Compliance 
X
X
X
X
X
Subject Diary
X
X
X
X
X
X
Xf
X
X
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Continued
a Occurs at enrollment (before screening).
b Including documented history of prophylaxis treatment for the past 12 months (up to 24 months if available) and a documented history, e.g., patient 
charts and prescription information, of all bleeding episodes within the past 12 (up to 24) months. 
c Including all medications and non- drug therapies taken in the 2 weeks prior to study entry and all the concomitant medications and non-drug therapies 
during the course of the study.
d Vital signs: height, weight, body temperature, pulse rate, respiratory rate, and blood pressure. Height is only required at the screening visit. The time 
points for pre- and post-infusion measurements are (weight is measured pre-infusion only): within 30 minutes before infusion start and 30 ± 15 minutes 
post-infusion.
e IP treatment after the prophylactic treatment initiation visit at the site will be continued as home-treatment if the subject qualifies; a wash-out period of at 
least 72 hours is required after the last IP infusion before the follow-up visit. IP infusion will be given at the study site after the blood sample for 
immunology testing and IR determination is drawn.
f Can be done either at the screening or the prophylaxis initiation visit.
g Time points for PK blood draws: within 30 minutes pre-infusion, and at 11 time points post infusion: 15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 
3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours and 96 ± 2 hours ( the 96 hr sampling can be 
omitted if not allowed by the dosing interval).
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20.2.1 Summary Schedule of Visit Assesments for Surgical Bleeding
Table 7
Summary Schedule of Visit Assesments for Surgical Bleeding
Procedures/
Assessments
Surgical procedure
Post-Operative 
Day 7 Visit
(± 1 day)
Post-Operative 
Day 14 Visit
(± 2 day)
Priming Dose 
Procedures 
(12-24 hours prior 
to surgery)
Loading Dose 
Procedures 
(≤3 hours prior
to surgery)
Intraoperative
Postoperative 
(day 1 → end of 
perioperative IP 
treatment)a
ECG
X
Physical examinationb
X
X
X
X
X
Adverse events
X
X
X
X
X
X
Laboratoriesc
X
X
X
X
X
X
Vital signsd
X
X
X
X
X
X
IP treatment: rVWF (vonicog 
alfa):ADVATE (rFVIII, octocog 
alfa) or rVWF (vonicog alfa) only 
infusion
X
X
X
as required
X
as required
X
as required
X
as required
Concomitant medications and non-
drug therapy
X
X
X
X
X
X
X
Hemostatic efficacy assessmentse
X
X
X
X
Blood loss
X
estimated
X
actual
X
Xf
Xf
Treatment days estimate
X
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Continued
a The assessments will be performed daily until perioperative IP treatment end (potentially multi-visits)
b Physical Examination: within 2 hours prior to IP infusion start
c For laboratory assessments, see Table 9
d Vital signs: within 30 minutes before infusion start and 30 ± 15 minutes post-infusion
e Completed immediately postsurgery by the operating surgeon 24 hours post last IP infusion or at Day 14 visit (whichever occurs first) by the investigator
f In case bleeding still ongoing
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20.3 Clinical Laboratory Assessments
Table 8a
Clinical Laboratory Assessments for On-demand Subject
Procedures/
Assessments
Screening Visit
Baseline Visit 
(PK-assessment visit)
Prophylaxis Initiation 
Visitk
Interval/Follow-Up 
Study Visits
PK Assessmentm at 
Study Completion
Termination 
Visit
Pre-infusion
Infusion
Post-infusion
1 month ± 
1 week
2 month ± 
1 week 
3 month ± 
2 weeks
6 month ± 
2 weeks 
9 month ± 
2 weeks
Pre-
infusion
Infusion
Post-
infusion
Conducted 
at the 
96 hour 
postinfusion 
PK 
Assessment
12 month± 
2 weeks
Hematologya
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Chemistryb
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation Panel/ PK 
assessmentc
X
X
X
X
X
X
X
X
X
X
X
Immunogenicityd
X
X
Xl
X
X
X
X
X
X
X
Viral Serologye
X
Urinalysisf
X
VWD Gene Mutational 
Analysis / HLA genotype 
analysis and Analysis of 
VWF multimersg
X
sP-selectin and D-dimer
Xh
Blood Groupi 
X
Pregnancy Testj
X
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Continued
a Hematology assessments include: complete blood count [hemoglobin, hematocrit, erythrocytes (i.e. red blood cell count), mean corpuscular volume 
(MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), leukocytes (i.e. white blood cell count)] with 
differential (i.e. basophils, eosinophils, lymphocytes, monocytes, neutrophils) and platelet counts. Hematology assessments during PK assessments will 
be determined prior to IP infusion and 24 ± 2 hours, 48 ± 2 hours and 72 ± 2 hours thereafter. For other IP-associated visits, samplings are within 60 
minutes pre-infusion.
b Clinical chemistry assessments include: Sodium, potassium, chloride, glucose, creatinine, blood urea nitrogen (BUN), aspartate aminotransferase (AST), 
alanine aminotransferase (ALT) lactate dehydrogenase (LDH), alkaline phosphatase (AP), bilirubin. Clinical chemistry will be determined prior to IP 
infusion and after 24 ± 2 h, 48 ± 2 hours and 72 ± 2 hours during the PK assessments. For other IP-associated visits, samplings are within 60 minutes pre-
infusion.
c Coagulation panel/PK assessment (also refers to IR pre/post dose assessments at prophy initiation visit and each follow-up visit): PT, INR and aPTT 
(only for screening), VWF:RCo, VWF:Ag, VWF:CB, FVIII:C,; during the PK assessment at the baseline visit blood samples will be drawn 30 min prior 
PK infusion; once the PK infusion is completed 15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 
24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours and 96 ± 2 hours and VWF:RCo, VWF:CB, VWF:Ag, FVIII:C will be determined; for follow-up 
visits, IR samples will be drawn within 30 minutes pre-infusion and 30 5 minutes post-infusion. During screening and in case of thromboembolic event 
VWF multimers and ADAMTS13 will be analyzed to judge on a possibly relatedness to UHMW fractions of the IP.
d Immunogenicity assessment includes Neutralizing Antibodies (Ab) to FVIII –Neutralizing Ab to VWF:RCo, Neutralizing Ab to VWF:CB, Neutralizing 
Ab to VWF:FVIII, Binding Ab to VWF and FVIII, Binding Ab to CHO-Protein, Binding Ab to rFurin, Binding Ab to Murine IgG . In case of an SAE 
hypersensitivity reaction IgE antibodies to VWF will be determined. For on-demand subjects, a washout period of at least 72 hours after the last IP 
infusion is required before blood samples for immunogenicity assessments can be drawn. 
e Viral Serology Hepatitis A Antibody, Total - Hepatitis A Antibody, IgM - Hepatitis B Surface Antibody - Hepatitis B Core Ab, Total - Hepatitis B 
Surface Antigen - Hepatitis C Virus Antibody; Parvovirus B19; HIV-1/HIV-2 Antibodies 
f Urinalysis comprehends: erythrocytes, specific gravity, urobilinogen, ketones, glucose, protein, bilirubin, nitrite, and pH
g Not required if available in the subject’s medical history; VWF multimers: additionally in case of thromboembolic events
h At screening and in case of thromboembolic events
i Blood group assessment major blood group (local laboratory) only if not available in the subject’s medical history
j Serum pregnancy test (in females of child-bearing potential if no urine sample is available)
k The last post-infusion laboratory assessments coincide with the initiation visit for prophylactic treatment. After the blood samples are drawn for 
laboratory assessment for the 96 h post infusion PK assessment, the subject receives the first IP infusion for prophylactic treatment (prophylactic
treatment initiation visit). 
l Only needed for subjects without PK assessment prior to their first IP infusion in this study.
m A steady state full PK analysis will be performed at the end of the study. Blood samples will be drawn within 30 minutes pre-infusion, and at 11 time
points post-infusion (15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 
48 2 hours, 72 2 hours and 96 ± 2 hours), the 96 hr sampling can be omitted if not allowed by the dosinig interval.
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Table 8b
Clinical Laboratory Assessments for pdVWF Switch Subject
Procedures/
Assessments
Screening Visit
Prophylaxis Initiation Visit
PK Assessmentk
(at prophylaxis dose #5-6)
Interval/Follow-Up 
Study Visits
PK Assessmentk at 
Study Completion
Termination 
Visit
Pre-infusion
Infusion
Post-infusion
1 month ± 1 week
2 month ± 1 week 
3 month ± 2 weeks
6 month ± 2 weeks 
9 month ± 2 weeks
Pre-
infusion
Infusion
Post-
infusion
Conducted at 
the 96 hour 
postinfusion 
PK 
Assessment
12 month± 
2 weeks
Hematologya
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Chemistryb
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation Panel/PK 
assessmentc
X
X
X
X
X
X
X
X
X
X
X
Immunogenicityd
X
X
X
X
X
X
X
X
X
Viral Serologye
X
Urinalysisf
X
VWD Gene Mutational 
Analysis / HLA 
genotype analysis and 
Analysis of VWF 
multimersg
X
sP-selectin and D-dimer
Xh
Blood Groupi 
X
Pregnancy Testj
X
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Continued
a Hematology assessments include: complete blood count [hemoglobin, hematocrit, erythrocytes (i.e. red blood cell count), mean corpuscular volume 
(MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), leukocytes (i.e. white blood cell count)] with 
differential (i.e. basophils, eosinophils, lymphocytes, monocytes, neutrophils) and platelet counts. Hematology assessments during PK assessments will 
be determined prior to IP infusion and 24 ± 2 hours, 48 ± 2 hours and 72 ± 2 hours thereafter. For other IP-associated visits, samplings are within 60 
minutes pre-infusion.
b Clinical chemistry assessments include: Sodium, potassium, chloride, glucose, creatinine, blood urea nitrogen (BUN), aspartate aminotransferase (AST), 
alanine aminotransferase (ALT) lactate dehydrogenase (LDH), alkaline phosphatase (AP), bilirubin. Clinical chemistry will be determined prior to IP 
infusion and after 24 ± 2 h, 48 ± 2 hours and 72 ± 2 hours during the PK assessments. For other IP-associated visits, samplings are within 60 minutes pre-
infusion.
c Coagulation panel/PK assessment (also refers to IR pre/post dose assessments at prophy initiation visit and each follow-up visit): PT, INR and aPTT 
(only for screening), VWF:RCo, VWF:Ag, VWF:CB, FVIII:C,; during the PK assessment blood samples will be drawn 30 min prior PK infusion; once 
the PK infusion is completed 15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 
48 2 hours, 72 2 hours and 96 ± 2 hours and VWF:RCo, VWF:CB, VWF:Ag, FVIII:C will be determined; for follow-up visits, IR samples will be 
drawn within 30 minutes pre-infusion and 30 5 minutes post-infusion. During screening and in case of thromboembolic event VWF multimers and 
ADAMTS13 will be analyzed to judge on a possibly relatedness to UHMW fractions of the IP.
d Immunogenicity assessment includes Neutralizing Antibodies (Ab) to FVIII –Neutralizing Ab to VWF:RCo, Neutralizing Ab to VWF:CB, Neutralizing 
Ab to VWF:FVIII, Binding Ab to VWF and FVIII, Binding Ab to CHO-Protein, Binding Ab to rFurin, Binding Ab to Murine IgG. In case of an SAE 
hypersensitivity reaction IgE antibodies to VWF will be determined. For switch subjects, the wash out period may be reduced to the time interval 
between their pdVWF prophy infusions.
e Viral Serology Hepatitis A Antibody, Total - Hepatitis A Antibody, IgM - Hepatitis B Surface Antibody - Hepatitis B Core Ab, Total - Hepatitis B 
Surface Antigen - Hepatitis C Virus Antibody; Parvovirus B19; HIV-1/HIV-2 Antibodies 
f Urinalysis comprehends: erythrocytes, specific gravity, urobilinogen, ketones, glucose, protein, bilirubin, nitrite, and pH
g Not required if available in the subject’s medical history; VWF multimers: additionally in case of thromboembolic events
h At screening and in case of thromboembolic events
i Blood group assessment major blood group (local laboratory) only if not available in the subject’s medical history
j Serum pregnancy test (in females of child-bearing potential if no urine sample is available)
k A full steady state PK analysis will be performed. Blood samples will be drawn within 30 minutes pre-infusion, and at 11 time points post-infusion 
(15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours 
and 96 ± 2 hours) , the 96 hr sampling can be omitted if not allowed by the dosinig interval.
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20.3.1 Laboratory Sampling for Surgical Bleeding
Table 9
Laboratory Samplinga for Surgical Bleeding
Procedures/
Assessments
Surgical procedure
Post-Operative 
Day 7 Visit
(± 1 day)
Post-Operative 
Day 14 Visit
(± 2 day)
Priming Dose 
Procedures 
(12-24 hours prior 
to surgery)
Loading Dose 
Procedures 
(≤3 hours prior 
to surgery)
Intraoperative
Postoperative 
(day 1 → end of 
perioperative IP 
treatment)b
Hematologyc
X
(w/o Differential)
Xd
(w/o 
Differential)
X
(w/o Differential)
X
X
Clinical Chemistrye
X
Xd
X
X
Coagulation panelf
X
X
X
X
X
X
VWF inhibitory and binding 
antibodies, antibodies to other 
proteinsg
X
X
X
if excessive or 
unexplained
bleeding
X
X
X
Urinalysish
X
X
VWF Multimersi
Anti VWF IgE antibody testing
only in case of allergic reaction/ 
anaphylaxis
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Continued
a Blood draws are within 3 hrs  prior to infusion start, expect that for the priming dose blood draw is within 30 minutes prior to infusion start. For 
coagulation panel, an additional 30 ± 5 minutes post-infusion blood draw is needed.
b The assessments will be performed daily until perioperative IP treatment end (potentially multi-visits)
c Hematology assessments include: complete blood count [hemoglobin, hematocrit, erythrocytes (i.e. red blood cell count), mean corpuscular volume 
(MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), leukocytes (i.e. white blood cell count)] with 
differential (i.e. basophils, eosinophils, lymphocytes, monocytes, neutrophils) and platelet counts. 
d Not required if sample already drawn at the time of the priming dose
e Clinical chemistry assessments include: Sodium, potassium, chloride, glucose, creatinine, blood urea nitrogen (BUN), aspartate aminotransferase (AST), 
alanine aminotransferase (ALT) lactate dehydrogenase (LDH), alkaline phosphatase (AP), bilirubin. 
f Coagulation panel: VWF:RCo, VWF:Ag, FVIII:C PT INR and aPTT; in additiona to pre-infusion, 30 ± 5 minutes post infusion blood draw is needed. 
g Immunogenicity assessment includes Neutralizing Antibodies (Ab) to FVIII – Neutralizing and Neutralizing Ab to VWF:RCo, Neutralizing Ab to 
VWF:CB, Neutralizing Ab to VWF:FVIII, Binding Ab to VWF and FVIII, Binding Ab to CHO-Protein, Binding Ab to rFurin, Binding Ab to Murine 
IgG. In case of an SAE hypersensitivity reaction IgE antibodies to VWF will be determined.
h Urinalysis comprehends: erythrocytes, specific gravity, urobilinogen, ketones, glucose, protein, bilirubin, nitrite, and pH
i VWD multimers and ADAMTS13 during the study only in case of thrombotic events
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20.4 Contraceptive Methods for Female Subjects of Childbearing Potential
In this study, subjects who are women of childbearing potential must agree to utilize a 
highly effective contraceptive measure throughout the course of the study and for 30 days 
after the last administration ofIP. In accordance with the Clinical Trial Facilitation Group 
(CTFG) recommendations related to contraception and pregnancy testing in clinical trials 
(version 2014-09-15)ii, birth control methods which may be considered as highly 
effective include the following:

Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation:

oral

intravaginal

transdermal

Progestogen-only hormonal contraception associated with inhibition of ovulation:

oral

injectable

implantableiii

Intrauterine device (IUD)iii

Intrauterine hormone-releasing system (IUS) iii

Bilateral tubal occlusioniii

Vasectomised partner(s)iii

Sexual abstinence during the entire study period
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhoea method (LAM) are 
not acceptable methods of contraception. Female condom and male condom should not 
be used together.
                                                
ii Clinical Trial Facilitation Group (CTFG) recommendations related to contraception and pregnancy 
testing in clinical trials: http://www.hma.eu/fileadmin/dateien/ 
Human_Medicines/01About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf.
iii Contraception methods that are considered to have low user dependency.
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21. REFERENCES
1.
Committee for Medicinal Products for Human Use. Guideline on clinical 
investigation of human plasma derived von Willebrand factor products.
CPMP/BPWG/220/02, 12. 11-17-2005:London, European Medicines Agency 
(EMA). Web Link: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/201
0/01/WC500067126.pdf
2.
Mannucci PM. Treatment of von Willebrand's Disease. N Engl J Med. 
2004;351(7):683-694.
3.
Goudemand J, Scharrer I, Berntorp E, et al. Pharmacokinetic studies on Wilfactin, a 
von Willebrand factor concentrate with a low factor VIII content treated with three 
virus-inactivations/removal methods. J Thromb Haemost. 2005;3(10):2219-2227.
4.
Abshire T. The role of prophylaxis in the management of von Willebrand disease: 
today and tomorrow. Thromb Res. 2009;124 Suppl 1:S15-S19.
5.
Nilsson IM, Blombäck M, Jorpes E, Blombäck B, Johansson SA. V. Willebrand's 
disease and its correction with human plasma fraction 1-0. Acta Med Scand. 
1957;159(3):179-188.
6.
Berntorp E, Petrini P. Long-term prophylaxis in von Willebrand disease. Blood 
Coagul Fibrinolysis. 2005;16 Suppl 1:S23-S26.
7.
Berntorp E. Prophylaxis and treatment of bleeding complications in von Willebrand 
disease type 3. Semin Thromb Hemost. 2006;32(6):621-625.
8.
Federici AB. Highly purified VWF/FVIII concentrates in the treatment and 
prophylaxis of von Willebrand disease: the PRO.WILL Study. Haemophilia. 
2007;13 Suppl 5:15-24.
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9.
Halimeh S, Krümpel A, Rott H, et al. Long-term secondary prophylaxis in children, 
adolescents and young adults with von Willebrand disease. Results of a cohort 
study. Thromb Haemost. 2011;105(4):597-604.
10.
Abshire TC, Federici AB, Alvárez MT, et al. Prophylaxis in severe forms of von 
Willebrand's disease: results from the von Willebrand Disease Prophylaxis 
Network (VWD PN). Haemophilia. 2013;19(1):76-81.
11.
Abshire T, Cox-Gill J, Kempton CL, et al. Prophylaxis escalation in severe von 
Willebrand disease: A prospective study from the von Willebrand Disease 
Prophylaxis Network. J Thromb Haemost. 2015;13(9):1585-1589.
12.
Berntorp E. Prophylaxis in von Willebrand disease. Haemophilia. 2008;14 Suppl 
5:47-53.
13.
Varadi K, Rottensteiner H, Vejda S, et al. Species-dependent variability of 
ADAMTS13-mediated proteolysis of human recombinant von Willebrand factor. J 
Thromb Haemost. 2009;7(7):1134-1142.
14.
Mannucci PM, Kempton C, Millar C, et al. Pharmacokinetics and safety of a novel 
recombinant human von Willebrand factor manufactured with a plasma-free 
method: a prospective clinical trial. Blood. 2013;122(5):648-657.
15.
Gill JC, Castaman G, Windyga J, et al. Hemostatic efficacy, safety and 
pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand 
disease. Blood. 2015;126(17):2038-2046.
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16.
Committee for Medicinal Products for Human Use. Guideline on immunogenicity 
assessment of biotechnology-derived therapeutic proteins. 
CHMP/BMWP/14327/2006, 18. 12-13-2007:London, European Medicines Agency 
(EMA),. Web Link: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/200
9/09/WC500003946.pdf
17.
Kasper CK. Laboratory tests for factor VIII inhibitors, their variation, significance 
and interpretation. Blood Coagul Fibrinolysis. 1991;2 Suppl 1:7-10.
18.
Lillicrap D. Von Willebrand Factor. International Society for Thrombosis and 
Hemostasis (ISTH), 54th Annual Scientific and Standardization Committee 
Meeting - Scientific Subcommittee Minutes:2008:60-64. Web Link: 
http://c.ymcdn.com/sites/www.isth.org/resource/resmgr/yearly_subcommittee_min
utes/2008minutes.pdf?hhSearchTerms=lillicrap+and+2008
19.
 
20.
 
21.
 
 
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22. SUMMARY OF CHANGES
Protocol 071301: Local Amendment 8 (Czech Republic): 2018 MAY 18
Replaces: Local Amendment 5 (Czech Republic): 2017 AUG 08
In this section, changes from the previous local version of the protocol, dated 
2017 AUG 08, are described and their rationale is given.
1.
Throughout the document
Description of Change:
Minor grammatical and/or administrative changes and/or rewording have been 
made.
Purpose for Change: To improve the readability and/or clarity of the protocol.
2.
Throughout the document
Description of Change:
INN was added to rVWF and ADVATE by changing rVWF to rVWF (vonicog 
alfa) and changing ADVATE to ADVATE (rFVIII, octocog alfa).
Purpose for Change: To add INN.
3.
Section 2, Section 12.1.2
Description of Change:
Bleeding events that meet seriousness criteria should be reported on both SAE 
eCRF and SAE report form. Section 12.1.2.3 was added as a reference for SAE 
assessment.
Purpose for Change: To provide further clarifications on SAE reporting.
4.
Synopsis (Clinical condition(s)/indication(s)), Section 6.4, Section 13.1
Description of Change: 
Original text:
Subjects with severe von Willebrand disease (VWD) requiring prophylactic 
treatment with coagulation factor replacement.
New text:
Subjects with severe von Willebrand disease (VWD) (baseline VWF:RCo 
<20 IU/dL) requiring prophylactic treatment with coagulation factor replacement.
Purpose for Change: To add definition of severe VWD.
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5.
Synopsis (Planned study period), Section 8.2
Description of Change:
The initiation/completion and duration of the study were updated per the new 
timeline.
Purpose for Change: To reflect the new study timeline.
6.
Synopsis (Study purpose, Study design), Section 7.1, Section 8.1
Description of Change:
Hypersensitivity was added for safety evaluation; PK and pharmacoecnomics 
evaluation was added.
Purpose for Change: To provide further clarifications to the purpose of the study.
7.
Synopsis (Primary objective), Section 7.2
Description of Change:
Original text:
The primary objective of this study is to prospectively evaluate the annualized 
bleeding rate (ABR) for spontaneous bleeding episodes while on prophylactic 
treatment with rVWF and to compare it to the subject’s historical ABR for 
spontaneous bleeding episodes during on-demand treatment.
New text:
The primary objective of this study is to prospectively evaluate the annualized 
bleeding rate (ABR) for spontaneous bleeding episodes while on prophylactic 
treatment with rVWF and to compare it to the subject’s historical ABR for 
spontaneous bleeding episodes. 
Purpose for Change: To remove wording to accommodate pdVWF switch subject 
cohort, which is a new study cohort added in this amendment.
8.
Synopsis (Secondary objectives), Section 7.3
Description of Change: 
 
 Additional wording was added to clarify the objectives.
Purpose for Change: Remove some of the objectives (
 
) and add clarification.
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9.
Synopsis (Exploratory objectives, Exploratory outcome measures), 
Section 7.4, Section 8.3.3
Description of Change: 
  
 
 and additional wording was added to clarify the assessments.
Purpose for Change: Clarification and adding additional objectives/assessments.
10. Synopsis (Study Design), Section 8.1
Description of Change: 
Additional details about the study design were added for on-demand and the switch 
cohort.
Purpose for Change: To provide further clarification and to add study design for the 
switch cohort.
11. Synopsis (Primary outcome measure), Section 8.3.1
Description of Change: 
Original text:
Prospectively recorded ABR for spontaneous (not related to trauma) bleeding 
episodes during prophylactic treatment with rVWF and the subjects’ historical 
ABR for spontaneous bleeding episodes during on-demand treatment.
New text:
Annualized bleeding rate (ABR) for spontaneous (not related to trauma) bleeding 
episodes during prophylactic treatment with rVWF (vonicog alfa).
Purpose for Change: To remove the unnecessary text.
12. Synopsis (Secondary outcome measures), Section 8.3.2
Description of Change:
Rewording some of the exisiting secondary outcome measures (efficacy and safety) 
to provide clarification. New efficacy outcome measures were added to further 
access the efficacy of prophylaxis for switch subjects. Clinically significant 
changes in vital signs and clinical laboratory parameters were added as one 
additional safety measure. New steady-state PK parameters were added. PD 
parameters were added. 
 
Purpose for Change: To provide further clarifications and to add new outcome 
measures for switch subjects. And to remove some of the outcome measures (
 
)
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13. Synopsis (Investigational product(s), dose and mode of administration)
Description of Change: 
Prophylaxis dosing guidelines were added for the pdVWF switch subjects.
Purpose for Change: To add dosing guide for the switch subjects.
14. Synopsis (Targeted accrual, sample size calculation), Section 6.4, Section 13.1
Description of Change:
Sample size was increased and targeted accrual of each cohort was added and a 
followup period of 12 months was added.
Purpose for Change: To update the sample to reflect the adding of switch cohort.
15. Synopsis (Inclusion criteria, Exclusion criteria), Section 9.1, Section 9.2
Description of Change: 
Criteria for the switch subjects were added.
Criteria added to clarify no pre-planned surgery is allowed.
Purpose for Change: To update for the eligibility of switch subjects and to add 
some clarity.
16. Synopsis (Inclusion Criteria), Section 9.1
Description of Change:
Original text:
Subject is ≥18 years old at the time of screening and has a body mass index ≥18 but 
<30 kg/m2.
New text:
Subject is ≥18 years old at the time of screening and has a body mass index 
≥1817.5 but <3040 kg/m2.
PurposeforChange: To update the BMI value from “18-30” range to “17.5-40”
range, in response to query received from regulatory authority in Czech Republic
only.
17. Synopsis (Planned statistical analysis), Section 13.4
Description of Change: 
Changes were made throughout the section according to the updated outcome 
measures. Remove the planned analysis of exploratory outcome measure from 
synopsis to avoid redundance
Purpose for Change: To better test the updated outcome measures.
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18. Section 5
Description of Change: 
New abbreviations were added.
Purpose for Change: Clarification.
19. Section 6.5, Section 6.5.2, Section 6.5.2.4, Section 6.5.2.5
Description of Change: 
Summary of recently completed clinical study 071101 was added as 
Section 6.5.2.4, the summary of 071401 was moved to Section 6.5.2.5 .
Purpose for Change: To provide clinical study summary for study 071101.
20. Section 6.5.2.3
Description of Change: 
To add wording about the basis of the dosing for the current study.
Purpose for Change: To provide clarification.
21. Section 6.6
Description of Change: 
Original text:
He/she may benefit from a product that minimizes excessive FVIII administration.
New text:
He/she may benefit from a product that minimizes excessive FVIII administration 
and thus allowing individualized dosing of VWF at optimal levels. 
Original text:
By using a recombinant product, the risk of contamination with blood derived 
viruses or variant Creutzfeldt-Jakob Disease associated with the use of products 
of human or animal origin has been virtually eliminated.
New text:
By using a recombinant product, the risk of transmission of adventitious agents 
and other blood-borne pathogens associated with the use of products of human or 
animal origin has been eliminated.
Purpose for Change: To provide accuracy and clarification.
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22. Section 6.6
Description of Change: 
Original text:
These benefits outweigh the following potential risks of rVWF.
New text:
These benefits outweigh the following identified or potential risks of rVWF
Purpose for Change: To provide accuracy since thromboembolic events has been 
upgraded to identified risk.
23. Section 8.5
Description of Change: 
Updates were made based on safety considerations.
Purpose for Change: To avoid unnecessary study stop.
24. Section 8.6.3
Description of Change: 
Wording was added to clarify that partial vials are not allowed to use. 
Wording about mixing of two products was removed as it is not allowed any more.
Purpose for Change: To provide clarification on IP administration.
25. Section 8.6.4.1
Description of Change: 
Details about PK assessment IP treatment were added for both on-demand and 
switch cohorts.
Purpose for Change: To provide more details and clarifications.
26. Section 8.6.4.2
Description of Change:
Prophylaxis initiation treatment was updated to be also applicable to the switch 
subjects and the dosing details were removed from this section (moved to 
Section 8.6.4.3).
Purpose for Change: To provide details to accommodate newly added switch 
cohort.
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27. Section 8.6.4.3, Section 8.6.4.3.1, Section 8.6.4.3.2
Description of Change:
Detailed instructions of prophylaxis dosing and dosing adjustment were added to 
this section for both on-demand and pdVWF switch subjects. Home treatment rules 
were also made applicable to switch subjects, and made correction that the 
investigator is responsible for the home treatment procedures.
Purpose for Change: To provide details and clarifications to accommodate newly 
added switch cohort.
28. Section 8.6.4.4.1, Section 10.3.1
Description of Change:
Added the requirement of documentation the reason for the use of any non-IP 
product or therapy.
Purpose for Change: To ensure proper documentation of non-IP product use.
29. Section 8.6.4.4.2
Description of Change: 
Added the wording about dose adjustment and the optional use of ADVATE.
Purpose for Change: To provide further clarification.
30. Section 8.6.4.5
Description of Change: 
Sentence was added to clarify no pre-planned surgery is allowed.
Purpose for Change: To add some clarity.
31. Section 8.6.4.5.2
Description of Change:
Added description of priming dose for surgery.
Purpose for Change: To provide further clarification.
32. Section 8.6.4.5.3
Description of Change:
Added description of loading dose for surgery.
Purpose for Change: To provide further clarification.
33. Section 8.6.4.6, Section 12.6.1
Description of Change:
Added the details about prophylaxis measures against thromboembolism.
Purpose for Change: To ensure safety monitoring of thromboembolic events.
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34. Section 8.6.5
Description of Change:
Added the wording about the requirement to monitor temperature excursions at the 
subject’s home.
Purpose for Change: To ensure IP is stored as specified in the Pharmacy Manual.
35. Section 9.4
Description of Change: 
Original text:
Subjects who develop a neutralizing inhibitor to rVWF and/or ADVATE 
(biological assays). 
New text:
Subjects who develop a neutralizing inhibitor to rVWF and/or ADVATE 
(biological assays) that results in significant clinical effect, including but not 
limited to increasing the weekly dose of rVWF by ≥50%.
Purpose for Change: To provide more clarifications.
36. Section 9.4
Description of Change:
One more discontinuation criteria was added.
Purpose for Change: To avoid the continue of non-compliance subjects.
37. Section 10.3.1
Description of Change:
Added the wording to clarify the wash-out period of the screening visit and the 
timing of the subsequent visit for switch subjects.
Purpose for Change: To clarify for switch subjects.
38. Section 10.3.2
Description of Change: 
Wording was added to specify this visit only applicable to on-demand cohort.
Purpose for Change: To provide clarification.
39. Section 10.3.3
Description of Change: 
Wording was added to specify the timing of this visit for the switch cohort.
Purpose for Change: To provide clarification.
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40. Section 10.3.4
Description of Change:
The initial steady-state PK assessment that only applicable to the switch subjects 
was specified in this section.
Purpose for Change: To accommodate PK assessment of switch subjects.
41. Section 10.3.5, Section 10.3.6, Section 10.3.7, Section 10.3.8, Section 10.3.9
Description of Change: 
The original Sections from 10.3.4 – 10.3.8 became 10.3.5 – 10.3.9 due to the 
insertion of new Section 10.3.4.
Purpose for Change: To accommodate the insertion of new Section 10.3.4.
42. Section 10.3.7
Description of Change: 
The value of prophylaxis dose was removed since it was not correct for switch 
patients. The different wash-out period for switch subjects was specified.
Purpose for Change: To make corrections and to make clarifications for switch 
subjects.
43. Section 10.3.9
Description of Change:
Wording was added to clarify that the EOS PK assessment also applicabe for 
switch subjects and the wash-out requirement for switch subjects was added. The 
details about PK parameters were removed (specified in other sections).
Purpose for Change: To provide clarifications for switch subjects.
44. Section 10.4
Description of Change: 
Added more clarification about the use of Antifibrinolytics.
Purpose for Change: To provide further clarifications.
45. Section 10.5
Description of Change:
Added more details about what would be recorded in the diary.
Purpose for Change: To provide further clarifications.
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46. Section 11.2, Section 12.5
Description of Change:
Specified the need of location for historical bleeds records. Clarified that it is good 
to have upto 24 months of historical records if available.
Purpose for Change: To provide further clarifications.
47. Section 11.3
Description of Change:
Added more details about what would be needed for switch subjects as the 
historical factor dosing and consumption records.
Purpose for Change: To provide further clarifications.
48. Section 11.5
Description of Change:
Clarify the assessment of overall assessment of hemostatic efficacy.
Purpose for Change: To provide clarifications.
49. Section 11.6
Description of Change:
Section title was updated to add PD assessment.
PK/PD assessment details including schedule, dosing, parameters, etc.
Purpose for Change: To provide instruction/protocol for PK/PD assessment.
50. Section 12.1.1.1
Description of Change: 
More details about hypersensitivity reactions were specified. SAE reporting 
reference was added. 
Purpose for Change: To provide further clarification.
51. Section 12.1.1.2
Description of Change:
More clarifications about SUSAR were added. 
Purpose for Change: To provide further clarification.
52. Section 12.1.1.3
Description of Change: 
More details about criteria of serious AE were added. 
Purpose for Change: To provide further clarification.
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53. Section 12.1.2
Description of Change: 
Some wording of clarification was added for assessment of AE. 
Purpose for Change: To provide further clarification.
54. Section 12.1.2.2
Description of Change: 
Original text:
Is not associated with the IP (i.e., does not follow a reasonable temporal 
relationship to the administration of IP or has a much more likely alternative 
etiology).
New text:
Is not associated with the IP (i.e., does not follow a reasonable temporal 
relationship to the administration of IP, is not biologically plausible per 
mechanism of action of the IP, or has a much more likely alternative etiology).
Purpose for Change: To provide more clarifications.
55. Section 12.1.2.3
Description of Change: 
More details about hypersensitivity reactions were specified. SAE reporting 
reference was added. 
Purpose for Change: To provide further clarification.
56. Section 12.7
Description of Change: 
Added clarification that height is only assessed on screening visit. 
Purpose for Change: To provide further clarification.
57. Section 12.9, Section 12.9.14.1
Description of Change: 
“Abnormal laboratory values deemed clinically significant by the investigator are 
to be recorded as AEs (see Section 12.1.2).” was removed due to inaccuracy.
New Text added: “Any abnormal laboratory value that is considered clinically 
significant by the investigator based on a local laboratory test result (reference 
range and the units to be provided) should be confirmed by a central laboratory test 
result for which the sample is drawn/collected within 24 hours of the abnormal 
finding by the local laboratory”. 
Purpose for Change: To provide accuracy and further clarification.
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58. Section 12.9.1
Description of Change: 
Section title was updated to add PD assessment.
Text was removed, and refered to Section 11.6. 
Purpose for Change: To avoid duplicated text.
59. Section 12.9.3.4
Description of Change: 
Wording added to specify that only confirmed positive anti-VWF inhibitor test 
result will be reported and will be considered as a medically significant SAE. 
Purpose for Change: To clarify.
60. Section 12.10.2
Description of Change:
 
 
Purpose for Change: 
61. Section 13.2.2
Description of Change: 
Original text:
The Full Analysis Set (FAS) will be composed of all subjects with available 
bleeding data gathered during prophylaxis IP treatment.
New text:
The Full Analysis Set (FAS) will be composed of all subjects who receive
prophylaxis IP treatment.
Purpose for Change: To re-define FAS.
62. Section 13.2.3
Description of Change: 
Details were added on how to measure the compliance. 
Purpose for Change: To add clarifications.
63. Section 13.2.4
Description of Change: 
Wording added to clarify PK analysis set is also for PD analysis. 
Purpose for Change: To add clarifications.
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64. Section 13.4.2.2, Section 13.4.2.3 
Description of Change:
 
 
 
 
Purpose for Change:
 
65. Section 13.4.3.1, Section 13.4.3.2, Section 13.4.3.3 and Section 13.4.3.4
Description of Change: 
 
 
 
 
Purpose for Change: 
 
66. Section 13.5
Description of Change:
Removed the interim analysis 
Purpose for Change: No interim analysis is planned.
67. Section 15.5
Description of Change:
Additional instruction was provided to ensure the compliance by adding the text 
“Also, the investigator will notify the sponsor immediately by phone and confirm 
notification to the sponsor in writing whenever pdVWF is used instead of rVWF. 
The reason for this use must also be provided to the sponsor”.
Purpose for Change: To ensure compliance.
68. Section 20.1
Description of Change: 
The study flow chart was updated to reflect the addition of switch cohort and to 
illustrate the study design for this new cohort.
Purpose for Change: To update the study design.
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69. Section 20.2, Section 20.2.1
Description of Change:
Some clarifications were made to the tables and the footnotes, the original Table 6 
was changed to 6a and specified just for on-demand subjects, Table 6b that is for 
switch subjects was added. 
Purpose for Change: To provide schedule for the switch subjects and to provide 
clarifications for surgery procedure schedule.
70. Section 20.3, Section 20.3.1
Description of Change: 
Some clarifications were made to the tables and the footnotes, the original Table 8 
was changed to 8a and specified just for on-demand subjects, Table 8b that is for 
switch subjects was added. 
Purpose for Change: To provide schedule for the switch subjects and to provide 
clarifications for surgery lab assessments.
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INVESTIGATOR ACKNOWLEDGEMENT
RECOMBINANT VON WILLEBRAND FACTOR (rVWF)
A prospective, phase 3, open-label, international multicenter study on efficacy and 
safety of prophylaxis with rVWF in severe von Willebrand Disease
PROTOCOL IDENTIFIER: 071301
CLINICAL TRIAL PHASE 3
LOCAL AMENDMENT 8 (CZECH REPUBLIC): 2018 MAY 18
Replaces: LOCAL AMENDMENT 5 (CZECH REPUBLIC): 2017 AUG 08
OTHER PROTOCOL ID(s)
NCT Number: NCT02973087
EudraCT Number: 2016-001478-14
IND NUMBER: 013657
By signing below, the investigator acknowledges that he/she has read and understands 
this protocol, and will comply with the requirements for obtaining informed consent from 
all study subjects prior to initiating any protocol-specific procedures, obtaining written 
initial and ongoing EC(s) protocol review and approval, understands and abides by the 
requirements for maintenance of source documentation, and provides assurance that this 
study will be conducted according to all requirements as defined in this protocol, Clinical 
Trial Agreement, ICH GCP guidelines, and all applicable national and local regulatory 
requirements.
Signature of Principal Investigator
Date
Print Name of Principal Investigator
For non-commercial use only

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CLINICAL STUDY PROTOCOL
PRODUCT: Recombinant Von Willebrand Factor (rVWF, vonicog alfa)
STUDY TITLE: A PROSPECTIVE, PHASE 3, OPEN-LABEL, INTERNATIONAL 
MULTICENTER STUDY ON EFFICACY AND SAFETY OF PROPHYLAXIS 
WITH rVWF IN SEVERE VON WILLEBRAND DISEASE
STUDY SHORT TITLE: rVWF IN PROPHYLAXIS
PROTOCOL IDENTIFIER: 071301
CLINICAL TRIAL PHASE 3
LOCAL AMENDMENT 9 (TURKEY): 2018 SEP 13
Replaces: 
AMENDMENT 6: 2018 MAR 12
ALL VERSIONS: 
Local (Turkey) Amendment 9: 2018 SEP 13
Local (Czech Republic) Amendment 8: 2018 MAY 18
Local (Germany) Amendment 7: 2018 MAY 18
Amendment 6: 2018 MAR 12 
Local (Czech) Amendment 5: 2017 AUG 08
Local (Germany) Amendment 4: 2017 AUG 04
Amendment 3: 2017 AUG 03
Amendment 2: 2016 DEC 15
Amendment 1: 2016 APR 08
Original: 2014 FEB 09
OTHER ID(s)
NCT Number: NCT02973087
EudraCT Number: 2016-001478-14
IND NUMBER: 013657
Study Sponsor(s):
Baxalta US Inc.
300 Shire Way
Lexington, MA 02421,US
Baxalta Innovations GmbH
Industriestrasse 67
A-1221 Vienna, AUSTRIA
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1. STUDY PERSONNEL
1.1 Authorized Representative (Signatory) / Responsible Party
, MD
Global Clinical Development Operations
Baxalta Innovations GmbH
1.2 Study Organization
The name and contact information of the responsible party and individuals involved with 
the study (e.g. investigator(s), sponsor’s medical expert and study monitor, sponsor’s 
representative(s), laboratories, steering committees, and oversight committees [including 
ethics committees (ECs)], as applicable) will be maintained by the sponsor and provided 
to the investigator.
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2. SERIOUS ADVERSE EVENT REPORTING
The investigator will comply with applicable laws/requirements for reporting serious 
adverse events (SAEs) and suspected unexpected serious adverse events (SUSARs) to the 
ECs.
ALL SAEs, INCLUDING SUSARs, ARE TO BE REPORTED ON THE SERIOUS 
ADVERSE EVENT REPORT (SAER) FORM AND TRANSMITTED TO THE 
SPONSOR WITHIN 24 HOURS AFTER BECOMING AWARE OF THE EVENT.
Bleeding events that meet seriousness criteria (death, life-threatening, 
hospitalizing/prolongation of hospitalization, disability, congenital anomaly, or medically 
significant and if not urgently treated would result in one of the above) should be reported 
on the SAE eCRF and SAE Report form as an SAE.
Drug Safety contact information:
Baxalta Global Drug Safety fax number:  
OR 
email: 
For definitions and information on the assessment of these events, refer to the following:

Adverse Events (AEs), Section 12.1

SAEs, Section 12.1.1.1

SUSARs, Section 12.1.1.2

Assessment of AEs, Section 12.1.2

Safety Reporting, Section 12.1.2.3
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3. SYNOPSIS
INVESTIGATIONAL PRODUCT
Name of Investigational Product (IP)
Recombinant von Willebrand factor (rVWF, vonicog alpha)
Name(s) of Active Ingredient(s)
Recombinant von Willebrand factor (rVWF, vonicog alpha)
CLINICAL CONDITION(S)/INDICATION(S)
Subjects with severe von Willebrand disease (VWD) (baseline VWF: Ristocetin cofactor activity
(VWF:RCo) <20 IU/dL) requiring prophylactic treatment with coagulation factor replacement
PROTOCOL ID
071301
PROTOCOL TITLE
A prospective, phase 3, open-label, international multicenter 
study on efficacy and safety of prophylaxis with rVWF in severe 
von Willebrand disease
Short Title
rVWF in prophylaxis
STUDY PHASE
Phase 3
PLANNED STUDY PERIOD
Initiation
2017 OCT
Primary Completion
2019 Q4
Study Completion
2019 Q4
Duration
27 months
STUDY OBJECTIVES AND PURPOSE
Study Purpose
The purpose of this phase 3 study is to investigate the efficacy and safety, including immunogenicity, 
thrombogenicity and hypersensitivity reactions, as well as pharmacokinetics (PK), 
 
 and 
 of prophylactic treatment with rVWF (vonicog alfa) in adult 
subjects with severe VWD.
Primary Objective
The primary objective of this study is to prospectively evaluate the annualized bleeding rate (ABR) for 
spontaneous bleeding episodes while on prophylactic treatment with rVWF (vonicog alfa) and to compare 
it to the subject’s historical ABR for spontaneous bleeding episodes. 
Secondary Objectives
Secondary Objectives are to assess

Additional efficacy of prophylactic treatment with rVWF (vonicog alfa)

Safety of rVWF (vonicog alfa), including immunogenicity, thrombogenicity and hypersensitivity 

Pharmacokinetics (PK) of rVWF (vonicog alfa) and Pharmacodynamics (PD) of rVWF (vonicog alfa) 
as measured in FVIII activity
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Exploratory Objectives
 
 
 
 
STUDY DESIGN
Study Type/ Classification/ Discipline
Efficacy and Safety 
Control Type
No control
Study Indication Type
Prophylaxis and treatment of bleeding episodes
Intervention model 
Single-group
Blinding/Masking
Open-label
Study Design
This is a phase 3, prospective, open-label, uncontrolled, non-
randomized, international multicenter study evaluating efficacy, 
safety, including immunogenicity, thrombogenicity and 
hypersensitivity reactions, as well as PK, 
 and 
 of prophylactic treatment regimen with 
rVWF (vonicog alfa) in adult subjects with severe VWD.
Subjects transitioning from on-demand treatment (OD subjects) 
or subjects switching from prophylactic treatment with pdVWF 
(pdVWF switch subjects) will receive prophylactic treatment 
with rVWF (vonicog alfa) for a 12-month period (up to 15 
months for the qualified subjects to rollover into the continuation 
study, if the continuation study start up is delayed beyond the 
completion of subject’s 12-month visit).
Planned Duration of Subject 
Participation
Approximately 15 to 18* months 
* Study treatment period is extended by 3 months to 
accommodate participation in the continuation study for the 
qualified subjects and will be exercised only if the continuation 
study start up is delayed beyond the completion of subject’s 12-
month visit.
Primary Outcome Measure 
Efficacy

Annualized bleeding rate (ABR) for spontaneous (not related to trauma) bleeding episodes during 
prophylactic treatment with rVWF (vonicog alfa)
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Secondary Outcome Measures
Additional efficacy of prophylactic treatment with rVWF (vonicog alfa)

ABR percent reduction success for OD subjects defined as at least 25% reduction of ABR for 
spontaneous (not related to trauma) bleeding episodes during rVWF (vonicog alfa) prophylaxis 
relative to the subject’s own historical ABR during on-demand treatment 

ABR preservation success for pdVWF switch subjects defined as achieving an ABR for spontaneous 
bleeding episodes during rVWF (vonicog alfa) prophylaxis that is no greater than the subject’s own 
historical ABR during prophylactic treatment with pdVWF 

Categorized spontaneous ABR defined as 0, 1-2, 3-5, or >5 bleeding episodes during the prophylactic 
treatment with rVWF (vonicog alfa)

Total number of infusions and the average number of infusions per week during prophylactic 
treatment with rVWF (vonicog alfa)

Total weight adjusted consumption of rVWF (vonicog alfa) during prophylactic treatment

Spontaneous ABR by location of bleeding (Gastrointestinal [GI], epistaxis, joint bleeding, 
menorrhagia, oral and other mucosa, muscle and soft tissue, etc.) while on prophylactic treatment with 
rVWF (vonicog alfa) 
Safety

Adverse events (AEs) : incidence, severity, causality

Thromboembolic events 

Hypersensitivity reactions 

Development of neutralizing antibodies to VWF and FVIII 

Development of total binding antibodies to VWF and FVIII

Development of binding antibodies to Chinese hamster ovary (CHO) proteins, mouse 
immunoglobulin G (IgG) and rFurin

Clinically significant changes in vital signs and clinical laboratory parameters relative to baseline
Pharmacokinetics (PK) and Pharmacodynamics (PD)

PK parameters after a washout for on-demand subjects: incremental recovery (IR), terminal half-life 
(T1/2), mean residence time (MRT), area under the concentration versus time curve from 0 to infinity 
(AUC0-), area under the concentration versus time curve from 0 to the last measurable concentration 
(AUC0-tlast), maximum concentration (Cmax), minimum time to reach the maximum concentration 
(Tmax), volume of distribution at steady state (Vss) and clearance (CL) based on VWF:RCo, Von 
Willebrand factor antigen (VWF:Ag), Von Willebrand collagen binding activity (VWF:CB).

PD parameters after a washout for on-demand subjects: Cmax, Tmax, and AUC0-tlast as measured in 
FVIII activity by the 1-stage clotting assay (FVIII:C). 

PK parameters at steady state for on-demand and switch subjects: area under the concentration versus 
time curve from 0 to end of the partial dosing interval (AUC0- tau;ss), maximum concentration during 
the partial dosing interval (Cmax;ss), minimum time to reach the maximum concentration (Tmax;ss) and 
minimum concentration during the partial dosing interval (Cmin;ss) based on VWF:RCo, VWF:Ag and 
VWF:CB. PK parameters at steady state will be assessed shortly after reaching steady state for switch 
subjects and at the end of the study for on-demand as well as for switch subjects all based on the 
longer interval of the irregular dosing intervals employed. 
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
PD parameters at steady state for on-demand and switch subjects: AUC0-tau;ss, Cmax;ss, Tmax;ss, and Cmin;ss
as measured in FVIII actvitiy by the 1-stage clotting assay (FVIII:C). PD parameters at steady state 
will be assessed shortly after reaching steady state for switch subjects and at the end of the study for 
on-demand as well as for switch subjects all based on the longer interval of the irregular dosing 
intervals employed.

Time course of FVIII clotting activity (FVIII:C) levels.
Exploratory Outcome Measures
 
 
 
 
 
 
 
 
 
 
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INVESTIGATIONAL PRODUCT(S), DOSE AND MODE OF ADMINISTRATION
Active Product
Dosage form: powder and solvent for solution for injection
Dosage frequency:
Prophylactic Treatment
Subjects transitioning from on-demand treatment will receive twice weekly 
infusion with rVWF (vonicog alfa) at doses of 50 ± 10 IU/kg rVWF:RCo. 
Dosage may be individualized within this range based on: 

available historical PK data

type and severity of bleeding episodes the subject has experienced in the past

monitoring of appropriate clinical and laboratory measures
The starting dose can, after consultation with the Sponsor, be increased up to 
80 U/kg if considered necessary to assure effective prophylaxis.
Subjects switching from pdVWF prophylaxis treatment: the weekly dose (IU/kg) 
of rVWF (vonicog alfa) for each patient will be equivalent (± 10%) to the weekly 
VWF dose received during prophylactic treatment with pdVWF. The weekly 
dose should be divided into 2 infusions, with a maximum of 80 IU/kg/infusion. If 
needed, based on the total weekly dose or other clinical judgements, the weekly 
dose may be given as three infusions. A once weekly dose regimen will be 
allowed after switch to rVWF (vonicog alfa) if the patient has been on a once 
weekly dose regimen with pdVWF. Dose and dose interval may, after 
consultation with the sponsor, be further individualized based on: 

available historical PK data

type and severity of bleeding episodes the subject has experienced in the past

monitoring of appropriate clinical and laboratory measures
Treatment of Bleeding Episodes:
Dosage must be individualized based on the subject’s weight, type and severity 
of bleeding episode and monitoring of appropriate clinical and laboratory 
measures. In general, an initial dose of 40-60 IU/kg VWF:RCo with or without
30-45 IU rFVIII [ADVATE, octocog alfa]/kg is recommended (rVWF:rFVIII 
ratio of 1.3:1: ± 0.2). In cases of major bleeding episodes, a dose of up to 
80 IU/kg VWF:RCo may be infused. Subsequent doses, if necessary, will be 
administered with or without ADVATE (rFVIII, octocog alfa) to maintain 
VWF:RCo and FVIII levels for as long as deemed necessary by the investigator.
Mode of Administration: intravenous
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SUBJECT SELECTION
Targeted Accrual
Approximately 22 adult subjects with severe VWD will be included to have 
≥8 subjects in each cohort (OD and switch). A total of at least 5 type 3 VWD 
subjects will be followed for 12 months. 
Number of Groups/ 
Arms/ Cohorts
Single-group
Inclusion Criteria
Subjects who meet ALL of the following criteria are eligible for this study:
1. Subject has a documented diagnosis of severe VWD (baseline VWF:RCo <20 IU/dL) with a history of 
requiring substitution therapy with von Willebrand factor concentrate to control bleeding:
a. Type 1 (VWF:RCo <20 IU/dL) or,
b. Type 2A (as verified by multimer pattern), Type 2B (as diagnosed by genotype), Type 2M or,
c. Type 3 (VWF:Ag ≤3 IU/dL).
2. Diagnosis is confirmed by genetic testing and multimer analysis, documented in patient history or at 
screening.
3. For on-demand patient group, subject currently receiving on-demand treatment for whom prophylactic 
treatment is recommended by the investigator. 
4. For pdVWF switch patient group, subject has been receiving prophylactic treatment of pdVWF 
products for no less than 12 months prior to screening.
5. For on-demand patient group, subject has ≥3 documented spontaneous bleeds (not including 
menorrhagia) requiring VWF treatment during the past 12 months. 
6. Availability of records to reliably evaluate type, frequency and treatment of bleeding episodes during 
at least 12 months preceding enrollment. Up to 24 months of retrospective data should be collected if 
available. Availability of dosing and factor consumption during 12 months (up to 24 months) of
treatment prior to enrollment is required for pdVWF switch subjects and is desired (but not a 
requirement) for on-demand subjects.
7. Subject is ≥18 years old at the time of screening and has a body mass index ≥15 but <40 kg/m2.
8. If female of childbearing potential, subject presents with a negative blood/urine pregnancy test at 
screening and agrees to employ adequate birth control measures for the duration of the study.
9. Subject is willing and able to comply with the requirements of the protocol.
Exclusion Criteria
Subjects who meet ANY of the following criteria are not eligible for this study:
1. The subject has been diagnosed with Type 2N VWD, pseudo VWD, or another hereditary or acquired 
coagulation disorder other than VWD (e.g., qualitative and quantitative platelet disorders or elevated 
prothrombin time (PT)/international normalized ratio [INR] 1.4).
2. The subject is currently receiving prophylactic treatment with more than 5 infusions per week.
3. The subject is currently receiving prophylactic treatment with a weekly dose exceeding 240 IU/kg.
4. The subject has a history or presence of a VWF inhibitor at screening.
5. The subject has a history or presence of a FVIII inhibitor with a titer ≥0.4 Bethesda units (BU) 
(by Nijmegen modified Bethesda assay) or ≥0.6 BU (by Bethesda assay).
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6. The subject has a known hypersensitivity to any of the components of the study drugs, such as to 
mouse or hamster proteins.
7. The subject has a medical history of immunological disorders, excluding seasonal allergic 
rhinitis/conjunctivitis, mild asthma, food allergies or animal allergies.
8. The subject has a medical history of a thromboembolic event.
9. The subject is human immunodeficiency virus (HIV) positive with an absolute Helper T cell 
(CD4) count 200/mm3.
10. The subject has been diagnosed with significant liver disease per investigator’s medical assessment of 
the subject’s current condition or medical history or as evidenced by any of the following: serum 
alanine aminotransferase (ALT) greater than 5 times the upper limit of normal; hypoalbuminemia; 
portal vein hypertension (e.g., presence of otherwise unexplained splenomegaly, history of esophageal 
varices).
11. The subject has been diagnosed with renal disease, with a serum creatinine (CR) level ≥2.5 mg/dL.
12. The subject has a platelet count <100,000/mL at screening.
13. The subject has been treated with an immunomodulatory drug, excluding topical treatment (e.g., 
ointments, nasal sprays), within 30 days prior to signing the informed consent.
14. The subject is pregnant or lactating at the time of enrollment.
15. Patient has cervical or uterine conditions causing menorrhagia or metrorrhagia (including infection, 
dysplasia).
16. The subject has participated in another clinical study involving another investigational product (IP) or 
investigational device within 30 days prior to enrollment or is scheduled to participate in another 
clinical study involving an IP or investigational device during the course of this study.
17. The subject has a progressive fatal disease and/or life expectancy of less than 15 months.
18. The subject is scheduled for a surgical intervention.
19. The subject is identified by the investigator as being unable or unwilling to cooperate with study 
procedures.
20. The subject has a mental condition rendering him/her unable to understand the nature, scope and 
possible consequences of the study and/or evidence of an uncooperative attitude.
21. The subject is in prison or compulsory detention by regulatory and/or juridical order
22. The subject is member of the study team or in a dependent relationship with one of the study team 
members which includes close relatives (i.e., children, partner/spouse, siblings and parents) as well as 
employees.
Delay criteria
1. If the subject presents with an acute bleeding episodes or acute illness (e.g., influenza, flu-like 
syndrome, allergic rhinitis/conjunctivitis, non-seasonal asthma) the screening visit will be postponed 
until the subject has recovered.
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STATISTICAL ANALYSIS
Sample Size Calculation
Approximately 22 adult subjects with severe VWD will be included in the study. The aim is to have 
≥8 subjects in each cohort (OD and switch). A total of at least five type 3 VWD subjects will be followed 
for 12 months. The sample size is driven by practical considerations (primarily the enrollment of a rare 
patient population) and EMA Guideline on the Clinical Investigation of Human Plasma Derived von 
Willebrand Factor Products (CPMP/BPWG/220/02).1
Planned Statistical Analysis
The Full Analysis Set (FAS) will be composed of all subjects who receive prophylaxis IP treatment.
The Safety Analysis Set will be composed of all subjects who received any amount of IP  (rVWF, vonicog 
alpha).
The Per-Protocol (PP) Analysis Set will be composed of subjects who are at least 70% compliant regarding 
the number of scheduled prophylactic infusions. Only subjects who meet all study entry criteria and who 
have no major protocol violations that might impact primary efficacy assessments will be included in the 
PP analysis set.
The Pharmacokinetic Full Analysis Set (PKFAS) will be composed of all subjects who received the PK 
infusion and who provided acceptable data for PK and PD analysis. Acceptable PK/PD data will be defined 
in the Statistical Analysis Plan.
Primary Outcome Measure:
No formal statistical hypothesis test is planned for the analysis. Spontaneous ABR while treated with rVWF 
(vonicog alfa) for each cohort, on demand and switch subjects, will be estimated using a negative binomial 
regression. The prior ABR for each cohort will be based on historical data collected from each enrolled 
subject. The two ABRs (observed on the study and historical) will be assessed using a generalized linear 
mixed-effects model (GLMM) with the negative binomial distribution as a family and with a logarithmic 
link function (the default). The ABR ratio together with a two-sided, 95% confidence interval (CI) will be 
reported for each cohort.
The difference in on-study ABR relative to historical ABR will be summarized descriptively.
The primary efficacy analysis will be based on the FAS and will be summarized by the two cohorts: on-
demand and switch subjects. As a supportive analysis, the same analysis will also be carried out on the per-
PP analysis set.
Secondary Outcome Measures:
In general, data for  secondary efficacy analysis will be summarized by the two cohorts: on-demand and 
switch subjects and when applicable overall. Mean, standard deviation, median, range, quartiles will be 
calculated for continuous endpoints. Proportions will be calculated for categorical endpoints. Confidence 
intervals at the 95% level will be provided when appropriate. 
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Additional efficacy of prophylactic treatment with  rVWF (vonicog alfa):
The number  and proportion of on-demand subjects with ABR percent reduction success (i.e. ≥ 25% ) will 
be calculated together with a two-sided 95% CI for the proportion. 
The number  and proportion of pdVWF switch subjects with ABR preservation success will be reported 
together with the corresponding 95% two-sided CIs for the proportion. 
The number and proportion of subjects with categorized spontaneous ABR (i.e. 0, 1-2, 3-5, more than 
5 bleeds) will be reported descriptively.
Summary statistics for the total number of infusions, as well as average number of infusions per week will 
be provided. The total weight adjusted consumption of rVWF (vonicog alfa) during prophylactic treatment 
will be provided. If applicable, historical data on consumption of pdVWF prior to the study will be 
summarized as well.
The change in spontaneous ABR from the historical rate to that during the rVWF (vonicog alfa) 
prophylaxis period will be summarized by location of bleeding (GI, epistaxis, joint bleeding, 
menorrhagia, oral and other mucosa, muscle and soft tissue, etc.).
Pharmacokinetics (PK) and Pharmacodynamics (PD):
The following PK parameters, based on the initial PK assessment after a washout for on-demand subjects, 
will be listed and summarized descriptively for VWF:RCo, VWF:Ag and VWF:CB: IR, T1/2, MRT, 
AUC0-, AUC0-tlast, Cmax, Tmax, Vss, and CL. The corresponding pharmacodynamics (PD) of rVWF 
(vonicog alfa) as measured in FVIII activity (FVIII:C), based on the initial PK assessment after a 
washout for on-demand subjects will be assessed using Cmax, Tmax, and AUC0-tlast. These PD parameters 
will be listed and summarized descriptively. 
PK parameters at steady state (AUC0-tau;ss, Cmax;ss, Tmax;ss, and Cmin;ss) for the partial dosing interval will be 
listed for on-demand subjects at the end of the study and for switch subjects shortly after reaching steady 
state and at the end of the study for VWF:RCo, VWF:Ag and VWF:CB and summarized descriptively for 
subjects with the same dosing regimens. The corresponding pharmacodynamics (PD) of rVWF (vonicog 
alfa) as measured in FVIII activity (FVIII:C) will be assessed using AUC0-tau;ss, Cmax;ss, Tmax;ss, and Cmin;ss. 
These PD parameters will be listed for on-demand subjects at the end of the study and for switch subjects 
shortly after reaching steady state and at the end of the study and will be summarized descriptively for 
subjects with the same dosing regimens. 
For the on-demand subjects, the PK of VWF:RCo will be analyzed using a population PK approach to 
characterize the single and multiple dose pharmacokinetics, including associated variability, of VWF:RCo 
in the study population.
For the switch subjects, differences in AUC0-tau;ss, Cmax;ss, and Cmin;ss assessess shortly after reaching steady 
state and assessed at the end of the study will be assessed by ratio of geometric means and corresponding 
two-sided 95% confidence intervals for VWF:RCo, VWF:Ag, VWF:CB, and FVIII:C. The difference in 
Tmax;ss, between first and second pharmacokinetic assessment will be summarized by the median and range 
(minimum to maximum) for VWF:RCo, VWF:Ag,VWF:CB, and FVIII:C.
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Descriptive statistics will be used to summarize VWF:RCo, VWF:Ag, VWF:CB,  and FVIII:C levels for 
each nominal time point on the PK curve. For all subjects activity/concentration vs. time curves will be 
prepared.
Safety:
Safety analysis will be performed overall and by the two cohorts: on-demand and switch subjects.
Treatment-emergent AEs (TEAEs) are defined as AEs with start dates on or after the first exposure to IP. 
Summaries of AEs will be based on TEAEs unless otherwise indicated.
Occurrence of AEs and serious AEs (SAEs) will be summarized descriptively, by system organ class and 
preferred term. The number and percentage of subjects who experienced AEs and SAEs, and the number of 
AEs and SAEs will be tabulated. In addition, the number of subjects who experienced AEs assessed as 
related to IP by the investigator, and the number of IP-related AEs will be tabulated. The number of 
patients with AEs by severity will be presented similarly.
A listing of all AEs will be presented by subject identifier, age, sex, preferred term and reported term of the 
AE, duration, severity, seriousness, action taken, outcome, causality assessment by investigator, onset date, 
stop date and medication or non-drug therapy to treat the AE. 
Temporally associated AEs are defined as AEs that begin during infusion or within 24 hours (or 1 day 
where time of onset is not available) after completion of infusion, irrespective of being related or not 
related to treatment. Temporally associated AEs will be presented in summary tables.
Adverse events of special interest (AESI), such as hypersensitivity reactions and thromboembolic events,  
will be monitored throughout the study and statistical analysis will be conducted based on the search 
criteria (eg, standardized MedDRA queries [SMQ]) determined prior to database lock, and summarized.
For immunogenicity analysis frequency counts and proportions will be calculated for subjects with the 
occurrence of neutralizing (inhibitory) antibodies to VWF and FVIII, occurrence of binding antibodies to 
VWF and FVIII, and occurrence of binding antibodies to CHO proteins, mouse immunoglobulin G (IgG) 
and rFurin.
Clinically significant changes relative to baseline in vital signs and clinical laboratory parameters 
(hematology, clinical chemistry) will be reported.
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4. TABLE OF CONTENTS
1. STUDY PERSONNEL.................................................................................................. 2
1.1 Authorized Representative (Signatory) / Responsible Party .............................. 2
1.2 Study Organization................................................................................................. 2
2. SERIOUS ADVERSE EVENT REPORTING........................................................... 3
3. SYNOPSIS..................................................................................................................... 4
4. TABLE OF CONTENTS ........................................................................................... 14
5. LIST OF ABBREVIATIONS .................................................................................... 20
6. BACKGROUND INFORMATION .......................................................................... 24
6.1 Description of Investigational Product ............................................................... 24
6.2 Clinical Condition/Indication .............................................................................. 25
6.3 The Role of Prophylaxis in the Management of VWD...................................... 26
6.4 Populations to be Studied..................................................................................... 28
6.5 Findings from Nonclinical and Clinical Studies................................................. 28
6.5.1 Findings from Nonclinical Studies ............................................................... 28
6.5.1.1 Primary Pharmacodynamics ................................................................. 28
6.5.1.2 Safety Pharmacology.............................................................................. 29
6.5.1.3 Pharmacokinetics.................................................................................... 29
6.5.1.4 Toxicology................................................................................................ 29
6.5.2 Findings from Clinical Studies ..................................................................... 30
6.5.2.1 Study 070701 ........................................................................................... 31
6.5.2.2 Study 071104 ........................................................................................... 32
6.5.2.3 Study 071001 ........................................................................................... 33
6.5.2.4 Study 071101 ........................................................................................... 35
6.5.2.5 Study 071401: Single Subject with von Willebrand Disease............... 37
6.6 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) 
to Human Subjects................................................................................................ 37
6.7 Compliance Statement.......................................................................................... 38
7. STUDY PURPOSE AND OBJECTIVES ................................................................. 39
7.1 Study Purpose ....................................................................................................... 39
7.2 Primary Objective................................................................................................. 39
7.3 Secondary Objectives ........................................................................................... 39
7.4 Exploratory Objectives......................................................................................... 39
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10.2 Subject Identification Code................................................................................ 63
10.3 Screening and Study Visits................................................................................. 63
10.3.1 Screening Visit.............................................................................................. 63
10.3.2 Baseline Visit – Initial PK Assessment (On-demand Subjects Only)...... 64
10.3.3 Prophylaxis Initiation Visit......................................................................... 65
10.3.4 Initial Steady State PK-Assessment (pdVWF switch subjects only)....... 65
10.3.5 Treatment of Bleeding Episodes................................................................. 66
10.3.6 Perioperative Visits (only applicable if surgery is needed)...................... 66
10.3.7 Follow-Up Visits........................................................................................... 66
10.3.8 Unscheduled Visits....................................................................................... 68
10.3.9 End of Study PK Assessment and Study Termination Visit.................... 68
10.4 Medications and Non-Drug Therapies.............................................................. 69
10.5 Subject Diary....................................................................................................... 70
10.6 Subject Completion/Discontinuation ................................................................ 70
10.7 Procedures for Monitoring Subject Compliance ............................................. 71
11. ASSESSMENT OF EFFICACY AND PHARMACOKINETICS........................ 72
11.1 Assessment of Spontaneous Bleeding Episodes/Annualized Bleed Rate........ 72
11.2 Evaluation of ABR Before rVWF Prophylaxis and ABR Under rVWF 
Prophylactic Treatment........................................................................................ 73
11.3 Number of Infusions and Total Weight Adjusted Consumption of rVWF and 
ADVATE and historical prophylaxis dosing and factor consumption during 
pdVWF prophylaxis treatment prior to enrollment.......................................... 73
11.4 Assessment of Efficacy for Treatment of Bleeding Episode ........................... 73
11.5 Assessment of Efficacy for Treatment for Surgical Bleeding......................... 74
11.6 rVWF Pharmacokinetics and Pharmacodynamics ......................................... 75
12. ASSESSMENT OF SAFETY................................................................................... 77
12.1 Adverse Events.................................................................................................... 77
12.1.1 Definitions..................................................................................................... 77
12.1.1.1 Serious Adverse Event.......................................................................... 77
12.1.1.2 Suspected Unexpected Serious Adverse Reaction (SUSAR)............. 78
12.1.1.3 Non-Serious Adverse Event ................................................................. 78
12.1.1.4 Unexpected Adverse Events................................................................. 79
12.1.1.5 Preexisting Disease................................................................................ 79
12.1.2 Assessment of Adverse Events.................................................................... 79
12.1.2.1 Severity .................................................................................................. 81
12.1.2.2 Causality................................................................................................ 81
12.1.2.3 Safety Reporting ................................................................................... 82
12.2 Urgent Safety Measures ..................................................................................... 84
12.3 Untoward Medical Occurrences........................................................................ 85
12.4 Non-Medical Complaints ................................................................................... 85
12.5 Medical, Medication, and Non-Drug Therapy History................................... 85
12.6 Physical Examinations........................................................................................ 86
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19. PUBLICATION POLICY...................................................................................... 112
20. SUPPLEMENTS..................................................................................................... 113
20.1 Study Flow Chart.............................................................................................. 113
20.2 Schedule of Study Procedures and Assessments............................................ 114
20.2.1 Summary Schedule of Visit Assesments for Surgical Bleeding............. 118
20.3 Clinical Laboratory Assessments .................................................................... 120
20.3.1 Laboratory Sampling for Surgical Bleeding ........................................... 124
20.4 Contraceptive Methods for Female Subjects of Childbearing Potential..... 126
21. REFERENCES........................................................................................................ 127
22. SUMMARY OF CHANGES.................................................................................. 130
INVESTIGATOR ACKNOWLEDGEMENT............................................................ 133
Tables
Table 1 rVWF (vonicog alfa) Dosing Schedule Examples: Schedules A and B............. 48
Table 2 Criteria for Escalation Specific to Each Bleeding Indication............................. 50
Table 3 rVWF:RCo Dosing Recommendations for the Treatment of Bleeding Episodes 
Due to VWD ............................................................................................................. 54
Table 4 Efficacy Rating Scale.......................................................................................... 74
Table 5 Assessment of Hemostatic Efficacy ................................................................... 75
Table 6a Schedule of Study Procedures and Assessments for On-demand Subject...... 114
Table 7 Summary Schedule of Visit Assesments for Surgical Bleeding....................... 118
Table 8a Clinical Laboratory Assessments for On-demand Subject ............................. 120
Table 9 Laboratory Samplinga for Surgical Bleeding ................................................... 124
Figures
Figure 1 Study Design for Baxalta Clinical Study 071301............................................ 113
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5. LIST OF ABBREVIATIONS
Abbreviation
Definition
ABR
Annualized bleeding rate 
ADAMTS13
A Disintegrin And Metalloproteinase with a Thrombospondin type 1 motif, number 13
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine aminotransferase
AP
Alkaline phosphatase
AST
Aspartate aminotransferase
AUC0-∞
Area under the plasma concentration /time curve from time 0 to infinity
AUC0-tau;ss
Area under the plasma concentration /time curve from time 0 to end of the partial 
dosing interval
AUC0-tlast
Area under the plasma concentration /time curve from 0 to the last measurable 
concentration
aPTT
Activated partial thromboplastin time
B19V
Parvovirus B19
BP
Blood pressure
BU
Bethesda Unit
BUN
Blood urea nitrogen
BW
Body weight
CAM
Cell adhesion molecule
CBC
Complete blood count
CD4
Helper T cell
CHO
Chinese hamster ovary
CI
Confidence interval
Cl
Chloride
CL
Clearance
Cmax
Maximum plasma concentration
Cmax;ss
Maximum plasma concentration during the partial dosing interval at steady state
Cmin;ss
Minimum plasma concentration during the partial dosing interval at steady state
CR
Creatinine
CTA
Clinical Trial Agreement
eCRF
Electronic case report form
DMC
Data monitoring committee
DIC
Disseminated intravascular coagulation
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Abbreviation
Definition
DVT
Deep vein thrombosis
EC
Ethics committee
ECG
Electrocardiogram 
EDC
Electronic Data Capture
EDTA
Ethylenediaminetetraacetic acid
ELISA
Enzyme-linked immunosorbent assay
FAS
Full analysis set
FVIII
Factor VIII
FVIII:C
Factor VIII clotting activity
GCP
Good Clinical Practice
GI
Gastrointestinal
Glu
Glucose
HAMA
Human anti- mouse antibodies
HAV
Hepatitis A virus
HB
Hepatitis B
HBs
Hepatitis B surface
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HEV
Hepatitis E virus
HIV
Human immunodeficiency virus 
HLA
Human leukocyte antigen
HRP
Horseradish peroxidase
IB
Investigator's brochure
ICH
International Council for Harmonisation
Ig
Immunoglobulin
INN
International Nonproprietary Name
INR
International normalized ratio
IP
Investigational product
IR
Incremental recovery
i.v.
Intravenous
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Abbreviation
Definition
K
Potassium
k.o.
Knock out
LDH
Lactate Dehydrogenase
Na
Sodium
NMC
Non-medical complaint
NOAEL
No observed adverse effect level
MRI
Magnetic resonance imaging
MRT
Mean residence time
pdVWF
Plasma derived VWF product
pdVWF/FVIII
Plasma derived VWF product containing fractions of FVIII
PBAC
Pictorial Blood Assessment Chart
PCR
Polymerase Chain Reaction
PEF
Peak expiratory flow
PK
Pharmacokinetic
PKFAS
Pharmacokinetic Full Analysis Set
PKPPAS
Pharmacokinetic Per Protocol Analysis Set
PP
Per protocol 
PT
Prothrombin time
Q1, Q3
Quartile
rFVIII
Recombinant factor VIII
rVWF
Recombinant von Willebrand factor
RBC
Red blood cell count
SAE
Serious adverse event
SAER
Serious adverse event report
SDS-PAGE
Sodium dodecyl sulfate polyacrylamide gel electrophoresis
SIC
Subject identification code
SMQ
Standardised MedDRA queries 
sP-selectin
Soluble P-selectin
SUSAR
Suspected unexpected serious adverse reaction
T1/2
Terminal phase half life
TEAE
Treatment-emergent adverse event
TIA
Transient ischemic attack
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Abbreviation
Definition
Tmax
Minimum time to reach the maximum concentration
Tmax;ss
Minimum time to reach the maximum concentration at steady state
TTP
Thrombotic thrombocytopenic purpura
ULMW
Ultra-large molecular weight 
ULN
Upper limit of normal
Vss
Volume of distribution at steady state
VTE
Venous thromboembolism 
VWD
von Willebrand disease
VWF
Von Willebrand factor
VWF:Ag
Von Willebrand factor antigen
VWF:CB
Von Willebrand Factor collagen binding
VWF:RCo
Von Willebrand factor: Ristocetin cofactor activity
WBC
White blood cell
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6. BACKGROUND INFORMATION
6.1 Description of Investigational Product
Baxalta US Inc. (hereafter referred to as Baxalta or sponsor) has developed a human 
recombinant von Willebrand Factor (rVWF, vonicog alpha), which is co-expressed with 
recombinant factor VIII (rFVIII) in a Chinese hamster ovary (CHO) cell line and 
separated during the subsequent downstream process. To address concerns regarding the 
risk of transmission of blood-borne pathogens that may be introduced by human plasma, 
no exogenously added raw materials of human or animal origin are employed in the cell 
culture, purification, or formulation of the final container product. The only proteins 
present in the final container product other than rVWF (vonicog alfa) are trace quantities 
of murine immunoglobulin (IgG, from the immunoaffinity purification), host cell (i.e., 
CHO) protein, rFurin (used to further process rVWF). rVWF (vonicog alfa) is intended 
for the treatment of von Willebrand disease (VWD).
rVWF (vonicog alfa) has been developed under the Baxalta internal code BAX111 and is 
used as investigational product (IP) in this study. rVWF (vonicog alfa) may be used with 
or without ADVATE (rFVIII, octocog alfa) for the treatment of bleeding episodes (see 
Section 8.6.4.4). See Section 8.6 for further information on the IPs and their usage in this 
study. A detailed description of rVWF (vonicog alfa) is also provided in the 
Investigator’s Brochure (IB).
rVWF (vonicog alfa) was granted licensure in the United States in December 2015 under 
the brand name VONVENDI for the on-demand treatment and control of bleeding 
episodes in adults diagnosed with VWD and it has been available on the market in the US 
since 09 August 2016. In April 2018, VONVENDI was also granted licensure in the US 
by the FDA for an additional indication of perioperative management of bleeding in 
adults (age 18 and older) diagnosed with VWD. On 31st of August 2018, European 
Commission implemented the decision for granting marketing authorization for 
VEYVONDI (vonicog alfa) for the treatment of haemorrhage and surgical bleeding and 
for the prevention of surgical bleeding in adults (age 18 and older) diagnosed with VWD, 
when desmopressin (DDAVP) treatment alone is ineffective or not indicated.
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6.2 Clinical Condition/Indication
Von Willebrand Factor (VWF) is a large multimeric glycoprotein with a molecular 
weight that varies from 500 to 20,000 kDa. VWF is normally found in plasma and
produced in the alpha-granules of platelets and in endothelial cell organelles known as the 
Weibel-Palade bodies. VWF mediates platelet adhesion and aggregation at sites of 
vascular injury, one of the key functions in primary hemostasis. VWF also serves to 
stabilize coagulation factor VIII (FVIII), where FVIII is an essential cofactor of 
secondary hemostasis, which leads to fibrin clot formation.2 Qualitative and/or 
quantitative deficiencies of VWF lead to a highly variable bleeding diathesis known as 
VWD, the most common of the hereditary coagulation factor deficiencies. Penetrance of 
VWD is highly variable, with only a small fraction of mildly affected patients displaying 
clinical symptoms or a family history of a bleeding diathesis.
The current biochemical-based classification distinguishes disorders arising from partial 
quantitative (type 1), qualitative (type 2), or virtually complete (type 3) deficiencies of 
VWF. Up to 70% of VWD patients are diagnosed with type 1 VWD, which may also be 
associated with minor functional defects in the molecule. In general, patients with type 1 
VWD display mild clinical symptoms. Approximately 20 to 30% of VWD patients are 
diagnosed with type 2 VWD. Type 2 VWD is further divided into 4 subtypes (A, B, N, 
and M), reflecting distinct classes of functional abnormalities. These defects result in 
abnormal functional and/or multimeric distribution patterns that facilitate their diagnosis. 
The bleeding diathesis is usually moderate and primarily affects the mucosal tissues. 
Type 2N VWD patients are sometimes misdiagnosed as mild hemophilia A. Finally, 
approximately 1% percent of VWD patients exhibit a total or near total absence of VWF, 
which is classified as type 3 VWD. The incidence of type 3 VWD is estimated at 
0.5-1.0 x 106. This type is also associated with a very low FVIII level (typically <5%) 
because the VWF carrier function for FVIII is lost. Replacement of VWF alone stabilizes 
endogenous FVIII, resulting in hemostatic levels within several hours post-infusion. 
Published results from studies of a plasma-derived VWF (pdVWF) concentrate 
demonstrated an increase of FVIII at an approximate rate of 5.8 1 IU dL-1 h-1.3 Type 3 
VWD patients display severe hemorrhagic symptoms with bleeding predominantly in 
mucosal tissues, muscle and joints. All VWD patients, particularly those with type 2 or 
type 3 VWD, are at an increased risk for life-threatening bleeding episodes.
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6.3 The Role of Prophylaxis in the Management of VWD
The goals of long term prophylaxis in VWD are to maintain VWF and FVIII at sufficient 
levels to reduce the frequency and duration of bleeding episodes, the need for red blood 
cell transfusions, and the risk of complications, such as arthropathy.4 In contrast to 
hemophilia, routine prophylaxis is not as established in VWD, although prophylaxis for 
patients with severe VWD was in use in Sweden already during the 1950s.5 In those early 
days of VWD treatment, plasma FVIII concentrates containing VWF fractions were 
applied for replacement therapy, which then were followed by plasma derived VWF 
products containing fractions of FVIII (pdVWF/FVIII). 
A Swedish cohort including 37 patients with type 3 VWD under prophylactic median 
treatment of 11 years (range 2 to 45 years) was retrospectively analyzed.6,7 The 
doses used for prophylaxis, given once weekly for at least 45 weeks per year, were 
calculated based on 12 to 50 IU/kg body weight (BW) of FVIII clotting activity (FVIII:C)
which approximately corresponded to 24-100 IU/kg von Willebrand factor: Ristocetin 
cofactor activity (VWF:RCo) considering that mainly Haemate with a known 
VWF:RCo/FVIII:C ratio of about 2 was used. An escalation of doses from 1 to 3 dose 
levels was allowed depending on the frequency and severity of bleeding episodes. 
The results demonstrate that under long-term prophylaxis the number of bleeds could be 
reduced dramatically. Whereas the median value for bleeds per year was about 10 before 
prophylaxis this value could be reduced to less than 1 bleed per year during prophylaxis.
The benefit of prophylaxis for such indications was retrospectively also demonstrated in a 
cohort of Italian patients including type 3, 2A, 2M and type 1 patients. Prophylaxis was 
started after severe gastrointestinal or joint bleeding episodes and completely prevented 
bleeding episodes in 8 of these 11 patients and largely reduced the need of blood 
transfusions in the remaining 3. A regimen of 40 IU rVWF:RCo/kg was applied every 
other day or twice a week. A prospective study on prophylaxis, the PRO.WILL study, has 
been initiated in Italy.8
The results of a prospective study investigating the prophylaxis in children and young 
adults showed a significantly reduced bleeding frequency and bleeding score (3 vs. 0.07; 
3 vs. 0. p<0.001) compared to the pre-prophylaxis values. The median dose was 
40 (20-47) IU/kg VWF:RCo administered mainly twice weekly in 23 patients, 3 times a 
week in 7 patients and 4 times a week in 2 children.9
The VWD Prophylaxis Network initiated the VWD International Prophylaxis (VIP) 
trial to investigate the role of prophylaxis in patients with severe VWD including 
Type 1, 2, and 3. The dose of the factor replacement product was 50 IU /kgVWF:RCo. 
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The frequency of the dose depended on the type of bleeding and could be increased from 
once weekly to twice weekly or 3 times per week. For the treatment of menorrhagia the 
dose of 50 IU/kg VWF:RCo was given on the first day of menses for 2 cycles. The 
frequency could be increased to Day 1 and 2 for 2 cycles or to Day 1, 2, and 3 of menses.
The study contains both retrospective and prospective study components. Results from
the retrospective study component were published, including 61 subjects on prophylactic 
regimen in the past 6 months prior to enrollment or subjects with a history of prophylaxis 
over at least 6 month.10 Differences in annualized bleeding rates (ABR) within 
individuals (during prophylaxis – before prophylaxis) were significant for those with 
primary indications of epistaxis (P = 0.0005), joint bleeding (P = 0.002) and GI bleeding 
(P = 0.001). The difference in the group whose primary indication for treatment was 
abnormally heavy bleeding at menstruation (n = 4) was not significant (P = 0.25). The 
reduction of mucosal bleeding likely not only dependents on normal circulating levels of 
active VWF, but also on the presence of discrete concentrations of normal VWF inside 
the platelets and within endothelial matrices. The low subject number (n=4) and the 
treatment scheme for menorrhagia on Days 1, 2, and 3 of menses which might represent 
rather on-demand than prophylactic treatment may also account for the outcome in this 
study.
Results from the prospective study component were reported recently.11 Eleven subjects 
completed the study. Six subjects had type 2A, and 5 subjects had type 3 VWD. 
Six subjects presented with epistaxis, 3 with GI bleeding, and 2 with joint bleeding. 
Seven subjects had dose escalation above the first level. Among the 10 subjects with 
evaluable bleeding log data, the use of prophylaxis decreased the median ABR from 25 to 
6.1 (95% confidence interval [CI] of the rate difference: -51.6 to -1.7), and the median 
ABR was even lower (4.0; 95% CI: -57.5 to -5.3) when the subjects reached their final 
dosing level. The authors concluded that this was the first prospective study to 
demonstrate that prophylaxis with VWF concentrates is highly effective in reducing 
mucosal and joint bleeding rates in clinically severe VWD.
The results of the VIP study and previous investigations suggest that VWD patients with 
recurrent bleeding episodes and severe menorrhagia will benefit from a prophylactic 
VWF replacement therapy. There is evidence that up to 40% of patients with type 3 
VWD experience joint bleeding which can lead to hemophilic arthropathy. Other 
potential indications for prophylaxis include patients with type 2A or 2B VWD with 
recurrent gastrointestinal bleeding, menorrhagia or frequent epistaxis.4 Long-term 
prophylaxis for most patients with type 3 VWD and in some patients with type 1 or 
2 VWD, depending on the pattern of bleeding, may be the treatment option of choice.
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Although the main experience with long-term prophylaxis is with secondary prophylaxis, 
primary prophylaxis starting at young age is recommended to prevent arthropathy in 
patients with severe VWD.12
However, further studies are needed to develop evidence-based guidelines for 
prophylactic treatment in VWD.
6.4 Populations to be Studied
A total of approximately 22 eligible, adult subjects with severe VWD (baseline 
VWF:RCo <20 IU/dL) are planned to be enrolled. Two cohorts of patients will be 
included: patients currently receiving on-demand VWF treatment (OD subjects) and 
patients currently on prophylactic treatment with pdVWF (pdVWF switch subjects), and 
the aim is to have ≥8 subjects in each of the 2 cohorts, with a total of at least 5 type 3 
VWD subjects followed for 12 months. Enrolled subjects (i.e., subjects who have signed 
the informed consent form) will be eligible to participate in the study if they meet all of 
the inclusion criteria (see Section 9.1) and none of the exclusion criteria (see Section 9.2).
6.5 Findings from Nonclinical and Clinical Studies
The following summarizes the key findings from relevant nonclinical studies as well as 
from the completed clinical studies 070701 (Phase 1 pharmacokinetics [PK] and safety in 
VWD), 071001 (Phase 3 safety and efficacy in the treatment of bleeding episodes in 
VWD), 071101 (Phase 3 efficacy and safety in VWD subjects undergo elective surgical 
procedures), 071104 (Phase 1 safety and PK in hemophilia A), and 071401 (Phase 3, 
expanded access in a single subject with VWD). Potential risks and efficacy of rVWF 
(vonicog alfa):ADVATE (rFVIII, octocog alfa) are summarized in the following sections. 
For additional information on nonclinical and clinical Phase 1 results refer to the rVWF 
(vonicog alfa) IB.
6.5.1 Findings from Nonclinical Studies
6.5.1.1 Primary Pharmacodynamics
Efficacy of rVWF (vonicog alfa) combined with ADVATE (rFVIII, octocog alfa) was 
shown in VWD animal models, which have also low endogenous FVIII levels. Time to 
occlusion and stable thrombus formation was assessed in the carotid occlusion model in 
VWD mice. The results demonstrated that rVWF (vonicog alfa) in combination with 
ADVATE (rFVIII, octocog alfa) acted efficiently in a dose-dependent manner and had 
higher efficacy than rVWF (vonicog alfa) alone or plasma derived (pd)VWF. These 
results were confirmed in an additional study assessing blood loss and survival in a tail 
tip bleeding model in VWD mice. In a VWD dog, rVWF (vonicog alfa) stabilized canine 
FVIII in the circulation and significantly reduced the bleeding time.
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6.5.1.2 Safety Pharmacology
The anaphylactoid and thrombogenic potential of the co-infusion of ADVATE (rFVIII, 
octocog alfa) and rVWF (vonicog alfa) and the co-infused product’s effects on blood 
pressure, cardiac and respiratory function and parameters of coagulation activation were 
investigated in 4 in vivo studies in different animal models. Safety pharmacology studies 
in rats, guinea pigs, rabbits, and dogs revealed no risks for anaphylactoid and 
thrombogenic potential of ADVATE (rFVIII, octocog alfa) in combination with rVWF 
(vonicog alfa). All observations in safety pharmacology studies are considered to lie 
within the biological variability of animal models or occurred due to known species-
specific anaphylactoid effects of excipients.
6.5.1.3 Pharmacokinetics
Pharmacokinetic studies of both rVWF (vonicog alfa) alone and combined with human 
rFVIII (rVWF+ADVATE) were conducted in VWD mice, VWD dogs, VWD pigs, rats,
and cynomolgus monkeys. Human rVWF (vonicog alfa) stabilized the endogenous FVIII 
in VWD mice, VWD pigs, and VWD dogs. Furthermore, the hypotheses that the area 
under the curve (AUC) with rVWF alone and rVWF+ADVATE is not inferior to the 
AUC with pdVWF (Haemate P) was tested and confirmed statistically in normal rats.
The PK characteristics of ADVATE (rFVIII, octocog alfa) were not affected by co-
administration of rVWF (vonicog alfa) in cynomolgus monkeys. The PK data in the 
FVIII knock out (k.o.) mice model are inconclusive and might not be relevant for the 
clinical situation. However, a stabilizing effect of VWF on FVIII could be shown in a 
double k.o. model in a dose dependent manner.
6.5.1.4 Toxicology
Single dose toxicity studies were conducted in C57BL/6J-mice, VWD mice, rats, rabbits, 
and cynomolgus monkeys. Rats, rabbits, and cynomolgus monkeys showed no signs of 
toxicity. Signs of microthrombosis, an exaggerated pharmacological effect, were 
observed in mice. Mice are not capable of sufficiently cleaving the rVWF (vonicog alfa) 
subunit as murine disintegrin and metalloproteinase with a thrombospondin type 1 motif, 
number 13 (ADAMTS13) does not decrease the ultra-large molecular weight multimers 
of rVWF (vonicog alfa).13 The observed symptoms of microthrombosis are interpreted as 
a species-specific exaggerated pharmacological effect. Studies evaluating the safety of 
repeated administration of rVWF (vonicog alfa) with or without ADVATE (rFVIII, 
octocog alfa) (daily over 14 days) were performed in a rodent (rat) and non-rodent 
(cynomolgus monkey) species. Reversible signs of exaggerated pharmacological effects 
(regenerative anemia, thrombocytopenia, and treatment-related histopathologic changes 
in the heart, liver, and spleen) were observed in rats that were administered 1400 U 
VWF:RCo/kg /day + 1080 IU ADVATE/kg/day intravenously once daily for 14 days. 
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Also, these findings are interpreted as a species-specific exaggerated pharmacological 
effect due to the low susceptibility of human rVWF (vonicog alfa) to cleavage by rodent 
ADAMTS13.13 No toxicologically relevant changes were evident for clinical 
observations, body weight, feed consumption, ophthalmology, urinalysis, coagulation,
and serum chemistry parameters, platelet aggregation, and gross pathology. rVWF 
(vonicog alfa) combined with ADVATE (rFVIII, octocog alfa) was well tolerated in 
cynomolgus monkeys after daily intravenous (i.v.) (bolus) administration of 100 U 
VWF:RCo/kg rVWF (vonicog alfa) combined with 77 IU/kg ADVATE (rFVIII, octocog 
alfa) over a period of 14 days. No adverse effects could be detected in this species. 
There were no signs of hemolysis, thrombosis, or thrombocytopenia after repeated 
intravenous application of rVWF (vonicog alfa) with or without ADVATE (rFVIII, 
octocog alfa). Therefore, 100 U VWF:RCo/kg/day rVWF (vonicog alfa) with or without 
77 IU/kg ADVATE (rFVIII, octocog alfa) was considered the no observed adverse effect 
level (NOAEL) in this study, which was the highest dose tested. Anti-drug antibodies, 
however, were formed in both species and resulted in a significant reduction in drug 
exposure after 14 applications as compared to a single application. These antibodies 
substantially reduced the systemic exposure to the test substance as compared to a single 
dose administration. No adverse effects due to antibody formation were observed in both 
species.
rVWF (vonicog alfa) combined with ADVATE (rFVIII, octocog alfa) was well tolerated 
locally and no genotoxic potential was evident after 2 in vitro and 1 in vivo genotoxicity 
study. A study on the influence of co-administration of VWF and ADVATE (rFVIII, 
octocog alfa) on the immunogenicity of ADVATE (rFVIII, octocog alfa) in 3 different 
hemophilic mouse models (E17 hemophilic Balb/c mice, E17 hemophilic C57BL/6J 
mice, and E17 hemophilic human F8 transgenic mice) showed that rVWF (vonicog alfa) 
does not negatively impact the immunogenicity of ADVATE (rFVIII, octocog alfa) in 
any of the three different hemophilic mouse models.
6.5.2 Findings from Clinical Studies
The clinical safety, efficacy and PK were assessed in 4 completed trials: one phase 1 
study (070701)) and two phase 3 studies (071001 and 071101) that enrolled patients with 
VWD; one phase 1 study (071104) that enrolled patients with hemophilia A. Details on 
study design, populations enrolled, and safety and efficacy outcomes of the phase 1 
studies are presented in Section 6.5.2.1 and Section 6.5.2.2, the phase 3 study in 
Section 6.5.2.3, and the phase 3 surgery study in Section 6.5.2.4. Information on a single 
subject with VWD in Study 071401 is presented in Section 6.5.2.5.
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6.5.2.1 Study 070701
Phase 1 clinical study 070701 was a multicenter, controlled, randomized, single-blind,
prospective 3-step, dose escalation study to investigate safety, tolerability, and PK of 
rVWF (vonicog alfa) combined at a fixed ratio with ADVATE (VWF:RCo/FVIII:C of 
1.3 ± 0.2:1) in adults with severe VWD.14 Subjects were enrolled in sequential cohorts in 
a dose escalating manner: Cohort 1, 2, and 3 received a single intravenous infusion of 
rVWF:ADVATE at the following doses: 2 IU/kg VWF:RCo (Cohort 1), 7.5 IU/kg 
VWF:RCo (Cohort 2), and 20 IU/kg VWF:RCo (Cohort 3). Subjects in Cohort 4 received 
a single intravenous infusion of rVWF:ADVATE and pdVWF/ADVATE at 50 IU/kg 
VWF:RCo in random order.
The primary endpoint was the tolerability and safety after single dose injections of 
rVWF:ADVATE at 2, 7.5, 20, and 50 IU/kg VWF:RCo for up to 30 days after the last IP 
infusion. The data generated in this phase 1 study suggest that rVWF:ADVATE up to the 
highest investigated dose of 50 IU/kg VWF:RCo is well tolerated and safe in adults with 
severe VWD. No thrombogenic risk or thrombotic thrombocytopenic purpura (TTP)-like 
syndrome was observed, and no neutralizing antibodies to VWF or FVIII were identified. 
There were no deaths or other serious adverse reactions, and no infusions were 
interrupted or stopped due to an AE. Overall, the reported AE profile was similar 
between the recombinant and plasma-derived concentrates.
Secondary endpoints were the PK assessment of VWF:RCo, von Willebrand factor 
antigen (VWF:Ag) and multimeric composition of rVWF (vonicog alfa) as well as 
FVIII:C at standardized time points after single injections of rVWF:ADVATE and 
pdVWF:FVIII. 
The median VWF:RCo terminal half-life (T1/2) of rVWF (vonicog alfa) at the 50 IU/kg 
dose was 16 hours. T1/2 with pdVWF:FVIII at the same dose level appeared shorter at 
12.58 hours, however, the limits of the 90% CI were similar (11.73 to 17.7 hours vs. 
11.87 to 18.03 hours). The median T1/2 of VWF:RCo were shorter with the lower 
investigated doses: 7.13 hours and 13.23 hours with the 7.5 IU/kg and 20 IU/kg doses, 
although these data were derived from a much smaller number of subjects.
In consequence of the missing ADAMTS13 cleavage, ultra-large molecular weight 
(ULMW) multimers are contained in the rVWF (vonicog alfa) final product. The 
immediate cleavage of these ultra-large multimers by ADAMTS13 upon release into the 
circulation could be demonstrated applying sodium dodecyl sulfate polyacrylamide gel 
electrophoresis (SDS-PAGE)/Immunoblot with polyclonal anti-VWF antibodies to detect 
the resulting rVWF (vonicog alfa) subunit cleavage fragments.
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Overall the data generated in this phase 1 study suggest that rVWF (vonicog 
alfa):ADVATE (rFVIII, octocog alfa) is well tolerated and safe in adults with severe 
VWD.
6.5.2.2 Study 071104
This study was a prospective, uncontrolled, non-randomized, multicenter proof of 
concept study to assess safety and PK of the addition of rVWF (vonicog alfa) to 
ADVATE (rFVIII, octocog alfa) treatment in 12 evaluable subjects with severe 
hemophilia A. All subjects underwent 3 PK analyses: the first after infusion with 
ADVATE (rFVIII, octocog alfa) alone, the second after infusion with ADVATE (rFVIII, 
octocog alfa) plus 10 IU/kg rVWF (vonicog alfa) and the third after infusion with 
ADVATE (rFVIII, octocog alfa) plus 50 IU/kg rVWF (vonicog alfa).
The PK analysis was performed at intervals of approximately 8 to 14 days. Before each 
infusion for PK assessment, there was a wash-out period of at least 5 days and the 
subjects were not actively bleeding. 
Primary outcome measures indicate that co-administration of rVWF (vonicog alfa) 
slightly sustain ADVATE activity with the highest observed ADVATE (rFVIII, octocog 
alfa) half-life of 13.74 h (CI 11.44 to 16.52) after co-infusion of 50 IU/kg ADVATE plus 
50 IU/kg rVWF:RCo.
The highest improvement in ADVATE (rFVIII, octocog alfa) circulating half-life was 
observed in subjects with VWF:Ag levels below 100% which indicates an association 
between baseline VWF:Ag levels and ADVATE (rFVIII, octocog alfa) half-life increase.
No treatment related AEs or SAEs were reported. No subject withdrew due to an AE and 
there were no deaths. No binding antibodies to VWF, CHO, and rFurin were detectable in 
the confirmatory assay and no signs of a hypersensitivity to rVWF (vonicog alfa) or 
ADVATE (rFVIII, octocog alfa) antigen were observed. Laboratory values over time did 
not indicate any potential safety risk for hemophilia A patients treated with rVWF 
(vonicog alfa) and ADVATE (rFVIII, octocog alfa) in combination.
In summary, the data indicate that rVWF (vonicog alfa) co-administered with ADVATE 
(rFVIII, octocog alfa) up to the highest dose of 50 IU/kg VWF:RCo is well tolerated and 
safe in hemophilia A patients. 
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6.5.2.3 Study 071001
This was a phase 3, multicenter, open-label, part-randomized clinical study to assess the 
PK, safety, and efficacy of rVWF:rFVIII and rVWF in the treatment of bleeding episodes 
in adult subjects with severe type 3 and severe non-type 3 VWD.15 A total of 49 subjects 
were enrolled (signed informed consent) and screened, 18 subjects were randomized 
(randomization only applies to Arm 1[PK50 with treatment of BE] and Arm 2 [PK50
only] see below), 37 subjects were treated with IP (all study arms), and 30 subjects 
completed the study.
The study consisted of 2 parts (Part A and Part B). Part A consisted of PK assessments 
alone (Arm 2: PK50 only [without treatment of bleeding episodes]), or PK assessments 
(Arm 1: PK50 and Arm 3: PK80) plus on-demand treatment period(s) of 6 months for 
bleeding episodes, or on-demand treatment for bleeding episodes only (Arm 4). Except 
for subjects in arm 2 who completed study after second PK assessment, subjects  
receiving treatment for PK assessments and/or bleeding episodes in Part A were to be 
entered into Part B to continue on-demand treatment for bleeding episodes for 
6 additional months for a total of 12 months in the study. 
The primary outcome measure was the number of subjects with “treatment success” 
(extent of control of bleeding episodes), which was defined as a mean efficacy rating 
score of <2.5 for a subject’s IP-treated bleeding episodes during the study. The rate of 
subjects with treatment success was 100% (Clopper-Pearson exact 90% CI: 84.7 to 
100.0) for bleeds where the assessments were made prospectively and excluding GI 
bleeds. Sensitivity analyses confirmed the results of the primary analysis.
Crossover results at 50 IU/kg VWF:RCo showed that the PK profile for rVWF (vonicog 
alfa) VWF:RCo was independent of administration alone or with rFVIII (ADVATE, 
octocog alpha) (T1/2: 19.4 hours for rVWF and 16.6 hours for rVWF:rFVIII; IR: 1.8 U/dL 
per IU/kg infused for both rVWF and rVWF:rFVIII; mean residence time (MRT): 
26.7 hours for rVWF and 25.2 hours for rVWF:rFVIII). FVIII levels increased 
substantially with a median peak at 24 hours of 111.0 U/dL for rVWF:rFVIII and 
86.0 U/dL after rVWF alone, indicating that rVWF (vonicog alfa) induces a sustained 
increase in endogenous FVIII activity. The rVWF (vonicog alfa) PK profile was 
comparable at 50 IU/kg and 80 IU/kg VWF:RCo, and repeated PK at 80 IU/kg 
VWF:RCo showed close agreement between pretreatment and end-of-study results.
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Further analysis of the PK data from the 071001 study supports the initial use of 50 IU/kg 
twice weekly for prophylaxis dosing in the present study for those subjects who are 
moving from on-demand to prophylaxis. Using 50 IU/kg for PK measurements, subjects 
in the 071001 study exhibiting a T1/2 for rVWF of 14, 16, or 19 hours had rVWF plasma 
concentrations at 72 hours after administration of 2.55, 4.01, and 6.49% above baseline, 
respectively, and plasma concentrations at 96 hours after administration of 0.78, 1.40, and 
2.71% above baseline, respectively. In this context it should be noted that subjects in the 
present study who have significant spontaneous bleeding while on twice weekly
prophylaxis will have their regimen increased to 3 times per week based on clear criteria 
for different bleeding locations (for details see Section 8.6.4.3.1). Subjects in the present 
study who are switching from prophylaxis with a pdVWF product will begin on rVWF 
(vonicog alfa) using their same weekly total dose in IU/kg VWF:RCo used during their 
pdVWF prophylaxis divided into twice weekly infusions (for details see section 8.6.4.3).
A total of 125 AEs occurred in 25/37 (67.7%) subjects (62/318 infusions [19.5%]) during 
or after infusion with IP. Of these, 116/125 were non-serious (all mild or moderate; none 
were severe), and 9 SAEs were reported in 7 subjects. Of 125 total AEs, 38 were 
temporally associated with IP; 8 AEs were considered causally related to IP: 
6 non-serious related AEs (tachycardia, infusion site paraesthesia, electrocardiogram 
[ECG] t-wave inversion, dysgeusia, generalized pruritis, and hot flush) occurred in 
4 subjects, and 2 related SAEs (chest discomfort and increased heart rate) occurred in 
1 subject. No deaths occurred during this study. 
None of the subjects developed anti-VWF or anti-FVIII neutralizing antibodies and no 
binding antibodies to VWF or rFurin, or antibodies against CHO protein or anti-Murine 
IgG were observed. No clinical or subclinical signs or symptoms of a thrombogenic event 
were observed in this study. Following an initial increase in ultralarge VWF multimers 
after administration of rVWF (vonicog alfa), a notable decrease in the proportion of large 
VWF multimers occurred between 12 and 24 hours post infusion, due to degradation by 
the endogenous ADAMTS13 followed by a continued decline until the end of the 96-hour 
follow-up period. 
Overall, the data support the safe and effective use of rVWF (vonicog alfa) with or 
without rFVIII (ADVATE, octocog alpha) in the treatment of bleeds in patients with 
VWD.
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6.5.2.4 Study 071101
This was a phase 3, prospective, open-label, multicenter clinical study to evaluate 
efficacy and safety of rVWF (vonicog alfa) with or without ADVATE (rFVIII, octocog 
alfa) in elective surgical procedures in adult subjects with severe VWD. A total of 
24 subjects were enrolled (signed informed consent) and screened, 15 subjects were
treated with rVWF (vonicog alfa), and 15 subjects completed the study. 
Eleven subjects underwent a PK assessment by infusion of 50 ± 5 IU/kg rVWF:RCo at an 
infusion rate of up to 4 mL/min. 12 to 24 hours before surgery, subjects received a dose 
of 40 to 60 IU/kg rVWF:RCo. Within 3 hours prior to surgery, the subject’s FVIII:C 
levels were assessed with a target of 30 IU/dL for minor and oral surgeries and 60 IU/dL 
for major surgeries. Within 1 hour prior to surgery, subjects received a dose of rVWF 
(vonicog alfa) with or without ADVATE (rFVIII, octocog alfa) (depending on the target 
FVIII:C levels at the 3 hour assessment). VWF and FVIII IR and T1/2 for each subject, 
when known, were used to guide the initial dose and subsequent doses.
The primary outcome measure was the overall assessment of hemostatic efficacy assessed 
by the investigator (hemophilia physician) 24 hours after last perioperative IP infusion or 
at completion of day 14 visit, whichever occurred earlier, and was summarized by the 
percentage of subjects in each efficacy category (“excellent”, “good”, “moderate” and 
“none”). Point estimate and corresponding 90% two-sided exact CI was calculated for the 
rate of subjects with an overall assessment of hemostatic efficacy. All 15 subjects treated 
with rVWF (vonicog alfa) (with or without ADVATE) for major (10), minor (4), and oral 
(1) elective surgical procedures had overall hemostatic efficacy ratings of “excellent” or 
“good”. Most (73.3%) subjects had “excellent” overall hemostatic efficacy ratings; of 
these, 7 underwent major surgery and 4 underwent minor surgery. The remaining 26.7% 
subjects had “good” overall hemostatic efficacy ratings: 3 underwent major surgery and 
1 underwent oral surgery. All 8 subjects with VWD Type 3, the subtype classified as 
absolute VWF deficiency, had overall hemostatic efficacy ratings of “excellent” (87.5%) 
or “good” (12.5%).
Intraoperative hemostatic efficacy ratings were also rated as “excellent” or “good” for all 
15 treated subjects. Most (86.7%) subjects had “excellent” intraoperative hemostatic 
efficacy ratings; of these, 8 underwent major surgery, 4 underwent minor surgery, and 
1 underwent oral surgery. Two (13.3%) subjects who underwent major surgery had 
“good” intraoperative hemostatic efficacy ratings. Intraoperative hemostatic efficacy 
was rated as “excellent” or “good” for all subjects with VWD Type 3: “excellent” for 
7 (87.5%) subjects and “good” for 1 (12.5%) subject. 
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Only 1 subject received an intraoperative dose of rVWF (18.1 IU/kg) and ADVATE 
(8.1 IU/kg). The median daily postoperative weight-adjusted dose of rVWF (vonicog 
alfa) (with or without ADVATE) was 23.5 IU/kg on postoperative Day 1 (n=3) and 
25.5 IU/kg on postoperative Day 14 (n=2). In subjects treated with rVWF:ADVATE, the 
daily postoperative weight-adjusted dose was 16.9 IU/kg rVWF and 7.6 IU/kg ADVATE 
on postoperative Day 1 (n=1) and decreased to 50.8 IU/kg rVWF and 7.6 IU/kg
ADVATE on postoperative Day 7 (n=1). For subjects treated with rVWF alone, the 
median weight-adjusted dose (Q1, Q3) of rVWF was 35.4 IU/kg on postoperative Day 1 
(n=2) and decreased to 23.7 IU/kg on postoperative Day 7 (n=4) and 25.5 IU/kg on 
postoperative Day 14 (n=2).
A total of 11 subjects were evaluated for PK in the study. As expected, postinfusion 
increases in concentrations of VWF:RCo, VWF:Ac, VWF:Ag, and VWF collagen 
binding (VWF:CB) were observed. Mean values for VWF:RCo were as follows: 
AUC0-∞/dose was 37.50 hours*IU/dL per IU/kg infused; AUC0-72h/dose was 
34.08 hours*IU/dL per IU/kg infused; T1/2 was 17.83 hours; MRT was 24.32 hours; 
CL was 0.03117 dL/hour/kg; and volume of distribution at steady state (Vss) was 
0.6837 dL/kg. Median values for VWF:RCo were as follows: AUC0-∞/dose was 
32.94 hours*IU/dL per IU/kg infused; AUC0-72h/dose was 31.70 hours*IU/dL per IU/kg 
infused; T1/2 was 14.62 hours; MRT was 21.80 hours; CL was 0.03036 dL/hour/kg; and 
Vss was 0.7078 dL/kg. The VWF:RCo activity was consistent with that previously 
observed in clinical studies 071001 and 070701.
rVWF (vonicog alfa) was safe and well tolerated in adults with severe VWD undergoing 
major, minor, and oral elective surgical procedures. Of the 12 total treatment-emergent 
AEs (TEAEs) that occurred during the study, 2 deep vein thrombosis events (1 non-
serious and 1 serious, as a part of one case) reported in one subject, who underwent total 
hip replacement surgery and who had concurrent condition of obesity, was assessed by 
the sponsor as possibly causally-related to study treatment. None of the TEAEs were 
either a severe allergic or hypersensitivity reaction or developed due to a severe allergic 
reaction. 
One subject with VWD Type 3 who had an intraoperative transfusion of packed red 
blood cells during total knee replacement surgery tested positive for binding antibodies to 
VWF on postoperative Day 7 through study completion. No subjects developed 
neutralizing antibodies to rFVIII or binding antibodies to CHO, rFurin, or murine IgG.
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In summary, the data support the safe and effective use of rVWF (vonicog alfa) with or 
without ADVATE (rFVIII, octocog alfa) in achieving intra- and post-operative 
hemostasis in adult subjects with severe VWD undergoing major, minor, and oral elective 
surgical procedures.
6.5.2.5 Study 071401: Single Subject with von Willebrand Disease
One subject who exhibited allergic reactions to currently marketed pdVWF products was 
treated in the single-subject study 071401 with rVWF (vonicog alfa) only for the bleed 
treatment of continued hematuria, and for biopsy and surgical resection of a left-kidney 
mass.
For the initial rVWF (vonicog alfa) infusion, the subject received a test dose of 5% of 
the total dose of 60 IU/kg rVWF:RCo at an infusion rate of 1 mL/min. After a 10 to 
15-minute observation period, no adverse symptoms or signs were noted and the subject 
received the remaining 95% of the total dose. The subject was monitored for any signs of 
an allergic reaction, and none were noted. Treatment with rVWF (vonicog alfa) every 
12 to 24 hours was to continue at the discretion of the investigator based on VWF levels 
and clinical symptomatology. The subject had an excellent response and recovery, which 
allowed for daily dosing of rVWF (vonicog alfa) and, within 24 hours, the subject’s 
bleeding had stopped. Daily dosing of rVWF (vonicog alfa) was maintained and the 
subject received his last dose on 
.
The subject also received rVWF (vonicog alfa) for 7 days for prophylaxis for surgery 
(surgical resection of a left-kidney mass). The subject experienced no hemorrhagic 
complications and no AEs that were considered related to the use of rVWF (vonicog 
alfa).
6.6 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) to 
Human Subjects
Current treatment of VWD patients relies on desmopressin and VWF products 
manufactured from pooled human plasma. Human VWF produced by recombinant 
technology could offer a new perspective in treatment of VWD. The benefit for the 
individual subject is anticipated to be significant during this clinical study. He/she may 
benefit from a product that minimizes excessive FVIII administration and thus allowing 
individualized dosing of VWF at optimal levels. Variations in VWF multimeric 
composition may lead to variability with respect to treating or preventing bleeds in 
VWD subjects, especially mucosal bleeds which are especially problematic. rVWF 
(vonicog alfa) product manufactured by Baxalta consistently contains ULMW VWF 
multimers due to the fact that the product has not been exposed to ADAMTS13. 
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The initial presence of these ULMW VWF multimers, which are subsequently cleaved by 
the subject’s endogenous ADAMTS13, may result in improved platelet and collagen 
binding and therefore provide more predictable treatment outcomes.
By using a recombinant product, the risk of transmission of adventitious agents and other 
blood-borne pathogens associated with the use of products of human or animal origin has 
been eliminated. At this stage of product development, the key societal benefit is a better 
understanding of advanced treatment options for VWD and enhanced product 
availability.
These benefits outweigh the following identified or potential risks of rVWF (vonicog 
alfa):

allergic-type hypersensitivity reactions as with any intravenous protein product

the occurrence of thromboembolic events

the development of neutralizing antibodies to VWF
Refer to the IB for further details on benefits and risks of the IP.
6.7 Compliance Statement
This study will be conducted in accordance with this protocol, the International Council 
for Harmonisation Guideline for Good Clinical Practice E6 (ICH GCP, April 1996, with 
Addendum E6(R2) dated Nov 2016 EMA/CHMP/ICH/135/1995), Title 21 of the US 
Code of Federal Regulations (US CFR), the EU Directives 2001/20/EC and 2005/28/EC, 
the Declaration of Helsinki and applicable national and local regulatory requirements.
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7. STUDY PURPOSE AND OBJECTIVES
7.1 Study Purpose
The purpose of this phase 3 study is to investigate the efficacy and safety, including 
immunogenicity, thrombogenicity and hypersensitivity reactions, as well as 
pharmacokinetics (PK), 
and 
 
of prophylactic treatment with rVWF (vonicog alfa) in adult subjects with severe VWD.
7.2 Primary Objective
The primary objective of this study is to prospectively evaluate the ABR for spontaneous 
bleeding episodes while on prophylactic treatment with rVWF (vonicog alfa) and to 
compare it to the subject’s historical ABR for spontaneous bleeding episodes.
7.3 Secondary Objectives
Secondary Objectives are to assess:

Additional efficacy of prophylactic treatment with rVWF (vonicog alfa)

Safety of rVWF (vonicog alfa), including immunogenicity, thrombogenicity and 
hypersensitivity

Pharmacokinetics (PK) of rVWF (vonicog alfa) and pharmacodynamics (PD) of 
rVWF (vonicog alfa) as measured in FVIII activity 
7.4 Exploratory Objectives
 
 
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8. STUDY DESIGN
8.1 Overall Study Design 
This is a prospective, open label, uncontrolled, non-randomized, international, 
multicenter phase 3 study to evaluate efficacy, safety (including immunogenicity,
thrombogenicity and hypersensitivity reactions), as well as PK, 
 and 
 of prophylactic treatment regimen with rVWF (vonicog alfa) in adult 
patients with severe VWD. 
Subjects transitioning from on-demand treatment (OD subjects) or subjects switching 
from prophylactic treatment with pdVWF (pdVWF switch subjects) will receive 
prophylactic treatment with rVWF (vonicog alfa) for a 12-month period (up to 15 months 
for the qualified subjects to rollover into the continuation study, if the continuation study 
start up is delayed beyond the completion of subject’s 12-month visit). The dose will be 
50 ± 10 IU/kg rVWF twice weekly for OD subjects or will be based on their prior 
pdVWF dose for pdVWF switch subjects, and dose may be further individualized based 
on the PK data, subject’s history of bleeding episodes, and the results from clinical and 
laboratory assessments (see Section 8.6.4.3).
The overall duration of prophylactic treatment with rVWF per subject will be at least 
12 up to 15* months.
During this period any bleeding episodes requiring substitution therapy with VWF 
concentrate to control bleeding will be treated with rVWF (vonicog alfa) with or without 
ADVATE (rFVIII, octocog alfa). The dose will be according to the bleeding type and 
severity and it will be adjusted to the clinical response (see Section 8.6.4.4.2).
The overall study design is illustrated in Figure 1.
* Study treatment period is extended by 3 months to accommodate participation in the 
continuation study for the qualified subjects and will be exercised only if the continuation study 
start up is delayed beyond the completion of subject’s 12-month visit. 
8.2 Duration of Study Period(s) and Subject Participation
The overall duration of the study is approximately 27 months from study initiation 
(i.e., first subject enrolled) to study completion (i.e., last subject last visit). The subject 
participation period is approximately 15 to 18* months from enrollment to completion 
(i.e, last study visit), unless the subject is prematurely discontinued.
* Study treatment period is extended by 3 months to accommodate participation in the 
continuation study for the qualified subjects and will be exercised only if the continuation study 
start up is delayed beyond the completion of subject’s 12-month visit. 
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8.3 Outcome Measures
8.3.1 Primary Outcome Measure
8.3.1.1 Efficacy 

Annualized bleeding rate (ABR) for spontaneous (not related to trauma) bleeding 
episodes during prophylactic treatment with rVWF (vonicog alfa)
8.3.2 Secondary Outcome Measures
8.3.2.1 Additional efficacy of Prophylactic Treatment with rVWF (vonicog alfa)

ABR percent reduction success for OD subjects defined as at least 25% reduction 
of ABR for spontaneous (not related to trauma) bleeding episodes during rVWF 
(vonicog alfa) prophylaxis relative to the subject’s own historical ABR during on-
demand treatment

ABR preservation success for pdVWF switch subjects defined as achieving an 
ABR for spontaneous bleeding episodes during rVWF (vonicog alfa) prophylaxis 
that is no greater than the  subject’s own historical ABR during prophylactic 
treatment with pdVWF

Categorized spontaneous ABR defined as 0, 1-2, 3-5, or >5 bleeding episodes
during the prophylactic treatment with rVWF (vonicog alfa)

Total number of infusions and the average number of infusions per week during 
prophylactic treatment with rVWF (vonicog alfa)

Total weight adjusted consumption of rVWF (vonicog alfa) during prophylactic 
treatment 

Spontaneous ABR by location of bleeding (GI, epistaxis, joint bleeding, 
menorrhagia, oral and other mucosa, muscle and soft tissue, etc.) while on 
prophylactic treatment with rVWF (vonicog alfa)
8.3.2.2 Safety

AEs: incidence, severity, causality

Thromboembolic events 

Hypersensitivity reactions

Development of neutralizing antibodies to VWF and FVIII 

Development of total binding antibodies to VWF and FVIII
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
Development of binding antibodies to CHO proteins, mouse immunoglobulin G 
(IgG) and rFurin

Clinically significant changes in vital signs and clinical laboratory parameters
relative to baseline
8.3.2.3 Pharmacokinetics (PK) and Pharmacodynamics (PD)

PK parameters after a washout for on-demand subjects: incremental recovery 
(IR), T1/2, MRT, area under the concentration versus time curve from 0 to infinity 
(AUC0-), area under the concentration versus time curve from 0 to the last 
measurable concentration (AUC0-tlast), maximum plasma concentration (Cmax), 
minimum time to reach the maximum concentration (Tmax), volume of distribution 
at steady state (Vss) and clearance (CL) based on VWF:Rco activity, VWF:Ag, 
VWF:CB activity. 

PD parameters after a washout for on-demand subjects: Cmax, Tmax, and AUC0-tlast
as measured in FVIII activity by the 1-stage clotting assay (FVIII:C). 

PK parameters at steady state for on-demand and switch subjects: area under the 
concentration versus time curve from 0 to end of the partial dosing interval 
(AUC0-tau;ss), maximum concentration during the partial dosing interval (Cmax;ss), 
minimum time to reach the maximum concentration (Tmax;ss) and minimum 
concentration during the partial dosing interval (Cmin;ss) based on VWF:RCo, 
VWF:Ag and VWF:CB. PK parameters at steady state will be assessed shortly 
after reaching steady state for switch subjects and at the end of the study for on-
demand as well as for switch subjects all based on the longer interval of the 
irregular dosing intervals employed. 

PD parameters at steady state for on-demand and switch subjects: AUC0-tau;ss, 
Cmax;ss, Tmax;ss, and Cmin;ss as measured in FVIII activity by the 1-stage clotting 
assay. PD parameters at steady state will be assessed shortly after reaching steady 
state for switch subjects and at the end of the study for on-demand as well as for 
switch subjects all based on the longer interval of the irregular dosing intervals 
employed.

Time course of FVIII clotting activity (FVIII:C) levels.
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8.3.3 Exploratory Outcomes Measures
8.3.3.1
 
 
 
 
 
8.3.3.2
 
 
 
 
 
8.3.3.3
 
8.3.3.4
 
 
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8.4 Randomization and Blinding
This is a non-randomized open-label, active treatment clinical study. 
8.5 Study Stopping Criteria 
This study will be stopped if 1 or more of the following criteria are met in the absence of 
any other possible and medically plausible causal attribution (eg, underlying or 
concurrent condition, use of concomitant medication, subject’s medical history, etc):
1.
Two subjects develop a life-threatening or fatal thromboembolic event
2.
Two subjects develop life-threatening or fatal severe hypersensitivity reactions 
(e.g., anaphylaxis)
3.
Any subject develops acute hepatic failure 
4.
Two subjects develop rVWF neutralizing antibodies that are considered clinically 
significant by the investigators and are associated with significant decrease of 
efficacy or serious adverse reactions.
The study may be stopped at any time by the sponsor.
The sponsor ultimately will decide whether to terminate, temporarily halt or modify the 
study based on the data monitoring committee (DMC)’s review and recommendation on 
all relevant cases including those that meet the stopping criteria listed above.
8.6 Investigational Product(s)
8.6.1 Packaging, Labeling, and Storage
8.6.1.1 rVWF (Recombinant von Willebrand Factor, vonicog alfa)
rVWF (vonicog alfa) will be packaged in boxes with 2 glass vials, one containing the 
rVWF powder, and the second vial containing the diluent (water for injection). Further 
details are provided in the IB and Pharmacy Manual. The rVWF label will include, at a 
minimum, the actual VWF:RCo potency and the date of expiration.
rVWF (vonicog alfa) is a powder that should be stored refrigerated (2-8°C [36-46°F]) . 
Deviations from the storage condition have to be communicated and followed up with the 
sponsor. Inadequately stored product will have to be placed in quarantine and may only 
be used after written IP administration authorization by the sponsor. After removal of the 
product from the refrigerator the product must not be returned to the refrigerator. The 
reconstituted product has to be used immediately (at least within 3 hours). rVWF 
(vonicog alfa) must not be used beyond the expiration date printed on the vial label. 
Avoid freezing at all times.
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8.6.1.2 rFVIII (Recombinant Factor VIII, octocog alfa /ADVATE)
ADVATE (rFVIII, octocog alfa) will be packaged in boxes with 2 glass vials, one 
containing the lyophilized rFVIII, and the second vial containing the diluent. Further 
details are provided in the IB and Pharmacy Manual. The ADVATE label will include, 
at a minimum, the actual FVIII:C potency and the date of expiration. 
ADVATE (rFVIII, octocog alfa) should be refrigerated (2-8°C [36-46°F]) in powder 
form and should not be used beyond the expiration date printed on the vial. 
Deviations from the storage condition have to be communicated and followed up with the 
sponsor. Inadequately stored product will have to be placed in quarantine and may only 
be used after written IP administration authorization by the sponsor. After removal of the 
product from the refrigerator the product must not be returned to the refrigerator and has 
to be used immediately. Avoid freezing at all times.
8.6.2 Reconstitution
The reconstitution procedures for both rVWF (vonicog alfa) and ADVATE (rFVIII, 
octocog alfa) products are detailed in the Pharmacy Manual. 
8.6.3 Administration
Following reconstitution, rVWF (vonicog alfa) and ADVATE (rFVIII, octocog alfa) (in 
case of bleeding episode treatment) should be administered to study subjects at room 
temperature and within 3 hours of reconstitution. The reconstituted rVWF (vonicog alfa) 
and ADVATE (rFVIII, octocog alfa), should be inspected for particulate matter and 
discoloration prior to administration, whenever the solution and container permit. The 
solution should be clear and colorless in appearance. If not, do not administer the product. 
Plastic syringes provided by the sponsor must be used since coagulation factors tend to 
stick to the surface of glass syringes.
Investigational product infusions should be given at a slow enough rate to ensure the 
subject’s comfort. The rate should not exceed 4 mL/minute The investigator/ subject shall 
ensure that no visible residual volume remains in the syringe(s) and that the complete 
content is administered. Upon completion of the infusion, the butterfly catheter should be 
flushed with at least 2 mL of saline solution. In case of a (central) venous access device, 
the flush should be with at least 10 mL of saline solution. The IP infusions should be 
administered over a duration of 2 to 20 minutes, depending on the volume.
Only the actual potencies of rVWF (vonicog alfa) and ADVATE (rFVIII, octocog alfa) 
as stated on the vial labels and described in the Pharmacy Manual should be used. 
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A variation of up to 10% of the intended dose for prophylactic infusions and of the 
intended dose for treatment of bleeding episodes is permissible and the exact dose should 
be recorded on the Case Report Form (CRF). Using of partial vials is not allowed.
At study visits where recovery analysis is being done, vials with the same lot numbers 
should be used throughout the PK IP infusion per subject.
For treatment of bleeding episodes, sequential administration will be done: separate 
syringes of the appropriate dose of rVWF (vonicog alfa) and ADVATE (rFVIII, octocog 
alfa) will be prepared for sequential infusion. rVWF (vonicog alfa) should be infused first 
sequentially followed preferably within 10 minutes by infusion of ADVATE (rFVIII, 
octocog alfa). Only the actual potencies of rVWF (vonicog alfa) and ADVATE (rFVIII, 
octocog alfa) as stated on the vial labels and described in the Pharmacy Manual should be 
used. 
The final dose of rVWF (vonicog alfa):ADVATE (rFVIII, octocog alfa) should be at a 
ratio of 1.3:1 ± 0.2.
8.6.4 Description of Treatment
8.6.4.1 PK-Assessment Treatment
For on-demand subjects, two PK assessments will be performed: an initial PK 
assessment after a wash-out period and a steady state PK assessments at the end of the 
study. The IP infusion for the initial PK assessment is scheduled on the baseline visit, 
which should be within 42 days after the completion of screening procedures and 
confirmation of eligibility. At the baseline visit the subjects will receive a dose of 
50 ± 5 IU/kg rVWF:RCo for PK assessment. Blood samples will be drawn within 
30 minutes pre-infusion, and at 11 time points post-infusion (15 ± 5 minutes, 
30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 
24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours and 96 ± 2 hours). A washout 
period of at least 5 days is required prior to infusion of rVWF (vonicog alpha) for PK 
assessment. The 2nd PK assessment for on-demand subjects will be performed at steady 
state at the end of the study(see Section 11.6). Subjects previously enrolled in rVWF 
studies 070701, 071001 or 071101 and having previously undergone PK assessments in 
these studies are required to repeat the PK assessment due to different dose and time 
points used in these former studies.
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For pdVWF switch subjects, two steady state PK assessments will be performed. 
The 1st PK will be assessed shortly after reaching steady state, which is expected to be 
11 days after the 1st prophylactic dose for majority of the subjects, around the 
prophylactic dose #5-6. The 2nd PK will be at the end of the study. For steady state PK, 
blood samples will be drawn within 30 minutes pre-infusion, and at 11 time points post-
infusion (15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 
12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours and 96 ± 2 hours) 
as long as it won’t interfere with subject’s the normal dosing schedule, otherwise the 
96 hr sampling can be omitted (see Section 11.6). Final sample for PK analysis should be 
taken before next dose is administered.
8.6.4.2 Prophylaxis Initiation Treatment 
The rVWF (vonicog alfa) prophylaxis initiation treatment visit will coincide with the 
96 2 h initial PK assessment for on-demand subjects. For pdVWF switch subjects, the 
rVWF (vonicog alfa) prophylaxis initiation treatment visit should occur within 42 days 
after the completion of screening procedures and confirmation of eligibility. At this visit 
subjects will receive their prophylaxis initiation dose. The prophylaxis doses are 
described in Section 8.6.4.3.
The subject will be trained on IP reconstitution and administration and may then qualify 
for home treatment (see Section 8.6.4.3.2). Refer toTable 6 (a/b) for study procedures and 
Table 8(a/b) for clinical laboratory assessments.
8.6.4.3 Prophylaxis Treatment
For on-demand subjects, the standard prophylactic dose is 50 ± 10 IU/kg rVWF:RCo, 
which may be increased up to 80 IU/kg. All on-demand subjects will initially receive 
rVWF (vonicog alfa) twice per week (Table 1, Schedule A). Examples of all dosing 
schedules are provided in Table 1.
For pdVWF switch subjects, the weekly dose (IU/kg) of IP for each patient will be 
equivalent (± 10%) to the weekly VWF dose received during prophylactic treatment with 
pdVWF. The weekly dose of IP should be divided into 2 infusions (Table 1, Schedule A), 
with a maximum of 80 IU/kg/infusion. If needed, based on the total weekly dose or other 
clinical judgements, the weekly dose may be given as three infusions (Table 1, 
Schedule B). A once weekly dose regimen will be allowed after switch to rVWF 
(vonicog alfa) only if the patient has been on a once weekly dose regimen with pdVWF.
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Table 1
rVWF (vonicog alfa) Dosing Schedule Examples: Schedules A and B
Example
M
T
W
Th
F
Sat
Sun
M
T
W
Th
F
Sat
Sun
Schedule A
X
X
X
X
Schedule B
X
X
X
X
X
X
The prophylaxis dose may be further individualized within the range based on:

available historical PK data

type and severity of bleeding episodes the subject has experienced in the past and

monitoring of appropriate clinical and laboratory measures
The individualized prophylaxic dose assignment will have to be agreed with the sponsor 
in advance, and the rationale should be well documented.
8.6.4.3.1 Adjustment of Dose or Dose Interval
In general, the dose and/or dose interval for each subject should not be changed unless 
prompted by clear medical needs. Dose and frequency adjustments should be agreed with 
the sponsor in advance unless it constitutes an urgent safety measure. The rationale for 
dosing adjustments needs to be documented in the subject’s medical record.
For both OD and switch patients, dose escalations (not exceeding the upper dose limit of 
80 IU/kg rVWF:RCo) and increase of dose frequency will only be allowed in case of 
insufficient therapeutic response with breakthrough bleeding episodes. The criteria for 
dose and/or frequency escalation are specific to each bleeding indication but, overall, 
involve 1 significant breakthrough bleeding episode despite the subject being compliant 
with scheduled prophylaxis treatment. For switch patients  who require a dose escalation 
due to a breakthrough bleed, the frequency should be kept the same but the dose 
(IU VWF:RCo per infusion) should be increased up to 80 IU VWF:RCo. Following that,
increases in frequency may be considered upon consultation with the Sponsor. For on 
demand subjects who require a dose escalation, at the discretion of the PI upon 
consultation with the Sponsor, the frequency may be kept the same but the dose 
(IU VWF:RCo per infusion) should be increased up to 80 IU VWF:RCo. If this proves to 
be insufficient, then the dosing frequency may be increased in these subjects. Table 2
presents the criteria for dosing escalation per each bleeding indication taken 50 ± 10 IU 
VWF:RCo/kg twice weekly dose as an example of subject’s assigned starting dose.
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The criteria are applicable for both OD and switch subjects who were initially assigned 
to twice weekly dosing. Subjects entering the study will begin prophylaxis treatment 
according to Schedule A (Table 1) and will remain at this dose and frequency until 
meeting the criteria for escalation to the next higher schedule: for example, from 
2 infusions of 50 ± 10 IU VWF:RCo/kg/week to 3 infusions of 50 ± 10 IU 
VWF:RCo/kg/week (Schedule B) to achieve an adequate therapeutic response. If a 
subject started with a weekly dose (possible for switch subjects), similar criteria would 
apply except that the subject will be excalated to twice weekly dosing if frequency 
change is necessary.
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Table 2
Criteria for Escalation Specific to Each Bleeding Indication
Schedule A
Schedule B
Joint bleeding
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) twice per week. In the event a 
spontaneous joint bleeding episode occurs 
while on this regimen, the subject will escalate 
to up to 80 IU/kg twice per week or, if 
necessary, to Schedule B following its 
resolution
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week.
GI bleeding
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) twice per week. In the event a 
severe GI bleeding episode, i.e., requiring red 
blood cell transfusion, occurs while on this 
regimen, the subject will escalate to up to 
80 IU/kg twice per week or, if necessary, to 
Schedule B following its resolution
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week.
Menorrhagia
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) on days 1 and 2 of menses for 
2 cycles. Menstrual flow will be monitored by 
the PBAC score. If the average pictorial chart 
score is > 185, then the subject will escalate to 
up to 80 IU/kg or, if necessary, to Schedule B
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) on days 1, 2, 
and 3 of menses. Menstrual flow 
will be monitored by the PBAC 
score.
Epistaxis
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) twice per week. The subject will 
escalate to up to 80 IU/kg twice per week or, if 
necessary, to Schedule B in the event of 
1 occurrence of breakthrough bleeding 
requiring intervention such as iron 
replacement therapy, transfusion, packing, 
hospitalization; or 2 bleeding events that 
require treatment with factor replacement
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week. 
Oral and Other 
Mucosa
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) twice per week. The subject will 
escalate to up to 80 IU/kg twice per week or, if 
necessary, to Schedule B in the event of 
1 occurrence of breakthrough bleeding 
requiring intervention such as iron 
replacement therapy, transfusion, packing, 
hospitalization; or 2 bleeding events that 
require treatment with factor replacement.
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week.
Muscle and Soft 
Tissue
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) twice per week. In the event a 
spontaneous bleeding episode occurs while on 
this schedule, the subject will escalate to up to 
80 IU/kg twice per week or, if necessary, to 
Schedule B following its resolution.
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week.
Abbreviations:  GI: gastrointestinal; PBAC: Pictorial Blood Assessment Chart.
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If a subject does not adequately respond to rVWF (vonicog alfa) therapy, he/she will be 
evaluated for the presence of neutralizing and total binding anti-VWF antibodies (see 
Section 12.9.3.2).
If a subject experiences a bleed while receiving rVWF (vonicog alfa) three times per 
week, the investigator should treat the bleed with rVWF (vonicog alfa) at doses up to 
80 IU VWF:RCo/kg at a frequency determined by the investigator until the bleed 
resolves. Upon resolution of the bleeding event, the subject will return to their assigned 
prophylaxis regimen. 
It is essential for the success of this study that the subjects adhere to treatment regimens. 
Therefore, procedures for monitoring subject’s compliance are implemented (see 
Section 10.7).
If 1 infusion of IP is missed, the subject may administer the IP as soon as possible. The 
subject should adhere to their treatment scheme ensuring a minimum interval of 12 hours 
between this and the previous IP infusion. For example, a subject routinely infuses IP on 
Monday and Thursday, he/she misses the Monday time point and therefore may infuse 
the IP on the next day (Tuesday) and thereafter proceed with infusing the IP on Thursday
(considering a minimum 12 hours between the infusions) and return to the initial 
schedule.
If more than 30% of infusions of IP are missed within the visit interval of 3 months the 
subject will be discontinued from the study (see Section 9.4).
8.6.4.3.2 General Instructions for Home Treatment for Prophylaxis
At the discretion of the investigator, a subject may be considered suitable for home 
treatment only after the subject has received at least 1 infusion of IP in the clinic, either 
during planned prophylactic IP exposure or during the treatment of bleeding episodes, 
and meets the following additional criteria:
1.
Fully understands the concept of a clinical study and related documentation 
(documented training of at least 30 minutes), 
2.
Has a history of previous experience with home treatment including 
self-administration and treatment with VWF containing concentrates, 
3.
Has adequate time for initial training of the study drug preparation (preparation, 
mixing and infusion of the IP(s) (documented training of at least 30 minutes).
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This applies both to subjects who were on prior on-demand treatment and to subjects 
switching form prophylaxis with pdVWF. In the event a healthcare professional is 
required to administer IP, he/she must be trained and qualified by the investigator on the 
above procedures prior to the decision for home treatment. A Subject Guideline detailing 
all instructions and information listed above will be provided to each subject.
8.6.4.4 Treatment of Bleeding Episodes
8.6.4.4.1 General Instructions for Home Treatment of Bleeding Episodes
If a subject experiences a bleeding episode, he/she should contact the study site 
immediately and the site investigator should provide instructions on the treatment 
regimen. If the subject initiates the treatment at home, he/she should at least follow up 
with the study site if a visit is needed as per the standard of care at the center.
In the event a healthcare professional is required to administer treatment at the subject’s 
home, he/she must be trained and qualified by the site investigator on the above 
procedures prior to the decision for home treatment. Once a subject has received 
1 infusion of rVWF (vonicog alfa) in the clinic (either during planned IP exposure or 
during the treatment of a bleeding episode) and meets the criteria for home treatment, the 
treatment of bleeding episodes with IP can be conducted at home (see Section 8.6.4.3.2).
If a subject is not qualified for home treatment, rVWF (vonicog alfa) infusions must be 
administered at the study site.
If a subject experiences a bleeding episode that requires treatment between the screening 
and the prophylaxis initiation visit, the subject will be treated with IP (rVWF with or 
without ADVATE). Treatment with IP must occur at the study site unless the subject has 
previously qualified for home treatment with rVWF (vonicog alfa). If rVWF (vonicog 
alfa) treatment is not feasible, the subject may use his/her standard of care, such as 
commercial pdVWF/FVIII products. In any case a washout period of at least 5 days is 
required prior to rVWF (vonicog alfa) PK infusion at the initial PK assessment visit for 
on-demand subjects.
If a subject experiences a bleeding episode requiring treatment during the PK assessment, 
rVWF (vonicog alfa) should be used to treat the bleed. Blood draws for PK assessment 
will be stopped and the PK assessments will be repeated once the bleed has resolved and 
the subject is free of any symptoms related with the bleeding episode. Dose and 
frequency of rVWF (vonicog alfa) infusions or any other replacement therapy to stop the 
bleed should be recorded in the electronic Case Report Form (eCRF), and the reason for 
the use of any non-IP product or therapy should be documented.
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8.6.4.4.2 Dosing Recommendations for Treatment of Bleeding Episodes 
If an acute bleeding episode occurs, the subject will be treated with rVWF (vonicog alfa) 
with or without ADVATE (rFVIII, octocog alfa). It is the sponsor’s opinion that, in many 
cases, treatment with ADVATE (rFVIII, octocog alfa) may not be necessary, since rVWF 
(vonicog alfa) prophylaxis will serve to increase endogenous FVIII levels. However, if 
endogenous FVIII is below 30-40 % or is unknown and cannot be estimated from the 
subject’s PK study, an infusion of rVWF: ADVATE at an rVWF: ADVATE ratio of 
1.3:1± 0.2 should be administered initially. Subsequent infusions should be with 
rVWF:RCo 40 to 60 IU/kg with or, in  many cases,without 30 to 45 IU/kg ADVATE 
(only to be administered if plasma FVIII levels fall below 30 IU/L during the treatment 
period). Dosing may be adjusted downward or upward up to 80 IU/kg rVWF at the 
treating physician’s discretion based upon the subject’s prior history, PK and other 
factors.
If FVIII levels are not available, dosing is at the discretion of the investigator based upon 
the individual subject’s PK data. Using ADVATE (rFVIII, octocog alfa) in addition to 
rVWF (vonicog alfa) in subsequent doses carries the risk of an excessive rise in FVIII:C. 
Therefore, reduced doses of ADVATE (rFVIII, octocog alfa) and/or prolongation of the 
dose interval should be considered. 
The following is general guidance and the sponsor’s suggestion for treatment of 
breakthrough bleeds, however each PI will determine the treatment based on the local 
acceptable practice how to monitor and adjust treatment for a bleeding episode. An effort 
should be made to discuss with the sponsor (or sponsor’s delegate) the treatment strategy.
In general the aim of the initial dose should be full replacement of VWF with VWF:RCo 
levels of >0.6 IU/ml (60%) and FVIII:C of >0.4 IU/mL (40%). In major bleeding 
episodes, subsequent doses should keep the trough level of VWF:RCo >50% for 3 days 
and then as deemed necessary by the investigator for subsequent days. In moderate 
bleeding episodes, the dose and trough level may be reduced to >30% for as long as 
deemed necessary by the investigator. Treatment for minor bleeding episodes will 
generally consist of only 1 or 2 doses of rVWF (vonicog alfa) IP. 
If the VWF:RCo level is above 150%, a planned treatment should be delayed by at least 
12 hours; if the VWF:RCo level is above 200%, a planned treatment should be delayed 
by at least 24 hours. In either case, a lower subsequent dose (e.g., 20 IU/kg VWF:RCo) 
may be appropriate.
Dosing recommendations are listed in Table 3.
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Dosage must be individualized based on the subject’s weight, VWD type, and the 
severity of the bleeding episode, as well as on monitoring of appropriate clinical and 
laboratory measures. In the phase 1 study 070701, 1.0 IU/kg VWF:RCo raised the 
circulating level of VWF:RCo by 0.017 IU/mL (1.7 %). In the same study, the observed 
mean half-life for rVWF (vonicog alfa) was 19.3 hours, with a standard deviation of 
10.9 hours.
Table 3
rVWF:RCo Dosing Recommendations for the Treatment of Bleeding Episodes Due to VWD
Classification of 
VWD
Hemorrhage
Dosage (IU VWF:RCo/kg BW)
Type 1 
Severe (Baseline 
VWF:RCo activity 
typically <20%) 
Minor (e.g., epistaxis, oral 
bleeding, menorrhagiaa) 
40 to 50 IU/kg (1 or 2 doses)
Major (e.g., severe or 
refractory epistaxis, 
menorrhagia*, GI bleeding, 
CNS trauma, hemarthrosis, 
or traumatic hemorrhage)
Initial dose 50 to 75 IU/kg, then 40 to 60 IU/kg 
every 8 to 12 hours for 3 days to keep the trough 
level of VWF:RCo >50%; then 40 to 60 IU/kg daily 
for a total of up to 7 days of treatment
Type 2 (all variants) 
and Type 3 
Minor (clinical indications 
above) 
40 to 50 IU/kg (1 or 2 doses)
Major (clinical indications 
above)
Initial dose of 60 to 80 IU/kg, then 40 to 60 IU/kg 
every 8 to 12 hours for 3 days to keep the trough 
level of VWF:RCo >50%; then 40 to 60 IU/kg daily 
for a total of up to 7 days of treatment
a Menorrhagia is defined as excessive bleeding during menstruation. A diagnosis of menorrhagia will be 
defined by a prospectively completed Pictorial Blood Assessment Chart (PBAC) score >185 and normal 
cervical cytology or requiring use of a VWF-containing concentrate for treatment of excessive 
menstrual bleeding for at least one menstrual cycle during the prior year.
Variances of up to 10% in dosing are permissible during treatment of bleeding episodes, 
but rounding to the nearest vial size should be avoided.
Subjects with non-neutralizing binding anti-VWF antibodies should initially be treated 
with a dose known to be efficacious based on the subject’s medical treatment history
which may differ from the recommendations provided in Table 3. Subjects should be 
monitored for lack of efficacy as well as for FVIII (mandatory), VWF:RCo (mandatory), 
and VWF:Ag (optional where testing is not available) levels after 3 to 6 hours. Re-dosing 
with rVWF (vonicog alfa) in combination with ADVATE (rFVIII, octocog alfa) using the 
same (initial) dose and adaptation of the dosing frequency should be considered until 
cessation of the bleed, if the FVIII and/or VWF:RCo levels drop below 30%-50% 
depending on bleeding severity.
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The number of subsequent infusions and the dosage levels prescribed will be determined 
by the investigator on the basis of the clinical severity, response to current therapy, 
available laboratory data, and the subject’s historical treatment for similar bleeding 
episodes.
8.6.4.5 Treatment of Surgical Bleeding
Subjects enrolled in this study who require surgery or dental procedures will be treated 
with IP to manage their surgical bleeding then afterwards will resume their prophylactic 
rVWF (vonicog alfa) treatment schedule. Subjects who at time of screening have an 
already scheduled surgical intervention are not eligible for participation in the study.
8.6.4.5.1 Major, Minor and Oral Surgery Definition
The following definitions and criteria are used to serve as a guidance for major, minor 
and oral surgery.
Major surgeries generally refer to major orthopedic surgery (e.g., joint replacement, 
arthroscopic or open synovectomy, arthrodesis, hardware removals like plates or 
intramedullary nails, etc.), major abdominal surgery (e.g. open or laparoscopic 
hernioplasty, cholecystectomy, colon or small bowel resection, etc.), major gynecological 
surgery (e.g. open or laparoscopic myomectomy, hysterectomy, removal of 
endometriosis, polyps, cysts, adhesiolysis, etc.), major head and neck surgery (e.g.: 
tonsillectomy, adenoidectomy, rhinoplasty, lymphadenectomy, thyroidectomy, 
parotidectomy. etc.), any intracranial , cardiovascular or spinal surgery and any other 
surgery which has a significant risk of large volume blood loss or blood loss into a 
confined anatomical space. Extraction of impacted third molars is generally also 
considered major surgery due to the expected difficulty of surgery and the expected blood 
loss.
Minor surgeries generally refer to interventions such as placement of intravenous access 
devices, removal of small skin lesions, arthroscopy, gastroscopy, colonoscopy or 
conisation.
Oral surgeries comprise extractions of fewer than three teeth, if the teeth are non-molars 
and have no bony involvement.
A summary schedule of visit assessments and laboratory sampling is included in 
Supplement tables in Section 20.2.1 and Section 20.3.1.
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8.6.4.5.2 Preoperative Priming Dose
12- 24 hours prior to surgery, a priming dose with rVWF (vonicog alfa), using the rVWF 
IR and T1/2 for this subject , will be infused to allow the endogenous FVIII levels to raise 
to at least 30 IU/dL (minor, oral surgery), or 60 IU/dL (major surgery) at the time of the 
loading dose of rVWF (vonicog alfa) is infused.
As a general guidance a priming dose of 40-60 IU/kg rVWF:RCo will be administered. If 
not assessed prior to the preoperative priming dose, a IR recovery may be calculated for 
subjects undergoing minor and oral surgery.
8.6.4.5.3 Preoperative Loading Dose
An rVWF (vonicog alfa) loading dose should be administed within 3 hours before 
surgery. VWF and FVIII levels should be assessed within 3 hours prior to surgery 
initiation and results must be available prior to administering the loading dose. If FVIII 
levels prior to loading dose administration are not at least 30 IU/dL (minor, oral surgery), 
or 60 IU/dL (major surgery) ADVATE (rFVIII, octocog alfa) will be administered in 
addition to rVWF (vonicog alfa) in order to raise FVIII:C levels to recommended levels.
The preoperative loading dose will be calculated as the difference in the target peak and 
baseline plasma VWF:RCo levels divided by the IR (ΔVWF:RCo x BW (kg) /IR). The 
PK results will be provided prior to the planned surgery. If the IR is not available, assume 
an IR of 1.7 IU/dL per IU/kg and calculate the initial dose as follows: (100 – baseline 
plasma VWF:RCo) x BW (kg) / 1.7. For minor and oral surgery, the IR from the 
Preoperative Priming Dose visit will be used to guide dosing and the target peak is 
50-60 IU/dL VWF:RCo and 40-50 IU/dL FVIII. For major surgery, the target peak is 
100IU/dL VWF:RCo and 80-100 IU/dL FVIII.
The surgery may only start after normalization of the activated partial 
thromboplastin time (aPTT).
8.6.4.5.4 Intra- and Postoperative (maintenance) Dosing
After the preoperative loading dose(s), subjects who have not achieved the desired 
postinfusion recovery will continue to receive rVWF (vonicog alfa) with or without 
ADVATE (rFVIII, octocog alfa) as a bolus infusion, depending on VWF and FVIII 
levels. The peri- and post-operative substitution regimen will be individualized according 
to the PK results, intensity and duration of the hemostatic challenge, and the institution’s 
standard of care.
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Subjects undergoing minor surgery will be infused with rVWF (vonicog alfa) every 
12-24 hours or every other day, targerting >30IU/dL (rVWF and FVIII) for at least the 
first 48 hours.
Subjects undergoing oral surgery will be infused with rVWF (vonicog alfa) at least once 
within the first 8-12 hours, targeting >30 IU/dL (rVWF and FVIII).
Subjects undergoing major surgery will be infused with rVWF (vonicog alfa) every 
12-24 hours for at least the first 72 hours post-surgery, targeting a VWF:RCo and 
FVIII:C trough plasma level >50 IU/dL, followed by further treatment post-72 hours for 
as long as deemed necessary by the Investigator, targeting a VWF:RCo and FVIII:C 
trough plasma level of >30 IU/dL.
Dose modifications based on pre-infusion VWF/FVIII levels will be performed as 
needed. For subsequent infusions post surgery, in case pre-infusion levels are not 
available prior to the consecutive infusion in a timely manner, pre-infusion levels from 
the previous dose may be used by the investigator for dosing guidance.
Peak plasma level guidance is matching to Section 8.6.4.4.2
A schedule of all perioperative visit assessments and laboratory sampling can be found in 
supplement tables in Section 20.2.1 and Section 20.3.1.
8.6.4.6 Thrombosis Prophylaxis
Thromboembolic events have been reported in patients who have VWD, especially in the 
setting of known risk factors for thrombosis including low ADAMTS13 levels. 
Therefore, subjects who are at risk for developing thromboembolic events should be 
monitored for early signs of thrombosis, and prophylaxis measures against
thromboembolism should be instituted according to current recommendations and 
standard of care. For all subjects who are VWD patients and are receiving VWF 
concentrate, attention should be given to avoid exceeding maximal recommended plasma 
activity levels of VWF:RCo (250 IU/dL) and FVIII (250 IU/dL).
Anticoagulation measures, such as heparin, are acceptable and should follow study site 
standards. The investigator will record the use and reasons for such measures/agents on 
the appropriate CRF.
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8.6.5 Investigational Product Accountability
The investigator will ensure that the IP(s) is stored as specified in the Pharmacy Manual
and that the storage area is secured, with access limited to authorized study personnel. All 
temperature excursions at the subject’s home need to be monitored by the site (please 
refer to the pharmacy manual). The investigator will maintain records that the IP(s) was 
received, including the date received, drug identity code, date of manufacture or 
expiration date, amount received and disposition. The IP(s) must be dispensed only at the 
study site or other suitable location (e.g., infusion center; home, as applicable per study 
design), as specified in the protocol (see Section 10). Records will be maintained that 
includes the subject identification code (SIC), dispensation date, and amount dispensed. 
All remaining partially used and/or unused IP(s) will be returned to the sponsor or 
sponsor’s representative after study completion/termination, or destroyed with the 
permission of the sponsor in accordance with applicable laws and study site procedures. 
If IP(s) is to be destroyed, the investigator will provide documentation in accordance with
sponsor’s specifications.
8.7 Source Data
Per ICH E6(R2) on GCP, source data are defined as all information in original records 
and certified copies of original records of clinical findings, observations, or other 
activities in a clinical trial that are necessary for the reconstruction and evaluation of the 
trial. Source data are contained in source documents (original records or certified copies). 
These may be in paper and/or electronic format. Source documents for this study 
comprise the following: hospital records, medical records, clinical and office charts, 
laboratory notes, memoranda, subjects' diaries or evaluation checklists, outcomes 
reported by subjects, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate copies, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, 
and records kept at the pharmacy, at the laboratories and at medico-technical departments 
involved in the clinical study.
No data will be entered directly onto the CRF.
For additional information on study documentation and CRFs refer to Section 17.2. The 
use of subject diaries is described in Section 10.5. 
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9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION
9.1 Inclusion Criteria
Subjects who meet ALL of the following criteria are eligible for this study:
1.
Subject has a documented diagnosis of severe VWD (baseline VWF:RCo 
<20 IU/dL) with a history of requiring substitution therapy with von Willebrand 
factor concentrate to control bleeding
a. Type 1 (VWF:RCo <20 IU/dL) or,
b. Type 2A (as verified by multimer pattern), Type 2B (as diagnosed by 
genotype), Type 2M or,
c. Type 3 (VWF:Ag ≤3 IU/dL).
2.
Diagnosis is confirmed by genetic testing and multimer analysis, documented in 
patient history or at screening.
3.
For on-demand patient group, subject currently receiving on-demand treatment for 
whom prophylactic treatment is recommended by the investigator.
4.
For pdVWF switch patient group, subject has been receiving prophylactic 
treatmentof pdVWF products for no less than 12 months prior to screening.
5.
For on-demand patient group, subject has ≥3 documented spontaneous bleeds (not 
including menorrhagia) requiring VWF treatment during the past 12 months.
6.
Availability of records to reliably evaluate type, frequency and treatment of 
bleeding episodes during at least 12 months preceding enrollment. Up to 
24 months retrospective data should be collected if available. Availability of 
dosing and factor consumption during 12 months (up to 24 months) of treatment 
prior to enrollment is required for pdVWF switch subjects and is desired (but not 
a requirement) for on-demand subjects.
7.
Subject is ≥18 years old at the time of screening and has a body mass index 
≥15 but <40 kg/m2.
8.
If female of childbearing potential, subject presents with a negative blood/urine 
pregnancy test at screening and agrees to employ adequate birth control measures 
for the duration of the study.i
9.
Subject is willing and able to comply with the requirements of the protocol.
                                                
i Refer to Section 20.4 for a list of adequate contraceptive methods for females of childbearing potential.
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9.2 Exclusion Criteria
Subjects who meet ANY of the following criteria are not eligible for this study:
1.
The subject has been diagnosed with Type 2N VWD, pseudo VWD, or another 
hereditary or acquired coagulation disorder other than VWD (eg qualitative and 
quantitative platelet disorders or prothrombin time (PT)/international normalized 
ratio [INR] 1.4).
2.
The subject is currently receiving prophylactic treatment with more than 
5 infusions per week.
3.
The subject is currently receiving prophylactic treatment with a weekly dose 
exceeding 240 IU/kg.
4.
The subject has a history or presence of a VWF inhibitor at screening.
5.
The subject has a history or presence of a FVIII inhibitor with a titer 
≥0.4 Bethesda units (BU) (by Nijmegen modified Bethesda assay) or ≥0.6 BU
(by Bethesda assay).
6.
The subject has a known hypersensitivity to any of the components of the study 
drugs, such as to mouse or hamster proteins.
7.
The subject has a medical history of immunological disorders, excluding seasonal 
allergic rhinitis/conjunctivitis, mild asthma, food allergies or animal allergies.
8.
The subject has a medical history of a thromboembolic event.
9.
The subject is human immunodeficiency virus (HIV) positive with an absolute 
Helper T cell (CD4) count 200/mm3.
10. The subject has been diagnosed with significant liver disease per investigator’s 
medical assessment of the subject’s current condition or medical history or as 
evidenced by any of the following: serum alanine aminotransferase (ALT) greater 
than 5 times the upper limit of normal; hypoalbuminemia; portal vein 
hypertension (e.g., presence of otherwise unexplained splenomegaly, history of 
esophageal varices).
11. The subject has been diagnosed with renal disease, with a serum creatinine (CR)
level ≥2.5 mg/dL.
12. The subject has a platelet count <100,000/mL at screening.
13. The subject has been treated with an immunomodulatory drug, excluding topical 
treatment (e.g., ointments, nasal sprays), within 30 days prior to signing the 
informed consent.
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14. The subject is pregnant or lactating at the time of enrollment.
15. Patient has cervical or uterine conditions causing menorrhagia or metrorrhagia 
(including infection, dysplasia).
16. The subject has participated in another clinical study involving another IP or 
investigational device within 30 days prior to enrollment or is scheduled to 
participate in another clinical study involving an IP or investigational device 
during the course of this study.
17. The subject has a progressive fatal disease and/or life expectancy of less than 
15 months.
18. The subject is scheduled for a surgical intervention.
19. The subject is identified by the investigator as being unable or unwilling to 
cooperate with study procedures.
20. The subject has a mental condition rendering him/her unable to understand the 
nature, scope and possible consequences of the study and/or evidence of an 
uncooperative attitude.
21. The subject is in prison or compulsory detention by regulatory and/or juridical 
order.
22. The subject is member of the study team or in a dependent relationship with one 
of the study team members which includes close relatives (i.e., children, 
partner/spouse, siblings and parents) as well as employees.
9.3 Delay Criteria
1.
If the subject has an acute bleeding episode or presents with an acute illness 
(e.g., influenza, flu-like syndrome, allergic rhinitis/conjunctivitis, non-seasonal 
asthma) the screening visit will be postponed until the subject has recovered.
9.4 Withdrawal and Discontinuation
Any subject may voluntarily withdraw (i.e., reduce the degree of participation in the 
study) consent for continued participation and data collection. The reason for withdrawal 
will be recorded on the End of Study CRF. Assessments to be performed at the 
termination visit (including cases of withdrawal or discontinuation) are described in 
Section 10.6 and Section 20.2. 
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Discontinuation (i.e., complete withdrawal from study participation) may be due to 
dropout (i.e., active discontinuation by subject) or loss to follow-up (i.e., discontinuation 
by subject without notice or action). Additionally, the investigator and sponsor have the 
discretion to discontinue any subject from the study if, in their judgment, continued 
participation would pose an unacceptable risk for the subject.
Subjects also will be withdrawn from treatment or discontinued from further study 
participation for the following reasons:
1.
The subject is scheduled for an extended treatment period 3 months with 
non-topical immunomodulating drugs other than anti-retroviral chemotherapy 
(e.g., -interferon, corticosteroid agents [equivalent to hydrocortisone greater than 
10 mg/day]) during the course of the study.
2.
Subjects with chronic hepatitis B or C develop ALT/AST levels exceeding 5 times 
the ULN for 1 month.
3.
Subjects who experience severe hypersensitivity reactions, e.g., anaphylaxis upon 
exposure to rVWF (vonicog alfa).
4.
Subjects who develop a neutralizing inhibitor to rVWF (vonicog alfa) and/or 
ADVATE (rFVIII, octocog alfa) (biological assays) that results in significant 
clinical effect, including but not limited to increasing the weekly dose of rVWF 
by > 50%.
5.
Subjects who demonstrate clinical signs of thromboembolic events.
6.
The subject becomes pregnant. IP exposure will be discontinued. Attempts will be 
made to follow the subject through completion of the pregnancy and up to 1 year 
post delivery, if feasible. The investigator will record a narrative description of 
the course of the pregnancy and its outcome. 
7.
The subject begins lactating. IP exposure will be discontinued. The investigator 
will record a narrative description of the course of the baby’s development. 
8.
The subject is not compliant with the prophylactic treatment regimen and does not 
adhere to the frequency of IP administration. Once >30% of infusions are missed 
within a visit interval (3 months), the subject will be discontinued from further 
participation in the study. 
9.
The subject repeatedly uses other VWF products for prophylaxis or for the 
treatment of bleeding episodes in the absence of an acceptable justification to the 
sponsor. 
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10. STUDY PROCEDURES
10.1 Informed Consent and Enrollment
Any patient who provides informed consent (i.e., signs and dates the informed consent 
form) is considered a subject enrolled in the study.
10.2 Subject Identification Code
The following series of numbers will comprise the SIC: protocol identifier (e.g., 071301) 
to be provided by the sponsor, 2- or 3-digit number study site number (e.g., 02) to be 
provided by the sponsor, and 3- or 4-digit subject number (e.g., 0003) reflecting the order 
of enrollment (i.e., signing the informed consent form). For example, the third subject 
who signed an informed consent form at study site 02 will be identified as Subject 
071301-020003. All study documents (e.g., CRFs, clinical documentation, sample 
containers, drug accountability logs, etc.) will be identified with the SIC. Additionally, a 
uniquely coded SIC(s) is permitted as long as it does not contain a combination of 
information that allows identification of a subject (e.g., collection of a subject’s initials 
and birth date would not be permitted), in compliance with laws governing data privacy.
10.3 Screening and Study Visits
The study site is responsible for maintaining a screening log that includes all subjects 
who provided informed consent. The log also will serve to document the reason for 
screening failure. All screening data will be collected and reported in CRF, regardless of 
screening outcome. If a subject is re-screened, the End of Study CRF should be 
completed, and a new ICF, new SIC and new CRF are required for that subject.
The overall study design is illustrated in the Figure 1. Details on the procedures to be 
performed at each study visit, including screening, are provided in Supplement 20.2
„Schedule of Study Procedures and Assessments“ and Supplement 20.3 „Clinical 
Laboratory Assessments“. 
10.3.1 Screening Visit
Written informed consent must be obtained from each subject before any study 
related procedures are performed. To initiate screening procedures, at least 72 hours 
must have elapsed since the last VWF administration for on-demand subjects and the 
subject must not be actively bleeding at the time of screening. For switch subjects, 
the usual interval between their pdVWF prophy infusions must have elapsed since 
the last VWF administration and the subject must not be actively bleeding at the 
time of screening. Multimer analysis and VWD gene mutation analysis should be 
performed at screening if not available in the subject’s medical history.
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The screening visit will be delayed if the subjects presents with an acute bleeding 
episodes or acute illness (e.g., influenza, flu-like symptoms, inflammatory diseases) until 
the event has resolved. All screening procedures and confirmation of eligibility shall take 
place within 42 days prior to the first infusion of IP. If the IP is not infused within 
42 days, all screening assessments except blood group, human leukocyte antigen (HLA), 
genetics, multimeric pattern and 
, must be repeated to reconfirm eligibility. Refer 
to Supplement 20.2 and Supplement 20.3. Upon completion of screening procedures, 
subject eligibility will be confirmed by the sponsor on a subject eligibility form before 
additional study procedures are undertaken. The subject will maintain a diary that will 
include infusion logs (see Section 10.5). The allocation of IP will be initiated after the 
subject has qualified for home treatment (see Section 8.6.4.3.2).
In the event of a subject experiencing a bleeding episode that requires treatment between 
the screening visit and the subsequent visit (i.e. initial PK assessment visit for on-demand 
subjects or prophylaxis initiation visit for switch subjects), the subject will be treated with 
rVWF (vonicog alfa). If rVWF (vonicog alfa) is not available for any reason, e.g., subject 
not yet trained on IP administration, study site visit for IP administration not feasible, 
etc., the subject may use his/her standard of care, such as commercial pdVWF/FVIII 
products, and the reason for the use of non-IP products should be clearly documented.
10.3.2 Baseline Visit – Initial PK Assessment (On-demand Subjects Only)
After screening and confirmation of eligibility on-demand subjects will undergo an initial 
PK assessment. Subjects will receive a dose of 50 ± 5 IU/kg rVWF:RCo to determine 
VWF and FVIII levels. Blood samples will be drawn within 30 minutes pre-infusion, and 
at 11 time points post-infusion (15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 
3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 
72 2 hours and 96 ± 2 hours). See Section 20.2 and Section 20.3. IP infusion vials from 
the same lot number should be used for all PK-assessments per subject. Samples for 
measurement of FVIII and VWF activity taken through to 6 hours post-infusion will be 
obtained from an extremity different from that used for the infusion of IP. Where needed, 
the phlebotomy site will be kept patent via an infusion of normal saline. In this event, at 
least 5 mL of blood will be collected and discarded before collection of the next test 
sample into a fresh syringe.
If the subject has a central venous catheter, the central line should be used to administer 
the infusion and a peripheral venipuncture should be used to collect the blood samples. 
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In the event that a blood sample must be drawn through the central line used for 
administration of IP, the line must first be flushed with at least 10 mL normal saline or 
other suitable catheter flush solution that does not contain anticoagulant. At least 5 mL of 
whole blood must be collected and discarded prior to obtaining the sample. 
If a subject experiences a bleeding episode during the PK assessment no subsequent 
blood sample will be drawn in that specific PK period. The guidance provided in 
Section 8.6.4.4 has to be followed for the treatment of the bleeding episode. The subject 
once recovered is eligible to repeat the PK assessment. 
For pdVWF switch subjects, PK profile will not be assessed until reaching steady state 
after initiation of prophylaxis (see Section 10.3.4). 
10.3.3 Prophylaxis Initiation Visit
The prophylaxis initiation visit will occur after the blood sample for the 96 hour PK 
assessment is drawn for on-demand subjects or within 42 days after screening and 
confirmation of eligibility for pdVWF switch subjects. The subject will receive the first 
rVWF (vonicog alfa) prophylactic dose of rVWF: RCo. Details on dose are provided in 
Section 8.6.4.3. 
Procedures and assessments at this visit include (but are not limited to): AEs, bleeding 
episodes, medications taken, and non-drug therapies. Within 2 hours prior the IP infusion, 
a physical examination will be performed. Vital signs will be assessed within 30 minutes 
prior to IP rVWF (vonicog alfa) infusion and 30 minutes ± 15 minutes after IP infusion.
Further details are provided in Supplement 20.2 and Supplement 20.3.
10.3.4 Initial Steady State PK-Assessment (pdVWF switch subjects only)
For pdVWF switch subjects, a full PK profile will be assessed at steady state conditions 
on two occasions. The initial PK assessment will be performed shortly after reaching 
steady state after starting prophylaxis dosing, which is suggested after 11 days post the 
1st, around prophylaxis dose #5-6. The 2nd PK assessment at steady state will be 
performed at the end of the study.
Blood samples will be drawn within 30 minutes pre-infusion, and at 11 time points 
post-infusion (15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 
6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours 
and 96 ± 2 hours). In case the dosing schedule does not permit the 96 hr sampling, 
this sampling time point can be omitted (See Section 11.6). IP infusion vials from 
the same lot number should be used for all PK-assessments per subject. 
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Samples for measurement of FVIII and VWF activity taken through to 6 hours post-
infusion will be obtained from an extremity different from that used for the infusion of 
IP. Where needed, the phlebotomy site will be kept patent via an infusion of normal 
saline. In this event, at least 5 mL of blood will be collected and discarded before 
collection of the next test sample into a fresh syringe.
If the subject has a central venous catheter, the central line should be used to administer 
the infusion and a peripheral venipuncture should be used to collect the blood samples. 
In the event that a blood sample must be drawn through the central line used for 
administration of IP, the line must first be flushed with at least 10 mL normal saline or 
other suitable catheter flush solution that does not contain anticoagulant. At least 5 mL of 
whole blood must be collected and discarded prior to obtaining the sample. 
If a subject experiences a bleeding episode during the PK assessment no subsequent 
blood sample will be drawn in that specific PK period. The guidance provided in 
Section 8.6.4.4 has to be followed for the treatment of the bleeding episode. The subject 
once recovered is eligible to repeat the PK assessment. In case of surgery or bleeding, the 
PK assessment should be performed after 11 days after 1st prophylactic dose after re-start 
of prophylactic regimen. See section 11.6 for more details.
10.3.5 Treatment of Bleeding Episodes
Treatment of bleeding episodes is described in detail in Section 8.6.4.4 and treatment of 
perioperative bleeding is described in detail in Section 8.6.4.5.
10.3.6 Perioperative Visits (only applicable if surgery is needed)
The perioperative visits from priming dose through postoperative day 14 will be required 
to check daily intra- and postoperative weight-adjusted dose of rVWF (vonicog alfa) with 
or without ADVATE (rFVIII, octocog alfa). Details on the procedures and assessments 
performed at each visit can be found in supplement tables in Section 20.2.1 and 
Section 20.3.1.
10.3.7 Follow-Up Visits 
Visits will be performed after the prophylaxis initiation visit at 1 month ± 1 week, 
2 months ± 1 week, and 3 months ± 2 weeks and thereafter every three months
± 2 weeks. Additional visits may occur if clinically indicated (see Section 10.3.8). 
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When possible, site visits should be scheduled on days when the subject is expected to 
infuse rVWF (vonicog alfa). Within 2 hours prior to the rVWF (vonicog alfa) IP infusion, 
a physical examination will be performed. Vital signs will be assessed within 30 minutes 
prior to IP infusion and 30 minutes ± 15 minutes after IP infusion. Incremental recovery 
(IR) will be determined at each follow-up visit based on VWF:RCo activity assessed 
prior to and after IP infusion.
The blood sample for IR analysis will be drawn within 30 minutes prior to IP infusion 
and 30 minutes ± 5 minutes after IP infusion. rVWF (vonicog alfa) will be infused at the 
regular prophylactic dose. For each subject’s recovery analysis IP infusion, vials from the 
same lot number should be used. 
Testing for VWF:RCo VWF:CB, rVWF:Ag, and FVIII:C level will be performed using 
the blood sample obtained before and after IP infusion. 
The blood sample prior to IP infusion will also be used for the assessment of neutralizing 
and binding antibodies, clinical chemistry and hematology. For on-demand subjects, a 
washout period of at least 72 hours after the last infusion applies before the blood draw 
for the immunogenicity assays. For switch subjects, the wash out period may be reduced 
to the time interval between their pdVWF prophy infusions Bleeding episodes and the 
hemostatic efficacy will be evaluated based on the review of the patient diary. See
Section 20.2 and Section 20.3. The evaluation of IP consumption and treatment 
compliance will be performed based on subject’s diary entries. If a subject is not 
compliant with the prophylactic treatment regimen and does not adhere to the required 
frequency of administration of IP infusions (>30% of infusions were missed within a visit 
interval [3 months]) the subject will be withdrawn from the study. 
At the 6 months ± 2 week visit an ECG will be performed and 
 data will be 
collected. 
For the hemostatic efficacy assessment the following information will be recorded by the 
subject in the patient diary: bleeding location, type, severity, onset and resolution date 
and time, infusion date and time, clinical efficacy according to the rating scale. If at any 
time during the study a subject’s bleeding episode does not adequately respond to rVWF 
(vonicog alfa) therapy, he/she will be evaluated for the presence of neutralizing and total 
binding antibodies. Refer to Section 12.9.3.2.
Further guidance on completing the subject’s diary will be provided to the subjects during 
training for home treatment (see Section 8.6.4.3.2).
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10.3.8 Unscheduled Visits
For any unscheduled visit (except for collection of IP) a clinical assessment will be 
performed as per the scheduled follow-up visits with the exception of 
, ECG, and 
IR determination (refer to Supplement 20.2 and Supplement 20.3).
Subjects who have more than one bleeding episode in 3 months, or an increased 
frequency of bleeding, should go to the study site for an unscheduled visit.
Follow-up visits after the subject has experienced a bleed may be requested by the 
investigator. Additional assessments may be required which are at the discretion of the 
investigator. 
10.3.9 End of Study PK Assessment and Study Termination Visit 
At the 12* month ± 2 week visit, a full PK analysis at steady state will be performed for 
both cohorts: on-demand and switch subjects. Blood samples will be drawn within 
30 minutes pre-infusion, and at 11 time points post-infusion (15 ± 5 minutes, 
30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 
24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours and 96 ± 2 hours) unless dosing 
schedule does not permit, in which case the 96 hr sampling can be omitted. If a subject 
experiences a bleeding episode during the PK assessment no subsequent blood sample 
will be drawn in that specific PK period. The guidance provided in Section 8.6.4.4 has to 
be followed for the treatment of the bleeding episode. The subject once recovered is 
eligible to repeat the PK assessment and the PK assessment should be performed after 
11 days after 1st prophylactic dose after re-start of prophylactic regimen. See section 11.6
for more details.
Refer to Supplement 20.2 and Supplement 20.3 for the other assessments to be performed 
at the PK assessment and study completion visits.
For on-demand subjects, a washout period of at least 72 hours is required between the PK
infusion and the study termination visit (at the time of the 96 hour postinfusion PK 
assessment). For switch subjects,  the wash out period may be reduced to the time interval 
between their rVWF (vonicog alfa) prophy infusions.Refer to Supplement 20.2 and 
Supplement 20.3 for the list of assessments to be performed at the termination visit.
Subjects will be offered the option to continue to receive rVWF (vonicog alfa) in a 
long-term continuation study*.
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* Study treatment period is extended by 3 months to accommodate participation in the 
continuation study for the qualified subjects and will be exercised only if the continuation study 
start up is delayed beyond the completion of subject’s 12-month visit. 
For subjects whose completion date is extended beyond the 12-month visit due to delay in 
continuation study start-up, the 12-month ± 2 weeks visit will be considered as a follow-up visit, 
and EOS visit will be performed once the subject can rollover into the continuation study, from 
12 month ± 2 weeks to 15 month ± 2 weeks post prophylaxis initiation visit, as applicable.. Both 
the 12-month ± 2 weeks visit rescheduled as a follow-up visit, and the rescheduled EOS visit will 
be recorded in the CRF. 
10.4 Medications and Non-Drug Therapies 
The following medications and non-drug therapies are not permitted within 30 days 
before study entry and during the course of the study:
Medications:

Immunomodulating drugs other than anti-retroviral chemotherapy (e.g.,
-interferon, or corticosteroid agents at a dose equivalent to hydrocortisone 
greater than 10 mg/day) and an extended treatment period 3 months.

Another investigational and/or interventional study drug (except rVWF and FVIII 
administered under the surgery protocol).
A subject who has taken any of these medications or received any of these non-drug 
therapies during the study will be withdrawn from the study. 
The following medications are permitted during the course of the study:

Antifibrinolytics (e.g., tranexamic acid, -amino caproic acid) or topical 
hemostats as needed, according to each institution’s standard of care. These may 
be used, in accordance with local standard clinical practice, as the initial or only 
treatment for minor and moderate bleeding events. However, if the bleeding has 
not stopped within 24 hour following administration of this non-VWF treatment, 
infusion(s) with rVWF (vonicog alfa) should be started per protocol

Emergent use of a VWF concentrate other than rVWF (vonicog alfa) may be 
permissible under certain circumstances (see Section 8.6.4.4.1)
Details of all adjunctive hemostatic medication used, including dose and reason for use, 
must be recorded in the eCRF.
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10.5 Subject Diary
An electronic subject diary will be provided to each subject at the screening visit to
record the following information:
1. IP infusions to include date, start and stop times of the infusion, number of vials 
utilized, and infusion volume for prophylactic treatment or treatment of 
spontaneous and traumatic bleeding episodes 
2. Details of bleeding episodes (site, type, severity and date/time of bleeding) and 
response to treatment as described in Section 8.6.4.4
3. Subjective hemostatic efficacy assessments
4. Untoward events/unwanted experiences
5. Concomitant medications (including immunizations) and non-drug therapies
6. Patient Reported Outcomes (PROs)
Subjects and/or their legally authorized representatives will be trained on use of the diary. 
The diary will be provided in electronic format and remain with the subject for the 
duration of the study. The investigator will review the diary for completeness and request 
missing information periodically and in a timely manner. The investigator will 
record/capture any unwanted experience reported by the subject which may qualify as an 
AE on the AE eCRF.
Infusions performed at the study site will first be recorded in the site’s source documents 
and not in the patient diary.
Subject entries in the diary will serve as source records. During study participation the 
investigator has access to the database holding the subject diary data. After study closure, 
the investigator will receive the diary records for their subjects, including audit trail 
records, in PDF format. The data will be transmitted to the CRF by a validated transfer. 
Paper diary may be utilized in rare case where electronic diary use is not possible.
10.6 Subject Completion/Discontinuation
A subject is considered to have completed the study when he/she ceases active 
participation in the study because the subject has, or is presumed to have completed all 
study procedures according with the protocol (with or without protocol deviations).
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Reasons for completion/discontinuation will be reported on the 
Completion/Discontinuation CRF, including: completed, screen failure, AE (e.g., death), 
discontinuation by subject (e.g., lost to follow-up [defined as 3 documented unsuccessful 
attempts to contact the subject], dropout), physician decision (e.g., pregnancy, 
progressive disease, non-compliance with IP/protocol violation(s), recovery), study 
terminated by sponsor, or other (reason to be specified by the investigator, e.g., technical 
problems). Regardless of the reason, all data available for the subject up to the time of 
completion/discontinuation should be recorded on the appropriate CRF. 
Every effort will be made to have discontinued subjects complete the study 
termination visit. If the termination visit is done as an additional, unscheduled 
visit, the assessment results shall be recorded with the termination visit. 
If a subject terminates participation in the study and does not return for termination visit, 
his/her last recorded assessments shall remain with the last visit. The reason for 
discontinuation will be recorded, and the data collected up to the time of discontinuation 
will be used in the analysis and included in the clinical study report. If additional 
assessments are required, the assessments shall be recorded separately. Assessments to be 
performed at the termination visit (including in cases of withdraw or discontinuation) can 
be found in Supplement 20.2 Schedule of Study Procedures and Assessments and 
Supplement 20.3 Clinical Laboratory Assessments.
In the event of subject discontinuation due to an AE, clinical and/or laboratory 
investigations that are beyond the scope of the required study observations/assessments 
may be performed as part of the evaluation of the event. These investigations will take 
place under the direction of the investigator in consultation with the sponsor, and the 
details of the outcome may be reported to the appropriate regulatory authorities by the 
sponsor. 
10.7 Procedures for Monitoring Subject Compliance
Subject compliance with the procedures of this study (treatment regimens and study 
visits) will be monitored by the investigator or/a licensed healthcare professional at the 
study site.
During the regular scheduled follow-up visits a direct review of the subject’s source data 
(e-diaries) will be performed at the sites and evaluated against the protocol requirements. 
In addition drug accountability will be evaluated at each follow-up study visit and the 
study termination visit by comparing the infusions recorded in the subject diary with
empty vials returned by each subject to the study site, and the study site’s dispensing 
record. Protocol deviations will be noted in the final report.
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11. ASSESSMENT OF EFFICACY AND PHARMACOKINETICS
11.1 Assessment of Spontaneous Bleeding Episodes/Annualized Bleed Rate 
The annualized bleed rate (ABR) will be assessed based upon each individual 
spontaneous bleed, requiring coagulation factor replacement therapy, i.e., rVWF 
(vonicog alfa) treatment. The following details on bleeding episodes will be recorded by 
the subject in the electronic diary (for home treatment), the subject’s healthcare provider 
in the site’s source documents (for treatments away from the primary investigative site), 
or by authorized, qualified personnel at the participating site in the subject’s medical 
records (for hospital-based treatment):

Location of bleed; i.e., joint, menorrhagia, epistaxis, gastrointestinal, soft tissue, 
muscle, body cavity, intracranial, etc.

Type of bleed; i.e., spontaneous, traumatic, unknown

Severity of bleed; i.e., minor, moderate, and major (see Table 3)

Date and time of onset of bleed

Date and time of each infusion of rVWF (vonicog alfa) or rVWF (vonicog alfa)-
ADVATE (rFVIII, octocog alfa) used to treat a bleeding episode

Date and time of resolution of the bleeding episode
Study site personnel are qualified after they have undergone training during the 
qualification of the site.
All types of bleeds, including traumatic bleeds, will be recorded. Bleeding episodes 
should be organized by where they occur in addition to whether they occurred 
spontaneously or due to a traumatic event.
Bleeds occurring at the same anatomical location (e.g., right knee) with the same etiology 
(i.e., spontaneous versus injury) within 24 hours after onset of the first bleed will be 
considered a single bleed. Bleeding occurring at multiple locations related to the same 
injury (e.g., knee and ankle bleeds following a fall) will be counted as a single bleeding 
episode.
All efforts should be made to use rVWF (vonicog alfa) for treatment of bleeding 
episodes. If needed, the use of a VWF concentrate other than IP for the treatment of 
bleeding episodes will not disqualify the subject from further participation in the study.
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11.2 Evaluation of ABR Before rVWF Prophylaxis and ABR Under rVWF
Prophylactic Treatment
At screening, the subject’s medical history will be recorded, including the number and 
location of all spontaneous and traumatic bleeding episodes within the past 12 months (up 
to 24 months if available). The maximum interval of bleed-free periods as well as trauma 
induced bleeding episodes will also be recorded (prospectively and retrospectively).
11.3 Number of Infusions and Total Weight Adjusted Consumption of rVWF and 
ADVATE and historical prophylaxis dosing and factor consumption during 
pdVWF prophylaxis treatment prior to enrollment
The number of rVWF (vonicog alfa) and ADVATE (rFVIII, octocog alfa) (in case of 
bleeding episode treatment) infusions will be logged in the subject diary. Based on these 
entries the weight adjusted consumption will be calculated. 
At the screening, historical pdVWF dosage and dosing frequency during 12 and up to 
24 months of pdVWF prophylactic treatment prior to enrollment will be recorded for the 
pdVWF switch subjects in order to calculate the consumption of pdVWF.
11.4 Assessment of Efficacy for Treatment of Bleeding Episode
Investigators will be asked to assess and record hemostatic efficacy after resolution of 
each bleeding episode using the 4-scale rating system outlined in Table 4. 
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Table 4
Efficacy Rating Scale
Rating
Efficacy Rating Criterion
Minor and Moderate Bleeding Events
Major Bleeding Events
Excellent (=1)
Actual number of infusions ≤ estimated 
number of infusions required to treat that 
bleeding episode
No additional VWF containing 
coagulation factor containing product 
required
Actual number of infusions ≤ estimated 
number of infusions required to treat that 
bleeding episode
No additional VWF containing coagulation 
factor containing product required
Good (=2)
1-2 infusions greater than estimated 
required to control that bleeding episode
No additional VWF containing 
coagulation factor containing product 
required
< 1.5 x infusions greater than estimated 
required to control that bleeding episode
No additional VWF containing coagulation 
factor containing product required
Moderate (=3)
3 or more infusions greater than estimated 
required to control that bleeding episode
No additional VWF containing 
coagulation factor containing product 
required
≥1.5 x infusions greater than estimated 
required to control that bleeding episode
No additional VWF containing coagulation 
factor containing product required
None (=4)
Severe uncontrolled bleeding or intensity 
of bleeding not changed
Additional VWF containing coagulation 
factor containing product required
Severe uncontrolled bleeding or intensity 
of bleeding not changed
Additional VWF containing coagulation 
factor containing product required
11.5 Assessment of Efficacy for Treatment for Surgical Bleeding
For those undergoing surgery, the operating surgeon will be asked to assess and record 
actual versus predicated blood loss and intraoperative hemostatic efficacy immediately 
after surgery. 
The investigator will be asked to assess and record an overall assessment of hemostatic 
efficacy 24 hours after the last perioperative rVWF (vonicog alfa) infusion or at day 14 
post-operation, whichever occurs first, using the 4-scale rating system described in 
Table 5.
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Table 5
Assessment of Hemostatic Efficacy
Rating
Overall Assessment of Hemostatic Efficacy 24 Hours After the Last Perioperative
rVWF Infusion
Excellent (1)
Intra- and post-operative hemostasis achieved with rVWF (vonicog alfa) with or without 
ADVATE (rFVIII, octocog alfa) was as good or better than that expected for the type of 
surgical procedure performed in a hemostatically normal subject
Good (2)
Intra- and post-operative hemostasis achieved with rVWF (vonicog alfa) with or without 
ADVATE (rFVIII, octocog alfa) was probably as good as that expected for the type of 
surgical procedure performed in a hemostatically normal subject
Moderate (3)
Intra- and post-operative hemostasis with rVWF (vonicog alfa) with or without ADVATE 
(rFVIII, octocog alfa) was clearly less than optimal for the type of procedure performed but 
was maintained without the need to change the rVWF (vonicog alfa) concentrate
None (4)
Subject experienced uncontrolled bleeding that was the result of inadequate therapeutic 
response despite proper dosing, necessitating a change of rVWF (vonicog alfa) concentrate
11.6 rVWF Pharmacokinetics and Pharmacodynamics 
PK will be assessed twice for all subjects.
For on-demand subjects, an initial PK assessment using a dose of 50 IU ± 5 IU/kg 
rVWF:RCo will be performed at the baseline visit, and a washout period of at least 
5 days is required before the infusion of rVWF (vonicog alfa) for PK assessment can 
be administered. At the 12 month ± 2 week visit, a steady state PK analysis will be 
performed based on the longer interval of the irregular dosing intervals employed. For 
both assessments, blood samples will be drawn within 30 minutes pre-infusion, and at 
11 time points post-infusion (15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 
3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 
72 2 hours and 96 ± 2 hours). VWF activity will be determined using the VWF:RCo, 
VWF:CB and the VWF: Ag assay. Endogenous FVIII activity will be measured using the 
1-stage clotting assay to assess the pharmacodynamics of rVWF (vonicog alfa). 
For pdVWF switch subjects, the initial PK assessment using the subject’s individualized 
dose will be performed shortly after reaching steady state, which is estimated to be 
reached for the majority of subjects after  approximately 11 days from the 1st prophylactic 
dose. To fit any logistical requirements, samples for PK analysis can be taken after 
prophylaxis dose #5-6, and whenever possible, sample collections should be during the 
longer partial interval of the alternating irregular dosing intervals. For example, if a 
subject follows a dosing regimen as follows:
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Date
Weekday
Dose number
Interval
Time from 1st dose in hours
8.1.18 8:00
Monday
1
0
0
12.1.18 8:00
Friday
2
4
96
15.1.18 8:00
Monday
3
3
168
19.1.18 8:00
Friday
4
4
264
22.1.18 8:00
Monday
5
3
336
26.1.18 8:00
Friday
6
4
432
After reaching the steady state, the PK assessment can be done at dose 5 to allow the 96h 
post-infusion sampling, before the next scheduled dose (for patients on a twice per week 
dosing schedule). A similar 2nd full PK profile will be assessed at the end of the study, i.e. 
12* month ± 2 week visit with a PK infusion at the same dosing partial interval (96h 
interval in this case). Blood samples will be drawn within 30 minutes pre-infusion, 
and at 11 time points post-infusion (15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 
3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 
72 2 hours, and 96 ± 2 hours). If the dosing interval for a certain switch subject 
wouldn’t allow for the full 11 post-infusion timepoints sample collection, the 96-hour 
sampling timepoint can be omitted, but it is critical that the assessments are at the same 
partial interval, thereby same number of sampling timepoints, for the 1st and 2nd PK for an 
individual switch subject.
If a subject experiences a bleeding episode during the PK assessment no subsequent 
blood sample will be drawn in that specific PK period. The guidance provided in 
Section 8.6.4.4 has to be followed for the treatment of the bleeding episode. The subject 
once recovered is eligible to repeat the PK assessment. In case of surgery or bleeding, the 
PK assessment should be performed after 11 days after 1st prophylactic dose after restart 
of prophylactic regimen.
* Study treatment period is extended by 3 months to accommodate participation in the 
continuation study for the qualified subjects and will be exercised only if the continuation study 
start up is delayed beyond the completion of subject’s 12-month visit.
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12. ASSESSMENT OF SAFETY
12.1 Adverse Events
12.1.1 Definitions
An AE is defined as any untoward medical occurrence in a subject administered IP that 
does not necessarily have a causal relationship with the treatment. An AE can therefore 
be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom 
(e.g., rash, pain, discomfort, fever, dizziness, etc.), disease (e.g., peritonitis, bacteremia, 
etc.), or outcome of death temporally associated with the use of an IP, whether or not 
considered causally related to the IP.
12.1.1.1 Serious Adverse Event 
An SAE is defined as an untoward medical occurrence that, at any dose, meets one or 
more of the following criteria:

Outcome is fatal/results in death (including fetal death)

Is life-threatening – defined as an event in which the subject was, in the judgment 
of the investigator, at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death had it been more severe.

Requires inpatient hospitalization or results in prolongation of an existing 
hospitalization – inpatient hospitalization refers to any inpatient admission, 
regardless of length of stay.

Results in persistent or significant disability/incapacity (i.e., a substantial 
disruption of a person’s ability to conduct normal life functions)

Is a congenital anomaly/birth defect

Is a medically important event – a medical event that may not be immediately 
life-threatening or result in death or require hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the definitions above. Examples of such events are (including 
but not limited to): 

Intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias, or convulsions that do not result in 
hospitalization, or development of drug dependence or drug abuse 

Reviewed and confirmed seroconversion for HIV, hepatitis A virus (HAV), 
hepatitis B virus (HBV), hepatitis C virus
(HCV), hepatitis E virus (HEV), or parvovirus B19 (B19V)
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
Development of clinically significant neutralizing VWF antibodies

Development of neutralizing antibodies to FVIII (titer ≥0.4 BU [by 
Nijmegen- modified Bethesda assay] or ≥0.6 BU [by Bethesda assay])

Thromboembolic events (e.g., myocardial infarction, stroke, transient 
ischemic attack [TIA], deep vein thrombosis [DVT] or pulmonary 
embolism)

Hypersensitivity reactions (e.g., anaphylaxis [for definition, refer to 
Section 12.6.2] and other immediate and delayed hypersensitivity reactions 
which may manifest with urticarial rash, pruritus, flushing, angioedema of 
the face, extremities, or laryngeal tissues [leading to throat tightness with 
stridor], wheezing, gastrointestinal symptoms, and/or hypotension) 
Uncomplicated pregnancies, following maternal or paternal exposure to IP are not 
considered an AE/SAE; however, any pregnancy complication or pregnancy termination 
by therapeutic, elective, or spontaneous abortion shall be considered an SAE and should 
be reported per SAE reporting guidelines provided in Section 12.1.2.3 (Safety Reporting).
12.1.1.2 Suspected Unexpected Serious Adverse Reaction (SUSAR)
Any suspected adverse reaction to study treatment that is both serious and unexpected is 
considered a SUSAR. 
The event(s) must meet all of the following:

Suspected adverse reaction (which implies that there is reasonable evidence 
indicating a causal relationship between the event and the study treatment),

Unexpected (per Reference Safety Information (RSI)/IB), and

Serious
Once determined to meet the criteria for a SUSAR, the sponsor will ensure expedited 
SUSAR reporting is completed in line with the regulatory requirements in participating 
countries as outlined in the Safety Management Plan. 
12.1.1.3 Non-Serious Adverse Event
A non-serious AE is an AE that does not meet any of the seriousness criteria (death, 
life-threatening, hospitalizing/prolongation of hospitalization, disability, congenital 
anomaly, or medically significant and if not urgently treated would result in one of the 
above) listed in section 12.1.1.1.
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12.1.1.4 Unexpected Adverse Events
An unexpected adverse event is an AE whose nature, severity, specificity, or outcome is 
not consistent with the term, representation, or description used in the Reference Safety 
Information (e.g., IB, PI [prescribing information]). “Unexpected” also refers to the AEs 
that are mentioned in the IB as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring 
with the particular drug under investigation.
12.1.1.5 Preexisting Disease
Preexisting diseases that are present before entry in to the study are described in the 
medical history, and those that manifest with the same severity, frequency, or duration 
after IP exposure will not be recorded as AEs. However, when there is an increase in the 
severity, duration, or frequency of a preexisting disease, the event must be described as 
“worsening” of the pre-existing condition on the AE CRF.
12.1.2 Assessment of Adverse Events
For the purposes of this study, the following will not be considered as AEs and will not 
be included in the analysis of AEs.

Bleeding episodes are part of the underlying disease and therefore are not AEs; 
they will be evaluated in the context of efficacy.

For non-serious bleeding episodes caused by an injury, the injury would not 
be reported as an AE, unless it resulted in a medical finding other than a 
bleeding episode (e.g., abrasion of skin). Therefore, any VWD-related 
bleeding event (e.g., epistaxis, gastrointestinal bleeding, musculo-skeletal 
bleeding, menorrhagia) that is non-serious will not be reported as an AE. 
However, the investigator may decide that the event is an AE if the event also 
would have occurred in a healthy individual under the same circumstances.

For serious bleeding episodes (bleeding SAEs): Bleeding events that meet 
seriousness criteria (death, life-threatening, hospitalizing/prolongation of 
hospitalization, disability, congenital anomaly, or medically significant and if 
not urgently treated would result in one of the above) should be captured on 
the SAE eCRF and reported as an SAE to the Sponsor or designee (e.g., 
CRO) on an SAE Report form as described in Section 12.1.2.3 (Safety 
Reporting).

Seroconversion after documented HAV/HBV vaccination prior to or during the 
study period.
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Each AE from the first IP exposure to the study completion date will be described on the 
AE CRF using the term representing medical diagnosis (preferred), or, if no diagnosis 
could be established at the time of reporting the AE, a symptom or sign, in standard 
medical terminology in order to avoid the use of vague, ambiguous, or colloquial 
verbatim expressions (see definition in Section 12.1). Each AE will be evaluated by the 
investigator for:

Seriousness as defined in Section 12.1.1.1

Severity as defined in Section 12.1.2.1

Causal relationship to IP exposure or study procedure as defined in 
Section 12.1.2.2
For each AE, the outcome (i.e., recovering/resolving, recovered/resolved, 
recovered/resolved with sequelae, not recovered/not resolved, fatal, unknown) and if 
applicable, action taken with regards to the study treatment (i.e., dose increased, dose not 
changed, dose reduced, drug interrupted, drug withdrawn, not applicable, or unknown) 
will also be recorded on the AE CRF. Recovering/resolving AEs will be followed until 
resolution or until the subject’s condition returns to the level at the baseline for pre-
existing conditions. 
If the severity rating for an ongoing AE changes before the event resolves, the original 
AE report will be revised (i.e., the event will not be reported as separate AE). During the 
course of any AE, the highest severity rating will be reported.
Deviations from the protocol-specified dosage (including underdosing /overdosing 
[<20 IU/kg rVWF:RCo or >100 rVWF:RCo], abuse, and withdrawal, treatment errors 
(including incorrect route of administration, use of an incorrect product, and deviations 
from the protocol-defined dosing schedule), failures of expected pharmacological actions, 
and unexpected therapeutic or clinical benefits will be followed with regard to occurrence 
of AEs, lack of efficacy, and/or other observations because these events may be 
reportable to regulatory authorities. 
Any pregnancy that occurs after administration of IP will be reported on a Pregnancy 
Form and followed-up at 1 year post-delivery, if feasible. 
If an investigator becomes aware of an SAE occurring in a subject after study completion, 
the SAE must be reported on the SAE Form within 24 hours after awareness: no 
additional reporting on CRFs is necessary.
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12.1.2.1 Severity
The investigator will assess the severity of each AE using his/her clinical expertise and 
judgment based on the most appropriate description below:

Mild
The AE is a transient discomfort and does not interfere in a significant manner 
with the subject’s normal functioning level.
The AE resolves spontaneously or may require minimal therapeutic 
intervention.

Moderate
The AE produces limited impairment of function and may require therapeutic 
intervention.
The AE produces no sequela/sequelae.

Severe
The AE results in a marked impairment of function and may lead to temporary 
inability to resume usual life pattern.
The AE produces sequela/sequelae, which require (prolonged) therapeutic 
intervention.
These severity definitions will also be used to assess the severity of an AE with a study-
related procedure(s), if necessary.
12.1.2.2 Causality
Causality is a determination of whether there is a reasonable possibility that the IP is 
etiologically related to/associated with the AE. Causality assessment includes, e.g., 
assessment of temporal relationships, dechallenge/rechallenge information, association 
(or lack of association) with underlying disease, presence (or absence) of a more likely 
cause, and physiological plausibility. For each AE, the investigator will assess the causal 
relationship between the IP and the AE using his/her clinical expertise and judgment 
according to the following most appropriate algorithm for the circumstances of the AE:

Not related (both circumstances must be met)
Is due to underlying or concurrent illness, complications, concurrent 
treatments, or effects of concurrent drugs
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Is not associated with the IP (i.e., does not follow a reasonable temporal 
relationship to the administration of IP, is not biologically plausible per 
mechanism of action of the IP, or has a much more likely alternative etiology). 

Unlikely related (either 1 or both circumstances are met)
Has little or no temporal relationship to the IP 
A more likely alternative etiology exists

Possibly related (both circumstances must be met)
Follows a reasonable temporal relationship to the administration of IP
An alternative etiology is equally or less likely compared to the potential 
relationship to the IP

Probably related (both circumstances must be met)
Follows a strong temporal relationship to the administration of IP, which may 
include but is not limited to the following: 
o
Reappearance of a similar reaction upon re-administration (positive re-
challenge)
o
Positive results in a drug sensitivity test (skin test, etc.)
o
Toxic level of the IP as evidenced by measurement of the IP 
concentrations in the blood or other bodily fluid
Another etiology is unlikely or significantly less likely
For events assessed as not related or unlikely related and occurring within 5 days after IP 
infusion, the investigator shall provide the alternative etiology. These causality 
definitions will also be used to assess the relationship of an AE with a study-related 
procedure(s), if necessary.
12.1.2.3 Safety Reporting
AEs and SAEs will be assessed at all study visits as outlined in the Schedule of Study 
Procedures and Assessments (see Section 20.2) and Section 12.1.2.
Adverse Events and SAEs are to be recorded on the AE page of the eCRF. Each event 
should be recorded separately.
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Any SAE, including death due to any cause, which occurs during this study, whether or 
not related to the IP, must be reported immediately (within 24 hours of the study center’s 
first knowledge of the event). All SAEs must be reported in English via the Electronic 
Data Capture (EDC) system by completing the relevant eCRF page(s) and also by SAE 
Report Form via fax/email to Sponsor’s Global Drug Safety (Baxalta GDS) department 
within 24 hours of becoming aware of the event for SAEs (for contacts, instructions, and
additional details, refer to the SAER form).
Within 24 hours of site awareness of a SAE (or Pregnancy) study sites will complete and 
send all SAE (or Pregnancy) reports to a dedicated:
Baxalta Global Drug Safety fax number:  
OR 
email: 
The responsible Site Monitor will review the SAE (or Pregnancy) Reports for 
completeness, will reconcile the reports against the EDC database, and will follow-up 
with sites to obtain missing information and/or information requiring clarification. Any 
SAE associated with a pregnancy must be reported on the SAER Form.
For Follow-up Reports, the site shall use a new SAER form (marked as Follow-up) and 
the new information should be entered together with a brief narrative identifying the 
updated data. 
An SAER should include the following minimum information:
1.
Protocol Number (on all pages)
2.
Subject identification number (on all pages) and demographics (gender, age at 
onset of event and/or date of birth)
3.
Investigational product and treatment regimen (including date of the first dose of 
IP, date of the last dose of IP prior to the onset of the SAE)
4.
Medical Term for Event (Diagnosis preferably) 
5.
Description of the SAE, including:

Date of onset

Causal relationship assessment by the Investigator
6.
Seriousness criteria (e.g., death, life-threatening, hospitalization, medically 
significant, or other criterion)
7.
Name, address, fax number, email, and telephone number of the 
reporter/Investigator 
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Post-trial SAE Reporting: In compliance to EudraLex Volume 10 (Clinical trials 
guidelines, Chapter II: Safety Reporting from the European Commission), which 
references an EMA guidance (ICH Topic E 2 A - Clinical Safety Data Management: 
Definitions and Standards for Expedited Reporting), clinical sites/the investigator should 
report to the Sponsor SAEs after a subject´s study completion. Study sites will be 
provided a Post-Trial SAER form to complete and report these post-study SAEs to the 
Sponsor within the 24 hours of their awareness. Site Monitor will instruct the site that any 
such Post-Trial SAEs should be reported on the study-specific Post-Trial SAER form 
if/when the site becomes aware of it. Such information will not be actively monitored by 
the sponsor after completion of the study.
These events shall be reported to Baxalta GDS who will process them in the same way as 
SAEs occurring during the study. Post-Trial SAEs do not need to be captured in the study 
EDC database if it is already locked. Irrespective if captured in the EDC database or not, 
such Post-Trial SAEs will become part of the GDS database. The monitor should remind 
the clinical site about the post-trial SAE reporting requirements during interim 
monitoring visits, upon each subject’s study completion as well as during the close-out 
visit.
12.2 Urgent Safety Measures
An urgent safety measure is an immediate action taken, which is not defined by the 
protocol, in order to protect subjects participating in a clinical trial from immediate harm. 
Urgent safety measures may be taken by the sponsor or clinical investigator, and may 
include any of the following: 

Immediate change in study design or study procedures

Temporary or permanent halt of the clinical trial 

Any other immediate action taken in order to protect clinical trial participants 
from immediate hazard to their health and safety
The investigator may take appropriate urgent safety measures in order to protect subjects 
against any immediate hazard to their health or safety. The measures should be taken 
immediately and may be taken without prior authorization from the sponsor. 
In the event(s) of an apparent immediate hazard to the subject, the investigator will notify 
the sponsor immediately by phone and confirm notification to the sponsor in writing as 
soon as possible, but within 1 calendar day after the change is implemented. The sponsor 
will also ensure the responsible ethics committees (ECs) and relevant competent 
authority(s) are notified of the urgent measures taken in such cases according to local 
regulations.
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12.3 Untoward Medical Occurrences
Untoward medical occurrences occurring before the first exposure to IP are not 
considered AEs (according to the definition of AE, see Section 12.1.1). However, each 
serious untoward medical occurrence experienced before the first IP exposure (i.e., from 
the time of signed informed consent up to but not including the first IP exposure) will be 
described on the SAER. These events will not be considered as SAEs and will not be 
included in the analysis of SAEs. 
12.4 Non-Medical Complaints
A non-medical complaint (NMC) is any alleged product deficiency that relates to 
identity, quality, durability, reliability, safety and performance of the product but did not 
result in an AE. NMCs include but are not limited to the following:

A failure of a product to exhibit its expected pharmacological activity and/or 
design function, e.g. reconstitution difficulty

Missing components

Damage to the product or unit carton

A mislabeled product (e.g., potential counterfeiting/tampering)

A bacteriological, chemical, or physical change or deterioration of the product 
causing it to malfunction or to present a hazard or fail to meet label claims
Any NMCs of the product will be documented on an NMC form and reported to the 
sponsor within 1 business day. If requested, defective product(s) will be returned to the 
sponsor for inspection and analysis according to procedures.
12.5 Medical, Medication, and Non-Drug Therapy History
At screening, the subject’s medical history will be described for the following body 
systems including severity (defined in Section 12.1.2.1) or surgery and start and end 
dates, if known: eyes, ears, nose, and throat; respiratory; cardiovascular; gastrointestinal; 
musculoskeletal; neurological; endocrine; hematopoietic/lymphatic; dermatological; and 
genitourinary. The subject’s medical history will also include documented history of 
on-demand or pdVWF prophylaxis treatment for at least the past 12 months and a 
documented history, e.g., patient charts and prescription information, of all bleeding 
episodes within the past 12 months (up to 24 months if available).
All medications taken and non-drug therapies received in the 2 weeks prior to study entry 
and all concomitant medications and non-drug therapies during study will be recorded on 
the CRFs.
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Data on medical history, drug and non-drug therapy history of those subjects who 
transition from surgery rVWF (vonicog alfa) study will be used from the eCRF of the 
main studies, will be updated, if applicable, and transcribed into the respective eCRF of 
the prophy study. 
12.6 Physical Examinations
At screening and subsequent study visits (as described in Section 10.3), a physical 
examination will be performed on the following body systems: general appearance, head 
and neck, eyes and ears, nose and throat, chest, lungs, heart, abdomen, extremities and 
joints, lymph nodes, skin, and neurological. At screening, if an abnormal condition is 
detected, the condition will be described on the medical history CRF. At study visits, if a 
new abnormal or worsened abnormal pre-existing condition is detected, the condition will 
be described on the AE CRF. If the abnormal value was not deemed an AE because it 
was due to an error, due to a preexisting disease (described in Section 12.1.1.5), not 
clinically significant, a symptom of a new/worsened condition already recorded as an AE, 
or due to another issue that will be specified, the investigator will record the justification 
on the source record.
12.6.1 Thromboembolic Events
There is a risk of occurrence of thrombotic events, particularly in patients with known 
clinical or laboratory risk factors for thrombosis including low ADAMTS13 levels.  
Therefore, patients at risk must be monitored for early signs of thrombosis during the 
study and prophylaxis measures against thromboembolism should be instituted according 
to current recommendations and standard of care. Additional diagnostic procedures are 
required according to each institution’s standard of care which may consist of, but are not 
limited to the following:

For DVT: Magnetic Resonance Imaging (MRI), compression ultrasound or 
impedance plethysmography.

For pulmonary embolism: ECG, chest radiography, perfusion/scintiscan or MRI. 

For myocardial infarction: ECG, cardiac enzymes, echocardiography

For stroke: diffusion-weighted magnetic resonance imaging or computed 
tomography, ABCD scoring, carotid imaging 
Results of diagnostic procedures may be forwarded to the sponsor to be reviewed by an 
independent external expert panel, such as the DMC, if applicable.
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12.6.2 Anaphylaxis
The diagnosis of anaphylaxis is highly likely when any of the following 3 criteria are 
fulfilled:
1.
Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue or both (e.g, generalized urticaria, pruritus or flushing, swollen 
lips-tongue-uvula) and at least one of the following:
a. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced peak expiratory flow [PEF], hypoxemia)
b. Reduced blood pressure (BP) or associated symptoms of end-organ 
dysfunction (e.g., hypotonia [collapse], syncope, incontinence)
2.
Two or more of the following that occur rapidly after exposure to a likely allergen 
for that patient (minutes to several hours):
a. Involvement of the skin or mucosal tissue (e.g., generalized urticaria, pruritus 
or flushing, swollen lips-tongue-uvula)
b. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced PEF, hypoxemia)
c. Reduced BP or associated symptoms (hypotonia [collapse], syncope, 
incontinence)
d. Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)
3.
Reduced BP after exposure to a known allergen for that patient (minutes to 
several hours):
a. Infants and children: low systolic BP (age specific) or greater than 30% 
decrease in systolic BP
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from 
that person’s baseline BP
If a subject develops anaphylaxis in the course of the clinical study, this needs to be 
reported as SAE (Section 12.1.1.1). Additional blood will be drawn for Anti-VWF IgE 
antibody testing (Section 12.9.13).
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12.7 Vital Signs
Vital signs will be assessed pre- and post-infusion at each visit, if not stated otherwise:

Height (cm) (Screening only) and weight (kg) (pre-infusion only)

Blood pressure: Systolic/diastolic blood pressure (mmHg) baseline measurements 
will be measured after a 10-minute rest in the supine/semi-recumbent position.

Pulse rate: Pulse rate (beats/min) will be measured at the distal radial arteries 
under the same conditions as above.

Respiratory rate: Respiratory rate (breaths/min) will be measured over a period of 
1 minute under the same conditions as above.

Temperature: Body temperature (oC or oF) may be determined by oral, rectal, 
axillary, or tympanic measurement at the discretion of the investigator. However, 
the same method should be used for all measurements in 1 subject.
Vital signs (pulse rate, respiratory rate, and blood pressure) should be recorded within 
30 min before and after IP administration. The assessment of vital signs per planned 
study visit is outlined in Supplement 20.2.
Vital sign values are to be recorded on the physical examination eCRF. For each vital 
sign value, the investigator will determine whether the value is considered an AE (see 
definition in Section 12.1). If assessed as an AE, the medical diagnosis (preferably), 
symptom, or sign, will be recorded on the AE eCRF. Additional tests and other 
evaluations required to establish the significance or etiology of an abnormal result, or to 
monitor the course of an AE, should be obtained when clinically indicated. Any abnormal 
value that persists should be followed at the discretion of the investigator.
12.8 Electrocardiogram 
A standard 12-lead ECG at rest will be performed at screening, at the 6 month follow-up 
visit and at the study termination visit and evaluated for medical significance by the 
investigator.
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12.9 Clinical Laboratory Parameters
Refer to the Laboratory Manual for information on collection and processing of samples.
In general all laboratory tests will be performed at central laboratories, except the 
pregnancy and blood group test which will be performed at the local laboratory. In 
addition, relevant critical safety laboratory tests for complete blood count (CBC), serum 
chemistry and/or coagulation parameters such as VWF and FVIII activity may also be 
performed in the local laboratory to ensure that results will be available immediately to 
the investigator. In principle, results from the central laboratory will be used for data 
analysis purposes. The assays performed in the central laboratories are specified in the 
Laboratory Manual. The investigator will supply the sponsor with a list of the normal 
ranges and units of measurement for the laboratory variables to be determined at the site. 
Laboratory values such as antibodies to other proteins are not required immediately and 
will be assessed later during the course of the study. 
Any abnormal laboratory value that is considered clinically significant by the investigator 
based on a local laboratory test result (reference range and the units to be provided) 
should be confirmed by a central laboratory test result for which the sample is 
drawn/collected within 24 hours of the abnormal finding by the local laboratory.
12.9.1 rVWF Pharmacokinetics and Pharmacodynamics
Details on pharmacokinetic and pharmacodynamics assessments are provided in 
Section 11.6.
12.9.2 Hematology and Clinical Chemistry
The hematology panel will consist of CBC [hemoglobin, hematocrit, erythrocytes (ie, red 
blood cell count [RBC]; mean corpuscular volume [MCV], mean corpuscular hemoglobin 
(MCH), mean corpuscular hemoglobin concentration [MCHC]), and leukocytes (i.e., 
white blood cell count [WBC])] with differential (i.e., basophils, eosinophils, 
lymphocytes, monocytes, neutrophils) and platelet counts.
The clinical chemistry panel will consist of sodium (Na), potassium (K), chloride (Cl), 
ALT, lactate dehydrogenase (LDH), aspartate aminotransferase (AST), bilirubin, alkaline 
phosphatase (AP), blood urea nitrogen (BUN), CR, and glucose (Glu).
Blood will be obtained for assessment of hematology and clinical chemistry parameters 
at screening, during PK-assessment prior to rVWF (vonicog alfa) IP infusion, after 
24 ± 2 hours, 48 ± 2 hours and 72 ± 2 hours post rVWF (vonicog alfa) IP infusion, at all 
follow-up visits as per schedule (refer to Supplement 20.3 Clinical Laboratory 
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Assessments), i.e., 4 weeks ± 1 week, 8 weeks ± 1 week and every 3 months ± 2 weeks, 
and at study completion. Hematology and clinical chemistry assessments will be 
performed on Ethylenediaminetetraacetic acid (EDTA)-anticoagulated whole blood and 
serum, respectively, at the central laboratory.
12.9.3 Immunology
12.9.3.1 Antibodies to VWF and FVIII
All subjects will be tested for binding and neutralizing antibodies to VWF and FVIII at 
screening, at initial PK assessment, at each of the scheduled follow-up visits and at the 
study completion visit. Testing will be done prior to IP infusion and with at least a 
72 hour wash out period since the last IP infusion. If there is any suspicion of inhibitor 
development (e.g. excessive bleeding) binding and neutralizing antibodies to VWF and 
FVIII may be tested at the discretion of the investigator. 
12.9.3.2 Neutralizing and Total Binding Anti-VWF Antibodies
The assays to establish the presence of neutralizing and total binding anti-VWF 
antibodies have been established in the absence of international standards and with only 
limited numbers of positive controls. Therefore, caution is advised in interpreting positive 
results. In particular, any clinical association, changes in the natural history of the 
disease, effect of therapy, etc. needs to be taken into account for final judgment. 
The sponsor’s Medical Director should be consulted for additional advice. As part of the 
AE follow-up, any sample testing positive needs to be confirmed after 2-4 weeks for 
central laboratory testing. Only confirmed neutralizing anti -VWF antibodies are 
considered inhibitors (see Section 12.9.3.4). These subjects need to be closely monitored 
and therapy adjusted accordingly. 
12.9.3.3 Binding antibodies to VWF 
The presence of total binding anti-VWF antibodies will be determined by an enzyme-
linked immunosorbent assay (ELISA) employing polyclonal anti-human Immunoglobulin
(Ig) antibodies (IgG, IgM and IgA). For this assay (ELISA), recombinant human VWF 
will be coated onto a microtiter plate, then incubated with dilutions of the positive 
control, the negative control or test sample. Antibodies against human VWF that are 
present in the samples bind to the coated antigen and will be detected with a horseradish 
peroxidase (HRP)-coupled goat anti-human antibody (secondary antibody). The positive 
control for this assay will be a human monoclonal antibody specific for human VWF 
spiked into the negative control. The negative control for this assay is pooled normal 
human plasma.
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Plasma samples are analyzed for binding antibodies against the specific antigen in two 
steps. First, the sample is screened for antibodies and the titer of binding antibodies is 
determined. Second, the specificity of positive antibody results is confirmed.16
In brief, all samples are serially diluted (initial dilution 1:20 and further diluted 1:2).
The titer endpoint, defined as the highest dilution that still gives a positive signal above 
cut off level, is determined in two independent duplicates. The cut off level is established 
based on background signal level of healthy plasma donors (n=160) and set to include 5% 
false positives to be as sensitive as possible (95% percentile). The ELISA assay is 
validated allowing an assay variability of ± 1 titer step. Therefore, differences ≤ 2 titers 
steps may be due to variability of the ELISA assay. Specificity has to be confirmed in a 
competition assay when a sample has a titer of 1:80 or higher in the screening assay. 
Based on the validation criteria samples tested in the screening assay at 1:20 or 1:40 
cannot be confirmed in the competition assay. A positive screening value is confirmed if 
the difference between the titers determined for the subject sample (re-screen) and for the 
subject sample with pre-incubation (confirmation sample) is > 2 titer steps. Antibody 
titers of subject samples will only be reported as positive, if the results of the screening 
and confirmatory analysis fulfill these acceptance criteria. The titer to be reported is 
always the one determined in the original screening procedure (independent of the result 
of the re-screening in the confirmation procedure). 
A more detailed test procedure will be supplied upon request or pro-actively if a sample 
tests positive. A treatment related increase of the binding anti-VWF antibodies is 
expected, if the titer increases by more than 2 titration steps. These subjects need to be 
closely monitored and therapy adjusted accordingly.
12.9.3.4 Neutralizing Antibodies to VWF
Three functional VWF assays, VWF:CB, VWF:RCo and VWF:FVIIIB assays, will be 
used to test for the presence of neutralizing anti-VWF antibodies. Neutralizing antibodies 
to VWF:RCo, VWF:CB and VWF:FVIIIB activities will be measured by assays based on 
the Bethesda assay established for quantitative analysis of FVIII inhibitors (Nijmegen 
modification of the Bethesda assay).17 The amount of inhibitor is expressed as BU per 
mL. One BU is thereby defined as the amount of inhibitor that decreases the measured 
activity in the assays to 50% of that of the negative control samples. The assays were 
validated using human plasma samples from two type 3 VWD patients with low 
(1-2 BU/mL) and high (~10 BU/mL) titer inhibitors and plasma samples from 
non-human primates immunized with human rVWF (vonicog alfa) (>100 BU/mL).
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If a subject has a measurable baseline level of VWF activity in the respective assay, it is 
taken into account in the calculation of the residual activity. However, if baseline levels 
are too high (>15% VWF:RCo), inhibitors may not be reliably detected.
To exclude false positive results, the detection limit for anti-VWF inhibitors was set to 
1 BU/ml for all 3 assays. The rationale for this cut-off value is the relatively high CI of 
the underlying assays, making determinations at the end of the evaluation range of the 
Bethesda reference curve uncertain.18 A more detailed test procedure may be requested to 
further characterize the anti-VWF inhibitors, if detected.
Only confirmed positive anti-VWF inhibitor test result will be reported and will be
considered as a medically significant SAE.
12.9.3.5 Binding Antibodies to FVIII
Binding antibodies against FVIII will be analyzed using a proprietary enzyme 
immunoassay. The testing strategy will be as described for binding anti-VWF antibodies. 
Antibody-containing samples will be identified in a screening assay followed by a 
confirmatory assay to exclude false positive results.
12.9.3.6 Neutralizing Antibodies (Inhibitors) to FVIII 
Neutralizing antibodies (inhibitors) to FVIII will be assessed by the Nijmegen 
modification of the Bethesda assay in a central laboratory. To verify a FVIII inhibitor, 
additional testing (such as tests for Lupus anticoagulants) may be initiated. Positive FVIII 
inhibitor tests will be defined as ≥0.4 BU by the Nijmegen-modified Bethesda assay that 
is confirmed by a second test performed on an independent sample obtained 2-4 weeks 
following the first test. Only confirmed positive FVIII inhibitor test result will be 
reported.
12.9.4 Antibodies to Other Proteins
Plasma will be assayed for the presence of antibodies against CHO protein (total Ig), 
murine IgG and human Furin (total Ig) using proprietary enzyme immunoassays. The 
testing strategy will be as described for binding anti- VWF antibodies. 
Antibody-containing samples will be identified in a screening assay followed by a 
confirmatory assay to exclude false positive results.
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12.9.4.1 Anti-CHO Protein
Total Ig antibodies (IgG, IgA, IgM) against CHO protein will be analyzed. For this assay 
(ELISA), CHO protein derived from cultures of untransfected cells and propagated under 
the identical cell culture conditions used for ADVATE (rFVIII, octocog alfa) production 
will be coated onto a microtiter plate, then incubated with dilutions of the positive 
control, negative control or test sample. Antibodies against CHO protein that are present 
in the samples bind to the coated antigen and will be detected with a HRP-coupled goat 
anti-human antibody (secondary antibody). The positive control for this assay will be a 
polyclonal goat anti-CHO protein antibody spiked into the negative control. The negative 
control for this assay is pooled normal human plasma.
12.9.4.2 Anti-Murine IgG
A commercially available ELISA (Medac, Hamburg, Germany) will be used to detect and 
to quantify IgG antibodies originating from human plasma that are directed against 
mouse-IgG (HAMA: human anti- mouse antibodies). Microtiter plates coated with 
mouse IgG will be incubated with dilutions of the standard, the positive control, the 
negative control or the test sample. Antibodies against mouse IgG that are present in 
the samples bind to the coated antigen and form a bridge to a peroxidase coupled mouse 
IgG antibody that will be used for detection (bridging format of the ELISA assay). 
The positive control for this assay will be a polyclonal goat anti-murine IgG spiked into 
the negative control. The negative control for this assay is pooled normal human plasma.
12.9.4.3 Antibodies to Human Furin
Total Ig antibodies (IgG, IgA, IgM) against human Furin will be analyzed. For this assay 
(ELISA), recombinant human Furin will be coated onto a microtiter plate, then incubated
with dilutions of the positive control, the negative control or test sample. Antibodies 
against human Furin that are present in the samples bind to the coated antigen and will be 
detected with a HRP-coupled goat anti-human antibody (secondary antibody). The 
positive control for this assay will be a human monoclonal antibody specific for human 
Furin spiked into the negative control. The negative control for this assay is pooled 
normal human plasma.
12.9.5 Viral Serology
The following viral seromarkers will be assessed at screening:

HIV: anti-HIV 1, HIV 2 

HAV: anti-HAV (IgG and immunoglobulin M [IgM])

HBV: Hepatitis B surface antigen (HbsAg), anti-Hepatitis B (HB) core, anti-HBs
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
HCV: anti-HCV ELISA

Parvovirus B19: anti-B19V (IgG and IgM)
Virus serology will be established during the screening period. The relevant confirmatory 
Polymerase Chain Reaction (PCR) testing may be performed from appropriate left-over 
samples as needed. 
12.9.6 Urinalysis (Dipstick)
The urinalysis will include assessments for erythrocytes, specific gravity, urobilinogen, 
ketones, glucose, protein, bilirubin, nitrite and pH and will be performed at the central 
laboratory.
12.9.7 Pregnancy Test
A pregnancy test for females of child-bearing potential will be performed at the local 
laboratory primarily from urine. If no urine sample is available, the pregnancy testing will 
be done from serum. The pregnancy test may need to be repeated during the course of 
study in countries where mandated by national law.
12.9.8 VWD Mutational Analysis, Multimer Analysis and Human Leukocyte 
Antigen Genotyping 
A cell pellet (buffy coat and erythrocytes) will be retained at the screening visit for VWD 
gene mutational analysis, VWF multimer analysis and HLA genotype determination if the 
information is not already available in the subject’s medical history. Results from 
multimer analysis (see Section 12.9.10.1) may contribute to VWD gene mutational 
analysis. The genetic testing will be done, when the subject consents to the genetic 
testing.
12.9.9 Blood Group Analysis
The blood group needs to be determined during the screening period. If the information is 
not already available in the subject’s medical history, it has to be determined at the local 
lab.
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12.9.10 Additional Laboratory Testing in Case of Thromboembolic Events 
rVWF (vonicog alfa) contains ULMW multimers because of a lack of exposure to 
endogenous VWF protease (a disintegrin and metalloproteinase with a thrombospondin 
type 1 motif, member 13 (ADAMTS13) during the manufacturing process. In vitro and in 
vivo cleavage of these ultralarge molecular fractions by ADAMTS13 and generation of 
characteristic satellite bands has been extensively demonstrated during nonclinical and 
clinical development. Nevertheless, the potential elevated risk of thrombosis and/or other 
thromboembolic complications due to the administration of ultra large molecular VWF 
multimers in subjects with normal levels of VWF cannot be completely excluded. 
Therefore VWF multimer analysis will not only be performed routinely at screening but 
in case of thromboembolic events, both VWF multimer analysis as well as ADAMTS13 
activity will be determined to assess any relatedness of these occurrences with IP 
treatment. 
12.9.10.1 VWF Multimer Analysis 
The VWF multimer pattern will be assessed using low-resolution sodium dodecyl sulfate 
(SDS)–agarose gel electrophoresis. High-resolution SDS–agarose gel electrophoresis, 
with agarose concentrations 1.5%, will be used to determine the satellite band structure 
of VWF. These analyses will employ Western blot with luminescence video imaging.
12.9.10.2 ADAMTS13 Activity 
VWF73 was identified as the 73 amino acid minimal region of the VWF A2 domain 
required for ADAMTS13 cleavage. The cleavage of this substrate will be detected by a 
commercially available ELISA-based Chromogenic assay (Technoclone Austria):
Cleavage of immobilized VWF73 substrate is detected by a HRP-labeled antibody 
directed against the cleavage site of VWF73. The amount of bound antibody, which is the 
function of the ADAMTS13 cleavage is detected by a chromogenic substrate.
12.9.11 Soluble P-Selectin (sP-Selectin)
sP-selectin is a cell adhesion molecule (CAM) found in granules in endothelial cells 
(cells lining blood vessels) and activated platelets. Data for an association between the 
sP-selectin concentration, TTP and venous thromboembolism (VTE) are limited and the 
predictive value has not yet established. A commercial ELISA assay will be employed as 
an exploratory test. sP-selectin will be determined at the Screening visit and used as 
indicator for an increased thrombotic risk.
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12.9.12 D-Dimer
D-dimer will be used as a marker for DVT and disseminated intravascular coagulation
(DIC). While a negative result practically rules out thrombosis, a positive result can 
indicate thrombosis but does not rule out other potential etiologies, including a recent 
hemorrhage. Its main use, therefore, is to exclude thromboembolic disease where the 
probability is low. D-Dimer will be measured at the Screening visit and used as indicator 
for an increased thrombotic risk.
12.9.13 Additional Laboratory Testing in Case of Severe Hypersensitivity Reactions 
If a subject develops a severe hypersensitivity reaction in the course of the clinical 
study, additional blood will be drawn for anti-VWF IgE antibody testing. The presence of 
anti-VWF IgE will be determined by using the ImmunoCAP®, a VWF-specific IgE 
blood test (Thermo Scientific). The basis of the ImmunoCAP® technology is a cellulose 
polymer as solid phase in a plastic capsule providing a large surface for protein binding. 
rVWF (vonicog alfa) as antigen is covalently coupled to the cellulose polymer. 
Detection of specific anti-VWF IgE bound to the antigen will be accomplished by a 
secondary enzyme-labeled anti-human IgE antibody. Testing for binding anti-human 
VWF IgE antibodies will be done with 0.5 mL plasma. Antibody containing samples will 
be identified and quantified in a screening assay followed by a confirmatory assay to 
exclude false positive results.
12.9.14 Assessment of Laboratory Values
12.9.14.1 Assessment of Abnormal Laboratory Values 
For VWF and FVIII laboratory assessments no evaluation of clinical significance is 
necessary.
Each other laboratory value (except results to determine genetics of the underlying VWD 
disease and blood group) has to be assessed by the investigator and the assessment will be 
recorded on the eCRF. The investigator will determine for each abnormal laboratory 
value whether the value is considered clinically significant or not and provide the 
reference range including the units. For clinically significant values, the investigator will 
indicate if the value constitutes a new AE (see definition in Section 12.1) and record the 
sign, symptom, or medical diagnosis on the AE CRF, is a symptom or related to a 
previously recorded AE, is due to a pre-existing disease (described in Section 12.1.1.5), 
or is due to another issue that will be specified. If the abnormal value was not clinically 
significant, the investigator will indicate the reason, i.e. because it is due to a preexisting 
disease, due to a lab error, due to variation or due to another issue that will be specified. 
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Additional tests and other evaluations required to establish the significance or etiology of 
an abnormal value, or to monitor the course of an AE should be obtained when clinically 
indicated. Any abnormal value that persists should be followed at the discretion of the 
investigator. Any abnormal laboratory value that is considered clinically significant by 
the investigator based on a local laboratory test result (reference range and the units to be 
provided) should be confirmed by a central laboratory test result for which the sample is 
drawn/collected within 24 hours of the abnormal finding by the local laboratory.
Any seroconversion result for HIV, HAV, hepatitis B virus (HBV), HCV, HEV, or B19V 
shall be re-tested.
12.10
12.10.1
 
 
 
 
 
 
 
 
 
 
 
12.10.2
 
 
 
 
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13. STATISTICS
13.1 Sample Size and Power Calculations
Approximately 22 adult subjects with severe VWD (baseline VWF:RCo <20 IU/dL) will 
be included in the study. The aim is to have at least 8 subjects in each cohort (OD and 
switch). A total of at least 5 type 3 VWD subjects will be followed for 12 months. The 
sample size is driven by practical considerations (primarily the enrollment of a rare 
patient population) and EMA Guideline on the Clinical Investigation of Human Plasma 
Derived von Willebrand Factor Products (CPMP/BPWG/220/02).1
13.2 Datasets and Analysis Cohorts
13.2.1 Safety Analysis Set
The Safety Analysis Set will be composed of all subjects who received any amount of IP 
(rVWF, vonicog alpha). 
13.2.2 Full Analysis Dataset
The Full Analysis Set (FAS) will be composed of all subjects who receive prophylaxis IP 
treatment.
13.2.3 Per-Protocol Analysis Set
The Per-Protocol (PP) Analysis Set will be composed of subjects who are at least 70% 
compliant regarding the number of scheduled prophylactic infusions (as measured by the 
ratio of actual number of infusions to planned number of infusions). Only subjects who 
met all study entry criteria and who had no major protocol violations that might impact 
primary efficacy assessments will be included in the PP analysis set.
13.2.4 PK Full Analysis Set
The Pharmacokinetic Full Analysis Set (PKFAS) will be composed of all subjects who 
received the PK infusion and who provided acceptable data for PK and PD analysis. 
Acceptable PK/PD data will be defined in the Statistical Analysis Plan. 
13.2.5 PK Per Protocol Analysis Set 
The Pharmacokinetic Per Protocol Analysis Set (PKPPAS) is defined as a subset of the 
PKFAS. Subjects who met the following additional criteria will be included in the 
PKPPAS: had no major violation of affecting the PK period of the study as defined in the
detailed Statistical Analysis Plan. 
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13.3 Handling of Missing, Unused, and Spurious Data
13.3.1 General
Statistical techniques will not be used to identify and exclude any observations as outliers 
from the analyses. If data are considered spurious, e.g. for lack of biological plausibility, 
it will be documented to include the reason for exclusion and the analyses from which the 
data were excluded.
13.3.2 Other
1.
Regarding missing data in PK records:

Body weight: If a subject’s weight is missing from the PK infusion record, the 
subject’s last recorded weight will be used to calculate the weight-adjusted 
dose.

Concentration:

Baseline concentration levels reported as below the limit of quantification 
will be considered to be 0. Missing VWF baseline concentration levels 
(VWF: RCo, VWF: AG or VWF: CB) for Type 3 subjects will be set to 0.

Time:

If start time of infusion is missing (but stop time is available) and actual 
collection time is available, then stop time of infusion will be taken for 
further calculation (i.e. time difference between actual end date/time of 
infusion and date/time blood sample drawn).

If actual collection date/time is missing and planned collection date/time is 
missing, then this PK time point will be taken out from the PK analysis 
(i.e. no data entry for this time point). 

For all other scenarios, the planned collection date/time will be taken for 
further calculation.
2.
Regarding missing data in AE records:

Handling of unknown causality assessment:

If a subject experiences an AE with a missing causality assessment, the 
relationship of the AE will be counted as “related.”
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
Handling of unknown severity grades:

If a subject experiences more than one AE categorized under the same 
preferred term, one of them is categorized as “severe” and one of them is 
categorized as “unknown”, then the maximum severity for this preferred 
term should be counted as “severe” for this subject.

If a subject experiences more than one AE categorized under the same 
preferred term, one of them is categorized as “mild” or “moderate” and 
one of them is categorized as “unknown”, then the maximum severity for 
this preferred term should be counted as “unknown” for this subject.
13.4 Methods of Analysis
The study success criteria are the objectives as stated in Section 7. “Treatment success” 
was defined as the extent of control of bleeding episodes achieved during this study.
13.4.1 Primary Outcome Measure
The primary outcome measure is ABR for spontaneous (not related to trauma) bleeding 
episodes during prophylactic treatment with rVWF (vonicog alfa). No formal statistical 
hypothesis test is planned for the analysis. The primary efficacy analysis will be based on 
the FAS and will be summarized by the two cohorts: on-demand and switch subjects. As 
a supportive analysis, the same analysis will also be carried out on the PP analysis set.
The spontaneous ABR while treated with rVWF (vonicog alfa) for each cohort will be 
estimated using a negative binomial regression. The prior ABR will be based on 
historical data collected from each enrolled subject. 
The two ABRs (prior to prophylaxis treatment and while on prophylaxis) for each cohort 
will be compared within each subject using a generalized linear mixed-effects model 
(GLMM)  (with a logarithmic link function, the default for the negative binomial 
distribution), accounting for the fixed effect of the two treatments. The follow-up time 
(in years) will be specified as an offset. The ratio of ABR while in the study to historical 
ABR  will be estimated and reported together with the 95% confidence interval for each 
of the two cohorts.
The difference in on-study ABR relative to historical ABR will be also summarized 
descriptively.
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13.4.2 Secondary Outcome Measures 
In general, data for  secondary efficacy analysis will be summarized by the two cohorts: 
on-demand and switch subjects and when applicable overall.  Mean, standard deviation, 
median, range, quartiles will be calculated for continuous endpoints.  Proportions, will be 
calculated for categorical endpoints. Confidence intervals at the two-sided 95% level will 
be provided when appropriate.
13.4.2.1 Additional Efficacy of Prophylaxis Treatment with rVWF 
The number  and proportion of on-demand subjects with ABR percent reduction success 
(i.e.≥ 25%) will be calculated together with a two-sided, 95% CI for the proportion.
The number  and proportion of pdVWF switch subjects ABR preservation success will be 
reported together with the corresponding 95% two-sided CIs for the proportion.
The number and proportion of subjects with categorized spontaneous ABR 
(i.e. 0, 1-2, 3-5, more than 5 bleeds) will be reported descriptively.
Summary statistics for the total number of infusions, as well as average number of 
infusions per week will be provided. The total weight adjusted consumption of rVWF 
(vonicog alfa) during prophylactic treatment will be provided. If applicable, historical 
data on consumption of pdVWF prior to the study will be summarized as well.
The change in spontaneous ABR from the historical rate to that during the rVWF 
(vonicog alfa) prophylaxis period will be summarized by location of bleeding 
(GI, epistaxis, joint bleeding, menorrhagia, oral and other mucosa, muscle and soft 
tissue, etc.).
13.4.2.2 Pharmacokinetic and Pharmacodynamic Analysis
All PK and PD analyses will use the actual sampling times, not nominal times specified 
in the protocol, wherever possible. Actual sampling times will be defined as time from 
the start of infusion to the blood sample collection time. A deviation from the protocol-
specified blood sample drawing time window will not be a reason to exclude an 
observation from the analysis. Samples with unknown actual and planned collection 
date/time or where the concentration could not be determined, or where results were 
biologically implausible will be eliminated from the analysis.
If any concentration data are considered spurious (e.g. lack of biological plausibility), the 
reason for exclusion from the analysis and the analysis from which the data point was 
excluded will be documented.
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Details of calculation of PK and PD parameters and corresponding analysis will be given 
in the statistical analysis plan. 
The following PK parameters, based on the initial PK assessment after a washout for on-
demand subjects, will be listed and summarized descriptively for VWF:RCo, VWF:Ag 
and VWF:CB: IR, T1/2, MRT, AUC0-, AUC0-tlast, Cmax, Tmax, Vss, and CL. The 
corresponding pharmacodynamics (PD) of rVWF (vonicog alfa) as measured in FVIII 
activity, based on the initial PK assessment after a washout for on-demand subjects will 
be assessed using Cmax, Tmax, and AUC0-tlast. These PD parameters will be listed and 
summarized descriptively. PK parameters at steady state (AUC0-tau;ss, Cmax;ss, Tmax;ss, and 
Cmin;ss) for the partial dosing interval will be listed for on-demand subjects at the end of 
the study and for switch subjects shortly after reaching steady state and at the end of the 
study for VWF:RCo, VWF:Ag and VWF:CB and summarized descriptively for subjects 
with the same dosing regimens. The corresponding pharmacodynamics (PD) of rVWF 
(vonicog alfa) as measured in FVIII activity will be assessed using AUC0-tau;ss, Cmax;ss, 
Tmax;ss, and Cmin;ss. These PD parameters will be listed for on-demand subjects at the end 
of the study and for switch subjects shortly after reaching steady state and at the end of 
the study and will be summarized descriptively for subjects with the same dosing 
regimens.
For the on-demand subjects, the PK of VWF:RCo will be analyzed using a population PK 
approach to characterize the single and multiple dose pharmacokinetics, including 
associated variability assessed at after washout and at end of study, respectively. The 
population PK analysis will be performed in a stepwise manner as outlined below.
1.
Exploratory graphical analysis of VWF:RCo versus time data for identification of 
potential outliers and to inform the pharmacometric analysis.
2.
Population PK model development for rVWF (vonicog alfa):
a.
Evaluate alternative structural and stochastic models to describe the typical 
and individual rVWF (vonicog alfa) profiles.
b.
Investigate and characterize the potential for a time dependency in CL of 
rVWF (vonicog alfa). 
c.
Evaluate, and if necessary refine, the candidate final model
Details of this Population PK analysis will be given in a separate Population PK analysis 
plan.
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For the switch subjects, differences in AUC0-tau;ss, Cmax;ss, and Cmin;ss assessess shortly 
after reaching steady state and assessed at the end of the study will be assessed by the 
ratio of geometric means and corresponding two-sided 95% confidence intervals for 
VWF:RCo, VWF:Ag,VWF:CB, and FVIII:C. These analyses will be performed using a 
linear mixed effects model with PK assessment (i.e. factor of two levels relating to the 
PK assessment shortly after reaching steady state and the PK assessment at end of study, 
respectively) as a fixed effect and subject as a random effect based on log-transformed 
PK parameters. The difference in Tmax;ss, between first and second pharmacokinetic 
assessment will be summarized by the median and range (minimum to maximum) for 
VWF:RCo, VWF:Ag,VWF:CB, and FVIII:C.
Descriptive statistics will be used to summarize VWF:RCo, VWF:AG and VWF:CB and 
FVIII:C levels for each nominal time point on the PK curve.
For all subjects in the PKFAS activity/concentration vs. time curves will be prepared.
Formulas for PK parameters IR, T1/2, MRT, AUC0-, AUC0-tlast, Cmax, Tmax, Vss, and CL, 
AUC0-tau;ss, Cmax;ss, Tmax;ss ,and Cmin;ss will be given in the statistical analysis plan and will 
be derived using non-compartmental methods in WinNonlin. Analysis of these 
parameters will be carried out on the PKFAS as well as on the PKPPAS.
13.4.2.3 Safety
Safety analysis will be performed overall and by the two cohorts: on-demand and switch 
subjects.
TEAEs are defined as AEs with start dates on or after the first exposure to IP. Summaries 
of AEs will be based on TEAEs unless otherwise indicated.
Occurrence of AEs and SAEs will be summarized descriptively, by system organ class 
and preferred term. The number and percentage of subjects who experienced AEs and 
SAEs, and the number of AEs and SAEs will be tabulated. In addition, the number of 
subjects who experienced AEs assessed as related to IP by the investigator, and the 
number of IP-related AEs will be tabulated. The number of patients with AEs by severity 
will be presented similarly.
A listing of all AEs will be presented by subject identifier, age, sex, preferred term and 
reported term of the AE, duration, severity, seriousness, action taken, outcome, causality 
assessment by investigator, onset date, stop date and medication or non-drug therapy to 
treat the AE.
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Temporally associated AEs are defined as AEs that begin during infusion or within 
24 hours (or 1 day where time of onset is not available) after completion of infusion, 
irrespective of being related or not related to treatment. Temporally associated AEs will 
be presented in summary tables. 
AEs that occurred before first IP infusion will be listed separately.
Adverse events of special interest (AESI), such as hypersensitivity reactions and 
thromboembolic events,  will be monitored throughout the study and statistical analysis 
will be conducted based on the search criteria (eg, standardised MedDRA queries [SMQ]) 
determined prior to database lock, and summarized.
For immunogenicity, frequency counts and percentages will be calculated for the 
occurrence of neutralizing (inhibitory) antibodies to VWF and FVIII, occurrence of 
binding antibodies to VWF and FVIII, and occurrence of binding antibodies to CHO 
proteins, mouse immunoglobulin G (IgG) and rFurin. Clinically significant changes 
relative to baseline in vital signs and clinical laboratory parameters (hematology, clinical 
chemistry) will be reported.
13.4.3 Exploratory Outcome Measures
 
13.4.3.1
 
 
 
 
 
13.4.3.2
 
 
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13.4.3.3
 
 
 
13.4.3.4
 
 
 
 
 
13.5 Planned Interim Analysis of the Study
No formal interim analysis is planned for this study. 
14. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
The investigator/study site will cooperate and provide direct access to study documents 
and data, including source documentation for monitoring by the study monitor, audits by 
the sponsor or sponsor’s representatives, review by the EC, and inspections by applicable 
regulatory authorities, as described in the Clinical Trial Agreement (CTA). If contacted 
by an applicable regulatory authority, the investigator will notify the sponsor of contact, 
cooperate with the authority, provide the sponsor with copies of all documents received 
from the authority, and allow the sponsor to comment on any responses, as described in 
the CTA.
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15. QUALITY CONTROL AND QUALITY ASSURANCE
15.1 Investigator’s Responsibility
The investigator will comply with the protocol (which has been approved/given favorable 
opinion by the EC), ICH GCP, and applicable national and local regulatory requirements 
as described in the CTA. The investigator is ultimately responsible for the conduct of all 
aspects of the study at the study site and verifies by signature the integrity of all data 
transmitted to the sponsor. The term “investigator” as used in this protocol as well as in 
other study documents, refers to the investigator or authorized study personnel that the 
investigator has designated to perform certain duties. Sub-investigators or other 
authorized study personnel are eligible to sign for the investigator, except where the 
investigator’s signature is specifically required.
15.1.1 Investigator Report and Final Clinical Study Report 
The investigator, or coordinating investigator(s) for multicenter studies, will sign the 
clinical study report. The coordinating investigator will be selected before study start. 
15.2 Training
The study monitor will ensure that the investigator and study site personnel understand all 
requirements of the protocol, the investigational status of the IP, and his/her regulatory 
responsibilities as an investigator. Training may be provided at an investigator’s meeting, 
at the study site, and/or by instruction manuals. In addition, the study monitor will be 
available for consultation with the investigator and will serve as the liaison between the 
study site and the sponsor.
15.3 Monitoring
The study monitor is responsible for ensuring and verifying that each study site conducts 
the study according to the protocol, standard operating procedures other written 
instructions/agreements, ICH GCP, and applicable national and local regulatory 
guidelines/requirements. The investigator will permit the study monitor to visit the study 
site at appropriate intervals, as described in the CTA. Monitoring processes specific to the 
study will be described in the clinical monitoring plan. 
15.4 Auditing
The sponsor and/or sponsor’s representatives may conduct audits to evaluate study 
conduct and compliance with the protocol, standard operating procedures, other written 
instructions/agreements, ICH GCP, and applicable national and local regulatory 
guidelines/requirements. The investigator will permit auditors to visit the study site, as 
described in the CTA. Auditing processes specific to the study will be described in the 
audit plan.
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15.5 Non-Compliance with the Protocol
The investigator may deviate from the protocol only to eliminate an apparent immediate 
hazard to the subject. In the event(s) of an apparent immediate hazard to the subject, the 
investigator will notify the sponsor immediately by phone and confirm notification to the 
sponsor in writing as soon as possible, but within 1 calendar day after the change is 
implemented. Also, the investigator will notify the sponsor immediately by phone and 
confirm notification to the sponsor in writing whenever pdVWF is used instead of rVWF 
(vonicog alfa). The reason for this use must also be provided to the sponsor.The sponsor 
(Baxalta) will also ensure the responsible EC and relevant competent authority are 
notified of the urgent measures taken in such cases according to local regulations.
If monitoring and/or auditing identify serious and/or persistent non-compliance with the 
protocol, the sponsor may terminate the investigator’s participation. The sponsor will 
notify the EC and applicable regulatory authorities of any investigator termination.
15.6 Laboratory and Reader Standardization
A central laboratory/reader will be used for all clinical assessments except for pregnancy 
testing and blood group test (refer to Section 12.9). Local laboratories are requested to 
provide their laboratory specifications of the individual tests that are also being tested 
locally.
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16. ETHICS 
16.1 Subject Privacy
The investigator will comply with applicable subject privacy regulations/guidance as 
described in the CTA.
16.2 Ethics Committee and Regulatory Authorities
Before enrollment of patients into this study, the protocol, informed consent form, any 
promotional material/advertisements, and any other written information to be provided 
will be reviewed and approved/given favorable opinion by the EC and applicable 
regulatory authorities. The IB will be provided for review. The EC’s composition or a 
statement that the EC’s composition meets applicable regulatory criteria will be 
documented. The study will commence only upon the sponsor’s receipt of 
approval/favorable opinion from the EC and, if required, upon the sponsor’s notification 
of applicable regulatory authority(ies) approval, as described in the CTA.
If the protocol or any other information given to the subject is amended, the revised 
documents will be reviewed and approved/given favorable opinion by the EC and 
applicable regulatory authorities, where applicable. The protocol amendment will only be 
implemented upon the sponsor’s receipt of approval and, if required, upon the sponsor’s 
notification of applicable regulatory authority(ies) approval.
16.3 Informed Consent
Investigators will choose patients for enrollment considering the study eligibility criteria. 
The investigator will exercise no selectivity so that no bias is introduced from this source. 
All patients and/or their legally authorized representative must sign an informed consent 
form before entering into the study according to applicable national and local regulatory 
requirements and ICH GCP. Before use, the informed consent form will be reviewed by 
the sponsor and approved by the EC and regulatory authority(ies), where applicable, (see 
Section 16.2). The informed consent form will include a comprehensive explanation of 
the proposed treatment without any exculpatory statements, in accordance with the 
elements required by ICH GCP and applicable national and local regulatory 
requirements. Patients or their legally-authorized representative(s) will be allowed 
sufficient time to consider participation in the study. By signing the informed consent 
form, patients or their legally authorized representative(s) agree that they will complete 
all evaluations required by the study, unless they withdraw voluntarily or are terminated 
from the study for any reason.
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The sponsor will provide to the investigator in written form any new information that 
significantly bears on the subjects’ risks associated with IP exposure. The informed 
consent will be updated, if necessary. This new information and/or revised informed 
consent form, which have been approved by the applicable EC and regulatory authorities, 
will be provided by the investigator to the subjects who consented to participate in the 
study 
16.4 Data Monitoring Committee
This study will be monitored by a DMC. The DMC is a group of individuals with 
pertinent expertise that reviews on a regular basis accumulating data from an ongoing 
clinical study. For this study, the DMC will be composed of recognized experts in the 
field of VWD clinical care and research who are not actively recruiting subjects, and an 
independent statistician. The DMC can stop a trial if it finds toxicities or if treatment is 
proven to be not beneficial. Details will be defined in the DMC charter.
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17. DATA HANDLING AND RECORD KEEPING
17.1 Confidentiality Policy
The investigator will comply with the confidentiality policy as described in the CTA.
17.2 Study Documentation and Case Report Forms
The investigator will maintain complete and accurate paper format study documentation 
in a separate file. Study documentation may include information defined as “source data” 
(see Section 8.7), records detailing the progress of the study for each subject, signed 
informed consent forms, correspondence with the EC and the study monitor/sponsor, 
enrollment and screening information, CRFs, SAERs, laboratory reports (if applicable), 
and data clarifications requested by the sponsor.
The investigator will comply with the procedures for data recording and reporting. Any 
corrections to paper study documentation must be performed as follows: 1) the first entry 
will be crossed out entirely, remaining legible; and 2) each correction must be dated and 
initialed by the person correcting the entry; the use of correction fluid and erasing are 
prohibited.
The investigator is responsible for the procurement of data and for the quality of data 
recorded on the CRFs. CRFs will be provided in electronic form. 
If electronic format CRFs are provided by the sponsor, only authorized study site 
personnel will record or change data on the CRFs. If data is not entered on the CRFs 
during the study visit the data will be recorded on paper and this documentation will be 
considered source documentation. Changes to a CRF will require documentation of the 
reason for each change. An identical (electronic/paper) version of the complete set of 
CRFs for each subject will remain in the investigator file at the study site in accordance 
with the data retention policy (see Section 17.3).
The handling of data by the sponsor, including data quality assurance, will comply with 
regulatory guidelines (e.g., ICH GCP) and the standard operating procedures of the 
sponsor. Data management and control processes specific to the study will be described 
in the data management plan. 
17.3 Document and Data Retention 
The investigator will retain study documentation and data (paper and electronic forms) in 
accordance with applicable regulatory requirements and the document and data retention 
policy, as described in the CTA.
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18. FINANCING AND INSURANCE
The investigator will comply with investigator financing, investigator/sponsor insurance, 
and subject compensation policies, if applicable, as described in the CTA.
19. PUBLICATION POLICY
The investigator will comply with the publication policy as described in the CTA. 
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20. SUPPLEMENTS
20.1 Study Flow Chart
Figure 1
Study Design for Baxalta Clinical Study 071301
* Study treatment period is extended by 3 months to accommodate participation in the continuation 
study for the qualified subjects and will be exercised only if the continuation study start up is delayed 
beyond the completion of subject’s 12-month visit.
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20.2 Schedule of Study Procedures and Assessments
Table 6a
Schedule of Study Procedures and Assessments for On-demand Subject
Procedures/
Assessments
Screening Visit
Baseline Visit 
(PK-assessment visit)
Prophylaxis 
Initiation Visit
Interval/Follow-Up 
Study Visits
PK Assessment at 
Study Completion
Termination 
Visit
Pre-
infusiong
Infusion
Post-
infusiong
1 month ± 
1 week
2 month ± 
1 week 
3 month ± 
2 weeks
6 month ± 
2 weeks 
9 month ± 
2 weeks
Pre-
infusiong
Infusion
Post-
infusiong
Conducted at 
the 96 hour 
postinfusion 
PK 
Assessment
12-15i month ± 2 weeks
Informed Consent a
X
Eligibility Criteria
X
Medical Historyb
X
Concomitant Medicationsc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Non-drug Therapiesc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
Bleeding Episodes and 
Treatment and Hemostatic 
Efficacy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratories 
X
X
X
Xh
X
X
X
X
X
X
X
X
Vital Signsd
X
X
X
X
X
X
X
X
X
X
X
X
ECG
X
X
X
IP Treatmente
X
X
X
X
X
X
X
X
IP Consumption / Treatment 
Compliance 
X
X
X
X
X
Subject Diary
X
X
X
X
X
X
Xf
X
X
Continued on next page
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Continued
a) Occurs at enrollment (before screening).
b) Including documented history of on-demand treatment for the past 12 months (up to 24 months if available) and a documented history, e.g., patient charts 
and prescription information, of all bleeding episodes within the past 12 (up to 24) months. 
c) Including all medications and non- drug therapies taken in the 2 weeks prior to study entry and all the concomitant medications and non-drug therapies 
during the course of the study.
d) Vital signs: height, weight, body temperature, pulse rate, respiratory rate, and blood pressure. Height is only required at the screening visit. The time points 
for pre- and post-infusion measurements are (weight is measured pre-infusion only): within 30 minutes before infusion start and 30 ± 15 minutes post-
infusion.
e) IP treatment after the prophylactic treatment initiation visit at the site will be continued as home-treatment if the subject qualifies; a wash-out period of at 
least 72 hours is required after the last IP infusion before the follow-up visit. IP infusion will be given at the study site after the blood sample for 
immunology testing and IR determination is drawn.
f) Can be done either at the screening or the baseline visit.
g) Time points for PK blood draws: within 30 minutes pre-infusion, and at 11 time points post-infusion: 15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 
3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours and 96 ± 2 hours (the 96 hr sampling can be omitted 
if not allowed by the dosing interval).
h) If a subject did not undergo PK assessment, laboratory assessments will be performed at this visit.
i) Study treatment period is extended by 3 months to accommodate participation in the continuation study for the qualified subjects and will be exercised 
only if the continuation study start up is delayed beyond the completion of subject’s 12-month visit. In this case, 12 month ± 2 weeks visit is to be 
considered as a follow-up visit, and EOS visit is to be performed once the subject can rollover into the continuation study, from 12 month ± 2 weeks to 
15 month ± 2 weeks post prophylaxis initiation visit, as applicable.
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Table 6b
Schedule of Study Procedures and Assessments for pdVWF Switch Subject
Procedures/
Assessments
Screening Visit
Prophylaxis Initiation 
Visit
PK Assessment
(at prophylaxis dose #5-6)
Interval/Follow-Up 
Study Visits
PK Assessment at 
Study Completion
Termination 
Visit
Pre-infusiong
Infusion
Post-infusiong
1 month ± 
1 week
2 month ± 
1 week 
3 month ± 
2 weeks
6 month ± 
2 weeks 
9 month ± 
2 weeks
Pre-
infusiong
Infusion
Post-
infusiong
Conducted at 
the 96 hour 
postinfusion 
PK Assessment
12-15h month
± 2 weeks
Informed Consent a
X
Eligibility Criteria
X
Medical Historyb
X
Concomitant Medicationsc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Non-drug Therapiesc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
Bleeding Episodes and 
Treatment and Hemostatic 
Efficacy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratories 
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signsd
X
X
X
X
X
X
X
X
X
X
X
X
ECG
X
X
X
IP Treatmente
X
X
X
X
X
X
X
X
IP Consumption / Treatment 
Compliance 
X
X
X
X
X
Subject Diary
X
X
X
X
X
X
Xf
X
X
Continued on next page
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Continued
a) Occurs at enrollment (before screening).
b) Including documented history of prophylaxis treatment for the past 12 months (up to 24 months if available) and a documented history, e.g., patient charts 
and prescription information, of all bleeding episodes within the past 12 (up to 24) months. 
c) Including all medications and non- drug therapies taken in the 2 weeks prior to study entry and all the concomitant medications and non-drug therapies 
during the course of the study.
d) Vital signs: height, weight, body temperature, pulse rate, respiratory rate, and blood pressure. Height is only required at the screening visit. The time 
points for pre- and post-infusion measurements are (weight is measured pre-infusion only): within 30 minutes before infusion start and 30 ± 15 minutes 
post-infusion.
e) IP treatment after the prophylactic treatment initiation visit at the site will be continued as home-treatment if the subject qualifies; a wash-out period of at 
least 72 hours is required after the last IP infusion before the follow-up visit. IP infusion will be given at the study site after the blood sample for 
immunology testing and IR determination is drawn.
f) Can be done either at the screening or the prophylaxis initiation visit.
g) Time points for PK blood draws: within 30 minutes pre-infusion, and at 11 time points post infusion: 15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 
3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours and 96 ± 2 hours ( the 96 hr sampling can be 
omitted if not allowed by the dosing interval).
h) Study treatment period is extended by 3 months to accommodate participation in the continuation study for the qualified subjects and will be exercised 
only if the continuation study start up is delayed beyond the completion of subject’s 12-month visit. In this case, 12 month ± 2 weeks visit is to be 
considered as a follow-up visit, and EOS visit is to be performed once the subject can rollover into the continuation study, from 12 month ± 2 weeks to 
15 month ± 2 weeks post prophylaxis initiation visit, as applicable.
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20.2.1 Summary Schedule of Visit Assesments for Surgical Bleeding
Table 7
Summary Schedule of Visit Assesments for Surgical Bleeding
Procedures/
Assessments
Surgical procedure
Post-Operative 
Day 7 Visit
(± 1 day)
Post-Operative 
Day 14 Visit
(± 2 day)
Priming Dose 
Procedures 
(12-24 hours prior 
to surgery)
Loading Dose 
Procedures 
(≤3 hours prior
to surgery)
Intraoperative
Postoperative 
(day 1 → end of 
perioperative IP 
treatment)a
ECG
X
Physical examinationb
X
X
X
X
X
Adverse events
X
X
X
X
X
X
Laboratoriesc
X
X
X
X
X
X
Vital signsd
X
X
X
X
X
X
IP treatment: rVWF (vonicog 
alfa):ADVATE (rFVIII, octocog 
alfa) or rVWF (vonicog alfa) only 
infusion
X
X
X
as required
X
as required
X
as required
X
as required
Concomitant medications and non-
drug therapy
X
X
X
X
X
X
X
Hemostatic efficacy assessmentse
X
X
X
X
Blood loss
X
estimated
X
actual
X
Xf
Xf
Treatment days estimate
X
Continued on next page
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Continued 
a) The assessments will be performed daily until perioperative IP treatment end (potentially multi-visits)
b) Physical Examination: within 2 hours prior to IP infusion start
c) For laboratory assessments, see Table 9
d) Vital signs: within 30 minutes before infusion start and 30 ± 15 minutes post-infusion
e) Completed immediately postsurgery by the operating surgeon 24 hours post last IP infusion or at Day 14 visit (whichever occurs first) by the investigator
f) In case bleeding still ongoing
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20.3 Clinical Laboratory Assessments
Table 8a
Clinical Laboratory Assessments for On-demand Subject
Procedures/
Assessments
Screening Visit
Baseline Visit 
(PK-assessment visit)
Prophylaxis Initiation 
Visitk
Interval/Follow-Up 
Study Visits
PK Assessmentm at 
Study Completion
Termination 
Visit
Pre-infusion
Infusion
Post-infusion
1 month ± 
1 week
2 month ± 
1 week 
3 month ± 
2 weeks
6 month ± 
2 weeks 
9 month ± 
2 weeks
Pre-
infusion
Infusion
Post-
infusion
Conducted 
at the 
96 hour 
postinfusion 
PK 
Assessment
12-15n month± 
2 weeks
Hematology a
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Chemistryb
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation Panel/ PK 
assessmentc
X
X
X
X
X
X
X
X
X
X
X
Immunogenicityd
X
X
Xl
X
X
X
X
X
X
X
Viral Serologye
X
Urinalysisf
X
VWD Gene Mutational 
Analysis / HLA genotype 
analysis and Analysis of 
VWF multimersg
X
sP-selectin and D-dimer
Xh
Blood Groupi 
X
Pregnancy Testj
X
a) Hematology assessments include: complete blood count [hemoglobin, hematocrit, erythrocytes (i.e. red blood cell count), mean corpuscular volume 
(MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), leukocytes (i.e. white blood cell count)] with 
differential (i.e. basophils, eosinophils, lymphocytes, monocytes, neutrophils) and platelet counts. Hematology assessments during PK assessments will be 
determined prior to IP infusion and 24 ± 2 hours, 48 ± 2 hours and 72 ± 2 hours thereafter. For other IP-associated visits, samplings are within 60 minutes 
pre-infusion.
Continued on next page
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Continued
b) Clinical chemistry assessments include: Sodium, potassium, chloride, glucose, creatinine, blood urea nitrogen (BUN), aspartate aminotransferase (AST), 
alanine aminotransferase (ALT) lactate dehydrogenase (LDH), alkaline phosphatase (AP), bilirubin. Clinical chemistry will be determined prior to IP 
infusion and after 24 ± 2 h, 48 ± 2 hours and 72 ± 2 hours during the PK assessments. For other IP-associated visits, samplings are within 60 minutes pre-
infusion.
c) Coagulation panel/PK assessment (also refers to IR pre/post dose assessments at prophy initiation visit and each follow-up visit): PT, INR and aPTT (only 
for screening), VWF:RCo, VWF:Ag, VWF:CB, FVIII:C,; during the PK assessment at the baseline visit blood samples will be drawn 30 min prior PK 
infusion; once the PK infusion is completed 15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 
30 ± 2 hours, 48 2 hours, 72 2 hours and 96 ± 2 hours and VWF:RCo, VWF:CB, VWF:Ag, FVIII:C will be determined; for follow-up visits, IR 
samples will be drawn within 30 minutes pre-infusion and 30 5 minutes post-infusion. During screening and in case of thromboembolic event VWF 
multimers and ADAMTS13 will be analyzed to judge on a possibly relatedness to UHMW fractions of the IP.
d) Immunogenicity assessment includes Neutralizing Antibodies (Ab) to FVIII –Neutralizing Ab to VWF:RCo, Neutralizing Ab to VWF:CB, Neutralizing 
Ab to VWF:FVIII, Binding Ab to VWF and FVIII, Binding Ab to CHO-Protein, Binding Ab to rFurin, Binding Ab to Murine IgG . In case of an SAE 
hypersensitivity reaction IgE antibodies to VWF will be determined. For on-demand subjects, a washout period of at least 72 hours after the last IP 
infusion is required before blood samples for immunogenicity assessments can be drawn. 
e) Viral Serology Hepatitis A Antibody, Total - Hepatitis A Antibody, IgM - Hepatitis B Surface Antibody - Hepatitis B Core Ab, Total - Hepatitis B Surface 
Antigen - Hepatitis C Virus Antibody; Parvovirus B19; HIV-1/HIV-2 Antibodies 
f) Urinalysis comprehends: erythrocytes, specific gravity, urobilinogen, ketones, glucose, protein, bilirubin, nitrite, and pH
g) Not required if available in the subject’s medical history; VWF multimers: additionally in case of thromboembolic events
h) At screening and in case of thromboembolic events
i) Blood group assessment major blood group (local laboratory) only if not available in the subject’s medical history
j) Serum pregnancy test (in females of child-bearing potential if no urine sample is available)
k) The last post-infusion laboratory assessments coincidence with the initiation visit for prophylactic treatment. After the blood samples are drawn for 
laboratory assessment for the 96 h post infusion PK assessment, the subject receives the first IP infusion for prophylactic treatment (prophylactic treatment 
initiation visit). 
l) Only needed for subjects without PK assessment prior to their first IP infusion in this study.
m) A steady state full PK analysis will be performed at the end of the study. Blood samples will be drawn within 30 minutes pre-infusion, and at 11 time points 
post-infusion (15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 
72 2 hours and 96 ± 2 hours), the 96 hr sampling can be omitted if not allowed by the dosinig interval.
n) Study treatment period is extended by 3 months to accommodate participation in the continuation study for the qualified subjects and will be exercised only 
if the continuation study start up is delayed beyond the completion of subject’s 12-month visit. In this case, 12 month ± 2 weeks visit is to be considered as a 
follow-up visit, and EOS visit is to be performed once the subject can rollover into the continuation study, from 12 month ± 2 weeks to 15 month ± 2 weeks 
post prophylaxis initiation visit, as applicable.
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Table 8b
Clinical Laboratory Assessments for pdVWF Switch Subject
Procedures/
Assessments
Screening Visit
Prophylaxis Initiation Visit
PK Assessmentk
(at prophylaxis dose #5-6)
Interval/Follow-Up 
Study Visits
PK Assessmentk at 
Study Completion
Termination 
Visit
Pre-infusion
Infusion
Post-infusion
1 month ± 1 week
2 month ± 1 week 
3 month ± 2 weeks
6 month ± 2 weeks 
9 month ± 2 weeks
Pre-
infusion
Infusion
Post-
infusion
Conducted at 
the 96 hour 
postinfusion 
PK 
Assessment
12-15l month± 
2 weeks
Hematology a
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Chemistryb
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation Panel/PK 
assessmentc
X
X
X
X
X
X
X
X
X
X
X
Immunogenicityd
X
X
X
X
X
X
X
X
X
Viral Serologye
X
Urinalysisf
X
VWD Gene Mutational 
Analysis / HLA 
genotype analysis and 
Analysis of VWF 
multimersg
X
sP-selectin and D-dimer
Xh
Blood Groupi 
X
Pregnancy Testj
X
Continued on next page
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Continued
a) Hematology assessments include: complete blood count [hemoglobin, hematocrit, erythrocytes (i.e. red blood cell count), mean corpuscular volume 
(MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), leukocytes (i.e. white blood cell count)] with 
differential (i.e. basophils, eosinophils, lymphocytes, monocytes, neutrophils) and platelet counts. Hematology assessments during PK assessments will be 
determined prior to IP infusion and 24 ± 2 hours, 48 ± 2 hours and 72 ± 2 hours thereafter. For other IP-associated visits, samplings are within 60 minutes 
pre-infusion.
b) Clinical chemistry assessments include: Sodium, potassium, chloride, glucose, creatinine, blood urea nitrogen (BUN), aspartate aminotransferase (AST), 
alanine aminotransferase (ALT) lactate dehydrogenase (LDH), alkaline phosphatase (AP), bilirubin. Clinical chemistry will be determined prior to IP 
infusion and after 24 ± 2 h, 48 ± 2 hours and 72 ± 2 hours during the PK assessments. For other IP-associated visits, samplings are within 60 minutes pre-
infusion.
c) Coagulation panel/PK assessment (also refers to IR pre/post dose assessments at prophy initiation visit and each follow-up visit): PT, INR and aPTT (only 
for screening), VWF:RCo, VWF:Ag, VWF:CB, FVIII:C,; during the PK assessment blood samples will be drawn 30 min prior PK infusion; once the PK 
infusion is completed 15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 
48 2 hours, 72 2 hours and 96 ± 2 hours and VWF:RCo, VWF:CB, VWF:Ag, FVIII:C will be determined; for follow-up visits, IR samples will be 
drawn within 30 minutes pre-infusion and 30 5 minutes post-infusion. During screening and in case of thromboembolic event VWF multimers and 
ADAMTS13 will be analyzed to judge on a possibly relatedness to UHMW fractions of the IP.
d) Immunogenicity assessment includes Neutralizing Antibodies (Ab) to FVIII –Neutralizing Ab to VWF:RCo, Neutralizing Ab to VWF:CB, Neutralizing 
Ab to VWF:FVIII, Binding Ab to VWF and FVIII, Binding Ab to CHO-Protein, Binding Ab to rFurin, Binding Ab to Murine IgG. In case of an SAE 
hypersensitivity reaction IgE antibodies to VWF will be determined. For switch subjects, the wash out period may be reduced to the time interval between 
their pdVWF prophy infusions.
e) Viral Serology Hepatitis A Antibody, Total - Hepatitis A Antibody, IgM - Hepatitis B Surface Antibody - Hepatitis B Core Ab, Total - Hepatitis B Surface 
Antigen - Hepatitis C Virus Antibody; Parvovirus B19; HIV-1/HIV-2 Antibodies 
f) Urinalysis comprehends: erythrocytes, specific gravity, urobilinogen, ketones, glucose, protein, bilirubin, nitrite, and pH
g) Not required if available in the subject’s medical history; VWF multimers: additionally in case of thromboembolic events
h) At screening and in case of thromboembolic events
i) Blood group assessment major blood group (local laboratory) only if not available in the subject’s medical history
j) Serum pregnancy test (in females of child-bearing potential if no urine sample is available)
k) A full steady state PK analysis will be performed. Blood samples will be drawn within 30 minutes pre-infusion, and at 11 time points post-infusion
(15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours 
and 96 ± 2 hours) , the 96 hr sampling can be omitted if not allowed by the dosinig interval.
l) Study treatment period is extended by 3 months to accommodate participation in the continuation study for the qualified subjects and will be exercised only 
if the continuation study start up is delayed beyond the completion of subject’s 12-month visit. In this case, 12 month ± 2 weeks visit is to be considered as a 
follow-up visit, and EOS visit is to be performed once the subject can rollover into the continuation study, from 12 month ± 2 weeks to 15 month ± 2 weeks 
post prophylaxis initiation visit, as applicable.
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20.3.1 Laboratory Sampling for Surgical Bleeding
Table 9
Laboratory Samplinga for Surgical Bleeding
Procedures/
Assessments
Surgical procedure
Post-Operative 
Day 7 Visit
(± 1 day)
Post-Operative 
Day 14 Visit
(± 2 day)
Priming Dose 
Procedures 
(12-24 hours prior 
to surgery)
Loading Dose 
Procedures 
(≤3 hours prior 
to surgery)
Intraoperative
Postoperative 
(day 1 → end of 
perioperative IP 
treatment)b
Hematologyc
X
(w/o Differential)
Xd
(w/o Differential)
X
(w/o Differential)
X
X
Clinical Chemistrye
X
Xd
X
X
Coagulation panelf
X
X
X
X
X
X
VWF inhibitory and binding 
antibodies, antibodies to other 
proteinsg
X
X
X
if excessive or 
unexplainedbleeding
X
X
X
Urinalysish
X
X
VWF Multimersi
Anti VWF IgE antibody testing
only in case of allergic reaction/ 
anaphylaxis
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Continued
a) Blood draws are within 3 hrs  prior to infusion start, expect that for the priming dose blood draw is within 30 minutes prior to infusion start. For 
coagulation panel, an additional 30 ± 5 minutes post-infusion blood draw is needed.
b) The assessments will be performed daily until perioperative IP treatment end (potentially multi-visits)
c) Hematology assessments include: complete blood count [hemoglobin, hematocrit, erythrocytes (i.e. red blood cell count), mean corpuscular volume 
(MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), leukocytes (i.e. white blood cell count)] with 
differential (i.e. basophils, eosinophils, lymphocytes, monocytes, neutrophils) and platelet counts. 
d) Not required if sample already drawn at the time of the priming dose
e) Clinical chemistry assessments include: Sodium, potassium, chloride, glucose, creatinine, blood urea nitrogen (BUN), aspartate aminotransferase (AST), 
alanine aminotransferase (ALT) lactate dehydrogenase (LDH), alkaline phosphatase (AP), bilirubin. 
f) Coagulation panel: VWF:RCo, VWF:Ag, FVIII:C PT INR and aPTT; in additiona to pre-infusion, 30 ± 5 minutes post infusion blood draw is needed. 
g) Immunogenicity assessment includes Neutralizing Antibodies (Ab) to FVIII – Neutralizing and Neutralizing Ab to VWF:RCo, Neutralizing Ab to 
VWF:CB, Neutralizing Ab to VWF:FVIII, Binding Ab to VWF and FVIII, Binding Ab to CHO-Protein, Binding Ab to rFurin, Binding Ab to Murine IgG. 
In case of an SAE hypersensitivity reaction IgE antibodies to VWF will be determined.
h) Urinalysis comprehends: erythrocytes, specific gravity, urobilinogen, ketones, glucose, protein, bilirubin, nitrite, and pH
i) VWD multimers and ADAMTS13 during the study only in case of thrombotic events
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20.4 Contraceptive Methods for Female Subjects of Childbearing Potential
In this study, subjects who are women of childbearing potential must agree to utilize a 
highly effective contraceptive measure throughout the course of the study and for 30 days 
after the last administration ofIP. In accordance with the Clinical Trial Facilitation Group 
(CTFG) recommendations related to contraception and pregnancy testing in clinical trials 
(version 2014-09-15)ii, birth control methods which may be considered as highly 
effective include the following:

Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation:

oral

intravaginal

transdermal

Progestogen-only hormonal contraception associated with inhibition of ovulation:

oral

injectable

implantableiii

Intrauterine device (IUD)iii

Intrauterine hormone-releasing system (IUS) iii

Bilateral tubal occlusioniii

Vasectomised partner(s)iii

Sexual abstinence during the entire study period
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhoea method (LAM) are 
not acceptable methods of contraception. Female condom and male condom should not 
be used together.
                                                
ii Clinical Trial Facilitation Group (CTFG) recommendations related to contraception and pregnancy 
testing in clinical trials: http://www.hma.eu/fileadmin/dateien/ 
Human_Medicines/01About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf.
iii Contraception methods that are considered to have low user dependency.
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21. REFERENCES
1.
Committee for Medicinal Products for Human Use. Guideline on clinical 
investigation of human plasma derived von Willebrand factor products. 
CPMP/BPWG/220/02, 12. 11-17-2005:London, European Medicines Agency 
(EMA):2005. Web Link: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/201
0/01/WC500067126.pdf
2.
Mannucci PM. Treatment of von Willebrand's Disease. N Engl J Med. 
2004;351(7):683-694.
3.
Goudemand J, Scharrer I, Berntorp E, et al. Pharmacokinetic studies on Wilfactin, a 
von Willebrand factor concentrate with a low factor VIII content treated with three 
virus-inactivations/removal methods. J Thromb Haemost. 2005;3(10):2219-2227.
4.
Abshire T. The role of prophylaxis in the management of von Willebrand disease: 
today and tomorrow. Thromb Res. 2009;124 Suppl 1:S15-S19.
5.
Nilsson IM, Blombäck M, Jorpes E, Blombäck B, Johansson SA. V. Willebrand's 
disease and its correction with human plasma fraction 1-0. Acta Med Scand. 
1957;159(3):179-188.
6.
Berntorp E, Petrini P. Long-term prophylaxis in von Willebrand disease. Blood 
Coagul Fibrinolysis. 2005;16 Suppl 1:S23-S26.
7.
Berntorp E. Prophylaxis and treatment of bleeding complications in von Willebrand 
disease type 3. Semin Thromb Hemost. 2006;32(6):621-625.
8.
Federici AB. Highly purified VWF/FVIII concentrates in the treatment and 
prophylaxis of von Willebrand disease: the PRO.WILL Study. Haemophilia. 
2007;13 Suppl 5:15-24.
For non-commercial use only

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9.
Halimeh S, Krümpel A, Rott H, et al. Long-term secondary prophylaxis in children, 
adolescents and young adults with von Willebrand disease. Results of a cohort 
study. Thromb Haemost. 2011;105(4):597-604.
10.
Abshire TC, Federici AB, Alvárez MT, et al. Prophylaxis in severe forms of von 
Willebrand's disease: results from the von Willebrand Disease Prophylaxis Network 
(VWD PN). Haemophilia. 2013;19(1):76-81.
11.
Abshire T, Cox-Gill J, Kempton CL, et al. Prophylaxis escalation in severe von 
Willebrand disease: A prospective study from the von Willebrand Disease 
Prophylaxis Network. J Thromb Haemost. 2015;13(9):1585-1589.
12.
Berntorp E. Prophylaxis in von Willebrand disease. Haemophilia. 2008;14 Suppl 
5:47-53.
13.
Varadi K, Rottensteiner H, Vejda S, et al. Species-dependent variability of 
ADAMTS13-mediated proteolysis of human recombinant von Willebrand factor. J 
Thromb Haemost. 2009;7(7):1134-1142.
14.
Mannucci PM, Kempton C, Millar C, et al. Pharmacokinetics and safety of a novel 
recombinant human von Willebrand factor manufactured with a plasma-free 
method: a prospective clinical trial. Blood. 2013;122(5):648-657.
15.
Gill JC, Castaman G, Windyga J, et al. Hemostatic efficacy, safety and 
pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand 
disease. Blood. 2015;126(17):2038-2046.
16.
Committee for Medicinal Products for Human Use. Guideline on immunogenicity 
assessment of biotechnology-derived therapeutic proteins. 
CHMP/BMWP/14327/2006, 18. 12-13-2007:London, European Medicines Agency 
(EMA),:2007. Web Link: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/200
9/09/WC500003946.pdf
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17.
Kasper CK. Laboratory tests for factor VIII inhibitors, their variation, significance 
and interpretation. Blood Coagul Fibrinolysis. 1991;2 Suppl 1:7-10.
18.
Lillicrap D. Von Willebrand Factor. International Society for Thrombosis and 
Hemostasis (ISTH), 54th Annual Scientific and Standardization Committee 
Meeting - Scientific Subcommittee Minutes:2008:60-64. Web Link: 
http://c.ymcdn.com/sites/www.isth.org/resource/resmgr/yearly_subcommittee_min
utes/2008minutes.pdf?hhSearchTerms=lillicrap+and+2008
19.
20.
 
21.
 
 
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22. SUMMARY OF CHANGES
Protocol 071301: Local Amendment 9 (Turkey): 2018 SEP 13
Replaces: Global Amendment 6: 2018 MAR 12
In this section, changes from the previous version of the Protocol, dated 2018 MAR 12, 
are described and their rationale is given.
1.
Throughout the document
Description of Change:
Minor grammatical and/or administrative changes and/or rewording have been 
made.
Purpose for Change: To improve the readability and/or clarity of the protocol.
2.
Synopsis (Study Design), Section 8.1
Description of Change: 
Added the wording about the possible up-to 3 months’ extension of study 
participation for certain subjects.
Purpose for Change: To add information about possible extension of study 
participation for certain subjects.
3.
Synopsis (Planned Duration of Subject Participation), Section 8.2
Description of Change: 
Added the note about the possible up-to 3 months’ extension of study 
participation for certain subjects, and clarify that the planned duration of subject 
participation can therefore be extended to 18 months. 
Purpose for Change: To add information about possible extension of study 
participation for certain subjects.
4.
Synopsis (Secondary outcome measures), Section 8.3.2.1
Description of Change:
Original text:
Categorized spontaneous ABR defined as 0, 1-2, 3-5, or >5 bleeding episodes 
during the 12-month prophylactic treatment with rVWF (vonicog alfa)
New text:
Categorized spontaneous ABR defined as 0, 1-2, 3-5, or >5 bleeding episodes 
during the prophylactic treatment with rVWF (vonicog alfa)
Purpose for Change: To remove the exact prophylactic treatment period as it can 
be extended beyond 12 month for certain subjects.
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5.
Section 6.1
Description of Change: 
Updates were added to reflect the marketing authorization for Vonvendi in US 
and EU.
Purpose for Change: To provide updated marketing authorization for Vonvendi.
6.
Section 10.3.7
Description of Change: 
The detailed schedules of follow-up visits were removed as for certain subjects 
12-month follow-up visit will be scheduled with the need of participation 
extension.
Purpose for Change: To remove the details to avoid confusion of possible 12-
month follow-up visit.
7.
Section 10.3.9
Description of Change:
End of study visit time was removed as for certain subjects the EOS visit can 
occur after 12 months with the need of participation extension. 
Added the note about the possible up-to 3 months’ extension of study 
participation for certain subjects
Purpose for Change: To add information about possible extension of study 
participation for certain subjects and to remove the details to avoid confusion of 
possible delayed EOS visit.
8.
Section 11.6, Section 12.10.2
Description of Change: 
Added the note about the possible up-to 3 months’ extension of study 
participation for certain subjects. 
Purpose for Change: To add information about possible extension of study 
participation for certain subjects.
9.
Section 20.2 Table 6a 6b, Section 20.3 Table 8a 8b
Description of Change: 
Added the footnote to reflect the possible up-to 3 months’ extension of study 
participation for certain subjects.
Purpose for Change: To add note about possible extension of study participation 
for certain subjects.
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10.
Section 20.2 Table 6a 6b, Section 20.3 Table 8a 8b
Description of Change:
Some clarifications were made to the tables and the footnotes, to reflect the 
possible up-to 3 months’ extension of study participation for certain subjects. 
Purpose for Change: To add information about possible extension of study 
participation for certain subjects.
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INVESTIGATOR ACKNOWLEDGEMENT
RECOMBINANT VON WILLEBRAND FACTOR (rVWF)
A prospective, phase 3, open-label, international multicenter study on efficacy and 
safety of prophylaxis with rVWF in severe von Willebrand Disease
PROTOCOL IDENTIFIER: 071301
CLINICAL TRIAL PHASE 3
LOCAL AMENDMENT 9 (TURKEY): 2018  SEP 13
Replaces: GLOBAL AMENDMENT 6: 2018 MAR 12
OTHER PROTOCOL ID(s)
NCT Number: NCT02973087
EudraCT Number: 2016-001478-14
IND NUMBER: 013657
By signing below, the investigator acknowledges that he/she has read and understands 
this protocol, and will comply with the requirements for obtaining informed consent from 
all study subjects prior to initiating any protocol-specific procedures, obtaining written 
initial and ongoing EC(s) protocol review and approval, understands and abides by the 
requirements for maintenance of source documentation, and provides assurance that this 
study will be conducted according to all requirements as defined in this protocol, Clinical 
Trial Agreement, ICH GCP guidelines, and all applicable national and local regulatory 
requirements.
Signature of Principal Investigator
Date
Print Name of Principal Investigator
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CLINICAL STUDY PROTOCOL
PRODUCT: Recombinant Von Willebrand Factor (rVWF, vonicog alfa)
STUDY TITLE: A PROSPECTIVE, PHASE 3, OPEN-LABEL, INTERNATIONAL 
MULTICENTER STUDY ON EFFICACY AND SAFETY OF PROPHYLAXIS 
WITH rVWF IN SEVERE VON WILLEBRAND DISEASE
STUDY SHORT TITLE: rVWF IN PROPHYLAXIS
PROTOCOL IDENTIFIER: 071301
CLINICAL TRIAL PHASE 3
LOCAL AMENDMENT 10 (UNITED STATES): 2018 SEP 13
Replaces: 
AMENDMENT 6: 2018 MAR 12
ALL VERSIONS: 
Local (United States) Amendment 10: 2018 SEP 13 
Local (Turkey) Amendment 9: 2018 SEP 13
Local (Czech Republic) Amendment 8: 2018 MAY 18
Local (Germany) Amendment 7: 2018 MAY 18
Amendment 6: 2018 MAR 12 
Local (Czech) Amendment 5: 2017 AUG 08
Local (Germany) Amendment 4: 2017 AUG 04
Amendment 3: 2017 AUG 03
Amendment 2: 2016 DEC 15
Amendment 1: 2016 APR 08
Original: 2014 FEB 09
OTHER ID(s)
NCT Number: NCT02973087
EudraCT Number: 2016-001478-14
IND NUMBER: 013657
Study Sponsor(s):
Baxalta US Inc.
300 Shire Way
Lexington, MA 02421,US
Baxalta Innovations GmbH
Industriestrasse 67
A-1221 Vienna, AUSTRIA
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1. STUDY PERSONNEL
1.1 Authorized Representative (Signatory) / Responsible Party
, MD
Global Clinical Development Operations
Baxalta Innovations GmbH
1.2 Study Organization
The name and contact information of the responsible party and individuals involved with 
the study (e.g. investigator(s), sponsor’s medical expert and study monitor, sponsor’s 
representative(s), laboratories, steering committees, and oversight committees [including 
ethics committees (ECs)], as applicable) will be maintained by the sponsor and provided 
to the investigator.
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2. SERIOUS ADVERSE EVENT REPORTING
The investigator will comply with applicable laws/requirements for reporting serious 
adverse events (SAEs) and suspected unexpected serious adverse events (SUSARs) to the 
ECs.
ALL SAEs, INCLUDING SUSARs, ARE TO BE REPORTED ON THE SERIOUS 
ADVERSE EVENT REPORT (SAER) FORM AND TRANSMITTED TO THE 
SPONSOR WITHIN 24 HOURS AFTER BECOMING AWARE OF THE EVENT.
Bleeding events that meet seriousness criteria (death, life-threatening, 
hospitalizing/prolongation of hospitalization, disability, congenital anomaly, or medically 
significant and if not urgently treated would result in one of the above) should be reported 
on the SAE eCRF and SAE Report form as an SAE.
Drug Safety contact information:
Baxalta Global Drug Safety fax number:  
OR 
email: 
For definitions and information on the assessment of these events, refer to the following:

Adverse Events (AEs), Section 12.1

SAEs, Section 12.1.1.1

SUSARs, Section 12.1.1.2

Assessment of AEs, Section 12.1.2

Safety Reporting, Section 12.1.2.3
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3. SYNOPSIS
INVESTIGATIONAL PRODUCT
Name of Investigational Product (IP)
Recombinant von Willebrand factor (rVWF, vonicog alpha)
Name(s) of Active Ingredient(s)
Recombinant von Willebrand factor (rVWF, vonicog alpha)
CLINICAL CONDITION(S)/INDICATION(S)
Subjects with severe von Willebrand disease (VWD) (baseline VWF: Ristocetin cofactor activity
(VWF:RCo) <20 IU/dL) requiring prophylactic treatment with coagulation factor replacement
PROTOCOL ID
071301
PROTOCOL TITLE
A prospective, phase 3, open-label, international multicenter 
study on efficacy and safety of prophylaxis with rVWF in severe 
von Willebrand disease
Short Title
rVWF in prophylaxis
STUDY PHASE
Phase 3
PLANNED STUDY PERIOD
Initiation
2017 OCT
Primary Completion
2019 Q4
Study Completion
2019 Q4
Duration
27 months
STUDY OBJECTIVES AND PURPOSE
Study Purpose
The purpose of this phase 3 study is to investigate the efficacy and safety, including immunogenicity, 
thrombogenicity and hypersensitivity reactions, as well as pharmacokinetics (PK), 
 
 and 
 of prophylactic treatment with rVWF (vonicog alfa) in adult 
subjects with severe VWD.
Primary Objective
The primary objective of this study is to prospectively evaluate the annualized bleeding rate (ABR) for 
spontaneous bleeding episodes while on prophylactic treatment with rVWF (vonicog alfa) and to compare 
it to the subject’s historical ABR for spontaneous bleeding episodes. 
Secondary Objectives
Secondary Objectives are to assess

Additional efficacy of prophylactic treatment with rVWF (vonicog alfa)

Safety of rVWF (vonicog alfa), including immunogenicity, thrombogenicity and hypersensitivity 

Pharmacokinetics (PK) of rVWF (vonicog alfa) and Pharmacodynamics (PD) of rVWF (vonicog alfa) 
as measured in FVIII activity
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Exploratory Objectives
 
 
 
 
STUDY DESIGN
Study Type/ Classification/ Discipline
Efficacy and Safety 
Control Type
No control
Study Indication Type
Prophylaxis and treatment of bleeding episodes
Intervention model 
Single-group
Blinding/Masking
Open-label
Study Design
This is a phase 3, prospective, open-label, uncontrolled, non-
randomized, international multicenter study evaluating efficacy, 
safety, including immunogenicity, thrombogenicity and 
hypersensitivity reactions, as well as PK, 
 and 
 of prophylactic treatment regimen with 
rVWF (vonicog alfa) in adult subjects with severe VWD.
Subjects transitioning from on-demand treatment (OD subjects) 
or subjects switching from prophylactic treatment with pdVWF 
(pdVWF switch subjects) will receive prophylactic treatment 
with rVWF (vonicog alfa) for a 12-month period (up to 15 
months for the qualified subjects to rollover into the continuation 
study, if the continuation study start up is delayed beyond the 
completion of subject’s 12-month visit).
Planned Duration of Subject 
Participation
Approximately 15 to 18* months 
* Study treatment period is extended by 3 months to 
accommodate participation in the continuation study for the 
qualified subjects and will be exercised only if the continuation 
study start up is delayed beyond the completion of subject’s 12-
month visit.
Primary Outcome Measure 
Efficacy

Annualized bleeding rate (ABR) for spontaneous (not related to trauma) bleeding episodes during 
prophylactic treatment with rVWF (vonicog alfa)
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Secondary Outcome Measures
Additional efficacy of prophylactic treatment with rVWF (vonicog alfa)

ABR percent reduction success for OD subjects defined as at least 25% reduction of ABR for 
spontaneous (not related to trauma) bleeding episodes during rVWF (vonicog alfa) prophylaxis 
relative to the subject’s own historical ABR during on-demand treatment 

ABR preservation success for pdVWF switch subjects defined as achieving an ABR for spontaneous 
bleeding episodes during rVWF (vonicog alfa) prophylaxis that is no greater than the subject’s own 
historical ABR during prophylactic treatment with pdVWF 

Categorized spontaneous ABR defined as 0, 1-2, 3-5, or >5 bleeding episodes during the prophylactic 
treatment with rVWF (vonicog alfa)

Total number of infusions and the average number of infusions per week during prophylactic 
treatment with rVWF (vonicog alfa)

Total weight adjusted consumption of rVWF (vonicog alfa) during prophylactic treatment

Spontaneous ABR by location of bleeding (Gastrointestinal [GI], epistaxis, joint bleeding, 
menorrhagia, oral and other mucosa, muscle and soft tissue, etc.) while on prophylactic treatment with 
rVWF (vonicog alfa) 
Safety

Adverse events (AEs) : incidence, severity, causality

Thromboembolic events 

Hypersensitivity reactions 

Development of neutralizing antibodies to VWF and FVIII 

Development of total binding antibodies to VWF and FVIII

Development of binding antibodies to Chinese hamster ovary (CHO) proteins, mouse 
immunoglobulin G (IgG) and rFurin

Clinically significant changes in vital signs and clinical laboratory parameters relative to baseline
Pharmacokinetics (PK) and Pharmacodynamics (PD)

PK parameters after a washout for on-demand subjects: incremental recovery (IR), terminal half-life 
(T1/2), mean residence time (MRT), area under the concentration versus time curve from 0 to infinity 
(AUC0-), area under the concentration versus time curve from 0 to the last measurable concentration 
(AUC0-tlast), maximum concentration (Cmax), minimum time to reach the maximum concentration 
(Tmax), volume of distribution at steady state (Vss) and clearance (CL) based on VWF:RCo, Von 
Willebrand factor antigen (VWF:Ag), Von Willebrand collagen binding activity (VWF:CB).

PD parameters after a washout for on-demand subjects: Cmax, Tmax, and AUC0-tlast as measured in 
FVIII activity by the 1-stage clotting assay (FVIII:C). 

PK parameters at steady state for on-demand and switch subjects: area under the concentration versus 
time curve from 0 to end of the partial dosing interval (AUC0- tau;ss), maximum concentration during 
the partial dosing interval (Cmax;ss), minimum time to reach the maximum concentration (Tmax;ss) and 
minimum concentration during the partial dosing interval (Cmin;ss) based on VWF:RCo, VWF:Ag and 
VWF:CB. PK parameters at steady state will be assessed shortly after reaching steady state for switch 
subjects and at the end of the study for on-demand as well as for switch subjects all based on the 
longer interval of the irregular dosing intervals employed. 
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
PD parameters at steady state for on-demand and switch subjects: AUC0-tau;ss, Cmax;ss, Tmax;ss, and Cmin;ss
as measured in FVIII actvitiy by the 1-stage clotting assay (FVIII:C). PD parameters at steady state 
will be assessed shortly after reaching steady state for switch subjects and at the end of the study for 
on-demand as well as for switch subjects all based on the longer interval of the irregular dosing 
intervals employed.

Time course of FVIII clotting activity (FVIII:C) levels.
Exploratory Outcome Measures
 
 
 
 
 
 
 
 
 
 
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INVESTIGATIONAL PRODUCT(S), DOSE AND MODE OF ADMINISTRATION
Active Product
Dosage form: powder and solvent for solution for injection
Dosage frequency:
Prophylactic Treatment
Subjects transitioning from on-demand treatment will receive twice weekly 
infusion with rVWF (vonicog alfa) at doses of 50 ± 10 IU/kg rVWF:RCo. 
Dosage may be individualized within this range based on: 

available historical PK data

type and severity of bleeding episodes the subject has experienced in the past

monitoring of appropriate clinical and laboratory measures
The starting dose can, after consultation with the Sponsor, be increased up to 
80 U/kg if considered necessary to assure effective prophylaxis.
Subjects switching from pdVWF prophylaxis treatment: the weekly dose (IU/kg) 
of rVWF (vonicog alfa) for each patient will be equivalent (± 10%) to the weekly 
VWF dose received during prophylactic treatment with pdVWF. The weekly 
dose should be divided into 2 infusions, with a maximum of 80 IU/kg/infusion. If 
needed, based on the total weekly dose or other clinical judgements, the weekly 
dose may be given as three infusions. A once weekly dose regimen will be 
allowed after switch to rVWF (vonicog alfa) if the patient has been on a once 
weekly dose regimen with pdVWF. Dose and dose interval may, after 
consultation with the sponsor, be further individualized based on: 

available historical PK data

type and severity of bleeding episodes the subject has experienced in the past

monitoring of appropriate clinical and laboratory measures
Treatment of Bleeding Episodes:
Dosage must be individualized based on the subject’s weight, type and severity 
of bleeding episode and monitoring of appropriate clinical and laboratory 
measures. In general, an initial dose of 40-60 IU/kg VWF:RCo with or without
30-45 IU rFVIII [ADVATE, octocog alfa]/kg is recommended (rVWF:rFVIII 
ratio of 1.3:1: ± 0.2). In cases of major bleeding episodes, a dose of up to 80 
IU/kg VWF:RCo may be infused. Subsequent doses, if necessary, will be 
administered with or without ADVATE (rFVIII, octocog alfa) to maintain 
VWF:RCo and FVIII levels for as long as deemed necessary by the investigator.
Mode of Administration: intravenous
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SUBJECT SELECTION
Targeted Accrual
Approximately 22 adult subjects with severe VWD will be included to have 
≥8 subjects in each cohort (OD and switch). A total of at least 5 type 3 VWD 
subjects will be followed for 12 months. 
Number of Groups/ 
Arms/ Cohorts
Single-group
Inclusion Criteria
Subjects who meet ALL of the following criteria are eligible for this study:
1. Subject has a documented diagnosis of severe VWD (baseline VWF:RCo <20 IU/dL) with a history of 
requiring substitution therapy with von Willebrand factor concentrate to control bleeding:
a. Type 1 (VWF:RCo <20 IU/dL) or,
b. Type 2A (as verified by multimer pattern), Type 2B (as diagnosed by genotype), Type 2M or,
c. Type 3 (VWF:Ag ≤3 IU/dL).
2. Diagnosis is confirmed by genetic testing and multimer analysis, documented in patient history or at 
screening.
3. For on-demand patient group, subject currently receiving on-demand treatment for whom prophylactic 
treatment is recommended by the investigator. 
4. For pdVWF switch patient group, subject has been receiving prophylactic treatment of pdVWF 
products for no less than 12 months prior to screening.
5. For on-demand patient group, subject has ≥3 documented spontaneous bleeds (not including 
menorrhagia) requiring VWF treatment during the past 12 months. 
6. Availability of records to reliably evaluate type, frequency and treatment of bleeding episodes during 
at least 12 months preceding enrollment. Up to 24 months of retrospective data should be collected if 
available. Availability of dosing and factor consumption during 12 months (up to 24 months) of 
treatment prior to enrollment is required for pdVWF switch subjects and is desired (but not a 
requirement) for on-demand subjects.
7. Subject is ≥18 years old at the time of screening and has a body mass index ≥15 but <40 kg/m2.
8. If female of childbearing potential, subject presents with a negative blood/urine pregnancy test at 
screening and agrees to employ adequate birth control measures for the duration of the study.
9. Subject is willing and able to comply with the requirements of the protocol.
Exclusion Criteria
Subjects who meet ANY of the following criteria are not eligible for this study:
1. The subject has been diagnosed with Type 2N VWD, pseudo VWD, or another hereditary or acquired 
coagulation disorder other than VWD (e.g., qualitative and quantitative platelet disorders or elevated 
prothrombin time (PT)/international normalized ratio [INR] 1.4).
2. The subject is currently receiving prophylactic treatment with more than 5 infusions per week.
3. The subject is currently receiving prophylactic treatment with a weekly dose exceeding 240 IU/kg.
4. The subject has a history or presence of a VWF inhibitor at screening.
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5. The subject has a history or presence of a FVIII inhibitor with a titer ≥0.4 Bethesda units (BU) (by 
Nijmegen modified Bethesda assay) or ≥0.6 BU (by Bethesda assay).
6. The subject has a known hypersensitivity to any of the components of the study drugs, such as to 
mouse or hamster proteins.
7. The subject has a medical history of immunological disorders, excluding seasonal allergic 
rhinitis/conjunctivitis, mild asthma, food allergies or animal allergies.
8. The subject has a medical history of a thromboembolic event.
9. The subject is human immunodeficiency virus (HIV) positive with an absolute Helper T cell 
(CD4) count 200/mm3.
10. The subject has been diagnosed with significant liver disease per investigator’s medical assessment of 
the subject’s current condition or medical history or as evidenced by any of the following: serum 
alanine aminotransferase (ALT) greater than 5 times the upper limit of normal; hypoalbuminemia; 
portal vein hypertension (e.g., presence of otherwise unexplained splenomegaly, history of esophageal 
varices).
11. The subject has been diagnosed with renal disease, with a serum creatinine (CR) level ≥2.5 mg/dL.
12. The subject has a platelet count <100,000/mL at screening.
13. The subject has been treated with an immunomodulatory drug, excluding topical treatment (e.g., 
ointments, nasal sprays), within 30 days prior to signing the informed consent.
14. The subject is pregnant or lactating at the time of enrollment.
15. Patient has cervical or uterine conditions causing menorrhagia or metrorrhagia (including infection, 
dysplasia).
16. The subject has participated in another clinical study involving another investigational product (IP) or 
investigational device within 30 days prior to enrollment or is scheduled to participate in another 
clinical study involving an IP or investigational device during the course of this study.
17. The subject has a progressive fatal disease and/or life expectancy of less than 15 months.
18. The subject is scheduled for a surgical intervention.
19. The subject is identified by the investigator as being unable or unwilling to cooperate with study 
procedures.
20. The subject has a mental condition rendering him/her unable to understand the nature, scope and 
possible consequences of the study and/or evidence of an uncooperative attitude.
21. The subject is in prison or compulsory detention by regulatory and/or juridical order
22. The subject is member of the study team or in a dependent relationship with one of the study team 
members which includes close relatives (i.e., children, partner/spouse, siblings and parents) as well as 
employees.
Delay criteria
1. If the subject presents with an acute bleeding episodes or acute illness (e.g., influenza, flu-like 
syndrome, allergic rhinitis/conjunctivitis, non-seasonal asthma) the screening visit will be postponed 
until the subject has recovered.
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STATISTICAL ANALYSIS
Sample Size Calculation
Approximately 22 adult subjects with severe VWD will be included in the study. The aim is to have 
≥8 subjects in each cohort (OD and switch). A total of at least five type 3 VWD subjects will be followed 
for 12 months. The sample size is driven by practical considerations (primarily the enrollment of a rare 
patient population) and EMA Guideline on the Clinical Investigation of Human Plasma Derived von 
Willebrand Factor Products (CPMP/BPWG/220/02).1
Planned Statistical Analysis
The Full Analysis Set (FAS) will be composed of all subjects who receive prophylaxis IP treatment.
The Safety Analysis Set will be composed of all subjects who received any amount of IP  (rVWF, vonicog 
alpha).
The Per-Protocol (PP) Analysis Set will be composed of subjects who are at least 70% compliant regarding 
the number of scheduled prophylactic infusions. Only subjects who meet all study entry criteria and who 
have no major protocol violations that might impact primary efficacy assessments will be included in the 
PP analysis set.
The Pharmacokinetic Full Analysis Set (PKFAS) will be composed of all subjects who received the PK 
infusion and who provided acceptable data for PK and PD analysis. Acceptable PK/PD data will be defined 
in the Statistical Analysis Plan.
Primary Outcome Measure:
No formal statistical hypothesis test is planned for the analysis. Spontaneous ABR while treated with rVWF 
(vonicog alfa) for each cohort, on demand and switch subjects, will be estimated using a negative binomial 
regression. The prior ABR for each cohort will be based on historical data collected from each enrolled 
subject. The two ABRs (observed on the study and historical) will be assessed using a generalized linear 
mixed-effects model (GLMM) with the negative binomial distribution as a family and with a logarithmic 
link function (the default). The ABR ratio together with a two-sided, 95% confidence interval (CI) will be 
reported for each cohort.
The difference in on-study ABR relative to historical ABR will be summarized descriptively.
The primary efficacy analysis will be based on the FAS and will be summarized by the two cohorts: on-
demand and switch subjects. As a supportive analysis, the same analysis will also be carried out on the per-
PP analysis set.
Secondary Outcome Measures:
In general, data for  secondary efficacy analysis will be summarized by the two cohorts: on-demand and 
switch subjects and when applicable overall. Mean, standard deviation, median, range, quartiles will be 
calculated for continuous endpoints. Proportions will be calculated for categorical endpoints. Confidence 
intervals at the 95% level will be provided when appropriate. 
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Additional efficacy of prophylactic treatment with  rVWF (vonicog alfa):
The number  and proportion of on-demand subjects with ABR percent reduction success (i.e. ≥ 25% ) will 
be calculated together with a two-sided 95% CI for the proportion. 
The number  and proportion of pdVWF switch subjects with ABR preservation success will be reported 
together with the corresponding 95% two-sided CIs for the proportion. 
The number and proportion of subjects with categorized spontaneous ABR (i.e. 0, 1-2, 3-5, more than 
5 bleeds) will be reported descriptively.
Summary statistics for the total number of infusions, as well as average number of infusions per week will 
be provided. The total weight adjusted consumption of rVWF (vonicog alfa) during prophylactic treatment 
will be provided. If applicable, historical data on consumption of pdVWF prior to the study will be 
summarized as well.
The change in spontaneous ABR from the historical rate to that during the rVWF (vonicog alfa) 
prophylaxis period will be summarized by location of bleeding (GI, epistaxis, joint bleeding, 
menorrhagia, oral and other mucosa, muscle and soft tissue, etc.).
Pharmacokinetics (PK) and Pharmacodynamics (PD):
The following PK parameters, based on the initial PK assessment after a washout for on-demand subjects, 
will be listed and summarized descriptively for VWF:RCo, VWF:Ag and VWF:CB: IR, T1/2, MRT, 
AUC0-, AUC0-tlast, Cmax, Tmax, Vss, and CL. The corresponding pharmacodynamics (PD) of rVWF 
(vonicog alfa) as measured in FVIII activity (FVIII:C), based on the initial PK assessment after a 
washout for on-demand subjects will be assessed using Cmax, Tmax, and AUC0-tlast. These PD parameters 
will be listed and summarized descriptively. 
PK parameters at steady state (AUC0-tau;ss, Cmax;ss, Tmax;ss, and Cmin;ss) for the partial dosing interval will be 
listed for on-demand subjects at the end of the study and for switch subjects shortly after reaching steady 
state and at the end of the study for VWF:RCo, VWF:Ag and VWF:CB and summarized descriptively for 
subjects with the same dosing regimens. The corresponding pharmacodynamics (PD) of rVWF (vonicog 
alfa) as measured in FVIII activity (FVIII:C) will be assessed using AUC0-tau;ss, Cmax;ss, Tmax;ss, and Cmin;ss. 
These PD parameters will be listed for on-demand subjects at the end of the study and for switch subjects 
shortly after reaching steady state and at the end of the study and will be summarized descriptively for 
subjects with the same dosing regimens. 
For the on-demand subjects, the PK of VWF:RCo will be analyzed using a population PK approach to 
characterize the single and multiple dose pharmacokinetics, including associated variability, of VWF:RCo 
in the study population.
For the switch subjects, differences in AUC0-tau;ss, Cmax;ss, and Cmin;ss assessess shortly after reaching steady 
state and assessed at the end of the study will be assessed by ratio of geometric means and corresponding 
two-sided 95% confidence intervals for VWF:RCo, VWF:Ag, VWF:CB, and FVIII:C. The difference in 
Tmax;ss, between first and second pharmacokinetic assessment will be summarized by the median and range 
(minimum to maximum) for VWF:RCo, VWF:Ag,VWF:CB, and FVIII:C.
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Descriptive statistics will be used to summarize VWF:RCo, VWF:Ag, VWF:CB,  and FVIII:C levels for 
each nominal time point on the PK curve. For all subjects activity/concentration vs. time curves will be 
prepared.
Safety:
Safety analysis will be performed overall and by the two cohorts: on-demand and switch subjects.
Treatment-emergent AEs (TEAEs) are defined as AEs with start dates on or after the first exposure to IP. 
Summaries of AEs will be based on TEAEs unless otherwise indicated.
Occurrence of AEs and serious AEs (SAEs) will be summarized descriptively, by system organ class and 
preferred term. The number and percentage of subjects who experienced AEs and SAEs, and the number of 
AEs and SAEs will be tabulated. In addition, the number of subjects who experienced AEs assessed as 
related to IP by the investigator, and the number of IP-related AEs will be tabulated. The number of 
patients with AEs by severity will be presented similarly.
A listing of all AEs will be presented by subject identifier, age, sex, preferred term and reported term of the 
AE, duration, severity, seriousness, action taken, outcome, causality assessment by investigator, onset date, 
stop date and medication or non-drug therapy to treat the AE. 
Temporally associated AEs are defined as AEs that begin during infusion or within 24 hours (or 1 day 
where time of onset is not available) after completion of infusion, irrespective of being related or not 
related to treatment. Temporally associated AEs will be presented in summary tables.
Adverse events of special interest (AESI), such as hypersensitivity reactions and thromboembolic events,  
will be monitored throughout the study and statistical analysis will be conducted based on the search 
criteria (eg, standardized MedDRA queries [SMQ]) determined prior to database lock, and summarized.
For immunogenicity analysis frequency counts and proportions will be calculated for subjects with the 
occurrence of neutralizing (inhibitory) antibodies to VWF and FVIII, occurrence of binding antibodies to 
VWF and FVIII, and occurrence of binding antibodies to CHO proteins, mouse immunoglobulin G (IgG) 
and rFurin.
Clinically significant changes relative to baseline in vital signs and clinical laboratory parameters 
(hematology, clinical chemistry) will be reported.
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4. TABLE OF CONTENTS
1. STUDY PERSONNEL.................................................................................................. 2
1.1 Authorized Representative (Signatory) / Responsible Party .............................. 2
1.2 Study Organization................................................................................................. 2
2. SERIOUS ADVERSE EVENT REPORTING........................................................... 3
3. SYNOPSIS..................................................................................................................... 4
4. TABLE OF CONTENTS ........................................................................................... 14
5. LIST OF ABBREVIATIONS .................................................................................... 20
6. BACKGROUND INFORMATION .......................................................................... 24
6.1 Description of Investigational Product ............................................................... 24
6.2 Clinical Condition/Indication .............................................................................. 25
6.3 The Role of Prophylaxis in the Management of VWD...................................... 26
6.4 Populations to be Studied..................................................................................... 28
6.5 Findings from Nonclinical and Clinical Studies................................................. 28
6.5.1 Findings from Nonclinical Studies ............................................................... 28
6.5.1.1 Primary Pharmacodynamics ................................................................. 28
6.5.1.2 Safety Pharmacology.............................................................................. 29
6.5.1.3 Pharmacokinetics.................................................................................... 29
6.5.1.4 Toxicology................................................................................................ 29
6.5.2 Findings from Clinical Studies ..................................................................... 30
6.5.2.1 Study 070701 ........................................................................................... 31
6.5.2.2 Study 071104 ........................................................................................... 32
6.5.2.3 Study 071001 ........................................................................................... 33
6.5.2.4 Study 071101 ........................................................................................... 35
6.5.2.5 Study 071401: Single Subject with von Willebrand Disease............... 37
6.6 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) 
to Human Subjects................................................................................................ 37
6.7 Compliance Statement.......................................................................................... 38
7. STUDY PURPOSE AND OBJECTIVES ................................................................. 39
7.1 Study Purpose ....................................................................................................... 39
7.2 Primary Objective................................................................................................. 39
7.3 Secondary Objectives ........................................................................................... 39
7.4 Exploratory Objectives......................................................................................... 39
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10.2 Subject Identification Code................................................................................ 63
10.3 Screening and Study Visits................................................................................. 63
10.3.1 Screening Visit.............................................................................................. 63
10.3.2 Baseline Visit – Initial PK Assessment (On-demand Subjects Only)...... 64
10.3.3 Prophylaxis Initiation Visit......................................................................... 65
10.3.4 Initial Steady State PK-Assessment (pdVWF switch subjects only)....... 65
10.3.5 Treatment of Bleeding Episodes................................................................. 66
10.3.6 Perioperative Visits (only applicable if surgery is needed)...................... 66
10.3.7 Follow-Up Visits........................................................................................... 66
10.3.8 Unscheduled Visits....................................................................................... 68
10.3.9 End of Study PK Assessment and Study Termination Visit.................... 68
10.4 Medications and Non-Drug Therapies.............................................................. 69
10.5 Subject Diary....................................................................................................... 70
10.6 Subject Completion/Discontinuation ................................................................ 70
10.7 Procedures for Monitoring Subject Compliance ............................................. 71
11. ASSESSMENT OF EFFICACY AND PHARMACOKINETICS........................ 72
11.1 Assessment of Spontaneous Bleeding Episodes/Annualized Bleed Rate........ 72
11.2 Evaluation of ABR Before rVWF Prophylaxis and ABR Under rVWF 
Prophylactic Treatment........................................................................................ 73
11.3 Number of Infusions and Total Weight Adjusted Consumption of rVWF and 
ADVATE and historical prophylaxis dosing and factor consumption during 
pdVWF prophylaxis treatment prior to enrollment.......................................... 73
11.4 Assessment of Efficacy for Treatment of Bleeding Episode ........................... 73
11.5 Assessment of Efficacy for Treatment for Surgical Bleeding......................... 74
11.6 rVWF Pharmacokinetics and Pharmacodynamics ......................................... 75
12. ASSESSMENT OF SAFETY................................................................................... 77
12.1 Adverse Events.................................................................................................... 77
12.1.1 Definitions..................................................................................................... 77
12.1.1.1 Serious Adverse Event.......................................................................... 77
12.1.1.2 Suspected Unexpected Serious Adverse Reaction (SUSAR)............. 78
12.1.1.3 Non-Serious Adverse Event ................................................................. 78
12.1.1.4 Unexpected Adverse Events................................................................. 79
12.1.1.5 Preexisting Disease................................................................................ 79
12.1.2 Assessment of Adverse Events.................................................................... 79
12.1.2.1 Severity .................................................................................................. 81
12.1.2.2 Causality................................................................................................ 81
12.1.2.3 Safety Reporting ................................................................................... 82
12.2 Urgent Safety Measures ..................................................................................... 84
12.3 Untoward Medical Occurrences........................................................................ 85
12.4 Non-Medical Complaints ................................................................................... 85
12.5 Medical, Medication, and Non-Drug Therapy History................................... 85
12.6 Physical Examinations........................................................................................ 86
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19. PUBLICATION POLICY...................................................................................... 112
20. SUPPLEMENTS..................................................................................................... 113
20.1 Study Flow Chart.............................................................................................. 113
20.2 Schedule of Study Procedures and Assessments............................................ 114
20.2.1 Summary Schedule of Visit Assesments for Surgical Bleeding............. 118
20.3 Clinical Laboratory Assessments .................................................................... 120
20.3.1 Laboratory Sampling for Surgical Bleeding ........................................... 124
20.4 Contraceptive Methods for Female Subjects of Childbearing Potential..... 126
21. REFERENCES........................................................................................................ 127
22. SUMMARY OF CHANGES.................................................................................. 130
INVESTIGATOR ACKNOWLEDGEMENT............................................................ 133
Tables
Table 1 rVWF (vonicog alfa) Dosing Schedule Examples: Schedules A and B............. 48
Table 2 Criteria for Escalation Specific to Each Bleeding Indication............................. 50
Table 3 rVWF:RCo Dosing Recommendations for the Treatment of Bleeding Episodes 
Due to VWD ............................................................................................................. 54
Table 4 Efficacy Rating Scale.......................................................................................... 74
Table 5 Assessment of Hemostatic Efficacy ................................................................... 75
Table 6a Schedule of Study Procedures and Assessments for On-demand Subject...... 114
Table 7 Summary Schedule of Visit Assesments for Surgical Bleeding....................... 118
Table 8a Clinical Laboratory Assessments for On-demand Subject ............................. 120
Table 9 Laboratory Samplinga for Surgical Bleeding ................................................... 124
Figures
Figure 1 Study Design for Baxalta Clinical Study 071301............................................ 113
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5. LIST OF ABBREVIATIONS
Abbreviation
Definition
ABR
Annualized bleeding rate 
ADAMTS13
A Disintegrin And Metalloproteinase with a Thrombospondin type 1 motif, number 13
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine aminotransferase
AP
Alkaline phosphatase
AST
Aspartate aminotransferase
AUC0-∞
Area under the plasma concentration /time curve from time 0 to infinity
AUC0-tau;ss
Area under the plasma concentration /time curve from time 0 to end of the partial 
dosing interval
AUC0-tlast
Area under the plasma concentration /time curve from 0 to the last measurable 
concentration
aPTT
Activated partial thromboplastin time
B19V
Parvovirus B19
BP
Blood pressure
BU
Bethesda Unit
BUN
Blood urea nitrogen
BW
Body weight
CAM
Cell adhesion molecule
CBC
Complete blood count
CD4
Helper T cell
CHO
Chinese hamster ovary
CI
Confidence interval
Cl
Chloride
CL
Clearance
Cmax
Maximum plasma concentration
Cmax;ss
Maximum plasma concentration during the partial dosing interval at steady state
Cmin;ss
Minimum plasma concentration during the partial dosing interval at steady state
CR
Creatinine
CTA
Clinical Trial Agreement
eCRF
Electronic case report form
DMC
Data monitoring committee
DIC
Disseminated intravascular coagulation
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Abbreviation
Definition
DVT
Deep vein thrombosis
EC
Ethics committee
ECG
Electrocardiogram 
EDC
Electronic Data Capture
EDTA
Ethylenediaminetetraacetic acid
ELISA
Enzyme-linked immunosorbent assay
FAS
Full analysis set
FVIII
Factor VIII
FVIII:C
Factor VIII clotting activity
GCP
Good Clinical Practice
GI
Gastrointestinal
Glu
Glucose
HAMA
Human anti- mouse antibodies
HAV
Hepatitis A virus
HB
Hepatitis B
HBs
Hepatitis B surface
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HEV
Hepatitis E virus
HIV
Human immunodeficiency virus 
HLA
Human leukocyte antigen
HRP
Horseradish peroxidase
IB
Investigator's brochure
ICH
International Council for Harmonisation
Ig
Immunoglobulin
INN
International Nonproprietary Name
INR
International normalized ratio
IP
Investigational product
IR
Incremental recovery
i.v.
Intravenous
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Abbreviation
Definition
K
Potassium
k.o.
Knock out
LDH
Lactate Dehydrogenase
Na
Sodium
NMC
Non-medical complaint
NOAEL
No observed adverse effect level
MRI
Magnetic resonance imaging
MRT
Mean residence time
pdVWF
Plasma derived VWF product
pdVWF/FVIII
Plasma derived VWF product containing fractions of FVIII
PBAC
Pictorial Blood Assessment Chart
PCR
Polymerase Chain Reaction
PEF
Peak expiratory flow
PK
Pharmacokinetic
PKFAS
Pharmacokinetic Full Analysis Set
PKPPAS
Pharmacokinetic Per Protocol Analysis Set
PP
Per protocol 
PT
Prothrombin time
Q1, Q3
Quartile
rFVIII
Recombinant factor VIII
rVWF
Recombinant von Willebrand factor
RBC
Red blood cell count
SAE
Serious adverse event
SAER
Serious adverse event report
SDS-PAGE
Sodium dodecyl sulfate polyacrylamide gel electrophoresis
SIC
Subject identification code
SMQ
Standardised MedDRA queries 
sP-selectin
Soluble P-selectin
SUSAR
Suspected unexpected serious adverse reaction
T1/2
Terminal phase half life
TEAE
Treatment-emergent adverse event
TIA
Transient ischemic attack
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Abbreviation
Definition
Tmax
Minimum time to reach the maximum concentration
Tmax;ss
Minimum time to reach the maximum concentration at steady state
TTP
Thrombotic thrombocytopenic purpura
ULMW
Ultra-large molecular weight 
ULN
Upper limit of normal
Vss
Volume of distribution at steady state
VTE
Venous thromboembolism 
VWD
von Willebrand disease
VWF
Von Willebrand factor
VWF:Ag
Von Willebrand factor antigen
VWF:CB
Von Willebrand Factor collagen binding
VWF:RCo
Von Willebrand factor: Ristocetin cofactor activity
WBC
White blood cell
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6. BACKGROUND INFORMATION
6.1 Description of Investigational Product
Baxalta US Inc. (hereafter referred to as Baxalta or sponsor) has developed a human 
recombinant von Willebrand Factor (rVWF, vonicog alpha), which is co-expressed with 
recombinant factor VIII (rFVIII) in a Chinese hamster ovary (CHO) cell line and 
separated during the subsequent downstream process. To address concerns regarding the 
risk of transmission of blood-borne pathogens that may be introduced by human plasma, 
no exogenously added raw materials of human or animal origin are employed in the cell 
culture, purification, or formulation of the final container product. The only proteins 
present in the final container product other than rVWF (vonicog alfa) are trace quantities 
of murine immunoglobulin (IgG, from the immunoaffinity purification), host cell (i.e., 
CHO) protein, rFurin (used to further process rVWF). rVWF (vonicog alfa) is intended 
for the treatment of von Willebrand disease (VWD).
rVWF (vonicog alfa) has been developed under the Baxalta internal code BAX111 and is 
used as investigational product (IP) in this study. rVWF (vonicog alfa) may be used with 
or without ADVATE (rFVIII, octocog alfa) for the treatment of bleeding episodes (see 
Section 8.6.4.4). See Section 8.6 for further information on the IPs and their usage in this 
study. A detailed description of rVWF (vonicog alfa) is also provided in the 
Investigator’s Brochure (IB).
rVWF (vonicog alfa) was granted licensure in the United States in December 2015 under 
the brand name VONVENDI for the on-demand treatment and control of bleeding 
episodes in adults diagnosed with VWD and it has been available on the market in the US 
since 09 August 2016. In April 2018, VONVENDI was also granted licensure in the US 
by the FDA for an additional indication of perioperative management of bleeding in 
adults (age 18 and older) diagnosed with VWD. On 31st of August 2018, European 
Commission implemented the decision granting marketing authorization for VEYVONDI 
(vonicog alfa) for the treatment of haemorrhage and surgical bleeding and for the 
prevention of surgical bleeding in adults (age 18 and older) diagnosed with VWD, when 
desmopressin (DDAVP) treatment alone is ineffective or not indicated.
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6.2 Clinical Condition/Indication
Von Willebrand Factor (VWF) is a large multimeric glycoprotein with a molecular 
weight that varies from 500 to 20,000 kDa. VWF is normally found in plasma and 
produced in the alpha-granules of platelets and in endothelial cell organelles known 
as the Weibel-Palade bodies. VWF mediates platelet adhesion and aggregation at 
sites of vascular injury, one of the key functions in primary hemostasis. VWF also serves 
to stabilize coagulation factor VIII (FVIII), where FVIII is an essential cofactor of 
secondary hemostasis, which leads to fibrin clot formation.2 Qualitative and/or 
quantitative deficiencies of VWF lead to a highly variable bleeding diathesis known as 
VWD, the most common of the hereditary coagulation factor deficiencies. Penetrance of 
VWD is highly variable, with only a small fraction of mildly affected patients displaying 
clinical symptoms or a family history of a bleeding diathesis.
The current biochemical-based classification distinguishes disorders arising from partial 
quantitative (type 1), qualitative (type 2), or virtually complete (type 3) deficiencies of 
VWF. Up to 70% of VWD patients are diagnosed with type 1 VWD, which may also be 
associated with minor functional defects in the molecule. In general, patients with type 1 
VWD display mild clinical symptoms. Approximately 20 to 30% of VWD patients are 
diagnosed with type 2 VWD. Type 2 VWD is further divided into 4 subtypes (A, B, N, 
and M), reflecting distinct classes of functional abnormalities. These defects result in 
abnormal functional and/or multimeric distribution patterns that facilitate their diagnosis. 
The bleeding diathesis is usually moderate and primarily affects the mucosal tissues. 
Type 2N VWD patients are sometimes misdiagnosed as mild hemophilia A. Finally, 
approximately 1% percent of VWD patients exhibit a total or near total absence of VWF, 
which is classified as type 3 VWD. The incidence of type 3 VWD is estimated at 
0.5-1.0 x 106. This type is also associated with a very low FVIII level (typically <5%) 
because the VWF carrier function for FVIII is lost. Replacement of VWF alone stabilizes 
endogenous FVIII, resulting in hemostatic levels within several hours post-infusion. 
Published results from studies of a plasma-derived VWF (pdVWF) concentrate 
demonstrated an increase of FVIII at an approximate rate of 5.8 1 IU dL-1 h-1.3 Type 3 
VWD patients display severe hemorrhagic symptoms with bleeding predominantly in 
mucosal tissues, muscle and joints. All VWD patients, particularly those with type 2 or 
type 3 VWD, are at an increased risk for life-threatening bleeding episodes.
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6.3 The Role of Prophylaxis in the Management of VWD
The goals of long term prophylaxis in VWD are to maintain VWF and FVIII at sufficient 
levels to reduce the frequency and duration of bleeding episodes, the need for red blood 
cell transfusions, and the risk of complications, such as arthropathy.4 In contrast to 
hemophilia, routine prophylaxis is not as established in VWD, although prophylaxis for 
patients with severe VWD was in use in Sweden already during the 1950s.5 In those early 
days of VWD treatment, plasma FVIII concentrates containing VWF fractions were 
applied for replacement therapy, which then were followed by plasma derived VWF 
products containing fractions of FVIII (pdVWF/FVIII). 
A Swedish cohort including 37 patients with type 3 VWD under prophylactic median 
treatment of 11 years (range 2 to 45 years) was retrospectively analyzed.6,7 The 
doses used for prophylaxis, given once weekly for at least 45 weeks per year, were 
calculated based on 12 to 50 IU/kg body weight (BW) of FVIII clotting activity (FVIII:C)
which approximately corresponded to 24-100 IU/kg von Willebrand factor: Ristocetin 
cofactor activity (VWF:RCo) considering that mainly Haemate with a known 
VWF:RCo/FVIII:C ratio of about 2 was used. An escalation of doses from 1 to 3 dose 
levels was allowed depending on the frequency and severity of bleeding episodes. 
The results demonstrate that under long-term prophylaxis the number of bleeds could be 
reduced dramatically. Whereas the median value for bleeds per year was about 10 before 
prophylaxis this value could be reduced to less than 1 bleed per year during prophylaxis.
The benefit of prophylaxis for such indications was retrospectively also demonstrated in a 
cohort of Italian patients including type 3, 2A, 2M and type 1 patients. Prophylaxis was 
started after severe gastrointestinal or joint bleeding episodes and completely prevented 
bleeding episodes in 8 of these 11 patients and largely reduced the need of blood 
transfusions in the remaining 3. A regimen of 40 IU rVWF:RCo/kg was applied every 
other day or twice a week. A prospective study on prophylaxis, the PRO.WILL study, has 
been initiated in Italy.8
The results of a prospective study investigating the prophylaxis in children and young 
adults showed a significantly reduced bleeding frequency and bleeding score (3 vs. 0.07; 
3 vs. 0. p<0.001) compared to the pre-prophylaxis values. The median dose was 
40 (20-47) IU/kg VWF:RCo administered mainly twice weekly in 23 patients, 3 times a 
week in 7 patients and 4 times a week in 2 children.9
The VWD Prophylaxis Network initiated the VWD International Prophylaxis (VIP) trial 
to investigate the role of prophylaxis in patients with severe VWD including Type 1, 2,
and 3. The dose of the factor replacement product was 50 IU /kgVWF:RCo. 
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The frequency of the dose depended on the type of bleeding and could be increased from 
once weekly to twice weekly or 3 times per week. For the treatment of menorrhagia the 
dose of 50 IU/kg VWF:RCo was given on the first day of menses for 2 cycles. The 
frequency could be increased to Day 1 and 2 for 2 cycles or to Day 1, 2, and 3 of menses.
The study contains both retrospective and prospective study components. Results from
the retrospective study component were published, including 61 subjects on prophylactic 
regimen in the past 6 months prior to enrollment or subjects with a history of prophylaxis 
over at least 6 month.10 Differences in annualized bleeding rates (ABR) within 
individuals (during prophylaxis – before prophylaxis) were significant for those with 
primary indications of epistaxis (P = 0.0005), joint bleeding (P = 0.002) and GI bleeding 
(P = 0.001). The difference in the group whose primary indication for treatment was 
abnormally heavy bleeding at menstruation (n = 4) was not significant (P = 0.25). The 
reduction of mucosal bleeding likely not only dependents on normal circulating levels of 
active VWF, but also on the presence of discrete concentrations of normal VWF inside 
the platelets and within endothelial matrices. The low subject number (n=4) and the 
treatment scheme for menorrhagia on Days 1, 2, and 3 of menses which might represent 
rather on-demand than prophylactic treatment may also account for the outcome in this 
study.
Results from the prospective study component were reported recently.11 Eleven subjects 
completed the study. Six subjects had type 2A, and 5 subjects had type 3 VWD. 
Six subjects presented with epistaxis, 3 with GI bleeding, and 2 with joint bleeding. 
Seven subjects had dose escalation above the first level. Among the 10 subjects with 
evaluable bleeding log data, the use of prophylaxis decreased the median ABR from 25 to 
6.1 (95% confidence interval [CI] of the rate difference: -51.6 to -1.7), and the median 
ABR was even lower (4.0; 95% CI: -57.5 to -5.3) when the subjects reached their final 
dosing level. The authors concluded that this was the first prospective study to 
demonstrate that prophylaxis with VWF concentrates is highly effective in reducing 
mucosal and joint bleeding rates in clinically severe VWD.
The results of the VIP study and previous investigations suggest that VWD patients with 
recurrent bleeding episodes and severe menorrhagia will benefit from a prophylactic 
VWF replacement therapy. There is evidence that up to 40% of patients with type 3 
VWD experience joint bleeding which can lead to hemophilic arthropathy. Other 
potential indications for prophylaxis include patients with type 2A or 2B VWD with 
recurrent gastrointestinal bleeding, menorrhagia or frequent epistaxis.4 Long-term 
prophylaxis for most patients with type 3 VWD and in some patients with type 1 or 
2 VWD, depending on the pattern of bleeding, may be the treatment option of choice.
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Although the main experience with long-term prophylaxis is with secondary prophylaxis, 
primary prophylaxis starting at young age is recommended to prevent arthropathy in 
patients with severe VWD.12
However, further studies are needed to develop evidence-based guidelines for 
prophylactic treatment in VWD.
6.4 Populations to be Studied
A total of approximately 22 eligible, adult subjects with severe VWD (baseline 
VWF:RCo <20 IU/dL) are planned to be enrolled. Two cohorts of patients will be 
included: patients currently receiving on-demand VWF treatment (OD subjects) and 
patients currently on prophylactic treatment with pdVWF (pdVWF switch subjects), and 
the aim is to have ≥8 subjects in each of the 2 cohorts, with a total of at least 5 type 3 
VWD subjects followed for 12 months. Enrolled subjects (i.e., subjects who have signed 
the informed consent form) will be eligible to participate in the study if they meet all of 
the inclusion criteria (see Section 9.1) and none of the exclusion criteria (see Section 9.2).
6.5 Findings from Nonclinical and Clinical Studies
The following summarizes the key findings from relevant nonclinical studies as well as 
from the completed clinical studies 070701 (Phase 1 pharmacokinetics [PK] and safety in 
VWD), 071001 (Phase 3 safety and efficacy in the treatment of bleeding episodes in 
VWD), 071101 (Phase 3 efficacy and safety in VWD subjects undergo elective surgical 
procedures), 071104 (Phase 1 safety and PK in hemophilia A), and 071401 (Phase 3, 
expanded access in a single subject with VWD). Potential risks and efficacy of rVWF 
(vonicog alfa):ADVATE (rFVIII, octocog alfa) are summarized in the following sections. 
For additional information on nonclinical and clinical Phase 1 results refer to the rVWF 
(vonicog alfa) IB.
6.5.1 Findings from Nonclinical Studies
6.5.1.1 Primary Pharmacodynamics
Efficacy of rVWF (vonicog alfa) combined with ADVATE (rFVIII, octocog alfa) was 
shown in VWD animal models, which have also low endogenous FVIII levels. Time to 
occlusion and stable thrombus formation was assessed in the carotid occlusion model in 
VWD mice. The results demonstrated that rVWF (vonicog alfa) in combination with 
ADVATE (rFVIII, octocog alfa) acted efficiently in a dose-dependent manner and had 
higher efficacy than rVWF (vonicog alfa) alone or plasma derived (pd)VWF. These 
results were confirmed in an additional study assessing blood loss and survival in a tail 
tip bleeding model in VWD mice. In a VWD dog, rVWF (vonicog alfa) stabilized canine 
FVIII in the circulation and significantly reduced the bleeding time.
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6.5.1.2 Safety Pharmacology
The anaphylactoid and thrombogenic potential of the co-infusion of ADVATE (rFVIII, 
octocog alfa) and rVWF (vonicog alfa) and the co-infused product’s effects on blood 
pressure, cardiac and respiratory function and parameters of coagulation activation were 
investigated in 4 in vivo studies in different animal models. Safety pharmacology studies 
in rats, guinea pigs, rabbits, and dogs revealed no risks for anaphylactoid and 
thrombogenic potential of ADVATE (rFVIII, octocog alfa) in combination with rVWF 
(vonicog alfa). All observations in safety pharmacology studies are considered to lie 
within the biological variability of animal models or occurred due to known species-
specific anaphylactoid effects of excipients.
6.5.1.3 Pharmacokinetics
Pharmacokinetic studies of both rVWF (vonicog alfa) alone and combined with human 
rFVIII (rVWF+ADVATE) were conducted in VWD mice, VWD dogs, VWD pigs, rats,
and cynomolgus monkeys. Human rVWF (vonicog alfa) stabilized the endogenous FVIII 
in VWD mice, VWD pigs, and VWD dogs. Furthermore, the hypotheses that the area 
under the curve (AUC) with rVWF alone and rVWF+ADVATE is not inferior to the 
AUC with pdVWF (Haemate P) was tested and confirmed statistically in normal rats.
The PK characteristics of ADVATE (rFVIII, octocog alfa) were not affected by co-
administration of rVWF (vonicog alfa) in cynomolgus monkeys. The PK data in the 
FVIII knock out (k.o.) mice model are inconclusive and might not be relevant for the 
clinical situation. However, a stabilizing effect of VWF on FVIII could be shown in a 
double k.o. model in a dose dependent manner.
6.5.1.4 Toxicology
Single dose toxicity studies were conducted in C57BL/6J-mice, VWD mice, rats, rabbits, 
and cynomolgus monkeys. Rats, rabbits, and cynomolgus monkeys showed no signs of 
toxicity. Signs of microthrombosis, an exaggerated pharmacological effect, were 
observed in mice. Mice are not capable of sufficiently cleaving the rVWF (vonicog alfa) 
subunit as murine disintegrin and metalloproteinase with a thrombospondin type 1 motif, 
number 13 (ADAMTS13) does not decrease the ultra-large molecular weight multimers 
of rVWF (vonicog alfa).13 The observed symptoms of microthrombosis are interpreted as 
a species-specific exaggerated pharmacological effect. Studies evaluating the safety of 
repeated administration of rVWF (vonicog alfa) with or without ADVATE (rFVIII, 
octocog alfa) (daily over 14 days) were performed in a rodent (rat) and non-rodent 
(cynomolgus monkey) species. Reversible signs of exaggerated pharmacological effects 
(regenerative anemia, thrombocytopenia, and treatment-related histopathologic changes 
in the heart, liver, and spleen) were observed in rats that were administered 1400 U 
VWF:RCo/kg /day + 1080 IU ADVATE/kg/day intravenously once daily for 14 days. 
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Also, these findings are interpreted as a species-specific exaggerated pharmacological 
effect due to the low susceptibility of human rVWF (vonicog alfa) to cleavage by rodent 
ADAMTS13.13 No toxicologically relevant changes were evident for clinical 
observations, body weight, feed consumption, ophthalmology, urinalysis, coagulation,
and serum chemistry parameters, platelet aggregation, and gross pathology. rVWF 
(vonicog alfa) combined with ADVATE (rFVIII, octocog alfa) was well tolerated in 
cynomolgus monkeys after daily intravenous (i.v.) (bolus) administration of 100 U 
VWF:RCo/kg rVWF (vonicog alfa) combined with 77 IU/kg ADVATE (rFVIII, octocog 
alfa) over a period of 14 days. No adverse effects could be detected in this species. 
There were no signs of hemolysis, thrombosis, or thrombocytopenia after repeated 
intravenous application of rVWF (vonicog alfa) with or without ADVATE (rFVIII, 
octocog alfa). Therefore, 100 U VWF:RCo/kg/day rVWF (vonicog alfa) with or without 
77 IU/kg ADVATE (rFVIII, octocog alfa) was considered the no observed adverse effect 
level (NOAEL) in this study, which was the highest dose tested. Anti-drug antibodies, 
however, were formed in both species and resulted in a significant reduction in drug 
exposure after 14 applications as compared to a single application. These antibodies 
substantially reduced the systemic exposure to the test substance as compared to a single 
dose administration. No adverse effects due to antibody formation were observed in both 
species.
rVWF (vonicog alfa) combined with ADVATE (rFVIII, octocog alfa) was well tolerated 
locally and no genotoxic potential was evident after 2 in vitro and 1 in vivo genotoxicity 
study. A study on the influence of co-administration of VWF and ADVATE (rFVIII, 
octocog alfa) on the immunogenicity of ADVATE (rFVIII, octocog alfa) in 3 different 
hemophilic mouse models (E17 hemophilic Balb/c mice, E17 hemophilic C57BL/6J 
mice, and E17 hemophilic human F8 transgenic mice) showed that rVWF (vonicog alfa) 
does not negatively impact the immunogenicity of ADVATE (rFVIII, octocog alfa) in 
any of the three different hemophilic mouse models.
6.5.2 Findings from Clinical Studies
The clinical safety, efficacy and PK were assessed in 4 completed trials: one phase 1 
study (070701)) and two phase 3 studies (071001 and 071101) that enrolled patients with 
VWD; one phase 1 study (071104) that enrolled patients with hemophilia A. Details on 
study design, populations enrolled, and safety and efficacy outcomes of the phase 1 
studies are presented in Section 6.5.2.1 and Section 6.5.2.2, the phase 3 study in 
Section 6.5.2.3, and the phase 3 surgery study in Section 6.5.2.4. Information on a single 
subject with VWD in Study 071401 is presented in Section 6.5.2.5.
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6.5.2.1 Study 070701
Phase 1 clinical study 070701 was a multicenter, controlled, randomized, single-blind,
prospective 3-step, dose escalation study to investigate safety, tolerability, and PK of 
rVWF (vonicog alfa) combined at a fixed ratio with ADVATE (VWF:RCo/FVIII:C of 
1.3 ± 0.2:1) in adults with severe VWD.14 Subjects were enrolled in sequential cohorts in 
a dose escalating manner: Cohort 1, 2, and 3 received a single intravenous infusion of 
rVWF:ADVATE at the following doses: 2 IU/kg VWF:RCo (Cohort 1), 7.5 IU/kg 
VWF:RCo (Cohort 2), and 20 IU/kg VWF:RCo (Cohort 3). Subjects in Cohort 4 received 
a single intravenous infusion of rVWF:ADVATE and pdVWF/ADVATE at 50 IU/kg 
VWF:RCo in random order.
The primary endpoint was the tolerability and safety after single dose injections of 
rVWF:ADVATE at 2, 7.5, 20, and 50 IU/kg VWF:RCo for up to 30 days after the last IP 
infusion. The data generated in this phase 1 study suggest that rVWF:ADVATE up to the 
highest investigated dose of 50 IU/kg VWF:RCo is well tolerated and safe in adults with 
severe VWD. No thrombogenic risk or thrombotic thrombocytopenic purpura (TTP)-like 
syndrome was observed, and no neutralizing antibodies to VWF or FVIII were identified. 
There were no deaths or other serious adverse reactions, and no infusions were 
interrupted or stopped due to an AE. Overall, the reported AE profile was similar 
between the recombinant and plasma-derived concentrates.
Secondary endpoints were the PK assessment of VWF:RCo, von Willebrand factor 
antigen (VWF:Ag) and multimeric composition of rVWF (vonicog alfa) as well as 
FVIII:C at standardized time points after single injections of rVWF:ADVATE and 
pdVWF:FVIII. 
The median VWF:RCo terminal half-life (T1/2) of rVWF (vonicog alfa) at the 50 IU/kg 
dose was 16 hours. T1/2 with pdVWF:FVIII at the same dose level appeared shorter at 
12.58 hours, however, the limits of the 90% CI were similar (11.73 to 17.7 hours vs. 
11.87 to 18.03 hours). The median T1/2 of VWF:RCo were shorter with the lower 
investigated doses: 7.13 hours and 13.23 hours with the 7.5 IU/kg and 20 IU/kg doses, 
although these data were derived from a much smaller number of subjects.
In consequence of the missing ADAMTS13 cleavage, ultra-large molecular weight 
(ULMW) multimers are contained in the rVWF (vonicog alfa) final product. The 
immediate cleavage of these ultra-large multimers by ADAMTS13 upon release into the 
circulation could be demonstrated applying sodium dodecyl sulfate polyacrylamide gel 
electrophoresis (SDS-PAGE)/Immunoblot with polyclonal anti-VWF antibodies to detect 
the resulting rVWF (vonicog alfa) subunit cleavage fragments.
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Overall the data generated in this phase 1 study suggest that rVWF (vonicog 
alfa):ADVATE (rFVIII, octocog alfa) is well tolerated and safe in adults with severe 
VWD.
6.5.2.2 Study 071104
This study was a prospective, uncontrolled, non-randomized, multicenter proof of 
concept study to assess safety and PK of the addition of rVWF (vonicog alfa) to 
ADVATE (rFVIII, octocog alfa) treatment in 12 evaluable subjects with severe 
hemophilia A. All subjects underwent 3 PK analyses: the first after infusion with 
ADVATE (rFVIII, octocog alfa) alone, the second after infusion with ADVATE (rFVIII, 
octocog alfa) plus 10 IU/kg rVWF (vonicog alfa) and the third after infusion with 
ADVATE (rFVIII, octocog alfa) plus 50 IU/kg rVWF (vonicog alfa).
The PK analysis was performed at intervals of approximately 8 to 14 days. Before each 
infusion for PK assessment, there was a wash-out period of at least 5 days and the 
subjects were not actively bleeding. 
Primary outcome measures indicate that co-administration of rVWF (vonicog alfa) 
slightly sustain ADVATE activity with the highest observed ADVATE (rFVIII, octocog 
alfa) half-life of 13.74 h (CI 11.44 to 16.52) after co-infusion of 50 IU/kg ADVATE plus 
50 IU/kg rVWF:RCo.
The highest improvement in ADVATE (rFVIII, octocog alfa) circulating half-life was 
observed in subjects with VWF:Ag levels below 100% which indicates an association 
between baseline VWF:Ag levels and ADVATE (rFVIII, octocog alfa) half-life increase. 
No treatment related AEs or SAEs were reported. No subject withdrew due to an AE and 
there were no deaths. No binding antibodies to VWF, CHO, and rFurin were detectable in 
the confirmatory assay and no signs of a hypersensitivity to rVWF (vonicog alfa) or 
ADVATE (rFVIII, octocog alfa) antigen were observed. Laboratory values over time did 
not indicate any potential safety risk for hemophilia A patients treated with rVWF 
(vonicog alfa) and ADVATE (rFVIII, octocog alfa) in combination.
In summary, the data indicate that rVWF (vonicog alfa) co-administered with ADVATE 
(rFVIII, octocog alfa) up to the highest dose of 50 IU/kg VWF:RCo is well tolerated and 
safe in hemophilia A patients. 
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6.5.2.3 Study 071001
This was a phase 3, multicenter, open-label, part-randomized clinical study to assess the 
PK, safety, and efficacy of rVWF:rFVIII and rVWF in the treatment of bleeding episodes 
in adult subjects with severe type 3 and severe non-type 3 VWD.15 A total of 49 subjects 
were enrolled (signed informed consent) and screened, 18 subjects were randomized 
(randomization only applies to Arm 1[PK50 with treatment of BE] and Arm 2 [PK50
only] see below), 37 subjects were treated with IP (all study arms), and 30 subjects 
completed the study.
The study consisted of 2 parts (Part A and Part B). Part A consisted of PK assessments 
alone (Arm 2: PK50 only [without treatment of bleeding episodes]), or PK assessments 
(Arm 1: PK50 and Arm 3: PK80) plus on-demand treatment period(s) of 6 months for 
bleeding episodes, or on-demand treatment for bleeding episodes only (Arm 4). Except 
for subjects in arm 2 who completed study after second PK assessment, subjects  
receiving treatment for PK assessments and/or bleeding episodes in Part A were to be 
entered into Part B to continue on-demand treatment for bleeding episodes for 
6 additional months for a total of 12 months in the study. 
The primary outcome measure was the number of subjects with “treatment success” 
(extent of control of bleeding episodes), which was defined as a mean efficacy rating 
score of <2.5 for a subject’s IP-treated bleeding episodes during the study. The rate of 
subjects with treatment success was 100% (Clopper-Pearson exact 90% CI: 84.7 to 
100.0) for bleeds where the assessments were made prospectively and excluding GI 
bleeds. Sensitivity analyses confirmed the results of the primary analysis.
Crossover results at 50 IU/kg VWF:RCo showed that the PK profile for rVWF (vonicog 
alfa) VWF:RCo was independent of administration alone or with rFVIII (ADVATE, 
octocog alpha) (T1/2: 19.4 hours for rVWF and 16.6 hours for rVWF:rFVIII; IR: 1.8 U/dL 
per IU/kg infused for both rVWF and rVWF:rFVIII; mean residence time (MRT): 
26.7 hours for rVWF and 25.2 hours for rVWF:rFVIII). FVIII levels increased 
substantially with a median peak at 24 hours of 111.0 U/dL for rVWF:rFVIII and 
86.0 U/dL after rVWF alone, indicating that rVWF (vonicog alfa) induces a sustained 
increase in endogenous FVIII activity. The rVWF (vonicog alfa) PK profile was 
comparable at 50 IU/kg and 80 IU/kg VWF:RCo, and repeated PK at 80 IU/kg 
VWF:RCo showed close agreement between pretreatment and end-of-study results.
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Further analysis of the PK data from the 071001 study supports the initial use of 50 IU/kg 
twice weekly for prophylaxis dosing in the present study for those subjects who are 
moving from on-demand to prophylaxis. Using 50 IU/kg for PK measurements, subjects 
in the 071001 study exhibiting a T1/2 for rVWF of 14, 16, or 19 hours had rVWF plasma 
concentrations at 72 hours after administration of 2.55, 4.01, and 6.49% above baseline, 
respectively, and plasma concentrations at 96 hours after administration of 0.78, 1.40, and 
2.71% above baseline, respectively. In this context it should be noted that subjects in the 
present study who have significant spontaneous bleeding while on twice weekly
prophylaxis will have their regimen increased to 3 times per week based on clear criteria 
for different bleeding locations (for details see Section 8.6.4.3.1). Subjects in the present 
study who are switching from prophylaxis with a pdVWF product will begin on rVWF 
(vonicog alfa) using their same weekly total dose in IU/kg VWF:RCo used during their
pdVWF prophylaxis divided into twice weekly infusions (for details see section 8.6.4.3).
A total of 125 AEs occurred in 25/37 (67.7%) subjects (62/318 infusions [19.5%]) during 
or after infusion with IP. Of these, 116/125 were non-serious (all mild or moderate; none 
were severe), and 9 SAEs were reported in 7 subjects. Of 125 total AEs, 38 were 
temporally associated with IP; 8 AEs were considered causally related to IP: 
6 non-serious related AEs (tachycardia, infusion site paraesthesia, electrocardiogram 
[ECG] t-wave inversion, dysgeusia, generalized pruritis, and hot flush) occurred in 
4 subjects, and 2 related SAEs (chest discomfort and increased heart rate) occurred in 
1 subject. No deaths occurred during this study. 
None of the subjects developed anti-VWF or anti-FVIII neutralizing antibodies and no 
binding antibodies to VWF or rFurin, or antibodies against CHO protein or anti-Murine 
IgG were observed. No clinical or subclinical signs or symptoms of a thrombogenic event 
were observed in this study. Following an initial increase in ultralarge VWF multimers 
after administration of rVWF (vonicog alfa), a notable decrease in the proportion of large 
VWF multimers occurred between 12 and 24 hours post infusion, due to degradation by 
the endogenous ADAMTS13 followed by a continued decline until the end of the 96-hour 
follow-up period. 
Overall, the data support the safe and effective use of rVWF (vonicog alfa) with or 
without rFVIII (ADVATE, octocog alpha) in the treatment of bleeds in patients with 
VWD.
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6.5.2.4 Study 071101
This was a phase 3, prospective, open-label, multicenter clinical study to evaluate 
efficacy and safety of rVWF (vonicog alfa) with or without ADVATE (rFVIII, octocog 
alfa) in elective surgical procedures in adult subjects with severe VWD. A total of 
24 subjects were enrolled (signed informed consent) and screened, 15 subjects were 
treated with rVWF (vonicog alfa), and 15 subjects completed the study. 
Eleven subjects underwent a PK assessment by infusion of 50 ± 5 IU/kg rVWF:RCo at an 
infusion rate of up to 4 mL/min. 12 to 24 hours before surgery, subjects received a dose 
of 40 to 60 IU/kg rVWF:RCo. Within 3 hours prior to surgery, the subject’s FVIII:C 
levels were assessed with a target of 30 IU/dL for minor and oral surgeries and 60 IU/dL 
for major surgeries. Within 1 hour prior to surgery, subjects received a dose of rVWF 
(vonicog alfa) with or without ADVATE (rFVIII, octocog alfa) (depending on the target 
FVIII:C levels at the 3 hour assessment). VWF and FVIII IR and T1/2 for each subject, 
when known, were used to guide the initial dose and subsequent doses.
The primary outcome measure was the overall assessment of hemostatic efficacy assessed 
by the investigator (hemophilia physician) 24 hours after last perioperative IP infusion or 
at completion of day 14 visit, whichever occurred earlier, and was summarized by the 
percentage of subjects in each efficacy category (“excellent”, “good”, “moderate” and 
“none”). Point estimate and corresponding 90% two-sided exact CI was calculated for the 
rate of subjects with an overall assessment of hemostatic efficacy. All 15 subjects treated 
with rVWF (vonicog alfa) (with or without ADVATE) for major (10), minor (4), and oral 
(1) elective surgical procedures had overall hemostatic efficacy ratings of “excellent” or 
“good”. Most (73.3%) subjects had “excellent” overall hemostatic efficacy ratings; of 
these, 7 underwent major surgery and 4 underwent minor surgery. The remaining 26.7% 
subjects had “good” overall hemostatic efficacy ratings: 3 underwent major surgery and 
1 underwent oral surgery. All 8 subjects with VWD Type 3, the subtype classified as 
absolute VWF deficiency, had overall hemostatic efficacy ratings of “excellent” (87.5%) 
or “good” (12.5%).
Intraoperative hemostatic efficacy ratings were also rated as “excellent” or “good” for all 
15 treated subjects. Most (86.7%) subjects had “excellent” intraoperative hemostatic 
efficacy ratings; of these, 8 underwent major surgery, 4 underwent minor surgery, and 
1 underwent oral surgery. Two (13.3%) subjects who underwent major surgery had 
“good” intraoperative hemostatic efficacy ratings. Intraoperative hemostatic efficacy 
was rated as “excellent” or “good” for all subjects with VWD Type 3: “excellent” for 
7 (87.5%) subjects and “good” for 1 (12.5%) subject. 
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Only 1 subject received an intraoperative dose of rVWF (18.1 IU/kg) and ADVATE 
(8.1 IU/kg). The median daily postoperative weight-adjusted dose of rVWF (vonicog 
alfa) (with or without ADVATE) was 23.5 IU/kg on postoperative Day 1 (n=3) and 
25.5 IU/kg on postoperative Day 14 (n=2). In subjects treated with rVWF:ADVATE, the 
daily postoperative weight-adjusted dose was 16.9 IU/kg rVWF and 7.6 IU/kg ADVATE 
on postoperative Day 1 (n=1) and decreased to 50.8 IU/kg rVWF and 7.6 IU/kg
ADVATE on postoperative Day 7 (n=1). For subjects treated with rVWF alone, the 
median weight-adjusted dose (Q1, Q3) of rVWF was 35.4 IU/kg on postoperative Day 1 
(n=2) and decreased to 23.7 IU/kg on postoperative Day 7 (n=4) and 25.5 IU/kg on 
postoperative Day 14 (n=2).
A total of 11 subjects were evaluated for PK in the study. As expected, postinfusion 
increases in concentrations of VWF:RCo, VWF:Ac, VWF:Ag, and VWF collagen 
binding (VWF:CB) were observed. Mean values for VWF:RCo were as follows: 
AUC0-∞/dose was 37.50 hours*IU/dL per IU/kg infused; AUC0-72h/dose was 
34.08 hours*IU/dL per IU/kg infused; T1/2 was 17.83 hours; MRT was 24.32 hours; 
CL was 0.03117 dL/hour/kg; and volume of distribution at steady state (Vss) was 
0.6837 dL/kg. Median values for VWF:RCo were as follows: AUC0-∞/dose was 
32.94 hours*IU/dL per IU/kg infused; AUC0-72h/dose was 31.70 hours*IU/dL per IU/kg 
infused; T1/2 was 14.62 hours; MRT was 21.80 hours; CL was 0.03036 dL/hour/kg; and 
Vss was 0.7078 dL/kg. The VWF:RCo activity was consistent with that previously 
observed in clinical studies 071001 and 070701.
rVWF (vonicog alfa) was safe and well tolerated in adults with severe VWD undergoing 
major, minor, and oral elective surgical procedures. Of the 12 total treatment-emergent 
AEs (TEAEs) that occurred during the study, 2 deep vein thrombosis events (1 non-
serious and 1 serious, as a part of one case) reported in one subject, who underwent total 
hip replacement surgery and who had concurrent condition of obesity, was assessed by 
the sponsor as possibly causally-related to study treatment. None of the TEAEs were 
either a severe allergic or hypersensitivity reaction or developed due to a severe allergic 
reaction. 
One subject with VWD Type 3 who had an intraoperative transfusion of packed red 
blood cells during total knee replacement surgery tested positive for binding antibodies to 
VWF on postoperative Day 7 through study completion. No subjects developed 
neutralizing antibodies to rFVIII or binding antibodies to CHO, rFurin, or murine IgG.
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In summary, the data support the safe and effective use of rVWF (vonicog alfa) with or 
without ADVATE (rFVIII, octocog alfa) in achieving intra- and post-operative 
hemostasis in adult subjects with severe VWD undergoing major, minor, and oral elective 
surgical procedures.
6.5.2.5 Study 071401: Single Subject with von Willebrand Disease
One subject who exhibited allergic reactions to currently marketed pdVWF products was 
treated in the single-subject study 071401 with rVWF (vonicog alfa) only for the bleed 
treatment of continued hematuria, and for biopsy and surgical resection of a left-kidney 
mass.
For the initial rVWF (vonicog alfa) infusion, the subject received a test dose of 5% of 
the total dose of 60 IU/kg rVWF:RCo at an infusion rate of 1 mL/min. After a 10 to 
15-minute observation period, no adverse symptoms or signs were noted and the subject 
received the remaining 95% of the total dose. The subject was monitored for any signs of 
an allergic reaction, and none were noted. Treatment with rVWF (vonicog alfa) every 
12 to 24 hours was to continue at the discretion of the investigator based on VWF levels 
and clinical symptomatology. The subject had an excellent response and recovery, which 
allowed for daily dosing of rVWF (vonicog alfa) and, within 24 hours, the subject’s 
bleeding had stopped. Daily dosing of rVWF (vonicog alfa) was maintained and the 
subject received his last dose on 
.
The subject also received rVWF (vonicog alfa) for 7 days for prophylaxis for surgery 
(surgical resection of a left-kidney mass). The subject experienced no hemorrhagic 
complications and no AEs that were considered related to the use of rVWF (vonicog 
alfa).
6.6 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) to 
Human Subjects
Current treatment of VWD patients relies on desmopressin and VWF products 
manufactured from pooled human plasma. Human VWF produced by recombinant 
technology could offer a new perspective in treatment of VWD. The benefit for the 
individual subject is anticipated to be significant during this clinical study. He/she may 
benefit from a product that minimizes excessive FVIII administration and thus allowing 
individualized dosing of VWF at optimal levels. Variations in VWF multimeric 
composition may lead to variability with respect to treating or preventing bleeds in 
VWD subjects, especially mucosal bleeds which are especially problematic. rVWF 
(vonicog alfa) product manufactured by Baxalta consistently contains ULMW VWF 
multimers due to the fact that the product has not been exposed to ADAMTS13. 
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The initial presence of these ULMW VWF multimers, which are subsequently cleaved by 
the subject’s endogenous ADAMTS13, may result in improved platelet and collagen 
binding and therefore provide more predictable treatment outcomes.
By using a recombinant product, the risk of transmission of adventitious agents and other 
blood-borne pathogens associated with the use of products of human or animal origin has 
been eliminated. At this stage of product development, the key societal benefit is a better 
understanding of advanced treatment options for VWD and enhanced product 
availability.
These benefits outweigh the following identified or potential risks of rVWF (vonicog 
alfa):

allergic-type hypersensitivity reactions as with any intravenous protein product

the occurrence of thromboembolic events

the development of neutralizing antibodies to VWF
Refer to the IB for further details on benefits and risks of the IP.
6.7 Compliance Statement
This study will be conducted in accordance with this protocol, the International Council 
for Harmonisation Guideline for Good Clinical Practice E6 (ICH GCP, April 1996, with 
Addendum E6(R2) dated Nov 2016 EMA/CHMP/ICH/135/1995), Title 21 of the US 
Code of Federal Regulations (US CFR), the EU Directives 2001/20/EC and 2005/28/EC, 
the Declaration of Helsinki and applicable national and local regulatory requirements.
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7. STUDY PURPOSE AND OBJECTIVES
7.1 Study Purpose
The purpose of this phase 3 study is to investigate the efficacy and safety, including 
immunogenicity, thrombogenicity and hypersensitivity reactions, as well as 
pharmacokinetics (PK), 
and 
 
of prophylactic treatment with rVWF (vonicog alfa) in adult subjects with severe VWD.
7.2 Primary Objective
The primary objective of this study is to prospectively evaluate the ABR for spontaneous 
bleeding episodes while on prophylactic treatment with rVWF (vonicog alfa) and to 
compare it to the subject’s historical ABR for spontaneous bleeding episodes.
7.3 Secondary Objectives
Secondary Objectives are to assess:

Additional efficacy of prophylactic treatment with rVWF (vonicog alfa)

Safety of rVWF (vonicog alfa), including immunogenicity, thrombogenicity and 
hypersensitivity

Pharmacokinetics (PK) of rVWF (vonicog alfa) and pharmacodynamics (PD) of 
rVWF (vonicog alfa) as measured in FVIII activity 
7.4 Exploratory Objectives
 
 
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8. STUDY DESIGN
8.1 Overall Study Design 
This is a prospective, open label, uncontrolled, non-randomized, international, 
multicenter phase 3 study to evaluate efficacy, safety (including immunogenicity,
thrombogenicity and hypersensitivity reactions), as well as PK, 
 and 
 of prophylactic treatment regimen with rVWF (vonicog alfa) in adult 
patients with severe VWD. 
Subjects transitioning from on-demand treatment (OD subjects) or subjects switching 
from prophylactic treatment with pdVWF (pdVWF switch subjects) will receive 
prophylactic treatment with rVWF (vonicog alfa) for a 12-month period (up to 15 months 
for the qualified subjects to rollover into the continuation study, if the continuation study 
start up is delayed beyond the completion of subject’s 12-month visit). The dose will be 
50 ± 10 IU/kg rVWF twice weekly for OD subjects or will be based on their prior 
pdVWF dose for pdVWF switch subjects, and dose may be further individualized based 
on the PK data, subject’s history of bleeding episodes, and the results from clinical and 
laboratory assessments (see Section 8.6.4.3).
The overall duration of prophylactic treatment with rVWF per subject will be at least 
12 up to 15* months.
During this period any bleeding episodes requiring substitution therapy with VWF 
concentrate to control bleeding will be treated with rVWF (vonicog alfa) with or without 
ADVATE (rFVIII, octocog alfa). The dose will be according to the bleeding type and 
severity and it will be adjusted to the clinical response (see Section 8.6.4.4.2).
The overall study design is illustrated in Figure 1.
* Study treatment period is extended by 3 months to accommodate participation in the 
continuation study for the qualified subjects and will be exercised only if the continuation study 
start up is delayed beyond the completion of subject’s 12-month visit. 
8.2 Duration of Study Period(s) and Subject Participation
The overall duration of the study is approximately 27 months from study initiation 
(i.e., first subject enrolled) to study completion (i.e., last subject last visit). The subject 
participation period is approximately 15 to 18* months from enrollment to completion 
(i.e, last study visit), unless the subject is prematurely discontinued.
* Study treatment period is extended by 3 months to accommodate participation in the 
continuation study for the qualified subjects and will be exercised only if the continuation study 
start up is delayed beyond the completion of subject’s 12-month visit. 
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8.3 Outcome Measures
8.3.1 Primary Outcome Measure
8.3.1.1 Efficacy 

Annualized bleeding rate (ABR) for spontaneous (not related to trauma) bleeding 
episodes during prophylactic treatment with rVWF (vonicog alfa)
8.3.2 Secondary Outcome Measures
8.3.2.1 Additional efficacy of Prophylactic Treatment with rVWF (vonicog alfa)

ABR percent reduction success for OD subjects defined as at least 25% reduction 
of ABR for spontaneous (not related to trauma) bleeding episodes during rVWF 
(vonicog alfa) prophylaxis relative to the subject’s own historical ABR during on-
demand treatment

ABR preservation success for pdVWF switch subjects defined as achieving an 
ABR for spontaneous bleeding episodes during rVWF (vonicog alfa) prophylaxis 
that is no greater than the  subject’s own historical ABR during prophylactic 
treatment with pdVWF

Categorized spontaneous ABR defined as 0, 1-2, 3-5, or >5 bleeding episodes
during the prophylactic treatment with rVWF (vonicog alfa)

Total number of infusions and the average number of infusions per week during 
prophylactic treatment with rVWF (vonicog alfa)

Total weight adjusted consumption of rVWF (vonicog alfa) during prophylactic 
treatment 

Spontaneous ABR by location of bleeding (GI, epistaxis, joint bleeding, 
menorrhagia, oral and other mucosa, muscle and soft tissue, etc.) while on 
prophylactic treatment with rVWF (vonicog alfa)
8.3.2.2 Safety

AEs: incidence, severity, causality

Thromboembolic events 

Hypersensitivity reactions

Development of neutralizing antibodies to VWF and FVIII 

Development of total binding antibodies to VWF and FVIII
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
Development of binding antibodies to CHO proteins, mouse immunoglobulin G 
(IgG) and rFurin

Clinically significant changes in vital signs and clinical laboratory parameters
relative to baseline
8.3.2.3 Pharmacokinetics (PK) and Pharmacodynamics (PD)

PK parameters after a washout for on-demand subjects: incremental recovery 
(IR), T1/2, MRT, area under the concentration versus time curve from 0 to infinity 
(AUC0-), area under the concentration versus time curve from 0 to the last 
measurable concentration (AUC0-tlast), maximum plasma concentration (Cmax), 
minimum time to reach the maximum concentration (Tmax), volume of distribution 
at steady state (Vss) and clearance (CL) based on VWF:Rco activity, VWF:Ag, 
VWF:CB activity. 

PD parameters after a washout for on-demand subjects: Cmax, Tmax, and AUC0-tlast
as measured in FVIII activity by the 1-stage clotting assay (FVIII:C). 

PK parameters at steady state for on-demand and switch subjects: area under the 
concentration versus time curve from 0 to end of the partial dosing interval 
(AUC0-tau;ss), maximum concentration during the partial dosing interval (Cmax;ss), 
minimum time to reach the maximum concentration (Tmax;ss) and minimum 
concentration during the partial dosing interval (Cmin;ss) based on VWF:RCo, 
VWF:Ag and VWF:CB. PK parameters at steady state will be assessed shortly 
after reaching steady state for switch subjects and at the end of the study for on-
demand as well as for switch subjects all based on the longer interval of the 
irregular dosing intervals employed. 

PD parameters at steady state for on-demand and switch subjects: AUC0-tau;ss, 
Cmax;ss, Tmax;ss, and Cmin;ss as measured in FVIII activity by the 1-stage clotting 
assay. PD parameters at steady state will be assessed shortly after reaching steady 
state for switch subjects and at the end of the study for on-demand as well as for 
switch subjects all based on the longer interval of the irregular dosing intervals 
employed.

Time course of FVIII clotting activity (FVIII:C) levels.
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8.3.3 Exploratory Outcomes Measures
8.3.3.1
 
 
 
 
 
8.3.3.2
 
 
 
 
 
8.3.3.3
 
8.3.3.4
 
 
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8.4 Randomization and Blinding
This is a non-randomized open-label, active treatment clinical study. 
8.5 Study Stopping Criteria 
This study will be stopped if 1 or more of the following criteria are met in the absence of 
any other possible and medically plausible causal attribution (eg, underlying or 
concurrent condition, use of concomitant medication, subject’s medical history, etc):
1.
Two subjects develop a life-threatening or fatal thromboembolic event
2.
Two subjects develop life-threatening or fatal severe hypersensitivity reactions 
(e.g., anaphylaxis)
3.
Any subject develops acute hepatic failure 
4.
Two subjects develop rVWF neutralizing antibodies that are considered clinically 
significant by the investigators and are associated with significant decrease of 
efficacy or serious adverse reactions.
The study may be stopped at any time by the sponsor.
The sponsor ultimately will decide whether to terminate, temporarily halt or modify the 
study based on the data monitoring committee (DMC)’s review and recommendation on 
all relevant cases including those that meet the stopping criteria listed above.
8.6 Investigational Product(s)
8.6.1 Packaging, Labeling, and Storage
8.6.1.1 rVWF (Recombinant von Willebrand Factor, vonicog alfa)
rVWF (vonicog alfa) will be packaged in boxes with 2 glass vials, one containing the 
rVWF powder, and the second vial containing the diluent (water for injection). Further 
details are provided in the IB and Pharmacy Manual. The rVWF label will include, at a 
minimum, the actual VWF:RCo potency and the date of expiration.
rVWF (vonicog alfa) is a powder that should be stored refrigerated (2-8°C [36-46°F]) . 
Deviations from the storage condition have to be communicated and followed up with 
the sponsor. Inadequately stored product will have to be placed in quarantine and may 
only be used after written IP administration authorization by the sponsor. After removal 
of the product from the refrigerator the product must not be returned to the refrigerator. 
The reconstituted product has to be used immediately (at least within 3 hours). 
rVWF (vonicog alfa) must not be used beyond the expiration date printed on the vial
label. Avoid freezing at all times.
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8.6.1.2 rFVIII (Recombinant Factor VIII, octocog alfa /ADVATE)
ADVATE (rFVIII, octocog alfa) will be packaged in boxes with 2 glass vials, one 
containing the lyophilized rFVIII, and the second vial containing the diluent. Further 
details are provided in the IB and Pharmacy Manual. The ADVATE label will include, 
at a minimum, the actual FVIII:C potency and the date of expiration. 
ADVATE (rFVIII, octocog alfa) should be refrigerated (2-8°C [36-46°F]) in powder 
form and should not be used beyond the expiration date printed on the vial. 
Deviations from the storage condition have to be communicated and followed up with the 
sponsor. Inadequately stored product will have to be placed in quarantine and may only 
be used after written IP administration authorization by the sponsor. After removal of the 
product from the refrigerator the product must not be returned to the refrigerator and has 
to be used immediately. Avoid freezing at all times.
8.6.2 Reconstitution
The reconstitution procedures for both rVWF (vonicog alfa) and ADVATE (rFVIII, 
octocog alfa) products are detailed in the Pharmacy Manual. 
8.6.3 Administration
Following reconstitution, rVWF (vonicog alfa) and ADVATE (rFVIII, octocog alfa) (in 
case of bleeding episode treatment) should be administered to study subjects at room 
temperature and within 3 hours of reconstitution. The reconstituted rVWF (vonicog alfa) 
and ADVATE (rFVIII, octocog alfa), should be inspected for particulate matter and 
discoloration prior to administration, whenever the solution and container permit. The 
solution should be clear and colorless in appearance. If not, do not administer the product. 
Plastic syringes provided by the sponsor must be used since coagulation factors tend to 
stick to the surface of glass syringes.
Investigational product infusions should be given at a slow enough rate to ensure the 
subject’s comfort. The rate should not exceed 4 mL/minute The investigator/ subject shall 
ensure that no visible residual volume remains in the syringe(s) and that the complete 
content is administered. Upon completion of the infusion, the butterfly catheter should be 
flushed with at least 2 mL of saline solution. In case of a (central) venous access device, 
the flush should be with at least 10 mL of saline solution. The IP infusions should be 
administered over a duration of 2 to 20 minutes, depending on the volume.
Only the actual potencies of rVWF (vonicog alfa) and ADVATE (rFVIII, octocog alfa) as 
stated on the vial labels and described in the Pharmacy Manual should be used.
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A variation of up to 10% of the intended dose for prophylactic infusions and of the 
intended dose for treatment of bleeding episodes is permissible and the exact dose should 
be recorded on the Case Report Form (CRF). Using of partial vials is not allowed.
At study visits where recovery analysis is being done, vials with the same lot numbers 
should be used throughout the PK IP infusion per subject.
For treatment of bleeding episodes, sequential administration will be done: separate 
syringes of the appropriate dose of rVWF (vonicog alfa) and ADVATE (rFVIII, octocog 
alfa) will be prepared for sequential infusion. rVWF (vonicog alfa) should be infused first 
sequentially followed preferably within 10 minutes by infusion of ADVATE (rFVIII, 
octocog alfa). Only the actual potencies of rVWF (vonicog alfa) and ADVATE (rFVIII, 
octocog alfa) as stated on the vial labels and described in the Pharmacy Manual should be 
used. 
The final dose of rVWF (vonicog alfa):ADVATE (rFVIII, octocog alfa) should be at a 
ratio of 1.3:1 ± 0.2.
8.6.4 Description of Treatment
8.6.4.1 PK-Assessment Treatment
For on-demand subjects, two PK assessments will be performed: an initial PK 
assessment after a wash-out period and a steady state PK assessments at the end of the 
study. The IP infusion for the initial PK assessment is scheduled on the baseline visit, 
which should be within 42 days after the completion of screening procedures and 
confirmation of eligibility. At the baseline visit the subjects will receive a dose of 
50 ± 5 IU/kg rVWF:RCo for PK assessment. Blood samples will be drawn within 
30 minutes pre-infusion, and at 11 time points post-infusion (15 ± 5 minutes, 
30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 
24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours and 96 ± 2 hours). A washout 
period of at least 5 days is required prior to infusion of rVWF (vonicog alpha) for PK 
assessment. The 2nd PK assessment for on-demand subjects will be performed at steady 
state at the end of the study(see Section 11.6). Subjects previously enrolled in rVWF 
studies 070701, 071001 or 071101 and having previously undergone PK assessments in 
these studies are required to repeat the PK assessment due to different dose and time 
points used in these former studies.
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For pdVWF switch subjects, two steady state PK assessments will be performed. 
The 1st PK will be assessed shortly after reaching steady state, which is expected to be 
11 days after the 1st prophylactic dose for majority of the subjects, around the 
prophylactic dose #5-6. The 2nd PK will be at the end of the study. For steady state PK, 
blood samples will be drawn within 30 minutes pre-infusion, and at 11 time points post-
infusion (15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 
12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours and 96 ± 2 hours) 
as long as it won’t interfere with subject’s the normal dosing schedule, otherwise the 
96 hr sampling can be omitted (see Section 11.6). Final sample for PK analysis should be 
taken before next dose is administered.
8.6.4.2 Prophylaxis Initiation Treatment 
The rVWF (vonicog alfa) prophylaxis initiation treatment visit will coincide with the 
96 2 h initial PK assessment for on-demand subjects. For pdVWF switch subjects, the 
rVWF (vonicog alfa) prophylaxis initiation treatment visit should occur within 42 days 
after the completion of screening procedures and confirmation of eligibility. At this visit 
subjects will receive their prophylaxis initiation dose. The prophylaxis doses are 
described in Section 8.6.4.3.
The subject will be trained on IP reconstitution and administration and may then qualify 
for home treatment (see Section 8.6.4.3.2). Refer toTable 6 (a/b) for study procedures and 
Table 8(a/b) for clinical laboratory assessments.
8.6.4.3 Prophylaxis Treatment
For on-demand subjects, the standard prophylactic dose is 50 ± 10 IU/kg rVWF:RCo, 
which may be increased up to 80 IU/kg. All on-demand subjects will initially receive 
rVWF (vonicog alfa) twice per week (Table 1, Schedule A). Examples of all dosing 
schedules are provided in Table 1.
For pdVWF switch subjects, the weekly dose (IU/kg) of IP for each patient will be 
equivalent (± 10%) to the weekly VWF dose received during prophylactic treatment with 
pdVWF. The weekly dose of IP should be divided into 2 infusions (Table 1, Schedule A), 
with a maximum of 80 IU/kg/infusion. If needed, based on the total weekly dose or other 
clinical judgements, the weekly dose may be given as three infusions (Table 1, 
Schedule B). A once weekly dose regimen will be allowed after switch to rVWF 
(vonicog alfa) only if the patient has been on a once weekly dose regimen with pdVWF.
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Table 1
rVWF (vonicog alfa) Dosing Schedule Examples: Schedules A and B
Example
M
T
W
Th
F
Sat
Sun
M
T
W
Th
F
Sat
Sun
Schedule A
X
X
X
X
Schedule B
X
X
X
X
X
X
The prophylaxis dose may be further individualized within the range based on:

available historical PK data

type and severity of bleeding episodes the subject has experienced in the past and

monitoring of appropriate clinical and laboratory measures
The individualized prophylaxic dose assignment will have to be agreed with the sponsor 
in advance, and the rationale should be well documented.
8.6.4.3.1 Adjustment of Dose or Dose Interval
In general, the dose and/or dose interval for each subject should not be changed unless 
prompted by clear medical needs. Dose and frequency adjustments should be agreed with 
the sponsor in advance unless it constitutes an urgent safety measure. The rationale for 
dosing adjustments needs to be documented in the subject’s medical record.
For both OD and switch patients, dose escalations (not exceeding the upper dose limit of 
80 IU/kg rVWF:RCo) and increase of dose frequency will only be allowed in case of 
insufficient therapeutic response with breakthrough bleeding episodes. The criteria for 
dose and/or frequency escalation are specific to each bleeding indication but, overall, 
involve 1 significant breakthrough bleeding episode despite the subject being compliant 
with scheduled prophylaxis treatment. For switch patients  who require a dose escalation 
due to a breakthrough bleed, the frequency should be kept the same but the dose 
(IU VWF:RCo per infusion) should be increased up to 80 IU VWF:RCo. Following that, 
increases in frequency may be considered upon consultation with the Sponsor. For on 
demand subjects who require a dose escalation, at the discretion of the PI upon 
consultation with the Sponsor, the frequency may be kept the same but the dose 
(IU VWF:RCo per infusion) should be increased up to 80 IU VWF:RCo. If this proves to 
be insufficient, then the dosing frequency may be increased in these subjects. Table 2
presents the criteria for dosing escalation per each bleeding indication taken 50 ± 10 IU 
VWF:RCo/kg twice weekly dose as an example of subject’s assigned starting dose. 
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The criteria are applicable for both OD and switch subjects who were initially assigned to 
twice weekly dosing. Subjects entering the study will begin prophylaxis treatment 
according to Schedule A (Table 1) and will remain at this dose and frequency until 
meeting the criteria for escalation to the next higher schedule: for example, from 
2 infusions of 50 ± 10 IU VWF:RCo/kg/week to 3 infusions of 50 ± 10 IU 
VWF:RCo/kg/week (Schedule B) to achieve an adequate therapeutic response. If a 
subject started with a weekly dose (possible for switch subjects), similar criteria would 
apply except that the subject will be excalated to twice weekly dosing if frequency 
change is necessary.
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Table 2
Criteria for Escalation Specific to Each Bleeding Indication
Schedule A
Schedule B
Joint bleeding
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) twice per week. In the event a 
spontaneous joint bleeding episode occurs 
while on this regimen, the subject will escalate 
to up to 80 IU/kg twice per week or, if 
necessary, to Schedule B following its 
resolution
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week.
GI bleeding
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) twice per week. In the event a 
severe GI bleeding episode, i.e., requiring red 
blood cell transfusion, occurs while on this 
regimen, the subject will escalate to up to 
80 IU/kg twice per week or, if necessary, to 
Schedule B following its resolution
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week.
Menorrhagia
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) on days 1 and 2 of menses for 
2 cycles. Menstrual flow will be monitored by 
the PBAC score. If the average pictorial chart 
score is > 185, then the subject will escalate to 
up to 80 IU/kg or, if necessary, to Schedule B
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) on days 1, 2, 
and 3 of menses. Menstrual flow 
will be monitored by the PBAC 
score.
Epistaxis
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) twice per week. The subject will 
escalate to up to 80 IU/kg twice per week or, if 
necessary, to Schedule B in the event of 
1 occurrence of breakthrough bleeding 
requiring intervention such as iron 
replacement therapy, transfusion, packing, 
hospitalization; or 2 bleeding events that 
require treatment with factor replacement
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week. 
Oral and Other 
Mucosa
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) twice per week. The subject will 
escalate to up to 80 IU/kg twice per week or, if 
necessary, to Schedule B in the event of 
1 occurrence of breakthrough bleeding 
requiring intervention such as iron 
replacement therapy, transfusion, packing, 
hospitalization; or 2 bleeding events that 
require treatment with factor replacement.
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week.
Muscle and Soft 
Tissue
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) twice per week. In the event a 
spontaneous bleeding episode occurs while on 
this schedule, the subject will escalate to up to 
80 IU/kg twice per week or, if necessary, to 
Schedule B following its resolution.
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week.
Abbreviations:  GI: gastrointestinal; PBAC: Pictorial Blood Assessment Chart.
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If a subject does not adequately respond to rVWF (vonicog alfa) therapy, he/she will be 
evaluated for the presence of neutralizing and total binding anti-VWF antibodies (see 
Section 12.9.3.2).
If a subject experiences a bleed while receiving rVWF (vonicog alfa) three times per 
week, the investigator should treat the bleed with rVWF (vonicog alfa) at doses up to 
80 IU VWF:RCo/kg at a frequency determined by the investigator until the bleed 
resolves. Upon resolution of the bleeding event, the subject will return to their assigned 
prophylaxis regimen. 
It is essential for the success of this study that the subjects adhere to treatment regimens. 
Therefore, procedures for monitoring subject’s compliance are implemented (see 
Section 10.7).
If 1 infusion of IP is missed, the subject may administer the IP as soon as possible. The 
subject should adhere to their treatment scheme ensuring a minimum interval of 12 hours 
between this and the previous IP infusion. For example, a subject routinely infuses IP on 
Monday and Thursday, he/she misses the Monday time point and therefore may infuse 
the IP on the next day (Tuesday) and thereafter proceed with infusing the IP on Thursday
(considering a minimum 12 hours between the infusions) and return to the initial 
schedule.
If more than 30% of infusions of IP are missed within the visit interval of 3 months the 
subject will be discontinued from the study (see Section 9.4).
8.6.4.3.2 General Instructions for Home Treatment for Prophylaxis
At the discretion of the investigator, a subject may be considered suitable for home 
treatment only after the subject has received at least 1 infusion of IP in the clinic, either 
during planned prophylactic IP exposure or during the treatment of bleeding episodes, 
and meets the following additional criteria:
1.
Fully understands the concept of a clinical study and related documentation 
(documented training of at least 30 minutes), 
2.
Has a history of previous experience with home treatment including 
self-administration and treatment with VWF containing concentrates, 
3.
Has adequate time for initial training of the study drug preparation (preparation, 
mixing and infusion of the IP(s) (documented training of at least 30 minutes).
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This applies both to subjects who were on prior on-demand treatment and to subjects 
switching form prophylaxis with pdVWF. In the event a healthcare professional is 
required to administer IP, he/she must be trained and qualified by the investigator on the 
above procedures prior to the decision for home treatment. A Subject Guideline detailing 
all instructions and information listed above will be provided to each subject.
8.6.4.4 Treatment of Bleeding Episodes
8.6.4.4.1 General Instructions for Home Treatment of Bleeding Episodes
If a subject experiences a bleeding episode, he/she should contact the study site 
immediately and the site investigator should provide instructions on the treatment 
regimen. If the subject initiates the treatment at home, he/she should at least follow up 
with the study site if a visit is needed as per the standard of care at the center.
In the event a healthcare professional is required to administer treatment at the subject’s 
home, he/she must be trained and qualified by the site investigator on the above 
procedures prior to the decision for home treatment. Once a subject has received 
1 infusion of rVWF (vonicog alfa) in the clinic (either during planned IP exposure or 
during the treatment of a bleeding episode) and meets the criteria for home treatment, the 
treatment of bleeding episodes with IP can be conducted at home (see Section 8.6.4.3.2).
If a subject is not qualified for home treatment, rVWF (vonicog alfa) infusions must be 
administered at the study site.
If a subject experiences a bleeding episode that requires treatment between the screening 
and the prophylaxis initiation visit, the subject will be treated with IP (rVWF with or 
without ADVATE). Treatment with IP must occur at the study site unless the subject has 
previously qualified for home treatment with rVWF (vonicog alfa). If rVWF (vonicog 
alfa) treatment is not feasible, the subject may use his/her standard of care, such as 
commercial pdVWF/FVIII products. In any case a washout period of at least 5 days is 
required prior to rVWF (vonicog alfa) PK infusion at the initial PK assessment visit for 
on-demand subjects.
If a subject experiences a bleeding episode requiring treatment during the PK assessment, 
rVWF (vonicog alfa) should be used to treat the bleed. Blood draws for PK assessment 
will be stopped and the PK assessments will be repeated once the bleed has resolved and 
the subject is free of any symptoms related with the bleeding episode. Dose and 
frequency of rVWF (vonicog alfa) infusions or any other replacement therapy to stop the 
bleed should be recorded in the electronic Case Report Form (eCRF), and the reason for 
the use of any non-IP product or therapy should be documented.
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8.6.4.4.2 Dosing Recommendations for Treatment of Bleeding Episodes 
If an acute bleeding episode occurs, the subject will be treated with rVWF (vonicog alfa) 
with or without ADVATE (rFVIII, octocog alfa). It is the sponsor’s opinion that, in many 
cases, treatment with ADVATE (rFVIII, octocog alfa) may not be necessary, since rVWF 
(vonicog alfa) prophylaxis will serve to increase endogenous FVIII levels. However, if 
endogenous FVIII is below 30-40 % or is unknown and cannot be estimated from the 
subject’s PK study, an infusion of rVWF: ADVATE at an rVWF: ADVATE ratio of 
1.3:1± 0.2 should be administered initially. Subsequent infusions should be with 
rVWF:RCo 40 to 60 IU/kg with or, in  many cases,without 30 to 45 IU/kg ADVATE 
(only to be administered if plasma FVIII levels fall below 30 IU/L during the treatment 
period). Dosing may be adjusted downward or upward up to 80 IU/kg rVWF at the 
treating physician’s discretion based upon the subject’s prior history, PK and other 
factors.
If FVIII levels are not available, dosing is at the discretion of the investigator based upon 
the individual subject’s PK data. Using ADVATE (rFVIII, octocog alfa) in addition to 
rVWF (vonicog alfa) in subsequent doses carries the risk of an excessive rise in FVIII:C. 
Therefore, reduced doses of ADVATE (rFVIII, octocog alfa) and/or prolongation of the 
dose interval should be considered. 
The following is general guidance and the sponsor’s suggestion for treatment of 
breakthrough bleeds, however each PI will determine the treatment based on the local 
acceptable practice how to monitor and adjust treatment for a bleeding episode. An effort 
should be made to discuss with the sponsor (or sponsor’s delegate) the treatment strategy.
In general the aim of the initial dose should be full replacement of VWF with VWF:RCo 
levels of >0.6 IU/ml (60%) and FVIII:C of >0.4 IU/mL (40%). In major bleeding 
episodes, subsequent doses should keep the trough level of VWF:RCo >50% for 3 days 
and then as deemed necessary by the investigator for subsequent days. In moderate 
bleeding episodes, the dose and trough level may be reduced to >30% for as long as 
deemed necessary by the investigator. Treatment for minor bleeding episodes will 
generally consist of only 1 or 2 doses of rVWF (vonicog alfa) IP. 
If the VWF:RCo level is above 150%, a planned treatment should be delayed by at least 
12 hours; if the VWF:RCo level is above 200%, a planned treatment should be delayed 
by at least 24 hours. In either case, a lower subsequent dose (e.g., 20 IU/kg VWF:RCo) 
may be appropriate.
Dosing recommendations are listed in Table 3.
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Dosage must be individualized based on the subject’s weight, VWD type, and the 
severity of the bleeding episode, as well as on monitoring of appropriate clinical and 
laboratory measures. In the phase 1 study 070701, 1.0 IU/kg VWF:RCo raised the 
circulating level of VWF:RCo by 0.017 IU/mL (1.7 %). In the same study, the observed 
mean half-life for rVWF (vonicog alfa) was 19.3 hours, with a standard deviation of 
10.9 hours.
Table 3
rVWF:RCo Dosing Recommendations for the Treatment of Bleeding Episodes Due to VWD
Classification of 
VWD
Hemorrhage
Dosage (IU VWF:RCo/kg BW)
Type 1 
Severe (Baseline 
VWF:RCo activity 
typically <20%) 
Minor (e.g., epistaxis, oral 
bleeding, menorrhagiaa) 
40 to 50 IU/kg (1 or 2 doses)
Major (e.g., severe or 
refractory epistaxis, 
menorrhagia*, GI bleeding, 
CNS trauma, hemarthrosis, 
or traumatic hemorrhage)
Initial dose 50 to 75 IU/kg, then 40 to 60 IU/kg 
every 8 to 12 hours for 3 days to keep the trough 
level of VWF:RCo >50%; then 40 to 60 IU/kg daily 
for a total of up to 7 days of treatment
Type 2 (all variants) 
and Type 3 
Minor (clinical indications 
above) 
40 to 50 IU/kg (1 or 2 doses)
Major (clinical indications 
above)
Initial dose of 60 to 80 IU/kg, then 40 to 60 IU/kg 
every 8 to 12 hours for 3 days to keep the trough 
level of VWF:RCo >50%; then 40 to 60 IU/kg daily 
for a total of up to 7 days of treatment
a Menorrhagia is defined as excessive bleeding during menstruation. A diagnosis of menorrhagia will be 
defined by a prospectively completed Pictorial Blood Assessment Chart (PBAC) score >185 and normal 
cervical cytology or requiring use of a VWF-containing concentrate for treatment of excessive 
menstrual bleeding for at least one menstrual cycle during the prior year.
Variances of up to 10% in dosing are permissible during treatment of bleeding episodes, 
but rounding to the nearest vial size should be avoided.
Subjects with non-neutralizing binding anti-VWF antibodies should initially be treated 
with a dose known to be efficacious based on the subject’s medical treatment history
which may differ from the recommendations provided in Table 3. Subjects should be 
monitored for lack of efficacy as well as for FVIII (mandatory), VWF:RCo (mandatory), 
and VWF:Ag (optional where testing is not available) levels after 3 to 6 hours. Re-dosing 
with rVWF (vonicog alfa) in combination with ADVATE (rFVIII, octocog alfa) using the 
same (initial) dose and adaptation of the dosing frequency should be considered until 
cessation of the bleed, if the FVIII and/or VWF:RCo levels drop below 30%-50% 
depending on bleeding severity.
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The number of subsequent infusions and the dosage levels prescribed will be determined 
by the investigator on the basis of the clinical severity, response to current therapy, 
available laboratory data, and the subject’s historical treatment for similar bleeding 
episodes.
8.6.4.5 Treatment of Surgical Bleeding
Subjects enrolled in this study who require surgery or dental procedures will be treated 
with IP to manage their surgical bleeding then afterwards will resume their prophylactic 
rVWF (vonicog alfa) treatment schedule. Subjects who at time of screening have an 
already scheduled surgical intervention are not eligible for participation in the study.
8.6.4.5.1 Major, Minor and Oral Surgery Definition
The following definitions and criteria are used to serve as a guidance for major, minor 
and oral surgery.
Major surgeries generally refer to major orthopedic surgery (e.g., joint replacement, 
arthroscopic or open synovectomy, arthrodesis, hardware removals like plates or 
intramedullary nails, etc.), major abdominal surgery (e.g. open or laparoscopic 
hernioplasty, cholecystectomy, colon or small bowel resection, etc.), major gynecological 
surgery (e.g. open or laparoscopic myomectomy, hysterectomy, removal of 
endometriosis, polyps, cysts, adhesiolysis, etc.), major head and neck surgery (e.g.: 
tonsillectomy, adenoidectomy, rhinoplasty, lymphadenectomy, thyroidectomy, 
parotidectomy. etc.), any intracranial , cardiovascular or spinal surgery and any other 
surgery which has a significant risk of large volume blood loss or blood loss into a 
confined anatomical space. Extraction of impacted third molars is generally also 
considered major surgery due to the expected difficulty of surgery and the expected blood 
loss.
Minor surgeries generally refer to interventions such as placement of intravenous access 
devices, removal of small skin lesions, arthroscopy, gastroscopy, colonoscopy or 
conisation.
Oral surgeries comprise extractions of fewer than three teeth, if the teeth are non-molars 
and have no bony involvement.
A summary schedule of visit assessments and laboratory sampling is included in 
Supplement tables in Section 20.2.1 and Section 20.3.1.
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8.6.4.5.2 Preoperative Priming Dose
12- 24 hours prior to surgery, a priming dose with rVWF (vonicog alfa), using the rVWF 
IR and T1/2 for this subject , will be infused to allow the endogenous FVIII levels to raise 
to at least 30 IU/dL (minor, oral surgery), or 60 IU/dL (major surgery) at the time of the 
loading dose of rVWF (vonicog alfa) is infused.
As a general guidance a priming dose of 40-60 IU/kg rVWF:RCo will be administered. If 
not assessed prior to the preoperative priming dose, a IR recovery may be calculated for 
subjects undergoing minor and oral surgery.
8.6.4.5.3 Preoperative Loading Dose
An rVWF (vonicog alfa) loading dose should be administed within 3 hours before 
surgery. VWF and FVIII levels should be assessed within 3 hours prior to surgery 
initiation and results must be available prior to administering the loading dose. If FVIII 
levels prior to loading dose administration are not at least 30 IU/dL (minor, oral surgery), 
or 60 IU/dL (major surgery) ADVATE (rFVIII, octocog alfa) will be administered in 
addition to rVWF (vonicog alfa) in order to raise FVIII:C levels to recommended levels.
The preoperative loading dose will be calculated as the difference in the target peak and 
baseline plasma VWF:RCo levels divided by the IR (ΔVWF:RCo x BW (kg) /IR). The 
PK results will be provided prior to the planned surgery. If the IR is not available, assume 
an IR of 1.7 IU/dL per IU/kg and calculate the initial dose as follows: (100 – baseline 
plasma VWF:RCo) x BW (kg) / 1.7. For minor and oral surgery, the IR from the 
Preoperative Priming Dose visit will be used to guide dosing and the target peak is 
50-60 IU/dL VWF:RCo and 40-50 IU/dL FVIII. For major surgery, the target peak is 
100IU/dL VWF:RCo and 80-100 IU/dL FVIII.
The surgery may only start after normalization of the activated partial 
thromboplastin time (aPTT).
8.6.4.5.4 Intra- and Postoperative (maintenance) Dosing
After the preoperative loading dose(s), subjects who have not achieved the desired 
postinfusion recovery will continue to receive rVWF (vonicog alfa) with or without 
ADVATE (rFVIII, octocog alfa) as a bolus infusion, depending on VWF and FVIII 
levels. The peri- and post-operative substitution regimen will be individualized according 
to the PK results, intensity and duration of the hemostatic challenge, and the institution’s 
standard of care.
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Subjects undergoing minor surgery will be infused with rVWF (vonicog alfa) every 
12-24 hours or every other day, targerting >30IU/dL (rVWF and FVIII) for at least the 
first 48 hours.
Subjects undergoing oral surgery will be infused with rVWF (vonicog alfa) at least once 
within the first 8-12 hours, targeting >30 IU/dL (rVWF and FVIII).
Subjects undergoing major surgery will be infused with rVWF (vonicog alfa) every 
12-24 hours for at least the first 72 hours post-surgery, targeting a VWF:RCo and 
FVIII:C trough plasma level >50 IU/dL, followed by further treatment post-72 hours for 
as long as deemed necessary by the Investigator, targeting a VWF:RCo and FVIII:C 
trough plasma level of >30 IU/dL.
Dose modifications based on pre-infusion VWF/FVIII levels will be performed as 
needed. For subsequent infusions post surgery, in case pre-infusion levels are not 
available prior to the consecutive infusion in a timely manner, pre-infusion levels from 
the previous dose may be used by the investigator for dosing guidance.
Peak plasma level guidance is matching to Section 8.6.4.4.2
A schedule of all perioperative visit assessments and laboratory sampling can be found in 
supplement tables in Section 20.2.1 and Section 20.3.1.
8.6.4.6 Thrombosis Prophylaxis
Thromboembolic events have been reported in patients who have VWD, especially in the 
setting of known risk factors for thrombosis including low ADAMTS13 levels. 
Therefore, subjects who are at risk for developing thromboembolic events should be 
monitored for early signs of thrombosis, and prophylaxis measures against 
thromboembolism should be instituted according to current recommendations and 
standard of care. For all subjects who are VWD patients and are receiving VWF 
concentrate, attention should be given to avoid exceeding maximal recommended plasma 
activity levels of VWF:RCo (250 IU/dL) and FVIII (250 IU/dL).
Anticoagulation measures, such as heparin, are acceptable and should follow study site 
standards. The investigator will record the use and reasons for such measures/agents on 
the appropriate CRF.
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8.6.5 Investigational Product Accountability
The investigator will ensure that the IP(s) is stored as specified in the Pharmacy Manual
and that the storage area is secured, with access limited to authorized study personnel. All 
temperature excursions at the subject’s home need to be monitored by the site (please 
refer to the pharmacy manual). The investigator will maintain records that the IP(s) was 
received, including the date received, drug identity code, date of manufacture or 
expiration date, amount received and disposition. The IP(s) must be dispensed only at the 
study site or other suitable location (e.g., infusion center; home, as applicable per study 
design), as specified in the protocol (see Section 10). Records will be maintained that 
includes the subject identification code (SIC), dispensation date, and amount dispensed. 
All remaining partially used and/or unused IP(s) will be returned to the sponsor or 
sponsor’s representative after study completion/termination, or destroyed with the 
permission of the sponsor in accordance with applicable laws and study site procedures. 
If IP(s) is to be destroyed, the investigator will provide documentation in accordance with 
sponsor’s specifications.
8.7 Source Data
Per ICH E6(R2) on GCP, source data are defined as all information in original records 
and certified copies of original records of clinical findings, observations, or other 
activities in a clinical trial that are necessary for the reconstruction and evaluation of the 
trial. Source data are contained in source documents (original records or certified copies). 
These may be in paper and/or electronic format. Source documents for this study 
comprise the following: hospital records, medical records, clinical and office charts, 
laboratory notes, memoranda, subjects' diaries or evaluation checklists, outcomes 
reported by subjects, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate copies, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, 
and records kept at the pharmacy, at the laboratories and at medico-technical departments 
involved in the clinical study.
No data will be entered directly onto the CRF.
For additional information on study documentation and CRFs refer to Section 17.2. The 
use of subject diaries is described in Section 10.5. 
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9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION
9.1 Inclusion Criteria
Subjects who meet ALL of the following criteria are eligible for this study:
1.
Subject has a documented diagnosis of severe VWD (baseline VWF:RCo 
<20 IU/dL) with a history of requiring substitution therapy with von Willebrand 
factor concentrate to control bleeding
a. Type 1 (VWF:RCo <20 IU/dL) or,
b. Type 2A (as verified by multimer pattern), Type 2B (as diagnosed by 
genotype), Type 2M or,
c. Type 3 (VWF:Ag ≤3 IU/dL).
2.
Diagnosis is confirmed by genetic testing and multimer analysis, documented in 
patient history or at screening.
3.
For on-demand patient group, subject currently receiving on-demand treatment for 
whom prophylactic treatment is recommended by the investigator.
4.
For pdVWF switch patient group, subject has been receiving prophylactic 
treatmentof pdVWF products for no less than 12 months prior to screening.
5.
For on-demand patient group, subject has ≥3 documented spontaneous bleeds (not 
including menorrhagia) requiring VWF treatment during the past 12 months.
6.
Availability of records to reliably evaluate type, frequency and treatment of 
bleeding episodes during at least 12 months preceding enrollment. Up to 
24 months retrospective data should be collected if available. Availability of 
dosing and factor consumption during 12 months (up to 24 months) of treatment 
prior to enrollment is required for pdVWF switch subjects and is desired (but not 
a requirement) for on-demand subjects.
7.
Subject is ≥18 years old at the time of screening and has a body mass index 
≥15 but <40 kg/m2.
8.
If female of childbearing potential, subject presents with a negative blood/urine 
pregnancy test at screening and agrees to employ adequate birth control measures 
for the duration of the study.i
9.
Subject is willing and able to comply with the requirements of the protocol.
                                                
i Refer to Section 20.4 for a list of adequate contraceptive methods for females of childbearing potential.
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9.2 Exclusion Criteria
Subjects who meet ANY of the following criteria are not eligible for this study:
1.
The subject has been diagnosed with Type 2N VWD, pseudo VWD, or another 
hereditary or acquired coagulation disorder other than VWD (eg qualitative and 
quantitative platelet disorders or prothrombin time (PT)/international normalized 
ratio [INR] 1.4).
2.
The subject is currently receiving prophylactic treatment with more than 
5 infusions per week.
3.
The subject is currently receiving prophylactic treatment with a weekly dose 
exceeding 240 IU/kg.
4.
The subject has a history or presence of a VWF inhibitor at screening.
5.
The subject has a history or presence of a FVIII inhibitor with a titer 
≥0.4 Bethesda units (BU) (by Nijmegen modified Bethesda assay) or ≥0.6 BU
(by Bethesda assay).
6.
The subject has a known hypersensitivity to any of the components of the study 
drugs, such as to mouse or hamster proteins.
7.
The subject has a medical history of immunological disorders, excluding seasonal 
allergic rhinitis/conjunctivitis, mild asthma, food allergies or animal allergies.
8.
The subject has a medical history of a thromboembolic event.
9.
The subject is human immunodeficiency virus (HIV) positive with an absolute 
Helper T cell (CD4) count 200/mm3.
10. The subject has been diagnosed with significant liver disease per investigator’s 
medical assessment of the subject’s current condition or medical history or as 
evidenced by any of the following: serum alanine aminotransferase (ALT) greater 
than 5 times the upper limit of normal; hypoalbuminemia; portal vein 
hypertension (e.g., presence of otherwise unexplained splenomegaly, history of 
esophageal varices).
11. The subject has been diagnosed with renal disease, with a serum creatinine (CR)
level ≥2.5 mg/dL.
12. The subject has a platelet count <100,000/mL at screening.
13. The subject has been treated with an immunomodulatory drug, excluding topical 
treatment (e.g., ointments, nasal sprays), within 30 days prior to signing the 
informed consent.
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14. The subject is pregnant or lactating at the time of enrollment.
15. Patient has cervical or uterine conditions causing menorrhagia or metrorrhagia 
(including infection, dysplasia).
16. The subject has participated in another clinical study involving another IP or 
investigational device within 30 days prior to enrollment or is scheduled to 
participate in another clinical study involving an IP or investigational device 
during the course of this study.
17. The subject has a progressive fatal disease and/or life expectancy of less than 
15 months.
18. The subject is scheduled for a surgical intervention.
19. The subject is identified by the investigator as being unable or unwilling to 
cooperate with study procedures.
20. The subject has a mental condition rendering him/her unable to understand the 
nature, scope and possible consequences of the study and/or evidence of an 
uncooperative attitude.
21. The subject is in prison or compulsory detention by regulatory and/or juridical 
order.
22. The subject is member of the study team or in a dependent relationship with one 
of the study team members which includes close relatives (i.e., children, 
partner/spouse, siblings and parents) as well as employees.
9.3 Delay Criteria
1.
If the subject has an acute bleeding episode or presents with an acute illness 
(e.g., influenza, flu-like syndrome, allergic rhinitis/conjunctivitis, non-seasonal 
asthma) the screening visit will be postponed until the subject has recovered.
9.4 Withdrawal and Discontinuation
Any subject may voluntarily withdraw (i.e., reduce the degree of participation in the 
study) consent for continued participation and data collection. The reason for withdrawal 
will be recorded on the End of Study CRF. Assessments to be performed at the 
termination visit (including cases of withdrawal or discontinuation) are described in 
Section 10.6 and Section 20.2. 
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Discontinuation (i.e., complete withdrawal from study participation) may be due to 
dropout (i.e., active discontinuation by subject) or loss to follow-up (i.e., discontinuation 
by subject without notice or action). Additionally, the investigator and sponsor have the 
discretion to discontinue any subject from the study if, in their judgment, continued 
participation would pose an unacceptable risk for the subject.
Subjects also will be withdrawn from treatment or discontinued from further study 
participation for the following reasons:
1.
The subject is scheduled for an extended treatment period 3 months with 
non-topical immunomodulating drugs other than anti-retroviral chemotherapy 
(e.g., -interferon, corticosteroid agents [equivalent to hydrocortisone greater than 
10 mg/day]) during the course of the study.
2.
Subjects with chronic hepatitis B or C develop ALT/AST levels exceeding 5 times 
the ULN for 1 month.
3.
Subjects who experience severe hypersensitivity reactions, e.g., anaphylaxis upon 
exposure to rVWF (vonicog alfa).
4.
Subjects who develop a neutralizing inhibitor to rVWF (vonicog alfa) and/or 
ADVATE (rFVIII, octocog alfa) (biological assays) that results in significant 
clinical effect, including but not limited to increasing the weekly dose of rVWF 
by > 50%.
5.
Subjects who demonstrate clinical signs of thromboembolic events.
6.
The subject becomes pregnant. IP exposure will be discontinued. Attempts will be 
made to follow the subject through completion of the pregnancy and up to 1 year 
post delivery, if feasible. The investigator will record a narrative description of 
the course of the pregnancy and its outcome. 
7.
The subject begins lactating. IP exposure will be discontinued. The investigator 
will record a narrative description of the course of the baby’s development. 
8.
The subject is not compliant with the prophylactic treatment regimen and does not 
adhere to the frequency of IP administration. Once >30% of infusions are missed 
within a visit interval (3 months), the subject will be discontinued from further 
participation in the study. 
9.
The subject repeatedly uses other VWF products for prophylaxis or for the 
treatment of bleeding episodes in the absence of an acceptable justification to the 
sponsor. 
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10. STUDY PROCEDURES
10.1 Informed Consent and Enrollment
Any patient who provides informed consent (i.e., signs and dates the informed consent 
form) is considered a subject enrolled in the study.
10.2 Subject Identification Code
The following series of numbers will comprise the SIC: protocol identifier (e.g., 071301)
to be provided by the sponsor, 2- or 3-digit number study site number (e.g., 02) to be 
provided by the sponsor, and 3- or 4-digit subject number (e.g., 0003) reflecting the order 
of enrollment (i.e., signing the informed consent form). For example, the third subject 
who signed an informed consent form at study site 02 will be identified as Subject 
071301-020003. All study documents (e.g., CRFs, clinical documentation, sample 
containers, drug accountability logs, etc.) will be identified with the SIC. Additionally, a 
uniquely coded SIC(s) is permitted as long as it does not contain a combination of 
information that allows identification of a subject (e.g., collection of a subject’s initials 
and birth date would not be permitted), in compliance with laws governing data privacy.
10.3 Screening and Study Visits
The study site is responsible for maintaining a screening log that includes all subjects 
who provided informed consent. The log also will serve to document the reason for 
screening failure. All screening data will be collected and reported in CRF, regardless of 
screening outcome. If a subject is re-screened, the End of Study CRF should be 
completed, and a new ICF, new SIC and new CRF are required for that subject.
The overall study design is illustrated in the Figure 1. Details on the procedures to be 
performed at each study visit, including screening, are provided in Supplement 20.2
„Schedule of Study Procedures and Assessments“ and Supplement 20.3 „Clinical 
Laboratory Assessments“. 
10.3.1 Screening Visit
Written informed consent must be obtained from each subject before any study 
related procedures are performed. To initiate screening procedures, at least 72 hours 
must have elapsed since the last VWF administration for on-demand subjects and the 
subject must not be actively bleeding at the time of screening. For switch subjects, the 
usual interval between their pdVWF prophy infusions must have elapsed since the last 
VWF administration and the subject must not be actively bleeding at the time of 
screening. Multimer analysis and VWD gene mutation analysis should be performed 
at screening if not available in the subject’s medical history.
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The screening visit will be delayed if the subjects presents with an acute bleeding 
episodes or acute illness (e.g., influenza, flu-like symptoms, inflammatory diseases) until 
the event has resolved. All screening procedures and confirmation of eligibility shall take 
place within 42 days prior to the first infusion of IP. If the IP is not infused within 
42 days, all screening assessments except blood group, human leukocyte antigen (HLA), 
genetics, multimeric pattern and 
, must be repeated to reconfirm eligibility. Refer 
to Supplement 20.2 and Supplement 20.3. Upon completion of screening procedures, 
subject eligibility will be confirmed by the sponsor on a subject eligibility form before 
additional study procedures are undertaken. The subject will maintain a diary that will 
include infusion logs (see Section 10.5). The allocation of IP will be initiated after the 
subject has qualified for home treatment (see Section 8.6.4.3.2).
In the event of a subject experiencing a bleeding episode that requires treatment between 
the screening visit and the subsequent visit (i.e. initial PK assessment visit for on-demand 
subjects or prophylaxis initiation visit for switch subjects), the subject will be treated with 
rVWF (vonicog alfa). If rVWF (vonicog alfa) is not available for any reason, e.g., subject 
not yet trained on IP administration, study site visit for IP administration not feasible, 
etc., the subject may use his/her standard of care, such as commercial pdVWF/FVIII 
products, and the reason for the use of non-IP products should be clearly documented.
10.3.2 Baseline Visit – Initial PK Assessment (On-demand Subjects Only)
After screening and confirmation of eligibility on-demand subjects will undergo an initial 
PK assessment. Subjects will receive a dose of 50 ± 5 IU/kg rVWF:RCo to determine 
VWF and FVIII levels. Blood samples will be drawn within 30 minutes pre-infusion, and 
at 11 time points post-infusion (15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 
3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 
72 2 hours and 96 ± 2 hours). See Section 20.2 and Section 20.3. IP infusion vials from 
the same lot number should be used for all PK-assessments per subject. Samples for 
measurement of FVIII and VWF activity taken through to 6 hours post-infusion will be 
obtained from an extremity different from that used for the infusion of IP. Where needed, 
the phlebotomy site will be kept patent via an infusion of normal saline. In this event, at 
least 5 mL of blood will be collected and discarded before collection of the next test 
sample into a fresh syringe.
If the subject has a central venous catheter, the central line should be used to administer 
the infusion and a peripheral venipuncture should be used to collect the blood samples. 
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In the event that a blood sample must be drawn through the central line used for 
administration of IP, the line must first be flushed with at least 10 mL normal saline or 
other suitable catheter flush solution that does not contain anticoagulant. At least 5 mL of 
whole blood must be collected and discarded prior to obtaining the sample. 
If a subject experiences a bleeding episode during the PK assessment no subsequent 
blood sample will be drawn in that specific PK period. The guidance provided in 
Section 8.6.4.4 has to be followed for the treatment of the bleeding episode. The subject 
once recovered is eligible to repeat the PK assessment. 
For pdVWF switch subjects, PK profile will not be assessed until reaching steady state 
after initiation of prophylaxis (see Section 10.3.4). 
10.3.3 Prophylaxis Initiation Visit
The prophylaxis initiation visit will occur after the blood sample for the 96 hour PK 
assessment is drawn for on-demand subjects or within 42 days after screening and 
confirmation of eligibility for pdVWF switch subjects. The subject will receive the first 
rVWF (vonicog alfa) prophylactic dose of rVWF: RCo. Details on dose are provided in 
Section 8.6.4.3. 
Procedures and assessments at this visit include (but are not limited to): AEs, bleeding 
episodes, medications taken, and non-drug therapies. Within 2 hours prior the IP infusion, 
a physical examination will be performed. Vital signs will be assessed within 30 minutes 
prior to IP rVWF (vonicog alfa) infusion and 30 minutes ± 15 minutes after IP infusion.
Further details are provided in Supplement 20.2 and Supplement 20.3.
10.3.4 Initial Steady State PK-Assessment (pdVWF switch subjects only)
For pdVWF switch subjects, a full PK profile will be assessed at steady state conditions 
on two occasions. The initial PK assessment will be performed shortly after reaching 
steady state after starting prophylaxis dosing, which is suggested after 11 days post the 
1st, around prophylaxis dose #5-6. The 2nd PK assessment at steady state will be 
performed at the end of the study.
Blood samples will be drawn within 30 minutes pre-infusion, and at 11 time points 
post-infusion (15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 
6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours 
and 96 ± 2 hours). In case the dosing schedule does not permit the 96 hr sampling, 
this sampling time point can be omitted (See Section 11.6). IP infusion vials from 
the same lot number should be used for all PK-assessments per subject. 
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Samples for measurement of FVIII and VWF activity taken through to 6 hours post-
infusion will be obtained from an extremity different from that used for the infusion of 
IP. Where needed, the phlebotomy site will be kept patent via an infusion of normal 
saline. In this event, at least 5 mL of blood will be collected and discarded before 
collection of the next test sample into a fresh syringe.
If the subject has a central venous catheter, the central line should be used to administer 
the infusion and a peripheral venipuncture should be used to collect the blood samples. 
In the event that a blood sample must be drawn through the central line used for 
administration of IP, the line must first be flushed with at least 10 mL normal saline or 
other suitable catheter flush solution that does not contain anticoagulant. At least 5 mL of 
whole blood must be collected and discarded prior to obtaining the sample. 
If a subject experiences a bleeding episode during the PK assessment no subsequent 
blood sample will be drawn in that specific PK period. The guidance provided in 
Section 8.6.4.4 has to be followed for the treatment of the bleeding episode. The subject 
once recovered is eligible to repeat the PK assessment. In case of surgery or bleeding, the 
PK assessment should be performed after 11 days after 1st prophylactic dose after re-start 
of prophylactic regimen. See section 11.6 for more details.
10.3.5 Treatment of Bleeding Episodes
Treatment of bleeding episodes is described in detail in Section 8.6.4.4 and treatment of 
perioperative bleeding is described in detail in Section 8.6.4.5.
10.3.6 Perioperative Visits (only applicable if surgery is needed)
The perioperative visits from priming dose through postoperative day 14 will be required 
to check daily intra- and postoperative weight-adjusted dose of rVWF (vonicog alfa) with 
or without ADVATE (rFVIII, octocog alfa). Details on the procedures and assessments 
performed at each visit can be found in supplement tables in Section 20.2.1 and 
Section 20.3.1.
10.3.7 Follow-Up Visits 
Visits will be performed after the prophylaxis initiation visit at 1 month ± 1 week, 
2 months ± 1 week, and 3 months ± 2 weeks and thereafter every three months
± 2 weeks. Additional visits may occur if clinically indicated (see Section 10.3.8). 
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When possible, site visits should be scheduled on days when the subject is expected to 
infuse rVWF (vonicog alfa). Within 2 hours prior to the rVWF (vonicog alfa) IP infusion, 
a physical examination will be performed. Vital signs will be assessed within 30 minutes 
prior to IP infusion and 30 minutes ± 15 minutes after IP infusion. Incremental recovery 
(IR) will be determined at each follow-up visit based on VWF:RCo activity assessed 
prior to and after IP infusion.
The blood sample for IR analysis will be drawn within 30 minutes prior to IP infusion 
and 30 minutes ± 5 minutes after IP infusion. rVWF (vonicog alfa) will be infused at the 
regular prophylactic dose. For each subject’s recovery analysis IP infusion, vials from the 
same lot number should be used. 
Testing for VWF:RCo VWF:CB, rVWF:Ag, and FVIII:C level will be performed using 
the blood sample obtained before and after IP infusion. 
The blood sample prior to IP infusion will also be used for the assessment of neutralizing 
and binding antibodies, clinical chemistry and hematology. For on-demand subjects, a 
washout period of at least 72 hours after the last infusion applies before the blood draw 
for the immunogenicity assays. For switch subjects, the wash out period may be reduced 
to the time interval between their pdVWF prophy infusions Bleeding episodes and the 
hemostatic efficacy will be evaluated based on the review of the patient diary. See
Section 20.2 and Section 20.3. The evaluation of IP consumption and treatment 
compliance will be performed based on subject’s diary entries. If a subject is not 
compliant with the prophylactic treatment regimen and does not adhere to the required 
frequency of administration of IP infusions (>30% of infusions were missed within a visit 
interval [3 months]) the subject will be withdrawn from the study. 
At the 6 months ± 2 week visit an ECG will be performed and 
 data will be 
collected. 
For the hemostatic efficacy assessment the following information will be recorded by the 
subject in the patient diary: bleeding location, type, severity, onset and resolution date 
and time, infusion date and time, clinical efficacy according to the rating scale. If at any 
time during the study a subject’s bleeding episode does not adequately respond to rVWF 
(vonicog alfa) therapy, he/she will be evaluated for the presence of neutralizing and total 
binding antibodies. Refer to Section 12.9.3.2.
Further guidance on completing the subject’s diary will be provided to the subjects during 
training for home treatment (see Section 8.6.4.3.2).
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10.3.8 Unscheduled Visits
For any unscheduled visit (except for collection of IP) a clinical assessment will be 
performed as per the scheduled follow-up visits with the exception of 
, ECG, and 
IR determination (refer to Supplement 20.2 and Supplement 20.3).
Subjects who have more than one bleeding episode in 3 months, or an increased 
frequency of bleeding, should go to the study site for an unscheduled visit.
Follow-up visits after the subject has experienced a bleed may be requested by the 
investigator. Additional assessments may be required which are at the discretion of the 
investigator. 
10.3.9 End of Study PK Assessment and Study Termination Visit 
At the 12* month ± 2 week visit, a full PK analysis at steady state will be performed for 
both cohorts: on-demand and switch subjects. Blood samples will be drawn within 
30 minutes pre-infusion, and at 11 time points post-infusion (15 ± 5 minutes, 
30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 
24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours and 96 ± 2 hours) unless dosing 
schedule does not permit, in which case the 96 hr sampling can be omitted. If a subject 
experiences a bleeding episode during the PK assessment no subsequent blood sample 
will be drawn in that specific PK period. The guidance provided in Section 8.6.4.4 has to 
be followed for the treatment of the bleeding episode. The subject once recovered is 
eligible to repeat the PK assessment and the PK assessment should be performed after 
11 days after 1st prophylactic dose after re-start of prophylactic regimen. See section 11.6
for more details.
Refer to Supplement 20.2 and Supplement 20.3 for the other assessments to be performed 
at the PK assessment and study completion visits.
For on-demand subjects, a washout period of at least 72 hours is required between the PK
infusion and the study termination visit (at the time of the 96 hour postinfusion PK 
assessment). For switch subjects,  the wash out period may be reduced to the time interval 
between their rVWF (vonicog alfa) prophy infusions.Refer to Supplement 20.2 and 
Supplement 20.3 for the list of assessments to be performed at the termination visit.
Subjects will be offered the option to continue to receive rVWF (vonicog alfa) in a 
long-term continuation study*.
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* Study treatment period is extended by 3 months to accommodate participation in the 
continuation study for the qualified subjects and will be exercised only if the continuation 
study start up is delayed beyond the completion of subject’s 12-month visit. For subjects 
whose completion date is extended beyond the 12-month visit due to delay in continuation 
study start-up, the 12-month ± 2 weeks visit will be considered as a follow-up visit, and EOS 
visit will be performed once the subject can rollover into the continuation study, from 
12 month ± 2 weeks to 15 month ± 2 weeks post prophylaxis initiation visit, as applicable.
Both the 12-month ± 2 weeks visit rescheduled as a follow-up visit, and the rescheduled EOS 
visit will be recorded in the CRF.
10.4 Medications and Non-Drug Therapies 
The following medications and non-drug therapies are not permitted within 30 days 
before study entry and during the course of the study:
Medications:

Immunomodulating drugs other than anti-retroviral chemotherapy (e.g.,
-interferon, or corticosteroid agents at a dose equivalent to hydrocortisone 
greater than 10 mg/day) and an extended treatment period 3 months.

Another investigational and/or interventional study drug (except rVWF and FVIII 
administered under the surgery protocol).
A subject who has taken any of these medications or received any of these non-drug 
therapies during the study will be withdrawn from the study. 
The following medications are permitted during the course of the study:

Antifibrinolytics (e.g., tranexamic acid, -amino caproic acid) or topical 
hemostats as needed, according to each institution’s standard of care. These may 
be used, in accordance with local standard clinical practice, as the initial or only 
treatment for minor and moderate bleeding events. However, if the bleeding has 
not stopped within 24 hour following administration of this non-VWF treatment, 
infusion(s) with rVWF (vonicog alfa) should be started per protocol

Emergent use of a VWF concentrate other than rVWF (vonicog alfa) may be 
permissible under certain circumstances (see Section 8.6.4.4.1)
Details of all adjunctive hemostatic medication used, including dose and reason for use, 
must be recorded in the eCRF.
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10.5 Subject Diary
An electronic subject diary will be provided to each subject at the screening visit to
record the following information:
1.
IP infusions to include date, start and stop times of the infusion, number of vials 
utilized, and infusion volume for prophylactic treatment or treatment of 
spontaneous and traumatic bleeding episodes 
2.
Details of bleeding episodes (site, type, severity and date/time of bleeding) and 
response to treatment as described in Section 8.6.4.4
3.
Subjective hemostatic efficacy assessments
4.
Untoward events/unwanted experiences
5.
Concomitant medications (including immunizations) and non-drug therapies
6.
Patient Reported Outcomes (PROs)
Subjects and/or their legally authorized representatives will be trained on use of the diary. 
The diary will be provided in electronic format and remain with the subject for the 
duration of the study. The investigator will review the diary for completeness and request 
missing information periodically and in a timely manner. The investigator will 
record/capture any unwanted experience reported by the subject which may qualify as an 
AE on the AE eCRF.
Infusions performed at the study site will first be recorded in the site’s source documents 
and not in the patient diary.
Subject entries in the diary will serve as source records. During study participation the 
investigator has access to the database holding the subject diary data. After study closure, 
the investigator will receive the diary records for their subjects, including audit trail 
records, in PDF format. The data will be transmitted to the CRF by a validated transfer. 
Paper diary may be utilized in rare case where electronic diary use is not possible.
10.6 Subject Completion/Discontinuation
A subject is considered to have completed the study when he/she ceases active 
participation in the study because the subject has, or is presumed to have completed all 
study procedures according with the protocol (with or without protocol deviations).
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Reasons for completion/discontinuation will be reported on the 
Completion/Discontinuation CRF, including: completed, screen failure, AE (e.g., death), 
discontinuation by subject (e.g., lost to follow-up [defined as 3 documented unsuccessful 
attempts to contact the subject], dropout), physician decision (e.g., pregnancy, 
progressive disease, non-compliance with IP/protocol violation(s), recovery), study 
terminated by sponsor, or other (reason to be specified by the investigator, e.g., technical 
problems). Regardless of the reason, all data available for the subject up to the time of 
completion/discontinuation should be recorded on the appropriate CRF. 
Every effort will be made to have discontinued subjects complete the study 
termination visit. If the termination visit is done as an additional, unscheduled 
visit, the assessment results shall be recorded with the termination visit. 
If a subject terminates participation in the study and does not return for termination visit, 
his/her last recorded assessments shall remain with the last visit. The reason for 
discontinuation will be recorded, and the data collected up to the time of discontinuation 
will be used in the analysis and included in the clinical study report. If additional 
assessments are required, the assessments shall be recorded separately. Assessments to be 
performed at the termination visit (including in cases of withdraw or discontinuation) can 
be found in Supplement 20.2 Schedule of Study Procedures and Assessments and 
Supplement 20.3 Clinical Laboratory Assessments.
In the event of subject discontinuation due to an AE, clinical and/or laboratory 
investigations that are beyond the scope of the required study observations/assessments 
may be performed as part of the evaluation of the event. These investigations will take 
place under the direction of the investigator in consultation with the sponsor, and the 
details of the outcome may be reported to the appropriate regulatory authorities by the 
sponsor. 
10.7 Procedures for Monitoring Subject Compliance
Subject compliance with the procedures of this study (treatment regimens and study 
visits) will be monitored by the investigator or/a licensed healthcare professional at the 
study site.
During the regular scheduled follow-up visits a direct review of the subject’s source data 
(e-diaries) will be performed at the sites and evaluated against the protocol requirements. 
In addition drug accountability will be evaluated at each follow-up study visit and the 
study termination visit by comparing the infusions recorded in the subject diary with
empty vials returned by each subject to the study site, and the study site’s dispensing 
record. Protocol deviations will be noted in the final report. 
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11. ASSESSMENT OF EFFICACY AND PHARMACOKINETICS
11.1 Assessment of Spontaneous Bleeding Episodes/Annualized Bleed Rate 
The annualized bleed rate (ABR) will be assessed based upon each individual 
spontaneous bleed, requiring coagulation factor replacement therapy, i.e., rVWF 
(vonicog alfa) treatment. The following details on bleeding episodes will be recorded by 
the subject in the electronic diary (for home treatment), the subject’s healthcare provider 
in the site’s source documents (for treatments away from the primary investigative site), 
or by authorized, qualified personnel at the participating site in the subject’s medical 
records (for hospital-based treatment):

Location of bleed; i.e., joint, menorrhagia, epistaxis, gastrointestinal, soft tissue, 
muscle, body cavity, intracranial, etc.

Type of bleed; i.e., spontaneous, traumatic, unknown

Severity of bleed; i.e., minor, moderate, and major (see Table 3)

Date and time of onset of bleed

Date and time of each infusion of rVWF (vonicog alfa) or rVWF (vonicog alfa)-
ADVATE (rFVIII, octocog alfa) used to treat a bleeding episode

Date and time of resolution of the bleeding episode
Study site personnel are qualified after they have undergone training during the 
qualification of the site.
All types of bleeds, including traumatic bleeds, will be recorded. Bleeding episodes 
should be organized by where they occur in addition to whether they occurred 
spontaneously or due to a traumatic event.
Bleeds occurring at the same anatomical location (e.g., right knee) with the same etiology 
(i.e., spontaneous versus injury) within 24 hours after onset of the first bleed will be 
considered a single bleed. Bleeding occurring at multiple locations related to the same 
injury (e.g., knee and ankle bleeds following a fall) will be counted as a single bleeding 
episode.
All efforts should be made to use rVWF (vonicog alfa) for treatment of bleeding
episodes. If needed, the use of a VWF concentrate other than IP for the treatment of 
bleeding episodes will not disqualify the subject from further participation in the study.
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11.2 Evaluation of ABR Before rVWF Prophylaxis and ABR Under rVWF
Prophylactic Treatment
At screening, the subject’s medical history will be recorded, including the number and 
location of all spontaneous and traumatic bleeding episodes within the past 12 months (up 
to 24 months if available). The maximum interval of bleed-free periods as well as trauma 
induced bleeding episodes will also be recorded (prospectively and retrospectively).
11.3 Number of Infusions and Total Weight Adjusted Consumption of rVWF and 
ADVATE and historical prophylaxis dosing and factor consumption during 
pdVWF prophylaxis treatment prior to enrollment
The number of rVWF (vonicog alfa) and ADVATE (rFVIII, octocog alfa) (in case of 
bleeding episode treatment) infusions will be logged in the subject diary. Based on these 
entries the weight adjusted consumption will be calculated. 
At the screening, historical pdVWF dosage and dosing frequency during 12 and up to 
24 months of pdVWF prophylactic treatment prior to enrollment will be recorded for the 
pdVWF switch subjects in order to calculate the consumption of pdVWF.
11.4 Assessment of Efficacy for Treatment of Bleeding Episode
Investigators will be asked to assess and record hemostatic efficacy after resolution of 
each bleeding episode using the 4-scale rating system outlined in Table 4. 
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Table 4
Efficacy Rating Scale
Rating
Efficacy Rating Criterion
Minor and Moderate Bleeding Events
Major Bleeding Events
Excellent (=1)
Actual number of infusions ≤ estimated 
number of infusions required to treat that 
bleeding episode
No additional VWF containing 
coagulation factor containing product 
required
Actual number of infusions ≤ estimated 
number of infusions required to treat that 
bleeding episode
No additional VWF containing coagulation 
factor containing product required
Good (=2)
1-2 infusions greater than estimated 
required to control that bleeding episode
No additional VWF containing 
coagulation factor containing product 
required
< 1.5 x infusions greater than estimated 
required to control that bleeding episode
No additional VWF containing coagulation 
factor containing product required
Moderate (=3)
3 or more infusions greater than estimated 
required to control that bleeding episode
No additional VWF containing 
coagulation factor containing product 
required
≥1.5 x infusions greater than estimated 
required to control that bleeding episode
No additional VWF containing coagulation 
factor containing product required
None (=4)
Severe uncontrolled bleeding or intensity 
of bleeding not changed
Additional VWF containing coagulation 
factor containing product required
Severe uncontrolled bleeding or intensity 
of bleeding not changed
Additional VWF containing coagulation 
factor containing product required
11.5 Assessment of Efficacy for Treatment for Surgical Bleeding
For those undergoing surgery, the operating surgeon will be asked to assess and record 
actual versus predicated blood loss and intraoperative hemostatic efficacy immediately 
after surgery. 
The investigator will be asked to assess and record an overall assessment of hemostatic 
efficacy 24 hours after the last perioperative rVWF (vonicog alfa) infusion or at day 14 
post-operation, whichever occurs first, using the 4-scale rating system described in 
Table 5.
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Table 5
Assessment of Hemostatic Efficacy
Rating
Overall Assessment of Hemostatic Efficacy 24 Hours After the Last Perioperative
rVWF Infusion
Excellent (1)
Intra- and post-operative hemostasis achieved with rVWF (vonicog alfa) with or without 
ADVATE (rFVIII, octocog alfa) was as good or better than that expected for the type of 
surgical procedure performed in a hemostatically normal subject
Good (2)
Intra- and post-operative hemostasis achieved with rVWF (vonicog alfa) with or without 
ADVATE (rFVIII, octocog alfa) was probably as good as that expected for the type of 
surgical procedure performed in a hemostatically normal subject
Moderate (3)
Intra- and post-operative hemostasis with rVWF (vonicog alfa) with or without ADVATE 
(rFVIII, octocog alfa) was clearly less than optimal for the type of procedure performed but 
was maintained without the need to change the rVWF (vonicog alfa) concentrate
None (4)
Subject experienced uncontrolled bleeding that was the result of inadequate therapeutic 
response despite proper dosing, necessitating a change of rVWF (vonicog alfa) concentrate
11.6 rVWF Pharmacokinetics and Pharmacodynamics 
PK will be assessed twice for all subjects.
For on-demand subjects, an initial PK assessment using a dose of 50 IU ± 5 IU/kg 
rVWF:RCo will be performed at the baseline visit, and a washout period of at least 
5 days is required before the infusion of rVWF (vonicog alfa) for PK assessment can 
be administered. At the 12 month ± 2 week visit, a steady state PK analysis will be 
performed based on the longer interval of the irregular dosing intervals employed. For 
both assessments, blood samples will be drawn within 30 minutes pre-infusion, and at 
11 time points post-infusion (15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 
3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 
72 2 hours and 96 ± 2 hours). VWF activity will be determined using the VWF:RCo, 
VWF:CB and the VWF: Ag assay. Endogenous FVIII activity will be measured using the 
1-stage clotting assay to assess the pharmacodynamics of rVWF (vonicog alfa). 
For pdVWF switch subjects, the initial PK assessment using the subject’s individualized 
dose will be performed shortly after reaching steady state, which is estimated to be 
reached for the majority of subjects after  approximately 11 days from the 1st prophylactic 
dose. To fit any logistical requirements, samples for PK analysis can be taken after 
prophylaxis dose #5-6, and whenever possible, sample collections should be during the 
longer partial interval of the alternating irregular dosing intervals. For example, if a 
subject follows a dosing regimen as follows:
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Date
Weekday
Dose number
Interval
Time from 1st dose in hours
8.1.18 8:00
Monday
1
0
0
12.1.18 8:00
Friday
2
4
96
15.1.18 8:00
Monday
3
3
168
19.1.18 8:00
Friday
4
4
264
22.1.18 8:00
Monday
5
3
336
26.1.18 8:00
Friday
6
4
432
After reaching the steady state, the PK assessment can be done at dose 5 to allow the 96h 
post-infusion sampling, before the next scheduled dose (for patients on a twice per week 
dosing schedule). A similar 2nd full PK profile will be assessed at the end of the study, i.e. 
12* month ± 2 week visit with a PK infusion at the same dosing partial interval (96h 
interval in this case). Blood samples will be drawn within 30 minutes pre-infusion, 
and at 11 time points post-infusion (15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 
3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 
72 2 hours, and 96 ± 2 hours). If the dosing interval for a certain switch subject 
wouldn’t allow for the full 11 post-infusion timepoints sample collection, the 96-hour 
sampling timepoint can be omitted, but it is critical that the assessments are at the same 
partial interval, thereby same number of sampling timepoints, for the 1st and 2nd PK for an 
individual switch subject.
If a subject experiences a bleeding episode during the PK assessment no subsequent 
blood sample will be drawn in that specific PK period. The guidance provided in 
Section 8.6.4.4 has to be followed for the treatment of the bleeding episode. The subject 
once recovered is eligible to repeat the PK assessment. In case of surgery or bleeding, the 
PK assessment should be performed after 11 days after 1st prophylactic dose after restart 
of prophylactic regimen.
* Study treatment period is extended by 3 months to accommodate participation in the 
continuation study for the qualified subjects and will be exercised only if the continuation study 
start up is delayed beyond the completion of subject’s 12-month visit.
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12. ASSESSMENT OF SAFETY
12.1 Adverse Events
12.1.1 Definitions
An AE is defined as any untoward medical occurrence in a subject administered IP that 
does not necessarily have a causal relationship with the treatment. An AE can therefore 
be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom 
(e.g., rash, pain, discomfort, fever, dizziness, etc.), disease (e.g., peritonitis, bacteremia, 
etc.), or outcome of death temporally associated with the use of an IP, whether or not 
considered causally related to the IP.
12.1.1.1 Serious Adverse Event 
An SAE is defined as an untoward medical occurrence that, at any dose, meets one or 
more of the following criteria:

Outcome is fatal/results in death (including fetal death)

Is life-threatening – defined as an event in which the subject was, in the judgment 
of the investigator, at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death had it been more severe.

Requires inpatient hospitalization or results in prolongation of an existing 
hospitalization – inpatient hospitalization refers to any inpatient admission, 
regardless of length of stay.

Results in persistent or significant disability/incapacity (i.e., a substantial 
disruption of a person’s ability to conduct normal life functions)

Is a congenital anomaly/birth defect

Is a medically important event – a medical event that may not be immediately 
life-threatening or result in death or require hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the definitions above. Examples of such events are (including 
but not limited to): 

Intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias, or convulsions that do not result in 
hospitalization, or development of drug dependence or drug abuse 

Reviewed and confirmed seroconversion for HIV, hepatitis A virus (HAV), 
hepatitis B virus (HBV), hepatitis C virus
(HCV), hepatitis E virus (HEV), or parvovirus B19 (B19V)
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
Development of clinically significant neutralizing VWF antibodies

Development of neutralizing antibodies to FVIII (titer ≥0.4 BU [by 
Nijmegen- modified Bethesda assay] or ≥0.6 BU [by Bethesda assay])

Thromboembolic events (e.g., myocardial infarction, stroke, transient 
ischemic attack [TIA], deep vein thrombosis [DVT] or pulmonary 
embolism)

Hypersensitivity reactions (e.g., anaphylaxis [for definition, refer to 
Section 12.6.2] and other immediate and delayed hypersensitivity reactions 
which may manifest with urticarial rash, pruritus, flushing, angioedema of 
the face, extremities, or laryngeal tissues [leading to throat tightness with 
stridor], wheezing, gastrointestinal symptoms, and/or hypotension) 
Uncomplicated pregnancies, following maternal or paternal exposure to IP are not 
considered an AE/SAE; however, any pregnancy complication or pregnancy termination 
by therapeutic, elective, or spontaneous abortion shall be considered an SAE and should 
be reported per SAE reporting guidelines provided in Section 12.1.2.3 (Safety Reporting).
12.1.1.2 Suspected Unexpected Serious Adverse Reaction (SUSAR)
Any suspected adverse reaction to study treatment that is both serious and unexpected is 
considered a SUSAR. 
The event(s) must meet all of the following:

Suspected adverse reaction (which implies that there is reasonable evidence 
indicating a causal relationship between the event and the study treatment),

Unexpected (per Reference Safety Information (RSI)/IB), and

Serious
Once determined to meet the criteria for a SUSAR, the sponsor will ensure expedited 
SUSAR reporting is completed in line with the regulatory requirements in participating 
countries as outlined in the Safety Management Plan. 
12.1.1.3 Non-Serious Adverse Event
A non-serious AE is an AE that does not meet any of the seriousness criteria (death, 
life-threatening, hospitalizing/prolongation of hospitalization, disability, congenital 
anomaly, or medically significant and if not urgently treated would result in one of the 
above) listed in section 12.1.1.1.
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12.1.1.4 Unexpected Adverse Events
An unexpected adverse event is an AE whose nature, severity, specificity, or outcome is 
not consistent with the term, representation, or description used in the Reference Safety 
Information (e.g., IB, PI [prescribing information]). “Unexpected” also refers to the AEs 
that are mentioned in the IB as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring 
with the particular drug under investigation.
12.1.1.5 Preexisting Disease
Preexisting diseases that are present before entry in to the study are described in the 
medical history, and those that manifest with the same severity, frequency, or duration 
after IP exposure will not be recorded as AEs. However, when there is an increase in the 
severity, duration, or frequency of a preexisting disease, the event must be described as 
“worsening” of the pre-existing condition on the AE CRF.
12.1.2 Assessment of Adverse Events
For the purposes of this study, the following will not be considered as AEs and will not 
be included in the analysis of AEs.

Bleeding episodes are part of the underlying disease and therefore are not AEs; 
they will be evaluated in the context of efficacy.

For non-serious bleeding episodes caused by an injury, the injury would not 
be reported as an AE, unless it resulted in a medical finding other than a 
bleeding episode (e.g., abrasion of skin). Therefore, any VWD-related 
bleeding event (e.g., epistaxis, gastrointestinal bleeding, musculo-skeletal 
bleeding, menorrhagia) that is non-serious will not be reported as an AE. 
However, the investigator may decide that the event is an AE if the event also 
would have occurred in a healthy individual under the same circumstances.

For serious bleeding episodes (bleeding SAEs): Bleeding events that meet 
seriousness criteria (death, life-threatening, hospitalizing/prolongation of 
hospitalization, disability, congenital anomaly, or medically significant and if 
not urgently treated would result in one of the above) should be captured on 
the SAE eCRF and reported as an SAE to the Sponsor or designee (e.g., 
CRO) on an SAE Report form as described in Section 12.1.2.3 (Safety 
Reporting).

Seroconversion after documented HAV/HBV vaccination prior to or during the 
study period.
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Each AE from the first IP exposure to the study completion date will be described on the 
AE CRF using the term representing medical diagnosis (preferred), or, if no diagnosis 
could be established at the time of reporting the AE, a symptom or sign, in standard 
medical terminology in order to avoid the use of vague, ambiguous, or colloquial 
verbatim expressions (see definition in Section 12.1). Each AE will be evaluated by the 
investigator for:

Seriousness as defined in Section 12.1.1.1

Severity as defined in Section 12.1.2.1

Causal relationship to IP exposure or study procedure as defined in 
Section 12.1.2.2
For each AE, the outcome (i.e., recovering/resolving, recovered/resolved, 
recovered/resolved with sequelae, not recovered/not resolved, fatal, unknown) and if 
applicable, action taken with regards to the study treatment (i.e., dose increased, dose not 
changed, dose reduced, drug interrupted, drug withdrawn, not applicable, or unknown) 
will also be recorded on the AE CRF. Recovering/resolving AEs will be followed until 
resolution or until the subject’s condition returns to the level at the baseline for pre-
existing conditions. 
If the severity rating for an ongoing AE changes before the event resolves, the original 
AE report will be revised (i.e., the event will not be reported as separate AE). During the 
course of any AE, the highest severity rating will be reported.
Deviations from the protocol-specified dosage (including underdosing /overdosing 
[<20 IU/kg rVWF:RCo or >100 rVWF:RCo], abuse, and withdrawal, treatment errors 
(including incorrect route of administration, use of an incorrect product, and deviations 
from the protocol-defined dosing schedule), failures of expected pharmacological actions, 
and unexpected therapeutic or clinical benefits will be followed with regard to occurrence 
of AEs, lack of efficacy, and/or other observations because these events may be 
reportable to regulatory authorities. 
Any pregnancy that occurs after administration of IP will be reported on a Pregnancy 
Form and followed-up at 1 year post-delivery, if feasible. 
If an investigator becomes aware of an SAE occurring in a subject after study completion, 
the SAE must be reported on the SAE Form within 24 hours after awareness: no 
additional reporting on CRFs is necessary.
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12.1.2.1 Severity
The investigator will assess the severity of each AE using his/her clinical expertise and 
judgment based on the most appropriate description below:

Mild
The AE is a transient discomfort and does not interfere in a significant manner 
with the subject’s normal functioning level.
The AE resolves spontaneously or may require minimal therapeutic 
intervention.

Moderate
The AE produces limited impairment of function and may require therapeutic 
intervention.
The AE produces no sequela/sequelae.

Severe
The AE results in a marked impairment of function and may lead to temporary 
inability to resume usual life pattern.
The AE produces sequela/sequelae, which require (prolonged) therapeutic 
intervention.
These severity definitions will also be used to assess the severity of an AE with a study-
related procedure(s), if necessary.
12.1.2.2 Causality
Causality is a determination of whether there is a reasonable possibility that the IP is 
etiologically related to/associated with the AE. Causality assessment includes, e.g., 
assessment of temporal relationships, dechallenge/rechallenge information, association 
(or lack of association) with underlying disease, presence (or absence) of a more likely 
cause, and physiological plausibility. For each AE, the investigator will assess the causal 
relationship between the IP and the AE using his/her clinical expertise and judgment 
according to the following most appropriate algorithm for the circumstances of the AE:

Not related (both circumstances must be met)
Is due to underlying or concurrent illness, complications, concurrent 
treatments, or effects of concurrent drugs
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Is not associated with the IP (i.e., does not follow a reasonable temporal 
relationship to the administration of IP, is not biologically plausible per 
mechanism of action of the IP, or has a much more likely alternative etiology). 

Unlikely related (either 1 or both circumstances are met)
Has little or no temporal relationship to the IP 
A more likely alternative etiology exists

Possibly related (both circumstances must be met)
Follows a reasonable temporal relationship to the administration of IP
An alternative etiology is equally or less likely compared to the potential 
relationship to the IP

Probably related (both circumstances must be met)
Follows a strong temporal relationship to the administration of IP, which may 
include but is not limited to the following: 
o
Reappearance of a similar reaction upon re-administration (positive re-
challenge)
o
Positive results in a drug sensitivity test (skin test, etc.)
o
Toxic level of the IP as evidenced by measurement of the IP 
concentrations in the blood or other bodily fluid
Another etiology is unlikely or significantly less likely
For events assessed as not related or unlikely related and occurring within 5 days after IP 
infusion, the investigator shall provide the alternative etiology. These causality 
definitions will also be used to assess the relationship of an AE with a study-related 
procedure(s), if necessary.
12.1.2.3 Safety Reporting
AEs and SAEs will be assessed at all study visits as outlined in the Schedule of Study 
Procedures and Assessments (see Section 20.2) and Section 12.1.2.
Adverse Events and SAEs are to be recorded on the AE page of the eCRF. Each event 
should be recorded separately.
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Any SAE, including death due to any cause, which occurs during this study, whether or 
not related to the IP, must be reported immediately (within 24 hours of the study center’s 
first knowledge of the event). All SAEs must be reported in English via the Electronic 
Data Capture (EDC) system by completing the relevant eCRF page(s) and also by SAE 
Report Form via fax/email to Sponsor’s Global Drug Safety (Baxalta GDS) department 
within 24 hours of becoming aware of the event for SAEs (for contacts, instructions, and
additional details, refer to the SAER form).
Within 24 hours of site awareness of a SAE (or Pregnancy) study sites will complete and 
send all SAE (or Pregnancy) reports to a dedicated:
Baxalta Global Drug Safety fax number:  
OR 
email: 
The responsible Site Monitor will review the SAE (or Pregnancy) Reports for 
completeness, will reconcile the reports against the EDC database, and will follow-up 
with sites to obtain missing information and/or information requiring clarification. Any 
SAE associated with a pregnancy must be reported on the SAER Form.
For Follow-up Reports, the site shall use a new SAER form (marked as Follow-up) and 
the new information should be entered together with a brief narrative identifying the 
updated data. 
An SAER should include the following minimum information:
1.
Protocol Number (on all pages)
2.
Subject identification number (on all pages) and demographics (gender, age at 
onset of event and/or date of birth)
3.
Investigational product and treatment regimen (including date of the first dose of 
IP, date of the last dose of IP prior to the onset of the SAE)
4.
Medical Term for Event (Diagnosis preferably) 
5.
Description of the SAE, including:

Date of onset

Causal relationship assessment by the Investigator
6.
Seriousness criteria (e.g., death, life-threatening, hospitalization, medically 
significant, or other criterion)
7.
Name, address, fax number, email, and telephone number of the 
reporter/Investigator 
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Post-trial SAE Reporting: In compliance to EudraLex Volume 10 (Clinical trials 
guidelines, Chapter II: Safety Reporting from the European Commission), which 
references an EMA guidance (ICH Topic E 2 A - Clinical Safety Data Management: 
Definitions and Standards for Expedited Reporting), clinical sites/the investigator should 
report to the Sponsor SAEs after a subject´s study completion. Study sites will be 
provided a Post-Trial SAER form to complete and report these post-study SAEs to the 
Sponsor within the 24 hours of their awareness. Site Monitor will instruct the site that any 
such Post-Trial SAEs should be reported on the study-specific Post-Trial SAER form 
if/when the site becomes aware of it. Such information will not be actively monitored by 
the sponsor after completion of the study.
These events shall be reported to Baxalta GDS who will process them in the same way as 
SAEs occurring during the study. Post-Trial SAEs do not need to be captured in the study 
EDC database if it is already locked. Irrespective if captured in the EDC database or not, 
such Post-Trial SAEs will become part of the GDS database. The monitor should remind 
the clinical site about the post-trial SAE reporting requirements during interim 
monitoring visits, upon each subject’s study completion as well as during the close-out 
visit.
12.2 Urgent Safety Measures
An urgent safety measure is an immediate action taken, which is not defined by the 
protocol, in order to protect subjects participating in a clinical trial from immediate harm. 
Urgent safety measures may be taken by the sponsor or clinical investigator, and may 
include any of the following: 

Immediate change in study design or study procedures

Temporary or permanent halt of the clinical trial 

Any other immediate action taken in order to protect clinical trial participants 
from immediate hazard to their health and safety
The investigator may take appropriate urgent safety measures in order to protect subjects 
against any immediate hazard to their health or safety. The measures should be taken 
immediately and may be taken without prior authorization from the sponsor. 
In the event(s) of an apparent immediate hazard to the subject, the investigator will notify 
the sponsor immediately by phone and confirm notification to the sponsor in writing as 
soon as possible, but within 1 calendar day after the change is implemented. The sponsor 
will also ensure the responsible ethics committees (ECs) and relevant competent 
authority(s) are notified of the urgent measures taken in such cases according to local 
regulations.
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12.3 Untoward Medical Occurrences
Untoward medical occurrences occurring before the first exposure to IP are not 
considered AEs (according to the definition of AE, see Section 12.1.1). However, each 
serious untoward medical occurrence experienced before the first IP exposure (i.e., from 
the time of signed informed consent up to but not including the first IP exposure) will be 
described on the SAER. These events will not be considered as SAEs and will not be 
included in the analysis of SAEs. 
12.4 Non-Medical Complaints
A non-medical complaint (NMC) is any alleged product deficiency that relates to 
identity, quality, durability, reliability, safety and performance of the product but did not 
result in an AE. NMCs include but are not limited to the following:

A failure of a product to exhibit its expected pharmacological activity and/or 
design function, e.g. reconstitution difficulty

Missing components

Damage to the product or unit carton

A mislabeled product (e.g., potential counterfeiting/tampering)

A bacteriological, chemical, or physical change or deterioration of the product 
causing it to malfunction or to present a hazard or fail to meet label claims
Any NMCs of the product will be documented on an NMC form and reported to the 
sponsor within 1 business day. If requested, defective product(s) will be returned to the 
sponsor for inspection and analysis according to procedures.
12.5 Medical, Medication, and Non-Drug Therapy History
At screening, the subject’s medical history will be described for the following body 
systems including severity (defined in Section 12.1.2.1) or surgery and start and end 
dates, if known: eyes, ears, nose, and throat; respiratory; cardiovascular; gastrointestinal; 
musculoskeletal; neurological; endocrine; hematopoietic/lymphatic; dermatological; and 
genitourinary. The subject’s medical history will also include documented history of 
on-demand or pdVWF prophylaxis treatment for at least the past 12 months and a 
documented history, e.g., patient charts and prescription information, of all bleeding 
episodes within the past 12 months (up to 24 months if available).
All medications taken and non-drug therapies received in the 2 weeks prior to study entry 
and all concomitant medications and non-drug therapies during study will be recorded on 
the CRFs.
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Data on medical history, drug and non-drug therapy history of those subjects who 
transition from surgery rVWF (vonicog alfa) study will be used from the eCRF of the 
main studies, will be updated, if applicable, and transcribed into the respective eCRF of 
the prophy study. 
12.6 Physical Examinations
At screening and subsequent study visits (as described in Section 10.3), a physical 
examination will be performed on the following body systems: general appearance, head 
and neck, eyes and ears, nose and throat, chest, lungs, heart, abdomen, extremities and 
joints, lymph nodes, skin, and neurological. At screening, if an abnormal condition is 
detected, the condition will be described on the medical history CRF. At study visits, if a 
new abnormal or worsened abnormal pre-existing condition is detected, the condition will 
be described on the AE CRF. If the abnormal value was not deemed an AE because it 
was due to an error, due to a preexisting disease (described in Section 12.1.1.5), not 
clinically significant, a symptom of a new/worsened condition already recorded as an AE, 
or due to another issue that will be specified, the investigator will record the justification 
on the source record.
12.6.1 Thromboembolic Events
There is a risk of occurrence of thrombotic events, particularly in patients with known 
clinical or laboratory risk factors for thrombosis including low ADAMTS13 levels.  
Therefore, patients at risk must be monitored for early signs of thrombosis during the 
study and prophylaxis measures against thromboembolism should be instituted according 
to current recommendations and standard of care. Additional diagnostic procedures are 
required according to each institution’s standard of care which may consist of, but are not 
limited to the following:

For DVT: Magnetic Resonance Imaging (MRI), compression ultrasound or 
impedance plethysmography.

For pulmonary embolism: ECG, chest radiography, perfusion/scintiscan or MRI. 

For myocardial infarction: ECG, cardiac enzymes, echocardiography

For stroke: diffusion-weighted magnetic resonance imaging or computed 
tomography, ABCD scoring, carotid imaging
Results of diagnostic procedures may be forwarded to the sponsor to be reviewed by an 
independent external expert panel, such as the DMC, if applicable.
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12.6.2 Anaphylaxis
The diagnosis of anaphylaxis is highly likely when any of the following 3 criteria are 
fulfilled:
1.
Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue or both (e.g, generalized urticaria, pruritus or flushing, swollen 
lips-tongue-uvula) and at least one of the following:
a. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced peak expiratory flow [PEF], hypoxemia)
b. Reduced blood pressure (BP) or associated symptoms of end-organ 
dysfunction (e.g., hypotonia [collapse], syncope, incontinence)
2.
Two or more of the following that occur rapidly after exposure to a likely allergen 
for that patient (minutes to several hours):
a. Involvement of the skin or mucosal tissue (e.g., generalized urticaria, pruritus 
or flushing, swollen lips-tongue-uvula)
b. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced PEF, hypoxemia)
c. Reduced BP or associated symptoms (hypotonia [collapse], syncope, 
incontinence)
d. Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)
3.
Reduced BP after exposure to a known allergen for that patient (minutes to 
several hours):
a. Infants and children: low systolic BP (age specific) or greater than 30% 
decrease in systolic BP
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from 
that person’s baseline BP
If a subject develops anaphylaxis in the course of the clinical study, this needs to be 
reported as SAE (Section 12.1.1.1). Additional blood will be drawn for Anti-VWF IgE 
antibody testing (Section 12.9.13).
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12.7 Vital Signs
Vital signs will be assessed pre- and post-infusion at each visit, if not stated otherwise:

Height (cm) (Screening only) and weight (kg) (pre-infusion only)

Blood pressure: Systolic/diastolic blood pressure (mmHg) baseline measurements 
will be measured after a 10-minute rest in the supine/semi-recumbent position.

Pulse rate: Pulse rate (beats/min) will be measured at the distal radial arteries 
under the same conditions as above.

Respiratory rate: Respiratory rate (breaths/min) will be measured over a period of 
1 minute under the same conditions as above.

Temperature: Body temperature (oC or oF) may be determined by oral, rectal, 
axillary, or tympanic measurement at the discretion of the investigator. However, 
the same method should be used for all measurements in 1 subject.
Vital signs (pulse rate, respiratory rate, and blood pressure) should be recorded within 
30 min before and after IP administration. The assessment of vital signs per planned 
study visit is outlined in Supplement 20.2.
Vital sign values are to be recorded on the physical examination eCRF. For each vital 
sign value, the investigator will determine whether the value is considered an AE (see 
definition in Section 12.1). If assessed as an AE, the medical diagnosis (preferably), 
symptom, or sign, will be recorded on the AE eCRF. Additional tests and other 
evaluations required to establish the significance or etiology of an abnormal result, or to 
monitor the course of an AE, should be obtained when clinically indicated. Any abnormal 
value that persists should be followed at the discretion of the investigator.
12.8 Electrocardiogram 
A standard 12-lead ECG at rest will be performed at screening, at the 6 month follow-up 
visit and at the study termination visit and evaluated for medical significance by the 
investigator.
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12.9 Clinical Laboratory Parameters
Refer to the Laboratory Manual for information on collection and processing of samples.
In general all laboratory tests will be performed at central laboratories, except the 
pregnancy and blood group test which will be performed at the local laboratory. In 
addition, relevant critical safety laboratory tests for complete blood count (CBC), serum 
chemistry and/or coagulation parameters such as VWF and FVIII activity may also be 
performed in the local laboratory to ensure that results will be available immediately to 
the investigator. In principle, results from the central laboratory will be used for data 
analysis purposes. The assays performed in the central laboratories are specified in the 
Laboratory Manual. The investigator will supply the sponsor with a list of the normal 
ranges and units of measurement for the laboratory variables to be determined at the site. 
Laboratory values such as antibodies to other proteins are not required immediately and 
will be assessed later during the course of the study. 
Any abnormal laboratory value that is considered clinically significant by the investigator 
based on a local laboratory test result (reference range and the units to be provided) 
should be confirmed by a central laboratory test result for which the sample is 
drawn/collected within 24 hours of the abnormal finding by the local laboratory.
12.9.1 rVWF Pharmacokinetics and Pharmacodynamics
Details on pharmacokinetic and pharmacodynamics assessments are provided in 
Section 11.6.
12.9.2 Hematology and Clinical Chemistry
The hematology panel will consist of CBC [hemoglobin, hematocrit, erythrocytes (ie, red 
blood cell count [RBC]; mean corpuscular volume [MCV], mean corpuscular hemoglobin 
(MCH), mean corpuscular hemoglobin concentration [MCHC]), and leukocytes (i.e., 
white blood cell count [WBC])] with differential (i.e., basophils, eosinophils, 
lymphocytes, monocytes, neutrophils) and platelet counts.
The clinical chemistry panel will consist of sodium (Na), potassium (K), chloride (Cl), 
ALT, lactate dehydrogenase (LDH), aspartate aminotransferase (AST), bilirubin, alkaline 
phosphatase (AP), blood urea nitrogen (BUN), CR, and glucose (Glu).
Blood will be obtained for assessment of hematology and clinical chemistry parameters 
at screening, during PK-assessment prior to rVWF (vonicog alfa) IP infusion, after 
24 ± 2 hours, 48 ± 2 hours and 72 ± 2 hours post rVWF (vonicog alfa) IP infusion, at all 
follow-up visits as per schedule (refer to Supplement 20.3 Clinical Laboratory 
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Assessments), i.e., 4 weeks ± 1 week, 8 weeks ± 1 week and every 3 months ± 2 weeks, 
and at study completion. Hematology and clinical chemistry assessments will be 
performed on Ethylenediaminetetraacetic acid (EDTA)-anticoagulated whole blood and 
serum, respectively, at the central laboratory.
12.9.3 Immunology
12.9.3.1 Antibodies to VWF and FVIII
All subjects will be tested for binding and neutralizing antibodies to VWF and FVIII at 
screening, at initial PK assessment, at each of the scheduled follow-up visits and at the 
study completion visit. Testing will be done prior to IP infusion and with at least a 
72 hour wash out period since the last IP infusion. If there is any suspicion of inhibitor 
development (e.g. excessive bleeding) binding and neutralizing antibodies to VWF and 
FVIII may be tested at the discretion of the investigator. 
12.9.3.2 Neutralizing and Total Binding Anti-VWF Antibodies
The assays to establish the presence of neutralizing and total binding anti-VWF 
antibodies have been established in the absence of international standards and with only 
limited numbers of positive controls. Therefore, caution is advised in interpreting positive 
results. In particular, any clinical association, changes in the natural history of the 
disease, effect of therapy, etc. needs to be taken into account for final judgment. 
The sponsor’s Medical Director should be consulted for additional advice. As part of the 
AE follow-up, any sample testing positive needs to be confirmed after 2-4 weeks for 
central laboratory testing. Only confirmed neutralizing anti -VWF antibodies are 
considered inhibitors (see Section 12.9.3.4). These subjects need to be closely monitored 
and therapy adjusted accordingly. 
12.9.3.3 Binding antibodies to VWF 
The presence of total binding anti-VWF antibodies will be determined by an enzyme-
linked immunosorbent assay (ELISA) employing polyclonal anti-human Immunoglobulin
(Ig) antibodies (IgG, IgM and IgA). For this assay (ELISA), recombinant human VWF 
will be coated onto a microtiter plate, then incubated with dilutions of the positive 
control, the negative control or test sample. Antibodies against human VWF that are 
present in the samples bind to the coated antigen and will be detected with a horseradish 
peroxidase (HRP)-coupled goat anti-human antibody (secondary antibody). The positive 
control for this assay will be a human monoclonal antibody specific for human VWF 
spiked into the negative control. The negative control for this assay is pooled normal 
human plasma.
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Plasma samples are analyzed for binding antibodies against the specific antigen in two 
steps. First, the sample is screened for antibodies and the titer of binding antibodies is 
determined. Second, the specificity of positive antibody results is confirmed.16
In brief, all samples are serially diluted (initial dilution 1:20 and further diluted 1:2).
The titer endpoint, defined as the highest dilution that still gives a positive signal above 
cut off level, is determined in two independent duplicates. The cut off level is established 
based on background signal level of healthy plasma donors (n=160) and set to include 5% 
false positives to be as sensitive as possible (95% percentile). The ELISA assay is 
validated allowing an assay variability of ± 1 titer step. Therefore, differences ≤ 2 titers 
steps may be due to variability of the ELISA assay. Specificity has to be confirmed in a 
competition assay when a sample has a titer of 1:80 or higher in the screening assay. 
Based on the validation criteria samples tested in the screening assay at 1:20 or 1:40 
cannot be confirmed in the competition assay. A positive screening value is confirmed if 
the difference between the titers determined for the subject sample (re-screen) and for the 
subject sample with pre-incubation (confirmation sample) is > 2 titer steps. Antibody 
titers of subject samples will only be reported as positive, if the results of the screening 
and confirmatory analysis fulfill these acceptance criteria. The titer to be reported is 
always the one determined in the original screening procedure (independent of the result 
of the re-screening in the confirmation procedure). 
A more detailed test procedure will be supplied upon request or pro-actively if a sample 
tests positive. A treatment related increase of the binding anti-VWF antibodies is 
expected, if the titer increases by more than 2 titration steps. These subjects need to be 
closely monitored and therapy adjusted accordingly.
12.9.3.4 Neutralizing Antibodies to VWF
Three functional VWF assays, VWF:CB, VWF:RCo and VWF:FVIIIB assays, will be 
used to test for the presence of neutralizing anti-VWF antibodies. Neutralizing antibodies 
to VWF:RCo, VWF:CB and VWF:FVIIIB activities will be measured by assays based on 
the Bethesda assay established for quantitative analysis of FVIII inhibitors (Nijmegen 
modification of the Bethesda assay).17 The amount of inhibitor is expressed as BU per 
mL. One BU is thereby defined as the amount of inhibitor that decreases the measured 
activity in the assays to 50% of that of the negative control samples. The assays were 
validated using human plasma samples from two type 3 VWD patients with low 
(1-2 BU/mL) and high (~10 BU/mL) titer inhibitors and plasma samples from 
non-human primates immunized with human rVWF (vonicog alfa) (>100 BU/mL).
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If a subject has a measurable baseline level of VWF activity in the respective assay, it is 
taken into account in the calculation of the residual activity. However, if baseline levels 
are too high (>15% VWF:RCo), inhibitors may not be reliably detected.
To exclude false positive results, the detection limit for anti-VWF inhibitors was set to 
1 BU/ml for all 3 assays. The rationale for this cut-off value is the relatively high CI of 
the underlying assays, making determinations at the end of the evaluation range of the 
Bethesda reference curve uncertain.18 A more detailed test procedure may be requested to 
further characterize the anti-VWF inhibitors, if detected.
Only confirmed positive anti-VWF inhibitor test result will be reported and will be
considered as a medically significant SAE.
12.9.3.5 Binding Antibodies to FVIII
Binding antibodies against FVIII will be analyzed using a proprietary enzyme 
immunoassay. The testing strategy will be as described for binding anti-VWF antibodies. 
Antibody-containing samples will be identified in a screening assay followed by a 
confirmatory assay to exclude false positive results.
12.9.3.6 Neutralizing Antibodies (Inhibitors) to FVIII 
Neutralizing antibodies (inhibitors) to FVIII will be assessed by the Nijmegen 
modification of the Bethesda assay in a central laboratory. To verify a FVIII inhibitor, 
additional testing (such as tests for Lupus anticoagulants) may be initiated. Positive FVIII 
inhibitor tests will be defined as ≥0.4 BU by the Nijmegen-modified Bethesda assay that 
is confirmed by a second test performed on an independent sample obtained 2-4 weeks 
following the first test. Only confirmed positive FVIII inhibitor test result will be 
reported.
12.9.4 Antibodies to Other Proteins
Plasma will be assayed for the presence of antibodies against CHO protein (total Ig), 
murine IgG and human Furin (total Ig) using proprietary enzyme immunoassays. The 
testing strategy will be as described for binding anti- VWF antibodies. 
Antibody-containing samples will be identified in a screening assay followed by a 
confirmatory assay to exclude false positive results.
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12.9.4.1 Anti-CHO Protein
Total Ig antibodies (IgG, IgA, IgM) against CHO protein will be analyzed. For this assay 
(ELISA), CHO protein derived from cultures of untransfected cells and propagated under 
the identical cell culture conditions used for ADVATE (rFVIII, octocog alfa) production 
will be coated onto a microtiter plate, then incubated with dilutions of the positive 
control, negative control or test sample. Antibodies against CHO protein that are present 
in the samples bind to the coated antigen and will be detected with a HRP-coupled goat 
anti-human antibody (secondary antibody). The positive control for this assay will be a 
polyclonal goat anti-CHO protein antibody spiked into the negative control. The negative 
control for this assay is pooled normal human plasma.
12.9.4.2 Anti-Murine IgG
A commercially available ELISA (Medac, Hamburg, Germany) will be used to detect and 
to quantify IgG antibodies originating from human plasma that are directed against 
mouse-IgG (HAMA: human anti- mouse antibodies). Microtiter plates coated with 
mouse IgG will be incubated with dilutions of the standard, the positive control, the 
negative control or the test sample. Antibodies against mouse IgG that are present in 
the samples bind to the coated antigen and form a bridge to a peroxidase coupled mouse 
IgG antibody that will be used for detection (bridging format of the ELISA assay). 
The positive control for this assay will be a polyclonal goat anti-murine IgG spiked into 
the negative control. The negative control for this assay is pooled normal human plasma.
12.9.4.3 Antibodies to Human Furin
Total Ig antibodies (IgG, IgA, IgM) against human Furin will be analyzed. For this assay 
(ELISA), recombinant human Furin will be coated onto a microtiter plate, then incubated 
with dilutions of the positive control, the negative control or test sample. Antibodies 
against human Furin that are present in the samples bind to the coated antigen and will be 
detected with a HRP-coupled goat anti-human antibody (secondary antibody). The 
positive control for this assay will be a human monoclonal antibody specific for human 
Furin spiked into the negative control. The negative control for this assay is pooled 
normal human plasma.
12.9.5 Viral Serology
The following viral seromarkers will be assessed at screening:

HIV: anti-HIV 1, HIV 2 

HAV: anti-HAV (IgG and immunoglobulin M [IgM])

HBV: Hepatitis B surface antigen (HbsAg), anti-Hepatitis B (HB) core, anti-HBs
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
HCV: anti-HCV ELISA

Parvovirus B19: anti-B19V (IgG and IgM)
Virus serology will be established during the screening period. The relevant confirmatory 
Polymerase Chain Reaction (PCR) testing may be performed from appropriate left-over 
samples as needed. 
12.9.6 Urinalysis (Dipstick)
The urinalysis will include assessments for erythrocytes, specific gravity, urobilinogen, 
ketones, glucose, protein, bilirubin, nitrite and pH and will be performed at the central 
laboratory.
12.9.7 Pregnancy Test
A pregnancy test for females of child-bearing potential will be performed at the local 
laboratory primarily from urine. If no urine sample is available, the pregnancy testing will 
be done from serum. The pregnancy test may need to be repeated during the course of 
study in countries where mandated by national law.
12.9.8 VWD Mutational Analysis, Multimer Analysis and Human Leukocyte 
Antigen Genotyping 
A cell pellet (buffy coat and erythrocytes) will be retained at the screening visit for VWD 
gene mutational analysis, VWF multimer analysis and HLA genotype determination if the 
information is not already available in the subject’s medical history. Results from 
multimer analysis (see Section 12.9.10.1) may contribute to VWD gene mutational 
analysis. The genetic testing will be done, when the subject consents to the genetic 
testing.
12.9.9 Blood Group Analysis
The blood group needs to be determined during the screening period. If the information is 
not already available in the subject’s medical history, it has to be determined at the local 
lab.
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12.9.10 Additional Laboratory Testing in Case of Thromboembolic Events 
rVWF (vonicog alfa) contains ULMW multimers because of a lack of exposure to 
endogenous VWF protease (a disintegrin and metalloproteinase with a thrombospondin 
type 1 motif, member 13 (ADAMTS13) during the manufacturing process. In vitro and in 
vivo cleavage of these ultralarge molecular fractions by ADAMTS13 and generation of 
characteristic satellite bands has been extensively demonstrated during nonclinical and 
clinical development. Nevertheless, the potential elevated risk of thrombosis and/or other 
thromboembolic complications due to the administration of ultra large molecular VWF 
multimers in subjects with normal levels of VWF cannot be completely excluded. 
Therefore VWF multimer analysis will not only be performed routinely at screening but 
in case of thromboembolic events, both VWF multimer analysis as well as ADAMTS13 
activity will be determined to assess any relatedness of these occurrences with IP 
treatment. 
12.9.10.1 VWF Multimer Analysis 
The VWF multimer pattern will be assessed using low-resolution sodium dodecyl sulfate 
(SDS)–agarose gel electrophoresis. High-resolution SDS–agarose gel electrophoresis, 
with agarose concentrations 1.5%, will be used to determine the satellite band structure 
of VWF. These analyses will employ Western blot with luminescence video imaging.
12.9.10.2 ADAMTS13 Activity 
VWF73 was identified as the 73 amino acid minimal region of the VWF A2 domain 
required for ADAMTS13 cleavage. The cleavage of this substrate will be detected by a 
commercially available ELISA-based Chromogenic assay (Technoclone Austria):
Cleavage of immobilized VWF73 substrate is detected by a HRP-labeled antibody 
directed against the cleavage site of VWF73. The amount of bound antibody, which is the 
function of the ADAMTS13 cleavage is detected by a chromogenic substrate.
12.9.11 Soluble P-Selectin (sP-Selectin)
sP-selectin is a cell adhesion molecule (CAM) found in granules in endothelial cells 
(cells lining blood vessels) and activated platelets. Data for an association between the 
sP-selectin concentration, TTP and venous thromboembolism (VTE) are limited and the 
predictive value has not yet established. A commercial ELISA assay will be employed as 
an exploratory test. sP-selectin will be determined at the Screening visit and used as 
indicator for an increased thrombotic risk.
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12.9.12 D-Dimer
D-dimer will be used as a marker for DVT and disseminated intravascular coagulation
(DIC). While a negative result practically rules out thrombosis, a positive result can 
indicate thrombosis but does not rule out other potential etiologies, including a recent 
hemorrhage. Its main use, therefore, is to exclude thromboembolic disease where the 
probability is low. D-Dimer will be measured at the Screening visit and used as indicator 
for an increased thrombotic risk.
12.9.13 Additional Laboratory Testing in Case of Severe Hypersensitivity Reactions 
If a subject develops a severe hypersensitivity reaction in the course of the clinical 
study, additional blood will be drawn for anti-VWF IgE antibody testing. The presence of 
anti-VWF IgE will be determined by using the ImmunoCAP®, a VWF-specific IgE 
blood test (Thermo Scientific). The basis of the ImmunoCAP® technology is a cellulose 
polymer as solid phase in a plastic capsule providing a large surface for protein binding. 
rVWF (vonicog alfa) as antigen is covalently coupled to the cellulose polymer. 
Detection of specific anti-VWF IgE bound to the antigen will be accomplished by a 
secondary enzyme-labeled anti-human IgE antibody. Testing for binding anti-human 
VWF IgE antibodies will be done with 0.5 mL plasma. Antibody containing samples will 
be identified and quantified in a screening assay followed by a confirmatory assay to 
exclude false positive results.
12.9.14 Assessment of Laboratory Values
12.9.14.1 Assessment of Abnormal Laboratory Values 
For VWF and FVIII laboratory assessments no evaluation of clinical significance is 
necessary.
Each other laboratory value (except results to determine genetics of the underlying VWD 
disease and blood group) has to be assessed by the investigator and the assessment will be 
recorded on the eCRF. The investigator will determine for each abnormal laboratory 
value whether the value is considered clinically significant or not and provide the 
reference range including the units. For clinically significant values, the investigator will 
indicate if the value constitutes a new AE (see definition in Section 12.1) and record the 
sign, symptom, or medical diagnosis on the AE CRF, is a symptom or related to a 
previously recorded AE, is due to a pre-existing disease (described in Section 12.1.1.5), 
or is due to another issue that will be specified. If the abnormal value was not clinically 
significant, the investigator will indicate the reason, i.e. because it is due to a preexisting 
disease, due to a lab error, due to variation or due to another issue that will be specified. 
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Additional tests and other evaluations required to establish the significance or etiology of 
an abnormal value, or to monitor the course of an AE should be obtained when clinically 
indicated. Any abnormal value that persists should be followed at the discretion of the 
investigator. Any abnormal laboratory value that is considered clinically significant by 
the investigator based on a local laboratory test result (reference range and the units to be 
provided) should be confirmed by a central laboratory test result for which the sample is 
drawn/collected within 24 hours of the abnormal finding by the local laboratory.
Any seroconversion result for HIV, HAV, hepatitis B virus (HBV), HCV, HEV, or B19V 
shall be re-tested.
12.10
12.10.1
 
 
 
 
 
 
 
 
 
 
 
12.10.2
 
 
 
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13. STATISTICS
13.1 Sample Size and Power Calculations
Approximately 22 adult subjects with severe VWD (baseline VWF:RCo <20 IU/dL) will 
be included in the study. The aim is to have at least 8 subjects in each cohort (OD and 
switch). A total of at least 5 type 3 VWD subjects will be followed for 12 months. The 
sample size is driven by practical considerations (primarily the enrollment of a rare 
patient population) and EMA Guideline on the Clinical Investigation of Human Plasma 
Derived von Willebrand Factor Products (CPMP/BPWG/220/02).1
13.2 Datasets and Analysis Cohorts
13.2.1 Safety Analysis Set
The Safety Analysis Set will be composed of all subjects who received any amount of IP 
(rVWF, vonicog alpha). 
13.2.2 Full Analysis Dataset
The Full Analysis Set (FAS) will be composed of all subjects who receive prophylaxis IP 
treatment.
13.2.3 Per-Protocol Analysis Set
The Per-Protocol (PP) Analysis Set will be composed of subjects who are at least 70% 
compliant regarding the number of scheduled prophylactic infusions (as measured by the 
ratio of actual number of infusions to planned number of infusions). Only subjects who 
met all study entry criteria and who had no major protocol violations that might impact 
primary efficacy assessments will be included in the PP analysis set.
13.2.4 PK Full Analysis Set
The Pharmacokinetic Full Analysis Set (PKFAS) will be composed of all subjects who 
received the PK infusion and who provided acceptable data for PK and PD analysis. 
Acceptable PK/PD data will be defined in the Statistical Analysis Plan. 
13.2.5 PK Per Protocol Analysis Set 
The Pharmacokinetic Per Protocol Analysis Set (PKPPAS) is defined as a subset of the 
PKFAS. Subjects who met the following additional criteria will be included in the 
PKPPAS: had no major violation of affecting the PK period of the study as defined in the
detailed Statistical Analysis Plan. 
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13.3 Handling of Missing, Unused, and Spurious Data
13.3.1 General
Statistical techniques will not be used to identify and exclude any observations as outliers 
from the analyses. If data are considered spurious, e.g. for lack of biological plausibility, 
it will be documented to include the reason for exclusion and the analyses from which the 
data were excluded.
13.3.2 Other
1.
Regarding missing data in PK records:

Body weight: If a subject’s weight is missing from the PK infusion record, the 
subject’s last recorded weight will be used to calculate the weight-adjusted 
dose.

Concentration:

Baseline concentration levels reported as below the limit of quantification 
will be considered to be 0. Missing VWF baseline concentration levels 
(VWF: RCo, VWF: AG or VWF: CB) for Type 3 subjects will be set to 0.

Time:

If start time of infusion is missing (but stop time is available) and actual 
collection time is available, then stop time of infusion will be taken for 
further calculation (i.e. time difference between actual end date/time of 
infusion and date/time blood sample drawn).

If actual collection date/time is missing and planned collection date/time is 
missing, then this PK time point will be taken out from the PK analysis 
(i.e. no data entry for this time point). 

For all other scenarios, the planned collection date/time will be taken for 
further calculation.
2.
Regarding missing data in AE records:

Handling of unknown causality assessment:

If a subject experiences an AE with a missing causality assessment, the 
relationship of the AE will be counted as “related.”
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
Handling of unknown severity grades:

If a subject experiences more than one AE categorized under the same 
preferred term, one of them is categorized as “severe” and one of them is 
categorized as “unknown”, then the maximum severity for this preferred 
term should be counted as “severe” for this subject.

If a subject experiences more than one AE categorized under the same 
preferred term, one of them is categorized as “mild” or “moderate” and 
one of them is categorized as “unknown”, then the maximum severity for 
this preferred term should be counted as “unknown” for this subject.
13.4 Methods of Analysis
The study success criteria are the objectives as stated in Section 7. “Treatment success” 
was defined as the extent of control of bleeding episodes achieved during this study.
13.4.1 Primary Outcome Measure
The primary outcome measure is ABR for spontaneous (not related to trauma) bleeding 
episodes during prophylactic treatment with rVWF (vonicog alfa). No formal statistical 
hypothesis test is planned for the analysis. The primary efficacy analysis will be based on 
the FAS and will be summarized by the two cohorts: on-demand and switch subjects. As 
a supportive analysis, the same analysis will also be carried out on the PP analysis set.
The spontaneous ABR while treated with rVWF (vonicog alfa) for each cohort will be 
estimated using a negative binomial regression. The prior ABR will be based on 
historical data collected from each enrolled subject. 
The two ABRs (prior to prophylaxis treatment and while on prophylaxis) for each cohort 
will be compared within each subject using a generalized linear mixed-effects model 
(GLMM)  (with a logarithmic link function, the default for the negative binomial 
distribution), accounting for the fixed effect of the two treatments. The follow-up time 
(in years) will be specified as an offset. The ratio of ABR while in the study to historical 
ABR  will be estimated and reported together with the 95% confidence interval for each 
of the two cohorts.
The difference in on-study ABR relative to historical ABR will be also summarized 
descriptively.
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13.4.2 Secondary Outcome Measures 
In general, data for  secondary efficacy analysis will be summarized by the two cohorts: 
on-demand and switch subjects and when applicable overall.  Mean, standard deviation, 
median, range, quartiles will be calculated for continuous endpoints.  Proportions, will be 
calculated for categorical endpoints. Confidence intervals at the two-sided 95% level will 
be provided when appropriate.
13.4.2.1 Additional Efficacy of Prophylaxis Treatment with rVWF 
The number  and proportion of on-demand subjects with ABR percent reduction success 
(i.e.≥ 25%) will be calculated together with a two-sided, 95% CI for the proportion.
The number  and proportion of pdVWF switch subjects ABR preservation success will be 
reported together with the corresponding 95% two-sided CIs for the proportion.
The number and proportion of subjects with categorized spontaneous ABR 
(i.e. 0, 1-2, 3-5, more than 5 bleeds) will be reported descriptively.
Summary statistics for the total number of infusions, as well as average number of 
infusions per week will be provided. The total weight adjusted consumption of rVWF 
(vonicog alfa) during prophylactic treatment will be provided. If applicable, historical 
data on consumption of pdVWF prior to the study will be summarized as well.
The change in spontaneous ABR from the historical rate to that during the rVWF 
(vonicog alfa) prophylaxis period will be summarized by location of bleeding 
(GI, epistaxis, joint bleeding, menorrhagia, oral and other mucosa, muscle and soft 
tissue, etc.).
13.4.2.2 Pharmacokinetic and Pharmacodynamic Analysis
All PK and PD analyses will use the actual sampling times, not nominal times specified 
in the protocol, wherever possible. Actual sampling times will be defined as time from 
the start of infusion to the blood sample collection time. A deviation from the protocol-
specified blood sample drawing time window will not be a reason to exclude an 
observation from the analysis. Samples with unknown actual and planned collection 
date/time or where the concentration could not be determined, or where results were 
biologically implausible will be eliminated from the analysis.
If any concentration data are considered spurious (e.g. lack of biological plausibility), the 
reason for exclusion from the analysis and the analysis from which the data point was 
excluded will be documented.
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Details of calculation of PK and PD parameters and corresponding analysis will be given 
in the statistical analysis plan. 
The following PK parameters, based on the initial PK assessment after a washout for on-
demand subjects, will be listed and summarized descriptively for VWF:RCo, VWF:Ag 
and VWF:CB: IR, T1/2, MRT, AUC0-, AUC0-tlast, Cmax, Tmax, Vss, and CL. The 
corresponding pharmacodynamics (PD) of rVWF (vonicog alfa) as measured in FVIII 
activity, based on the initial PK assessment after a washout for on-demand subjects will 
be assessed using Cmax, Tmax, and AUC0-tlast. These PD parameters will be listed and 
summarized descriptively. PK parameters at steady state (AUC0-tau;ss, Cmax;ss, Tmax;ss, and 
Cmin;ss) for the partial dosing interval will be listed for on-demand subjects at the end of 
the study and for switch subjects shortly after reaching steady state and at the end of the 
study for VWF:RCo, VWF:Ag and VWF:CB and summarized descriptively for subjects 
with the same dosing regimens. The corresponding pharmacodynamics (PD) of rVWF 
(vonicog alfa) as measured in FVIII activity will be assessed using AUC0-tau;ss, Cmax;ss, 
Tmax;ss, and Cmin;ss. These PD parameters will be listed for on-demand subjects at the end 
of the study and for switch subjects shortly after reaching steady state and at the end of 
the study and will be summarized descriptively for subjects with the same dosing 
regimens.
For the on-demand subjects, the PK of VWF:RCo will be analyzed using a population PK 
approach to characterize the single and multiple dose pharmacokinetics, including 
associated variability assessed at after washout and at end of study, respectively. The 
population PK analysis will be performed in a stepwise manner as outlined below.
1.
Exploratory graphical analysis of VWF:RCo versus time data for identification of 
potential outliers and to inform the pharmacometric analysis.
2.
Population PK model development for rVWF (vonicog alfa):
a.
Evaluate alternative structural and stochastic models to describe the typical 
and individual rVWF (vonicog alfa) profiles.
b.
Investigate and characterize the potential for a time dependency in CL of 
rVWF (vonicog alfa). 
c.
Evaluate, and if necessary refine, the candidate final model
Details of this Population PK analysis will be given in a separate Population PK analysis 
plan.
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For the switch subjects, differences in AUC0-tau;ss, Cmax;ss, and Cmin;ss assessess shortly 
after reaching steady state and assessed at the end of the study will be assessed by the 
ratio of geometric means and corresponding two-sided 95% confidence intervals for 
VWF:RCo, VWF:Ag,VWF:CB, and FVIII:C. These analyses will be performed using a 
linear mixed effects model with PK assessment (i.e. factor of two levels relating to the 
PK assessment shortly after reaching steady state and the PK assessment at end of study, 
respectively) as a fixed effect and subject as a random effect based on log-transformed 
PK parameters. The difference in Tmax;ss, between first and second pharmacokinetic 
assessment will be summarized by the median and range (minimum to maximum) for 
VWF:RCo, VWF:Ag,VWF:CB, and FVIII:C.
Descriptive statistics will be used to summarize VWF:RCo, VWF:AG and VWF:CB and 
FVIII:C levels for each nominal time point on the PK curve.
For all subjects in the PKFAS activity/concentration vs. time curves will be prepared.
Formulas for PK parameters IR, T1/2, MRT, AUC0-, AUC0-tlast, Cmax, Tmax, Vss, and CL, 
AUC0-tau;ss, Cmax;ss, Tmax;ss ,and Cmin;ss will be given in the statistical analysis plan and will 
be derived using non-compartmental methods in WinNonlin. Analysis of these 
parameters will be carried out on the PKFAS as well as on the PKPPAS.
13.4.2.3 Safety
Safety analysis will be performed overall and by the two cohorts: on-demand and switch 
subjects.
TEAEs are defined as AEs with start dates on or after the first exposure to IP. Summaries 
of AEs will be based on TEAEs unless otherwise indicated.
Occurrence of AEs and SAEs will be summarized descriptively, by system organ class 
and preferred term. The number and percentage of subjects who experienced AEs and 
SAEs, and the number of AEs and SAEs will be tabulated. In addition, the number of 
subjects who experienced AEs assessed as related to IP by the investigator, and the
number of IP-related AEs will be tabulated. The number of patients with AEs by severity 
will be presented similarly.
A listing of all AEs will be presented by subject identifier, age, sex, preferred term and 
reported term of the AE, duration, severity, seriousness, action taken, outcome, causality 
assessment by investigator, onset date, stop date and medication or non-drug therapy to 
treat the AE.
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Temporally associated AEs are defined as AEs that begin during infusion or within 
24 hours (or 1 day where time of onset is not available) after completion of infusion, 
irrespective of being related or not related to treatment. Temporally associated AEs will 
be presented in summary tables. 
AEs that occurred before first IP infusion will be listed separately.
Adverse events of special interest (AESI), such as hypersensitivity reactions and 
thromboembolic events,  will be monitored throughout the study and statistical analysis 
will be conducted based on the search criteria (eg, standardised MedDRA queries [SMQ])
determined prior to database lock, and summarized.
For immunogenicity, frequency counts and percentages will be calculated for the 
occurrence of neutralizing (inhibitory) antibodies to VWF and FVIII, occurrence of 
binding antibodies to VWF and FVIII, and occurrence of binding antibodies to CHO 
proteins, mouse immunoglobulin G (IgG) and rFurin. Clinically significant changes 
relative to baseline in vital signs and clinical laboratory parameters (hematology, clinical 
chemistry) will be reported.
13.4.3 Exploratory Outcome Measures
 
13.4.3.1
 
 
 
 
 
13.4.3.2
 
 
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13.4.3.3
 
 
 
13.4.3.4
 
 
 
 
 
13.5 Planned Interim Analysis of the Study
No formal interim analysis is planned for this study. 
14. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
The investigator/study site will cooperate and provide direct access to study documents 
and data, including source documentation for monitoring by the study monitor, audits by 
the sponsor or sponsor’s representatives, review by the EC, and inspections by applicable 
regulatory authorities, as described in the Clinical Trial Agreement (CTA). If contacted 
by an applicable regulatory authority, the investigator will notify the sponsor of contact, 
cooperate with the authority, provide the sponsor with copies of all documents received 
from the authority, and allow the sponsor to comment on any responses, as described in 
the CTA.
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15. QUALITY CONTROL AND QUALITY ASSURANCE
15.1 Investigator’s Responsibility
The investigator will comply with the protocol (which has been approved/given favorable 
opinion by the EC), ICH GCP, and applicable national and local regulatory requirements 
as described in the CTA. The investigator is ultimately responsible for the conduct of all 
aspects of the study at the study site and verifies by signature the integrity of all data 
transmitted to the sponsor. The term “investigator” as used in this protocol as well as in 
other study documents, refers to the investigator or authorized study personnel that the 
investigator has designated to perform certain duties. Sub-investigators or other 
authorized study personnel are eligible to sign for the investigator, except where the 
investigator’s signature is specifically required.
15.1.1 Investigator Report and Final Clinical Study Report 
The investigator, or coordinating investigator(s) for multicenter studies, will sign the 
clinical study report. The coordinating investigator will be selected before study start. 
15.2 Training
The study monitor will ensure that the investigator and study site personnel understand all 
requirements of the protocol, the investigational status of the IP, and his/her regulatory 
responsibilities as an investigator. Training may be provided at an investigator’s meeting, 
at the study site, and/or by instruction manuals. In addition, the study monitor will be 
available for consultation with the investigator and will serve as the liaison between the 
study site and the sponsor.
15.3 Monitoring
The study monitor is responsible for ensuring and verifying that each study site conducts 
the study according to the protocol, standard operating procedures other written 
instructions/agreements, ICH GCP, and applicable national and local regulatory 
guidelines/requirements. The investigator will permit the study monitor to visit the study 
site at appropriate intervals, as described in the CTA. Monitoring processes specific to the 
study will be described in the clinical monitoring plan. 
15.4 Auditing
The sponsor and/or sponsor’s representatives may conduct audits to evaluate study 
conduct and compliance with the protocol, standard operating procedures, other written 
instructions/agreements, ICH GCP, and applicable national and local regulatory 
guidelines/requirements. The investigator will permit auditors to visit the study site, as 
described in the CTA. Auditing processes specific to the study will be described in the 
audit plan.
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15.5 Non-Compliance with the Protocol
The investigator may deviate from the protocol only to eliminate an apparent immediate 
hazard to the subject. In the event(s) of an apparent immediate hazard to the subject, the 
investigator will notify the sponsor immediately by phone and confirm notification to the 
sponsor in writing as soon as possible, but within 1 calendar day after the change is 
implemented. Also, the investigator will notify the sponsor immediately by phone and 
confirm notification to the sponsor in writing whenever pdVWF is used instead of rVWF 
(vonicog alfa). The reason for this use must also be provided to the sponsor.The sponsor 
(Baxalta) will also ensure the responsible EC and relevant competent authority are 
notified of the urgent measures taken in such cases according to local regulations.
If monitoring and/or auditing identify serious and/or persistent non-compliance with the 
protocol, the sponsor may terminate the investigator’s participation. The sponsor will 
notify the EC and applicable regulatory authorities of any investigator termination.
15.6 Laboratory and Reader Standardization
A central laboratory/reader will be used for all clinical assessments except for pregnancy 
testing and blood group test (refer to Section 12.9). Local laboratories are requested to 
provide their laboratory specifications of the individual tests that are also being tested 
locally.
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16. ETHICS 
16.1 Subject Privacy
The investigator will comply with applicable subject privacy regulations/guidance as 
described in the CTA.
16.2 Ethics Committee and Regulatory Authorities
Before enrollment of patients into this study, the protocol, informed consent form, any 
promotional material/advertisements, and any other written information to be provided 
will be reviewed and approved/given favorable opinion by the EC and applicable 
regulatory authorities. The IB will be provided for review. The EC’s composition or a 
statement that the EC’s composition meets applicable regulatory criteria will be 
documented. The study will commence only upon the sponsor’s receipt of 
approval/favorable opinion from the EC and, if required, upon the sponsor’s notification 
of applicable regulatory authority(ies) approval, as described in the CTA.
If the protocol or any other information given to the subject is amended, the revised 
documents will be reviewed and approved/given favorable opinion by the EC and 
applicable regulatory authorities, where applicable. The protocol amendment will only be 
implemented upon the sponsor’s receipt of approval and, if required, upon the sponsor’s 
notification of applicable regulatory authority(ies) approval.
16.3 Informed Consent
Investigators will choose patients for enrollment considering the study eligibility criteria. 
The investigator will exercise no selectivity so that no bias is introduced from this source. 
All patients and/or their legally authorized representative must sign an informed consent 
form before entering into the study according to applicable national and local regulatory 
requirements and ICH GCP. Before use, the informed consent form will be reviewed by 
the sponsor and approved by the EC and regulatory authority(ies), where applicable, (see 
Section 16.2). The informed consent form will include a comprehensive explanation of 
the proposed treatment without any exculpatory statements, in accordance with the 
elements required by ICH GCP and applicable national and local regulatory 
requirements. Patients or their legally-authorized representative(s) will be allowed 
sufficient time to consider participation in the study. By signing the informed consent 
form, patients or their legally authorized representative(s) agree that they will complete 
all evaluations required by the study, unless they withdraw voluntarily or are terminated 
from the study for any reason.
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The sponsor will provide to the investigator in written form any new information that 
significantly bears on the subjects’ risks associated with IP exposure. The informed 
consent will be updated, if necessary. This new information and/or revised informed 
consent form, which have been approved by the applicable EC and regulatory authorities, 
will be provided by the investigator to the subjects who consented to participate in the 
study 
16.4 Data Monitoring Committee
This study will be monitored by a DMC. The DMC is a group of individuals with 
pertinent expertise that reviews on a regular basis accumulating data from an ongoing 
clinical study. For this study, the DMC will be composed of recognized experts in the 
field of VWD clinical care and research who are not actively recruiting subjects, and an 
independent statistician. The DMC can stop a trial if it finds toxicities or if treatment is 
proven to be not beneficial. Details will be defined in the DMC charter.
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17. DATA HANDLING AND RECORD KEEPING
17.1 Confidentiality Policy
The investigator will comply with the confidentiality policy as described in the CTA.
17.2 Study Documentation and Case Report Forms
The investigator will maintain complete and accurate paper format study documentation 
in a separate file. Study documentation may include information defined as “source data” 
(see Section 8.7), records detailing the progress of the study for each subject, signed 
informed consent forms, correspondence with the EC and the study monitor/sponsor, 
enrollment and screening information, CRFs, SAERs, laboratory reports (if applicable), 
and data clarifications requested by the sponsor.
The investigator will comply with the procedures for data recording and reporting. Any 
corrections to paper study documentation must be performed as follows: 1) the first entry 
will be crossed out entirely, remaining legible; and 2) each correction must be dated and 
initialed by the person correcting the entry; the use of correction fluid and erasing are 
prohibited.
The investigator is responsible for the procurement of data and for the quality of data 
recorded on the CRFs. CRFs will be provided in electronic form. 
If electronic format CRFs are provided by the sponsor, only authorized study site 
personnel will record or change data on the CRFs. If data is not entered on the CRFs 
during the study visit the data will be recorded on paper and this documentation will be 
considered source documentation. Changes to a CRF will require documentation of the 
reason for each change. An identical (electronic/paper) version of the complete set of 
CRFs for each subject will remain in the investigator file at the study site in accordance 
with the data retention policy (see Section 17.3).
The handling of data by the sponsor, including data quality assurance, will comply with 
regulatory guidelines (e.g., ICH GCP) and the standard operating procedures of the 
sponsor. Data management and control processes specific to the study will be described 
in the data management plan. 
17.3 Document and Data Retention 
The investigator will retain study documentation and data (paper and electronic forms) in 
accordance with applicable regulatory requirements and the document and data retention 
policy, as described in the CTA.
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18. FINANCING AND INSURANCE
The investigator will comply with investigator financing, investigator/sponsor insurance, 
and subject compensation policies, if applicable, as described in the CTA.
19. PUBLICATION POLICY
The investigator will comply with the publication policy as described in the CTA. 
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20. SUPPLEMENTS
20.1 Study Flow Chart
Figure 1
Study Design for Baxalta Clinical Study 071301
* Study treatment period is extended by 3 months to accommodate participation in the continuation 
study for the qualified subjects and will be exercised only if the continuation study start up is 
delayed beyond the completion of subject’s 12-month visit.
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20.2 Schedule of Study Procedures and Assessments
Table 6a
Schedule of Study Procedures and Assessments for On-demand Subject
Procedures/
Assessments
Screening Visit
Baseline Visit 
(PK-assessment visit)
Prophylaxis 
Initiation Visit
Interval/Follow-Up 
Study Visits
PK Assessment at 
Study Completion
Termination 
Visit
Pre-
infusiong
Infusion
Post-
infusiong
1 month ± 
1 week
2 month ± 
1 week 
3 month ± 
2 weeks
6 month ± 
2 weeks 
9 month ± 
2 weeks
Pre-
infusiong
Infusion
Post-
infusiong
Conducted at 
the 96 hour 
postinfusion 
PK 
Assessment
12-15i month ± 2 weeks
Informed Consent a
X
Eligibility Criteria
X
Medical Historyb
X
Concomitant Medicationsc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Non-drug Therapiesc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
Bleeding Episodes and 
Treatment and Hemostatic 
Efficacy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratories 
X
X
X
Xh
X
X
X
X
X
X
X
X
Vital Signsd
X
X
X
X
X
X
X
X
X
X
X
X
ECG
X
X
X
IP Treatmente
X
X
X
X
X
X
X
X
IP Consumption / Treatment 
Compliance 
X
X
X
X
X
Subject Diary
X
X
X
X
X
X
Xf
X
X
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Continued
a) Occurs at enrollment (before screening).
b) Including documented history of on-demand treatment for the past 12 months (up to 24 months if available) and a documented history, e.g., patient charts 
and prescription information, of all bleeding episodes within the past 12 (up to 24) months. 
c) Including all medications and non- drug therapies taken in the 2 weeks prior to study entry and all the concomitant medications and non-drug therapies 
during the course of the study.
d) Vital signs: height, weight, body temperature, pulse rate, respiratory rate, and blood pressure. Height is only required at the screening visit. The time points 
for pre- and post-infusion measurements are (weight is measured pre-infusion only): within 30 minutes before infusion start and 30 ± 15 minutes post-
infusion.
e) IP treatment after the prophylactic treatment initiation visit at the site will be continued as home-treatment if the subject qualifies; a wash-out period of at 
least 72 hours is required after the last IP infusion before the follow-up visit. IP infusion will be given at the study site after the blood sample for 
immunology testing and IR determination is drawn.
f) Can be done either at the screening or the baseline visit.
g) Time points for PK blood draws: within 30 minutes pre-infusion, and at 11 time points post-infusion: 15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 
3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours and 96 ± 2 hours (the 96 hr sampling can be omitted 
if not allowed by the dosing interval).
h) If a subject did not undergo PK assessment, laboratory assessments will be performed at this visit.
i) Study treatment period is extended by 3 months to accommodate participation in the continuation study for the qualified subjects and will be exercised 
only if the continuation study start up is delayed beyond the completion of subject’s 12-month visit. In this case, 12 month ± 2 weeks visit is to be 
considered as a follow-up visit, and EOS visit is to be performed once the subject can rollover into the continuation study, from 12 month ± 2 weeks to 
15 month ± 2 weeks post prophylaxis initiation visit, as applicable.
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Table 6b
Schedule of Study Procedures and Assessments for pdVWF Switch Subject
Procedures/
Assessments
Screening Visit
Prophylaxis Initiation 
Visit
PK Assessment
(at prophylaxis dose #5-6)
Interval/Follow-Up 
Study Visits
PK Assessment at 
Study Completion
Termination 
Visit
Pre-infusiong
Infusion
Post-infusiong
1 month ± 
1 week
2 month ± 
1 week 
3 month ± 
2 weeks
6 month ± 
2 weeks 
9 month ± 
2 weeks
Pre-
infusiong
Infusion
Post-
infusiong
Conducted at 
the 96 hour 
postinfusion 
PK Assessment
12-15h month
± 2 weeks
Informed Consent a
X
Eligibility Criteria
X
Medical Historyb
X
Concomitant Medicationsc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Non-drug Therapiesc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
Bleeding Episodes and 
Treatment and Hemostatic 
Efficacy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratories 
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signsd
X
X
X
X
X
X
X
X
X
X
X
X
ECG
X
X
X
IP Treatmente
X
X
X
X
X
X
X
X
IP Consumption / Treatment 
Compliance 
X
X
X
X
X
Subject Diary
X
X
X
X
X
X
Xf
X
X
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Continued
a) Occurs at enrollment (before screening).
b) Including documented history of prophylaxis treatment for the past 12 months (up to 24 months if available) and a documented history, e.g., patient charts 
and prescription information, of all bleeding episodes within the past 12 (up to 24) months. 
c) Including all medications and non- drug therapies taken in the 2 weeks prior to study entry and all the concomitant medications and non-drug therapies 
during the course of the study.
d) Vital signs: height, weight, body temperature, pulse rate, respiratory rate, and blood pressure. Height is only required at the screening visit. The time 
points for pre- and post-infusion measurements are (weight is measured pre-infusion only): within 30 minutes before infusion start and 30 ± 15 minutes 
post-infusion.
e) IP treatment after the prophylactic treatment initiation visit at the site will be continued as home-treatment if the subject qualifies; a wash-out period of at 
least 72 hours is required after the last IP infusion before the follow-up visit. IP infusion will be given at the study site after the blood sample for 
immunology testing and IR determination is drawn.
f) Can be done either at the screening or the prophylaxis initiation visit.
g) Time points for PK blood draws: within 30 minutes pre-infusion, and at 11 time points post infusion: 15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 
3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours and 96 ± 2 hours ( the 96 hr sampling can be 
omitted if not allowed by the dosing interval).
h) Study treatment period is extended by 3 months to accommodate participation in the continuation study for the qualified subjects and will be exercised 
only if the continuation study start up is delayed beyond the completion of subject’s 12-month visit. In this case, 12 month ± 2 weeks visit is to be 
considered as a follow-up visit, and EOS visit is to be performed once the subject can rollover into the continuation study, from 12 month ± 2 weeks to 
15 month ± 2 weeks post prophylaxis initiation visit, as applicable.
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20.2.1 Summary Schedule of Visit Assesments for Surgical Bleeding
Table 7
Summary Schedule of Visit Assesments for Surgical Bleeding
Procedures/
Assessments
Surgical procedure
Post-Operative 
Day 7 Visit
(± 1 day)
Post-Operative 
Day 14 Visit
(± 2 day)
Priming Dose 
Procedures 
(12-24 hours prior 
to surgery)
Loading Dose 
Procedures 
(≤3 hours prior
to surgery)
Intraoperative
Postoperative 
(day 1 → end of 
perioperative IP 
treatment)a
ECG
X
Physical examinationb
X
X
X
X
X
Adverse events
X
X
X
X
X
X
Laboratoriesc
X
X
X
X
X
X
Vital signsd
X
X
X
X
X
X
IP treatment: rVWF (vonicog 
alfa):ADVATE (rFVIII, octocog 
alfa) or rVWF (vonicog alfa) only 
infusion
X
X
X
as required
X
as required
X
as required
X
as required
Concomitant medications and non-
drug therapy
X
X
X
X
X
X
X
Hemostatic efficacy assessmentse
X
X
X
X
Blood loss
X
estimated
X
actual
X
Xf
Xf
Treatment days estimate
X
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Continued 
a) The assessments will be performed daily until perioperative IP treatment end (potentially multi-visits)
b) Physical Examination: within 2 hours prior to IP infusion start
c) For laboratory assessments, see Table 9
d) Vital signs: within 30 minutes before infusion start and 30 ± 15 minutes post-infusion
e) Completed immediately postsurgery by the operating surgeon 24 hours post last IP infusion or at Day 14 visit (whichever occurs first) by the investigator
f) In case bleeding still ongoing
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20.3 Clinical Laboratory Assessments
Table 8a
Clinical Laboratory Assessments for On-demand Subject
Procedures/
Assessments
Screening Visit
Baseline Visit 
(PK-assessment visit)
Prophylaxis Initiation 
Visitk
Interval/Follow-Up 
Study Visits
PK Assessmentm at 
Study Completion
Termination 
Visit
Pre-infusion
Infusion
Post-infusion
1 month ± 
1 week
2 month ± 
1 week 
3 month ± 
2 weeks
6 month ± 
2 weeks 
9 month ± 
2 weeks
Pre-
infusion
Infusion
Post-
infusion
Conducted 
at the 
96 hour 
postinfusion 
PK 
Assessment
12-15n month± 
2 weeks
Hematology a
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Chemistryb
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation Panel/ PK 
assessmentc
X
X
X
X
X
X
X
X
X
X
X
Immunogenicityd
X
X
Xl
X
X
X
X
X
X
X
Viral Serologye
X
Urinalysisf
X
VWD Gene Mutational 
Analysis / HLA genotype 
analysis and Analysis of 
VWF multimersg
X
sP-selectin and D-dimer
Xh
Blood Groupi 
X
Pregnancy Testj
X
a) Hematology assessments include: complete blood count [hemoglobin, hematocrit, erythrocytes (i.e. red blood cell count), mean corpuscular volume 
(MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), leukocytes (i.e. white blood cell count)] with 
differential (i.e. basophils, eosinophils, lymphocytes, monocytes, neutrophils) and platelet counts. Hematology assessments during PK assessments will be 
determined prior to IP infusion and 24 ± 2 hours, 48 ± 2 hours and 72 ± 2 hours thereafter. For other IP-associated visits, samplings are within 60 minutes 
pre-infusion.
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Continued
b) Clinical chemistry assessments include: Sodium, potassium, chloride, glucose, creatinine, blood urea nitrogen (BUN), aspartate aminotransferase (AST), 
alanine aminotransferase (ALT) lactate dehydrogenase (LDH), alkaline phosphatase (AP), bilirubin. Clinical chemistry will be determined prior to IP 
infusion and after 24 ± 2 h, 48 ± 2 hours and 72 ± 2 hours during the PK assessments. For other IP-associated visits, samplings are within 60 minutes pre-
infusion.
c) Coagulation panel/PK assessment (also refers to IR pre/post dose assessments at prophy initiation visit and each follow-up visit): PT, INR and aPTT (only 
for screening), VWF:RCo, VWF:Ag, VWF:CB, FVIII:C,; during the PK assessment at the baseline visit blood samples will be drawn 30 min prior PK 
infusion; once the PK infusion is completed 15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 
30 ± 2 hours, 48 2 hours, 72 2 hours and 96 ± 2 hours and VWF:RCo, VWF:CB, VWF:Ag, FVIII:C will be determined; for follow-up visits, IR 
samples will be drawn within 30 minutes pre-infusion and 30 5 minutes post-infusion. During screening and in case of thromboembolic event VWF 
multimers and ADAMTS13 will be analyzed to judge on a possibly relatedness to UHMW fractions of the IP.
d) Immunogenicity assessment includes Neutralizing Antibodies (Ab) to FVIII –Neutralizing Ab to VWF:RCo, Neutralizing Ab to VWF:CB, Neutralizing 
Ab to VWF:FVIII, Binding Ab to VWF and FVIII, Binding Ab to CHO-Protein, Binding Ab to rFurin, Binding Ab to Murine IgG . In case of an SAE 
hypersensitivity reaction IgE antibodies to VWF will be determined. For on-demand subjects, a washout period of at least 72 hours after the last IP 
infusion is required before blood samples for immunogenicity assessments can be drawn. 
e) Viral Serology Hepatitis A Antibody, Total - Hepatitis A Antibody, IgM - Hepatitis B Surface Antibody - Hepatitis B Core Ab, Total - Hepatitis B Surface 
Antigen - Hepatitis C Virus Antibody; Parvovirus B19; HIV-1/HIV-2 Antibodies 
f) Urinalysis comprehends: erythrocytes, specific gravity, urobilinogen, ketones, glucose, protein, bilirubin, nitrite, and pH
g) Not required if available in the subject’s medical history; VWF multimers: additionally in case of thromboembolic events
h) At screening and in case of thromboembolic events
i) Blood group assessment major blood group (local laboratory) only if not available in the subject’s medical history
j) Serum pregnancy test (in females of child-bearing potential if no urine sample is available)
k) The last post-infusion laboratory assessments coincidence with the initiation visit for prophylactic treatment. After the blood samples are drawn for 
laboratory assessment for the 96 h post infusion PK assessment, the subject receives the first IP infusion for prophylactic treatment (prophylactic treatment 
initiation visit). 
l) Only needed for subjects without PK assessment prior to their first IP infusion in this study.
m) A steady state full PK analysis will be performed at the end of the study. Blood samples will be drawn within 30 minutes pre-infusion, and at 11 time points 
post-infusion (15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 
72 2 hours and 96 ± 2 hours), the 96 hr sampling can be omitted if not allowed by the dosinig interval.
n) Study treatment period is extended by 3 months to accommodate participation in the continuation study for the qualified subjects and will be exercised only 
if the continuation study start up is delayed beyond the completion of subject’s 12-month visit. In this case, 12 month ± 2 weeks visit is to be considered as a 
follow-up visit, and EOS visit is to be performed once the subject can rollover into the continuation study, from 12 month ± 2 weeks to 15 month ± 2 weeks 
post prophylaxis initiation visit, as applicable.
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Table 8b
Clinical Laboratory Assessments for pdVWF Switch Subject
Procedures/
Assessments
Screening Visit
Prophylaxis Initiation Visit
PK Assessmentk
(at prophylaxis dose #5-6)
Interval/Follow-Up 
Study Visits
PK Assessmentk at 
Study Completion
Termination 
Visit
Pre-infusion
Infusion
Post-infusion
1 month ± 1 week
2 month ± 1 week 
3 month ± 2 weeks
6 month ± 2 weeks 
9 month ± 2 weeks
Pre-
infusion
Infusion
Post-
infusion
Conducted at 
the 96 hour 
postinfusion 
PK 
Assessment
12-15l month± 
2 weeks
Hematology a
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Chemistryb
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation Panel/PK 
assessmentc
X
X
X
X
X
X
X
X
X
X
X
Immunogenicityd
X
X
X
X
X
X
X
X
X
Viral Serologye
X
Urinalysisf
X
VWD Gene Mutational 
Analysis / HLA 
genotype analysis and 
Analysis of VWF 
multimersg
X
sP-selectin and D-dimer
Xh
Blood Groupi 
X
Pregnancy Testj
X
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Continued
a) Hematology assessments include: complete blood count [hemoglobin, hematocrit, erythrocytes (i.e. red blood cell count), mean corpuscular volume 
(MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), leukocytes (i.e. white blood cell count)] with 
differential (i.e. basophils, eosinophils, lymphocytes, monocytes, neutrophils) and platelet counts. Hematology assessments during PK assessments will be 
determined prior to IP infusion and 24 ± 2 hours, 48 ± 2 hours and 72 ± 2 hours thereafter. For other IP-associated visits, samplings are within 60 minutes 
pre-infusion.
b) Clinical chemistry assessments include: Sodium, potassium, chloride, glucose, creatinine, blood urea nitrogen (BUN), aspartate aminotransferase (AST), 
alanine aminotransferase (ALT) lactate dehydrogenase (LDH), alkaline phosphatase (AP), bilirubin. Clinical chemistry will be determined prior to IP 
infusion and after 24 ± 2 h, 48 ± 2 hours and 72 ± 2 hours during the PK assessments. For other IP-associated visits, samplings are within 60 minutes pre-
infusion.
c) Coagulation panel/PK assessment (also refers to IR pre/post dose assessments at prophy initiation visit and each follow-up visit): PT, INR and aPTT (only 
for screening), VWF:RCo, VWF:Ag, VWF:CB, FVIII:C,; during the PK assessment blood samples will be drawn 30 min prior PK infusion; once the PK 
infusion is completed 15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 
48 2 hours, 72 2 hours and 96 ± 2 hours and VWF:RCo, VWF:CB, VWF:Ag, FVIII:C will be determined; for follow-up visits, IR samples will be 
drawn within 30 minutes pre-infusion and 30 5 minutes post-infusion. During screening and in case of thromboembolic event VWF multimers and 
ADAMTS13 will be analyzed to judge on a possibly relatedness to UHMW fractions of the IP.
d) Immunogenicity assessment includes Neutralizing Antibodies (Ab) to FVIII –Neutralizing Ab to VWF:RCo, Neutralizing Ab to VWF:CB, Neutralizing 
Ab to VWF:FVIII, Binding Ab to VWF and FVIII, Binding Ab to CHO-Protein, Binding Ab to rFurin, Binding Ab to Murine IgG. In case of an SAE 
hypersensitivity reaction IgE antibodies to VWF will be determined. For switch subjects, the wash out period may be reduced to the time interval between 
their pdVWF prophy infusions.
e) Viral Serology Hepatitis A Antibody, Total - Hepatitis A Antibody, IgM - Hepatitis B Surface Antibody - Hepatitis B Core Ab, Total - Hepatitis B Surface 
Antigen - Hepatitis C Virus Antibody; Parvovirus B19; HIV-1/HIV-2 Antibodies 
f) Urinalysis comprehends: erythrocytes, specific gravity, urobilinogen, ketones, glucose, protein, bilirubin, nitrite, and pH
g) Not required if available in the subject’s medical history; VWF multimers: additionally in case of thromboembolic events
h) At screening and in case of thromboembolic events
i) Blood group assessment major blood group (local laboratory) only if not available in the subject’s medical history
j) Serum pregnancy test (in females of child-bearing potential if no urine sample is available)
k) A full steady state PK analysis will be performed. Blood samples will be drawn within 30 minutes pre-infusion, and at 11 time points post-infusion
(15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours 
and 96 ± 2 hours) , the 96 hr sampling can be omitted if not allowed by the dosinig interval.
l) Study treatment period is extended by 3 months to accommodate participation in the continuation study for the qualified subjects and will be exercised only 
if the continuation study start up is delayed beyond the completion of subject’s 12-month visit. In this case, 12 month ± 2 weeks visit is to be considered as a 
follow-up visit, and EOS visit is to be performed once the subject can rollover into the continuation study, from 12 month ± 2 weeks to 15 month ± 2 weeks 
post prophylaxis initiation visit, as applicable.
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20.3.1 Laboratory Sampling for Surgical Bleeding
Table 9
Laboratory Samplinga for Surgical Bleeding
Procedures/
Assessments
Surgical procedure
Post-Operative 
Day 7 Visit
(± 1 day)
Post-Operative 
Day 14 Visit
(± 2 day)
Priming Dose 
Procedures 
(12-24 hours prior 
to surgery)
Loading Dose 
Procedures 
(≤3 hours prior 
to surgery)
Intraoperative
Postoperative 
(day 1 → end of 
perioperative IP 
treatment)b
Hematologyc
X
(w/o Differential)
Xd
(w/o Differential)
X
(w/o Differential)
X
X
Clinical Chemistrye
X
Xd
X
X
Coagulation panelf
X
X
X
X
X
X
VWF inhibitory and binding 
antibodies, antibodies to other 
proteinsg
X
X
X
if excessive or 
unexplainedbleeding
X
X
X
Urinalysish
X
X
VWF Multimersi
Anti VWF IgE antibody testing
only in case of allergic reaction/ 
anaphylaxis
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Continued
a) Blood draws are within 3 hrs  prior to infusion start, expect that for the priming dose blood draw is within 30 minutes prior to infusion start. For 
coagulation panel, an additional 30 ± 5 minutes post-infusion blood draw is needed.
b) The assessments will be performed daily until perioperative IP treatment end (potentially multi-visits)
c) Hematology assessments include: complete blood count [hemoglobin, hematocrit, erythrocytes (i.e. red blood cell count), mean corpuscular volume 
(MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), leukocytes (i.e. white blood cell count)] with 
differential (i.e. basophils, eosinophils, lymphocytes, monocytes, neutrophils) and platelet counts. 
d) Not required if sample already drawn at the time of the priming dose
e) Clinical chemistry assessments include: Sodium, potassium, chloride, glucose, creatinine, blood urea nitrogen (BUN), aspartate aminotransferase (AST), 
alanine aminotransferase (ALT) lactate dehydrogenase (LDH), alkaline phosphatase (AP), bilirubin. 
f) Coagulation panel: VWF:RCo, VWF:Ag, FVIII:C PT INR and aPTT; in additiona to pre-infusion, 30 ± 5 minutes post infusion blood draw is needed. 
g) Immunogenicity assessment includes Neutralizing Antibodies (Ab) to FVIII – Neutralizing and Neutralizing Ab to VWF:RCo, Neutralizing Ab to 
VWF:CB, Neutralizing Ab to VWF:FVIII, Binding Ab to VWF and FVIII, Binding Ab to CHO-Protein, Binding Ab to rFurin, Binding Ab to Murine IgG. 
In case of an SAE hypersensitivity reaction IgE antibodies to VWF will be determined.
h) Urinalysis comprehends: erythrocytes, specific gravity, urobilinogen, ketones, glucose, protein, bilirubin, nitrite, and pH
i) VWD multimers and ADAMTS13 during the study only in case of thrombotic events
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20.4 Contraceptive Methods for Female Subjects of Childbearing Potential
In this study, subjects who are women of childbearing potential must agree to utilize a 
highly effective contraceptive measure throughout the course of the study and for 30 days 
after the last administration ofIP. In accordance with the Clinical Trial Facilitation Group 
(CTFG) recommendations related to contraception and pregnancy testing in clinical trials 
(version 2014-09-15)ii, birth control methods which may be considered as highly 
effective include the following:

Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation:

oral

intravaginal

transdermal

Progestogen-only hormonal contraception associated with inhibition of ovulation:

oral

injectable

implantableiii

Intrauterine device (IUD)iii

Intrauterine hormone-releasing system (IUS) iii

Bilateral tubal occlusioniii

Vasectomised partner(s)iii

Sexual abstinence during the entire study period
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhoea method (LAM) are 
not acceptable methods of contraception. Female condom and male condom should not 
be used together.
                                                
ii Clinical Trial Facilitation Group (CTFG) recommendations related to contraception and pregnancy 
testing in clinical trials: http://www.hma.eu/fileadmin/dateien/ 
Human_Medicines/01About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf.
iii Contraception methods that are considered to have low user dependency.
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21. REFERENCES
1.
Committee for Medicinal Products for Human Use. Guideline on clinical 
investigation of human plasma derived von Willebrand factor products. 
CPMP/BPWG/220/02, 12. 11-17-2005:London, European Medicines Agency 
(EMA):2005. Web Link: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/201
0/01/WC500067126.pdf
2.
Mannucci PM. Treatment of von Willebrand's Disease. N Engl J Med. 
2004;351(7):683-694.
3.
Goudemand J, Scharrer I, Berntorp E, et al. Pharmacokinetic studies on Wilfactin, a 
von Willebrand factor concentrate with a low factor VIII content treated with three 
virus-inactivations/removal methods. J Thromb Haemost. 2005;3(10):2219-2227.
4.
Abshire T. The role of prophylaxis in the management of von Willebrand disease: 
today and tomorrow. Thromb Res. 2009;124 Suppl 1:S15-S19.
5.
Nilsson IM, Blombäck M, Jorpes E, Blombäck B, Johansson SA. V. Willebrand's 
disease and its correction with human plasma fraction 1-0. Acta Med Scand. 
1957;159(3):179-188.
6.
Berntorp E, Petrini P. Long-term prophylaxis in von Willebrand disease. Blood 
Coagul Fibrinolysis. 2005;16 Suppl 1:S23-S26.
7.
Berntorp E. Prophylaxis and treatment of bleeding complications in von Willebrand 
disease type 3. Semin Thromb Hemost. 2006;32(6):621-625.
8.
Federici AB. Highly purified VWF/FVIII concentrates in the treatment and 
prophylaxis of von Willebrand disease: the PRO.WILL Study. Haemophilia. 
2007;13 Suppl 5:15-24.
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9.
Halimeh S, Krümpel A, Rott H, et al. Long-term secondary prophylaxis in children, 
adolescents and young adults with von Willebrand disease. Results of a cohort 
study. Thromb Haemost. 2011;105(4):597-604.
10.
Abshire TC, Federici AB, Alvárez MT, et al. Prophylaxis in severe forms of von 
Willebrand's disease: results from the von Willebrand Disease Prophylaxis Network 
(VWD PN). Haemophilia. 2013;19(1):76-81.
11.
Abshire T, Cox-Gill J, Kempton CL, et al. Prophylaxis escalation in severe von 
Willebrand disease: A prospective study from the von Willebrand Disease 
Prophylaxis Network. J Thromb Haemost. 2015;13(9):1585-1589.
12.
Berntorp E. Prophylaxis in von Willebrand disease. Haemophilia. 2008;14 Suppl 
5:47-53.
13.
Varadi K, Rottensteiner H, Vejda S, et al. Species-dependent variability of 
ADAMTS13-mediated proteolysis of human recombinant von Willebrand factor. J 
Thromb Haemost. 2009;7(7):1134-1142.
14.
Mannucci PM, Kempton C, Millar C, et al. Pharmacokinetics and safety of a novel 
recombinant human von Willebrand factor manufactured with a plasma-free 
method: a prospective clinical trial. Blood. 2013;122(5):648-657.
15.
Gill JC, Castaman G, Windyga J, et al. Hemostatic efficacy, safety and 
pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand 
disease. Blood. 2015;126(17):2038-2046.
16.
Committee for Medicinal Products for Human Use. Guideline on immunogenicity 
assessment of biotechnology-derived therapeutic proteins. 
CHMP/BMWP/14327/2006, 18. 12-13-2007:London, European Medicines Agency 
(EMA),:2007. Web Link: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/200
9/09/WC500003946.pdf
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17.
Kasper CK. Laboratory tests for factor VIII inhibitors, their variation, significance 
and interpretation. Blood Coagul Fibrinolysis. 1991;2 Suppl 1:7-10.
18.
Lillicrap D. Von Willebrand Factor. International Society for Thrombosis and 
Hemostasis (ISTH), 54th Annual Scientific and Standardization Committee 
Meeting - Scientific Subcommittee Minutes:2008:60-64. Web Link: 
http://c.ymcdn.com/sites/www.isth.org/resource/resmgr/yearly_subcommittee_min
utes/2008minutes.pdf?hhSearchTerms=lillicrap+and+2008
19.
 
20.
 
21.
 
 
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22. SUMMARY OF CHANGES
Protocol 071301: Local Amendment 10 (United States): 2018 SEP 13
Replaces: Global Amendment 6: 2018 MAR 12
In this section, changes from the previous version of the Protocol, dated 2018 MAR 12, 
are described and their rationale is given.
1.
Throughout the document
Description of Change:
Minor grammatical and/or administrative changes and/or rewording have been 
made.
Purpose for Change: To improve the readability and/or clarity of the protocol.
2.
Synopsis (Study Design), Section 8.1
Description of Change: 
Added the wording about the possible up-to 3 months’ extension of study 
participation for certain subjects.
Purpose for Change: To add information about possible extension of study 
participation for certain subjects.
3.
Synopsis (Planned Duration of Subject Participation), Section 8.2
Description of Change: 
Added the note about the possible up-to 3 months’ extension of study 
participation for certain subjects, and clarify that the planned duration of subject 
participation can therefore be extended to 18 months. 
Purpose for Change: To add information about possible extension of study 
participation for certain subjects.
4.
Synopsis (Secondary outcome measures), Section 8.3.2.1
Description of Change:
Original text:
Categorized spontaneous ABR defined as 0, 1-2, 3-5, or >5 bleeding episodes 
during the 12-month prophylactic treatment with rVWF (vonicog alfa)
New text:
Categorized spontaneous ABR defined as 0, 1-2, 3-5, or >5 bleeding episodes 
during the prophylactic treatment with rVWF (vonicog alfa)
Purpose for Change: To remove the exact prophylactic treatment period as it can 
be extended beyond 12 month for certain subjects.
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5.
Section 6.1
Description of Change: 
Updates were added to reflect the marketing authorization for Vonvendi in US 
and EU.
Purpose for Change: To provide updated marketing authorization for Vonvendi.
6.
Section 10.3.7
Description of Change:
The detailed schedules of follow-up visits were removed as for certain subjects 
12-month follow-up visit will be scheduled with the need of participation 
extension.
Purpose for Change: To remove the details to avoid confusion of possible 12-
month follow-up visit.
7.
Section 10.3.9
Description of Change:
End of study visit time was removed as for certain subjects the EOS visit can 
occur after 12 months with the need of participation extension. 
Added the note about the possible up-to 3 months’ extension of study 
participation for certain subjects
Purpose for Change: To add information about possible extension of study 
participation for certain subjects and to remove the details to avoid confusion of 
possible delayed EOS visit.
8.
Section 11.6, Section 12.10.2
Description of Change: 
Added the note about the possible up-to 3 months’ extension of study 
participation for certain subjects. 
Purpose for Change: To add information about possible extension of study 
participation for certain subjects.
9.
Section 20.2 Table 6a 6b, Section 20.3 Table 8a 8b
Description of Change: 
Added the footnote to reflect the possible up-to 3 months’ extension of study 
participation for certain subjects.
Purpose for Change: To add note about possible extension of study participation 
for certain subjects.
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10.
Section 20.2 Table 6a 6b, Section 20.3 Table 8a 8b
Description of Change:
Some clarifications were made to the tables and the footnotes, to reflect the 
possible up-to 3 months’ extension of study participation for certain subjects. 
Purpose for Change: To add information about possible extension of study 
participation for certain subjects.
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INVESTIGATOR ACKNOWLEDGEMENT
RECOMBINANT VON WILLEBRAND FACTOR (rVWF)
A prospective, phase 3, open-label, international multicenter study on efficacy and 
safety of prophylaxis with rVWF in severe von Willebrand Disease
PROTOCOL IDENTIFIER: 071301
CLINICAL TRIAL PHASE 3
LOCAL AMENDMENT 10 (UNITED STATES): 2018  SEP 13
Replaces: GLOBAL AMENDMENT 6: 2018 MAR 12
OTHER PROTOCOL ID(s)
NCT Number: NCT02973087
EudraCT Number: 2016-001478-14
IND NUMBER: 013657
By signing below, the investigator acknowledges that he/she has read and understands 
this protocol, and will comply with the requirements for obtaining informed consent from 
all study subjects prior to initiating any protocol-specific procedures, obtaining written 
initial and ongoing EC(s) protocol review and approval, understands and abides by the 
requirements for maintenance of source documentation, and provides assurance that this 
study will be conducted according to all requirements as defined in this protocol, Clinical 
Trial Agreement, ICH GCP guidelines, and all applicable national and local regulatory 
requirements.
Signature of Principal Investigator
Date
Print Name of Principal Investigator
For non-commercial use only

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BAXALTA CONFIDENTIAL – RESTRICTED: DO NOT DISTRIBUTE WITHOUT PRIOR APPROVAL
CLINICAL STUDY PROTOCOL
PRODUCT: Recombinant Von Willebrand Factor (rVWF, vonicog alfa)
STUDY TITLE: A PROSPECTIVE, PHASE 3, OPEN-LABEL, INTERNATIONAL 
MULTICENTER STUDY ON EFFICACY AND SAFETY OF PROPHYLAXIS 
WITH rVWF IN SEVERE VON WILLEBRAND DISEASE
STUDY SHORT TITLE: rVWF IN PROPHYLAXIS
PROTOCOL IDENTIFIER: 071301
CLINICAL TRIAL PHASE 3
LOCAL AMENDMENT 11 (RUSSIA): 2019 JAN 28
Replaces: 
AMENDMENT 6: 2018 MAR 12
ALL VERSIONS: 
Local (Russia) Amendment 11: 2019 JAN 28
Local (United States) Amendment 10: 2018 SEP 13 
Local (Turkey) Amendment 9: 2018 SEP 13
Local (Czech Republic) Amendment 8: 2018 MAY 18
Local (Germany) Amendment 7: 2018 MAY 18
Amendment 6: 2018 MAR 12 
Local (Czech) Amendment 5: 2017 AUG 08
Local (Germany) Amendment 4: 2017 AUG 04
Amendment 3: 2017 AUG 03
Amendment 2: 2016 DEC 15
Amendment 1: 2016 APR 08
Original: 2014 FEB 09
OTHER ID(s)
NCT Number: NCT02973087
EudraCT Number: 2016-001478-14
IND NUMBER: 013657
Study Sponsor(s):
Baxalta US Inc.
300 Shire Way
Lexington, MA 02421, US
Baxalta Innovations GmbH
Industriestrasse 67
A-1221 Vienna, AUSTRIA
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1. STUDY PERSONNEL
1.1 Authorized Representative (Signatory) / Responsible Party
, MD
Global Clinical Development Operations
Baxalta Innovations GmbH
1.2 Study Organization
The name and contact information of the responsible party and individuals involved with 
the study (e.g. investigator(s), sponsor’s medical expert and study monitor, sponsor’s 
representative(s), laboratories, steering committees, and oversight committees [including 
ethics committees (ECs)], as applicable) will be maintained by the sponsor and provided 
to the investigator.
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2. SERIOUS ADVERSE EVENT REPORTING
The investigator will comply with applicable laws/requirements for reporting serious 
adverse events (SAEs) and suspected unexpected serious adverse events (SUSARs) to the 
ECs.
ALL SAEs, INCLUDING SUSARs, ARE TO BE REPORTED ON THE SERIOUS 
ADVERSE EVENT REPORT (SAER) FORM AND TRANSMITTED TO THE 
SPONSOR WITHIN 24 HOURS AFTER BECOMING AWARE OF THE EVENT.
Bleeding events that meet seriousness criteria (death, life-threatening, 
hospitalizing/prolongation of hospitalization, disability, congenital anomaly, or medically 
significant and if not urgently treated would result in one of the above) should be reported 
on the SAE eCRF and SAE Report form as an SAE.
Drug Safety contact information:
Baxalta Global Drug Safety fax number:  
  
OR 
email: 
For definitions and information on the assessment of these events, refer to the following:

Adverse Events (AEs), Section 12.1

SAEs, Section 12.1.1.1

SUSARs, Section 12.1.1.2

Assessment of AEs, Section 12.1.2

Safety Reporting, Section 12.1.2.3
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3. SYNOPSIS
INVESTIGATIONAL PRODUCT
Name of Investigational Product (IP)
Recombinant von Willebrand factor (rVWF, vonicog alpha)
Name(s) of Active Ingredient(s)
Recombinant von Willebrand factor (rVWF, vonicog alpha)
CLINICAL CONDITION(S)/INDICATION(S)
Subjects with severe von Willebrand disease (VWD) (baseline VWF: Ristocetin cofactor activity 
(VWF:RCo) <20 IU/dL) requiring prophylactic treatment with coagulation factor replacement
PROTOCOL ID
071301
PROTOCOL TITLE
A prospective, phase 3, open-label, international multicenter 
study on efficacy and safety of prophylaxis with rVWF in severe 
von Willebrand disease
Short Title
rVWF in prophylaxis
STUDY PHASE
Phase 3
PLANNED STUDY PERIOD
Initiation
2017 OCT
Primary Completion
2019 Q4
Study Completion
2019 Q4
Duration
27 months
STUDY OBJECTIVES AND PURPOSE
Study Purpose
The purpose of this phase 3 study is to investigate the efficacy and safety, including immunogenicity, 
thrombogenicity and hypersensitivity reactions, as well as pharmacokinetics (PK), 
 
 and 
 of prophylactic treatment with rVWF (vonicog alfa) in adult 
subjects with severe VWD.
Primary Objective
The primary objective of this study is to prospectively evaluate the annualized bleeding rate (ABR) for 
spontaneous bleeding episodes while on prophylactic treatment with rVWF (vonicog alfa) and to compare 
it to the subject’s historical ABR for spontaneous bleeding episodes. 
Secondary Objectives
Secondary Objectives are to assess

Additional efficacy of prophylactic treatment with rVWF (vonicog alfa)

Safety of rVWF (vonicog alfa), including immunogenicity, thrombogenicity and hypersensitivity 

Pharmacokinetics (PK) of rVWF (vonicog alfa) and Pharmacodynamics (PD) of rVWF (vonicog alfa) 
as measured in FVIII activity
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Exploratory Objectives
 
 
 
 
STUDY DESIGN
Study Type/ Classification/ Discipline
Efficacy and Safety 
Control Type
No control
Study Indication Type
Prophylaxis and treatment of bleeding episodes
Intervention model 
Single-group
Blinding/Masking
Open-label
Study Design
This is a phase 3, prospective, open-label, uncontrolled, non-
randomized, international multicenter study evaluating efficacy, 
safety, including immunogenicity, thrombogenicity and 
hypersensitivity reactions, as well as PK, 
 and 
 of prophylactic treatment regimen with 
rVWF (vonicog alfa) in adult subjects with severe VWD.
Subjects transitioning from on-demand treatment (OD subjects) 
or subjects switching from prophylactic treatment with pdVWF 
(pdVWF switch subjects) will receive prophylactic treatment 
with rVWF (vonicog alfa) for a 12-month period (up to 
15 months for the qualified subjects to rollover into the 
continuation study, if the continuation study start up is delayed 
beyond the completion of subject’s 12-month visit).
Planned Duration of Subject 
Participation
Approximately 15 to 18* months 
* Study treatment period is extended by 3 months to 
accommodate participation in the continuation study for the 
qualified subjects and will be exercised only if the continuation 
study start up is delayed beyond the completion of subject’s 
12-month visit.
Primary Outcome Measure 
Efficacy

Annualized bleeding rate (ABR) for spontaneous (not related to trauma) bleeding episodes during 
prophylactic treatment with rVWF (vonicog alfa)
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Secondary Outcome Measures
Additional efficacy of prophylactic treatment with rVWF (vonicog alfa)

ABR percent reduction success for OD subjects defined as at least 25% reduction of ABR for 
spontaneous (not related to trauma) bleeding episodes during rVWF (vonicog alfa) prophylaxis 
relative to the subject’s own historical ABR during on-demand treatment 

ABR preservation success for pdVWF switch subjects defined as achieving an ABR for spontaneous 
bleeding episodes during rVWF (vonicog alfa) prophylaxis that is no greater than the subject’s own 
historical ABR during prophylactic treatment with pdVWF 

Categorized spontaneous ABR defined as 0, 1-2, 3-5, or >5 bleeding episodes during the prophylactic 
treatment with rVWF (vonicog alfa)

Total number of infusions and the average number of infusions per week during prophylactic 
treatment with rVWF (vonicog alfa)

Total weight adjusted consumption of rVWF (vonicog alfa) during prophylactic treatment

Spontaneous ABR by location of bleeding (Gastrointestinal [GI], epistaxis, joint bleeding, 
menorrhagia, oral and other mucosa, muscle and soft tissue, etc.) while on prophylactic treatment with 
rVWF (vonicog alfa) 
Safety

Adverse events (AEs) : incidence, severity, causality

Thromboembolic events 

Hypersensitivity reactions 

Development of neutralizing antibodies to VWF and FVIII 

Development of total binding antibodies to VWF and FVIII

Development of binding antibodies to Chinese hamster ovary (CHO) proteins, mouse 
immunoglobulin G (IgG) and rFurin

Clinically significant changes in vital signs and clinical laboratory parameters relative to baseline
Pharmacokinetics (PK) and Pharmacodynamics (PD)

PK parameters after a washout for on-demand subjects: incremental recovery (IR), terminal half-life 
(T1/2), mean residence time (MRT), area under the concentration versus time curve from 0 to infinity 
(AUC0-), area under the concentration versus time curve from 0 to the last measurable concentration 
(AUC0-tlast), maximum concentration (Cmax), minimum time to reach the maximum concentration 
(Tmax), volume of distribution at steady state (Vss) and clearance (CL) based on VWF:RCo, Von 
Willebrand factor antigen (VWF:Ag), Von Willebrand collagen binding activity (VWF:CB).

PD parameters after a washout for on-demand subjects: Cmax, Tmax, and AUC0-tlast as measured in 
FVIII activity by the 1-stage clotting assay (FVIII:C). 

PK parameters at steady state for on-demand and switch subjects: area under the concentration versus 
time curve from 0 to end of the partial dosing interval (AUC0- tau;ss), maximum concentration during 
the partial dosing interval (Cmax;ss), minimum time to reach the maximum concentration (Tmax;ss) and 
minimum concentration during the partial dosing interval (Cmin;ss) based on VWF:RCo, VWF:Ag and 
VWF:CB. PK parameters at steady state will be assessed shortly after reaching steady state for switch 
subjects and at the end of the study for on-demand as well as for switch subjects all based on the 
longer interval of the irregular dosing intervals employed. 
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
PD parameters at steady state for on-demand and switch subjects: AUC0-tau;ss, Cmax;ss, Tmax;ss, and Cmin;ss
as measured in FVIII activity by the 1-stage clotting assay (FVIII:C). PD parameters at steady state 
will be assessed shortly after reaching steady state for switch subjects and at the end of the study for 
on-demand as well as for switch subjects all based on the longer interval of the irregular dosing 
intervals employed.

Time course of FVIII clotting activity (FVIII:C) levels.
Exploratory Outcome Measures
 
 
 
 
 
 
 
 
 
 
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INVESTIGATIONAL PRODUCT(S), DOSE AND MODE OF ADMINISTRATION
Active Product
Dosage form: powder and solvent for solution for injection
Dosage frequency:
Prophylactic Treatment
Subjects transitioning from on-demand treatment will receive twice weekly 
infusion with rVWF (vonicog alfa) at doses of 50 ± 10 IU/kg rVWF:RCo. 
Dosage may be individualized within this range based on: 

available historical PK data

type and severity of bleeding episodes the subject has experienced in the past

monitoring of appropriate clinical and laboratory measures
The starting dose can, after consultation with the Sponsor, be increased up to 
80 U/kg if considered necessary to assure effective prophylaxis.
Subjects switching from pdVWF prophylaxis treatment: the weekly dose (IU/kg) 
of rVWF (vonicog alfa) for each patient will be equivalent (± 10%) to the weekly 
VWF dose received during prophylactic treatment with pdVWF. The weekly 
dose should be divided into 2 infusions, with a maximum of 80 IU/kg/infusion. If 
needed, based on the total weekly dose or other clinical judgements, the weekly 
dose may be given as three infusions. A once weekly dose regimen will be 
allowed after switch to rVWF (vonicog alfa) if the patient has been on a once 
weekly dose regimen with pdVWF. Dose and dose interval may, after 
consultation with the sponsor, be further individualized based on: 

available historical PK data

type and severity of bleeding episodes the subject has experienced in the past

monitoring of appropriate clinical and laboratory measures
Treatment of Bleeding Episodes:
Dosage must be individualized based on the subject’s weight, type and severity 
of bleeding episode and monitoring of appropriate clinical and laboratory 
measures. In general, an initial dose of 40-60 IU/kg VWF:RCo with or without
30-45 IU rFVIII [ADVATE, octocog alfa]/kg is recommended (rVWF:rFVIII 
ratio of 1.3:1: ± 0.2). In cases of major bleeding episodes, a dose of up to 80 
IU/kg VWF:RCo may be infused. Subsequent doses, if necessary, will be 
administered with or without ADVATE (rFVIII, octocog alfa) to maintain 
VWF:RCo and FVIII levels for as long as deemed necessary by the investigator.
Mode of Administration: intravenous
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SUBJECT SELECTION
Targeted Accrual
Approximately 22 adult subjects with severe VWD will be included to have 
≥8 subjects in each cohort (OD and switch). A total of at least 5 type 3 VWD 
subjects will be followed for 12 months. 
Number of Groups/ 
Arms/ Cohorts
Single-group
Inclusion Criteria
Subjects who meet ALL of the following criteria are eligible for this study:
1. Subject has a documented diagnosis of severe VWD (baseline VWF:RCo <20 IU/dL) with a history of 
requiring substitution therapy with von Willebrand factor concentrate to control bleeding:
a. Type 1 (VWF:RCo <20 IU/dL) or,
b. Type 2A (as verified by multimer pattern), Type 2B (as diagnosed by genotype), Type 2M or,
c. Type 3 (VWF:Ag ≤3 IU/dL).
2. Diagnosis is confirmed by genetic testing and multimer analysis, documented in patient history or at 
screening.
3. For on-demand patient group, subject currently receiving on-demand treatment for whom prophylactic 
treatment is recommended by the investigator. 
4. For pdVWF switch patient group, subject has been receiving prophylactic treatment of pdVWF 
products for no less than 12 months prior to screening.
5. For on-demand patient group, subject has ≥3 documented spontaneous bleeds (not including 
menorrhagia) requiring VWF treatment during the past 12 months. 
6. Availability of records to reliably evaluate type, frequency and treatment of bleeding episodes during 
at least 12 months preceding enrollment. Up to 24 months of retrospective data should be collected if 
available. Availability of dosing and factor consumption during 12 months (up to 24 months) of 
treatment prior to enrollment is required for pdVWF switch subjects and is desired (but not a 
requirement) for on-demand subjects.
7. Subject is ≥18 years old at the time of screening and has a body mass index ≥15 but <40 kg/m2.
8. If female of childbearing potential, subject presents with a negative blood/urine pregnancy test at 
screening and agrees to employ adequate birth control measures for the duration of the study.
9. Subject is willing and able to comply with the requirements of the protocol.
Exclusion Criteria
Subjects who meet ANY of the following criteria are not eligible for this study:
1. The subject has been diagnosed with Type 2N VWD, pseudo VWD, or another hereditary or acquired 
coagulation disorder other than VWD (e.g., qualitative and quantitative platelet disorders or elevated 
prothrombin time (PT)/international normalized ratio [INR] 1.4).
2. The subject is currently receiving prophylactic treatment with more than 5 infusions per week.
3. The subject is currently receiving prophylactic treatment with a weekly dose exceeding 240 IU/kg.
4. The subject has a history or presence of a VWF inhibitor at screening.
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5. The subject has a history or presence of a FVIII inhibitor with a titer ≥0.4 Bethesda units (BU) (by 
Nijmegen modified Bethesda assay) or ≥0.6 BU (by Bethesda assay).
6. The subject has a known hypersensitivity to any of the components of the study drugs, such as to 
mouse or hamster proteins.
7. The subject has a medical history of immunological disorders, excluding seasonal allergic 
rhinitis/conjunctivitis, mild asthma, food allergies or animal allergies.
8. The subject has a medical history of a thromboembolic event.
9. The subject is human immunodeficiency virus (HIV) positive with an absolute Helper T cell 
(CD4) count 200/mm3.
10. The subject has been diagnosed with significant liver disease per investigator’s medical assessment of 
the subject’s current condition or medical history or as evidenced by any of the following: serum 
alanine aminotransferase (ALT) greater than 5 times the upper limit of normal; hypoalbuminemia; 
portal vein hypertension (e.g., presence of otherwise unexplained splenomegaly, history of esophageal 
varices).
11. The subject has been diagnosed with renal disease, with a serum creatinine (CR) level ≥2.5 mg/dL.
12. The subject has a platelet count <100,000/mL at screening.
13. The subject has been treated with an immunomodulatory drug, excluding topical treatment (e.g., 
ointments, nasal sprays), within 30 days prior to signing the informed consent.
14. The subject is pregnant or lactating at the time of enrollment.
15. Patient has cervical or uterine conditions causing menorrhagia or metrorrhagia (including infection, 
dysplasia).
16. The subject has participated in another clinical study involving another investigational product (IP) or 
investigational device within 30 days prior to enrollment or is scheduled to participate in another 
clinical study involving an IP or investigational device during the course of this study.
17. The subject has a progressive fatal disease and/or life expectancy of less than 15 months.
18. The subject is scheduled for a surgical intervention.
19. The subject is identified by the investigator as being unable or unwilling to cooperate with study 
procedures.
20. The subject has a mental condition rendering him/her unable to understand the nature, scope and 
possible consequences of the study and/or evidence of an uncooperative attitude.
21. The subject is in prison or compulsory detention by regulatory and/or juridical order
22. The subject is member of the study team or in a dependent relationship with one of the study team 
members which includes close relatives (i.e., children, partner/spouse, siblings and parents) as well as 
employees.
Delay criteria
1. If the subject presents with an acute bleeding episodes or acute illness (e.g., influenza, flu-like 
syndrome, allergic rhinitis/conjunctivitis, non-seasonal asthma) the screening visit will be postponed 
until the subject has recovered.
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STATISTICAL ANALYSIS
Sample Size Calculation
Approximately 22 adult subjects with severe VWD will be included in the study. The aim is to have 
≥8 subjects in each cohort (OD and switch). A total of at least five type 3 VWD subjects will be followed 
for 12 months. The sample size is driven by practical considerations (primarily the enrollment of a rare 
patient population) and EMA Guideline on the Clinical Investigation of Human Plasma Derived von 
Willebrand Factor Products (CPMP/BPWG/220/02).1
Planned Statistical Analysis
The Full Analysis Set (FAS) will be composed of all subjects who receive prophylaxis IP treatment.
The Safety Analysis Set will be composed of all subjects who received any amount of IP  (rVWF, vonicog 
alpha).
The Per-Protocol (PP) Analysis Set will be composed of subjects who are at least 70% compliant regarding 
the number of scheduled prophylactic infusions. Only subjects who meet all study entry criteria and who 
have no major protocol violations that might impact primary efficacy assessments will be included in the 
PP analysis set.
The Pharmacokinetic Full Analysis Set (PKFAS) will be composed of all subjects who received the PK 
infusion and who provided acceptable data for PK and PD analysis. Acceptable PK/PD data will be defined 
in the Statistical Analysis Plan.
Primary Outcome Measure:
No formal statistical hypothesis test is planned for the analysis. Spontaneous ABR while treated with rVWF 
(vonicog alfa) for each cohort, on demand and switch subjects, will be estimated using a negative binomial 
regression. The prior ABR for each cohort will be based on historical data collected from each enrolled 
subject. The two ABRs (observed on the study and historical) will be assessed using a generalized linear 
mixed-effects model (GLMM) with the negative binomial distribution as a family and with a logarithmic 
link function (the default). The ABR ratio together with a two-sided, 95% confidence interval (CI) will be 
reported for each cohort.
The difference in on-study ABR relative to historical ABR will be summarized descriptively.
The primary efficacy analysis will be based on the FAS and will be summarized by the two cohorts: on-
demand and switch subjects. As a supportive analysis, the same analysis will also be carried out on the per-
PP analysis set.
Secondary Outcome Measures:
In general, data for  secondary efficacy analysis will be summarized by the two cohorts: on-demand and 
switch subjects and when applicable overall. Mean, standard deviation, median, range, quartiles will be 
calculated for continuous endpoints. Proportions will be calculated for categorical endpoints. Confidence 
intervals at the 95% level will be provided when appropriate. 
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Additional efficacy of prophylactic treatment with  rVWF (vonicog alfa):
The number  and proportion of on-demand subjects with ABR percent reduction success (i.e. ≥ 25% ) will 
be calculated together with a two-sided 95% CI for the proportion. 
The number  and proportion of pdVWF switch subjects with ABR preservation success will be reported 
together with the corresponding 95% two-sided CIs for the proportion. 
The number and proportion of subjects with categorized spontaneous ABR (i.e. 0, 1-2, 3-5, more than 
5 bleeds) will be reported descriptively.
Summary statistics for the total number of infusions, as well as average number of infusions per week will 
be provided. The total weight adjusted consumption of rVWF (vonicog alfa) during prophylactic treatment 
will be provided. If applicable, historical data on consumption of pdVWF prior to the study will be 
summarized as well.
The change in spontaneous ABR from the historical rate to that during the rVWF (vonicog alfa) 
prophylaxis period will be summarized by location of bleeding (GI, epistaxis, joint bleeding, 
menorrhagia, oral and other mucosa, muscle and soft tissue, etc.).
Pharmacokinetics (PK) and Pharmacodynamics (PD):
The following PK parameters, based on the initial PK assessment after a washout for on-demand subjects, 
will be listed and summarized descriptively for VWF:RCo, VWF:Ag and VWF:CB: IR, T1/2, MRT, 
AUC0-, AUC0-tlast, Cmax, Tmax, Vss, and CL. The corresponding pharmacodynamics (PD) of rVWF 
(vonicog alfa) as measured in FVIII activity (FVIII:C), based on the initial PK assessment after a 
washout for on-demand subjects will be assessed using Cmax, Tmax, and AUC0-tlast. These PD parameters 
will be listed and summarized descriptively. 
PK parameters at steady state (AUC0-tau;ss, Cmax;ss, Tmax;ss, and Cmin;ss) for the partial dosing interval will be 
listed for on-demand subjects at the end of the study and for switch subjects shortly after reaching steady 
state and at the end of the study for VWF:RCo, VWF:Ag and VWF:CB and summarized descriptively for 
subjects with the same dosing regimens. The corresponding pharmacodynamics (PD) of rVWF (vonicog 
alfa) as measured in FVIII activity (FVIII:C) will be assessed using AUC0-tau;ss, Cmax;ss, Tmax;ss, and Cmin;ss. 
These PD parameters will be listed for on-demand subjects at the end of the study and for switch subjects 
shortly after reaching steady state and at the end of the study and will be summarized descriptively for 
subjects with the same dosing regimens. 
For the on-demand subjects, the PK of VWF:RCo will be analyzed using a population PK approach to 
characterize the single and multiple dose pharmacokinetics, including associated variability, of VWF:RCo 
in the study population.
For the switch subjects, differences in AUC0-tau;ss, Cmax;ss, and Cmin;ss assesses shortly after reaching steady 
state and assessed at the end of the study will be assessed by ratio of geometric means and corresponding 
two-sided 95% confidence intervals for VWF:RCo, VWF:Ag, VWF:CB, and FVIII:C. The difference in 
Tmax;ss, between first and second pharmacokinetic assessment will be summarized by the median and range 
(minimum to maximum) for VWF:RCo, VWF:Ag,VWF:CB, and FVIII:C.
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Descriptive statistics will be used to summarize VWF:RCo, VWF:Ag, VWF:CB,  and FVIII:C levels for 
each nominal time point on the PK curve. For all subjects activity/concentration vs. time curves will be 
prepared.
Safety:
Safety analysis will be performed overall and by the two cohorts: on-demand and switch subjects.
Treatment-emergent AEs (TEAEs) are defined as AEs with start dates on or after the first exposure to IP. 
Summaries of AEs will be based on TEAEs unless otherwise indicated.
Occurrence of AEs and serious AEs (SAEs) will be summarized descriptively, by system organ class and 
preferred term. The number and percentage of subjects who experienced AEs and SAEs, and the number of 
AEs and SAEs will be tabulated. In addition, the number of subjects who experienced AEs assessed as 
related to IP by the investigator, and the number of IP-related AEs will be tabulated. The number of 
patients with AEs by severity will be presented similarly.
A listing of all AEs will be presented by subject identifier, age, sex, preferred term and reported term of the 
AE, duration, severity, seriousness, action taken, outcome, causality assessment by investigator, onset date, 
stop date and medication or non-drug therapy to treat the AE. 
Temporally associated AEs are defined as AEs that begin during infusion or within 24 hours (or 1 day 
where time of onset is not available) after completion of infusion, irrespective of being related or not 
related to treatment. Temporally associated AEs will be presented in summary tables.
Adverse events of special interest (AESI), such as hypersensitivity reactions and thromboembolic events,  
will be monitored throughout the study and statistical analysis will be conducted based on the search 
criteria (eg, standardized MedDRA queries [SMQ]) determined prior to database lock, and summarized.
For immunogenicity analysis frequency counts and proportions will be calculated for subjects with the 
occurrence of neutralizing (inhibitory) antibodies to VWF and FVIII, occurrence of binding antibodies to 
VWF and FVIII, and occurrence of binding antibodies to CHO proteins, mouse immunoglobulin G (IgG) 
and rFurin.
Clinically significant changes relative to baseline in vital signs and clinical laboratory parameters 
(hematology, clinical chemistry) will be reported.
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4. TABLE OF CONTENTS
1. STUDY PERSONNEL.................................................................................................. 2
1.1 Authorized Representative (Signatory) / Responsible Party .............................. 2
1.2 Study Organization................................................................................................. 2
2. SERIOUS ADVERSE EVENT REPORTING........................................................... 3
3. SYNOPSIS..................................................................................................................... 4
4. TABLE OF CONTENTS ........................................................................................... 14
5. LIST OF ABBREVIATIONS .................................................................................... 20
6. BACKGROUND INFORMATION .......................................................................... 24
6.1 Description of Investigational Product ............................................................... 24
6.2 Clinical Condition/Indication .............................................................................. 25
6.3 The Role of Prophylaxis in the Management of VWD...................................... 26
6.4 Populations to be Studied..................................................................................... 28
6.5 Findings from Nonclinical and Clinical Studies................................................. 28
6.5.1 Findings from Nonclinical Studies ............................................................... 28
6.5.1.1 Primary Pharmacodynamics ................................................................. 28
6.5.1.2 Safety Pharmacology.............................................................................. 29
6.5.1.3 Pharmacokinetics.................................................................................... 29
6.5.1.4 Toxicology................................................................................................ 29
6.5.2 Findings from Clinical Studies ..................................................................... 30
6.5.2.1 Study 070701 ........................................................................................... 31
6.5.2.2 Study 071104 ........................................................................................... 32
6.5.2.3 Study 071001 ........................................................................................... 33
6.5.2.4 Study 071101 ........................................................................................... 35
6.5.2.5 Study 071401: Single Subject with von Willebrand Disease............... 37
6.6 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) 
to Human Subjects................................................................................................ 37
6.7 Compliance Statement.......................................................................................... 38
7. STUDY PURPOSE AND OBJECTIVES ................................................................. 39
7.1 Study Purpose ....................................................................................................... 39
7.2 Primary Objective................................................................................................. 39
7.3 Secondary Objectives ........................................................................................... 39
7.4 Exploratory Objectives......................................................................................... 39
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10.2 Subject Identification Code................................................................................ 63
10.3 Screening and Study Visits................................................................................. 63
10.3.1 Screening Visit.............................................................................................. 63
10.3.2 Baseline Visit – Initial PK Assessment (On-demand Subjects Only)...... 64
10.3.3 Prophylaxis Initiation Visit......................................................................... 65
10.3.4 Initial Steady State PK-Assessment (pdVWF switch subjects only)....... 65
10.3.5 Treatment of Bleeding Episodes................................................................. 66
10.3.6 Perioperative Visits (only applicable if surgery is needed)...................... 66
10.3.7 Follow-Up Visits........................................................................................... 66
10.3.8 Unscheduled Visits....................................................................................... 68
10.3.9 End of Study PK Assessment and Study Termination Visit.................... 68
10.4 Medications and Non-Drug Therapies.............................................................. 69
10.5 Subject Diary....................................................................................................... 70
10.6 Subject Completion/Discontinuation ................................................................ 70
10.7 Procedures for Monitoring Subject Compliance ............................................. 71
11. ASSESSMENT OF EFFICACY AND PHARMACOKINETICS........................ 72
11.1 Assessment of Spontaneous Bleeding Episodes/Annualized Bleed Rate........ 72
11.2 Evaluation of ABR Before rVWF Prophylaxis and ABR Under rVWF 
Prophylactic Treatment........................................................................................ 73
11.3 Number of Infusions and Total Weight Adjusted Consumption of rVWF and 
ADVATE and historical prophylaxis dosing and factor consumption during 
pdVWF prophylaxis treatment prior to enrollment.......................................... 73
11.4 Assessment of Efficacy for Treatment of Bleeding Episode ........................... 73
11.5 Assessment of Efficacy for Treatment for Surgical Bleeding......................... 74
11.6 rVWF Pharmacokinetics and Pharmacodynamics ......................................... 75
12. ASSESSMENT OF SAFETY................................................................................... 77
12.1 Adverse Events.................................................................................................... 77
12.1.1 Definitions..................................................................................................... 77
12.1.1.1 Serious Adverse Event.......................................................................... 77
12.1.1.2 Suspected Unexpected Serious Adverse Reaction (SUSAR)............. 78
12.1.1.3 Non-Serious Adverse Event ................................................................. 78
12.1.1.4 Unexpected Adverse Events................................................................. 79
12.1.1.5 Preexisting Disease................................................................................ 79
12.1.2 Assessment of Adverse Events.................................................................... 79
12.1.2.1 Severity .................................................................................................. 81
12.1.2.2 Causality................................................................................................ 81
12.1.2.3 Safety Reporting ................................................................................... 82
12.2 Urgent Safety Measures ..................................................................................... 84
12.3 Untoward Medical Occurrences........................................................................ 85
12.4 Non-Medical Complaints ................................................................................... 85
12.5 Medical, Medication, and Non-Drug Therapy History................................... 85
12.6 Physical Examinations........................................................................................ 86
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19. PUBLICATION POLICY...................................................................................... 112
20. SUPPLEMENTS..................................................................................................... 113
20.1 Study Flow Chart.............................................................................................. 113
20.2 Schedule of Study Procedures and Assessments............................................ 114
20.2.1 Summary Schedule of Visit Assesments for Surgical Bleeding............. 118
20.3 Clinical Laboratory Assessments .................................................................... 120
20.3.1 Laboratory Sampling for Surgical Bleeding ........................................... 124
20.4 Contraceptive Methods for Female Subjects of Childbearing Potential..... 126
21. REFERENCES........................................................................................................ 127
22. SUMMARY OF CHANGES.................................................................................. 130
INVESTIGATOR ACKNOWLEDGEMENT............................................................ 133
Tables
Table 1 rVWF (vonicog alfa) Dosing Schedule Examples: Schedules A and B............. 48
Table 2 Criteria for Escalation Specific to Each Bleeding Indication............................. 50
Table 3 rVWF:RCo Dosing Recommendations for the Treatment of Bleeding Episodes 
Due to VWD ............................................................................................................. 54
Table 4 Efficacy Rating Scale.......................................................................................... 74
Table 5 Assessment of Hemostatic Efficacy ................................................................... 75
Table 6a Schedule of Study Procedures and Assessments for On-demand Subject...... 114
Table 7 Summary Schedule of Visit Assesments for Surgical Bleeding....................... 118
Table 8a Clinical Laboratory Assessments for On-demand Subject ............................. 120
Table 9 Laboratory Samplinga for Surgical Bleeding.................................................... 124
Figures
Figure 1 Study Design for Baxalta Clinical Study 071301............................................ 113
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5. LIST OF ABBREVIATIONS
Abbreviation
Definition
ABR
Annualized bleeding rate 
ADAMTS13
A Disintegrin And Metalloproteinase with a Thrombospondin type 1 motif, number 13
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine aminotransferase
AP
Alkaline phosphatase
AST
Aspartate aminotransferase
AUC0-∞
Area under the plasma concentration /time curve from time 0 to infinity
AUC0-tau;ss
Area under the plasma concentration /time curve from time 0 to end of the partial 
dosing interval
AUC0-tlast
Area under the plasma concentration /time curve from 0 to the last measurable 
concentration
aPTT
Activated partial thromboplastin time
B19V
Parvovirus B19
BP
Blood pressure
BU
Bethesda Unit
BUN
Blood urea nitrogen
BW
Body weight
CAM
Cell adhesion molecule
CBC
Complete blood count
CD4
Helper T cell
CHO
Chinese hamster ovary
CI
Confidence interval
Cl
Chloride
CL
Clearance
Cmax
Maximum plasma concentration
Cmax;ss
Maximum plasma concentration during the partial dosing interval at steady state
Cmin;ss
Minimum plasma concentration during the partial dosing interval at steady state
CR
Creatinine
CTA
Clinical Trial Agreement
eCRF
Electronic case report form
DDAVP
Desmopressin acetate
DMC
Data monitoring committee
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Abbreviation
Definition
DIC
Disseminated intravascular coagulation
DVT
Deep vein thrombosis
EC
Ethics committee
ECG
Electrocardiogram 
EDC
Electronic Data Capture
EDTA
Ethylenediaminetetraacetic acid
ELISA
Enzyme-linked immunosorbent assay
FAS
Full analysis set
FVIII
Factor VIII
FVIII:C
Factor VIII clotting activity
GCP
Good Clinical Practice
GI
Gastrointestinal
Glu
Glucose
HAMA
Human anti- mouse antibodies
HAV
Hepatitis A virus
HB
Hepatitis B
HBs
Hepatitis B surface
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HEV
Hepatitis E virus
HIV
Human immunodeficiency virus 
HLA
Human leukocyte antigen
HRP
Horseradish peroxidase
IB
Investigator's brochure
ICH
International Council for Harmonisation
Ig
Immunoglobulin
INN
International Nonproprietary Name
INR
International normalized ratio
IP
Investigational product
IR
Incremental recovery
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Abbreviation
Definition
i.v.
Intravenous
K
Potassium
k.o.
Knock out
LDH
Lactate Dehydrogenase
Na
Sodium
NMC
Non-medical complaint
NOAEL
No observed adverse effect level
MRI
Magnetic resonance imaging
MRT
Mean residence time
pdVWF
Plasma derived VWF product
pdVWF/FVIII
Plasma derived VWF product containing fractions of FVIII
PBAC
Pictorial Blood Assessment Chart
PCR
Polymerase Chain Reaction
PEF
Peak expiratory flow
PK
Pharmacokinetic
PKFAS
Pharmacokinetic Full Analysis Set
PKPPAS
Pharmacokinetic Per Protocol Analysis Set
PP
Per protocol 
PT
Prothrombin time
Q1, Q3
Quartile
rFVIII
Recombinant factor VIII
rVWF
Recombinant von Willebrand factor
RBC
Red blood cell count
SAE
Serious adverse event
SAER
Serious adverse event report
SDS-PAGE
Sodium dodecyl sulfate polyacrylamide gel electrophoresis
SIC
Subject identification code
SMQ
Standardised MedDRA queries 
sP-selectin
Soluble P-selectin
SUSAR
Suspected unexpected serious adverse reaction
T1/2
Terminal phase half life
TEAE
Treatment-emergent adverse event
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Abbreviation
Definition
TIA
Transient ischemic attack
Tmax
Minimum time to reach the maximum concentration
Tmax;ss
Minimum time to reach the maximum concentration at steady state
TTP
Thrombotic thrombocytopenic purpura
ULMW
Ultra-large molecular weight 
ULN
Upper limit of normal
Vss
Volume of distribution at steady state
VTE
Venous thromboembolism 
VWD
von Willebrand disease
VWF
Von Willebrand factor
VWF:Ag
Von Willebrand factor antigen
VWF:CB
Von Willebrand Factor collagen binding
VWF:RCo
Von Willebrand factor: Ristocetin cofactor activity
WBC
White blood cell
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6. BACKGROUND INFORMATION
6.1 Description of Investigational Product
Baxalta US Inc. (hereafter referred to as Baxalta or sponsor) has developed a human 
recombinant von Willebrand Factor (rVWF, vonicog alpha), which is co-expressed with 
recombinant factor VIII (rFVIII) in a Chinese hamster ovary (CHO) cell line and 
separated during the subsequent downstream process. To address concerns regarding the 
risk of transmission of blood-borne pathogens that may be introduced by human plasma, 
no exogenously added raw materials of human or animal origin are employed in the cell 
culture, purification, or formulation of the final container product. The only proteins 
present in the final container product other than rVWF (vonicog alfa) are trace quantities 
of murine immunoglobulin (IgG, from the immunoaffinity purification), host cell (i.e., 
CHO) protein, rFurin (used to further process rVWF). rVWF (vonicog alfa) is intended 
for the treatment of von Willebrand disease (VWD).
rVWF (vonicog alfa) has been developed under the Baxalta internal code BAX111 and is 
used as investigational product (IP) in this study. rVWF (vonicog alfa) may be used with 
or without ADVATE (rFVIII, octocog alfa) for the treatment of bleeding episodes (see 
Section 8.6.4.4). See Section 8.6 for further information on the IPs and their usage in this 
study. A detailed description of rVWF (vonicog alfa) is also provided in the 
Investigator’s Brochure (IB).
rVWF (vonicog alfa) was granted licensure in the United States in December 2015 under 
the brand name VONVENDI for the on-demand treatment and control of bleeding 
episodes in adults diagnosed with VWD and it has been available on the market in the US 
since 09 August 2016. In April 2018, VONVENDI was also granted licensure in the US 
by the FDA for an additional indication of perioperative management of bleeding in 
adults (age 18 and older) diagnosed with VWD. On 31st of August 2018, European 
Commission implemented the decision granting marketing authorization for VEYVONDI 
(vonicog alfa) for the treatment of haemorrhage and surgical bleeding and for the 
prevention of surgical bleeding in adults (age 18 and older) diagnosed with VWD, when 
desmopressin (DDAVP) treatment alone is ineffective or not indicated. VEYVONDI 
should not be used in the treatment of Haemophilia A. On 4 October 2018, VEYVONDI 
(vonicog alfa) was granted licensure in Switzerland by Swissmedic for the treatment of 
haemorrhage or surgical bleeding in VWD, when desmopressin (DDAVP) treatment 
alone is ineffective or contra-indicated. VEYVONDI should not be used in the treatment 
of Haemophilia A. On 10 January 2019, VONVENDI was authorized in Canada for the 
treatment and control of bleeding episodes, and perioperative management of bleeding in 
adults (age ≥18) diagnosed with VWD.
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6.2 Clinical Condition/Indication
Von Willebrand Factor (VWF) is a large multimeric glycoprotein with a molecular 
weight that varies from 500 to 20,000 kDa. VWF is normally found in plasma and 
produced in the alpha-granules of platelets and in endothelial cell organelles known 
as the Weibel-Palade bodies. VWF mediates platelet adhesion and aggregation at 
sites of vascular injury, one of the key functions in primary hemostasis. VWF also serves 
to stabilize coagulation factor VIII (FVIII), where FVIII is an essential cofactor of 
secondary hemostasis, which leads to fibrin clot formation.2 Qualitative and/or 
quantitative deficiencies of VWF lead to a highly variable bleeding diathesis known as 
VWD, the most common of the hereditary coagulation factor deficiencies. Penetrance of 
VWD is highly variable, with only a small fraction of mildly affected patients displaying 
clinical symptoms or a family history of a bleeding diathesis.
The current biochemical-based classification distinguishes disorders arising from partial 
quantitative (type 1), qualitative (type 2), or virtually complete (type 3) deficiencies of 
VWF. Up to 70% of VWD patients are diagnosed with type 1 VWD, which may also be 
associated with minor functional defects in the molecule. In general, patients with type 1 
VWD display mild clinical symptoms. Approximately 20 to 30% of VWD patients are 
diagnosed with type 2 VWD. Type 2 VWD is further divided into 4 subtypes (A, B, N, 
and M), reflecting distinct classes of functional abnormalities. These defects result in 
abnormal functional and/or multimeric distribution patterns that facilitate their diagnosis. 
The bleeding diathesis is usually moderate and primarily affects the mucosal tissues. 
Type 2N VWD patients are sometimes misdiagnosed as mild hemophilia A. Finally, 
approximately 1% percent of VWD patients exhibit a total or near total absence of VWF, 
which is classified as type 3 VWD. The incidence of type 3 VWD is estimated at 
0.5-1.0 x 106. This type is also associated with a very low FVIII level (typically <5%) 
because the VWF carrier function for FVIII is lost. Replacement of VWF alone stabilizes 
endogenous FVIII, resulting in hemostatic levels within several hours post-infusion. 
Published results from studies of a plasma-derived VWF (pdVWF) concentrate 
demonstrated an increase of FVIII at an approximate rate of 5.8 1 IU dL-1 h-1.3 Type 3 
VWD patients display severe hemorrhagic symptoms with bleeding predominantly in 
mucosal tissues, muscle and joints. All VWD patients, particularly those with type 2 or 
type 3 VWD, are at an increased risk for life-threatening bleeding episodes.
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6.3 The Role of Prophylaxis in the Management of VWD
The goals of long term prophylaxis in VWD are to maintain VWF and FVIII at sufficient 
levels to reduce the frequency and duration of bleeding episodes, the need for red blood 
cell transfusions, and the risk of complications, such as arthropathy.4 In contrast to 
hemophilia, routine prophylaxis is not as established in VWD, although prophylaxis for 
patients with severe VWD was in use in Sweden already during the 1950s.5 In those early 
days of VWD treatment, plasma FVIII concentrates containing VWF fractions were 
applied for replacement therapy, which then were followed by plasma derived VWF 
products containing fractions of FVIII (pdVWF/FVIII). 
A Swedish cohort including 37 patients with type 3 VWD under prophylactic median 
treatment of 11 years (range 2 to 45 years) was retrospectively analyzed.6,7 The 
doses used for prophylaxis, given once weekly for at least 45 weeks per year, were 
calculated based on 12 to 50 IU/kg body weight (BW) of FVIII clotting activity (FVIII:C) 
which approximately corresponded to 24-100 IU/kg von Willebrand factor: Ristocetin 
cofactor activity (VWF:RCo) considering that mainly Haemate with a known 
VWF:RCo/FVIII:C ratio of about 2 was used. An escalation of doses from 1 to 3 dose 
levels was allowed depending on the frequency and severity of bleeding episodes. 
The results demonstrate that under long-term prophylaxis the number of bleeds could be 
reduced dramatically. Whereas the median value for bleeds per year was about 10 before 
prophylaxis this value could be reduced to less than 1 bleed per year during prophylaxis.
The benefit of prophylaxis for such indications was retrospectively also demonstrated in a 
cohort of Italian patients including type 3, 2A, 2M and type 1 patients. Prophylaxis was 
started after severe gastrointestinal or joint bleeding episodes and completely prevented 
bleeding episodes in 8 of these 11 patients and largely reduced the need of blood 
transfusions in the remaining 3. A regimen of 40 IU rVWF:RCo/kg was applied every 
other day or twice a week. A prospective study on prophylaxis, the PRO.WILL study, has 
been initiated in Italy.8
The results of a prospective study investigating the prophylaxis in children and young 
adults showed a significantly reduced bleeding frequency and bleeding score (3 vs. 0.07; 
3 vs. 0. p<0.001) compared to the pre-prophylaxis values. The median dose was 
40 (20-47) IU/kg VWF:RCo administered mainly twice weekly in 23 patients, 3 times a 
week in 7 patients and 4 times a week in 2 children.9
The VWD Prophylaxis Network initiated the VWD International Prophylaxis (VIP) trial 
to investigate the role of prophylaxis in patients with severe VWD including Type 1, 2,
and 3. The dose of the factor replacement product was 50 IU /kgVWF:RCo. 
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The frequency of the dose depended on the type of bleeding and could be increased from 
once weekly to twice weekly or 3 times per week. For the treatment of menorrhagia the 
dose of 50 IU/kg VWF:RCo was given on the first day of menses for 2 cycles. The 
frequency could be increased to Day 1 and 2 for 2 cycles or to Day 1, 2, and 3 of menses.
The study contains both retrospective and prospective study components. Results from 
the retrospective study component were published, including 61 subjects on prophylactic 
regimen in the past 6 months prior to enrollment or subjects with a history of prophylaxis 
over at least 6 month.10 Differences in annualized bleeding rates (ABR) within 
individuals (during prophylaxis – before prophylaxis) were significant for those with 
primary indications of epistaxis (P = 0.0005), joint bleeding (P = 0.002) and GI bleeding 
(P = 0.001). The difference in the group whose primary indication for treatment was 
abnormally heavy bleeding at menstruation (n = 4) was not significant (P = 0.25). The 
reduction of mucosal bleeding likely not only dependents on normal circulating levels of 
active VWF, but also on the presence of discrete concentrations of normal VWF inside 
the platelets and within endothelial matrices. The low subject number (n=4) and the 
treatment scheme for menorrhagia on Days 1, 2, and 3 of menses which might represent 
rather on-demand than prophylactic treatment may also account for the outcome in this 
study.
Results from the prospective study component were reported recently.11 Eleven subjects 
completed the study. Six subjects had type 2A, and 5 subjects had type 3 VWD. 
Six subjects presented with epistaxis, 3 with GI bleeding, and 2 with joint bleeding. 
Seven subjects had dose escalation above the first level. Among the 10 subjects with 
evaluable bleeding log data, the use of prophylaxis decreased the median ABR from 25 to 
6.1 (95% confidence interval [CI] of the rate difference: -51.6 to -1.7), and the median 
ABR was even lower (4.0; 95% CI: -57.5 to -5.3) when the subjects reached their final 
dosing level. The authors concluded that this was the first prospective study to 
demonstrate that prophylaxis with VWF concentrates is highly effective in reducing 
mucosal and joint bleeding rates in clinically severe VWD.
The results of the VIP study and previous investigations suggest that VWD patients with 
recurrent bleeding episodes and severe menorrhagia will benefit from a prophylactic 
VWF replacement therapy. There is evidence that up to 40% of patients with type 3 
VWD experience joint bleeding which can lead to hemophilic arthropathy. Other 
potential indications for prophylaxis include patients with type 2A or 2B VWD with 
recurrent gastrointestinal bleeding, menorrhagia or frequent epistaxis.4 Long-term 
prophylaxis for most patients with type 3 VWD and in some patients with type 1 or 
2 VWD, depending on the pattern of bleeding, may be the treatment option of choice. 
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Although the main experience with long-term prophylaxis is with secondary prophylaxis, 
primary prophylaxis starting at young age is recommended to prevent arthropathy in 
patients with severe VWD.12
However, further studies are needed to develop evidence-based guidelines for 
prophylactic treatment in VWD.
6.4 Populations to be Studied
A total of approximately 22 eligible, adult subjects with severe VWD (baseline 
VWF:RCo <20 IU/dL) are planned to be enrolled. Two cohorts of patients will be 
included: patients currently receiving on-demand VWF treatment (OD subjects) and 
patients currently on prophylactic treatment with pdVWF (pdVWF switch subjects), and 
the aim is to have ≥8 subjects in each of the 2 cohorts, with a total of at least 5 type 3 
VWD subjects followed for 12 months. Enrolled subjects (i.e., subjects who have signed 
the informed consent form) will be eligible to participate in the study if they meet all of 
the inclusion criteria (see Section 9.1) and none of the exclusion criteria (see Section 9.2).
6.5 Findings from Nonclinical and Clinical Studies
The following summarizes the key findings from relevant nonclinical studies as well as 
from the completed clinical studies 070701 (Phase 1 pharmacokinetics [PK] and safety in 
VWD), 071001 (Phase 3 safety and efficacy in the treatment of bleeding episodes in 
VWD), 071101 (Phase 3 efficacy and safety in VWD subjects undergo elective surgical 
procedures), 071104 (Phase 1 safety and PK in hemophilia A), and 071401 (Phase 3, 
expanded access in a single subject with VWD). Potential risks and efficacy of rVWF 
(vonicog alfa):ADVATE (rFVIII, octocog alfa) are summarized in the following sections. 
For additional information on nonclinical and clinical Phase 1 results refer to the rVWF 
(vonicog alfa) IB.
6.5.1 Findings from Nonclinical Studies
6.5.1.1 Primary Pharmacodynamics
Efficacy of rVWF (vonicog alfa) combined with ADVATE (rFVIII, octocog alfa) was 
shown in VWD animal models, which have also low endogenous FVIII levels. Time to 
occlusion and stable thrombus formation was assessed in the carotid occlusion model in 
VWD mice. The results demonstrated that rVWF (vonicog alfa) in combination with 
ADVATE (rFVIII, octocog alfa) acted efficiently in a dose-dependent manner and had 
higher efficacy than rVWF (vonicog alfa) alone or plasma derived (pd)VWF. These 
results were confirmed in an additional study assessing blood loss and survival in a tail 
tip bleeding model in VWD mice. In a VWD dog, rVWF (vonicog alfa) stabilized canine 
FVIII in the circulation and significantly reduced the bleeding time.
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6.5.1.2 Safety Pharmacology
The anaphylactoid and thrombogenic potential of the co-infusion of ADVATE (rFVIII, 
octocog alfa) and rVWF (vonicog alfa) and the co-infused product’s effects on blood 
pressure, cardiac and respiratory function and parameters of coagulation activation were 
investigated in 4 in vivo studies in different animal models. Safety pharmacology studies 
in rats, guinea pigs, rabbits, and dogs revealed no risks for anaphylactoid and 
thrombogenic potential of ADVATE (rFVIII, octocog alfa) in combination with rVWF 
(vonicog alfa). All observations in safety pharmacology studies are considered to lie 
within the biological variability of animal models or occurred due to known species-
specific anaphylactoid effects of excipients.
6.5.1.3 Pharmacokinetics
Pharmacokinetic studies of both rVWF (vonicog alfa) alone and combined with human 
rFVIII (rVWF+ADVATE) were conducted in VWD mice, VWD dogs, VWD pigs, rats,
and cynomolgus monkeys. Human rVWF (vonicog alfa) stabilized the endogenous FVIII 
in VWD mice, VWD pigs, and VWD dogs. Furthermore, the hypotheses that the area 
under the curve (AUC) with rVWF alone and rVWF+ADVATE is not inferior to the 
AUC with pdVWF (Haemate P) was tested and confirmed statistically in normal rats. 
The PK characteristics of ADVATE (rFVIII, octocog alfa) were not affected by co-
administration of rVWF (vonicog alfa) in cynomolgus monkeys. The PK data in the 
FVIII knock out (k.o.) mice model are inconclusive and might not be relevant for the 
clinical situation. However, a stabilizing effect of VWF on FVIII could be shown in a 
double k.o. model in a dose dependent manner.
6.5.1.4 Toxicology
Single dose toxicity studies were conducted in C57BL/6J-mice, VWD mice, rats, rabbits, 
and cynomolgus monkeys. Rats, rabbits, and cynomolgus monkeys showed no signs of 
toxicity. Signs of microthrombosis, an exaggerated pharmacological effect, were 
observed in mice. Mice are not capable of sufficiently cleaving the rVWF (vonicog alfa) 
subunit as murine disintegrin and metalloproteinase with a thrombospondin type 1 motif, 
number 13 (ADAMTS13) does not decrease the ultra-large molecular weight multimers 
of rVWF (vonicog alfa).13 The observed symptoms of microthrombosis are interpreted as 
a species-specific exaggerated pharmacological effect. Studies evaluating the safety of 
repeated administration of rVWF (vonicog alfa) with or without ADVATE (rFVIII, 
octocog alfa) (daily over 14 days) were performed in a rodent (rat) and non-rodent 
(cynomolgus monkey) species. Reversible signs of exaggerated pharmacological effects 
(regenerative anemia, thrombocytopenia, and treatment-related histopathologic changes 
in the heart, liver, and spleen) were observed in rats that were administered 1400 U 
VWF:RCo/kg /day + 1080 IU ADVATE/kg/day intravenously once daily for 14 days. 
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Also, these findings are interpreted as a species-specific exaggerated pharmacological 
effect due to the low susceptibility of human rVWF (vonicog alfa) to cleavage by rodent 
ADAMTS13.13 No toxicologically relevant changes were evident for clinical 
observations, body weight, feed consumption, ophthalmology, urinalysis, coagulation,
and serum chemistry parameters, platelet aggregation, and gross pathology. rVWF 
(vonicog alfa) combined with ADVATE (rFVIII, octocog alfa) was well tolerated in 
cynomolgus monkeys after daily intravenous (i.v.) (bolus) administration of 100 U 
VWF:RCo/kg rVWF (vonicog alfa) combined with 77 IU/kg ADVATE (rFVIII, octocog 
alfa) over a period of 14 days. No adverse effects could be detected in this species. 
There were no signs of hemolysis, thrombosis, or thrombocytopenia after repeated 
intravenous application of rVWF (vonicog alfa) with or without ADVATE (rFVIII, 
octocog alfa). Therefore, 100 U VWF:RCo/kg/day rVWF (vonicog alfa) with or without 
77 IU/kg ADVATE (rFVIII, octocog alfa) was considered the no observed adverse effect 
level (NOAEL) in this study, which was the highest dose tested. Anti-drug antibodies, 
however, were formed in both species and resulted in a significant reduction in drug 
exposure after 14 applications as compared to a single application. These antibodies 
substantially reduced the systemic exposure to the test substance as compared to a single 
dose administration. No adverse effects due to antibody formation were observed in both 
species.
rVWF (vonicog alfa) combined with ADVATE (rFVIII, octocog alfa) was well tolerated 
locally and no genotoxic potential was evident after 2 in vitro and 1 in vivo genotoxicity 
study. A study on the influence of co-administration of VWF and ADVATE (rFVIII, 
octocog alfa) on the immunogenicity of ADVATE (rFVIII, octocog alfa) in 3 different 
hemophilic mouse models (E17 hemophilic Balb/c mice, E17 hemophilic C57BL/6J 
mice, and E17 hemophilic human F8 transgenic mice) showed that rVWF (vonicog alfa) 
does not negatively impact the immunogenicity of ADVATE (rFVIII, octocog alfa) in 
any of the three different hemophilic mouse models.
6.5.2 Findings from Clinical Studies
The clinical safety, efficacy and PK were assessed in 4 completed trials: one phase 1 
study (070701)) and two phase 3 studies (071001 and 071101) that enrolled patients with 
VWD; one phase 1 study (071104) that enrolled patients with hemophilia A. Details on 
study design, populations enrolled, and safety and efficacy outcomes of the phase 1 
studies are presented in Section 6.5.2.1 and Section 6.5.2.2, the phase 3 study in 
Section 6.5.2.3, and the phase 3 surgery study in Section 6.5.2.4. Information on a single 
subject with VWD in Study 071401 is presented in Section 6.5.2.5.
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6.5.2.1 Study 070701
Phase 1 clinical study 070701 was a multicenter, controlled, randomized, single-blind,
prospective 3-step, dose escalation study to investigate safety, tolerability, and PK of 
rVWF (vonicog alfa) combined at a fixed ratio with ADVATE (VWF:RCo/FVIII:C of 
1.3 ± 0.2:1) in adults with severe VWD.14 Subjects were enrolled in sequential cohorts in 
a dose escalating manner: Cohort 1, 2, and 3 received a single intravenous infusion of 
rVWF:ADVATE at the following doses: 2 IU/kg VWF:RCo (Cohort 1), 7.5 IU/kg 
VWF:RCo (Cohort 2), and 20 IU/kg VWF:RCo (Cohort 3). Subjects in Cohort 4 received 
a single intravenous infusion of rVWF:ADVATE and pdVWF/ADVATE at 50 IU/kg 
VWF:RCo in random order.
The primary endpoint was the tolerability and safety after single dose injections of 
rVWF:ADVATE at 2, 7.5, 20, and 50 IU/kg VWF:RCo for up to 30 days after the last IP 
infusion. The data generated in this phase 1 study suggest that rVWF:ADVATE up to the 
highest investigated dose of 50 IU/kg VWF:RCo is well tolerated and safe in adults with 
severe VWD. No thrombogenic risk or thrombotic thrombocytopenic purpura (TTP)-like 
syndrome was observed, and no neutralizing antibodies to VWF or FVIII were identified. 
There were no deaths or other serious adverse reactions, and no infusions were 
interrupted or stopped due to an AE. Overall, the reported AE profile was similar 
between the recombinant and plasma-derived concentrates.
Secondary endpoints were the PK assessment of VWF:RCo, von Willebrand factor 
antigen (VWF:Ag) and multimeric composition of rVWF (vonicog alfa) as well as 
FVIII:C at standardized time points after single injections of rVWF:ADVATE and 
pdVWF:FVIII. 
The median VWF:RCo terminal half-life (T1/2) of rVWF (vonicog alfa) at the 50 IU/kg 
dose was 16 hours. T1/2 with pdVWF:FVIII at the same dose level appeared shorter at 
12.58 hours, however, the limits of the 90% CI were similar (11.73 to 17.7 hours vs. 
11.87 to 18.03 hours). The median T1/2 of VWF:RCo were shorter with the lower 
investigated doses: 7.13 hours and 13.23 hours with the 7.5 IU/kg and 20 IU/kg doses, 
although these data were derived from a much smaller number of subjects.
In consequence of the missing ADAMTS13 cleavage, ultra-large molecular weight 
(ULMW) multimers are contained in the rVWF (vonicog alfa) final product. The 
immediate cleavage of these ultra-large multimers by ADAMTS13 upon release into the 
circulation could be demonstrated applying sodium dodecyl sulfate polyacrylamide gel 
electrophoresis (SDS-PAGE)/Immunoblot with polyclonal anti-VWF antibodies to detect 
the resulting rVWF (vonicog alfa) subunit cleavage fragments.
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Overall the data generated in this phase 1 study suggest that rVWF (vonicog 
alfa):ADVATE (rFVIII, octocog alfa) is well tolerated and safe in adults with severe 
VWD.
6.5.2.2 Study 071104
This study was a prospective, uncontrolled, non-randomized, multicenter proof of 
concept study to assess safety and PK of the addition of rVWF (vonicog alfa) to 
ADVATE (rFVIII, octocog alfa) treatment in 12 evaluable subjects with severe 
hemophilia A. All subjects underwent 3 PK analyses: the first after infusion with 
ADVATE (rFVIII, octocog alfa) alone, the second after infusion with ADVATE (rFVIII, 
octocog alfa) plus 10 IU/kg rVWF (vonicog alfa) and the third after infusion with
ADVATE (rFVIII, octocog alfa) plus 50 IU/kg rVWF (vonicog alfa).
The PK analysis was performed at intervals of approximately 8 to 14 days. Before each 
infusion for PK assessment, there was a wash-out period of at least 5 days and the 
subjects were not actively bleeding. 
Primary outcome measures indicate that co-administration of rVWF (vonicog alfa) 
slightly sustain ADVATE activity with the highest observed ADVATE (rFVIII, octocog 
alfa) half-life of 13.74 h (CI 11.44 to 16.52) after co-infusion of 50 IU/kg ADVATE plus 
50 IU/kg rVWF:RCo.
The highest improvement in ADVATE (rFVIII, octocog alfa) circulating half-life was 
observed in subjects with VWF:Ag levels below 100% which indicates an association 
between baseline VWF:Ag levels and ADVATE (rFVIII, octocog alfa) half-life increase. 
No treatment related AEs or SAEs were reported. No subject withdrew due to an AE and 
there were no deaths. No binding antibodies to VWF, CHO, and rFurin were detectable in 
the confirmatory assay and no signs of a hypersensitivity to rVWF (vonicog alfa) or 
ADVATE (rFVIII, octocog alfa) antigen were observed. Laboratory values over time did 
not indicate any potential safety risk for hemophilia A patients treated with rVWF 
(vonicog alfa) and ADVATE (rFVIII, octocog alfa) in combination.
In summary, the data indicate that rVWF (vonicog alfa) co-administered with ADVATE 
(rFVIII, octocog alfa) up to the highest dose of 50 IU/kg VWF:RCo is well tolerated and 
safe in hemophilia A patients. 
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6.5.2.3 Study 071001
This was a phase 3, multicenter, open-label, part-randomized clinical study to assess the 
PK, safety, and efficacy of rVWF:rFVIII and rVWF in the treatment of bleeding episodes 
in adult subjects with severe type 3 and severe non-type 3 VWD.15 A total of 49 subjects 
were enrolled (signed informed consent) and screened, 18 subjects were randomized 
(randomization only applies to Arm 1[PK50 with treatment of BE] and Arm 2 [PK50 
only] see below), 37 subjects were treated with IP (all study arms), and 30 subjects 
completed the study.
The study consisted of 2 parts (Part A and Part B). Part A consisted of PK assessments 
alone (Arm 2: PK50 only [without treatment of bleeding episodes]), or PK assessments 
(Arm 1: PK50 and Arm 3: PK80) plus on-demand treatment period(s) of 6 months for 
bleeding episodes, or on-demand treatment for bleeding episodes only (Arm 4). Except 
for subjects in arm 2 who completed study after second PK assessment, subjects  
receiving treatment for PK assessments and/or bleeding episodes in Part A were to be 
entered into Part B to continue on-demand treatment for bleeding episodes for 
6 additional months for a total of 12 months in the study. 
The primary outcome measure was the number of subjects with “treatment success” 
(extent of control of bleeding episodes), which was defined as a mean efficacy rating 
score of <2.5 for a subject’s IP-treated bleeding episodes during the study. The rate of 
subjects with treatment success was 100% (Clopper-Pearson exact 90% CI: 84.7 to 
100.0) for bleeds where the assessments were made prospectively and excluding GI 
bleeds. Sensitivity analyses confirmed the results of the primary analysis.
Crossover results at 50 IU/kg VWF:RCo showed that the PK profile for rVWF (vonicog 
alfa) VWF:RCo was independent of administration alone or with rFVIII (ADVATE, 
octocog alpha) (T1/2: 19.4 hours for rVWF and 16.6 hours for rVWF:rFVIII; IR: 1.8 U/dL 
per IU/kg infused for both rVWF and rVWF:rFVIII; mean residence time (MRT): 
26.7 hours for rVWF and 25.2 hours for rVWF:rFVIII). FVIII levels increased 
substantially with a median peak at 24 hours of 111.0 U/dL for rVWF:rFVIII and 
86.0 U/dL after rVWF alone, indicating that rVWF (vonicog alfa) induces a sustained 
increase in endogenous FVIII activity. The rVWF (vonicog alfa) PK profile was 
comparable at 50 IU/kg and 80 IU/kg VWF:RCo, and repeated PK at 80 IU/kg 
VWF:RCo showed close agreement between pretreatment and end-of-study results.
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Further analysis of the PK data from the 071001 study supports the initial use of 50 IU/kg 
twice weekly for prophylaxis dosing in the present study for those subjects who are 
moving from on-demand to prophylaxis. Using 50 IU/kg for PK measurements, subjects 
in the 071001 study exhibiting a T1/2 for rVWF of 14, 16, or 19 hours had rVWF plasma 
concentrations at 72 hours after administration of 2.55, 4.01, and 6.49% above baseline, 
respectively, and plasma concentrations at 96 hours after administration of 0.78, 1.40, and 
2.71% above baseline, respectively. In this context it should be noted that subjects in the 
present study who have significant spontaneous bleeding while on twice weekly
prophylaxis will have their regimen increased to 3 times per week based on clear criteria 
for different bleeding locations (for details see Section 8.6.4.3.1). Subjects in the present 
study who are switching from prophylaxis with a pdVWF product will begin on rVWF 
(vonicog alfa) using their same weekly total dose in IU/kg VWF:RCo used during their 
pdVWF prophylaxis divided into twice weekly infusions (for details see section 8.6.4.3).
A total of 125 AEs occurred in 25/37 (67.7%) subjects (62/318 infusions [19.5%]) during 
or after infusion with IP. Of these, 116/125 were non-serious (all mild or moderate; none 
were severe), and 9 SAEs were reported in 7 subjects. Of 125 total AEs, 38 were 
temporally associated with IP; 8 AEs were considered causally related to IP: 
6 non-serious related AEs (tachycardia, infusion site paraesthesia, electrocardiogram 
[ECG] t-wave inversion, dysgeusia, generalized pruritis, and hot flush) occurred in 
4 subjects, and 2 related SAEs (chest discomfort and increased heart rate) occurred in 
1 subject. No deaths occurred during this study. 
None of the subjects developed anti-VWF or anti-FVIII neutralizing antibodies and no 
binding antibodies to VWF or rFurin, or antibodies against CHO protein or anti-Murine 
IgG were observed. No clinical or subclinical signs or symptoms of a thrombogenic event 
were observed in this study. Following an initial increase in ultralarge VWF multimers 
after administration of rVWF (vonicog alfa), a notable decrease in the proportion of large 
VWF multimers occurred between 12 and 24 hours post infusion, due to degradation by 
the endogenous ADAMTS13 followed by a continued decline until the end of the 96-hour 
follow-up period. 
Overall, the data support the safe and effective use of rVWF (vonicog alfa) with or 
without rFVIII (ADVATE, octocog alpha) in the treatment of bleeds in patients with 
VWD.
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6.5.2.4 Study 071101
This was a phase 3, prospective, open-label, multicenter clinical study to evaluate 
efficacy and safety of rVWF (vonicog alfa) with or without ADVATE (rFVIII, octocog 
alfa) in elective surgical procedures in adult subjects with severe VWD. A total of 
24 subjects were enrolled (signed informed consent) and screened, 15 subjects were 
treated with rVWF (vonicog alfa), and 15 subjects completed the study. 
Eleven subjects underwent a PK assessment by infusion of 50 ± 5 IU/kg rVWF:RCo at an 
infusion rate of up to 4 mL/min. 12 to 24 hours before surgery, subjects received a dose 
of 40 to 60 IU/kg rVWF:RCo. Within 3 hours prior to surgery, the subject’s FVIII:C 
levels were assessed with a target of 30 IU/dL for minor and oral surgeries and 60 IU/dL 
for major surgeries. Within 1 hour prior to surgery, subjects received a dose of  rVWF 
(vonicog alfa) with or without ADVATE (rFVIII, octocog alfa) (depending on the target 
FVIII:C levels at the 3 hour assessment). VWF and FVIII IR and T1/2 for each subject, 
when known, were used to guide the initial dose and subsequent doses.
The primary outcome measure was the overall assessment of hemostatic efficacy assessed 
by the investigator (hemophilia physician) 24 hours after last perioperative IP infusion or 
at completion of day 14 visit, whichever occurred earlier, and was summarized by the 
percentage of subjects in each efficacy category (“excellent”, “good”, “moderate” and 
“none”). Point estimate and corresponding 90% two-sided exact CI was calculated for the 
rate of subjects with an overall assessment of hemostatic efficacy. All 15 subjects treated 
with rVWF (vonicog alfa) (with or without ADVATE) for major (10), minor (4), and oral 
(1) elective surgical procedures had overall hemostatic efficacy ratings of “excellent” or 
“good”. Most (73.3%) subjects had “excellent” overall hemostatic efficacy ratings; of 
these, 7 underwent major surgery and 4 underwent minor surgery. The remaining 26.7% 
subjects had “good” overall hemostatic efficacy ratings: 3 underwent major surgery and 
1 underwent oral surgery. All 8 subjects with VWD Type 3, the subtype classified as 
absolute VWF deficiency, had overall hemostatic efficacy ratings of “excellent” (87.5%) 
or “good” (12.5%).
Intraoperative hemostatic efficacy ratings were also rated as “excellent” or “good” for all 
15 treated subjects. Most (86.7%) subjects had “excellent” intraoperative hemostatic 
efficacy ratings; of these, 8 underwent major surgery, 4 underwent minor surgery, and 
1 underwent oral surgery. Two (13.3%) subjects who underwent major surgery had 
“good” intraoperative hemostatic efficacy ratings. Intraoperative hemostatic efficacy 
was rated as “excellent” or “good” for all subjects with VWD Type 3: “excellent” for 
7 (87.5%) subjects and “good” for 1 (12.5%) subject. 
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Only 1 subject received an intraoperative dose of rVWF (18.1 IU/kg) and ADVATE 
(8.1 IU/kg). The median daily postoperative weight-adjusted dose of rVWF (vonicog 
alfa) (with or without ADVATE) was 23.5 IU/kg on postoperative Day 1 (n=3) and 
25.5 IU/kg on postoperative Day 14 (n=2). In subjects treated with rVWF:ADVATE, the 
daily postoperative weight-adjusted dose was 16.9 IU/kg rVWF and 7.6 IU/kg ADVATE 
on postoperative Day 1 (n=1) and decreased to 50.8 IU/kg rVWF and 7.6 IU/kg 
ADVATE on postoperative Day 7 (n=1). For subjects treated with rVWF alone, the 
median weight-adjusted dose (Q1, Q3) of rVWF was 35.4 IU/kg on postoperative Day 1 
(n=2) and decreased to 23.7 IU/kg on postoperative Day 7 (n=4) and 25.5 IU/kg on 
postoperative Day 14 (n=2).
A total of 11 subjects were evaluated for PK in the study. As expected, postinfusion 
increases in concentrations of VWF:RCo, VWF:Ac, VWF:Ag, and VWF collagen 
binding (VWF:CB) were observed. Mean values for VWF:RCo were as follows: 
AUC0-∞/dose was 37.50 hours*IU/dL per IU/kg infused; AUC0-72h/dose was 
34.08 hours*IU/dL per IU/kg infused; T1/2 was 17.83 hours; MRT was 24.32 hours; 
CL was 0.03117 dL/hour/kg; and volume of distribution at steady state (Vss) was 
0.6837 dL/kg. Median values for VWF:RCo were as follows: AUC0-∞/dose was 
32.94 hours*IU/dL per IU/kg infused; AUC0-72h/dose was 31.70 hours*IU/dL per IU/kg 
infused; T1/2 was 14.62 hours; MRT was 21.80 hours; CL was 0.03036 dL/hour/kg; and 
Vss was 0.7078 dL/kg. The VWF:RCo activity was consistent with that previously 
observed in clinical studies 071001 and 070701.
rVWF (vonicog alfa) was safe and well tolerated in adults with severe VWD undergoing 
major, minor, and oral elective surgical procedures. Of the 12 total treatment-emergent 
AEs (TEAEs) that occurred during the study, 2 deep vein thrombosis events (1 non-
serious and 1 serious, as a part of one case) reported in one subject, who underwent total 
hip replacement surgery and who had concurrent condition of obesity, was assessed by 
the sponsor as possibly causally-related to study treatment. None of the TEAEs were 
either a severe allergic or hypersensitivity reaction or developed due to a severe allergic 
reaction. 
One subject with VWD Type 3 who had an intraoperative transfusion of packed red 
blood cells during total knee replacement surgery tested positive for binding antibodies to 
VWF on postoperative Day 7 through study completion. No subjects developed 
neutralizing antibodies to rFVIII or binding antibodies to CHO, rFurin, or murine IgG.
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In summary, the data support the safe and effective use of rVWF (vonicog alfa) with or 
without ADVATE (rFVIII, octocog alfa) in achieving intra- and post-operative 
hemostasis in adult subjects with severe VWD undergoing major, minor, and oral elective 
surgical procedures.
6.5.2.5 Study 071401: Single Subject with von Willebrand Disease
One subject who exhibited allergic reactions to currently marketed pdVWF products was 
treated in the single-subject study 071401 with rVWF (vonicog alfa) only for the bleed 
treatment of continued hematuria, and for biopsy and surgical resection of a left-kidney 
mass.
For the initial rVWF (vonicog alfa) infusion, the subject received a test dose of 5% of 
the total dose of 60 IU/kg rVWF:RCo at an infusion rate of 1 mL/min. After a 10 to 
15-minute observation period, no adverse symptoms or signs were noted and the subject 
received the remaining 95% of the total dose. The subject was monitored for any signs of 
an allergic reaction, and none were noted. Treatment with rVWF (vonicog alfa) every 
12 to 24 hours was to continue at the discretion of the investigator based on VWF levels 
and clinical symptomatology. The subject had an excellent response and recovery, which 
allowed for daily dosing of rVWF (vonicog alfa) and, within 24 hours, the subject’s 
bleeding had stopped. Daily dosing of rVWF (vonicog alfa) was maintained and the 
subject received his last dose on 
.
The subject also received rVWF (vonicog alfa) for 7 days for prophylaxis for surgery 
(surgical resection of a left-kidney mass). The subject experienced no hemorrhagic 
complications and no AEs that were considered related to the use of rVWF (vonicog 
alfa).
6.6 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) to 
Human Subjects
Current treatment of VWD patients relies on desmopressin and VWF products 
manufactured from pooled human plasma. Human VWF produced by recombinant 
technology could offer a new perspective in treatment of VWD. The benefit for the 
individual subject is anticipated to be significant during this clinical study. He/she may 
benefit from a product that minimizes excessive FVIII administration and thus allowing 
individualized dosing of VWF at optimal levels. Variations in VWF multimeric 
composition may lead to variability with respect to treating or preventing bleeds in 
VWD subjects, especially mucosal bleeds which are especially problematic. rVWF 
(vonicog alfa) product manufactured by Baxalta consistently contains ULMW VWF 
multimers due to the fact that the product has not been exposed to ADAMTS13. 
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The initial presence of these ULMW VWF multimers, which are subsequently cleaved by 
the subject’s endogenous ADAMTS13, may result in improved platelet and collagen 
binding and therefore provide more predictable treatment outcomes.
By using a recombinant product, the risk of transmission of adventitious agents and other 
blood-borne pathogens associated with the use of products of human or animal origin has 
been eliminated. At this stage of product development, the key societal benefit is a better 
understanding of advanced treatment options for VWD and enhanced product 
availability.
These benefits outweigh the following identified or potential risks of rVWF (vonicog 
alfa):

allergic-type hypersensitivity reactions as with any intravenous protein product

the occurrence of thromboembolic events

the development of neutralizing antibodies to VWF
Refer to the IB for further details on benefits and risks of the IP.
6.7 Compliance Statement
This study will be conducted in accordance with this protocol, the International Council 
for Harmonisation Guideline for Good Clinical Practice E6 (ICH GCP, April 1996, with 
Addendum E6(R2) dated Nov 2016 EMA/CHMP/ICH/135/1995), Title 21 of the US 
Code of Federal Regulations (US CFR), the EU Directives 2001/20/EC and 2005/28/EC, 
the Declaration of Helsinki and applicable national and local regulatory requirements.
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7. STUDY PURPOSE AND OBJECTIVES
7.1 Study Purpose
The purpose of this phase 3 study is to investigate the efficacy and safety, including 
immunogenicity, thrombogenicity and hypersensitivity reactions, as well as 
pharmacokinetics (PK), 
 and 
 
of prophylactic treatment with rVWF (vonicog alfa) in adult subjects with severe VWD.
7.2 Primary Objective
The primary objective of this study is to prospectively evaluate the ABR for spontaneous 
bleeding episodes while on prophylactic treatment with rVWF (vonicog alfa) and to 
compare it to the subject’s historical ABR for spontaneous bleeding episodes.
7.3 Secondary Objectives
Secondary Objectives are to assess:

Additional efficacy of prophylactic treatment with rVWF (vonicog alfa)

Safety of rVWF (vonicog alfa), including immunogenicity, thrombogenicity and 
hypersensitivity 

Pharmacokinetics (PK) of rVWF (vonicog alfa) and pharmacodynamics (PD) of 
rVWF (vonicog alfa) as measured in FVIII activity 
7.4 Exploratory Objectives
 
 
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8. STUDY DESIGN
8.1 Overall Study Design 
This is a prospective, open label, uncontrolled, non-randomized, international, 
multicenter phase 3 study to evaluate efficacy, safety (including immunogenicity, 
thrombogenicity and hypersensitivity reactions), as well as PK, 
 and 
 of prophylactic treatment regimen with rVWF (vonicog alfa) in adult 
patients with severe VWD. 
Subjects transitioning from on-demand treatment (OD subjects) or subjects switching 
from prophylactic treatment with pdVWF (pdVWF switch subjects) will receive 
prophylactic treatment with rVWF (vonicog alfa) for a 12-month period (up to 15 months 
for the qualified subjects to rollover into the continuation study, if the continuation study 
start up is delayed beyond the completion of subject’s 12-month visit). The dose will be 
50 ± 10 IU/kg rVWF twice weekly for OD subjects or will be based on their prior 
pdVWF dose for pdVWF switch subjects, and dose may be further individualized based 
on the PK data, subject’s history of bleeding episodes, and the results from clinical and 
laboratory assessments (see Section 8.6.4.3).
The overall duration of prophylactic treatment with rVWF per subject will be at least 
12 up to 15* months.
During this period any bleeding episodes requiring substitution therapy with VWF 
concentrate to control bleeding will be treated with rVWF (vonicog alfa) with or without 
ADVATE (rFVIII, octocog alfa). The dose will be according to the bleeding type and 
severity and it will be adjusted to the clinical response (see Section 8.6.4.4.2).
The overall study design is illustrated in Figure 1.
* Study treatment period is extended by 3 months to accommodate participation in the 
continuation study for the qualified subjects and will be exercised only if the continuation study 
start up is delayed beyond the completion of subject’s 12-month visit. 
8.2 Duration of Study Period(s) and Subject Participation
The overall duration of the study is approximately 27 months from study initiation 
(i.e., first subject enrolled) to study completion (i.e., last subject last visit). The subject 
participation period is approximately 15 to 18* months from enrollment to completion 
(i.e, last study visit), unless the subject is prematurely discontinued.
* Study treatment period is extended by 3 months to accommodate participation in the 
continuation study for the qualified subjects and will be exercised only if the continuation study 
start up is delayed beyond the completion of subject’s 12-month visit. 
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8.3 Outcome Measures
8.3.1 Primary Outcome Measure
8.3.1.1 Efficacy 

Annualized bleeding rate (ABR) for spontaneous (not related to trauma) bleeding 
episodes during prophylactic treatment with rVWF (vonicog alfa)
8.3.2 Secondary Outcome Measures
8.3.2.1 Additional efficacy of Prophylactic Treatment with rVWF (vonicog alfa)

ABR percent reduction success for OD subjects defined as at least 25% reduction 
of ABR for spontaneous (not related to trauma) bleeding episodes during rVWF 
(vonicog alfa) prophylaxis relative to the subject’s own historical ABR during on-
demand treatment 

ABR preservation success for pdVWF switch subjects defined as achieving an 
ABR for spontaneous bleeding episodes during rVWF (vonicog alfa) prophylaxis 
that is no greater than the  subject’s own historical ABR during prophylactic 
treatment with pdVWF

Categorized spontaneous ABR defined as 0, 1-2, 3-5, or >5 bleeding episodes 
during the prophylactic treatment with rVWF (vonicog alfa)

Total number of infusions and the average number of infusions per week during 
prophylactic treatment with rVWF (vonicog alfa)

Total weight adjusted consumption of rVWF (vonicog alfa) during prophylactic 
treatment 

Spontaneous ABR by location of bleeding (GI, epistaxis, joint bleeding, 
menorrhagia, oral and other mucosa, muscle and soft tissue, etc.) while on 
prophylactic treatment with rVWF (vonicog alfa)
8.3.2.2 Safety

AEs: incidence, severity, causality

Thromboembolic events 

Hypersensitivity reactions

Development of neutralizing antibodies to VWF and FVIII 

Development of total binding antibodies to VWF and FVIII
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
Development of binding antibodies to CHO proteins, mouse immunoglobulin G 
(IgG) and rFurin

Clinically significant changes in vital signs and clinical laboratory parameters
relative to baseline
8.3.2.3 Pharmacokinetics (PK) and Pharmacodynamics (PD)

PK parameters after a washout for on-demand subjects: incremental recovery 
(IR), T1/2, MRT, area under the concentration versus time curve from 0 to infinity 
(AUC0-), area under the concentration versus time curve from 0 to the last 
measurable concentration (AUC0-tlast), maximum plasma concentration (Cmax), 
minimum time to reach the maximum concentration (Tmax), volume of distribution 
at steady state (Vss) and clearance (CL) based on VWF:Rco activity, VWF:Ag, 
VWF:CB activity. 

PD parameters after a washout for on-demand subjects: Cmax, Tmax, and AUC0-tlast
as measured in FVIII activity by the 1-stage clotting assay (FVIII:C). 

PK parameters at steady state for on-demand and switch subjects: area under the 
concentration versus time curve from 0 to end of the partial dosing interval 
(AUC0-tau;ss), maximum concentration during the partial dosing interval (Cmax;ss), 
minimum time to reach the maximum concentration (Tmax;ss) and minimum 
concentration during the partial dosing interval (Cmin;ss) based on VWF:RCo, 
VWF:Ag and VWF:CB. PK parameters at steady state will be assessed shortly 
after reaching steady state for switch subjects and at the end of the study for on-
demand as well as for switch subjects all based on the longer interval of the 
irregular dosing intervals employed. 

PD parameters at steady state for on-demand and switch subjects: AUC0-tau;ss, 
Cmax;ss, Tmax;ss, and Cmin;ss as measured in FVIII activity by the 1-stage clotting 
assay. PD parameters at steady state will be assessed shortly after reaching steady 
state for switch subjects and at the end of the study for on-demand as well as for 
switch subjects all based on the longer interval of the irregular dosing intervals 
employed.

Time course of FVIII clotting activity (FVIII:C) levels.
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8.3.3 Exploratory Outcomes Measures
8.3.3.1
 
 
 
 
 
8.3.3.2
 
 
 
 
 
8.3.3.3
 
8.3.3.4
 
 
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8.4 Randomization and Blinding
This is a non-randomized open-label, active treatment clinical study. 
8.5 Study Stopping Criteria 
This study will be stopped if 1 or more of the following criteria are met in the absence of 
any other possible and medically plausible causal attribution (eg, underlying or 
concurrent condition, use of concomitant medication, subject’s medical history, etc):
1.
Two subjects develop a life-threatening or fatal thromboembolic event
2.
Two subjects develop life-threatening or fatal severe hypersensitivity reactions 
(e.g., anaphylaxis)
3.
Any subject develops acute hepatic failure 
4.
Two subjects develop rVWF neutralizing antibodies that are considered clinically 
significant by the investigators and are associated with significant decrease of 
efficacy or serious adverse reactions.
The study may be stopped at any time by the sponsor.
The sponsor ultimately will decide whether to terminate, temporarily halt or modify the 
study based on the data monitoring committee (DMC)’s review and recommendation on 
all relevant cases including those that meet the stopping criteria listed above.
8.6 Investigational Product(s)
8.6.1 Packaging, Labeling, and Storage
8.6.1.1 rVWF (Recombinant von Willebrand Factor, vonicog alfa)
rVWF (vonicog alfa) will be packaged in boxes with 2 glass vials, one containing the 
rVWF powder, and the second vial containing the diluent (water for injection). Further 
details are provided in the IB and Pharmacy Manual. The rVWF label will include, at a 
minimum, the actual VWF:RCo potency and the date of expiration.
rVWF (vonicog alfa) is a powder that should be stored refrigerated (2-8°C [36-46°F]) . 
Deviations from the storage condition have to be communicated and followed up with 
the sponsor. Inadequately stored product will have to be placed in quarantine and may 
only be used after written IP administration authorization by the sponsor. After removal 
of the product from the refrigerator the product must not be returned to the refrigerator. 
The reconstituted product has to be used immediately (at least within 3 hours). 
rVWF (vonicog alfa) must not be used beyond the expiration date printed on the vial 
label. Avoid freezing at all times.
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8.6.1.2 rFVIII (Recombinant Factor VIII, octocog alfa /ADVATE)
ADVATE (rFVIII, octocog alfa) will be packaged in boxes with 2 glass vials, one 
containing the lyophilized rFVIII, and the second vial containing the diluent. Further 
details are provided in the IB and Pharmacy Manual. The ADVATE label will include, 
at a minimum, the actual FVIII:C potency and the date of expiration. 
ADVATE (rFVIII, octocog alfa) should be refrigerated (2-8°C [36-46°F]) in powder 
form and should not be used beyond the expiration date printed on the vial. 
Deviations from the storage condition have to be communicated and followed up with the 
sponsor. Inadequately stored product will have to be placed in quarantine and may only 
be used after written IP administration authorization by the sponsor. After removal of the 
product from the refrigerator the product must not be returned to the refrigerator and has 
to be used immediately. Avoid freezing at all times.
8.6.2 Reconstitution
The reconstitution procedures for both rVWF (vonicog alfa) and ADVATE (rFVIII, 
octocog alfa) products are detailed in the Pharmacy Manual. 
8.6.3 Administration
Following reconstitution, rVWF (vonicog alfa) and ADVATE (rFVIII, octocog alfa) (in 
case of bleeding episode treatment) should be administered to study subjects at room 
temperature and within 3 hours of reconstitution. The reconstituted rVWF (vonicog alfa) 
and ADVATE (rFVIII, octocog alfa), should be inspected for particulate matter and 
discoloration prior to administration, whenever the solution and container permit. The 
solution should be clear and colorless in appearance. If not, do not administer the product. 
Plastic syringes provided by the sponsor must be used since coagulation factors tend to 
stick to the surface of glass syringes.
Investigational product infusions should be given at a slow enough rate to ensure the 
subject’s comfort. The rate should not exceed 4 mL/minute The investigator/ subject shall 
ensure that no visible residual volume remains in the syringe(s) and that the complete 
content is administered. Upon completion of the infusion, the butterfly catheter should be 
flushed with at least 2 mL of saline solution. In case of a (central) venous access device, 
the flush should be with at least 10 mL of saline solution. The IP infusions should be 
administered over a duration of 2 to 20 minutes, depending on the volume.
Only the actual potencies of rVWF (vonicog alfa) and ADVATE (rFVIII, octocog alfa) as 
stated on the vial labels and described in the Pharmacy Manual should be used.
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A variation of up to 10% of the intended dose for prophylactic infusions and of the 
intended dose for treatment of bleeding episodes is permissible and the exact dose should 
be recorded on the Case Report Form (CRF). Using of partial vials is not allowed.
At study visits where recovery analysis is being done, vials with the same lot numbers 
should be used throughout the PK IP infusion per subject.
For treatment of bleeding episodes, sequential administration will be done: separate 
syringes of the appropriate dose of rVWF (vonicog alfa) and ADVATE (rFVIII, octocog 
alfa) will be prepared for sequential infusion. rVWF (vonicog alfa) should be infused first 
sequentially followed preferably within 10 minutes by infusion of ADVATE (rFVIII, 
octocog alfa). Only the actual potencies of rVWF (vonicog alfa) and ADVATE (rFVIII, 
octocog alfa) as stated on the vial labels and described in the Pharmacy Manual should be 
used. 
The final dose of rVWF (vonicog alfa):ADVATE (rFVIII, octocog alfa) should be at a 
ratio of 1.3:1 ± 0.2.
8.6.4 Description of Treatment
8.6.4.1 PK-Assessment Treatment
For on-demand subjects, two PK assessments will be performed: an initial PK 
assessment after a wash-out period and a steady state PK assessments at the end of the 
study. The IP infusion for the initial PK assessment is scheduled on the baseline visit, 
which should be within 42 days after the completion of screening procedures and 
confirmation of eligibility. At the baseline visit the subjects will receive a dose of 
50 ± 5 IU/kg rVWF:RCo for PK assessment. Blood samples will be drawn within 
30 minutes pre-infusion, and at 11 time points post-infusion (15 ± 5 minutes, 
30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 
24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours and 96 ± 2 hours). A washout 
period of at least 5 days is required prior to infusion of rVWF (vonicog alpha) for PK 
assessment. The 2nd PK assessment for on-demand subjects will be performed at steady 
state at the end of the study(see Section 11.6). Subjects previously enrolled in rVWF 
studies 070701, 071001 or 071101 and having previously undergone PK assessments in 
these studies are required to repeat the PK assessment due to different dose and time 
points used in these former studies.
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For pdVWF switch subjects, two steady state PK assessments will be performed. 
The 1st PK will be assessed shortly after reaching steady state, which is expected to be 
11 days after the 1st prophylactic dose for majority of the subjects, around the 
prophylactic dose #5-6. The 2nd PK will be at the end of the study. For steady state PK, 
blood samples will be drawn within 30 minutes pre-infusion, and at 11 time points post-
infusion (15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 
12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours and 96 ± 2 hours) 
as long as it won’t interfere with subject’s the normal dosing schedule, otherwise the 
96 hr sampling can be omitted (see Section 11.6). Final sample for PK analysis should be 
taken before next dose is administered.
8.6.4.2 Prophylaxis Initiation Treatment 
The rVWF (vonicog alfa) prophylaxis initiation treatment visit will coincide with the 
96 2 h initial PK assessment for on-demand subjects. For pdVWF switch subjects, the 
rVWF (vonicog alfa) prophylaxis initiation treatment visit should occur within 42 days 
after the completion of screening procedures and confirmation of eligibility. At this visit 
subjects will receive their prophylaxis initiation dose. The prophylaxis doses are 
described in Section 8.6.4.3.
The subject will be trained on IP reconstitution and administration and may then qualify 
for home treatment (see Section 8.6.4.3.2). Refer to Table 6 (a/b) for study procedures 
and Table 8(a/b) for clinical laboratory assessments.
8.6.4.3 Prophylaxis Treatment
For on-demand subjects, the standard prophylactic dose is 50 ± 10 IU/kg rVWF:RCo, 
which may be increased up to 80 IU/kg. All on-demand subjects will initially receive 
rVWF (vonicog alfa) twice per week (Table 1, Schedule A). Examples of all dosing 
schedules are provided in Table 1.
For pdVWF switch subjects, the weekly dose (IU/kg) of IP for each patient will be 
equivalent (± 10%) to the weekly VWF dose received during prophylactic treatment with 
pdVWF. The weekly dose of IP should be divided into 2 infusions (Table 1, Schedule A), 
with a maximum of 80 IU/kg/infusion. If needed, based on the total weekly dose or other 
clinical judgements, the weekly dose may be given as three infusions (Table 1, 
Schedule B). A once weekly dose regimen will be allowed after switch to rVWF 
(vonicog alfa) only if the patient has been on a once weekly dose regimen with pdVWF.
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Table 1
rVWF (vonicog alfa) Dosing Schedule Examples: Schedules A and B
Example
M
T
W
Th
F
Sat
Sun
M
T
W
Th
F
Sat
Sun
Schedule A
X
X
X
X
Schedule B
X
X
X
X
X
X
The prophylaxis dose may be further individualized within the range based on:

available historical PK data

type and severity of bleeding episodes the subject has experienced in the past and

monitoring of appropriate clinical and laboratory measures
The individualized prophylaxic dose assignment will have to be agreed with the sponsor 
in advance, and the rationale should be well documented.
8.6.4.3.1 Adjustment of Dose or Dose Interval
In general, the dose and/or dose interval for each subject should not be changed unless 
prompted by clear medical needs. Dose and frequency adjustments should be agreed with 
the sponsor in advance unless it constitutes an urgent safety measure. The rationale for 
dosing adjustments needs to be documented in the subject’s medical record.
For both OD and switch patients, dose escalations (not exceeding the upper dose limit of 
80 IU/kg rVWF:RCo) and increase of dose frequency will only be allowed in case of 
insufficient therapeutic response with breakthrough bleeding episodes. The criteria for 
dose and/or frequency escalation are specific to each bleeding indication but, overall, 
involve 1 significant breakthrough bleeding episode despite the subject being compliant 
with scheduled prophylaxis treatment. For switch patients  who require a dose escalation 
due to a breakthrough bleed, the frequency should be kept the same but the dose 
(IU VWF:RCo per infusion) should be increased up to 80 IU VWF:RCo. Following that, 
increases in frequency may be considered upon consultation with the Sponsor. For on 
demand subjects who require a dose escalation, at the discretion of the PI upon 
consultation with the Sponsor, the frequency may be kept the same but the dose 
(IU VWF:RCo per infusion) should be increased up to 80 IU VWF:RCo. If this proves to 
be insufficient, then the dosing frequency may be increased in these subjects. Table 2
presents the criteria for dosing escalation per each bleeding indication taken 50 ± 10 IU 
VWF:RCo/kg twice weekly dose as an example of subject’s assigned starting dose. 
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The criteria are applicable for both OD and switch subjects who were initially assigned to 
twice weekly dosing. Subjects entering the study will begin prophylaxis treatment 
according to Schedule A (Table 1) and will remain at this dose and frequency until 
meeting the criteria for escalation to the next higher schedule: for example, from 
2 infusions of 50 ± 10 IU VWF:RCo/kg/week to 3 infusions of 50 ± 10 IU 
VWF:RCo/kg/week (Schedule B) to achieve an adequate therapeutic response. If a 
subject started with a weekly dose (possible for switch subjects), similar criteria would 
apply except that the subject will be excalated to twice weekly dosing if frequency 
change is necessary.
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Table 2
Criteria for Escalation Specific to Each Bleeding Indication
Schedule A
Schedule B
Joint bleeding
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) twice per week. In the event a 
spontaneous joint bleeding episode occurs 
while on this regimen, the subject will escalate 
to up to 80 IU/kg twice per week or, if 
necessary, to Schedule B following its 
resolution
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week.
GI bleeding
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) twice per week. In the event a 
severe GI bleeding episode, i.e., requiring red 
blood cell transfusion, occurs while on this 
regimen, the subject will escalate to up to 
80 IU/kg twice per week or, if necessary, to 
Schedule B following its resolution
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week.
Menorrhagia
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) on days 1 and 2 of menses for 
2 cycles. Menstrual flow will be monitored by 
the PBAC score. If the average pictorial chart 
score is > 185, then the subject will escalate to 
up to 80 IU/kg or, if necessary, to Schedule B
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) on days 1, 2, 
and 3 of menses. Menstrual flow 
will be monitored by the PBAC 
score.
Epistaxis
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) twice per week. The subject will 
escalate to up to 80 IU/kg twice per week or, if 
necessary, to Schedule B in the event of 
1 occurrence of breakthrough bleeding 
requiring intervention such as iron 
replacement therapy, transfusion, packing, 
hospitalization; or 2 bleeding events that 
require treatment with factor replacement
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week. 
Oral and Other 
Mucosa
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) twice per week. The subject will 
escalate to up to 80 IU/kg twice per week or, if 
necessary, to Schedule B in the event of 
1 occurrence of breakthrough bleeding 
requiring intervention such as iron 
replacement therapy, transfusion, packing, 
hospitalization; or 2 bleeding events that 
require treatment with factor replacement.
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week.
Muscle and Soft 
Tissue
50 ± 10 IU VWF:RCo/kg (rounded up to the 
nearest vial) twice per week. In the event a 
spontaneous bleeding episode occurs while on 
this schedule, the subject will escalate to up to 
80 IU/kg twice per week or, if necessary, to 
Schedule B following its resolution.
50 ± 10 IU VWF:RCo/kg (rounded 
up to the nearest vial) 3 times per 
week.
Abbreviations:  GI: gastrointestinal; PBAC: Pictorial Blood Assessment Chart.
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If a subject does not adequately respond to rVWF (vonicog alfa) therapy, he/she will be 
evaluated for the presence of neutralizing and total binding anti-VWF antibodies (see 
Section 12.9.3.2).
If a subject experiences a bleed while receiving rVWF (vonicog alfa) three times per 
week, the investigator should treat the bleed with rVWF (vonicog alfa) at doses up to 
80 IU VWF:RCo/kg at a frequency determined by the investigator until the bleed 
resolves. Upon resolution of the bleeding event, the subject will return to their assigned 
prophylaxis regimen. 
It is essential for the success of this study that the subjects adhere to treatment regimens. 
Therefore, procedures for monitoring subject’s compliance are implemented (see 
Section 10.7).
If 1 infusion of IP is missed, the subject may administer the IP as soon as possible. The 
subject should adhere to their treatment scheme ensuring a minimum interval of 12 hours 
between this and the previous IP infusion. For example, a subject routinely infuses IP on 
Monday and Thursday, he/she misses the Monday time point and therefore may infuse 
the IP on the next day (Tuesday) and thereafter proceed with infusing the IP on Thursday
(considering a minimum 12 hours between the infusions) and return to the initial 
schedule.
If more than 30% of infusions of IP are missed within the visit interval of 3 months the 
subject will be discontinued from the study (see Section 9.4).
8.6.4.3.2 General Instructions for Home Treatment for Prophylaxis
At the discretion of the investigator, a subject may be considered suitable for home 
treatment only after the subject has received at least 1 infusion of IP in the clinic, either 
during planned prophylactic IP exposure or during the treatment of bleeding episodes, 
and meets the following additional criteria:
1.
Fully understands the concept of a clinical study and related documentation 
(documented training of at least 30 minutes), 
2.
Has a history of previous experience with home treatment including 
self-administration and treatment with VWF containing concentrates, 
3.
Has adequate time for initial training of the study drug preparation (preparation, 
mixing and infusion of the IP(s) (documented training of at least 30 minutes).
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This applies both to subjects who were on prior on-demand treatment and to subjects 
switching form prophylaxis with pdVWF. In the event a healthcare professional is 
required to administer IP, he/she must be trained and qualified by the investigator on the 
above procedures prior to the decision for home treatment. A Subject Guideline detailing 
all instructions and information listed above will be provided to each subject.
8.6.4.4 Treatment of Bleeding Episodes
8.6.4.4.1 General Instructions for Home Treatment of Bleeding Episodes
If a subject experiences a bleeding episode, he/she should contact the study site 
immediately and the site investigator should provide instructions on the treatment 
regimen. If the subject initiates the treatment at home, he/she should at least follow up 
with the study site if a visit is needed as per the standard of care at the center.
In the event a healthcare professional is required to administer treatment at the subject’s 
home, he/she must be trained and qualified by the site investigator on the above 
procedures prior to the decision for home treatment. Once a subject has received 
1 infusion of rVWF (vonicog alfa) in the clinic (either during planned IP exposure or 
during the treatment of a bleeding episode) and meets the criteria for home treatment, the 
treatment of bleeding episodes with IP can be conducted at home (see Section 8.6.4.3.2).
If a subject is not qualified for home treatment, rVWF (vonicog alfa) infusions must be 
administered at the study site.
If a subject experiences a bleeding episode that requires treatment between the screening 
and the prophylaxis initiation visit, the subject will be treated with IP (rVWF with or 
without ADVATE). Treatment with IP must occur at the study site unless the subject has 
previously qualified for home treatment with rVWF (vonicog alfa). If rVWF (vonicog 
alfa) treatment is not feasible, the subject may use his/her standard of care, such as 
commercial pdVWF/FVIII products. In any case a washout period of at least 5 days is 
required prior to rVWF (vonicog alfa) PK infusion at the initial PK assessment visit for 
on-demand subjects.
If a subject experiences a bleeding episode requiring treatment during the PK assessment, 
rVWF (vonicog alfa) should be used to treat the bleed. Blood draws for PK assessment 
will be stopped and the PK assessments will be repeated once the bleed has resolved and 
the subject is free of any symptoms related with the bleeding episode. Dose and 
frequency of rVWF (vonicog alfa) infusions or any other replacement therapy to stop the 
bleed should be recorded in the electronic Case Report Form (eCRF), and the reason for 
the use of any non-IP product or therapy should be documented.
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8.6.4.4.2 Dosing Recommendations for Treatment of Bleeding Episodes 
If an acute bleeding episode occurs, the subject will be treated with rVWF (vonicog alfa) 
with or without ADVATE (rFVIII, octocog alfa). It is the sponsor’s opinion that, in many 
cases, treatment with ADVATE (rFVIII, octocog alfa) may not be necessary, since rVWF 
(vonicog alfa) prophylaxis will serve to increase endogenous FVIII levels. However, if 
endogenous FVIII is below 30-40 % or is unknown and cannot be estimated from the 
subject’s PK study, an infusion of rVWF: ADVATE at an rVWF: ADVATE ratio of 
1.3:1± 0.2 should be administered initially. Subsequent infusions should be with 
rVWF:RCo 40 to 60 IU/kg with or, in  many cases, without 30 to 45 IU/kg ADVATE 
(only to be administered if plasma FVIII levels fall below 30 IU/L during the treatment 
period). Dosing may be adjusted downward or upward up to 80 IU/kg rVWF at the 
treating physician’s discretion based upon the subject’s prior history, PK and other 
factors.
If FVIII levels are not available, dosing is at the discretion of the investigator based upon 
the individual subject’s PK data. Using ADVATE (rFVIII, octocog alfa) in addition to 
rVWF (vonicog alfa) in subsequent doses carries the risk of an excessive rise in FVIII:C. 
Therefore, reduced doses of ADVATE (rFVIII, octocog alfa) and/or prolongation of the 
dose interval should be considered. 
The following is general guidance and the sponsor’s suggestion for treatment of 
breakthrough bleeds, however each PI will determine the treatment based on the local 
acceptable practice how to monitor and adjust treatment for a bleeding episode. An effort 
should be made to discuss with the sponsor (or sponsor’s delegate) the treatment strategy.
In general the aim of the initial dose should be full replacement of VWF with VWF:RCo 
levels of >0.6 IU/ml (60%) and FVIII:C of >0.4 IU/mL (40%). In major bleeding 
episodes, subsequent doses should keep the trough level of VWF:RCo >50% for 3 days 
and then as deemed necessary by the investigator for subsequent days. In moderate 
bleeding episodes, the dose and trough level may be reduced to >30% for as long as 
deemed necessary by the investigator. Treatment for minor bleeding episodes will 
generally consist of only 1 or 2 doses of rVWF (vonicog alfa) IP. 
If the VWF:RCo level is above 150%, a planned treatment should be delayed by at least 
12 hours; if the VWF:RCo level is above 200%, a planned treatment should be delayed 
by at least 24 hours. In either case, a lower subsequent dose (e.g., 20 IU/kg VWF:RCo) 
may be appropriate.
Dosing recommendations are listed in Table 3.
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Dosage must be individualized based on the subject’s weight, VWD type, and the 
severity of the bleeding episode, as well as on monitoring of appropriate clinical and 
laboratory measures. In the phase 1 study 070701, 1.0 IU/kg VWF:RCo raised the 
circulating level of VWF:RCo by 0.017 IU/mL (1.7 %). In the same study, the observed 
mean half-life for rVWF (vonicog alfa) was 19.3 hours, with a standard deviation of 
10.9 hours.
Table 3
rVWF:RCo Dosing Recommendations for the Treatment of Bleeding Episodes Due 
to VWD
Classification of 
VWD
Hemorrhage
Dosage (IU VWF:RCo/kg BW)
Type 1 
Severe (Baseline 
VWF:RCo activity 
typically <20%) 
Minor (e.g., epistaxis, oral 
bleeding, menorrhagiaa) 
40 to 50 IU/kg (1 or 2 doses)
Major (e.g., severe or 
refractory epistaxis, 
menorrhagia*, GI bleeding, 
CNS trauma, hemarthrosis, 
or traumatic hemorrhage)
Initial dose 50 to 75 IU/kg, then 40 to 60 IU/kg 
every 8 to 12 hours for 3 days to keep the trough 
level of VWF:RCo >50%; then 40 to 60 IU/kg daily 
for a total of up to 7 days of treatment
Type 2 (all variants) 
and Type 3 
Minor (clinical indications 
above) 
40 to 50 IU/kg (1 or 2 doses)
Major (clinical indications 
above)
Initial dose of 60 to 80 IU/kg, then 40 to 60 IU/kg 
every 8 to 12 hours for 3 days to keep the trough 
level of VWF:RCo >50%; then 40 to 60 IU/kg daily 
for a total of up to 7 days of treatment
a Menorrhagia is defined as excessive bleeding during menstruation. A diagnosis of menorrhagia will be 
defined by a prospectively completed Pictorial Blood Assessment Chart (PBAC) score >185 and normal 
cervical cytology or requiring use of a VWF-containing concentrate for treatment of excessive 
menstrual bleeding for at least one menstrual cycle during the prior year.
Variances of up to 10% in dosing are permissible during treatment of bleeding episodes, 
but rounding to the nearest vial size should be avoided.
Subjects with non-neutralizing binding anti-VWF antibodies should initially be treated 
with a dose known to be efficacious based on the subject’s medical treatment history 
which may differ from the recommendations provided in Table 3. Subjects should be 
monitored for lack of efficacy as well as for FVIII (mandatory), VWF:RCo (mandatory), 
and VWF:Ag (optional where testing is not available) levels after 3 to 6 hours. Re-dosing 
with rVWF (vonicog alfa) in combination with ADVATE (rFVIII, octocog alfa) using the 
same (initial) dose and adaptation of the dosing frequency should be considered until 
cessation of the bleed, if the FVIII and/or VWF:RCo levels drop below 30%-50% 
depending on bleeding severity.
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The number of subsequent infusions and the dosage levels prescribed will be determined 
by the investigator on the basis of the clinical severity, response to current therapy, 
available laboratory data, and the subject’s historical treatment for similar bleeding 
episodes.
8.6.4.5 Treatment of Surgical Bleeding
Subjects enrolled in this study who require surgery or dental procedures will be treated 
with IP to manage their surgical bleeding then afterwards will resume their prophylactic 
rVWF (vonicog alfa) treatment schedule. Subjects who at time of screening have an 
already scheduled surgical intervention are not eligible for participation in the study.
8.6.4.5.1 Major, Minor and Oral Surgery Definition
The following definitions and criteria are used to serve as a guidance for major, minor 
and oral surgery.
Major surgeries generally refer to major orthopedic surgery (e.g., joint replacement, 
arthroscopic or open synovectomy, arthrodesis, hardware removals like plates or 
intramedullary nails, etc.), major abdominal surgery (e.g. open or laparoscopic 
hernioplasty, cholecystectomy, colon or small bowel resection, etc.), major gynecological 
surgery (e.g. open or laparoscopic myomectomy, hysterectomy, removal of 
endometriosis, polyps, cysts, adhesiolysis, etc.), major head and neck surgery (e.g.: 
tonsillectomy, adenoidectomy, rhinoplasty, lymphadenectomy, thyroidectomy, 
parotidectomy. etc.), any intracranial , cardiovascular or spinal surgery and any other 
surgery which has a significant risk of large volume blood loss or blood loss into a 
confined anatomical space. Extraction of impacted third molars is generally also 
considered major surgery due to the expected difficulty of surgery and the expected blood 
loss.
Minor surgeries generally refer to interventions such as placement of intravenous access 
devices, removal of small skin lesions, arthroscopy, gastroscopy, colonoscopy or 
conisation.
Oral surgeries comprise extractions of fewer than three teeth, if the teeth are non-molars 
and have no bony involvement.
A summary schedule of visit assessments and laboratory sampling is included in 
Supplement tables in Section 20.2.1 and Section 20.3.1.
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8.6.4.5.2 Preoperative Priming Dose
12- 24 hours prior to surgery, a priming dose with rVWF (vonicog alfa), using the rVWF 
IR and T1/2 for this subject , will be infused to allow the endogenous FVIII levels to raise 
to at least 30 IU/dL (minor, oral surgery), or 60 IU/dL (major surgery) at the time of the 
loading dose of rVWF (vonicog alfa) is infused.
As a general guidance a priming dose of 40-60 IU/kg rVWF:RCo will be administered. If 
not assessed prior to the preoperative priming dose, a IR recovery may be calculated for 
subjects undergoing minor and oral surgery.
8.6.4.5.3 Preoperative Loading Dose
An rVWF (vonicog alfa) loading dose should be administed within 3 hours before 
surgery. VWF and FVIII levels should be assessed within 3 hours prior to surgery 
initiation and results must be available prior to administering the loading dose. If FVIII 
levels prior to loading dose administration are not at least 30 IU/dL (minor, oral surgery), 
or 60 IU/dL (major surgery) ADVATE (rFVIII, octocog alfa) will be administered in 
addition to rVWF (vonicog alfa) in order to raise FVIII:C levels to recommended levels.
The preoperative loading dose will be calculated as the difference in the target peak and 
baseline plasma VWF:RCo levels divided by the IR (ΔVWF:RCo x BW (kg) /IR). The 
PK results will be provided prior to the planned surgery. If the IR is not available, assume 
an IR of 1.7 IU/dL per IU/kg and calculate the initial dose as follows: (100 – baseline 
plasma VWF:RCo) x BW (kg) / 1.7. For minor and oral surgery, the IR from the 
Preoperative Priming Dose visit will be used to guide dosing and the target peak is 
50-60 IU/dL VWF:RCo and 40-50 IU/dL FVIII. For major surgery, the target peak is 
100IU/dL VWF:RCo and 80-100 IU/dL FVIII.
The surgery may only start after normalization of the activated partial 
thromboplastin time (aPTT).
8.6.4.5.4 Intra- and Postoperative (maintenance) Dosing
After the preoperative loading dose(s), subjects who have not achieved the desired 
postinfusion recovery will continue to receive rVWF (vonicog alfa) with or without 
ADVATE (rFVIII, octocog alfa) as a bolus infusion, depending on VWF and FVIII 
levels. The peri- and post-operative substitution regimen will be individualized according 
to the PK results, intensity and duration of the hemostatic challenge, and the institution’s 
standard of care.
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Subjects undergoing minor surgery will be infused with rVWF (vonicog alfa) every 
12-24 hours or every other day, targeting >30IU/dL (rVWF and FVIII) for at least the 
first 48 hours.
Subjects undergoing oral surgery will be infused with rVWF (vonicog alfa) at least once 
within the first 8-12 hours, targeting >30 IU/dL (rVWF and FVIII).
Subjects undergoing major surgery will be infused with rVWF (vonicog alfa) every 
12-24 hours for at least the first 72 hours post-surgery, targeting a VWF:RCo and 
FVIII:C trough plasma level >50 IU/dL, followed by further treatment post-72 hours for 
as long as deemed necessary by the Investigator, targeting a VWF:RCo and FVIII:C 
trough plasma level of >30 IU/dL.
Dose modifications based on pre-infusion VWF/FVIII levels will be performed as 
needed. For subsequent infusions post surgery, in case pre-infusion levels are not 
available prior to the consecutive infusion in a timely manner, pre-infusion levels from 
the previous dose may be used by the investigator for dosing guidance.
Peak plasma level guidance is matching to Section 8.6.4.4.2
A schedule of all perioperative visit assessments and laboratory sampling can be found in 
supplement tables in Section 20.2.1 and Section 20.3.1.
8.6.4.6 Thrombosis Prophylaxis
Thromboembolic events have been reported in patients who have VWD, especially in the 
setting of known risk factors for thrombosis including low ADAMTS13 levels. 
Therefore, subjects who are at risk for developing thromboembolic events should be 
monitored for early signs of thrombosis, and prophylaxis measures against 
thromboembolism should be instituted according to current recommendations and
standard of care. For all subjects who are VWD patients and are receiving VWF 
concentrate, attention should be given to avoid exceeding maximal recommended plasma 
activity levels of VWF:RCo (250 IU/dL) and FVIII (250 IU/dL).
Anticoagulation measures, such as heparin, are acceptable and should follow study site 
standards. The investigator will record the use and reasons for such measures/agents on 
the appropriate CRF.
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8.6.5 Investigational Product Accountability
The investigator will ensure that the IP(s) is stored as specified in the Pharmacy Manual
and that the storage area is secured, with access limited to authorized study personnel. All 
temperature excursions at the subject’s home need to be monitored by the site (please 
refer to the pharmacy manual). The investigator will maintain records that the IP(s) was 
received, including the date received, drug identity code, date of manufacture or 
expiration date, amount received and disposition. The IP(s) must be dispensed only at the 
study site or other suitable location (e.g., infusion center; home, as applicable per study 
design), as specified in the protocol (see Section 10). Records will be maintained that 
includes the subject identification code (SIC), dispensation date, and amount dispensed. 
All remaining partially used and/or unused IP(s) will be returned to the sponsor or 
sponsor’s representative after study completion/termination, or destroyed with the 
permission of the sponsor in accordance with applicable laws and study site procedures. 
If IP(s) is to be destroyed, the investigator will provide documentation in accordance with 
sponsor’s specifications.
8.7 Source Data
Per ICH E6(R2) on GCP, source data are defined as all information in original records 
and certified copies of original records of clinical findings, observations, or other 
activities in a clinical trial that are necessary for the reconstruction and evaluation of the 
trial. Source data are contained in source documents (original records or certified copies). 
These may be in paper and/or electronic format. Source documents for this study 
comprise the following: hospital records, medical records, clinical and office charts, 
laboratory notes, memoranda, subjects' diaries or evaluation checklists, outcomes 
reported by subjects, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate copies, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, 
and records kept at the pharmacy, at the laboratories and at medico-technical departments 
involved in the clinical study.
No data will be entered directly onto the CRF.
For additional information on study documentation and CRFs refer to Section 17.2. The 
use of subject diaries is described in Section 10.5. 
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9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION
9.1 Inclusion Criteria
Subjects who meet ALL of the following criteria are eligible for this study:
1.
Subject has a documented diagnosis of severe VWD (baseline VWF:RCo 
<20 IU/dL) with a history of requiring substitution therapy with von Willebrand 
factor concentrate to control bleeding
a. Type 1 (VWF:RCo <20 IU/dL) or,
b. Type 2A (as verified by multimer pattern), Type 2B (as diagnosed by 
genotype), Type 2M or,
c. Type 3 (VWF:Ag ≤3 IU/dL).
5.
Diagnosis is confirmed by genetic testing and multimer analysis, documented in 
patient history or at screening.
6.
For on-demand patient group, subject currently receiving on-demand treatment for 
whom prophylactic treatment is recommended by the investigator. 
7.
For pdVWF switch patient group, subject has been receiving prophylactic 
treatment of pdVWF products for no less than 12 months prior to screening.
8.
For on-demand patient group, subject has ≥3 documented spontaneous bleeds (not 
including menorrhagia) requiring VWF treatment during the past 12 months. 
9.
Availability of records to reliably evaluate type, frequency and treatment of 
bleeding episodes during at least 12 months preceding enrollment. Up to 
24 months retrospective data should be collected if available. Availability of 
dosing and factor consumption during 12 months (up to 24 months) of treatment 
prior to enrollment is required for pdVWF switch subjects and is desired (but not 
a requirement) for on-demand subjects.
10. Subject is ≥18 years old at the time of screening and has a body mass index 
≥15 but <40 kg/m2.
11. If female of childbearing potential, subject presents with a negative blood/urine 
pregnancy test at screening and agrees to employ adequate birth control measures 
for the duration of the study.i
12. Subject is willing and able to comply with the requirements of the protocol.
                                                
i Refer to Section 20.4 for a list of adequate contraceptive methods for females of childbearing potential.
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9.2 Exclusion Criteria
Subjects who meet ANY of the following criteria are not eligible for this study:
1.
The subject has been diagnosed with Type 2N VWD, pseudo VWD, or another 
hereditary or acquired coagulation disorder other than VWD (eg qualitative and 
quantitative platelet disorders or prothrombin time (PT)/international normalized 
ratio [INR] 1.4).
2.
The subject is currently receiving prophylactic treatment with more than 5 infusions 
per week.
3.
The subject is currently receiving prophylactic treatment with a weekly dose 
exceeding 240 IU/kg.
4.
The subject has a history or presence of a VWF inhibitor at screening.
5.
The subject has a history or presence of a FVIII inhibitor with a titer ≥0.4 Bethesda 
units (BU) (by Nijmegen modified Bethesda assay) or ≥0.6 BU (by Bethesda 
assay).
6.
The subject has a known hypersensitivity to any of the components of the study 
drugs, such as to mouse or hamster proteins.
7.
The subject has a medical history of immunological disorders, excluding seasonal 
allergic rhinitis/conjunctivitis, mild asthma, food allergies or animal allergies.
8.
The subject has a medical history of a thromboembolic event.
9.
The subject is human immunodeficiency virus (HIV) positive with an absolute 
Helper T cell (CD4) count 200/mm3.
10. The subject has been diagnosed with significant liver disease per investigator’s 
medical assessment of the subject’s current condition or medical history or as 
evidenced by any of the following: serum alanine aminotransferase (ALT) greater 
than 5 times the upper limit of normal; hypoalbuminemia; portal vein hypertension 
(e.g., presence of otherwise unexplained splenomegaly, history of esophageal 
varices).
11. The subject has been diagnosed with renal disease, with a serum creatinine (CR)
level ≥2.5 mg/dL.
12. The subject has a platelet count <100,000/mL at screening.
13. The subject has been treated with an immunomodulatory drug, excluding topical 
treatment (e.g., ointments, nasal sprays), within 30 days prior to signing the 
informed consent.
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14. The subject is pregnant or lactating at the time of enrollment.
15. Patient has cervical or uterine conditions causing menorrhagia or metrorrhagia 
(including infection, dysplasia).
16. The subject has participated in another clinical study involving another IP or 
investigational device within 30 days prior to enrollment or is scheduled to 
participate in another clinical study involving an IP or investigational device during 
the course of this study.
17. The subject has a progressive fatal disease and/or life expectancy of less than 
15 months.
18. The subject is scheduled for a surgical intervention.
19. The subject is identified by the investigator as being unable or unwilling to 
cooperate with study procedures.
20. The subject has a mental condition rendering him/her unable to understand the 
nature, scope and possible consequences of the study and/or evidence of an 
uncooperative attitude.
21. The subject is in prison or compulsory detention by regulatory and/or juridical 
order.
22. The subject is member of the study team or in a dependent relationship with one of 
the study team members which includes close relatives (i.e., children, 
partner/spouse, siblings and parents) as well as employees.
9.3 Delay Criteria
1.
If the subject has an acute bleeding episode or presents with an acute illness 
(e.g., influenza, flu-like syndrome, allergic rhinitis/conjunctivitis, non-seasonal 
asthma) the screening visit will be postponed until the subject has recovered.
9.4 Withdrawal and Discontinuation
Any subject may voluntarily withdraw (i.e., reduce the degree of participation in the 
study) consent for continued participation and data collection. The reason for withdrawal 
will be recorded on the End of Study CRF. Assessments to be performed at the 
termination visit (including cases of withdrawal or discontinuation) are described in 
Section 10.6 and Section 20.2. 
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Discontinuation (i.e., complete withdrawal from study participation) may be due to 
dropout (i.e., active discontinuation by subject) or loss to follow-up (i.e., discontinuation 
by subject without notice or action). Additionally, the investigator and sponsor have the 
discretion to discontinue any subject from the study if, in their judgment, continued 
participation would pose an unacceptable risk for the subject.
Subjects also will be withdrawn from treatment or discontinued from further study 
participation for the following reasons:
1.
The subject is scheduled for an extended treatment period 3 months with 
non-topical immunomodulating drugs other than anti-retroviral chemotherapy 
(e.g., -interferon, corticosteroid agents [equivalent to hydrocortisone greater than 
10 mg/day]) during the course of the study.
2.
Subjects with chronic hepatitis B or C develop ALT/AST levels exceeding 5 times 
the ULN for 1 month.
3.
Subjects who experience severe hypersensitivity reactions, e.g., anaphylaxis upon 
exposure to rVWF (vonicog alfa).
4.
Subjects who develop a neutralizing inhibitor to rVWF (vonicog alfa) and/or 
ADVATE (rFVIII, octocog alfa) (biological assays) that results in significant 
clinical effect, including but not limited to increasing the weekly dose of rVWF by 
> 50%.
5.
Subjects who demonstrate clinical signs of thromboembolic events.
6.
The subject becomes pregnant. IP exposure will be discontinued. Attempts will be 
made to follow the subject through completion of the pregnancy and up to 1 year 
post delivery, if feasible. The investigator will record a narrative description of the 
course of the pregnancy and its outcome. 
7.
The subject begins lactating. IP exposure will be discontinued. The investigator will 
record a narrative description of the course of the baby’s development. 
8.
The subject is not compliant with the prophylactic treatment regimen and does not 
adhere to the frequency of IP administration. Once >30% of infusions are missed 
within a visit interval (3 months), the subject will be discontinued from further 
participation in the study. 
9.
The subject repeatedly uses other VWF products for prophylaxis or for the 
treatment of bleeding episodes in the absence of an acceptable justification to the 
sponsor. 
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10. STUDY PROCEDURES
10.1 Informed Consent and Enrollment
Any patient who provides informed consent (i.e., signs and dates the informed consent 
form) is considered a subject enrolled in the study.
10.2 Subject Identification Code
The following series of numbers will comprise the SIC: protocol identifier (e.g., 071301) 
to be provided by the sponsor, 2- or 3-digit number study site number (e.g., 02) to be 
provided by the sponsor, and 3- or 4-digit subject number (e.g., 0003) reflecting the order 
of enrollment (i.e., signing the informed consent form). For example, the third subject 
who signed an informed consent form at study site 02 will be identified as Subject 
071301-020003. All study documents (e.g., CRFs, clinical documentation, sample 
containers, drug accountability logs, etc.) will be identified with the SIC. Additionally, a 
uniquely coded SIC(s) is permitted as long as it does not contain a combination of 
information that allows identification of a subject (e.g., collection of a subject’s initials 
and birth date would not be permitted), in compliance with laws governing data privacy.
10.3 Screening and Study Visits
The study site is responsible for maintaining a screening log that includes all subjects 
who provided informed consent. The log also will serve to document the reason for 
screening failure. All screening data will be collected and reported in CRF, regardless of 
screening outcome. If a subject is re-screened, the End of Study CRF should be 
completed, and a new ICF, new SIC and new CRF are required for that subject.
The overall study design is illustrated in the Figure 1. Details on the procedures to be 
performed at each study visit, including screening, are provided in Supplement 20.2
„Schedule of Study Procedures and Assessments“ and Supplement 20.3 „Clinical 
Laboratory Assessments“. 
10.3.1 Screening Visit
Written informed consent must be obtained from each subject before any study 
related procedures are performed. To initiate screening procedures, at least 72 hours 
must have elapsed since the last VWF administration for on-demand subjects and the 
subject must not be actively bleeding at the time of screening. For switch subjects, the 
usual interval between their pdVWF prophy infusions must have elapsed since the last 
VWF administration and the subject must not be actively bleeding at the time of 
screening. Multimer analysis and VWD gene mutation analysis should be performed 
at screening if not available in the subject’s medical history.
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The screening visit will be delayed if the subjects presents with an acute bleeding 
episodes or acute illness (e.g., influenza, flu-like symptoms, inflammatory diseases) until 
the event has resolved. All screening procedures and confirmation of eligibility shall take 
place within 42 days prior to the first infusion of IP. If the IP is not infused within 
42 days, all screening assessments except blood group, human leukocyte antigen (HLA), 
genetics, multimeric pattern and 
, must be repeated to reconfirm eligibility. Refer 
to Supplement 20.2 and Supplement 20.3. Upon completion of screening procedures, 
subject eligibility will be confirmed by the sponsor on a subject eligibility form before 
additional study procedures are undertaken. The subject will maintain a diary that will 
include infusion logs (see Section 10.5). The allocation of IP will be initiated after the 
subject has qualified for home treatment (see Section 8.6.4.3.2).
In the event of a subject experiencing a bleeding episode that requires treatment between 
the screening visit and the subsequent visit (i.e. initial PK assessment visit for on-demand 
subjects or prophylaxis initiation visit for switch subjects), the subject will be treated with 
rVWF (vonicog alfa). If rVWF (vonicog alfa) is not available for any reason, e.g., subject 
not yet trained on IP administration, study site visit for IP administration not feasible, 
etc., the subject may use his/her standard of care, such as commercial pdVWF/FVIII 
products, and the reason for the use of non-IP products should be clearly documented.
10.3.2 Baseline Visit – Initial PK Assessment (On-demand Subjects Only)
After screening and confirmation of eligibility on-demand subjects will undergo an initial 
PK assessment. Subjects will receive a dose of 50 ± 5 IU/kg rVWF:RCo to determine 
VWF and FVIII levels. Blood samples will be drawn within 30 minutes pre-infusion, and 
at 11 time points post-infusion (15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 
3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 
72 2 hours and 96 ± 2 hours). See Section 20.2 and Section 20.3. IP infusion vials from 
the same lot number should be used for all PK-assessments per subject. Samples for 
measurement of FVIII and VWF activity taken through to 6 hours post-infusion will be
obtained from an extremity different from that used for the infusion of IP. Where needed, 
the phlebotomy site will be kept patent via an infusion of normal saline. In this event, at 
least 5 mL of blood will be collected and discarded before collection of the next test 
sample into a fresh syringe.
If the subject has a central venous catheter, the central line should be used to administer 
the infusion and a peripheral venipuncture should be used to collect the blood samples. 
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In the event that a blood sample must be drawn through the central line used for 
administration of IP, the line must first be flushed with at least 10 mL normal saline or 
other suitable catheter flush solution that does not contain anticoagulant. At least 5 mL of 
whole blood must be collected and discarded prior to obtaining the sample. 
If a subject experiences a bleeding episode during the PK assessment no subsequent 
blood sample will be drawn in that specific PK period. The guidance provided in 
Section 8.6.4.4 has to be followed for the treatment of the bleeding episode. The subject 
once recovered is eligible to repeat the PK assessment. 
For pdVWF switch subjects, PK profile will not be assessed until reaching steady state 
after initiation of prophylaxis (see Section 10.3.4). 
10.3.3 Prophylaxis Initiation Visit
The prophylaxis initiation visit will occur after the blood sample for the 96 hour PK 
assessment is drawn for on-demand subjects or within 42 days after screening and 
confirmation of eligibility for pdVWF switch subjects. The subject will receive the first 
rVWF (vonicog alfa) prophylactic dose of rVWF: RCo. Details on dose are provided in 
Section 8.6.4.3. 
Procedures and assessments at this visit include (but are not limited to): AEs, bleeding 
episodes, medications taken, and non-drug therapies. Within 2 hours prior the IP infusion, 
a physical examination will be performed. Vital signs will be assessed within 30 minutes 
prior to IP rVWF (vonicog alfa) infusion and 30 minutes ± 15 minutes after IP infusion.
Further details are provided in Supplement 20.2 and Supplement 20.3.
10.3.4 Initial Steady State PK-Assessment (pdVWF switch subjects only)
For pdVWF switch subjects, a full PK profile will be assessed at steady state conditions 
on two occasions. The initial PK assessment will be performed shortly after reaching 
steady state after starting prophylaxis dosing, which is suggested after 11 days post the 
1st, around prophylaxis dose #5-6. The 2nd PK assessment at steady state will be 
performed at the end of the study.
Blood samples will be drawn within 30 minutes pre-infusion, and at 11 time points 
post-infusion (15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 
6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours 
and 96 ± 2 hours). In case the dosing schedule does not permit the 96 hr sampling, 
this sampling time point can be omitted (See Section 11.6). IP infusion vials from 
the same lot number should be used for all PK-assessments per subject. 
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Samples for measurement of FVIII and VWF activity taken through to 6 hours post-
infusion will be obtained from an extremity different from that used for the infusion of 
IP. Where needed, the phlebotomy site will be kept patent via an infusion of normal 
saline. In this event, at least 5 mL of blood will be collected and discarded before 
collection of the next test sample into a fresh syringe.
If the subject has a central venous catheter, the central line should be used to administer 
the infusion and a peripheral venipuncture should be used to collect the blood samples. 
In the event that a blood sample must be drawn through the central line used for 
administration of IP, the line must first be flushed with at least 10 mL normal saline or 
other suitable catheter flush solution that does not contain anticoagulant. At least 5 mL of 
whole blood must be collected and discarded prior to obtaining the sample. 
If a subject experiences a bleeding episode during the PK assessment no subsequent 
blood sample will be drawn in that specific PK period. The guidance provided in 
Section 8.6.4.4 has to be followed for the treatment of the bleeding episode. The subject 
once recovered is eligible to repeat the PK assessment. In case of surgery or bleeding, the 
PK assessment should be performed after 11 days after 1st prophylactic dose after re-start 
of prophylactic regimen. See section 11.6 for more details.
10.3.5 Treatment of Bleeding Episodes
Treatment of bleeding episodes is described in detail in Section 8.6.4.4 and treatment of 
perioperative bleeding is described in detail in Section 8.6.4.5.
10.3.6 Perioperative Visits (only applicable if surgery is needed)
The perioperative visits from priming dose through postoperative day 14 will be required 
to check daily intra- and postoperative weight-adjusted dose of rVWF (vonicog alfa) with 
or without ADVATE (rFVIII, octocog alfa). Details on the procedures and assessments 
performed at each visit can be found in supplement tables in Section 20.2.1 and 
Section 20.3.1.
10.3.7 Follow-Up Visits 
Visits will be performed after the prophylaxis initiation visit at 1 month ± 1 week, 
2 months ± 1 week, and 3 months ± 2 weeks and thereafter every three months
± 2 weeks. Additional visits may occur if clinically indicated (see Section 10.3.8). 
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When possible, site visits should be scheduled on days when the subject is expected to 
infuse rVWF (vonicog alfa). Within 2 hours prior to the rVWF (vonicog alfa) IP infusion, 
a physical examination will be performed. Vital signs will be assessed within 30 minutes 
prior to IP infusion and 30 minutes ± 15 minutes after IP infusion. Incremental recovery 
(IR) will be determined at each follow-up visit based on VWF:RCo activity assessed 
prior to and after IP infusion.
The blood sample for IR analysis will be drawn within 30 minutes prior to IP infusion 
and 30 minutes ± 5 minutes after IP infusion. rVWF (vonicog alfa) will be infused at the 
regular prophylactic dose. For each subject’s recovery analysis IP infusion, vials from the 
same lot number should be used. 
Testing for VWF:RCo VWF:CB, rVWF:Ag, and FVIII:C level will be performed using 
the blood sample obtained before and after IP infusion. 
The blood sample prior to IP infusion will also be used for the assessment of neutralizing 
and binding antibodies, clinical chemistry and hematology. For on-demand subjects, a 
washout period of at least 72 hours after the last infusion applies before the blood draw 
for the immunogenicity assays. For switch subjects, the wash out period may be reduced 
to the time interval between their pdVWF prophy infusions Bleeding episodes and the 
hemostatic efficacy will be evaluated based on the review of the patient diary. See
Section 20.2 and Section 20.3. The evaluation of IP consumption and treatment 
compliance will be performed based on subject’s diary entries. If a subject is not 
compliant with the prophylactic treatment regimen and does not adhere to the required 
frequency of administration of IP infusions (>30% of infusions were missed within a visit 
interval [3 months]) the subject will be withdrawn from the study. 
At the 6 months ± 2 week visit an ECG will be performed and 
 data will be 
collected. 
For the hemostatic efficacy assessment the following information will be recorded by the 
subject in the patient diary: bleeding location, type, severity, onset and resolution date 
and time, infusion date and time, clinical efficacy according to the rating scale. If at any 
time during the study a subject’s bleeding episode does not adequately respond to rVWF 
(vonicog alfa) therapy, he/she will be evaluated for the presence of neutralizing and total 
binding antibodies. Refer to Section 12.9.3.2.
Further guidance on completing the subject’s diary will be provided to the subjects during 
training for home treatment (see Section 8.6.4.3.2).
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10.3.8 Unscheduled Visits
For any unscheduled visit (except for collection of IP) a clinical assessment will be 
performed as per the scheduled follow-up visits with the exception of 
, ECG, and 
IR determination (refer to Supplement 20.2 and Supplement 20.3).
Subjects who have more than one bleeding episode in 3 months, or an increased 
frequency of bleeding, should go to the study site for an unscheduled visit.
Follow-up visits after the subject has experienced a bleed may be requested by the 
investigator. Additional assessments may be required which are at the discretion of the 
investigator. 
10.3.9 End of Study PK Assessment and Study Termination Visit 
At the 12* month ± 2 week visit, a full PK analysis at steady state will be performed for 
both cohorts: on-demand and switch subjects. Blood samples will be drawn within 
30 minutes pre-infusion, and at 11 time points post-infusion (15 ± 5 minutes, 
30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 
24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours and 96 ± 2 hours) unless dosing 
schedule does not permit, in which case the 96 hr sampling can be omitted. If a subject 
experiences a bleeding episode during the PK assessment no subsequent blood sample 
will be drawn in that specific PK period. The guidance provided in Section 8.6.4.4 has to 
be followed for the treatment of the bleeding episode. The subject once recovered is 
eligible to repeat the PK assessment and the PK assessment should be performed after 
11 days after 1st prophylactic dose after re-start of prophylactic regimen. See section 11.6
for more details.
Refer to Supplement 20.2 and Supplement 20.3 for the other assessments to be performed 
at the PK assessment and study completion visits.
For on-demand subjects, a washout period of at least 72 hours is required between the PK
infusion and the study termination visit (at the time of the 96 hour postinfusion PK 
assessment). For switch subjects,  the wash out period may be reduced to the time interval 
between their rVWF (vonicog alfa) prophy infusions. Refer to Supplement 20.2 and 
Supplement 20.3 for the list of assessments to be performed at the termination visit.
Subjects will be offered the option to continue to receive rVWF (vonicog alfa) in a 
long-term continuation study*.
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* Study treatment period is extended by 3 months to accommodate participation in the 
continuation study for the qualified subjects and will be exercised only if the continuation 
study start up is delayed beyond the completion of subject’s 12-month visit. For subjects 
whose completion date is extended beyond the 12-month visit due to delay in continuation 
study start-up, the 12-month ± 2 weeks visit will be considered as a follow-up visit, and EOS 
visit will be performed once the subject can rollover into the continuation study, from 
12 month ± 2 weeks to 15 month ± 2 weeks post prophylaxis initiation visit, as applicable.
Both the 12-month ± 2 weeks visit rescheduled as a follow-up visit, and the rescheduled EOS 
visit will be recorded in the CRF.
10.4 Medications and Non-Drug Therapies 
The following medications and non-drug therapies are not permitted within 30 days 
before study entry and during the course of the study:
Medications:

Immunomodulating drugs other than anti-retroviral chemotherapy (e.g.,
-interferon, or corticosteroid agents at a dose equivalent to hydrocortisone 
greater than 10 mg/day) and an extended treatment period 3 months.

Another investigational and/or interventional study drug (except rVWF and FVIII 
administered under the surgery protocol).
A subject who has taken any of these medications or received any of these non-drug 
therapies during the study will be withdrawn from the study. 
The following medications are permitted during the course of the study:

Antifibrinolytics (e.g., tranexamic acid, -amino caproic acid) or topical 
hemostats as needed, according to each institution’s standard of care. These may 
be used, in accordance with local standard clinical practice, as the initial or only 
treatment for minor and moderate bleeding events. However, if the bleeding has 
not stopped within 24 hour following administration of this non-VWF treatment, 
infusion(s) with rVWF (vonicog alfa) should be started per protocol

Emergent use of a VWF concentrate other than rVWF (vonicog alfa) may be 
permissible under certain circumstances (see Section 8.6.4.4.1)
Details of all adjunctive hemostatic medication used, including dose and reason for use, 
must be recorded in the eCRF.
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10.5 Subject Diary
An electronic subject diary will be provided to each subject at the screening visit to 
record the following information:
1.
IP infusions to include date, start and stop times of the infusion, number of vials 
utilized, and infusion volume for prophylactic treatment or treatment of 
spontaneous and traumatic bleeding episodes 
2.
Details of bleeding episodes (site, type, severity and date/time of bleeding) and 
response to treatment as described in Section 8.6.4.4
3.
Subjective hemostatic efficacy assessments
4.
Untoward events/unwanted experiences
5.
Concomitant medications (including immunizations) and non-drug therapies
6.
Patient Reported Outcomes (PROs)
Subjects and/or their legally authorized representatives will be trained on use of the diary. 
The diary will be provided in electronic format and remain with the subject for the 
duration of the study. The investigator will review the diary for completeness and request 
missing information periodically and in a timely manner. The investigator will 
record/capture any unwanted experience reported by the subject which may qualify as an 
AE on the AE eCRF.
Infusions performed at the study site will first be recorded in the site’s source documents 
and not in the patient diary.
Subject entries in the diary will serve as source records. During study participation the 
investigator has access to the database holding the subject diary data. After study closure, 
the investigator will receive the diary records for their subjects, including audit trail 
records, in PDF format. The data will be transmitted to the CRF by a validated transfer. 
Paper diary may be utilized in rare case where electronic diary use is not possible.
10.6 Subject Completion/Discontinuation
A subject is considered to have completed the study when he/she ceases active 
participation in the study because the subject has, or is presumed to have completed all 
study procedures according with the protocol (with or without protocol deviations).
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Reasons for completion/discontinuation will be reported on the 
Completion/Discontinuation CRF, including: completed, screen failure, AE (e.g., death), 
discontinuation by subject (e.g., lost to follow-up [defined as 3 documented unsuccessful 
attempts to contact the subject], dropout), physician decision (e.g., pregnancy, 
progressive disease, non-compliance with IP/protocol violation(s), recovery), study 
terminated by sponsor, or other (reason to be specified by the investigator, e.g., technical 
problems). Regardless of the reason, all data available for the subject up to the time of 
completion/discontinuation should be recorded on the appropriate CRF. 
Every effort will be made to have discontinued subjects complete the study 
termination visit. If the termination visit is done as an additional, unscheduled 
visit, the assessment results shall be recorded with the termination visit. 
If a subject terminates participation in the study and does not return for termination visit, 
his/her last recorded assessments shall remain with the last visit. The reason for 
discontinuation will be recorded, and the data collected up to the time of discontinuation 
will be used in the analysis and included in the clinical study report. If additional 
assessments are required, the assessments shall be recorded separately. Assessments to be 
performed at the termination visit (including in cases of withdraw or discontinuation) can 
be found in Supplement 20.2 Schedule of Study Procedures and Assessments and 
Supplement 20.3 Clinical Laboratory Assessments.
In the event of subject discontinuation due to an AE, clinical and/or laboratory 
investigations that are beyond the scope of the required study observations/assessments 
may be performed as part of the evaluation of the event. These investigations will take 
place under the direction of the investigator in consultation with the sponsor, and the 
details of the outcome may be reported to the appropriate regulatory authorities by the 
sponsor. 
10.7 Procedures for Monitoring Subject Compliance
Subject compliance with the procedures of this study (treatment regimens and study 
visits) will be monitored by the investigator or/a licensed healthcare professional at the 
study site.
During the regular scheduled follow-up visits a direct review of the subject’s source data 
(e-diaries) will be performed at the sites and evaluated against the protocol requirements. 
In addition drug accountability will be evaluated at each follow-up study visit and the 
study termination visit by comparing the infusions recorded in the subject diary with 
empty vials returned by each subject to the study site, and the study site’s dispensing 
record. Protocol deviations will be noted in the final report. 
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11. ASSESSMENT OF EFFICACY AND PHARMACOKINETICS
11.1 Assessment of Spontaneous Bleeding Episodes/Annualized Bleed Rate 
The annualized bleed rate (ABR) will be assessed based upon each individual 
spontaneous bleed, requiring coagulation factor replacement therapy, i.e., rVWF 
(vonicog alfa) treatment. The following details on bleeding episodes will be recorded by 
the subject in the electronic diary (for home treatment), the subject’s healthcare provider 
in the site’s source documents (for treatments away from the primary investigative site), 
or by authorized, qualified personnel at the participating site in the subject’s medical 
records (for hospital-based treatment):

Location of bleed; i.e., joint, menorrhagia, epistaxis, gastrointestinal, soft tissue, 
muscle, body cavity, intracranial, etc.

Type of bleed; i.e., spontaneous, traumatic, unknown

Severity of bleed; i.e., minor, moderate, and major (see Table 3)

Date and time of onset of bleed

Date and time of each infusion of rVWF (vonicog alfa) or rVWF (vonicog alfa)-
ADVATE (rFVIII, octocog alfa) used to treat a bleeding episode

Date and time of resolution of the bleeding episode
Study site personnel are qualified after they have undergone training during the 
qualification of the site.
All types of bleeds, including traumatic bleeds, will be recorded. Bleeding episodes 
should be organized by where they occur in addition to whether they occurred 
spontaneously or due to a traumatic event.
Bleeds occurring at the same anatomical location (e.g., right knee) with the same etiology 
(i.e., spontaneous versus injury) within 24 hours after onset of the first bleed will be 
considered a single bleed. Bleeding occurring at multiple locations related to the same 
injury (e.g., knee and ankle bleeds following a fall) will be counted as a single bleeding 
episode.
All efforts should be made to use rVWF (vonicog alfa) for treatment of bleeding 
episodes. If needed, the use of a VWF concentrate other than IP for the treatment of 
bleeding episodes will not disqualify the subject from further participation in the study.
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11.2 Evaluation of ABR Before rVWF Prophylaxis and ABR Under rVWF
Prophylactic Treatment
At screening, the subject’s medical history will be recorded, including the number and 
location of all spontaneous and traumatic bleeding episodes within the past 12 months (up 
to 24 months if available). The maximum interval of bleed-free periods as well as trauma 
induced bleeding episodes will also be recorded (prospectively and retrospectively).
11.3 Number of Infusions and Total Weight Adjusted Consumption of rVWF and 
ADVATE and historical prophylaxis dosing and factor consumption during 
pdVWF prophylaxis treatment prior to enrollment
The number of rVWF (vonicog alfa) and ADVATE (rFVIII, octocog alfa) (in case of 
bleeding episode treatment) infusions will be logged in the subject diary. Based on these 
entries the weight adjusted consumption will be calculated. 
At the screening, historical pdVWF dosage and dosing frequency during 12 and up to 
24 months of pdVWF prophylactic treatment prior to enrollment will be recorded for the 
pdVWF switch subjects in order to calculate the consumption of pdVWF.
11.4 Assessment of Efficacy for Treatment of Bleeding Episode
Investigators will be asked to assess and record hemostatic efficacy after resolution of 
each bleeding episode using the 4-scale rating system outlined in Table 4. 
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Table 4
Efficacy Rating Scale
Rating
Efficacy Rating Criterion
Minor and Moderate Bleeding Events
Major Bleeding Events
Excellent (=1)
Actual number of infusions ≤ estimated 
number of infusions required to treat that 
bleeding episode
No additional VWF containing 
coagulation factor containing product 
required
Actual number of infusions ≤ estimated 
number of infusions required to treat that 
bleeding episode
No additional VWF containing coagulation 
factor containing product required
Good (=2)
1-2 infusions greater than estimated 
required to control that bleeding episode
No additional VWF containing 
coagulation factor containing product 
required
< 1.5 x infusions greater than estimated 
required to control that bleeding episode
No additional VWF containing coagulation 
factor containing product required
Moderate (=3)
3 or more infusions greater than estimated 
required to control that bleeding episode
No additional VWF containing 
coagulation factor containing product 
required
≥1.5 x infusions greater than estimated 
required to control that bleeding episode
No additional VWF containing coagulation 
factor containing product required
None (=4)
Severe uncontrolled bleeding or intensity 
of bleeding not changed
Additional VWF containing coagulation 
factor containing product required
Severe uncontrolled bleeding or intensity 
of bleeding not changed
Additional VWF containing coagulation 
factor containing product required
11.5 Assessment of Efficacy for Treatment for Surgical Bleeding
For those undergoing surgery, the operating surgeon will be asked to assess and record 
actual versus predicated blood loss and intraoperative hemostatic efficacy immediately 
after surgery. 
The investigator will be asked to assess and record an overall assessment of hemostatic 
efficacy 24 hours after the last perioperative rVWF (vonicog alfa) infusion or at day 14 
post-operation, whichever occurs first, using the 4-scale rating system described in 
Table 5.
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Table 5
Assessment of Hemostatic Efficacy
Rating
Overall Assessment of Hemostatic Efficacy 24 Hours After the Last Perioperative
rVWF Infusion
Excellent (1)
Intra- and post-operative hemostasis achieved with rVWF (vonicog alfa) with or without 
ADVATE (rFVIII, octocog alfa) was as good or better than that expected for the type of 
surgical procedure performed in a hemostatically normal subject
Good (2)
Intra- and post-operative hemostasis achieved with rVWF (vonicog alfa) with or without 
ADVATE (rFVIII, octocog alfa) was probably as good as that expected for the type of 
surgical procedure performed in a hemostatically normal subject
Moderate (3)
Intra- and post-operative hemostasis with rVWF (vonicog alfa) with or without ADVATE 
(rFVIII, octocog alfa) was clearly less than optimal for the type of procedure performed but 
was maintained without the need to change the rVWF (vonicog alfa) concentrate
None (4)
Subject experienced uncontrolled bleeding that was the result of inadequate therapeutic 
response despite proper dosing, necessitating a change of rVWF (vonicog alfa) concentrate
11.6 rVWF Pharmacokinetics and Pharmacodynamics 
PK will be assessed twice for all subjects.
For on-demand subjects, an initial PK assessment using a dose of 50 IU ± 5 IU/kg 
rVWF:RCo will be performed at the baseline visit, and a washout period of at least 
5 days is required before the infusion of rVWF (vonicog alfa) for PK assessment can 
be administered. At the 12 month ± 2 week visit, a steady state PK analysis will be 
performed based on the longer interval of the irregular dosing intervals employed. For 
both assessments, blood samples will be drawn within 30 minutes pre-infusion, and at 
11 time points post-infusion (15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 
3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 
72 2 hours and 96 ± 2 hours). VWF activity will be determined using the VWF:RCo, 
VWF:CB and the VWF: Ag assay. Endogenous FVIII activity will be measured using the 
1-stage clotting assay to assess the pharmacodynamics of rVWF (vonicog alfa). 
For pdVWF switch subjects, the initial PK assessment using the subject’s individualized 
dose will be performed shortly after reaching steady state, which is estimated to be 
reached for the majority of subjects after  approximately 11 days from the 1st prophylactic 
dose. To fit any logistical requirements, samples for PK analysis can be taken after 
prophylaxis dose #5-6, and whenever possible, sample collections should be during the 
longer partial interval of the alternating irregular dosing intervals. For example, if a 
subject follows a dosing regimen as follows:
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Date
Weekday
Dose number
Interval
Time from 1st dose in hours
8.1.18 8:00
Monday
1
0
0
12.1.18 8:00
Friday
2
4
96
15.1.18 8:00
Monday
3
3
168
19.1.18 8:00
Friday
4
4
264
22.1.18 8:00
Monday
5
3
336
26.1.18 8:00
Friday
6
4
432
After reaching the steady state, the PK assessment can be done at dose 5 to allow the 96h 
post-infusion sampling, before the next scheduled dose (for patients on a twice per week 
dosing schedule). A similar 2nd full PK profile will be assessed at the end of the study, i.e. 
12* month ± 2 week visit with a PK infusion at the same dosing partial interval (96h 
interval in this case). Blood samples will be drawn within 30 minutes pre-infusion, 
and at 11 time points post-infusion (15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 
3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 
72 2 hours, and 96 ± 2 hours). If the dosing interval for a certain switch subject 
wouldn’t allow for the full 11 post-infusion timepoints sample collection, the 96-hour 
sampling timepoint can be omitted, but it is critical that the assessments are at the same 
partial interval, thereby same number of sampling timepoints, for the 1st and 2nd PK for an 
individual switch subject.
If a subject experiences a bleeding episode during the PK assessment no subsequent 
blood sample will be drawn in that specific PK period. The guidance provided in 
Section 8.6.4.4 has to be followed for the treatment of the bleeding episode. The subject 
once recovered is eligible to repeat the PK assessment. In case of surgery or bleeding, the 
PK assessment should be performed after 11 days after 1st prophylactic dose after restart 
of prophylactic regimen.
* Study treatment period is extended by 3 months to accommodate participation in the 
continuation study for the qualified subjects and will be exercised only if the continuation study 
start up is delayed beyond the completion of subject’s 12-month visit.
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12. ASSESSMENT OF SAFETY
12.1 Adverse Events
12.1.1 Definitions
An AE is defined as any untoward medical occurrence in a subject administered IP that 
does not necessarily have a causal relationship with the treatment. An AE can therefore 
be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom 
(e.g., rash, pain, discomfort, fever, dizziness, etc.), disease (e.g., peritonitis, bacteremia, 
etc.), or outcome of death temporally associated with the use of an IP, whether or not 
considered causally related to the IP.
12.1.1.1 Serious Adverse Event 
An SAE is defined as an untoward medical occurrence that, at any dose, meets one or 
more of the following criteria:

Outcome is fatal/results in death (including fetal death)

Is life-threatening – defined as an event in which the subject was, in the judgment 
of the investigator, at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death had it been more severe.

Requires inpatient hospitalization or results in prolongation of an existing 
hospitalization – inpatient hospitalization refers to any inpatient admission, 
regardless of length of stay.

Results in persistent or significant disability/incapacity (i.e., a substantial 
disruption of a person’s ability to conduct normal life functions)

Is a congenital anomaly/birth defect

Is a medically important event – a medical event that may not be immediately 
life-threatening or result in death or require hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the definitions above. Examples of such events are (including 
but not limited to): 

Intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias, or convulsions that do not result in 
hospitalization, or development of drug dependence or drug abuse 

Reviewed and confirmed seroconversion for HIV, hepatitis A virus (HAV), 
hepatitis B virus (HBV), hepatitis C virus
(HCV), hepatitis E virus (HEV), or parvovirus B19 (B19V)
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
Development of clinically significant neutralizing VWF antibodies

Development of neutralizing antibodies to FVIII (titer ≥0.4 BU [by 
Nijmegen- modified Bethesda assay] or ≥0.6 BU [by Bethesda assay])

Thromboembolic events (e.g., myocardial infarction, stroke, transient 
ischemic attack [TIA], deep vein thrombosis [DVT] or pulmonary 
embolism)

Hypersensitivity reactions (e.g., anaphylaxis [for definition, refer to 
Section 12.6.2] and other immediate and delayed hypersensitivity reactions 
which may manifest with urticarial rash, pruritus, flushing, angioedema of 
the face, extremities, or laryngeal tissues [leading to throat tightness with 
stridor], wheezing, gastrointestinal symptoms, and/or hypotension) 
Uncomplicated pregnancies, following maternal or paternal exposure to IP are not 
considered an AE/SAE; however, any pregnancy complication or pregnancy termination 
by therapeutic, elective, or spontaneous abortion shall be considered an SAE and should 
be reported per SAE reporting guidelines provided in Section 12.1.2.3 (Safety Reporting).
12.1.1.2 Suspected Unexpected Serious Adverse Reaction (SUSAR)
Any suspected adverse reaction to study treatment that is both serious and unexpected is 
considered a SUSAR. 
The event(s) must meet all of the following:

Suspected adverse reaction (which implies that there is reasonable evidence 
indicating a causal relationship between the event and the study treatment),

Unexpected (per Reference Safety Information (RSI)/IB), and

Serious
Once determined to meet the criteria for a SUSAR, the sponsor will ensure expedited 
SUSAR reporting is completed in line with the regulatory requirements in participating 
countries as outlined in the Safety Management Plan. 
12.1.1.3 Non-Serious Adverse Event
A non-serious AE is an AE that does not meet any of the seriousness criteria (death, 
life-threatening, hospitalizing/prolongation of hospitalization, disability, congenital 
anomaly, or medically significant and if not urgently treated would result in one of the 
above) listed in section 12.1.1.1.
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12.1.1.4 Unexpected Adverse Events
An unexpected adverse event is an AE whose nature, severity, specificity, or outcome is 
not consistent with the term, representation, or description used in the Reference Safety 
Information (e.g., IB, PI [prescribing information]). “Unexpected” also refers to the AEs 
that are mentioned in the IB as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring 
with the particular drug under investigation.
12.1.1.5 Preexisting Disease
Preexisting diseases that are present before entry in to the study are described in the 
medical history, and those that manifest with the same severity, frequency, or duration 
after IP exposure will not be recorded as AEs. However, when there is an increase in the 
severity, duration, or frequency of a preexisting disease, the event must be described as 
“worsening” of the pre-existing condition on the AE CRF.
12.1.2 Assessment of Adverse Events
For the purposes of this study, the following will not be considered as AEs and will not 
be included in the analysis of AEs.

Bleeding episodes are part of the underlying disease and therefore are not AEs; 
they will be evaluated in the context of efficacy.

For non-serious bleeding episodes caused by an injury, the injury would not 
be reported as an AE, unless it resulted in a medical finding other than a 
bleeding episode (e.g., abrasion of skin). Therefore, any VWD-related 
bleeding event (e.g., epistaxis, gastrointestinal bleeding, musculo-skeletal 
bleeding, menorrhagia) that is non-serious will not be reported as an AE. 
However, the investigator may decide that the event is an AE if the event also 
would have occurred in a healthy individual under the same circumstances.

For serious bleeding episodes (bleeding SAEs): Bleeding events that meet 
seriousness criteria (death, life-threatening, hospitalizing/prolongation of 
hospitalization, disability, congenital anomaly, or medically significant and if 
not urgently treated would result in one of the above) should be captured on 
the SAE eCRF and reported as an SAE to the Sponsor or designee (e.g., 
CRO) on an SAE Report form as described in Section 12.1.2.3 (Safety 
Reporting).

Seroconversion after documented HAV/HBV vaccination prior to or during the 
study period.
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Each AE from the first IP exposure to the study completion date will be described on the 
AE CRF using the term representing medical diagnosis (preferred), or, if no diagnosis 
could be established at the time of reporting the AE, a symptom or sign, in standard 
medical terminology in order to avoid the use of vague, ambiguous, or colloquial 
verbatim expressions (see definition in Section 12.1). Each AE will be evaluated by the 
investigator for:

Seriousness as defined in Section 12.1.1.1

Severity as defined in Section 12.1.2.1

Causal relationship to IP exposure or study procedure as defined in 
Section 12.1.2.2
For each AE, the outcome (i.e., recovering/resolving, recovered/resolved, 
recovered/resolved with sequelae, not recovered/not resolved, fatal, unknown) and if 
applicable, action taken with regards to the study treatment (i.e., dose increased, dose not 
changed, dose reduced, drug interrupted, drug withdrawn, not applicable, or unknown) 
will also be recorded on the AE CRF. Recovering/resolving AEs will be followed until 
resolution or until the subject’s condition returns to the level at the baseline for pre-
existing conditions. 
If the severity rating for an ongoing AE changes before the event resolves, the original 
AE report will be revised (i.e., the event will not be reported as separate AE). During the 
course of any AE, the highest severity rating will be reported.
Deviations from the protocol-specified dosage (including underdosing /overdosing 
[<20 IU/kg rVWF:RCo or >100 rVWF:RCo], abuse, and withdrawal, treatment errors 
(including incorrect route of administration, use of an incorrect product, and deviations 
from the protocol-defined dosing schedule), failures of expected pharmacological actions, 
and unexpected therapeutic or clinical benefits will be followed with regard to occurrence 
of AEs, lack of efficacy, and/or other observations because these events may be 
reportable to regulatory authorities. 
Any pregnancy that occurs after administration of IP will be reported on a Pregnancy 
Form and followed-up at 1 year post-delivery, if feasible. 
If an investigator becomes aware of an SAE occurring in a subject after study completion, 
the SAE must be reported on the SAE Form within 24 hours after awareness: no 
additional reporting on CRFs is necessary.
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12.1.2.1 Severity
The investigator will assess the severity of each AE using his/her clinical expertise and 
judgment based on the most appropriate description below:

Mild
The AE is a transient discomfort and does not interfere in a significant manner 
with the subject’s normal functioning level.
The AE resolves spontaneously or may require minimal therapeutic 
intervention.

Moderate
The AE produces limited impairment of function and may require therapeutic 
intervention.
The AE produces no sequela/sequelae.

Severe
The AE results in a marked impairment of function and may lead to temporary 
inability to resume usual life pattern.
The AE produces sequela/sequelae, which require (prolonged) therapeutic 
intervention.
These severity definitions will also be used to assess the severity of an AE with a study-
related procedure(s), if necessary.
12.1.2.2 Causality
Causality is a determination of whether there is a reasonable possibility that the IP is 
etiologically related to/associated with the AE. Causality assessment includes, e.g., 
assessment of temporal relationships, dechallenge/rechallenge information, association 
(or lack of association) with underlying disease, presence (or absence) of a more likely 
cause, and physiological plausibility. For each AE, the investigator will assess the causal 
relationship between the IP and the AE using his/her clinical expertise and judgment 
according to the following most appropriate algorithm for the circumstances of the AE:

Not related (both circumstances must be met)
Is due to underlying or concurrent illness, complications, concurrent 
treatments, or effects of concurrent drugs
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Is not associated with the IP (i.e., does not follow a reasonable temporal 
relationship to the administration of IP, is not biologically plausible per 
mechanism of action of the IP, or has a much more likely alternative etiology). 

Unlikely related (either 1 or both circumstances are met)
Has little or no temporal relationship to the IP 
A more likely alternative etiology exists

Possibly related (both circumstances must be met)
Follows a reasonable temporal relationship to the administration of IP
An alternative etiology is equally or less likely compared to the potential 
relationship to the IP

Probably related (both circumstances must be met)
Follows a strong temporal relationship to the administration of IP, which may 
include but is not limited to the following: 
o
Reappearance of a similar reaction upon re-administration (positive re-
challenge)
o
Positive results in a drug sensitivity test (skin test, etc.)
o
Toxic level of the IP as evidenced by measurement of the IP 
concentrations in the blood or other bodily fluid
Another etiology is unlikely or significantly less likely
For events assessed as not related or unlikely related and occurring within 5 days after IP 
infusion, the investigator shall provide the alternative etiology. These causality 
definitions will also be used to assess the relationship of an AE with a study-related 
procedure(s), if necessary.
12.1.2.3 Safety Reporting
AEs and SAEs will be assessed at all study visits as outlined in the Schedule of Study 
Procedures and Assessments (see Section 20.2) and Section 12.1.2.
Adverse Events and SAEs are to be recorded on the AE page of the eCRF. Each event 
should be recorded separately.
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Any SAE, including death due to any cause, which occurs during this study, whether or 
not related to the IP, must be reported immediately (within 24 hours of the study center’s 
first knowledge of the event). All SAEs must be reported in English via the Electronic 
Data Capture (EDC) system by completing the relevant eCRF page(s) and also by SAE 
Report Form via fax/email to Sponsor’s Global Drug Safety (Baxalta GDS) department 
within 24 hours of becoming aware of the event for SAEs (for contacts, instructions, and 
additional details, refer to the SAER form).
Within 24 hours of site awareness of a SAE (or Pregnancy) study sites will complete and 
send all SAE (or Pregnancy) reports to a dedicated:
Baxalta Global Drug Safety fax number:  
  
OR 
email: 
The responsible Site Monitor will review the SAE (or Pregnancy) Reports for 
completeness, will reconcile the reports against the EDC database, and will follow-up 
with sites to obtain missing information and/or information requiring clarification. Any 
SAE associated with a pregnancy must be reported on the SAER Form.
For Follow-up Reports, the site shall use a new SAER form (marked as Follow-up) and 
the new information should be entered together with a brief narrative identifying the 
updated data. 
An SAER should include the following minimum information:
1.
Protocol Number (on all pages)
2.
Subject identification number (on all pages) and demographics (gender, age at 
onset of event and/or date of birth)
3.
Investigational product and treatment regimen (including date of the first dose of 
IP, date of the last dose of IP prior to the onset of the SAE)
4.
Medical Term for Event (Diagnosis preferably) 
5.
Description of the SAE, including:

Date of onset

Causal relationship assessment by the Investigator
6.
Seriousness criteria (e.g., death, life-threatening, hospitalization, medically 
significant, or other criterion)
7.
Name, address, fax number, email, and telephone number of the 
reporter/Investigator 
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Post-trial SAE Reporting: In compliance to EudraLex Volume 10 (Clinical trials 
guidelines, Chapter II: Safety Reporting from the European Commission), which 
references an EMA guidance (ICH Topic E 2 A - Clinical Safety Data Management: 
Definitions and Standards for Expedited Reporting), clinical sites/the investigator should 
report to the Sponsor SAEs after a subject´s study completion. Study sites will be 
provided a Post-Trial SAER form to complete and report these post-study SAEs to the 
Sponsor within the 24 hours of their awareness. Site Monitor will instruct the site that any 
such Post-Trial SAEs should be reported on the study-specific Post-Trial SAER form 
if/when the site becomes aware of it. Such information will not be actively monitored by 
the sponsor after completion of the study.
These events shall be reported to Baxalta GDS who will process them in the same way as 
SAEs occurring during the study. Post-Trial SAEs do not need to be captured in the study 
EDC database if it is already locked. Irrespective if captured in the EDC database or not, 
such Post-Trial SAEs will become part of the GDS database. The monitor should remind 
the clinical site about the post-trial SAE reporting requirements during interim 
monitoring visits, upon each subject’s study completion as well as during the close-out 
visit.
12.2 Urgent Safety Measures
An urgent safety measure is an immediate action taken, which is not defined by the 
protocol, in order to protect subjects participating in a clinical trial from immediate harm. 
Urgent safety measures may be taken by the sponsor or clinical investigator, and may 
include any of the following: 

Immediate change in study design or study procedures

Temporary or permanent halt of the clinical trial 

Any other immediate action taken in order to protect clinical trial participants 
from immediate hazard to their health and safety
The investigator may take appropriate urgent safety measures in order to protect subjects 
against any immediate hazard to their health or safety. The measures should be taken 
immediately and may be taken without prior authorization from the sponsor. 
In the event(s) of an apparent immediate hazard to the subject, the investigator will notify 
the sponsor immediately by phone and confirm notification to the sponsor in writing as 
soon as possible, but within 1 calendar day after the change is implemented. The sponsor 
will also ensure the responsible ethics committees (ECs) and relevant competent 
authority(s) are notified of the urgent measures taken in such cases according to local 
regulations.
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12.3 Untoward Medical Occurrences
Untoward medical occurrences occurring before the first exposure to IP are not 
considered AEs (according to the definition of AE, see Section 12.1.1). However, each 
serious untoward medical occurrence experienced before the first IP exposure (i.e., from 
the time of signed informed consent up to but not including the first IP exposure) will be 
described on the SAER. These events will not be considered as SAEs and will not be 
included in the analysis of SAEs. 
12.4 Non-Medical Complaints
A non-medical complaint (NMC) is any alleged product deficiency that relates to 
identity, quality, durability, reliability, safety and performance of the product but did not 
result in an AE. NMCs include but are not limited to the following:

A failure of a product to exhibit its expected pharmacological activity and/or 
design function, e.g. reconstitution difficulty

Missing components

Damage to the product or unit carton

A mislabeled product (e.g., potential counterfeiting/tampering)

A bacteriological, chemical, or physical change or deterioration of the product 
causing it to malfunction or to present a hazard or fail to meet label claims
Any NMCs of the product will be documented on an NMC form and reported to the 
sponsor within 1 business day. If requested, defective product(s) will be returned to the 
sponsor for inspection and analysis according to procedures.
12.5 Medical, Medication, and Non-Drug Therapy History
At screening, the subject’s medical history will be described for the following body 
systems including severity (defined in Section 12.1.2.1) or surgery and start and end 
dates, if known: eyes, ears, nose, and throat; respiratory; cardiovascular; gastrointestinal; 
musculoskeletal; neurological; endocrine; hematopoietic/lymphatic; dermatological; and 
genitourinary. The subject’s medical history will also include documented history of 
on-demand or pdVWF prophylaxis treatment for at least the past 12 months and a 
documented history, e.g., patient charts and prescription information, of all bleeding 
episodes within the past 12 months (up to 24 months if available).
All medications taken and non-drug therapies received in the 2 weeks prior to study entry 
and all concomitant medications and non-drug therapies during study will be recorded on 
the CRFs.
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Data on medical history, drug and non-drug therapy history of those subjects who 
transition from surgery rVWF (vonicog alfa) study will be used from the eCRF of the 
main studies, will be updated, if applicable, and transcribed into the respective eCRF of 
the prophy study. 
12.6 Physical Examinations
At screening and subsequent study visits (as described in Section 10.3), a physical 
examination will be performed on the following body systems: general appearance, head 
and neck, eyes and ears, nose and throat, chest, lungs, heart, abdomen, extremities and 
joints, lymph nodes, skin, and neurological. At screening, if an abnormal condition is 
detected, the condition will be described on the medical history CRF. At study visits, if a 
new abnormal or worsened abnormal pre-existing condition is detected, the condition will 
be described on the AE CRF. If the abnormal value was not deemed an AE because it 
was due to an error, due to a preexisting disease (described in Section 12.1.1.5), not 
clinically significant, a symptom of a new/worsened condition already recorded as an AE, 
or due to another issue that will be specified, the investigator will record the justification 
on the source record.
12.6.1 Thromboembolic Events
There is a risk of occurrence of thrombotic events, particularly in patients with known 
clinical or laboratory risk factors for thrombosis including low ADAMTS13 levels.  
Therefore, patients at risk must be monitored for early signs of thrombosis during the 
study and prophylaxis measures against thromboembolism should be instituted according 
to current recommendations and standard of care. Additional diagnostic procedures are 
required according to each institution’s standard of care which may consist of, but are not 
limited to the following:

For DVT: Magnetic Resonance Imaging (MRI), compression ultrasound or 
impedance plethysmography.

For pulmonary embolism: ECG, chest radiography, perfusion/scintiscan or MRI. 

For myocardial infarction: ECG, cardiac enzymes, echocardiography

For stroke: diffusion-weighted magnetic resonance imaging or computed 
tomography, ABCD scoring, carotid imaging
Results of diagnostic procedures may be forwarded to the sponsor to be reviewed by an 
independent external expert panel, such as the DMC, if applicable.
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12.6.2 Anaphylaxis
The diagnosis of anaphylaxis is highly likely when any of the following 3 criteria are 
fulfilled:
1.
Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue or both (e.g, generalized urticaria, pruritus or flushing, swollen 
lips-tongue-uvula) and at least one of the following:
a. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced peak expiratory flow [PEF], hypoxemia)
b. Reduced blood pressure (BP) or associated symptoms of end-organ 
dysfunction (e.g., hypotonia [collapse], syncope, incontinence)
2.
Two or more of the following that occur rapidly after exposure to a likely allergen 
for that patient (minutes to several hours):
a. Involvement of the skin or mucosal tissue (e.g., generalized urticaria, pruritus 
or flushing, swollen lips-tongue-uvula)
b. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced PEF, hypoxemia)
c. Reduced BP or associated symptoms (hypotonia [collapse], syncope, 
incontinence)
d. Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)
3.
Reduced BP after exposure to a known allergen for that patient (minutes to 
several hours):
a. Infants and children: low systolic BP (age specific) or greater than 30% 
decrease in systolic BP
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from 
that person’s baseline BP
If a subject develops anaphylaxis in the course of the clinical study, this needs to be 
reported as SAE (Section 12.1.1.1). Additional blood will be drawn for Anti-VWF IgE 
antibody testing (Section 12.9.13).
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12.7 Vital Signs
Vital signs will be assessed pre- and post-infusion at each visit, if not stated otherwise:

Height (cm) (Screening only) and weight (kg) (pre-infusion only)

Blood pressure: Systolic/diastolic blood pressure (mmHg) baseline measurements 
will be measured after a 10-minute rest in the supine/semi-recumbent position.

Pulse rate: Pulse rate (beats/min) will be measured at the distal radial arteries 
under the same conditions as above.

Respiratory rate: Respiratory rate (breaths/min) will be measured over a period of 
1 minute under the same conditions as above.

Temperature: Body temperature (oC or oF) may be determined by oral, rectal, 
axillary, or tympanic measurement at the discretion of the investigator. However, 
the same method should be used for all measurements in 1 subject.
Vital signs (pulse rate, respiratory rate, and blood pressure) should be recorded within 
30 min before and after IP administration. The assessment of vital signs per planned 
study visit is outlined in Supplement 20.2.
Vital sign values are to be recorded on the physical examination eCRF. For each vital 
sign value, the investigator will determine whether the value is considered an AE (see 
definition in Section 12.1). If assessed as an AE, the medical diagnosis (preferably), 
symptom, or sign, will be recorded on the AE eCRF. Additional tests and other 
evaluations required to establish the significance or etiology of an abnormal result, or to 
monitor the course of an AE, should be obtained when clinically indicated. Any abnormal 
value that persists should be followed at the discretion of the investigator.
12.8 Electrocardiogram 
A standard 12-lead ECG at rest will be performed at screening, at the 6 month follow-up 
visit and at the study termination visit and evaluated for medical significance by the 
investigator.
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12.9 Clinical Laboratory Parameters
Refer to the Laboratory Manual for information on collection and processing of samples.
In general all laboratory tests will be performed at central laboratories, except the 
pregnancy and blood group test which will be performed at the local laboratory. In 
addition, relevant critical safety laboratory tests for complete blood count (CBC), serum 
chemistry and/or coagulation parameters such as VWF and FVIII activity may also be 
performed in the local laboratory to ensure that results will be available immediately to 
the investigator. In principle, results from the central laboratory will be used for data 
analysis purposes. The assays performed in the central laboratories are specified in the 
Laboratory Manual. The investigator will supply the sponsor with a list of the normal 
ranges and units of measurement for the laboratory variables to be determined at the site. 
Laboratory values such as antibodies to other proteins are not required immediately and 
will be assessed later during the course of the study. 
Any abnormal laboratory value that is considered clinically significant by the investigator 
based on a local laboratory test result (reference range and the units to be provided) 
should be confirmed by a central laboratory test result for which the sample is 
drawn/collected within 24 hours of the abnormal finding by the local laboratory.
12.9.1 rVWF Pharmacokinetics and Pharmacodynamics
Details on pharmacokinetic and pharmacodynamics assessments are provided in 
Section 11.6.
12.9.2 Hematology and Clinical Chemistry
The hematology panel will consist of CBC [hemoglobin, hematocrit, erythrocytes (ie, red 
blood cell count [RBC]; mean corpuscular volume [MCV], mean corpuscular hemoglobin 
(MCH), mean corpuscular hemoglobin concentration [MCHC]), and leukocytes (i.e., 
white blood cell count [WBC])] with differential (i.e., basophils, eosinophils, 
lymphocytes, monocytes, neutrophils) and platelet counts.
The clinical chemistry panel will consist of sodium (Na), potassium (K), chloride (Cl), 
ALT, lactate dehydrogenase (LDH), aspartate aminotransferase (AST), bilirubin, alkaline 
phosphatase (AP), blood urea nitrogen (BUN), CR, and glucose (Glu).
Blood will be obtained for assessment of hematology and clinical chemistry parameters 
at screening, during PK-assessment prior to rVWF (vonicog alfa) IP infusion, after 
24 ± 2 hours, 48 ± 2 hours and 72 ± 2 hours post rVWF (vonicog alfa) IP infusion, at all 
follow-up visits as per schedule (refer to Supplement 20.3 Clinical Laboratory 
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Assessments), i.e., 4 weeks ± 1 week, 8 weeks ± 1 week and every 3 months ± 2 weeks, 
and at study completion. Hematology and clinical chemistry assessments will be 
performed on Ethylenediaminetetraacetic acid (EDTA)-anticoagulated whole blood and 
serum, respectively, at the central laboratory.
12.9.3 Immunology
12.9.3.1 Antibodies to VWF and FVIII
All subjects will be tested for binding and neutralizing antibodies to VWF and FVIII at 
screening, at initial PK assessment, at each of the scheduled follow-up visits and at the 
study completion visit. Testing will be done prior to IP infusion and with at least a 
72 hour wash out period since the last IP infusion. If there is any suspicion of inhibitor 
development (e.g. excessive bleeding) binding and neutralizing antibodies to VWF and 
FVIII may be tested at the discretion of the investigator. 
12.9.3.2 Neutralizing and Total Binding Anti-VWF Antibodies
The assays to establish the presence of neutralizing and total binding anti-VWF 
antibodies have been established in the absence of international standards and with only 
limited numbers of positive controls. Therefore, caution is advised in interpreting positive 
results. In particular, any clinical association, changes in the natural history of the 
disease, effect of therapy, etc. needs to be taken into account for final judgment. 
The sponsor’s Medical Director should be consulted for additional advice. As part of the 
AE follow-up, any sample testing positive needs to be confirmed after 2-4 weeks for 
central laboratory testing. Only confirmed neutralizing anti -VWF antibodies are 
considered inhibitors (see Section 12.9.3.4). These subjects need to be closely monitored
and therapy adjusted accordingly. 
12.9.3.3 Binding antibodies to VWF 
The presence of total binding anti-VWF antibodies will be determined by an enzyme-
linked immunosorbent assay (ELISA) employing polyclonal anti-human Immunoglobulin
(Ig) antibodies (IgG, IgM and IgA). For this assay (ELISA), recombinant human VWF 
will be coated onto a microtiter plate, then incubated with dilutions of the positive 
control, the negative control or test sample. Antibodies against human VWF that are 
present in the samples bind to the coated antigen and will be detected with a horseradish 
peroxidase (HRP)-coupled goat anti-human antibody (secondary antibody). The positive 
control for this assay will be a human monoclonal antibody specific for human VWF 
spiked into the negative control. The negative control for this assay is pooled normal 
human plasma.
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Plasma samples are analyzed for binding antibodies against the specific antigen in two 
steps. First, the sample is screened for antibodies and the titer of binding antibodies is 
determined. Second, the specificity of positive antibody results is confirmed.16
In brief, all samples are serially diluted (initial dilution 1:20 and further diluted 1:2).
The titer endpoint, defined as the highest dilution that still gives a positive signal above 
cut off level, is determined in two independent duplicates. The cut off level is established 
based on background signal level of healthy plasma donors (n=160) and set to include 5% 
false positives to be as sensitive as possible (95% percentile). The ELISA assay is 
validated allowing an assay variability of ± 1 titer step. Therefore, differences ≤ 2 titers 
steps may be due to variability of the ELISA assay. Specificity has to be confirmed in a 
competition assay when a sample has a titer of 1:80 or higher in the screening assay. 
Based on the validation criteria samples tested in the screening assay at 1:20 or 1:40 
cannot be confirmed in the competition assay. A positive screening value is confirmed if 
the difference between the titers determined for the subject sample (re-screen) and for the 
subject sample with pre-incubation (confirmation sample) is > 2 titer steps. Antibody 
titers of subject samples will only be reported as positive, if the results of the screening 
and confirmatory analysis fulfill these acceptance criteria. The titer to be reported is
always the one determined in the original screening procedure (independent of the result 
of the re-screening in the confirmation procedure). 
A more detailed test procedure will be supplied upon request or pro-actively if a sample 
tests positive. A treatment related increase of the binding anti-VWF antibodies is 
expected, if the titer increases by more than 2 titration steps. These subjects need to be 
closely monitored and therapy adjusted accordingly.
12.9.3.4 Neutralizing Antibodies to VWF
Three functional VWF assays, VWF:CB, VWF:RCo and VWF:FVIIIB assays, will be 
used to test for the presence of neutralizing anti-VWF antibodies. Neutralizing antibodies 
to VWF:RCo, VWF:CB and VWF:FVIIIB activities will be measured by assays based on 
the Bethesda assay established for quantitative analysis of FVIII inhibitors (Nijmegen 
modification of the Bethesda assay).17 The amount of inhibitor is expressed as BU per 
mL. One BU is thereby defined as the amount of inhibitor that decreases the measured 
activity in the assays to 50% of that of the negative control samples. The assays were 
validated using human plasma samples from two type 3 VWD patients with low 
(1-2 BU/mL) and high (~10 BU/mL) titer inhibitors and plasma samples from 
non-human primates immunized with human rVWF (vonicog alfa) (>100 BU/mL).
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If a subject has a measurable baseline level of VWF activity in the respective assay, it is 
taken into account in the calculation of the residual activity. However, if baseline levels 
are too high (>15% VWF:RCo), inhibitors may not be reliably detected.
To exclude false positive results, the detection limit for anti-VWF inhibitors was set to 
1 BU/ml for all 3 assays. The rationale for this cut-off value is the relatively high CI of 
the underlying assays, making determinations at the end of the evaluation range of the 
Bethesda reference curve uncertain.18 A more detailed test procedure may be requested to 
further characterize the anti-VWF inhibitors, if detected. 
Only confirmed positive anti-VWF inhibitor test result will be reported and will be 
considered as a medically significant SAE.
12.9.3.5 Binding Antibodies to FVIII
Binding antibodies against FVIII will be analyzed using a proprietary enzyme 
immunoassay. The testing strategy will be as described for binding anti-VWF antibodies. 
Antibody-containing samples will be identified in a screening assay followed by a 
confirmatory assay to exclude false positive results.
12.9.3.6 Neutralizing Antibodies (Inhibitors) to FVIII 
Neutralizing antibodies (inhibitors) to FVIII will be assessed by the Nijmegen 
modification of the Bethesda assay in a central laboratory. To verify a FVIII inhibitor, 
additional testing (such as tests for Lupus anticoagulants) may be initiated. Positive FVIII 
inhibitor tests will be defined as ≥0.4 BU by the Nijmegen-modified Bethesda assay that 
is confirmed by a second test performed on an independent sample obtained 2-4 weeks 
following the first test. Only confirmed positive FVIII inhibitor test result will be 
reported.
12.9.4 Antibodies to Other Proteins
Plasma will be assayed for the presence of antibodies against CHO protein (total Ig), 
murine IgG and human Furin (total Ig) using proprietary enzyme immunoassays. The 
testing strategy will be as described for binding anti- VWF antibodies. 
Antibody-containing samples will be identified in a screening assay followed by a 
confirmatory assay to exclude false positive results.
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12.9.4.1 Anti-CHO Protein
Total Ig antibodies (IgG, IgA, IgM) against CHO protein will be analyzed. For this assay 
(ELISA), CHO protein derived from cultures of untransfected cells and propagated under 
the identical cell culture conditions used for ADVATE (rFVIII, octocog alfa) production 
will be coated onto a microtiter plate, then incubated with dilutions of the positive 
control, negative control or test sample. Antibodies against CHO protein that are present 
in the samples bind to the coated antigen and will be detected with a HRP-coupled goat 
anti-human antibody (secondary antibody). The positive control for this assay will be a 
polyclonal goat anti-CHO protein antibody spiked into the negative control. The negative 
control for this assay is pooled normal human plasma.
12.9.4.2 Anti-Murine IgG
A commercially available ELISA (Medac, Hamburg, Germany) will be used to detect and 
to quantify IgG antibodies originating from human plasma that are directed against 
mouse-IgG (HAMA: human anti- mouse antibodies). Microtiter plates coated with 
mouse IgG will be incubated with dilutions of the standard, the positive control, the 
negative control or the test sample. Antibodies against mouse IgG that are present in 
the samples bind to the coated antigen and form a bridge to a peroxidase coupled mouse 
IgG antibody that will be used for detection (bridging format of the ELISA assay). 
The positive control for this assay will be a polyclonal goat anti-murine IgG spiked into 
the negative control. The negative control for this assay is pooled normal human plasma.
12.9.4.3 Antibodies to Human Furin
Total Ig antibodies (IgG, IgA, IgM) against human Furin will be analyzed. For this assay 
(ELISA), recombinant human Furin will be coated onto a microtiter plate, then incubated 
with dilutions of the positive control, the negative control or test sample. Antibodies 
against human Furin that are present in the samples bind to the coated antigen and will be 
detected with a HRP-coupled goat anti-human antibody (secondary antibody). The 
positive control for this assay will be a human monoclonal antibody specific for human 
Furin spiked into the negative control. The negative control for this assay is pooled 
normal human plasma.
12.9.5 Viral Serology
The following viral seromarkers will be assessed at screening:

HIV: anti-HIV 1, HIV 2 

HAV: anti-HAV (IgG and immunoglobulin M [IgM])

HBV: Hepatitis B surface antigen (HbsAg), anti-Hepatitis B (HB) core, anti-HBs
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
HCV: anti-HCV ELISA

Parvovirus B19: anti-B19V (IgG and IgM)
Virus serology will be established during the screening period. The relevant confirmatory 
Polymerase Chain Reaction (PCR) testing may be performed from appropriate left-over 
samples as needed. 
12.9.6 Urinalysis (Dipstick)
The urinalysis will include assessments for erythrocytes, specific gravity, urobilinogen, 
ketones, glucose, protein, bilirubin, nitrite and pH and will be performed at the central 
laboratory.
12.9.7 Pregnancy Test
A pregnancy test for females of child-bearing potential will be performed at the local 
laboratory primarily from urine. If no urine sample is available, the pregnancy testing will 
be done from serum. The pregnancy test may need to be repeated during the course of 
study in countries where mandated by national law.
12.9.8 VWD Mutational Analysis, Multimer Analysis and Human Leukocyte 
Antigen Genotyping 
A cell pellet (buffy coat and erythrocytes) will be retained at the screening visit for VWD 
gene mutational analysis, VWF multimer analysis and HLA genotype determination if the 
information is not already available in the subject’s medical history. Results from 
multimer analysis (see Section 12.9.10.1) may contribute to VWD gene mutational 
analysis. The genetic testing will be done, when the subject consents to the genetic 
testing.
12.9.9 Blood Group Analysis
The blood group needs to be determined during the screening period. If the information is 
not already available in the subject’s medical history, it has to be determined at the local 
lab.
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12.9.10 Additional Laboratory Testing in Case of Thromboembolic Events 
rVWF (vonicog alfa) contains ULMW multimers because of a lack of exposure to 
endogenous VWF protease (a disintegrin and metalloproteinase with a thrombospondin 
type 1 motif, member 13 (ADAMTS13) during the manufacturing process. In vitro and in 
vivo cleavage of these ultralarge molecular fractions by ADAMTS13 and generation of 
characteristic satellite bands has been extensively demonstrated during nonclinical and 
clinical development. Nevertheless, the potential elevated risk of thrombosis and/or other 
thromboembolic complications due to the administration of ultra large molecular VWF 
multimers in subjects with normal levels of VWF cannot be completely excluded. 
Therefore VWF multimer analysis will not only be performed routinely at screening but 
in case of thromboembolic events, both VWF multimer analysis as well as ADAMTS13 
activity will be determined to assess any relatedness of these occurrences with IP 
treatment. 
12.9.10.1 VWF Multimer Analysis 
The VWF multimer pattern will be assessed using low-resolution sodium dodecyl sulfate 
(SDS)–agarose gel electrophoresis. High-resolution SDS–agarose gel electrophoresis, 
with agarose concentrations 1.5%, will be used to determine the satellite band structure 
of VWF. These analyses will employ Western blot with luminescence video imaging.
12.9.10.2 ADAMTS13 Activity 
VWF73 was identified as the 73 amino acid minimal region of the VWF A2 domain 
required for ADAMTS13 cleavage. The cleavage of this substrate will be detected by a 
commercially available ELISA-based Chromogenic assay (Technoclone Austria):
Cleavage of immobilized VWF73 substrate is detected by a HRP-labeled antibody 
directed against the cleavage site of VWF73. The amount of bound antibody, which is the 
function of the ADAMTS13 cleavage is detected by a chromogenic substrate.
12.9.11 Soluble P-Selectin (sP-Selectin)
sP-selectin is a cell adhesion molecule (CAM) found in granules in endothelial cells 
(cells lining blood vessels) and activated platelets. Data for an association between the 
sP-selectin concentration, TTP and venous thromboembolism (VTE) are limited and the 
predictive value has not yet established. A commercial ELISA assay will be employed as 
an exploratory test. sP-selectin will be determined at the Screening visit and used as 
indicator for an increased thrombotic risk.
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12.9.12 D-Dimer
D-dimer will be used as a marker for DVT and disseminated intravascular coagulation 
(DIC). While a negative result practically rules out thrombosis, a positive result can 
indicate thrombosis but does not rule out other potential etiologies, including a recent 
hemorrhage. Its main use, therefore, is to exclude thromboembolic disease where the 
probability is low. D-Dimer will be measured at the Screening visit and used as indicator 
for an increased thrombotic risk.
12.9.13 Additional Laboratory Testing in Case of Severe Hypersensitivity Reactions 
If a subject develops a severe hypersensitivity reaction in the course of the clinical 
study, additional blood will be drawn for anti-VWF IgE antibody testing. The presence of 
anti-VWF IgE will be determined by using the ImmunoCAP®, a VWF-specific IgE 
blood test (Thermo Scientific). The basis of the ImmunoCAP® technology is a cellulose 
polymer as solid phase in a plastic capsule providing a large surface for protein binding. 
rVWF (vonicog alfa) as antigen is covalently coupled to the cellulose polymer. 
Detection of specific anti-VWF IgE bound to the antigen will be accomplished by a 
secondary enzyme-labeled anti-human IgE antibody. Testing for binding anti-human 
VWF IgE antibodies will be done with 0.5 mL plasma. Antibody containing samples will 
be identified and quantified in a screening assay followed by a confirmatory assay to 
exclude false positive results.
12.9.14 Assessment of Laboratory Values
12.9.14.1 Assessment of Abnormal Laboratory Values 
For VWF and FVIII laboratory assessments no evaluation of clinical significance is 
necessary.
Each other laboratory value (except results to determine genetics of the underlying VWD 
disease and blood group) has to be assessed by the investigator and the assessment will be 
recorded on the eCRF. The investigator will determine for each abnormal laboratory 
value whether the value is considered clinically significant or not and provide the 
reference range including the units. For clinically significant values, the investigator will 
indicate if the value constitutes a new AE (see definition in Section 12.1) and record the 
sign, symptom, or medical diagnosis on the AE CRF, is a symptom or related to a 
previously recorded AE, is due to a pre-existing disease (described in Section 12.1.1.5), 
or is due to another issue that will be specified. If the abnormal value was not clinically 
significant, the investigator will indicate the reason, i.e. because it is due to a preexisting 
disease, due to a lab error, due to variation or due to another issue that will be specified. 
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Additional tests and other evaluations required to establish the significance or etiology of 
an abnormal value, or to monitor the course of an AE should be obtained when clinically 
indicated. Any abnormal value that persists should be followed at the discretion of the 
investigator. Any abnormal laboratory value that is considered clinically significant by 
the investigator based on a local laboratory test result (reference range and the units to be 
provided) should be confirmed by a central laboratory test result for which the sample is 
drawn/collected within 24 hours of the abnormal finding by the local laboratory.
Any seroconversion result for HIV, HAV, hepatitis B virus (HBV), HCV, HEV, or B19V 
shall be re-tested.
12.10
12.10.1
 
 
 
 
 
 
 
 
 
 
 
12.10.2
 
 
 
 
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13. STATISTICS
13.1 Sample Size and Power Calculations
Approximately 22 adult subjects with severe VWD (baseline VWF:RCo <20 IU/dL) will 
be included in the study. The aim is to have at least 8 subjects in each cohort (OD and 
switch). A total of at least 5 type 3 VWD subjects will be followed for 12 months. The 
sample size is driven by practical considerations (primarily the enrollment of a rare 
patient population) and EMA Guideline on the Clinical Investigation of Human Plasma 
Derived von Willebrand Factor Products (CPMP/BPWG/220/02).1
13.2 Datasets and Analysis Cohorts
13.2.1 Safety Analysis Set
The Safety Analysis Set will be composed of all subjects who received any amount of IP 
(rVWF, vonicog alpha). 
13.2.2 Full Analysis Dataset
The Full Analysis Set (FAS) will be composed of all subjects who receive prophylaxis IP 
treatment.
13.2.3 Per-Protocol Analysis Set
The Per-Protocol (PP) Analysis Set will be composed of subjects who are at least 70% 
compliant regarding the number of scheduled prophylactic infusions (as measured by the 
ratio of actual number of infusions to planned number of infusions). Only subjects who 
met all study entry criteria and who had no major protocol violations that might impact 
primary efficacy assessments will be included in the PP analysis set.
13.2.4 PK Full Analysis Set
The Pharmacokinetic Full Analysis Set (PKFAS) will be composed of all subjects who 
received the PK infusion and who provided acceptable data for PK and PD analysis. 
Acceptable PK/PD data will be defined in the Statistical Analysis Plan. 
13.2.5 PK Per Protocol Analysis Set 
The Pharmacokinetic Per Protocol Analysis Set (PKPPAS) is defined as a subset of the 
PKFAS. Subjects who met the following additional criteria will be included in the 
PKPPAS: had no major violation of affecting the PK period of the study as defined in the 
detailed Statistical Analysis Plan. 
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13.3 Handling of Missing, Unused, and Spurious Data
13.3.1 General
Statistical techniques will not be used to identify and exclude any observations as outliers 
from the analyses. If data are considered spurious, e.g. for lack of biological plausibility, 
it will be documented to include the reason for exclusion and the analyses from which the 
data were excluded.
13.3.2 Other
1.
Regarding missing data in PK records:

Body weight: If a subject’s weight is missing from the PK infusion record, the 
subject’s last recorded weight will be used to calculate the weight-adjusted 
dose.

Concentration:

Baseline concentration levels reported as below the limit of quantification 
will be considered to be 0. Missing VWF baseline concentration levels 
(VWF: RCo, VWF: AG or VWF: CB) for Type 3 subjects will be set to 0.

Time:

If start time of infusion is missing (but stop time is available) and actual 
collection time is available, then stop time of infusion will be taken for 
further calculation (i.e. time difference between actual end date/time of 
infusion and date/time blood sample drawn).

If actual collection date/time is missing and planned collection date/time is 
missing, then this PK time point will be taken out from the PK analysis 
(i.e. no data entry for this time point). 

For all other scenarios, the planned collection date/time will be taken for 
further calculation.
2.
Regarding missing data in AE records:

Handling of unknown causality assessment:

If a subject experiences an AE with a missing causality assessment, the 
relationship of the AE will be counted as “related.”
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
Handling of unknown severity grades:

If a subject experiences more than one AE categorized under the same 
preferred term, one of them is categorized as “severe” and one of them is 
categorized as “unknown”, then the maximum severity for this preferred 
term should be counted as “severe” for this subject.

If a subject experiences more than one AE categorized under the same 
preferred term, one of them is categorized as “mild” or “moderate” and 
one of them is categorized as “unknown”, then the maximum severity for 
this preferred term should be counted as “unknown” for this subject.
13.4 Methods of Analysis
The study success criteria are the objectives as stated in Section 7. “Treatment success” 
was defined as the extent of control of bleeding episodes achieved during this study.
13.4.1 Primary Outcome Measure
The primary outcome measure is ABR for spontaneous (not related to trauma) bleeding 
episodes during prophylactic treatment with rVWF (vonicog alfa). No formal statistical 
hypothesis test is planned for the analysis. The primary efficacy analysis will be based on 
the FAS and will be summarized by the two cohorts: on-demand and switch subjects. As 
a supportive analysis, the same analysis will also be carried out on the PP analysis set.
The spontaneous ABR while treated with rVWF (vonicog alfa) for each cohort will be 
estimated using a negative binomial regression. The prior ABR will be based on 
historical data collected from each enrolled subject. 
The two ABRs (prior to prophylaxis treatment and while on prophylaxis) for each cohort 
will be compared within each subject using a generalized linear mixed-effects model 
(GLMM)  (with a logarithmic link function, the default for the negative binomial 
distribution), accounting for the fixed effect of the two treatments. The follow-up time 
(in years) will be specified as an offset. The ratio of ABR while in the study to historical 
ABR  will be estimated and reported together with the 95% confidence interval for each 
of the two cohorts.
The difference in on-study ABR relative to historical ABR will be also summarized 
descriptively.
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13.4.2 Secondary Outcome Measures 
In general, data for  secondary efficacy analysis will be summarized by the two cohorts: 
on-demand and switch subjects and when applicable overall.  Mean, standard deviation, 
median, range, quartiles will be calculated for continuous endpoints.  Proportions, will be 
calculated for categorical endpoints. Confidence intervals at the two-sided 95% level will 
be provided when appropriate.
13.4.2.1 Additional Efficacy of Prophylaxis Treatment with rVWF 
The number  and proportion of on-demand subjects with ABR percent reduction success 
(i.e.≥ 25%) will be calculated together with a two-sided, 95% CI for the proportion.
The number  and proportion of pdVWF switch subjects ABR preservation success will be 
reported together with the corresponding 95% two-sided CIs for the proportion.
The number and proportion of subjects with categorized spontaneous ABR 
(i.e. 0, 1-2, 3-5, more than 5 bleeds) will be reported descriptively.
Summary statistics for the total number of infusions, as well as average number of 
infusions per week will be provided. The total weight adjusted consumption of rVWF 
(vonicog alfa) during prophylactic treatment will be provided. If applicable, historical 
data on consumption of pdVWF prior to the study will be summarized as well.
The change in spontaneous ABR from the historical rate to that during the rVWF 
(vonicog alfa) prophylaxis period will be summarized by location of bleeding 
(GI, epistaxis, joint bleeding, menorrhagia, oral and other mucosa, muscle and soft 
tissue, etc.).
13.4.2.2 Pharmacokinetic and Pharmacodynamic Analysis
All PK and PD analyses will use the actual sampling times, not nominal times specified 
in the protocol, wherever possible. Actual sampling times will be defined as time from 
the start of infusion to the blood sample collection time. A deviation from the protocol-
specified blood sample drawing time window will not be a reason to exclude an 
observation from the analysis. Samples with unknown actual and planned collection 
date/time or where the concentration could not be determined, or where results were 
biologically implausible will be eliminated from the analysis.
If any concentration data are considered spurious (e.g. lack of biological plausibility), the 
reason for exclusion from the analysis and the analysis from which the data point was 
excluded will be documented.
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Details of calculation of PK and PD parameters and corresponding analysis will be given 
in the statistical analysis plan. 
The following PK parameters, based on the initial PK assessment after a washout for on-
demand subjects, will be listed and summarized descriptively for VWF:RCo, VWF:Ag 
and VWF:CB: IR, T1/2, MRT, AUC0-, AUC0-tlast, Cmax, Tmax, Vss, and CL. The 
corresponding pharmacodynamics (PD) of rVWF (vonicog alfa) as measured in FVIII 
activity, based on the initial PK assessment after a washout for on-demand subjects will 
be assessed using Cmax, Tmax, and AUC0-tlast. These PD parameters will be listed and 
summarized descriptively. PK parameters at steady state (AUC0-tau;ss, Cmax;ss, Tmax;ss, and 
Cmin;ss) for the partial dosing interval will be listed for on-demand subjects at the end of 
the study and for switch subjects shortly after reaching steady state and at the end of the 
study for VWF:RCo, VWF:Ag and VWF:CB and summarized descriptively for subjects 
with the same dosing regimens. The corresponding pharmacodynamics (PD) of rVWF 
(vonicog alfa) as measured in FVIII activity will be assessed using AUC0-tau;ss, Cmax;ss, 
Tmax;ss, and Cmin;ss. These PD parameters will be listed for on-demand subjects at the end 
of the study and for switch subjects shortly after reaching steady state and at the end of 
the study and will be summarized descriptively for subjects with the same dosing 
regimens.
For the on-demand subjects, the PK of VWF:RCo will be analyzed using a population PK 
approach to characterize the single and multiple dose pharmacokinetics, including 
associated variability assessed at after washout and at end of study, respectively. The 
population PK analysis will be performed in a stepwise manner as outlined below.
1.
Exploratory graphical analysis of VWF:RCo versus time data for identification of 
potential outliers and to inform the pharmacometric analysis.
2.
Population PK model development for rVWF (vonicog alfa):
a.
Evaluate alternative structural and stochastic models to describe the typical 
and individual rVWF (vonicog alfa) profiles.
b.
Investigate and characterize the potential for a time dependency in CL of 
rVWF (vonicog alfa). 
c.
Evaluate, and if necessary refine, the candidate final model
Details of this Population PK analysis will be given in a separate Population PK analysis 
plan.
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For the switch subjects, differences in AUC0-tau;ss, Cmax;ss, and Cmin;ss assessess shortly 
after reaching steady state and assessed at the end of the study will be assessed by the 
ratio of geometric means and corresponding two-sided 95% confidence intervals for 
VWF:RCo, VWF:Ag,VWF:CB, and FVIII:C. These analyses will be performed using a 
linear mixed effects model with PK assessment (i.e. factor of two levels relating to the 
PK assessment shortly after reaching steady state and the PK assessment at end of study, 
respectively) as a fixed effect and subject as a random effect based on log-transformed 
PK parameters.  The difference in Tmax;ss, between first and second pharmacokinetic 
assessment will be summarized by the median and range (minimum to maximum) for 
VWF:RCo, VWF:Ag,VWF:CB, and FVIII:C.
Descriptive statistics will be used to summarize VWF:RCo, VWF:AG and VWF:CB and 
FVIII:C levels for each nominal time point on the PK curve.
For all subjects in the PKFAS activity/concentration vs. time curves will be prepared.
Formulas for PK parameters IR, T1/2, MRT, AUC0-, AUC0-tlast, Cmax, Tmax, Vss, and CL, 
AUC0-tau;ss, Cmax;ss, Tmax;ss ,and Cmin;ss will be given in the statistical analysis plan and will 
be derived using non-compartmental methods in WinNonlin. Analysis of these 
parameters will be carried out on the PKFAS as well as on the PKPPAS.
13.4.2.3 Safety
Safety analysis will be performed overall and by the two cohorts: on-demand and switch 
subjects.
TEAEs are defined as AEs with start dates on or after the first exposure to IP. Summaries 
of AEs will be based on TEAEs unless otherwise indicated.
Occurrence of AEs and SAEs will be summarized descriptively, by system organ class 
and preferred term. The number and percentage of subjects who experienced AEs and 
SAEs, and the number of AEs and SAEs will be tabulated. In addition, the number of 
subjects who experienced AEs assessed as related to IP by the investigator, and the 
number of IP-related AEs will be tabulated. The number of patients with AEs by severity 
will be presented similarly.
A listing of all AEs will be presented by subject identifier, age, sex, preferred term and 
reported term of the AE, duration, severity, seriousness, action taken, outcome, causality 
assessment by investigator, onset date, stop date and medication or non-drug therapy to 
treat the AE.
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Temporally associated AEs are defined as AEs that begin during infusion or within 
24 hours (or 1 day where time of onset is not available) after completion of infusion, 
irrespective of being related or not related to treatment. Temporally associated AEs will 
be presented in summary tables. 
AEs that occurred before first IP infusion will be listed separately.
Adverse events of special interest (AESI), such as hypersensitivity reactions and 
thromboembolic events,  will be monitored throughout the study and statistical analysis 
will be conducted based on the search criteria (eg, standardised MedDRA queries [SMQ]) 
determined prior to database lock, and summarized.
For immunogenicity, frequency counts and percentages will be calculated for the 
occurrence of neutralizing (inhibitory) antibodies to VWF and FVIII, occurrence of 
binding antibodies to VWF and FVIII, and occurrence of binding antibodies to CHO 
proteins, mouse immunoglobulin G (IgG) and rFurin. Clinically significant changes 
relative to baseline in vital signs and clinical laboratory parameters (hematology, clinical 
chemistry) will be reported.
13.4.3 Exploratory Outcome Measures
 
13.4.3.1
 
 
 
 
 
13.4.3.2
 
 
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13.4.3.3
 
 
 
13.4.3.4
 
 
 
 
 
13.5 Planned Interim Analysis of the Study
No formal interim analysis is planned for this study. 
14. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
The investigator/study site will cooperate and provide direct access to study documents 
and data, including source documentation for monitoring by the study monitor, audits by 
the sponsor or sponsor’s representatives, review by the EC, and inspections by applicable 
regulatory authorities, as described in the Clinical Trial Agreement (CTA). If contacted 
by an applicable regulatory authority, the investigator will notify the sponsor of contact, 
cooperate with the authority, provide the sponsor with copies of all documents received 
from the authority, and allow the sponsor to comment on any responses, as described in 
the CTA.
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15. QUALITY CONTROL AND QUALITY ASSURANCE
15.1 Investigator’s Responsibility
The investigator will comply with the protocol (which has been approved/given favorable 
opinion by the EC), ICH GCP, and applicable national and local regulatory requirements 
as described in the CTA. The investigator is ultimately responsible for the conduct of all 
aspects of the study at the study site and verifies by signature the integrity of all data 
transmitted to the sponsor. The term “investigator” as used in this protocol as well as in 
other study documents, refers to the investigator or authorized study personnel that the 
investigator has designated to perform certain duties. Sub-investigators or other 
authorized study personnel are eligible to sign for the investigator, except where the 
investigator’s signature is specifically required.
15.1.1 Investigator Report and Final Clinical Study Report 
The investigator, or coordinating investigator(s) for multicenter studies, will sign the 
clinical study report. The coordinating investigator will be selected before study start. 
15.2 Training
The study monitor will ensure that the investigator and study site personnel understand all 
requirements of the protocol, the investigational status of the IP, and his/her regulatory 
responsibilities as an investigator. Training may be provided at an investigator’s meeting, 
at the study site, and/or by instruction manuals. In addition, the study monitor will be 
available for consultation with the investigator and will serve as the liaison between the 
study site and the sponsor.
15.3 Monitoring
The study monitor is responsible for ensuring and verifying that each study site conducts 
the study according to the protocol, standard operating procedures other written 
instructions/agreements, ICH GCP, and applicable national and local regulatory 
guidelines/requirements. The investigator will permit the study monitor to visit the study 
site at appropriate intervals, as described in the CTA. Monitoring processes specific to the 
study will be described in the clinical monitoring plan. 
15.4 Auditing
The sponsor and/or sponsor’s representatives may conduct audits to evaluate study 
conduct and compliance with the protocol, standard operating procedures, other written 
instructions/agreements, ICH GCP, and applicable national and local regulatory 
guidelines/requirements. The investigator will permit auditors to visit the study site, as 
described in the CTA. Auditing processes specific to the study will be described in the 
audit plan.
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15.5 Non-Compliance with the Protocol
The investigator may deviate from the protocol only to eliminate an apparent immediate 
hazard to the subject. In the event(s) of an apparent immediate hazard to the subject, the 
investigator will notify the sponsor immediately by phone and confirm notification to the 
sponsor in writing as soon as possible, but within 1 calendar day after the change is 
implemented.  Also, the investigator will notify the sponsor immediately by phone and 
confirm notification to the sponsor in writing whenever pdVWF is used instead of rVWF 
(vonicog alfa). The reason for this use must also be provided to the sponsor.The sponsor 
(Baxalta) will also ensure the responsible EC and relevant competent authority are 
notified of the urgent measures taken in such cases according to local regulations.
If monitoring and/or auditing identify serious and/or persistent non-compliance with the 
protocol, the sponsor may terminate the investigator’s participation. The sponsor will 
notify the EC and applicable regulatory authorities of any investigator termination.
15.6 Laboratory and Reader Standardization
A central laboratory/reader will be used for all clinical assessments except for pregnancy 
testing and blood group test (refer to Section 12.9). Local laboratories are requested to 
provide their laboratory specifications of the individual tests that are also being tested 
locally.
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16. ETHICS 
16.1 Subject Privacy
The investigator will comply with applicable subject privacy regulations/guidance as 
described in the CTA.
16.2 Ethics Committee and Regulatory Authorities
Before enrollment of patients into this study, the protocol, informed consent form, any 
promotional material/advertisements, and any other written information to be provided 
will be reviewed and approved/given favorable opinion by the EC and applicable 
regulatory authorities. The IB will be provided for review. The EC’s composition or a 
statement that the EC’s composition meets applicable regulatory criteria will be 
documented. The study will commence only upon the sponsor’s receipt of 
approval/favorable opinion from the EC and, if required, upon the sponsor’s notification 
of applicable regulatory authority(ies) approval, as described in the CTA.
If the protocol or any other information given to the subject is amended, the revised 
documents will be reviewed and approved/given favorable opinion by the EC and 
applicable regulatory authorities, where applicable. The protocol amendment will only be 
implemented upon the sponsor’s receipt of approval and, if required, upon the sponsor’s 
notification of applicable regulatory authority(ies) approval.
16.3 Informed Consent
Investigators will choose patients for enrollment considering the study eligibility criteria. 
The investigator will exercise no selectivity so that no bias is introduced from this source. 
All patients and/or their legally authorized representative must sign an informed consent 
form before entering into the study according to applicable national and local regulatory 
requirements and ICH GCP. Before use, the informed consent form will be reviewed by 
the sponsor and approved by the EC and regulatory authority(ies), where applicable, (see 
Section 16.2). The informed consent form will include a comprehensive explanation of 
the proposed treatment without any exculpatory statements, in accordance with the 
elements required by ICH GCP and applicable national and local regulatory 
requirements. Patients or their legally-authorized representative(s) will be allowed 
sufficient time to consider participation in the study. By signing the informed consent 
form, patients or their legally authorized representative(s) agree that they will complete 
all evaluations required by the study, unless they withdraw voluntarily or are terminated 
from the study for any reason.
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The sponsor will provide to the investigator in written form any new information that 
significantly bears on the subjects’ risks associated with IP exposure. The informed 
consent will be updated, if necessary. This new information and/or revised informed 
consent form, which have been approved by the applicable EC and regulatory authorities, 
will be provided by the investigator to the subjects who consented to participate in the 
study 
16.4 Data Monitoring Committee
This study will be monitored by a DMC. The DMC is a group of individuals with 
pertinent expertise that reviews on a regular basis accumulating data from an ongoing 
clinical study. For this study, the DMC will be composed of recognized experts in the 
field of VWD clinical care and research who are not actively recruiting subjects, and an 
independent statistician. The DMC can stop a trial if it finds toxicities or if treatment is 
proven to be not beneficial. Details will be defined in the DMC charter.
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17. DATA HANDLING AND RECORD KEEPING
17.1 Confidentiality Policy
The investigator will comply with the confidentiality policy as described in the CTA.
17.2 Study Documentation and Case Report Forms
The investigator will maintain complete and accurate paper format study documentation 
in a separate file. Study documentation may include information defined as “source data” 
(see Section 8.7), records detailing the progress of the study for each subject, signed 
informed consent forms, correspondence with the EC and the study monitor/sponsor, 
enrollment and screening information, CRFs, SAERs, laboratory reports (if applicable), 
and data clarifications requested by the sponsor.
The investigator will comply with the procedures for data recording and reporting. Any 
corrections to paper study documentation must be performed as follows: 1) the first entry 
will be crossed out entirely, remaining legible; and 2) each correction must be dated and 
initialed by the person correcting the entry; the use of correction fluid and erasing are 
prohibited.
The investigator is responsible for the procurement of data and for the quality of data 
recorded on the CRFs. CRFs will be provided in electronic form. 
If electronic format CRFs are provided by the sponsor, only authorized study site 
personnel will record or change data on the CRFs. If data is not entered on the CRFs 
during the study visit the data will be recorded on paper and this documentation will be 
considered source documentation. Changes to a CRF will require documentation of the 
reason for each change. An identical (electronic/paper) version of the complete set of 
CRFs for each subject will remain in the investigator file at the study site in accordance 
with the data retention policy (see Section 17.3).
The handling of data by the sponsor, including data quality assurance, will comply with 
regulatory guidelines (e.g., ICH GCP) and the standard operating procedures of the 
sponsor. Data management and control processes specific to the study will be described 
in the data management plan. 
17.3 Document and Data Retention 
The investigator will retain study documentation and data (paper and electronic forms) in 
accordance with applicable regulatory requirements and the document and data retention 
policy, as described in the CTA.
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18. FINANCING AND INSURANCE
The investigator will comply with investigator financing, investigator/sponsor insurance, 
and subject compensation policies, if applicable, as described in the CTA.
19. PUBLICATION POLICY
The investigator will comply with the publication policy as described in the CTA. 
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20. SUPPLEMENTS
20.1 Study Flow Chart
Figure 1
Study Design for Baxalta Clinical Study 071301
* Study treatment period is extended by 3 months to accommodate participation in the continuation 
study for the qualified subjects and will be exercised only if the continuation study start up is 
delayed beyond the completion of subject’s 12-month visit.
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20.2 Schedule of Study Procedures and Assessments
Table 6a
Schedule of Study Procedures and Assessments for On-demand Subject
Procedures/
Assessments
Screening Visit
Baseline Visit 
(PK-assessment visit)
Prophylaxis 
Initiation Visit
Interval/Follow-Up 
Study Visits
PK Assessment at 
Study Completion
Termination 
Visit
Pre-
infusiong
Infusion
Post-
infusiong
1 month ± 
1 week
2 month ± 
1 week 
3 month ± 
2 weeks
6 month ± 
2 weeks 
9 month ± 
2 weeks
Pre-
infusiong
Infusion
Post-
infusiong
Conducted at 
the 96 hour 
postinfusion 
PK 
Assessment
12-15i month ± 2 weeks
Informed Consent a
X
Eligibility Criteria
X
Medical Historyb
X
Concomitant Medicationsc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Non-drug Therapiesc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
Bleeding Episodes and Treatment 
and Hemostatic Efficacy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratories 
X
X
X
Xh
X
X
X
X
X
X
X
X
Vital Signsd
X
X
X
X
X
X
X
X
X
X
X
X
ECG
X
X
X
IP Treatmente
X
X
X
X
X
X
X
X
IP Consumption / Treatment 
Compliance 
X
X
X
X
X
Subject Diary
X
X
X
X
X
X
Xf
X
X
Continued on next page
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Continued
a) Occurs at enrollment (before screening).
b) Including documented history of on-demand treatment for the past 12 months (up to 24 months if available) and a documented history, e.g., patient charts 
and prescription information, of all bleeding episodes within the past 12 (up to 24) months. 
c) Including all medications and non- drug therapies taken in the 2 weeks prior to study entry and all the concomitant medications and non-drug therapies 
during the course of the study.
d) Vital signs: height, weight, body temperature, pulse rate, respiratory rate, and blood pressure. Height is only required at the screening visit. The time points 
for pre- and post-infusion measurements are (weight is measured pre-infusion only): within 30 minutes before infusion start and 30 ± 15 minutes post-
infusion.
e) IP treatment after the prophylactic treatment initiation visit at the site will be continued as home-treatment if the subject qualifies; a wash-out period of at 
least 72 hours is required after the last IP infusion before the follow-up visit. IP infusion will be given at the study site after the blood sample for 
immunology testing and IR determination is drawn.
f) Can be done either at the screening or the baseline visit.
g) Time points for PK blood draws: within 30 minutes pre-infusion, and at 11 time points post-infusion: 15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 
3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours and 96 ± 2 hours (the 96 hr sampling can be omitted 
if not allowed by the dosing interval).
h) If a subject did not undergo PK assessment, laboratory assessments will be performed at this visit.
i) Study treatment period is extended by 3 months to accommodate participation in the continuation study for the qualified subjects and will be exercised 
only if the continuation study start up is delayed beyond the completion of subject’s 12-month visit. In this case, 12 month ± 2 weeks visit is to be 
considered as a follow-up visit, and EOS visit is to be performed once the subject can rollover into the continuation study, from 12 month ± 2 weeks to 
15 month ± 2 weeks post prophylaxis initiation visit, as applicable.
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Table 6b
Schedule of Study Procedures and Assessments for pdVWF Switch Subject
Procedures/
Assessments
Screening Visit
Prophylaxis Initiation 
Visit
PK Assessment
(at prophylaxis dose #5-6)
Interval/Follow-Up 
Study Visits
PK Assessment at 
Study Completion
Termination 
Visit
Pre-infusiong
Infusion
Post-infusiong
1 month ± 
1 week
2 month ± 
1 week 
3 month ± 
2 weeks
6 month ± 
2 weeks 
9 month ± 
2 weeks
Pre-
infusiong
Infusion
Post-
infusiong
Conducted at 
the 96 hour 
postinfusion 
PK Assessment
12-15h month
± 2 weeks
Informed Consent a
X
Eligibility Criteria
X
Medical Historyb
X
Concomitant Medicationsc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Non-drug Therapiesc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
Bleeding Episodes and Treatment 
and Hemostatic Efficacy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratories 
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signsd
X
X
X
X
X
X
X
X
X
X
X
X
ECG
X
X
X
IP Treatmente
X
X
X
X
X
X
X
X
IP Consumption / Treatment 
Compliance 
X
X
X
X
X
Subject Diary
X
X
X
X
X
X
Xf
X
X
Continued on next page
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Continued
a) Occurs at enrollment (before screening).
b) Including documented history of prophylaxis treatment for the past 12 months (up to 24 months if available) and a documented history, e.g., patient charts 
and prescription information, of all bleeding episodes within the past 12 (up to 24) months. 
c) Including all medications and non- drug therapies taken in the 2 weeks prior to study entry and all the concomitant medications and non-drug therapies 
during the course of the study.
d) Vital signs: height, weight, body temperature, pulse rate, respiratory rate, and blood pressure. Height is only required at the screening visit. The time 
points for pre- and post-infusion measurements are (weight is measured pre-infusion only): within 30 minutes before infusion start and 30 ± 15 minutes 
post-infusion.
e) IP treatment after the prophylactic treatment initiation visit at the site will be continued as home-treatment if the subject qualifies; a wash-out period of at 
least 72 hours is required after the last IP infusion before the follow-up visit. IP infusion will be given at the study site after the blood sample for 
immunology testing and IR determination is drawn.
f) Can be done either at the screening or the prophylaxis initiation visit.
g) Time points for PK blood draws: within 30 minutes pre-infusion, and at 11 time points post infusion: 15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 
3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours and 96 ± 2 hours ( the 96 hr sampling can be 
omitted if not allowed by the dosing interval).
h) Study treatment period is extended by 3 months to accommodate participation in the continuation study for the qualified subjects and will be exercised 
only if the continuation study start up is delayed beyond the completion of subject’s 12-month visit. In this case, 12 month ± 2 weeks visit is to be 
considered as a follow-up visit, and EOS visit is to be performed once the subject can rollover into the continuation study, from 12 month ± 2 weeks to 
15 month ± 2 weeks post prophylaxis initiation visit, as applicable.
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20.2.1 Summary Schedule of Visit Assesments for Surgical Bleeding
Table 7
Summary Schedule of Visit Assessments for Surgical Bleeding
Procedures/
Assessments
Surgical procedure
Post-Operative 
Day 7 Visit
(± 1 day)
Post-Operative 
Day 14 Visit
(± 2 day)
Priming Dose 
Procedures 
(12-24 hours prior 
to surgery)
Loading Dose 
Procedures 
(≤3 hours prior
to surgery)
Intraoperative
Postoperative 
(day 1 → end of 
perioperative IP 
treatment)a
ECG
X
Physical examinationb
X
X
X
X
X
Adverse events
X
X
X
X
X
X
Laboratoriesc
X
X
X
X
X
X
Vital signsd
X
X
X
X
X
X
IP treatment: rVWF (vonicog 
alfa):ADVATE (rFVIII, octocog 
alfa) or rVWF (vonicog alfa) only 
infusion
X
X
X
as required
X
as required
X
as required
X
as required
Concomitant medications and non-
drug therapy
X
X
X
X
X
X
X
Hemostatic efficacy assessmentse
X
X
X
X
Blood loss
X
estimated
X
actual
X
Xf
Xf
Treatment days estimate
X
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Continued 
a) The assessments will be performed daily until perioperative IP treatment end (potentially multi-visits)
b) Physical Examination: within 2 hours prior to IP infusion start
c) For laboratory assessments, see Table 9
d) Vital signs: within 30 minutes before infusion start and 30 ± 15 minutes post-infusion
e) Completed immediately postsurgery by the operating surgeon 24 hours post last IP infusion or at Day 14 visit (whichever occurs first) by the investigator
f) In case bleeding still ongoing
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20.3 Clinical Laboratory Assessments
Table 8a
Clinical Laboratory Assessments for On-demand Subject
Procedures/
Assessments
Screening Visit
Baseline Visit 
(PK-assessment visit)
Prophylaxis 
Initiation Visitk
Interval/Follow-Up 
Study Visits
PK Assessmentm at 
Study Completion
Termination 
Visit
Pre-infusion
Infusion
Post-infusion
1 month ± 
1 week
2 month ± 
1 week 
3 month ± 
2 weeks
6 month ± 
2 weeks 
9 month ± 
2 weeks
Pre-
infusion
Infusion
Post-
infusion
Conducted 
at the 
96 hour 
postinfusion 
PK 
Assessment
12-15n month± 2 weeks
Hematology a
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Chemistryb
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation Panel/ PK 
assessmentc
X
X
X
X
X
X
X
X
X
X
X
Immunogenicityd
X
X
Xl
X
X
X
X
X
X
X
Viral Serologye
X
Urinalysisf
X
VWD Gene Mutational 
Analysis / HLA genotype 
analysis and Analysis of 
VWF multimersg
X
sP-selectin and D-dimer
Xh
Blood Groupi 
X
Pregnancy Testj
X
a) Hematology assessments include: complete blood count [hemoglobin, hematocrit, erythrocytes (i.e. red blood cell count), mean corpuscular volume 
(MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), leukocytes (i.e. white blood cell count)] with 
differential (i.e. basophils, eosinophils, lymphocytes, monocytes, neutrophils) and platelet counts. Hematology assessments during PK assessments will be 
determined prior to IP infusion and 24 ± 2 hours, 48 ± 2 hours and 72 ± 2 hours thereafter. For other IP-associated visits, samplings are within 60 minutes 
pre-infusion.
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Continued
b) Clinical chemistry assessments include: Sodium, potassium, chloride, glucose, creatinine, blood urea nitrogen (BUN), aspartate aminotransferase (AST), 
alanine aminotransferase (ALT) lactate dehydrogenase (LDH), alkaline phosphatase (AP), bilirubin. Clinical chemistry will be determined prior to IP 
infusion and after 24 ± 2 h, 48 ± 2 hours and 72 ± 2 hours during the PK assessments. For other IP-associated visits, samplings are within 60 minutes pre-
infusion.
c) Coagulation panel/PK assessment (also refers to IR pre/post dose assessments at prophy initiation visit and each follow-up visit): PT, INR and aPTT (only 
for screening), VWF:RCo, VWF:Ag, VWF:CB, FVIII:C,; during the PK assessment at the baseline visit blood samples will be drawn 30 min prior PK 
infusion; once the PK infusion is completed 15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 
30 ± 2 hours, 48 2 hours, 72 2 hours and 96 ± 2 hours and VWF:RCo, VWF:CB, VWF:Ag, FVIII:C will be determined; for follow-up visits, IR 
samples will be drawn within 30 minutes pre-infusion and 30 5 minutes post-infusion. During screening and in case of thromboembolic event VWF 
multimers and ADAMTS13 will be analyzed to judge on a possibly relatedness to UHMW fractions of the IP.
d) Immunogenicity assessment includes Neutralizing Antibodies (Ab) to FVIII –Neutralizing Ab to VWF:RCo, Neutralizing Ab to VWF:CB, Neutralizing 
Ab to VWF:FVIII, Binding Ab to VWF and FVIII, Binding Ab to CHO-Protein, Binding Ab to rFurin, Binding Ab to Murine IgG . In case of an SAE 
hypersensitivity reaction IgE antibodies to VWF will be determined. For on-demand subjects, a washout period of at least 72 hours after the last IP 
infusion is required before blood samples for immunogenicity assessments can be drawn. 
e) Viral Serology Hepatitis A Antibody, Total - Hepatitis A Antibody, IgM - Hepatitis B Surface Antibody - Hepatitis B Core Ab, Total - Hepatitis B Surface 
Antigen - Hepatitis C Virus Antibody; Parvovirus B19; HIV-1/HIV-2 Antibodies 
f) Urinalysis comprehends: erythrocytes, specific gravity, urobilinogen, ketones, glucose, protein, bilirubin, nitrite, and pH
g) Not required if available in the subject’s medical history; VWF multimers: additionally in case of thromboembolic events
h) At screening and in case of thromboembolic events
i) Blood group assessment major blood group (local laboratory) only if not available in the subject’s medical history
j) Serum pregnancy test (in females of child-bearing potential if no urine sample is available)
k) The last post-infusion laboratory assessments coincidence with the initiation visit for prophylactic treatment. After the blood samples are drawn for 
laboratory assessment for the 96 h post infusion PK assessment, the subject receives the first IP infusion for prophylactic treatment (prophylactic treatment 
initiation visit). 
l) Only needed for subjects without PK assessment prior to their first IP infusion in this study.
m) A steady state full PK analysis will be performed at the end of the study. Blood samples will be drawn within 30 minutes pre-infusion, and at 11 time points 
post-infusion (15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 
72 2 hours and 96 ± 2 hours), the 96 hr sampling can be omitted if not allowed by the dosinig interval.
n) Study treatment period is extended by 3 months to accommodate participation in the continuation study for the qualified subjects and will be exercised only 
if the continuation study start up is delayed beyond the completion of subject’s 12-month visit. In this case, 12 month ± 2 weeks visit is to be considered as a 
follow-up visit, and EOS visit is to be performed once the subject can rollover into the continuation study, from 12 month ± 2 weeks to 15 month ± 2 weeks 
post prophylaxis initiation visit, as applicable.
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Table 8b
Clinical Laboratory Assessments for pdVWF Switch Subject
Procedures/
Assessments
Screening Visit
Prophylaxis Initiation Visit
PK Assessmentk
(at prophylaxis dose #5-6)
Interval/Follow-Up 
Study Visits
PK Assessmentk at 
Study Completion
Termination 
Visit
Pre-infusion
Infusion
Post-infusion
1 month ± 1 week
2 month ± 1 week 
3 month ± 2 weeks
6 month ± 2 weeks 
9 month ± 2 weeks
Pre-
infusion
Infusion
Post-
infusion
Conducted at 
the 96 hour 
postinfusion 
PK 
Assessment
12-15l month± 
2 weeks
Hematology a
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Chemistryb
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation Panel/PK 
assessmentc
X
X
X
X
X
X
X
X
X
X
X
Immunogenicityd
X
X
X
X
X
X
X
X
X
Viral Serologye
X
Urinalysisf
X
VWD Gene Mutational 
Analysis / HLA 
genotype analysis and 
Analysis of VWF 
multimersg
X
sP-selectin and D-dimer
Xh
Blood Groupi 
X
Pregnancy Testj
X
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Continued
a) Hematology assessments include: complete blood count [hemoglobin, hematocrit, erythrocytes (i.e. red blood cell count), mean corpuscular volume 
(MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), leukocytes (i.e. white blood cell count)] with 
differential (i.e. basophils, eosinophils, lymphocytes, monocytes, neutrophils) and platelet counts. Hematology assessments during PK assessments will be 
determined prior to IP infusion and 24 ± 2 hours, 48 ± 2 hours and 72 ± 2 hours thereafter. For other IP-associated visits, samplings are within 60 minutes 
pre-infusion.
b) Clinical chemistry assessments include: Sodium, potassium, chloride, glucose, creatinine, blood urea nitrogen (BUN), aspartate aminotransferase (AST), 
alanine aminotransferase (ALT) lactate dehydrogenase (LDH), alkaline phosphatase (AP), bilirubin. Clinical chemistry will be determined prior to IP 
infusion and after 24 ± 2 h, 48 ± 2 hours and 72 ± 2 hours during the PK assessments. For other IP-associated visits, samplings are within 60 minutes pre-
infusion.
c) Coagulation panel/PK assessment (also refers to IR pre/post dose assessments at prophy initiation visit and each follow-up visit): PT, INR and aPTT (only 
for screening), VWF:RCo, VWF:Ag, VWF:CB, FVIII:C,; during the PK assessment blood samples will be drawn 30 min prior PK infusion; once the PK 
infusion is completed 15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 
48 2 hours, 72 2 hours and 96 ± 2 hours and VWF:RCo, VWF:CB, VWF:Ag, FVIII:C will be determined; for follow-up visits, IR samples will be 
drawn within 30 minutes pre-infusion and 30 5 minutes post-infusion. During screening and in case of thromboembolic event VWF multimers and 
ADAMTS13 will be analyzed to judge on a possibly relatedness to UHMW fractions of the IP.
d) Immunogenicity assessment includes Neutralizing Antibodies (Ab) to FVIII –Neutralizing Ab to VWF:RCo, Neutralizing Ab to VWF:CB, Neutralizing 
Ab to VWF:FVIII, Binding Ab to VWF and FVIII, Binding Ab to CHO-Protein, Binding Ab to rFurin, Binding Ab to Murine IgG. In case of an SAE 
hypersensitivity reaction IgE antibodies to VWF will be determined. For switch subjects, the wash out period may be reduced to the time interval between 
their pdVWF prophy infusions.
e) Viral Serology Hepatitis A Antibody, Total - Hepatitis A Antibody, IgM - Hepatitis B Surface Antibody - Hepatitis B Core Ab, Total - Hepatitis B Surface 
Antigen - Hepatitis C Virus Antibody; Parvovirus B19; HIV-1/HIV-2 Antibodies 
f) Urinalysis comprehends: erythrocytes, specific gravity, urobilinogen, ketones, glucose, protein, bilirubin, nitrite, and pH
g) Not required if available in the subject’s medical history; VWF multimers: additionally in case of thromboembolic events
h) At screening and in case of thromboembolic events
i) Blood group assessment major blood group (local laboratory) only if not available in the subject’s medical history
j) Serum pregnancy test (in females of child-bearing potential if no urine sample is available)
k) A full steady state PK analysis will be performed. Blood samples will be drawn within 30 minutes pre-infusion, and at 11 time points post-infusion
(15 ± 5 minutes, 30 5 minutes, 60 5 minutes, 3 ± 0.5 hours, 6 0.5 hours, 12 0.5 hours, 24 0.5 hours, 30 ± 2 hours, 48 2 hours, 72 2 hours 
and 96 ± 2 hours) , the 96 hr sampling can be omitted if not allowed by the dosinig interval.
l) Study treatment period is extended by 3 months to accommodate participation in the continuation study for the qualified subjects and will be exercised only 
if the continuation study start up is delayed beyond the completion of subject’s 12-month visit. In this case, 12 month ± 2 weeks visit is to be considered as a 
follow-up visit, and EOS visit is to be performed once the subject can rollover into the continuation study, from 12 month ± 2 weeks to 15 month ± 2 weeks 
post prophylaxis initiation visit, as applicable.
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20.3.1 Laboratory Sampling for Surgical Bleeding
Table 9
Laboratory Samplinga for Surgical Bleeding
Procedures/
Assessments
Surgical procedure
Post-Operative 
Day 7 Visit
(± 1 day)
Post-Operative 
Day 14 Visit
(± 2 day)
Priming Dose 
Procedures 
(12-24 hours prior 
to surgery)
Loading Dose 
Procedures 
(≤3 hours prior 
to surgery)
Intraoperative
Postoperative 
(day 1 → end of 
perioperative IP 
treatment)b
Hematologyc
X
(w/o Differential)
Xd
(w/o Differential)
X
(w/o Differential)
X
X
Clinical Chemistrye
X
Xd
X
X
Coagulation panelf
X
X
X
X
X
X
VWF inhibitory and binding 
antibodies, antibodies to other 
proteinsg
X
X
X
if excessive or 
unexplainedbleeding
X
X
X
Urinalysish
X
X
VWF Multimersi
Anti VWF IgE antibody testing
only in case of allergic reaction/ 
anaphylaxis
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Continued
a) Blood draws are within 3 hrs  prior to infusion start, expect that for the priming dose blood draw is within 30 minutes prior to infusion start. For 
coagulation panel, an additional 30 ± 5 minutes post-infusion blood draw is needed.
b) The assessments will be performed daily until perioperative IP treatment end (potentially multi-visits)
c) Hematology assessments include: complete blood count [hemoglobin, hematocrit, erythrocytes (i.e. red blood cell count), mean corpuscular volume 
(MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), leukocytes (i.e. white blood cell count)] with 
differential (i.e. basophils, eosinophils, lymphocytes, monocytes, neutrophils) and platelet counts. 
d) Not required if sample already drawn at the time of the priming dose
e) Clinical chemistry assessments include: Sodium, potassium, chloride, glucose, creatinine, blood urea nitrogen (BUN), aspartate aminotransferase (AST), 
alanine aminotransferase (ALT) lactate dehydrogenase (LDH), alkaline phosphatase (AP), bilirubin. 
f) Coagulation panel: VWF:RCo, VWF:Ag, FVIII:C PT INR and aPTT; in additiona to pre-infusion, 30 ± 5 minutes post infusion blood draw is needed. 
g) Immunogenicity assessment includes Neutralizing Antibodies (Ab) to FVIII – Neutralizing and Neutralizing Ab to VWF:RCo, Neutralizing Ab to 
VWF:CB, Neutralizing Ab to VWF:FVIII, Binding Ab to VWF and FVIII, Binding Ab to CHO-Protein, Binding Ab to rFurin, Binding Ab to Murine IgG. 
In case of an SAE hypersensitivity reaction IgE antibodies to VWF will be determined.
h) Urinalysis comprehends: erythrocytes, specific gravity, urobilinogen, ketones, glucose, protein, bilirubin, nitrite, and pH
i) VWD multimers and ADAMTS13 during the study only in case of thrombotic events
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20.4 Contraceptive Methods for Female Subjects of Childbearing Potential
In this study, subjects who are women of childbearing potential must agree to utilize a 
highly effective contraceptive measure throughout the course of the study and for 30 days 
after the last administration ofIP. In accordance with the Clinical Trial Facilitation Group 
(CTFG) recommendations related to contraception and pregnancy testing in clinical trials 
(version 2014-09-15)ii, birth control methods which may be considered as highly 
effective include the following:

Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation:

oral

intravaginal

transdermal

Progestogen-only hormonal contraception associated with inhibition of ovulation:

oral

injectable

implantableiii

Intrauterine device (IUD)iii

Intrauterine hormone-releasing system (IUS) iii

Bilateral tubal occlusioniii

Vasectomised partner(s)iii

Sexual abstinence during the entire study period
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhoea method (LAM) are 
not acceptable methods of contraception. Female condom and male condom should not 
be used together.
                                                
ii Clinical Trial Facilitation Group (CTFG) recommendations related to contraception and pregnancy 
testing in clinical trials: http://www.hma.eu/fileadmin/dateien/ 
Human_Medicines/01About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf.
iii Contraception methods that are considered to have low user dependency.
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21. REFERENCES
1.
Committee for Medicinal Products for Human Use. Guideline on clinical 
investigation of human plasma derived von Willebrand factor products. 
CPMP/BPWG/220/02, 12. 11-17-2005:London, European Medicines Agency 
(EMA):2005. Web Link: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/201
0/01/WC500067126.pdf
2.
Mannucci PM. Treatment of von Willebrand's Disease. N Engl J Med. 
2004;351(7):683-694.
3.
Goudemand J, Scharrer I, Berntorp E, et al. Pharmacokinetic studies on Wilfactin, a 
von Willebrand factor concentrate with a low factor VIII content treated with three 
virus-inactivations/removal methods. J Thromb Haemost. 2005;3(10):2219-2227.
4.
Abshire T. The role of prophylaxis in the management of von Willebrand disease: 
today and tomorrow. Thromb Res. 2009;124 Suppl 1:S15-S19.
5.
Nilsson IM, Blombäck M, Jorpes E, Blombäck B, Johansson SA. V. Willebrand's 
disease and its correction with human plasma fraction 1-0. Acta Med Scand. 
1957;159(3):179-188.
6.
Berntorp E, Petrini P. Long-term prophylaxis in von Willebrand disease. Blood 
Coagul Fibrinolysis. 2005;16 Suppl 1:S23-S26.
7.
Berntorp E. Prophylaxis and treatment of bleeding complications in von Willebrand 
disease type 3. Semin Thromb Hemost. 2006;32(6):621-625.
8.
Federici AB. Highly purified VWF/FVIII concentrates in the treatment and 
prophylaxis of von Willebrand disease: the PRO.WILL Study. Haemophilia. 
2007;13 Suppl 5:15-24.
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9.
Halimeh S, Krümpel A, Rott H, et al. Long-term secondary prophylaxis in children, 
adolescents and young adults with von Willebrand disease. Results of a cohort 
study. Thromb Haemost. 2011;105(4):597-604.
10.
Abshire TC, Federici AB, Alvárez MT, et al. Prophylaxis in severe forms of von 
Willebrand's disease: results from the von Willebrand Disease Prophylaxis Network 
(VWD PN). Haemophilia. 2013;19(1):76-81.
11.
Abshire T, Cox-Gill J, Kempton CL, et al. Prophylaxis escalation in severe von 
Willebrand disease: A prospective study from the von Willebrand Disease 
Prophylaxis Network. J Thromb Haemost. 2015;13(9):1585-1589.
12.
Berntorp E. Prophylaxis in von Willebrand disease. Haemophilia. 2008;14 Suppl 
5:47-53.
13.
Varadi K, Rottensteiner H, Vejda S, et al. Species-dependent variability of 
ADAMTS13-mediated proteolysis of human recombinant von Willebrand factor. J 
Thromb Haemost. 2009;7(7):1134-1142.
14.
Mannucci PM, Kempton C, Millar C, et al. Pharmacokinetics and safety of a novel 
recombinant human von Willebrand factor manufactured with a plasma-free 
method: a prospective clinical trial. Blood. 2013;122(5):648-657.
15.
Gill JC, Castaman G, Windyga J, et al. Hemostatic efficacy, safety and 
pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand 
disease. Blood. 2015;126(17):2038-2046.
16.
Committee for Medicinal Products for Human Use. Guideline on immunogenicity 
assessment of biotechnology-derived therapeutic proteins. 
CHMP/BMWP/14327/2006, 18. 12-13-2007:London, European Medicines Agency 
(EMA),:2007. Web Link: 
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9/09/WC500003946.pdf
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17.
Kasper CK. Laboratory tests for factor VIII inhibitors, their variation, significance 
and interpretation. Blood Coagul Fibrinolysis. 1991;2 Suppl 1:7-10.
18.
Lillicrap D. Von Willebrand Factor. International Society for Thrombosis and 
Hemostasis (ISTH), 54th Annual Scientific and Standardization Committee 
Meeting - Scientific Subcommittee Minutes:2008:60-64. Web Link: 
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19.
 
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22. SUMMARY OF CHANGES
Protocol 071301: Local Amendment 11 (Russia): 2019 JAN 28
Replaces: Global Amendment 6: 2018 MAR 12
In this section, changes from the previous version of the Protocol, dated 2018 MAR 12, 
are described and their rationale is given.
1.
Throughout the document
Description of Change:
Minor grammatical and/or administrative changes and/or rewording have been 
made.
Purpose for Change: To improve the readability and/or clarity of the protocol.
2.
Synopsis (Study Design), Section 8.1
Description of Change: 
Added the wording about the possible up-to 3 months’ extension of study 
participation for certain subjects.
Purpose for Change: To add information about possible extension of study 
participation for certain subjects.
3.
Synopsis (Planned Duration of Subject Participation), Section 8.2
Description of Change: 
Added the note about the possible up-to 3 months’ extension of study 
participation for certain subjects, and clarify that the planned duration of subject 
participation can therefore be extended to 18 months. 
Purpose for Change: To add information about possible extension of study 
participation for certain subjects.
4.
Synopsis (Secondary outcome measures), Section 8.3.2.1
Description of Change:
Original text:
Categorized spontaneous ABR defined as 0, 1-2, 3-5, or >5 bleeding episodes 
during the 12-month prophylactic treatment with rVWF (vonicog alfa)
New text:
Categorized spontaneous ABR defined as 0, 1-2, 3-5, or >5 bleeding episodes 
during the prophylactic treatment with rVWF (vonicog alfa)
Purpose for Change: To remove the exact prophylactic treatment period as it can 
be extended beyond 12 month for certain subjects.
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5.
Section 6.1
Description of Change: 
Updates were added to reflect the marketing authorization for 
Vonvendi/Veyvondi in US, EU, Switzerland and Canada.
Purpose for Change: To provide updated marketing authorization for 
Vonvendi/Veyvondi.
6.
Section 10.3.7
Description of Change:
The detailed schedules of follow-up visits were removed as for certain subjects 
12-month follow-up visit will be scheduled with the need of participation 
extension.
Purpose for Change: To remove the details to avoid confusion of possible 
12-month follow-up visit.
7.
Section 10.3.9
Description of Change:
End of study visit time was removed as for certain subjects the EOS visit can 
occur after 12 months with the need of participation extension. 
Added the note about the possible up-to 3 months’ extension of study 
participation for certain subjects
Purpose for Change: To add information about possible extension of study 
participation for certain subjects and to remove the details to avoid confusion of 
possible delayed EOS visit.
8.
Section 11.6, Section 12.10.2
Description of Change: 
Added the note about the possible up-to 3 months’ extension of study 
participation for certain subjects. 
Purpose for Change: To add information about possible extension of study 
participation for certain subjects.
9.
Section 20.2 Table 6a 6b, Section 20.3 Table 8a 8b
Description of Change: 
Added the footnote to reflect the possible up-to 3 months’ extension of study 
participation for certain subjects.
Purpose for Change: To add note about possible extension of study participation 
for certain subjects.
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10.
Section 20.2 Table 6a 6b, Section 20.3 Table 8a 8b
Description of Change:
Some clarifications were made to the tables and the footnotes, to reflect the 
possible up-to 3 months’ extension of study participation for certain subjects. 
Purpose for Change: To add information about possible extension of study 
participation for certain subjects.
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INVESTIGATOR ACKNOWLEDGEMENT
RECOMBINANT VON WILLEBRAND FACTOR (rVWF)
A prospective, phase 3, open-label, international multicenter study on efficacy and 
safety of prophylaxis with rVWF in severe von Willebrand Disease
PROTOCOL IDENTIFIER: 071301
CLINICAL TRIAL PHASE 3
LOCAL AMENDMENT 11 (RUSSIA): 2019  JAN 28
Replaces: GLOBAL AMENDMENT 6: 2018 MAR 12
OTHER PROTOCOL ID(s)
NCT Number: NCT02973087
EudraCT Number: 2016-001478-14
IND NUMBER: 013657
By signing below, the investigator acknowledges that he/she has read and understands 
this protocol, and will comply with the requirements for obtaining informed consent from 
all study subjects prior to initiating any protocol-specific procedures, obtaining written 
initial and ongoing EC(s) protocol review and approval, understands and abides by the 
requirements for maintenance of source documentation, and provides assurance that this 
study will be conducted according to all requirements as defined in this protocol, Clinical 
Trial Agreement, ICH GCP guidelines, and all applicable national and local regulatory 
requirements.
Signature of Principal Investigator
Date
Print Name of Principal Investigator
For non-commercial use only

For non-commercial use only