Type 3 Von Willebrand International Registries Inhibitor Prospective Study
Conditions: Type 3 Von Willebrand's Disease
Sponsor: Fondazione Angelo Bianchi Bonomi

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
CONFIDENTIAL 
1/46 
 
 
 
 
FONDAZIONE BIANCHI BONOMI 
Piazza Castello, 2 – 20121 Milan, Italy 
 
 
 
 
 TYPE 3 VON WILLEBRAND INTERNATIONAL 
REGISTRIES INHIBITOR PROSPECTIVE STUDY 
(3WINTERS-IPS) 
EXTENDED 
 
A 8-year International Registries and  
Prospective Study on VWD Type 3 Patients 
 
 
STUDY CODE:   
 
ABB-11-01 
PROTOCOL VERSION:  
Amendment 2, 28th January 2020 
 
 
 
Scientific Coordination and Supervision: 
 
PROF. A. B. FEDERICI  
 
 
 
With the Working Group on VWD3 recognized by the  
European Association of Haemophilia and Allied Disorders (EAHAD) 
and Sub-Committee on VWF Scientific Standardization Committees of the  
International Society on Thrombosis and Haemostasis (SC-VWF, SSC-ISTH) 

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
CONFIDENTIAL 
2/46 
TABLE OF CONTENTS 
 
ABBREVIATIONS ............................................................................................................................ 4 
INVESTIGATOR’S AGREEMENT ................................................................................................ 5 
STUDY SYNOPSIS............................................................................................................................ 6 
1. 
STUDY BACKGROUND ............................................................................................... 11 
2. 
OBJECTIVES AND EXPECTED ACHIEVEMENTS................................................... 12 
2.1 
Measurable Objectives ..................................................................................................... 13 
2.2 
Expected Achievements ................................................................................................... 13 
3. 
STUDY DESIGN AND PROJECT WORKING PACKAGES ...................................... 14 
3.1 
General description of the project .................................................................................... 14 
3.1.1 
First part of the Study................................................................................................... 15 
3.1.2 
Second & third parts of the Study ................................................................................ 15 
4. 
STUDY DURATION AND TIMELINES ...................................................................... 19 
5. 
STUDY POPULATION .................................................................................................. 20 
5.1 
ELIGIBILITY CRITERIA .............................................................................................. 20 
5.2 
ENROLMENT STRATEGIES ........................................................................................ 20 
6. 
STUDY PROCEDURES ................................................................................................. 21 
6.1 
ENROLMENT – FIRST PART OF THE STUDY ......................................................... 21 
6.1.1 
Enrolment visit ............................................................................................................. 21 
6.2 
FOLLOW-UP – SECOND PART OF THE STUDY ...................................................... 21 
6.2.1 
Control visit.................................................................................................................. 21 
6.2.2 
Final visit...................................................................................................................... 22 
7. 
DATA POINTS ............................................................................................................... 22 
8. 
STATISTICAL ANALYSIS ........................................................................................... 24 
8.1 
PRIMARY ANALYSIS .................................................................................................. 24 
8.2 
STATISTICAL ANALYSIS ........................................................................................... 25 
9. 
PROJECT MANAGEMENT AND COORDINATION ................................................. 25 
10. 
SAFETY .......................................................................................................................... 26 
10.1 
Safety Information ....................................................................................................... 26 
11. 
ETHICAL ASPECTS ...................................................................................................... 27 
11.1 
Study supervision ......................................................................................................... 28 
11.2 
Privacy of personal data ............................................................................................... 28 
11.3 
Confidentiality ............................................................................................................. 28 
11.4 
Protocol compliance ..................................................................................................... 29 
11.5 
Protocol modifications ................................................................................................. 29 
11.6 
Subject identification register and subject screening log ............................................. 30 
12. 
PUBLICATION POLICY ............................................................................................... 30 
13. 
GENERAL REFERENCES............................................................................................. 31 
APPENDIX 1 .................................................................................................................................... 42 
STUDY FLOWCHART .................................................................................................................. 42 
APPENDIX 2 .................................................................................................................................... 43 
MEMBERS OF THE WORKING GROUP ON THE 
3WINTERS-IPS STEERING COMMITTEE ............................................................................... 43 
APPENDIX 3 .................................................................................................................................... 45 
WORKING PACKAGES ................................................................................................................ 45 
APPENDIX 4 .................................................................................................................................... 46 
PRELIMINARY INFORMATION COLLECTED 
DURING THE STUDY ................................................................................................................... 46 
 

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
CONFIDENTIAL 
4/46 
ABBREVIATIONS 
 
AC 
 
 
Assistant Coordinator 
AE 
 
 
Adverse Event 
ANGDYS 
 
Angiodysplasia 
CP 
 
 
Cell Pellet 
CRF 
 
 
Case Report Form 
CRO  
 
Contract Research Organization 
DDAVP 
 
Desmopressin 
DMC  
 
Data Monitoring Committee 
EAHAD 
 
European Association of Haemophilia and Allied Disorders 
EC 
 
 
Ethics Committee 
FC 
 
 
Financial Coordinator 
FVIII  
 
Factor VIII 
FVIII:C 
 
Factor VIII clotting activity 
GCP   
 
Good Clinical Practice 
GIB 
 
 
Gastro-Intestinal Bleeding 
HCV  
 
Hepatitis C Virus 
HIV 
 
 
Human Immunodeficiency Virus 
IRB 
 
 
Institutional Review Board 
ISTH  
 
International Society on Thrombosis and Haemostasis 
MCV  
 
Mean Corpuscular Volume 
MPV  
 
Mean Platelet Volume 
  
PC 
 
 
Publication Coordinator 
PPP 
 
 
Platelet Poor Plasma 
PT 
 
 
Prothrombin Time 
PTT 
 
 
Partial Thromboplastin Time 
SAE 
 
 
Serious Adverse Event 
SAP 
 
 
Statistical Analysis Plan 
SC 
 
 
Steering Committee 
SS 
 
 
Study Supervisor 
US 
 
 
United States (of America) 
VWD  
 
Von Willebrand Disease  
VWD3 
 
Type 3 Von Willebrand Disease  
VWF  
 
Von Willebrand factor 
VWF:Ag 
 
Von WIllebrand factor Antigen 
VWF:RCo 
 
Von Willebrand Ristocetin Cofactor 
WHO  
 
World Health Organization 
WP 
 
 
Working Package 
 
 

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
CONFIDENTIAL 
5/46 
INVESTIGATOR’S AGREEMENT 
 
 
Study title:  
Type 3 Von Willebrand International Registries Inhibitor 
Prospective Study - (3WINTERS-IPS) - EXTENDED 
 
 
Investigator name:   
Prof./Dr. ________________________________________________ 
 
 
Center address: 
 
_______________________________________________________ 
 
 
 
 
 
_______________________________________________________ 
 
 
Center Number: 
 
|____|____|____|____| 
 
 
I declare that I have exhaustively discussed the objectives of this study and the contents of this 
protocol with the representatives of the Sponsor/Steering Committee/CRO.  
 
I agree to conduct the study described in this protocol according to the procedures and ethical and 
patient safety aspects reported herein, and in accordance with Good Clinical Practice and the 
Helsinki Declaration.  
 
If the Sponsor decides for whatever reason and at any time to suspend the study or end it 
prematurely, this will be communicated to me in writing. If I decide to withdraw from performing 
the study, I will immediately inform the Sponsor/Steering Committee/CRO of this decision in 
writing.  
 
Principal Investigator 
 
 
 
_________________________________ 
 
__________________ 
Signature 
 
 
 
 
 
 
Date 
 

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
CONFIDENTIAL 
6/46 
STUDY SYNOPSIS 
 
Study title 
Type 3 Von Willebrand International Registries Inhibitor 
Prospective Study - (3WINTERS-IPS) - EXTENDED 
Study background 
Von Willebrand Disease (VWD) is the most common inherited 
bleeding disorder, characterized by a quantitative (VWD types 1 
and 3) and/or qualitative (VWD types 2A, 2B, 2M and 2N) 
deficiency of von Willebrand factor (VWF), the large multi-
functional plasma glycoprotein that plays a major role in early 
phases of haemostasis. VWD type 3 (VWD3) is due to virtually 
complete deficiency of VWF and, for this reason, has been also 
described as “severe VWD”. Recurrent Gastro-Intestinal Bleeds 
(GIB) is one of the most challenging complications encountered 
in the management of patients with VWD. The commonest cause 
is angiodysplasia (ANGDYS), but often no cause is identified 
due to the difficulty in making the diagnosis. In recent years, 
research from several laboratories has identified multiple roles 
for VWF in the control of vascular function. Globally, these 
findings provide the first possible explanation for the presence of 
ANGDYS in patients with VWD. These vascular malformations 
in the gastrointestinal (GI) tract are characterized by fragile, 
leaky mucosal vessels. Combined with the hemostatic 
dysfunction, these can lead to severe intractable bleeding 
including GIB. VWD3 patients by definition are characterized by 
undetectable levels of VWF antigen (VWF:Ag) in plasma and by 
reduced concentrations (< 10 IU/dL) of factor VIII (FVIII). 
These baseline levels usually do not increase in plasma following 
desmopressin (DDAVP), the drug which can release VWF from 
endothelium. VWD3 is inherited as a recessive trait and 
heterozygous relatives have mild or no bleeding symptoms.  The 
prevalence of VWD3 is very low, ranging from 0.1 to 5.3 per 
million and differing considerably between countries. The 
highest rate is found in Iran and the lowest in southern Europe. 
However, the actual prevalence of VWD3 is still unknown in 
most countries, due to the lack of retrospective or prospective 
studies. Although rare, VWD3 is of major interest because of its 
severe clinical presentation, the need for replacement therapy 
with plasma-derived and/or recombinant VWF concentrates and 
the risk of occurrence of anti-VWF inhibitors after the infusion 
of VWF concentrates, for which risk factors have not been 
systematically determined.  
Study objectives 
 International  network among  European (approximately 
125 cases) and Iranian (approximately 125 cases) centers; 
 Prospective enrollment of at least 250 VWD3 patients 
using a common database online; 
 Detailed information about previous bleedings and 
exposure to plasma-derived and/or recombinant VWF 
concentrates of identified VWD3 patients; 

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
CONFIDENTIAL 
7/46 
 Bleeding severity score of identified VWD3 patients 
calculated with a common questionnaire; 
 Collection of plasma and DNA samples from all the 
identified VWD3 patients enrolled for centralized 
analyses; 
 Confirmation of the local VWD3 diagnosis using 
centralized tests; 
 Evaluation of VWF gene defects, VWF phenotype and 
risk of anti-VWF inhibitors through common methods; 
 Evaluation of potential correlations between phenotypic 
results (including markers of angiogenesis) and GIB 
occurrence; 
 Objective evaluation of severity of GIB in VWD3 
patients; 
 Assessment of frequency and sites of bleeding in VWD3 
patients followed-up for 2 prospective observation 
periods (2 years each: 2017-2018 and 2020-2021); 
 Efficacy assessment of the plasma-derived and/or 
recombinant VWF concentrates used to treat VWD3 (on 
demand versus prophylaxis) using the most objective 
criteria for efficacy during 2 prospective observation 
periods (2 years each: 2017-2018 and 2020-2021); 
 
Evaluation of the efficacy and safety of plasma-derived 
and/or  recombinant VWF concentrates in the treatment 
of GIB during 2 prospective observation periods (2 years 
each: 2017-2018 and 2020-2021), in comparison to the 
use of anti-angiogenetic agents within the standard 
clinical setting. 
Study design 
No-profit, investigators initiated, multi-center, European-Iranian 
observational, retrospective and prospective study on patients 
with diagnosis of Type 3 von Willebrand Disease. 
Study Centers 
A total of 20 Investigational sites will be involved in this project 
in 9 European countries: Finland, France, Germany, Hungary, 
Italy, The Netherlands, Spain, Sweden, UK and other 7 sites in 
Iran.  
Study population 
A cohort of at least 250 patients with diagnosis of Type 3 von 
Willebrand Disease will be enrolled using homogenous and 
standardized criteria. 

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
CONFIDENTIAL 
8/46 
Eligibility criteria 
Inclusion Criteria 
 All ages, both genders; 
 Informed Consent obtained (parents will sign for 
children); 
 Previous documented diagnosis of VWD3 (VWF antigen 
undetectable or <5 U/dL); 
 Detailed information on inherited pattern, history of 
bleeding, previous exposure to blood products; 
 Availability of plasma and DNA samples at enrolment. 
Exclusion Criteria 
 Patient who, at the enrolment, are not available for 
follow-up. 
Study procedures 
The work planned to achieve the objectives of the project will be 
divided in two parts:   
 the first part deals with standardized criteria for 
enrolment, collection of retrospective clinical and 
laboratory data, further characterization of clinical and 
laboratory parameters to be confirmed by centralized 
laboratories, prevalence of anti-VWF inhibitors and 
standardized 
assays 
to 
measure 
these 
anti-VWF 
inhibitors, advanced laboratory tests to further identify 
VWD3 patients, mutations analyses of the VWF gene;  
 the second part of the study for the first time deals with 
the prospective clinical observation in a large cohort of 
VWD3 patients all previously well characterized by an 
international panel of experts to assess number, types and 
risk factors for bleeding in the first part of the study and 
to assess the efficacy and safety of plasma-derived and/or 
recombinant VWF concentrates used to treat them.   
 
Study timelines 
 Study period:  
 
First part of the study (retrospective survey and 
centralized confirmation): approximately 36 months 
(years 2014 to 2016). 
 
Second part of the study (prospective observation): 
approximately 24 months (years 2017 – 2018). 
 
Confirmation of clinical phase data: approximately 12 
months (year 2019). 
 

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
CONFIDENTIAL 
9/46 
Second prospective observation: approximately 24 
months (years 2020 – 2021). 
 
Total study duration: approximately 96 months. 
 
 Individual subject participation:  
 
First part of the study: approximately 1 month. 
 
Second part of the study: 4 years (2 prospective 
observation periods of 2 years each: 2017-2018 and 
2020-2021). 
 
Data points 
First part of the study 
 Informed Consent collection 
 Eligibility Criteria verification  
 Patient ID Assignment  
 Demographics  
 Bleeding History and Previous Use of Blood Components  
 General Laboratory Test with Local Assays for VWD3 
Diagnosis  
 Family History in parents and relatives  
 Blood Withdrawal for Central Laboratory Assessment 
 Mutation analysis in VWD3 
 Inhibitors assessment 
 
Optional (in patient relatives) 
 Informed Consent collection 
 Historical information 
 Blood Sampling for Local Laboratory Assessment 
 Second part of the study 
 Bleeding episodes 
 Use of plasma-derived and/or recombinant VWF 
Concentrates and comparison between patients treated 
with VWF concentrates under on demand versus 
secondary long-term prophylaxis regimens 
 Blood Withdrawal for Central Laboratory Assessment 
only in case of anti-VWF inhibitors 
 Concomitant medication and Adverse Events  
 Patients with recurrent GIB who might benefit of 
treatment with VWF concentrates and correlation of 
angiogenesis markers with previous GIB episodes 
recorded 

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
CONFIDENTIAL 
10/46 
Statistical Analysis 
Analytic techniques will be pertinent to the observational design 
of the registry. Basic analyses will be descriptive and associative. 
Study management 
Sintesi Research S.r.l, Via Matteo Bandello, 6 – 20123 Milan 
(Italy) has been assigned to coordinate and manage the study 
conduction in every phase. 

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
CONFIDENTIAL 
11/46 
1. STUDY BACKGROUND  
Von Willebrand Disease (VWD) is the most common inherited bleeding disorder, characterized by 
a quantitative (VWD types 1 and 3) and/or qualitative (VWD types 2A, 2B, 2M and 2N) deficiency 
of von Willebrand Factor (VWF), the large multifunctional plasma glycoprotein that plays a major 
role in early phases of Haemostasis. Recurrent Gastro-Intestinal Bleeds (GIB) is one of the most 
challenging complications encountered in the management of patients with VWD. The commonest 
cause is angiodysplasia (ANGDYS), but often no cause is identified due to the difficulty in making 
the diagnosis. In recent years, research from several laboratories has identified multiple roles for 
VWF in the control of vascular function. In vivo studies in the VWF-deficient mouse have 
demonstrated a role for VWF in vascular development and angiogenesis.  In vitro inhibition of 
VWF expression using siRNA in HUVEC results in increased proliferation, migration and 
angiogenesis. Other studies have suggested that VWF is also involved in controlling blood vessel 
permeability, although its effect on this crucial vascular property may be organ-specific and depend 
on tissue microenvironment. Globally, these findings provide the first possible explanation for the 
presence of ANGDYS in patients with VWD. These vascular malformations in the gastrointestinal 
(GI) tract are characterized by fragile, leaky mucosal vessels. Combined with the hemostatic 
dysfunction, these can lead to severe intractable bleeding including GIB. 
Interestingly, VWD patients can show GIB and ANGDYS; whether the same pathways are 
implicated remains to be established. The direct role of VWF in the development of ANGDYS is 
best exemplified in the condition known as “Heyde’s Syndrome”. The GIB in Aortic Stenosis (AS) 
was indeed shown to be proportional to the severity of AS and to be reversible following 
replacement of the aortic valve. The pathophysiology of this association is thought to be the 
unfolding of the VWF due to the high shear as the blood flows through the stenotic valve making it 
more readily accessible to proteolysis by the VWF-cleaving protease ADAMTS13. Similar VWF 
defects have been recently observed in patients exposed to Cardiovascular Assisted Devices (CAD). 
GIB with or without ANGDYS can be difficult to diagnose and treat. The diagnosis is challenging 
due to accessibility, especially when the lesions are in the small bowel, and the requirement that 
active bleeding be present at the time of the examination for optimal identification.  
Whilst treatment of acute bleeding is fairly standard, a major issue is the recurrent nature of the GIB 
and its prevention. Multiple physical and pharmacological therapies have been reported but none 
proven to be fully effective in every case. A further difficulty is the low frequency of the 
complication in a rare disease, making collaboration desirable among Centers to study the disorder. 
The optimal treatment to prevent recurrences of GIB episodes remains still unknown.  

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
CONFIDENTIAL 
12/46 
Since a specific abnormality of VWF is always present in VWD patients with recurrent GIB with or 
without ANGDYS, the main objective of the 3WINTERS-EXTENDED project is to demonstrate if 
the regular (on demand and/or secondary long-term prophylaxis) administration of plasma-derived 
and/or recombinant VWF concentrates can reduce the number of recurrent GIB episodes in VWD 
patients. 
VWD3 patients by definition are characterized by undetectable levels of VWF antigen (VWF:Ag) 
in both plasma and by reduced concentrations (< 10 IU/dL) of factor VIII (FVIII). These baseline 
levels usually do not increase in plasma following desmopressin (DDAVP), the drug which can 
release VWF from endothelium. Therefore VWD3 patients must be treated with exogenous VWF 
contained in VWF concentrates.  
VWD3 is inherited as a recessive trait and heterozygous relatives have mild or no bleeding 
symptoms.  The prevalence of VWD3 is very low, ranging from 0.1 to 5.3 per million and differing 
considerably between countries. The highest rate is found in Iran and the lowest in southern Europe. 
However, the actual prevalence of VWD3 is still unknown in most countries, due to the lack of 
retrospective or prospective studies. In the Italian registry on Hemophilia and allied disorders 
organized on behalf of the Italian Association of Hemophilia Center, 96 VWD3 patients (5.8%) 
have been recently identified among the 1650 cases (prevalence of 1.6 per million): however, many 
clinical and laboratory parameters for diagnosis and treatment of VWD3 are still not available. 
Other national registries on VWD have been organized in several counties (France, Germany, Iran, 
The Netherlands, Spain, UK, USA) but data on prevalence of VWD3 are not available so far. 
Although rare, VWD3 is of major interest because of its severe clinical presentation, the need for 
replacement therapy with plasma-derived and/or recombinant VWF concentrates and the risk of 
occurrence of anti-VWF inhibitors after the infusion of VWF concentrates, for which risk factors 
have not been systematically determined.  
2. OBJECTIVES AND EXPECTED ACHIEVEMENTS 
Aims of this project are to evaluate: 1)  the prevalence, clinical and laboratory parameters of a large 
cohort (at least 250 cases) of patients with local diagnosis of VWD3 enrolled by European 
(approximately 125 cases) and by Iranian (approximately 125 cases) centers using homogeneous 
and standardized criteria; 2) role of VWF phenotypic data measured with standardized clinical and 
laboratory markers on the bleeding tendency; 3) frequency of bleeding and the requirement for 
VWF concentrates in VWD3; 4) correlation between clinical and molecular markers and bleeding 
tendency, response to therapy with plasma-derived and/or recombinant VWF concentrates and risk 
of anti-VWF inhibitors.  

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
CONFIDENTIAL 
13/46 
2.1 Measurable Objectives 
1) International network among  European (approximately 125 cases) and Iranian 
(approximately 125 cases) centers; 
2) Prospective enrollment of at least 250 VWD3 patients using a common database online; 
3) Detailed information about previous bleedings and exposure to plasma-derived and/or 
recombinant VWF concentrates of identified VWD3 patients; 
4) Bleeding severity score of identified VWD3 patients calculated with a common 
questionnaire; 
5) Collection of plasma and DNA samples from all the identified VWD3 patients enrolled for 
centralized analyses; 
6) Confirmation of the local VWD3 diagnosis using centralized tests; 
7) Evaluation of VWF gene defects, VWF phenotype and risk of anti-VWF inhibitors through 
common methods; 
8) Evaluation of potential correlations between phenotypic results (including markers of 
angiogenesis) and GIB occurrence; 
9) Objective evaluation of severity of GIB in VWD3 patients; 
10) Assessment of frequency and sites of bleeding in VWD3 patients followed-up for 4 years (2 
prospective observation periods of 2 years each: 2017-2018 and 2020-2021); 
11) Efficacy assessment of the plasma-derived and/or recombinant VWF concentrates used to 
treat VWD3 (on demand versus prophylaxis) using the most objective criteria for efficacy 
during the 4-year observation period (2 prospective observation periods of 2 years each: 
2017-2018 and 2020-2021); 
12) Evaluation of the efficacy and safety of plasma-derived and/or recombinant VWF 
concentrates in the treatment of GIB during the 4-year observation period (2 prospective 
observation periods of 2 years each: 2017-2018 and 2020-2021), in comparison to the use of 
anti-angiogenetic agents within the standard clinical setting. 
2.2 Expected Achievements 
1) Natural history, predictors, clinical and molecular markers for bleeding in a large cohort of 
patients with VWD3 identified in developed (Europe) and developing (Iran) countries; 
2) Common clinical and lab methods to identify VWD3 patients; 
3) Guidelines for management of VWD3 without and with anti-VWF inhibitors. 
 

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
CONFIDENTIAL 
14/46 
3. STUDY DESIGN AND PROJECT WORKING PACKAGES 
This is a no-profit, investigators initiated, multi-center, European-Iranian observational, 
retrospective and prospective study on patients with diagnosis of Type 3 von Willebrand disease 
(VWD3). Patients meeting the enrolment criteria will be consecutively enrolled at each 
participating Center and data entered in the register. Upon confirmation of VWD3 diagnosis from 
the Central Laboratories, the patients will enter the second part of the study and will be 
prospectively observed for 24 months (2 years). After confirmation of clinical phase data (taking 
approximately 12 months), the patients will be observed within a second prospective period of 24 
months (2 years) to collect additional information related to study endpoints. 
A total of 20 Investigational sites will be involved in this project in 9 European countries: Finland, 
France, Germany, Hungary, Italy, The Netherlands, Spain, Sweden, UK and other 7 sites in Iran. 
The investigational sites’ names and address are detailed separately.  
3.1 General description of the project    
The work planned to achieve the objectives of the project will take place over a 8-year period and 
will be divided in three parts: a) the first part deals with standardized criteria for enrollment, 
collection of retrospective clinical and laboratory data, further characterization of clinical and 
laboratory parameters to be confirmed by centralized laboratories, prevalence of anti-VWF 
inhibitors and standardized assays to measure these anti-VWF inhibitors, advance laboratory tests to 
further identify VWD3 types, mutations analyses of the VWF gene; b) the second part of the study 
for the first time deals with the prospective clinical observation in a large cohort of VWD3 patients 
all previously well characterized by an international panel of experts to assess number, types and 
risk factors for bleeding in at least 250 patients and to assess the efficacy and safety of plasma-
derived and/or recombinant VWF concentrates used to treat them; c) the third part of the study 
(after 12 months of evaluation of the collected data by the Study Coordinators) will replicate the 
second part to collect additional information related to study endpoints aiming to a better 
characterization of the observed patients. 
This will be achieved through the implementation of a Working Packages Plan as indicated in 
Appendix 3 to this study protocol. 
 

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
CONFIDENTIAL 
15/46 
3.1.1 First part of the Study 
The first critical phase of the project, to be completed over the initial 36-month period, will be the 
recruitment of at least 250 patients with VWD3, approximately 125 in Europe and 125 in Iran.  
After the approval of the study protocol of the Study by the reference Ethics Committee for each 
Center and the organization of the network within a common database, the enrolled patients will be 
characterized by clinical and family history at the Centers (WP1).  
A detailed clinical history to aid diagnosis will be obtained by interview and use of a questionnaire 
previously tested in a large cohort of VWD1 patients. In case of VWD3 patients, detailed history 
about previous exposure to blood products will be collected and blood samples obtained will be 
separately coded and stored (WP2).  
Basic laboratory testing with use of WHO International plasma standards for VWF/FVIII activities 
will be an essential part of this initial recruitment and analyses as detailed in WP2. All basic 
laboratory tests data (WP2) and patient and family details (WP1) will be sent in coded form to the 
Coordinators for data storage as outlined in WP8. Each Center will also obtain the best possible 
patient and optionally family resource, basic laboratory tests as performed locally: these tests will 
be confirmed centrally by laboratories known for their expertise (WP3). Initial and confirmatory 
data will be included into the database.  
Advanced tests for the evaluation of antibodies against VWF in each enrolled family will be 
centralized in a few expert laboratories (WP4). Intra-platelet VWF quality and quantity will be 
assessed in all VWD3 patients and will be measured centrally following receipt of a lysed platelet 
preparation (WP4). An important part of the project will be the analysis of results obtained with all 
the advanced tests leading to detailed analysis of their value as markers for the diagnosis and 
management of VWD3, particularly when compared to the basic tests as in WP2.  
Mutation analysis will start only when most of the patients will have been enrolled and evaluated at 
the end of the retrospective survey (month 24th). Since this gene analyses might require more time, 
the central laboratories involved in this first part of the study will continue their tests also during the 
second part of the study and should provide all data completed within month 48th. The presence of 
VWF gene defects will be correlated with the presence of inhibitors (WP5).  
3.1.2 Second & third parts of the Study  
The novelty of this project consists in the correlation between clinical and molecular markers and 
bleeding tendency as well as with response to therapy with VWF concentrates and risk of anti-VWF 
inhibitors. Therefore the second part should start only when all clinical, laboratory and molecular 
markers will be available at the end of the first part of the study. 

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
CONFIDENTIAL 
16/46 
Clinical and laboratory predictors of bleeding (WP6) will be evaluated in all patients with 
confirmed diagnosis of VWD3 who can be followed prospectively for 24 months and, after 12 
months of evaluation of the collected data by the Study Coordinators, the patients will be observed 
for additional 24 months to collect additional information related to study endpoints aiming to a 
better characterization of the observed patients. 
Bleeding severity score, baseline levels of VWF and FVIII, the presence of anti-VWF inhibitors and 
several modifiers will be tested as clinical and laboratory predictors of  bleeding in VWD3.  
The current treatments of VWD3 patients will be also evaluated during this study (WP7). It is 
important to say that during the 48-month follow-up (2 observation phases), all the VWD3 patients 
will continue the current type of treatment using the same type of VWF concentrate with or without 
FVIII available in their own countries at the time of enrollment in this study. The information on the 
amounts of concentrates (U/month or U/year), the number of exposure days/year, the efficacy and 
safety of each VWF concentrates used in these patients will be collected and will be available at the 
end of the study.  Moreover, the previous exposure to VWF concentrates will be analyzed as well as 
the frequency of the major side effects, including anaphylaxis in VWD3 with anti-VWF inhibitors.  
Efficacy assessment of the VWF concentrates used to treat VWD3 using the most recent objective 
criteria for efficacy. Site and type of bleedings and specific approaches to VWD3 patients with anti-
VWF inhibitors will be recorded.  
The use of plasma-derived and/or recombinant VWF concentrates will be evaluated comparing the 
regimens adopted for patients treated with VWF concentrates under on demand versus secondary 
long-term prophylaxis. 
In addition, a detailed evaluation of type, severity and characterization of GIB episodes and of the 
type, dosage and frequency of administration of VWF concentrates related to GIB will be 
performed in a small group of patients only (WP7b). The type of diagnosis and site of bleeding 
should be evaluated at each bleeding episode by performing a complete endoscopic examination of 
the GI tract, including esophagogastroduodenoscopy, colonoscopy and videocapsule enteroscopy, 
unless the diagnosis has been confidently reached by one the exams and/or the clinical presentation 
is indicative of the recurrence of a previously diagnosed event. The severity of each event, either 
retrospectively or prospectively collected, will be evaluated according to the Blatchford Score (see 
below) when data can be accurately obtained: 
 
 
 
 
 

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
CONFIDENTIAL 
17/46 
Calculation of prognostic severity of GIB episodes 
Blood Nitrogen 
<18.2 mg/dL  
(<6.5 mmol/L) 
0 points* 
≥18.2 and <22.4 mg/dL 
 (≥6.5 and <8 mmol/L) 
2 points 
≥22.4 and <28 mg/dL  
(≥8 and <10 mmol/L) 
3 points 
≥28 and <70 mg/dL  
(≥10 and <25 mmol/L) 
4 points 
≥70 mg/dL  
(≥25 mmol/L) 
6 points 
Hemoglobin 
MALE: 
≥13 g/dL (≥130 g/L) 
0 points* 
MALE: 
≥12 and <13 g/dL  
(≥120 and <130 g/L) 
1 point 
MALE: 
≥10 and <12 g/dL  
(≥100 and <120 g/L) 
3 points 
FEMALE: 
≥12 g/dL (≥120 g/L) 
0 points* 
FEMALE: 
≥10 and <12 g/dL  
(≥100 and <120 g/L) 
1 point 
MALE / FEMALE: 
<10 g/dL (<100 g/L) 
6 points 
Blood Pressure 
≥110 mmHg 
0 points* 
100 to 109 mmHg 
1 point 
90 to 99 mmHg 
2 points 
<90 mmHg 
3 points 
Other markers 
Heart Rate: 
≥100 per minute 
1 point 
Melena at presentation 
1 point 
Syncope at presentation 
2 points 
Presence of hepatic disease 
2 points 
Presence of cardiac failure 
2 points 
* A score of zero is associated with a low risk of the need for endoscopic intervention. 

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
CONFIDENTIAL 
18/46 
Should all the above parameters be not available, a “simplified score” should be proposed, which 
includes: 
 Signs of hypovolemia (tachycardia > 100 bpm and arterial pressure < 100 mmHg; 
alternatively a shock index (RPM/AP > 1));  
 Signs of ongoing bleeding (hematemesis or proctorragia or melena); 
 Hgb < 10 g/dL; 
 Transfusional need of > 2 units during the event. 
On the long term, particularly in case of occult or non-acute bleeding, the entity of transfusional 
need for time unit is considered an accurate measure of GI bleeding and will be recorded for each 
patient. 
In case of the few patients with GIB recurrence an additional blood sample will be collected upon 
request and approval by the Steering Committee and shipped to the Central Laboratory deputed to 
the analysis of angiogenesis markers (Angiopoietin-1, Angiopoietin-2, Osteoprotegerin, Galectin-3, 
CXCL8/IL-8, Tie-2, VEGF) in order to evaluate the presence of ANGDYS.  
All the clinical and laboratory data collected during this 8-year project will provide the actual 
information on the management of this rare but complex inherited bleeding disorder and will allow 
preparation of novel guidelines on VWD3 diagnosis and treatment (WP8) based on the most recent 
results of a prospective study.   
 
3.2 General Management of the Study  
The overall objective of this proposal is to utilize and combine clinical knowledge and technical 
expertise of clinicians well known for their ability to diagnose and manage patients with VWD3 and 
scientists well known for their innovative research in the field of thrombosis and Haemostasis. This 
international combination of clinical and technical expertise will allow us to substantially improve 
the available information on the clinical aspects of rare VWD3 as well as clinical and laboratory 
predictors of the bleeding diathesis of these patients. This effort is highly relevant, as it will inform 
us on issues like duration of hospitalization, frequency of doctor visits and severity and frequency 
of bleeding. Little if any information on these VWD3 patients to be investigated by this study is 
available to Haematologists, Patient Organizations and Health Authorities. Moreover, our studies 
will allow the translation from clinical observations to basic research and back, which will 
contribute significantly to our understanding of the marked variability observed between patients 
with this rare inherited bleeding disorder.  
 
 

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
CONFIDENTIAL 
19/46 
We expect that via the execution of this study, we will be able to establish:  
a) An international database with clinical and laboratory information of patients with VWD3; 
b) A better understanding of the basic molecular mechanisms of VWD3 that will allow a more 
specific therapeutic approach to these VWD3 patients.  
Taken together, this international collaborative effort will translate in better diagnostic and 
therapeutic tools to manage this rare but severe bleeding disorder. 
The proposed project involves 8 different Working packages in order to reach the objectives 
necessary to improve the knowledge on the basic molecular mechanisms of VWD3. The 
information available in this International Registry (European and Iranian) will be exchanged and 
compared among the different partners involved in this 8-year study by using a common database. 
Start and completion dates, responsibilities, involvement and work duties of the different partners 
will be reported in each Working package. A detailed description for each and every Working 
Package will be available separately in Appendix 3. 
4.  STUDY DURATION AND TIMELINES 
Study period:  
 
 First part of the study (retrospective survey and centralized confirmation): 
approximately 36 months (years 2014 to 2016) 
 
 Second part of the study (prospective observation): approximately 24 months (years 
2017 – 2018) 
 
 Confirmation of clinical phase data: approximately 12 months (year 2019) 
 
 Second prospective observation: approximately 24 months (years 2020 – 2021) 
 
 Total study duration: approximately 96 months 
 
Individual subject participation:  
 
 First part of the study: approximately 1 month 
 
 Second part of the study: 4 years (2 prospective observation periods of 2 years each: 
2017-2018 and 2020-2021). 
 
 
 
 

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
CONFIDENTIAL 
20/46 
5. STUDY POPULATION 
A large cohort of at least 250 patients with diagnosis of Type 3 von Willebrand Disease will be 
enrolled in Europe (approximately 125 cases) and in Iran (approximately 125 cases) at 
approximately 27 investigational sites using homogenous and standardized criteria (20 in Europe + 
7 in Iran). 
5.1 ELIGIBILITY CRITERIA 
All patients with diagnosis of  Type 3 von Willebrand Disease will be enrolled. 
 
Inclusion criteria: 
 Male and female of any age, including infants, children, adolescent and adults 
 Informed Consent obtained (parents should sign for patients < 18 y.o.) 
 Previous Diagnosis of VWD3 (VWF antigen: undetectable or <5 U/dL) 
 Detailed information on inherited pattern, history of bleeding, previous exposure to blood 
products 
 Availability of plasma and DNA samples  
 
Exclusion criteria: 
 VWD3 patients who may not be available for follow-up 
 
5.2 ENROLMENT STRATEGIES 
The recruitment of at least 250 patients with VWD3 as determined by a family history and basic 
laboratory tests will be completed within 36 months.  
All the Centers involved will gather retrospective data on patients already diagnosed at the Center 
as VWD3 patients and who are eligible for this study. 
Each and every subject will be asked to read, understand and sign the Informed Consent Form to 
authorize his participation in the study before  entering into the study. 
Optional: for relatives who accept the following will be collected: 
 Informed Consent collection 
 Historical Information 
 Blood Sampling for Local Laboratory Assessment 

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
CONFIDENTIAL 
21/46 
6. STUDY PROCEDURES 
6.1 ENROLMENT – FIRST PART OF THE STUDY 
6.1.1 Enrolment visit 
Before any screening activity may be performed, a signed and dated Informed Consent form must 
have been obtained from patient. The medical history (demography, bleeding history, previous 
treatments, previous diagnosis and familiarity of VWD3) will be collected to assess a subject’s 
eligibility for this study. If the patient satisfy the enrolment criteria a blood sample of 20 ml will be 
withdrawn for adults and 10 ml for children. For children below 12 y.o. blood sampling should be 
part of the regular management adapted to the age. 
The central laboratory evaluations are detailed in the following paragraph 7. 
Each blood sample will be stored locally at -70°C and subsequently sent to the designed Central 
Laboratory for the assessment. If a -70° C freezer is not available at sites, a -20° C freezer can be 
used but the shipment to central laboratory should be done within 3 months from the sampling. 
All samples will be collected and processed according to the central laboratory manual. Handling 
and shipment of the samples and the materials will be described in the manual as well. 
Medical history will include concomitant diseases, concomitant medications and previous 
treatments for VWD3, if any. A familiar pattern form will be evaluated. Past bleeding episode(s) 
history and severity score will be recorded on CRF. 
For the optional family members the same procedures will be followed. 
 
6.2 FOLLOW-UP – SECOND PART OF THE STUDY 
6.2.1 Control visit 
Upon confirmation of the diagnosis of VWD3 from the assigned Central Laboratory, the patient 
will enter into the second part (prospective observation) of the study. Due to the observational 
nature of the study, all patients will be treated at each Investigational site according to the Center 
standard clinical practice with none interference in the treatment and care in relation to this study. 
The patients will be asked to visit the site regularly according to the standard clinical practice at 
each investigational site (at least once in a year). No additional visits nor instrumental assessments 
will be required.  
At each visit all information about bleeding events will be collected and recorded on subject’s case 
history and on CRF. All medications taken, prescription or over-the counter continued at the start of 
the study or started during the study must be documented in source documents and entered in the 
CRF. 
AEs and SAEs will be recorded/communicated according to the applicable procedure. 

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
CONFIDENTIAL 
22/46 
Bleeding episode(s) occurred between visits will be recorded on CRF. In details, the points below 
itemized will be checked: 
 date and site 
 bleeding score  
 treatment  
Additional blood withdrawal of 5 ml will be performed only in case of anti-VWF inhibitors 
development for confirmation at Central Laboratory. 
 
6.2.2 Final visit 
Bleeding episode(s) occurred since previous visit will be recorded on CRF. 
VWF containing concentrates and Concomitant Medications, on-going at the end, discontinued or 
stopped during the study will be reported.  
AEs and SAEs will be recorded and reconciled with source documents. 
7. DATA POINTS 
The site will determine whether the patient qualifies for the study before entering the patient into 
the registry. Sites will assign a patient identification (ID) number to each patient that enters the 
registry. Therefore, the patient ID will consist of 11 digits as follows: 
 
 Site code: composed by two capital letters for the Country and two number for the site 
(centrally assigned) 
 Family code: composed by the capital letter “F” and followed by two numbers starting from 
01 and assigned in sequential order to identify the family in case two or more patients are 
relatives  
 Generation: can be I, II, III or IV 
 Individual code: composed by the capital letter “P” (patient) or “R” (relative) to specify if 
the subject is a VWD3 patient or a relative (in case any relative of VWD3 patient is enrolled – 
optional) and followed by two numbers starting from 01 and assigned in sequential order. 
 
Example:  
|N| L|0|1|-| F|0|1|-|II|-|P|0|1| 
 
The patient ID number will be used to identify the patient in the study and must be used on all study 
documentation related to that patient and must not be changed at any time. Entry is defined as the 
day the patient consents to participate. 

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
CONFIDENTIAL 
23/46 
The following data will be collected for each and every patient included in the study and who 
signed the Informed Consent Form before enrolment. 
 
First part of the study 
 
1. Informed Consent collection – If Informed Consent is required, the patient will sign Informed 
Consent before the patient ID is assigned and data collection. The Informed Consent process 
will be clearly documented into the patient’s chart. 
2. Eligibility Verification – The eligibility criteria will be confirmed for the patient. If the patient 
meets the eligibility criteria, the patient will be entered into the registry. 
3. Patient ID Assignment – Once all the eligibility criteria have been confirmed, the patient will 
be assigned a patient 11 digits ID number. 
4. Demographics – Age, race and gender of the patient will be documented. 
5. Bleeding History and Previous Use of Blood Components – The year, month and day the 
patient was diagnosed for VWD3; the Site and Score of bleeding for the calculation of the 
Bleeding Severity Score and the type of Blood Products used with reference to the year of first 
exposure and the units used will be documented. The negativity/positivity to Blood-borne 
infections (HCV and HIV) will be assessed too. 
6. General Laboratory Test with Local Assays for VWD3 Diagnosis -  In case a Local assays has 
not been done within 1 year ,a blood sample will be collected at enrolment to determine locally 
the following parameters: Hemoglobin, MCV, Leucocytes, Platelet count, MPV, Ferritine, 
Prothrombin Time, PTT, PTT mix, either Bleeding Time or Closure Time,  FVIII:C, 
VWF:RCo and VWF:Ag. 
7. Family History in the Parents and relatives Tree and Pedigree. 
8. Blood Withdrawal for Central Laboratory Assessment for VWD3 patients – A venous blood 
sample will be withdrawn from the patients for a total amount of  20 ml for adults and 10 for 
children. These amount of samples will be used to optain both  citrated Platelet Poor Plasma 
(PPP) for VWF assays and Cell Pellet (CP) for DNA extraction. For  PPP analysis each tube 
will be filled in with  0.3 ml (the total amount of 0.3 ml tubes should be at least 24 for adults 
and 12 for children) while in case of CP analysis the sample should be divided equally into at 
least 2-4 tubes respectively for children and adults.  All these tubes must be stored locally at –
80 C° .and sent to the European Central Laboratories. For the analysis of PPP, CP and DNA, 
samples will be evaluated in 5-6 assigned European Laboratories. The details of the Central 
Laboratories will be distributed separately (Working Packages). 

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
CONFIDENTIAL 
24/46 
9. Optional:  Bleeding history and blood withdrawal for Local Laboratory Assessment will be 
collected for subject’s parents and relatives who agree to participate. 
 
Second part of the study 
 
1. Bleedings – All  bleeding experienced during the study will be documented and detailed for 
number, types and risk factors for all patients with confirmed diagnosis of VWD3. 
2. VWF Concentrates – All different VWF-containing concentrates used during the study will be 
documented and described in quantities, efficacy and safety for all patients enrolled in the 
study. The number of patients treated with plasma-derived and/or recombinant VWF 
concentrates under on demand versus secondary long-term prophylaxis regimens will be 
evaluated. 
3. Concomitant medication and Adverse Events – all other medication in use and all adverse 
events occurred during the study course will be collected and entered in CRF. 
4. Patients with recurrent GIB who might benefit of treatment with VWF concentrates and 
correlation of angiogenesis markers with previous GIB episodes recorded – within the 
identification of a pool of VWD3 patients with GIB according to standardized and objective 
criteria, the data collected retrospectively in these patients will be evaluated and correlated with 
phenotype (including markers of angiogenesis) and genotype centralized results. This will help 
identifying potential correlations between phenotype/genotype and GIB occurrence. The 
VWD3 patients with GIB occurrence will be tested centrally for angiogenesis markers 
(Angiopoietin-1, Angiopoietin-2, Osteoprotegerin, Galectin-3, CXCL8/IL-8, Tie-2, VEGF) in 
order to evaluate the presence of ANGDYS. In addition, the efficacy and safety of plasma-
derived and/or recombinant VWF concentrates used to treat patients’ GIB during the 
prospective observation period, in relation to the use of anti-angiogenetic agents within the 
standard clinical setting, will be evaluated. 
 
Additional blood withdrawal of 5 ml will be performed only in case of anti-VWF inhibitors 
development for confirmation at Central Laboratory. 
 
8. STATISTICAL ANALYSIS 
8.1 PRIMARY ANALYSIS  
Consistently with the objectives of the retrospective and prospective observational study and 
appropriate to the data being collected, a Statistical Analysis Plan (SAP) will be developed. Given 

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
CONFIDENTIAL 
25/46 
the observational design of the registry, the primary analysis will be descriptive and associative. 
The SAP will describe, in the form of annotated tables, figures and listings, the analyses to be 
conducted. 
Analyses will first present the patient clinical and demographic characteristics of the patients being 
treated for VWD3 at the investigational sites in Europe and in Iran. Next, analyses will be 
conducted to identify clinical and laboratory predictors of bleeding. 
The SAP will also provide details on how the effectiveness variables will be derived, how the 
missing values will be handled, and how these variables will be analyzed. 
8.2 STATISTICAL ANALYSIS 
Analytic techniques will be pertinent to the observational design of the registry. Basic analysis will 
be descriptive and associative. Tables of baseline clinical and demographic characteristics, 
treatment patterns, clinical outcomes, and health care resource utilization will be compiled for all 
patients, and other techniques may be employed to assess association of covariates, including 
treatments and outcomes (including clinical and laboratory outcomes). 
9. PROJECT MANAGEMENT AND COORDINATION   
Fondazione Bianchi Bonomi shall assign Sintesi Research S.r.l, Via Matteo Bandello, 6 – 20123 
Milan (Italy) to coordinate and manage the study conduction in every phase. Sintesi Research will 
assure to act in compliance with the local guidelines and legislations, in the respect of the protocol 
and timelines agreed in the same.   
Sintesi Research, thorough its personnel, will be responsible for the following: 
1) Request of authorization for study conduction – Sintesi Research will perform all the 
necessary steps to obtain the authorization for the study conduction in all the investigational 
sites involved in Europe (documents preparation, request of authorization dossier 
preparation and submission) 
2) Sites activation – upon authorization from the Central and Local Competent Authorities and 
Ethics Committees accordingly to the country specific requirements and procedures, the 
sites will receive the personal access details for the project data base; the Investigator Site 
File containing the documentation, template, forms and training material for the study 
conduction. 
3) Study management – the assigned Project Manager will coordinate and manage the survey  
conduction particularly (but not limited to) in the following activities: 

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
CONFIDENTIAL 
26/46 
a. He/she will supervise the sites and patients enrolment thorough the web site and the 
direct communication with site personnel;  
b. He/she will be responsible to maintain contact with and supervise the blood samples 
shipments from the investigational sites to the reference central laboratories;  
c. He/she will guarantee the standardization of the study procedures and the 
distribution of the right and proper documentation to the sites; 
d. He/she assists and supports the sites for any issue occurring during the study course 
e. He/she takes all the measure to guarantee that the patient privacy is protected and the 
data quality respect the standards required.  
f. He/she verifies that the study conduction always occurs in compliance with all the 
applicable regulations. 
A web based project portal and database (www.vwd-3winters-ips.com) will be developed by Sintesi 
Research for the overall study management and data collection. The portal will be used as virtual 
archive for the study documentation, communication, updates, and to share information, 
experiences, opinion among participants.  The database will serve to collect the data points as 
specified in Paragraph 6 of this study protocol. Each single site member involved in the project will 
confidentially receive personal access to the web site and at the level of functionality assigned to 
his/her role in the study. 
The on-site monitoring of the Centers is not planned. The sites will be monitored remotely through 
the web site. Nevertheless, for those Centers that require patient Informed Consent the Sponsor's 
monitors may, on occasion, visit the site during the study to ensure GCP Guidelines have been 
followed to protect patient confidentiality. 
10. SAFETY 
10.1Safety Information 
An adverse event (AE) is defined as any new medical problem or exacerbation of an existing 
problem, associated with the use of a drug in humans, whether or not the event is considered drug 
related. A serious adverse event (SAE) includes any event that results in any of the following 
outcomes: 
a) death 
b) life-threatening, i.e., the subject was, in the opinion of the investigator, at immediate risk 
of death from the event as it occurred. It does not include an event that, had it occurred in a 
more severe form, might have caused death. 
c) persistent or significant disability/incapacity 

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
CONFIDENTIAL 
27/46 
d) requires in-patient hospitalization or prolongs hospitalization 
e) congenital anomaly/birth defect 
f) other medically significant events that, based upon appropriate medical judgment, may 
jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed above, e.g., allergic bronchospasm requiring intensive treatment in an 
emergency room or home, blood dyscrasias or convulsions that do not result in 
hospitalization, or the development of drug dependency or drug abuse. 
Non-serious adverse events are all adverse events that do not meet the criteria for a "serious" 
adverse event. For adverse events associated with the use of any other treatment, the investigator 
will be encouraged to contact the manufacturer or the regulatory authorities to report the adverse 
event. A copy of any form submitted to the manufacturer or regulatory authorities must be 
submitted to Sponsor. 
An Independent Data Monitoring Committee (DMC) will be appointed for data monitoring and will 
be extended for the entire duration of the prospective observation.  
The designed DMC members are: 
Craig KESSLER, MD 
Lombardi Cancer Ctr. 
Georgetown University 
Washington, USA 
 
David LILLICRAP  
Queens University 
Kingston, Canada 
 
Robert R MONTGOMERY 
Department of Pediatrics Blood Center 
Milwaukee, USA 
 
11. ETHICAL ASPECTS  
The 3WINTERS-IPS study is Sponsored by a Non-Profit Organization, Angelo Bianchi Bonomi 
Foundation, Milan, Italy, and it will be conducted in collaboration with Centers belonging to the 
Group on VWD3 recognized by the European Association of Haemophilia and Allied Disorders 
(EAHAD) and Sub-Committee on VWF Scientific Standardization Committees of the International 
Society on Thrombosis and Haemostasis (SC-VWF, SSC-ISTH). This study must be conducted in 
compliance with the protocol and all other applicable local laws and regulatory requirements. Each 
study site will seek approval by an IRB or EC according to regional requirements. The IRB/IEC 

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
CONFIDENTIAL 
28/46 
will evaluate the ethical, scientific and medical appropriateness of the study. Further, in preparing 
and handling CRF and EDC, the investigator, sub-investigator and their staff will take measures to 
ensure adequate care in protecting patient privacy. To this end, a patient identification code will be 
used to identify each patient. 
11.1Study supervision 
The 3WINTERS-IPS Steering Committee (SC) whose members are all the Partners Responsible 
persons, will supervise the conduction of the study. The SC will be regularly updated on the study 
progress by the Study Project Manager and it is the organ which finally will take any decision on 
any issues that should derive from the study conduction. 
11.2Privacy of personal data 
In order to maintain patients’ privacy, all CRFs, study reports and communications will identify the 
patient by the assigned patient number. The Investigator will grant monitor(s) and auditor(s) from 
the Sponsor or its designee and regulatory authority(ies) access to the patient’s original medical 
records for verification of data entered into the CRFs and to audit the data collection process. The 
patient’s confidentiality will be maintained and will not be made publicly available to the extent 
permitted by the applicable laws and regulations. The data collected properly coded will remain 
within the investigational Center where the patient is recruited, the Central Laboratories involved 
for clinical and molecular analysis, the study Sponsor and the Members appointed for data review 
(DMC and SC) and verification (CRO). 
11.3Confidentiality 
The collection and processing of personal data from subjects enrolled in this study will be limited to 
those data that are necessary to the study purposes only. These data must be collected and processed 
with adequate precautions to ensure confidentiality and compliance with applicable data privacy 
protection laws and regulations, in particular the General Data Protection Regulation (GDPR) n. 
2016/679 on the protection of natural persons with regard to the processing of personal data and on the 
free movement of such data. 
The Sponsor ensures that the personal data will be: 
 processed fairly and lawfully 
 collected for specified, explicit, and legitimate purposes and not further processed in a way 
incompatible with these purposes 
 adequate, relevant, and not excessive in relation to said purposes 
 accurate and, where necessary, kept current 

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
CONFIDENTIAL 
29/46 
Explicit consent for the processing of personal data will be obtained from the patients before 
collection of data. Such consent should also address the transfer of the data to other entities and to 
other countries. The patients have the right to request through the investigator access to personal 
data and the right to request rectification of any data that are not correct or complete. Reasonable 
steps should be taken to respond to such a request, taking into consideration the nature of the 
request, the conditions of the study, and the applicable laws and regulations. Appropriate technical 
and organizational measures to protect the personal data against unauthorized disclosures or access, 
accidental or unlawful destruction, or accidental loss or alteration must be put in place. Sponsor 
personnel whose responsibilities require access to personal data agree to keep the identity of study 
subjects confidential. 
11.4Protocol compliance 
The Investigator will conduct the study in compliance with the protocol provided by the Sponsor, 
and given approval/favourable opinion by the IRB/EC and the appropriate regulatory authority(ies). 
Modifications to the protocol should not be made without agreement of both the Investigator and 
the Sponsor. Changes to the protocol will require written IRB/EC approval/favourable opinion prior 
to implementation, except when the modification is needed to eliminate an immediate hazard(s) to 
patients. The IRB/EC may provide, if applicable regulatory authority(ies) permit, expedited review 
and approval/favourable opinion for minor change(s) in ongoing studies that have the 
approval/favourable opinion of the IRB/EC. The Sponsor or its designees will submit all protocol 
modifications to the regulatory authority(ies) in accordance with the governing regulations. 
11.5Protocol modifications 
Neither the investigator nor the Sponsor will modify this protocol without a formal amendment. All 
protocol amendments must be issued by the Sponsor, and signed and dated by the investigator. 
Protocol amendments must not be implemented without prior IEC/IRB approval, or when the 
relevant competent authority has raised any grounds for non-acceptance, except when necessary to 
eliminate immediate hazards to the subjects, in which case the amendment must be promptly 
submitted to the IEC/IRB and relevant competent authority. When the change(s) involves only 
logistic or administrative aspects of the study, the IRB (and IEC where required) only needs to be 
notified. In situations requiring a departure from the protocol, the investigator or other physician in 
attendance will contact the appropriate Sponsor representative by fax or telephone (see Contact 
Information pages provided separately in the Investigator Site File). If  possible, this contact will be 
made before implementing any departure from the protocol. In all cases, contact with the  Sponsor 
must be made as soon as possible in order to discuss the situation and agree on an appropriate 

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
CONFIDENTIAL 
30/46 
course of action. The data recorded in the CRF and source document will reflect any departure from 
the protocol, and the source documents will describe this  departure and the circumstances requiring 
it. When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to  
patients, the Investigator will contact the Sponsor or its designees, if circumstances permit, to 
discuss the planned course of action. Any departures from the protocol must be fully documented in 
the CRF and source documentation. 
11.6Subject identification register and subject screening log 
The investigator agrees to complete a subject identification register to permit easy identification of 
each subject during and after the study. This document will be reviewed by the Sponsor site contact 
for completeness. The subject identification register will be treated as confidential and will be filed 
by the investigator in the Investigator Site File. To ensure subject confidentiality, no copy will be 
made. All reports and communications relating to the study will identify subjects by initials and 
assigned number only. The investigator must also complete a subject-screening log, which reports 
on all subjects who were seen to determine eligibility for inclusion in the study. 
12. PUBLICATION POLICY 
The results of this study will be presented at scientific meetings and/or published in a peer reviewed 
scientific or medical journal. A Publications Committee, comprised of investigators participating in 
the study, as appropriate, will be formed to oversee the publication of the study results, which will 
reflect the experience of all participating study Centers. 
All reports (including abstracts) and publications shall be approved by the Steering Committee prior 
to submission. The authorship of publications shall reflect the input of individual collaborators into 
the work and recognize the role of the project. The aim is to include at least one author from each 
participating Center, however this is subject to specific journal requirements. 
Studies performed with a recruited family and relating to the project should be reported as part of 
the project. Studies performed with a recruited family that are not related to the project may be 
published by the individual investigator after consultation with the Publications Committee and 
should make reference to the project. 
 

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
 
CONFIDENTIAL 
31/46 
13. GENERAL REFERENCES 
 
1. Marchese M, De Cristofaro R, Federici AB, Biondi A, Petruzziello L, Tringali A, Spada C, 
Mutignani M, Ronconi P, Costamagna G. “Duodenal and gastric Dieulafoy's lesions in a 
patient with type 2A von Willebrand's disease.” Gastrointest Endosc. 2005 Feb;61(2):322-5. 
 
2. Tosetto A, Rodeghiero F, Castaman G, Bernardi M, Bertoncello K, Goodeve A, Federici 
AB, Batlle J, Meyer D, Mazurier C, Goudemand J, Eikenboom J, Schneppenheim R, Budde 
U, Ingerslev J, Vorlova Z, Habart D, Holmberg L, Lethagen S, Pasi J, Hill F, Peake I. 
“Impact of plasma von Willebrand Factor levels in the diagnosis of type 1 von Willebrand 
Disease: results from a multicenter European study (MCMDM-1VWD).” J Thromb 
Haemost. 2007 Apr;5(4):715-21. 
 
3. Federici AB. “Highly purified VWF/FVIII concentrates in the treatment and prophylaxis of 
von Willebrand Disease: the PRO. WILL Study.” Haemophilia. 2007 Dec;13 Suppl 5:15-24.  
 
4. Federici AB, Mannucci PM, Castaman G, Baronciani L, Bucciarelli P, Canciani MT, Pecci 
A, Lenting PJ, De Groot PG. “Clinical and molecular predictors of thrombocytopenia and 
risk of bleeding in patients with von Willebrand Disease type 2B: a cohort study of 67 
patients.” Blood. 2009 Jan 15;113(3):526-34.  
 
5. Gritti G, Cortelezzi A, Bucciarelli P, Rezzonico F, Lonati S, La Marca S, Silvestris I, 
Federici AB. “Circulating and progenitor endothelial cells are abnormal in patients with 
different types of von Willebrand Disease and correlate with markers of angiogenesis.” Am 
J Haematol. 2011 Aug;86(8):650-6.  
 
6. Abshire TC, Federici AB, Alvárez MT, Bowen J, Carcao MD, Cox Gill J, Key NS, Kouides 
PA, Kurnik K, Lail AE, Leebeek FW, Makris M, Mannucci PM, Winikoff R, Berntorp E; 
VWD PN. “Prophylaxis in severe forms of von Willebrand's disease: results from the von 
Willebrand Disease Prophylaxis Network (VWD PN).” Haemophilia. 2013 Jan;19(1):76-81. 
 
7. Castaman G, Goodeve A, Eikenboom J; European Group on von Willebrand Disease. 
“Principles of care for the diagnosis and treatment of von Willebrand Disease.” 
Haematologica. 2013 May;98(5):667-74.  
 
8. Federici AB, Bucciarelli P, Castaman G, Mazzucconi MG, Morfini M, Rocino A, Schiavoni 
M, Peyvandi F, Rodeghiero F, Mannucci PM. “The bleeding score predicts clinical 
outcomes and replacement therapy in adults with von Willebrand Disease.” Blood. 2014 Jun 
26;123(26):4037-44.  
 
 
 

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
 
CONFIDENTIAL 
32/46 
9. Abdul-Kadir R, McLintock C, Ducloy AS, El-Refaey H, England A, Federici AB, Grotegut 
CA, Halimeh S, Herman JH, Hofer S, James AH, Kouides PA, Paidas MJ, Peyvandi F, 
Winikoff R. “Evaluation and management of postpartum hemorrhage: consensus from an 
international expert panel.” Transfusion. 2014 Jul;54(7):1756-68.  
 
10. Makris M, Federici AB, Mannucci PM, Bolton-Maggs PH, Yee TT, Abshire T, Berntorp E. 
“The natural history of occult or angiodysplastic gastrointestinal bleeding in von Willebrand 
Disease.” Haemophilia. 2015 May;21(3):338-42.  
 
11. Federici AB. “Clinical and laboratory diagnosis of VWD.” Haematology Am Soc Haematol 
Educ Program. 2014 Dec 5;2014(1):524-30.  
 
12. Holm E, Abshire TC, Bowen J, Álvarez MT, Bolton-Maggs P, Carcao M, Federici AB, Gill 
JC, Halimeh S, Kempton C, Key NS, Kouides P, Lail A, Landorph A, Leebeek F, Makris M, 
Mannucci P, Mauser-Bunschoten EP, Nugent D, Valentino LA, Winikoff R, Berntorp E. 
“Changes in bleeding patterns in von Willebrand Disease after institution of long-term 
replacement therapy: results from the von Willebrand Disease Prophylaxis Network.” Blood 
Coagul Fibrinolysis. 2015 Jun;26(4):383-8.  
 
13. Randi AM, Laffan MA. “Von Willebrand Factor and angiogenesis: basic and applied 
issues.” J Thromb Haemost. 2016 Oct 25.  
 
14. Federici AB. “Current and emerging approaches for assessing von Willebrand Disease in 
2016.” Int J Lab Haematol. 2016 May;38 Suppl 1:41-9.  
 
15. De Jong A, Eikenboom J. “Developments in the diagnostic procedures for von Willebrand 
Disease.” J Thromb Haemost. 2016 Mar;14(3):449-60.  
 
16. Abshire T, Cox-Gill J, Kempton CL,4, Leebeek FW, Carcao M, Kouides P, Donfield S, 
Berntorp E. “Prophylaxis escalation in severe von Willebrand Disease: a prospective study 
from the von Willebrand Disease Prophylaxis Network.” J Thromb Haemost. 2015 
Sep;13(9):1585-9.  
 
17. Engelen ET, van Galen KP, Schutgens RE. “Thalidomide for treatment of gastrointestinal 
bleedings due to angiodysplasia: a case report in acquired von Willebrand syndrome and 
review of the literature.” Haemophilia. 2015 Jul;21(4):419-29.  
 
18. Holm E, Abshire TC, Bowen J, Álvarez MT, Bolton-Maggs P, Carcao M, Federici AB, Gill 
JC, Halimeh S, Kempton C, Key NS, Kouides P, Lail A, Landorph A, Leebeek F, Makris M, 
Mannucci P, Mauser-Bunschoten EP, Nugent D, Valentino LA, Winikoff R, Berntorp E. 
“Changes in bleeding patterns in von Willebrand Disease after institution of long-term 
replacement therapy: results from the von Willebrand Disease Prophylaxis Network.” Blood 
Coagul Fibrinolysis. 2015 Jun;26(4):383-8.  
 

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
 
CONFIDENTIAL 
33/46 
19. Franchini M, Mannucci PM. “Gastrointestinal angiodysplasia and bleeding in von 
Willebrand Disease.” Thromb Haemost. 2014 Sep 2;112(3):427-31.  
 
20. Randi AM, Laffan MA, Starke RD. “Von Willebrand Factor, angiodysplasia and 
angiogenesis.” Mediterr J Haematol Infect Dis. 2013 Sep 2;5(1):e2013060.  
 
21. Thachil J, Hay CR, Campbell S. “Tamoxifen for recurrent bleeds due to angiodysplasia in 
von Willebrand's disease.” Haemophilia. 2013 Sep;19(5):e313-5.  
 
22. Castaman G, Federici AB, Tosetto A, La Marca S, Stufano F, Mannucci PM, Rodeghiero F. 
“Different bleeding risk in type 2A and 2M von Willebrand Disease: a 2-year prospective 
study in 107 patients.” J Thromb Haemost. 2012 Apr;10(4):632-8.  
 
23. Starke RD, Ferraro F, Paschalaki KE, Dryden NH, McKinnon TA, Sutton RE, Payne EM, 
Haskard DO, Hughes AD, Cutler DF, Laffan MA, Randi AM. “Endothelial von Willebrand 
Factor regulates angiogenesis.” Blood. 2011 Jan 20;117(3):1071-80.  
 
24. Veyradier A, Balian A, Wolf M, Giraud V, Montembault S, Obert B, Dagher I, Chaput JC, 
Meyer D, Naveau S. “Abnormal von Willebrand Factor in bleeding angiodysplasias of the 
digestive tract.” Gastroenterology. 2001 Feb;120(2):346-53. 
 
25. Bowers M, McNulty O, Mayne E. “Octreotide in the treatment of gastrointestinal bleeding 
caused by angiodysplasia in two patients with von Willebrand's disease.” Br J Haematol. 
2000 Mar;108(3):524-7. 
 
26. Van Belle E, Rauch A, Vincent F, Robin E, Kibler M, Labreuche J, Jeanpierre E, Levade M, 
Hurt C, Rousse N, Dally JB, Debry N, Dallongeville J, Vincentelli A, Delhaye C, Auffray 
JL, Juthier F, Schurtz G, Lemesle G, Caspar T, Morel O, Dumonteil N, Duhamel A, Paris C, 
Dupont-Prado A, Legendre P, Mouquet F, Marchant B, Hermoire S, Corseaux D, Moussa K, 
Manchuelle A, Bauchart JJ, Loobuyck V, Caron C, Zawadzki C, Leroy F, Bodart JC, Staels 
B, Goudemand J, Lenting PJ, Susen S. “Von Willebrand Factor Multimers during 
Transcatheter Aortic-Valve Replacement.” N Engl J Med. 2016 Jul 28;375(4):335-44.  
 
27. Susen S, Rauch A, Van Belle E, Vincentelli A, Lenting PJ. “Circulatory support devices: 
fundamental aspects and clinical management of bleeding and thrombosis.” J Thromb 
Haemost. 2015 Oct;13(10):1757-67.  
 
28. Blatchford O, Murray WR, Blatchford M. “A risk score to predict need for treatment for 
upper-gastrointestinal haemorrhage.” Lancet. 2000 Oct 14;356(9238):1318-21. 
 
29. Gerson LB, Fidler JL, Cave DR, Leighton JA. “ACG Clinical Guideline: Diagnosis and 
Management of Small Bowel Bleeding.” Am J Gastroenterol. 2015 Sep;110(9):1265-87. 
 

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
 
CONFIDENTIAL 
34/46 
30. Strate LL, Gralnek IM. “ACG Clinical Guideline: Management of Patients With Acute 
Lower Gastrointestinal Bleeding.” Am J Gastroenterol. 2016 Apr;111(4):459-74. 
 
31. Jackson CS, Gerson LB. “Management of gastrointestinal angiodysplastic lesions (GIADs): 
a systematic review and meta-analysis.” Am J Gastroenterol. 2014 Apr;109(4):474-83. 
 
32. Martin-Grace J, Tamagno G. “Somatostatin analogs in the medical management of occult 
bleeding of the lower digestive tract.” Gastroenterol Res Pract. 2015;2015:702921. 
 
33. Holleran G, Hall B, Breslin N, McNamara D. “Long-acting somatostatin analogues provide 
significant beneficial effect in patients with refractory small bowel angiodysplasia: Results 
from a proof of concept open label mono-centre trial.” United European Gastroenterol J. 
2016 Feb;4(1):70-6. 
 
34. Eikenboom JC. (2001) Congenital von Willebrand disease type 3: clinical manifestations, 
pathophysiology and molecular biology. Best Pract Res Clin Haematol 14, 365-379. 
 
35. Sadler JE, Budde U, Eikenboom JC et al. (2006) Update on the pathophysiology and 
classification of von Willebrand disease: a report of the Subcommittee on von Willebrand 
Factor. J Thromb Haemost 4, 2103-2114. 
36. von Willebrand EA. (1926) Hereditär Pseudohemofili. Finska Läkaresällskapets Handlingar 
68, 87-112. 
37. Nilsson IM. (1999) Commentary to Erik von Willebrand's original paper from 1926 
'Hereditar pseudohemofili'. Haemophilia 5, 220-221. 
38. Nilsson IM, Blomback M, Blomback B. (1959) von Willebrand's disease in Sweden.  Its 
pathogenesis and treatment. Acta Med Scand 164, 263-278. 
39. Mannucci PM, Bloom AL, Larrieu MJ et al. (1984) Atherosclerosis and von Willebrand 
factor.  I. Prevalence of severe von Willebrand's disease in western Europe and Israel. Br J 
Haematol 57, 163-169. 
40. Weiss HJ, Ball AP, Mannucci PM. (1982) Incidence of severe von Willebrand's disease 
(letter). N Engl J Med 307, 127 
41. Berliner SA, Seligsohn U, Zivelin A et al. (1986) A relatively high frequency of severe (type 
III) von Willebrand's disease in Israel. Br J Haematol 62, 535-543. 
42. Iorio A, Oliovecchio E, Morfini M et al. (2008) Italian Registry of Haemophilia and Allied 
Disorders. Objectives, methodology and data analysis. Haemophilia 14, 444-453. 
43. Federici AB, Mannucci PM. (2007) Management of inherited von Willebrand disease in 
2007. Ann Med 39, 346-358. 
44. Silwer J. (1973) von Willebrand's disease in Sweden. Acta Paediat Scand 238, 1-159. 

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
 
CONFIDENTIAL 
35/46 
45. Lak M, Peyvandi F, Mannucci PM. (2000) Clinical manifestations and complications of 
childbirth and replacement therapy in 385 Iranian patients with type 3 von Willebrand 
disease. Br J Haematol 111, 1236-1239. 
46. Federici AB, Castaman G, Mannucci PM. (2002) Guidelines for the diagnosis and 
management of von Willebrand disease in Italy. Haemophilia 8, 607-621. 
47. Rodeghiero F, Castaman G, Tosetto A et al. (2005) The discriminant power of bleeding 
history for the diagnosis of type 1 von Willebrand disease: an international, multiCenter 
study. J Thromb Haemost 3, 2619-2626. 
48. Tosetto A, Rodeghiero F, Castaman G et al. (2006) A quantitative analysis of bleeding 
symptoms in type 1 von Willebrand disease: results from a multiCenter European study 
(MCMDM-1 VWD). J Thromb Haemost 4, 766-773. 
49. Federici AB, Bucciarelli P, Castaman G et al. (2007) Incidence and determinants of bleeding 
in different types of von Willebrand disease:results of the first prospective multiCenter study 
on 814 Italian patients Blood  110, 713 
50. Cattaneo M, Federici AB, Lecchi A et al. (1999) Evaluation of the PFA-100 system in the 
diagnosis and therapeutic monitoring of patients with von Willebrand disease. Thromb 
Haemost 82, 35-39. 
51. Mannucci PM, Lattuada A, Castaman G et al. (1989) Heterogeneous phenotypes of platelet 
and plasma von Willebrand factor in obligatory heterozygotes for severe von Willebrand 
disease. Blood 74, 2433-2436. 
52. Mannucci PM, Federici AB. (1995) Antibodies to von Willebrand factor in von Willebrand 
disease. Adv Exp Med Biol 386, 87-92. 
53. Federici AB. (2008) Clinical and molecular markers of inherited von Willebrand disease 
type 3: are deletions of the VWF gene associated with alloantibodies to VWF? J Thromb 
Haemost 6, 1726-1728. 
54. Veltkamp JJ, van Tilburg NH. (1973) Detection of heterozygotes for recessive von 
Willebrand's disease by the assay of antihemophilic-factor-like antigen. N Engl J Med 289, 
882-885. 
55. Shelton-Inloes BB, Chehab FF, Mannucci PM et al. (1987) Gene deletions correlate with the 
development of alloantibodies in von Willebrand disease. J Clin Invest 79, 1459-1465. 
56. Ngo KY, Glotz VT, Koziol JA et al. (1988) Homozygous and heterozygous deletions of the 
von Willebrand factor gene in patients and carriers of severe von Willebrand diease. Proc 
Natl Acad Sci USA 85, 2753-2757. 
57. Schneppenheim R, Krey S, Bergmann F et al. (1994) Genetic heterogeneity of severe von 
Willebrand disease type III in the German population. Hum Genet 94, 640-652. 
58. Eikenboom JCJ, Castaman G, Vos HL et al. (1998) Characterization of the genetic defects 
in recessive type 1 and type 3 von Willebrand disease patients of Italian origin. Thromb 
Haemost 79, 709-717. 

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
 
CONFIDENTIAL 
36/46 
59. Schneppenheim R, Castaman G, Federici AB et al. (2007) A common 253-kb deletion 
involving VWF and TMEM16B in German and Italian patients with severe von Willebrand 
disease type 3. J Thromb Haemost 5, 722-728. 
60. Peake IR, Liddell MB, Moodie P et al. (1990) Severe type III von Willebrand's disease 
caused by deletion of exon 42 of the von Willebrand factor gene: Family studies that 
identify carriers of the condition and a compound heterozygous individual. Blood 75, 654-
661. 
61. Mancuso DJ, Tuley EA, Castillo R et al. (1994) Characterization of partial gene deletions in 
type III von Willebrand disease with alloantibody inhibitors. Thromb Haemost 72, 180-185. 
62. Baronciani L, Cozzi G, Canciani MT et al. (2000) Molecular characterization of a 
multiethnic group of 21 patients with type-3 von Willebrand disease. Thromb Haemost 84, 
536-540. 
63. Abuzenadah AM, Gursel T, Ingerslev J et al. (1999) Mutational analysis of the von 
Willebrand factor gene in 27 families from Turkey with von Willebrand disease Thromb 
Haemost  82 (Suppl), 283 
64. Mohl A, Marschalek R, Masszi T et al. (2008) An Alu-mediated novel large deletion is the 
most frequent cause of type 3 von Willebrand disease in Hungary. J Thromb Haemost 6, 
1729-1735. 
65. Xie F, Wang X, Cooper DN et al. (2006) A novel Alu-mediated 61-kb deletion of the von 
Willebrand factor (VWF) gene whose breakpoints co-locate with putative matrix attachment 
regions. Blood Cells Mol Dis 36, 385-391. 
66. Cooper DN, Krawczak M. (1990) The mutational spectrum of single base-pair substitutions 
causing human genetic disease: patterns and predictions. Hum Genet 85, 55-74. 
67. Zhang ZP, Lindstedt M, Falk G et al. (1992) Nonsense mutations of the von Willebrand 
factor gene in patients with von Willebrand disease type III and type I. Am J Hum Genet 51, 
850-858. 
68. Eikenboom JCJ, Ploos van Amstel HK, Reitsma PH et al. (1992) Mutations in severe  type 
III von Willebrand's disease in the Dutch population: candidate missense and nonsense 
mutations associated with reduced levels of von Willebrand factor messenger RNA. Thromb 
Haemost 68, 448-454. 
69. Bahnak BR, Lavergne JM, Rothschild C et al. (1991) A stop codon in a patient with severe 
type III von Willebrand disease. Blood 78, 1148-1149. 
70. Zhang ZP, Falk G, Blombäck M et al. (1992) Identification of a new nonsense mutation in 
the von Willebrand factor gene in patients with von Willebrand disease type III. Hum Molec 
Gen 1, 61-62. 
71. Zhang ZP, Blombäck M, Egberg N et al. (1994) Characterization of the von Willebrand 
factor gene (vWF) in von Willebrand disease type III patients from 24 families of Swedish 
and Finnish origin. Genomics 21, 188-193. 

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
 
CONFIDENTIAL 
37/46 
72. Hagiwara T, Inaba H, Yoshida S et al. (1996) A novel mutation Gly 1672->Arg in type 2A 
and a homozygous mutation in type 2B von Willebrand disease. Thromb Haemost 76, 253-
257. 
73. Gupta PK, Saxena R, Adamtziki E et al. (2008) Genetic defects in von Willebrand disease 
type 3 in Indian and Greek patients. Blood Cells Mol Dis 41, 219-222. 
74. Casana P, Martinez F, Haya S et al. (2000) Q1311X: a novel nonsense mutation of putative 
ancient origin in the von Willebrand factor gene. Br J Haematol 111, 552-555. 
75. Surdhar GK, Enayat MS, Lawson S et al. (2001) Homozygous gene conversion in von 
Willebrand factor gene as a cause of type 3 von Willebrand disease and predisposition to 
inhibitor development. Blood 98, 248-250. 
76. Baronciani L, Cozzi G, Canciani MT et al. (2003) Molecular defects in type 3 von 
Willebrand disease: updated results from 40 multiethnic patients. Blood Cells,Mol & Dis 30, 
264-270. 
77. Gupta PK, Adamtziki E, Budde U et al. (2005) Gene conversions are a common cause of 
von Willebrand disease. Brit J Haematol 130, 752-758. 
78. Eikenboom JCJ, Vink T, Briët E et al. (1994) Multiple substitutions in the von Willebrand 
factor gene that mimic the pseudogene sequence. Proc Natl Acad Sci USA 91, 2221-2224. 
79. Zhang ZP, Falk G, Blombäck M et al. (1992) A single cytosine deletion in exon 18 of the 
von Willebrand factor gene is the most common mutation in Swedish von Willebrand 
disease type III patients. Hum Molec Gen 1, 767-768. 
80. Xie F, Wang X, Cooper DN et al. (2007) Compound heterozygosity for two novel mutations 
(1203insG/Y1456X) in the von Willebrand factor gene causing type 3 von Willebrand 
disease. Haemophilia 13, 645-648. 
81. Castaman G, Giacomelli SH, Coppola A et al. (2008) Molecular bases of type 3 von 
Willebrand disease in Italy: report on 12 families Blood Transfus  Suppl 3, 44 
82. Gazda H, Budde U, Krey S et al. (1997) Delta C in exon 18 of the von Willebrand factor 
gene is the most common mutation in patients with severe von Willebrand disease type 3 in 
Poland Blood  90 (Suppl 1), 94b 
83. Wetzstein V, Budde U, Oyen F et al. (2006) Intracranial hemorrhage in a term newborn with 
severe von Willebrand disease type 3 associated with sinus venous thrombosis. 
Haematologica 91, 163-165. 
84. Krawczak M, Cooper DN. (1991) Gene deletions causing human genetic disease: 
mechanisms of mutagenesis and the role of the local DNA sequence environment. Hum 
Genet 86, 425-441. 
85. Efstratiadis A, Posakony JW, Maniatis T et al. (1980) The structure and evolution of the 
human beta-globin gene family. Cell 21, 653-668. 
86. Zhang ZP, Blombäck M, Nyman D et al. (1993) Mutations of von Willebrand factor gene in 
families with von Willebrand disease in the Aland Islands. Proc Natl Acad Sci USA 90, 
7937-7940. 

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
 
CONFIDENTIAL 
38/46 
87. Mohlke KL, Nichols WC, Rehemtulla A et al. (1996) A common frameshift mutation in von 
Willebrand factor does not alter mRNA stability but interferes with normal propeptide 
processing. Br J Haematol 95, 184-191. 
88. Eikenboom JCJ, Reitsma PH, van der Velden PA et al.(1993) Instability of repeats of the 
von Willebrand factor gene variable number tandem repeat sequence in intron 40. Br J 
Haematol 84, 533-535. 
89. Antonarakis SE. (1998) Recommendations for a nomenclature system for human gene 
mutations. Nomenclature Working Group. Hum Mutat 11, 1-3. 
90. Mertes G, Ludwig M, Finkelnburg B et al. (1994) A G+3-to-T donor splice site mutation 
leads to skipping of exon 50 in von Willebrand factor mRNA. Genomics 24, 190-191. 
91. Zhang ZP, Lindstedt M, Blombäck M et al. (1995) Effects of the mutant von Willebrand 
factor gene in von Willebrand disease. Hum Genet 96, 388-394. 
92. Allen S, Abuzenadah AM, Hinks J et al. (2000) A novel von Willebrand disease-causing 
mutation (Arg273Trp) in the von Willebrand factor propeptide that results in defective 
multimerization and secretion. Blood 96, 560-568. 
93. Titapiwatanakun R, Guenther JC, Asmann YW et al. (2007) Novel Mutations in Types 2 & 
3 von Willebrand Disease and Correlation with von Willebrand Factor Multimer Patterns. 
Blood 110, 2136 
94. Montgomery RR, Jozwiak MA, Hutter JJ et al. (1999) A homozygous variant of the von 
Willebrand factor (VWF) that fails to c-terminal dimerize resulting in loss of VWF 
multimers larger than dimer Blood  94 (Suppl 1), 443a 
95. Schneppenheim R, Budde U, Drewke E et al. (1999) Cysteine mutations of von Willebrand 
factor correlate with different types of von Willebrand disease Thromb Haemost  82 (Suppl), 
283 
96. Enayat MS, Guilliatt AM, Surdhar GK et al. (2001) Identification of five novel mutations in 
families with type 3 von Willebrand's disease Thromb Haemost  86 (Suppl), P1810 
97. Castaman G, Lattuada A, Mannucci PM et al. (1995) Factor VIII: C increases after 
desmopressin in a subgroup of patients with autosomal recessive severe von Willebrand 
disease. Br J Haematol 89, 147-151. 
98. Tjernberg P, Castaman G, Vos HL et al. (2006) Homozygous C2362F von Willebrand factor 
induces intracellular retention of mutant von Willebrand factor resulting in autosomal 
recessive severe von Willebrand disease. Br J Haematol 133, 409-418. 
99. Castaman G, Eikenboom JC, Lattuada A et al. (2000) Heightened proteolysis of the von 
Willebrand factor subunit in patients with von Willebrand disease hemizygous or 
homozygous for the C2362F mutation. Br J Haematol 108, 188-190. 
100. 
Baronciani L, Federici AB, Cozzi G et al. (2008) Expression studies of missense 
mutations p.D141Y, p.C275S located in the propeptide of von Willebrand factor in patients 
with type 3 von Willebrand disease. Haemophilia 14, 549-555. 

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
 
CONFIDENTIAL 
39/46 
101. 
Voorberg J, Fontijn R, Calafat J et al. (1991) Assembly and routing of von 
Willebrand factor variants:  the requirements for disulfide-linked dimerization reside within 
the carboxy-terminal 151 amino acids. J Cell Biol 113, 195-205. 
102. 
Peake IR, Bowen D, Bignell P et al. (1990) Family studies and prenatal diagnosis in 
severe von Willebrand disease by polymerase chain reaction amplification of a variable 
number tandem repeat region of the von Willebrand factor gene. Blood 76, 555-561. 
103. 
Mannucci PM. (2004) Treatment of von Willebrand's Disease. N Engl J Med 351, 
683-694. 
104. 
Federici AB, Mazurier C, Berntorp E et al. (2004) Biologic response to desmopressin 
in patients with severe type 1 and type 2 von Willebrand disease: results of a multiCenter 
European study. Blood 103, 2032-2038. 
105. 
Castaman G, Lethagen S, Federici AB et al. (2008) Response to desmopressin is 
influenced by the genotype and phenotype in type 1 von Willebrand disease (VWD): results 
from the European Study MCMDM-1VWD. Blood 111, 3531-3539. 
106. 
Cattaneo M, Moia M, Della Valle P et al. (1989) DDAVP shortens the prolonged 
bleeding times of patients with severe von Willebrand disease treated with cryoprecipitate. 
Evidence for a mechanism of action independent of released von Willebrand factor. Blood 
74, 1972-1975. 
107. 
Mannucci PM, Chediak J, Hanna W et al. (2002) Treatment of von Willebrand 
disease with a high-purity factor VIII/von Willebrand factor concentrate: a prospective, 
multiCenter study. Blood 99, 450-456. 
108. 
Federici AB, Baudo F, Caracciolo C et al. (2002) Clinical efficacy of highly purified, 
doubly virus-inactivated factor VIII/von Willebrand factor concentrate (Fanhdi) in the 
treatment of von Willebrand disease: a retrospective clinical study. Haemophilia 8, 761-767. 
109. 
Bello IF, Yuste VJ, Molina MQ et al. (2007) Fanhdi, efficacy and safety in von 
Willebrand's disease: prospective international study results. Haemophilia 13 Suppl 5:25-
32., 25-32. 
110. 
Federici AB, Barillari G, Zanon E et al. (2008) Efficacy and safety of highly-
purified, doubly virus-inactivated VWF/FVIII concentrates in patients with von Willebrand 
disease: an Italian retrospective study on 120 cases. Haemophilia Submitted. 
111. 
Dobrkovska A, Krzensk U, Chediak JR. (1998) Pharmacokinetics, efficacy and 
safety of Humate-P in von Willebrand disease. Haemophilia 4 Suppl 3, 33-39. 
112. 
Lillicrap D, Poon MC, Walker I et al. (2002) Efficacy and safety of the factor 
VIII/von Willebrand factor concentrate, haemate-P/humate-P: ristocetin cofactor unit dosing 
in patients with von Willebrand disease. Thromb Haemost 87, 224-230. 
113. 
Franchini M, Rossetti G, Tagliaferri A et al. (2003) Efficacy and safety of factor 
VIII/von Willebrand's factor concentrate (Haemate-P) in preventing bleeding during surgery 
or invasive procedures in patients with von Willebrand disease. Haematologica 88, 1279-
1283. 

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
 
CONFIDENTIAL 
40/46 
114. 
Federici AB, Castaman G, Franchini M et al. (2007) Clinical use of Haemate P in 
inherited von Willebrand's disease: a cohort study on 100 Italian patients. Haematologica 
92, 944-951. 
115. 
Gill JC, Ewenstein BM, Thompson AR et al. (2003) Successful treatment of urgent 
bleeding in von Willebrand disease with factor VIII/VWF concentrate (Humate-P): use of 
the ristocetin cofactor assay (VWF:RCo) to measure potency and to guide therapy. 
Haemophilia 9, 688-695. 
116. 
Thompson AR, Gill JC, Ewenstein BM et al. (2004) Successful treatment for patients 
with von Willebrand disease undergoing urgent surgery using factor VIII/VWF concentrate 
(Humate-P). Haemophilia 10, 42-51. 
117. 
Lethagen S, Kyrle PA, Castaman G et al. (2007) von Willebrand factor/factor VIII 
concentrate (Haemate P) dosing based on pharmacokinetics: a prospective multiCenter trial 
in elective surgery. J Thromb Haemost 5, 1420-1430. 
118. 
Stadler M, Gruber G, Kannicht C et al. (2006) Characterisation of a novel high-
purity, double virus inactivated von Willebrand Factor and Factor VIII concentrate (Wilate). 
Biologicals 34, 281-288. 
119. 
Favaloro EJ, Lloyd J, Rowell J et al. (2007) Comparison of the pharmacokinetics of 
two von Willebrand factor concentrates [Biostate and AHF (High Purity)] in people with 
von Willebrand disorder. A randomised cross-over, multi-Center study. Thromb Haemost 
97, 922-930. 
120. 
Shortt J, Dunkley S, Rickard K et al. (2007) Efficacy and safety of a high purity, 
double virus inactivated factor VIII/von Willebrand factor concentrate (Biostate) in patients 
with von Willebrand disorder requiring invasive or surgical procedures. Haemophilia 13, 
144-148. 
121. 
Menache D, Aronson DL, Darr F et al. (1996) Pharmacokinetics of von Willebrand 
factor and factor VIIIC in patients with severe von Willebrand disease (type 3 VWD): 
estimation of the rate of factor VIIIC synthesis. Cooperative Study Groups. Br J Haematol 
94, 740-745. 
122. 
Goudemand J, Scharrer I, Berntorp E et al. (2005) Pharmacokinetic studies on 
Wilfactin, a von Willebrand factor concentrate with a low factor VIII content treated with 
three virus-inactivation/removal methods. J Thromb Haemost 3, 2219-2227. 
123. 
Borel-Derlon A, Federici AB, Roussel-Robert V et al. (2007) Treatment of severe 
von Willebrand disease with a high-purity von Willebrand factor concentrate (Wilfactin): a 
prospective study of 50 patients. J Thromb Haemost 5, 1115-1124. 
124. 
Bergamaschini L, Mannucci PM, Federici AB et al. (1995) Postranfusion 
anaphylactic reaction in a patient with severe von Willebrand disease: role of complement 
and alloantibodies to von Willebrand factor. J Lab Clin Med 125, 348-355. 
125. 
Ciavarella N, Schiavoni M, Valenzano E et al. (1996) Use of recombinant factor 
VIIa (NovoSeven) in the treatment of two patients with type III von Willebrand's disease 
and an inhibitor against von Willebrand factor. Haemostasis 26 (Suppl 1), 150-154. 

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
 
CONFIDENTIAL 
41/46 
126. 
Boyer-Neumann C, Dreyfus M, Wolf M et al. (2003) Multi-therapeutic approach to 
manage delivery in an alloimmunized patient with type 3 von Willebrand disease. J Thromb 
Haemost 1, 190-192. 
127. 
Berntorp E, Petrini P. (2005) Long-term prophylaxis in von Willebrand disease. 
Blood Coagul Fibrinolysis 16 Suppl 1, S23-S26 
128. 
Federici AB, Gianniello F, Canciani MT et al. (2005) Secondary long-term 
prophylaxis in severe patients with von Willebrand disease: an Italian cohort study Blood  
106, 507a 
129. 
De Meyer SF, Vanhoorelbeke K, Chuah MK et al. (2006) Phenotypic correction of 
von Willebrand disease type 3 blood-derived endothelial cells with lentiviral vectors 
expressing von Willebrand factor. Blood 107, 4728-4736. 
 
 

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
 
CONFIDENTIAL 
42/46 
 APPENDIX 1 
 
STUDY FLOWCHART 
 
 
Activity 
FIRST PART 
retrospective phase 
(approx. 1 year) 
+ 
diagnosis confirmatory 
phase 
(approx. 1 year) 
SECOND PART 
first observation period (approx. 2 years) 
+ 
confirmation of clinical phase data (approx. 1 year) 
+ 
second observation period (approx. 2 years) 
Enrolment Visit 
Enrolment 
Visit 
Control visit* 
Final Visit 
1 month 
4 years (including two observation  
periods of 2 years each) 
Informed 
Consent 
x 
 
 
 
Eligibility 
verification 
x 
 
 
 
Patient ID 
assignment 
x 
 
 
 
Demographics 
x 
 
 
 
Medical History 
x 
 
 
 
Previous 
diagnosis of 
VWD3 
x 
 
 
 
Bleeding History 
x 
 
 
 
Previous 
Treatments for 
VWD3 
x 
 
 
 
Family history in 
parents and 
relatives 
x 
 
 
 
Blood sample for 
local assessment 
x 
X (if not 
performed 
within 1 year 
before the study 
start) 
 
x 
Blood sample for 
Central Lab. 
assessment 
x 
 
 
 
Bleedings 
 
x 
x 
x 
VWF 
concentrates 
x 
x 
x 
x 
Concomitant 
medications 
x 
x 
x 
x 
Adverse Events 
 
x 
x 
x 
* a Control Visit should be performed at least once in a year according to the standard clinical 
practice at each investigational site  

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
 
CONFIDENTIAL 
43/46 
APPENDIX 2 
 
MEMBERS OF THE WORKING GROUP ON THE  
3WINTERS-IPS STEERING COMMITTEE 
 
Sponsor 
Barbara BIANCHI BONOMI 
Bianchi Bonomi Foundation 
P.za Castello, 2  
20121 Milan, Italy 
SPONSOR 
Scientific Coordinator 
 
Augusto B FEDERICI 
Haematology and Transfusion Medicine 
L. Sacco University Hospital 
Via GB Grassi, 74 
20154 Milan, Italy 
SC 
Financial Committee 
Coordinator 
Ian R PEAKE, PhD 
Department of Cardiovascular Science 
University of Sheffield - Medical School 
Beech Hill Road, Sheffield, S10 2RX, UK 
FC 
Publication Committee 
Coordinator, Assistant 
Coordinator Phenotype 
Jeroen EIKENBOOM, MD, PhD 
Leiden University Medical Center 
Department of Thrombosis and 
Haemostasis, Building 1:CR-2  
PO Box 9600, 2300 RC Leiden, The 
Netherlands 
PC, AC 
Iranian Study Coordinator, 
Assistant Coordinator 
Phenotype 
Flora PEYVANDI, MD, PhD 
A. B. Bonomi Hemophilia Center 
IRCCS Maggiore Hospital Cà Granda 
Foundation 
Via Pace 9  20122 Milan, Italy 
AC 
Assistant Coordinator 
Phenotype 
Ulrich BUDDE, MD 
Coagulation Laboratory 
Aesculabor Hamburg 
Haferweg 36 
Hamburg D-22760, Germany 
AC 
Assistant Coordinator 
Phenotype 
Alberto TOSETTO, MD 
San Bartolo Hospital 
Haematology Department 
36100 Vicenza, Italy 
AC 
Assistant Coordinator 
Phenotype 
Luciano BARONCIANI 
Policlinico of Milan,  
General Medicine – Haemostasis & 
Thrombosis 
Via F. Sforza 35, 20122 Milan, Italy 
AC 
Assistant Coordinator 
Genotype 
Anne GOODEVE, PhD 
Department of Cardiovascular Science 
University of Sheffield - Medical School 
Beech Hill Road, Sheffield, S10 2RX, UK 
AC 

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
 
CONFIDENTIAL 
44/46 
Assistant Coordinator 
Genotype 
Reinhard SCHNEPPENHEIM, MD, PhD 
University Children's Hospital 
Division of Pediatric Haematology and 
Oncology - Martinistrasse 52,  
20246 Hamburg, Germany 
AC 
Assistant Coordinator 
Phenotype 
Jenny GOUDEMAND, MD 
University of Lille 
Haematology Department 
59011 Lille, France 
AC 
Assistant Coordinator 
Phenotype & Genotype 
Giancarlo CASTAMAN, MD 
Careggi University Hospital 
Hemophilia Agency, Reference Center for 
Congenital Coagulopathies 
Via delle Oblate, 1 
50141 – Firenze, Italy 
AC 
Assistant Coordinator 
Phenotype 
Anna RANDI, MD 
Imperial College of London 
The Hammersmith Hospital, 
Du Cane Road, 
London W12 0NN, UK 
AC 
Assistant Coordinator 
Phenotype 
Maurizio VECCHI, MD 
Gastroenterology and Endoscopy Unit  
IRCCS Ca’ Granda Ospedale Maggiore 
Policlinico Foundation 
University of Milan 
Via Francesco Sforza 35 
20122 – Milan, Italy 
AC 
Contract Research 
Organization 
Paolo DE SIMONI 
Sintesi Research S.r.l. 
Via Matteo Bandello, 6 
20123 Milan, Italy 
CRO 
 
Legenda:  
SS=Scientific Supervisor; SC= Scientific Coordinator; FC= Financial Coordinator;  
AC= Assistant Coordinator; PC= Publication Coordinator;  

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
 
CONFIDENTIAL 
45/46 
APPENDIX 3 
 
WORKING PACKAGES 
 
 
 WP1a Study documents set-up and finalization 
 WP1b  Network and Data Base of the study 
 WP1c  Regulatory process for the study 
 WP1d  Study initiation and patients’ recruitment 
 WP2 Collection of retrospective data & blood sample withdrawal for VWD3 diagnosis 
 
confirmation 
 WP3a  Centralized evaluation of VWF antigen (VWF:Ag) levels for the VWD3 diagnosis 
 
confirmation  
 WP3b  Centralized evaluation of FVIII levels (FVIII:C, FVIII:Amidolytic, FVIII:Ag) levels 
 
for VWD3 diagnosis confirmation  
 WP3c  Centralized evaluation of VWF multimer profile for VWD3 diagnosis confirmation  
 WP3d Centralized evaluation of anti-VWF inhibitors presence in the VWD3 patients 
 
enrolled  
 WP3e Centralized evaluation of VWF propeptide levels for VWD3 diagnosis confirmation  
 WP3f  Centralized confirmation of VWD diagnosis (genotype) 
 WP4 Number, types and risk factors of bleeding in patients with confirmed VWD3 
 
diagnosis  
 WP5 Quantities, Efficacy and Safety of different plasma-derived or recombinant VWF 
 
concentrates in patients with confirmed VWD3 diagnosis  
 WP6  Regulatory process for the study amendment related to 2-year extension of 
 
prospective observation 
 WP7a Evaluation of Gastro-Intestinal Bleeding recurrence in patients with confirmed 
 
VWD3 diagnosis  
 WP7b Centralized evaluation of angiogenesis markers in patients with confirmed VWD3 
 
diagnosis experiencing recurrent GIB  
 WP8  Recommendations on the use of plasma-derived or recombinant VWF concentrates 
 
in patients with confirmed VWD3 diagnosis  
 

Study Code: 3WINTERS-IPS - EXTENDED 
 
 
Study Protocol – Amendment 2 dated 28th January 2020 
 
 
CONFIDENTIAL 
46/46 
APPENDIX 4 
 
PRELIMINARY INFORMATION COLLECTED 
DURING THE STUDY