Type 3 Von Willebrand's Disease3WINTERS-IPSNCT02460458
Type 3 Von Willebrand International Registries Inhibitor Prospective Study
An observational study of Type 3 Von Willebrand's Disease, run by Fondazione Angelo Bianchi Bonomi at 25 sites in 10 countries.
Trial summary
International Registries and Prospective Study on Type 3 Von Willebrand's Disease (VWD3), aimed to assess number, types and risk factors for bleeding and the efficacy and safety of plasma-derived and/or recombinant Von Willebrand Factor (VWF) concentrates used to treat VWD patients. Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- Type 3 Von Willebrand's Disease
- What is being tested?
- Von Willebrand Factor
- How many people
- 265 participants
- Where
- 25 sitesin 10 countries
- Study dates
- 5 Nov 2012to 17 Apr 2023
- Phase
- Observational
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Study population: A large cohort of patients with diagnosis of Type 3 Von Willebrand's Disease (VWD3), enrolled in Europe and in Iran using homogeneous and standardized criteria.
Who may be able to join
- 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
Who cannot join
- VWD3 patients who may not be available for follow-up
Trial locations and contacts
25 sites in 10 countries.
25 sites in 10 countries
Iran7 sites
Ahvaz Jundishpur University of Medical Sciences - Research Center for Thalassemia & Hemoglobinopathy - Division of Hematology & Oncology
Ahvāz
Seid-ol-Shohada Hospital - Hemophilia Center - Esfahan University of Medical Science
Isfahan
Hemophilia- Thalassaemia Center of Mashhad (Sarvar Clinic) - Mashad University of Medical Science
Mashhad
Nemazee Hospital Hemophilia Center - Shiraz University of Medical Science
Shiraz
Iranian Hemophilia Comprehensive Treatment Centre - Iranian Hemophilia Society
Tehran
Mofid Comprehensive Care Centre for Children with Hemophilia - Shahid Beheshti University of Medical Science
Tehran
Thrombosis Hemostasis Research Center - Vali-Asr Hospital - Emam Khmeini Complex Hospital - Tehran University of Medical Science
Tehran
Italy5 sites
Azienda Ospedaliera Policlinico Consorziale di Bari - Unità Operativa Semplice di Emostasi e Trombosi
Bari, 70124
Azienda Ospedaliera Universitaria Careggi - Agenzia per l'Emofilia - Centro di Riferimento Coagulopatie Congenite
Florence, 50141
Centro Emofilia e Trombosi - Fondazione Angelo Bianchi Bonomi - IRCCS Ospedale Ca' Granda - Dip. di Medicina Interna - Università degli Studi di Milano
Milan, 20122
Dipartimento di Biotecnologie Cellulari ed Ematologia - Università "Sapienza" di Roma - Policlinico Umberto I
Roma, 00161
Dipartimento di Terapie Cellulari ed Ematologia - Centro Malattie Emorragiche e Trombotiche - Ospedale San Bortolo
Vicenza, 36100
Germany3 sites
University Clinic Bonn - Institute of Experimental Haematology & Transfusion Medicine
Bonn, 53127
University Children's Hospital - Department of Pediatric Hematology and Oncology
Hamburg, 20246
Department of Haematology, Haemostasis, Oncology and Stem Cell Transplantation - Hannover Medical School - Haemophilia Care Centre
Hanover, 30625
France2 sites
Institut d'Hématologie - Hôpital Cardiologique - University of Lille - Haematology Department
Lille, 59037
Centre Régional de Traitement de l'Hémophilie - Laboratoire d'Hématologie
Nantes, 44093
Netherlands2 sites
Leiden University Medical Center - Department of Hematology - Hemostasis and Thrombosis Center
Leiden, 2333
Erasmus Medical Center - Department of Hematology
Rotterdam, 3015
Spain2 sites
Complejo Hospitalario Universitario de A Coruña - Servicio de Hematología y Hemoterapia
A Coruña, 15006
Hospital Universitari General Vall d'Hebron - Unidad de Hemofilia
Barcelona, 08035
Finland1 site
Helsinki University Central Hospital, Department Internal Medicine, Coagulation Disorders, at Haematology and Laboratory Services
Helsinki, FIN-00029 HUS
Hungary1 site
St. Istvan & St. Laszlo Hospital of Budapest - Hematology and Stem Cell Transplantation
Budapest, 1097
Sweden1 site
Lund University - Centre for Thrombosis and Haemostasis - Skane University Hospital
Malmö, 205 02
United Kingdom1 site
Central Manchester University Hospital NHS Foundation Trust - Manchester Royal Infirmary - Manchester Royal Eye Hospital
Manchester, M13 9WL
About this study
International Registries and Prospective Study on Type 3 Von Willebrand's Disease (VWD3), aimed to assess number, types and risk factors for bleeding and the efficacy and safety of plasma-derived and/or recombinant Von Willebrand Factor (VWF) concentrates used to treat VWD patients.
Read the detailed description
Von Willebrand's Disease (VWD) is the most common inherited bleeding disorder, characterized by a quantitative and/or qualitative deficiency of Von Willebrand Factor (VWF), that plays a major role in early phases of hemostasis. Type 3 Von Willebrand's Disease (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 is inherited as a recessive trait and heterozygous relatives have mild or no bleeding symptoms. Even if the prevalence of VWD3 is very low, 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.
The major objectives of the study are: to create an international network among European and Iranian Centers (ratio 1:1), the prospective enrollment of at least 250 VWD3 patients using a common database online, the collection of detailed information about previous bleedings and exposure to plasma-derived and/or recombinant VWF concentrates, the use of bleeding severity score of VWD3 calculated with a common questionnaire, the collection of plasma and DNA samples from all the identified VWD3 patients enrolled for centralized analyses, the 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, the evaluation of potential correlations between phenotypic results (including markers of angiogenesis) and GIB occurrence, the objective evaluation of severity of GIB in VWD3 patients, the assessment of frequency and sites of bleeding in VWD3 patients followed-up for 2 prospective observation periods (2 years each: 2017-2018 and 2020-2022), the 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 2020-2022), the 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 2020-2022), in comparison to the use of anti-angiogenetic agents within the standard clinical setting.
To these purposes, a cohort of at least 250 patients with diagnosis of VWD3 will be enrolled using homogenous and standardized criteria.
The work planned to achieve the objectives of the project will be divided in three parts:
- the first part deals with standardized criteria for enrolment and collection of retrospective clinical and laboratory data, to be confirmed by centralized laboratories;
- the second part involves a further characterization of clinical and laboratory parameters, collected in the retrospective phase, including prevalence of anti-VWF inhibitors, advanced laboratory tests to further identify VWD3, mutations analyses of the VWF gene;
- the third part of the study is divided in two parts: a first prospective observation and a second prospective observation. The third part 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.
- Conditions
- Type 3 Von Willebrand's Disease
- Being tested
- Von Willebrand Factor
- Keywords
- Factor VIII, Hemorrhage, Type 3 Von Willebrand's Disease, Von Willebrand Factor, Von Willebrand's Disease, Hemostasis, Gastro-Intestinal Bleeds
- Medical subject headings
- von Willebrand Disease, Type 3, Hemophilia A, Hemorrhage, von Willebrand Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Von Willebrand FactorDrug
Also called Plasma-derived and/or recombinantVon Willebrand Factor (VWF) concentrates
Replacement therapy with plasma-derived and/or recombinant VWF concentrates on-demand or under prophylaxis therapeutic scheme.
| Study group | Role | What they receive |
|---|---|---|
| Type 3 Von Willebrand's Disease (VWD3) | Patients with diagnosis of Type 3 Von Willebrand's Disease Receives: Drug: Von Willebrand Factor |
What is being measured
The primary outcome is the main question the study is designed to answer.
Centralized Factor VIII (FVIII) Procoagulant Activity (FVIII:C) Laboratory Test for Type 3 Von Willebrand's Disease (VWD3) Diagnosis
Measurement of the Factor VIII (FVIII) Procoagulant Activity (FVIII:C) in the blood through one-stage clotting test. Only patients with FVIII:C less or equal to 5 IU/dL were considered for the analysis.
Measured: 12 months (confirmatory phase)
Centralized Von Willebrand Factor Antigen (VWF:Ag) Laboratory Test for Type 3 Von Willebrand's Disease (VWD3) Diagnosis
Measurement of the amount of Von Willebrand Factor (VWF) protein in the blood through Von Willebrand Factor Antigen (VWF:Ag) test. Only patients with VWF:Ag less or equal to 5 IU/dL were considered for the analysis.
Measured: 12 months (confirmatory phase)
Centralized Factor VIII (FVIII) Amidolytic Activity (FVIII:Am) Laboratory Test for Type 3 Von Willebrand's Disease (VWD3) Diagnosis
Measurement of Factor VIII (FVIII) Amidolytic Activity (FVIII:Am) in the blood through chromogenic test. Only patients with FVIII:Am less or equal to 5 IU/dL were considered for the analysis.
Measured: 12 months (confirmatory phase)
Centralized Factor VIII (FVIII) Antigen (FVIII:Ag) Laboratory Test for Type 3 Von Willebrand's Disease (VWD3) Diagnosis
Measurement of the amount of Factor VIII (FVIII) protein in the blood through FVIII:Ag test. Only patients with FVIII:Ag less or equal to 5 IU/dL were considered for the analysis.
Measured: 12 months (confirmatory phase)
Centralized Von Willebrand Factor (VWF) Multimer Analysis for Type 3 Von Willebrand's Disease (VWD3) Diagnosis
Multimer analysis of Von Willebrand Factor (VWF) was carried out by electrophoresis of blood samples collected by investigational sites. The number of patients belonging of each multimer profile group (1 - Homozygotes / 2 - Only Protomers / 3 - 2-4 Bands) was calculated. The qualitative evaluation of VWF multimers is part of the diagnostic process of VWD3.
Measured: 12 months (confirmatory phase)
Centralized Von Willebrand Factor (VWF) Propeptide Laboratory Test for Type 3 Von Willebrand's Disease (VWD3) Diagnosis
Measurement of Von Willebrand Factor (VWF) Propeptide levels in the blood through VWF Propeptide test. This test has been performed according to the most recent methods and the results are important to characterize the molecular aspects of VWD patients.
Measured: 12 months (confirmatory phase)
Centralized Molecular Type 3 Von Willebrand's Disease (VWD3) Diagnosis Through DNA Analysis
Evaluation of the presence of Von Willebrand Factor (VWF) gene defects (confirmation or screening for the first time).
Measured: 12 months (confirmatory phase)
Record of Bleeding Episodes
Record of all bleedings occurred during the prospective phase of the study.
Measured: 24 months (first prospective phase) + 24 months (second prospective phase)
Adverse Events
Record of all adverse events occurred during the prospective phase of the study.
Measured: 24 months (first prospective phase) + 24 months (second prospective phase)
Type of Von Willebrand Factor / Factor VIII (VWF/FVIII)-Containing Concentrates in Use
Record of any Von Willebrand Factor / Factor VIII (VWF/FVIII)-containing concentrates used and currently in use, including the current schedule type of treatment.
Measured: 24 months (first prospective phase) + 24 months (second prospective phase)
Secondary outcomes (4)
Patients Experiencing Allergic Reactions During Use of Von Willebrand Factor (VWF)-Containing Concentrates
Record of any allergic and anaphylactic reactions occurred in the past due to the use of any Von Willebrand Factor (VWF) concentrate and the date of onset.
Measured: 24 months (retrospective phase)
Number of Participants With Previous Use of Blood Products
Record of any product used during the retrospective phase (collected type of blood products/Von Willebrand Factor (VWF) concentrate, year of first exposure, units used).
Measured: 24 months (retrospective phase)
Number of Patients With Available Local Laboratory Test for Anti-Von Willebrand Factor (Anti-VWF) Antibodies
Evaluation of the titre of Anti-Von Willebrand Factor (anti-VWF) Antibodies through Bethesda Test.
Measured: 24 months (retrospective phase)
Local Laboratory Tests for Type 3 Von Willebrand's Disease (VWD3) Diagnosis (Composite)
Number of patients for who the following tests have been performed:
Hemoglobin (mmol/L), Hemagglutination Titer (HT) (%), Mean Corpuscular Volume (MVC) (fl), Leucocytes (E9/L), Neutrophils (%), Basophils (%), Eosinophils (%), Lymphocytes (%), Platelet Count (E9/L), Mean Platelet Volume (MPV) (fl), Prothrombin Time (sec), Partial Thromboplastin Time (PTT) (sec), Partial Thromboplastin Time Mix 50:50 (PTT mix 50:50) (sec), Ferritin (ug/l), Bleeding Time (min:sec), Closure Time (sec), Collagen/ADP (sec), Collagen/Epinephrine (sec); Factor VIII Procoagulant Activity (FVIII:C) (IU/mL), Von Willebrand Factor Ristocetin Cofactor (VWF:RCo) (IU/mL), Won Willebrand Factor Antigen (VWF:Ag) (IU/mL).
Measured: 24 months (retrospective phase)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Jun 2015 (estimated)
- Study start5 Nov 2012
- Primary completion28 Mar 2023
- Study completion17 Apr 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (128)Papers the sponsor has linked to this study.
- Other trials for Type 3 Von Willebrand's DiseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Other
- Enrolment
- 265 participants (actual)
Sponsor and investigators
- Lead sponsor
- Fondazione Angelo Bianchi Bonomi
- Sponsor type
- University, hospital or other
- Collaborators
- Sintesi Research Srl
- Responsible party
- Sponsor
- Investigators
- Augusto B. Federici, MD, Study director, Hematology and Transfusion Medicine, L. Sacco University Hospital, University of Milan, Via G. B. Grassi, 74 20157 Milan, Italy
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02460458
- Sponsor's protocol ID
- ABB-11-01
- Acronym
- 3WINTERS-IPS
- Status last verified
- Dec 2024
- First submitted
- 27 May 2015
- Last updated
- 27 Dec 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
Eikenboom JC. Congenital von Willebrand disease type 3: clinical manifestations, pathophysiology and molecular biology. Best Pract Res Clin Haematol. 2001 Jun;14(2):365-79. doi: 10.1053/beha.2001.0139.
PubMed 11686105Sadler JE, Budde U, Eikenboom JC, Favaloro EJ, Hill FG, Holmberg L, Ingerslev J, Lee CA, Lillicrap D, Mannucci PM, Mazurier C, Meyer D, Nichols WL, Nishino M, Peake IR, Rodeghiero F, Schneppenheim R, Ruggeri ZM, Srivastava A, Montgomery RR, Federici AB; Working Party on von Willebrand Disease Classification. Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor. J Thromb Haemost. 2006 Oct;4(10):2103-14. doi: 10.1111/j.1538-7836.2006.02146.x. Epub 2006 Aug 2.
PubMed 16889557Nilsson IM. Commentary to Erik von Willebrand's original paper from 1926 'Hereditar pseudohemofili'. Haemophilia. 1999 May;5(3):220-1. doi: 10.1046/j.1365-2516.1999.0320a.x. No abstract available.
PubMed 10444292NILSSON IM, BLOMBACK M, BLOMBACK B. v. Willebrand's disease in Sweden; its pathogenesis and treatment. Acta Med Scand. 1959 Jun 30;164:263-78. No abstract available.
PubMed 14427267Mannucci PM, Bloom AL, Larrieu MJ, Nilsson IM, West RR. Atherosclerosis and von Willebrand factor. I. Prevalence of severe von Willebrand's disease in western Europe and Israel. Br J Haematol. 1984 May;57(1):163-9. doi: 10.1111/j.1365-2141.1984.tb02876.x.
PubMed 6609712Weiss HJ, Ball AP, Mannucci PM. Incidence of severe von Willebrand's disease. N Engl J Med. 1982 Jul 8;307(2):127. doi: 10.1056/NEJM198207083070222. No abstract available.
PubMed 6979706Berliner SA, Seligsohn U, Zivelin A, Zwang E, Sofferman G. A relatively high frequency of severe (type III) von Willebrand's disease in Israel. Br J Haematol. 1986 Mar;62(3):535-43. doi: 10.1111/j.1365-2141.1986.tb02966.x.
PubMed 3082350Iorio A, Oliovecchio E, Morfini M, Mannucci PM; Association of Italian Hemophilia Centres Directors. Italian Registry of Haemophilia and Allied Disorders. Objectives, methodology and data analysis. Haemophilia. 2008 May;14(3):444-53. doi: 10.1111/j.1365-2516.2008.01679.x. Epub 2008 Mar 18.
PubMed 18355268Federici AB, Mannucci PM. Management of inherited von Willebrand disease in 2007. Ann Med. 2007;39(5):346-58. doi: 10.1080/07853890701513738.
PubMed 17701477Silwer J. von Willebrand's disease in Sweden. Acta Paediatr Scand Suppl. 1973;238:1-159. No abstract available.
PubMed 4550005Lak M, Peyvandi F, Mannucci PM. Clinical manifestations and complications of childbirth and replacement therapy in 385 Iranian patients with type 3 von Willebrand disease. Br J Haematol. 2000 Dec;111(4):1236-9. doi: 10.1046/j.1365-2141.2000.02507.x.
PubMed 11167767Federici AB, Castaman G, Mannucci PM; Italian Association of Hemophilia Centers (AICE). Guidelines for the diagnosis and management of von Willebrand disease in Italy. Haemophilia. 2002 Sep;8(5):607-21. doi: 10.1046/j.1365-2516.2002.00672.x.
PubMed 12199668Rodeghiero F, Castaman G, Tosetto A, Batlle J, Baudo F, Cappelletti A, Casana P, De Bosch N, Eikenboom JC, Federici AB, Lethagen S, Linari S, Srivastava A. The discriminant power of bleeding history for the diagnosis of type 1 von Willebrand disease: an international, multicenter study. J Thromb Haemost. 2005 Dec;3(12):2619-26. doi: 10.1111/j.1538-7836.2005.01663.x.
PubMed 16359502Tosetto A, Rodeghiero F, Castaman G, Goodeve A, Federici AB, Batlle J, Meyer D, Fressinaud E, 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. A quantitative analysis of bleeding symptoms in type 1 von Willebrand disease: results from a multicenter European study (MCMDM-1 VWD). J Thromb Haemost. 2006 Apr;4(4):766-73. doi: 10.1111/j.1538-7836.2006.01847.x.
PubMed 16634745Cattaneo M, Federici AB, Lecchi A, Agati B, Lombardi R, Stabile F, Bucciarelli P. Evaluation of the PFA-100 system in the diagnosis and therapeutic monitoring of patients with von Willebrand disease. Thromb Haemost. 1999 Jul;82(1):35-9.
PubMed 10456451