Type 3 Von Willebrand International Registries Inhibitor Prospective Study (3WINTERS-IPS)

December 23, 2024 updated by: Fondazione Angelo Bianchi Bonomi
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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Observational

Enrollment (Actual)

265

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Finland
      • Helsinki, Finland, FIN-00029 HUS
        • Helsinki University Central Hospital, Department Internal Medicine, Coagulation Disorders, at Haematology and Laboratory Services
  • France
      • Lille Cedex, France, 59037
        • Institut d'Hématologie - Hôpital Cardiologique - University of Lille - Haematology Department
      • Nantes Cedex 1, France, 44093
        • Centre Régional de Traitement de l'Hémophilie - Laboratoire d'Hématologie
  • Germany
      • Bonn, Germany, 53127
        • University Clinic Bonn - Institute of Experimental Haematology & Transfusion Medicine
      • Hamburg, Germany, 20246
        • University Children's Hospital - Department of Pediatric Hematology and Oncology
      • Hannover, Germany, 30625
        • Department of Haematology, Haemostasis, Oncology and Stem Cell Transplantation - Hannover Medical School - Haemophilia Care Centre
  • Hungary
      • Budapest, Hungary, 1097
        • St. Istvan & St. Laszlo Hospital of Budapest - Hematology and Stem Cell Transplantation
  • Iran, Islamic Republic of
      • Ahvaz, Iran, Islamic Republic of
        • Ahvaz Jundishpur University of Medical Sciences - Research Center for Thalassemia & Hemoglobinopathy - Division of Hematology & Oncology
      • Esfahan, Iran, Islamic Republic of
        • Seid-ol-Shohada Hospital - Hemophilia Center - Esfahan University of Medical Science
      • Mashhad, Iran, Islamic Republic of
        • Hemophilia- Thalassaemia Center of Mashhad (Sarvar Clinic) - Mashad University of Medical Science
      • Shiraz, Iran, Islamic Republic of
        • Nemazee Hospital Hemophilia Center - Shiraz University of Medical Science
      • Tehran, Iran, Islamic Republic of
        • Iranian Hemophilia Comprehensive Treatment Centre - Iranian Hemophilia Society
      • Tehran, Iran, Islamic Republic of
        • Mofid Comprehensive Care Centre for Children with Hemophilia - Shahid Beheshti University of Medical Science
      • Tehran, Iran, Islamic Republic of
        • Thrombosis Hemostasis Research Center - Vali-Asr Hospital - Emam Khmeini Complex Hospital - Tehran University of Medical Science
  • Italy
      • Bari, Italy, 70124
        • Azienda Ospedaliera Policlinico Consorziale di Bari - Unità Operativa Semplice di Emostasi e Trombosi
      • Firenze, Italy, 50141
        • Azienda Ospedaliera Universitaria Careggi - Agenzia per l'Emofilia - Centro di Riferimento Coagulopatie Congenite
      • Milano, Italy, 20122
        • Centro Emofilia e Trombosi - Fondazione Angelo Bianchi Bonomi - IRCCS Ospedale Ca' Granda - Dip. di Medicina Interna - Università degli Studi di Milano
      • Roma, Italy, 00161
        • Dipartimento di Biotecnologie Cellulari ed Ematologia - Università "Sapienza" di Roma - Policlinico Umberto I
      • Vicenza, Italy, 36100
        • Dipartimento di Terapie Cellulari ed Ematologia - Centro Malattie Emorragiche e Trombotiche - Ospedale San Bortolo
  • Netherlands
      • Leiden, Netherlands, 2333
        • Leiden University Medical Center - Department of Hematology - Hemostasis and Thrombosis Center
      • Rotterdam, Netherlands, 3015
        • Erasmus Medical Center - Department of Hematology
  • Spain
      • A Coruña, Spain, 15006
        • Complejo Hospitalario Universitario de A Coruña - Servicio de Hematología y Hemoterapia
      • Barcelona, Spain, 08035
        • Hospital Universitari General Vall d'Hebron - Unidad de Hemofilia
  • Sweden
      • Malmö, Sweden, 205 02
        • Lund University - Centre for Thrombosis and Haemostasis - Skane University Hospital
  • United Kingdom
      • Manchester, United Kingdom, M13 9WL
        • Central Manchester University Hospital NHS Foundation Trust - Manchester Royal Infirmary - Manchester Royal Eye Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

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.

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Other

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Type 3 Von Willebrand's Disease (VWD3)
Patients with diagnosis of Type 3 Von Willebrand's Disease
Drug: Von Willebrand Factor
Replacement therapy with plasma-derived and/or recombinant VWF concentrates on-demand or under prophylaxis therapeutic scheme.
Other Names:
  • Plasma-derived and/or recombinantVon Willebrand Factor (VWF) concentrates

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Centralized Factor VIII (FVIII) Procoagulant Activity (FVIII:C) Laboratory Test for Type 3 Von Willebrand's Disease (VWD3) Diagnosis
Time Frame: 12 months (confirmatory phase)
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.
12 months (confirmatory phase)
Centralized Von Willebrand Factor Antigen (VWF:Ag) Laboratory Test for Type 3 Von Willebrand's Disease (VWD3) Diagnosis
Time Frame: 12 months (confirmatory phase)
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.
12 months (confirmatory phase)
Centralized Factor VIII (FVIII) Amidolytic Activity (FVIII:Am) Laboratory Test for Type 3 Von Willebrand's Disease (VWD3) Diagnosis
Time Frame: 12 months (confirmatory phase)
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.
12 months (confirmatory phase)
Centralized Factor VIII (FVIII) Antigen (FVIII:Ag) Laboratory Test for Type 3 Von Willebrand's Disease (VWD3) Diagnosis
Time Frame: 12 months (confirmatory phase)
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.
12 months (confirmatory phase)
Centralized Von Willebrand Factor (VWF) Multimer Analysis for Type 3 Von Willebrand's Disease (VWD3) Diagnosis
Time Frame: 12 months (confirmatory phase)
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.
12 months (confirmatory phase)
Centralized Molecular Type 3 Von Willebrand's Disease (VWD3) Diagnosis Through DNA Analysis
Time Frame: 12 months (confirmatory phase)
Evaluation of the presence of Von Willebrand Factor (VWF) gene defects (confirmation or screening for the first time).
12 months (confirmatory phase)
Adverse Events
Time Frame: 24 months (first prospective phase) + 24 months (second prospective phase)
Record of all adverse events occurred during the prospective phase of the study.
24 months (first prospective phase) + 24 months (second prospective phase)
Type of Von Willebrand Factor / Factor VIII (VWF/FVIII)-Containing Concentrates in Use
Time Frame: 24 months (first prospective phase) + 24 months (second prospective phase)
Record of any Von Willebrand Factor / Factor VIII (VWF/FVIII)-containing concentrates used and currently in use, including the current schedule type of treatment.
24 months (first prospective phase) + 24 months (second prospective phase)
Centralized Von Willebrand Factor (VWF) Propeptide Laboratory Test for Type 3 Von Willebrand's Disease (VWD3) Diagnosis
Time Frame: 12 months (confirmatory phase)
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.
12 months (confirmatory phase)
Record of Bleeding Episodes
Time Frame: 24 months (first prospective phase) + 24 months (second prospective phase)
Record of all bleedings occurred during the prospective phase of the study.
24 months (first prospective phase) + 24 months (second prospective phase)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Patients Experiencing Allergic Reactions During Use of Von Willebrand Factor (VWF)-Containing Concentrates
Time Frame: 24 months (retrospective phase)
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.
24 months (retrospective phase)
Number of Participants With Previous Use of Blood Products
Time Frame: 24 months (retrospective phase)
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).
24 months (retrospective phase)
Number of Patients With Available Local Laboratory Test for Anti-Von Willebrand Factor (Anti-VWF) Antibodies
Time Frame: 24 months (retrospective phase)
Evaluation of the titre of Anti-Von Willebrand Factor (anti-VWF) Antibodies through Bethesda Test.
24 months (retrospective phase)
Local Laboratory Tests for Type 3 Von Willebrand's Disease (VWD3) Diagnosis (Composite)
Time Frame: 24 months (retrospective phase)

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).
24 months (retrospective phase)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Fondazione Angelo Bianchi Bonomi

Collaborators

Sintesi Research Srl

Investigators

  • Study Director: Augusto B. Federici, MD, Hematology and Transfusion Medicine, L. Sacco University Hospital, University of Milan, Via G. B. Grassi, 74 20157 Milan, Italy

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 5, 2012

Primary Completion (Actual)

March 28, 2023

Study Completion (Actual)

April 17, 2023

Study Registration Dates

First Submitted

May 27, 2015

First Submitted That Met QC Criteria

June 1, 2015

First Posted (Estimated)

June 2, 2015

Study Record Updates

Last Update Posted (Actual)

March 25, 2025

Last Update Submitted That Met QC Criteria

December 23, 2024

Last Verified

December 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ABB-11-01

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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