Type 3 Von Willebrand International Registries Inhibitor Prospective Study

Type 3 Von Willebrand's Disease Clinical Trial

— 3WINTERSIPSEXT  

Official title:

Type 3 Von Willebrand International Registries Inhibitor Prospective Study

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02460458
• Other study ID #: ABB-11-01
• Status: Active, not recruiting
• Start date: November 5, 2012
• Est. completion date: December 2022

Study information

• Verified date: March 2022
• Source: Fondazione Angelo Bianchi Bonomi
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 265
• Est. completion date: December 2022
• Est. primary completion date: October 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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

Related Conditions & MeSH terms

• Type 3 Von Willebrand's Disease
• Von Willebrand Diseases

Intervention

Drug:
• Von Willebrand Factor
Replacement therapy with plasma-derived and/or recombinant VWF concentrates on-demand or under prophylaxis therapeutic scheme.

Locations

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

Sponsors (2)

Lead Sponsor	Collaborator
Fondazione Angelo Bianchi Bonomi	Sintesi Research Srl

Countries where clinical trial is conducted

Finland,  France,  Germany,  Hungary,  Iran, Islamic Republic of,  Italy,  Netherlands,  Spain,  Sweden,  United Kingdom, 

References & Publications (128)

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* Note: There are 128 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	12 months (confirmatory phase)
Primary	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.	12 months (confirmatory phase)
Primary	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.	12 months (confirmatory phase)
Primary	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.	12 months (confirmatory phase)
Primary	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.	12 months (confirmatory phase)
Primary	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.	12 months (confirmatory phase)
Primary	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).	12 months (confirmatory phase)
Primary	Record of Bleeding Episodes	Bleeding: severity, start date, stop date; Treatment: Product name, start date, stop date, Total IU, Total of Exposure Days (ED).	24 months (first prospective phase) + 24 months (second prospective phase)
Primary	Adverse Events	Record of all adverse events occurred during the prospective phase of the study.	24 months (first prospective phase) + 24 months (second prospective phase)
Primary	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.	24 months (first prospective phase) + 24 months (second prospective phase)
Secondary	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.	24 months (retrospective phase)
Secondary	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).	24 months (retrospective phase)
Secondary	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.	24 months (retrospective phase)
Secondary	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).	24 months (retrospective phase)