Clinical trial NCT02460458: Type 3 Von Willebrand International Registries Inhibitor Prospective Study
Official title: Type 3 Von Willebrand International Registries Inhibitor Prospective Study
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Type 3 Von Willebrand's Disease
Keywords: Factor VIII
Hemorrhage
Type 3 Von Willebrand's Disease
Von Willebrand Factor
Von Willebrand's Disease
Hemostasis
Gastro-Intestinal Bleeds
Lead sponsor: Fondazione Angelo Bianchi Bonomi
Sponsor class: OTHER
Collaborators: name: Sintesi Research Srl
First posted: 2015-06-02
Enrollment: 265
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: OTHER
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.

Brief 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Centralized Factor VIII (FVIII) Procoagulant Activity (FVIII:C) Laboratory Test for Type 3 Von Willebrand's Disease (VWD3) Diagnosis
timeFrame: 12 months (confirmatory phase)
measure: Centralized Von Willebrand Factor Antigen (VWF:Ag) Laboratory Test for Type 3 Von Willebrand's Disease (VWD3) Diagnosis
timeFrame: 12 months (confirmatory phase)
measure: Centralized Factor VIII (FVIII) Amidolytic Activity (FVIII:Am) Laboratory Test for Type 3 Von Willebrand's Disease (VWD3) Diagnosis
timeFrame: 12 months (confirmatory phase)
measure: Centralized Factor VIII (FVIII) Antigen (FVIII:Ag) Laboratory Test for Type 3 Von Willebrand's Disease (VWD3) Diagnosis
timeFrame: 12 months (confirmatory phase)
measure: Centralized Von Willebrand Factor (VWF) Multimer Analysis for Type 3 Von Willebrand's Disease (VWD3) Diagnosis
timeFrame: 12 months (confirmatory phase)
measure: Centralized Von Willebrand Factor (VWF) Propeptide Laboratory Test for Type 3 Von Willebrand's Disease (VWD3) Diagnosis
timeFrame: 12 months (confirmatory phase)
measure: Centralized Molecular Type 3 Von Willebrand's Disease (VWD3) Diagnosis Through DNA Analysis
timeFrame: 12 months (confirmatory phase)
measure: Record of Bleeding Episodes
timeFrame: 24 months (first prospective phase) + 24 months (second prospective phase)
measure: Adverse Events
timeFrame: 24 months (first prospective phase) + 24 months (second prospective phase)
measure: Type of Von Willebrand Factor / Factor VIII (VWF/FVIII)-Containing Concentrates in Use
timeFrame: 24 months (first prospective phase) + 24 months (second prospective phase)
Secondary outcomes:
measure: Patients Experiencing Allergic Reactions During Use of Von Willebrand Factor (VWF)-Containing Concentrates
timeFrame: 24 months (retrospective phase)
measure: Number of Participants With Previous Use of Blood Products
timeFrame: 24 months (retrospective phase)
measure: Number of Patients With Available Local Laboratory Test for Anti-Von Willebrand Factor (Anti-VWF) Antibodies
timeFrame: 24 months (retrospective phase)
measure: Local Laboratory Tests for Type 3 Von Willebrand's Disease (VWD3) Diagnosis (Composite)
timeFrame: 24 months (retrospective phase)
Other outcomes:
Locations:
city: Helsinki
country: Finland
facility: Helsinki University Central Hospital, Department Internal Medicine, Coagulation Disorders, at Haematology and Laboratory Services
city: Lille Cedex
country: France
facility: Institut d'Hématologie - Hôpital Cardiologique - University of Lille - Haematology Department
city: Nantes Cedex 1
country: France
facility: Centre Régional de Traitement de l'Hémophilie - Laboratoire d'Hématologie
city: Bonn
country: Germany
facility: University Clinic Bonn - Institute of Experimental Haematology & Transfusion Medicine
city: Hamburg
country: Germany
facility: University Children's Hospital - Department of Pediatric Hematology and Oncology
city: Hannover
country: Germany
facility: Department of Haematology, Haemostasis, Oncology and Stem Cell Transplantation - Hannover Medical School - Haemophilia Care Centre
city: Budapest
country: Hungary
facility: St. Istvan & St. Laszlo Hospital of Budapest - Hematology and Stem Cell Transplantation
city: Ahvaz
country: Iran, Islamic Republic of
facility: Ahvaz Jundishpur University of Medical Sciences - Research Center for Thalassemia & Hemoglobinopathy - Division of Hematology & Oncology
city: Esfahan
country: Iran, Islamic Republic of
facility: Seid-ol-Shohada Hospital - Hemophilia Center - Esfahan University of Medical Science
city: Mashhad
country: Iran, Islamic Republic of
facility: Hemophilia- Thalassaemia Center of Mashhad (Sarvar Clinic) - Mashad University of Medical Science
city: Shiraz
country: Iran, Islamic Republic of
facility: Nemazee Hospital Hemophilia Center - Shiraz University of Medical Science
city: Tehran
country: Iran, Islamic Republic of
facility: Iranian Hemophilia Comprehensive Treatment Centre - Iranian Hemophilia Society
city: Tehran
country: Iran, Islamic Republic of
facility: Mofid Comprehensive Care Centre for Children with Hemophilia - Shahid Beheshti University of Medical Science
city: Tehran
country: Iran, Islamic Republic of
facility: Thrombosis Hemostasis Research Center - Vali-Asr Hospital - Emam Khmeini Complex Hospital - Tehran University of Medical Science
city: Bari
country: Italy
facility: Azienda Ospedaliera Policlinico Consorziale di Bari - Unità Operativa Semplice di Emostasi e Trombosi
city: Firenze
country: Italy
facility: Azienda Ospedaliera Universitaria Careggi - Agenzia per l'Emofilia - Centro di Riferimento Coagulopatie Congenite
city: Milano
country: Italy
facility: Centro Emofilia e Trombosi - Fondazione Angelo Bianchi Bonomi - IRCCS Ospedale Ca' Granda - Dip. di Medicina Interna - Università degli Studi di Milano
city: Roma
country: Italy
facility: Dipartimento di Biotecnologie Cellulari ed Ematologia - Università "Sapienza" di Roma - Policlinico Umberto I
city: Vicenza
country: Italy
facility: Dipartimento di Terapie Cellulari ed Ematologia - Centro Malattie Emorragiche e Trombotiche - Ospedale San Bortolo
city: Leiden
country: Netherlands
facility: Leiden University Medical Center - Department of Hematology - Hemostasis and Thrombosis Center
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center - Department of Hematology
city: A Coruña
country: Spain
facility: Complejo Hospitalario Universitario de A Coruña - Servicio de Hematología y Hemoterapia
city: Barcelona
country: Spain
facility: Hospital Universitari General Vall d'Hebron - Unidad de Hemofilia
city: Malmö
country: Sweden
facility: Lund University - Centre for Thrombosis and Haemostasis - Skane University Hospital
city: Manchester
country: United Kingdom
facility: Central Manchester University Hospital NHS Foundation Trust - Manchester Royal Infirmary - Manchester Royal Eye Hospital
Study officials:
affiliation: Hematology and Transfusion Medicine, L. Sacco University Hospital, University of Milan, Via G. B. Grassi, 74 20157 Milan, Italy
name: Augusto B. Federici, MD
role: STUDY_DIRECTOR
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