Type 3 Von Willebrand International Registries Inhibitor Prospective Study

Study Overview
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Brief Summary
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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
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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.

Official Title
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Type 3 Von Willebrand International Registries Inhibitor Prospective Study

Conditions
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Type 3 Von Willebrand's Disease

Intervention / Treatment
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* Drug: Von Willebrand Factor


Participation Criteria
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Eligibility Criteria
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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
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Type 3 Von Willebrand's Disease (VWD3)<br>Patients with diagnosis of Type 3 Von Willebrand's Disease | Drug: Von Willebrand Factor<br>* Replacement therapy with plasma-derived and/or recombinant VWF concentrates on-demand or under prophylaxis therapeutic scheme.<br>* Other names: Plasma-derived and/or recombinantVon Willebrand Factor (VWF) concentrates;|

What is the study measuring?
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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 | 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 | 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 | 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 | 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 | 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 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 
| 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) | 
| 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) | 
| 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Factor VIII, Hemorrhage, Type 3 Von Willebrand's Disease, Von Willebrand Factor, Von Willebrand's Disease, Hemostasis, Gastro-Intestinal Bleeds