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Rare Bleeding Disorders in the Netherlands (RBIN)

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ClinicalTrials.gov Identifier: NCT03347591
Recruitment Status : Recruiting
First Posted : November 20, 2017
Last Update Posted : August 31, 2018
Sponsor:
Collaborators:
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Academisch Ziekenhuis Maastricht
Erasmus Medical Center
Maxima Medical Center
Academisch Ziekenhuis Groningen
UMC Utrecht
Leiden University Medical Center
Haga Hospital
Information provided by (Responsible Party):
Radboud University

Brief Summary:

Rationale: Rare bleeding disorders (deficiency of fibrinogen, factor II, V, V&VIII, VII, X, XI, XIII, α2-antiplasmin or plasminogen activator inhibitor 1) are not well defined with respect to their clinical phenotype, laboratory phenotype en genotype. At present, little is known about their clinical presentation, bleeding scores, bleeding episodes, health-related quality of life, laboratory parameters, genetics and current treatment. There are large differences in bleeding tendency and weak correlations with the level of factor deficiencies. Therefore, it is essential to perform thorough research in patients with rare bleeding disorders and perform laboratory and genetic tests, to seek explanations for the variety in clinical phenotype.

Objective: The purpose of the RBIN study is to describe the epidemiology, bleeding tendency, laboratory parameters, quality of life and genetics of all known patients in the Netherlands with rare bleeding disorders. In addition, the study aims to examine the relationship between clinical phenotype, laboratory phenotype and genotype.

Study design: explorative cross-sectional multicenter observational study Study population: all patients registered in Dutch Haemophilia Treatment Centers with known disorders of the coagulation factors fibrinogen, factor II, V, V & VIII, VII, X, XI, XIII, α2-antiplasmin and plasminogen activator inhibitor type 1, aged 1 years and older.

Main study parameters/endpoints:

Description of the clinical phenotype, laboratory phenotype, genotype and quality of life.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: participating patients will be invited for one visit to their treatment center in order to draw blood, take a saliva sample and perform questionnaires. This will take approximately 40 to 120 minutes. Since the population of patients with rare bleeding disorders is very small it is important to include all patients, also minors (children <18 years), in the study (around one third of known patients are minors). Therefore, this study may be regarded as group-related. The risk associated with participation is negligible.


Condition or disease Intervention/treatment
Rare Bleeding Disorders Genetic: WES Diagnostic Test: Several assays

Detailed Description:

Primary objectives:

  • Describe the epidemiology, clinical presentation, bleeding score, bleeding episodes, quality of life, laboratory parameters, genetics and treatment of homozygous and known heterozygous individuals (of all ages) with rare bleeding disorders (disorders of fibrinogen, FII, FV, FV & VIII, FVII, FX, FXI, FXIII, alpha-2-antiplasmin and PAI-1 deficiency) in the Netherlands;
  • Examine the relationship between the clinical and laboratory presentation (clinical and laboratory phenotype), and between phenotypes and genetics (genotype);
  • Examine the relationship between quality of life, phenotype and genotype;
  • Validate the established factor activity levels for patients to remain without symptoms.

Secondary objectives:

  • Compare the clinical presentation, bleeding score, quality of life and laboratory parameters of individuals with a rare bleeding disorder (disorders of fibrinogen, FII, FV, FV & VIII, FVII, FX, FXI, FXIII, alpha-2-antiplasmin and PAI-1 deficiency) to those of individuals with haemophilia A or B in cooperation with the HIN-6 investigators
  • Establish a firm base for a future Dutch registry for homozygous and known heterozygous individuals with rare bleeding disorders
  • To develop a standard set of patient-reported, clinical and administrative data to be collected on a regular basis
  • Liaise with the pro-RBDD study, a similar study in Italy, to work towards a pan-European study linking phenotype to genotype in individuals with rare bleeding disorders
  • To assess if the NHA can distinguish mild clinical phenotypes in patients with similar factor activity levels
  • To evaluate the usefulness of saliva coagulation biomarker tests in the management of patients with a rare bleeding disorder
  • To examine whether age-dependent laboratory changes in factor concentrations and fibrinolysis occur in individuals with rare bleeding disorders and if so, whether they influence clinical phenotype
  • To evaluate if patients with rare bleeding disorders are protected from arterial thrombosis

Study Type : Observational
Estimated Enrollment : 300 participants
Observational Model: Case-Only
Time Perspective: Cross-Sectional
Official Title: Rare Bleeding Disorders in the Netherlands
Actual Study Start Date : November 7, 2017
Estimated Primary Completion Date : September 1, 2018
Estimated Study Completion Date : September 1, 2018

Resource links provided by the National Library of Medicine


Group/Cohort Intervention/treatment
Patients with rare bleeding disorders
All patients registered in Dutch Haemophilia Treatment Centers with known disorders of the coagulation factors fibrinogen, factor II, V, V & VIII, VII, X, XI, XIII, α2-antiplasmin and plasminogen activator inhibitor type 1, aged 1 years and older.
Genetic: WES
136 bleeding related OMIM (Online Mendelian Inheritance in Man)-proved genes involved in haemostasis will be selected from Whole Exome Sequencing (WES)

Diagnostic Test: Several assays
Patients will be approached by their own treating physician. Data will be collected through questionnaires, a clinical interview, a blood and saliva sample obtained from each participant, and thorough review of electronic patient records. All procedures are study related. In case a physician visit with the treating physician is already planned, or in case a venepuncture for regular diagnostics or treatment is already planned, this can be combined with the study procedures to prevent an extra visit.
Other Names:
  • Hemostasis (several screening tests, several diagnostic tests, global assay)
  • Fibrinolysis
  • Lupus anticoagulans
  • Anti β2 glycoprotein




Primary Outcome Measures :
  1. Epidemiology [ Time Frame: 1 year ]
    Determine the prevalence of rare bleeding disorders in the Netherlands by evaluating all patients known in all Dutch Haemophilia Treatment Centers

  2. Phenotype [ Time Frame: 1 year ]
    Clinical phenotype will be measured by bleeding scores measured as ISTH-BAT.

  3. Laboratory phenotype [ Time Frame: 1 year ]
    Measure the factor concentrations of all patients known with a Rare Bleeding Disorder in the Netherlands

  4. Quality of Life [ Time Frame: 2 years ]
    Quality of life will be measured using the RAND-36 questionnaire

  5. Genotype [ Time Frame: 2 years ]
    Determine the genotype of patients (homozygous, heterozygous, compound heterozygous) by whole exome sequencing


Secondary Outcome Measures :
  1. Minimum factor level [ Time Frame: 1 year ]
    The minimum factor level necessary to remain without bleeding will be calculated by measuring factor levels in all patients and their bleeding scores by ISTH-BAT

  2. Age [ Time Frame: 1 Year ]
    To examine whether age-dependent laboratory changes in factor concentrations and fibrinolysis occur in individuals with rare bleeding disorders and if so, whether they influence clinical phenotype.


Biospecimen Retention:   Samples With DNA
Blood and saliva


Information from the National Library of Medicine

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Ages Eligible for Study:   1 Year and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population

To date, 394 patients with a rare bleeding disorder are known to the eight Dutch centers that treat such patients. Approximately one third of these patients are homozygous; and around two thirds are heterozygous individuals.

All known homozygous and heterozygous patients with a rare bleeding disorder will be invited to participate.

Criteria

Inclusion Criteria:

  • Established homozygous or known heterozygous rare bleeding disorder due to deficiency or dysfunction of fibrin, FII, FV, FV & FVIII, FVII, FX, FXI, FXIII, alpha-2-antiplasmin and PAI-1 ;
  • Age 1 year and older;
  • For patients ≥ 16 years old; written informed consent.
  • For patients 12-16 years old; written informed consent from both the patient and their parents/legal guardian(s).
  • For patients <12 years old; written informed consent from their parents/legal guardian(s).

Exclusion Criteria:

  • No informed consent given;
  • Residency outside of the Netherlands

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03347591


Contacts
Contact: J. Saes, Drs. 0031243614794 Joline.Saes@radboudumc.nl
Contact: S. P. Smeekens, PhD 0031243655772 sanne.smeekens@radboudumc.nl

Locations
Netherlands
Academisch Medisch Centrum Recruiting
Amsterdam, Netherlands
Contact: Marjolein Peters, Dr.       m.peters@amc.uva.nl   
Haga hospital Recruiting
Den Haag, Netherlands, 2545AA
Contact: Paul Ypma       P.Ypma@hagaziekenhuis.nl   
Maxima Medisch Centrum Recruiting
Eindhoven, Netherlands, 6500 PD
Contact: Laurens Nieuwenhuizen, PhD         
University Medical Center Groningen (UMCG) Recruiting
Groningen, Netherlands
Contact: Vellenga, Prof MD PhD    +31 (0)50 3613385    hematologiestudie@umcg.nl   
Principal Investigator: Vellenga, Prof MD PhD         
Maatricht UMC+ Recruiting
Maastricht, Netherlands, 6202 AZ
Contact: Erik Beckers, Dr.       eam.beckers@mumc.nl   
Radboud university medical center Recruiting
Nijmegen, Netherlands, 6525 GA
Contact: Postbus Trialbureau Hematologie-Oncologie    +31 24 36 14 794    trialbureauhemat-onco@radboudumc.nl   
Principal Investigator: S. Schols, MD PhD         
Erasmus MC Recruiting
Rotterdam, Netherlands, 3000CA
Contact: Marjon Cnossen       m.cnossen@erasmusumc.nl   
Sponsors and Collaborators
Radboud University
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Academisch Ziekenhuis Maastricht
Erasmus Medical Center
Maxima Medical Center
Academisch Ziekenhuis Groningen
UMC Utrecht
Leiden University Medical Center
Haga Hospital
Investigators
Principal Investigator: S. Schols, PhD Radboud University
  Study Documents (Full-Text)

Documents provided by Radboud University:

Responsible Party: Radboud University
ClinicalTrials.gov Identifier: NCT03347591     History of Changes
Other Study ID Numbers: HEMSTOL47
First Posted: November 20, 2017    Key Record Dates
Last Update Posted: August 31, 2018
Last Verified: February 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: Undecided

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Radboud University:
Fibrinogen
Factor II
Factor V
Factor V & VIII
Factor VII
Factor X
Factor XI
Factor XIII
α2-antiplasmin
Plasminogen activator inhibitor 1
Epidemiology
Genetics
Phenotype

Additional relevant MeSH terms:
Hemorrhage
Disease
Blood Coagulation Disorders
Hemostatic Disorders
Hemorrhagic Disorders
Pathologic Processes
Hematologic Diseases
Vascular Diseases
Cardiovascular Diseases
Plasminogen
Plasminogen Inactivators
Plasminogen Activator Inhibitor 1
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors