The European Paediatric Network for Haemophilia Management ( PedNet Registry)

Factor VIII Deficiency Clinical Trial

— PedNet  

Official title:

The European Paediatric Network for Haemophilia Management and the PedNet Haemophilia Registry

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02979119
• Other study ID #: Version 6.4 November 2022
• Status: Recruiting
• Start date: June 2014
• Est. completion date: December 2029

Study information

• Verified date: October 2023
• Source: PedNet Haemophilia Research Foundation
• Contact: Cindy Machielse
• Phone: +31850299993
• Email: c.s.machielse[@]pednet.eu
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial Summary

Rationale:

Haemophilia is a rare disease; to improve knowledge international collaboration is needed. Well-defined clinical data will be collected from complete cohorts in order to prevent selection bias.

Objective:

To collect data on bleeding during neonatal period, endogenous (genetic) and exogenous (treatment-related) determinants of inhibitor development and long term outcome.

Description:

Design: Multicenter Prospective Observational Birth Cohort Study

Population:

Patients with haemophilia A and B with FVIII/IX levels of <1 to 25% born between 1-1-2000 and 1-1-2030.

Intervention:

No intervention; only documentation of patient characteristics and parameters of routine patient care and outcome

Main outcome parameters:

Outcome: clinically relevant inhibitor development, bleeding pattern and joint status on physical examination and imaging.

Determinants: baseline FVIII/IX levels, measurement of inhibitory antibodies, family history, FVIII/IX gene mutation, details on replacement therapy (according to each infusion for the first 50 treatment days, and annually thereafter) and surgeries.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness:

• No burden for the patients. Well-defined clinical data will be collected from the medical files. Participating in this registry will not change the number of visits to the clinic. All outcome parameters that are collected (including laboratory results) are part of routine clinical care.

• Direct benefit is not to be expected. However, the direct interaction between centres that treat patients with rare diseases improves both clinical care and will result in better guidelines and as such may provide indirect benefit.

• Multicentre participation: haemophilia is a very rare condition. Therefore, collecting data on a multi-centre observational cohort is the only way to study this specific population.

• The registry concerns young boys and girls with haemophilia and cannot be performed in older patients, as >90% of inhibitors occur develop during the first 50 exposure days, and the results of prophylactic replacement therapy are highly dependent on the initiation of this treatment.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 4000
• Est. completion date: December 2029
• Est. primary completion date: December 2029
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

Inclusion Criteria:

• Diagnosed with Haemophilia A or B

• Factor VIII/ IX activity of <1 to 25%

• Complete records of Factor treatment and bleeds

• Treated in one of the participating centres

Exclusion Criteria:

• Patients referred because of an inhibitor*

• Informed consent not obtained

Related Conditions & MeSH terms

• Factor IX Deficiency
• Factor VIII Deficiency
• Hemophilia A
• Hemophilia B

Locations

Country	Name	City	State
Austria	Universitäts-Klinik für Kinder- und Jugendheilkunde	Graz
Austria	Medical University of Vienna - Department of Paediatrics	Vienna
Belgium	Service of Pediatric Haematology University Hospital Leuven	Leuven
Canada	Division of Hematology/Oncology Hôpital St Justine	Montréal
Canada	Division of Haematology/Oncology Hospital for Sick Children	Toronto
Czechia	Haemophilia Comprehensive Care Centre, Centre for Thrombosis and Haemostasis Children's University Hospital Brno	Brno
Czechia	Department of Paediatric Haematology/oncology - University Hospital Motol	Praha
Denmark	Department of Pediatrics Århus Kommunehospital Skejby Sygehus	Aarhus
Finland	Children's Hospital Helsinki University Hospital	Helsinki
France	Service Hématologique Centre Regional Traitement d'Hemophilie Bicetre	Le Kremlin Bicêtre
France	Service d'Hématologie Pédiatrique Hôpital Universitaire La Timone	Marseille Cedex-05
France	Centre de traitement des hémophiles Hôpital Universitaire Purpan	Toulouse
Germany	Institut für Experimentelle Hämatologie und Transfusionsmedizin Universitätsklinikum Bonn	Bonn
Germany	Klinik Bremen-Mitte Prof.-Hess-Kinderklinik	Bremen
Germany	University Hospital Frankfurt & Goethe University - Clinical and Molecular Hemostasis, Department of Pediatrics	Frankfurt am Main
Germany	Hämophilie Zentrum Rhein Main	Mörfelden-Walldorf
Germany	Dr. v. Haunersches Kinderspital University of Munich	Munich
Greece	Haemophilia-Haemostasis Unit St. Sophia Children's Hospital	Athens
Ireland	Dept of Paediatric Haematology Our Lady's Children's Hospital for Sick Children Crumlin	Dublin
Israel	The National Hemophilia Center Sheba Medical Center, Tel Hashomer	Ramat Gan
Italy	Azienda Ospedaliero Universitaria Careggi	Florence
Italy	Gaslini Hospital	Genova
Italy	A. Bianchi Bonomi Hemophilia and Thrombosis Centre IRCCS Ca' Granda Ospedale Maggiore Policlinico	Milano
Netherlands	Van Creveld Kliniek University Medical Center Utrecht	Utrecht
Norway	Oslo University Hospital	Oslo
Portugal	Centro Hospitalar São João, S. Imuno-hemoterapia	Porto
Spain	Unitat Hemofilia Hospital Vall d'Hebron	Barcelona
Spain	Unidad de Coagulopatías Hospital Universitario La Paz	Madrid
Spain	Hospital General Unidad de Hemofilia 1 Sur Hospitales Universitarios Virgen del Rocio	Seville
Spain	Unidad de Coagulopatias Congenitas Hospital Universitario la Fe	Valencia
Sweden	Lund University Hospital	Malmo
Sweden	Department of Pediatrics, Clinic of Coag. Disorders Karolinska Hospital	Stockholm
Switzerland	Inselspital Bern, University Children's Hospital	Bern
United Kingdom	Birmingham Children's Hospital NHS Trust - Department of Haematology	Birmingham
United Kingdom	Royal Hospital for Sick Children	Edinburgh
United Kingdom	Department of Haematology Royal Hospital for Sick Children	Glasgow
United Kingdom	Haemophila Center Great Ormond Street Hospital for Children	London

Sponsors (1)

Lead Sponsor	Collaborator
PedNet Haemophilia Research Foundation

Countries where clinical trial is conducted

Austria,  Belgium,  Canada,  Czechia,  Denmark,  Finland,  France,  Germany,  Greece,  Ireland,  Israel,  Italy,  Netherlands,  Norway,  Portugal,  Spain,  Sweden,  Switzerland,  United Kingdom, 

References & Publications (25)

Alvarez-Roman MT, Kurnik K; PedNet Study Group. Care for children with haemophilia during COVID-19: Data of the PedNet study group. Haemophilia. 2021 Jul;27(4):e537-e539. doi: 10.1111/hae.14286. Epub 2021 Mar 8. No abstract available. — View Citation

Andersson NG, Auerswald G, Barnes C, Carcao M, Dunn AL, Fijnvandraat K, Hoffmann M, Kavakli K, Kenet G, Kobelt R, Kurnik K, Liesner R, Makipernaa A, Manco-Johnson MJ, Mancuso ME, Molinari AC, Nolan B, Perez Garrido R, Petrini P, Platokouki HE, Shapiro AD, — View Citation

Andersson NG, Chalmers EA, Kenet G, Ljung R, Makipernaa A, Chambost H; PedNet Haemophilia Research Foundation. Mode of delivery in hemophilia: vaginal delivery and Cesarean section carry similar risks for intracranial hemorrhages and other major bleeds. H — View Citation

Andersson NG, Labarque V, Letelier A, Mancuso ME, Buhrlen M, Fischer K, Kartal-Kaess M, Koskenvuo M, Mikkelsen T, Ljung R; PedNet study group. Novel F8 and F9 gene variants from the PedNet hemophilia registry classified according to ACMG/AMP guidelines. H — View Citation

Andersson NG, Wu R, Carcao M, Claeyssens-Donadel S, Kobelt R, Liesner R, Makipernaa A, Ranta S, Ljung R; ICH study group. Long-term follow-up of neonatal intracranial haemorrhage in children with severe haemophilia. Br J Haematol. 2020 Jul;190(2):e101-e10 — View Citation

Carcao MD, van den Berg HM, Ljung R, Mancuso ME; PedNet and the Rodin Study Group. Correlation between phenotype and genotype in a large unselected cohort of children with severe hemophilia A. Blood. 2013 May 9;121(19):3946-52, S1. doi: 10.1182/blood-2012 — View Citation

Clausen N, Petrini P, Claeyssens-Donadel S, Gouw SC, Liesner R; PedNet and Research of Determinants of Inhibitor development (RODIN) Study Group. Similar bleeding phenotype in young children with haemophilia A or B: a cohort study. Haemophilia. 2014 Nov;2 — View Citation

Fischer K, Carcao M, Male C, Ranta S, Pergantou H, Kenet G, Kartal-Kaess M, Konigs C, Carvalho M, Alvarez MT, Brakenhoff T, Chambost H, van den Berg HM. Different inhibitor incidence for individual factor VIII concentrates in 1076 previously untreated pat — View Citation

Fischer K, Ljung R, Platokouki H, Liesner R, Claeyssens S, Smink E, van den Berg HM. Prospective observational cohort studies for studying rare diseases: the European PedNet Haemophilia Registry. Haemophilia. 2014 Jul;20(4):e280-6. doi: 10.1111/hae.12448. — View Citation

Gouw SC, van den Berg HM, Fischer K, Auerswald G, Carcao M, Chalmers E, Chambost H, Kurnik K, Liesner R, Petrini P, Platokouki H, Altisent C, Oldenburg J, Nolan B, Garrido RP, Mancuso ME, Rafowicz A, Williams M, Clausen N, Middelburg RA, Ljung R, van der — View Citation

Gouw SC, van der Bom JG, Ljung R, Escuriola C, Cid AR, Claeyssens-Donadel S, van Geet C, Kenet G, Makipernaa A, Molinari AC, Muntean W, Kobelt R, Rivard G, Santagostino E, Thomas A, van den Berg HM; PedNet and RODIN Study Group. Factor VIII products and i — View Citation

Hashemi SM, Fischer K, Moons KGM, van den Berg HM; PedNet Study group. Validation of the prediction model for inhibitor development in PUPs with severe haemophilia A. Haemophilia. 2016 Mar;22(2):e116-e118. doi: 10.1111/hae.12895. Epub 2016 Feb 8. No abstr — View Citation

Jonker CJ, Oude Rengerink K, Hoes AW, Mol PGM, van den Berg HM. Inhibitor development in previously untreated patients with severe haemophilia: A comparison of included patients and outcomes between a clinical study and a registry-based study. Haemophilia — View Citation

Khair K, Ranta S, Thomas A, Lindvall K; PedNet study group. The impact of clinical practice on the outcome of central venous access devices in children with haemophilia. Haemophilia. 2017 Jul;23(4):e276-e281. doi: 10.1111/hae.13241. Epub 2017 May 24. — View Citation

Labarque V, Mancuso ME, Kartal-Kaess M, Ljung R, Mikkelsen TS, Andersson NG. F8/F9 variants in the population-based PedNet Registry cohort compared with locus-specific genetic databases of the European Association for Haemophilia and Allied Disorders and — View Citation

Ljung R, de Kovel M, van den Berg HM; PedNet study group. Primary prophylaxis in children with severe haemophilia A and B-Implementation over the last 20 years as illustrated in real-world data in the PedNet cohorts. Haemophilia. 2023 Mar;29(2):498-504. d — View Citation

Male C, Andersson NG, Rafowicz A, Liesner R, Kurnik K, Fischer K, Platokouki H, Santagostino E, Chambost H, Nolan B, Konigs C, Kenet G, Ljung R, Van den Berg M. Inhibitor incidence in an unselected cohort of previously untreated patients with severe haemo — View Citation

Mancuso ME, Fischer K, Santagostino E, Oldenburg J, Platokouki H, Konigs C, Escuriola-Ettingshausen C, Rivard GE, Cid AR, Carcao M, Ljung R, Petrini P, Altisent C, Kenet G, Liesner R, Kurnik K, Auerswald G, Chambost H, Makipernaa A, Molinari AC, Williams — View Citation

Minna K, Anne M, Beatrice N, Rainer K, Susanna R. Correction of haemostasis can be reduced to four days for CVAD implantation in severe haemophilia A patients: Data from the PedNet study group. Haemophilia. 2021 May;27(3):392-397. doi: 10.1111/hae.14231. — View Citation

Platokouki H, Fischer K, Gouw SC, Rafowicz A, Carcao M, Kenet G, Liesner R, Kurnik K, Rivard GE, van den Berg HM. Vaccinations are not associated with inhibitor development in boys with severe haemophilia A. Haemophilia. 2018 Mar;24(2):283-290. doi: 10.11 — View Citation

Ranta S, Motwani J, Blatny J, Buhrlen M, Carcao M, Chambost H, Escuriola C, Fischer K, Kartal-Kaess M, de Kovel M, Kenet G, Male C, Nolan B, d'Oiron R, Olivieri M, Zapotocka E, Andersson NG, Konigs C. Dilemmas on emicizumab in children with haemophilia A: — View Citation

Schmidt DE, Michalopoulou A, Fischer K, Motwani J, Andersson NG, Pergantou H, Ranta S; PedNet Study Group. Long-term joint outcomes in adolescents with moderate or severe haemophilia A. Haemophilia. 2022 Nov;28(6):1054-1061. doi: 10.1111/hae.14636. Epub 2 — View Citation

van den Berg HM, Fischer K, Carcao M, Chambost H, Kenet G, Kurnik K, Konigs C, Male C, Santagostino E, Ljung R; PedNet Study Group. Timing of inhibitor development in more than 1000 previously untreated patients with severe hemophilia A. Blood. 2019 Jul 1 — View Citation

van den Berg HM, Gouw SC, van der Bom JG. Factor VIII products and inhibitors in severe hemophilia A. N Engl J Med. 2013 Apr 11;368(15):1457. doi: 10.1056/NEJMc1301995. No abstract available. — View Citation

van den Berg HM, Mancuso ME, Konigs C, D'Oiron R, Platokouki H, Mikkelsen TS, Motwani J, Nolan B, Santagostino E; European Pediatric Network for Haemophilia Management (PedNet). ITI Treatment is not First-Choice Treatment in Children with Hemophilia A and — View Citation

* Note: There are 25 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of patients with antibody development to exogenous clotting factors	Allo-antibodies against Factor VIII and IX; Blood test: measurement in Bethesda units (BU), positive according to local standards, for most labs >0.5 BU	Until patient reaches age of 18
Secondary	Long term outcome of haemophilia on joint status using the Hemophilia Joint Health Score (HJHS) and MRI techniques.	Effect of different prophylactic regimen on bleeding and joint damage	From diagnose every 5 years until patient reaches age of 18
Secondary	Long term outcome different Immune Tolerance Induction (ITI) therapies in patients with inhibitor.	Effect of different ITI therapies on bleeding and joint damage. Joint damage is assessed using the HJHS and MRI.	From date first positive inhibitor titer preferably every 3 years until patient reaches age of 18

External Links

•   Website of the PedNet Registry