The European Paediatric Network for Haemophilia Management ( PedNet Registry)

Official title

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

Overview

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.

Detailed 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 1-1-2040.

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.

Primary outcome measures

• Number of patients with antibody development to exogenous clotting factors [Time frame: Until patient reaches age of 18]

Secondary outcome measures (2)

• Long term outcome of haemophilia on joint status using the Hemophilia Joint Health Score (HJHS) and MRI techniques. [Time frame: From diagnose every 5 years until patient reaches age of 18]
• Long term outcome different Immune Tolerance Induction (ITI) therapies in patients with inhibitor. [Time frame: From date first positive inhibitor titer preferably every 3 years until patient reaches age of 18]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

Germany · 7 centers

• Charité Campus Virchow Klinikum, Klinik für Pädiatrie m.S. Onkologie und Hämatologie — Berlin
• Department of Internal Medicine, Hemophilia Treatment Center, Vivantes Klinikum im Friedri — Berlin
• Institut für Experimentelle Hämatologie und Transfusionsmedizin Universitätsklinikum Bonn — Bonn
• Klinik Bremen-Mitte Prof.-Hess-Kinderklinik — Bremen
• Hämophilie Zentrum Rhein Main — Frankfurt
• University Hospital Frankfurt & Goethe University - Clinical and Molecular Hemostasis, Dep — Frankfurt am Main
• Dr. v. Haunersches Kinderspital University of Munich — Munich

Spain · 4 centers

• Unitat Hemofilia Hospital Vall d'Hebron — Barcelona
• Unidad de Coagulopatías Hospital Universitario La Paz — Madrid
• Hospital General Unidad de Hemofilia 1 Sur Hospitales Universitarios Virgen del Rocio — Seville
• Unidad de Coagulopatias Congenitas Hospital Universitario la Fe — Valencia

United Kingdom · 4 centers

• Birmingham Children's Hospital NHS Trust - Department of Haematology — Birmingham
• Royal Hospital for Sick Children — Edinburgh
• Department of Haematology Royal Hospital for Sick Children — Glasgow
• Haemophila Center Great Ormond Street Hospital for Children — London

France · 3 centers

• Service Hématologique Centre Regional Traitement d'Hemophilie Bicetre — Le Kremlin-Bicêtre
• Service d'Hématologie Pédiatrique Hôpital Universitaire La Timone — Marseille Cedex-05
• Centre de traitement des hémophiles Hôpital Universitaire Purpan — Toulouse

Italy · 3 centers

• Azienda Ospedaliero Universitaria Careggi — Florence
• Gaslini Hospital — Genova
• A. Bianchi Bonomi Hemophilia and Thrombosis Centre IRCCS Ca' Granda Ospedale Maggiore Poli — Milan

Austria · 2 centers

• Universitäts-Klinik für Kinder- und Jugendheilkunde — Graz
• Medical University of Vienna - Department of Paediatrics — Vienna

Canada · 2 centers

• Division of Hematology/Oncology Hôpital St Justine — Montreal
• Division of Haematology/Oncology Hospital for Sick Children — Toronto

Czechia · 2 centers

• Haemophilia Comprehensive Care Centre, Centre for Thrombosis and Haemostasis Children's Un — Brno
• Department of Paediatric Haematology/oncology - University Hospital Motol — Prague

Sweden · 2 centers

• Lund University Hospital — Malmö
• Department of Pediatrics, Clinic of Coag. Disorders Karolinska Hospital — Stockholm

Belgium · 1 center

• Service of Pediatric Haematology University Hospital Leuven — Leuven

Denmark · 1 center

• Department of Pediatrics Århus Kommunehospital Skejby Sygehus — Aarhus

Finland · 1 center

• Children's Hospital Helsinki University Hospital — Helsinki

Greece · 1 center

• Haemophilia-Haemostasis Unit St. Sophia Children's Hospital — Athens

Ireland · 1 center

• Children's Health Ireland (CHI) at Crumlin — Dublin

Israel · 1 center

• The National Hemophilia Center Sheba Medical Center, Tel Hashomer — Ramat Gan

Netherlands · 1 center

• Van Creveld Kliniek University Medical Center Utrecht — Utrecht

Norway · 1 center

• Oslo University Hospital — Oslo

Portugal · 1 center

• Centro Hospitalar São João, S. Imuno-hemoterapia — Porto

Switzerland · 1 center

• Inselspital Bern, University Children's Hospital — Bern

Publications

• de Kovel M, van Haaster AC, Carcao M, Ranta S, Glosli H, Rivard GE, Kenet G, Kurnik K, Van Geet C, Carvalho M, Andersson NG, Kartal-Kaess M, Ljung R, van den Berg HM; PedNet Study Group. Blood Group O Does Not Increase the Risk of Inhibitors in Severe Haemophilia A: Data from the PedNet Study Group. Haemophilia. 2025 May;31(3):419-423. doi: 10.1111/hae.70035. Epub 2025 Mar 23. PMID 40123267
• Carcao M, Konigs C, Andersson NG, de Kovel M, de Boer-Verdonk E, Motwani J, Blatny J, Olivieri M, van den Berg M, Fischer K. Predictors of immune tolerance induction success in 231 children with severe hemophilia A with high-titer inhibitors - lessons learned from the PedNet prospective cohort study. J Thromb Haemost. 2025 Oct;23(10):3134-3147. doi: 10.1016/j.jtha.2025.07.010. Epub 2025 Jul 22. PMID 40706963
• Mendoza A, Rivas I, Hidalgo OB, Cid AR, Olivieri M, Ranta S, Labarque V, Andersson NG, de Kovel M, Alvarez-Roman MT. Impact of Family History of Haemophilia on Diagnosis, Management and Outcomes in Severe Haemophilia. Haemophilia. 2025 Jul;31(4):679-686. doi: 10.1111/hae.70018. Epub 2025 May 30. PMID 40444652
• Ranta S, Zapotocka E, Andersson NG, Fischer K, Kenet G, de Kovel M, Konigs C, Labarque V, Male C, Olivieri M, Motwani J. A survey on clinical practice in monitoring and management of bleeding in children with haemophilia A on emicizumab prophylaxis in the PedNet centres. Thromb Res. 2025 May;249:109307. doi: 10.1016/j.thromres.2025.109307. Epub 2025 Mar 19. No abstract available. PMID 40120320
• 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. PMID 23574131
• 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 Bom JG; PedNet and Research of Determinants of INhibitor development (RODIN) Study Group. Intensity of factor VIII treatment and inhibitor develo PMID 23553768
• 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-2012-11-469403. Epub 2013 Mar 12. PMID 23482934
• 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;20(6):747-55. doi: 10.1111/hae.12470. Epub 2014 Jun 3. PMID 24893572

Identifiers

NCT: NCT02979119 · Version 6.4 November 2022

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗