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PedNet Hemophilia Registry

PedNet Hemophilia Registry European Paediatric Network for Hemophilia Management, an infrastructure for ongoing clinical research among children with hemophilia. Aims To exchange experiences on paediatric care of hemophilia To facilitate basic and clinical research endeavours specific to hemophilia treatment and outcome.

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PedNet Hemophilia Registry

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    1. My brief presentation covers 3 studies focused My brief presentation covers 3 studies focused

    5. RODIN Centres Barcelona, Spain Bonn, Germany Glasgow, Scotland Madrid, Spain Milan, Italy Montreal, Canada Paris, France Tel-Hashomer,Israel Toronto, Canada Valencia, Spain

    6. PedNet/RODIN Patients PedNet: patients with severe (<1%), moderate (1-5%) and mild (5-25%) hemophilia A and B RODIN: patients with severe HA (FVIII<1%) Born after January 1st, 2000 Treated in one of the participating European hemophilia treatment centers Well-documented patient history and treatment data from diagnosis onwards

    7. PedNet/RODIN Design At every out-patient clinic visit, specific assessment forms First 75 exposure days logbook (clotting factor infusions, medications, vaccinations, infections) Registration of patient data (FVIII genotype, inhibitor test, FVIII recovery), no additional tests Central databases: www.Pednet.nl www.Rodinstudy.eu

    8. Primary outcome Clinically relevant inhibitor development, defined as at least 2 positive titers combined with a decreased in vivo FVIII recovery (<66% of the expected value). Secondary outcome High-titer inhibitor development, defined as the occurrence of a clinically relevant inhibitor with a peak titer >5 BU/ml

    9. Enrolments - September 2009 PedNet Total registry: 662 patients with HA/HB Severe HA/HB: 398 (61%) Mild/Moderate: 254 (39%) RODIN Total: 79 patients with severe HA

    10. Principal investigators Marijke van den Berg RODIN Rolf Ljung PedNet Clinical epidemiologists Kathelijn Fischer PedNet Johanna van der Bom RODIN Coordination Ella Smink PedNet/RODIN Registry Staff

    12. Inhibitor Development in PUPs or Minimally Blood Component-Treated Patients (MBCTPs) when Exposed to VWF/FVIII Concentrates and to rFVIII Concentrates: An Independent, International, Multicentre, Prospective, Controlled, Randomised, Open Label, Clinical Trial (Phase IV)

    13. Primary Objective To assess the immunogenicity of VWF/FVIII and of rFVIII concentrates by determining the frequency of inhibitor development in PUPs and MBCTs in the first 50 EDs or in the first 3 years from enrolment, whichever comes first.

    14. Secondary Objectives To evaluate clinical factors associated with inhibitor development: Age at 1° exposure, Tx modality (dose and regimen) Vaccinations, infections, CVC-related complications Type of delivery, breast-feeding… To evaluate laboratory factors associated with inhibitor development: FVIII gene defect FVIII:Ag VWF Ag & RCof

    15. Main Enrolment Criteria Males with severe hemophilia A (FVIII:C<1%), as confirmed by the central laboratory Any ethnicity Age <6 years Previously untreated (0 EDs to any FVIII concentrate or blood products), or Minimally exposed (<5 EDs) to blood components (whole blood, FFP, PRBC, platelets or cryoprecipitate) Negative inhibitor measurement at both local and central laboratory at screening

    16. Study Treatment Recombinant arm: Products belonging to the class of rFVIII concentrates, not containing VWF (Recombinate and Advate, Baxter; Kogenate, Bayer; Refacto AF, Wyeth) FVIII/VWF arm: Products belonging to the class of plasma-derived FVIII concentrates containing VWF (Alphanate and Fanhdi, Grifols; Emoclot, Kedrion; Factane, LFB)

    17. Sample Size: 300 patients

    18. Centralized Inhibitor Assay Modification of Nijmegen-Bethesda method In house-made buffered normal pooled plasma FVIII-deficient plasma with VWF present Positives repeated at multiple dilutions

    19. Inhibitor Monitoring Locally and at the central lab: every 3-4 EDs or every 3 mos, whichever comes first, until 20 EDs every 10 EDs or every 3 mos, whichever comes first, after 20 EDs in case of treatment failure or clinical suspicion inhibitor detection confirmed on a 2nd sample obtained within 2 weeks inhibitor titers monitored monthly for 6 mos. epitope analysis on stored samples

    20. FVIII Mutation Analysis Inversions of intron 22 and intron 1 in the FVIII gene are examined by PCR. The FVIII gene is sequenced in both directions by automated sequencer. The promoter, exons, intron-exon junctions, and the 3’ untranslated regions are examined.

    21. SIPPET Steering Committee Mannucci PM. Gringeri A. Aznar J. Chambost H. Goudemand J.

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