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  • Desmopressin treatment combined with clotting factor VIII concentrates in patients with non-severe haemophilia A: protocol for a multicentre single-armed trial, the DAVID study

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Haematology (incl blood transfusion)
Protocol
Desmopressin treatment combined with clotting factor VIII concentrates in patients with non-severe haemophilia A: protocol for a multicentre single-armed trial, the DAVID study
  1. Lisette M Schütte1,
  2. Marjon H Cnossen2,
  3. Reinier M van Hest3,
  4. Mariette H E Driessens4,
  5. Karin Fijnvandraat5,6,
  6. Suzanne Polinder7,
  7. Erik A M Beckers8,
  8. Michiel Coppens9,
  9. Jeroen Eikenboom10,
  10. Britta A P Laros-van Gorkom11,
  11. Karina Meijer12,
  12. Laurens Nieuwenhuizen13,
  13. Evelien P Mauser-Bunschoten14,
  14. Frank W G Leebeek1,
  15. Ron A A Mathôt3,
  16. Marieke J H A Kruip1
  1. 1 Department of Haematology, Erasmus University Medical Centre, Rotterdam, The Netherlands
  2. 2 Department of Paediatric Haematology, Erasmus University Medical Centre-Sophia Children’s Hospital, Rotterdam, The Netherlands
  3. 3 Department of Hospital Pharmacy–Clinical Pharmacology Unit, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
  4. 4 Netherlands Haemophilia Patient Society, (NVHP), Nijkerk, The Netherlands
  5. 5 Department of Paediatric Haematology, Amsterdam UMC, Emma Children’s Hospital, Amsterdam, The Netherlands
  6. 6 Department of Plasma Proteins, Sanquin Research, Amsterdam, The Netherlands
  7. 7 Department of Public Health, Erasmus University Medical Centre, Rotterdam, The Netherlands
  8. 8 Department of Haematology, Maastricht University Medical Centre, Maastricht, The Netherlands
  9. 9 Department of Vascular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
  10. 10 Department of Thrombosis and Haemostasis, Leids Universitair Medisch Centrum, Leiden, The Netherlands
  11. 11 Department of Haematology, Radboud University Medical Centre, Nijmegen, The Netherlands
  12. 12 Department of Haematology, Universitair Medisch Centrum Groningen, Groningen, The Netherlands
  13. 13 Department of Haematology, Maxima Medical Centre, Eindhoven, Eindhoven, Noord-Brabant, The Netherlands
  14. 14 Van Creveldclinic, University Medical Centre Utrecht, Utrecht, The Netherlands
  1. Correspondence to Dr Marieke J H A Kruip; m.kruip{at}erasmusmc.nl

Abstract

Introduction Haemophilia A is an inherited bleeding disorder characterised by factor VIII (FVIII) deficiency. In patients with non-severe haemophilia A, surgery and bleeding are the main indications for treatment with FVIII concentrate. A recent study reported that standard dosing frequently results in FVIII levels (FVIII:C) below or above FVIII target ranges, leading to respectively a bleeding risk or excessive costs. In addition, FVIII concentrate treatment carries a risk of development of neutralising antibodies. An alternative is desmopressin, which releases endogenous FVIII and von Willebrand factor. In most patients with non-severe haemophilia A, desmopressin alone is not enough to achieve FVIII target levels during surgery or bleeding. We hypothesise that combined pharmacokinetic (PK)-guided administration of desmopressin and FVIII concentrate may improve dosing accuracy and reduces FVIII concentrate consumption.

Methods and analysis In the DAVID study, 50 patients with non-severe haemophilia A (FVIII:C ≥0.01 IU/mL) with a bleeding episode or undergoing surgery will receive desmopressin and FVIII concentrate combination treatment. The necessary dose of FVIII concentrate to reach FVIII target levels after desmopressin administration will be calculated with a population PK model. The primary endpoint is the proportion of patients reaching FVIII target levels during the first 72 hours after start of the combination treatment. This approach was successfully tested in one pilot patient who received perioperative combination treatment.

Ethics and dissemination The DAVID study was approved by the medical ethics committee of the Erasmus MC. Results of the study will be communicated trough publication in international scientific journals and presentation at (inter)national conferences.

Trial registration number NTR5383; Pre-results.

  • haemophilia A
  • desmopressin
  • fviii concentrate
  • surgery
  • pharmacokinetic modelling

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

https://doi.org/10.1136/bmjopen-2018-022719

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    Footnotes

    • Contributors MJHAK, MHC, FWGL and RAAM designed the study and critically revised the manuscript. LMS, SP and RMvH wrote the manuscript and refined the study design. MHED, KF, EAMB, MC, JE, BAPL-vG, KM, LN and EPM-B critically revised the manuscript and refined the study design.

    • Funding This work was supported by ZonMw, (grant number 836031003), the Dutch organisation for Health Research and Development.

    • Competing interests LMS: received reimbursement from CSL-Behring for attending a symposium, not related to this study. MHC: received unrestricted research/educational funding for various projects as well as travel fees from the following institutions and companies: ZonMW, Innovatiefonds, Pfizer, Baxalta/Shire, Bayer Schering Pharma, Novo Nordisk, Novartis, Roche and CSL Behring, all not related to this study. RMvH, EAMB, MC, MHED, LN, SP: nothing to disclose relevant to the DAVID study. KF: is a member of the European Hemophilia Treatment and Standardization Board sponsored by Baxter, has received unrestricted research grants from CSL Behring and Bayer and has given lectures at educational symposiums organized by Pfizer, Bayer and Baxter. JE: received research funding from CSL Behring and honorarium for educational activity from Roche, not related to this study. BAPL-vG: received unrestricted educational grants from Baxter and CSL Behring and speaker fees from Sanquin. KM: research support from Bayer, Sanquin and Pfizer; speaker fees from Bayer, Sanquin, Boehringer Ingelheim, BMS and Aspen; consulting fees from Uniqure, not related to this study; FWGL: received unrestricted research grants from CSL-Behring and Baxalta/Shire not related to this study. He is consulant for Shire, NovoNordisk and UniQure. Fees go to the university. RAAM: received personal fees from Merck Sharp & Dohme and Zeria and grants from Bayer, UCB Pharma and Hoffman La Roche with no involvement in this study. MJHAK: received unrestricted research grants from Pfizer, Innovatiefonds and Ferring with no involvement in this study.

    • Ethics approval Medical Ethics Committee of the Erasmus University Medical Centre Rotterdam, the Netherlands.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Correction notice This article has been corrected since it first published online. The open access licence type has been amended.

    • Patient consent for publication Obtained.