Is pharmacokinetic-guided dosing of desmopressin and von Willebrand factor-containing concentrates in individuals with von Willebrand disease or low von Willebrand factor reliable and feasible? A protocol for a multicentre, non-randomised, open label cohort trial, the OPTI-CLOT: To WiN study
Heijdra, Jessica M.; Al Arashi, Wala; De Jager, Nico C.B.; Cloesmeijer, Michael E.; Bukkems, Laura H.; Zwaan, Christian M.; Leebeek, Frank W.G.; Mathôt, Ron A.A.; Cnossen, Marjon H.; Cnossen, M. H.; Leebeek, F. W.G.; Zwaan, Christian M.; Van Vliet, I.; Fijnvandraat, K.; Mathot, R. A.A.; Meijer, K.; Kruip, M. J.H.A.; S Polinder, Polinder; Coppens, M.; Tamminga, R. Y.J.; Meijer, K.; Laros-Van, B. A.P.; Brons, P.; Schols, S. E.M.; Van Der Meer, F. J.M.; Eikenboom, H. C.J.; Schutgens, R. E.G.; Fischer, K.; Heubel-Moenen, F.; Nieuwenhuizen, L.; Ypma, P.; Driessens, M. H.E.; Pw Collins, Collins; Liesner, R.; Chowdary, P.; Keeling, D.
(2022) BMJ Open, volume 12, issue 2, pp. 1 - 6
(Article)
Abstract
Introduction Von Willebrand disease (VWD) is a bleeding disorder, caused by a deficiency or defect of von Willebrand factor (VWF). In case of medical procedures or bleeding, patients are treated with desmopressin and/or VWF-containing concentrates to increase plasma VWF and factor VIII (FVIII). However, in many cases these factor levels
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are outside the targeted range. Therefore, population pharmacokinetic (PK) models have been developed, which aim to quantify and explain intraindividual and interindividual differences in treatment response. These models enable calculation of individual PK parameters by Bayesian analysis, based on an individual desmopressin test or PK profile with a VWF-containing concentrate. Subsequently, the dose necessary for an individual to achieve coagulation factor target levels can be calculated. Methods and analysis Primary aim of this study is to assess the predictive performance (the difference between predicted and measured von VWF activity and FVIII levels) of Bayesian forecasting using the developed population PK models in four different situations: (A) desmopressin testing (n≥30); (B) medical procedures (n=70; 30 receiving desmopressin, 30 receiving VWF-containing concentrate and 10 receiving a combination of both); (C) bleeding episodes (n=20; 10 receiving desmopressin and 10 receiving VWF-containing concentrate) and (D) prophylaxis with a VWF-containing concentrate (n=3 to 5). Individuals with all types of VWD and individuals with low VWF (VWF 0.30-0.60 IU/mL) will be included. Reliability and feasibility of PK-guided dosing will be tested by assessing predictive performance, treatment duration, haemostasis, patient satisfaction and physician satisfaction. Ethics and dissemination The OPTI-CLOT:to WiN study was approved by the medical ethics committee of the Erasmus MC, University Medical Centre Rotterdam, the Netherlands. Results of the study will be communicated through publication in international scientific journals and presentation at (inter)national conferences. Trial registration number NL7212 (NTR7411); Pre-results, EudraCT 2018-001631-46.
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Keywords: bleeding disorders & coagulopathies, clinical trials, protocols & guidelines, Reproducibility of Results, Multicenter Studies as Topic, Deamino Arginine Vasopressin, Humans, Bayes Theorem, von Willebrand Diseases/drug therapy, von Willebrand Factor, General Medicine, Research Support, Non-U.S. Gov't, Journal Article
ISSN: 2044-6055
Publisher: BMJ Publishing Group
Note: Funding Information: Competing interests JMH has received an award from CSL Behring outside the submitted work. CMZ had received research grants from Pfizer, Celgene, Daiichi-Sankyo and is a consultant for Incyte, Sanofi and Pfizer. FWGL has received unrestricted research grants from CSL Behring, Takeda and uniQure, and is consultant for Takeda, uniQure and Biomarin. He is DSMB member for a study sponsored by Roche. RAAM has received travel grants from Shire and Bayer. MHC has received grants from governmental research institutes such as NWO, ZonMW, Innovation fund, institutional grants and unrestricted investigator research grants/ educational and travel funding from the following companies over the years: Pfizer, Baxter/Baxalta/Shire, Bayer Schering Pharma, CSL Behring, Sobi Biogen, Novo Nordisk, Novartis and Nordic Pharma, and has served as a member on steering boards of Roche, Bayer and Octapharma. The remaining authors declare no competing financial interests. All unrestricted research grants, awards, educational grants and consultancy fees of all authors were forwarded to the respective institutions. Publisher Copyright: ©
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