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

IntroductionVon 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). Howev...

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Published in:	BMJ open Vol. 12; no. 2; p. e049493
Main Authors:	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, MH, Leebeek, FWG, Fijnvandraat, K, Mathôt, RAA, Meijer, K, Kruip, MJHA, Polinder, S, Coppens, M, Tamminga, RYJ, Laros-van Gorkom, BAP, Brons, P, Schols, SEM, van der Meer, FJM, Eikenboom, HCJ, Schutgens, REG, Fischer, K, Heubel-Moenen, F, Nieuwenhuizen, L, Ypma, P, Driessens, MHE, Zwaan, CM, van Vliet, I, Collins, PW, Liesner, R, Chowdary, P, Keeling, D, Lock, J, Hazendonk, HCAM, van Moort, I, Preijers, T, Heijdra, JM, de Jager, NCB, Goedhart, MCHJ, Bukkems, LH, Al Arashi, W, Cloesmeijer, ME, Janssen, A
Format:	Journal Article
Language:	English
Published:	England British Medical Journal Publishing Group 15-02-2022 BMJ Publishing Group LTD BMJ Publishing Group
Series:	Protocol
Subjects:	Bayes Theorem bleeding disorders & coagulopathies clinical trials Consent Deamino Arginine Vasopressin Disease prevention Drug dosages Haematology (incl blood transfusion) Hemophilia Humans Multicenter Studies as Topic Patient satisfaction Patients Pharmacokinetics Plasma Population protocols & guidelines Reproducibility of Results Surgery von Willebrand Diseases - drug therapy von Willebrand Factor Netherlands protocols & guidelines clinical trials bleeding disorders & coagulopathies
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Summary:	IntroductionVon 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 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 analysisPrimary 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 disseminationThe 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 numberNL7212 (NTR7411); Pre-results, EudraCT 2018-001631-46.
Bibliography:	Protocol ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Undefined-3
ISSN:	2044-6055 2044-6055
DOI:	10.1136/bmjopen-2021-049493