PMID- 30362288 OWN - NLM STAT- MEDLINE DCOM- 20200413 LR - 20230829 IS - 1538-7836 (Electronic) IS - 1538-7933 (Print) IS - 1538-7836 (Linking) VI - 17 IP - 1 DP - 2019 Jan TI - Phase 3 study of recombinant von Willebrand factor in patients with severe von Willebrand disease who are undergoing elective surgery. PG - 52-62 LID - 10.1111/jth.14313 [doi] AB - Essentials Recombinant von Willebrand factor (rVWF) is effective in von Willebrand disease (VWD). A phase 3 study of rVWF, with/without recombinant factor VIII (rFVIII) before surgery in VWD. Overall rVWF's efficacy was rated excellent/good; rVWF was administered alone in most patients. rVWF was well-tolerated and hemostasis was achieved in patients with severe VWD undergoing surgery. SUMMARY: Background Recombinant von Willebrand factor (rVWF) has demonstrated efficacy for on-demand treatment of bleeding in severe von Willebrand disease (VWD), warranting evaluation in the surgical setting. Objectives This study (NCT02283268) evaluated the hemostatic efficacy/safety profile of rVWF, with/without recombinant factor VIII (rFVIII), in patients with severe VWD undergoing surgery. Patients/Methods Patients received rVWF 40-60 IU kg(-1) , VWF ristocetin cofactor activity was measured 12-24 h before surgery. If endogenous FVIII activity (FVIII:C) target levels were achieved 3 h before surgery, rVWF was administered alone 1 h before surgery; rVWF was co-administered with rFVIII if target endogenous FVIII levels were not achieved. rVWF was infused postoperatively to maintain target trough levels. Overall and intraoperative hemostatic efficacy, the pharmacodynamics of rVWF administration and the incidence of adverse events (AEs) were assessed. Results All patients treated with rVWF for major (n = 10), minor (n = 4) and oral (n = 1) surgery had overall and intraoperative hemostatic efficacy ratings of excellent (73.3% and 86.7%) or good (26.7% and 13.3%). Most rVWF infusions (89.4%) were administered alone, resulting in hemostatically effective levels of endogenous FVIII within 6 h, which were sustained for 72-96 h; 70% (n = 7/10) of major surgeries were performed without rFVIII co-administration. Six patients reported 12 treatment-emergent AEs. Two patients each had one serious AE: diverticulitis (not treatment related) and deep vein thrombosis (sponsor-assessed as possibly treatment related). No severe allergic reactions or inhibitory antibodies were reported. Conclusions These data support the efficacy and safety profile of rVWF in patients with severe VWD undergoing elective surgery. CI - (c) 2018 Shire International GmbH Journal of Thrombosis and Haemostasis (c) 2018 International Society on Thrombosis and Haemostasis. FAU - Peyvandi, F AU - Peyvandi F AD - Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy. AD - Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy. FAU - Mamaev, A AU - Mamaev A AD - Regional State Budgetary Healthcare Institution "Regional Clinical Hospital", Barnaul, Altai Region, Russian Federation. FAU - Wang, J-D AU - Wang JD AD - Center for Rare Diseases and Hemophilia Center, Taichung Veterans General Hospital, Taichung, Taiwan. FAU - Stasyshyn, O AU - Stasyshyn O AD - SI Institute of Blood Pathology and Transfusion Medicine of NAMS of Ukraine, Lviv, Ukraine. FAU - Timofeeva, M AU - Timofeeva M AD - Federal State Budgetary Research Institution "Kirov Scientific and Research Institute of Hematology and Blood Transfusion of Federal Medico-Biological Agency of Russia", Kirov, Russian Federation. FAU - Curry, N AU - Curry N AD - The Oxford Haemophilia and Thrombosis Centre, Churchill Hospital and NIHR BRC, Blood Theme, Oxford, UK. FAU - Cid, A R AU - Cid AR AD - Hospital Universitario y Politecnico La Fe Hemostasia y Trombosis, Valencia, Spain. FAU - Yee, T T AU - Yee TT AD - Royal Free London NHS Foundation Trust, Katharine Dormandy Haemophilia and Thrombosis Centre, London, UK. FAU - Kavakli, K AU - Kavakli K AD - Ege Universitesi Tip Fakultesi Hematoloji Bilim Dali, Bornova, Izmir, Turkey. FAU - Castaman, G AU - Castaman G AD - Center for Bleeding Disorders and Coagulation, Department of Oncology, Careggi University Hospital, Florence, Italy. FAU - Sytkowski, A AU - Sytkowski A AD - Shire, Cambridge, MA, USA. LA - eng GR - Baxalta/International PT - Clinical Trial, Phase III PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't DEP - 20181220 PL - England TA - J Thromb Haemost JT - Journal of thrombosis and haemostasis : JTH JID - 101170508 RN - 0 (Coagulants) RN - 0 (Recombinant Proteins) RN - 0 (von Willebrand Factor) SB - IM CIN - J Thromb Haemost. 2019 Aug;17(8):1403-1405. PMID: 31058403 CIN - J Thromb Haemost. 2019 Aug;17(8):1405-1406. PMID: 31368219 MH - Adult MH - Aged MH - Blood Loss, Surgical/*prevention & control MH - Coagulants/*administration & dosage/adverse effects/pharmacokinetics MH - *Elective Surgical Procedures/adverse effects MH - Female MH - Hemostasis/*drug effects MH - Humans MH - Male MH - Middle Aged MH - Prospective Studies MH - Recombinant Proteins/administration & dosage MH - Severity of Illness Index MH - Time Factors MH - Treatment Outcome MH - Young Adult MH - von Willebrand Diseases/blood/complications/diagnosis/*drug therapy MH - von Willebrand Factor/*administration & dosage/adverse effects/pharmacokinetics PMC - PMC7379610 OTO - NOTNLM OT - clinical trial OT - general surgery OT - pharmacodynamics OT - von Willebrand disease OT - von Willebrand factor COIS- F. Peyvandi has worked as a consultant for Kedrion and Octapharma, received speaker fees for educational meetings at Ablynx and Shire, and is a member of advisory boards at Ablynx and F. Hoffmann-La Roche. A. Mamaev is the principal investigator on clinical trials at Baxalta, Octapharma, Generium, Hoffmann la Roche and Green Cross and has worked as lector providing educational background for physicians at Octapharma, Baxter, Hoffmann la Roche, CSL Behring and Generium. J.-D. Wang has received research funding from Shire and honoraria from Shire, Bayer and Novo Nordisk. O. Stasyshyn has worked as a consultant for Novo Nordisk and Pfizer. N. Curry has worked as a consultant for LFB and Bayer, has received research funding from CSL Behring, and serves as a member of Sobi's board of directors, speaker's bureau and advisory committee. R. Cid has received honoraria from Novo Nordisk, Shire and LFB. K. Kavakli has received honoraria from Shire, and is a member of an advisory board at Shire. G. Castaman has received research funding (directly to the institution) from Pfizer and CSL Behring, and has served as a member on the board of directors, speaker's bureau or advisory committee of CSL Behring, Shire, Bayer, Sobi, Novo Nordisk, Kedrion, Genzyme and Pfizer. A. Sytkowski was an employee of Shire US Inc. at the time of the study. M. Timofeeva and T.T. Yee declare that they have no conflict of interest. EDAT- 2018/10/27 06:00 MHDA- 2020/04/14 06:00 PMCR- 2020/07/24 CRDT- 2018/10/27 06:00 PHST- 2018/04/24 00:00 [received] PHST- 2018/10/27 06:00 [pubmed] PHST- 2020/04/14 06:00 [medline] PHST- 2018/10/27 06:00 [entrez] PHST- 2020/07/24 00:00 [pmc-release] AID - S1538-7836(22)03020-3 [pii] AID - JTH14313 [pii] AID - 10.1111/jth.14313 [doi] PST - ppublish SO - J Thromb Haemost. 2019 Jan;17(1):52-62. doi: 10.1111/jth.14313. Epub 2018 Dec 20.