title: Hemostatic efficacy, safety, and pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand disease.
abstract: This phase 3 trial evaluated the safety and hemostatic efficacy of a recombinant von Willebrand factor (rVWF) for treatment of bleeds in severe von Willebrand disease (VWD). rVWF was initially administered together with recombinant factor VIII (rFVIII) and subsequently alone, as long as hemostatic factor VIII activity (FVIII : C) levels were maintained. Pharmacokinetics (PK) were evaluated in a randomized cross-over design (rVWF vs rVWF:rFVIII at 50 IU VWF:ristocetin cofactor activity [RCo]/kg). Bleed control for all treated bleeds (N = 192 bleeds in 22 subjects) was rated good or excellent (96.9% excellent; 119 of 122 minor, 59 of 61 moderate, and 6 of 7 major bleeds) on a 4-point scale (4 = none to 1 = excellent). A single infusion was effective in 81.8% of bleeds. Treatment success, defined as the number of subjects with a mean efficacy rating of <2.5, was 100%. The PK profile of rVWF was not influenced by rFVIII (mean VWF:RCo terminal half-life: 21.9 hours for rVWF and 19.6 hours for rVWF:rFVIII). FVIII : C levels increased rapidly after rVWF alone, with hemostatic levels achieved within 6 hours and sustained through 72 hours after infusion. Eight adverse events (AEs; 6 nonserious AEs in 4 subjects and 2 serious AEs [chest discomfort and increased heart rate, without cardiac symptomatology] concurrently in 1 subject) were associated with rVWF. There were no thrombotic events or severe allergic reactions. No VWF or FVIII inhibitors, anti-VWF binding antibodies, or antibodies against host cell proteins were detected. These results show that rVWF was safe and effective in treating bleeds in VWD patients and stabilizes endogenous FVIII : C, which may eliminate the need for rFVIII after the first infusion. This trial was registered at www.clinicaltrials.gov as #NCT01410227.
authors.affiliation: Blood Center of Wisconsin, Milwaukee, WI; Medical College of Wisconsin, Milwaukee, WI;
authors.forename: Joan C
authors.initials: JC
authors.lastname: Gill
authors.affiliation: Department of Hematology, San Bortolo Hospital, Vicenza, Italy; University Hospital, Center for Bleeding Disorders, Florence, Italy;
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Castaman
authors.affiliation: Institute of Hematology and Transfusion Medicine, Warsaw, Poland;
authors.forename: Jerzy
authors.initials: J
authors.lastname: Windyga
authors.affiliation: University of Rochester School of Medicine, Rochester, NY; Mary Gooley Hemophilia Center, Rochester, NY;
authors.forename: Peter
authors.initials: P
authors.lastname: Kouides
authors.affiliation: University of Pittsburgh, Pittsburgh, PA; Hemophilia Center of Western Pennsylvania, Pittsburgh, PA;
authors.forename: Margaret
authors.initials: M
authors.lastname: Ragni
authors.affiliation: Erasmus University Medical Center, Rotterdam, The Netherlands;
authors.forename: Frank W G
authors.initials: FW
authors.lastname: Leebeek
authors.affiliation: Baxalta Innovations, GmbH, Vienna, Austria; and.
authors.forename: Ortrun
authors.initials: O
authors.lastname: Obermann-Slupetzky
authors.affiliation: Baxalta Innovations, GmbH, Vienna, Austria; and.
authors.forename: Miranda
authors.initials: M
authors.lastname: Chapman
authors.affiliation: Baxalta Innovations, GmbH, Vienna, Austria; and.
authors.forename: Sandor
authors.initials: S
authors.lastname: Fritsch
authors.affiliation: Baxalta Innovations, GmbH, Vienna, Austria; and.
authors.forename: Borislava G
authors.initials: BG
authors.lastname: Pavlova
authors.affiliation: Baxalta Innovations, GmbH, Vienna, Austria; and.
authors.forename: Isabella
authors.initials: I
authors.lastname: Presch
authors.affiliation: Baxalta US Inc, Cambridge, MA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Ewenstein
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001780:Blood Coagulation Tests; D018592:Cross-Over Studies; D005260:Female; D005500:Follow-Up Studies; D006207:Half-Life; D006490:Hemostatics; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011446:Prospective Studies; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D055815:Young Adult; D014842:von Willebrand Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014841:von Willebrand Factor / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D006490:Hemostatics; D011994:Recombinant Proteins; D014841:von Willebrand Factor