Abstract

Optimal dosing to prevent excessive surgical bleeding in VWD is being investigated in an ongoing prospective, uncontrolled, open-labeled study to establish the safety and efficacy of replacement therapy with a VWF/FVIII concentrate (Humate-P®). This protocol-defined interim analysis describes the results in the first eighteen (18) patients (6 males, 12 females) of a total of 30 planned. Seven patients had Type 1 VWD, 6 had Type 2 (2 with 2A, 3 with 2B, 1 with 2M), and 5 had Type 3. All patients had pre-operative pharmacokinetic assessments to individualize the loading and maintenance doses of VWF/FVIII concentrate utilized for surgery. Fourteen patients had major surgical procedures including neurosurgery, joint replacement, tonsillectomy and complete oral restoration; three had minor procedures; and one had oral surgery. Hemostatic efficacy was assessed by investigators on a four-point scale (excellent, good, moderate/poor, none) immediately after surgery, 24 hours after the last VWF/FVIII concentrate infusion, and 14 days post-op. Good and excellent efficacy were combined into one endpoint of effective hemostasis. Expected estimated blood loss (EBL) was defined prior to the procedure, and actual EBL was recorded post-op. Adverse events were collected throughout the trial until follow-up 4 weeks post-op. Hemostasis was effective in 17/18 patients (94.4%) immediately after surgery; in 17/17 patients (100%) 24 hours after the last VWF/FVIII conc infusion; and in 18/18 (100%) patients 14 days after surgery. Median actual EBL did not exceed expected EBL in any surgery category. Four patients received transfusions (one for pre-existing anemia, three for serious adverse events). Loading doses of VWF/FVIII concentrate ranged from 36 to 135 IU/kg. Maintenance doses were determined by daily monitoring of plasma coagulation factor levels. Median durations of treatment were 2 days for oral surgery, and 4 days for both minor and major surgery. Post-op nausea (n=5) and fever (n=3) were the most commonly reported adverse events. Nausea, headache, and dizziness were considered possibly related to VWF/FVIII concentrate in one patient each; these events were mild in severity and resolved without sequelae. Bleeding-related serious adverse events were reported in three patients: one with GI bleeding post-laparoscopic gastro-jejunal bypass; one with post-craniotomy subdural and intracranial bleeding; and one with post-hysteroscopy/dilatation & curettage hemorrhage followed by hysterectomy. Hemostasis was considered effective in these 3 by the investigators, and in 2 patients by an independent DSMB review; hemostasis was considered ineffective by the DSMB only in the patient with post-hysteroscopy bleeding. No thromboembolic complications or changes in viral titers were observed. This analysis supports VWF/FVIII concentrate safety and efficacy to prevent excessive bleeding during and after a range of surgical procedures in patients with VWD. Enrollment in the trial continues.

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