Gill Joan C, Castaman Giancarlo, Windyga Jerzy, Kouides Peter, Ragni Margaret, Leebeek Frank W G, Obermann-Slupetzky Ortrun, Chapman Miranda, Fritsch Sandor, Pavlova Borislava G, Presch Isabella, Ewenstein Bruce
Blood Center of Wisconsin, Milwaukee, WI; Medical College of Wisconsin, Milwaukee, WI;
Department of Hematology, San Bortolo Hospital, Vicenza, Italy; University Hospital, Center for Bleeding Disorders, Florence, Italy;
Blood. 2015 Oct 22;126(17):2038-46. doi: 10.1182/blood-2015-02-629873. Epub 2015 Aug 3.
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.
这项3期试验评估了重组血管性血友病因子（rVWF）治疗重度血管性血友病（VWD）出血的安全性和止血疗效。rVWF最初与重组凝血因子VIII（rFVIII）联合给药，随后单独给药，只要止血因子VIII活性（FVIII:C）水平得以维持。采用随机交叉设计（50 IU血管性血友病因子：瑞斯托霉素辅因子活性[RCo]/kg剂量下的rVWF与rVWF:rFVIII）评估药代动力学（PK）。所有接受治疗的出血事件（22名受试者中192次出血）的止血控制情况在4分制量表（4 =无出血至1 =极佳）上被评为良好或极佳（96.9%为极佳；122次轻微出血中的119次、61次中度出血中的59次以及7次严重出血中的6次）。单次输注对81.8%的出血有效。治疗成功定义为平均疗效评分为<2.5的受试者数量，成功率为100%。rVWF的PK曲线不受rFVIII影响（平均血管性血友病因子：RCo终末半衰期：rVWF为21.9小时，rVWF:rFVIII为19.6小时）。单独使用rVWF后，FVIII:C水平迅速升高，输注后6小时内达到止血水平，并持续至72小时。8例不良事件（AE；4名受试者中有6例非严重AE，1名受试者同时出现2例严重AE[胸部不适和心率加快，无心脏症状]）与rVWF相关。未发生血栓事件或严重过敏反应。未检测到血管性血友病因子或FVIII抑制剂、抗血管性血友病因子结合抗体或针对宿主细胞蛋白的抗体。这些结果表明，rVWF治疗VWD患者出血安全有效，并能稳定内源性FVIII:C，这可能在首次输注后无需再使用rFVIII。该试验已在www.clinicaltrials.gov注册，编号为#NCT01410227。
