Von Willebrand Disease Minimize Menorrhagia (VWDMin) Trial

摘要 血管性血友病(VWD)是最常见的先天性出血性疾病，发生在1%的 人群中有症状的占0.1%。VWD是由von Willebrand因子(VWF)缺陷或缺陷引起的， 12号染色体上编码的一种多聚体蛋白，导致粘膜出血。在患有VWD的女性中， 月经过多是最常见的症状，发生在80%-90%，并与缺铁有关，减少 身体和认知功能、焦虑、抑郁和生活质量差。目前荷尔蒙和非荷尔蒙 激素治疗受到无效和不耐受的限制，而且几乎没有随机试验可以用来 指导治疗。目前治疗月经过多的非激素性药物氨甲环酸(LYSTEDA®，TA)是 50%的患者受到恶心的限制，30%的患者激素治疗无效，20%的患者耐受性差。因此， VWD女性月经过多缺乏安全有效的治疗是一个主要的公共卫生问题 有问题。一种新的重组von Willebrand因子(Vonveni®，rVWF)，具有更高的效力、纯度和 半衰期，已被证明是安全和有效的治疗VWD患者的出血，并且是 目前正在接受FDA的审查。然而，用于全身出血的剂量和频率不适用于 月经过多。在一项对101名患有VWD的妇女的调查和文献综述中，VWF的使用源自血浆 (PdVWF)或重组(RVWF)，导致月经失血量减少95%以上，且无不良反应 事件。然而，VWF的最佳剂量、频率和可接受性需要静脉注射， 尚未在月经过多的女性身上得到证实。我们假设静脉注射重组von 出血第1天应用Willebrand因子(RVWF)比第1-5天口服氨甲环酸(TA)更有效 在连续两个月经周期中的每一个月经周期出血，以减少月经过多和提高生活质量， 尽管它的成本和静脉给药途径较高。 因此，拟议的Collaborative R01 Investigator发起的多站点临床试验设计于 对融资机会公告的回应PAR-13-128作为多中心预期、随机、 交叉第三阶段临床试验，Von Willebrand最小化(VWDMin)试验，其目的是 评估rVWF在减少VWD妇女月经过多方面是否优于TA 连续两个月经周期，每次超过24周。该试验由伊利诺伊大学临床协调 匹兹堡和匹兹堡研究中心医疗数据中心(CRHC DC)的数据协调是可行的 因为1)试验设计已经针对这一罕见人群进行了优化；2)结构化访谈表明医生 和家长对试验概念的接受；3)指导委员会表示一致同意 研究药物的选择和剂量；4)调查表明有足够的血友病治疗中心(HTCs) 以及符合条件的受试者进行试验。这一概念影响很大，因为它解决了最大的未得到满足的问题 VWD女性的医疗需求，如果有效，将改变做法。 月经过多用图画血液评估表(PBAC)进行评估。安全性、耐受性和 可接受性将通过a)对研究药物或救援无反应的月经周期频率来衡量， 记录在患者日记中；b)周期严重程度分级；c)周期长度；以及d)生活质量问卷和 满意度调查。对研究治疗的反应将通过VWF分析和基因分型进行比较。

ABSTRACT Von Willebrand disease (VWD) is the most common congenital bleeding disorder, occurring in 1% of the population and symptomatic in 0.1%. VWD is caused by defective or deficient von Willebrand factor (VWF), a multimeric protein encoded for on chromosome 12, which results in mucosal bleeding. In women with VWD, menorrhagia is the most common symptom, occurring in 80-90% and associated with iron deficiency, reduced physical and cognitive function, anxiety, depression, and poor quality of life. Current hormonal and non- hormonal therapies are limited by ineffectiveness and intolerance, and few randomized trials are available to guide treatment. The current non-hormonal agent of choice for menorrhagia, tranexamic acid (Lysteda®, TA) is limited by nausea in 50%, and hormonal therapy is ineffective in 30% and poorly tolerated in 20%. Thus, the lack of safe, effective treatment for menorrhagia in women with VWD constitutes a major public health problem. A new recombinant von Willebrand factor (Vonvendi®, rVWF), with improved potency, purity, and half-life, has been shown to be safe and effective in the treatment of bleeds in individuals with VWD, and is currently under review by the FDA. However, the dose and frequency used for general bleeds do not apply to menorrhagia. In a survey and literature review of 101 women with VWD, the use of VWF, plasma-derived (pdVWF) or recombinant (rVWF), resulted in reduced menstrual blood loss in over 95% with no adverse events. Yet, the optimal dose, frequency, and acceptability of VWF, which requires intravenous administration, have not been established in women with menorrhagia. We hypothesize that intravenous recombinant von Willebrand factor (rVWF) on day 1 of bleeding is more effective than oral tranexamic acid (TA) on day 1-5 of bleeding, on each of two consecutive menstrual cycles, in reducing menorrhagia and improving quality of life, despite its higher cost and intravenous route of administration. The proposed Collaborative R01 Investigator-Initiated Multi-Site Clinical Trial, therefore, is designed in response to Funding Opportunity Announcement PAR-13-128 as a multi-center prospective, randomized, crossover Phase III clinical trial, Von Willebrand Minimize (VWDMin) Trial, the purpose of which is to evaluate if rVWF is superior to TA in reducing menorrhagia in women with VWD when given during bleeding in two consecutive menstrual cycles each over 24 weeks. The trial, with clinical coordination by the University of Pittsburgh and data coordination by Pitt’s Center for Research Healthcare Data Center (CRHC DC) is feasible as 1) the trial design has been optimized for this rare population; 2) structured interviews indicate physician and parent acceptance of the trial concept; 3) the Steering Committee indicated unanimous consensus on study drug choice and dosing; and 4) surveys indicate there are sufficient hemophilia treatment centers (HTCs) and eligible subjects to conduct the trial. The concept is high-impact as it addresses the greatest unmet healthcare need in women with VWD, and, if effective, will be practice-changing. Menorrhagia will be assessed by pictorial blood assessment chart, PBAC. Safety, tolerability and acceptability will be measured by a) frequency of menstrual cycles unresponsive to study drug or rescue, recorded in a patient diary; b) cycle severity rating; c) cycle length; and d) quality-of-life questionnaires and satisfaction survey. Response to study treatment will be compared by VWF assays and genotype.