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， 人群中有症状的占0.1%。VWD是由血管性血友病因子（VWF）缺陷或缺乏引起的， 一种在12号染色体上编码的多聚体蛋白，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，发生率为80-90%，与缺铁有关， 身体和认知功能，焦虑，抑郁和生活质量差。目前的激素和非- 激素疗法因无效和不耐受而受到限制，很少有随机试验可用于 指导治疗。目前用于月经过多的非激素药物氨甲环酸（Lysteda®，TA）是 50%受恶心限制，30%激素治疗无效，20%耐受性差。因此 缺乏安全、有效治疗女性外阴残割症的方法是一个主要的公共卫生问题 问题.一种新的重组血管性血友病因子（Vonvendi®，rVWF），具有改善的效力、纯度和生物学活性。 半衰期，已被证明是安全和有效的治疗出血的个人与VWD， 目前正在接受FDA的审查。然而，用于一般出血的剂量和频率不适用于 月经过多。在对101名VWD妇女的调查和文献回顾中， （pdVWF）或重组（rVWF），导致超过95%的月经失血量减少，无不良反应。 事件然而，VWF的最佳剂量，频率和可接受性，需要静脉给药， 在月经过多的妇女中尚未确立。我们假设静脉注射重组von 出血第1天的Willebrand因子（rVWF）比出血第1-5天的口服氨甲环酸（TA）更有效。 在连续两个月经周期中的每一个月经周期中，减少月经过多和改善生活质量， 尽管其成本较高且静脉内给药途径。 因此，拟定的协作R 01研究者发起的多中心临床试验设计如下： 对资金机会公告PAR-13-128的回应，作为一项多中心前瞻性，随机， 交叉III期临床试验，Von Willebrand Minimize（VWDMin）试验，其目的是 评估在出血期间给予rVWF是否在减少VWD女性月经过多方面上级TA， 连续两个月经周期，每个周期超过24周。该试验，与临床协调的大学， 匹兹堡和皮特的研究中心医疗保健数据中心（CRHC DC）的数据协调是可行的 因为1）试验设计已针对这一罕见人群进行了优化; 2）结构化访谈表明， 和家长接受试验概念; 3）指导委员会表示一致同意， 研究药物选择和给药;和4）调查表明有足够的血友病治疗中心（HTC） 和合格的受试者进行试验。这一概念具有高度影响力，因为它解决了最大的未满足问题 VWD妇女的医疗保健需求，如果有效，将改变实践。 将通过图形血液评估表（PBAC）评估月经过多。安全性、耐受性和 可接受性将通过a）对研究药物或补救无反应的月经周期的频率， 记录在患者日记中; B）周期严重程度评级; c）周期长度;和d）生活质量问卷，以及 满意度调查将通过VWF测定和基因型比较对研究治疗的应答。

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.