3 型冯维勒布兰德国际注册抑制剂前瞻性研究 (3WINTERS-IPS)
2024年12月23日 更新者：Fondazione Angelo Bianchi Bonomi
3 型冯维勒布兰德病 (VWD3) 的国际注册和前瞻性研究，旨在评估出血的数量、类型和危险因素，以及用于治疗 VWD 的血浆衍生和/或重组冯维勒布兰德因子 (VWF) 浓缩物的有效性和安全性患者。
研究概览
详细说明
冯维勒布兰德病 (VWD) 是最常见的遗传性出血性疾病，其特征是冯维勒布兰德因子 (VWF) 的定量和/或定性缺陷，VWF 在止血的早期阶段起着重要作用。 3 型冯维勒布兰德病 (VWD3) 是由于几乎完全缺乏 VWF，因此也被描述为“严重 VWD”。 复发性胃肠道出血 (GIB) 是 VWD 患者治疗中遇到的最具挑战性的并发症之一。 最常见的原因是血管发育不良 (ANGDYS)，但由于难以做出诊断，通常无法确定原因。 近年来，多个实验室的研究已经确定了 VWF 在控制血管功能方面的多重作用。 在全球范围内，这些发现为 VWD 患者存在 ANGDYS 提供了第一个可能的解释。 这些胃肠道 (GI) 血管畸形的特征是粘膜血管脆弱、渗漏。 结合止血功能障碍，这些可导致严重的顽固性出血，包括胃肠道出血。 VWD3 作为隐性特征遗传，杂合子亲属有轻微或无出血症状。 即使 VWD3 的患病率很低，伊朗的患病率最高，南欧的患病率最低。 然而，由于缺乏回顾性或前瞻性研究，VWD3 的实际患病率在大多数国家仍然未知。 尽管罕见，但 VWD3 由于其严重的临床表现、需要用血浆衍生和/或重组 VWF 浓缩物进行替代治疗以及输注 VWF 浓缩物后出现抗 VWF 抑制剂的风险而引起了人们的极大兴趣，为此风险因素尚未系统地确定。
该研究的主要目标是：在欧洲和伊朗的中心之间建立一个国际网络（比例为 1:1），使用公共在线数据库前瞻性地招募至少 250 名 VWD3 患者，收集有关既往出血和暴露的详细信息血浆衍生和/或重组 VWF 浓缩物，使用通过共同问卷计算的 VWD3 出血严重程度评分，收集所有已识别的 VWD3 患者的血浆和 DNA 样本进行集中分析，确认当地 VWD3 诊断使用集中测试，通过常用方法评估 VWF 基因缺陷、VWF 表型和抗 VWF 抑制剂的风险，评估表型结果（包括血管生成标志物）与 GIB 发生之间的潜在相关性，客观评估 VWD3 中 GIB 的严重程度患者，评估 VWD3 患者的出血频率和部位，随访 2 个前瞻性观察期（每个 2 年：2017-2018 年和 2020-2022 年），对使用的血浆衍生和/或重组 VWF 浓缩物的疗效评估在 2 个前瞻性观察期（每个 2 年：2017-2018 年和 2020-2022 年）期间使用最客观的疗效标准治疗 VWD3（按需与预防），评估血浆衍生和/或重组的疗效和安全性与在标准临床环境中使用抗血管生成剂相比，VWF 在 2 个前瞻性观察期（每个 2 年：2017-2018 年和 2020-2022 年）期间专注于 GIB 的治疗。
为此，将使用同质和标准化标准招募至少 250 名诊断为 VWD3 的患者。
为实现项目目标而计划开展的工作将分为三个部分：
- 第一部分涉及登记和收集回顾性临床和实验室数据的标准化标准，由中央实验室确认；
- 第二部分涉及在回顾阶段收集的临床和实验室参数的进一步表征，包括抗 VWF 抑制剂的流行、进一步鉴定 VWD3 的高级实验室测试、VWF 基因的突变分析；
- 第三部分研究分为两部分：第一前瞻性观察和第二前瞻性观察。 第三部分首次涉及大型 VWD3 患者队列的前瞻性临床观察，这些患者之前均由国际专家小组进行了很好的表征。
研究类型
观察性的
注册 (实际的)
265
联系人和位置
本节提供了进行研究的人员的详细联系信息，以及有关进行该研究的地点的信息。
学习地点
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Ahvaz、伊朗伊斯兰共和国
- Ahvaz Jundishpur University of Medical Sciences - Research Center for Thalassemia & Hemoglobinopathy - Division of Hematology & Oncology
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Esfahan、伊朗伊斯兰共和国
- Seid-ol-Shohada Hospital - Hemophilia Center - Esfahan University of Medical Science
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Mashhad、伊朗伊斯兰共和国
- Hemophilia- Thalassaemia Center of Mashhad (Sarvar Clinic) - Mashad University of Medical Science
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Shiraz、伊朗伊斯兰共和国
- Nemazee Hospital Hemophilia Center - Shiraz University of Medical Science
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Tehran、伊朗伊斯兰共和国
- Iranian Hemophilia Comprehensive Treatment Centre - Iranian Hemophilia Society
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Tehran、伊朗伊斯兰共和国
- Mofid Comprehensive Care Centre for Children with Hemophilia - Shahid Beheshti University of Medical Science
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Tehran、伊朗伊斯兰共和国
- Thrombosis Hemostasis Research Center - Vali-Asr Hospital - Emam Khmeini Complex Hospital - Tehran University of Medical Science
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Budapest、匈牙利、1097
- St. Istvan & St. Laszlo Hospital of Budapest - Hematology and Stem Cell Transplantation
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Bonn、德国、53127
- University Clinic Bonn - Institute of Experimental Haematology & Transfusion Medicine
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Hamburg、德国、20246
- University Children's Hospital - Department of Pediatric Hematology and Oncology
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Hannover、德国、30625
- Department of Haematology, Haemostasis, Oncology and Stem Cell Transplantation - Hannover Medical School - Haemophilia Care Centre
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Bari、意大利、70124
- Azienda Ospedaliera Policlinico Consorziale di Bari - Unità Operativa Semplice di Emostasi e Trombosi
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Firenze、意大利、50141
- Azienda Ospedaliera Universitaria Careggi - Agenzia per l'Emofilia - Centro di Riferimento Coagulopatie Congenite
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Milano、意大利、20122
- Centro Emofilia e Trombosi - Fondazione Angelo Bianchi Bonomi - IRCCS Ospedale Ca' Granda - Dip. di Medicina Interna - Università degli Studi di Milano
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Roma、意大利、00161
- Dipartimento di Biotecnologie Cellulari ed Ematologia - Università "Sapienza" di Roma - Policlinico Umberto I
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Vicenza、意大利、36100
- Dipartimento di Terapie Cellulari ed Ematologia - Centro Malattie Emorragiche e Trombotiche - Ospedale San Bortolo
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Lille Cedex、法国、59037
- Institut d'Hématologie - Hôpital Cardiologique - University of Lille - Haematology Department
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Nantes Cedex 1、法国、44093
- Centre Régional de Traitement de l'Hémophilie - Laboratoire d'Hématologie
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Malmö、瑞典、205 02
- Lund University - Centre for Thrombosis and Haemostasis - Skane University Hospital
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Helsinki、芬兰、FIN-00029 HUS
- Helsinki University Central Hospital, Department Internal Medicine, Coagulation Disorders, at Haematology and Laboratory Services
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Manchester、英国、M13 9WL
- Central Manchester University Hospital NHS Foundation Trust - Manchester Royal Infirmary - Manchester Royal Eye Hospital
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Leiden、荷兰、2333
- Leiden University Medical Center - Department of Hematology - Hemostasis and Thrombosis Center
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Rotterdam、荷兰、3015
- Erasmus Medical Center - Department of Hematology
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A Coruña、西班牙、15006
- Complejo Hospitalario Universitario de A Coruña - Servicio de Hematología y Hemoterapia
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Barcelona、西班牙、08035
- Hospital Universitari General Vall d'Hebron - Unidad de Hemofilia
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参与标准
研究人员寻找符合特定描述的人，称为资格标准。这些标准的一些例子是一个人的一般健康状况或先前的治疗。
资格标准
适合学习的年龄
- 孩子
- 成人
- 年长者
接受健康志愿者
不
取样方法
非概率样本
研究人群
一大群诊断为 3 型冯维勒布兰德病 (VWD3) 的患者使用同质和标准化标准在欧洲和伊朗登记。
描述
纳入标准：
- 任何年龄的男性和女性，包括婴儿、儿童、青少年和成人
- 获得知情同意书（父母应为 < 18 岁的患者签名）
- VWD3 的先前诊断（VWF 抗原：检测不到或 <5 U/dL）
- 有关遗传模式、出血史、以前接触过血液制品的详细信息
- 血浆和 DNA 样本的可用性
排除标准：
• 可能无法进行随访的 VWD3 患者
学习计划
本节提供研究计划的详细信息，包括研究的设计方式和研究的衡量标准。
研究是如何设计的？
设计细节
- 观测模型：队列
- 时间观点：其他
队列和干预
团体/队列 |
干预/治疗 |
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3 型冯维勒布兰德病 (VWD3)
诊断为 3 型冯维勒布兰德病的患者
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血浆衍生和/或重组 VWF 浓缩物按需或在预防治疗方案下的替代疗法。
其他名称：
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研究衡量的是什么？
主要结果指标
结果测量 |
措施说明 |
大体时间 |
|---|---|---|
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3 型血管性血友病 (VWD3) 诊断的集中因子 VIII (FVIII) 促凝血活性 (FVIII:C) 实验室测试
大体时间：12个月（确认阶段）
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通过一级凝血试验测量血液中的因子 VIII (FVIII) 促凝血活性 (FVIII:C)。
只有 FVIII:C 小于或等于 5 IU/dL 的患者被考虑用于分析。
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12个月（确认阶段）
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用于 3 型冯维勒布兰德病 (VWD3) 诊断的集中血管性血友病因子抗原 (VWF:Ag) 实验室检测
大体时间：12个月（确认阶段）
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通过 Von Willebrand 因子抗原 (VWF:Ag) 测试测量血液中 Von Willebrand 因子 (VWF) 蛋白的量。
只有 VWF:Ag 小于或等于 5 IU/dL 的患者才被考虑用于分析。
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12个月（确认阶段）
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集中因子 VIII (FVIII) 酰胺分解活性 (FVIII:Am) 3 型冯维勒布兰德病 (VWD3) 诊断的实验室测试
大体时间：12个月（确认阶段）
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通过显色试验测量血液中因子 VIII (FVIII) 的酰胺分解活性 (FVIII:Am)。
只有 FVIII:Am 小于或等于 5 IU/dL 的患者被考虑用于分析。
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12个月（确认阶段）
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3 型血管性血友病 (VWD3) 诊断的集中因子 VIII (FVIII) 抗原 (FVIII:Ag) 实验室检测
大体时间：12个月（确认阶段）
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通过 FVIII:Ag 测试测量血液中因子 VIII (FVIII) 蛋白的量。
只有 FVIII:Ag 小于或等于 5 IU/dL 的患者被考虑用于分析。
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12个月（确认阶段）
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用于 3 型冯维勒布兰德病 (VWD3) 诊断的集中式冯维勒布兰德因子 (VWF) 多聚体分析
大体时间：12个月（确认阶段）
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冯维勒布兰德因子 (VWF) 的多聚体分析是通过对研究地点收集的血样进行电泳来进行的。
计算了属于每个多聚体概况组（1 - 纯合子/2 - 仅原体/3 - 2-4 条带）的患者数量。
VWF 多聚体的定性评估是 VWD3 诊断过程的一部分。
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12个月（确认阶段）
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通过 DNA 分析集中分子 3 型冯维勒布兰德病 (VWD3) 诊断
大体时间：12个月（确认阶段）
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评估是否存在冯维勒布兰德因子 (VWF) 基因缺陷（首次确认或筛选）。
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12个月（确认阶段）
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不良事件
大体时间：24个月（第一准期）+24个月（第二准期）
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记录在研究的前瞻性阶段发生的所有不良事件。
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24个月（第一准期）+24个月（第二准期）
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使用中含有冯维勒布兰德因子/因子 VIII (VWF/FVIII) 的浓缩物的类型
大体时间：24个月（第一准期）+24个月（第二准期）
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记录使用过和目前正在使用的任何含有冯维勒布兰德因子/因子 VIII (VWF/FVIII) 的浓缩物，包括当前的治疗计划类型。
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24个月（第一准期）+24个月（第二准期）
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用于 3 型血管性血友病 (VWD3) 诊断的集中式血管性血友病因子 (VWF) 前肽实验室测试
大体时间：12个月（确认阶段）
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通过 VWF 前肽测试测量血液中的血管性血友病因子 (VWF) 前肽水平。
该测试是根据最新方法进行的，结果对于表征 VWD 患者的分子方面非常重要。
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12个月（确认阶段）
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出血记录
大体时间：24 个月（第一预期阶段）+ 24 个月（第二预期阶段）
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记录研究前瞻性阶段发生的所有出血。
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24 个月（第一预期阶段）+ 24 个月（第二预期阶段）
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次要结果测量
结果测量 |
措施说明 |
大体时间 |
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在使用含有血管性血友病因子 (VWF) 的浓缩物期间出现过敏反应的患者
大体时间：24个月（追溯阶段）
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过去因使用任何血管性血友病因子 (VWF) 浓缩物而发生的任何变态反应和过敏反应的记录以及发生日期。
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24个月（追溯阶段）
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以前使用过血液制品的参与者人数
大体时间：24个月（追溯阶段）
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回顾阶段使用的任何产品的记录（收集的血液制品类型/血管性血友病因子 (VWF) 浓缩物、首次接触年份、使用的单位）。
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24个月（追溯阶段）
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可用当地实验室检测抗血管性血友病因子（抗 VWF）抗体的患者人数
大体时间：24个月（追溯阶段）
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通过 Bethesda 测试评估抗血管性血友病因子（抗 VWF）抗体的滴度。
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24个月（追溯阶段）
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3 型冯维勒布兰德病 (VWD3) 诊断的当地实验室检查（综合）
大体时间：24个月（追溯阶段）
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进行了以下测试的患者人数： 血红蛋白 (mmol/L)、血凝滴度 (HT) (%)、平均红细胞体积 (MVC) (fl)、白细胞 (E9/L)、中性粒细胞 (%)、嗜碱性粒细胞 (%)、嗜酸性粒细胞 (%)、淋巴细胞 ( %)、血小板计数 (E9/L)、平均血小板体积 (MPV) (fl)、凝血酶原时间 (秒)、部分凝血活酶时间 (PTT) (秒)、部分凝血活酶时间混合 50:50 (PTT 混合 50:50 )（秒）、铁蛋白（微克/升）、出血时间（分钟：秒）、闭合时间（秒）、胶原蛋白/ADP（秒）、胶原蛋白/肾上腺素（秒）；凝血因子 VIII 促凝活性 (FVIII:C) (IU/mL)，血管性血友病因子瑞斯托西汀辅助因子 (VWF:RCo) (IU/mL)，Won Willebrand 因子抗原 (VWF:Ag) (IU/mL)。 |
24个月（追溯阶段）
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合作者和调查者
在这里您可以找到参与这项研究的人员和组织。
调查人员
- 研究主任：Augusto B. Federici, MD、Hematology and Transfusion Medicine, L. Sacco University Hospital, University of Milan, Via G. B. Grassi, 74 20157 Milan, Italy
出版物和有用的链接
负责输入研究信息的人员自愿提供这些出版物。这些可能与研究有关。
一般刊物
- Veyradier A, Balian A, Wolf M, Giraud V, Montembault S, Obert B, Dagher I, Chaput JC, Meyer D, Naveau S. Abnormal von Willebrand factor in bleeding angiodysplasias of the digestive tract. Gastroenterology. 2001 Feb;120(2):346-53. doi: 10.1053/gast.2001.21204.
- Blatchford O, Murray WR, Blatchford M. A risk score to predict need for treatment for upper-gastrointestinal haemorrhage. Lancet. 2000 Oct 14;356(9238):1318-21. doi: 10.1016/S0140-6736(00)02816-6.
- Eikenboom JC. Congenital von Willebrand disease type 3: clinical manifestations, pathophysiology and molecular biology. Best Pract Res Clin Haematol. 2001 Jun;14(2):365-79. doi: 10.1053/beha.2001.0139.
- Sadler JE, Budde U, Eikenboom JC, Favaloro EJ, Hill FG, Holmberg L, Ingerslev J, Lee CA, Lillicrap D, Mannucci PM, Mazurier C, Meyer D, Nichols WL, Nishino M, Peake IR, Rodeghiero F, Schneppenheim R, Ruggeri ZM, Srivastava A, Montgomery RR, Federici AB; Working Party on von Willebrand Disease Classification. Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor. J Thromb Haemost. 2006 Oct;4(10):2103-14. doi: 10.1111/j.1538-7836.2006.02146.x. Epub 2006 Aug 2.
- Nilsson IM. Commentary to Erik von Willebrand's original paper from 1926 'Hereditar pseudohemofili'. Haemophilia. 1999 May;5(3):220-1. doi: 10.1046/j.1365-2516.1999.0320a.x. No abstract available.
- NILSSON IM, BLOMBACK M, BLOMBACK B. v. Willebrand's disease in Sweden; its pathogenesis and treatment. Acta Med Scand. 1959 Jun 30;164:263-78. No abstract available.
- Mannucci PM, Bloom AL, Larrieu MJ, Nilsson IM, West RR. Atherosclerosis and von Willebrand factor. I. Prevalence of severe von Willebrand's disease in western Europe and Israel. Br J Haematol. 1984 May;57(1):163-9. doi: 10.1111/j.1365-2141.1984.tb02876.x.
- Weiss HJ, Ball AP, Mannucci PM. Incidence of severe von Willebrand's disease. N Engl J Med. 1982 Jul 8;307(2):127. doi: 10.1056/NEJM198207083070222. No abstract available.
- Berliner SA, Seligsohn U, Zivelin A, Zwang E, Sofferman G. A relatively high frequency of severe (type III) von Willebrand's disease in Israel. Br J Haematol. 1986 Mar;62(3):535-43. doi: 10.1111/j.1365-2141.1986.tb02966.x.
- Iorio A, Oliovecchio E, Morfini M, Mannucci PM; Association of Italian Hemophilia Centres Directors. Italian Registry of Haemophilia and Allied Disorders. Objectives, methodology and data analysis. Haemophilia. 2008 May;14(3):444-53. doi: 10.1111/j.1365-2516.2008.01679.x. Epub 2008 Mar 18. Erratum In: Haemophilia. 2009 Mar;15(2):637.
- Federici AB, Mannucci PM. Management of inherited von Willebrand disease in 2007. Ann Med. 2007;39(5):346-58. doi: 10.1080/07853890701513738.
- Silwer J. von Willebrand's disease in Sweden. Acta Paediatr Scand Suppl. 1973;238:1-159. No abstract available.
- Lak M, Peyvandi F, Mannucci PM. Clinical manifestations and complications of childbirth and replacement therapy in 385 Iranian patients with type 3 von Willebrand disease. Br J Haematol. 2000 Dec;111(4):1236-9. doi: 10.1046/j.1365-2141.2000.02507.x.
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- Federici AB, Bucciarelli P, Castaman G, Mazzucconi MG, Morfini M, Rocino A, Schiavoni M, Peyvandi F, Rodeghiero F, Mannucci PM. The bleeding score predicts clinical outcomes and replacement therapy in adults with von Willebrand disease. Blood. 2014 Jun 26;123(26):4037-44. doi: 10.1182/blood-2014-02-557264. Epub 2014 Apr 30.
- Abdul-Kadir R, McLintock C, Ducloy AS, El-Refaey H, England A, Federici AB, Grotegut CA, Halimeh S, Herman JH, Hofer S, James AH, Kouides PA, Paidas MJ, Peyvandi F, Winikoff R. Evaluation and management of postpartum hemorrhage: consensus from an international expert panel. Transfusion. 2014 Jul;54(7):1756-68. doi: 10.1111/trf.12550. Epub 2014 Mar 12. Erratum In: Transfusion. 2015 Mar;55(3):691.
- Makris M, Federici AB, Mannucci PM, Bolton-Maggs PHB, Yee TT, Abshire T, Berntorp E. The natural history of occult or angiodysplastic gastrointestinal bleeding in von Willebrand disease. Haemophilia. 2015 May;21(3):338-342. doi: 10.1111/hae.12571. Epub 2014 Nov 7.
- Federici AB. Clinical and laboratory diagnosis of VWD. Hematology Am Soc Hematol Educ Program. 2014 Dec 5;2014(1):524-30. doi: 10.1182/asheducation-2014.1.524. Epub 2014 Nov 18.
- Holm E, Abshire TC, Bowen J, Alvarez MT, Bolton-Maggs P, Carcao M, Federici AB, Gill JC, Halimeh S, Kempton C, Key NS, Kouides P, Lail A, Landorph A, Leebeek F, Makris M, Mannucci P, Mauser-Bunschoten EP, Nugent D, Valentino LA, Winikoff R, Berntorp E. Changes in bleeding patterns in von Willebrand disease after institution of long-term replacement therapy: results from the von Willebrand Disease Prophylaxis Network. Blood Coagul Fibrinolysis. 2015 Jun;26(4):383-8. doi: 10.1097/MBC.0000000000000257.
- Randi AM, Laffan MA. Von Willebrand factor and angiogenesis: basic and applied issues. J Thromb Haemost. 2017 Jan;15(1):13-20. doi: 10.1111/jth.13551.
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研究记录日期
这些日期跟踪向 ClinicalTrials.gov 提交研究记录和摘要结果的进度。研究记录和报告的结果由国家医学图书馆 (NLM) 审查，以确保它们在发布到公共网站之前符合特定的质量控制标准。
研究主要日期
学习开始 (实际的)
2012年11月5日
初级完成 (实际的)
2023年3月28日
研究完成 (实际的)
2023年4月17日
研究注册日期
首次提交
2015年5月27日
首先提交符合 QC 标准的
2015年6月1日
首次发布 (估计的)
2015年6月2日
研究记录更新
最后更新发布 (实际的)
2025年3月25日
上次提交的符合 QC 标准的更新
2024年12月23日
最后验证
2024年12月1日
更多信息
此信息直接从 clinicaltrials.gov 网站检索，没有任何更改。如果您有任何更改、删除或更新研究详细信息的请求，请联系 register@clinicaltrials.gov. clinicaltrials.gov 上实施更改，我们的网站上也会自动更新.
3 型血管性血友病的临床试验
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Swedish Orphan BiovitrumPSI CRO招聘中
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Hospitales Universitarios Virgen del Rocío完全的
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Octapharma完全的严重血友病 A保加利亚, 波兰, 匈牙利, 罗马尼亚, 俄罗斯联邦
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