Feasibility of the Hemophilia INHIBIT Trial

描述（由申请方提供）：血友病A是一种X连锁出血性疾病，由因子VIII缺乏引起，特征为关节、肌肉和体腔出血。血友病治疗最严重的并发症是抑制物形成，即25-35%的患者发生针对输注的因子VIII抑制物抗体的抗体，并导致不受控制的出血和显著的发病率。抑制剂风险与强化治疗相关，例如用于大出血或 手术，其中组织损伤和炎症激活免疫系统。越来越多的证据表明，如果能够避免所谓的“危险”信号，就可以防止抑制剂的形成。 本U34探索性临床研究补助金的目的是建立进行重组因子VIII（rF.VIII）的III期试验的可行性， 在重度血友病A儿童中，首次出血前每周一次与首次出血后开始的标准每周三次rF.VIII。本研究的原始概念是由六名血友病治疗中心（HTC）医生开发的四个临床试验概念之一，他们是NHBLI科学状态（SoS）血友病小组委员会的成员，也是本研究指导委员会的成员。我们假设，重组F.VIII（rF.VIII）预防给予先发制人的第一次出血前，在没有“危险”，将防止抑制物的形成，与标准的每周三次预防后开始的第一次出血。这是一个创新的概念，因为它挑战了目前的治疗方法，如果成功，将改变实践。在通过ELISPOT测定来评估F. VIII特异性T细胞应答以确定抑制剂形成和耐受的机制方面也是创新的。本项目的最终目标是识别和解决未来III期随机对照临床试验的障碍，其具体目标是：目标1。建立由60多名HTC医生组成的HTC基础设施，共同就试验设计、受试者招募和参与达成共识，以确保有足够数量的合格受试者进行未来R 01 48周随机试验，以比较预先每周一次与标准每周三次rF.VIII预防在重度血友病A儿童中预防抑制物形成的效果。HTC网络将通过以下方式运作：1）与HTC医生和家长进行便利的结构化访谈，以确定试验设计和参与潜力的可接受性; 2)与指导委员会和U24临床资源合作，以优化试验设计、招募策略，并准备病例报告表和操作手册; 3）开发和试点测试基于网络的数据输入系统; 4）与外国HTC医生进行探索性会议，以确定参与试验和受试者招募的可能性;以及5）雇用两名专职护士协调员为HTC准备IRB提交文件和合同。目标二。确定一项为期48周的III期、开放标签、随机临床试验的可行性，该试验比较了在首次出血前开始的每周一次预先rF.VIII预防与在首次出血后开始的每周三次标准rF.VIII预防，入选当地HTC的重度血友病A（F.VIII<0. 01 U/ml）儿童。这将通过以下方式实现：1）验证和优化抗F.VIII抑制剂抗体，主要终点，用于儿科体积、低滴度和高滴度抗体以及运输; 2）验证F. VIII特异性T细胞ELISPOT测定，次要终点，用于评估成人抑制剂样品中的抑制剂机制，并优化其用于儿科体积和运输; 3）建立安全停止指南以确保干预的安全性，以最小化出血事件和中心线感染; 4）建立通过基于网络的数据输入与研究受试者数据相关联的血液样品的储存库;以及5）寻求社区咨询委员会的意见，以提供反馈并促进关于未来III期试验的沟通。

DESCRIPTION (provided by applicant): Hemophilia A is an X-linked bleeding disorder resulting from deficiency of factor VIII, and characterized by bleeding into joints, muscles, and body cavities. Among the most serious complications of hemophilia treatment is inhibitor formation, that is, the development of antibodies directed against infused factor VIII Inhibitor antibodies occur in 25-35% of patients and result in uncontrolled bleeding and significant morbidity. Inhibitor risk is associated with intensive treatment, such as given for major bleeds or surgeries, in which tissue damage and inflammation activate the immune system. Increasing evidence suggests if so-called "danger" signals could be avoided, inhibitor formation could be prevented. The purpose of this U34 Exploratory Clinical Research Grant is to establish the feasibility of conducting a Phase III trial of recombinant factor VIII (rF.VIII) begun preemptively weekly before the first bleed versus standard three-times weekly rF.VIII begun after the first bleed in children with severe hemophilia A. The original concept for this study was developed as one of four clinical trial concepts by six hemophilia treatment center (HTC) physicians, members of the NHBLI State of the Science (SoS) Hemophilia Subcommittee, who are members of the Steering Committee for this study. We hypothesize that recombinant F.VIII (rF.VIII) prophylaxis given preemptively before the first bleed, in the absence of "danger", will prevent inhibitor formation, as compared with standard three times weekly prophylaxis begun after the first bleed. This is an innovative concept as it challenges current treatment, and, if successful, will be practice-changing. It is also innovative in evaluating F.VIII-specific T cell responses by ELISPOT assay to determine the mechanism of inhibitor formation and tolerance. The ultimate goal of this project is to identify and resolve barriers to the conduct of a future phase III randomized, controlled clinical trial, the specific aims of which are: Aim 1. To establish an HTC infrastructur of 60+ HTC physicians to jointly build consensus on trial design, subject recruitment and participation to assure a sufficient number of eligible subjects to conduct a future R01 48-week randomized trial to compare preemptive weekly vs. standard three times weekly rF.VIII prophylaxis in the prevention of inhibitor formation in children with severe hemophilia A. The HTC network will be operationalized by 1) conducting facilitated structured interviews with HTC physicians and with parents to determine acceptability of trial design and participation potential; 2) collaborating with a Steering Committee and the U24 Clinical Resource to optimize trial design, recruitment strategy, and to prepare case report forms and a manual of operations; 3) developing and pilot-testing a web-based data entry system; 4) conducting exploratory meetings with foreign HTC physicians to determine potential for trial participation and subject recruitment; and 5) hiring two dedicated nurse coordinators to prepare IRB submissions and contracts for HTCs. Aim 2. To determine the feasibility of a phase III 48-week, open-label, randomized clinical trial comparing preemptive weekly rF.VIII prophylaxis begun before the first bleed versus standard three times weekly rF.VIII prophylaxis begun after the first bleed in children with severe hemophilia A, F.VIII<0.01 U/ml, enrolled at local HTCs. This will be accomplished by 1) validating and optimizing the anti-F.VIII inhibitor antibody, the primary endpoint, for pediatric volumes, low- and high-titer antibodies, and shipping; 2) validating the F.VIII-specific T cell ELISPOT assay, a secondary endpoint to assess inhibitor mechanism, in adult inhibitor samples and optimizing it for pediatric volumes and shipping; 3) establishing safety stopping guidelines to assure safety of the intervention, to minimize bleeding events and central line infections; 4) setting up a repository of blood samples linked to study subject data via web-based data entry; and 5) seeking advice of a community advisory board to provide feedback and promote communication regarding the future phase III trial.