Hemophilia Adult Prophylaxis Study

描述(由申请人提供)：拟议的R34探索性临床研究拨款是为了响应计划公告PAR-10-005而设计的，以确定进行第三阶段随机临床试验的可行性，比较两种剂量的重组第八因子(r.FVIII)预防成人严重血友病A的可行性。这将通过以下方式完成：1)在六个核心血友病治疗中心(HTC)进行试点临床试验，这些中心的主任通过参与NHLBI科学状况(SOS)血友病和Von Willebrand疾病小组委员会参与了这一概念的初步设计和规划；2)建立由47名以上HTC医生组成的基础设施，就研究设计、受试者招募和研究参与达成共识，并将基础设施投入运营，实现IRB和合同的集中提交和充分的招生。综合血友病护理的一个主要目标是通过预防或每周三次定期预防因素来预防出血的发生。尽管预防措施在减少儿童出血和关节损伤方面有效，但是否有必要继续到成年尚不清楚。我们假设，具有成熟软骨和关节的成年人不太容易受到关节出血和关节损伤的影响，每周一次r.FVIII预防，每周最多两次抢救剂量，在减少出血频率方面与每周三次预防有效，但成本更低，生活质量更高，更容易接受。该项目的最终目标是确定和解决在成人血友病患者中进行预防的未来第三阶段随机对照临床试验的障碍。通过这种方法，我们希望准备、改进和优化方法、形式和操作程序，并确保足够数量的参与地点和合格的可用对象，以确保在成人重度血友病A中进行预防第三阶段随机对照试验的可行性，其具体目的是：目的1.通过在20名成年男性重度血友病A患者中进行初步试验，确定成人预防严重血友病A的第三阶段随机、非劣势、交叉临床试验的可行性。这项研究将在六个核心HTC中进行，旨在比较每周一次和每周三次rF.VIII在52周内的差异。主要疗效终点将是关节出血频率。还将确定关节活动范围、因子使用、成本、生活质量以及凝血酶生成时间和F.VIII活性所导致的剂量间低凝状态。安全性将通过对最多两次救援治疗无反应的出血频率来衡量。安全性将通过对最多两次救援治疗无反应的出血频率来衡量。将确定受试者接受和遵守治疗干预措施；将评估基于网络的病例报告表格、关节活动范围的数字成像、生活质量表格；以及优化血液样本采集和运输。目的2.通过促进焦点小组和面对面会议，建立由47名以上HTC医生组成的HTC基础设施，共同就试验设计、受试者招募和试验参与达成共识，以确保有足够数量的合格受试者进行未来R01 52周的随机交叉试验。HTC基础设施将通过聘请一名专门的护士协调员来准备IRB提交和参与HTC的合同来运作。HTC的六名核心医生将审查和敲定未来R01试验的病例报告表和操作手册，并将与外国HTC医生举行探索性会议，以确定参与研究和招募受试者的可能性，以确保未来进行第三阶段随机临床试验的可行性。

DESCRIPTION (provided by applicant): The proposed R34 Exploratory Clinical Research Grant is designed in response to Program Announcement PAR-10-005, to determine the feasibility of conducting a Phase III randomized clinical trial comparing two doses of recombinant factor VIII (r.FVIII) prophylaxis in adults with severe hemophilia A. This will be accomplished by 1) conducting a pilot clinical trial at six core hemophilia treatment centers (HTCs), the Directors of which participated in initial design and planning of this concept through participation in the NHLBI State of the Science (SoS) Hemophilia and Von Willebrand Disease Subcommittee; and 2) setting up an infrastructure of 47+ HTC physicians to reach consensus on study design, subject recruitment, and study participation, and operationalizing the infrastructure to accomplish centralized IRB and contract submission and adequate enrollment. A major goal of comprehensive hemophilia care is to prevent occurrence of bleeds by prophylaxis, or regular preventive factor three times weekly. Although prophylaxis is effective in reducing bleeding and joint damage in children, whether it is necessary to continue into adulthood is not known. We hypothesize that adults with mature cartilage and joints are less susceptible to joint bleeds and joint damage, and that once weekly r.FVIII prophylaxis, with up to two rescue doses per week, is as effective as thrice-weekly prophylaxis in reducing bleeding frequency, but less costly and more acceptable with higher quality-of-life. The ultimate goal of this project is to identify and resolve barriers to the conduct of a future phase III randomized, controlled clinical trial of prophylaxis in adults with hemophilia. By this approach, we hope to prepare, refine, and optimize methods, forms, and operating procedures; and assure a sufficient number of participating sites and eligible available subjects, in order to assure the feasibility of conducting a Phase III randomized controlled trial of prophylaxis in adults with severe hemophilia A, the specific aims of which are: Aim 1. To determine the feasibility of a phase III randomized, non-inferiority, cross-over clinical trial of adult prophylaxis in severe hemophilia A by conducting a pilot trial in 20 adult men with severe hemophilia A, F.VIII <0.01 U/ml, and age > 18 years. The study will be conducted in six core HTCs and designed to compare once-weekly vs. thrice-weekly rF.VIII for 52 weeks. The primary efficacy endpoint will be joint bleeding frequency. Joint range of motion, factor usage, cost, quality-of-life, and inter-dose hypocoagulability by thrombin generation time and F.VIII activity will also be determined. Safety will be measured by the frequency of bleeding unresponsive to up to two rescue treatments. Safety will be measured by the frequency of bleeding unresponsive to up to two rescue treatments. Subject acceptance and adherence to the treatment interventions will be determined; web-based case report forms, digital imaging for joint range of motion, quality-of-life forms will be assessed; and blood sample collection and shipping optimized. Aim 2. To establish an HTC infrastructure of 47+ HTC physicians through facilitated focus groups and in- person meetings to jointly build consensus on trial design, subject recruitment, and trial participation to assure a sufficient number of eligible subjects to conduct a future R01 52-week randomized cross-over trial. The HTC infrastructure will be operationalized by hiring a dedicated nurse coordinator to prepare IRB submission and contracts for participating HTCs. The six core HTC physicians will review and finalize case report forms and the manual of operations for the future R01 trial, and exploratory meetings will be held with foreign HTC physicians to determine the potential for study participation and subject recruitment to assure the feasibility of conducting a future Phase III randomized clinical trial.