Hemophilia Adult Prophylaxis Study

描述（由申请人提供）：拟定的R34探索性临床研究补助金旨在响应计划公告PAR-10-005，以确定在重度血友病A成人中进行III期随机临床试验的可行性，该试验比较了两种剂量的重组因子VIII（r.FVIII）预防。这将通过以下方式实现：1）在六个核心血友病治疗中心（HTC）开展试点临床试验，这些中心的负责人通过参与NHLBI科学现状（SoS）血友病和血管性血友病小组委员会，参与了该概念的初始设计和规划;和2）建立由47名以上HTC医生组成的基础设施，以就研究设计、受试者招募和研究参与达成共识，并使基础设施运作起来，以实现集中的IRB和合同提交以及充分的入组。血友病综合治疗的一个主要目标是通过预防或每周三次的常规预防因素来预防出血的发生。虽然预防在减少儿童出血和关节损伤方面是有效的，但是否有必要持续到成年还不清楚。我们假设软骨和关节成熟的成人对关节出血和关节损伤的敏感性较低，每周一次的r.FVIII预防，每周最多两次的补救剂量，在减少出血频率方面与每周三次的预防一样有效，但成本更低，更容易接受，生活质量更高。 本项目的最终目标是确定和解决未来在血友病成人中进行预防性治疗的III期随机对照临床试验的障碍。通过这种方法，我们希望准备、完善和优化方法、表格和操作程序;并确保有足够数量的参与研究中心和合格的可用受试者，以确保在重度血友病A成人中进行预防性III期随机对照试验的可行性，其具体目的是：目的1。通过在20例重度血友病A（F.VIII <0. 01 U/ml且年龄> 18岁）成人男性中进行初步试验，确定成人预防性治疗重度血友病A的III期随机、非劣效性、交叉临床试验的可行性。本研究将在6个核心HTC中进行，旨在比较每周一次与每周三次rF.VIII治疗52周。主要疗效终点为关节出血频率。还将通过凝血酶生成时间和F.VIII活性确定关节活动度、因子使用、成本、生活质量和剂量间低凝状态。安全性将通过对最多两次补救治疗无反应的出血频率来衡量。安全性将通过对最多两次补救治疗无反应的出血频率来衡量。将确定受试者对治疗干预的接受程度和依从性;将评估基于网络的病例报告表、关节活动度的数字成像、生活质量表;并优化血样采集和运输。目标二。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的R 01 52周随机交叉试验。HTC基础设施将通过雇用一名专门的护士协调员为参与HTC准备IRB提交材料和合同来运作。6名核心HTC医生将审查并最终确定未来R 01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，以确保进行未来III期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.