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根据项目公告PAR-10-005设计的，旨在确定进行一项比较两种剂量重组因子VIII （r.FVIII）预防成人严重a型血友病的III期随机临床试验的可行性。该试验将通过以下方式完成：1)在六个核心血友病治疗中心（HTCs）进行一项试点临床试验；其主任通过参与NHLBI血友病和血管性血友病科学状况小组委员会，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，并使基础设施运行，以完成集中的IRB和合同提交以及充分的入组。血友病综合护理的一个主要目标是通过预防性治疗或每周三次定期预防因素预防出血的发生。虽然预防在减少儿童出血和关节损伤方面是有效的，但是否有必要继续到成年尚不清楚。我们假设软骨和关节成熟的成年人不太容易发生关节出血和关节损伤，并且每周一次rfviii预防，每周最多两次拯救剂量，在减少出血频率方面与每周三次预防一样有效，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并解决未来进行成人血友病预防的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、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受试者，以确保对成人严重血友病a进行预防的III期随机对照试验的可行性，其具体目标是：通过对20名成年严重血友病a患者（fviii <0.01 U/ml，年龄bb0 ~ 18岁）进行试点试验，确定成人预防严重血友病a的III期随机、非劣效性、交叉临床试验的可行性。该研究将在六个核心HTCs中进行，旨在比较每周一次和三次的rF。VIII为52周。主要疗效终点为关节出血频率。通过凝血酶生成时间和fviii活性来确定关节活动范围、因子使用、成本、生活质量和剂量间低凝性。安全性将通过对最多两次抢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抢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措施的接受程度和依从性；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；血样采集和运输也得到了优化。目标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符合条件的受试者进行未来的R01 52周随机交叉试验。HTC的基础设施将通过雇用专门的护士协调员来准备参与HTC的IRB提交和合同来运作。6名核心HTC医生将审查并最终确定未来R01试验的病例报告表格和操作手册，并与国外HTC医生举行探索性会议，以确定研究参与和受试者招募的潜力，以确保开展未来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. PUBLIC HEALTH RELEVANCE: The purpose of this R34 grant application is to determine the feasibility of a randomized clinical trial to determine whether once-weekly prophylaxis (prevention) with recombinant factor VIII is as good as thrice- weekly prophylaxis in reducing joint bleeds in adults with hemophilia. In order to assess feasibility, we will conduct a pilot trial in 20 adult men with hemophilia to assess joint bleeding frequency, factor use, and quality of life; and we will set up a hemophilia center network through facilitated focus groups to build consensus, promote enrollment, and coordinate IRB submission to assure feasibility of large randomized phase III trial.