Hemophilia Adult Prophylaxis Study

血友病成人预防研究

• 批准号: 8189710
• 负责人: MARGARET VICTORIA RAGNI
• 金额: $ 42.02万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-20 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8189710
• 关键词: 18 year old; Adherence; Adult; Applications Grants; Articular Range of Motion; Blood specimen; Caring; Cartilage; Case Report Form; Child; Clinical Research; Clinical Trials; Clinical Trials Design; Consensus; Contracts; Cross-Over Studies; Data; Dose; Enrollment; Focus Groups; Frequencies; Future; Generations; Genetic Crossing Over; Goals; Health Care Costs; Hemophilia A; Hemorrhage; Inferior; Institutional Review Boards; Intervention; Joints; Manuals; Measures; Methods; NIH Program Announcements; National Heart, Lung, and Blood Institute; Nurses; Online Systems; Patients; Persons; Phase; Phase III Clinical Trials; Physicians; Pilot Projects; Prevention; Preventive; Procedures; Prophylactic treatment; Protocols documentation; Quality of life; Quality-of-Life Assessment; Randomized; Randomized Clinical Trials; Randomized Controlled Clinical Trials; Randomized Controlled Trials; Recruitment Activity; Research Design; Research Infrastructure; Research Project Grants; Safety; Science; Shipping; Ships; Site; Testing; Thrombin; Time; cost; design; digital imaging; insight; joint injury; meetings; men; novel strategies; operation; pilot trial; prevent; recombinant antihemophilic factor VIII; response; sample collection; tool; treatment center; trial comparing; von Willebrand Disease

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.

说明（由申请人提供）：拟议的 R34 探索性临床研究补助金旨在响应计划公告 PAR-10-005，以确定进行 III 期随机临床试验的可行性，该试验比较两种剂量的重组因子 VIII (r.FVIII) 对成人严重血友病 A 的预防作用。这将通过以下方式完成：1) 在六个核心血友病治疗中心进行试点临床试验 (HTC)，其董事通过参加 NHLBI 科学状况 (SoS) 血友病和冯维勒布兰德病小组委员会，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，以就研究设计、受试者招募和研究参与达成共识，并运营该基础设施以实现集中的 IRB 和合同提交以及充足的入组。血友病综合护理的一个主要目标是通过预防或每周三次常规预防措施来防止出血的发生。尽管预防可以有效减少儿童出血和关节损伤，但是否有必要持续到成年尚不清楚。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，并且每周一次的 r.FVIII 预防（每周最多两次救援剂量）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，更容易被接受，生活质量更高。 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治疗的 III 期随机对照临床试验的障碍。通过这种方式，我们希望准备、细化、优化方法、形式、操作流程；并确保有足够数量的参与地点和合格受试者，以确保对成人严重甲型血友病预防进行 III 期随机对照试验的可行性，其具体目标是： 目标 1. 通过在 20 年进行预试验，确定成人严重甲型血友病预防的 III 期随机、非劣效性、交叉临床试验的可行性 患有严重血友病 A、F.VIII <0.01 U/ml 且年龄 > 18 岁的成年男性。该研究将在六个核心 HTC 中进行，旨在比较每周一次与每周三次的 rF.VIII，为期 52 周。主要疗效终点是关节出血频率。还将确定关节活动范围、因子使用、成本、生活质量以及由凝血酶生成时间和 F.VIII 活性引起的剂量间低凝性。安全性将通过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。将确定受试者对治疗干预措施的接受度和依从性；将评估基于网络的病例报告表、关节活动范围的数字成像、生活质量表；并优化了血液样本的采集和运输。目标 2. 通过协调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来进行未来的 R01 52 周随机交叉试验。 HTC 基础设施的运营将通过聘请一名专门的护士协调员来为参与的 HTC 准备 IRB 提交文件和合同。六名核心HTC医生将审查并最终确定未来R01试验的病例报告表和操作手册，并将与外国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，以确保未来进行III期随机临床试验的可行性。 公共健康相关性：本 R34 拨款申请的目的是确定一项随机临床试验的可行性，以确定每周一次的重组因子 VIII 预防（预防）是否与每周三次的预防在减少血友病成人关节出血方面效果一样好。为了评估可行性，我们将在 20 名患有血友病的成年男性中进行试点试验，以评估关节出血频率、因子使用和生活质量；我们将通过焦点小组建立血友病中心网络，以建立共识，促进入组，并协调IRB提交，以确保大型随机III期试验的可行性。