BEST-CLI Trial - Cost-Effectiveness of Treatments for Critical Limb Ischemia

描述（由申请人提供）： 此次重新提交包括三项申请（临床和数据协调中心（CCC，DCC）和成本效益分析核心）。我们建议在美国和加拿大进行一项大型（N=2100）简单优效性试验- BEST -比较最佳开放手术与最佳血管内血运重建，以预防严重肢体缺血（CLI）目标肢体的死亡、截肢或进一步血运重建，符合评估比较有效性的当前要求。试验领导层由来自CCC（Brigham and Women's Hospital，BWH，Boston University Medical Center，BUMC和马萨诸塞州医院，MGH，Boston，MA）、DCC（新英格兰研究所，Inc.，沃特敦，马萨诸塞州）和该领域的专家执行委员会。BWH的卫生经济学小组将与DCC密切合作，以解决生活质量和成本效益（C-E）的评估问题。该试验将在美国和加拿大的约120个研究中心进行，以先前的可行性数据为基础，并努力解决该领域当前研究的局限性。 70岁以上的外周动脉疾病患病率为15-20%，吸烟者和糖尿病患者的患病率更高。在CLI亚组中，40%需要截肢，年死亡率超过20%。随着血管内血运重建技术的出现，我们从我们完成的调查中证明，在大多数CLI病例中，从业者之间的最佳治疗目前处于平衡状态。BEST试验将首次为C-E背景下的CLI管理提供迫切需要的临床指导，方法是使用：务实的设计，包括一系列已建立的技术;新的主要终点-男性（重大不良肢体事件，包括肢体截肢或重大再介入、旁路移植物/移植物翻修或血栓切除术/溶栓）-无生存期;血管外科医生、介入心脏病专家和放射科医生的多学科招聘;以及创新的、具有成本效益的C-E方法。其他终点包括其他临床事件发生率、功能状态、QOL和C-E，均使用标准定义和工具。将联系北美的140家合格临床试验机构，以确保120家临床试验机构启动研究，80家临床试验机构在27个月的累积期内每家每月招募1例受试者。试验持续时间为4.25年- 2.25年入组和2.0年最短随访。将研究两个队列：全静脉（N=1620）和人工导管（N=480）。在每个队列中，试验根据2个因素（4层）进行分层：组织缺损vs.孤立性静息痛和腹股沟下伴/不伴显著膝下闭塞性疾病。在全静脉队列中，BEST有85%的把握度检测主要终点（无男性生存期）中EVT与OPEN的风险比为1.25，考虑了交叉率以及2%的失访。在假体导管队列中，有80%的把握度检测到主要终点的风险比为0.70。此次重新提交充分解决了所有先前审查员的担忧，以成功有效地执行试验，为CLI社区提供重要信息。

DESCRIPTION (provided by applicant): This resubmission is comprised of three applications (Clinical and Data Coordinating Centers (CCC, DCC) and Cost-Effectiveness Analysis Core). We propose to conduct a large (N=2100) simple, superiority trial in the US and Canada - BEST - comparing best open surgery to best endovascular revascularization to prevent mortality, limb-amputation or further revascularization in a target limb with critical limb ischemia (CLI), meeting the current mandate for assessing comparative effectiveness. Trial leadership is comprised of a closely integrated and highly experienced group of investigators based at a CCC (Brigham and Women's Hospital, BWH , Boston University Medical Center, BUMC, and Massachusetts Hospital, MGH, Boston, MA), a DCC (New England Research Institutes, Inc., Watertown, MA) and an Executive Committee of experts in the field. The Health Economics Group at BWH will work closely with the DCC to address assessment of quality of life and cost-effectiveness (C-E). The trial will be conducted at approximately 120 sites in the U.S. and Canada, builds upon prior feasibility data and endeavors to address limitations of current research in this area. Peripheral artery disease prevalence is 15-20% over 70 years, with higher rates in smokers and diabetics. In the subset with CLI, 40% require limb amputation and annual mortality exceeds 20%. With the advent of endovascular techniques for revascularization, we demonstrate from our completed surveys that there is current equipoise among practitioners with respect to best therapy in the majority of CLI cases. The BEST trial will provide, for the first time, urgently needed clinical guidance for CLI management in the context of C-E by using: a pragmatic design, including a range of established techniques; a novel primary endpoint - MALE (major adverse limb event including limb amputation or major re-intervention, bypass graft/graft revision or thrombectomy/thrombolysis) - free survival; multi-disciplinary recruitment of vascular surgeons and interventional cardiologists and radiologists; and an innovative, cost-efficient C-E approach. Additional endpoints include other clinical event rates, functional status and QOL and C-E, all using standard definitions and instruments. 140 eligible centers in North America will be approached to ensure 120 are initiated and 80 sites each recruit 1 subject/month over 27 months accrual. Trial duration is 4.25 yrs - 2.25 yrs accrual and 2.0 yrs minimum follow-up. Two cohorts will be studied: All-Vein (N=1620) and Prosthetic Conduit (N=480). Within each cohort, the trial is stratified on 2 factors (4 strata): tissue loss vs. isolated rest pain and infrainguinl with/without significant infrapopliteal occlusive disease. In the All-Vein cohort, BEST has 85% power to detect an EVT vs. OPEN hazard ratio of 1.25 in the primary endpoint (MALE-free survival) with crossover rates accounted for, as well as 2% loss to follow-up. In the Prosthetic Conduit cohort, there is 80% power to detect a hazard ratio of 0.70 for the primary endpoint. This resubmission fully addresses all prior reviewer concerns, to successfully and efficiently execute a trial that will provide important information for the CLI community.