Doxycycline Treatment of Abdominal Aortic Aneurysm: Planning

描述（由申请人提供）：腹主动脉瘤（AAA）是一种常见的（2-3%的受影响人群）和致命问题，在美国每年因破裂导致15，000例死亡。唯一可接受的治疗是AAA修复术，在美国每年对40，000例大型AAA进行修复。随着最近的广泛筛查，将检测到更多的小型（<5.5 cm）。AAA的自然病程是扩张到破裂风险大大增加的尺寸。目前还没有经过证实的医疗干预措施可以阻止或延缓这种进展。在缺乏有效医疗的情况下，昂贵的替代方案（20，000美元/手术）覆膜支架修复术可能成为小动脉瘤的首选治疗方法。有实验和临床证据表明，称为基质金属蛋白酶（MMPs）的基质降解蛋白家族参与AAA的发生和进展。有实验室、动物模型和观察证据表明，多西环素作为MMP抑制剂可以预防AAA的进展，尽管这种作用的临床证据是初步的。测试多西环素治疗腹主动脉瘤的安全性和有效性的公共卫生影响来自大量患者（数十万），他们可以避免手术或覆膜支架治疗（每年花费超过200，000，000美元）或可以避免被推荐无效治疗。我们将汇集具有血管外科、临床试验设计、数据分析和管理、AAA图像分析和反映动脉瘤生长的循环生物标志物分析方面专业知识的研究人员。本提案的目的是开展一项前瞻性随机试验，以检验多西环素将抑制小AAA生长的假设。我们的具体目标是：1）组建临床试验研究团队（具体说明临床研究中心、可用患者的数量和性别/种族/民族、中心机构的作用和研究中心）; 2）开发数据管理和研究监督工具（质量控制/保证程序、安全性监测计划、方法、硬件、软件和数据收集传输系统以及研究人员培训计划）; 3）定义我们的招聘策略（确认资格标准、征聘和留用计划）; 4）最后确定议定书（实验设计、假设、成像程序、其他结果、图像和数据分析、样本量）;和5）制定程序手册，包括确定确保程序标准化的手段（评估、随机化、治疗、随访、统计分析、给药）。这些努力将导致向国家老龄化研究所（NIA）提交研究者发起的拨款申请，以测试多西环素对这一具有大的公共卫生影响的问题的作用。测试多西环素治疗腹主动脉瘤的安全性和有效性的公共卫生影响来自大量患者（数十万），他们可以避免手术或覆膜支架治疗（每年花费超过200，000，000美元）或可以避免被推荐无效治疗。

DESCRIPTION (provided by applicant): Abdominal aortic aneurysms (AAA) are a common (2-3% of population affected) and lethal problem causing 15,000 deaths/year from rupture in the U.S. The only accepted treatment is repair of the AAA which is performed for 40,000 large AAA annually in the U.S. With recent widespread screening, many more small (<5.5 cm) will be detected. The natural history of AAA is expansion to a size at which the risk of rupture greatly increases. There is no proven medical intervention that will prevent or delay this progression. In the absence of effective medical treatment, a costly alternative ($20,000/procedure), endograft repair, may become the treatment of choice for small aneurysms. There is experimental and clinical evidence that a family of matrix degrading proteins called matrix metalloproteinases (MMPs) are involved in initiation and progression of AAA. There is laboratory, animal model and observational evidence that doxycycline, working as an MMP inhibitor, can prevent progression of AAA, although the clinical evidence for this effect is preliminary. The public health impact of testing the safety and efficacy of doxycycline in the treatment of abdominal aortic aneurysms derives from the large number of patients (hundreds of thousands) who could avoid surgical or endograft therapy (costing in excess of $200,000,000 per year) or who could avoid being recommended an inefficacious therapy. We will bring together investigators with expertise in vascular surgery, clinical trial design, data analysis and management, image analysis of AAA and analysis of circulating biomarkers that reflect aneurysm growth. The purpose of this proposal is to develop a prospective, randomized trial to test the hypothesis that doxycycline will inhibit the growth of small AAA. Our specific aims are to: 1) Establish the research team for the clinical trial (specifying clinical sites, number and gender/race/ethnicity of patients available, central facility roles and sites); 2) Develop tools for data management and oversight of research (quality control/assurance procedures, safety monitoring plan, methods, hardware, software, and transmittal systems for data collection and plan for training study personnel); 3) Define our recruitment strategy (confirming eligibility criteria, plans for recruitment and retention); 4) Finalize the Protocol (experimental design, hypotheses, imaging procedures, other outcomes, image and data analysis, sample size); and 5) Develop the procedures manual including establishing the means to assure standardization of procedures (evaluations, randomizations, treatment, follow-up, statistical analysis, administration). These efforts will lead to submission of an investigator- initiated grant application to the National Institute on Aging (NIA) to test the role of doxycycline for this problem with large public health impact. The public health impact of testing the safety and efficacy of doxycycline in the treatment of abdominal aortic aneurysms derives from the large number of patients (hundreds of thousands) who could avoid surgical or endograft therapy (costing in excess of $200,000,000 per year) or who could avoid being recommended an inefficacious therapy.