Non-Invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (N-TA^3CT )

描述(申请人提供)：腹主动脉瘤(AAA)是一种常见的(2-5%的65岁人口：4-9%的男性，0.5-1.5%的女性)和致命的问题，每年导致15,000人因破裂而死亡。唯一接受的治疗是AAA的修复，这在美国每年为40,000大型AAA进行。随着最近的广泛筛查，将检测到更多的小AAA(男性5.0厘米，女性4.5厘米)。AAA的自然历史是扩张到一个破裂的风险大大增加的大小。目前还没有得到证实的医学干预措施可以阻止或延缓这种进展，而且手术选择对于小动脉瘤来说是昂贵的和不必要的风险。有实验和临床证据表明，基质金属蛋白酶(MMPs)家族参与了AAA的发生和发展。最近来自实验室、动物模型和观察性研究的证据表明，多西环素作为一种基质金属蛋白酶抑制剂，可以防止AAA的进展。最近的研究表明：(1)多西环素可以抑制实验性腹主动脉瘤的生长；(2)抑制主动脉平滑肌细胞和移植瘤组织中基质金属蛋白酶的产生；(3)在动脉瘤修补术前患者接受治疗时，降低动脉瘤组织中基质金属蛋白酶的表达；(4)降低腹主动脉瘤患者循环中的基质金属蛋白酶水平；(5)在有限的临床试验中，降低小腹主动脉瘤的生长速度。我们已经证明，小AAA患者对多西环素耐受性良好。我们将汇集在血管外科、临床试验设计、数据分析和管理、AAA图像分析以及反映动脉瘤生长的循环生物标记物分析方面的专业研究人员。我们将测试与多西环素是否(40%)抑制肾下AAA(男性3.5-5.0厘米，女性3.5-4.5厘米)生长有关的主要和次要假说和作用机制。我们将在24个月的时间内确定多西环素对所有患者小AAA扩张率的影响，并考虑到因原因(死亡或动脉瘤修复)或不明原因而导致的结果缺失。这将通过一项针对248名患者的前瞻性、双盲、安慰剂对照临床试验来完成。患者将被随机分配接受安慰剂或多西环素(100 mg，2次)。主要终点将是通过半年一次的CT扫描确定的动脉瘤生长速度。测试多西环素治疗腹主动脉瘤的安全性和有效性对公众健康的影响源于没有任何药物治疗来避免开放手术或移植物内修复。在没有药物治疗的情况下，超声波筛查只在选定的患者中被认为是经济有效的。有效的药物治疗将使早期发现更容易被接受，因为它提供了一种替代侵入性修复AAA的方法。

DESCRIPTION (provided by applicant): Abdominal aortic aneurysms (AAA) are a common (2-5% of the population e 65 years: 4-9% men; 0.5- 1.5% women) and lethal problem causing 15,000 deaths annually 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 (<5.0 cm in men, <4.5 cm in women) AAA 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, and surgical options are expensive and unnecessarily risky 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. Recent evidence from laboratory, animal models and observational studies demonstrate that doxycycline, working as an MMP inhibitor, can prevent progression of AAA. In recent studies, doxycycline has been shown to: (1) inhibit the growth of experimental abdominal aortic aneurysms; (2) inhibit MMP production in aortic smooth muscle cells and in explanted aneurysm tissue; (3) reduce MMP expression in aneurysm tissue when patients are treated prior to operation for aneurysm repair; (4) reduce circulating MMP levels in AAA patients; (5) decrease the growth rate of small AAA in a limited clinical trial. We have demonstrated that doxycycline is well-tolerated in patients with small AAA. 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. We will test primary and secondary hypotheses and mechanisms of action related to whether or not doxycycline will inhibit (>40%) the growth of small (3.5 - 5.0 cm in men, 3.5 - 4.5 cm in women) infrarenal AAA. We will determine the effects of doxycycline on the expansion rate of small AAA over a 24-month period for all patients with allowance made for outcomes missing for cause (death or aneurysm repair) or undetermined reasons. This will be done through a prospective, double blind, placebo controlled clinical trial of 248 patients. Patients will be randomly assigned to receive placebo or doxycycline (100 mg bid). The primary end point will be aneurysm growth rate determined by semiannual CT scan. The public health impact of testing the safety and efficacy of doxycycline in the treatment of abdominal aortic aneurysms derives from the absence of any medical therapy to avoid open surgery or endograft repair. Without medical therapy, ultrasound screening is considered cost-effective in selected patients only. Effective medical therapy would make early detection even more acceptable by providing an alternative to invasive repair of AAA.