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65岁以上人口的2-5%：4-9%为男性; 0.5- 1.5%的女性）和致命问题，在美国每年造成15，000例破裂死亡。唯一接受的治疗是AAA修复术，在美国每年对40，000例大型AAA进行修复。广泛的筛查，将检测到更多的小AAA（男性<5.0 cm，女性<4.5 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迟这种进展，对于小动脉瘤来说，手术选择是昂贵的，而且有不必要的风险。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。实验室、动物模型和观察性研究的最新证据表明，多西环素作为MMP抑制剂，可以预防AAA的进展。在最近的研究中，多西环素已显示：（1）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动脉瘤组织中MMP的产生;（3）当患者在动脉瘤修复手术前接受治疗时，降低动脉瘤组织中MMP的表达;（4）降低AAA患者的循环MMP水平;（5）在有限的临床试验中降低小AAA的生长速度。我们已经证明，多西环素在小AAA患者中耐受性良好。 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。我们将检验与多西环素是否会抑制（>40%）肾下小AAA（男性3.5 - 5.0 cm，女性3.5 - 4.5 cm）生长相关的主要和次要假设和作用机制。我们将确定24个月期间多西环素对所有患者的小AAA扩张率的影响，并考虑因原因（死亡或动脉瘤修复）或原因不明而缺失的结局。这将通过248例患者的前瞻性、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 bid）。主要终点将是通过半年一次的CT扫描确定的动脉瘤生长率。 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于没有任何药物治疗来避免开放手术或覆膜支架修复。在没有药物治疗的情况下，超声筛查仅被认为对选定的患者具有成本效益。有效的药物治疗将使早期检测更容易接受，因为它提供了一种替代AAA侵入性修复的方法。

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.