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.
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 open surgery or endograft repair (saving in excess of $500,000,000 per year) or, if we do not find doxycycline to be beneficial, who could avoid having an inefficacious therapy recommended. This clinical trial will be definitive for the management of small abdominal aortic aneurysm patients because progression to aneurysm repair is the state-of-the-art management for a known aneurysm that reaches a diameter threshold associated with increased risk of rupture.
|Sergin, Ismail; Bhattacharya, Somashubhra; Emanuel, Roy et al. (2016) Inclusion bodies enriched for p62 and polyubiquitinated proteins in macrophages protect against atherosclerosis. Sci Signal 9:ra2|
|Baxter, B Timothy; Matsumura, Jon; Curci, John et al. (2016) Non-invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (N-TA(3)CT): Design of a Phase IIb, placebo-controlled, double-blind, randomized clinical trial of doxycycline for the reduction of growth of small abdominal aortic aneurysm. Contemp Clin Trials 48:91-8|
|Dale, Matthew A; Xiong, Wanfen; Carson, Jeffrey S et al. (2016) Elastin-Derived Peptides Promote Abdominal Aortic Aneurysm Formation by Modulating M1/M2 Macrophage Polarization. J Immunol 196:4536-43|
|Engelbert, Travis L; Fernandes-Taylor, Sara; Gupta, Prateek K et al. (2014) Clinical characteristics associated with readmission among patients undergoing vascular surgery. J Vasc Surg 59:1349-55|
|Blose, Kory J; Ennis, Terri L; Arif, Batool et al. (2014) Periadventitial adipose-derived stem cell treatment halts elastase-induced abdominal aortic aneurysm progression. Regen Med 9:733-41|
|Airhart, Nathan; Brownstein, Bernard H; Cobb, J Perren et al. (2014) Smooth muscle cells from abdominal aortic aneurysms are unique and can independently and synergistically degrade insoluble elastin. J Vasc Surg 60:1033-41; discussion 1041-2|
|Curci, John A; Kraiss, Larry; Dalman, Ronald L et al. (2013) The Vascular Research Initiatives Conference and over 25 years of conversations on the science of vascular disease. J Vasc Surg 57:501-7|