Fenofibrate in the management of AbdoMinal aortic anEurysm (FAME)-2: the study protocol for a multi-centre, randomised, placebo-controlled trial

Authors

  • Sophie E. Rowbotham Queensland Research Centre for Peripheral Vascular Disease; College of Medicine and Dentistry, James Cook University, Townsville QLD 4811, Australia
  • Bernie Bourke Gosford Vascular Services, Gosford NSW 2250, Australia
  • Michael Bourke Queensland Research Centre for Peripheral Vascular Disease; College of Medicine and Dentistry, James Cook University, Townsville QLD 4811, Australia; Gosford Vascular Services, Gosford NSW 2250, Australia
  • Rene Jaeggi Queensland Research Centre for Peripheral Vascular Disease; College of Medicine and Dentistry, James Cook University, Townsville QLD 4811, Australia
  • Jason S. Jenkins Department of Vascular Surgery, The Royal Brisbane and Women’s Hospital, Herston QLD 4029, Australia
  • Joseph V. Moxon Queensland Research Centre for Peripheral Vascular Disease; College of Medicine and Dentistry, James Cook University, Townsville QLD 4811, Australia
  • Jenna L. Pinchbeck Queensland Research Centre for Peripheral Vascular Disease; College of Medicine and Dentistry, James Cook University, Townsville QLD 4811, Australia
  • Christopher M. Reid School of Public Health, Curtin University, Perth, WA 6000, Australia; School of Public Health and Preventive Medicine, Monash University, Melbourne VIC 3004, Australia
  • Ramesh Velu Department of Vascular and Endovascular Surgery, The Townsville Hospital, Townsville QLD 4814, Australia
  • Jonathan Golledge Department of Vascular and Endovascular Surgery, The Townsville Hospital, Townsville QLD 4814, Australia

DOI:

https://doi.org/10.18203/2349-3259.ijct20163960

Keywords:

Abdominal aortic aneurysm, Fenofibrate, Clinical trial, Osteopontin, Kallistatin

Abstract

Background: Abdominal aortic aneurysms (AAAs) are a leading cause of mortality worldwide but have no recognised medical therapy. Pre-clinical studies indicate that osteopontin plays an important role in the pathogenesis of AAA via a number of mechanisms. This trial aims to assess the potential of fenofibrate to favourably alter biomarkers associated with AAA pathology.

Methods: Fenofibrate in the management of AbdoMinal aortic anEurysm (FAME)-2 is a multi-centre, prospective, randomised, double-blind, placebo-controlled clinical trial to assess the effect of 24 weeks of oral therapy with 145 mg of fenofibrate on key pathological markers of AAA. A total of 140 participants with an AAA measuring between 35-49 mm will be randomly assigned to either 145 mg of fenofibrate once per day or identical placebo for a period of 24 weeks. Primary outcome measures will be serum concentrations of osteopontin and kallistatin. Secondary outcome measures will include serum levels of resistin, lipids, matrix metalloproteinases and pro-inflammatory cytokines, circulating concentrations of AAA biomarkers, and AAA diameter as assessed by ultrasound.

Conclusions: This study represents the next step in the assessment of a potential novel medical therapy for AAA.

References

Moxon JV, Parr A, Emeto TI, Walker P, Norman PE, Golledge J. Diagnosis and monitoring of abdominal aortic aneurysm: current status and future prospects. Curr Probl Cardiol. 2010;35(10):512-48.

Sakalihasan N, Limet R, Defawe OD. Defawe, Abdominal aortic aneurysm. Lancet. 2005;365(9470):1577-89.

Ashton HA, Buxton MJ, Day NE, Kim LG, Marteau TM, Scott RA, et al. The Multicentre Aneurysm Screening Study (MASS) into the effect of abdominal aortic aneurysm screening on mortality in men: a randomised controlled trial. Lancet. 2002;360(9345):1531-9.

Ashton HA, Gao IU, Kim LG, Scott RAP. Fifteen-year follow-up of a randomized clinical trial of ultrasonographic screening for abdominal aortic aneurysms. Br J Surg. 2007;94(6):696-701.

Lindholt, J.S., et al., Screening for abdominal aortic aneurysms: single centre randomised controlled trial. BMJ. 2005;330(7494):750.

Norman PE, Jamrozik K, Lawrence-Brown MM, Le MT, Spencer CA, Tuohy RJ, et al. Population based randomised controlled trial on impact of screening on mortality from abdominal aortic aneurysm. BMJ. 2004;329(7477):1259.

Scott RA, Bridgewater SG, Ashton HA. Randomized clinical trial of screening for abdominal aortic aneurysm in women. Br J Surg. 2002;89(3):283-5.

Rooke TW, Hirsch AT, Misra S, Sidawy AN, Beckman JA, Findeiss LK, et al. 2011 ACCF/AHA Focused Update of the Guideline for the Management of Patients With Peripheral Artery Disease (updating the 2005 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2011;58(19):2020-45.

Golledge J, Cullen B, Rush C, Moran CS, Secomb E, Wood F, et al. Peroxisome proliferator-activated receptor ligands reduce aortic dilatation in a mouse model of aortic aneurysm. Atherosclerosis. 2010;210(1):51-6.

Krishna SM, Seto SW, Moxon JV, Rush C, Walker PJ, Norman PE, et al. Fenofibrate increases high-density lipoprotein and sphingosine 1 phosphate concentrations limiting abdominal aortic aneurysm progression in a mouse model. Am J Pathol. 2012;181(2):706-18.

Bruemmer D, Collins AR, Noh G, Wang W, Territo M, Arias-Magallona S, et al. Angiotensin II-accelerated atherosclerosis and aneurysm formation is attenuated in osteopontin-deficient mice. J Clin Invest. 2003;112(9):1318-31.

Golledge J, Muller J, Shephard N, Clancy P, Smallwood L, Moran C, et al. Association between osteopontin and human abdominal aortic aneurysm. Arterioscler Thromb Vasc Biol. 2007;27(3):655-60.

Gavrila D, Li WG, McCormick ML, Thomas M, Daugherty A, Cassis LA, et al. Vitamin E inhibits abdominal aortic aneurysm formation in angiotensin II-infused apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol. 2005;25(8):1671-7.

Golledge J, Muller J, Daugherty A, Norman P. Abdominal aortic aneurysm: pathogenesis and implications for management. Arterioscler Thromb Vasc Biol. 2006;26(12):2605-13.

Ichihara S, Noda A, Nagata K, Obata K, Xu J, Ichihara G, et al. Attenuation of cardiac dysfunction by a PPAR-alpha agonist is associated with down-regulation of redox-regulated transcription factors. J Mol Cell Cardiol. 2006;41(2):318-29.

Park CW, Kim HW, Ko SH, Chung HW, Lim SW, Yang CW, et al. Accelerated diabetic nephropathy in mice lacking the peroxisome proliferator-activated receptor alpha. Diabetes. 2006;55(4):885-93.

Nakamachi T, Nomiyama T, Gizard F, Heywood EB, Jones KL, Zhao Y, et al. PPARalpha agonists suppress osteopontin expression in macrophages and decrease plasma levels in patients with type 2 diabetes. Diabetes. 2007;56(6):1662-70.

Guerin M, Bruckert E, Dolphin PJ, Turpin G, Chapman MJ. Fenofibrate reduces plasma cholesteryl ester transfer from HDL to VLDL and normalizes the atherogenic, dense LDL profile in combined hyperlipidemia. Arterioscler Thromb Vasc Biol. 1996;16(6):763-72.

Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005;366(9500):1849-61.

Otto C, Otto B, Frost RJA, Vogeser M, Pfeiffer AFH, Spranger J, et al. Short-term therapy with atorvastatin or fenofibrate does not affect plasma ghrelin, resistin or adiponectin levels in type 2 diabetic patients with mixed hyperlipoproteinaemia. Acta Diabetol. 2007;44(2):65-8.

Golledge J, Tsao PS, Dalman RL, Norman PE. Circulating markers of abdominal aortic aneurysm presence and progression. Circulation. 2008;118(23):2382-92.

Golledge J, van Bockxmeer F, Jamrozik K. Association between serum lipoproteins and abdominal aortic aneurysm. Am J Cardiol. 2010;105(10):1480-4.

Singh K, Bønaa KH, Jacobsen BK, Bjørk L, Solberg S. Prevalence of and risk factors for abdominal aortic aneurysms in a population-based study : The Tromso Study. Am J Epidemiol. 2001;154(3):236-44.

Golledge J, Clancy P, Jamrozik K, Norman PE. Obesity, adipokines, and abdominal aortic aneurysm: Health in Men study. Circulation. 2007;116(20):2275-9.

Krysiak R, Labuzek K, Okopien B. Effect of atorvastatin and fenofibric acid on adipokine release from visceral and subcutaneous adipose tissue of patients with mixed dyslipidemia and normolipidemic subjects. Pharmacol Rep. 2009;61(6):1134-45.

Police SB, Thatcher SE, Charnigo R, Daugherty A, Cassis LA. Obesity promotes inflammation in periaortic adipose tissue and angiotensin II-induced abdominal aortic aneurysm formation. Arterioscler Thromb Vasc Biol. 2009;29(10):1458-64.

Pyo R, Lee JK, Shipley JM, Curci JA, Mao D, Ziporin SJ, et al. Targeted gene disruption of matrix metalloproteinase-9 (gelatinase B) suppresses development of experimental abdominal aortic aneurysms. J Clin Invest. 2000;105(11):1641-9.

Agnihotri R, Crawford HC, Haro H, Matrisian LM, Havrda MC, Liaw L. Osteopontin, a novel substrate for matrix metalloproteinase-3 (stromelysin-1) and matrix metalloproteinase-7 (matrilysin). J Biol Chem. 2001;276(30):28261-7.

Takafuji V, Forgues M, Unsworth E, Goldsmith P, Wang XW. An osteopontin fragment is essential for tumor cell invasion in hepatocellular carcinoma. Oncogene. 2007;26(44):6361-71.

Lin R, Liu J, Gan W, Yang G. C-reactive protein-induced expression of CD40-CD40L and the effect of lovastatin and fenofibrate on it in human vascular endothelial cells. Biol Pharm Bull. 2004;27(10):1537-43.

Rival Y, Beneteau N, Chapuis V, Taillandier T, Lestienne F, Dupont-Passelaigue E, et al. Cardiovascular drugs inhibit MMP-9 activity from human THP-1 macrophages. DNA Cell Biol. 2004;23(5):283-92.

Shu H, Wong B, Zhou G, Li Y, Berger J, Woods JW, et al. Activation of PPARalpha or gamma reduces secretion of matrix metalloproteinase 9 but not interleukin 8 from human monocytic THP-1 cells. Biochem Biophys Res Commun. 2000;267(1):345-9.

Wolf WC, Harley RA, Sluce D, Chao L, Chao J. Localization and expression of tissue kallikrein and kallistatin in human blood vessels. J Histochem Cytochem. 1999;47(2):221-8.

Chao J, Stallone JN, Liang YM, Chen LM, Wang DZ, Chao L. Kallistatin is a potent new vasodilator. J Clin Invest. 1997;100(1):11-7.

Liu Y, Bledsoe G, Hagiwara M, Shen B, Chao L, Chao J. Depletion of endogenous kallistatin exacerbates renal and cardiovascular oxidative stress, inflammation, and organ remodeling. Am J Physiol Renal Physiol. 2012;303(8):230-8.

Lu SL, Tsai CY, Luo YH, Kuo CF, Lin WC, Chang YT, et al. Kallistatin modulates immune cells and confers anti-inflammatory response to protect mice from group A streptococcal infection. Antimicrob Agents Chemother. 2013;57(11):5366-72.

Wang CR, Chen SY, Wu CL, Liu MF, Jin YT, Chao L, et al. Prophylactic adenovirus-mediated human kallistatin gene therapy suppresses rat arthritis by inhibiting angiogenesis and inflammation. Arthritis Rheum. 2005;52(4):1319-24.

Yin H, Gao L, Shen B, Chao L, Chao J. Kallistatin inhibits vascular inflammation by antagonizing tumor necrosis factor-alpha-induced nuclear factor kappaB activation. Hypertension. 2010;56(2):260-7.

Shen B, Gao L, Hsu YT, Bledsoe G, Hagiwara M, Chao L, et al. Kallistatin attenuates endothelial apoptosis through inhibition of oxidative stress and activation of Akt-eNOS signaling. Am J Physiol Heart Circ Physiol. 2010;299(5):1419-27.

Huang KF, Huang XP , Xiao GQ , Yang HY , Lin JS , Diao Y. Kallistatin, a novel anti-angiogenesis agent, inhibits angiogenesis via inhibition of the NF-kappaB signaling pathway. Biomed Pharmacother. 2014;68(4):455-61.

Huang KF, Yang HY, Xing YM, Lin JS, Diao Y. Recombinant human kallistatin inhibits angiogenesis by blocking VEGF signaling pathway. J Cell Biochem. 2014;115(3):575-84.

Chen LM, Chao L, Chao J. Adenovirus-mediated delivery of human kallistatin gene reduces blood pressure of spontaneously hypertensive rats. Hum Gene Ther. 1997;8(3):341-7.

Chen LM, Ma J x, Liang YM, Chao L, Chao J. Tissue kallikrein-binding protein reduces blood pressure in transgenic mice. J Biol Chem. 1996;271(44):27590-4.

Biros, E, Walker PJ, Nataatmadja M, West M, Golledge J. Downregulation of transforming growth factor, beta receptor 2 and Notch signaling pathway in human abdominal aortic aneurysm. Atherosclerosis. 2012;221(2):383-6.

Smallwood L, Allcock R, van Bockxmeer F, Warrington N, Palmer LJ, Iacopetta B, et al. Polymorphisms of the matrix metalloproteinase 9 gene and abdominal aortic aneurysm. Br J Surg. 2008;95(10):1239-44.

Golledge J, Biros E, Cooper M, Warrington N, Palmer LJ, Norman PE. Apolipoprotein E genotype is associated with serum C-reactive protein but not abdominal aortic aneurysm. Atherosclerosis. 2010;209(2):487-91.

Rush C, Nyara M, Moxon JV, Trollope A, Cullen B, Golledge J. Whole genome expression analysis within the angiotensin II-apolipoprotein E deficient mouse model of abdominal aortic aneurysm. BMC Genomics. 2009;10:298.

Davis TM, Ting R, Best JD, Donoghoe MW, Drury PL, Sullivan DR. Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study. Diabetologia. 2011;54(2):280-90.

Golledge J, Norman PE. Current status of medical management for abdominal aortic aneurysm. Atherosclerosis. 2011;217(1):57-63.

Meijer CA, Stijnen T, Wasser MN, Hamming JF, van Bockel JH, Lindeman JH. Doxycycline for stabilization of abdominal aortic aneurysms: a randomized trial. Ann Intern Med. 2013;159(12):815-23.

Propanolol Aneurysm Trial Investigators. Propranolol for small abdominal aortic aneurysms: results of a randomized trial. J Vasc Surg. 2002.35(1):72-9.

Rughani, G, Robertson L, Clarke M. Medical treatment for small abdominal aortic aneurysms. Cochrane Database Syst Rev. 2012;9: CD009536.

Cao P, De Rango P, Verzini F, Parlani G, Romano L, Cieri E. Comparison of surveillance versus aortic endografting for small aneurysm repair (CAESAR): results from a randomised trial. Eur J Vasc Endovasc Surg. 2011;41(1):13-25.

Lederle FA, Wilson SE, Johnson GR, Reinke DB, Littooy FN, Acher CW, et al. Immediate repair compared with surveillance of small abdominal aortic aneurysms. N Engl J Med. 2002;346(19):1437-44.

Ouriel, K, Clair DG, Kent KC, Zarins CK. Endovascular repair compared with surveillance for patients with small abdominal aortic aneurysms. J Vasc Surg. 2010;51(5):1081-7.

United Kingdom Small Aneurysm Trial Participants. Long-term outcomes of immediate repair compared with surveillance of small abdominal aortic aneurysms. N Engl J Med. 2002;346(19):1445-52.

Downloads

Published

2016-10-22

Issue

Section

Original Research Articles