Clinical Drug Investigation

, Volume 28, Issue 10, pp 625–634 | Cite as

Evaluation of a New Formulation of Fenofibric Acid, ABT-335,Co-Administered with Statins

Study Design and Rationale of a Phase III Clinical Programme
  • Peter H. Jones
  • Harold E. Bays
  • Michael H. Davidson
  • Maureen T. Kelly
  • Susan M. Buttler
  • Carolyn M. Setze
  • Darryl J. Sleep
  • James C. Stolzenbach
Original Research Article


Background and objective:

Atherogenic lipid parameters in patients with mixed dyslipidaemia have been demonstrated to increase atherosclerotic coronary heart disease (CHD) risk. Clinical studies have shown that HMG-CoA reductase inhibitor (statin) and fibric acid derivative (fibrate) combination therapy is effective at improving multiple lipid abnormalities in different patient populations at increased risk of CHD. However, inconsistencies with respect to trial designs and safety issues have limited the clinical use of this combination therapy. A comprehensive, controlled clinical trial programme was thus designed to evaluate three separate statins in combination with ABT-335, a new formulation of fenofibric acid.


Three separate 22-week, phase III, double-blind, active-controlled trials will evaluate combination therapy with ABT-335 135 mg/day and either rosuvastatin (10 mg/day and 20 mg/day), atorvastatin (20 mg/day and 40 mg/day) or simvastatin (20 mg/day and 40 mg/day) in comparison to either ABT-335 or the corresponding statin monotherapy. An approximate total of 2400 patients with elevated triglycerides (TG) [≥150 mg/dL], reduced high-density lipoprotein cholesterol (HDL-C) [<40 mg/dL for men and <50 mg/dL for women], and elevated low-density lipoprotein cholesterol (LDL-C) [≥130 mg/dL] will be randomized to one of six intervention arms per trial (two combination therapy and four monotherapy groups). The pre-specified primary efficacy endpoint is a composite of the mean percent changes in HDL-C and TG (comparing each combination therapy with the corresponding statin monotherapy dose) and LDL-C (comparing each combination therapy with ABT-335 monotherapy). Secondary endpoints include mean percent changes in non-HDL-C, very LDL-C, total cholesterol, apolipoprotein B and high sensitivity C-reactive protein levels. At study end, patients may enrol in a 12-month open-label extension study that will evaluate the longterm efficacy and safety of combination therapy.


This is the largest phase III randomized, controlled clinical programme to date evaluating the efficacy and safety of the combined use of a new formulation of fenofibric acid (ABT-335) with three commonly prescribed statins in patients with mixed dyslipidaemia.



Abbott provided financial support for the study design, collection of data, and manuscript writing. Dr Peter Jones has served as a consultant and a member of advisory panels and/or speakers’ bureaus for Abbott, AstraZeneca and Merck. He has also received research support from Abbott and AstraZeneca. Dr Harold Bays has received research grants from and served as a consultant, speaker and/or advisor to Abbott, AstraZeneca, Merck, Merck/Schering Plough and Pfizer. Dr Michael Davidson has received research support and an honorarium and served as a consultant/on speakers’ bureaus for Abbott, AstraZeneca, Merck and Pfizer. Dr Maureen Kelly, Susan Buttler, Carolyn Setze, Dr Darryl Sleep and Dr James Stolzenbach are employed by Abbott. Dr Erin Blondell provided assistance in manuscript writing and preparation.


  1. 1.
    Assmann G, Schulte H. Role of triglycerides in coronary artery disease: lessons from the Prospective Cardiovascular Munster Study. Am J Cardiol 1992 Dec 14; 70(19): 10H–3HPubMedCrossRefGoogle Scholar
  2. 2.
    Assmann G, Schulte H. Relation of high-density lipoprotein cholesterol and triglycerides to incidence of atherosclerotic coronary artery disease (the PROCAM experience). Prospective Cardiovascular Munster study. Am J Cardiol 1992 Sep 15; 70(7): 733–7PubMedCrossRefGoogle Scholar
  3. 3.
    Gordon T, Castelli WP, Hjortland MC, et al. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med 1977 May; 62(5): 707–14PubMedCrossRefGoogle Scholar
  4. 4.
    Manninen V, Tenkanen L, Koskinen P, et al. Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study: implications for treatment. Circulation 1992 Jan; 85(1): 37–45PubMedCrossRefGoogle Scholar
  5. 5.
    Hopkins PN, Wu LL, Hunt SC, et al. Plasma triglycerides and type III hyperlipidemia are independently associated with premature familial coronary artery disease. J Am Coll Cardiol 2005 Apr 5; 45(7): 1003–12PubMedCrossRefGoogle Scholar
  6. 6.
    Barter P, Gotto AM, LaRosa JC, et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med 2007 Sep 27; 357(13): 1301–10PubMedCrossRefGoogle Scholar
  7. 7.
    Abdel-Maksoud MF, Hokanson JE. The complex role of triglycerides in cardiovascular disease. Semin Vasc Med 2002 Aug; 2(3): 325–33PubMedCrossRefGoogle Scholar
  8. 8.
    Minino AM, Heron MP, Murphy SL, et al. Deaths: final data for 2004. Natl Vital Stat Rep 2007, 55: 1–119PubMedGoogle Scholar
  9. 9.
    Sarwar N, Danesh J, Eiriksdottir G, et al. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies. Circulation 2007 Jan 30; 115(4): 450–8PubMedCrossRefGoogle Scholar
  10. 10.
    Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002 Dec 17; 106(25): 3143–421Google Scholar
  11. 11.
    American Diabetes Association. Standards of medical care in diabetes: 2007. Diabetes Care 2007 Jan; 30 Suppl. 1: S4-S41Google Scholar
  12. 12.
    Graham I, Atar D, Borch-Johnsen K, et al. European guidelines on cardiovascular disease prevention in clinical practice: full text. Fourth Joint Task Force of the European Society of Cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of nine societies and by invited experts). Eur J Cardiovasc Prev Rehabil 2007 Sep; 14Suppl. 2: S1–113PubMedCrossRefGoogle Scholar
  13. 13.
    Executive summary of the third report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001 May 16; 285 (19): 2486-97Google Scholar
  14. 14.
    Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004 Jul 13; 110(2): 227–39PubMedCrossRefGoogle Scholar
  15. 15.
    Sacks FM. The role of high-density lipoprotein (HDL) cholesterol in the prevention and treatment of coronary heart disease: expert group recommendations. Am J Cardiol 2002 Jul 15; 90(2): 139–43PubMedCrossRefGoogle Scholar
  16. 16.
    Alsheikh-Ali AA, Lin JL, Abourjaily P, et al. Extent to which accepted serum lipid goals are achieved in a contemporary general medical population with coronary heart disease risk equivalents. Am J Cardiol 2006 Nov 1; 98(9): 1231–3PubMedCrossRefGoogle Scholar
  17. 17.
    Ansell BJ, Fonarow GC, Maki KC, et al. Reduced treatment success in lipid management among women with coronary heart disease or risk equivalents: results of a national survey. Am Heart J 2006 Nov; 152(5): 976–81PubMedCrossRefGoogle Scholar
  18. 18.
    Ford ES, Giles WH, Mokdad AH. Increasing prevalence of the metabolic syndrome among US adults. Diabetes Care 2004 Oct; 27(10): 2444–9PubMedCrossRefGoogle Scholar
  19. 19.
    Stacy TA, Egger A. Results of retrospective chart review to determine improvement in lipid goal attainment in patients treated by high-volume prescribers of lipid-modifying drugs. J Manag Care Pharm 2006 Nov-Dec; 12(9): 745–51PubMedGoogle Scholar
  20. 20.
    Stanek EJ, Sarawate C, Willey VJ, et al. Risk of cardiovascular events in patients at optimal values for combined lipid parameters. Curr Med Res Opin 2007 Mar; 23(3): 553–63PubMedCrossRefGoogle Scholar
  21. 21.
    Sattar N, Gaw A, Scherbakova O, et al. Metabolic syndrome with and without C-reactive protein as a predictor of coronary heart disease and diabetes in the West of Scotland Coronary Prevention Study. Circulation 2003 Jul 29; 108(4): 414–9PubMedCrossRefGoogle Scholar
  22. 22.
    JBS 2: Joint British Societies’ guidelines on prevention of cardiovascular disease in clinical practice. Heart 2005 Dec; 91Suppl. 5: v1–52Google Scholar
  23. 23.
    Keevil JG, Cullen MW, Gangnon R, et al. Implications of cardiac risk and low-density lipoprotein cholesterol distributions in the United States for the diagnosis and treatment of dyslipidemia: data from National Health and Nutrition Examination Survey 1999 to 2002. Circulation 2007 Mar 20; 115(11): 1363–70PubMedCrossRefGoogle Scholar
  24. 24.
    Sueta CA, Chowdhury M, Boccuzzi SJ, et al. Analysis of the degree of undertreatment of hyperlipidemia and congestive heart failure secondary to coronary artery disease. Am J Cardiol 1999 May 1; 83(9): 1303–7PubMedCrossRefGoogle Scholar
  25. 25.
    Yan AT, Yan RT, Tan M, et al. Contemporary management of dyslipidemia in high-risk patients: targets still not met. Am J Med 2006 Aug; 119(8): 676–83PubMedCrossRefGoogle Scholar
  26. 26.
    Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. J Cardiovasc Risk 1996 Apr; 3(2): 213–9PubMedCrossRefGoogle Scholar
  27. 27.
    Miller M, Cannon CP, Murphy SA, et al. Impact of triglyceride levels beyond low-density lipoprotein cholesterol after acute coronary syndrome in the PROVE IT-TIMI 22 trial. J Am Coll Cardiol 2008 Feb 19; 51(7): 724–30PubMedCrossRefGoogle Scholar
  28. 28.
    Goldberg AC. Combination therapy of dyslipidemia. Curr Treat Options Cardiovasc Med 2007 Aug; 9(4): 249–58PubMedCrossRefGoogle Scholar
  29. 29.
    Miller M. Optimal treatment of dyslipidemia in high-risk patients: intensive statin treatment or combination therapy? Prev Cardiol 2007 Winter; 10(1): 31–5PubMedCrossRefGoogle Scholar
  30. 30.
    Shek A, Ferrill MJ. Statin-fibrate combination therapy. Ann Pharmacother 2001 Jul-Aug; 35(7-8): 908–17PubMedCrossRefGoogle Scholar
  31. 31.
    Stein EA. Managing dyslipidemia in the high-risk patient. Am J Cardiol 2002 Mar 7; 89(5A): 50C–7CPubMedCrossRefGoogle Scholar
  32. 32.
    Wierzbicki AS, Mikhailidis DP, Wray R, et al. Statin-fibrate combination: therapy for hyperlipidemia. A review. Curr Med Res Opin2003; 19(3): 155–68PubMedCrossRefGoogle Scholar
  33. 33.
    Athyros VG, Papageorgiou AA, Athyrou VV, et al. Atorvastatin and micronized fenofibrate alone and in combination in type 2 diabetes with combined hyperlipidemia. Diabetes Care 2002 Jul; 25(7): 1198–202PubMedCrossRefGoogle Scholar
  34. 34.
    Durrington PN, Tuomilehto J, Hamann A, et al. Rosuvastatin and fenofibrate alone and in combination in type 2 diabetes patients with combined hyperlipidaemia. Diabetes Res Clin Pract 2004 May; 64(2): 137–51PubMedCrossRefGoogle Scholar
  35. 35.
    Grundy SM, Vega GL, Yuan Z, et al. Effectiveness and tolerability of simvastatin plus fenofibrate for combined hyperlipidemia (the SAFARI trial). Am J Cardiol 2005 Feb 15; 95(4): 462–8PubMedCrossRefGoogle Scholar
  36. 36.
    Koh KK, Quon MJ, Han SH, et al. Additive beneficial effects of fenofibrate combined with atorvastatin in the treatment of combined hyperlipidemia. J Am Coll Cardiol 2005 May 17; 45(10): 1649–53PubMedCrossRefGoogle Scholar
  37. 37.
    Davidson MH. Statin/fibrate combination in patients with metabolic syndrome or diabetes: evaluating the risks of pharmacokinetic drug interactions. Expert Opin Drug Saf 2006 Jan; 5(1): 145–56PubMedCrossRefGoogle Scholar
  38. 38.
    Fazio S, Linton MF. The role of fibrates in managing hyperlipidemia: mechanisms of action and clinical efficacy. Curr Atheroscler Rep} 2004; 6 148-57Google Scholar
  39. 39.
    Zocor (simvastatin) product package insert. West Point (PA): Merck & Co., Inc., Jun 2008Google Scholar
  40. 40.
    Lipitor (atorvastatin calcium) product package insert. New York (NY): Pfizer Inc., Nov 2007Google Scholar
  41. 41.
    Crestor (rosuvastatin calcium) product package insert. Wilmington (DE): AstraZeneca Pharmaceuticals LP, Nov 2007Google Scholar
  42. 42.
    TriCor (fenofibrate tablets) product package insert. Abbott Park (IL): Abbott, Oct 2007Google Scholar
  43. 43.
    American Heart Association. An eating plan for healthy Americans: our American Heart Association diet. AHA publication no. 50-1481AGoogle Scholar
  44. 44.
    Rifai N, Warnick GR, Dominiczak MH, editors. Handbook of lipoprotein testing. 2nd ed. Washington, DC: AACC Press, 2000Google Scholar
  45. 45.
    Jones PH, Davidson MH, Stein EA, et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial). Am J Cardiol 2003 Jul 15; 92(2): 152–60PubMedCrossRefGoogle Scholar
  46. 46.
    Smith Jr SC, Allen J, Blair SN, et al. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update. Endorsed by the National Heart, Lung, and Blood Institute. Circulation 2006 May 16; 113(19): 2363–72PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2008

Authors and Affiliations

  • Peter H. Jones
    • 1
  • Harold E. Bays
    • 2
  • Michael H. Davidson
    • 3
  • Maureen T. Kelly
    • 4
  • Susan M. Buttler
    • 4
  • Carolyn M. Setze
    • 4
  • Darryl J. Sleep
    • 4
  • James C. Stolzenbach
    • 4
  1. 1.Baylor College of MedicineHoustonUSA
  2. 2.Louisville Metabolic and Atherosclerosis Research CenterLouisvilleKentuckyUSA
  3. 3.Pritzker School of MedicineUniversity of ChicagoChicagoUSA
  4. 4.AbbottAbbott ParkUSA

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