title: Evaluation of a new formulation of fenofibric acid, ABT-335, co-administered with statins : study design and rationale of a phase III clinical programme.
abstract: 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.
  
  
  METHODS
  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) [> or =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) [> or =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 enroll in a 12-month open-label extension study that will evaluate the long-term efficacy and safety of combination therapy.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Baylor College of Medicine, Houston, Texas, USA. jones@bcm.tmc.edu
authors.forename: Peter H
authors.initials: PH
authors.lastname: Jones
authors.forename: Harold E
authors.initials: HE
authors.lastname: Bays
authors.forename: Michael H
authors.initials: MH
authors.lastname: Davidson
authors.forename: Maureen T
authors.initials: MT
authors.lastname: Kelly
authors.forename: Susan M
authors.initials: SM
authors.lastname: Buttler
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Setze
authors.forename: Darryl J
authors.initials: DJ
authors.lastname: Sleep
authors.forename: James C
authors.initials: JC
authors.lastname: Stolzenbach
mesh_terms: D000704:Analysis of Variance; D000069059:Atorvastatin; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D050171:Dyslipidemias / Q000188:drug therapy*; D005260:Female; D011345:Fenofibrate / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005464:Fluorobenzenes / Q000009:adverse effects / Q000627:therapeutic use; D006538:Heptanoic Acids / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D000960:Hypolipidemic Agents / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D011446:Prospective Studies; D011743:Pyrimidines / Q000009:adverse effects / Q000627:therapeutic use; D011758:Pyrroles / Q000009:adverse effects / Q000627:therapeutic use; D012107:Research Design; D000068718:Rosuvastatin Calcium; D019821:Simvastatin / Q000009:adverse effects / Q000627:therapeutic use; D013449:Sulfonamides / Q000009:adverse effects / Q000627:therapeutic use; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: C533234:2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanoic acid; D005464:Fluorobenzenes; D006538:Heptanoic Acids; D000960:Hypolipidemic Agents; D011743:Pyrimidines; D011758:Pyrroles; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D000069059:Atorvastatin; D019821:Simvastatin; C006012:fenofibric acid; D011345:Fenofibrate
references.citation: Circulation. 2007 Jan 30;115(4):450-8
references.pmid: 17190864
references.citation: Circulation. 2004 Jul 13;110(2):227-39
references.pmid: 15249516
references.citation: Am J Med. 2006 Aug;119(8):676-83
references.pmid: 16887414
references.citation: Am J Med. 1977 May;62(5):707-14
references.pmid: 193398
references.citation: Circulation. 2007 Mar 20;115(11):1363-70
references.pmid: 17353444
references.citation: Am J Cardiol. 1999 May 1;83(9):1303-7
references.pmid: 10235085
references.citation: Am J Cardiol. 2002 Mar 7;89(5A):50C-57C
references.pmid: 11900720
references.citation: Circulation. 2006 May 16;113(19):2363-72
references.pmid: 16702489
references.citation: J Am Coll Cardiol. 2008 Feb 19;51(7):724-30
references.pmid: 18279736
references.citation: Curr Med Res Opin. 2007 Mar;23(3):553-63
references.pmid: 17357251
references.citation: Am J Cardiol. 2006 Nov 1;98(9):1231-3
references.pmid: 17056335
references.citation: Diabetes Care. 2004 Oct;27(10):2444-9
references.pmid: 15451914
references.citation: Am Heart J. 2006 Nov;152(5):976-81
references.pmid: 17070174
references.citation: Am J Cardiol. 2003 Jul 15;92(2):152-60
references.pmid: 12860216
references.citation: Circulation. 2002 Dec 17;106(25):3143-421
references.pmid: 12485966
references.citation: Curr Atheroscler Rep. 2004 Mar;6(2):148-57
references.pmid: 15023300
references.citation: Diabetes Res Clin Pract. 2004 May;64(2):137-51
references.pmid: 15063607
references.citation: Circulation. 1992 Jan;85(1):37-45
references.pmid: 1728471
references.citation: Prev Cardiol. 2007 Winter;10(1):31-5
references.pmid: 17215631
references.citation: Curr Med Res Opin. 2003;19(3):155-68
references.pmid: 12814127
references.citation: Diabetes Care. 2002 Jul;25(7):1198-202
references.pmid: 12087019
references.citation: Diabetes Care. 2007 Jan;30 Suppl 1:S4-S41
references.pmid: 17192377
references.citation: Am J Cardiol. 1992 Sep 15;70(7):733-7
references.pmid: 1519522
references.citation: Ann Pharmacother. 2001 Jul-Aug;35(7-8):908-17
references.pmid: 11485144
references.citation: Curr Treat Options Cardiovasc Med. 2007 Aug;9(4):249-58
references.pmid: 17761110
references.citation: Eur J Cardiovasc Prev Rehabil. 2007 Sep;14 Suppl 2:S1-113
references.pmid: 17726407
references.citation: J Cardiovasc Risk. 1996 Apr;3(2):213-9
references.pmid: 8836866
references.citation: Am J Cardiol. 2002 Jul 15;90(2):139-43
references.pmid: 12106843
references.citation: J Manag Care Pharm. 2006 Nov-Dec;12(9):745-51
references.pmid: 17249907
references.citation: Am J Cardiol. 1992 Dec 14;70(19):10H-13H
references.pmid: 1466311
references.citation: Semin Vasc Med. 2002 Aug;2(3):325-33
references.pmid: 16222622
references.citation: JAMA. 2001 May 16;285(19):2486-97
references.pmid: 11368702
references.citation: N Engl J Med. 2007 Sep 27;357(13):1301-10
references.pmid: 17898099
references.citation: J Am Coll Cardiol. 2005 Apr 5;45(7):1003-12
references.pmid: 15808755
references.citation: Heart. 2005 Dec;91 Suppl 5:v1-52
references.pmid: 16365341
references.citation: Am J Cardiol. 2005 Feb 15;95(4):462-8
references.pmid: 15695129
references.citation: Natl Vital Stat Rep. 2007 Aug 21;55(19):1-119
references.pmid: 17867520
references.citation: J Am Coll Cardiol. 2005 May 17;45(10):1649-53
references.pmid: 15893182
references.citation: Circulation. 2003 Jul 29;108(4):414-9
references.pmid: 12860911
references.citation: Expert Opin Drug Saf. 2006 Jan;5(1):145-56
references.pmid: 16370963