Study of Trilipix Effects on Lipids and Arteries

Mechanisms of Atheroprotection by Fenofibric Acid (ABT 335) Added to a Statin in Subjects With Insulin Resistance (Hypertriglyceridemia and Low HDL-C)

Fibrates reduce atherosclerosis and cardiovascular disease events. A major mechanism of this benefit appears to be their ability to raise plasma high density lipoprotein cholesterol (HDL-C), especially in patients with high triglyceride levels. This study will investigate the effects of the addition of Trilipix (fenofibric acid) versus placebo to ongoing statin treatment on high density lipoprotein (HDL) composition and arterial function in subjects with insulin resistance.

Study Overview

• Status: Terminated
• Conditions: Dyslipidemia
• Intervention / Treatment: Drug: Trilipix; Drug: placebo

Detailed Description

The field of lipid treatment for atheroprevention, and of HDL-raising in particular, was shaken by the unexpected finding of a net adverse clinical effect of torcetrapib, a Cholesteryl ester transfer protein (CETP) inhibitor with HDL-raising effects far more dramatic than that of niacin or fenofibrate.

Trilipix (ABT 335, choline fenofibrate, or fenofibric acid) is approved by the FDA (12/2008) for treatment of dyslipidemia and may act as a new fibrate for treatment of dyslipidemia and atheroprevention. It is the first fibrate with sufficient evidence for safety in combination use with a statin to receive an FDA indication for that combination use. Thus, there is minimal safety risk to prospective research subjects, who in any case will have the very dyslipidemia for which this combination is approved and recommended. With the ongoing development of this agent through a time of great scientific controversy regarding torcetrapib and HDL, it is urgent to explore the HDL-related mechanisms by which Trilipix may be atheroprotective, with special attention to changes in HDL composition and function.

Novel methods have been developed for measuring HDL composition and function and have been added to state-of-the-art technologies to assemble the uniquely comprehensive panel of HDL parameters in this study. Such methods can now be employed in exploring potentially beneficial effects of promising HDL-active agents such as Trilipix. In addition, improvements in HDL with fibrates appear to be related to other favorable lipoprotein changes, such as reduced remnant levels and increased LDL particle size, and these likely help explain arterial benefits with these agents.

The recent advent and validation of many non-invasive methods for measuring arterial function allows characterization of arterial effects of lipid agents in a time- and cost-effective way, alternative to standard event-driven trials. This study offers a uniquely comprehensive panel of these arterial parameters in order to characterize the likely atheropreventive effects of Trilipix.

This study will investigate changes in both panels of endpoints (state-of-the-art measures of HDL and related lipoproteins, and of arterial function) with Trilipix, which will more clearly and broadly define the benefits of this agent than has been done for any other lipid therapy. In addition, analyses of the intercorrelations of the changes among these several parameters should strongly suggest mechanisms of atheropreventive benefits of Trilipix.

Finally, with regard to subject selection, most patients with insulin resistance are at high risk for atherosclerosis, even those without concurrent diabetes mellitus. Importantly, favorable effects of fibrates are most pronounced in patients with insulin resistance, whether manifested traditionally by central obesity, adiposity, glucose and insulin abnormalities. Beta-cell dysfunction, generally seen in conjunction with insulin resistance, might also predict benefit with fibrate therapy. Body composition (as adiposity or central obesity) is a strong correlate of these abnormalities and will be measured during the study. Already at present, and more so in the future, the standard of care for insulin resistant patients will be statin monotherapy. In addition, however, fibrates are being increasingly advocated as adjunctive therapy for patients with residual abnormalities of triglyceride and HDL-C after statin monotherapy. Thus, the best way to assess the likely benefits of Trilipix in the usual clinical practice setting is to do so against a background of stable statin therapy.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Triglyceride 150-500 mg/dL
• HDL-C < 45 mg/dL in men, < 55 in women
• LDL-C < 130 mg/dL
• stable statin dose x 8 weeks

Exclusion Criteria:

• Prior use of a fibrate > 4 weeks ever (minimum 12 months off fibrate)
• Intolerance to medications to be used in study (fenofibric acid, albuterol, nitroglycerin)
• Niacin or thiazolidinedione within the prior 12 months, or anticipated need to add either during 6-month study period
• Diabetes Mellitus if either (1) diagnosed less than 3 months ago, (2) treated with insulin, or (3) with an A1c >8%
• Anticipated need to change treatment regimen of statin (or other lipid agent) or glycemic treatment during 6-month study period
• Uncontrolled hypertension (BP > 140/90 mm Hg), or changes in BP meds within prior 4 weeks, or anticipated need to change BP meds during 6-month study period
• Documented cardiovascular disease event (heart attack, stroke, or hospitalization for unstable angina or revascularization procedure) in the past 6 months
• Use of warfarin (potential to interact adversely with fibrate therapy)
• Uncontrolled thyroid disease (TSH outside of normal range)
• Renal insufficiency (calculated Glomerular Filtration Rate <50 ml/min)
• Hepatic disease (ALT > 1.5x Upper Limit of Normal, diagnosis of hepatitis, cirrhosis)
• Active cholecystitis/cholelithiasis
• Active cancer (except basal cell or squamous cell skin cancer)
• Pregnancy, plan/desire to become pregnant, breast feeding
• Inability or unwillingness to provide informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Trilipix; Trilipix (fenofibric acid) 135 mg tablet orally, once daily for 12 weeks	Drug: Trilipix; 135 mg po daily; Other Names: fenofibric acid
Placebo Comparator: Placebo; Matching placebo tablet orally, once daily for 12 weeks	Drug: placebo; one tablet po daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Apolipoprotein A-I Serum Concentration	Comparison of apolipoprotein A-I concentrations after 12 weeks of treatment with either Trilipix or placebo	12 weeks

Collaborators and Investigators

• Sponsor: University of Utah
• Collaborators: Abbott
• Investigators: Principal Investigator: Eliot Brinton, MD, University of Utah

Study record dates

Study Major Dates

• Study Start: November 1, 2009
• Primary Completion (Actual): March 1, 2011
• Study Completion (Actual): March 1, 2011

Study Registration Dates

• First Submitted: December 1, 2009
• First Submitted That Met QC Criteria: December 2, 2009
• First Posted (Estimate): December 3, 2009

Study Record Updates

• Last Update Posted (Estimate): September 1, 2016
• Last Update Submitted That Met QC Criteria: July 19, 2016
• Last Verified: July 1, 2016

More Information

Terms related to this study

• Keywords: high density lipoprotein; arterial compliance; brachial artery flow-mediated dilatation
• Additional Relevant MeSH Terms: Metabolic Diseases; Lipid Metabolism Disorders; Dyslipidemias; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Fenofibric acid
• Other Study ID Numbers: 00030151

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No