ABT-335 (Choline Fenofibrate) Reverse Cholesterol Transport (RCT) Study

Study Overview
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Brief Summary
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The objectives of the study are: To evaluate the effect of ABT-335 (choline fenofibrate) on several parameters of RCT (reverse cholesterol transport) in men and post-menopausal women diagnosed with dyslipidemia (i.e., low high-density lipoprotein [HDL] cholesterol levels and elevated triglyceride [TG] concentrations). To evaluate longitudinal changes in several parameters of RCT in subjects with low HDL. To obtain pilot data for power calculations for subsequent comparative study.

Detailed Description
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This trial assesses the effects of ABT-335 on RCT as measured by cholesterol efflux or rate of appearance of cholesterol (Ra in mg/kg/hr), cholesterol excretion (%/day), RCT efflux (mg/kg/day) and de novo cholesterol synthesis (%) during a baseline period (7 days) and during a treatment period (94 days). The goal of using RCT to reverse atherosclerosis is to increase the rate of cholesterol export or efflux from the tissues and plaques. An increase in this cholesterol efflux rate should shrink arterial plaques by decreasing their static accumulation of cholesterol. While some currently marketed drugs have a positive impact on RCT by increasing the rate of cholesterol excretion from the body, no drug has yet been approved to increase the rate of cholesterol efflux from the tissues

Official Title
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ABT-335 (Choline Fenofibrate)Reverse Cholesterol Transport (RCT) Study

Conditions
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Dyslipidemia

Intervention / Treatment
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* Drug: choline fenofibrate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male, non-smoker, 21 - 75 years of age inclusive. Female, non-smoker, 40 - 75 years of age inclusive. Post-menopausal women, as defined by lack of menses for at least 2 years and age > 55, OR history of documented bilateral surgical oophorectomy, confirmed with an elevated follicle-stimulating hormone (FSH) at screening. HDL concentration (≤ 50 mg/dl women, ≤ 40mg/dl men) TG concentration 150-500 mg/dl, inclusive Ability to give informed consent Exclusion Criteria: Subject has history of diabetes mellitus, active hepatitis, gall bladder disease, gastric bypass surgery, or clinically significant abnormalities on screening (prestudy) physical examination or laboratory tests. Screening laboratory tests with hematocrit <30%, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) > 2X upper limit of normal, abnormal thyroid-stimulating hormone (TSH), fasting glucose ≥126 mg/dl. Renal impairment with creatinine clearance < 80 ml/min. Treatment within the last 6 months with drugs known to alter lipid metabolism including beta blockers, thiazide diuretics, bile acid resins, ezetimibe, fibrates, niacin, and fish oils (see Appendix 1). Washout of fibrates is not permitted. Treatment with drugs known to interact with ABT-335, e.g., warfarin (see Appendix 1). Treatment with HMG CoA reductase inhibitors (statins) within the past 4 weeks (see Appendix 1). History of allergy to egg or soy products. History of coronary heart disease (CHD), stroke or revascularization procedure in the six months prior to Visit 1. Current or recent history (past 12 months) of drug abuse or alcohol abuse. Alcohol abuse will be defined as >14 drinks per week (1 drink = 12 oz beer, 5 oz wine, or 1.5 oz hard liquor). Participation in another clinical trial or exposure to any investigational agent within 30 days before visit 1. Individual has a condition the Principal Investigator believes would interfere with his/her ability to provide informed consent, comply with study instructions, or which might confound the interpretation of the study results or put the subject at undue risk.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Abt-335<br>ABT-335 (choline fenofibrate) | Drug: choline fenofibrate<br>* 135 mg choline fenofibrate daily(oral, capsule)<br>* Other names: ABT-335;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change in Calculated Low Density Lipoprotein Cholesterol | Mean change in calculated LDL, baseline (average Day 0, 1 10) to end-of-treatment (12 weeks treatment,average Day 95) | baseline to 12 weeks | 
| Mean Change in Plasma Triglycerides | Change in plasma triglyceride, baseline (average Day 0, 1 10) to end-of-treatment (12 weeks treatment,Day 95) | baseline to 12 weeks | 
| Mean Change in High Density Lipoprotein Cholesterol | Mean change in plasma high density plasma lipoprotein cholesterol (HDL-C)baseline (average Day 0, 1 10) to end-of-treatment (12 weeks treatment,Day 95) | Baseline to 12 weeks | 
| Total Cholesterol | Mean Change in total cholesterol from baseline to End-of-treatment (Day 95) | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Cholesterol Efflux | Change in efflux rate from baseline to end-of-treatment. The efflux rate of cholesterol from peripheral tissues into the plasma was measured as mg/kg/hr. An IV infusion of [13C2] cholesterol mixed in 10% Intralipid® or Liposyn® and 10 % ethanol was given piggy-backed into normal saline over 24 hours. This was used to determine rate of appearance (Ra) cholesterol, measured by dilution of infused [13C2] cholesterol during the plateau phase of plasma enrichment (approximately the last 4 hours of the infusion), as well as to provide the plasma cholesterol traced into biliary sterols. | 12 weeks | 
| Change in Plasma Cholesterol Ester Fractional Catabolic Rate (FCR) | Change in FCR from baseline to end-of-treatment (12 weeks) | Baseline to 12 weeks | 
| Percent Change in de Novo Cholesterol Synthesis | Plasma DNC was measured three times from blood draws on the 3 visits in the 10 day period following the isotope infusion at baseline and again at end-of-treatment at 12 weeks, and expressed in percent. Change from baseline to end-of-treatment expressed as percent. | Baseline to 12 weeks | 
| Change in Neutral Sterol Excretion | The excretion rate of fecal neutral and acidic sterols was measured as mg/day, for each individual three times during the 10 day period following the isotope infusions at baseline and end-of-treatment. | baseline to 12 weeks | 
| Change in Bile Acid Excretion | Change in bile acid excretion from baseline to end-of-treatment | Baseline to 12 weeks | 
| Neutral Sterol Endogenous Excretion | Change in neutral sterol endogenous excretion from baseline to end-of-treatment | 12 weeks | 
| Endogenous Bile Acid Excretion | Change in endogenous bile acid excretion from baseline to end-of-treatment | 12 weeks |