Combined Effects of Non-statin Treatments on Apolipoprotein A-I Up-Regulation (CENTAUR): A Feasibility Study

The investigators propose to investigate if using a combination of medications that may improve cholesterol give additional benefit to that gained from the statin medication, Lipitor. It is recommended that patients who meet certain criteria for risk of heart disease take a statin medication to improve cholesterol and hopefully reduce risk of heart disease. The combination therapy will include Lipitor, Niaspan, and investigational medication (known as ABT335) in a class of drugs called fibrates. We are looking to see if and how these three medications together might improve risk factors for atherosclerosis and influence HDL cholesterol. The study will also look at the safety and any side effects that might be associated with this combination of medications.

Objectives Summary

\* To investigate whether the progressive addition of a fibrate and niacin to baseline statin therapy will improve apolipoprotein A-I kinetics, postprandial lipidemia, and postabsorptive lipoproteins and metabolism in adult men and women with atherogenic dyslipidemia.

Major Efficacy Aims

* Objective 1 is to test the hypothesis that the fibrate ABT335 and extended release (ER) niacin progressively improve apolipoprotein A-I kinetics when added sequentially to baseline therapy with atorvastatin. The key outcomes include the apolipoprotein AI rate of catabolism and rate of production.
* Objective 2 is to test the hypothesis that the fibrate ABT335 and ER niacin progressively improve postprandial lipidemia by oral fat challenge when added sequentially to baseline therapy with atorvastatin. Key outcomes include the incremental area under the curve for triglycerides and high-density lipoprotein cholesterol.
* Objective 3 is to test the hypothesis that the fibrate ABT335 and ER niacin progressively improve markers of postabsorptive lipoproteins and metabolism when added sequentially to baseline therapy with atorvastatin. Key outcomes include a. fasting cholesterol efflux, b. HDL cholesterol, apolipoprotein A-I, and enzymes that remodel HDL, c. atherogenic lipoproteins, and d. markers of energy metabolism and e. markers of inflammation.

Additional Aims

\* Objective 4 is to assess tolerability and adverse events when ABT335 and ER niacin are added sequentially to atorvastatin. Specifically, we will assess changes in hepatobiliary laboratory tests (including incidence of elevation), incidence of symptomatic myalgia, and incidence of flushing. On an exploratory basis, we will enhance the flushing evaluation with objective and subjective measurements of flushing during inpatient visits.

Study Design:

This is an open-label feasibility study of fixed-sequence addition of lipid-altering medications, in which comparisons are made to the baseline for each subject. Subjects begin a lead-in phase in which they start the study statin (atorvastatin) or switch from previous statin therapy to the study statin. Subjects will wash off other excluded lipid-altering drugs during the lead-in. Subjects return for the first inpatient visit, where they have baseline studies on statin monotherapy. At the end of this visit, subjects are started on fibrate therapy (ABT335). They repeat the studies on dual therapy with statin and fibrate, and then add niacin (ER niacin). To minimize flushing during chronic treatment, they start aspirin 325 mg daily, or titrate to 325 mg if they are taking a lower dose of aspirin (e.g. 81 mg). Finally, they repeat the studies on triple therapy with statin, fibrate, and niacin/aspirin.

Eligibility Criteria:
Inclusion Criteria:

1. Men/women aged 18-80 years.
2. Low HDL-C, adjusted for baseline statin use

   1. Not on statin: Men with HDL \<= 40 or women with HDL \<= 50 mg/dL
   2. On statin: Men with HDL \<= 42 or women with HDL \<= 52 mg/dL
3. TG/HDL ratio \>= 3.5
4. Able to understand and agree to informed consent
5. Women of child-bearing age must test negative on a urine pregnancy test and agree to use reliable birth control during the study and for 1 month after last dose of study drugs. Reliable methods include oral contraceptives, a barrier method, intrauterine device, partner with vasectomy, or abstinence.
6. Willing to be available for study duration and follow study procedures

Exclusion Criteria:

1. Subjects with following lipoprotein disorders:

   1. Patients on high-potency lipid-lowering regimen, defined as two or more prescription lipid-altering medications (excluding fish oils) where one is a high-dose statin (40 mg/day of rosuvastatin, 80 mg/day of other approved statins). Those on combination therapy with a lower statin dose or those taking high-dose statin monotherapy (excluding fish oils) may participate. Patients will switch to atorvastatin 10 mg and/or wash off other lipid medications to participate
   2. LDL \> 190 mg/dL
   3. TG \> 750 mg/dL or pancreatitis from triglyceridemia, regardless of current TG levels
   4. Dysbetalipoproteinemia (VLDL/TG \> 0.3 -AND- TG \> 200 mg/dL).
2. Use of non-statin lipid therapy prior to study initiation is exclusionary if (n.b. washout of non-statins is permitted):

   1. Niacin \> 250 mg/ day within 6 weeks: Advicor, Niaspan, Niacor, Simcor, Slo-Niacin, or supplemental niacin
   2. Fibrates within 12 weeks: fenofibrate (Antara, Lofibra, Tricor, Triglide), gemfibrozil (Lopid), or clofibrate
   3. Enterically active drugs within 4 weeks: colestipol, cholestyramine, colesevelam, ezetimibe, orlistat.
   4. Red yeast rice during the treatment phase of the study (i.e. must be switched to study statin)
   5. Fish oil \> 2 g/day within 4 weeks: Lovaza (née Omacor), numerous supplements
   6. Altered dose of a selective estrogen receptor modulator (SERM) within 4 weeks
3. Intolerance to statin, fibrate, aspirin, deuterated leucine, or niacin
4. Contraindications to medications, including chronic muscle disease, history of rhabdomyolysis, moderate-severe gout, severe peptic ulcer disease, bleeding disorders, and aspirin-sensitive asthma.
5. Diabetics, or fasting glucose \> 110 mg/dL on two different days during screening, or use of anti-diabetic medications within 6 weeks of screening visit
6. Chronic renal insufficiency, nephrotic syndrome, or current serum creatinine \> 2.5 mg/dL, or GFR \< 60 mL/min/1.73m2 by the MDRD equation.
7. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin \> 2 X the upper limit of normal (ULN), albumin of \< 2.5 mg/dL, prothrombin time (PT) \> 1.5 X ULN, partial thromboplastin time (PTT) \> 1.5 X ULN, or current active hepatobiliary disease
8. Hemoglobin (Hgb) \< 10 mg/dL
9. Weight \< 110 lbs
10. Use of an investigational drug within 6 weeks prior to screening visit
11. Major surgery within the previous 6 weeks, or anticipated major surgery during course of study, or any history of organ transplant
12. Non-skin malignancy within previous 5 years
13. Drug abuse within past 3 years, or regular alcohol use \>14 drinks/week
14. Women who are pregnant, plan to conceive, or breast-feed
15. Any serious or unstable medical or psychological conditions that, in investigator's opinion would compromise subject safety or successful participation.
16. Currently adhering to, planning to adhere to or used within 3 months prior to screening, supplements intended for weight loss or adopt diets with aggressive carbohydrate restrictions, such as but not limited to Atkins or South Beach diets.
17. Currently taking Vitamin A supplements (multivitamins allowed)(washout permitted)
18. Excluded concomitant medications

    1. Immunosuppressants within 2 months prior to screening or are likely to require such treatment during the course of the study
    2. Warfarin.
19. Disinclination to dairy products (e.g. inviolable dietary restrictions or lactose intolerance to an 8oz glass of milk despite lactase supplementation) Lactase supplementation is allowed during the study.
20. Regular consumers of grapefruit juice, or currently taking medications metabolized by CYP 3A4 (cyclosporine, itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, and nefazodone)
21. History of pancreatitis or gallbladder disease
22. History of coronary heart disease
23. History of intolerance/adverse reaction to heparin or women who have dysfunctional uterine bleeding
24. Thrombocytopenia at screening
25. History of intracerebral or significant GI bleed
26. Subjects doing regular strenuous activity or have a CK \> 3x ULN at screening