Combined Effects of Non-statin Treatments on Apolipoprotein A-I Up-Regulation (CENTAUR): A Feasibility Study
Condition: Dyslipidemia
MeSH terms: Dyslipidemias
Intervention: Atorvastatin; ABT335; ER Niacin
Intervention description: 10 mg QD for 4 weeks; 135 mg QD added to atorvastatin for 8 weeks; 2000 mg QD added to atorvastatin and ABT335 for 10 weeks
Intervention MeSH terms: Niacin; Atorvastatin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 25.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: Low HDL cholesterol; High triglycerides; niacin; fibrate

Summary:

      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.
    

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