Combined Effects of Non-statin Treatments on Apolipoprotein A-I Up-Regulation (CENTAUR): A Feasibility Study
Condition: Dyslipidemia
MeSH terms: Dyslipidemias
Study type: Interventional
Phase: Phase 2

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.
    

Detailed description: 
      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.
    

Intervention name(s): Atorvastatin; ABT335; ER Niacin
Intervention type(s): Drug; Drug; Drug
Intervention description(s): 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
Other intervention name(s): Lipitor; Trilipex; Niaspan
Intervention MeSH terms: Niacin; Atorvastatin
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Low HDL cholesterol; High triglycerides; niacin; fibrate