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

NCT00728910 | Completed Phase 2 Results

• 2 other identifiers: 807965 CNTRCTRC #1123
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Dyslipidemia

Keywords

Low HDL cholesterol; High triglycerides; niacin; fibrate

Outcome Measures

Primary Outcomes (3)

• The Apolipoprotein A-I Fractional Catabolic Rate (FCR)

  After receiving total daily caloric intake over 20 hrs as 20 identical small meals, starting at 0600 hrs, subjects took study medications at 0800 hrs. Five hours after the first meal, i.v. 5,5,5-2H3-L-leucine was administered, followed by a primed-constant infusion at 10 mol/kg body weight per hr for 15 hrs during which 14 blood samples were collected. Isotopic enrichment of leucine in apoA1 band excised from polyacrylamide gel was calculated. Assuming steady state apo A-I metabolism, we used a compartment model to fit data, consisting a precursor compartment (Compartment 1), the plasma leucine pool, an intracellular compartment accounting for apoA1 synthesis and lipoprotein assembly (Compartment 2), and compartments to account for dispositional kinetics of the subfractions including a plasma pool compartment (Compartment 3). The apoA1 FCR corresponds to the rate of irreversible loss of leucine pools from Compartment 3.

  4 weeks, 12 weeks and 22 weeks

• Apo-A1 Production Rate

  The apolipoprotein A-I production rate using (5,5,5-2H3-L-leucine) was measured following each of the three study periods i.e following 4 weeks of atorvastatin 10 mg/day, following 8 further weeks of ABT335 135 mg/day added to atorvastatin and following 10 further weeks of ER niacin 2000 mg/day and aspirin 325 mg/day added to atorvastatin+ABT335.

  4 weeks, 12 weeks and 22 weeks

• Post-prandial Triglyceride Incremental Area Under the Curve (iAUC)

  Triglyceride iAUC was measured during an oral fat tolerance test administered after 4 weeks of atorvastatin 10 mg/day , a further 8 weeks of atorvastatin 10mg /day+ABT335 135mg/day and then after a further 10 weeks of atorvastatin 10 mg/day+ABT335 135 mg/day+Niaspan 2000 mg/day. The standardized oral fat load was administered one hour post medication dosing and blood was collected prior to drug dosing, prior to the oral fat load and hourly thereafter for 10 hours (0,1,2,3,4,5,6,7,8,9,10,12 hrs post drug dosing)

  4 weeks, 12 weeks, 22 weeks

Study Arms (3)

Atorvastatin

ACTIVE COMPARATOR

atorvastatin 10 mg/day by mouth for a total duration of 4 weeks

Drug: Atorvastatin

ABT335

ACTIVE COMPARATOR

ABT335 135 mg/day by mouth added to atorvastatin for a total duration of at least 8

Drug: Atorvastatin; Drug: ABT335

ER niacin

ACTIVE COMPARATOR

ER niacin titrated up to 2 g/day with aspirin 325 mg/day by mouth added to atorvastatin and ABT335 for 10 weeks

Drug: Atorvastatin; Drug: ABT335; Drug: ER Niacin

Interventions

Atorvastatin DRUG

10 mg QD for 4 weeks

Also known as: Lipitor

ABT335; Atorvastatin; ER niacin

ABT335 DRUG

135 mg QD added to atorvastatin for 8 weeks

Also known as: Trilipex

ABT335; ER niacin

ER Niacin DRUG

2000 mg QD added to atorvastatin and ABT335 for 10 weeks

Also known as: Niaspan

ER niacin

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Men/women aged 18-80 years.
• Low HDL-C, adjusted for baseline statin use
• Not on statin: Men with HDL \<= 40 or women with HDL \<= 50 mg/dL
• On statin: Men with HDL \<= 42 or women with HDL \<= 52 mg/dL
• TG/HDL ratio \>= 3.5
• Able to understand and agree to informed consent
• 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.
• Willing to be available for study duration and follow study procedures

You may not qualify if:

• Subjects with following lipoprotein disorders:
• 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
• LDL \> 190 mg/dL
• TG \> 750 mg/dL or pancreatitis from triglyceridemia, regardless of current TG levels
• Dysbetalipoproteinemia (VLDL/TG \> 0.3 -AND- TG \> 200 mg/dL).
• Niacin \> 250 mg/ day within 6 weeks: Advicor, Niaspan, Niacor, Simcor, Slo-Niacin, or supplemental niacin
• Fibrates within 12 weeks: fenofibrate (Antara, Lofibra, Tricor, Triglide), gemfibrozil (Lopid), or clofibrate
• Enterically active drugs within 4 weeks: colestipol, cholestyramine, colesevelam, ezetimibe, orlistat.
• Red yeast rice during the treatment phase of the study (i.e. must be switched to study statin)
• Fish oil \> 2 g/day within 4 weeks: Lovaza (née Omacor), numerous supplements
• Altered dose of a selective estrogen receptor modulator (SERM) within 4 weeks
• Intolerance to statin, fibrate, aspirin, deuterated leucine, or niacin
• Contraindications to medications, including chronic muscle disease, history of rhabdomyolysis, moderate-severe gout, severe peptic ulcer disease, bleeding disorders, and aspirin-sensitive asthma.
• 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
• Chronic renal insufficiency, nephrotic syndrome, or current serum creatinine \> 2.5 mg/dL, or GFR \< 60 mL/min/1.73m2 by the MDRD equation.

Sponsors & Collaborators

• University of Pennsylvania: lead
• Abbott: collaborator

Study Sites (1)

CTRC (Clinical Translational Research Center)

Philadelphia, Pennsylvania, 19104, United States

Location

MeSH Terms

Conditions

Dyslipidemias; Hypertriglyceridemia

Interventions

Atorvastatin; 2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanoic acid; Niacin

Condition Hierarchy (Ancestors)

Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Hyperlipidemias

Intervention Hierarchy (Ancestors)

Pyrroles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heptanoic Acids; Fatty Acids; Lipids; Nicotinic Acids; Acids, Heterocyclic; Pyridines

Results Point of Contact

• Title: Richard Dunbar MD
• Organization: University of Pennsylvania

richard.dunbar@uphs.upenn.edu

215-662-9024

Study Officials

• Richard L Dunbar, MD

  University of Pennsylvania

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: August 4, 2008
• First Posted: August 6, 2008
• Study Start: June 1, 2008
• Primary Completion: August 1, 2009
• Study Completion: August 1, 2009
• Last Updated: February 29, 2016
• Results First Posted: February 29, 2016

Record last verified: 2016-01

Locations

US (1)