Effect of Niacin on Transport of HDL and Relationship to Atherogenic Lipoproteins and Lipolysis (ENTHRALL)

A Randomized, Double-Blind, Placebo Controlled Study Evaluating the Effects Of Niacin On Reverse Cholesterol Transport As Measured Using [1,2-3H]-Cholesterol (3H-cholesterol) in Healthy Volunteers.

This study looks at whether niacin improves reverse cholesterol transport (RCT) in healthy volunteers. 3H-Cholesterol will be used to measure RCT by analyzing changes in the tracer activity in total plasma, lipoproteins, red blood cells (RBCs) and stool. The hypothesis is that niacin augments reverse cholesterol transport.

Study Overview

• Status: Completed
• Conditions: Dyslipidemias
• Intervention / Treatment: Other: Placebo; Drug: Niacin

Detailed Description

The study will use 3H-cholesterol bound to albumin (particulate cholesterol) to assess the ability of high density lipoprotein (HDL) to transport cholesterol to the liver to be eliminated. This process is called Reverse Cholesterol transport and is one of the main mechanisms by which HDL protect against atherosclerotic cardiovascular disease. The availability of a method to assess RCT is important for the development of new drugs which affect RCT and may result in useful treatments for atherosclerosis.

This study will evaluate the use of radiolabeled particulate cholesterol administered intravenously in association with albumin, as a method to study reverse cholesterol transport (RCT) in humans before and after treatment by niacin by analyzing changes in the tracer activity in total plasma and lipoproteins. The study population is healthy volunteers.

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Men and women between the ages of 18 and 75 inclusive
• HDL cholesterol >= 25 mg/dL in all subjects, and <= 60 mg/dL in men and <= 70 mg/dL in women
• Women must be of non-childbearing potential. They must have been surgically sterilized at least 6 months prior to screening or be postmenopausal. Postmenopausal women must have no regular menstrual bleeding for at least 2 years prior to inclusion.
• Subjects must be in good overall health.
• Subjects must be able to comprehend and willing to provide a signed Institutional Regulatory Board (IRB) approved Informed Consent Form.
• Subjects must be willing to comply with all study-related procedures.
• Subjects must weigh at least 140 pounds to participate in the HDL kinetics Substudy.

Exclusion Criteria:

• Clinically-manifest cardiovascular disease, including coronary disease, cerebrovascular disease, or peripheral vascular disease
• History of diabetes mellitus or fasting glucose > 126 mg/dL at the screening visit
• Presence of New York Heart Association (NYHA) Class III or IV chronic heart failure or unstable angina pectoris
• History of any other endocrine disease
• History of a non-skin malignancy within the previous 5 years
• Anemia defined as hemoglobin less than 12 g/dL
• Renal insufficiency as defined by creatinine ³ 1.3 mg/dl
• Any major active rheumatologic, pulmonary, or dermatologic disease or inflammatory condition
• Uncontrolled hypertension (Systolic >160 mm Hg and/or Diastolic >100 mmHg on two consecutive measurements
• Use of warfarin, or any known coagulopathy and /or elevated Prothrombin time/Partial Thromboplastin Time (PT/PTT) >1.5 x upper limit of normal (ULN)
• Self-reported history of Human immunodeficiency virus (HIV) positive
• Previous organ transplantation
• Clinical evidence of liver disease or liver injury as indicated by abnormal liver function tests such as Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2x ULN, or self-reported history of positive for Hepatitis B or Hepatitis C
• Any major surgical procedure that occurred within the previous 3 months of the screening visit
• History of illicit drug abuse (< 1 year)
• Regular use of alcoholic beverages (> 2 drinks/day)
• Body mass index (BMI) > 35 kg/m2 or < 18.5 kg/m2
• Administration of an investigational drug within 6 weeks prior to the screening visit
• Serious or unstable medical or psychological conditions that, in the opinion of the investigator, would compromise the subject's safety or successful participation in the study will be excluded.

• Use of daily lipid-altering therapy prior to the initiation of study medication is exclusionary under the following circumstances (washout of non-statins is permitted):

  • Statins within 4 weeks
  • 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 lipid-altering drugs within 4 weeks: colestipol (Colestid), cholestyramine (Questran), colesevelam (Welchol), ezetimibe (Zetia, Vytorin), orlistat (Xenical, Alli)
  • Red yeast rice
  • 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
• History of severe intolerance of niacin
• Men who plan to conceive a child within 3 months of the conclusion of the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Niacin; Niacin taken orally for 12 weeks at the highest tolerated dose (up to 6 grams), and at least 2 grams daily and up to the maximum approved dose. Subjects will initiate therapy with Niaspan and will advance to Niacor as tolerated.	Drug: Niacin; Niacin taken orally for 12 weeks at the highest tolerated dose (up to 6 grams), and at least 2 grams daily and up to the maximum approved dose. Subjects will initiate therapy with Niaspan and will advance to Niacor as tolerated.; Other Names: Niacor and Niaspan
Placebo Comparator: Placebo; Placebo tablet with 50 mg niacin for the first 4 weeks to maintain blinding of the study team and subjects, changed to pure placebo after that.	Other: Placebo; Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Appearance of 3H Cholesterol in the Total HDL Fraction Before and After 12 Weeks of Treatment With Niacin	Subjects were injected with a bolus of 3-H cholesterol mixed with human serum albumin as an intravenous bolus. This injected labelled cholesterol is taken up by macrophages. The rate of appearance of labelled cholesterol in plasma HDL- cholesterol is a measure of reverse cholesterol transport. We assessed HDL cholesterol enrichment as percent of injected tritiated tracer appearing in plasma total HDL cholesterol between 60 and 240 minutes post-injection expressed as percent 3-H cholesterol/mol HDL cholesterol/hour. The tracer study was performed at baseline and after 12 weeks of niacin or placebo.	Baseline and 12 weeks

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Richard Dunbar, MD MSTR, University of Pennsylvania

Study record dates

Study Major Dates

• Study Start: November 1, 2010
• Primary Completion (Actual): May 1, 2011
• Study Completion (Actual): May 1, 2011

Study Registration Dates

• First Submitted: November 29, 2010
• First Submitted That Met QC Criteria: November 30, 2010
• First Posted (Estimate): December 1, 2010

Study Record Updates

• Last Update Posted (Estimate): July 28, 2016
• Last Update Submitted That Met QC Criteria: June 24, 2016
• Last Verified: June 1, 2016

More Information

Terms related to this study

• Keywords: HDL; Niacin; Reverse cholesterol transport
• Additional Relevant MeSH Terms: Metabolic Diseases; Lipid Metabolism Disorders; Dyslipidemias; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Antimetabolites; Micronutrients; Hypolipidemic Agents; Lipid Regulating Agents; Vitamins; Vitamin B Complex; Niacin
• Other Study ID Numbers: 811956; K23HL091130 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO