Physiological Study of Human Cholesterol Metabolism and Excretion

May 5, 2016 updated by: Richard E. Ostlund Jr., MD

Reverse Cholesterol Transport in Humans

The underlying hypothesis is that whole body cholesterol - including cholesterol present in tissues that cannot be measured by standard blood tests - is related to heart disease risk. Endogenous cholesterol will be labeled with an intravenous infusion of one type of cholesterol tracer and dietary cholesterol will be labeled with another. These tracers will be used to measure how fast cholesterol is synthesized and excreted using mass spectrometry to distinguish the tracers. Data will be related to circulating biomarkers (blood tests) and to the thickness of the lining of the carotid artery. The effect of the drug ezetimibe on these processes will also be determined. Successful completion of this study will give us more knowledge about cholesterol metabolism that may be useful in designing new drugs and treatments for patients with heart disease, especially those that are already receiving maximum amounts of current medications.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

The central hypothesis of this proposal is that reverse cholesterol transport is related to coronary heart disease (CHD) risk. It is complementary to the concept that reduction of cholesterol biosynthesis with statin drugs prevents CHD, but it focuses on whole body cholesterol metabolism and kinetic cholesterol transport rather than on static levels of circulating lipoproteins. Although this is an old idea, it has not been adequately tested in humans because of lack of suitable methods. In this proposal we will apply innovative stable isotope and mass spectroscopic technology to study reverse cholesterol transport in human subjects. The first specific aim is to improve the preparation of intravenous deuterated cholesterol tracer, a critical limiting element in the study of whole body cholesterol metabolism. The second aim is to use that intravenous tracer, along with a different oral tracer, to partition fecal cholesterol into excreted endogenous cholesterol, unabsorbed dietary cholesterol and newly-synthesized cholesterol derived from the liver and intestine. Measurements will be made during consumption of a controlled diet provided by the metabolic kitchen. The pool size of the rapidly-mixing body cholesterol pool will be measured along with the fractional rate of cholesterol catabolism. These direct measures of reverse cholesterol transport will be correlated with plasma biomarkers and with metabolic covariates. The relation of reverse cholesterol transport to carotid intima-media thickness will be determined. The third specific aim will use similar methods to study the mechanism of action for the widely-used drug ezetimibe. The fractional rate of endogenous cholesterol excretion and the rate of plasma cholesterol turnover will be determined in two periods, one with drug and one with placebo treatment. This work represents a new direction for cholesterol research with the potential to develop new and complementary methods of reducing CHD risk that can be added to diet and statin drug treatment.

Study Type

Interventional

Enrollment (Actual)

132

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Missouri
      • St. Louis, Missouri, United States, 63110
        • Washington University School of Medicine

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Aim II. 100 subjects aged 30-80 with stable medical and/or surgical illnesses.
  • Aim III. 30 subjects age 18-80 with LDL cholesterol <190, fasting triglycerides<250 and stable medical or surgical illnesses.

Exclusion Criteria:

  • Aim II. Subjects taking ezetimibe, bile acid sequestrants or with gastrointestinal or liver disease will be excluded since these may affect whole body cholesterol metabolism.
  • Subjects with coronary heart disease or other medical illnesses will not be excluded if medically stable.
  • Adults under age 30 and children will be excluded because in our current database there is no relation between carotid intima-media thickness and cardiovascular risk factors in this younger group.
  • Aim III. Individuals have risk factors for coronary heart disease that mandate drug treatment according to the National Cholesterol Education Program guidelines will be excluded.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
No Intervention: Observational Arm
Cholesterol metabolic parameters will be measured in 100 subjects in an observational study. Results will be related to circulating biomarkers and carotid intima-media thickness.
Placebo Comparator: Ezetimibe Interventional Arm
Cholesterol metabolic parameters will be measured before and after ezetimibe or placebo intervention. Changes due to ezetimibe will be determined
Drug: Ezetimibe
Ezetimibe 10 mg/day or placebo will be given for 6 weeks
Other Names:
  • Zetia

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Fractional Excretion of Endogenous Cholesterol
Time Frame: 4 years
The fractional rate of endogenous cholesterol excretion will be measured and related to circulating biomarkers and carotid intima-media thickness (Aim #2) or the change in fractional endogenous cholesterol excretion after treatment with ezetimibe will be determined (Aim #3)
4 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Richard E. Ostlund Jr., MD

Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

  • Principal Investigator: Richard E Ostlund, MD, Washington University School of Medicine

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2014

Primary Completion (Actual)

June 1, 2015

Study Completion (Actual)

June 1, 2015

Study Registration Dates

First Submitted

May 18, 2012

First Submitted That Met QC Criteria

May 21, 2012

First Posted (Estimate)

May 23, 2012

Study Record Updates

Last Update Posted (Estimate)

May 6, 2016

Last Update Submitted That Met QC Criteria

May 5, 2016

Last Verified

May 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 201110042
  • R01HL108160 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

IPD Plan Description

Data will be shared subject to IRB and HIPAA restrictions.

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Cardiovascular Disease

Clinical Trials on Ezetimibe

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in United Kingdom

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Subscribe