Physiological Study of Human Cholesterol Metabolism and Excretion

This study is not yet open for participant recruitment.
Verified May 2012 by Washington University School of Medicine
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Richard E. Ostlund Jr., MD, Washington University
ClinicalTrials.gov Identifier:
NCT01603758
First received: May 18, 2012
Last updated: May 21, 2012
Last verified: May 2012
  Purpose

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.


Condition Intervention Phase
Coronary Heart Disease
Cardiovascular Disease
Dyslipidemia
Disorder of Cholesterol Metabolism
Drug: Ezetimibe
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Reverse Cholesterol Transport in Humans

Resource links provided by NLM:


Further study details as provided by Washington University School of Medicine:

Primary Outcome Measures:
  • Fractional Excretion of Endogenous Cholesterol [ Time Frame: 4 years ] [ Designated as safety issue: No ]
    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)


Estimated Enrollment: 130
Study Start Date: September 2012
Estimated Study Completion Date: January 2016
Estimated Primary Completion Date: July 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: Zetia

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.

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

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.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01603758

Contacts
Contact: Susan B Racette, Ph.D. 314-286-1424 racettes@wusm.wustl.edu

Locations
United States, Missouri
Washington University School of Medicine Not yet recruiting
St. Louis, Missouri, United States, 63110
Contact: Susan B Racette, Ph.D.    314-286-1424    racettes@wusm.wustl.edu   
Sponsors and Collaborators
Richard E. Ostlund Jr., MD
Investigators
Principal Investigator: Richard E Ostlund, MD Washington University
  More Information

No publications provided

Responsible Party: Richard E. Ostlund Jr., MD, Professor of Medicine, Washington University
ClinicalTrials.gov Identifier: NCT01603758     History of Changes
Other Study ID Numbers: 201110042, R01HL108160
Study First Received: May 18, 2012
Last Updated: May 21, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by Washington University School of Medicine:
Cholesterol
Spectrometry, mass
Deuterium
Kinetics
Cholesterol absorption
Coronary Heart Disease

Additional relevant MeSH terms:
Cardiovascular Diseases
Coronary Artery Disease
Myocardial Ischemia
Coronary Disease
Heart Diseases
Dyslipidemias
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Lipid Metabolism Disorders
Metabolic Diseases
Ezetimibe
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Lipid Regulating Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on April 17, 2014