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Ezetimibe Reverse Cholesterol Transport (RCT) Pilot Study

Primary Purpose

Hypercholesterolemia

Status

Completed

Phase

Phase 4

Locations

United States

Study Type

Interventional

Intervention

ezetimibe

Placebo

About this trial

This is an interventional treatment trial for Hypercholesterolemia focused on measuring metabolic diseases, metabolic disorder, dyslipidemias, lipid metabolism disorders

Eligibility Criteria

21 Years - 75 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

male, non-smoker, 21-75 years of age
female, non-smoker, 40-75 years of age
post-menopausal women, as defined by lack of menses for at least 2 years and age >55, OR history of documented bilateral oophorectomy, confirmed with an elevated FSH at screening
low-density lipoprotein (LDL) concentration between 130-200 mg/dL.
triglyceride (TG) concentration <350 mg/dL, inclusive
high-density lipoprotein (HDL) between 30-60 mg/dL for men and 40 -70 mg/dL for women
ability to give informed consent

Exclusion Criteria:

Subject has history of diabetes mellitus, active hepatitis, gall bladder disease, gastric or ileal bypass surgery, irritable bowel syndrome, and gastrointestinal disorder/condition associated with malabsorption, or clinically significant abnormalities on screening (prestudy) physical examination of laboratory tests.
Screening laboratory tests with hematocrit <30%, aspartate aminotransferase/alanine aminotransferase (AST/ALT) >2*upper limit of normal, abnormal thyroid-stimulating hormone (TSH), fasting glucose >=126mg/dL
renal impairment with creatinine clearance (CRCl)<80ml/min
treatment within the last 2 months with drugs known to alter lipid metabolism including beta blockers, thiazide diuretics, bile acid resins, statins, ezetimibe, niacin, fibrates, plant stanol esters (eg Benecol,phyto sterols) and fishoils
history of known coronary heart disease (CHD), stroke or prior revascularization procedure or peripheral vascular disease
history of allergy to egg or soy products
current or recent (past 12 months) of drug abuse or alcohol abuse. Alcohol use must be limited to no more than 2 drinks/day (1 drink=12 oz beer, 5 oz wine, or 1.5 oz hard liquor). Subject must be willing to avoid large day-to-day fluctuations in alcohol intake.
participation in another clinical trial or exposure to any investigational agent within 30 days prior to Visit 1
Individual has a condition the Principal Investigator believes would interfere with his/her ability to provide informed consent, comply with study instructions, or which might confound the interpretation of the study results, or put the subject at undue risk

Sites / Locations

Radiant Research

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Arm Description

ezetimibe (10mg/day)for 7 weeks

Placebo control

Outcomes

Primary Outcome Measures

Fecal Excretion of Plasma-derived Cholesterol

(Fecal excretion of plasma-derived cholesterol):The following measurements will be made following isotope infusion: The composition of fecal neutral and acidic sterols will be measured as % of total. The excretion rate of fecal neutral and acidic sterols will be measured as mg/day. The isotopic enrichment of both fecal neutral and acidic sterols will be measured as atomic percent excess (% APE). Fecal isotope excretion, or recovery, of plasma-derived cholesterol will be calculated as %/day.

Secondary Outcome Measures

Change From Baseline in Total Cholesterol, From Fasting Plasma Samples

plasma levels of total cholesterol

de Novo Cholesterol Synthesis (DNC)

Plasma DNC will be measured following the isotope infusion of deuterated water, expressed as %.

Cholesterol Efflux Rate (Ra Cholesterol)

The efflux, or mobilization, rate of cholesterol from peripheral tissues into the plasma will be measured as mg/kg/hr. An IV infusion of [13C2] cholesterol mixed in 10% Intralipid® and 10 % ethanol is given piggy-backed into normal saline over 20 hours (4pm - 12 noon). This is used to determine rate of appearance (Ra) cholesterol, which will be measured by dilution of infused [13C2] cholesterol during the plateau phase of plasma enrichment (approximately the last 4 hours of the infusion), as well as to provide the plasma cholesterol that will be traced into biliary sterols.

Triglycerides (TG)

Change from baseline in plasma triglycerides, measured in fasting blood samples

Low-density Lipoprotein (LDL);

Change from baseline in plasma low-density lipoprotein(LDL), measured in fasting blood samples

High-density Lipoprotein (HDL)

Change from baseline in plasma HDL, measured in fasting blood samples

Full Information

NCT ID

NCT00701727

First Posted

June 17, 2008

Last Updated

March 14, 2011

Sponsor

Radiant Research

1. Study Identification

Unique Protocol Identification Number

NCT00701727

Brief Title

Ezetimibe Reverse Cholesterol Transport (RCT) Pilot Study

Official Title

Ezetimibe Reverse Cholesterol Transport (RCT) Pilot Study

Study Type

Interventional

2. Study Status

Record Verification Date

March 2011

Overall Recruitment Status

Completed

Study Start Date

June 2008 (undefined)

Primary Completion Date

March 2009 (Actual)

Study Completion Date

March 2009 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor

Radiant Research

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

This is a prospective, placebo-controlled, cross-over trial comparing the the effects of approximately 7 weeks of placebo treatment to 7 weeks of ezetimibe (10mg/day) treatment on several parameters of reverse cholesterol transport (RCT) in men and post-menopausal women diagnosed with hypercholesterolemia. The primary hypothesis is that the ezetimibe treatment will increase the excretion of endogenous (plasma-derived) cholesterol as fecal sterols, with secondary hypotheses that there will be a significant increase in de novo cholesterol synthesis, treatment will increase cholesterol efflux from tissues into the bloodstream, and increase global RCT.

Detailed Description

The study will compare the effects of approximately 7 weeks of placebo treatment to 7 weeks of ezetimibe (10mg/day) on: 1) the efficiency of endogenous (plasma-derived) cholesterol excretion (%/day) 2) de novo cholesterol (DNC) synthesis ((%/day) 3) cholesterol efflux from tissues into blood (Ra), and 4) global RCT (efflux from tissues that is excreted as fecal sterols). Subjects will receive 7 weeks of either treatment or placebo, undergo RCT and DNC measurements, taking 10 days, then cross-over to the alternate placebo or treatment for an additional 7 weeks, followed by a second set of RCT and DNC measurements.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hypercholesterolemia

Keywords

metabolic diseases, metabolic disorder, dyslipidemias, lipid metabolism disorders

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Crossover Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

31 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm Type

Experimental

Arm Description

ezetimibe (10mg/day)for 7 weeks

Arm Title

Arm Type

Placebo Comparator

Arm Description

Placebo control

Intervention Type

Drug

Intervention Name(s)

ezetimibe

Intervention Description

1 tablet,10mg, once a day, for 7 weeks

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

1 tablet, once a day, for 7 weeks

Primary Outcome Measure Information:

Title

Fecal Excretion of Plasma-derived Cholesterol

Description

Time Frame

7 weeks

Secondary Outcome Measure Information:

Title

Change From Baseline in Total Cholesterol, From Fasting Plasma Samples

Description

plasma levels of total cholesterol

Time Frame

7 weeks

Title

de Novo Cholesterol Synthesis (DNC)

Description

Plasma DNC will be measured following the isotope infusion of deuterated water, expressed as %.

Time Frame

7 weeks

Title

Cholesterol Efflux Rate (Ra Cholesterol)

Description

Time Frame

7 weeks

Title

Triglycerides (TG)

Description

Change from baseline in plasma triglycerides, measured in fasting blood samples

Time Frame

7 weeks

Title

Low-density Lipoprotein (LDL);

Description

Change from baseline in plasma low-density lipoprotein(LDL), measured in fasting blood samples

Time Frame

7 weeks

Title

High-density Lipoprotein (HDL)

Description

Change from baseline in plasma HDL, measured in fasting blood samples

Time Frame

7 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

21 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: male, non-smoker, 21-75 years of age female, non-smoker, 40-75 years of age post-menopausal women, as defined by lack of menses for at least 2 years and age >55, OR history of documented bilateral oophorectomy, confirmed with an elevated FSH at screening low-density lipoprotein (LDL) concentration between 130-200 mg/dL. triglyceride (TG) concentration <350 mg/dL, inclusive high-density lipoprotein (HDL) between 30-60 mg/dL for men and 40 -70 mg/dL for women ability to give informed consent Exclusion Criteria: Subject has history of diabetes mellitus, active hepatitis, gall bladder disease, gastric or ileal bypass surgery, irritable bowel syndrome, and gastrointestinal disorder/condition associated with malabsorption, or clinically significant abnormalities on screening (prestudy) physical examination of laboratory tests. Screening laboratory tests with hematocrit <30%, aspartate aminotransferase/alanine aminotransferase (AST/ALT) >2*upper limit of normal, abnormal thyroid-stimulating hormone (TSH), fasting glucose >=126mg/dL renal impairment with creatinine clearance (CRCl)<80ml/min treatment within the last 2 months with drugs known to alter lipid metabolism including beta blockers, thiazide diuretics, bile acid resins, statins, ezetimibe, niacin, fibrates, plant stanol esters (eg Benecol,phyto sterols) and fishoils history of known coronary heart disease (CHD), stroke or prior revascularization procedure or peripheral vascular disease history of allergy to egg or soy products current or recent (past 12 months) of drug abuse or alcohol abuse. Alcohol use must be limited to no more than 2 drinks/day (1 drink=12 oz beer, 5 oz wine, or 1.5 oz hard liquor). Subject must be willing to avoid large day-to-day fluctuations in alcohol intake. participation in another clinical trial or exposure to any investigational agent within 30 days prior to Visit 1 Individual has a condition the Principal Investigator believes would interfere with his/her ability to provide informed consent, comply with study instructions, or which might confound the interpretation of the study results, or put the subject at undue risk

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Michael H Davidson, Md. FACC

Organizational Affiliation

Radiant Research

Official's Role

Principal Investigator

Facility Information:

Facility Name

Radiant Research

City

Chicago

State/Province

Illinois

ZIP/Postal Code

60610

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

24075764

Citation

Davidson MH, Voogt J, Luchoomun J, Decaris J, Killion S, Boban D, Glass A, Mohammad H, Lu Y, Villegas D, Neese R, Hellerstein M, Neff D, Musliner T, Tomassini JE, Turner S. Inhibition of intestinal cholesterol absorption with ezetimibe increases components of reverse cholesterol transport in humans. Atherosclerosis. 2013 Oct;230(2):322-9. doi: 10.1016/j.atherosclerosis.2013.08.006. Epub 2013 Aug 13.

Results Reference

derived

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Ezetimibe Reverse Cholesterol Transport (RCT) Pilot Study

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