Hypercholesterolemia
Conditions
Keywords
metabolic diseases, metabolic disorder, dyslipidemias, lipid metabolism disorders
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.
Interventions
DRUGezetimibe
1 tablet,10mg, once a day, for 7 weeks
DRUGPlacebo
1 tablet, once a day, for 7 weeks
Sponsors
Radiant Research
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
21 Years to 75 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Fecal Excretion of Plasma-derived Cholesterol | 7 weeks | (Fecal excretion of plasma-derived cholesterol):The following measurements will be made following isotope infusion: 1. The composition of fecal neutral and acidic sterols will be measured as % of total. 2. The excretion rate of fecal neutral and acidic sterols will be measured as mg/day. 3. The isotopic enrichment of both fecal neutral and acidic sterols will be measured as atomic percent excess (% APE). 4. Fecal isotope excretion, or recovery, of plasma-derived cholesterol will be calculated as %/day. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| de Novo Cholesterol Synthesis (DNC) | 7 weeks | Plasma DNC will be measured following the isotope infusion of deuterated water, expressed as %. |
| Cholesterol Efflux Rate (Ra Cholesterol) | 7 weeks | 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. |
| Change From Baseline in Total Cholesterol, From Fasting Plasma Samples | 7 weeks | plasma levels of total cholesterol |
| Low-density Lipoprotein (LDL); | 7 weeks | Change from baseline in plasma low-density lipoprotein(LDL), measured in fasting blood samples |
| High-density Lipoprotein (HDL) | 7 weeks | Change from baseline in plasma HDL, measured in fasting blood samples |
| Triglycerides (TG) | 7 weeks | Change from baseline in plasma triglycerides, measured in fasting blood samples |
Countries
United States
Participant flow
Recruitment details
Participants recruited at a research clinic, Chicago, IL, from June 2008 to October 2008
Pre-assignment details
61 subjects screened, 30 subjects excluded(8 failed inclusion criteria, 9 failed exclusion criteria, 3 had unsuitable veins, 5 failed a drug screen, 1 was lost-to-follow-up, 4 were excluded when enrollment was complete), 31 subjects randomized.
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population Includes groups randomized to receive ezetimibe first and placebo first | 31 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Treatment Period | Adverse Event | 0 | 0 |
| First Treatment Period | Lost to Follow-up | 0 | 1 |
| First Treatment Period | sponsor decision | 0 | 1 |
| First Treatment Period | Withdrawal by Subject | 1 | 0 |
| Second Treatment Period | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 4 Participants |
| Age, Categorical Between 18 and 65 years | 27 Participants |
| Region of Enrollment United States | 31 participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 15 / 31 | 15 / 31 |
| serious Total, serious adverse events | 0 / 31 | 0 / 31 |
Outcome results
Primary
Fecal Excretion of Plasma-derived Cholesterol
(Fecal excretion of plasma-derived cholesterol):The following measurements will be made following isotope infusion: 1. The composition of fecal neutral and acidic sterols will be measured as % of total. 2. The excretion rate of fecal neutral and acidic sterols will be measured as mg/day. 3. The isotopic enrichment of both fecal neutral and acidic sterols will be measured as atomic percent excess (% APE). 4. Fecal isotope excretion, or recovery, of plasma-derived cholesterol will be calculated as %/day.
Time frame: 7 weeks
Population: Per Protocol,all subjects
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Fecal Excretion of Plasma-derived Cholesterol | 1593 mg/day cholesterol excreted | Standard Deviation 1287 |
| Ezetimibe | Fecal Excretion of Plasma-derived Cholesterol | 1950 mg/day cholesterol excreted | Standard Deviation 915 |
p-value: 0.019t-test, 2 sided
Secondary
Change From Baseline in Total Cholesterol, From Fasting Plasma Samples
plasma levels of total cholesterol
Time frame: 7 weeks
Population: per protocol, all subjects
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Total Cholesterol, From Fasting Plasma Samples | 219 mg/dL total cholesterol | Standard Deviation 26 |
| Ezetimibe | Change From Baseline in Total Cholesterol, From Fasting Plasma Samples | 187 mg/dL total cholesterol | Standard Deviation 24 |
p-value: <0.0001t-test, 2 sided
Secondary
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.
Time frame: 7 weeks
Population: per protocol, all subjects
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Cholesterol Efflux Rate (Ra Cholesterol) | 4.6 mg/kg/hr cholesterol | Standard Deviation 0.5 |
| Ezetimibe | Cholesterol Efflux Rate (Ra Cholesterol) | 4.4 mg/kg/hr cholesterol | Standard Deviation 0.7 |
p-value: 0.12t-test, 2 sided
Secondary
de Novo Cholesterol Synthesis (DNC)
Plasma DNC will be measured following the isotope infusion of deuterated water, expressed as %.
Time frame: 7 weeks
Population: per protocol, all subjects
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | de Novo Cholesterol Synthesis (DNC) | 3.4 %/day plasma DNC | Standard Deviation 0.1 |
| Ezetimibe | de Novo Cholesterol Synthesis (DNC) | 4.7 %/day plasma DNC | Standard Deviation 0.1 |
p-value: <0.001t-test, 2 sided
Secondary
High-density Lipoprotein (HDL)
Change from baseline in plasma HDL, measured in fasting blood samples
Time frame: 7 weeks
Population: per protocol, all subjects
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | High-density Lipoprotein (HDL) | 46 mg/dL HDL | Standard Deviation 9 |
| Ezetimibe | High-density Lipoprotein (HDL) | 45 mg/dL HDL | Standard Deviation 11 |
p-value: 0.95t-test, 2 sided
Secondary
Low-density Lipoprotein (LDL);
Change from baseline in plasma low-density lipoprotein(LDL), measured in fasting blood samples
Time frame: 7 weeks
Population: per protocol, all subjects
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Low-density Lipoprotein (LDL); | 148 mg/dL LDL | Standard Deviation 24 |
| Ezetimibe | Low-density Lipoprotein (LDL); | 116 mg/dL LDL | Standard Deviation 20 |
p-value: <0.0001t-test, 2 sided
Secondary
Triglycerides (TG)
Change from baseline in plasma triglycerides, measured in fasting blood samples
Time frame: 7 weeks
Population: per protocol, all subjects
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Triglycerides (TG) | 128 mg/dL TG | Standard Deviation 48 |
| Ezetimibe | Triglycerides (TG) | 121 mg/dL TG | Standard Deviation 50 |
p-value: >0.05t-test, 2 sided