Hypercholesterolemia
Conditions
Keywords
Hypercholesterolemia, Oxysterol, Ezetimibe, Zetia
Brief summary
The purpose of this study is to test the effects of Zetia™ (ezetimibe) 10 milligrams (mg) on the absorption of oxysterol into the blood following a meal containing oxysterol.
Detailed description
There are a number of cholesterol-lowering drugs available that can lower blood cholesterol to a healthier level. Zetia™ (ezetimibe) 10 mg is available by prescription for the treatment of high cholesterol. While Zetia has been shown to inhibit the absorption of dietary cholesterol into the bloodstream, its effects on oxysterol absorption from the diet have not been completely evaluated.
Interventions
DRUGezetimibe
Blinded study medication (ezetimibe 10 mg in tablet form) will be taken orally once daily in the morning on rising. Single-blind ezetimibe placebo will be taken during the Run-In Period. Patients will be issued one bottle containing either active drug or placebo for each treatment period.
DRUGplacebo
Blinded study medication (matched placebo) will be taken orally once daily in the morning on rising. Single-blind ezetimibe placebo will be taken during the Run-In Period. Patients will be issued one bottle containing either active drug or placebo for each treatment period.
Sponsors
Merck Schering-Plough
UCSF Benioff Children's Hospital Oakland
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
* Not currently pregnant or lactating and is highly unlikely to conceive * Body Mass Index (BMI) between 20-30 kilograms per meter squared (kg/m2) inclusive. * Body weight, as reported by patient, stable (±2 kg) for \>6 weeks * Plasma low density lipoprotein cholesterol (LDL-C) between 130 and 180 milligrams per deciliter (mg/dL) inclusive. Note: One retest allowed. * Triglyceride (TG) concentrations ≤150 mg/dL. Note: One retest allowed. * Fasting blood glucose \<110 mg/dL and hemoglobin A1c (HbA1C) ≤ 6 percent at Visit 1. Note: One retest allowed. * Liver transaminases (ALT, AST) ≤1.5 x upper limit of normal (ULN) and no active liver disease. Note: One retest allowed. * Creatine Phosphokinase (CPK) ≤2x ULN. Note: One retest allowed. * Willingness to maintain a stable diet for the duration of the study. * Can understand and comply with study procedures and signs a written informed consent. * Patient is ≥80 precent compliant with dosing during Placebo Run-In Period or, in the opinion of the investigator, is able to maintain ≥80 percent therapy compliance during the active treatment period of the study.
Exclusion criteria
* Lipid-lowering therapy and replacement of this therapy with study medication is considered inappropriate by the investigator. * Consumes an average of more than 2 alcoholic drinks per day. * Smokes. * Currently engages in a vigorous exercise regimen or intensive exercise bouts \>4x per month. * Treated with any other investigational drug within 30 days of Visit 1. * Hypersensitivity or intolerance to ezetimibe or any component of this medication. * Any condition or situation which poses a risk to the patient or interfere with participation in the study. * Congestive heart failure. * Uncontrolled cardiac arrhythmias. * History of myocardial infarction, stroke, or any other clinical manifestation of coronary, cerebral, or peripheral vascular disease. * Uncontrolled hypertension * Impaired renal function, nephrotic syndrome or other clinically significant renal disease at Visit 1. * Active or chronic hepatobiliary or hepatic disease. * History of irritable bowel syndrome, ileal bypass, gastric bypass or any gastrointestinal disorder/condition associated with malabsorption. * Uncontrolled endocrine or metabolic disease known to influence serum lipids or lipoproteins. * Type I or Type II diabetes mellitus. * Disorders of the hematologic, digestive, or central nervous systems including cerebrovascular disease and degenerative disease that would limit study evaluation or participation. * Human Immunodeficiency Virus (HIV) positive. * History of cancer within the past 5 years (except for successfully treated basal and squamous cell carcinomas). * History of uncontrolled psychiatric illness or drug/alcohol abuse within the past 5 years. Individuals with psychiatric illness adequately controlled and stable on pharmacotherapy may be enrolled at the discretion of the investigator. * Lipid-lowering agents taken within 6 weeks and fibrates taken within 8 weeks prior to visit 3. * Cardiovascular medications are acceptable provided the patient has been on a stable regimen for at least 6 weeks prior to Visit 3 and indicates a willingness to continue the stable regimen for the duration of the study. * Supplementation with antioxidants beyond a standard multivitamin for the duration of the study. * Psyllium, other fiber-based laxatives, and/or over the counter (OTC) therapies known to affect serum lipid levels taken within 6 weeks of Visit 3. * Female patients receiving hormone replacement therapy, any estrogen antagonist/agonist or hormonal contraceptives. * Treatment with cyclosporine except for ophthalmic indication * Anti-obesity medications such as orlistat or sibutramine taken within 3 months prior to Visit 1. * Therapeutic doses of systemic corticosteroids except inhaled steroid therapy (for example, Pulmicort®) maintained on a stable dosing regimen for at least 6 weeks prior to randomization (Visit 3) and throughout the duration of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Log[Area-under-the-plasma-concentration-curve(AUC) 0-8 Hours 7-ketocholesterol] After an Oral Bolus | 6 weeks | Log of Area-under-the-plasma-concentration curve (AUC 0-8hrs) of 7-ketocholesterol after an oral bolus in patients with primary hypercholesterolemia after treatment with ezetimibe versus placebo |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Log(Maximal Plasma Concentration (Cmax) of 7-ketocholesterol) After an Oral Bolus | 6 weeks | Log Cmax of 7 ketocholesterol after an oral bolus in patients with primary hypercholesterolemia. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Log (AUC of Plasma Triglyceride) After an Oral Bolus | 6 weeks | Area under the curve (AUC) calculated over 8 hours |
| Percent Change of Fasting Apolipoprotein B From Baseline | Baseline (placebo run-in) and 6 weeks | Change = \[(Week 6 - baseline)/baseline value \*100\] |
| Log(Fasting Plasma Levels of Diet-derived Oxysterols (7-ketocholesterol)) | 6 weeks | — |
| Percent Change in Fasting High Density Lipoprotein Cholesterol | Baseline (placebo run-in) and 6 weeks | Change = \[(Week 6 - baseline)/baseline value \*100\] |
| Percent Change of Fasting Non-high Density Lipoprotein Cholesterol From Baseline | Baseline (placebo run-in) and 6 weeks | Change = \[(Week 6 - baseline)/baseline value \*100\] |
| Percent Change of Fasting Low Density Lipoprotein Cholesterol From Baseline | Baseline (placebo run-in) and 6 weeks | Change = \[(Week 6 - baseline)/baseline value \*100\] |
| Log (AUC of Plasma Total Cholesterol) After an Oral Bolus | 6 weeks | Area under the curve (AUC) calculated over 8 hours |
Countries
United States
Participant flow
Recruitment details
Recruitment took place in 2007 through search of a clinical research center database, mailings to homes, and posted flyers in the Berkeley, California area.
Pre-assignment details
55 participants screened; 29 excluded because they did not meet inclusion criteria
Participants by arm
| Arm | Count |
|---|---|
| Ezetimibe Ezetimibe (10 mg/day) once daily received as the first or second intervention | 11 |
| Placebo Placebo once daily received as the first or second intervention | 13 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Placebo | Ezetimibe | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 0 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 11 Participants | 22 Participants |
| Age, Continuous | 50.09 years STANDARD_DEVIATION 14.28 | 52.05 years STANDARD_DEVIATION 7.54 | 50.99 years STANDARD_DEVIATION 11.49 |
| Region of Enrollment United States | 13 participants | 11 participants | 24.0 participants |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 6 Participants |
| Sex: Female, Male Male | 11 Participants | 7 Participants | 18 Participants |
Outcome results
Primary
Log[Area-under-the-plasma-concentration-curve(AUC) 0-8 Hours 7-ketocholesterol] After an Oral Bolus
Log of Area-under-the-plasma-concentration curve (AUC 0-8hrs) of 7-ketocholesterol after an oral bolus in patients with primary hypercholesterolemia after treatment with ezetimibe versus placebo
Time frame: 6 weeks
Population: per protocol
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ezetimibe | Log[Area-under-the-plasma-concentration-curve(AUC) 0-8 Hours 7-ketocholesterol] After an Oral Bolus | 1.925 Log(mg*hr/dl) | Standard Error 0.166 |
| Placebo | Log[Area-under-the-plasma-concentration-curve(AUC) 0-8 Hours 7-ketocholesterol] After an Oral Bolus | 2.177 Log(mg*hr/dl) | Standard Error 0.142 |
Comparison: Statistical significance was determined for a standard two-period crossover design using JMP software (Version 5.0, SAS Institute. Cary, NC).p-value: 0.03ANOVA
Secondary
Log(Maximal Plasma Concentration (Cmax) of 7-ketocholesterol) After an Oral Bolus
Log Cmax of 7 ketocholesterol after an oral bolus in patients with primary hypercholesterolemia.
Time frame: 6 weeks
Population: Per protocol
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ezetimibe | Log(Maximal Plasma Concentration (Cmax) of 7-ketocholesterol) After an Oral Bolus | 0.973 Log(mg/dl) | Standard Error 0.156 |
| Placebo | Log(Maximal Plasma Concentration (Cmax) of 7-ketocholesterol) After an Oral Bolus | 1.246 Log(mg/dl) | Standard Error 0.133 |
p-value: 0.01ANOVA
Other Pre-specified
Log (AUC of Plasma Total Cholesterol) After an Oral Bolus
Area under the curve (AUC) calculated over 8 hours
Time frame: 6 weeks
Population: Per protocol, restricted to changes that were nonnegative because there is no log for a negative number
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ezetimibe | Log (AUC of Plasma Total Cholesterol) After an Oral Bolus | 2.928 Log(mg*hr/dl) | Standard Error 0.213 |
| Placebo | Log (AUC of Plasma Total Cholesterol) After an Oral Bolus | 2.719 Log(mg*hr/dl) | Standard Error 0.346 |
p-value: 0.67ANOVA
Other Pre-specified
Log (AUC of Plasma Triglyceride) After an Oral Bolus
Area under the curve (AUC) calculated over 8 hours
Time frame: 6 weeks
Population: Per protocol, one subject eliminated because the AUC was negative and cannot be log transformed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ezetimibe | Log (AUC of Plasma Triglyceride) After an Oral Bolus | 4.894 Log(mg*hr/dl) | Standard Error 0.139 |
| Placebo | Log (AUC of Plasma Triglyceride) After an Oral Bolus | 5.044 Log(mg*hr/dl) | Standard Error 0.126 |
p-value: 0.3ANOVA
Other Pre-specified
Log(Fasting Plasma Levels of Diet-derived Oxysterols (7-ketocholesterol))
Time frame: 6 weeks
Population: Per protocol
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ezetimibe | Log(Fasting Plasma Levels of Diet-derived Oxysterols (7-ketocholesterol)) | -1.119 Log(mg/dl) | Standard Error 0.124 |
| Placebo | Log(Fasting Plasma Levels of Diet-derived Oxysterols (7-ketocholesterol)) | -1.070 Log(mg/dl) | Standard Error 0.107 |
p-value: 0.6ANOVA
Other Pre-specified
Percent Change in Fasting High Density Lipoprotein Cholesterol
Change = \[(Week 6 - baseline)/baseline value \*100\]
Time frame: Baseline (placebo run-in) and 6 weeks
Population: Per protocol
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ezetimibe | Percent Change in Fasting High Density Lipoprotein Cholesterol | -1.936 percent change from baseline | Standard Error 2.134 |
| Placebo | Percent Change in Fasting High Density Lipoprotein Cholesterol | -7.333 percent change from baseline | Standard Error 1.86 |
p-value: 0.009ANOVA
Other Pre-specified
Percent Change of Fasting Apolipoprotein B From Baseline
Change = \[(Week 6 - baseline)/baseline value \*100\]
Time frame: Baseline (placebo run-in) and 6 weeks
Population: Per protocol
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ezetimibe | Percent Change of Fasting Apolipoprotein B From Baseline | -17.990 percent change from baseline | Standard Error 1.648 |
| Placebo | Percent Change of Fasting Apolipoprotein B From Baseline | -2.577 percent change from baseline | Standard Error 2.113 |
p-value: <0.0001ANOVA
Other Pre-specified
Percent Change of Fasting Low Density Lipoprotein Cholesterol From Baseline
Change = \[(Week 6 - baseline)/baseline value \*100\]
Time frame: Baseline (placebo run-in) and 6 weeks
Population: Per protocol
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ezetimibe | Percent Change of Fasting Low Density Lipoprotein Cholesterol From Baseline | -22.891 percent change from baseline | Standard Error 2.497 |
| Placebo | Percent Change of Fasting Low Density Lipoprotein Cholesterol From Baseline | -1.045 percent change from baseline | Standard Error 2.454 |
p-value: <1e-7ANOVA
Other Pre-specified
Percent Change of Fasting Non-high Density Lipoprotein Cholesterol From Baseline
Change = \[(Week 6 - baseline)/baseline value \*100\]
Time frame: Baseline (placebo run-in) and 6 weeks
Population: Per protocol
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ezetimibe | Percent Change of Fasting Non-high Density Lipoprotein Cholesterol From Baseline | -22.675 percent change from baseline | Standard Error 2.326 |
| Placebo | Percent Change of Fasting Non-high Density Lipoprotein Cholesterol From Baseline | -1.322 percent change from baseline | Standard Error 1.871 |
p-value: <1e-7ANOVA