Effects of Ezetimibe on the Absorption of Oxidized Cholesterol

• Sponsor: UCSF Benioff Children's Hospital Oakland (Other)
• Overall Status: Completed
• CT.gov ID: NCT00794677
• Collaborator: Merck Schering-Plough (Other)
• Enrollment: 26
• Location: 1
• Arms: 2
• Duration (Months): 27
• Patients Per Site Per Month: 1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Hypercholesterolemia	Drug: ezetimibe; Drug: placebo	Phase 4

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 26 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Basic Science
• Official Title: A Randomized, Double-Blind, Placebo-Controlled, 2-Period, Crossover Study to Evaluate the Effects of Ezetimibe on the Plasma Appearance of 7-Ketocholesterol After an Oral Bolus in Patients With Primary Hypercholesterolemia
• Study Start Date: Jun 1, 2006
• Actual Primary Completion Date: Feb 1, 2008
• Actual Study Completion Date: Sep 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Sugar Pill Placebo medication will be taken orally once daily in the morning on rising either during the first intervention period or the second intervention period. 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.	Drug: placebo; 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.; Other Names: Sugar Pill
Experimental: ezetimibe 10 mg medication will be taken orally once daily in the morning on rising either during the first intervention period or the second intervention period. 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.	Drug: ezetimibe; 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.; Other Names: Zetia

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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 Outcome Measures

1. Log(Fasting Plasma Levels of Diet-derived Oxysterols (7-ketocholesterol)) [6 weeks]

2. Log (AUC of Plasma Total Cholesterol) After an Oral Bolus [6 weeks]

   Area under the curve (AUC) calculated over 8 hours

3. Log (AUC of Plasma Triglyceride) After an Oral Bolus [6 weeks]

   Area under the curve (AUC) calculated over 8 hours

4. Percent Change of Fasting Apolipoprotein B From Baseline [Baseline (placebo run-in) and 6 weeks]

   Change = [(Week 6 - baseline)/baseline value *100]

5. Percent Change of Fasting Low Density Lipoprotein Cholesterol From Baseline [Baseline (placebo run-in) and 6 weeks]

   Change = [(Week 6 - baseline)/baseline value *100]

6. Percent Change in Fasting High Density Lipoprotein Cholesterol [Baseline (placebo run-in) and 6 weeks]

   Change = [(Week 6 - baseline)/baseline value *100]

7. 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]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cholesterol Research Center	Berkeley	California	United States	94705

Sponsors and Collaborators

• UCSF Benioff Children's Hospital Oakland
• Merck Schering-Plough

Investigators

• Principal Investigator: Ronald M Krauss, M.D., UCSF Benioff Children's Hospital Oakland

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: UCSF Benioff Children's Hospital Oakland
• ClinicalTrials.gov Identifier: NCT00794677
• Other Study ID Numbers: MM6997
• First Posted: Nov 20, 2008
• Last Update Posted: Mar 9, 2021
• Last Verified: Feb 1, 2021

• Keywords provided by UCSF Benioff Children's Hospital Oakland: Hypercholesterolemia; Oxysterol; Ezetimibe; Zetia
• Additional relevant MeSH terms: Hypercholesterolemia; Ezetimibe

Study Results

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 Detail	55 participants screened; 29 excluded because they did not meet inclusion criteria

Arm/Group Title	Placebo First	Ezetimibe First
Arm/Group Description	Placebo once daily in first intervention period and ezetimibe (10 mg/day) in second intervention period	Ezetimibe (10 mg/day) once daily in the first intervention period and placebo once daily in the second intervention period
Period Title: First Intervention
STARTED	13	13
COMPLETED	11	13
NOT COMPLETED	2	0
Period Title: First Intervention
STARTED	11	13
COMPLETED	11	13
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Ezetimibe	Placebo	Total
Arm/Group Description	Ezetimibe (10 mg/day) once daily received as the first or second intervention	Placebo once daily received as the first or second intervention	Total of all reporting groups
Overall Participants	11	13	24
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	11 100%	11 84.6%	22 91.7%
>=65 years	0 0%	2 15.4%	2 8.3%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52.05 (7.54)	50.09 (14.28)	50.99 (11.49)
Sex: Female, Male (Count of Participants)
Female	4 36.4%	2 15.4%	6 25%
Male	7 63.6%	11 84.6%	18 75%
Region of Enrollment (participants) [Number]
United States	11 100%	13 100%	24.0 100%

Outcome Measures

1. Primary Outcome

Title	Log[Area-under-the-plasma-concentration-curve(AUC) 0-8 Hours 7-ketocholesterol] After an Oral Bolus
Description	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

Outcome Measure Data

Analysis Population Description

per protocol

Arm/Group Title	Ezetimibe	Placebo
Arm/Group Description	Ezetimibe (10 mg/day) once daily received as the first or second intervention	Placebo once daily received as the first or second intervention
Measure Participants	24	24
Mean (Standard Error) [Log(mg*hr/dl)]	1.925 (0.166)	2.177 (0.142)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ezetimibe, Placebo
	Comments	Statistical significance was determined for a standard two-period crossover design using JMP software (Version 5.0, SAS Institute. Cary, NC).
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.03
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.252
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.112
	Estimation Comments

2. Secondary Outcome

Title	Log(Maximal Plasma Concentration (Cmax) of 7-ketocholesterol) After an Oral Bolus
Description	Log Cmax of 7 ketocholesterol after an oral bolus in patients with primary hypercholesterolemia.
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

Per protocol

Arm/Group Title	Ezetimibe	Placebo
Arm/Group Description	Ezetimibe (10 mg/day) once daily received as the first or second intervention	Placebo once daily received as the first or second intervention
Measure Participants	24	24
Mean (Standard Error) [Log(mg/dl)]	0.973 (0.156)	1.246 (0.133)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ezetimibe, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.01
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.273
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.102
	Estimation Comments

3. Other Pre-specified Outcome

Title	Log(Fasting Plasma Levels of Diet-derived Oxysterols (7-ketocholesterol))
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

Per protocol

Arm/Group Title	Ezetimibe	Placebo
Arm/Group Description	Ezetimibe (10 mg/day) once daily received as the first or second intervention	Placebo once daily received as the first or second intervention
Measure Participants	24	24
Mean (Standard Error) [Log(mg/dl)]	-1.119 (0.124)	-1.070 (0.107)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ezetimibe, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.60
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.048
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.089
	Estimation Comments

4. Other Pre-specified Outcome

Title	Log (AUC of Plasma Total Cholesterol) After an Oral Bolus
Description	Area under the curve (AUC) calculated over 8 hours
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

Per protocol, restricted to changes that were nonnegative because there is no log for a negative number

Arm/Group Title	Ezetimibe	Placebo
Arm/Group Description	Ezetimibe (10 mg/day) once daily received as the first or second intervention	Placebo once daily received as the first or second intervention
Measure Participants	9	9
Mean (Standard Error) [Log(mg*hr/dl)]	2.928 (0.213)	2.719 (0.346)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ezetimibe, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.67
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.209
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.470
	Estimation Comments

5. Other Pre-specified Outcome

Title	Log (AUC of Plasma Triglyceride) After an Oral Bolus
Description	Area under the curve (AUC) calculated over 8 hours
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

Per protocol, one subject eliminated because the AUC was negative and cannot be log transformed

Arm/Group Title	Ezetimibe	Placebo
Arm/Group Description	Ezetimibe (10 mg/day) once daily received as the first or second intervention	Placebo once daily received as the first or second intervention
Measure Participants	23	23
Mean (Standard Error) [Log(mg*hr/dl)]	4.894 (0.139)	5.044 (0.126)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ezetimibe, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.30
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.150
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.140
	Estimation Comments

6. Other Pre-specified Outcome

Title	Percent Change of Fasting Apolipoprotein B From Baseline
Description	Change = [(Week 6 - baseline)/baseline value *100]
Time Frame	Baseline (placebo run-in) and 6 weeks

Outcome Measure Data

Analysis Population Description

Per protocol

Arm/Group Title	Ezetimibe	Placebo
Arm/Group Description	Ezetimibe (10 mg/day) once daily received as the first or second intervention	Placebo once daily received as the first or second intervention
Measure Participants	24	24
Mean (Standard Error) [percent change from baseline]	-17.990 (1.648)	-2.577 (2.113)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ezetimibe, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-15.412
	Confidence Interval	(2-Sided) 95%; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.569
	Estimation Comments

7. Other Pre-specified Outcome

Title	Percent Change of Fasting Low Density Lipoprotein Cholesterol From Baseline
Description	Change = [(Week 6 - baseline)/baseline value *100]
Time Frame	Baseline (placebo run-in) and 6 weeks

Outcome Measure Data

Analysis Population Description

Per protocol

Arm/Group Title	Ezetimibe	Placebo
Arm/Group Description	Ezetimibe (10 mg/day) once daily received as the first or second intervention	Placebo once daily received as the first or second intervention
Measure Participants	24	24
Mean (Standard Error) [percent change from baseline]	-22.891 (2.497)	-1.045 (2.454)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ezetimibe, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0000001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-21.846
	Confidence Interval	(2-Sided) 95%; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.866
	Estimation Comments

8. Other Pre-specified Outcome

Title	Percent Change in Fasting High Density Lipoprotein Cholesterol
Description	Change = [(Week 6 - baseline)/baseline value *100]
Time Frame	Baseline (placebo run-in) and 6 weeks

Outcome Measure Data

Analysis Population Description

Per protocol

Arm/Group Title	Ezetimibe	Placebo
Arm/Group Description	Ezetimibe (10 mg/day) once daily received as the first or second intervention	Placebo once daily received as the first or second intervention
Measure Participants	24	24
Mean (Standard Error) [percent change from baseline]	-1.936 (2.134)	-7.333 (1.860)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ezetimibe, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.009
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	5.397
	Confidence Interval	(2-Sided) 95%; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.893
	Estimation Comments

9. Other Pre-specified Outcome

Title	Percent Change of Fasting Non-high Density Lipoprotein Cholesterol From Baseline
Description	Change = [(Week 6 - baseline)/baseline value *100]
Time Frame	Baseline (placebo run-in) and 6 weeks

Outcome Measure Data

Analysis Population Description

Per protocol

Arm/Group Title	Ezetimibe	Placebo
Arm/Group Description	Ezetimibe (10 mg/day) once daily received as the first or second intervention	Placebo once daily received as the first or second intervention
Measure Participants	24	24
Mean (Standard Error) [percent change from baseline]	-22.675 (2.326)	-1.322 (1.871)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ezetimibe, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0000001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-21.353
	Confidence Interval	(2-Sided) 95%; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.220
	Estimation Comments

Adverse Events

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.