Comparison of Ezetimibe Added to Ongoing Statin Therapy Versus Doubling the Dose of Statin in the Treatment of Hypercholesterolemia (P04355)

• Sponsor: Organon and Co (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00652327
• Collaborator: Merck Sharp & Dohme LLC (Industry)
• Enrollment: 83
• Arms: 2
• Duration (Months): 19

Study Details

Study Description

Brief Summary

This is a randomized, open label, parallel group comparison study. Following a 1-week screening period, patients will be randomized to 1 of 2 treatment groups: ezetimibe added to ongoing statin treatment (ezetimibe plus simvastatin, atorvastatin or pravastatin at doses of 10/20, 10/10 or 10/20 mg), or doubling the dose of ongoing statin (simvastatin 40 mg, atorvastatin 20 mg, or pravastatin 40 mg). Study drug will be administered once daily in the evening for 8 weeks. Patients will be instructed to follow a National Cholesterol Education Program (NCEP) or similar cholesterol-lowering dietary regimen throughout the study.

Condition or Disease	Intervention/Treatment	Phase
Hypercholesterolemia	Drug: Ezetimibe + Statin (simvastatin, atorvastatin, or pravastatin); Drug: Double Statin (simvastatin, atorvastatin, or pravastatin)	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 83 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Open-labeled, Parallel Group Comparison Study to Evaluate the Efficacy, Safety and Tolerability of Ezetimibe Added to Ongoing Statin Therapy Versus Doubling the Dose of Ongoing Statin in the Treatment of Hypercholesterolemia.
• Study Start Date: Dec 1, 2005
• Actual Primary Completion Date: Jul 1, 2007
• Actual Study Completion Date: Jul 1, 2007

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ezetimibe + Statin	Drug: Ezetimibe + Statin (simvastatin, atorvastatin, or pravastatin); ezetimibe 10 mg plus ongoing statin (simvastatin 20 mg or atorvastatin 10 mg or pravastatin 20 mg) once daily for 8 weeks
Active Comparator: Double Statin	Drug: Double Statin (simvastatin, atorvastatin, or pravastatin); simvastatin 40 mg or atorvastatin 20 mg or pravastatin 40 mg once daily for 8 weeks

Outcome Measures

Primary Outcome Measures

1. Percentage Change in Low Density Lipoprotein-Cholesterol (LDL-C) From Baseline at Study Endpoint, After 8 Weeks of Treatment [Assessed at the end of 8 weeks of treatment (from baseline to endpoint)]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

80-120 patients will be recruited in this study. All patients must meet the following criteria and follow an NCEP or similar cholesterol-lowering dietary regimen throughout the study:

• Men or women ≧18 and ≦80 years of age (Female patients receiving hormone therapy [including hormone replacement therapy, and estrogen antagonist/agonist, or oral contraceptives] and maintained on a stable dose and regimen for at least 8 weeks prior to visit 1 must be willing to continue the same regimen throughout the study. Females of childbearing potential must be using a medically acceptable method of birth control).

• Willing to follow an NCEP Therapeutic Lifestyle Changes (TLC) or similar cholesterol-lowering diet for the duration of the study.

• Patients with hypercholesterolemia who cannot achieve the optimal therapeutic goal with previous statin treatment (simvastatin 20 mg, atorvastatin 10 mg or pravastatin 20 mg alone for at least 12 weeks) will be enrolled into study. The treatment goal in primary prevention is LDL-C <160 mg/dL or LDL-C <130 mg/dL patient with ≧ 2 risk factors (risk factors: hypertension, male ≧ 45 years old, family of premature coronary artery disease [CAD], female ≧ 55 years old or menopause without hormone replace therapy, smoking); LDL-C ≤ 100 mg/dL in CAD patients (documented by coronary angiogram, positive treadmill test or thallium scan), or diabetes mellitus (DM) patients (Ante Cibum [AC][fasting plasma glucose] >126 mg/dL, Post Cibum [PC] [oral glucose tolerance test] > 200 mg/dL, World Health Organization criteria), ischemic stroke (neurological dysfunction with documented diagnosis with computed tomography [CT] or magnetic resonance imaging [MRI]), peripheral artery disease.

• Triglyceride (TG) concentrations ≦ 400 mg/dL.

• Liver transaminases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) ≦ 2 x upper limit of normal (ULN) with no active liver disease and creatine kinase (CK) ≦ 2 x ULN at screen visit.

Exclusion Criteria:

The following conditions preclude patients from entry into this study:

• Women who are pregnant or lactating.

• History of mental instability, drug/alcohol abuse within the past 5 years, or major psychiatric illness not adequately controlled and stable on pharmacotherapy

• Patients who have been treated with any other investigational drug within 3 months of visit 1.

• Patients previously randomized to a study with ezetimibe.

• Active liver disease or Impaired liver function tests (ALT, AST > 2xULN).

• Impaired renal function ( serum creatinine ≧1.5 mg/dL) or nephrotic syndrome at visit 1

• Unstable angina

• Acute myocardial infarction, coronary bypass surgery within the previous six months of visit 1.

• Uncontrolled cardiac arrhythmias

• Uncontrolled hypertension (treated or untreated) with systolic blood pressure > 160 mmHg or diastolic > 100 mmHg at visit 1.

• Poorly controlled diabetes mellitus patient (Patients who are under insulin injection and HbA1c>10.0%). If the patient is treated with medication for diabetes, the medication will be unchanged during the study period.

• Uncontrolled endocrine or metabolic disease known to influence serum lipids or lipoprotein, e.g. hypothyroidism (thyroid-stimulating hormone [TSH] > 5.5 uIU/mL). However, patients who are on a stable therapy of thyroid replacement therapy for at least 6 weeks are eligible for enrollment.

• Patients hypersensitive to HMG-CoA reductase inhibitors or ezetimibe.

• Patient who is unable to give informed consent (the patient with a legal representative to sign the informed consent is eligible to participate the study).

• Any condition or situation which, in the opinion of the investigator, might pose a risk to the patient or confound the results of the study.

• Prohibited concomitant therapies.

• Medications that are potent inhibitors of CYP3A4, including cyclosporine, systemic itraconazole or ketoconazole, erythromycin or clarithromycin, nefazodone, verapamil and human immunodeficiency virus (HIV) protease inhibitors.

• Lipid-lowering agents including fish oils, Cholestin, bile-acid sequestrants, and niacin (<200 mg/day) taken within 6 weeks and fibrates taken within 8 weeks prior to enrollment.

• Oral corticosteroids unless used as replacement therapy for pituitary/adrenal disease and treated with a stable regimen for at least 6 weeks prior to enrollment.

• Treatment with psylium, other fiber-based laxatives, and/or over-the-counter (OTC) therapies known to affect serum lipid levels, phytosterol margarines, unless treated with a stable regimen for at least 6 weeks prior to enrollment, and patient agrees to remain on constant regimen for the duration of the study.

• Patient is consuming > 250 ml of grapefruit juice per day.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Organon and Co
• Merck Sharp & Dohme LLC

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Organon and Co
• ClinicalTrials.gov Identifier: NCT00652327
• Other Study ID Numbers: P04355
• First Posted: Apr 3, 2008
• Last Update Posted: Feb 9, 2022
• Last Verified: Feb 1, 2022

• Additional relevant MeSH terms: Hypercholesterolemia; Atorvastatin; Simvastatin; Ezetimibe; Pravastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors

Study Results

Participant Flow

Pre-assignment Detail	A total of 202 potential participants signed informed consent during a screening visit. Of these, 119 did not meet protocol eligibility requirements. The remainder, 83, received randomized treatment assignment.

Arm/Group Title	Ezetimibe + Statin	Double Statin
Arm/Group Description	Once daily 10-mg ezetimibe tablet added to daily ongoing statin treatment (simvastatin 20 mg or atorvastatin 10 mg or pravastatin 20 mg) for 8 weeks	Double the dose of daily ongoing statin treatment (simvastatin 20 mg or atorvastatin 10 mg or pravastatin 20 mg) for 8 weeks
Period Title: Overall Study
STARTED	42	41
COMPLETED	42	36
NOT COMPLETED	0	5

Baseline Characteristics

Arm/Group Title	Ezetimibe + Statin	Double Statin	Total
Arm/Group Description	Once daily 10-mg ezetimibe tablet added to daily ongoing statin treatment (simvastatin 20 mg or atorvastatin 10 mg or pravastatin 20 mg) for 8 weeks	Double the dose of daily ongoing statin treatment (simvastatin 20 mg or atorvastatin 10 mg or pravastatin 20 mg) for 8 weeks	Total of all reporting groups
Overall Participants	42	41	83
Age, Customized (Number) [Number]
<=18 years	0 0%	0 0%	0 0%
Between 18 and 83 years	42 100%	41 100%	83 100%
>=83 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	19 45.2%	18 43.9%	37 44.6%
Male	23 54.8%	23 56.1%	46 55.4%
Region of Enrollment (Number) [Number]
Taiwan, Province Of China	42 100%	41 100%	83 100%

Outcome Measures

1. Primary Outcome

Title	Percentage Change in Low Density Lipoprotein-Cholesterol (LDL-C) From Baseline at Study Endpoint, After 8 Weeks of Treatment
Time Frame	Assessed at the end of 8 weeks of treatment (from baseline to endpoint)

Outcome Measure Data

Analysis Population Description

The population analyzed (intent-to-treat [ITT]) included all participants who had a post-randomization LDL-C laboratory evaluation. As such, 20 of the 83 participants who received treatment assignment were excluded from the ITT. The 5 participants who discontinued were included in the ITT as each had a post-randomization LDL-C lab evaluation.

Arm/Group Title	Ezetimibe + Statin	Double Statin
Arm/Group Description	Once daily 10-mg ezetimibe tablet added to daily ongoing statin treatment (simvastatin 20 mg or atorvastatin 10 mg or pravastatin 20 mg) for 8 weeks	Double the dose of daily ongoing statin treatment (simvastatin 20 mg or atorvastatin 10 mg or pravastatin 20 mg) for 8 weeks
Measure Participants	29	34
Mean (Standard Deviation) [Percentage change]	-26.56 (19.78)	-9.7 (21.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ezetimibe + Statin, Double Statin
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	.0026
	Comments
	Method	Wilcoxon rank sum test
	Comments

Adverse Events

Arm/Group Title	Ezetimibe + Statin		Double Statin
Arm/Group Description	Once daily 10-mg ezetimibe tablet added to daily ongoing statin treatment (simvastatin 20 mg or atorvastatin 10 mg or pravastatin 20 mg) for 8 weeks		Double the dose of daily ongoing statin treatment (simvastatin 20 mg or atorvastatin 10 mg or pravastatin 20 mg) for 8 weeks
All Cause Mortality
	Ezetimibe + Statin		Double Statin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Ezetimibe + Statin		Double Statin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/42 (2.4%)		0/41 (0%)
Infections and infestations
upper respiratory tract infection	1/42 (2.4%)	1	0/41 (0%)	0
Other (Not Including Serious) Adverse Events
	Ezetimibe + Statin		Double Statin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/42 (0%)		3/41 (7.3%)
Ear and labyrinth disorders
vertigo	0/42 (0%)	0	3/41 (7.3%)	3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.