Effects of Vytorin Versus Placebo in Subjects With Primary Hypercholesterolemia (Study P04420)

• Sponsor: Organon and Co (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00413972
• Collaborator: Schering-Plough (Industry), Merck Sharp & Dohme LLC (Industry)
• Enrollment: 392
• Arms: 4
• Duration (Months): 7

Study Details

Study Description

Brief Summary

This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group Phase 3 study of Vytorin 10/10 (ezetimibe 10 mg with simvastatin 10 mg), Vytorin 10/20 (ezetimibe 10 mg with simvastatin 20 mg), and Vytorin 10/40 (ezetimibe 10 mg with simvastatin 40 mg) compared to placebo administered daily for 8 consecutive weeks in subjects with primary hypercholesterolemia (LDL-C >3.64 mmol/L [140 mg/dL]). The efficacy of daily Vytorin versus placebo in reducing the concentration of LDL-C will be evaluated, and the efficacy of daily Vytorin versus placebo with respect to change in the concentrations of total cholesterol, triglycerides, and HDL-C will be compared. The safety of Vytorin versus placebo will also be assessed.

Condition or Disease	Intervention/Treatment	Phase
Hypercholesterolemia	Drug: ezetimibe with simvastatin; Drug: Ezetimibe with Simvastatin; Drug: Ezetimibe with Simvastatin; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 392 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Double-blind, Randomized, Placebo-controlled Parallel Groups Study Comparing the Efficacy and Safety of Vytorin Versus Placebo in Subjects With Primary Hypercholesterolemia
• Study Start Date: Apr 1, 2006
• Actual Primary Completion Date: Nov 1, 2006
• Actual Study Completion Date: Nov 1, 2006

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Vytorin 10/10 Ezetimibe 10 mg with Simvastatin 10 mg	Drug: ezetimibe with simvastatin; Ezetimibe 10 mg with Simvastatin 10 mg once daily for a total of eight weeks
Experimental: Vytorin 10/20 Ezetimibe 10 mg with Simvastatin 20 mg	Drug: Ezetimibe with Simvastatin; Ezetimibe 10 mg with Simvastatin 20 mg once daily for a total of eight weeks
Experimental: Vytorin 10/40 Ezetimibe 10 mg with Simvastatin 40 mg	Drug: Ezetimibe with Simvastatin; Ezetimibe 10 mg with Simvastatin 40 mg once daily for a total of eight weeks
Placebo Comparator: Placebo	Drug: Placebo; Placebo once daily for a total of eight weeks

Outcome Measures

Primary Outcome Measures

1. Percent Change in Low-density Lipoprotein Cholesterol (LDL-C) From Baseline to Endpoint After 8 Weeks of Treatment [Baseline, 8 weeks]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subjects must be >=18 years and <=75 years of age, male or female.

• Primary hypercholesterolemic subject with a plasma LDL cholesterol concentration >3.64 mmol/L (140 mg/dL) to <=6.3 mmol/L (250 mg/dL) using the Friedewald calculation; total cholesterol (TC) >5.2 mmol/L (200 mg/dL) to <12.7 mmol/L (500 mg/dL) and triglyceride concentrations of <=3.99 mmol/L (350 mg/dL) should be met at the same time. At the time of recruitment (Visit 1), these values may be lower if the subject is on lipid-lowering therapy. (ie, prior to the start of lipid lowering drug washout) or may be higher at the start of dietary therapy.

• Liver transaminases (ALT, AST) <=50% above the upper limit of normal, with no active liver disease and CK <=50% above the upper limit of normal.

• Clinical laboratory tests (complete blood count [CBC], blood chemistries, urinalysis) must be within normal limits, or clinically acceptable to the investigator/sponsor.

• Women of childbearing potential (includes women who are less than 1 year postmenopausal and women who become sexually active) must be using an acceptable method of birth control.

• Subjects must be free of any clinically significant diseases other than hyperlipidemia that would interfere with study evaluations.

• Subjects must understand and be able to adhere to the dosing and visit schedules.

• Subject must agree to remain on a cholesterol-lowering diet for the duration of the study (according to China Adult Treatment Panel of High Blood Cholesterol).

Exclusion Criteria:

• Subjects whose body mass index (BMI=weight [kg]/height2 [m]) is >=30 kg/m2 at Visit 3 (Baseline Visit).

• Subjects who have known hypersensitivity to HMG CoA reductase inhibitors.

• Subjects who consume >14 alcoholic drinks per week. (A drink is: a can of beer, glass of wine, or single measure of spirits).

• Any condition or situation, which in the opinion of the investigator, might pose a risk to the subject or interfere with participation in the study.

• Women who are pregnant or nursing.

• Subjects who have not observed the designated washout periods for any of the prohibited medications.

• Congestive heart failure defined by NYHA as Class III or IV.

• Uncontrolled cardiac arrhythmia.

• Myocardial infarction, coronary bypass surgery, or angioplasty within 6 months of study entry.

• Unstable or severe peripheral artery disease within 3 months of study entry.

• Unstable angina pectoris within 6 months of study entry.

• Uncontrolled hypertension (treated or untreated) with systolic blood pressure >160 mm Hg or diastolic >100 mm Hg at study entry.

• Uncontrolled (as determined by fasting glucose >180 mg/mL or HbA1c >9%) or newly diagnosed (within 1 month of study entry) diabetes mellitus.

• Uncontrolled endocrine or metabolic disease known to influence serum lipids or lipoproteins, ie, secondary causes of hyperlipidemia, such as secondary hypercholesterolemia due to hypothyroidism (thyroid stimulating hormone [TSH] above upper limit of normal). Subjects with a history of hypothyroidism who are on a stable therapy of thyroid hormone replacement for at least 6 weeks are eligible for enrollment if TSH levels are within normal limits before enrollment.

• Known impaired renal function (plasma creatinine >2.0 mg/dL), or nephrotic syndrome at study entry.

• Disorders of the hematologic, digestive, or central nervous systems, including cerebrovascular disease and degenerative disease that would limit study evaluation or participation.

• Known HIV positive.

• Cancer within the past 5 years (except for successfully treated basal and squamous cell carcinomas).

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

• Female subject receiving hormonal therapy, including hormone replacement, any estrogen antagonist/agonist, or oral contraceptives.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Organon and Co
• Schering-Plough
• 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: NCT00413972
• Other Study ID Numbers: P04420; SCH 465981
• First Posted: Dec 20, 2006
• Last Update Posted: Feb 9, 2022
• Last Verified: Feb 1, 2022

• Additional relevant MeSH terms: Hypercholesterolemia; Simvastatin; Ezetimibe

Study Results

Participant Flow

Arm/Group Title	Vytorin 10/10	Vytorin 10/20	Vytorin 10/40	Placebo
Arm/Group Description	Ezetimibe 10 mg with Simvastatin 10 mg	Ezetimibe 10 mg with Simvastatin 20 mg	Ezetimibe 10 mg with Simvastatin 40 mg
Period Title: Overall Study
STARTED	98	98	98	98
COMPLETED	91	90	88	95
NOT COMPLETED	7	8	10	3

Baseline Characteristics

Arm/Group Title	Vytorin 10/10	Vytorin 10/20	Vytorin 10/40	Placebo	Total
Arm/Group Description	Ezetimibe 10 mg with Simvastatin 10 mg	Ezetimibe 10 mg with Simvastatin 20 mg	Ezetimibe 10 mg with Simvastatin 40 mg	Total of all reporting groups
Overall Participants	97	97	98	97	389
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58.2 (10.7)	57.4 (9.7)	56.4 (10.3)	60.2 (9.2)	58.2 (10.07)
Sex: Female, Male (Count of Participants)
Female	59 60.8%	61 62.9%	66 67.3%	60 61.9%	246 63.2%
Male	38 39.2%	36 37.1%	32 32.7%	37 38.1%	143 36.8%
Region of Enrollment (participants) [Number]
China	97 100%	97 100%	98 100%	97 100%	389 100%

Outcome Measures

1. Primary Outcome

Title	Percent Change in Low-density Lipoprotein Cholesterol (LDL-C) From Baseline to Endpoint After 8 Weeks of Treatment
Time Frame	Baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

The number of participants for analysis included those from the ITT data set. 392 subjects were randomized in the study, but 3 of the randomized subjects were not treated and were excluded from the ITT data set. Therefore, only 389 subjects were included in the ITT data set.

Arm/Group Title	Vytorin 10/10	Vytorin 10/20	Vytorin 10/40	Placebo
Arm/Group Description	Ezetimibe 10 mg with Simvastatin 10 mg	Ezetimibe 10 mg with Simvastatin 20 mg	Ezetimibe 10 mg with Simvastatin 40 mg
Measure Participants	97	97	98	97
Mean (Standard Error) [percent change of LDL-C]	-41.69 (2.06)	-46.83 (2.08)	-49.10 (2.07)	-7.53 (2.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vytorin 10/10, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Vytorin 10/20, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Vytorin 10/40, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments

Adverse Events

Time Frame	9 weeks
Arm/Group Title	Vytorin 10/10		Vytorin 10/20		Vytorin 10/40		Placebo
Arm/Group Description	Ezetimibe 10 mg with Simvastatin 10 mg		Ezetimibe 10 mg with Simvastatin 20 mg		Ezetimibe 10 mg with Simvastatin 40 mg
All Cause Mortality
	Vytorin 10/10		Vytorin 10/20		Vytorin 10/40		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Vytorin 10/10		Vytorin 10/20		Vytorin 10/40		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/97 (0%)		0/97 (0%)		0/98 (0%)		0/97 (0%)
Other (Not Including Serious) Adverse Events
	Vytorin 10/10		Vytorin 10/20		Vytorin 10/40		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/97 (0%)		0/97 (0%)		0/98 (0%)		0/97 (0%)

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.