A Study to Evaluate the Effectiveness of Ezetimibe/Atorvastatin 10 mg/20 mg Combination Tablet Compared to Marketed Ezetimibe 10 mg and Atorvastatin 20 mg Tablets in Participants With High Cholesterol (MK-0653C-185 AM1)

• Sponsor: Organon and Co (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01370590
• Collaborator: (none)
• Enrollment: 406
• Arms: 2
• Duration (Months): 7

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether ezetimibe/atorvastatin 10 mg/20 mg combination tablet is equivalent to the coadministration of ezetimibe 10 mg and atorvastatin 20 mg in lowering low-density-lipoprotein-cholesterol (LDL-C) after 6 weeks of treatment.

Condition or Disease	Intervention/Treatment	Phase
Hypercholesterolemia	Drug: Atorvastatin; Drug: Ezetimibe; Drug: Ezetimibe/atorvastatin; Drug: Placebo to atorvastatin; Drug: Placebo to ezetimibe; Drug: Placebo to ezetimibe/atorvastatin	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 406 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Active-Controlled, Multicenter, Crossover Study to Evaluate the Efficacy and Safety of Ezetimibe/Atorvastatin 10 mg/20 mg Fixed-Dose Combination Tablet Compared to Co-administration of Marketed Ezetimibe 10 mg and Atorvastatin 20 mg in Patients With Primary Hypercholesterolemia
• Study Start Date: Sep 1, 2011
• Actual Primary Completion Date: Apr 1, 2012
• Actual Study Completion Date: Apr 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Ezetimibe and atorvastatin Medication will be administered in a double dummy fashion as 3 tablets orally on a daily basis, including 10 mg ezetimibe, 20 mg atorvastatin, and placebo to ezetimibe/atorvastatin.	Drug: Atorvastatin; 20 mg tablet administered orally once daily; Other Names: Lipitor® ; Drug: Ezetimibe; 10 mg tablet administered orally once daily; Other Names: Zetia® ; Drug: Placebo to ezetimibe/atorvastatin; Administered orally once daily
Experimental: Ezetimibe/atorvastatin combination Medication will be administered in a double dummy fashion as 3 tablets orally on a daily basis, including ezetimibe/atorvastatin 10 mg/20 mg, placebo to ezetimibe, and placebo to atorvastatin.	Drug: Ezetimibe/atorvastatin; Ezetimibe/atorvastatin 10 mg/20 mg combination tablet administered orally once daily; Other Names: Liptruzet® MK-0653C ; Drug: Placebo to atorvastatin; Administered orally once daily; Drug: Placebo to ezetimibe; Administered orally once daily

Outcome Measures

Primary Outcome Measures

1. Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) After 6 Weeks of Treatment [Baseline and Week 6]

   Serum LDL-C calculated using Friedewald formula at baseline and after 6 weeks of treatment in each of the 2 treatment periods.

Secondary Outcome Measures

1. Percent Change From Baseline in Total Cholesterol (TC) After 6 Weeks of Treatment [Baseline and Week 6]

   Serum TC measured at baseline and after 6 week of treatment in each of the 2 treatment periods.

2. Percent Change From Baseline in High-density Lipoprotein Cholesterol (HDL-C) After 6 Weeks of Treatment [Baseline and Week 6]

   Serum HDL-C calculated at baseline and after 6 weeks of treatment in each of the 2 treatment periods.

3. Percent Change From Baseline in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) After 6 Weeks of Treatment [Baseline and Week 6]

   Non-HDL-C measured at baseline and after 6 weeks of treatment in each of the 2 treatment periods.

4. Percent Change From Baseline in Apolipoprotein (Apo) B After 6 Weeks of Treatment [Baseline and Week 6]

   Serum Apo B measured at baseline and after 6 weeks of treatment in each of the 2 treatment periods.

5. Percent Change From Baseline in Triglycerides (TG) After 6 Weeks of Treatment [Baseline and Week 6]

   Serum TG measured at baseline and after 6 weeks of treatment in each of the 2 treatment periods.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 79 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

• At low, moderate, or moderately high cardiovascular risk (according to National Cholesterol Education Program adult treatment panel III [NCEP ATP III] guidelines) and either statin-naïve with LDL-C ≥130 mg/dL for low risk or ≥100 mg/dL for moderate or moderately high risk OR on an allowable statin with on-therapy LDL-C ≥100 mg/dL in acceptable range and can safely discontinue and switch to study medication.

• Is willing to maintain a cholesterol-lowering diet throughout the study.

• Female of reproductive potential agrees to remain abstinent or to use (or have their partner use) 2 acceptable methods of birth control throughout the study.

• Female receiving non-cyclical hormone therapy, if maintained on a stable dose and regimen for at least 8 weeks prior to the study and if willing to continue the same regimen throughout the study.

• Off-therapy LDL-C levels are: for low risk patients, ≥130 mg/dL and ≤300 mg/dL; for moderate risk patients, ≥100 mg/dL and ≤300 mg/dL; for moderately high risk patients, ≥100 mg/dL and ≤275 mg/dL.

• Has liver transaminases ≤2 X upper limit of normal (ULN) with no active liver disease.

• Has creatine kinase (CK) levels ≤3 X ULN.

• Has triglyceride (TG) concentrations ≤400 mg/dL.

Exclusion criteria:

• Hypersensitivity or intolerance to ezetimibe, atorvastatin, the ezetimibe/atorvastatin combination tablet, or any component of these medications, or a history of myopathy or rhabdomyolysis with ezetimibe or any statin.

• Routinely consumes more than 2 alcoholic drinks per day (average >14 alcoholic drinks per week).

• Is pregnant or lactating.

• Has been treated with any other investigational drug within 30 days of the study.

• Has any condition or situation that might pose a risk to the participant or interfere with participation in the study.

• Is high risk (according to NCEP ATP III guidelines), including but not limited to one or more of the following: diabetes mellitus (Type I or II), myocardial infarction, coronary artery bypass surgery, angioplasty, stable or unstable angina.

• Has any of the following medical conditions: congestive heart failure; uncontrolled cardiac arrhythmias or recent significant changes in electrocardiogram (ECG); homozygous familial hypercholesterolemia or has undergone LDL apheresis; partial ileal bypass, gastric bypass, or other significant intestinal malabsorption; uncontrolled hypertension; kidney disease; disease known to influence serum lipids or lipoproteins; hematologic, digestive, or central nervous systems disorder; known to be human immunodeficiency virus (HIV) positive; history of malignancy ≤5 years prior to the study, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer; mental instability; drug/alcohol abuse within the past 5 years, or major psychiatric illness not adequately controlled and stable on pharmacotherapy.

• Taking prohibited medications/foods including: systemic azole antifungals (e.g., fluconazole, ketoconazole), erythromycin or clarithromycin, and cyclosporine; ritonavir and saquinavir or lopinavir; >5 cups of grapefruit juice per day; combination therapies of ezetimibe + simvastatin (10/80 mg), ezetimibe + atorvastatin (10/40 mg or 10/80 mg), ezetimibe + rosuvastatin (10/10 mg, 10/20 mg, or 10/40 mg), ezetimibe + pitavastatin (10/4 mg); non-statin lipid-lowering agents including fish oils containing >900 mg/day of eicosapentaenoic acid and docosahexaenoic acid (EPA+DHA), red yeast extract, Cholestin™, bile acid sequestrants, other cholesterol-lowering agents, niacin (>200 mg/day), or fibrates; systemic corticosteroids; psyllium, other fiber-based laxatives, phytosterol margarines, and/or over the counter (OTC) therapies known to affect serum lipid levels; orlistat or other anti-obesity medications and not maintained on a stable dose; any cyclical hormones; warfarin treatment without a stable dose or a stable International Normalized Ratio (INR).

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Organon and Co

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Organon and Co
• ClinicalTrials.gov Identifier: NCT01370590
• Other Study ID Numbers: 0653C-185
• First Posted: Jun 10, 2011
• Last Update Posted: Feb 9, 2022
• Last Verified: Feb 1, 2022

• Additional relevant MeSH terms: Hypercholesterolemia; Atorvastatin; Ezetimibe

Study Results

Participant Flow

Arm/Group Title	Coadministered/Combination Sequence	Combination/Coadministered Sequence
Arm/Group Description	Co-administration Ezetimibe 10 mg and Atorvastatin 20 mg then Ezetimibe/Atorvastatin 10 mg/20 mg fixed-dose combination	Ezetimibe/Atorvastatin 10 mg/20 mg fixed-dose combination then Co-administration Ezetimibe 10 mg and Atorvastatin 20 mg
Period Title: Period 1
STARTED	203	203
COMPLETED	187	192
NOT COMPLETED	16	11
Period Title: Period 1
STARTED	187	192
COMPLETED	181	186
NOT COMPLETED	6	6
Period Title: Period 1
STARTED	181	186
COMPLETED	180	184
NOT COMPLETED	1	2

Baseline Characteristics

Arm/Group Title	Coadministered/Combination Sequence	Combination/Coadministered Sequence	Total
Arm/Group Description	Co-administration Ezetimibe 10 mg and Atorvastatin 20 mg then Ezetimibe/Atorvastatin 10 mg/20 mg fixed-dose combination	Ezetimibe/Atorvastatin 10 mg/20 mg fixed-dose combination then Co-administration Ezetimibe 10 mg and Atorvastatin 20 mg	Total of all reporting groups
Overall Participants	203	203	406
Age, Customized (Number) [Number]
30 to 39 years	14 6.9%	10 4.9%	24 5.9%
40 to 49 years	35 17.2%	28 13.8%	63 15.5%
50 to 59 years	78 38.4%	81 39.9%	159 39.2%
60 to 64 years	40 19.7%	51 25.1%	91 22.4%
≥65 years	36 17.7%	33 16.3%	69 17%
Sex: Female, Male (Count of Participants)
Female	126 62.1%	122 60.1%	248 61.1%
Male	77 37.9%	81 39.9%	158 38.9%

Outcome Measures

1. Primary Outcome

Title	Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) After 6 Weeks of Treatment
Description	Serum LDL-C calculated using Friedewald formula at baseline and after 6 weeks of treatment in each of the 2 treatment periods.
Time Frame	Baseline and Week 6

Outcome Measure Data

Analysis Population Description

Per-Protocol Population, which excluded participants due to important deviations from the protocol that may have substantially affected the results of the primary efficacy endpoint(s). A participant could be excluded from 1 or more of the analyses. Results are reported by treatment formulation and not by sequence.

Arm/Group Title	Ezetimibe/Atorva Fixed Dose Combination	Co-Administration Ezetimibe and Atorvastin
Arm/Group Description	Ezetimibe/atorvastatin 10 mg/20 mg combination tablet once daily for 6 weeks	Ezetimibe 10 mg co-administered with atorvastatin 20 mg once daily for 6 weeks
Measure Participants	353	346
Least Squares Mean (95% Confidence Interval) [Percentage Change]	-54.0	-53.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ezetimibe/Atorva Fixed Dose Combination, Co-Administration Ezetimibe and Atorvastin
	Comments	It was anticipated that 85% of the enrolled participants would be evaluable to achieve 95% power in order to establish equivalence between the Ezetimibe/Atorvastatin Fixed Dose Combination and the co-administration of Ezetimibe and Atorvastatin with respect to percent change from baseline in LDL-C after 6 weeks of treatment using two one-sided tests each at 2.5% α-level, assuming the underlying true treatment difference is ±1.4% and that the standard deviation of the difference is 12.8%.
	Type of Statistical Test	Non-Inferiority or Equivalence (legacy)
	Comments	Ezetimibe/atorvastatin 10 mg/20 mg combination tablet was considered equivalent to co-administration of ezetimibe 10 mg and atorvastatin 20 mg, if the two-sided 97.5% expanded confidence intervals of the treatment difference in least squares means for percent change in LDL-C from baseline after 6 weeks of treatment (combination minus co-administration) was contained within -4% and 4% (equivalence margins).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Least-square Means
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 97.5%; -1.7 to 3.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Percent Change From Baseline in Total Cholesterol (TC) After 6 Weeks of Treatment
Description	Serum TC measured at baseline and after 6 week of treatment in each of the 2 treatment periods.
Time Frame	Baseline and Week 6

Outcome Measure Data

Analysis Population Description

Per-Protocol Population, which excluded participants due to important deviations from the protocol that may have substantially affected the results of the primary efficacy endpoint(s). A participant could be excluded from 1 or more of the analyses. Results are reported by treatment formulation and not by sequence.

Arm/Group Title	Ezetimibe/Atorva Fixed Dose Combination	Co-Administration Ezetimibe and Atorvastin
Arm/Group Description	Ezetimibe/atorvastatin 10 mg/20 mg combination tablet once daily for 6 weeks	Ezetimibe 10 mg co-administered with atorvastatin 20 mg once daily for 6 weeks
Measure Participants	353	346
Least Squares Mean (95% Confidence Interval) [Percentage Change]	-38.1	-38.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ezetimibe/Atorva Fixed Dose Combination, Co-Administration Ezetimibe and Atorvastin
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Least-square means
	Estimated Value	0.3
	Confidence Interval	(2-Sided) 97.5%; -0.8 to 1.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Percent Change From Baseline in High-density Lipoprotein Cholesterol (HDL-C) After 6 Weeks of Treatment
Description	Serum HDL-C calculated at baseline and after 6 weeks of treatment in each of the 2 treatment periods.
Time Frame	Baseline and Week 6

Outcome Measure Data

Analysis Population Description

Per-Protocol Population, which excluded participants due to important deviations from the protocol that may have substantially affected the results of the primary efficacy endpoint(s). A participant could be excluded from 1 or more of the analyses. Results are reported by treatment formulation and not by sequence.

Arm/Group Title	Ezetimibe/Atorva Fixed Dose Combination	Co-Administration Ezetimibe and Atorvastin
Arm/Group Description	Ezetimibe/atorvastatin 10 mg/20 mg combination tablet once daily for 6 weeks	Ezetimibe 10 mg co-administered with atorvastatin 20 mg once daily for 6 weeks
Measure Participants	353	346
Least Squares Mean (95% Confidence Interval) [Percentage Change]	5.4	4.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ezetimibe/Atorva Fixed Dose Combination, Co-Administration Ezetimibe and Atorvastin
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Least-squares mean
	Estimated Value	0.8
	Confidence Interval	(2-Sided) 97.5%; -0.6 to 2.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Percent Change From Baseline in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) After 6 Weeks of Treatment
Description	Non-HDL-C measured at baseline and after 6 weeks of treatment in each of the 2 treatment periods.
Time Frame	Baseline and Week 6

Outcome Measure Data

Analysis Population Description

Per-Protocol Population, which excluded participants due to important deviations from the protocol that may have substantially affected the results of the primary efficacy endpoint(s). A participant could be excluded from 1 or more of the analyses. Results are reported by treatment formulation and not by sequence.

Arm/Group Title	Ezetimibe/Atorva Fixed Dose Combination	Co-Administration Ezetimibe and Atorvastin
Arm/Group Description	Ezetimibe/atorvastatin 10 mg/20 mg combination tablet once daily for 6 weeks	Ezetimibe 10 mg co-administered with atorvastatin 20 mg once daily for 6 weeks
Measure Participants	353	346
Least Squares Mean (95% Confidence Interval) [Percentage Change]	-50.1	-50.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ezetimibe/Atorva Fixed Dose Combination, Co-Administration Ezetimibe and Atorvastin
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in least-squares means
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 97.5%; -1.3 to 1.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Percent Change From Baseline in Apolipoprotein (Apo) B After 6 Weeks of Treatment
Description	Serum Apo B measured at baseline and after 6 weeks of treatment in each of the 2 treatment periods.
Time Frame	Baseline and Week 6

Outcome Measure Data

Analysis Population Description

Per-Protocol Population, which excluded participants due to important deviations from the protocol that may have substantially affected the results of the primary efficacy endpoint(s). A participant could be excluded from 1 or more of the analyses. Results are reported by treatment formulation and not by sequence.

Arm/Group Title	Ezetimibe/Atorva Fixed Dose Combination	Co-Administration Ezetimibe and Atorvastin
Arm/Group Description	Ezetimibe/atorvastatin 10 mg/20 mg combination tablet once daily for 6 weeks	Ezetimibe 10 mg co-administered with atorvastatin 20 mg once daily for 6 weeks
Measure Participants	352	345
Least Squares Mean (95% Confidence Interval) [Percentage Change]	-42.6	-43.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ezetimibe/Atorva Fixed Dose Combination, Co-Administration Ezetimibe and Atorvastin
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in least-squares means
	Estimated Value	0.7
	Confidence Interval	(2-Sided) 97.5%; -0.6 to 1.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Percent Change From Baseline in Triglycerides (TG) After 6 Weeks of Treatment
Description	Serum TG measured at baseline and after 6 weeks of treatment in each of the 2 treatment periods.
Time Frame	Baseline and Week 6

Outcome Measure Data

Analysis Population Description

Per-Protocol Population, which excluded participants due to important deviations from the protocol that may have substantially affected the results of the primary efficacy endpoint(s). A participant could be excluded from 1 or more of the analyses. Results are reported by treatment formulation and not by sequence.

Arm/Group Title	Ezetimibe/Atorva Fixed Dose Combination	Co-Administration Ezetimibe and Atorvastin
Arm/Group Description	Ezetimibe/atorvastatin 10 mg/20 mg combination tablet once daily for 6 weeks	Ezetimibe 10 mg co-administered with atorvastatin 20 mg once daily for 6 weeks
Measure Participants	353	346
Least Squares Mean (95% Confidence Interval) [Percentage Change]	-28.3	-29.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ezetimibe/Atorva Fixed Dose Combination, Co-Administration Ezetimibe and Atorvastin
	Comments	Analyses were based on log-transformed data.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in least-squares means
	Estimated Value	1.6
	Confidence Interval	(2-Sided) 97.5%; -3.2 to 6.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Adverse Event Reporting Description	All Patients as Treated Population defined as all randomized participants who received at least 1 dose of study drug. Adverse events were reported by actual treatment regardless of study period or assigned treatment sequence. Not all randomized participants entered Period 2 and therefore did not receive their assigned crossover treatment.
Arm/Group Title	Ezetimibe/Atorva Fixed Dose Combination		Co-Administration Ezetimibe and Atorvastin
Arm/Group Description	Ezetimibe/atorvastatin 10 mg/20 mg combination tablet once daily for 6 weeks		Ezetimibe 10 mg co-administered with atorvastatin 20 mg once daily for 6 weeks
All Cause Mortality
	Ezetimibe/Atorva Fixed Dose Combination		Co-Administration Ezetimibe and Atorvastin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Ezetimibe/Atorva Fixed Dose Combination		Co-Administration Ezetimibe and Atorvastin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/383 (0.5%)		4/388 (1%)
Cardiac disorders
Myocardial infarction	1/383 (0.3%)	1	0/388 (0%)	0
Stress cardiomyopathy	0/383 (0%)	0	1/388 (0.3%)	1
Ventricular extrasystoles	0/383 (0%)	0	1/388 (0.3%)	1
Gastrointestinal disorders
Colitis ischaemic	0/383 (0%)	0	1/388 (0.3%)	1
Metabolism and nutrition disorders
Hypokalaemia	1/383 (0.3%)	1	0/388 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	0/383 (0%)	0	1/388 (0.3%)	1
Other (Not Including Serious) Adverse Events
	Ezetimibe/Atorva Fixed Dose Combination		Co-Administration Ezetimibe and Atorvastin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/383 (0%)		0/388 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The SPONSOR must have the opportunity to review all proposed abstracts, manuscripts, or presentations regarding this study 60 days prior to submission for publication/presentation. Any information identified by the SPONSOR as confidential must be deleted prior to submission. SPONSOR review can be expedited to meet publication timelines.