A Study to Evaluate the Effectiveness of Ezetimibe/Atorvastatin 10 mg/40 mg Combination Tablet Compared to Marketed Ezetimibe 10 mg and Atorvastatin 40 mg Tablets in Participants With High Cholesterol (MK-0653C-190 AM1)
Study Details
Study Description
Brief Summary
The purpose of this study is to determine whether ezetimibe/atorvastatin 10 mg/40 mg combination tablet is equivalent to the coadministration of ezetimibe 10 mg and atorvastatin 40 mg in lowering low-density-lipoprotein-cholesterol (LDL-C) after 6 weeks of treatment.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Study Design
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, 40 mg atorvastatin, and placebo to ezetimibe/atorvastatin. |
Drug: Atorvastatin
40 mg tablet administered orally once daily
Other Names:
Drug: Ezetimibe
10 mg tablet administered orally once daily
Other Names:
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/40 mg, placebo to ezetimibe, and placebo to atorvastatin. |
Drug: Ezetimibe/atorvastatin
Ezetimibe/atorvastatin 10 mg/40 mg combination tablet administered orally once daily
Other Names:
Drug: Placebo to atorvastatin
Administered orally once daily
Drug: Placebo to ezetimibe
Administered orally once daily
|
Outcome Measures
Primary Outcome Measures
- 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
- 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.
- Percent Change From Baseline in High-density Lipoprotein Cholesterol (HDL-C) After 6 Weeks of Treatment [Baseline and Week 6]
Serum HDL-C measured at baseline and after 6 weeks of treatment in each of the 2 treatment periods.
- 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 calculated at baseline and after 6 weeks of treatment in each of the 2 treatment periods.
- 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.
- 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
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.
-
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 an 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 system 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 + atorvastatin (10/80 mg) or ezetimibe + rosuvastatin (10/20 mg or 10/40 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.- 0653C-190
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Co-administration/Combination Sequence | Combination/Co-administration Sequence |
|---|---|---|
| Arm/Group Description | Co-administration Ezetimibe 10 mg and Atorvastatin 40 mg then Ezetimibe/Atorvastatin 10 mg/40 mg fixed-dose combination | Ezetimibe/Atorvastatin 10 mg/40 mg fixed-dose combination then Co-administration Ezetimibe 10 mg and Atorvastatin 40 mg |
| Period Title: Period 1 | ||
| STARTED | 164 | 164 |
| COMPLETED | 150 | 154 |
| NOT COMPLETED | 14 | 10 |
| Period Title: Period 1 | ||
| STARTED | 150 | 154 |
| COMPLETED | 141 | 150 |
| NOT COMPLETED | 9 | 4 |
| Period Title: Period 1 | ||
| STARTED | 141 | 150 |
| COMPLETED | 138 | 146 |
| NOT COMPLETED | 3 | 4 |
Baseline Characteristics
| Arm/Group Title | Co-administration/Combination Sequence | Combination/Co-administration Sequence | Total |
|---|---|---|---|
| Arm/Group Description | Co-administration Ezetimibe 10 mg and Atorvastatin 40 mg then Ezetimibe/Atorvastatin 10 mg/40 mg fixed-dose combination | Ezetimibe/Atorvastatin 10 mg/40 mg fixed-dose combination then Co-administration Ezetimibe 10 mg and Atorvastatin 40 mg | Total of all reporting groups |
| Overall Participants | 164 | 164 | 328 |
| Age, Customized (Number) [Number] | |||
| 30 to 39 years |
10
6.1%
|
9
5.5%
|
19
5.8%
|
| 40 to 49 years |
35
21.3%
|
29
17.7%
|
64
19.5%
|
| 50 to 59 years |
74
45.1%
|
61
37.2%
|
135
41.2%
|
| 60 to 64 years |
20
12.2%
|
35
21.3%
|
55
16.8%
|
| ≥ 65 years |
25
15.2%
|
30
18.3%
|
55
16.8%
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
94
57.3%
|
92
56.1%
|
186
56.7%
|
| Male |
70
42.7%
|
72
43.9%
|
142
43.3%
|
Outcome Measures
| 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 (PP) 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 may have been a protocol violator in 1 treatment period and not in the other treatment period. |
| Arm/Group Title | Ezetimibe/Atorvastatin Fixed Dose Combination | Co-Administration Ezetimibe and Atorvastatin |
|---|---|---|
| Arm/Group Description | Ezetimibe/atorvastatin 10 mg/40 mg combination tablet once daily for 6 weeks | Ezetimibe 10 mg co-administered with atorvastatin 40 mg once daily for 6 weeks |
| Measure Participants | 280 | 280 |
| Least Squares Mean (95% Confidence Interval) [Percentage Change] |
-58.9
|
-58.7
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Ezetimibe/Atorvastatin Fixed Dose Combination, Co-Administration Ezetimibe and Atorvastatin |
|---|---|---|
| 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 ±1.08% and that the standard deviation of the difference is 12.8%. | |
| Type of Statistical Test | Non-Inferiority or Equivalence (legacy) | |
| Comments | Equivalence was declared if the 97.5% expanded confidence interval for the mean difference between the fixed-dose combination and co-administration in percent change from baseline was contained within ±4%. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference in Least-squares means |
| Estimated Value | -0.2 | |
| Confidence Interval |
(2-Sided) 97.5% -1.9 to 1.4 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| 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 (PP) 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 may have been a protocol violator in 1 treatment period and not in the other treatment period. |
| Arm/Group Title | Ezetimibe/Atorvastatin Fixed Dose Combination | Co-Administration Ezetimibe and Atorvastatin |
|---|---|---|
| Arm/Group Description | Ezetimibe/atorvastatin 10 mg/40 mg combination tablet once daily for 6 weeks | Ezetimibe 10 mg co-administered with atorvastatin 40 mg once daily for 6 weeks |
| Measure Participants | 280 | 280 |
| Least Squares Mean (95% Confidence Interval) [Percentage Change] |
-43.0
|
-42.9
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Ezetimibe/Atorvastatin Fixed Dose Combination, Co-Administration Ezetimibe and Atorvastatin |
|---|---|---|
| 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 | -0.1 | |
| Confidence Interval |
(2-Sided) 97.5% -1.4 to 1.2 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Percent Change From Baseline in High-density Lipoprotein Cholesterol (HDL-C) After 6 Weeks of Treatment |
|---|---|
| Description | Serum 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 (PP) 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 may have been a protocol violator in 1 treatment period and not in the other treatment period. |
| Arm/Group Title | Ezetimibe/Atorvastatin Fixed Dose Combination | Co-Administration Ezetimibe and Atorvastatin |
|---|---|---|
| Arm/Group Description | Ezetimibe/atorvastatin 10 mg/40 mg combination tablet once daily for 6 weeks | Ezetimibe 10 mg co-administered with atorvastatin 40 mg once daily for 6 weeks |
| Measure Participants | 280 | 280 |
| Least Squares Mean (95% Confidence Interval) [Percentage Change] |
2.3
|
2.6
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Ezetimibe/Atorvastatin Fixed Dose Combination, Co-Administration Ezetimibe and Atorvastatin |
|---|---|---|
| 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 | -0.3 | |
| Confidence Interval |
(2-Sided) 97.5% -1.8 to 1.2 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Percent Change From Baseline in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) After 6 Weeks of Treatment |
|---|---|
| Description | Non-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 (PP) 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 may have been a protocol violator in 1 treatment period and not in the other treatment period. |
| Arm/Group Title | Ezetimibe/Atorvastatin Fixed Dose Combination | Co-Administration Ezetimibe and Atorvastatin |
|---|---|---|
| Arm/Group Description | Ezetimibe/atorvastatin 10 mg/40 mg combination tablet once daily for 6 weeks | Ezetimibe 10 mg co-administered with atorvastatin 40 mg once daily for 6 weeks |
| Measure Participants | 280 | 280 |
| Least Squares Mean (95% Confidence Interval) [Percentage Change] |
-55.4
|
-55.2
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Ezetimibe/Atorvastatin Fixed Dose Combination, Co-Administration Ezetimibe and Atorvastatin |
|---|---|---|
| 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 | -0.2 | |
| Confidence Interval |
(2-Sided) 97.5% -1.7 to 1.4 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| 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 (PP) 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 may have been a protocol violator in 1 treatment period and not in the other treatment period. |
| Arm/Group Title | Ezetimibe/Atorvastatin Fixed Dose Combination | Co-Administration Ezetimibe and Atorvastatin |
|---|---|---|
| Arm/Group Description | Ezetimibe/atorvastatin 10 mg/40 mg combination tablet once daily for 6 weeks | Ezetimibe 10 mg co-administered with atorvastatin 40 mg once daily for 6 weeks |
| Measure Participants | 278 | 279 |
| Least Squares Mean (95% Confidence Interval) [Percentage Change] |
-48.7
|
-48.3
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Ezetimibe/Atorvastatin Fixed Dose Combination, Co-Administration Ezetimibe and Atorvastatin |
|---|---|---|
| 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 | -0.5 | |
| Confidence Interval |
(2-Sided) 97.5% -1.9 to 1.0 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| 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 (PP) 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 may have been a protocol violator in 1 treatment period and not in the other treatment period. |
| Arm/Group Title | Ezetimibe/Atorvastatin Fixed Dose Combination | Co-Administration Ezetimibe and Atorvastatin |
|---|---|---|
| Arm/Group Description | Ezetimibe/atorvastatin 10 mg/40 mg combination tablet once daily for 6 weeks | Ezetimibe 10 mg co-administered with atorvastatin 40 mg once daily for 6 weeks |
| Measure Participants | 280 | 280 |
| Least Squares Mean (95% Confidence Interval) [Percentage Change] |
-36.2
|
-36.2
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Ezetimibe/Atorvastatin Fixed Dose Combination, Co-Administration Ezetimibe and Atorvastatin |
|---|---|---|
| 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% -4.9 to 4.9 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Adverse Events
| Time Frame | 18 weeks | |||
|---|---|---|---|---|
| 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/Atorvastatin Fixed Dose Combination | Co-Administration Ezetimibe and Atorvastatin | ||
| Arm/Group Description | Ezetimibe/atorvastatin 10 mg/40 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/Atorvastatin Fixed Dose Combination | Co-Administration Ezetimibe and Atorvastatin | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | ||
Serious Adverse Events |
||||
| Ezetimibe/Atorvastatin Fixed Dose Combination | Co-Administration Ezetimibe and Atorvastatin | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 3/303 (1%) | 2/313 (0.6%) | ||
| Cardiac disorders | ||||
| Angina unstable | 1/303 (0.3%) | 1 | 0/313 (0%) | 0 |
| Coronary artery disease | 0/303 (0%) | 0 | 1/313 (0.3%) | 1 |
| Myocardial infarction | 0/303 (0%) | 0 | 1/313 (0.3%) | 1 |
| Hepatobiliary disorders | ||||
| Cholecystitis acute | 1/303 (0.3%) | 1 | 0/313 (0%) | 0 |
| Infections and infestations | ||||
| Sepsis | 1/303 (0.3%) | 1 | 0/313 (0%) | 0 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||
| Squamous cell carcinoma | 1/303 (0.3%) | 1 | 0/313 (0%) | 0 |
Other (Not Including Serious) Adverse Events |
||||
| Ezetimibe/Atorvastatin Fixed Dose Combination | Co-Administration Ezetimibe and Atorvastatin | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/303 (0%) | 0/313 (0%) | ||
Limitations/Caveats
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.
Results Point of Contact
| Name/Title | Senior Vice President, Global Clinical Development |
|---|---|
| Organization | Merck Sharp & Dohme Corp. |
| Phone | 1-800-672-6372 |
| ClinicalTrialsDisclosure@merck.com |
- 0653C-190