Hypercholesterolemia
Conditions
Keywords
High Cholesterol
Brief summary
A multicenter study to evaluate the safety and efficacy of ezetimibe/simvastatin versus atorvastatin in elderly patients with high cholesterol at high or moderately high risk for coronary heart disease.
Interventions
Atorvastatin 10 mg and Placebo for ezetimibe and placebo for simvastatin once daily for 12 weeks
DRUGEzetimibe 10 mg/simvastatin 20 mg
Ezetimibe 10 mg/simvastatin 20 mg and Placebo for atorvastatin once daily for 12 weeks
Atorvastatin 20 mg and Placebo for ezetimibe and placebo for simvastatin once daily for 12 weeks
DRUGEzetimibe 10 mg/simvastatin 40 mg
Ezetimibe 10 mg/simvastatin 40 mg and Placebo for atorvastatin once daily for 12 weeks
Atorvastatin 40 mg and Placebo for ezetimibe and placebo for simvastatin once daily for 12 weeks
Sponsors
Merck Shering-Plough JV Study
Organon and Co
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
65 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patient has a cholesterol level of 130 mg/dL or greater * Patient is willing to maintain a cholesterol lowering diet for as long as they are in the study * Patient is at moderate high risk or high risk for coronary heart disease per the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATPIII) guidelines
Exclusion criteria
* Patient weighs less than 100 lbs * Patient has an allergy to ezetimibe, simvastatin or atorvastatin
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percent Change From Baseline in Low Density Lipoprotein (LDL-C) at Week 12 | Baseline and 12 weeks |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Who Achieved LDL-C <70 mg/dL at Week 12 | 12 weeks | — |
| Percentage of Patients Without Atherosclerosis Vascular Disease (AVD) Who Achieved LDL-C <100 mg/dL or Patients With AVD Who Achieved LDL-C <70 mg/dL at Week 12 | 12 Weeks | Patients with AVD Who Achieved LDL-C \<70 mg/dL. AVD was defined as a history of myocardial infarction, stable angina, coronary artery procedures or evidence of clinically significant myocardial ischemia. |
| Percentage of Patients Who Achieved LDL-C <100 mg/dL at Week 12 | 12 Weeks | — |
| Percentage of Patients With High Risk for CHD Who Achieved LDL-C <70 mg/dL at Week 12 | 12 Weeks | Risk was assessed utilizing a history of established CHD or CHD risk equivalent and Framingham Risk scoring. |
| Percentage of Patients With AVD Who Achieved LDL-C <70 mg/dL at Week 12 | 12 Weeks | Patients with AVD Who Achieved LDL-C \<70 mg/dL. AVD was defined as a history of myocardial infarction, stable angina, coronary artery procedures or evidence of clinically significant myocardial ischemia. |
Participant flow
Recruitment details
Phase III First Patient In 08-Nov-2007; Last Patient Last Visit 23-Mar-2009 Eligible patients include drug-naïve patients or patients rendered naïve with the appropriate prior washout at moderately high or high risk for coronary heart disease 65 years and older.
Pre-assignment details
The study evaluated patients ≥ 65 years of age at moderately high or high risk for Coronary Heart Disease (CHD), with or without atherosclerotic vascular disease. The study was a 3-week single-blind placebo run-in period and a 12-week active treatment period where patients were equally randomized to one of 5 treatment groups for 12 weeks
Participants by arm
| Arm | Count |
|---|---|
| Atorvastatin 10 mg Atorvastatin (Atorva) 10 mg once daily for 12 weeks | 257 |
| Ezetimibe 10 mg/Simvastatin 20 mg Ezetimibe (EZ) 10 mg/simvastatin (Simva) 20 mg once daily for 12 weeks | 259 |
| Atorvastatin 20 mg Atorvastatin 20 mg once daily for 12 weeks | 259 |
| Ezetimibe 10 mg/Simvastatin 40 mg Ezetimibe 10 mg/simvastatin 40 mg once daily for 12 weeks | 257 |
| Atorva 40 mg Atorvastatin 40 mg once daily for 12 weeks | 257 |
| Total | 1,289 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 6 | 8 | 3 | 8 | 6 |
| Overall Study | Lost to Follow-up | 1 | 3 | 3 | 2 | 1 |
| Overall Study | Physician Decision | 3 | 2 | 0 | 1 | 1 |
| Overall Study | Protocol Violation | 2 | 2 | 2 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 5 | 11 | 10 | 10 | 8 |
Baseline characteristics
| Characteristic | Atorvastatin 10 mg | Ezetimibe 10 mg/Simvastatin 20 mg | Atorvastatin 20 mg | Ezetimibe 10 mg/Simvastatin 40 mg | Atorva 40 mg | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 72.1 years | 71.8 years | 71.7 years | 72.2 years | 72.1 years | 72.0 years |
| Race/Ethnicity, Customized Asian | 10 participants | 6 participants | 12 participants | 8 participants | 10 participants | 46 participants |
| Race/Ethnicity, Customized Black | 2 participants | 2 participants | 8 participants | 6 participants | 9 participants | 27 participants |
| Race/Ethnicity, Customized Other | 21 participants | 27 participants | 30 participants | 29 participants | 28 participants | 135 participants |
| Race/Ethnicity, Customized White | 224 participants | 224 participants | 209 participants | 214 participants | 210 participants | 1081 participants |
| Sex: Female, Male Female | 172 Participants | 146 Participants | 175 Participants | 153 Participants | 163 Participants | 809 Participants |
| Sex: Female, Male Male | 85 Participants | 113 Participants | 84 Participants | 104 Participants | 94 Participants | 480 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 26 / 257 | 32 / 256 | 26 / 258 | 32 / 257 | 30 / 256 |
| serious Total, serious adverse events | 4 / 257 | 8 / 256 | 3 / 258 | 3 / 257 | 5 / 256 |
Outcome results
Primary
Percent Change From Baseline in Low Density Lipoprotein (LDL-C) at Week 12
Time frame: Baseline and 12 weeks
Population: Full Analysis Set (FAS). The FAS population includes all randomized patients with baseline (BL) value and at least one valid after-BL value. After-BL measurements up to 3 days following the last dose of double-blind study medication were included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Atorvastatin 10 mg | Percent Change From Baseline in Low Density Lipoprotein (LDL-C) at Week 12 | -39.5 Percent change in LDL-C |
| Ezetimibe 10 mg/Simvastatin 20 mg | Percent Change From Baseline in Low Density Lipoprotein (LDL-C) at Week 12 | -54.2 Percent change in LDL-C |
| Atorvastatin 20 mg | Percent Change From Baseline in Low Density Lipoprotein (LDL-C) at Week 12 | -46.6 Percent change in LDL-C |
| Ezetimibe 10 mg/Simvastatin 40 mg | Percent Change From Baseline in Low Density Lipoprotein (LDL-C) at Week 12 | -59.1 Percent change in LDL-C |
| Atorva 40 mg | Percent Change From Baseline in Low Density Lipoprotein (LDL-C) at Week 12 | -50.8 Percent change in LDL-C |
p-value: <0.00195% CI: [-17.5, -12]ANCOVA
p-value: <0.00195% CI: [-10.3, -4.8]ANCOVA
p-value: <0.00195% CI: [-11, -5.5]ANCOVA
Secondary
Percentage of Patients Who Achieved LDL-C <100 mg/dL at Week 12
Time frame: 12 Weeks
Population: Full Analysis Set (FAS). The FAS population includes all randomized patients with baseline (BL) value and at least one valid after-BL value. After-BL measurements up to 3 days following the last dose of double-blind study medication were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Atorvastatin 10 mg | Percentage of Patients Who Achieved LDL-C <100 mg/dL at Week 12 | 58.7 Percent of Patients | Standard Error 3.17 |
| Ezetimibe 10 mg/Simvastatin 20 mg | Percentage of Patients Who Achieved LDL-C <100 mg/dL at Week 12 | 83.6 Percent of Patients | Standard Error 2.43 |
| Atorvastatin 20 mg | Percentage of Patients Who Achieved LDL-C <100 mg/dL at Week 12 | 76.9 Percent of Patients | Standard Error 2.73 |
| Ezetimibe 10 mg/Simvastatin 40 mg | Percentage of Patients Who Achieved LDL-C <100 mg/dL at Week 12 | 90.3 Percent of Patients | Standard Error 1.93 |
| Atorva 40 mg | Percentage of Patients Who Achieved LDL-C <100 mg/dL at Week 12 | 79.5 Percent of Patients | Standard Error 2.61 |
p-value: <0.00195% CI: [2.76, 7.24]Logistic Regression using GEE
p-value: 0.02695% CI: [1.07, 2.94]Logistic Regression using GEE
p-value: 0.01795% CI: [1.23, 4.18]Logistic Regression using GEE
Secondary
Percentage of Patients Who Achieved LDL-C <70 mg/dL at Week 12
Time frame: 12 weeks
Population: Full Analysis Set (FAS). The FAS population includes all randomized patients with baseline (BL) value and at least one valid after-BL value. After-BL measurements up to 3 days following the last dose of double-blind study medication were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Atorvastatin 10 mg | Percentage of Patients Who Achieved LDL-C <70 mg/dL at Week 12 | 9.9 Percent of Patients | Standard Error 1.92 |
| Ezetimibe 10 mg/Simvastatin 20 mg | Percentage of Patients Who Achieved LDL-C <70 mg/dL at Week 12 | 51.3 Percent of Patients | Standard Error 3.28 |
| Atorvastatin 20 mg | Percentage of Patients Who Achieved LDL-C <70 mg/dL at Week 12 | 26.1 Percent of Patients | Standard Error 2.85 |
| Ezetimibe 10 mg/Simvastatin 40 mg | Percentage of Patients Who Achieved LDL-C <70 mg/dL at Week 12 | 68.2 Percent of Patients | Standard Error 3.03 |
| Atorva 40 mg | Percentage of Patients Who Achieved LDL-C <70 mg/dL at Week 12 | 38.1 Percent of Patients | Standard Error 3.14 |
p-value: <0.00195% CI: [7.64, 20.83]Logistic Regression using GEE
p-value: <0.00195% CI: [2.51, 5.85]Logistic Regression using GEE
p-value: <0.00195% CI: [2.39, 5.6]Logistic Regression using GEE
Secondary
Percentage of Patients With AVD Who Achieved LDL-C <70 mg/dL at Week 12
Patients with AVD Who Achieved LDL-C \<70 mg/dL. AVD was defined as a history of myocardial infarction, stable angina, coronary artery procedures or evidence of clinically significant myocardial ischemia.
Time frame: 12 Weeks
Population: Patients with AVD in the Full Analysis Set (FAS). The FAS population includes all randomized patients with baseline (BL) value and at least one valid after-BL value. After-BL measurements up to 3 days following the last dose of double-blind study medication were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Atorvastatin 10 mg | Percentage of Patients With AVD Who Achieved LDL-C <70 mg/dL at Week 12 | 10.0 Percent of Patients | Standard Error 3.59 |
| Ezetimibe 10 mg/Simvastatin 20 mg | Percentage of Patients With AVD Who Achieved LDL-C <70 mg/dL at Week 12 | 44.4 Percent of Patients | Standard Error 5.52 |
| Atorvastatin 20 mg | Percentage of Patients With AVD Who Achieved LDL-C <70 mg/dL at Week 12 | 31.6 Percent of Patients | Standard Error 5.23 |
| Ezetimibe 10 mg/Simvastatin 40 mg | Percentage of Patients With AVD Who Achieved LDL-C <70 mg/dL at Week 12 | 65.8 Percent of Patients | Standard Error 5.34 |
| Atorva 40 mg | Percentage of Patients With AVD Who Achieved LDL-C <70 mg/dL at Week 12 | 44.4 Percent of Patients | Standard Error 5.86 |
p-value: <0.00195% CI: [2.71, 13.38]Logistic Regression using GEE
p-value: 0.06995% CI: [0.96, 2.6]Logistic Regression using GEE
p-value: 0.03995% CI: [1.1, 2.9]Logistic Regression using GEE
Secondary
Percentage of Patients With High Risk for CHD Who Achieved LDL-C <70 mg/dL at Week 12
Risk was assessed utilizing a history of established CHD or CHD risk equivalent and Framingham Risk scoring.
Time frame: 12 Weeks
Population: Patients with High Risk for CHD in the Full Analysis Set (FAS). The FAS population includes all randomized patients with baseline (BL) value and at least one valid after-BL value. After-BL measurements up to 3 days following the last dose of double-blind study medication were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Atorvastatin 10 mg | Percentage of Patients With High Risk for CHD Who Achieved LDL-C <70 mg/dL at Week 12 | 10.9 Percent of Patients | Standard Error 2.65 |
| Ezetimibe 10 mg/Simvastatin 20 mg | Percentage of Patients With High Risk for CHD Who Achieved LDL-C <70 mg/dL at Week 12 | 54.3 Percent of Patients | Standard Error 4.24 |
| Atorvastatin 20 mg | Percentage of Patients With High Risk for CHD Who Achieved LDL-C <70 mg/dL at Week 12 | 28.9 Percent of Patients | Standard Error 4.01 |
| Ezetimibe 10 mg/Simvastatin 40 mg | Percentage of Patients With High Risk for CHD Who Achieved LDL-C <70 mg/dL at Week 12 | 69.2 Percent of Patients | Standard Error 4.05 |
| Atorva 40 mg | Percentage of Patients With High Risk for CHD Who Achieved LDL-C <70 mg/dL at Week 12 | 38.2 Percent of Patients | Standard Error 4.17 |
p-value: <0.00195% CI: [4.31, 13.42]Logistic Regression using GEE
p-value: <0.00195% CI: [1.86, 4.67]Logistic Regression using GEE
p-value: <0.00195% CI: [1.42, 3.27]Logistic Regression using GEE
Secondary
Percentage of Patients Without Atherosclerosis Vascular Disease (AVD) Who Achieved LDL-C <100 mg/dL or Patients With AVD Who Achieved LDL-C <70 mg/dL at Week 12
Patients with AVD Who Achieved LDL-C \<70 mg/dL. AVD was defined as a history of myocardial infarction, stable angina, coronary artery procedures or evidence of clinically significant myocardial ischemia.
Time frame: 12 Weeks
Population: Full Analysis Set (FAS). The FAS population includes all randomized patients with baseline (BL) value and at least one valid after-BL value. After-BL measurements up to 3 days following the last dose of double-blind study medication were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Atorvastatin 10 mg | Percentage of Patients Without Atherosclerosis Vascular Disease (AVD) Who Achieved LDL-C <100 mg/dL or Patients With AVD Who Achieved LDL-C <70 mg/dL at Week 12 | 45.0 Percent of Patients | Standard Error 3.2 |
| Ezetimibe 10 mg/Simvastatin 20 mg | Percentage of Patients Without Atherosclerosis Vascular Disease (AVD) Who Achieved LDL-C <100 mg/dL or Patients With AVD Who Achieved LDL-C <70 mg/dL at Week 12 | 69.0 Percent of Patients | Standard Error 3.04 |
| Atorvastatin 20 mg | Percentage of Patients Without Atherosclerosis Vascular Disease (AVD) Who Achieved LDL-C <100 mg/dL or Patients With AVD Who Achieved LDL-C <70 mg/dL at Week 12 | 61.3 Percent of Patients | Standard Error 3.16 |
| Ezetimibe 10 mg/Simvastatin 40 mg | Percentage of Patients Without Atherosclerosis Vascular Disease (AVD) Who Achieved LDL-C <100 mg/dL or Patients With AVD Who Achieved LDL-C <70 mg/dL at Week 12 | 82.1 Percent of Patients | Standard Error 2.5 |
| Atorva 40 mg | Percentage of Patients Without Atherosclerosis Vascular Disease (AVD) Who Achieved LDL-C <100 mg/dL or Patients With AVD Who Achieved LDL-C <70 mg/dL at Week 12 | 69.9 Percent of Patients | Standard Error 2.97 |
p-value: <0.00195% CI: [2.04, 4.55]Logistic Regression using GEE
p-value: 0.03995% CI: [1.02, 2.32]Logistic Regression using GEE
p-value: 0.02395% CI: [1.14, 2.87]Logistic Regression using GEE