Hypercholesterolemia
Conditions
Brief summary
The purpose of this study is to evaluate and compare the efficacy and safety of ezetimibe plus atorvastatin versus atorvastatin in hypercholesterolemic patients at moderately high risk for coronary heart disease not adequately controlled on atorvastatin 20 mg.
Interventions
Atorvastatin 40mg tablet po qd (by mouth, once a day) for 6 weeks
DRUGComparator: Placebo
Atorvastatin 20mg Pbo and ezetimibe 10mg Pbo tablets po qd (by mouth, once a day). for 6 weeks
Atorvastatin 20mg and ezetimibe 10mg tablets po qd (by mouth, once a day). for 6 weeks.
DRUGComparator: Placebo.
Atorvastatin 40mg Pbo tablets po qd (by mouth, once a day). for 6 weeks.
Sponsors
Organon and Co
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 79 Years
Healthy volunteers
No
Inclusion criteria
* Patient with LDL-C \>100 mg/dL & on a stable dose of atorvastatin 20 mg
Exclusion criteria
* Pregnant or lactating women or intending to become pregnant * Patient with sensitivity or intolerance to ezetimibe or atorvastatin * Patient with diabetes or coronary heart disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Low Density Lipoprotein-Cholesterol (LDL-C) at Week 6 | 6 weeks | \[(6 week value - baseline value)/baseline value\]\*100%. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 6 | 6 Weeks | \[(6 week value - baseline value)/baseline value\]\*100%. |
| Percent Change From Baseline in Total-Cholesterol at Week 6 | 6 Weeks | (\[6 week value - baseline value)/baseline value\]\*100%. |
| Percent Change From Baseline in Triglycerides (TG) at Week 6 | 6 weeks | \[(6 week value - baseline value)/baseline value\]\*100%. |
| Percent Change From Baseline in Apolipoprotein B at Week 6 | 6 Weeks | \[(6 week value - baseline value)/baseline value\]\*100%. |
| Percent Change From Baseline in Total-Cholesterol:High Density Lipoprotein Cholesterol (HDL-C) Ratio at Week 6 | 6 Weeks | \[(6 week value - baseline value)/baseline value\]\*100%. |
| Percent Change in High Density Lipoprotein -Cholesterol (HDL-C)at Week 6 | 6 weeks | \[(6 week value - baseline value)/baseline value\]\*100%. |
| Percent Change From Baseline in Apolipoprotein B: Apolipoprotein A-I Ratio at Week 6 | 6 Weeks | \[(6 week value - baseline value)/baseline value\]\*100%. |
| Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (HDL-C):High Density Lipoprotein Cholesterol (HDL-C) Ratio at Week 6 | 6 Weeks | \[(6 week value - baseline value)/baseline value\]\*100%. |
| Percent Change From Baseline in C-Reactive Protein (CRP) at Week 6 | 6 Weeks | \[(6 week value - baseline value)/baseline value\]\*100%. |
| Number of Participants Who Attained Target LDL-C <100 mg/dL at Week 6 | 6 weeks | — |
| Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C):High Density Lipoprotein Cholesterol (HDL-C) Ratio at Week 6 | 6 Weeks | \[(6 week value - baseline value)/baseline value\]\*100%. |
Participant flow
Recruitment details
Phase III First Patient In: 4/5/2006; Last Patient Last Visit 1/17/2008 72 centers worldwide (US, Canada, Austria, Costa Rica) Eligible patients include those on a stable dose of atorvastatin 20 mg; or patients with adjusted LDL-C pre-screen ranges who were treated with other lipid modifying therapy, or were statin and/or ezetimibe naïve.
Pre-assignment details
Patients received and were blinded to atorvastatin 20 mg for a 4/5- week run-in period. Patients needed an LDL-C ≥ 100 mg/dL and ≤ 160 mg/dL at Visit 2 (week -1). Eligible patients were randomized at Visit 3 (Week 0) to either atorvastatin 40 mg or addition of ezetimibe 10 mg to their 20 mg dose of atorvastatin for a 6-week treatment period.
Participants by arm
| Arm | Count |
|---|---|
| Atorvastatin + Ezetimibe Atorvastatin 20 mg + Ezetemibe 10 mg daily for 6 weeks | 98 |
| Atorvastatin Atorvastatin 40 mg Daily for 6 weeks | 98 |
| Total | 196 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 |
| Overall Study | Lost to Follow-up | 2 | 2 |
| Overall Study | Protocol Violation | 4 | 3 |
Baseline characteristics
| Characteristic | Atorvastatin + Ezetimibe | Total | Atorvastatin |
|---|---|---|---|
| Age, Continuous | 56.4 years | 57.2 years | 58.0 years |
| Apolipoprotein A-I | 161.8 mg/dL STANDARD_DEVIATION 25.2 | 162.6 mg/dL STANDARD_DEVIATION 24.8 | 163.4 mg/dL STANDARD_DEVIATION 24.6 |
| Apolipoprotein A-I:Apolipoprotein B ratio | 0.8 Ratio STANDARD_DEVIATION 0.2 | 0.8 Ratio STANDARD_DEVIATION 0.2 | 0.7 Ratio STANDARD_DEVIATION 0.2 |
| Apolipoprotein B | 122.9 mg/dL STANDARD_DEVIATION 22.4 | 121.4 mg/dL STANDARD_DEVIATION 21.7 | 119.9 mg/dL STANDARD_DEVIATION 21 |
| C Reactive Protein | 1.6 mg/dL STANDARD_DEVIATION 2.6 | 1.5 mg/dL STANDARD_DEVIATION 2.1 | 1.2 mg/dL STANDARD_DEVIATION 1.7 |
| High Density Lipoprotein (HDL) | 51.1 mg/dL STANDARD_DEVIATION 12.1 | 51.4 mg/dL STANDARD_DEVIATION 11.8 | 51.7 mg/dL STANDARD_DEVIATION 11.5 |
| Low Density Lipoprotein Cholesterol (LDL-C):High Density Lipoprotein Cholesterol (HDL-C) ratio | 2.4 Ratio STANDARD_DEVIATION 0.6 | 2.4 Ratio STANDARD_DEVIATION 0.7 | 2.5 Ratio STANDARD_DEVIATION 0.7 |
| Low Density Lipoprotein (LDL) | 119.9 mg/dL STANDARD_DEVIATION 19.4 | 118.9 mg/dL STANDARD_DEVIATION 18.1 | 117.9 mg/dL STANDARD_DEVIATION 16.8 |
| NonHigh Density Lipoprotein-Cholesterol (NonHDL-C):High Density Lipoprotein-Cholesterol (HDL-C)ratio | 3.2 Ratio STANDARD_DEVIATION 1 | 3.1 Ratio STANDARD_DEVIATION 1 | 3.0 Ratio STANDARD_DEVIATION 0.9 |
| Non- High Density Lipoprotein (Non-HDL) Cholesterol | 151.6 mg/dL STANDARD_DEVIATION 24.1 | 150.0 mg/dL STANDARD_DEVIATION 22.7 | 148.4 mg/dL STANDARD_DEVIATION 21.1 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized Asian | 7 participants | 15 participants | 8 participants |
| Race/Ethnicity, Customized Black | 3 participants | 12 participants | 9 participants |
| Race/Ethnicity, Customized Multi-Racial | 29 participants | 50 participants | 21 participants |
| Race/Ethnicity, Customized White | 58 participants | 118 participants | 60 participants |
| Sex: Female, Male Female | 40 Participants | 89 Participants | 49 Participants |
| Sex: Female, Male Male | 58 Participants | 107 Participants | 49 Participants |
| Total Cholesterol | 202.6 mg/dL STANDARD_DEVIATION 25.2 | 201.3 mg/dL STANDARD_DEVIATION 23.4 | 200.0 mg/dL STANDARD_DEVIATION 21.5 |
| Total cholesterol:High Density Lipoprotein Cholesterol (HDL-C) ratio | 4.2 Ratio STANDARD_DEVIATION 1 | 4.1 Ratio STANDARD_DEVIATION 1 | 4.0 Ratio STANDARD_DEVIATION 0.9 |
| Triglycerides (TG) | 152.5 mg/dL STANDARD_DEVIATION 68.8 | 149.0 mg/dL STANDARD_DEVIATION 75.3 | 147.8 mg/dL STANDARD_DEVIATION 75.3 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 17 / 96 | 22 / 98 |
| serious Total, serious adverse events | 0 / 96 | 0 / 98 |
Outcome results
Primary
Percent Change From Baseline in Low Density Lipoprotein-Cholesterol (LDL-C) at Week 6
\[(6 week value - baseline value)/baseline value\]\*100%.
Time frame: 6 weeks
Population: Full Analysis Set (FAS): The FAS population includes all randomized patients who took at least 1 dose of study medication and had a baseline (BL) value and at least one post BL value. Post 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 + Ezetimibe | Percent Change From Baseline in Low Density Lipoprotein-Cholesterol (LDL-C) at Week 6 | -30.8 Percent |
| Atorvastatin | Percent Change From Baseline in Low Density Lipoprotein-Cholesterol (LDL-C) at Week 6 | -10.9 Percent |
p-value: <0.00195% CI: [-25.2, -14.5]ANCOVA
Secondary
Number of Participants Who Attained Target LDL-C <100 mg/dL at Week 6
Time frame: 6 weeks
Population: Full Analysis Set (FAS): The FAS population includes all randomized patients who took at least 1 dose of study medication and had a baseline (BL) value and at least one post BL value. Post BL measurements up to 3 days following the last dose of double-blind study medication were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Atorvastatin + Ezetimibe | Number of Participants Who Attained Target LDL-C <100 mg/dL at Week 6 | <100 mg/dL | 77 Participants |
| Atorvastatin + Ezetimibe | Number of Participants Who Attained Target LDL-C <100 mg/dL at Week 6 | ≥100 mg/dL | 15 Participants |
| Atorvastatin | Number of Participants Who Attained Target LDL-C <100 mg/dL at Week 6 | <100 mg/dL | 45 Participants |
| Atorvastatin | Number of Participants Who Attained Target LDL-C <100 mg/dL at Week 6 | ≥100 mg/dL | 47 Participants |
p-value: <0.00195% CI: [3.8, 19.47]Regression, Logistic
Secondary
Percent Change From Baseline in Apolipoprotein B: Apolipoprotein A-I Ratio at Week 6
\[(6 week value - baseline value)/baseline value\]\*100%.
Time frame: 6 Weeks
Population: Full Analysis Set (FAS): The FAS population includes all randomized patients who took at least 1 dose of study medication and had a baseline (BL) value and at least one post BL value. Post 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 + Ezetimibe | Percent Change From Baseline in Apolipoprotein B: Apolipoprotein A-I Ratio at Week 6 | -19.0 Percent |
| Atorvastatin | Percent Change From Baseline in Apolipoprotein B: Apolipoprotein A-I Ratio at Week 6 | -5.8 Percent |
p-value: <0.00195% CI: [-17.9, -8.3]ANCOVA
Secondary
Percent Change From Baseline in Apolipoprotein B at Week 6
\[(6 week value - baseline value)/baseline value\]\*100%.
Time frame: 6 Weeks
Population: Full Analysis Set (FAS): The FAS population includes all randomized patients who took at least 1 dose of study medication and had a baseline (BL) value and at least one post BL value. Post 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 + Ezetimibe | Percent Change From Baseline in Apolipoprotein B at Week 6 | -21.4 Percent |
| Atorvastatin | Percent Change From Baseline in Apolipoprotein B at Week 6 | -7.7 Percent |
p-value: <0.00195% CI: [-17.8, -9.6]ANCOVA
Secondary
Percent Change From Baseline in C-Reactive Protein (CRP) at Week 6
\[(6 week value - baseline value)/baseline value\]\*100%.
Time frame: 6 Weeks
Population: Full Analysis Set (FAS): The FAS population includes all randomized patients who took at least 1 dose of study medication and had a baseline (BL) value and at least one post BL value. Post 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 + Ezetimibe | Percent Change From Baseline in C-Reactive Protein (CRP) at Week 6 | -6.7 percent |
| Atorvastatin | Percent Change From Baseline in C-Reactive Protein (CRP) at Week 6 | -9.2 percent |
p-value: 0.84195% CI: [-23.8, 28.8]Longitudinal Data Analysis (LDA)
Secondary
Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C):High Density Lipoprotein Cholesterol (HDL-C) Ratio at Week 6
\[(6 week value - baseline value)/baseline value\]\*100%.
Time frame: 6 Weeks
Population: Full Analysis Set (FAS): The FAS population includes all randomized patients who took at least 1 dose of study medication and had a baseline (BL) value and at least one post BL value. Post 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 + Ezetimibe | Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C):High Density Lipoprotein Cholesterol (HDL-C) Ratio at Week 6 | -31.9 Percent |
| Atorvastatin | Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C):High Density Lipoprotein Cholesterol (HDL-C) Ratio at Week 6 | -11.0 Percent |
p-value: <0.00195% CI: [-26.5, -15.3]ANCOVA
Secondary
Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (HDL-C):High Density Lipoprotein Cholesterol (HDL-C) Ratio at Week 6
\[(6 week value - baseline value)/baseline value\]\*100%.
Time frame: 6 Weeks
Population: Full Analysis Set (FAS): The FAS population includes all randomized patients who took at least 1 dose of study medication and had a baseline (BL) value and at least one post BL value. Post 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 + Ezetimibe | Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (HDL-C):High Density Lipoprotein Cholesterol (HDL-C) Ratio at Week 6 | -27.2 Percent |
| Atorvastatin | Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (HDL-C):High Density Lipoprotein Cholesterol (HDL-C) Ratio at Week 6 | -9.9 Percent |
p-value: <0.00195% CI: [-23.2, -11.4]ANCOVA
Secondary
Percent Change From Baseline in Total-Cholesterol at Week 6
(\[6 week value - baseline value)/baseline value\]\*100%.
Time frame: 6 Weeks
Population: Full Analysis Set (FAS): The FAS population includes all randomized patients who took at least 1 dose of study medication and had a baseline (BL) value and at least one post BL value. Post 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 + Ezetimibe | Percent Change From Baseline in Total-Cholesterol at Week 6 | -19.7 percent |
| Atorvastatin | Percent Change From Baseline in Total-Cholesterol at Week 6 | -7.4 percent |
p-value: <0.00195% CI: [-15.8, -8.6]ANCOVA
Secondary
Percent Change From Baseline in Total-Cholesterol:High Density Lipoprotein Cholesterol (HDL-C) Ratio at Week 6
\[(6 week value - baseline value)/baseline value\]\*100%.
Time frame: 6 Weeks
Population: Full Analysis Set (FAS): The FAS population includes all randomized patients who took at least 1 dose of study medication and had a baseline (BL) value and at least one post BL value. Post 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 + Ezetimibe | Percent Change From Baseline in Total-Cholesterol:High Density Lipoprotein Cholesterol (HDL-C) Ratio at Week 6 | -20.6 Percent |
| Atorvastatin | Percent Change From Baseline in Total-Cholesterol:High Density Lipoprotein Cholesterol (HDL-C) Ratio at Week 6 | -7.5 Percent |
p-value: <0.00195% CI: [-17.5, -8.7]ANCOVA
Secondary
Percent Change From Baseline in Triglycerides (TG) at Week 6
\[(6 week value - baseline value)/baseline value\]\*100%.
Time frame: 6 weeks
Population: Full Analysis Set (FAS): The FAS population includes all randomized patients who took at least 1 dose of study medication and had a baseline (BL) value and at least one post BL value. Post 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 + Ezetimibe | Percent Change From Baseline in Triglycerides (TG) at Week 6 | -17.8 Percent |
| Atorvastatin | Percent Change From Baseline in Triglycerides (TG) at Week 6 | -5.5 Percent |
p-value: 0.15995% CI: [-17.7, -0.4]Nonparametric ANCOVA
Secondary
Percent Change in High Density Lipoprotein -Cholesterol (HDL-C)at Week 6
\[(6 week value - baseline value)/baseline value\]\*100%.
Time frame: 6 weeks
Population: Full Analysis Set (FAS): The FAS population includes all randomized patients who took at least 1 dose of study medication and had a baseline (BL) value and at least one post BL value. Post 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 + Ezetimibe | Percent Change in High Density Lipoprotein -Cholesterol (HDL-C)at Week 6 | 3.2 Percent |
| Atorvastatin | Percent Change in High Density Lipoprotein -Cholesterol (HDL-C)at Week 6 | 0.8 Percent |
p-value: 0.27395% CI: [-1.9, 6.6]ANCOVA
Secondary
Percent Change in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 6
\[(6 week value - baseline value)/baseline value\]\*100%.
Time frame: 6 Weeks
Population: Full Analysis Set (FAS): The FAS population includes all randomized patients who took at least 1 dose of study medication and had a baseline (BL) value and at least one post BL value. Post 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 + Ezetimibe | Percent Change in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 6 | -26.7 Percent |
| Atorvastatin | Percent Change in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 6 | -10.2 Percent |
p-value: <0.00195% CI: [-21.2, -11.7]ANCOVA
Post Hoc
Percent Change in Apolipoprotein A-I at Week 6
\[(6 week value - baseline value)/baseline value\]\*100%.
Time frame: 6 Weeks
Population: Full Analysis Set (FAS): The FAS population includes all randomized patients who took at least 1 dose of study medication and had a baseline (BL) value and at least one post BL value. Post 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 + Ezetimibe | Percent Change in Apolipoprotein A-I at Week 6 | -1.9 Percent |
| Atorvastatin | Percent Change in Apolipoprotein A-I at Week 6 | -1.2 Percent |
p-value: 0.68195% CI: [-3.9, 2.6]ANCOVA
Post Hoc
Percent Change in C-Reactive Protein (CRP) at Week 6
\[(6 week value - baseline value)/baseline value\]\*100%.
Time frame: 6 weeks
Population: Full Analysis Set (FAS): The FAS population includes all randomized patients who took at least 1 dose of study medication and had a baseline (BL) value and at least one post BL value. Post 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 + Ezetimibe | Percent Change in C-Reactive Protein (CRP) at Week 6 | -19.2 Percent |
| Atorvastatin | Percent Change in C-Reactive Protein (CRP) at Week 6 | -9.1 Percent |
p-value: 0.83995% CI: [-26.1, 8.3]Nonparametric ANCOVA