Hypercholesterolemia
Conditions
Brief summary
To Evaluate and Compare the Efficacy and Safety of Ezetimibe Plus Atorvastatin Versus Atorvastatin in Hypercholesterolemic Patients at High Risk for Coronary Heart Disease Not Adequately Controlled on Atorvastatin 40 mg.
Interventions
DRUGatorvastatin
Atorvastatin 80 mg tablet by mouth, once a day for 6 weeks
DRUGezetimibe
Ezetimibe 10 mg tablets 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 \>70 mg/dL & on a stable dose of atorvastatin 40 mg
Exclusion criteria
* Pregnant or lactating women or intending to become pregnant * Patient with sensitivity or intolerance to ezetimibe or atorvastatin
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline to Week 6 in Low-Density Lipoprotein (LDL)-C | Baseline and 6 weeks | Percent Change in LDL-C = \[(week 6 value - baseline value)/baseline value\]\*100% |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline to Week 6 in High-Density Lipoprotein Cholesterol (HDL-C) | Baseline and 6 weeks | Percent Change in HDL-C = \[(week 6 value - baseline value)/baseline value\]\*100% |
| Percent Change From Baseline to Week 6 in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) | Baseline and 6 Weeks | Percent Change in Non-HDL-C = \[(week 6 value - baseline value)/baseline value\]\*100% |
| Percent Change From Baseline to Week 6 in Total-Cholesterol | Baseline and 6 Weeks | Percent Change in Total-C = \[(week 6 value - baseline value)/baseline value\]\*100% |
| Percent Change From Baseline to Week 6 in Triglycerides (TG) | Baseline and 6 Weeks | Percent Change in TG = \[(week 6 value - baseline value)/baseline value\]\*100% |
| Percent Change From Baseline to Week 6 in Apolipoprotein B (Apo B) | Baseline and 6 Weeks | Percent Change in Apo B = \[(week 6 value - baseline value)/baseline value\]\*100% |
| Percent Change From Baseline to Week 6 in Apolipoprotein A-I (Apo A-I) | Baseline and 6 Weeks | Percent Change in Apo A-I = \[(week 6 value - baseline value)/baseline value\]\*100% |
| Percent Change From Baseline to Week 6 in Low-Density Lipoprotein-Cholesterol:High-Density Lipoprotein-Cholesterol (LDL-C:HDL-C) Ratio | Baseline and 6 Weeks | Percent Change in LDL-C:HDL-C Ratio = \[(week 6 ratio - baseline ratio)/baseline ratio\]\*100% |
| Percent Change From Baseline to Week 6 in Apolipoprotein B:Apolipoprotein A-I (Apo B:Apo A-I) Ratio | Baseline and 6 Weeks | Percent Change in Apo B:Apo A-I Ratio = \[(week 6 ratio - baseline ratio)/baseline ratio\]\*100% |
| Percent Change From Baseline to Week 6 in Non-High-Density Lipoprotein-Cholesterol:High-Density Lipoprotein-Cholesterol (Non-HDL-C:HDL-C) Ratio | Baseline and 6 Weeks | Percent Change in non-HDL-C:HDL-C Ratio = \[(week 6 ratio - baseline ratio)/baseline ratio\]\*100% |
| Percent Change From Baseline to Week 6 in C Reactive Protein (CRP) | Baseline and 6 Weeks | Percent Change in CRP = \[(week 6 value - baseline value)/baseline value\]\*100% |
| Number of Patients Who Attained Target Low-Density Lipoprotein Cholesterol (LDL-C) <70 mg/dL at Week 6 | 6 Weeks | — |
| Percent Change From Baseline to Week 6 in Total-Cholesterol (TC):High-Density Lipoprotein Cholesterol (HDL-C) Ratio | Baseline and 6 Weeks | Percent Change in TC:HDL-C Ratio = \[(week 6 ratio - baseline ratio)/baseline ratio\]\*100% |
Participant flow
Recruitment details
Phase III First Patient In: 4/6/2006; Last Patient Last Visit 2/26/2008 96 centers worldwide (US, Canada) Eligible patients include those on a stable dose of atorvastatin 40 mg; or patients with adjusted LDLC 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 40 mg for a 4/5- week run-in period. Patients needed an LDL-C ≥ 70 mg/dL and ≤ 160 mg/dL at Visit 2 (week -1). Eligible patients were randomized at Visit 3 (Week 0) to either atorvastatin 80 mg or addition of ezetimibe 10 mg to their 40 mg dose of atorvastatin for a 6-week treatment period.
Participants by arm
| Arm | Count |
|---|---|
| Atorvastatin + Ezetemibe Atorvastatin 40 mg + Ezetemibe 10 mg every day for 6 weeks | 288 |
| Atorvastatin Atorvastatin 80 mg every day for 6 weeks | 291 |
| Total | 579 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 7 |
| Overall Study | Could not take time off work | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 3 |
Baseline characteristics
| Characteristic | Atorvastatin | Total | Atorvastatin + Ezetemibe |
|---|---|---|---|
| Age, Continuous | 62 years | 61.3 years | 60.6 years |
| Apolipoprotein A-I | 154.6 mg/dL STANDARD_DEVIATION 25 | 154.3 mg/dL STANDARD_DEVIATION 25.3 | 154.0 mg/dL STANDARD_DEVIATION 25.5 |
| Apolipoprotein B | 102.0 mg/dL STANDARD_DEVIATION 18.8 | 101.7 mg/dL STANDARD_DEVIATION 18.9 | 101.3 mg/dL STANDARD_DEVIATION 19 |
| Apolipoprotein B:Apolipoprotein A-I ratio | 0.7 Ratio STANDARD_DEVIATION 0.2 | 0.7 Ratio STANDARD_DEVIATION 0.2 | 0.7 Ratio STANDARD_DEVIATION 0.2 |
| C Reactive Protein | 1.5 mg/dL STANDARD_DEVIATION 3 | 1.6 mg/dL STANDARD_DEVIATION 2.8 | 1.8 mg/dL STANDARD_DEVIATION 2.7 |
| High-Density Lipoprotein | 47.2 mg/dL STANDARD_DEVIATION 10.6 | 47.3 mg/dL STANDARD_DEVIATION 10.5 | 47.4 mg/dL STANDARD_DEVIATION 10.5 |
| Low-Density Lipoprotein | 89.8 mg/dL STANDARD_DEVIATION 16.2 | 89.4 mg/dL STANDARD_DEVIATION 16.2 | 88.8 mg/dL STANDARD_DEVIATION 16.2 |
| Low-Density Lipoprotein-C:High-Density Lipoprotein-C ratio | 2.0 Ratio STANDARD_DEVIATION 0.6 | 2.0 Ratio STANDARD_DEVIATION 0.6 | 2.0 Ratio STANDARD_DEVIATION 0.6 |
| Non-High-Density Lipoprotein-C:High-Density Lipoprotein-C ratio | 2.6 Ratio STANDARD_DEVIATION 0.8 | 2.6 Ratio STANDARD_DEVIATION 0.8 | 2.6 Ratio STANDARD_DEVIATION 0.8 |
| Non-High-Density Lipoprotein Cholesterol | 118.1 mg/dL STANDARD_DEVIATION 21.9 | 117.9 mg/dL STANDARD_DEVIATION 21.4 | 117.7 mg/dL STANDARD_DEVIATION 20.8 |
| Race/Ethnicity, Customized Asian | 8 Participants | 12 Participants | 4 Participants |
| Race/Ethnicity, Customized Black | 29 Participants | 61 Participants | 32 Participants |
| Race/Ethnicity, Customized Multi-Racial | 22 Participants | 37 Participants | 15 Participants |
| Race/Ethnicity, Customized White | 232 Participants | 469 Participants | 237 Participants |
| Sex: Female, Male Female | 113 Participants | 228 Participants | 115 Participants |
| Sex: Female, Male Male | 178 Participants | 351 Participants | 173 Participants |
| Total Cholesterol | 165.3 mg/dL STANDARD_DEVIATION 22.8 | 165.2 mg/dL STANDARD_DEVIATION 22.1 | 165.2 mg/dL STANDARD_DEVIATION 21.4 |
| Total cholesterol:High-Density Lipoprotein-C ratio | 3.6 Ratio STANDARD_DEVIATION 0.8 | 3.6 Ratio STANDARD_DEVIATION 0.8 | 3.6 Ratio STANDARD_DEVIATION 0.8 |
| Triglycerides | 134.0 mg/dL STANDARD_DEVIATION 72.1 | 133.5 mg/dL STANDARD_DEVIATION 72.1 | 132.5 mg/dL STANDARD_DEVIATION 72.1 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 63 / — | 61 / — |
| serious Total, serious adverse events | 9 / — | 5 / — |
Outcome results
Primary
Percent Change From Baseline to Week 6 in Low-Density Lipoprotein (LDL)-C
Percent Change in LDL-C = \[(week 6 value - baseline value)/baseline value\]\*100%
Time frame: Baseline and 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 + Ezetemibe | Percent Change From Baseline to Week 6 in Low-Density Lipoprotein (LDL)-C | -27.4 Percent Change |
| Atorvastatin | Percent Change From Baseline to Week 6 in Low-Density Lipoprotein (LDL)-C | -11.0 Percent Change |
p-value: <0.00195% CI: [-19.4, -13.2]ANCOVA
Secondary
Number of Patients Who Attained Target Low-Density Lipoprotein Cholesterol (LDL-C) <70 mg/dL at Week 6
Time frame: 6 Weeks
Population: Full Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Atorvastatin + Ezetemibe | Number of Patients Who Attained Target Low-Density Lipoprotein Cholesterol (LDL-C) <70 mg/dL at Week 6 | <70 mg/dL | 204 Participants |
| Atorvastatin + Ezetemibe | Number of Patients Who Attained Target Low-Density Lipoprotein Cholesterol (LDL-C) <70 mg/dL at Week 6 | >=70 mg/dL | 73 Participants |
| Atorvastatin | Number of Patients Who Attained Target Low-Density Lipoprotein Cholesterol (LDL-C) <70 mg/dL at Week 6 | <70 mg/dL | 88 Participants |
| Atorvastatin | Number of Patients Who Attained Target Low-Density Lipoprotein Cholesterol (LDL-C) <70 mg/dL at Week 6 | >=70 mg/dL | 191 Participants |
p-value: <0.00195% CI: [5.45, 12.84]Regression, Logistic
Secondary
Percent Change From Baseline to Week 6 in Apolipoprotein A-I (Apo A-I)
Percent Change in Apo A-I = \[(week 6 value - baseline value)/baseline value\]\*100%
Time frame: Baseline and 6 Weeks
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Atorvastatin + Ezetemibe | Percent Change From Baseline to Week 6 in Apolipoprotein A-I (Apo A-I) | -0.3 Percent Change |
| Atorvastatin | Percent Change From Baseline to Week 6 in Apolipoprotein A-I (Apo A-I) | -1.2 Percent Change |
p-value: 0.31395% CI: [-0.8, 2.5]ANCOVA
Secondary
Percent Change From Baseline to Week 6 in Apolipoprotein B (Apo B)
Percent Change in Apo B = \[(week 6 value - baseline value)/baseline value\]\*100%
Time frame: Baseline and 6 Weeks
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Atorvastatin + Ezetemibe | Percent Change From Baseline to Week 6 in Apolipoprotein B (Apo B) | -17.8 Percent Change |
| Atorvastatin | Percent Change From Baseline to Week 6 in Apolipoprotein B (Apo B) | -7.7 Percent Change |
p-value: <0.00195% CI: [-12.7, -7.6]ANCOVA
Secondary
Percent Change From Baseline to Week 6 in Apolipoprotein B:Apolipoprotein A-I (Apo B:Apo A-I) Ratio
Percent Change in Apo B:Apo A-I Ratio = \[(week 6 ratio - baseline ratio)/baseline ratio\]\*100%
Time frame: Baseline and 6 Weeks
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Atorvastatin + Ezetemibe | Percent Change From Baseline to Week 6 in Apolipoprotein B:Apolipoprotein A-I (Apo B:Apo A-I) Ratio | -16.9 Percent Change |
| Atorvastatin | Percent Change From Baseline to Week 6 in Apolipoprotein B:Apolipoprotein A-I (Apo B:Apo A-I) Ratio | -5.9 Percent Change |
p-value: <0.00195% CI: [-13.8, -8.2]ANCOVA
Secondary
Percent Change From Baseline to Week 6 in C Reactive Protein (CRP)
Percent Change in CRP = \[(week 6 value - baseline value)/baseline value\]\*100%
Time frame: Baseline and 6 Weeks
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Atorvastatin + Ezetemibe | Percent Change From Baseline to Week 6 in C Reactive Protein (CRP) | -18.3 Percent Change |
| Atorvastatin | Percent Change From Baseline to Week 6 in C Reactive Protein (CRP) | -11.5 Percent Change |
p-value: 0.17495% CI: [-17.1, 3.4]Longitudinal Data Analysis (LDA)
Secondary
Percent Change From Baseline to Week 6 in High-Density Lipoprotein Cholesterol (HDL-C)
Percent Change in HDL-C = \[(week 6 value - baseline value)/baseline value\]\*100%
Time frame: Baseline and 6 weeks
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Atorvastatin + Ezetemibe | Percent Change From Baseline to Week 6 in High-Density Lipoprotein Cholesterol (HDL-C) | -0.5 Percent Change |
| Atorvastatin | Percent Change From Baseline to Week 6 in High-Density Lipoprotein Cholesterol (HDL-C) | -1.0 Percent Change |
p-value: 0.55195% CI: [-1.1, 2.1]ANCOVA
Secondary
Percent Change From Baseline to Week 6 in Low-Density Lipoprotein-Cholesterol:High-Density Lipoprotein-Cholesterol (LDL-C:HDL-C) Ratio
Percent Change in LDL-C:HDL-C Ratio = \[(week 6 ratio - baseline ratio)/baseline ratio\]\*100%
Time frame: Baseline and 6 Weeks
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Atorvastatin + Ezetemibe | Percent Change From Baseline to Week 6 in Low-Density Lipoprotein-Cholesterol:High-Density Lipoprotein-Cholesterol (LDL-C:HDL-C) Ratio | -26.4 Percent change |
| Atorvastatin | Percent Change From Baseline to Week 6 in Low-Density Lipoprotein-Cholesterol:High-Density Lipoprotein-Cholesterol (LDL-C:HDL-C) Ratio | -9.9 Percent change |
p-value: <0.00195% CI: [-19.9, -13.1]ANCOVA
Secondary
Percent Change From Baseline to Week 6 in Non-High-Density Lipoprotein-Cholesterol:High-Density Lipoprotein-Cholesterol (Non-HDL-C:HDL-C) Ratio
Percent Change in non-HDL-C:HDL-C Ratio = \[(week 6 ratio - baseline ratio)/baseline ratio\]\*100%
Time frame: Baseline and 6 Weeks
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Atorvastatin + Ezetemibe | Percent Change From Baseline to Week 6 in Non-High-Density Lipoprotein-Cholesterol:High-Density Lipoprotein-Cholesterol (Non-HDL-C:HDL-C) Ratio | -22.2 Percent Change |
| Atorvastatin | Percent Change From Baseline to Week 6 in Non-High-Density Lipoprotein-Cholesterol:High-Density Lipoprotein-Cholesterol (Non-HDL-C:HDL-C) Ratio | -7.6 Percent Change |
p-value: <0.00195% CI: [-17.7, -11.3]ANCOVA
Secondary
Percent Change From Baseline to Week 6 in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C)
Percent Change in Non-HDL-C = \[(week 6 value - baseline value)/baseline value\]\*100%
Time frame: Baseline and 6 Weeks
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Atorvastatin + Ezetemibe | Percent Change From Baseline to Week 6 in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) | -23.3 Percent Change |
| Atorvastatin | Percent Change From Baseline to Week 6 in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) | -9.0 Percent Change |
p-value: <0.00195% CI: [-17.1, -11.6]ANCOVA
Secondary
Percent Change From Baseline to Week 6 in Total-Cholesterol
Percent Change in Total-C = \[(week 6 value - baseline value)/baseline value\]\*100%
Time frame: Baseline and 6 Weeks
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Atorvastatin + Ezetemibe | Percent Change From Baseline to Week 6 in Total-Cholesterol | -16.9 Percent Change |
| Atorvastatin | Percent Change From Baseline to Week 6 in Total-Cholesterol | -6.9 Percent Change |
p-value: <0.00195% CI: [-12, -7.9]ANCOVA
Secondary
Percent Change From Baseline to Week 6 in Total-Cholesterol (TC):High-Density Lipoprotein Cholesterol (HDL-C) Ratio
Percent Change in TC:HDL-C Ratio = \[(week 6 ratio - baseline ratio)/baseline ratio\]\*100%
Time frame: Baseline and 6 Weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Atorvastatin + Ezetemibe | Percent Change From Baseline to Week 6 in Total-Cholesterol (TC):High-Density Lipoprotein Cholesterol (HDL-C) Ratio | -16.0 Percent Change |
| Atorvastatin | Percent Change From Baseline to Week 6 in Total-Cholesterol (TC):High-Density Lipoprotein Cholesterol (HDL-C) Ratio | -5.6 Percent Change |
p-value: <0.00195% CI: [-12.6, -8.2]ANCOVA
Secondary
Percent Change From Baseline to Week 6 in Triglycerides (TG)
Percent Change in TG = \[(week 6 value - baseline value)/baseline value\]\*100%
Time frame: Baseline and 6 Weeks
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Atorvastatin + Ezetemibe | Percent Change From Baseline to Week 6 in Triglycerides (TG) | -12.3 Percent Change |
| Atorvastatin | Percent Change From Baseline to Week 6 in Triglycerides (TG) | -5.9 Percent Change |
p-value: <0.00195% CI: [-11.5, -3.1]Nonparametric ANCOVA