Atherosclerosis, Coronary Heart Disease, Hypercholesterolemia
Conditions
Keywords
Hypercholesterolaemia, Coronary Heart Disease (CHD), Atherosclerosis
Brief summary
The purpose of this study is to determine whether treatment of Rosuvastatin (CRESTOR™) or Simvastatin given as monotherapy or given in combination with Ezetimibe, will lower the Low Density Lipoprotein Cholesterol (LDL-C) in patients with Hypercholesterolaemia and Coronary Heart Disease (CHD) or a CHD Risk Equivalent, Atherosclerosis or a 10-year CHD Risk of \>20%
Interventions
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with with hypercholesterolaemia and CHD or a CHD risk equivalent, clinical evidence of atherosclerosis or a Framingham 10-year CHD risk score of \>20 * Patients will need to sign an informed consent before any visit procedures can be performed, including procedures for the optional genetic research and biomarker studies. * Patients must be 18 years or older and will be asked to stop taking any current cholesterol-lowering medications. Dietary counselling will be provided which will include an overview of the Therapeutic Lifestyle Change (TLC) diet the patients will be asked to follow
Exclusion criteria
* Use of lipid lowering drugs and other prohibited concomitant medications. History of statin-induced myopathy, or serious hypersensitivity reaction to other HMG-CoA reductase inhibitors (statins), including rosuvastatin, simvastatin and/or a history of hypersensitivity to any components of ezetimibe. * Patients considered to be unstable by their physician after the following events: a myocardial infarction, recent episode of unstable angina, myocardial revascularisation \[percutaneous transluminal coronary angioplasty (PTCA), coronary artery bypass graft (CABG) surgery or another revascularisation procedure\] or a transient ischaemic attack (TIA) or stroke and patients awaiting a planned myocardial revascularisation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) After 6 Weeks Combination Treatment | Mean of Weeks 4 and 6 on combination therapy (Last observation carried forward) | Percent change in LDL-C = (Combination treatment value - Baseline value)/Baseline value\*100 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Total Cholesterol (TC) After 6 Weeks Combination Treatment | Mean of Weeks 4 and 6 on combination therapy (Last observation carried forward) | Percent change in TC = (Combination treatment value - Baseline value)/Baseline value\*100 |
| Percent Change in Triglycerides (TG) After 6 Weeks Combination Treatment | Mean of Weeks 4 and 6 on combination therapy (Last observation carried forward) | Percent change in TG = (Combination treatment value - Baseline value)/Baseline value\*100 |
| Percent Change in Non-high-density Lipoprotein Cholesterol (nonHDL-C) After 6 Weeks Combination Treatment | Mean of Weeks 4 and 6 on combination therapy (Last observation carried forward) | Percent change in nonHDL-C = (Combination treatment value - Baseline value)/Baseline value\*100 |
| Percent Change in Apolipoprotein B (ApoB) After 6 Weeks Combination Treatment | Mean of Weeks 4 and 6 on combination therapy (Last observation carried forward) | Percent change in ApoB = (Combination treatment value - Baseline value)/Baseline value\*100 |
| Percent Change in Apolipoprotein A1 (ApoA-1) After 6 Weeks Combination Treatment | Mean of Weeks 4 and 6 on combination therapy (Last observation carried forward) | Percent change in ApoA-1 = (Combination treatment value - Baseline value)/Baseline value\*100 |
| Percent Change in High-density Lipoprotein Cholesterol (HDL-C) After 6 Weeks Combination Treatment | Mean of Weeks 4 and 6 on combination therapy (Last observation carried forward) | Percent change in HDL-C = (Combination treatment value - Baseline value)/Baseline value\*100 |
| Percent Change in LDL-C/HDL-C After 6 Weeks Combination Treatment | Mean of Weeks 4 and 6 on combination therapy (Last observation carried forward) | Percent change in LDL-C/HDL-C = (Combination treatment value - Baseline value)/Baseline value\*100 |
| Percent Change in Non-HDL-C/HDL-C After 6 Weeks Combination Treatment | Mean of Weeks 4 and 6 on combination therapy (Last observation carried forward) | Percent change in non-HDL-C/HDL-C = (Combination treatment value - Baseline value)/Baseline value\*100 |
| Percent Change in ApoB/ApoA-1 After 6 Weeks Combination Treatment | Mean of Weeks 4 and 6 on combination therapy (Last observation carried forward) | Percent change in ApoB/ApoA-1 = (Combination treatment value - Baseline value)/Baseline value\*100 |
| Percent Change in High-sensitivity C-reactive Protein (Hs-CRP) After 6 Weeks Combination Treatment | Mean of Weeks 4 and 6 on combination therapy (Last observation carried forward) | Percent change in hs-CRP = (Combination treatment value - Baseline value)/Baseline value\*100 |
| Percent Change in LDL-C After 6 Weeks Monotherapy | Mean of Weeks 4 and 6 on monotherapy (Last observation carried forward) | Percent change in LDL-C = (Monotherapy treatment value - Baseline value)/Baseline value\*100 |
| Percent Change in TC/HDL-C After 6 Weeks Combination Treatment | Mean of Weeks 4 and 6 on combination therapy (Last observation carried forward) | Percent change in TC/HDL-C = (Combination treatment value - Baseline value)/Baseline value\*100 |
Countries
Argentina, Brazil, Chile, Colombia, Lithuania, Netherlands, Peru, United States, Venezuela
Participant flow
Recruitment details
Eight hundred thirty-three patients (with hypercholesterolaemia and CHD or CHD risk equivalent, atherosclerosis or a 10-year CHD risk of \>20%) were randomized into the study, from 111 sites located in the United States (56), Peru (13), Netherlands (12), Colombia (8), Argentina (8), Brazil (6), Chile (4) and Lithuania (4).
Pre-assignment details
Patients underwent screening procedures (Week -6; Visit 1), and entered a 6-week dietary lead-in period. Those who fulfilled all eligibility criteria (Week -6; Visit 1) and had qualifying lipid values at Visit 2 were randomly allocated (1:1:1:1) to 1 of 4 treatments for a period of 12 weeks.
Participants by arm
| Arm | Count |
|---|---|
| R10 to R10 + E10 Rosuvastatin 10 mg followed by Rosuvastatin 10 mg + Ezetimibe 10 mg | 214 |
| R20 to R20 + E10 Rosuvastatin 20 mg followed by Rosuvastatin 20 mg + Ezetimibe 10 mg | 214 |
| S40 to S40 + E10 Simvastatin 40 mg followed by Simvastatin 40 mg + Ezetimibe 10 mg | 202 |
| S80 to S80 + E10 Simvastatin 80 mg followed by Simvastatin 80 mg + Ezetimibe 10 mg | 203 |
| Total | 833 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 7 | 11 | 6 | 7 |
| Overall Study | Incorrect enrolment/mis-randomisation | 1 | 2 | 1 | 2 |
| Overall Study | Lost to Follow-up | 4 | 2 | 4 | 0 |
| Overall Study | Other | 1 | 3 | 3 | 1 |
| Overall Study | Safety reasons | 1 | 0 | 1 | 0 |
| Overall Study | Severe non-compliance | 0 | 1 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 5 | 9 | 3 | 4 |
Baseline characteristics
| Characteristic | R10 to R10 + E10 | R20 to R20 + E10 | S40 to S40 + E10 | S80 to S80 + E10 | Total |
|---|---|---|---|---|---|
| Age Continuous | 62.2 years STANDARD_DEVIATION 10.14 | 61.8 years STANDARD_DEVIATION 9.93 | 61.9 years STANDARD_DEVIATION 9.37 | 62.1 years STANDARD_DEVIATION 9.17 | 62.0 years STANDARD_DEVIATION 9.66 |
| Sex: Female, Male Female | 91.0000 Participants | 97.0000 Participants | 97.0000 Participants | 90.0000 Participants | 375.0 Participants |
| Sex: Female, Male Male | 123.0000 Participants | 117.0000 Participants | 105.0000 Participants | 113.0000 Participants | 458.0 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 | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 25 / — | 31 / — | 28 / — | 26 / — | 18 / — | 23 / — | 24 / — | 21 / — |
| serious Total, serious adverse events | 3 / — | 5 / — | 1 / — | 3 / — | 4 / — | 1 / — | 7 / — | 4 / — |
Outcome results
Primary
Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) After 6 Weeks Combination Treatment
Percent change in LDL-C = (Combination treatment value - Baseline value)/Baseline value\*100
Time frame: Mean of Weeks 4 and 6 on combination therapy (Last observation carried forward)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| R10 to R10 + E10 | Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) After 6 Weeks Combination Treatment | -59.7200 Percentage | Standard Deviation 14.166 |
| R20 to R20 + E10 | Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) After 6 Weeks Combination Treatment | -63.4800 Percentage | Standard Deviation 16.697 |
| S40 to S40 + E10 | Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) After 6 Weeks Combination Treatment | -55.2200 Percentage | Standard Deviation 15.75 |
| S80 to S80 + E10 | Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) After 6 Weeks Combination Treatment | -57.4200 Percentage | Standard Deviation 20.466 |
Secondary
Percent Change in ApoB/ApoA-1 After 6 Weeks Combination Treatment
Percent change in ApoB/ApoA-1 = (Combination treatment value - Baseline value)/Baseline value\*100
Time frame: Mean of Weeks 4 and 6 on combination therapy (Last observation carried forward)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| R10 to R10 + E10 | Percent Change in ApoB/ApoA-1 After 6 Weeks Combination Treatment | -47.3900 Percentage | Standard Deviation 13.869 |
| R20 to R20 + E10 | Percent Change in ApoB/ApoA-1 After 6 Weeks Combination Treatment | -50.2400 Percentage | Standard Deviation 14.257 |
| S40 to S40 + E10 | Percent Change in ApoB/ApoA-1 After 6 Weeks Combination Treatment | -42.5400 Percentage | Standard Deviation 14.248 |
| S80 to S80 + E10 | Percent Change in ApoB/ApoA-1 After 6 Weeks Combination Treatment | -44.7600 Percentage | Standard Deviation 17.842 |
Secondary
Percent Change in Apolipoprotein A1 (ApoA-1) After 6 Weeks Combination Treatment
Percent change in ApoA-1 = (Combination treatment value - Baseline value)/Baseline value\*100
Time frame: Mean of Weeks 4 and 6 on combination therapy (Last observation carried forward)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| R10 to R10 + E10 | Percent Change in Apolipoprotein A1 (ApoA-1) After 6 Weeks Combination Treatment | 3.8100 Percentage | Standard Deviation 13.042 |
| R20 to R20 + E10 | Percent Change in Apolipoprotein A1 (ApoA-1) After 6 Weeks Combination Treatment | 2.6800 Percentage | Standard Deviation 11.502 |
| S40 to S40 + E10 | Percent Change in Apolipoprotein A1 (ApoA-1) After 6 Weeks Combination Treatment | 1.4900 Percentage | Standard Deviation 9.683 |
| S80 to S80 + E10 | Percent Change in Apolipoprotein A1 (ApoA-1) After 6 Weeks Combination Treatment | 2.1300 Percentage | Standard Deviation 10.741 |
Secondary
Percent Change in Apolipoprotein B (ApoB) After 6 Weeks Combination Treatment
Percent change in ApoB = (Combination treatment value - Baseline value)/Baseline value\*100
Time frame: Mean of Weeks 4 and 6 on combination therapy (Last observation carried forward)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| R10 to R10 + E10 | Percent Change in Apolipoprotein B (ApoB) After 6 Weeks Combination Treatment | -46.1100 Percentage | Standard Deviation 12.628 |
| R20 to R20 + E10 | Percent Change in Apolipoprotein B (ApoB) After 6 Weeks Combination Treatment | -49.5000 Percentage | Standard Deviation 13.821 |
| S40 to S40 + E10 | Percent Change in Apolipoprotein B (ApoB) After 6 Weeks Combination Treatment | -41.9500 Percentage | Standard Deviation 14.75 |
| S80 to S80 + E10 | Percent Change in Apolipoprotein B (ApoB) After 6 Weeks Combination Treatment | -44.1700 Percentage | Standard Deviation 17.179 |
Secondary
Percent Change in High-density Lipoprotein Cholesterol (HDL-C) After 6 Weeks Combination Treatment
Percent change in HDL-C = (Combination treatment value - Baseline value)/Baseline value\*100
Time frame: Mean of Weeks 4 and 6 on combination therapy (Last observation carried forward)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| R10 to R10 + E10 | Percent Change in High-density Lipoprotein Cholesterol (HDL-C) After 6 Weeks Combination Treatment | 6.4100 Percentage | Standard Deviation 13.934 |
| R20 to R20 + E10 | Percent Change in High-density Lipoprotein Cholesterol (HDL-C) After 6 Weeks Combination Treatment | 7.4600 Percentage | Standard Deviation 16.351 |
| S40 to S40 + E10 | Percent Change in High-density Lipoprotein Cholesterol (HDL-C) After 6 Weeks Combination Treatment | 3.9200 Percentage | Standard Deviation 12.683 |
| S80 to S80 + E10 | Percent Change in High-density Lipoprotein Cholesterol (HDL-C) After 6 Weeks Combination Treatment | 4.3400 Percentage | Standard Deviation 12.643 |
Secondary
Percent Change in High-sensitivity C-reactive Protein (Hs-CRP) After 6 Weeks Combination Treatment
Percent change in hs-CRP = (Combination treatment value - Baseline value)/Baseline value\*100
Time frame: Mean of Weeks 4 and 6 on combination therapy (Last observation carried forward)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| R10 to R10 + E10 | Percent Change in High-sensitivity C-reactive Protein (Hs-CRP) After 6 Weeks Combination Treatment | 107.1200 Percentage | Full Range -99 |
| R20 to R20 + E10 | Percent Change in High-sensitivity C-reactive Protein (Hs-CRP) After 6 Weeks Combination Treatment | -9.5300 Percentage | Full Range -97.9 |
| S40 to S40 + E10 | Percent Change in High-sensitivity C-reactive Protein (Hs-CRP) After 6 Weeks Combination Treatment | 15.0300 Percentage | Full Range -91.5 |
| S80 to S80 + E10 | Percent Change in High-sensitivity C-reactive Protein (Hs-CRP) After 6 Weeks Combination Treatment | 0.4200 Percentage | Full Range -94.9 |
Secondary
Percent Change in LDL-C After 6 Weeks Monotherapy
Percent change in LDL-C = (Monotherapy treatment value - Baseline value)/Baseline value\*100
Time frame: Mean of Weeks 4 and 6 on monotherapy (Last observation carried forward)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| R10 to R10 + E10 | Percent Change in LDL-C After 6 Weeks Monotherapy | -46.4900 Percentage | Standard Deviation 13.108 |
| R20 to R20 + E10 | Percent Change in LDL-C After 6 Weeks Monotherapy | -53.5900 Percentage | Standard Deviation 10.503 |
| S40 to S40 + E10 | Percent Change in LDL-C After 6 Weeks Monotherapy | -40.8600 Percentage | Standard Deviation 12.413 |
| S80 to S80 + E10 | Percent Change in LDL-C After 6 Weeks Monotherapy | -46.3500 Percentage | Standard Deviation 16.188 |
Secondary
Percent Change in LDL-C/HDL-C After 6 Weeks Combination Treatment
Percent change in LDL-C/HDL-C = (Combination treatment value - Baseline value)/Baseline value\*100
Time frame: Mean of Weeks 4 and 6 on combination therapy (Last observation carried forward)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| R10 to R10 + E10 | Percent Change in LDL-C/HDL-C After 6 Weeks Combination Treatment | -61.4700 Percentage | Standard Deviation 15.547 |
| R20 to R20 + E10 | Percent Change in LDL-C/HDL-C After 6 Weeks Combination Treatment | -65.2500 Percentage | Standard Deviation 16.68 |
| S40 to S40 + E10 | Percent Change in LDL-C/HDL-C After 6 Weeks Combination Treatment | -57.1300 Percentage | Standard Deviation 14.777 |
| S80 to S80 + E10 | Percent Change in LDL-C/HDL-C After 6 Weeks Combination Treatment | -58.6600 Percentage | Standard Deviation 21.13 |
Secondary
Percent Change in Non-HDL-C/HDL-C After 6 Weeks Combination Treatment
Percent change in non-HDL-C/HDL-C = (Combination treatment value - Baseline value)/Baseline value\*100
Time frame: Mean of Weeks 4 and 6 on combination therapy (Last observation carried forward)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| R10 to R10 + E10 | Percent Change in Non-HDL-C/HDL-C After 6 Weeks Combination Treatment | -56.4200 Percentage | Standard Deviation 15.415 |
| R20 to R20 + E10 | Percent Change in Non-HDL-C/HDL-C After 6 Weeks Combination Treatment | -60.8900 Percentage | Standard Deviation 15.503 |
| S40 to S40 + E10 | Percent Change in Non-HDL-C/HDL-C After 6 Weeks Combination Treatment | -51.1100 Percentage | Standard Deviation 15.38 |
| S80 to S80 + E10 | Percent Change in Non-HDL-C/HDL-C After 6 Weeks Combination Treatment | -53.5100 Percentage | Standard Deviation 20.223 |
Secondary
Percent Change in Non-high-density Lipoprotein Cholesterol (nonHDL-C) After 6 Weeks Combination Treatment
Percent change in nonHDL-C = (Combination treatment value - Baseline value)/Baseline value\*100
Time frame: Mean of Weeks 4 and 6 on combination therapy (Last observation carried forward)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| R10 to R10 + E10 | Percent Change in Non-high-density Lipoprotein Cholesterol (nonHDL-C) After 6 Weeks Combination Treatment | -54.6500 Percentage | Standard Deviation 13.677 |
| R20 to R20 + E10 | Percent Change in Non-high-density Lipoprotein Cholesterol (nonHDL-C) After 6 Weeks Combination Treatment | -58.9100 Percentage | Standard Deviation 14.932 |
| S40 to S40 + E10 | Percent Change in Non-high-density Lipoprotein Cholesterol (nonHDL-C) After 6 Weeks Combination Treatment | -49.9300 Percentage | Standard Deviation 14.738 |
| S80 to S80 + E10 | Percent Change in Non-high-density Lipoprotein Cholesterol (nonHDL-C) After 6 Weeks Combination Treatment | -52.3700 Percentage | Standard Deviation 18.429 |
Secondary
Percent Change in TC/HDL-C After 6 Weeks Combination Treatment
Percent change in TC/HDL-C = (Combination treatment value - Baseline value)/Baseline value\*100
Time frame: Mean of Weeks 4 and 6 on combination therapy (Last observation carried forward)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| R10 to R10 + E10 | Percent Change in TC/HDL-C After 6 Weeks Combination Treatment | -45.5200 Percentage | Standard Deviation 13.228 |
| R20 to R20 + E10 | Percent Change in TC/HDL-C After 6 Weeks Combination Treatment | -49.4600 Percentage | Standard Deviation 13.575 |
| S40 to S40 + E10 | Percent Change in TC/HDL-C After 6 Weeks Combination Treatment | -41.2700 Percentage | Standard Deviation 13.021 |
| S80 to S80 + E10 | Percent Change in TC/HDL-C After 6 Weeks Combination Treatment | -43.4500 Percentage | Standard Deviation 16.343 |
Secondary
Percent Change in Total Cholesterol (TC) After 6 Weeks Combination Treatment
Percent change in TC = (Combination treatment value - Baseline value)/Baseline value\*100
Time frame: Mean of Weeks 4 and 6 on combination therapy (Last observation carried forward)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| R10 to R10 + E10 | Percent Change in Total Cholesterol (TC) After 6 Weeks Combination Treatment | -43.0000 Percentage | Standard Deviation 11.208 |
| R20 to R20 + E10 | Percent Change in Total Cholesterol (TC) After 6 Weeks Combination Treatment | -46.6300 Percentage | Standard Deviation 12.818 |
| S40 to S40 + E10 | Percent Change in Total Cholesterol (TC) After 6 Weeks Combination Treatment | -39.5600 Percentage | Standard Deviation 12.664 |
| S80 to S80 + E10 | Percent Change in Total Cholesterol (TC) After 6 Weeks Combination Treatment | -41.7100 Percentage | Standard Deviation 15.15 |
Secondary
Percent Change in Triglycerides (TG) After 6 Weeks Combination Treatment
Percent change in TG = (Combination treatment value - Baseline value)/Baseline value\*100
Time frame: Mean of Weeks 4 and 6 on combination therapy (Last observation carried forward)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| R10 to R10 + E10 | Percent Change in Triglycerides (TG) After 6 Weeks Combination Treatment | -28.8500 Percentage | Standard Deviation 23.709 |
| R20 to R20 + E10 | Percent Change in Triglycerides (TG) After 6 Weeks Combination Treatment | -35.0000 Percentage | Standard Deviation 23.971 |
| S40 to S40 + E10 | Percent Change in Triglycerides (TG) After 6 Weeks Combination Treatment | -22.9500 Percentage | Standard Deviation 28.139 |
| S80 to S80 + E10 | Percent Change in Triglycerides (TG) After 6 Weeks Combination Treatment | -25.8200 Percentage | Standard Deviation 26.619 |