Hypercholesterolemia
Conditions
Brief summary
To evaluate the percentage of patients with either established cardiovascular disease (CVD), at high risk of developing CVD or with diabetes who are on simvastatin 40mg, with fasting LDL-C \> 2mmol/l, who are able to attain the recommended LDL-C target of \< 2mmol/l following 6 weeks treatment with either ezetimibe/simvastatin 10/40mg, atorvastatin 40mg or rosuvastatin 10mg.
Interventions
ezetimibe (+) simvastatin 10/40mg. once daily tablet formulation, all tablet form, taken orally, cholesterol lowering medication.
atorvastatin 40mg. once daily tablet formulation, all tablet form, taken orally
rosuvastatin 10 mg. once daily tablet formulation, all tablet form, taken orally.
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 No maximum
Healthy volunteers
No
Inclusion criteria
* Patient Is Male Or Female And Aged Over 18 * Patient Provides Written Informed Consent * Patient Has A Fasting Ldl-C Level \>2mmol/L At Both Visit 1 And Again At Visit 2 * Patient Has Established Cvd, Diabetes Or At High Risk Of Cvd (\>20 % Risk Over 10 Years, Framingham Scale) * Patient Has Taken Simvastatin 40mg Continuously For The Past 6 Weeks * Patient Has A Fasting Triglyceride Level Of \<3.7mmol/L * Patient Has Hba1c \<9% At Visit 1 * Patient Is 75% Compliant With Medication Between Visit 1 And Visit 2
Exclusion criteria
* Patient Is Hypersensitive To Any Of The Study Medications Or Their Components * Patient Has A History Of, Or Active Liver Disease (Persistent Elevation Of Alt / Ast (\>3xuln) * Patient Is Pregnant, Lactating, Or A Female Patient Of Childbearing Potential Not Using Adequate Contraception * Patient Has Severe Renal Impairment: Creatinine Clearance \<30ml/Min (Cockcroft-Gault Equation) (In Patients With Moderate Renal Impairment: \<60ml/Min, The Dose Of Rosuvastatin Will Be 5mg In Line With The Spc) * Patient Has Uncontrolled Endocrine Or Metabolic Disease Known To Influence Serum Lipids Or Lipoproteins (I.E. Secondary Causes Of Hyperlipidaemia Such As Hypothyroidism Or Hyperthyroidism) * Patient Has A Recent History Of, Or Current, Alcohol Abuse * Patient Has Ck \>10 X Uln At Visit 1 Or Visit 2 * Patient Has Fasting Ldl-C \>4.2mmol/L * Patient Has Any Acute Or Serious Condition, Or History Suggestive Of Myopathy Or Predisposing To The Development Of Renal Failure Secondary To Rhabdomyolysis (E.G. Sepsis, Hypotension, Major Surgery, Trauma, Severe Metabolic, Severe Endocrine And Electrolyte Disorders Or Uncontrolled Seizures)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Achieving a Target of Fasting LDL-C of <2mmol/l at Study End | 6 Weeks | Fasting LDL-C was the primary efficacy variable. The primary efficacy analysis was based on the proportion of patients achieving a target of \<2mmol/l in fasting LDL-C at study end. |
Participant flow
Recruitment details
Patients with diabetes, cardiovascular disease (CVD) or a high risk of developing CVD and a fasting LDL-C level of ≥2mmol/l, having been on simvastatin 40mg for 6 weeks were assigned to 10/40 mg ezetimibe/simvastatin; 40 mg atorvastatin; 10 mg rosuvastatin (5 mg in elderly/Asian patients (in line with UK SPC)) between 27/03/2007 and 31/03/2008
Pre-assignment details
All patients were subjected to a 6 week run-in period on open label 40 mg simvastatin to stabilise their LDL-C levels. Patients whose LDL-C at the end of this period was below 2.0 mmol/l or who were \<75% compliant with run-in medication, were excluded from the study
Participants by arm
| Arm | Count |
|---|---|
| Ezetimibe/Simvastatin ezetimibe (+) simvastatin 10/40mg. once daily tablet formulation, all tablet form, taken orally | 261 |
| Atorvostatin atorvastatin 40mg. once daily tablet formulation, all tablet form, taken orally | 263 |
| Rosuvastatin rosuvastatin 10 mg. once daily tablet formulation, all tablet form, taken orally | 262 |
| Total | 786 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 7 | 5 | 9 |
| Overall Study | Discontinued after 41 days Rx | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 1 | 1 | 1 |
| Overall Study | Protocol Violation | 0 | 2 | 1 |
| Overall Study | Withdrew consent | 3 | 3 | 0 |
Baseline characteristics
| Characteristic | Ezetimibe/Simvastatin | Atorvostatin | Rosuvastatin | Total |
|---|---|---|---|---|
| Age, Continuous | 64.7 years STANDARD_DEVIATION 8.65 | 64.2 years STANDARD_DEVIATION 8.44 | 63.9 years STANDARD_DEVIATION 8.61 | 64.3 years STANDARD_DEVIATION 8.56 |
| Age, Customized < 70 years | 185 participants | 187 participants | 195 participants | 567 participants |
| Age, Customized >=70 years | 76 participants | 76 participants | 67 participants | 219 participants |
| Race/Ethnicity, Customized Asian | 3 Participants | 0 Participants | 2 Participants | 5 Participants |
| Race/Ethnicity, Customized Black | 4 Participants | 0 Participants | 2 Participants | 6 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 254 Participants | 261 Participants | 257 Participants | 772 Participants |
| Sex: Female, Male Female | 101 Participants | 78 Participants | 84 Participants | 263 Participants |
| Sex: Female, Male Male | 160 Participants | 185 Participants | 178 Participants | 523 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 6 / — | 1 / — | 8 / — |
| serious Total, serious adverse events | 4 / — | 2 / — | 4 / — |
Outcome results
Primary
Percentage of Patients Achieving a Target of Fasting LDL-C of <2mmol/l at Study End
Fasting LDL-C was the primary efficacy variable. The primary efficacy analysis was based on the proportion of patients achieving a target of \<2mmol/l in fasting LDL-C at study end.
Time frame: 6 Weeks
Population: The Full Analysis Set (FAS) all patients who were:~* Randomised~* Took at least one dose of double-blind medication~* Had a baseline measurement of efficacy~* Had a post-baseline measurement of efficacy~Patients were analysed according to the treatment group they were randomised, regardless of the treatment they received
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ezetimibe/Simvastatin | Percentage of Patients Achieving a Target of Fasting LDL-C of <2mmol/l at Study End | 67.4 Percent |
| Atorvostatin | Percentage of Patients Achieving a Target of Fasting LDL-C of <2mmol/l at Study End | 36.3 Percent |
| Rosuvastatin | Percentage of Patients Achieving a Target of Fasting LDL-C of <2mmol/l at Study End | 17.4 Percent |
Comparison: Ho is no difference in proportion achieving the target of LDL-C \< 2mmol/l.. 240 patients per group give a power of at least 85% to detect a 15% difference in this proportion, assuming the percentage decrease from baseline in LDL-C was 25% in the E/S group and 15% in the two comparator groups. A two-sided 0.025 test to allow for multiple comparisons was used.p-value: <0.001Regression, Logistic
Comparison: Ho is no difference in proportion achieving the target of LDL-C \< 2mmol/l.. 240 patients per group give a power of at least 85% to detect a 15% difference in this proportion, assuming the percentage decrease from baseline in LDL-C was 25% in the E/S group and 15% in the two comparator groups. A two-sided 0.025 test to allow for multiple comparisons was used.p-value: <0.001Regression, Logistic