| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Dyslipidemia - Expert groups have identified low-density lipoprotein cholesterol (LDL-C) as the primary target for cholesterol lowering therapy because it is strongly associated with coronary heart disease (CHD) risk but, more importantly, clinical studies document that lowering LDL-C reduces the risk for major CHD events (Expert Panel NCEP ATP III 2001: De Backer et al 2003; American Heart Association (AHA)/American College of Cardiology (ACC): Smith et al 2006). |
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| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective of this study is to evaluate the LDL-C lowering efficacy of rosuvastatin 10 mg and 20 mg in combination with ezetimibe relative to that of simvastatin in a fixed dose combination with ezetimibe. This objective has 3 specific components:
1. Percentage change from baseline in LDL-C for rosuvastatin 20mg in combination with ezetimibe 10mg vs simvastatin 40mg in combination with ezetimibe 10mg after 6 weeks combination therapy (mean value of 4 and 6 weeks of combination therapy will be used)
2. Percentage change from baseline in LDL-C for rosuvastatin 10mg in combination with ezetimibe 10mg vs simvastatin 40mg in combination with ezetimibe 10mg after 6 weeks combination therapy (mean value of 4 and 6 weeks of combination therapy will be used)
3. Percentage change from baseline in LDL-C for rosuvastatin 20mg in combination with ezetimibe 10mg vs simvastatin 80mg in combination with ezetimibe 10mg after 6 weeks combination therapy |
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| E.2.2 | Secondary objectives of the trial |
1. The percent change in LDL-C of rosuva 10mg/ezetimibe 10 vs simva 80mg/ezetimibe 10 mg
2. The percent change in HDL-C, TC, TG, nonHDL-C, ApoB, ApoA-1 of of rosuva 10mg/ezetimibe 10 vs simva 80mg/ezetimibe 10 mg
3. rosuva 20/ezetimibe 10 vs simva 40 mg/ezetimibe 10mg on the proportion of patients achieving lipid goals after 6 weeks.
4. rosuva 10/ezetimibe 10 vs simva 40 mg/ezetimibe 10mg on the proportion of patients achieving lipid goals after 6 weeks.
5. rosuva 20/ezetimibe 10 vs simva 80 mg/ezetimibe 10mg on the proportion of patients achieving lipid goals after 6 weeks.
6. rosuva 10/ezetimibe 10 vs simva 80 mg/ezetimibe 10mg on the proportion of patients achieving lipid goals after 6 weeks.
7. To assess rosuva 10mg and 20mg with ezetimibe 10mg vs the same dose of rosuva alone on the percent change in lab values
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
There is an optional research activity that is contained with in the CSP in Appendix K. This is therefore under the same full title of the main study but has the following objective
Optional Genetic Research
To obtain, with appropriate informed consent, DNA samples for future exploratory research on the effects of genetic polymorphisms on
- Response to rosuvastatin and ezetimibe conbination therapy
-Susceptibility to and prognosis of coronary heart disease (CHD) and lipid disorders |
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| E.3 | Principal inclusion criteria |
At Visit 1 (Week -6)
For inclusion in the dietary lead-in phase, patients must fulfil all of the following criteria at Visit 1:
1. Provision of signed written informed consent
2. Male or female patients aged 18 years of age or older.
3. A history of CHD or a CHD risk equivalent, clinical evidence of atherosclerosis (definitions given in Appendix G) or a 10-year Framingham risk score of >20% for CHD, as described in NCEP ATP III guidelines
4. The patient must have a reasonable likelihood of attaining LDL-C values of ≥ 130 mg/dL to <220 mg/dL at Visit 2, in the opinion of the Investigator. Based upon the experience of previous studies, the following guidance can be used in interpreting Visit 1 LDL-C results:
o ≥ 125 mg/dL (3.24 mmol/L) to <220 mg/dL (5.69 mmol/L) in statin-naïve patients (patients who have not taken any lipid-lowering therapy known to affect LDL-C in the 4 weeks prior to Visit 1)
o ≥ 90 mg/dL (2.33 mmol/L) to <180 mg/dL (4.66 mmol/L) in patients who have taken lovastatin, fluvastatin, or pravastatin within 4 weeks of Visit 1
o ≥ 70 mg/dL (1.81 mmol/L) to <160 mg/dL (4.14 mmol/L) in patients who have taken simvastatin, atorvastatin, rosuvastatin or any statin in combination with ezetimibe within 4 weeks of Visit 1
5. Fasting TG concentrations <400 mg/dL (4.52 mmol/L)
6. Patients willing to follow all study procedures including attendance at clinics for scheduled study visits, fasting prior to clinic visits (all visits blood draws) and compliance with study treatment regimen
For inclusion in the biomarker research, patients must fulfil the following criterion:
· Provision of written informed consent for biomarker research.
For inclusion in the genetic research, patients must fulfil the following criterion:
· Provision of written informed consent for genetic research. Any additional criteria are provided in Appendix K
If a patient declines to participate in the biomarker or genetic research, there will be no penalty or loss of benefit to the patient. The patient will not be excluded from other aspects of the study described in this CSP, so long as they consent.
Randomised treatment period
For inclusion into the randomised treatment phase of the study, patients must fulfil the following criteria:
1. Fasting LDL-C concentrations of ≥ 130 mg/dL (3.36 mmol/L) to <220 mg/dL (5.69 mmol/L) at Visit 2
2. Fasting TG concentrations <400 mg/dL (4.52 mmol/L) at Visit 2
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| E.4 | Principal exclusion criteria |
At Visit 1 (Week -6)
Any of the following is regarded as a criterion for exclusion from the study:
1. Use of lipid lowering drugs and other prohibited concomitant medications from Visit 1 (see Section 3.7)
2. 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
3. Pregnant women, women who are breast feeding, and women of childbearing potential who are not using chemical or mechanical contraception or have a positive serum pregnancy test (serum β-HCG analysis)
4. Patients considered to be unstable by the Investigator after the following events (event within 8 to 12 weeks of study entry (Visit 1) at the Investigators discretion): 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. (These patients should be on a statin and should not be entered into a washout phase, therefore they are unsuitable for this study)
5. Severe congestive cardiac failure (New York Heart Association [NYHA] Class IIIb or IV) (see Appendix H). (There is no evidence that these patients benefit from statin therapy)
6. Patients awaiting a planned myocardial revascularisation prior to Visit 1. (These patients require statin therapy and so a washout phase is not appropriate; therefore they are unsuitable for this study)
7. History of malignancy with the exception of resected basal cell or squamous cell carcinoma of the skin. Women with a history of cervical dysplasia will be permitted to enter the study provided they have 3 consecutive clear Papanicolaou (Pap) smears. (So that patients who are at risk of recurrence of malignancy requiring treatment are not included)
8. History of homozygous familial hypercholesterolaemia (the severity of hypercholesterolaemia in these patients usually dictates the need for individualised treatment regimens which can include phoresis)
9. History of alcohol or drug abuse within the last 5 years
10. Current active liver disease [alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase (SGPT)) ≥ 2 x upper limit of normal (ULN)] or severe hepatic impairment
11. Participation in another investigational drug study (including a previous rosuvastatin study) <4 weeks before enrolment in the study, or according to patient’s local ethics committee requirements where a longer period is stipulated
12. Patients previously screened for this study
13. Serious or unstable medical or psychological conditions that, in the opinion of the Investigator, would compromise the patient’s safety or successful participation in the study
14. Patients whose hormone replacement therapy (HRT) or oral contraceptive therapy (OCT) was initiated or changed within the 3 months prior to enrolment in the dietary lead in phase. (Changes in female hormones can have an effect on lipid measurements)
At randomisation visit
15. Patients with uncontrolled hypothyroidism within 3 months prior to enrolment in the dietary lead-in phase, defined as a TSH >1.5 x ULN (this is due to the relationship between myopathy and patients with hypothyroidism undergoing statin therapy)
16. Patients with unexplained creatine kinase (CK) within 3 months prior to enrolment in the dietary lead-in phase, defined as >1 x ULN
17. Serum creatinine >176 μmol/L or 2.0 mg/dL at Visit 2. (This is consistent with other statin studies previously performed)
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary outcome variable:
· Percentage LDL-C change from baseline to 6 weeks (mean of weeks 4 and 6) of combination therapy
· Statistical significance of the following 3 comparisons will be tested simultaneously by a Hochberg procedure to control for multiple comparisons:
1. Rosuvastatin 20 mg + ezetimibe 10mg vs simvastatin 40 mg+ 10 mg ezetimibe.
2. Rosuvastatin 10 mg + ezetimibe 10mg vs simvastatin 40 mg+ 10 mg ezetimibe.
3. Rosuvastatin 20 mg + ezetimibe 10mg vs simvastatin 80 mg+ 10 mg ezetimibe
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Simvastatin, simvastatin/ezetimibe |
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| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 12 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 16 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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