| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hypercholesterolemia or Combined Dyslipidemia and 2 or more risk factors for coronary heart disease (CHD) |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 7.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10020604 |
|
| 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 |
| To demonstrate the non-inferiority of pitavastatin 4 mg once daily (QD) versus (vs.) simvastatin 40 mg QD, with respect to the reduction of LDL-C, when administered for 12 weeks using an up-titration regimen. |
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| E.2.2 | Secondary objectives of the trial |
To compare the efficacy of pitavastatin 4 mg QD vs. simvastatin 40 mg QD with respect to changes from baseline in other lipid and lipoprotein fractions (TC, HDL C, TC:HDL-C ratio, non-HDL:HDL ratio, TG, apolipoprotein B [Apo B] and apolipoprotein A1 [Apo-A1], , Apo-B:Apo-A1 ratio, high sensitivity C-reactive protein [hs-CRP], oxidized LDL, and LDL-C target attainment [European Atherosclerosis Society {EAS} and National Cholesterol Education Program {NCEP}])
To assess the safety and tolerability of pitavastatin 4 mg QD when administered for 12 weeks using an up-titration regimen. |
|
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1. Males and females (age range 18-75 years);
2. Non-pregnant, non-lactating females. Women of child bearing potential are allowed to enter the study ONLY if they use sustained contraceptive preparations (e.g., implants or intramuscular [IM] injections) or comply with an approved mechanical contraceptive method.
3. At least two cardiovascular disease risk factors have to be present:
- Cigarette smoking;
- Hypertension (blood pressure ≥140/90 mm Hg or on antihypertensive medication);
- Low HDL-C (<1.0 mmol/L [40 mg/dL]);
- Family history of premature (CHD in male first-degree relative <55 years of age; CHD in female first-degree relative <65 years of age) (if HDL-C is >60 mg/dL then the number of risk factors will be reduced by 1);
- Age (men ≥45 years, women ≥55 years).
4. Patients who are eligible and able to participate in the study and who have given informed consent after the purpose and nature of the investigation has been explained to them;
5. In order to qualify for randomization at Visit 4 (Week 0), patients must have been following a fat and cholesterol restrictive diet as advised by the EAS during the dietary stabilization lead-in period (i.e. for at least 8 weeks for those patients previously taking lipid lowering medication and at least 6 weeks for those not previously taking lipid lowering medication). Patients must also agree not to eat grapefruit or drink grapefruit juice for the duration of the study;
6. In order to qualify for randomization at Visit 4 (Week 0), patients must present with primary hypercholesterolemia or combined dyslipidemia, as defined by elevated plasma LDL C (LDL C ≥3.4 mmol/L [130 mg/dL] ≤5.7 mmol/L [220 mg/dL]) despite dietary therapy and elevated TG levels of ≤4.6 mmol/L (400 mg/dL) at 2 visits during the dietary lead-in period. If these criteria are not satisfied at Visit 2 (Week –2) and Visit 3 (Week –1), or if the LDL C concentration of the lower qualifying specimen differs by ≥15% from the higher qualifying specimen, 1 additional lipid sample will be permitted for both variables 1 week after Visit 3 (Visit 3A) to enable the patient to qualify for randomization
7. Patients have to agree to be available for every clinic visit, which will occur in the morning.
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|
| E.4 | Principal exclusion criteria |
1. Homozygous familial hypercholesterolemia (heterozygous component of familial hypercholesterolemia is acceptable for inclusion);
2. Any conditions which may cause secondary dyslipidemia.
3. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of any drug.
4. Any history of pancreatic injury or pancreatitis, or impaired pancreatic function/injury as indicated by abnormal lipase or amylase;
5. Liver injury, imparied renal function, uncontrolled diabetes mellitus
6. Current obstruction of the urinary tract or difficulty in voiding due to mechanical as well as inflammatory conditions, which is likely to require intervention during the course of the study or is regarded as clinically meaningful by the investigator;
7. Serum CK levels >5 x ULRR over the lead in period. For patients with unexplained serum CK >5 x ULRR at Visit 1 or 2, a repeat CK >5 x ULRR in the absence of conditions explaining the CK elevation is exclusionary;
8. Uncontrolled hypothyroidism.
9. Any severe acute illness or severe trauma in the last 3 months prior to Visit 1 (Week -8/-6);
10. Major surgery, during the 3 months prior to Visit 1 (Week -8/-6);
11. Significant CVD prior to randomization, such as myocardial infarction, coronary or peripheral artery angioplasty, bypass graft surgery or severe or unstable angina pectoris within the last 3 months;
12. Evidence of symptomatic heart failure (New York Heart Association [NYHA] class III or IV), gross cardiac enlargement (cardiothoracic ratio >0.5); significant heart block or cardiac arrhythmias.
13. Left ventricular (LV) ejection fraction <0.25;
14. History of symptomatic cerebrovascular disease including cerebrovascular hemorrhage, transient ischemic attack or carotid endarterectomy within 1 month prior to randomization;
15. Any other medical or surgical conditions at the discretion of the investigator which place the patient at higher risk derived from his/her participation in the study, which could confound the result of the study, or are likely to prevent the patient from complying with the requirements of the study or completing the study period;
16. Known Human Immunodeficiency Virus (HIV) infection;
17. Poorly controlled or uncontrolled hypertension. Patients must have a systolic blood pressure (SBP) £140 mm Hg and diastolic blood pressure (DBP) £90 mm Hg with or without antihypertensive therapy.
18. Prior or current known muscular or neuromuscular disease of any type;
19. Current active neoplastic disease or patients who may require antineoplastic treatment during the course of the study.
20. Within the last 2 years, a history of drug abuse or continuous consumption of more than 65 mL pure alcohol per day
21. Exposure to any investigational new drug within 30 days of study entry (Visit 1/Week –8/-6) or ingestion of any drug known to be toxic to a major organ system (such as those producing blood dyscrasias, nephrotoxicity, hepatotoxicity or neurotoxicity) within 12 weeks prior to the study entry (Visit 1/Week –8/-6);
22. Current or recent (within 4 weeks of Visit 1 [Weeks –8/-6]) use of supplements known to alter lipid metabolism e.g. soluble fibers (including >2 teaspoons Metamucil or psyllium containing supplement per day), or other dietary fiber supplements, fish oils, sterol/stanol products, or others at the discretion of the investigator;
23. History of hypersensitivity reactions to other HMG-CoA reductase inhibitors;
24. Any concomitant medication not permitted by this protocol (see Section 4.5.5, Concomitant Therapy);
25. History of being resistant to lipid-lowering medications. Known hypersensitivity or intolerance to any lipid lowering agent, i.e., elevated serum transaminases, myositis;
26. Excessive obesity defined as Body Mass Index (BMI) above 35 kg/m2 (BMI = body weight in kg divided by squared height [m2]). Body Mass Index values should be rounded to the nearest whole number: down at <0.5 and up at ≥0.5;
27. Any factor which makes regular clinic attendance in the morning impractical (e.g., shift and/or night work); and/or
28. Any signs of mental dysfunction or other factors (including language problems) likely to limit the ability of the patient to cooperate with the performance of the study.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| To demonstrate the non-inferiority of pitavastatin 4 mg once daily (QD) versus (vs.) simvastatin 40 mg QD. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Information not present in EudraCT |
| E.6.7 | Pharmacodynamic | Information not present in EudraCT |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Information not present in EudraCT |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Information not present in EudraCT |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Information not present in EudraCT |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
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