Double-blind follow-on study of Pitavastatin (4 mg) versus Simvastatin (40 mg and 80 mg), with a single-blind extension of treatment, in patients with Primary Hypercholesterolemia or Combined Dyslipidemia and 2 or more risk factors for Coronary Heart Disease

Participation in the previous Phase III study NK-104-304

The exclusion criteria of the NK-104-304 are still valid for the NK-104-309 study.
Patients participating in the study must not present any of the following conditions:
1. Familial hypercholesterolemia;
2. Any conditions which may cause secondary dyslipidemia. This includes, but is not restricted to alcoholism, auto-immune disease, nephrotic syndrome, uremia, any viral or non viral hepatitis clinically active within 12 months from study entry, obstructive hepatic or biliary disease, dys- or macroglobulinemia, multiple myeloma, glycogen storage disease, chronic pancreatitis, porphyria, and uncontrolled hypothyroidism or hyperthyroidism (controlled hypo- or hyperthyroidism [i.e., condition presenting with normal baseline serum thyroid stimulating hormone {TSH} and treatment stable during at least the last 2 months prior to study entry] will be permitted);
3. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of any drug. The investigator should be guided by the evidence of any of the following: history of major gastrointestinal tract surgery e.g. gastrectomy, gastroenterostomy, or small bowel resection, gastritis requiring active treatment, current active ulcers, gastrointestinal or rectal bleeding. Current active or recurrent irritable bowel syndrome (IBS) or history of inflammatory bowel syndrome. Patients with a past history of IBS without symptoms for at least the last 6 months prior to the study start will be allowed to enter the study;
4. Uncontrolled diabetes mellitus as defined by glycosylated hemoglobin A1c (HbA1c) >8%. Patients with controlled diabetes Type II are allowed, provided the disease has been stable during at least the last 3 months prior to study entry;
5. Any history of pancreatic injury or pancreatitis, or impaired pancreatic function/injury as indicated by abnormal lipase or amylase;
6. Liver injury as indicated by serum transaminase levels (ALAT/serum glutamic pyruvic transaminase [SGPT], ASAT/serum glutamic oxaloacetic transaminase [SGOT]) >1.5 x upper limit of the reference range (ULRR) over the lead in period. The ALAT/SGPT and ASAT/SGOT levels must be *1.5 x ULRR on at least 2 of the 3 evaluations between Visit 1 (Week -8/-6) and Visit 3 (Week -1) for the patient to be eligible for further study participation. If ALAT/SGPT and/or ASAT/SGOT is >2 x ULRR at any time point between Visit 1 (Week 8/-6) and Visit 3 (Week -1), the patient will be immediately excluded from further study participation;
7. Impaired renal function as indicated by serum creatinine levels >1.5 x ULRR at Visit 1 (Week -8/-6). However, if creatinine is between 1.5 and 2 x ULRR, 1 retest will be permitted at Visit 2 (Week -2), provided all other criteria are fulfilled. Serum creatinine must be *1.5 x ULRR at the retest for the patient to be eligible for further study participation. If serum creatinine is >2 x ULRR at Visit 1 (Week -8/-6), the patient will be immediately excluded from further study participation;
8. 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;
9. Serum CK >5 x ULRR. However, if at Visit 1 (Week-8/-6) serum CK is >5 x ULRR without a clinical explanation, one re-test will be allowed. If the repeat CK is >5 x ULRR in the absence of conditions explaining the CK elevation the patient will be immediately excluded from further study participation;
10. Uncontrolled hypothyroidism defined as TSH >ULRR. Patients with TSH >ULRR at Visit 1 are permitted to have a retest at Visit 2 and if TSH is also >ULRR at Visit 2 the patient will be excluded from the study;
11. Any severe acute illness or severe trauma in the last 3 months prior to Visit 1 (Week -8/-6);
12. Major surgery, during the 3 months prior to Visit 1 (Week -8/-6);
13. 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;
14. 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. History of uncontrolled complex ventricular arrhythmias, uncontrolled atrial fibrillation/flutter, or uncontrolled supraventricular tachycardias with a ventricular response rate of >100 beats per minute at rest. Patients whose electrophysiological instability are controlled with a pacemaker or implantable cardiac device are eligible;
15. Left ventricular (LV) ejection fraction <0.25;
16. History of symptomatic cerebrovascular disease including cerebrovascular hemorrhage, transient ischemic attack or carotid endarterectomy within 1 month prior to randomization;
17. 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;
18. Known Human Immunodeficiency Virus (HIV) infection;
19. 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;
20. Prior or current known muscular or neuromuscular disease of any type;
21. Current active neoplastic disease or patients who may require antineoplastic treatment during the course of the study. History of prior malignancy except those patients who have been cancer free for >10 years. Patients with prior history of basal cell carcinoma or squamous cell carcinoma of the skin remain eligible if they have been cancer free for >5 the past years;
22. Within the last 2 years, a history of drug abuse or continuous consumption of more than 65 mL pure alcohol per day (e.g., more than 4 x 125-mL glasses of wine or 3 glasses of spirits per day);
23. 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);
24. 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;
25. History of hypersensitivity reactions to other HMG-CoA reductase inhibitors;
26. Any concomitant medication not permitted by this protocol (see Section 4.5.5, Concomitant Therapy);
27. History of being resistant to lipid-lowering medications. Known hypersensitivity or intolerance to any lipid lowering agent, i.e., elevated serum transaminases, myositis;
28. 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;
29. Any factor which makes regular clinic attendance in the morning impractical (e.g., shift and/or night work); and/or
30. 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.