| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Type II Diabetes Mellitus and Combined Dyslipidemia |
|
| 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 | 10058110 |
|
| 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.) atorvastatin 20 mg QD with respect to the reduction of LDL-C, when administered for 12 weeks using an up titration regimen. |
|
| E.2.2 | Secondary objectives of the trial |
To compare the efficacy of pitavastatin 4 mg QD vs. atorvastatin 20 mg QD with respect to changes from baseline in other lipid and lipoprotein fractions (TC, HDL C, TC:HDL-C ratio, non-HDL:HDL-C ratio, TG, Apo B and apolipoprotein A1 [Apo-A1], Apo-B:Apo-A1 ratio, high sensitivity C-reactive protein [hs-CRP], adiponectin, small dense-LDL, remnant-like particle-cholesterol [RLP-C], 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 | No |
| E.3 | Principal inclusion criteria |
1. Males and females (age 18-75 years);
2. Type II DM treated with oral anti-diabetic medication (e.g., sulfonylurea, metformin or combination therapy) or insulin but excluding glitazones;
3. Glycosylated hemoglobin A1c (HbA1c) <7.5% (at Visit 1);
4. Absence of proliferative diabetic retinopathy, cataract(s) (if this precludes satisfactory ophthalmoscopic examination of the retina) and or diabetic nephropathy (other than microalbuminuria – urine albumin excretion <300 mg/24 hours);
5. Body Mass Index (BMI) ≤35 kg/m2;
6. 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. A woman is considered to be of childbearing potential unless she is post hysterectomy or at least 1-year post menopausal or post-tubal ligation. All women of child bearing potential must have a negative pregnancy test at the beginning of the dietary lead-in period (Visit 1/Week –8/-6), and before initiating active treatment (Visit 4/Week 0);
7. 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;
8. 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;
9. In order to qualify for randomization at Visit 4 (Week 0), patients must present with combined dyslipidemia, as defined by elevated plasma LDL C (LDL C ≥2.6 mmol/L [100 mg/dL] and ≤5.7 mmol/L [220 mg/dL]) despite dietary therapy and elevated TG levels of ≥1.7 mmol/L (150 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; and
10. Patients who 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. Uncontrolled diabetes mellitus as defined by glycosylated hemoglobin A1c (HbA1c) >7.5%.
4. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of any drug.
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).
7. Impaired renal function as indicated by serum creatinine levels >1.5 x ULRR at Visit 1 (Week –8/-6).
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 without a clinical explanation. However, if at Visit 1 (Week-8/-6) serum CK is > 5 x ULRR with a clinical explanation (such as extreme exertion or intramuscular injections, etc), one re-test will be allowed.
10. Uncontrolled hypothyroidism defined as TSH > ULRR.
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 arrhythmia.
15. In patients where the left ventricular ejection fraction (LVEF) is known this should be <0.25 (echographic confirmation of the LVEF is not a study requirement);
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) ≤160 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 3 x 125-mL glasses of wine or 1.5 glasses of spirits per day);
23. Exposure to any investigational new drug within 30 days of study entry
24. Current or recent (within 4 weeks of Visit 1/Week –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, or other products 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
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 BMI above 35 kg/m2
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.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The percent change from baseline LDL-C at Visit 8 (Week 12). Baseline is the mean of LDL-C measurements obtained at Visits 2 and 3. |
|
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| double dummy; non-inferiority |
|
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 47 |
| 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 |
|
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 11 |
| 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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