| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Mixed dyslipidemia (Frederickson Types IIa and IIb) | |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Classification code | 10058108 | |
| 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 and HDL C elevating efficacy of torcetrapib 60 mg administered in a fixed combination with atorvastatin 10 to 80 mg/day compared to atorvastatin alone or placebo in subjects with mixed dyslipidemia (Frederickson Types IIa and IIb). The LDL-C lowering and HDL-C elevating efficacy of the fixed combination will be tested within and across the 2 types of dyslipidemia to establish its incremental benefit over atorvastatin alone, both across and at each of 4 approved atorvastatin dose levels, and over placebo. | |
| E.2.2 | Secondary objectives of the trial | | The secondary objective is to evaluate the modulation of other lipids, apolipoproteins, glucose, and other CHD risk markers by torcetrapib 60 mg administered in a fixed combination with atorvastatin 10 to 80 mg/day compared to that by atorvastatin alone or placebo within and across the 2 types of dyslipidemia.Additional objectives are to characterize the safety and tolerability of torcetrapib/atorvastatin and the population pharmacokinetics of torcetrapib. | |
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria | | 1.Subject must meet the following lipid eligibility criteria based on fasting samples drawn at Q2 and Q3 following TLC and wash-out of all lipid-regulating drugs (for information on calculating CHD risk see Appendix D):·Fasting mean LDL-C:·³160 mg/dL (4.1 mmol/L) and <220 mg/dL (5.7 mmol/L) if 10-year CHD risk <10%·³130 mg/dL (3.4 mmol/L) and <190 mg/dL (4.9 mmol/L) if 10-year CHD risk ³10% and £20%·Fasting mean TG £500 mg/dl (5.6 mmol/L). Subjects with mean TG <150 mg/dL (1.7 mmol/L) will be randomized into the Frederickson Type IIa dyslipidemia stratum, and subjects with mean TG ³150 (1.7 mmol/L) and £500 (5.6 mmol/L) will be randomized into the Frederickson Type IIb dyslipidemia stratum. | |
| E.4 | Principal exclusion criteria | Subjects are excluded if they have any of the following:
1. Pregnancy or a plan to become pregnant or breastfeed during the study or for 30 days afterwards. Unless, for woman of childbearing potential use of contraception for the duration of the study and for 30 days following the last dose of study medication.
2. CHD or CHD risk equivalent, including carotid artery disease, peripheral arterial disease, abdominal aortic aneurysm, diabetes mellitus, pathologic Q waves on ECG, or persistent fasting glucose ³126 mg/dL.
3. Requirement for intermittent systemic corticosteroids at pharmacologic doses (intravenous, oral, or injectable, including joint injections). (see protocol for more details).
4. Primary hypothyroidism with thyroid stimulating hormone (TSH) >2 ´ Upper Limit of Normal (ULN).
5. Active liver disease; or AST (SGOT) or ALT (SGPT) >2.0 ´ ULN, alkaline phosphatase (ALK-P) >1.5 ´ ULN (with elevated liver isoform of alkaline phosphatase), or total bilirubin >1.5 ´ ULN at screening.
6. Intolerance to atorvastatin therapy.
7. Chronic systemic use of any medications known to be associated with an increased risk of myopathy in combination with HMG-CoA reductase inhibitors, or systemic use of any potent inhibitors of cytochrome P450 3A4 (CYP3A4).
8. Uncontrolled hypertension defined as average systolic blood pressure (SBP) >140 mm Hg or average diastolic blood pressure (DBP) >90 mm Hg at either Visit Q3 OR T4.
9. Unexplained serum creatine kinase (CK) >3 ´ ULN at screening (eg, not due to recent trauma, intramuscular injections, or heavy exercise). Subjects with a reason for CK elevation may continue in screening and should have the measurement repeated prior to randomization; a repeat CK >3 ´ ULN is exclusionary.
10. Current moderate or severe congestive heart failure (New York Heart Association [NYHA] Class III or IV.
11. Current significant renal dysfunction including serum creatinine >1.7 ´ ULN or nephrotic syndrome. Subjects with significant proteinuria on urine dipstick should have evaluation to rule out nephrotic syndrome prior to randomization.
12. Any prior history of malignancy (For exceptions, see protocol more details).
13. Gastrointestinal conditions that may limit drug absorption, such as chronic diarrhea, inflammatory bowel disease, partial ileal bypass, gastric stapling, or gastric banding.
14. Current alcohol and/or any other drug abuse or dependence.
15. Uncontrolled depression or psychosis. | |
| E.5 End points |
| E.5.1 | Primary end point(s) | | The primary endpoints are the changes in HDL-C and LDL-C from baseline to follow-up expressed as a percentage of the baseline value (percent change). | |
| 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 | Information not present in EudraCT |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| 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 | Yes |
| 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 | 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 | Information not present in EudraCT |
| 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 | 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 | 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 | |
| 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 | 8 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
