Efficacy and Safety of Gemcabene in Hypercholesterolemic Patients as Monotherapy or in Combination With Atorvastatin

An 8-Week, Double-Blind, Randomized, Placebo-Controlled, Dose-Ranging Study of the Efficacy and Safety of Gemcabene Administered as Monotherapy or in Combination With Atorvastatin in the Treatment of Hypercholesterolemic Patients

The primary purpose of this placebo-controlled study is to evaluate the low-density lipoprotein cholesterol (LDL-C) efficacy and dose-response of gemcabene 300, 600 and 900 mg/day administered as monotherapy or in combination with atorvastatin 10, 40, and 80 mg/day to hypercholesterolemic patients.

Secondary purposes include evaluating the effects of high-sensitivity C-reactive protein (hsCRP), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG) and apolipoprotein B (ApoB), and safety and efficacy of gemcabene monotherapy and gemcabene/atorvastatin combination.

Inclusion Criteria:

• Males and Females
• 18-70 years old
• Received a statin as monotherapy while having a LDL-C >100 mg d/L at initial clinical washout visit OR
• Received no lipid-altering drugs since the initial clinic washout visit and had a mean LDL-C as follows at 2 qualifying visits:
• ≥ 130 mg/dL if National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) Coronary Heard Disease (CHD) risk ≥ 10%; OR
• ≥ 160 mg/dL if NCEP ATP III CHD risk < 10%
• Had variability of 2 qualifying LDL-C <20% (i.e. lowest value/highest value >0.8). An additional qualifying visit may have been completed by patients who were washing off lipid medication in order to reassess LDL-C variability; and
• Had a mean LDL-C < 250 mg/dL at 2 qualifying visits

Exclusion Criteria:

• Women of childbearing potential, pregnant or lactating;
• Body Mass Index (BMI) >38kg/m²;
• TG >400 mg/dL at Visit B2 or B3
• Unexplained creatinine phosphokinase (CPK) > 3 x Upper Limit of Normal (ULN) or those with a history of unexplained myopathy (including rhabdomyolysis);
• Documented cardiac history of: Myocardial infarction*, severe or unstable angina pectoris, coronary angioplasty, coronary artery bypass graft, symptomatic carotid artery disease or peripheral artery disease, ventricular arrhythmias, recurrent supraventricular tachycardia, abnormal QTC interval (QT corrected > 0.44 sec), heart failure or any other major cardiovascular event resulting in hospitalization
• Uncontrolled hypertension*
• Type 1 diabetes mellitus or uncontrolled type 2 diabetes mellitus (HbA1c >8%) or any diabetic patient who takes insulin and/or thiazolidinediones
• Renal dysfunction including chronic renal failure or insufficiency, or creatinine >2.0 mg/dL;
• Hepatic dysfunction
• Uncontrolled hypothyroidism
• Abnormal urinalysis
• Currently taking any of the following medications:
• Potent CYP3A4 inhibitors including indinavir, nelfinavir, ritonavir, saquinavir, amiodarone, cimetidine, clarithromycin, erythromycin, erythromycin, fluoxetine, itraconazole, ketoconazole, nefazodone and troleandomycin as well as grapefruit juice;
• Thiazolidinediones (Avandia, Actos);
• Immunosuppressive agents;
• St. John's wort
• Taking any of the following lipid-altering medications within 5 weeks prior to randomization:
• Lipid-regulating drugs: Niacin (crystalline >500mg/day, slow release or time release), psyllium preparation such as Metamucil (>2 tablespoons/day), fibrates and derivatives, bile cholesterol absorption inhibitors including ezetimibe;
• Any supplement containing plan sterols/stanols (i.e. Benecol, beta-sitosterol, Cholestatin, Phytoquest, Take Control) or cholestin (i.e. Chinese red yeast, fermented on rice; Hong Qu, Hong Chu, Herbvalin, Ruby Monascus, Monascus purpureus rice);
• Neomycin (oral);
• Adrenocortical steroids*
• Sibutramine (Meridia);
• Insulin;
• Orlistat (Xenical);
• Isotretinoin