A multicenter, randomized, double-blind, placebo-controlled, factorial design study to evaluate the lipid-altering efficacy and safety profile of the ezetimibe/simvastatin tablet compared with ezetimibe and simvastatin monotherapy in patients with primary hypercholesterolemia

Objective: The purpose of this study was to evaluate the efficacy and safety profile of ezetimibe/simvastatin (EZE/SIMVA) combination tablet, relative to ezetimibe (EZE) and simvastatin (SIMVA) monotherapy, in patients with primary hypercholesterolemia. Methods: This was a randomized, multicenter, double-blind, placebo-controlled, factorial design study After a 6- to 8-week washout period and 4-week, single-blind, placebo run in, hypercholesterolemic patients (low-density lipoprotein cholesterol [LDL-C], 145-250 mg/dL; triglycerides [TG], less than or equal to350 mg/dL) were randomized equally to 1 of 10 daily treatments for 12 weeks: EZE/SIMVA 10/10, 10/20, 10/40, or 10/80 mg; SIMVA 10, 20, 40, or 80 mg; EZE 10 mg; or placebo. The primary efficacy analysis was mean percent change from baseline in LDL-C to study end point. Secondary end points included percent changes in other lipid variables and C-reactive protein [CRP]. Results: There were 1528 patients randomized to treatment (792 women, 736 men); mean (SD) age ranged from 54.9 (11.2) years to 56.4 (10.6) years across pooled treatment groups. The treatment groups were well balanced for baseline demographics. Pooled EZE/SIMVA was associated with greater reductions in LDL-C than pooled SIMVA or EZE alone (P < 0.001). Depending on dose, EZE/SIMVA was associated with reductions in LDL-C of -44.8% to -60.2%, non-high-density lipoprotein cholesterol of -40.5% to -55.7%, and TG of -22.5% to -30.7%; high-density lipoprotein cholesterol increased by 5.5% to 9.8%. EZE/SIMVA was associated with greater reductions in CRP and remnant-like particle-cholesterol than SIMVA alone (P < 0.001). More patients receiving EZE/SIMVA versus SIMVA achieved LDL-C concentrations <100 mg/dL (78.6% vs 45.9%; P < 0.001). EZE/SIMVA was generally well tolerated, with a safety profile similar to SIMVA monotherapy. There were no significant differences between EZE/SIMVA and SIMVA in the incidence of consecutive liver transaminase levels greater than or equal to3 times the upper limit of normal (ULN) (1.5% for EZE/SIMVA and 1.1% for SIMVA; P = NS) or creatine kinase levels greater than or equal to10 times ULN (0.0% for EZE/SIMVA and 0.2% for SIMVA; P = NS). Conclusion: The EZE/SIMVA tablet was a highly effective and well-tolerated LDL-C-lowering therapy in this study of patients with primary hypercholesterolemia. (C) 2004 Excerpta Medica, Inc.