Fixed-dose combination ezetimibe plus atorvastatin lowers LDL-C equivalent to co-administered components in randomized trials: use of a dose-response model

Co-administration of ezetimibe with atorvastatin is a generally well-tolerated treatment option that reduces LDL-C levels and improves other lipids with greater efficacy than doubling the atorvastatin dose. The objective of the study was to demonstrate the equivalent lipid-modifying efficacy of fixed-dose combination (FDC) ezetimibe/atorvastatin compared with the component agents co-administered individually in support of regulatory filing. Two randomized, 6-week, double-blind cross-over trials compared the lipid-modifying efficacy of ezetimibe/atorvastatin 10/20mg (n=353) or 10/40mg (n=280) vs. separate co-administration of ezetimibe 10mg plus atorvastatin 20mg (n=346) or 40mg (n=280), respectively, in hypercholesterolemic patients. Percent changes from baseline in LDL-C (primary endpoint) and other lipids (secondary endpoints) were assessed by analysis of covariance; triglycerides were evaluated by longitudinal-data analysis. Expected differences between FDC and the corresponding co-administered doses were predicted from a dose-response relationship model; sample size was estimated given the expected difference and equivalence margins (+/- 4%). LDL-C-lowering equivalence was based on 97.5% expanded confidence intervals (CI) for the difference contained within the margins; equivalence margins for other lipids were not prespecified. Ezetimibe/atorvastatin FDC 10/20mg was equivalent to co-administered ezetimibe+atorvastatin 20mg in reducing LDL-C levels (54.0% vs. 53.8%) as was FDC 10/40mg and ezetimibe+atorvastatin 40mg (58.9% vs. 58.7%), as predicted by the model. Changes in other lipids were consistent with equivalence (97.5% expanded CIs <+/- 3%, included 0); triglyceride changes varied more. All treatments were generally well tolerated. Hypercholesterolemic patients administered ezetimibe/atorvastatin 10/20 and 10/40mg FDC had equivalent LDL-C lowering. This FDC formulation proved to be an efficacious and generally well-tolerated lipid-lowering therapy.