title: Fixed-dose combination ezetimibe+atorvastatin lowers LDL-C equivalent to co-administered components in randomized trials: use of a dose-response model.
abstract: 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 10/20 mg (n = 353) or 10/40 mg (n = 280) vs. separate co-administration of ezetimibe 10 mg plus atorvastatin 20 mg (n = 346) or 40 mg (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 10/20 mg was equivalent to co-administered ezetimibe+atorvastatin 20 mg in reducing LDL-C levels (54.0% vs. 53.8%) as was FDC 10/40 mg and ezetimibe+atorvastatin 40 mg (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 10/40 mg FDC had equivalent LDL-C lowering. This FDC formulation proved to be an efficacious and generally well-tolerated lipid-lowering therapy.
authors.affiliation: Louisville Metabolic and Atherosclerosis Research Center, 3288 Illinois Avenue, Louisville, KY, 40213, USA.
authors.forename: Harold E
authors.initials: HE
authors.lastname: Bays
authors.forename: Erluo
authors.initials: E
authors.lastname: Chen
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Tomassini
authors.forename: Gail
authors.initials: G
authors.lastname: McPeters
authors.forename: Adam B
authors.initials: AB
authors.lastname: Polis
authors.forename: Joseph
authors.initials: J
authors.lastname: Triscari
mesh_terms: D000368:Aged; D000924:Anticholesteremic Agents / Q000008:administration & dosage*; D000069059:Atorvastatin / Q000008:administration & dosage*; D008078:Cholesterol, LDL / Q000037:antagonists & inhibitors* / Q000097:blood; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D000069438:Ezetimibe / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged
chemical_list: D000924:Anticholesteremic Agents; D008078:Cholesterol, LDL; D004338:Drug Combinations; D000069059:Atorvastatin; D000069438:Ezetimibe
keywords: LDL-C lowering; atorvastatin; clinical equivalence; ezetimibe; modeling and simulation