title: Comparison of PCSK9 Inhibitor Evolocumab vs Ezetimibe in Statin-Intolerant Patients: Design of the Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin-Intolerant Subjects 3 (GAUSS-3) Trial.
abstract: Statins are the accepted standard for lowering low-density lipoprotein cholesterol (LDL-C). However, 5% to 10% of statin-treated patients report intolerance, mostly due to muscle-related adverse effects. Challenges exist to objective identification of statin-intolerant patients. Evolocumab is a monoclonal antibody that binds proprotein convertase subtilisin/kexin type 9 (PCSK9), resulting in marked LDL-C reduction. We report the design of Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin-Intolerant Subjects 3 (GAUSS-3), a phase 3, multicenter, randomized, double-blind, ezetimibe-controlled study to compare effectiveness of 24 weeks of evolocumab 420 mg monthly vs ezetimibe 10 mg daily in hypercholesterolemic patients unable to tolerate an effective statin dose. The study incorporates a novel atorvastatin-controlled, double-blind, crossover phase to objectively identify statin intolerance. Eligible patients had LDL-C above the National Cholesterol Education Project Adult Treatment Panel III target level for the appropriate coronary heart disease risk category and were unable to tolerate ≥3 statins or 2 statins (one of which was atorvastatin ≤10 mg/d) or had a history of marked creatine kinase elevation accompanied by muscle symptoms while on 1 statin. This trial has 2 co-primary endpoints: mean percent change from baseline in LDL-C at weeks 22 and 24 and percent change from baseline in LDL-C at week 24. Key secondary efficacy endpoints include change from baseline in LDL-C, percent of patients attaining LDL-C <70 mg/dL (1.81 mmol/L), and percent change from baseline in total cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B. Recruitment of 511 patients was completed on November 28, 2014.
authors.affiliation: Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Nissen
authors.affiliation: Department of Clinical Development, and Biostatistics, Amgen Inc., Thousand Oaks, California.
authors.forename: Ricardo E
authors.initials: RE
authors.lastname: Dent-Acosta
authors.affiliation: The Cardiometabolic Disorders Unit, Mount Sinai Heart, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Rosenson
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: Stroes
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Naveed
authors.initials: N
authors.lastname: Sattar
authors.affiliation: Clinical Trial Service Unit and Epidemiological Services Unit, University of Oxford, Oxford, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Preiss
authors.affiliation: Department of Medicine, Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: G B John
authors.initials: GB
authors.lastname: Mancini
authors.affiliation: Department of Medicine, Baylor College of Medicine and Center for Cardiovascular Disease Prevention, Methodist DeBakey Heart and Vascular Center, Houston, Texas.
authors.forename: Christie M
authors.initials: CM
authors.lastname: Ballantyne
authors.affiliation: Department of Pharmacological Sciences, University of Milan, and IRCCS Multimedica, Milan, Italy.
authors.forename: Alberico
authors.initials: A
authors.lastname: Catapano
authors.affiliation: Center for Endocrinology, Diabetes and Preventive Medicine, University of Cologne, Cologne, Germany.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Gouni-Berthold
authors.affiliation: Metabolic and Atherosclerosis Research Center, Cincinnati, Ohio.
authors.forename: Evan A
authors.initials: EA
authors.lastname: Stein
authors.affiliation: Department of Clinical Development, and Biostatistics, Amgen Inc., Thousand Oaks, California.
authors.forename: Allen
authors.initials: A
authors.lastname: Xue
authors.affiliation: Department of Clinical Development, and Biostatistics, Amgen Inc., Thousand Oaks, California.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Wasserman
authors.affiliation: Department of Clinical Development, and Biostatistics, Amgen Inc., Thousand Oaks, California.
authors.forename: Rob
authors.initials: R
authors.lastname: Scott
authors.affiliation: Department of Cardiology, Hartford Hospital, Hartford, Connecticut.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Thompson
mesh_terms: D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000924:Anticholesteremic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D053299:Apolipoprotein B-100 / Q000097:blood; D015415:Biomarkers / Q000097:blood*; D008078:Cholesterol, LDL / Q000097:blood*; D002985:Clinical Protocols; D004311:Double-Blind Method; D000069438:Ezetimibe / Q000009:adverse effects / Q000627:therapeutic use*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects*; D006937:Hypercholesterolemia / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology; D009135:Muscular Diseases / Q000139:chemically induced; D000091362:PCSK9 Inhibitors; D000071449:Proprotein Convertase 9 / Q000378:metabolism; D012107:Research Design; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: C569471:APOB protein, human; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000924:Anticholesteremic Agents; D053299:Apolipoprotein B-100; D015415:Biomarkers; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000091362:PCSK9 Inhibitors; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D000069438:Ezetimibe; C577155:evolocumab