title: Design and rationale of the EBBINGHAUS trial: A phase 3, double-blind, placebo-controlled, multicenter study to assess the effect of evolocumab on cognitive function in patients with clinically evident cardiovascular disease and receiving statin background lipid-lowering therapy-A cognitive study of patients enrolled in the FOURIER trial.
abstract: Some observational studies raised concern that statins may cause memory impairment, leading to a US Food and Drug Administration warning. Similar questions were raised regarding proprotein convertase subtilisin/kexin-type 9 inhibitors (PCSK9i) and neurocognitive function. No prospectively designed study has evaluated the relationship between long-term PCSK9i use and cognition changes. Patients with prior cardiovascular disease treated with maximally tolerated statin enrolled in FOURIER (the randomized, double-blind, placebo-controlled cardiovascular outcome study of the PCSK9i evolocumab) could participate in this prospective assessment of cognitive function (EBBINGHAUS). Key additional exclusion criteria for EBBINGHAUS were dementia, cognitive impairment, or other significant mental or neurological disorder. Cognitive testing was performed using the Cambridge Neuropsychological Test Automated Battery, a tablet-based tool assessing executive function, working memory, memory function, and psychomotor speed at baseline, weeks 24 and 48, every 48 weeks thereafter, and study end. The primary endpoint was spatial working memory strategy index of executive function (SWMSI). The primary hypothesis was that evolocumab would be noninferior to placebo in the mean change from baseline over time in SWMSI. Fifteen hundred cognitively normal patients completing the assessments provided approximately 97% power to demonstrate that the upper 95% confidence interval for the treatment difference in mean change from baseline in SWMSI over time is <20% of the SD of the mean change in the placebo group. An exploratory analysis will compare neurocognitive function in patients with post-baseline low-density lipoprotein cholesterol <25 mg/dL. EBBINGHAUS will evaluate whether the addition of evolocumab to statin therapy affects cognitive function over time in patients with stable cardiovascular disease.
authors.affiliation: TIMI Study Group, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Robert P
authors.identifier: http://orcid.org/0000-0003-4110-7675
authors.initials: RP
authors.lastname: Giugliano
authors.affiliation: Division of Cardiology, Cantonal Hospital, Geneva University Hospitals, Geneva, Switzerland.
authors.forename: Francois
authors.initials: F
authors.lastname: Mach
authors.affiliation: Cambridge Cognition, Cambridge, United Kingdom.
authors.forename: Kenton
authors.initials: K
authors.lastname: Zavitz
authors.affiliation: Amgen, Thousand Oaks, California.
authors.forename: Christopher
authors.initials: C
authors.lastname: Kurtz
authors.affiliation: Amgen, Thousand Oaks, California.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Schneider
authors.affiliation: Amgen, Thousand Oaks, California.
authors.forename: Huei
authors.initials: H
authors.lastname: Wang
authors.affiliation: NHMRC Clinical Trials Centre, Sydney Medical School, the University of Sydney, Australia.
authors.forename: Anthony
authors.initials: A
authors.lastname: Keech
authors.affiliation: Center for Preventive Medicine, Oslo University Hospital, Ullevål; and Medical Faculty, University of Oslo, Norway.
authors.forename: Terje R
authors.initials: TR
authors.lastname: Pedersen
authors.affiliation: TIMI Study Group, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Marc S
authors.initials: MS
authors.lastname: Sabatine
authors.affiliation: International Centre for Circulatory Health, Imperial College London, London, United Kingdom.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Sever
authors.affiliation: Amgen, Thousand Oaks, California.
authors.forename: Narimon
authors.initials: N
authors.lastname: Honarpour
authors.affiliation: Amgen, Thousand Oaks, California.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Wasserman
authors.affiliation: Department of Neurology, the Warren Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Ott
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D002318:Cardiovascular Diseases / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D003071:Cognition / Q000187:drug effects*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D000960:Hypolipidemic Agents / Q000627:therapeutic use*; D008055:Lipids / Q000097:blood*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; D008055:Lipids; C577155:evolocumab
keywords: Clinical trials; Ischemic heart disease; Lipid; Lipidology; Preventive cardiology