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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.
Clin Cardiol. 2017 Feb; 40(2):59-65.CC

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+Show Affiliations

TIMI Study Group, Brigham and Women's Hospital, Boston, Massachusetts.Division of Cardiology, Cantonal Hospital, Geneva University Hospitals, Geneva, Switzerland.Cambridge Cognition, Cambridge, United Kingdom.Amgen, Thousand Oaks, California.Amgen, Thousand Oaks, California.Amgen, Thousand Oaks, California.NHMRC Clinical Trials Centre, Sydney Medical School, the University of Sydney, Australia.Center for Preventive Medicine, Oslo University Hospital, Ullevål; and Medical Faculty, University of Oslo, Norway.TIMI Study Group, Brigham and Women's Hospital, Boston, Massachusetts.International Centre for Circulatory Health, Imperial College London, London, United Kingdom.Amgen, Thousand Oaks, California.Amgen, Thousand Oaks, California.Department of Neurology, the Warren Alpert Medical School of Brown University, Providence, Rhode Island.No affiliation info available

Pub Type(s)

Clinical Trial, Phase III
Journal Article
Multicenter Study
Randomized Controlled Trial

Language

eng

PubMed ID

28207168

Citation

Giugliano, Robert P., et al. "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." Clinical Cardiology, vol. 40, no. 2, 2017, pp. 59-65.
Giugliano RP, Mach F, Zavitz K, et al. 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. Clin Cardiol. 2017;40(2):59-65.
Giugliano, R. P., Mach, F., Zavitz, K., Kurtz, C., Schneider, J., Wang, H., Keech, A., Pedersen, T. R., Sabatine, M. S., Sever, P. S., Honarpour, N., Wasserman, S. M., & Ott, B. R. (2017). 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. Clinical Cardiology, 40(2), 59-65. https://doi.org/10.1002/clc.22678
Giugliano RP, et al. 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. Clin Cardiol. 2017;40(2):59-65. PubMed PMID: 28207168.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Giugliano,Robert P, AU - Mach,Francois, AU - Zavitz,Kenton, AU - Kurtz,Christopher, AU - Schneider,Jingjing, AU - Wang,Huei, AU - Keech,Anthony, AU - Pedersen,Terje R, AU - Sabatine,Marc S, AU - Sever,Peter S, AU - Honarpour,Narimon, AU - Wasserman,Scott M, AU - Ott,Brian R, AU - ,, Y1 - 2017/02/16/ PY - 2016/12/21/received PY - 2017/01/08/revised PY - 2017/01/11/accepted PY - 2017/2/17/pubmed PY - 2017/6/16/medline PY - 2017/2/17/entrez KW - Clinical trials KW - Ischemic heart disease KW - Lipid KW - Lipidology KW - Preventive cardiology SP - 59 EP - 65 JF - Clinical cardiology JO - Clin Cardiol VL - 40 IS - 2 N2 - 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. SN - 1932-8737 UR - https://www.unboundmedicine.com/medline/citation/28207168/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_ L2 - https://doi.org/10.1002/clc.22678 DB - PRIME DP - Unbound Medicine ER -