Efficacy and Safety Study of Digital Cognitive Training and PCSK9 Inhibitor-Enhanced Lipid-lowering Strategy in Patients With Intracranial Atherosclerotic Stenosis: A 2×2 Randomized Controlled Trial

Summary

This study aims to evaluate whether digital cognitive training and/or intensive lipid-lowering therapy with a PCSK9 inhibitor can improve cognitive function in patients with intracranial atherosclerosis (ICAS). ICAS is a common cause of stroke and is also linked to thinking and memory problems. The study will enroll 420 adults aged 55-80 years who have 50-99% narrowing of an intracranial artery, subjective memory complaints, and LDL cholesterol ≥1.8 mmol/L, but who are not demented. Participants will be randomly assigned to one of four groups in a 2×2 factorial design: 1. No cognitive training + standard statin therapy 2. Cognitive training + standard statin therapy 3. No cognitive training + intensive statin plus PCSK9 inhibitor 4. Cognitive training + intensive statin plus PCSK9 inhibitor Cognitive training consists of 30 minutes of tablet-based exercises, 5 days per week for 12 weeks. The intensive lipid-lowering group receives a PCSK9 inhibitor (Recaticimab) injection at weeks 0, 4, and 12, on top of maximally tolerated statin. The main outcome is change in a composite cognitive score from baseline to 24 weeks. Secondary outcomes include changes in specific cognitive domains, MRI markers of brain structure and function, and safety measures. The study is multicenter, open-label with blinded outcome assessment, and is conducted under the approval of the ethics committee of Peking Union Medical College Hospital.

Timeline

Start

2026-05-25

Primary completion

2028-09-30

Completion

2029-07-31

Publications

• Background Giugliano RP, Sabatine MS, Ott BR. Cognitive Function in a Randomized Trial of Evolocumab. N Engl J Med. 2017 Nov 16;377(20):1997. doi: 10.1056/NEJMc1712102. No abstract available.
• Background Tang Y, Xing Y, Zhu Z, He Y, Li F, Yang J, Liu Q, Li F, Teipel SJ, Zhao G, Jia J. The effects of 7-week cognitive training in patients with vascular cognitive impairment, no dementia (the Cog-VACCINE study): A randomized controlled trial. Alzheimers Dement. 2019 May;15(5):605-614. doi: 10.1016/j.jalz.2019.01.009. Epub 2019 Mar 17.
• Background Chapman SB, Aslan S, Spence JS, Hart JJ Jr, Bartz EK, Didehbani N, Keebler MW, Gardner CM, Strain JF, DeFina LF, Lu H. Neural mechanisms of brain plasticity with complex cognitive training in healthy seniors. Cereb Cortex. 2015 Feb;25(2):396-405. doi: 10.1093/cercor/bht234. Epub 2013 Aug 28.
• Background Risk Reduction of Cognitive Decline and Dementia: WHO Guidelines. Geneva: World Health Organization; 2019. Available from http://www.ncbi.nlm.nih.gov/books/NBK542796/
• Background Chan ATC, Ip RTF, Tran JYS, Chan JYC, Tsoi KKF. Computerized cognitive training for memory functions in mild cognitive impairment or dementia: a systematic review and meta-analysis. NPJ Digit Med. 2024 Jan 3;7(1):1. doi: 10.1038/s41746-023-00987-5.
• Background Petersen RC, Lopez O, Armstrong MJ, Getchius TSD, Ganguli M, Gloss D, Gronseth GS, Marson D, Pringsheim T, Day GS, Sager M, Stevens J, Rae-Grant A. Practice guideline update summary: Mild cognitive impairment [RETIRED]: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018 Jan 16;90(3):126-135. doi: 10.1212/WNL.0000000000004826. Epub 2017 Dec 27.
• Background Graessel E, Jank M, Scheerbaum P, Scheuermann JS, Pendergrass A. Individualised computerised cognitive training (iCCT) for community-dwelling people with mild cognitive impairment (MCI): results on cognition in the 6-month intervention period of a randomised controlled trial (MCI-CCT study). BMC Med. 2024 Oct 15;22(1):472. doi: 10.1186/s12916-024-03647-x.
• Background Sabayan B, Goudarzi R, Ji Y, Borhani-Haghighi A, Olson-Bullis BA, Murray AM, Sedaghat S. Intracranial Atherosclerosis Disease Associated With Cognitive Impairment and Dementia: Systematic Review and Meta-Analysis. J Am Heart Assoc. 2023 Nov 21;12(22):e032506. doi: 10.1161/JAHA.123.032506. Epub 2023 Nov 20.
• Background Qureshi AI, Caplan LR. Intracranial atherosclerosis. Lancet. 2014 Mar 15;383(9921):984-98. doi: 10.1016/S0140-6736(13)61088-0. Epub 2013 Sep 2.
• Background Yang WJ, Wong KS, Chen XY. Intracranial Atherosclerosis: From Microscopy to High-Resolution Magnetic Resonance Imaging. J Stroke. 2017 Sep;19(3):249-260. doi: 10.5853/jos.2016.01956. Epub 2017 Sep 6.

Drugs

Indications