Framework for Clinical Trials in Cerebral Small Vessel Disease (FINESSE): A Review

Hugh S. Markus; Wiesje M. van Der Flier; Eric E. Smith; Philip Bath; Geert Jan Biessels; Emily Briceno; Amy Brodtman; Hugues Chabriat; Christopher Chen; Frank-Erik de Leeuw; Marco Egle; Aravind Ganesh; Marios K. Georgakis; Rebecca F. Gottesman; Sun Kwon; Lenore Launer; Vincent Mok; John O’Brien; Lois Ottenhoff; Sarah Pendlebury; Edo Richard; Perminder Sachdev; Reinhold Schmidt; Melanie Springer; Stefan Tiedt; Joanna M. Wardlaw; Ana Verdelho; Alastair Webb; David Werring; Marco Duering; Deborah Levine; Martin Dichgans

doi:10.1001/jamaneurol.2022.2262

Review

August 15, 2022

Framework for Clinical Trials in Cerebral Small Vessel Disease (FINESSE): A Review

Hugh S. Markus, DM¹; Wiesje M. van Der Flier, PhD¹; Eric E. Smith, MD²; et al Philip Bath, MD³; Geert Jan Biessels, MD⁴; Emily Briceno, PhD⁵; Amy Brodtman, MD^6,7,8; Hugues Chabriat, MD⁹; Christopher Chen, MD¹⁰; Frank-Erik de Leeuw, MD¹¹; Marco Egle, PhD¹²; Aravind Ganesh, MD²; Marios K. Georgakis, MD^13,14,15; Rebecca F. Gottesman, MD^16,17; Sun Kwon, MD¹⁸; Lenore Launer, PhD¹⁹; Vincent Mok, MD²⁰; John O’Brien, DM²¹; Lois Ottenhoff, MSc²²; Sarah Pendlebury, MD²³; Edo Richard, MD¹¹; Perminder Sachdev, MD²⁴; Reinhold Schmidt, MD²⁵; Melanie Springer, MD²⁶; Stefan Tiedt, MD^13,15; Joanna M. Wardlaw, MD²⁷; Ana Verdelho, MD²⁸; Alastair Webb, MD²⁹; David Werring, MD³⁰; Marco Duering, MD^13,15,31; Deborah Levine, MD³²; Martin Dichgans, MD^13,15

Author Affiliations Article Information

¹Alzheimer Center Amsterdam, Department of Neurology, Epidemiology and Data Science, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands
²Department of Clinical Neurosciences and Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
³Stroke Trials Unit, Mental Health & Clinical Neuroscience, University of Nottingham, Nottingham, United Kingdom
⁴Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, the Netherlands
⁵Department of Physical Medicine & Rehabilitation, University of Michigan Medical School, Ann Arbor
⁶Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia
⁷University of Melbourne, Melbourne, Victoria, Australia
⁸Monash University, Melbourne, Victoria, Australia
⁹Department of Neurology, FHU NeuroVasc, APHP, University of Paris, Paris, France
¹⁰Memory Aging and Cognition Centre, Departments of Pharmacology and Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
¹¹Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijimegen, the Netherlands
¹²Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
¹³Institute for Stroke and Dementia Research (ISD), LMU University Hospital, Munich, Germany
¹⁴Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston
¹⁵Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
¹⁶Now with National Institute of Neurological Disorders and Stroke Intramural Research Program, Bethesda, Maryland
¹⁷Johns Hopkins University School of Medicine, Baltimore, Maryland
¹⁸University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
¹⁹Intramural Research Program, National Institute on Aging, Baltimore, Maryland
²⁰Gerald Choa Neuroscience Centre, Lui Che Woo Institute of Innovative Medicine, Margaret K.L. Cheung Research Centre for Management of Parkinsonism, Division of Neurology, Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
²¹Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
²²Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam and the Netherlands and Brain Research Center Amsterdam, the Netherlands
²³Wolfson Centre for Prevention of Stroke and Dementia, Nuffield Department of Clinical Neurosciences, University of Oxford, NIHR Oxford Biomedical Research Centre, Departments of General (internal) Medicine and Geratology, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
²⁴Centre for Healthy Brain Ageing (CHeBA), University of New South Wales, Sydney, New South Wales, Australia
²⁵Department of Neurology, Clinical Division of Neurogeriatrics, Medical University Graz, Graz, Austria
²⁶Department of Neurology, University of Michigan, Ann Arbor
²⁷Centre for Clinical Brain Sciences, UK Dementia Research Institute Centre at the University of Edinburgh, Edinburgh, United Kingdom
²⁸Faculdade de Medicina, Department of Neurosciences and Mental Health, CHULN-Hospital de Santa Maria Instituto de Medicina Molecular (IMM) e Instituto de Saúde Ambiental (ISAMB), University of Lisbon, Lisbon, Portugal
²⁹Wolfson Centre for Prevention of Stroke and Dementia, Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
³⁰Stroke Research Centre, Department of Brain Repair and Rehabilitation, UCL Queen Square Institute of Neurology and the National Hospital for Neurology and Neurosurgery, London, United Kingdom
³¹Medical Image Analysis Center (MIAC AG) and Quantitative Biomedical Imaging Group, Department of Biomedical Engineering, University of Basel, Basel, Switzerland
³²Departments of Internal Medicine and Neurology, University of Michigan, Ann Arbor

JAMA Neurol. 2022;79(11):1187-1198. doi:10.1001/jamaneurol.2022.2262

Full Text

Abstract

Importance Cerebral small vessel disease (SVD) causes a quarter of strokes and is the most common pathology underlying vascular cognitive impairment and dementia. An important step to developing new treatments is better trial methodology. Disease mechanisms in SVD differ from other stroke etiologies; therefore, treatments need to be evaluated in cohorts in which SVD has been well characterized. Furthermore, SVD itself can be caused by a number of different pathologies, the most common of which are arteriosclerosis and cerebral amyloid angiopathy. To date, there have been few sufficiently powered high-quality randomized clinical trials in SVD, and inconsistent trial methodology has made interpretation of some findings difficult.

Observations To address these issues and develop guidelines for optimizing design of clinical trials in SVD, the Framework for Clinical Trials in Cerebral Small Vessel Disease (FINESSE) was created under the auspices of the International Society of Vascular Behavioral and Cognitive Disorders. Experts in relevant aspects of SVD trial methodology were convened, and a structured Delphi consensus process was used to develop recommendations. Areas in which recommendations were developed included optimal choice of study populations, choice of clinical end points, use of brain imaging as a surrogate outcome measure, use of circulating biomarkers for participant selection and as surrogate markers, novel trial designs, and prioritization of therapeutic agents using genetic data via Mendelian randomization.

Conclusions and Relevance The FINESSE provides recommendations for trial design in SVD for which there are currently few effective treatments. However, new insights into understanding disease pathogenesis, particularly from recent genetic studies, provide novel pathways that could be therapeutically targeted. In addition, whether other currently available cardiovascular interventions are specifically effective in SVD, as opposed to other subtypes of stroke, remains uncertain. FINESSE provides a framework for design of trials examining such therapeutic approaches.

Full Text

Framework for Clinical Trials in Cerebral Small Vessel Disease (FINESSE): A Review

Others Also Liked

Featured Articles

USPSTF Recommendation Statements

Blogs

Framework for Clinical Trials in Cerebral Small Vessel Disease (FINESSE): A Review

Read More About

Citation

Download citation file:

Others Also Liked

Select Your Interests