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Review
. 2022 Nov 1;79(11):1187-1198.
doi: 10.1001/jamaneurol.2022.2262.

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

Hugh S Markus  1 , Wiesje M van Der Flier  1 , Eric E Smith  2 , Philip Bath  3 , Geert Jan Biessels  4 , Emily Briceno  5 , Amy Brodtman  6   7   8 , Hugues Chabriat  9 , Christopher Chen  10 , Frank-Erik de Leeuw  11 , Marco Egle  12 , Aravind Ganesh  2 , Marios K Georgakis  13   14   15 , Rebecca F Gottesman  16   17 , Sun Kwon  18 , Lenore Launer  19 , Vincent Mok  20 , John O'Brien  21 , Lois Ottenhoff  22 , Sarah Pendlebury  23 , Edo Richard  11 , Perminder Sachdev  24 , Reinhold Schmidt  25 , Melanie Springer  26 , Stefan Tiedt  13   15 , Joanna M Wardlaw  27 , Ana Verdelho  28 , Alastair Webb  29 , David Werring  30 , Marco Duering  13   15   31 , Deborah Levine  32 , Martin Dichgans  13   15
Affiliations
Review

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

Hugh S Markus et al. JAMA Neurol. .

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Markus reported grants from University of Cambridge LMU during the conduct of the study. Dr van der Flier reported grants from Health~Holland during the conduct of the study; grants from ZonMW, NWO, Alzheimer Nederland, Hersenstichting, CardioVascular Onderzoek Nederland, Philips, Biogen, Novartis, Roche, Life-MI, AVID, Fujifilm, Combinostics, Alzheimer & Neuropsychiatrie Foundation, Dioraphte Foundation, Gieskes-Strijbis, Equilibrio, Edwin Bouw, and Pasman outside the submitted work; has performed contract research for Biogen and Boehringer Ingelheim (all funding is paid to her institution); has been an invited speaker at Boehringer Ingelheim, Biogen, Danone, Eisai, WebMD Neurology (Medscape), and Springer Healthcare (all funding is paid to her institution); is consultant to Oxford Health Policy Forum, Roche, and Biogen (all funding is paid to her institution); participated in advisory boards of Biogen and Roche (all funding is paid to her institution); is member of the steering committee of PAVE and Think Brain Health; served as associate editor of Alzheimer, Research & Therapy in 2020 and 2021; and is associate editor of Brain. Dr Smith reported personal fees from Eli Lilly and Company, Biogen, Bayer, and Cyclerion (consulting) outside the submitted work. Dr Bath reported personal fees from Phagenesis, Moleac, and DiaMedica outside the submitted work. Dr Briceno reported grants from the National Institutes of Health during the conduct of the study. Dr Brodtmann reported grants from Heart Foundation Future Leader Fellowship during the conduct of the study and personal fees from Biogen Australia and Roche Australia outside the submitted work. Dr Chabriat reported grants from Agence Nationale de la Recherche during the conduct of the study and personal fees from HOVID outside the submitted work. Dr Ganesh reported grants from Canadian Cardiovascular Society, Alberta Innovates, Canadian Institutes of Health Research, the University of Calgary, Campus Alberta Neuroscience, Sunnybrook Research Institute INOVAIT, the Government of Canada–New Frontiers in Research Fund, and Microvention; stock options from TheRounds.com, SnapDx, Advanced Health Analytics; personal fees from MD Analytics, MyMedicalPanel, Creative Research Designs, Figure 1, CTC Communications Corp, Atheneum, DeepBench, Research on Mind, and Alexion outside the submitted work; a patent for US 17/317,771 pending for a system to deliver remote ischemic conditioning or other cuff-based therapies; and is on the editorial board of journals Neurology: Clinical Practice, Neurology, Stroke, and Frontiers in Neurology. Dr Gottesman is a former associate editor of Neurology. Dr O’Brien reported grants from Medical Research Council during the conduct of the study; personal fees from TauRX, Axon, GE Healthcare, Novo Nordisk, Roche, and Biogen; nonfinancial support from Alliance Medical; and grants from MSD outside the submitted work. Dr Sachdev reported personal fees from Biogen Australia and Roche Australia outside the submitted work. Dr Springer reported grants from National Institutes of Health during the conduct of the study. Dr Wardlaw reported grants from British Heart Foundation and UK Medical Research Council during the conduct of the study; grants from Fondation Leducq, EU Horizon 2020, and Stroke Association outside the submitted work; and is author on a Guideline for Clinical Management of Cerebral Small Vessel Disease supported by the European Stroke Organisation. Dr Werring reported personal fees from Bayer, Alnylam, Alexion, and Novo Nordisk outside the submitted work. Dr Duering reported personal fees from Roche Pharma, Sanofi Genzyme, and Bayer outside the submitted work. Dr Levine reported grants from National Institutes of Health outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.
Different Radiological Features of Small Vessel Disease Visible on Magnetic Resonance Imaging (MRI) DTI indicates diffusion tensor imaging; DWI, diffusion-weighted image; FLAIR, fluid-attenuated inversion recovery; FLASH, fast low-angle shot; MD, mean diffusivity; WMH, white matter hyperintensities.
Figure 2.
Figure 2.
Flowchart Highlighting Key Points in Design of Clinical Trials in Small Vessel Disease (SVD) DTI indicates diffusion tensor imaging; MRI, magnetic resonance imaging.
See this image and copyright information in PMC

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