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

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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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Article Information

Accepted for Publication: June 17, 2022.

Published Online: August 15, 2022. doi:10.1001/jamaneurol.2022.2262

Corresponding Author: Hugh S. Markus, DM, Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, Cambridgeshire CB2 0QQ, United Kingdom (hsm32@medschl.cam.ac.uk); Martin Dichgans, MD, Institute for Stroke and Dementia Research, LMU University Hospital, Feodor-Lynen Str 17, Munich 81377, Germany (martin.dichgans@med.uni-muenchen.de).

Author Contributions: Drs Markus and Dichgans had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Markus, Smith, Biessels, Brodtmann, Chen, Egle, Ganesh, Gottesman, Launer, Mok, O’Brien, Ottenhoff, Pendlebury, Schmidt, Webb, Werring, Levine, Dichgans.

Acquisition, analysis, or interpretation of data: van der Flier, Bath, Briceno, Brodtmann, Chabriat, de Leeuw, Ganesh, Georgakis, Kwon, Launer, Mok, Richard, Sachdev, Springer, Tiedt, Wardlaw, Verdelho, Werring, Duering, Levine, Dichgans.

Drafting of the manuscript: Markus, Smith, Biessels, Brodtmann, Mok, Ottenhoff, Schmidt, Tiedt, Wardlaw, Webb, Levine, Dichgans.

Critical revision of the manuscript for important intellectual content: van der Flier, Bath, Biessels, Briceno, Brodtmann, Chabriat, Chen, de Leeuw, Egle, Ganesh, Georgakis, Gottesman, Kwon, Launer, Mok, O’Brien, Pendlebury, Richard, Sachdev, Schmidt, Springer, Tiedt, Wardlaw, Verdelho, Werring, Duering, Levine, Dichgans.

Statistical analysis: Webb.

Obtained funding: Markus, Launer, O’Brien.

Administrative, technical, or material support: Chabriat, Egle, Georgakis, Wardlaw, Levine.

Supervision: Markus, Brodtmann, de Leeuw, Kwon, Launer, Mok, Tiedt.

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.

Funding/Support: The workshops were supported by an LMU-University of Cambridge joint funding initiative. Profs Markus and O’Brien are supported by the National Institutes of Health Research Cambridge Biomedical Research Centre (grant BRC-1215-20014) and Dr Pendlebury is supported by the National Institutes of Health Research Oxford Biomedical Research Centre. Dr Tiedt is supported by the Corona Foundation and received funding from the Deutsche Forschungsgemeinschaft (grant 413635475) and the Munich Clinician Scientist Program of LMU Munich. Dr Levine was supported by the National Institutes of Health (grants R01 NS102715, R01 AG051827, and RF1 AG068410). Dr Launer is supported by the Intramural Research Program, National Institute on Aging. Dr van der Flier is supported by the Pasman stichting. Ms Ottenhoff is appointed on OTAPA, a collaboration cofunded by the PPP Allowance made available by Health~Holland and Brain Research Center (grant LSHM19051). Dr Ganesh reports funding from Alberta Innovates, the Canadian Institutes of Health Research, the Canadian Cardiovascular Society, the Sunnybrook Research Institute INOVAIT program, and the University of Calgary. Prof Wardlaw is supported by the UK Dementia Research Institute, which receives its funding from DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK and by the British Heart Foundation, the Stroke Association, the Fondation Leducq, the EU Horizon 2020, and Row Fogo Charitable Trust. Dr Chen is funded by the National Medical Research Council of Singapore. Dr Georgakis is supported by a Walter-Benjamin fellowship from the German Research Foundation (grant 3461/1-1). Dr Springer is funded by the National Institute of Neurological Disorders and Stroke (grant K01 NS117555). Dr Chabriat is funded by RHU TRT_cerebral small vessel diseases (Agence Nationale de la Recherche grant, Recherche Hospitalo-Universitaire TRT_cSVD; ANR:16-RHUS-0004) and Association de Recherche en Neurologie Vasculaire. Dr Dichgans is supported by the European Union’s Horizon 2020 research and innovation program No 666881, SVDs@target, the Munich Cluster for Systems Neurology (EXC 2145 SyNergy [ID 390857198]), and the Vascular Dementia Research Foundation.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The opinions expressed in this article are the authors’ own and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the US government.

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