TY - JOUR
T1 - Framework for Clinical Trials in Cerebral Small Vessel Disease (FINESSE)
T2 - A Review
AU - Markus, Hugh S.
AU - van der Flier, Wiesje M.
AU - Smith, Eric E.
AU - Bath, Philip
AU - Biessels, Geert Jan
AU - Briceno, Emily
AU - Brodtman, Amy
AU - Chabriat, Hugues
AU - Chen, Christopher
AU - de Leeuw, Frank-Erik
AU - Egle, Marco
AU - Ganesh, Aravind
AU - Georgakis, Marios K.
AU - Gottesman, Rebecca F.
AU - Kwon, Sun
AU - Launer, Lenore
AU - Mok, Vincent
AU - O'Brien, John
AU - Ottenhoff, Lois
AU - Pendlebury, Sarah
AU - Richard, Edo
AU - Sachdev, Perminder
AU - Schmidt, Reinhold
AU - Springer, Melanie
AU - Tiedt, Stefan
AU - Wardlaw, Joanna M.
AU - Verdelho, Ana
AU - Webb, Alastair
AU - Werring, David
AU - Duering, Marco
AU - Levine, Deborah
AU - Dichgans, Martin
N1 - Funding Information: 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. Publisher Copyright: © 2022 American Medical Association. All rights reserved.
PY - 2022/11/14
Y1 - 2022/11/14
N2 - 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..
AB - 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..
UR - http://www.scopus.com/inward/record.url?scp=85136548051&partnerID=8YFLogxK
U2 - https://doi.org/10.1001/jamaneurol.2022.2262
DO - https://doi.org/10.1001/jamaneurol.2022.2262
M3 - Review article
C2 - 35969390
SN - 2168-6149
VL - 79
SP - 1187
EP - 1198
JO - JAMA Neurology
JF - JAMA Neurology
IS - 11
ER -