Design of Trials for Cerebral Small Vessel Disease and Vascular Cognitive Impairment

Background/Objectives: Cerebral small vessel disease (cSVD) and vascular cognitive impairment (VCI) are major contributors to stroke and dementia. Despite their importance, there are few effective treatments for cSVD and VCI. Variability in cSVD/VCI populations, intervention targets, and outcome selection may contribute to inconsistencies and challenges in clinical trial design. We reviewed the design of cSVD and VCI clinical trials to describe current practice in the selection of populations, interventions, and outcomes. Methods: We systematically searched Ovid Medline, Embase, and PsychInfo databases for recently completed cSVD/VCI trials and searched online trial registries (ClinicalTrials.gov, European Union Clinical Trials Register, and International Clinical Trials Registry Platform) for ongoing cSVD/VCI trials. We determined the use of specific categories of inclusion and exclusion criteria, interventions, and outcomes in the included trials and described these as counts and percentages. Results: We included a total of 82 cSVD trials and 120 VCI trials. Neuroimaging features were most frequently used as inclusion criteria for cSVD (88%) and cognition for VCI (88%). There was substantial variation in eligible ages for participation. Both cSVD and VCI trials largely excluded patients with comorbidities, vascular risk factors, and neuropsychiatric disorders, with a notable proportion of cSVD trials excluding on the basis of functional impairment. The most studied intervention classes were repurposed cardiovascular drugs (40%) for cSVD and Traditional Chinese Medicine (35%) in VCI. The most common primary outcome category was neuroimaging for cSVD (53%) and cognition for VCI (86%). Notably, functional outcomes were underused in both cSVD and VCI trials (13% and 12%, respectively, for primary outcomes). Conclusions: We have identified substantial variability in all aspects of cSVD and VCI clinical trial design. Inconsistent neuroimaging criteria and exclusions based on common long-term conditions limit the generalisability of findings. There is a need for greater focus on clinical outcomes, particularly functional ability, to better reflect treatment impact. Increased integration and standardisation of cSVD and VCI trial design is needed to accelerate progress in developing treatments.