Table 1

Exemplar randomised controlled trials, and substudies where relevant, targeting people with cerebral small vessel disease including those with lacunar infarcts, white matter hyperintensities or sporadic intracerebral haemorrhage

Intervention	Trial	Target population	N	Outcome	FU (months)	Comment
Pharmacotherapy
Anti-inflammatory, minocycline	MINERVA69	LACI and WMH	44	BBB permeability, microglia activation	3	Completed
Antiplatelet, dual vs mono	SPS-36	LACI (on MRI)	2916	CASI	60	Neutral
BP lowering, perindopril±indapamide	PROGRESS70	Stroke (IS, ICH)	6105	Dementia, cognitive decline	47	Dementia/cognitive decline reduced
	PROGRESS47 71	Stroke (IS, ICH)	192	WMH	36	WMH progression reduced
BP lowering, telmisartan	PRoFESS54	Stroke (IS)	771	WMH	28	Neutral (but no BP difference)
BP lowering, intense v guideline	INFINITY43	WMH	199	Gait speed WMH	36	Neutral Reduced
	LEOPOLD (NCT02472028)	cSVD	820	WMH	36	Ongoing
	PODCAST72	IS, ICH	83	ACE-R	6–30	Neutral
	PRESERVE44	LACI+WMH	62/111	Cerebral perfusion	3	Neutral
	PRESERVE73	LACI+WMH	111	White matter diffusivity, cognition	24	Neutral (SBP −6.8 mm Hg)
	PROHIBIT-ICH (ISRCTN23416732)	ICH	112	MoCA	12	Ongoing
	SPRINT-MIND74	Hypertension (no diabetes/stroke)	9361	Dementia, cognitive impairment	40	Neutral, but less cognitive impairment
	SPRINT-MIND50	Hypertension (no diabetes/stroke)	454	WMH	48	Less increase in WMH volume, and more decrease in total brain volume (but diuretic effect?)
	SPS-36	LACI (on MRI)	2916	CASI	60	Neutral
GABA partial agonist (tramiprosate)	(NCT00056238)	CAA	24	Microbleeds	3	Neutral
Lipid lowering, pravastatin	PROSPER52	Vascular risk factors	535	New infarcts, WMH	33	Neutral
Lipid lowering, intense v guideline	PODCAST75	IS	77	ACE-R	6–30	Neutral. Post hoc analysis positive⁷⁵
Neurotransmission modulators (DL-3-n-butylphthalide)	(ChiCTR-TRC-09000440)76	cSVD+VCI	281	ADAS-cog, CIBIC-plus	5.5	Cognition and global functioning improved
Nitric oxide donor (ISMN)	LACI-111 35 77	LACI		Safety, tolerability	2	Safe, tolerable
	LACI-210	LACI	363	Feasibility	12	Composite, cognition, function
PDE3-I (cilostazol)	ECLIPSE78	Acute LACI	130	Pulsatility index, WMH	3	Reduced pulsatility index. Neutral for WMH
	LACI-111 35 77	LACI		Safety, tolerability	2	Safe, tolerable, WMH reduced
	LACI-210	LACI	363	Feasibility	12	Composite, cognition, function
	Lee et al 79	AD with WMH	36	WMH	6	Improved regional cerebral metabolism
PDE5-I (tadalafil)	PASTIS80	LACI/TIA+lacunes/WMH	55	Change in CBF	Single dose	Non-significant increase in CBF
Uric acid lowering (allopurinol)	XILO-FIST81	IS/TIA	464	WMH	24	Neutral, safe
Device
Remote ischaemic conditioning	Liao82	Subcortical VaD	37	Neuropsychological profile	6	Safe but neutral
Exercise
Aerobic dance	ADTSVD83	cSVD	110	Cognition, mood, mobility	6	Inconsistent benefits on memory and executive function
Multi-domain
Nurse-led multidimensional cardiovascular intervention	preDIVA84	Age 70–78 years	3526	Dementia and disability, WMH	80	Neutral on all outcomes. Cluster design, 116 practices

AD, Alzheimer’s disease; ADAS-cog, Alzheimer’s Disease Assessment Scale-Cognitive Subscale; ADCS-CGIC, Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change; BBB, blood-brain barrier; BMI, body mass index; BP, blood pressure; CAA, cerebral amyloid angiopathy; CASI, Cognitive Abilities Screening Instrument; CBF, cerebral blood flow; CIBIC-plus, Clinician’s Interview-Based Impression of Change Plus caregiver input; cSVD, cerebral small vessel disease; DSST, digit symbol substitution test; FU, follow-up; ICH, intracerebral haemorrhage; IS, ischaemic stroke; LDL-c, low density lipoprotein-cholesterol; MoCA, Montreal Cognitive Assessment; MRI-BOLD, MRI blood oxygenation level dependent; PDE3-I, phosphodiesterase-3 inhibition; PDE5-I, phosphodiesterase-5 inhibition; RCT, randomised controlled trial; SBP, systolic BP; TIA, transient ischaemic attack; VADAS-cog, Vascular Dementia Assessment Scale-Cognitive Subscale; WMD, white matter disease; WMH, white matter hyperintensities.