Table 3.

Clinical trials of immunomodulation after stroke. A summary of clinical trials targeting various aspects of the immune system after stroke. Studies are grouped by general mechanism of action of the pharmacological agent. Studies were not included if they did not have placebo or conventional therapy control arms

Drug; target	Study cohort	Treatment regimen	Outcome evaluation	Trial results	Ref.
Enlimomab: anti-ICAM-1 monoclonal antibody	32 patients with ischemic or hemorrhagic stroke	IV loading dose within 24 h of symptom onset; followed by 4 daily doses ranging from 140 to 480 mg	Risk of adverse events 30 days post-stroke	No change in risk of adverse events with increasing dose	[211]
	625 patients with ischemic stroke enlimomab (n = 317) or placebo (n = 308)	Treatment within 6 h of stroke onset given over 5 days	mRS evaluated at baseline and on days 5 and 90 after initiation of treatment; 6 and 12 months	Worse outcomes	[212]
Fingolimod:S1P analog	23 patients with primary supratentorial ICH	0.5-mg oral dose for 3 days within 72 h of stroke	Stroke volume (MRI), GCS and NIHSS at 7 days and 3 months post-stroke	Drug was safe and well tolerated, reduced stroke volume and improved neurological outcomes at 3 months post-stroke	[213]
	22 patients with AIS; n = 11 fingolimod, n = 11 placebo	0.5-mg oral dose for 3 days over 4.5 h post-stroke	Circulating lymphocyte counts, neurological function (NIHSS) 7 days post-stroke	Safe and well-tolerated, attenuated neurological deficit and promoted recovery	[214]
	22 patients with hemispheric ischemic stroke	0.5 mg for 3 days with alteplase, within 4.5 h of stroke	Circulating lymphocytes, lesion volumes, NIHSS score at 7 days and 90 days post-stroke	Combination therapy was well-tolerated, attenuated reperfusion injury and improved NIHSS scores 90 days post-stroke	[215]
Natalizumab: anti-α4-integrin monoclonal antibody	161 patients with acuteischemic stroke natalizumab (n = 79) or placebo (n = 82)	Administered a single IVinfusion up to 9 h after stroke	NIHSS, mRS, BI, SIS-16, and MoCA scores assessed at baseline (5 days post-stroke), 24 h, and days 5, 30, and 90 post-stroke	No change in infarct size; slight improvement in cognition at 90 days post-stroke	[216]
Anakinra: human recombinant IL-1 receptor antagonist	34 patients	100 mg IV loading dose over 60 s, followed by 2 mg/kg/h infusion over 72 h, within 6 h of stroke	NIHSS score; adverse events up to 90 days; 5–7 days infarct volume measured by CT	Drug is safe and well tolerated; improved outcomes at 90 days in patients with cortical stroke	[78]
	80 patients with AIS	Subcutaneous administration of 100 mg twice daily for 3 days within 5 h of stroke	Levels of inflammatory markers by 7 days post-stroke; mRS, survival, and length of stay at 90 d post-stoke	Drug is safe and well tolerated; reduces inflammatory markers in plasma by 3 days post-stroke	[79]
UK-279,276: recombinant glycoprotein with selective binding to CD11b	966 patients with stroke (887 ischemic)	Patients received 1 of 15 doses ranging from 10 to 120 mg treated within 6 h of stroke	SSS score from baseline to 30 days post-stroke	No effect; terminated early; no difference in adverse events	[217]
Fasudil: Rho kinase inhibitor	160 patients with AIS	IV: 60-mg dose over 60 min, twice daily for 14 days within 48 h of stroke	JSS score at end of treatment and mRS score 30 days post-stroke	Improved clinical outcomes at 14 days, and 30 days post-stroke	[218]
Minocycline: semi-synthetic tetracycline antibiotic	152 patients with AIS; n = 74 minocycline, n = 77 placebo	200-mg oral dose for 5 days; 6–24 h post-stroke	NIHSS, mRS, and BI score at 90 d post-stroke	Improved scores on days 7 and 30 post-stroke	[219]
	60 patients with AIS; 41 at 10 mg/kg dose	IV dose of 3, 4.5, 6, or 10 mg/kg dailyover 72 h; within 6 h of stroke	Adverse events	Safe and well tolerated	[220]
	139 patients with AIS; n = 69 minocycline, n = 70 placebo	Oral dose 3–48 h post-stroke	NIHSS, mRS, BI score, and vascular outcomes at 90 days post-stroke	No change in functional outcomes	[221]
Simvastatin: HMG-CoA reductase inhibitor	60 patients with cortical strokes; n = 30 simvastatin, n = 30 placebo	40 mg/day for 1 week; followed by 20 mg/day for 3 months; 3–12 h after stroke	Plasma markers of inflammation, neurological outcome (NIHSS and mRS)	No effect on plasma markers; improved neurological outcomes, but increased rates of mortality and infection	[222]
NXY-059: free radical trapping agent	1722 patients with AIS	72-h IV infusion; 6 h after stroke	mRS and NIHSS score 90 days post-stroke	mRS score improved at 90 days post-stroke; no effect on NIHSS score	[223]
	5028 patients with AIS	IV infusion within 6 h of stroke	mRS sore 90 days post-stroke	No effect	[224]
Tirilazad: lipid peroxidation inhibitor	1757 patients with AIS	Administered within 24 h	GOS and BI scores	Treatment increases risk of death or disability	[225]
Ebselen: antioxidant	302 patients with AIS; n = 151 ebselen, n = 149 placebo	150-mg granules for 2 weeks, within 48 of stroke	GOS, mMS, and BI scores at 1 and 3 months post-stroke	Treatment improves neurological outcomes at 1 month but no difference at 3 months	[226]

AIS: acute ischemic stroke; BI: Barthel Index; CT: computerized tomography; GOS: Glasgow outcome system; HMG-CoA: β-hydroxy β-methylglutaryl-CoA; ICAM: intracellular adhesion molecule; ICH: intracerebral hemorrhage; IV: intravenous; JSS: Motor System of Japan Stroke Scale; mg: milligram; mMS: modified Matthew Scale; MoCA: Montreal Cognitive Assessment; mRS: Modified Rankin Scale; MS: Matthew scale of neurological deficit; NIHSS: National Institute of Health Stroke Scale; NMDA: N-methyl-d-aspartic acid; SIS-16: Stroke Impact scale-16; SSS: Scandinavian stroke scale