Table 3.

Clinical trials of Neuro-Immunomodulatory therapies.

Drug	Subject	Treatment	Effects	Reference
IL-1
recombinant human IL-1 receptor antagonist (rhIL-1Ra)	Patients with acute stroke (<6 h)	An intravenous injection of a 100 mg bolus of rhIL-1Ra was followed by a continuous infusion of 2 mg/kg per hour for 72 h.	rhIL-1Ra can partially rescue the inhibition of peripheral innate immune system in the acute phase of stroke.	[154]
rhIL-1Ra (anakinra)	Patients with acute stroke (<5 h)	A subcutaneous injection of 100 mg of rhIL-1Ra (anakinra) was administered twice daily for a duration of 3 days.	RhIL-1Ra treatment decreased plasma inflammatory markers, but it did not have an effect on the modified Rankin Scale (mRS) score at three months.	[155]
TNF
Etanercept	Chronic stroke patients (3–120 months)	Etanercept was administered via perispinal, interspinous, and extrathecal injection at a dose of 25 mg.	The intervention resulted in improvements in motor impairment, spasticity, sensory impairment, cognition, psychological/behavioral function, aphasia, and pain.	[156]
Etanercept	Chronic stroke patients (13–36 months)	25 mg of Etanercept was injected via perispinal, interspinous, and extrathecal ways.	Neurological improvement in all patients	[157]
Etanercept	Patients with stroke occurred between 1 and 5 years	Perispinal administration	Ongoing trial	ACTRN12620001011976
Microglia
Minocycline	patients	i.v. 100 mg minocycline injection at 24 h after a stroke	Safe but not efficacious	[158]
leukocyte infiltration
Natalizumab	AIS patients, double-blind, phase 2 study	300 mg i.v. Injection	Natalizumab administered up to 9 h after stroke onset did not halt infarct growth	[125]
anti-ICAM-1 (Enlimomab)	IS patients (within 6 h)	Enlimomab on the first day followed by a maintenance bolus of 40 mg of Enlimomab over 5 min or placebo for 4 days	Enlimomab is not an effective IS treatment	[159]
Fingolimod
	Randomized, open-label, evaluator-blind, multicenter pilot trial	Fingolimod and alteplase combination orally once daily for 3 consecutive days	The administration of the combined therapy was well-tolerated and resulted in a reduction of reperfusion injury, ultimately leading to an improvement in clinical outcomes among patients diagnosed with acute IS.	[128]
	Open-label, evaluator-blind, parallel-group clinical pilot trial	Within 72 h of disease onset, Fingolimod was administered orally.	The intervention was safe and resulted in a limited amount of secondary cerebral injury from baseline to day seven. Additionally, it led to decreased leakage from microvessels, attenuated neurological deficits, and facilitated neuronal repair.	[160]
Edaravone dexborneol
	Phase III RCT, AIS patients	14-day infusion of edaravone dexborneo injection, first injection within 48 h	Higher rate of mRS ≤1 on day 90, and greater reduction in NIHSS	[131]
	phase II study	30 min i.v. Infusion every 12 h, for 14 consecutive days	Safe and well tolerated at all doses, although no significant neurological improvement at day 90	[132]
	Phase IV study	Not reported	Ongoing trial	ChiCTR2100053196 ChiCTR2100045950 ChiCTR2100048153
	Phase IV study	30 mg/7.5 mg twice daily i.v. Injection for 12 ± 2 days	Ongoing trial	ChiCTR2100048812
Dimethyl Fumarate	Phase II study	Dimethyl fumarate 240 mg orally, twice daily for 3 consecutive days	Ongoing trial	NCT04891497 NCT04890366 NCT04890353
Methylprednisolone + prednisolone	Phase III study	Methylprednisolone 20 mg/kg i.v. Infusion daily for 5 consecutive days followed by a 4-week course of tapering Prednisolone orally once daily	Ongoing trial	NCT03249844

Abbreviations: AIS: acute ischemic stroke (IS); ICAM-1: intercellular adhesion molecule-1; mRS: the Modified Rankin Scale; NIHSS: the National Institutes of Health Stroke Scale; rhIL-1Ra: recombinant human IL-1 receptor antagonist; RCT: randomized clinical trial.