Overview of human trials on neuroprotective agents in AIS

MechanismDrugTrialsStudy referencesOverall effect
NMDAR antagonistNA-1ESCAPE-NA1Hill et al. [8] 2020Negative overall, positive in patients without IV thrombolysis
Memantine-Beladi Moghadam et al. [11] 2021Positive in a small RCT
Aptiganel hydrochloride-Albers et al. [12] 2001Negative
AR-R15896AR-Lees et al. [13] 2001, Diener et al. [14] 2002Negative
SelfotelASSISTDavis et al. [15] 2000Negative
LubeluzoleSRMA of 5 trialsGandolfo et al. [16] 2002Negative
Gavestinel-Lees et al. [17] 2001Negative
GV150526-Lees et al. [18] 2000, Dyker and Lees [19] 1999Negative
Licostinel-Albers et al. [20] 1999Negative
Neu2000SONIC (ongoing)Hong et al. [21] 2018Ongoing
DAMPs antagonistZK 200775-Walters et al. [22] 2005Negative
GABA agonistClomethiazoleCLASS-ILyden et al. [23] 2002Negative
MagnesiumMagnesiumIMAGES, FAST-MAGIMAGES study investigators [24], Shkirkova [25] 2017, Afshari et al. [26] 2013Positive in 1 small RCT, negative in 2 larger RCTs
Free radical scavengersEdaravoneECCS-AIS, EDO, TASTEZheng and Chen [27] 2016, Sharma et al. [28] 2011, Enomoto et al. [29] 2019, Mitta et al. [30] 2012, Shinohara et al. [31] 2009, Xu et al. [32] 2021Positive
NXY-059SAINT I and IIDiener et al. [33] 2008, Shuaib et al. [34] 2007, Lees et al. [35] 2006Negative overall
Citicoline-Clark et al. [36] 1999, Agarwal et al. [37] 2022, Warach et al. [38] 2000, Dávalos et al. [39] 2002, Kuryata et al. [40] 2021Positive
Calcium channel blockersNimodipineSRMA of 12 trials, The American Nimodipine StudyThe American Nimodipine Study Group [41] 1992Negative overall, positive for 120 mg within 18 h in one trial
VerapamilSAVER-1Fraser et al. [42] 2017Safe and feasible, no efficacy data
Immune system modulationNatalizumabACTION IIElkind et al. [43] 2020Negative, reduced good outcome
MAPCMASTERSHess et al. [44] 2017Negative overall, positive < 36 h
MinocyclineSRMA of 7 small trialsNaderi et al. [45] 2020, Malhotra et al. [46] 2018Positive
Imatinib-Wahlgren et al. [47] 2017-
AntioxidantsNAC-Sabetghadam et al. [48] 2020Positive
co-ultraPEALut-Caltagirone et al. [49] 2016Positive compared to baseline in an observational study
ButylphthalideBASTZhang et al. [50] 2022Positive in observational study, ongoing RCT
HUKRESKNi et al. [51] 2021Positive, not placebo-controlled
MelatoninSRMA of 6 trialsRamos et al. [52] 2020Negative
Uric acidURICO-ICTUSChamorro et al. [53] 2014Negative
AlbuminALIASGinsberg et al. [54] 2013-
Hypoglycaemic agentsInsulinSHINEJohnston et al. [55] 2019Negative comparing intensive vs. standard glucose control
Glibenclamide-Caffes et al. [56] 2015Positive in retrospective study
GlyburideGAMES, GAMES-RPSheth et al. [57, 58] 2014, 2016Negative
OthersStatinsSRMA of 22 observational studies, ASSORTMontaner et al. [59] 2008, Yoshimura et al. [60] 2017, Guo et al. [61] 2021Negative in RCT, positive in SRMA of observational studies
CerebrolysinSRMA of 6 trialsWang et al. [62] 2017Negative
PiracetamSRMA of 3 trialsRicci et al. [63] 2012Negative
Theophylline-Modrau et al. [64] 2020Positive on NIHSS
GTNSRMA of 5 trials, MR ASAP trialBath et al. [65] 2016, van den Berg et al. [66] 2022Negative overall
EpoEpo strokeEhrenreich et al. [67] 2009Negative
DDFPe-Culp et al. [68] 2019Positive but small sample size
OtaplimastatSAFE-TPAKim et al. [69] 2020Negative
3K3A-activated protein CRHAPSODYLyden et al. [70] 2019Possible reduction in hemorrhagic rate
Dapsone-Nader-Kawachi et al. [71] 2007Positive in pilot trial

IV: intravenous; RCT: randomized controlled trial; ASSIST: acute stroke studies involving selfotel treatment; SRMA: systematic review and meta-analysis; SONIC: safety and optimal neuroprotection of neu2000 in AIS; GABA: gamma-aminobutyric acid; CLASS-I: clomethiazole acute stroke study in ischemic stroke; IMAGES: IV magnesium efficacy in stroke; FAST-MAG: field administration of stroke therapy-magnesium; ECCS-AIS: edaravone-citicoline comparative study in AIS; EDO: edaravone versus sodium ozagrel in acute noncardioembolic ischemic stroke; TASTE: treatment of AIS with edaravone dexborneol; NXY: disodium 2,4-sulphophenyl-N-tert-butylnitrone; SAINT: stroke-acute ischemic NXY treatment trial; SAVER: surgical anterior ventricular restoration; ACTION: safety and efficacy of IV natalizumab in AIS; MAPC: multipotent adult progenitor cells; MASTERS: MAPC in AIS; co-ultraPEALut: co-ultramicronized palmitoylethanolamide/luteolin; NAC: N-acetylcysteine; BAST: butylphthalide for patients who had acute ischaemic stroke receiving IVT or EVT; RESK: re-evaluate the efficacy and safety of HUK; URICO-ICTUS: safety and efficacy of uric acid in patients with acute stroke; ALIAS: High-dose albumin treatment for acute ischaemic stroke; SHINE: the stroke hyperglycemia insulin network effort; GAMES: glyburide advantage in malignant edema and stroke; GAMES-RP: GAMES-remedy pharmaceuticals; ASSORT: administration of statin on AIS patient; NIHSS: National Institutes of Health Stroke Scale; GTN: glyceryl trinitrate; MR ASAP: multicentre randomised trial of acute stroke treatment in the ambulance with a nitroglycerin patch; Epo: erythropoietin; DDFPe: dodecafluoropentane; SAFE-TPA: safety and efficacy of otaplimastat in patients with AIS requiring TPA; RHAPSODY: safety evaluation of 3K3A-APC in ischemic stroke