Table 2.

Interventions, outcome measures, and results in neuroprotective trials.

Agent	Method and duration of administration	Primary outcome measures	Secondary outcome measures	Results	Significant safety issues?
Ebselen	Oral administration <12 h of stroke onset, continued for 14 days	- CT infarct volume at 30 days - GOS at 30 days	- Modified Mathew scale at 30 days	No significant differences in primary or secondary outcomes in ITT analysis	No
Nalmefene	60 mg IV bolus dose of nalmefene followed by 50 mg continuous infusion for 24 h, started <12 h of stroke	- Proportion of patients with BI ≥ 60 at 3 months and a rating “moderate disability” or better on the GOS at 3 months	- NIHSS at 3 months - NIHSS success rate (≥4 points decrease from baseline) at 3 months - Success rates for BI at 3 months, GOS at 3 months, and combined BI+GOS at 3 months by patient age (< or ≥ 70 years)	Primary outcome did not differ for nalmefene treatment (66.9%) vs. placebo (62.3%) (p = 0.46). No treatment effect after 3 months on any of the outcome measures	No
Gavestinel	1,800 mg IV administered over three days started <6 h of stroke onset	- BI at 3 months, trichotomized to “independent = 95–100”, “assisted independence = 60–90” and “dependence = 0–55”	- BI at 7 days and 1 month - NIHSS at 1 and 3 months - mRS at 1 and 3 months	No improvement on BI trichotomy (p = 0.79), BI score 95–100 was 39% in gavestinel group vs. 37% in placebo. No difference in 3-month survival (Kaplan-Meier, p = 0.11). No other secondary outcome suggested benefit from gavestinel.	No
Clomethiazole	68 mg/kg IV in 24 h started <12 h of stroke	- Deaths - Adverse and serious adverse events	- BI - NIHSS - SSS - mRS	SAE 48 in treated group vs. 47 in placebo group, no significant differences in functional outcome	No
UK 279,276	Single IV infusion over 15 min <6 h of stroke onset	- SSS change baseline to 90 days	- NIHSS change baseline to 90 days - BI at 90 days - mRS at 90 days	No improved outcome on any of the efficacy parameters (posterior probability of futility, 0.89). The trial was stopped early for futility.	No
Uric acid	500 or 1,000 mg IV over 90 min started <3 h of stroke	- Safety at 90 days, primary safety end point was the rate of gout attack	- Mean NIHSS at 90 days - mRS at 90 days - vascular death at 90 days	No SAE in uric acid treated group. No significant difference in NIHSS (p = 0.24), mRS (p = 0.26) or vascular death (p = 0.58)	No
NXY-059	IV infusion over 72 h started <6 h of stroke onset	- Distribution of disability scores on the mRS at 90 days	- Neurologic and activities of daily living scores - Risk of Alteplase related hemorrhage	The distribution of scores was not different in the group treated with NXY-059 compared with placebo (OR for limiting disability 1.02; 95% CI, 0.92–1.13, P = 0.682). No decrease in rates of hemorrhage in IVT treated patients.	No
Erythropoietin	40.000IU IV at 0, 24, and 48 h after stroke, started <6 h of stroke onset	- BI at 90 days	- mRS at day 90 - NIHSS at day 90 - MRI variables	No effect om primary outcome (ITT: EPO vs. placebo: 56.9 ± 42 vs. 59.2 ± 41; 95% CI,−4.41 to 9.86; P = 0.45). Subgroup analysis shows improved delta NIHSS (day 1 minus day 90) in EPO group in the PP non-rtPA group vs. placebo (mean difference of 5.3 ± 5.3 in EPO vs. 3.2 ± 6.4 placebo; P <0.03)	More deaths in the EPO group (16.4 vs. 9.0%; OR, 1.98; CI, 1.16–3.38; P <0.01)
Repinotan	Continuous 72-h intravenous infusion started within 4.5 h of stroke onset	- BI ≥85 at 3 months	- mRS 0,1, or 2 at 3 months - NIHSS decrease ≥4 points at 3 months	BI ≥85 in 37.1% (repinotan) vs. 42.4% (placebo), (CMH probability value = 0.149). mRS 32.2 vs. 37.1% (CMH = 0.169). NIHSS decrease ≥4 66.7 vs. 69.6% (CMH = 0.413)	No
Hypothermia	24 h of endovascular cooling to 33°C followed by 12 h of controlled rewarming/normothermia started <6 h of stroke onset	- SAE at 3 months - Achievement of cooling to 33°C	- Incidence of hemorrhage at 36 h - Mortality at 90 days - NIHSS at 1, 30, and 90 days - mRS 0 or 1 at 90 days	Cooling was achieved in all but 2 patients due to technical difficulties. mRS 0 or 1 at 3 months 18% (hypothermia) vs. 24% (normothermia) (p <0.77). NIHSS mean at 90 days: 6.3 vs. 3.8 (p = 0.355)	Pneumonia more frequent after hypothermia (50 vs. 10%, p = 0.001)
Cerebrolysin	Intravenous infusion for 10 days started <12 h of stroke onset	- BI, mRS, and NIHSS evaluated in 1 global test at 90 days	- Responder analysis based on responder definitions for mRS, BI, and NIHSS.	Median NIHSS improvement of 6 (vs. 5 placebo), median BI improvement of 30 points (vs. 30 points), and final mRS 2 (vs. 2). No significant differences.	No
Albumin	2 g/kg IV administration over 2 h, started within 90 min of IV Alteplase	- Favorable outcome at 90 days defined as mRS 0 or 1, NIHSS 0 or 1, or both	- mRS - NIHSS - BI - Stroke specific QOL scale - Trailmaking A and B test	Favorable outcome at 90 days 44% (albumin) vs. 44% (placebo). RR 0.96 (CI 0.84–1.10). No significant differences in any of the secondary outcome measures	More pulmonary oedema and congestive heart failure in albumin treated group (13 vs. 1%, RR10.8 CI 4.37–26.72)
Cerebrolysin	IV administration in 30 min, continued for 10 consecutive days, started directly after IVT	- mRS at 90 days - Responder analysis (mRS 0 or 1 vs. 2–6)	- NIHSS change - BI - GOS	No significant differences in mRS (p = 0.629), NIHSS change (p = 0.981), BI (p = 0.988) or GOS (p = 0.845) at 90 days including responder analyses	No
Remote ischemic perconditioning	4 cycles of inflation/deflation during ambulance transport	- Penumbral salvage, defined as the volume of the perfusion–diffusion mismatch not progressing to infarction after 1 month.	- Final infarct size - Infarct growth - Clinical outcome at 3 months	Penumbral salvage (11.89 vs. 14.10 ml p = 0.20), final infarct size at 1 month (1.63 vs. 1.99 ml p = 0.97), infarct growth between baseline and 1 month (0 vs. 0.02 ml p = 0.79), and clinical outcome after 3 months did not differ among groups.	No
Magnesium	IV loading dose of magnesium sulfate followed by 24 h continuous infusion, started within 2 h of stroke onset	- mRS at 90 days	- Excellent outcome defined as mRS 0 or 1, NIHSS 0 or 1, BI ≥ 95, or GOS 1 at 90 days - Good outcome defined as modified Rankin score ≤ 2, Barthel Index ≥60, NIHSS score ≤ 8, and GOS score of 1 or 2 - Neurological deficit at 90 days (NIHSS)	No significant shift in mRS between magnesium treated patients and placebo (p = 0.28), no difference in mean mRS at 90 days (2.7 vs. 2.7, p = 1.00). No benefit of magnesium in prespecified secondary end points.	No
Transdermal Glyceryl Trinitrate	Single dose of transdermal glyceryl trinitrate within 6 h of stroke onset	- mRS at 90 days	- Intracerebral hemorrhage at 7 days - Recurrent stroke - NIHSS - SSS	mean mRS score 2.6 vs. 3.2, mean difference 0.65 (CI 0.22–1.08 p = 0.003). No significant treatment effect of glyceryl trinitrate in specified subgroups including use of Alteplase.	No
Simvastatin	Oral simvastatin 40 mg once daily for 90 days, started <12 h of stroke onset	- Proportion of independence defined as mRS ≤ 2 at 90 days	- NIHSS reduction at 90 days - Proportion of patients with NIHSS reduction ≤ 4 points at 7 days	Proportion of patients with mRS ≤ 2 at 90 days: 68.8% (simvastatin) vs. 70% (placebo), OR 0.99 (CI 0.35–2.76, p = 0.98). No significant differences in secondary outcomes.	No
Imatinib	Oral imatinib in three dose levels (400;600;800 mg) for 6 days	- Adverse events	- Hemorrhagic transformation - Infarct volume - Cerebral oedema - NIHSS at day 7 - mRS 0–2 at 90 days	- NIHSS improvement per dose group compared with controls, adjusted for EVT (low, median, high): 2 (p = 0.259), 3 (p = 0.106), 5 (p = 0.012) - mRS 0–2 72% (all treatment groups) vs. 61% controls (p = 0.296)	No
Epigallocatechin gallate	500 mg of epigallocatechin administered simultaneously with IVT, as a 10% bolus followed by continuous infusion of 1 h daily, for a total of 7 days.	- NIHSS at 1 day - NIHSS at 7 days	- Plasma levels MMP-2 and MMP-9 at day 1 and 7	No significant differences in early treated patients (0–3 h), NIHSS shift in favor of epigallocatechin in patients treated 3–5 h after onset, though no p-values reported.	No
Uric acid	1,000 mg intravenous infusion	- Rate of good outcome defined as mRS 0–2 at 90 days	- Shift analysis mRS - BI ≥ 95 at 90 days - NIHSS increment ≥ 4 points - Infarct growth - Infarct volume	mRS 0–2, 67% (uric acid) vs. 48% (placebo) (adjusted OR 6.12 95% CI 1.08−34.56). No significant shift in mRS. BI ≥ 95 67 vs. 43% (adjusted OR 9.20 95% CI 1.53 – 55.20). Infarct volume was nonsignificantly smaller in uric acid group, but infarct growth was reduced.	No
3K3A-APC	Intravenous administration of 3K3A-APC in different dose tiers up to 540 ug/kg, started after IVT	- Dose limiting toxicities	- Hemorrhage at 30 days - Microbleed incidence at 30 days - mRS 0 or 1 at 90 days - BI ≥ 90 at 90 days	- No difference in prespecified dose limiting toxicities (p = 0.43) - No difference in 90-day mRS, including all dose tiers together (45.2% treatment vs. 62.8% placebo). - No difference in BI ≥ 90 at 90 days 76.9 vs. 91.9%. ]-No difference in hemorrhage (p = 0.54) or microbleeds in infarct zone (p = 0.28)	No
Dodecafluoropentane	3 intravenous doses, 1 every 90 min, started <12 h of stroke onset	- SAE - NIHSS - mRS		mRS at 30 and 90 days significantly decreased comparing high-dose group vs. placebo (p = 0.01 and p = 0.03), though at baseline less severe strokes in the cohort of high-dosed patients.	No
Otaplimastat	40 or 80 mg administered intravenously twice daily, for a duration of 3 days, started <30 min after IVT	- Incidence of parenchymal hematoma <24 h	- Symptomatic intracranial hemorrhage (NIHHS detoriation ≥ 2 points) <5 days - Incidence of major systemic bleeding - mRS at 90 days - BI at 90 days - NIHSS change at 90 days - Infarct growth	- No difference in primary outcome or other bleeding complications - mRS at 90 days placebo vs. otaplimastat 40 mg: median 1.0 vs. 0.0, adjusted OR 3.2 (CI 0.9 – 10.9, p = 0.068). - mRS 90 days placebo vs. otaplimastat 80 mg 1.0 vs. 1.0, adjusted OR 2.0 (CI 0.6 – 6.7, p = 0.246) - No significant change in NIHSS (p>0.999)	No
Remote ischemic perconditioning	4 cycles of cuff inflation to 110 mmHg above systolic blood pressure for 5 min started <6 h of stroke onset	- Change in brain infarction volume at 24 h measured by DWI	- Relative change infarct volume (%) - NIHSS change at 24 h - BI ≥ 95 at 90 days - mRS 0 or 1 at 90 days - Successful recanalization defined as TICI scale 2b or 3	- No significant difference in primary or secondary outcomes - Median absolute infarct change 0.30 cm3 in treatment group vs. 0.37 cm3 controls (mean log−0.07, CI−0.33–0.18). - Excellent outcome at 90 days 51.1 vs. 40.7% (p = 0.12)	No
Nerinetide	Single intravenous dose 2.6 mg/kg administered in 10 min	- Good outcome defined as mRS 0–2 at 90 days	- BI ≥ 95 at 90 days - NIHSS 0–2 at 90 days - Excellent outcome defined as mRS 0 or 1 - Mortality rates	- Subgroup of patients not treated with Alteplase with better outcome, suspected interaction between nerinetide and Alteplase nullifying treatment effect. - mRS 0–2: adjusted RR 1.04 (CI 0.96–1.14) - NIHSS 0–2: adjusted RR 1.03 (CI 0.92–1.11) - mortality: adjusted RR 0.84 (CI 0.63–1.13) - mRS 0–2 in no Alteplase stratum: adjusted RR 1.18 (CI 1.01–1.38)	No
Remote ischemic perconditioning	5 cycles of inflation to 180 mmHg for 5 min on both arms, twice daily continued during hospital stay, started <3 h of IVT	- Favorable outcome defined as mRS 0 or 1 at 90 days	- mRS 0–2 at 90 days - NIHSS 0–2 at 90 days - BI ≥ 95 at 90 days	- mRS 0 or 1 at 90 days: 71.9 vs. 50% controls, adjusted OR 9.85 (CI 1.54–63.16, p = 0.016) - mRS 0–2 at 90 days: 81.3 vs. 58.8%, adjusted OR 8.25 (CI 1.4–48.7, p = 0.02) - NIHSS improvement ≥6 at 90 days: 41.9 vs. 16.1%, adjusted OR 8.2 (CI 1.17–17.75, p = 0.03)	No
Theophylline	220 mg theophylline intravenously administered in 15 min, started <30 min of IVT	- Early clinical improvement as absolute improvement in NIHSS score at 24 h - Infarct growth at 24 h at MRI	- Major clinical improvement at 24 h defined as NIHSS reduction ≥50% - mRS 0 or 1 at 90 days	- NIHSS improvement at 24 h: 4.7 (SD 5.6) in theophylline patients, vs. 1.3 (SD 7.5) placebo (p = 0.044), adjusted OR 3.6 (CI 0.1–7.1, p = 0.043) - Infarct growth 141.6% in theophylline group vs. 104.1% (p = 0.146) - NIHSS improvement >50% in 67 vs. 45% controls (p = 0.07) - mRS 0 or 1 at 90 days: 61 vs. 58% (p = 0.802)	No
Remote ischemic perconditioning	4 cycles of inflation to 200 mmHg for 5 min on the healthy arm at 6 and 18 h after IVT	- Rate of hemorrhagic transformation <7 days - Adverse events - hs-CRP and hcy at 24 h - Blood pressure in the first 24 h	- Distribution of mRS at 90 days - Ratio of mRS 0–1 at 90 days - NIHSS at 24 h, discharge/7 days and 30 days	- mRS ≤ 1 at 90 days 62.5 vs. 68% controls (p = 0.686) - No significant difference in mRS at 90 days (p = 0.350) - No significant difference in NIHSS at 24 h, 7 days, and 30 days (p = 1.00, 0.513, 0.910) - hs-CRP at 24 h lower (3.13) vs. controls (4.85) (p = 0.048)	No
Normobaric oxygen	high-flow normobaric oxygen (FiO2 50%, flow 15 L/min) for 6 h after recanalization	- mRS at 90 days	- mRS 0–2 at 90 days - NIHSS at 24 h - Infarct volume - Mortality - sICH	- Adjusted common odds ratio for improvement of 1 point mRS at 90 days 2.2 (95% CI, 1.26 to 3.87; p = 0.006) - Lower mortality vs. controls (adjusted risk ratio, 0.35; 95% CI, 0.13–0.93; p = 0.012). - Infarct volume 9.4 vs. 20.5 ml in controls (adjusted beta coefficient, −20.24; 95% CI, −35.93 to −4.55; p = 0.035)	No
Transcranial direct current stimulation	1.5 mA current for 20 min epochs, delivered every hour over a period of 6 h and 20 min	- Infarct growth at 24 h (MRI DWI)	- NIHSS at 7 days - mRS 0–2 at 90 days	- Infarct growth 5.4 vs. 8.3 ml in controls (p = 0.28) - NIHSS at 7 days −4.4 vs. −6.2 in controls (p = 0.39) - mRS 0–2 63.6 vs. 43.5% in controls (p = 0.18)	No

GOS, Glasgow outcome scale; ITT, Intention to treat; BI, Barthel index; NIHSS, National institutes of health stroke scale mRS, modified Rankin scale; SSS, Scandinavian stroke scale; SAE, serious adverse event; OR, odds ratio; CI, confidence interval; CMH, Cochran–Mantel–Haenszel; QOL, quality of life; MMP, matrix metalloproteinase; TICI, thrombolysis in cerebral infarction.