Clinical Trial Details

Safety and Efficacy of NA-1 in Subjects Undergoing Endovascular Thrombectomy for Stroke (ESCAPE-NA1)

The goal of the trial is to evaluate the efficacy and safety of Nerinetide (NA-1) in patients with AIS with small core infarct and good collaterals undergoing endovascular thrombectomy (EVT).

Trial summarized by: Vasu Saini
Content reviewed by: Karen Furie, MD, MPH

Key Findings

ESCAPE-NA-1 demonstrated that, among overall patients with acute ischemic stroke with small core and good collaterals undergoing endovascular thrombectomy improve the proportion of patients achieving good clinical outcomes compared to placebo (RR adj. 1.04, 95%CI .96-1.14). Due to notable treatment effect modification by alteplase, a subgroup analysis excluding patients who received alteplase showed significant benefit in achieving good clinical outcome in patients receiving nerinetide over placebo [9.5% absolute effect size; RR adj. 1.18 (1.01-1.38)].


Purpose: to evaluate the safety and efficacy of nerinetide (NA-1), a neuroprotectant, in patients with AIS from large vessel occlusion having endovascular therapy?

Trial Design: Phase 3, global, multicenter, double-blinded, placebo-controlled, parallel, safety and efficacy trial. N=1105. Patients with large vessel occlusion having endovascular therapy with usual care alteplase as indicated received either a single IV dose of NA-1 (2.6 mg/kg up to max of 270 mg) or placebo. 90-day follow-up for functional outcome.

Primary Endpoints: functional outcome at 90 days (0-2 mRS)?

Results Table
@ 90 days NA-1 Placebo Results
mRS 0-2 61.4% 59.2% RR
NIHSS 0-2 (neurological outcome) 58.3% 57.6%
Barthel Index gte;95 (functional independence - daily living) 62.1% 60.3% RR
Mortality 12.2% 14.4% RR

Results: for these patients with large vessel occlusion AIS, the percent of favorable functional outcomes at 90 days did not improve with the use of nerinetide.

Including all patients with acute ischemic stroke undergoing endovascular thrombectomy, nerinetide was not superior to placebo (2.1% effect size; RR adj. 1.04, 95%CI .96-1.14). However, there is notable effect modification by alteplase, supported by pharmacokinetic data suggesting large reduction in measurable nerinetide in the alteplase group. Therefore, on further analysis of the subset of the study population that did not receive intravenous alteplase showed benefit in achieving good clinical outcomes with nerinetide over placebo [9.5% absolute effect size; RR adj. 1.18 (1.01-1.38)]. The study highlights the first large attempt of evaluating neuroprotection in patients with acute ischemic stroke undergoing reperfusion and encourages future research to further expand the search for new therapeutic interventions in stroke.


Karen Furie, MD, interviews co-principal investigators of the ESCAPE-NA1 trial, Michael D. Hill, MD, MSc and Mayank Goyal, MD, PhD.

Detailed Results

1105 patients were randomly assigned to receive nerinetide (n=549) or placebo (n=556). 337 (61·4%) of 549 patients with nerinetide and 329 (59·2%) of 556 with placebo achieved an mRS score of 0–2 at 90 days (adjusted risk ratio 1·04, 95% CI 0·96–1·14; p=0·35). Secondary outcomes were similar between groups. Notable evidence of treatment effect modification resulting in inhibition of treatment effect in patients receiving alteplase. Serious adverse events occurred equally between groups.

Primary Endpoints:

  • mRS at 90 days (overall, N=1105)
    • Nerinetide 61.4% vs. placebo 59.2% (RR adj. 1.04, 95%CI .96-1.14, p .35)
  • mRS at 90 days (no alteplase group, N=446)
    • Nerinetide 59.3% (130/219) vs. placebo 49.8% (113/227) (RR adj. 1.18, 95%CI 1.01-1.38)

Secondary Endpoints:

  • NIHSS 0-2
    • Nerinetide 58.3% vs. placebo 57.6% (RR adj. 1.01, 95%CI .92-1.11)
  • Barthel Index score of ≥ 95
    • Nerinetide 62.1% vs. placebo 60.3% (RR adj. 1.03, 95%CI .94-1.12)
  • Functional Independence based on mRS 0-1
    • Nerinetide 40.4% vs. placebo 40.6% (RR adj. 0.98, 95%CI .85-1.12)
  • Infarct volume, as measured by MRI or hyperdense areas on NCCT if MRI not obtained or available
    • Nerinetide 23.7ml (6.4-78.9) vs. placebo 26ml (6.6-101.5) (β -0.29, 95%CI -0.87-0.30)*

* The β coefficient represents the adjusted reduction in mean cubic root volume (mL1/3) with nerinetide compared with that with placebo; the mean volumes were 73·1 mL (placebo) and 71·1 mL (nerinetide).

Safety Endpoints:

  • Any serious adverse event
    • Nerinetide 33.1% vs. placebo 35.7% (RR adj. 0.92, 95%CI 0.79-1.09)
  • sICH
    • Nerinetide 3.5% vs. placebo 4.3% (RR adj. 0.8, 95%CI 0.44-1.45)
  • Mortality Rate over 90 days
    • Nerinetide 12.2% vs. placebo 14.4% (RR adj. 0.84, 95%CI .63-1.13)

Recommended and supporting content:


Nerinetide, an eicosapeptide that interferes with post-synaptic density protein 95 (PSD-95 inhibitor), is a neuroprotectant that is effective in preclinical stroke models of ischemia-reperfusion³, and ENACT study, a phase 2 trial in patients undergoing endovascular aneurysm repair.

Reference3: Prof Michael D Hill, MD, et al.; Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, double-blind, randomised controlled trial. Lancet, February 20, 2020, DOI:

Trial Design:

This study is a Phase 3, randomized, multicentre, blinded, placebo-controlled, parallel group, single-dose design. 1105 subjects with AIS with small established infarct core and with good collateral circulation undergoing endovascular revascularization in accordance with local institutional practices across 48 centers in 8 countries, are given a single, 2.6 mg/kg (up to a maximum dose of 270 mg) intravenous dose of NA-1 or placebo as soon as they are deemed to have met the enrollment criteria and with the intention of starting administration within 30 minutes of randomization and 12 hours from symptoms onset or last-seen-well.

Randomization 1:1 Nerinetide to placebo, stratified by alteplase use and by declared first choice of device

Trial population:

N=1105, males and females over 18 years of age, enrolled and randomized.

  • Key inclusion criteria:
    • AIS patients, independent at baseline, with an intracranial large vessel occlusion (ICA or M1-MCA), ASPECTS ≥5 and moderate to good collaterals.
    • Onset (last-seen-well) time to randomization time within 12 hours.
    • Disabling stroke defined as a baseline National Institutes of Health Stroke Score (NIHSS) > 5 at the time of randomization.
  • Key exclusion criteria:
    • Established large core defined as ASPECTS 0-4.
    • Evidence of absence of collateral circulation on CTA (Collateral score of 0 or 1).
    • Severe known renal impairment defined as requiring dialysis (hemo- or peritoneal) or if known a creatinine clearance < 29 mL/min


  • Single, 10 ± 1 minutes infusion of 2.6 mg/kg intravenous dose of nerinetide (up to a maximum dose of 270 mg) or placebo (saline) as soon as enrollment criteria met, and started within 30 minutes of randomization.
  • All patients had EVT
  • Patients received intravenous alteplase according to current stroke guidelines (best medical management)

Primary endpoints:

  • mRS at 90 days

Secondary endpoints:

(90 days or the last rating)

  • mRS Shift Analysis
  • NIHSS Barthel Index score of ≥ 95
  • Mortality Rate
  • Functional Independence based on mRS 0-1

Safety endpoints:

  • Mortality rate over the 90 days period

Exploratory endpoints:

(90 Days or the last rating unless specified otherwise)

  • EQ-5D-5L
  • Stroke Volume
  • Volume of stroke as measured by MRI. If NCCT was done instead of MRI, Volume of stroke will be derived from hypodense areas.
  • Test of language function
  • Cognitive outcome - The 15-item Boston Naming Test (BNT15)
  • Test of hemi-spatial neglect
  • Cognitive Outcome - Sunnybrook hemi-spatial neglect procedure (SNAP)
  • Global test of cognitive function. Scale from 0 to 30 points.
  • Cognitive outcome - The Montreal Cognitive Assessment (MoCA)
  • Functional outcome based on mRS 0-2 (30 days)

Sponsors and collaborators— Canadian Institutes for Health Research, Alberta Innovates, NoNO Inc., University of Calgary

Related Science

Key Words

Nerinetide, Tat-NR2B9c, NA-1, Mechanical Thrombectomy, Endovascular Thrombectomy, Large vessel occlusion, Acute Ischemic Stroke, Neuroprotection

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Related Clinical Topics 

Endovascular thrombectomy in acute large vessel occlusion ischemic stroke, initial management strategies for cerebral revascularization, neuroprotection in acute ischemic stroke