ESCAPE-NA1
Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, double-blind, randomised controlled trial
Year of Publication: 2020
Authors: Hill MD, Goyal M, Menon BK, et al; ESCAPE-NA1 Investigators
Journal: The Lancet
Citation: Lancet 2020;395(10227):878-887. DOI: 10.1016/S0140-6736(20)30258-0
Link: https://doi.org/10.1016/S0140-6736(20)30258-0
PDF: https://www.thelancet.com/action/showPdf...6736(20)30258-0
PDF: Clinical Question
Does a single IV dose of nerinetide (an eicosapeptide PSD-95 inhibitor) improve 90-day functional outcomes in patients with acute ischaemic stroke from large vessel occlusion undergoing endovascular thrombectomy?
Bottom Line
In LVO stroke selected for endovascular thrombectomy, a single IV dose of nerinetide (2.6 mg/kg) did not improve the primary outcome of mRS 0–2 at 90 days (61.4% vs 59.2%; adjusted RR 1.04, 95% CI 0.96–1.14; p=0.35). An exploratory subgroup analysis suggested benefit in patients who did not receive alteplase (p-interaction=0.033), hypothesised to reflect plasmin-mediated cleavage of nerinetide when co-administered with alteplase.
Major Points
- Multicentre, double-blind, placebo-controlled, single-dose phase 3 trial at 48 acute care hospitals in 8 countries (Canada, USA, Germany, Australia, South Korea, Sweden, Ireland, UK).
- Enrolled 1105 patients with LVO ischaemic stroke (ICA or M1, ASPECTS 5–10, moderate/good collaterals) within 12 h and selected for EVT; 549 nerinetide and 556 placebo; randomisation stratified by IV alteplase use and declared first thrombectomy device.
- Primary outcome mRS 0–2 at 90 d: 337/549 (61.4%) nerinetide vs 329/556 (59.2%) placebo; adjusted RR 1.04 (95% CI 0.96–1.14); p=0.35 — trial NEGATIVE for the primary endpoint.
- Secondary efficacy outcomes were also neutral overall: NIHSS 0–2 58.3% vs 57.6% (RR 1.01); mBI 95–100 62.1% vs 60.3% (RR 1.03); mRS 0–1 40.4% vs 40.6% (RR 0.98); 90-d mortality 12.2% vs 14.4% (RR 0.84, 0.63–1.13).
- Prespecified subgroup by alteplase (exploratory after negative primary): in the no-alteplase stratum (n=446), mRS 0–2 was 130/219 (59.3%) nerinetide vs 113/227 (49.8%) placebo (adjusted RR 1.18, 1.01–1.38); mortality 12.8% vs 20.3% (adjusted RR 0.66, 0.44–0.99). In the alteplase stratum (n=659), no benefit (mRS 0–2 62.7% vs 65.7%; RR 0.97, 0.87–1.08). p-interaction 0.033 for mRS 0–2 and 0.040 for infarct volume.
- Pharmacokinetic substudy in 22 patients showed lower peak plasma nerinetide concentrations when co-administered with alteplase, consistent with plasmin-mediated cleavage — a biologically plausible explanation for the effect modification.
- Reperfusion quality was high and similar in both groups (eTICI 2b–3 in 87.2% nerinetide vs 86.3% placebo); median study-drug-to-reperfusion time was ~22 min.
- Safety was similar: any serious adverse event 181/547 (33.1%) nerinetide vs 198/554 (35.7%) placebo, RR 0.92 (0.79–1.09). Symptomatic ICH 19/547 (3.5%) vs 24/554 (4.3%); RR 0.80 (0.44–1.45). Numerically more transient hypotension (1.3% vs 0.2%), pneumonia (4.6% vs 3.1%), and congestive cardiac failure (1.6% vs 0.7%) with nerinetide.
- First large trial of any neuroprotectant in the modern EVT era; overall negative but generated the hypothesis, later tested in ESCAPE-NEXT, that nerinetide might benefit patients treated without alteplase.
Design
Study Type: Randomised, double-blind, placebo-controlled, parallel-group, single-dose phase 3 multicentre trial
Randomization: 1
Blinding: Double-blind; all trial personnel and patients masked. Nerinetide and placebo supplied as visually identical colourless solutions in numbered refrigerated vials; internet-based dynamic minimisation randomisation stratified by IV alteplase use and declared first EVT device.
Enrollment Period: Mar 1, 2017 - Aug 12, 2019
Follow-up Duration: 90 days (primary); imaging at 24 h; clinical follow-up at 30 and 90 days
Centers: 48
Countries: Canada, USA, Germany, Australia, South Korea, Sweden, Ireland, UK
Sample Size: 1105
Power Calculation: 80% power to detect an 8.7% absolute difference in mRS 0–2 at 90 d; two-sided α=0.05; O'Brien-Fleming interim (Z=2.784, p=0.003) after 600 patients completed 90-d follow-up; target 1076 evaluable inflated ~4% to a maximum of 1120
Analysis: Intention-to-treat for efficacy; adjusted analysis via multivariable Poisson regression with Huber-White robust variance (risk ratios), adjusting for age, sex, baseline NIHSS, ASPECTS, occlusion location, declared device, alteplase use, and site. Missing primary outcomes imputed as worst score. Hierarchical multiplicity control across primary and prespecified secondaries. Safety population = all who received any study drug (n=1101).
Inclusion Criteria
- Adults ≥18 years
- Acute ischaemic stroke considered disabling at randomisation with baseline NIHSS >5
- Independent functioning in the community before the stroke (Barthel Index >90)
- Randomisation up to 12 h from stroke onset (or last seen well)
- Non-contrast CT and multiphase CT angiography confirming proximal intracranial artery occlusion (intracranial ICA and/or first segment of the MCA)
- Small-to-moderate ischaemic core: ASPECTS 5–10
- Moderate-to-good collateral filling (≥50% of MCA pial arterial territory on CTA)
- Selected for endovascular thrombectomy at the endovascular centre
- Signed informed consent (patient, legally authorised representative, or, where required, independent-physician consent)
Exclusion Criteria
- Pre-stroke functional dependency (Barthel Index ≤90)
- Ischaemic core deemed too large (ASPECTS ≤4)
- Poor collateral circulation on multiphase CTA (<50% of MCA pial territory)
- No proximal intracranial ICA or M1 occlusion
- Not selected for endovascular thrombectomy
- Presentation >12 h from last seen well
- Contraindication to any component of the study drug or to receiving usual-care alteplase/EVT as clinically indicated
- (Full list of inclusion/exclusion criteria provided in the study protocol appendix)
Baseline Characteristics
| Characteristic | Nerinetide (n=549) | Placebo (n=556) |
|---|---|---|
| Median age (IQR), y | 71.5 (61.1-79.7) | 70.3 (60.4-80.1) |
| Female n (%) | 268 (48.8%) | 281 (50.5%) |
| Male n (%) | 281 (51.2%) | 275 (49.5%) |
| White n (%) | 436 (79.4%) | 453 (81.5%) |
| Asian n (%) | 55 (10.0%) | 52 (9.4%) |
| Hypertension | 378 (68.9%) | 396 (71.4%) |
| Hyperlipidaemia | 254 (46.3%) | 260 (46.9%) |
| Atrial fibrillation (history) | 195 (35.5%) | 192 (34.6%) |
| Ischaemic heart disease | 122 (22.3%) | 130 (23.4%) |
| Diabetes | 111 (20.2%) | 107 (19.3%) |
| Congestive heart failure | 72 (13.1%) | 65 (11.7%) |
| Any past stroke | 81 (14.8%) | 76 (13.7%) |
| Chronic renal failure | 35 (6.4%) | 28 (5.1%) |
| Median NIHSS (IQR) | 17 (12-21) | 17 (13-21) |
| ASPECTS median (IQR, core lab) | 8 (7-9) | 8 (7-9) |
| ICA occlusion (site determined) | 110 (20.0%) | 103 (18.5%) |
| Good collaterals (site determined) | 355 (65.4%) | 344 (62.0%) |
| Alteplase treatment n (%) | 330 (60.1%) | 329 (59.2%) |
| Interhospital transfer | 228 (41.5%) | 235 (42.3%) |
| General anaesthesia | 95 (17.4%) | 97 (17.4%) |
| Median onset-to-randomisation (min) | 186 (120-309) | 188 (122-311) |
| Median study drug start-to-reperfusion (min) | 21 (8-40) | 23 (8-42) |
| eTICI 2b-2c-3 n (%) | 476 (87.2%) | 480 (86.3%) |
Arms
| Field | Nerinetide | Control |
|---|---|---|
| Intervention | Single IV dose of nerinetide 2.6 mg/kg (max 270 mg) infused over 10 min through a dedicated line, given as soon as possible after randomisation and before arterial-access closure; all patients underwent EVT and received alteplase per usual care where indicated. | Matching saline placebo IV, single dose over 10 min, otherwise identical to the intervention arm; all patients underwent EVT and received alteplase per usual care. |
| N | 549 | 556 |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Favourable functional outcome defined as modified Rankin Scale (mRS) 0-2 at 90 days post-randomisation (in-person, or telephone if in-person visit not possible) | Primary | 329/556 (59.2%) | 337/549 (61.4%) | 0.35 | |
| NIHSS 0-2 at 90 d | Secondary | 320/556 (57.6%) | 320/549 (58.3%) | ||
| Modified Barthel Index 95-100 at 90 d | Secondary | 335/556 (60.3%) | 341/549 (62.1%) | ||
| All-cause mortality at 90 d (ITT with missing imputed as death) | Secondary | 80/556 (14.4%) | 67/549 (12.2%) | ||
| Excellent outcome: mRS 0-1 at 90 d | Secondary | 226/556 (40.6%) | 222/549 (40.4%) | ||
| Infarct volume at 24 h (median, IQR) | Secondary | 23.7 mL (6.6-101.5) | 26.0 mL (6.4-78.9) | ||
| Any serious adverse event | Safety | 198/554 (35.7%) | 181/547 (33.1%) | ||
| Symptomatic intracranial haemorrhage (MedDRA-composite) | Safety | 24/554 (4.3%) | 19/547 (3.5%) | ||
| Stroke-in-evolution (progression) | Safety | 43/554 (7.8%) | 36/547 (6.6%) | ||
| Recurrent or new ischaemic stroke | Safety | 20/554 (3.6%) | 18/547 (3.3%) | ||
| Pneumonia | Safety | 17/554 (3.1%) | 25/547 (4.6%) | ||
| Congestive cardiac failure | Safety | 4/554 (0.7%) | 9/547 (1.6%) | ||
| Hypotension (mostly on day of dosing) | Safety | 1/554 (0.2%) | 7/547 (1.3%) | ||
| Deep vein thrombosis or pulmonary embolism | Safety | 8/554 (1.4%) | 3/547 (0.5%) | ||
| Urinary tract infection | Safety | 7/554 (1.3%) | 8/547 (1.5%) | ||
| Angio-oedema | Safety | 1/554 (0.2%) | 1/547 (0.2%) | ||
| 90-day mortality (safety population, unimputed) | Safety | 74/550 (14%) | 64/546 (12%) |
Subgroup Analysis
Prespecified stratification by IV alteplase use showed significant effect modification (p-interaction=0.033 for mRS 0-2). No-alteplase stratum (n=446): mRS 0-2 was 130/219 (59.3%) nerinetide vs 113/227 (49.8%) placebo (adjusted RR 1.18, 95% CI 1.01-1.38); mortality 28/219 (12.8%) vs 46/227 (20.3%) (adjusted RR 0.66, 0.44-0.99); infarct-volume interaction p=0.040 favouring nerinetide. Alteplase stratum (n=659): mRS 0-2 207/330 (62.7%) nerinetide vs 216/329 (65.7%) placebo (adjusted RR 0.97, 0.87-1.08); no mortality benefit (adjusted RR 1.08, 0.70-1.66). Effect modification supported by pharmacokinetic substudy showing lower peak nerinetide concentrations in the alteplase stratum, consistent with plasmin-mediated cleavage of nerinetide. No effect modification observed by declared first EVT device (stent retriever vs aspiration); other prespecified subgroups showed no differential effect.
Criticisms
- Primary endpoint negative; the 'benefit in the no-alteplase stratum' is an exploratory subgroup finding after a failed primary and should be considered hypothesis-generating.
- The alteplase stratum is confounded by shorter onset-to-treatment times and different clinical selection (contra-indications to alteplase drive who is in the no-alteplase group), so effect modification could reflect population differences, not only a drug-drug interaction.
- Enrollment window (≤12 h) predates the DAWN/DEFUSE-3 based extended-window standard, and inclusion required moderate-to-good CTA collaterals — limiting generalisability to broader LVO populations.
- Randomisation stratified by 'declared' first device rather than actual device used; declared device proved unreliable as devices/practice evolved during the trial.
- Sponsor NoNO (manufacturer) participated in study design and had two members on the Publication Committee; the corresponding author had final publication responsibility but analyses were run jointly by an independent statistical group and academic investigators.
- Pharmacokinetic support for the plasmin-cleavage hypothesis came from only 22 patients.
- Not all patients had MRI-based infarct volumes (57.9% CT, 42.1% MRI).
Funding
Canadian Institutes for Health Research, Alberta Innovates, and NoNO (Toronto, ON, Canada). NoNO also funded the independent external statistical consulting group and supplied the study drug.
Based on: ESCAPE-NA1 (The Lancet, 2020)
Authors: Hill MD, Goyal M, Menon BK, et al; ESCAPE-NA1 Investigators
Citation: Lancet 2020;395(10227):878-887. DOI: 10.1016/S0140-6736(20)30258-0
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