Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair (ENACT): a phase 2, randomised, double-blind, placebo-controlled trial

Summary

Background

Neuroprotection with NA-1 (Tat-NR2B9c), an inhibitor of postsynaptic density-95 protein, has been shown in a primate model of stroke. We assessed whether NA-1 could reduce ischaemic brain damage in human beings.

Methods

For this double-blind, randomised, controlled study, we enrolled patients aged 18 years or older who had a ruptured or unruptured intracranial aneurysm amenable to endovascular repair from 14 hospitals in Canada and the USA. We used a computer-generated randomisation sequence to allocate patients to receive an intravenous infusion of either NA-1 or saline control at the end of their endovascular procedure (1:1; stratified by site, age, and aneurysm status). Both patients and investigators were masked to treatment allocation. The primary outcome was safety and primary clinical outcomes were the number and volume of new ischaemic strokes defined by MRI at 12–95 h after infusion. We used a modified intention-to-treat (mITT) analysis. This trial is registered with ClinicalTrials.gov, number NCT00728182.

Findings

Between Sept 16, 2008, and March 30, 2011, we randomly allocated 197 patients to treatment—12 individuals did not receive treatment because they were found to be ineligible after randomisation, so the mITT population consisted of 185 individuals, 92 in the NA-1 group and 93 in the placebo group. Two minor adverse events were adjudged to be associated with NA-1; no serious adverse events were attributable to NA-1. We recorded no difference between groups in the volume of lesions by either diffusion-weighted MRI (adjusted p value=0·120) or fluid-attenuated inversion recovery MRI (adjusted p value=0·236). Patients in the NA-1 group sustained fewer ischaemic infarcts than did patients in the placebo group, as gauged by diffusion-weighted MRI (adjusted incidence rate ratio 0·53, 95% CI 0·38–0·74) and fluid-attenuated inversion recovery MRI (0·59, 0·42–0·83).

Interpretation

Our findings suggest that neuroprotection in human ischaemic stroke is possible and that it should be investigated in larger trials.

Funding

NoNO Inc and Arbor Vita Corp.

Introduction

Safe pharmacological tissue neuroprotection, defined as salvage of brain tissue by enhancement of its resilience to ischaemia, is a major unmet need in stroke treatment. Translation from discovery in cells and rodents to clinical use has been unsuccessful in more than 1000 experimental treatments.1, 2, 3, 4 Potential barriers include the heterogeneity of clinical stroke syndromes, the complexity of the high-order gyrencephalic human brain, the variability of its collateral blood supply, and biological differences between animal models and people. Studies in people have not reproduced the controlled conditions of preclinical animal experiments, creating a translational gap between laboratory experiments and human trials.

To bridge this gap and to test the feasibility of pharmacological tissue neuroprotection, we assessed whether ischaemic brain tissue damage can be reduced in adult patients. We did a phase 2, randomised, double-blind, placebo-controlled multicentre trial modelled on two studies done in gyrencephalic old-world primates.5, 6 In both primate studies and the present study, neuroprotectants were given after the onset of multiple small embolic strokes under conditions in which general anaesthesia, meticulous physiological monitoring, and the administration of neuroprotectants were closely controlled. In primates, strokes were induced by the injection of synthetic emboli into the carotid artery.⁶ Up to 90% of human beings undergoing endovascular intracranial aneurysm repair show small, embolic, procedurally induced ischaemic strokes on diffusion-weighted (DWI) MRI (figure 1).⁷ We tested the tissue neuroprotection hypothesis in this population of patients.

The neuroprotectant tested in the Evaluating Neuroprotection in Aneurysm Coiling Therapy (ENACT) trial, NA-1 (also known as Tat-NR2B9c [NoNO Inc, Etobicoke, ON, Canada]), was developed in accordance with recommendations for stroke drug development established by the Stroke Academic Industry Roundtable (STAIR) committee.8, 9 NA-1 is a cell-permeant eicosapeptide that perturbs the protein–protein interactions of PSD-95, a postsynaptic scaffolding protein.¹⁰ PSD-95 links NMDA glutamate receptors to neurotoxic signalling pathways,11, 12 and NA-1 disrupts these links and inhibits stroke damage.13, 14, 15 In old-world primates, NA-1 treatment reduces the volume of strokes after middle cerebral artery occlusion⁵ and reduces the volume and number of strokes after the intra-arterial injection of small emboli.⁶

We assessed whether NA-1 would reduce the volume and number of peri-procedural ischaemic strokes, as detected by MRI, in patients undergoing endovascular repair of intracranial aneurysms. By using a potential neuroprotectant that had undergone extensive preclinical validation,5, 11, 12, 13, 14, 15, 16 including in a preclinical study that had a similar design in old-world primates,⁶ ENACT provides a direct step to testing one of the most elusive premises in stroke research: a test of the neuroprotection hypothesis in people.