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.
Author(s): Hill MD, Martin RH, Mikulis D, Wong JH, Silver FL, Terbrugge KG, Milot G, Clark
WM, Macdonald RL, Kelly ME, Boulton M, Fleetwood I, McDougall C, Gunnarsson T,
Chow M, Lum C, Dodd R, Poublanc J, Krings T, Demchuk AM, Goyal M, Anderson R,
Bishop J, Garman D, Tymianski M; ENACT trial investigators.
Affiliation(s): Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.
michael.hill@ucalgary.ca
Publication date & source: 2012, Lancet Neurol. , 11(11):942-50
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.
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