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.
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.


RESULTS
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).


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


BACKGROUND
NoNO Inc and Arbor Vita Corp.
Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada. michael.hill@ucalgary.ca
Michael D
MD
Hill
Renee H
RH
Martin
David
D
Mikulis
John H
JH
Wong
Frank L
FL
Silver
Karel G
KG
Terbrugge
Geneviève
G
Milot
Wayne M
WM
Clark
R Loch
RL
Macdonald
Michael E
ME
Kelly
Melford
M
Boulton
Ian
I
Fleetwood
Cameron
C
McDougall
Thorsteinn
T
Gunnarsson
Michael
M
Chow
Cheemun
C
Lum
Robert
R
Dodd
Julien
J
Poublanc
Timo
T
Krings
Andrew M
AM
Demchuk
Mayank
M
Goyal
Roberta
R
Anderson
Julie
J
Bishop
David
D
Garman
Michael
M
Tymianski
D000328:Adult; D000368:Aged; D002545:Brain Ischemia / Q000188:drug therapy / Q000517:prevention & control / Q000601:surgery; D004311:Double-Blind Method; D057510:Endovascular Procedures / Q000379:methods; D005260:Female; D006801:Humans; D007049:Iatrogenic Disease / Q000517:prevention & control; D002532:Intracranial Aneurysm / Q000188:drug therapy* / Q000601:surgery*; D008297:Male; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000009:adverse effects / Q000627:therapeutic use; D010455:Peptides / Q000009:adverse effects / Q000627:therapeutic use*; D010919:Placebos; D020521:Stroke / Q000188:drug therapy* / Q000517:prevention & control / Q000601:surgery*; D016896:Treatment Outcome
D018696:Neuroprotective Agents; D010455:Peptides; D010919:Placebos; C542597:Tat-NR2B9c