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

Michael D. Hill, Renee H. Martin, David Mikulis, John H. Wong, Frank L. Silver, Karel G. terBrugge, Geneviève Milot, Wayne Clark, R. Loch MacDonald, Michael E. Kelly, Melford Boulton, Ian Fleetwood, Cameron McDougall, Thorsteinn Gunnarsson, Michael Chow, Cheemun Lum, Robert Dodd, Julien Poublanc, Timo Krings, Andrew M. DemchukMayank Goyal, Roberta Anderson, Julie Bishop, David Garman, Michael Tymianski

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)942-950
Number of pages9
JournalThe Lancet Neurology
Volume11
Issue number11
DOIs
StatePublished - Nov 2012

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Aneurysm
Stroke
Placebos
Safety
Diffusion Magnetic Resonance Imaging
Random Allocation
Thuja
Endovascular Procedures
Intention to Treat Analysis
Intracranial Aneurysm
Double-Blind Method
Intravenous Infusions
Primates
Canada
Therapeutics
Research Personnel
Incidence
Brain
Population
Neuroprotection

ASJC Scopus subject areas

  • Clinical Neurology

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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. / Hill, Michael D.; Martin, Renee H.; Mikulis, David; Wong, John H.; Silver, Frank L.; terBrugge, Karel G.; Milot, Geneviève; Clark, Wayne; MacDonald, R. Loch; Kelly, Michael E.; Boulton, Melford; Fleetwood, Ian; McDougall, Cameron; Gunnarsson, Thorsteinn; Chow, Michael; Lum, Cheemun; Dodd, Robert; Poublanc, Julien; Krings, Timo; Demchuk, Andrew M.; Goyal, Mayank; Anderson, Roberta; Bishop, Julie; Garman, David; Tymianski, Michael.

In: The Lancet Neurology, Vol. 11, No. 11, 11.2012, p. 942-950.

Research output: Contribution to journalArticle

Hill, MD, Martin, RH, Mikulis, D, Wong, JH, Silver, FL, terBrugge, KG, Milot, G, Clark, W, 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 2012, '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', The Lancet Neurology, vol. 11, no. 11, pp. 942-950. https://doi.org/10.1016/S1474-4422(12)70225-9
Hill, Michael D. ; Martin, Renee H. ; Mikulis, David ; Wong, John H. ; Silver, Frank L. ; terBrugge, Karel G. ; Milot, Geneviève ; Clark, Wayne ; MacDonald, R. Loch ; Kelly, Michael E. ; Boulton, Melford ; Fleetwood, Ian ; McDougall, Cameron ; Gunnarsson, Thorsteinn ; Chow, Michael ; Lum, Cheemun ; Dodd, Robert ; Poublanc, Julien ; Krings, Timo ; Demchuk, Andrew M. ; Goyal, Mayank ; Anderson, Roberta ; Bishop, Julie ; Garman, David ; Tymianski, Michael. / 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. In: The Lancet Neurology. 2012 ; Vol. 11, No. 11. pp. 942-950.
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abstract = "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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T1 - Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair (ENACT)

T2 - A phase 2, randomised, double-blind, placebo-controlled trial

AU - Hill, Michael D.

AU - Martin, Renee H.

AU - Mikulis, David

AU - Wong, John H.

AU - Silver, Frank L.

AU - terBrugge, Karel G.

AU - Milot, Geneviève

AU - Clark, Wayne

AU - MacDonald, R. Loch

AU - Kelly, Michael E.

AU - Boulton, Melford

AU - Fleetwood, Ian

AU - McDougall, Cameron

AU - Gunnarsson, Thorsteinn

AU - Chow, Michael

AU - Lum, Cheemun

AU - Dodd, Robert

AU - Poublanc, Julien

AU - Krings, Timo

AU - Demchuk, Andrew M.

AU - Goyal, Mayank

AU - Anderson, Roberta

AU - Bishop, Julie

AU - Garman, David

AU - Tymianski, Michael

PY - 2012/11

Y1 - 2012/11

N2 - 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.

AB - 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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