Michael D Hill1, Mayank Goyal2, Bijoy K Menon2, Raul G Nogueira3, Ryan A McTaggart4, Andrew M Demchuk2, Alexandre Y Poppe5, Brian H Buck6, Thalia S Field7, Dar Dowlatshahi8, Brian A van Adel9, Richard H Swartz10, Ruchir A Shah11, Eric Sauvageau12, Charlotte Zerna2, Johanna M Ospel2, Manish Joshi2, Mohammed A Almekhlafi2, Karla J Ryckborst2, Mark W Lowerison13, Kathy Heard14, David Garman14, Diogo Haussen3, Shawna M Cutting4, Shelagh B Coutts2, Daniel Roy5, Jeremy L Rempel6, Axel Cr Rohr7, Daniela Iancu15, Demetrios J Sahlas9, Amy Y X Yu10, Thomas G Devlin11, Ricardo A Hanel12, Volker Puetz16, Frank L Silver17, Bruce C V Campbell18, René Chapot19, Jeanne Teitelbaum20, Jennifer L Mandzia21, Timothy J Kleinig22, David Turkel-Parrella23, Donald Heck24, Michael E Kelly25, Aditya Bharatha26, Oh Young Bang27, Ashutosh Jadhav28, Rishi Gupta29, Donald F Frei30, Jason W Tarpley31, Cameron G McDougall32, Staffan Holmin33, Joung-Ho Rha34, Ajit S Puri35, Marie-Christine Camden36, Götz Thomalla37, Hana Choe38, Stephen J Phillips39, Joseph L Schindler40, John Thornton41, Simon Nagel42, Ji Hoe Heo43, Sung-Il Sohn44, Marios-Nikos Psychogios45, Ronald F Budzik46, Sidney Starkman47, Coleman O Martin48, Paul A Burns49, Seán Murphy50, George A Lopez51, Joey English52, Michael Tymianski14. 1. Foothills Medical Centre, University of Calgary, Calgary, AB, Canada. Electronic address: michael.hill@ucalgary.ca. 2. Foothills Medical Centre, University of Calgary, Calgary, AB, Canada. 3. Emory University School of Medicine, Grady Memorial Hospital, Atlanta, GA, USA. 4. Warren Alpert School of Medicine, Brown University, Providence, RI, USA. 5. Centre Hospitalier de l'Université de Montréal, Montreal, QC, Canada. 6. University of Alberta Hospital, Edmonton, AB, Canada. 7. University of British Columbia, Vancouver, BC, Canada. 8. Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada. 9. McMaster University, Hamilton, ON, Canada. 10. Sunnybrook Health Sciences Centre, University of Toronto, Toronto ON, Canada. 11. Erlanger Hospital, Chattanooga, TN, USA. 12. Lyerly Neurosurgery, Baptist Hospital, Jacksonville, FL, USA. 13. Clinical Research Unit, University of Calgary, Calgary, AB, Canada. 14. NoNO, Toronto, ON, Canada. 15. Centre Hospitalier de l'Université de Montréal, Montreal, QC, Canada; Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada. 16. University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden Neurovascular Center, Dresden, Germany. 17. University Health Network, University of Toronto, Toronto, ON, Canada. 18. The Royal Melbourne Hospital, University of Melbourne, Parkville, VIC, Australia. 19. Department of Neuroradiology and Endovascular Therapy, Alfred Krupp Krankenhaus Hospital, Essen, Germany. 20. Montreal Neurological Institute, McGill University, Montreal, QC, Canada. 21. London Health Science Centre, Western University, London, ON, Canada. 22. Royal Adelaide Hospital, Adelaide, SA, Australia. 23. New York University School of Medicine, New York University, New York, NY, USA. 24. Forsyth Medical Center, Winston-Salem, NC, USA. 25. Royal University Hospital, University of Saskatchewan, Saskatoon, SK, Canada. 26. St Michael's Hospital, University of Toronto, Toronto, ON, Canada. 27. Samsung Medical Center, Departments of Neurology and Radiology, Sungkyunkwan University, Seoul, South Korea. 28. University of Pittsburgh Medical Centre, University of Pittsburgh, Pittsburgh, PA, USA. 29. Wellstar Health Systems, Kennestone Hospital, Marietta, GA, USA. 30. Swedish Medical Center, Colorado Neurological Institute, Denver, CO, USA. 31. Providence Little Company of Mary Medical Center, Providence Saint John's Health Center and The Pacific Neuroscience Institute, Torrance, CA, USA. 32. Swedish Neurological Institute, Seattle, WA, USA. 33. Department of Clinical Neuroscience, Karolinska Institutet and Departments of Neuroradiology and Neurology, Karolinska University Hospital, Stockholm, Sweden. 34. Inha University Hospital Neurology, Incheon, South Korea. 35. University of Massachusetts Medical Center, University of Massachusetts, Worcester, MA, USA. 36. Enfant-Jésus Hospital, Centre Hospitalier Universitaire de Québec, Laval University, Québec City, QC, Canada. 37. Department of Neurology and Department of Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 38. Neurosciences Institute, Abington Jefferson Hospital, Philadelphia, PA, USA. 39. Queen Elizabeth II Health Science Centre, Dalhousie University, Halifax, NS, Canada. 40. Yale University School of Medicine, New Haven, CT, USA. 41. Beaumont Hospital, Dublin, Ireland. 42. University Hospital Heidelberg, Heidelberg, Germany. 43. Yonsei University College of Medicine, Seoul, South Korea. 44. Dongsan Hospital, Keimyung University School of Medicine, Daegu, South Korea. 45. University Medical Center Göttingen, Göttingen, Germany. 46. Ohio Health, Riverside Methodist Hospital, Columbus, OH, USA. 47. UCLA Comprehensive Stroke Center, University of California, Los Angeles, Los Angeles, CA, USA. 48. Saint Luke's Hospital of Kansas City, Kansas City, MO, USA. 49. Royal Victoria Hospital, Belfast, UK. 50. Mater Misericordiae University Hospital, Dublin, Ireland. 51. Rush University Medical Center, Rush University, Chicago, IL, USA. 52. California Pacific Medical Center, Sutter Health, San Francisco, CA, USA.
Abstract
BACKGROUND:Nerinetide, an eicosapeptide that interferes with post-synaptic density protein 95, is a neuroprotectant that is effective in preclinical stroke models of ischaemia-reperfusion. In this trial, we assessed the efficacy and safety of nerinetide in human ischaemia-reperfusion that occurs with rapid endovascular thrombectomy in patients who had an acute ischaemic stroke. METHODS: For this multicentre, double-blind, randomised, placebo-controlled study done in 48 acute care hospitals in eight countries, we enrolled patients with acute ischaemic stroke due to large vessel occlusion within a 12 h treatment window. Eligible patients were aged 18 years or older with a disabling ischaemic stroke at the time of randomisation, had been functioning independently in the community before the stroke, had an Alberta Stroke Program Early CT Score (ASPECTS) greater than 4, and vascular imaging showing moderate-to-good collateral filling, as determined by multiphase CT angiography. Patients were randomly assigned (1:1) to receive intravenous nerinetide in a single dose of 2·6 mg/kg, up to a maximum dose of 270 mg, on the basis of estimated or actual weight (if known) or saline placebo by use of a real-time, dynamic, internet-based, stratified randomised minimisation procedure. Patients were stratified by intravenous alteplase treatment and declared endovascular device choice. All trial personnel and patients were masked to sequence and treatment allocation. All patients underwent endovascular thrombectomy and received alteplase in usual care when indicated. The primary outcome was a favourable functional outcome 90 days after randomisation, defined as a modified Rankin Scale (mRS) score of 0-2. Secondary outcomes were measures of neurological disability, functional independence in activities of daily living, excellent functional outcome (mRS 0-1), and mortality. The analysis was done in the intention-to-treat population and adjusted for age, sex, baseline National Institutes of Health Stroke Scale score, ASPECTS, occlusion location, site, alteplase use, and declared first device. The safety population included all patients who received any amount of study drug. This trial is registered with ClinicalTrials.gov, NCT02930018. FINDINGS:Between March 1, 2017, and Aug 12, 2019, 1105 patients were randomly assigned to receive nerinetide (n=549) or placebo (n=556). 337 (61·4%) of 549 patients with nerinetide and 329 (59·2%) of 556 withplacebo achieved an mRS score of 0-2 at 90 days (adjusted risk ratio 1·04, 95% CI 0·96-1·14; p=0·35). Secondary outcomes were similar between groups. We observed evidence of treatment effect modification resulting in inhibition of treatment effect in patients receiving alteplase. Serious adverse events occurred equally between groups. INTERPRETATION:Nerinetide did not improve the proportion of patients achieving good clinical outcomes after endovascular thrombectomy compared with patients receiving placebo. FUNDING: Canadian Institutes for Health Research, Alberta Innovates, and NoNO.
RCT Entities:
BACKGROUND:Nerinetide, an eicosapeptide that interferes with post-synaptic density protein 95, is a neuroprotectant that is effective in preclinical stroke models of ischaemia-reperfusion. In this trial, we assessed the efficacy and safety of nerinetide in humanischaemia-reperfusion that occurs with rapid endovascular thrombectomy in patients who had an acute ischaemic stroke. METHODS: For this multicentre, double-blind, randomised, placebo-controlled study done in 48 acute care hospitals in eight countries, we enrolled patients with acute ischaemic stroke due to large vessel occlusion within a 12 h treatment window. Eligible patients were aged 18 years or older with a disabling ischaemic stroke at the time of randomisation, had been functioning independently in the community before the stroke, had an Alberta Stroke Program Early CT Score (ASPECTS) greater than 4, and vascular imaging showing moderate-to-good collateral filling, as determined by multiphase CT angiography. Patients were randomly assigned (1:1) to receive intravenous nerinetide in a single dose of 2·6 mg/kg, up to a maximum dose of 270 mg, on the basis of estimated or actual weight (if known) or saline placebo by use of a real-time, dynamic, internet-based, stratified randomised minimisation procedure. Patients were stratified by intravenous alteplase treatment and declared endovascular device choice. All trial personnel and patients were masked to sequence and treatment allocation. All patients underwent endovascular thrombectomy and received alteplase in usual care when indicated. The primary outcome was a favourable functional outcome 90 days after randomisation, defined as a modified Rankin Scale (mRS) score of 0-2. Secondary outcomes were measures of neurological disability, functional independence in activities of daily living, excellent functional outcome (mRS 0-1), and mortality. The analysis was done in the intention-to-treat population and adjusted for age, sex, baseline National Institutes of Health Stroke Scale score, ASPECTS, occlusion location, site, alteplase use, and declared first device. The safety population included all patients who received any amount of study drug. This trial is registered with ClinicalTrials.gov, NCT02930018. FINDINGS: Between March 1, 2017, and Aug 12, 2019, 1105 patients were randomly assigned to receive nerinetide (n=549) or placebo (n=556). 337 (61·4%) of 549 patients with nerinetide and 329 (59·2%) of 556 with placebo achieved an mRS score of 0-2 at 90 days (adjusted risk ratio 1·04, 95% CI 0·96-1·14; p=0·35). Secondary outcomes were similar between groups. We observed evidence of treatment effect modification resulting in inhibition of treatment effect in patients receiving alteplase. Serious adverse events occurred equally between groups. INTERPRETATION:Nerinetide did not improve the proportion of patients achieving good clinical outcomes after endovascular thrombectomy compared with patients receiving placebo. FUNDING: Canadian Institutes for Health Research, Alberta Innovates, and NoNO.
Authors: Johanna M Ospel; Michael D Hill; Andrew Demchuk; Bijoy K Menon; John Thornton; Jeremy Rempel; Mohammed A Almekhlafi; Aravind Ganesh; Manon Kappelhof; Nishita Singh; Petra Cimflova; Nima Kashani; Fouzi Bala; Beom Joon Kim; Ryan McTaggart; Alexandre Poppe; Raul G Nogueira; Michael Tymianski; Mayank Goyal Journal: Neuroradiology Date: 2021-04-29 Impact factor: 2.804
Authors: Stefano G Daniele; Georg Trummer; Konstantin A Hossmann; Zvonimir Vrselja; Christoph Benk; Kevin T Gobeske; Domagoj Damjanovic; David Andrijevic; Jan-Steffen Pooth; David Dellal; Friedhelm Beyersdorf; Nenad Sestan Journal: Nat Rev Neurosci Date: 2021-07-21 Impact factor: 34.870