Kevin N Sheth1, Nils H Petersen2, Ken Cheung3, Jordan J Elm4, Holly E Hinson5, Bradley J Molyneaux6, Lauren A Beslow7, Gordon K Sze8, J Marc Simard9, W Taylor Kimberly10. 1. From the Division of Neurocritical Care and Emergency Neurology, Department of Neurology (K.N.S., N.H.P.) kevin.sheth@yale.edu wtkimberly@partners.org. 2. From the Division of Neurocritical Care and Emergency Neurology, Department of Neurology (K.N.S., N.H.P.). 3. Department of Biostatistics, Columbia University, New York, NY (K.C.). 4. Department of Public Health Sciences, Medical University of South Carolina, Charleston (J.J.E.). 5. Department of Neurology, Oregon Health Sciences University, Portland (H.E.H.). 6. Department of Neurology, University of Pittsburgh, PA (B.J.M.). 7. Division of Neurology, Children's Hospital of Philadelphia, Departments of Neurology and Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (L.A.B.). 8. Department of Radiology (G.K.S.), Yale University School of Medicine, New Haven, CT. 9. Department of Neurosurgery, University of Maryland School of Medicine, Baltimore (J.M.S.). 10. Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Massachusetts General Hospital, Boston (W.T.K.). kevin.sheth@yale.edu wtkimberly@partners.org.
Abstract
BACKGROUND AND PURPOSE: We aimed to determine whether subjects aged ≤70 years who were treated withintravenous glyburide (RP-1127; BIIB093; glibenclamide) would have better long-term outcomes than those who received placebo. METHODS:GAMES-RP (Glyburide Advantage in Malignant Edema and Stroke-Remedy Pharmaceuticals) was a prospective, double-blind, randomized, placebo-controlled phase 2 clinical trial. Eighty-six participants, aged 18 to 80 years, who presented to 18 centers with large hemispheric infarction (baseline diffusion-weighted imaging volumes, 82-300 cm3) randomized within 10 hours of symptom onset were enrolled. In the current exploratory analysis, we included participants aged ≤70 years treated withintravenous glyburide (n=35) orplacebo (n=30) who met per-protocol criteria. Intravenous glyburide or placebo was administered in a 1:1 ratio. We analyzed 90-day and 12-month mortality, functional outcome (modified Rankin Scale, Barthel Index), and quality of life (EuroQol group 5-dimension). Additional outcomes assessed included blood-brain barrier injury (MMP-9 [matrix metalloproteinase 9]) and cerebral edema (brain midline shift). RESULTS:Participants ≤70 years of age treated withintravenous glyburide had lower mortality at all time points (log-rank for survival hazards ratio, 0.34; P=0.04). After adjustment for age, the difference in functional outcome (modified Rankin Scale) demonstrated a trend toward benefit for intravenous glyburide-treated subjects at 90 days (odds ratio, 2.31; P=0.07). Repeated measures analysis at 90 days, 6 months, and 12 months using generalized estimating equations showed a significant treatment effect of intravenous glyburide on the Barthel Index (P=0.03) and EuroQol group 5-dimension (P=0.05). Participants treated with intravenous glyburide had lower plasma levels of MMP-9 (189 versus 376 ng/mL; P<0.001) and decreased midline shift (4.7 versus 9 mm; P<0.001) compared with participants who received placebo. CONCLUSIONS: In this exploratory analysis, participants ≤70 years of age with large hemispheric infarction have improved survival after acute therapy with intravenous glyburide. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01794182.
RCT Entities:
BACKGROUND AND PURPOSE: We aimed to determine whether subjects aged ≤70 years who were treated with intravenous glyburide (RP-1127; BIIB093; glibenclamide) would have better long-term outcomes than those who received placebo. METHODS: GAMES-RP (Glyburide Advantage in Malignant Edema and Stroke-Remedy Pharmaceuticals) was a prospective, double-blind, randomized, placebo-controlled phase 2 clinical trial. Eighty-six participants, aged 18 to 80 years, who presented to 18 centers with large hemispheric infarction (baseline diffusion-weighted imaging volumes, 82-300 cm3) randomized within 10 hours of symptom onset were enrolled. In the current exploratory analysis, we included participants aged ≤70 years treated with intravenous glyburide (n=35) or placebo (n=30) who met per-protocol criteria. Intravenous glyburide or placebo was administered in a 1:1 ratio. We analyzed 90-day and 12-month mortality, functional outcome (modified Rankin Scale, Barthel Index), and quality of life (EuroQol group 5-dimension). Additional outcomes assessed included blood-brain barrier injury (MMP-9 [matrix metalloproteinase 9]) and cerebral edema (brain midline shift). RESULTS:Participants ≤70 years of age treated with intravenous glyburide had lower mortality at all time points (log-rank for survival hazards ratio, 0.34; P=0.04). After adjustment for age, the difference in functional outcome (modified Rankin Scale) demonstrated a trend toward benefit for intravenous glyburide-treated subjects at 90 days (odds ratio, 2.31; P=0.07). Repeated measures analysis at 90 days, 6 months, and 12 months using generalized estimating equations showed a significant treatment effect of intravenous glyburide on the Barthel Index (P=0.03) and EuroQol group 5-dimension (P=0.05). Participants treated with intravenous glyburide had lower plasma levels of MMP-9 (189 versus 376 ng/mL; P<0.001) and decreased midline shift (4.7 versus 9 mm; P<0.001) compared with participants who received placebo. CONCLUSIONS: In this exploratory analysis, participants ≤70 years of age with large hemispheric infarction have improved survival after acute therapy with intravenous glyburide. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01794182.
Authors: Susan M Resnick; Dzung L Pham; Michael A Kraut; Alan B Zonderman; Christos Davatzikos Journal: J Neurosci Date: 2003-04-15 Impact factor: 6.167
Authors: Kevin N Sheth; Jordan J Elm; Bradley J Molyneaux; Holly Hinson; Lauren A Beslow; Gordon K Sze; Ann-Christin Ostwaldt; Gregory J Del Zoppo; J Marc Simard; Sven Jacobson; W Taylor Kimberly Journal: Lancet Neurol Date: 2016-08-23 Impact factor: 44.182
Authors: Marjolein Geurts; H Bart van der Worp; L Jaap Kappelle; G Johan Amelink; Ale Algra; Jeannette Hofmeijer Journal: Stroke Date: 2013-07-18 Impact factor: 7.914
Authors: Melika Hosseini; Robert H Wilson; Christian Crouzet; Arya Amirhekmat; Kevin S Wei; Yama Akbari Journal: Neurotherapeutics Date: 2020-04 Impact factor: 7.620
Authors: George W Farr; Christopher H Hall; Susan M Farr; Ramon Wade; Joshua M Detzel; Amielia G Adams; Jasen M Buch; Derek L Beahm; Christopher A Flask; Kui Xu; Joseph C LaManna; Paul R McGuirk; Walter F Boron; Marc F Pelletier Journal: Neuroscience Date: 2019-02-07 Impact factor: 3.590
Authors: Ruchira M Jha; Anupama Rani; Shashvat M Desai; Sudhanshu Raikwar; Sandra Mihaljevic; Amanda Munoz-Casabella; Patrick M Kochanek; Joshua Catapano; Ethan Winkler; Giuseppe Citerio; J Claude Hemphill; W Taylor Kimberly; Raj Narayan; Juan Sahuquillo; Kevin N Sheth; J Marc Simard Journal: Int J Mol Sci Date: 2021-11-02 Impact factor: 5.923
Authors: Melissa Pergakis; Neeraj Badjatia; Seemant Chaturvedi; Carolyn A Cronin; W Taylor Kimberly; Kevin N Sheth; J Marc Simard Journal: Expert Opin Investig Drugs Date: 2019-10-24 Impact factor: 6.206