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      Effect of IV glyburide on adjudicated edema endpoints in the GAMES-RP Trial

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          Abstract

          Objective

          In this secondary analysis of the Glyburide Advantage in Malignant Edema and Stroke (GAMES-RP) Trial, we report the effect of IV glyburide on adjudicated, edema-related endpoints.

          Methods

          Blinded adjudicators assigned designations for hemorrhagic transformation, neurologic deterioration, malignant edema, and edema-related death to patients from the GAMES-RP phase II randomized controlled trial of IV glyburide for large hemispheric infarct. Rates of these endpoints were compared between treatment arms in the per-protocol sample. In those participants with malignant edema, the effects of treatment on additional markers of edema and clinical deterioration were examined.

          Results

          In the per-protocol sample, 41 patients received glyburide and 36 received placebo. There was no difference in the frequency of hemorrhagic transformation (n = 24 [58.5%] in IV glyburide vs n = 23 [63.9%] in placebo, p = 0.91) or the incidence of malignant edema (n = 19 [46%] in IV glyburide vs n = 17 [47%] in placebo, p = 0.94). However, treatment with IV glyburide was associated with a reduced proportion of deaths attributed to cerebral edema (n = 1 [2.4%] with IV glyburide vs n = 8 [22.2%] with placebo, p = 0.01). In the subset of patients with malignant edema, those treated with IV glyburide had less midline shift ( p < 0.01) and reduced MMP-9 (matrix metalloproteinase 9) levels ( p < 0.01). The glyburide treatment group had lower rate of NIH Stroke Scale (NIHSS) increase of ≥4 during the infusion period (n = 7 [37%] in IV glyburide vs n = 12 [71%] in placebo, p = 0.043), and of change in level of alertness (NIHSS subscore 1a; n = 11 [58%] vs n = 15 [94%], p = 0.016).

          Conclusion

          IV glyburide was associated with improvements in midline shift, level of alertness, and NIHSS, and there were fewer deaths attributed to edema. Additional studies of IV glyburide in large hemispheric infarction are warranted to corroborate these findings.

          ClinicalTrials.gov identifier

          NCT01794182.

          Level of evidence

          This study provides Class II evidence that for patients with large hemispheric infarction, IV glyburide improves some edema-related endpoints.

          Related collections

          Author and article information

          Contributors
          W. Taylor Kimberly:
          Comment :

          Scientific Advisory Boards:

          1. NONE

          Gifts:

          1. NONE

          Funding for Travel or Speaker Honoraria:

          1. NONE

          Editorial Boards:

          1. NONE

          Patents:

          1. NONE

          Publishing Royalties:

          1. NONE

          Employment, Commercial Entity:

          1. NONE

          Consultancies:

          1. NONE

          Speakers' Bureaus:

          1. NONE

          Other Activities:

          1. NONE

          Clinical Procedures or Imaging Studies:

          1. NONE

          Research Support, Commercial Entities:

          1. Remedy Pharmaceuticals Inc Biogen Idec

          Research Support, Government Entities:

          1. NIH/NINDS, R01 NS099209, PI, 2016-present

          Research Support, Academic Entities:

          1. NONE

          Research Support, Foundations and Societies:

          1. American Heart Association, 17CSA33550004, Multi-PI, 2017- present

          Stock/Stock Options/Board of Directors Compensation:

          1. NONE

          License Fee Payments, Technology or Inventions:

          1. NONE

          Royalty Payments, Technology or Inventions:

          1. NONE

          Stock/Stock Options, Research Sponsor:

          1. NONE

          Stock/Stock Options, Medical Equipment & Materials:

          1. NONE

          Legal Proceedings:

          1. NONE

          Matthew B. Bevers:
          Comment :

          Scientific Advisory Boards:

          1. NONE

          Gifts:

          1. NONE

          Funding for Travel or Speaker Honoraria:

          1. NONE

          Editorial Boards:

          1. NONE

          Patents:

          1. NONE

          Publishing Royalties:

          1. NONE

          Employment, Commercial Entity:

          1. NONE

          Consultancies:

          1. NONE

          Speakers' Bureaus:

          1. NONE

          Other Activities:

          1. NONE

          Clinical Procedures or Imaging Studies:

          1. NONE

          Research Support, Commercial Entities:

          1. NONE

          Research Support, Government Entities:

          1. NONE

          Research Support, Academic Entities:

          1. NONE

          Research Support, Foundations and Societies:

          1. American Academy of Neurology

          Stock/Stock Options/Board of Directors Compensation:

          1. NONE

          License Fee Payments, Technology or Inventions:

          1. NONE

          Royalty Payments, Technology or Inventions:

          1. NONE

          Stock/Stock Options, Research Sponsor:

          1. NONE

          Stock/Stock Options, Medical Equipment & Materials:

          1. NONE

          Legal Proceedings:

          1. NONE

          Rüdiger von Kummer:
          Comment :

          Scientific Advisory Boards:

          1. (1) Applied Clinical Intelligence LLC; (2) Brainsgate; (2) Parexel; (4) Karolinska Institutet; (5) Remedy Pharmaceuticals

          Gifts:

          1. NONE

          Funding for Travel or Speaker Honoraria:

          1. NONE

          Editorial Boards:

          1. (1)Neuroradiology, Editor in Chief since 2017

          Patents:

          1. NONE

          Publishing Royalties:

          1. (1)Stroke,Pathophysiology, Diagnosis, and Management. Elsevier, 5th Edition, 2011

          Employment, Commercial Entity:

          1. NONE

          Consultancies:

          1. NONE

          Speakers' Bureaus:

          1. NONE

          Other Activities:

          1. NONE

          Clinical Procedures or Imaging Studies:

          1. NONE

          Research Support, Commercial Entities:

          1. NONE

          Research Support, Government Entities:

          1. NONE

          Research Support, Academic Entities:

          1. NONE

          Research Support, Foundations and Societies:

          1. NONE

          Stock/Stock Options/Board of Directors Compensation:

          1. NONE

          License Fee Payments, Technology or Inventions:

          1. NONE

          Royalty Payments, Technology or Inventions:

          1. NONE

          Stock/Stock Options, Research Sponsor:

          1. NONE

          Stock/Stock Options, Medical Equipment & Materials:

          1. NONE

          Legal Proceedings:

          1. NONE

          Andrew M. Demchuk:
          Comment :

          Scientific Advisory Boards:

          1. (1) Bayer, advisory board for Rivaroxaban, 2015-2018 (2) Pfizer/BMS, advisory board for Apixaban, 2014-2018

          Gifts:

          1. NONE

          Funding for Travel or Speaker Honoraria:

          1. NONE

          Editorial Boards:

          1. (1) Journal of Neuroimaging, member of editorial board, 2005 to present. (2) Stroke, member of editorial board, 2009 to 2014. (3) Int J Stroke, member of editorial board, 2010 to present.

          Patents:

          1. NONE

          Publishing Royalties:

          1. NONE

          Employment, Commercial Entity:

          1. NONE

          Consultancies:

          1. NONE

          Speakers' Bureaus:

          1. (1) Pfizer/BMS, honoraria for speaking engagements, 2012 to present. (2) Covidien/Medtronic honoraria for speaking engagements, 2012 to present.

          Other Activities:

          1. NONE

          Clinical Procedures or Imaging Studies:

          1. NONE

          Research Support, Commercial Entities:

          1. (1) Covidien, received research grant for ESCAPE study, (2013). (2) Cerenovus/JnJ, received research grant for ENDOLOW trial, (2018)

          Research Support, Government Entities:

          1. (1) NIH-NINDS, received research funding as principal investigator of CT imaging analysis centre in IMS-3 trial. 2006 to 2014. (2) NIH-NINDS SPOTRIAS, received funding as principal investigator of CT volume analysis in STOP-IT trial. 2010 to present. (3) CIHR, received funding as principal investigator of CT volume analysis in SPOTLIGHT trial. 2011 to present. (4) CIHR, received funding as principal investigator of INTERRSeCT trial. 2012 to present. Stock/Stock Options, Medical Equipment & Materials: (1) I own Calgary Scientific, Inc. shares purchased in 2009 and 2010. (2) I own Quikflo Health shares 2015-2018.

          Research Support, Academic Entities:

          1. NONE

          Research Support, Foundations and Societies:

          1. NONE

          Stock/Stock Options/Board of Directors Compensation:

          1. NONE

          License Fee Payments, Technology or Inventions:

          1. NONE

          Royalty Payments, Technology or Inventions:

          1. NONE

          Stock/Stock Options, Research Sponsor:

          1. NONE

          Stock/Stock Options, Medical Equipment & Materials:

          1. NONE

          Legal Proceedings:

          1. NONE

          Javier M. Romero:
          Comment :

          Scientific Advisory Boards:

          1. NONE

          Gifts:

          1. NONE

          Funding for Travel or Speaker Honoraria:

          1. NONE

          Editorial Boards:

          1. NONE

          Patents:

          1. NONE

          Publishing Royalties:

          1. NONE

          Employment, Commercial Entity:

          1. NONE

          Consultancies:

          1. NONE

          Speakers' Bureaus:

          1. NONE

          Other Activities:

          1. NONE

          Clinical Procedures or Imaging Studies:

          1. NONE

          Research Support, Commercial Entities:

          1. NONE

          Research Support, Government Entities:

          1. NONE

          Research Support, Academic Entities:

          1. NONE

          Research Support, Foundations and Societies:

          1. NONE

          Stock/Stock Options/Board of Directors Compensation:

          1. NONE

          License Fee Payments, Technology or Inventions:

          1. NONE

          Royalty Payments, Technology or Inventions:

          1. NONE

          Stock/Stock Options, Research Sponsor:

          1. NONE

          Stock/Stock Options, Medical Equipment & Materials:

          1. NONE

          Legal Proceedings:

          1. NONE

          Jordan J. Elm:
          Comment :

          Scientific Advisory Boards:

          1. JJE received personal fees from Remedy Pharmaceuticals for attending a 1 day scientific advisory meeting.

          Gifts:

          1. NONE

          Funding for Travel or Speaker Honoraria:

          1. NONE

          Editorial Boards:

          1. I am an Associate Editor for movement disorders (no compensation)

          Patents:

          1. NONE

          Publishing Royalties:

          1. NONE

          Employment, Commercial Entity:

          1. NONE

          Consultancies:

          1. NONE

          Speakers' Bureaus:

          1. NONE

          Other Activities:

          1. NONE

          Clinical Procedures or Imaging Studies:

          1. NONE

          Research Support, Commercial Entities:

          1. Research support from Remedy Pharmaceutical to support the statistics and data management (database development) for the GAMES-RP trial.

          Research Support, Government Entities:

          1. Grants from National Institute of Neurological Disorders and Stroke and National Institutes of Health outside of the submitted work.

          Research Support, Academic Entities:

          1. NONE

          Research Support, Foundations and Societies:

          1. Research support for Michael J Fox Foundation unrelated to this paper.

          Stock/Stock Options/Board of Directors Compensation:

          1. NONE

          License Fee Payments, Technology or Inventions:

          1. NONE

          Royalty Payments, Technology or Inventions:

          1. NONE

          Stock/Stock Options, Research Sponsor:

          1. NONE

          Stock/Stock Options, Medical Equipment & Materials:

          1. NONE

          Legal Proceedings:

          1. NONE

          Holly E. Hinson:
          Comment :

          Scientific Advisory Boards:

          1. (1) Biogen

          Gifts:

          1. NONE

          Funding for Travel or Speaker Honoraria:

          1. NONE

          Editorial Boards:

          1. NONE

          Patents:

          1. NONE

          Publishing Royalties:

          1. NONE

          Employment, Commercial Entity:

          1. NONE

          Consultancies:

          1. NONE

          Speakers' Bureaus:

          1. NONE

          Other Activities:

          1. NONE

          Clinical Procedures or Imaging Studies:

          1. NONE

          Research Support, Commercial Entities:

          1. NONE

          Research Support, Government Entities:

          1. 5 K12HL108974-04 Newgard (PI) 7/01/2013-6/30/2016 NIH/NHLBI Oregon Multidisciplinary Training Program for Emergency Medicine Clinical Research Sponsor: NHLBI grant #1K12HL108974 Title: Fever and Inflammation in Neurotrauma (FAINT) Role: Scholar

          Research Support, Academic Entities:

          1. NONE

          Research Support, Foundations and Societies:

          1. American Academy of Neurology 7/01/2012-6/30/2013 2012 American Brain Foundation Practice Research Training Fellowship Quantifying Paroxysmal Sympathetic Hyperactivity Principal Investigator: Holly Hinson

          Stock/Stock Options/Board of Directors Compensation:

          1. NONE

          License Fee Payments, Technology or Inventions:

          1. NONE

          Royalty Payments, Technology or Inventions:

          1. NONE

          Stock/Stock Options, Research Sponsor:

          1. NONE

          Stock/Stock Options, Medical Equipment & Materials:

          1. NONE

          Legal Proceedings:

          1. NONE

          Bradley J. Molyneaux:
          Comment :

          Scientific Advisory Boards:

          1. Scientific advisory board, Remedy Pharmaceuticals. Clinical trial steering committee, Biogen.

          Gifts:

          1. NONE

          Funding for travel or speaker honoraria:

          1. Remedy Pharmaceuticals, travel expenses for clinical trial meetings

          Editorial Boards:

          1. NONE

          Patents:

          1. NONE

          Publishing Royalties:

          1. NONE

          Employment, Commercial Entity:

          1. NONE

          Consultancies:

          1. NONE

          Speakers' Bureaus:

          1. NONE

          Other Activities:

          1. NONE

          Clinical Procedures or Imaging Studies:

          1. NONE

          Research Support, Commercial Entities:

          1. Remedy Pharmaceuticals

          Research Support, Government Entities:

          1. NONE

          Research Support, Academic Entities:

          1. NONE

          Research Support, Foundations and Societies:

          1. NONE

          Stock/Stock Options/Board of Directors Compensation:

          1. NONE

          License Fee Payments, Technology or Inventions:

          1. NONE

          Royalty Payments, Technology or Inventions:

          1. NONE

          Stock/Stock Options, Research Sponsor:

          1. NONE

          Stock/Stock Options, Medical Equipment & Materials:

          1. NONE

          Legal Proceedings:

          1. NONE

          J. Marc Simard:
          Comment :

          Scientific Advisory Boards:

          1. Remedy Pharmaceuticals Biogen

          Gifts:

          1. NONE

          Funding for travel or speaker honoraria:

          1. AANS

          Editorial Boards:

          1. J Neurotrauma

          Patents:

          1. patents related to brain swelling

          Publishing Royalties:

          1. NONE

          Employment, Commercial Entity:

          1. NONE

          Consultancies:

          1. NONE

          Speakers' Bureaus:

          1. NONE

          Other Activities:

          1. NONE

          Clinical Procedures or Imaging Studies:

          1. NONE

          Research Support, Commercial Entities:

          1. NONE

          Research Support, Government Entities:

          1. NIH VA DoD

          Research Support, Academic Entities:

          1. NONE

          Research Support, Foundations and Societies:

          1. NONE

          Stock/Stock Options/Board of Directors Compensation:

          1. NONE

          License Fee Payments, Technology or Inventions:

          1. NONE

          Royalty Payments, Technology or Inventions:

          1. NONE

          Stock/Stock Options, Research Sponsor:

          1. NONE

          Stock/Stock Options, Medical Equipment & Materials:

          1. NONE

          Legal Proceedings:

          1. NONE

          Kevin N. Sheth:
          Comment :

          Scientific Advisory Boards:

          1. NONE

          Gifts:

          1. NONE

          Funding for Travel or Speaker Honoraria:

          1. NONE

          Editorial Boards:

          1. Editorial Board, Stroke Edtorial Board, Neurology

          Patents:

          1. Provisional patent (1) Stroke detection technology

          Publishing Royalties:

          1. NONE

          Employment, Commercial Entity:

          1. NONE

          Consultancies:

          1. NONE

          Speakers' Bureaus:

          1. NONE

          Other Activities:

          1. NONE

          Clinical Procedures or Imaging Studies:

          1. NONE

          Research Support, Commercial Entities:

          1. Remedy Pharmaceuticals, Bard, Stryker, Novartis, Biogen, Hyperfine

          Research Support, Government Entities:

          1. (1) NIH U24NS107136, U24NS107215 (2) AHA 17CSA33550004

          Research Support, Academic Entities:

          1. NONE

          Research Support, Foundations and Societies:

          1. American Academy of Neurology Clinical Research Fellowship, American Heart Association Passano Foundation

          Stock/Stock Options/Board of Directors Compensation:

          1. NONE

          License Fee Payments, Technology or Inventions:

          1. NONE

          Royalty Payments, Technology or Inventions:

          1. NONE

          Stock/Stock Options, Research Sponsor:

          1. NONE

          Stock/Stock Options, Medical Equipment & Materials:

          1. NONE

          Legal Proceedings:

          1. Legal consultant

          Journal
          Journal ID (nlm-ta): Neurology
          Journal ID (iso-abbrev): Neurology
          Journal ID (hwp): neurology
          Journal ID (publisher-id): neur
          Journal ID (pmc): neurology
          Journal ID (publisher-id): NEUROLOGY
          Title: Neurology
          Publisher: Lippincott Williams & Wilkins (Hagerstown, MD )
          ISSN (Print): 0028-3878
          ISSN (Electronic): 1526-632X
          Publication date (Print): 04 December 2018
          Publication date PMC-release: 04 December 2019
          Volume: 91
          Issue: 23
          Pages: e2163-e2169
          Affiliations
          From the Department of Neurology and Center for Genomic Medicine (W.T.K.), and Department of Radiology, Division of Neuroradiology (J.M.R.), Massachusetts General Hospital, Boston; Divisions of Stroke, Cerebrovascular and Critical Care Neurology (M.B.B.), Brigham & Women's Hospital, Boston, MA; Department of Neuroradiology (R.v.K.), Universitätsklinikum Carl Gustav Carus, Dresden, Germany; Calgary Stroke Program (A.M.D.), Department of Clinical Neurosciences and Radiology, Hotchkiss Brain Institute, University of Calgary, Canada; Department of Public Health Sciences (J.J.E.), Medical University of South Carolina, Charleston; Department of Neurology (H.E.H.), Oregon Health Sciences University, Portland; Department of Neurology (B.J.M.), University of Pittsburgh, PA; Department of Neurosurgery (J.M.S.), University of Maryland School of Medicine, Baltimore; and Division of Neurocritical Care and Emergency Neurology (K.N.S.), Yale New Haven Hospital, CT.
          Author notes
          Correspondence Dr. Kimberly wtkimberly@ 123456mgh.harvard.edu or Dr. Sheth kevin.sheth@ 123456yale.edu
          [*]

          These authors contributed equally to this work.

          Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

          Article
          Accession ID: PMC6282228 Pmcid ID: PMC6282228 Pmc-uid ID: 6282228 Publisher ID: NEUROLOGY2018889162
          DOI: 10.1212/WNL.0000000000006618
          PMC ID: 6282228
          PubMed ID: 30446594
          SO-VID: a10eb649-1a21-468e-8485-c9a9e67b34e3
          Copyright © © 2018 American Academy of Neurology
          History
          Date received : 16 March 2018
          Date accepted : 23 August 2018
          Funding
          Funded by: NHLBI
          Award ID: R01 HL082517
          Funded by: NINDS
          Award ID: R01 NS060801, K23 NS076597, R01 NS099209, 14GRNT19060044, AHA 17CSA 33550004
          Categories
          Subject: 2
          Subject: 295
          Subject: Article
          Custom metadata
          STATUS ONLINE-ONLY

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