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Glyburide Advantage in Malignant Edema and Stroke (GAMES-RP) Trial: Rationale and Design

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Abstract

Background

Patients with large territory infarction are at high risk of cerebral edema and neurological deterioration, including death. Preclinical studies have shown that a continuous infusion of glyburide blocks edema formation and improves outcome. We hypothesize that treatment with RP-1127 (Glyburide for Injection) reduces formation of brain edema in patients after large anterior circulation infarction.

Methods

GAMES-RP is a prospective, randomized, double-blind, multicenter trial designed to evaluate RP-1127 in patients at high risk for the development of malignant cerebral edema. The study population consisted of subjects with a clinical diagnosis of acute severe anterior circulation ischemic stroke with a baseline diffusion-weighted image lesion between 82 and 300 cm3 who are 18–80 years of age. The target time from symptom onset to start of study infusion was ≤10 h. Subjects were randomized to RP-1127 (glyburide for injection) or placebo and treated with a continuous infusion for 72 h.

Results

The primary efficacy outcome was a composite of the modified Rankin Scale and the incidence of decompressive craniectomy, assessed at 90 days. Safety outcomes were the frequency and severity of adverse events, with a focus on cardiac- and glucose-related serious adverse events.

Conclusions

GAMES-RP was designed to provide critical information regarding glyburide for injection in patients with large hemispheric stroke and will inform the design of future studies.

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References

  1. Sacco RL, Adams R, Albers G, Alberts MJ, Benavente O, Furie K, Goldstein LB, Gorelick P, Halperin J, Harbaugh R, Johnston SC, Katzan I, Kelly-Hayes M, Kenton EJ, Marks M, Schwamm LH, Tomsick T, American Heart Association/American Stroke Association Council on Stroke, American Academy of Neurology. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American heart association/American stroke association council on stroke: co-sponsored by the council on cardiovascular radiology and intervention: the American academy of neurology affirms the value of this guideline. Circulation. 2006;113(10):e409–49.16534023.

    PubMed  Google Scholar 

  2. Hacke W, Schwab S, Horn M, Spranger M, De Georgia M, von Kummer R. ‘Malignant’ middle cerebral artery territory infarction: clinical course and prognostic signs. Arch. Neurol. 1996;53(4):309–315.8929152.

    Article  CAS  PubMed  Google Scholar 

  3. Wijdicks EF, Sheth KN, Carter BS, Greer DM, Kasner SE, Kimberly WT, Schwab S, Smith EE, Tamargo RJ, Wintermark M, American Heart Association Stroke Council. Recommendations for the management of cerebral and cerebellar infarction with swelling: a statement for healthcare professionals from the American heart association/American stroke association. Stroke. 2014;45(4):1222–1238.24481970.

    Article  PubMed  Google Scholar 

  4. Berrouschot J, Rossler A, Koster J, Schneider D. Mechanical ventilation in patients with hemispheric ischemic stroke. Crit. Care Med. 2000;28(8):2956–2961.10966278.

    Article  CAS  PubMed  Google Scholar 

  5. Vahedi K, Hofmeijer J, Juettler E, Vicaut E, George B, Algra A, Amelink GJ, Schmiedeck P, Schwab S, Rothwell PM, Bousser MG, van der Worp HB, Hacke W. DECIMAL, DESTINY, and HAMLET investigators. Early decompressive surgery in malignant infarction of the middle cerebral artery: a pooled analysis of three randomised controlled trials. Lancet Neurol. 2007;6(3):215–222.17303527.

    Article  PubMed  Google Scholar 

  6. Arac A, Blanchard V, Lee M, Steinberg GK. Assessment of outcome following decompressive craniectomy for malignant middle cerebral artery infarction in patients older than 60 years of age. Neurosurg. Focus. 2009;26(6):E3.19485716.

    Article  Google Scholar 

  7. Simard JM, Tsymbalyuk N, Tsymbalyuk O, Ivanova S, Yurovsky V, Gerzanich V. Glibenclamide is superior to decompressive craniectomy in a rat model of malignant stroke. Stroke. 2010;41(3):531–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Chen M, Simard JM. Cell swelling and a nonselective cation channel regulated by internal Ca2+ and ATP in native reactive astrocytes from adult rat brain. J. Neurosci. 2001;21(17):6512–6521.11517240.

    CAS  PubMed  Google Scholar 

  9. Chen M, Dong Y, Simard JM. Functional coupling between sulfonylurea receptor type 1 and a nonselective cation channel in reactive astrocytes from adult rat brain. J. Neurosci. 2003;23(24):8568–8577.13679426.

    CAS  PubMed  Google Scholar 

  10. Simard JM, Chen M, Tarasov KV, Bhatta S, Ivanova S, Melnitchenko L, Tsymbalyuk N, West GA, Gerzanich V. Newly expressed SUR1-regulated NC(ca-ATP) channel mediates cerebral edema after ischemic stroke. Nat. Med. 2006;12(4):433–40.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Simard JM, Kent TA, Chen M, Tarasov KV, Gerzanich V. Brain oedema in focal ischaemia: Molecular pathophysiology and theoretical implications. Lancet Neurol. 2007;6(3):258–68.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Woo SK, Kwon MS, Geng Z, Chen Z, Ivanov A, Bhatta S, Gerzanich V, Simard JM. Sequential activation of hypoxia-inducible factor 1 and specificity protein 1 is required for hypoxia-induced transcriptional stimulation of Abcc8. J. Cereb. Blood Flow Metab. 2012;32(3):525–36.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Sheth KN, Kimberly WT, Elm JJ, Kent TA, Mandava P, Yoo AJ, Thomalla G, Campbell B, Donnan GA, Davis SM, Albers GW, Jacobson S, Simard JM, Stern BJ. Pilot study of intravenous glyburide in patients with a large ischemic stroke. Stroke. 2014;45(1):281–283.24193798.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Sheth KN, Kimberly WT, Elm JJ, Kent TA, Yoo AJ, Thomalla G, Campbell B, Donnan GA, Davis SM, Albers GW, Jacobson S, del Zoppo G, Simard JM, Stern BJ, Mandava P. Exploratory analysis of glyburide as a novel therapy for preventing brain swelling. Neurocrit. Care. 2014;21(1):43–51.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Thomalla G, Hartmann F, Juettler E, Singer OC, Lehnhardt FG, Kohrmann M, Kersten JF, Krutzelmann A, Humpich MC, Sobesky J, Gerloff C, Villringer A, Fiehler J, Neumann-Haefelin T, Schellinger PD, Rother J, Clinical Trial Net of the German Competence Network Stroke. Prediction of malignant middle cerebral artery infarction by magnetic resonance imaging within 6 hours of symptom onset: a prospective multicenter observational study. Ann Neurol. 2010;68(4):435–445.20865766.

    Article  PubMed  Google Scholar 

  16. Sims JR, Gharai LR, Schaefer PW, Vangel M, Rosenthal ES, Lev MH, Schwamm LH. ABC/2 for rapid clinical estimate of infarct, perfusion, and mismatch volumes. Neurology. 2009;72(24):2104–10.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Broderick JP, Palesch YY, Demchuk AM, Yeatts SD, Khatri P, Hill MD, Jauch EC, Jovin TG, Yan B, Silver FL, von Kummer R, Molina CA, Demaerschalk BM, Budzik R, Clark WM, Zaidat OO, Malisch TW, Goyal M, Schonewille WJ, Mazighi M, Engelter ST, Anderson C, Spilker J, Carrozzella J, Ryckborst KJ, Janis LS, Martin RH, Foster LD, Tomsick TA, Interventional Management of Stroke (IMS) III Investigators. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N. Engl. J. Med. 2013;368(10):893–903.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Mlynash M, Lansberg MG, DA De Silva, Lee J, Christensen S, Straka M, Campbell BC, Bammer R, Olivot JM, Desmond P, Donnan GA, Davis SM, Albers GW, DEFUSE-EPITHET Investigators. Refining the definition of the malignant profile: insights from the DEFUSE-EPITHET pooled data set. Stroke. 2011;42(5):1270–5.

    Article  PubMed Central  PubMed  Google Scholar 

  19. Videen TO, Zazulia AR, Manno EM, Derdeyn CP, Adams RE, Diringer MN, Powers WJ. Mannitol bolus preferentially shrinks non-infarcted brain in patients with ischemic stroke. Neurology. 2001;57(11):2120–2122.11739839.

    Article  CAS  PubMed  Google Scholar 

  20. Simard JM, Woo SK, Tsymbalyuk N, Voloshyn O, Yurovsky V, Ivanova S, Lee R, Gerzanich V. Glibenclamide-10-h treatment window in a clinically relevant model of stroke. Transl. Stroke Res. 2012;3(2):286–95.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Yoo AJ, Barak ER, Copen WA, Kamalian S, Gharai LR, Pervez MA, Schwamm LH, Gonzalez RG, Schaefer PW. Combining acute diffusion-weighted imaging and mean transmit time lesion volumes with national institutes of health stroke scale score improves the prediction of acute stroke outcome. Stroke. 2010;41(8):1728–1735.20595665.

    Article  PubMed  Google Scholar 

  22. Wijdicks EF. Clinical scales for comatose patients: The glasgow coma scale in historical context and the new FOUR score. Rev. Neurol. Dis. 2006;3(3):109–117.17047576.

    PubMed  Google Scholar 

  23. Rahme R, Zuccarello M, Kleindorfer D, Adeoye OM, Ringer AJ. Decompressive hemicraniectomy for malignant middle cerebral artery territory infarction: is life worth living? J. Neurosurg. 2012;117(4):749–754.22920962.

    Article  PubMed  Google Scholar 

  24. Walcott BP, Kuklina EV, Nahed BV, George MG, Kahle KT, Simard JM, Asaad WF, Coumans JV. Craniectomy for malignant cerebral infarction: prevalence and outcomes in US hospitals. PLoS One. 2011;6(12):e29193.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Yoo AJ, Sheth KN, Kimberly WT, Chaudhry ZA, Elm JJ, Jacobson S, Davis SM, Donnan GA, Albers GW, Stern BJ, Gonzalez RG. Validating imaging biomarkers of cerebral edema in patients with severe ischemic stroke. J. Stroke Cerebrovasc. Dis. 2013;22(6):742–9.

    Article  PubMed Central  PubMed  Google Scholar 

  26. Battey TW, Karki M, Singhal AB, Wu O, Sadaghiani S, Campbell BC, Davis SM, Donnan GA, Sheth KN, Kimberly WT. Brain edema predicts outcome after nonlacunar ischemic stroke. Stroke. 2014;45(12):3643–3648.25336512.

    Article  PubMed Central  PubMed  Google Scholar 

  27. Jha R, Battey TW, Pham L, Lorenzano S, Furie KL, Sheth KN, Kimberly WT. Fluid-attenuated inversion recovery hyperintensity correlates with matrix metalloproteinase-9 level and hemorrhagic transformation in acute ischemic stroke. Stroke. 2014;45(4):1040–5.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Kimberly WT, Battey TW, Pham L, Wu O, Yoo AJ, Furie KL, Singhal AB, Elm JJ, Stern BJ, Sheth KN. Glyburide is associated with attenuated vasogenic edema in stroke patients. Neurocrit. Care. 2013;20:193–201.2624072459.

    Article  Google Scholar 

  29. Sheth KN. Novel approaches to the primary prevention of edema after ischemia. Stroke. 2013;44(6 Suppl 1):S136.23709712.

    Google Scholar 

  30. Juttler E, Unterberg A, Woitzik J, Bosel J, Amiri H, Sakowitz OW, Gondan M, Schiller P, Limprecht R, Luntz S, Schneider H, Pinzer T, Hobohm C, Meixensberger J, Hacke W, DESTINY II Investigators, 12. Hemicraniectomy in older patients with extensive middle-cerebral-artery stroke. N. Engl. J. Med. 2014;1100.24645942:1091–1100.24645942.

    Article  Google Scholar 

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Author information

Authors and Affiliations

  1. Division of Neurocritical Care & Emergency Neurology, Department of Neurology, Yale University School of Medicine, 15 York Street, LCI 1003, New Haven, CT, 06510, USA

    Kevin N. Sheth & Lauren A. Beslow

  2. Department of Public Health Sciences, Medical University of South Carolina, Charleston, USA

    Jordan J. Elm

  3. Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA

    Lauren A. Beslow

  4. Department of Radiology, Yale University School of Medicine, New Haven, CT, USA

    Gordon K. Sze

  5. Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA

    W. Taylor Kimberly

Authors
  1. Kevin N. Sheth
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  2. Jordan J. Elm
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Corresponding authors

Correspondence to Kevin N. Sheth or W. Taylor Kimberly.

Ethics declarations

Conflict of interest

The authors received research Grants from the sponsor of the study to conduct study activities. No author has received speaking honoraria, nor owns stock in the sponsoring company.

Funding

The sponsor of this phase II study, GAMES-RP, is Remedy Pharmaceuticals.

Additional information

The GAMES-RP Study Team members are listed in the Appendix.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 296 kb)

Supplementary material 2 (PDF 2279 kb)

Appendices

Executive Committee

Kevin N. Sheth, W. Taylor Kimberly, Sven Jacobson, Jordan Elm.

Neuroimaging and Biomarker Core

Lauren A. Beslow (Yale), Gordon K. Sze (Yale), Hannah J. Irvine (Massachusetts General Hospital), Thomas W. K. Battey (Massachusetts General Hospital), Ann-Christin Ostwaldt (Massachusetts General Hospital).

Data Monitoring Committee

J. Donald Easton (UCSF), Karen Johnston (University of Virginia), Michael Diringer (Washington University).

GAMES-RP Site Investigators

Bradley Molyneaux (University of Pittsburgh), Paul Muscat (Maine Medical Center), W. Taylor Kimberly (Massachusetts General Hospital), Kendra Drake (University of Arizona), Jennifer Majerisk (Utah), Edward Manno (Cleveland Clinic), Raphael Carandang (University of Massachusetts), Carolyn Cronin (University of Maryland), Michel Torbey (Ohio State), Shyam Prabhakaran (Northwestern), David Hwang (Yale), Scott Silliman (University of Florida), Osman Kozak (Abington), Holly Hinson (Oregon Health Sciences), Igor Rybinnik (Rutgers), Wei Liu (University of Louisville), Gregory Albers (Stanford), Edward Jauch (Medical University of South Carolina).

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Sheth, K.N., Elm, J.J., Beslow, L.A. et al. Glyburide Advantage in Malignant Edema and Stroke (GAMES-RP) Trial: Rationale and Design. Neurocrit Care 24, 132–139 (2016). https://doi.org/10.1007/s12028-015-0189-7

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  • DOI: https://doi.org/10.1007/s12028-015-0189-7

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