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

Sheth, Kevin N; Beslow, Lauren A.; Sze, Gordon; Kimberly, W. Taylor

doi:10.1007/s12028-015-0189-7

Cited by 49 publications

(43 citation statements)

References 32 publications

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“…We have exciting preliminary data suggesting human CSF Sur1 levels are undetectable in non-injured controls, elevated in patients with sTBI, and trajectories may correlate with CE and outcomes ( In Press , Critical Care Medicine, abstract presented at American Academy of Neurology, 2016[29]). The efficacy of inhibiting this pathway with Glyburide has shown promise, and is being evaluated by ongoing clinical trials[16,17]. Particularly in light of its regulated expression and regulatory function, genetic variability in the Sur1 gene, ABCC8 , could provide important information regarding patient risk-stratification, monitoring, efficacy of targeted therapies, and prognosis - not only in TBI but also in other neurologic diseases affected by CE like ischemic stroke.…”

Section: Discussionmentioning

confidence: 99%

ABCC8 Single Nucleotide Polymorphisms are Associated with Cerebral Edema in Severe TBI

et al. 2016

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Objective Cerebral Edema (CE) in TBI is the consequence of multiple underlying mechanisms, and is associated with unfavorable outcomes. Genetic variability in these pathways likely explains some of the clinical heterogeneity observed in edema development. A role for Sulfonylurea-receptor-1 (Sur1) in CE is supported. However, there are no prior studies examining the effect of genetic variability in the Sur1 gene (ABCC8) on the development of CE. We hypothesize that ABCC8 single nucleotide polymorphisms (SNP) are predictive of CE. Methods DNA was extracted from 385 patients. SNPs in ABCC8 were genotyped using the Human Core Exome v1.2 (Illumina). CE measurements included acute CT edema, mean and peak intracranial pressure (ICP), and need for decompressive craniotomy. Results 14 SNPs with minor-allele frequency>0.2 were identified. 4 SNPS rs2283261, rs3819521, rs2283258 and rs1799857 were associated with CE measures. In multiple regression models, homozygote-variant genotypes in rs2283261, rs3819521, and rs2283258 had increased odds of CT edema (OR=2.45, p=0.007; OR=2.95, p=0.025; OR=3.00, p=0.013), had higher mean (β=3.13,p=0.000; β=2.95,p=0.005; β=3.20,p=0.008) and peak (β=8.00,p=0.001; β=7.64,p=0.007; β=6.89,p=0.034) ICP. The homozygote wild-type genotype of rs1799857 had decreased odds of decompressive craniotomy (OR=0.47, p=0.004). Conclusions This is the first report assessing the impact of ABCC8 genetic variability on CE development in TBI. Minor allele ABCC8 SNP genotypes had increased risk of CE, while major SNP alleles were protective—potentially suggesting an evolutionary advantage. These findings could guide risk stratification, treatment responders, and the development of novel targeted or gene-based therapies against CE in TBI and other neurological disorders.

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Section: Discussionmentioning

confidence: 99%

ABCC8 Single Nucleotide Polymorphisms are Associated with Cerebral Edema in Severe TBI

et al. 2016

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“…Ultra-early administration of neuroprotectant agents within the first hour of symptoms onset in the field has been recently shown to be feasible. 17 Several agents with neuroprotectant properties, such as NA-1, 18 uric acid, 19 glyburide, 20 argatroban, 15 and activated protein C, 21 have recently been found to yield signals of potential benefit in phase II human studies with no associated major safety concerns. These encouraging preliminary results support randomized studies testing their benefit in conjunction with ET compared with ET alone.…”

Section: Adjuvant Approaches To Etmentioning

confidence: 99%

Stroke Treatment Academic Industry Roundtable

Jovin¹,

Albers²,

Liebeskind³

2016

Stroke

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Background and Purpose The STAIR (Stroke Treatment Academic Industry Roundtable) meeting aims to advance acute stroke therapy development through collaboration between academia, industry, and regulatory institutions. In pursuit of this goal and building on recently available level I evidence of benefit from endovascular therapy (ET) in large vessel occlusion stroke, STAIR IX consensus recommendations were developed that outline priorities for future research in ET. Methods Three key directions for advancing the field were identified: (1) development of systems of care for ET in large vessel occlusion stroke, (2) development of therapeutic approaches adjunctive to ET, and (3) exploring clinical benefit of ET in patient population insufficiently studied in recent trials. Methodological issues such as optimal trial design and outcome measures have also been addressed. Results Development of systems of care strategies should be geared both toward ensuring broad access to ET for eligible patients and toward shortening time to reperfusion to the minimum possible. Adjunctive therapy development includes neuroprotective approaches, adjuvant microcirculatory/collateral enhancing strategies, and periprocedural management. Future research priorities seeking to expand the eligible patient population are to determine benefit of ET in patients presenting beyond conventional time windows, in patients with large baseline ischemic core lesions, and in other important subgroups. Conclusions Research priorities in ET for large vessel occlusion stroke are to improve systems of care, investigate effective adjuvant therapies, and explore whether patient eligibility could be expanded.

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“…Recently, a 2-center, prospective, open label, Phase IIa “pilot” study of RP-1127 was completed (ClinicalTrials.gov Identifier: NCT01268683) [33]. This clinical trial tested the effect of RP-1127 in 10 patients with a severe anterior circulation ischemic stroke (baseline infarct volume ≥ 82 mL; mean, 102 ± 23 mL; baseline NIHSS score, 19 ± 8) at high risk for malignant cerebral edema.…”

Section: Reviewmentioning

confidence: 99%

“…A larger clinical trial studying the effect of RP-1127 in patients with large ischemic strokes currently is underway and actively recruiting patients (ClinicalTrials.gov Identifier: NCT01794182) [32]. The primary objective is to demonstrate the safety and efficacy of RP-1127 compared to placebo in subjects with a severe anterior circulation ischemic stroke who are likely to develop malignant edema.…”

Section: Reviewmentioning

confidence: 99%

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Glibenclamide for the Treatment of Acute CNS Injury

et al. 2013

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First introduced into clinical practice in 1969, glibenclamide (US adopted name, glyburide) is known best for its use in the treatment of diabetes mellitus type 2, where it is used to promote the release of insulin by blocking pancreatic KATP [sulfonylurea receptor 1 (Sur1)-Kir6.2] channels. During the last decade, glibenclamide has received renewed attention due to its pleiotropic protective effects in acute CNS injury. Acting via inhibition of the recently characterized Sur1-Trpm4 channel (formerly, the Sur1-regulated NCCa-ATP channel) and, in some cases, via brain KATP channels, glibenclamide has been shown to be beneficial in several clinically relevant rodent models of ischemic and hemorrhagic stroke, traumatic brain injury, spinal cord injury, neonatal encephalopathy of prematurity, and metastatic brain tumor. Glibenclamide acts on microvessels to reduce edema formation and secondary hemorrhage, it inhibits necrotic cell death, it exerts potent anti-inflammatory effects and it promotes neurogenesis—all via inhibition of Sur1. Two clinical trials, one in TBI and one in stroke, currently are underway. These recent findings, which implicate Sur1 in a number of acute pathological conditions involving the CNS, present new opportunities to use glibenclamide, a well-known, safe pharmaceutical agent, for medical conditions that heretofore had few or no treatment options.

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

Abstract: 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.

Cited by 49 publications

References 32 publications

ABCC8 Single Nucleotide Polymorphisms are Associated with Cerebral Edema in Severe TBI

ABCC8 Single Nucleotide Polymorphisms are Associated with Cerebral Edema in Severe TBI

Stroke Treatment Academic Industry Roundtable

Glibenclamide for the Treatment of Acute CNS Injury

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