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Kevin N Sheth - One of the best experts on this subject based on the ideXlab platform.

  • osmotherapy for Malignant cerebral Edema in a phase 2 prospective double blind randomized placebo controlled study of iv glibenclamide
    Journal of Stroke & Cerebrovascular Diseases, 2020
    Co-Authors: Holly E Hinson, Rüdiger Von Kummer, Bradley J Molyneaux, Taylor W Kimberly, ANDREW MICHAEL DEMCHUK, Javier Romero, Kevin N Sheth
    Abstract:

    Abstract Background/Objective Malignant Edema can be a life-threatening complication of large hemispheric infarction (LHI), and is often treated with osmotherapy. In this exploratory analysis of data from the GAMES-RP study, we hypothesized that patients receiving osmotherapy had symptomatic cerebral Edema, and that treatment with intravenous (IV) glibenclamide would modify osmotherapy use as compared with placebo. Methods GAMES-RP was a phase 2 multi-center prospective, double blind, randomized, placebo-controlled study in LHI. Patients were randomized to IV glibenclamide (e.g. IV glyburide) or placebo. Cerebral Edema therapies included osmotherapy and/or decompressive craniectomy at the discretion of the treating team. Total bolus osmotherapy dosing was quantified by “osmolar load”. Radiographic Edema was defined by dichotomizing midline shift at 24 h. Clinical changes were defined as any increase in NIHSS1a. Results Osmotherapy was administered to 40 of the 77 patients at a median of 39 [27–55] h after stroke onset. The median baseline DWI lesion volume was significantly larger in the osmotherapy treated group (167 [146–211] mL v. 139 [112–170] mL; P=0.046). Adjudicated Malignant Edema (75% v. 16%; P Conclusions In the GAMES-RP trial, osmolar therapies were most often administered in response to clinical symptoms of decreased consciousness. However, the optimal timing of administration and impact on outcome after LHI have yet to be defined.

  • Intravenous Glibenclamide Reduces Lesional Water Uptake in Large Hemispheric Infarction.
    Stroke, 2019
    Co-Authors: Pongpat Vorasayan, Lauren A. Beslow, Matthew B Bevers, Holly E Hinson, Bradley J Molyneaux, Kevin N Sheth, J. Marc Simard, Gordon Sze, Rüdiger Von Kummer, W. Taylor Kimberly
    Abstract:

    Background and Purpose- Prior studies have shown a linear relationship between computed tomography (CT)-derived radiodensity and water uptake, or brain Edema, within stroke lesions. To test the hypothesis that intravenous glibenclamide (glyburide; BIIB093) reduces ischemic brain water uptake, we quantified the lesional net water uptake (NWU) on serial CT scans from patients enrolled in the phase 2 GAMES-RP Trial (Glyburide Advantage in Malignant Edema and Stroke). Methods- This was a post hoc exploratory analysis of the GAMES-RP study. Noncontrast CT scans performed between admission and day 7 (n=264) were analyzed in the GAMES-RP modified intention-to-treat sample. Quantitative change in CT radiodensity (ie, NWU) and midline shift (MLS) was measured. The gray and white matter NWU were also examined separately. Repeated-measures mixed-effects models were used to assess the effect of intravenous glibenclamide on MLS or NWU. Results- A median of 3 CT scans (interquartile range, 2-4) were performed per patient during the first 7 days after stroke. In a repeated-measures regression model, greater NWU was associated with increased MLS (β=0.23; 95% CI, 0.20-0.26; P

  • effect of iv glyburide on adjudicated Edema endpoints in the games rp trial
    Neurology, 2018
    Co-Authors: Taylor W Kimberly, Rüdiger Von Kummer, Matthew B Bevers, Holly E Hinson, Bradley J Molyneaux, Marc J Simard, ANDREW MICHAEL DEMCHUK, Javier Romero, Kevin N Sheth
    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 p 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.

  • effect of iv glyburide on adjudicated Edema endpoints in the games rp trial
    Neurology, 2018
    Co-Authors: Taylor W Kimberly, Rüdiger Von Kummer, Matthew B Bevers, Holly E Hinson, Bradley J Molyneaux, Marc J Simard, ANDREW MICHAEL DEMCHUK, Javier Romero, Kevin N Sheth
    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 p 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.

  • profile of intravenous glyburide for the prevention of cerebral Edema following large hemispheric infarction evidence to date
    Drug Design Development and Therapy, 2018
    Co-Authors: Zachary A King, Taylor W Kimberly, Kevin N Sheth, Marc J Simard
    Abstract:

    : Glyburide (also known as glibenclamide) is a second-generation sulfonylurea drug that inhibits sulfonylurea receptor 1 (Sur1) at nanomolar concentrations. Long used to target KATP (Sur1-Kir6.2) channels for the treatment of diabetes mellitus type 2, glyburide was recently repurposed to target Sur1-transient receptor potential melastatin 4 (Trpm4) channels in acute central nervous system injury. Discovered nearly two decades ago, SUR1-TRPM4 has emerged as a critical target in stroke, specifically in large hemispheric infarction, which is characterized by Edema formation and life-threatening brain swelling. Following ischemia, SUR1-TRPM4 channels are transcriptionally upregulated in all cells of the neurovascular unit, including neurons, astrocytes, microglia, oligodendrocytes and microvascular endothelial cells. Work by several independent laboratories has linked SUR1-TRPM4 to Edema formation, with blockade by glyburide reducing brain swelling and death in preclinical models. Recent work showed that, following ischemia, SUR1-TRPM4 co-assembles with aquaporin-4 to mediate cellular swelling of astrocytes, which contributes to brain swelling. Additionally, recent work linked SUR1-TRPM4 to secretion of matrix metalloproteinase-9 (MMP-9) induced by recombinant tissue plasminogen activator in activated brain endothelial cells, with blockade of SUR1-TRPM4 by glyburide reducing MMP-9 and hemorrhagic transformation in preclinical models with recombinant tissue plasminogen activator. The recently completed GAMES (Glyburide Advantage in Malignant Edema and Stroke) clinical trials on patients with large hemispheric infarctions treated with intravenous glyburide (RP-1127) revealed promising findings with regard to brain swelling (midline shift), MMP-9, functional outcomes and mortality. Here, we review key elements of the basic science, preclinical experiments and clinical studies, both retrospective and prospective, on glyburide in focal cerebral ischemia and stroke.

W. Taylor Kimberly - One of the best experts on this subject based on the ideXlab platform.

  • Intravenous Glibenclamide Reduces Lesional Water Uptake in Large Hemispheric Infarction.
    Stroke, 2019
    Co-Authors: Pongpat Vorasayan, Lauren A. Beslow, Matthew B Bevers, Holly E Hinson, Bradley J Molyneaux, Kevin N Sheth, J. Marc Simard, Gordon Sze, Rüdiger Von Kummer, W. Taylor Kimberly
    Abstract:

    Background and Purpose- Prior studies have shown a linear relationship between computed tomography (CT)-derived radiodensity and water uptake, or brain Edema, within stroke lesions. To test the hypothesis that intravenous glibenclamide (glyburide; BIIB093) reduces ischemic brain water uptake, we quantified the lesional net water uptake (NWU) on serial CT scans from patients enrolled in the phase 2 GAMES-RP Trial (Glyburide Advantage in Malignant Edema and Stroke). Methods- This was a post hoc exploratory analysis of the GAMES-RP study. Noncontrast CT scans performed between admission and day 7 (n=264) were analyzed in the GAMES-RP modified intention-to-treat sample. Quantitative change in CT radiodensity (ie, NWU) and midline shift (MLS) was measured. The gray and white matter NWU were also examined separately. Repeated-measures mixed-effects models were used to assess the effect of intravenous glibenclamide on MLS or NWU. Results- A median of 3 CT scans (interquartile range, 2-4) were performed per patient during the first 7 days after stroke. In a repeated-measures regression model, greater NWU was associated with increased MLS (β=0.23; 95% CI, 0.20-0.26; P

  • Abstract TMP24: Analysis of Adjudicated Edema Endpoints in the Glyburide Advantage in Malignant Edema and Stroke (GAMES-RP) Trial
    Stroke, 2017
    Co-Authors: W. Taylor Kimberly, Holly E Hinson, Bradley J Molyneaux, ANDREW MICHAEL DEMCHUK, Javier Romero, Jordan J. Elm, Ruediger Von Kummer, Kevin N Sheth
    Abstract:

    Background: Patients with large hemispheric infarction are at high risk for cerebral Edema and death. Here we report pre-specified adjudicated Edema endpoints in the GAMES-RP trial. Objective: The ...

  • Outcomes in Severe Middle Cerebral Artery Ischemic Stroke
    Neurocritical Care, 2014
    Co-Authors: Brian P. Walcott, Jennifer C. Miller, Churl-su Kwon, Sameer A. Sheth, Marc Hiller, Carolyn A. Cronin, Lee H. Schwamm, J. Marc Simard, Kristopher T. Kahle, W. Taylor Kimberly
    Abstract:

    Background Severe middle cerebral artery stroke (MCA) is associated with a high rate of morbidity and mortality. We assessed the hypothesis that patient-specific variables may be associated with outcomes. We also sought to describe under-recognized patient-centered outcomes. Methods A consecutive, multi-institution, retrospective cohort of adult patients (≤70 years) was established from 2009 to 2011. We included patients with NIHSS score ≥15 and infarct volume ≥60 mL measured within 48 h of symptom onset. Malignant Edema was defined as the development of midline brain shift of ≥5 mm in the first 5 days. Exclusion criterion was enrollment in any experimental trial. A univariate and multivariate logistic regression analysis was performed to model and predict the factors related to outcomes. Results 46 patients (29 female, 17 male; mean age 57.3 ± 1.5 years) met study criteria. The mortality rate was 28 % ( n  = 13). In a multivariate analysis, only concurrent anterior cerebral artery (ACA) involvement was associated with mortality (OR 9.78, 95 % CI 1.15, 82.8, p  = 0.04). In the Malignant Edema subgroup ( n  = 23, 58 %), 4 died (17 %), 7 underwent decompressive craniectomy (30 %), 7 underwent tracheostomy (30 %), and 15 underwent gastrostomy (65 %). Conclusions Adverse outcomes after severe stroke are common. Concurrent ACA involvement predicts mortality in severe MCA stroke. It is useful to understand the incidence of life-sustaining procedures, such as tracheostomy and gastrostomy, as well as factors that contribute to their necessity.

  • Glyburide is Associated with Attenuated Vasogenic Edema in Stroke Patients
    Neurocritical Care, 2014
    Co-Authors: W. Taylor Kimberly, Albert J. Yoo, Jordan J. Elm, Thomas W. K. Battey, Ly Pham, Karen L. Furie, Aneesh B. Singhal, Barney J. Stern, Kevin N Sheth
    Abstract:

    Background Brain Edema is a serious complication of ischemic stroke that can lead to secondary neurological deterioration and death. Glyburide is reported to prevent brain swelling in preclinical rodent models of ischemic stroke through inhibition of a non-selective channel composed of sulfonylurea receptor 1 and transient receptor potential cation channel subfamily M member 4. However, the relevance of this pathway to the development of cerebral Edema in stroke patients is not known. Methods Using a case–control design, we retrospectively assessed neuroimaging and blood markers of cytotoxic and vasogenic Edema in subjects who were enrolled in the glyburide advantage in Malignant Edema and stroke-pilot (GAMES-Pilot) trial. We compared serial brain magnetic resonance images (MRIs) to a cohort with similar large volume infarctions. We also compared matrix metalloproteinase-9 (MMP-9) plasma level in large hemispheric stroke. Results We report that IV glyburide was associated with T2 fluid-attenuated inversion recovery signal intensity ratio on brain MRI, diminished the lesional water diffusivity between days 1 and 2 (pseudo-normalization), and reduced blood MMP-9 level. Conclusions Several surrogate markers of vasogenic Edema appear to be reduced in the setting of IV glyburide treatment in human stroke. Verification of these potential imaging and blood biomarkers is warranted in the context of a randomized, placebo-controlled trial.

  • Abstract TMP22: Intravenous Glyburide Treatment is Associated with Reduced Matrix Metalloproteinase-9 in Human Acute Stroke
    Stroke, 2013
    Co-Authors: Ly Pham, Kevin N Sheth, Karen Yarbrough, Sydney G. O’connor, Sven Jacobson, Barney J. Stern, W. Taylor Kimberly
    Abstract:

    Background: Elevated matrix metalloproteinase-9 (MMP-9) following acute ischemic stroke is associated with blood-brain barrier breakdown and hemorrhagic conversion. Prior retrospective evidence suggests that sulfonylurea use may be associated with reduced risk of hemorrhagic conversion. We hypothesized that sulfonylureas may reduce MMP-9 level in stroke patients. Methods: Using serial plasma samples from six subjects in the Glyburide Advantage in Malignant Edema and Stroke Pilot trial (GAMES-Pilot), we evaluated the level of MMP-9 in human subjects presenting with large hemispheric stroke who were treated with intravenous glyburide (RP-1127). MMP-9 was measured in a control cohort with large ischemic stroke who were not treated with glyburide. Commercially available ELISA kits and gel zymography were used to measure MMP-9 at baseline and at approximately 48 hours after stroke. GAMES subjects had additional time points analyzed until approximately 84 hours after stroke. Results: Average MMP-9 level in glyburide-treated stroke patients was 47.2 ± 8.0 ng/mL compared to 143.4 ± 60.35 ng/mL in untreated control subjects (p=0.004). Zymography analysis demonstrated a significant decrease in the pro-enzyme but no change in the active form of MMP-9. There was no difference in the level of the MMP-9 specific inhibitor, TIMP-1. No subjects exhibited parenchymal hemorrhagic conversion on 24 hour head CT scan. Conclusions: Glyburide treatment in human stroke patients with large hemispheric stroke is associated reduced level of MMP-9. Elucidating the underlying mechanism of glyburide’s effect on MMP-9 and the risk of hemorrhagic conversion may highlight future directions of therapy, including in combination with intravenous tissue plasminogen activator (IV t-PA).

Bradley J Molyneaux - One of the best experts on this subject based on the ideXlab platform.

  • osmotherapy for Malignant cerebral Edema in a phase 2 prospective double blind randomized placebo controlled study of iv glibenclamide
    Journal of Stroke & Cerebrovascular Diseases, 2020
    Co-Authors: Holly E Hinson, Rüdiger Von Kummer, Bradley J Molyneaux, Taylor W Kimberly, ANDREW MICHAEL DEMCHUK, Javier Romero, Kevin N Sheth
    Abstract:

    Abstract Background/Objective Malignant Edema can be a life-threatening complication of large hemispheric infarction (LHI), and is often treated with osmotherapy. In this exploratory analysis of data from the GAMES-RP study, we hypothesized that patients receiving osmotherapy had symptomatic cerebral Edema, and that treatment with intravenous (IV) glibenclamide would modify osmotherapy use as compared with placebo. Methods GAMES-RP was a phase 2 multi-center prospective, double blind, randomized, placebo-controlled study in LHI. Patients were randomized to IV glibenclamide (e.g. IV glyburide) or placebo. Cerebral Edema therapies included osmotherapy and/or decompressive craniectomy at the discretion of the treating team. Total bolus osmotherapy dosing was quantified by “osmolar load”. Radiographic Edema was defined by dichotomizing midline shift at 24 h. Clinical changes were defined as any increase in NIHSS1a. Results Osmotherapy was administered to 40 of the 77 patients at a median of 39 [27–55] h after stroke onset. The median baseline DWI lesion volume was significantly larger in the osmotherapy treated group (167 [146–211] mL v. 139 [112–170] mL; P=0.046). Adjudicated Malignant Edema (75% v. 16%; P Conclusions In the GAMES-RP trial, osmolar therapies were most often administered in response to clinical symptoms of decreased consciousness. However, the optimal timing of administration and impact on outcome after LHI have yet to be defined.

  • Intravenous Glibenclamide Reduces Lesional Water Uptake in Large Hemispheric Infarction.
    Stroke, 2019
    Co-Authors: Pongpat Vorasayan, Lauren A. Beslow, Matthew B Bevers, Holly E Hinson, Bradley J Molyneaux, Kevin N Sheth, J. Marc Simard, Gordon Sze, Rüdiger Von Kummer, W. Taylor Kimberly
    Abstract:

    Background and Purpose- Prior studies have shown a linear relationship between computed tomography (CT)-derived radiodensity and water uptake, or brain Edema, within stroke lesions. To test the hypothesis that intravenous glibenclamide (glyburide; BIIB093) reduces ischemic brain water uptake, we quantified the lesional net water uptake (NWU) on serial CT scans from patients enrolled in the phase 2 GAMES-RP Trial (Glyburide Advantage in Malignant Edema and Stroke). Methods- This was a post hoc exploratory analysis of the GAMES-RP study. Noncontrast CT scans performed between admission and day 7 (n=264) were analyzed in the GAMES-RP modified intention-to-treat sample. Quantitative change in CT radiodensity (ie, NWU) and midline shift (MLS) was measured. The gray and white matter NWU were also examined separately. Repeated-measures mixed-effects models were used to assess the effect of intravenous glibenclamide on MLS or NWU. Results- A median of 3 CT scans (interquartile range, 2-4) were performed per patient during the first 7 days after stroke. In a repeated-measures regression model, greater NWU was associated with increased MLS (β=0.23; 95% CI, 0.20-0.26; P

  • effect of iv glyburide on adjudicated Edema endpoints in the games rp trial
    Neurology, 2018
    Co-Authors: Taylor W Kimberly, Rüdiger Von Kummer, Matthew B Bevers, Holly E Hinson, Bradley J Molyneaux, Marc J Simard, ANDREW MICHAEL DEMCHUK, Javier Romero, Kevin N Sheth
    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 p 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.

  • effect of iv glyburide on adjudicated Edema endpoints in the games rp trial
    Neurology, 2018
    Co-Authors: Taylor W Kimberly, Rüdiger Von Kummer, Matthew B Bevers, Holly E Hinson, Bradley J Molyneaux, Marc J Simard, ANDREW MICHAEL DEMCHUK, Javier Romero, Kevin N Sheth
    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 p 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.

  • long term outcomes in patients aged 70 years with intravenous glyburide from the phase ii games rp study of large hemispheric infarction an exploratory analysis
    Stroke, 2018
    Co-Authors: Kevin N Sheth, Lauren A. Beslow, Holly E Hinson, Bradley J Molyneaux, Nils H. Petersen, Ken Cheung, Marc J Simard, Taylor W Kimberly
    Abstract:

    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 cm 3 ) 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 P 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.

Lauren A. Beslow - One of the best experts on this subject based on the ideXlab platform.

  • Intravenous Glibenclamide Reduces Lesional Water Uptake in Large Hemispheric Infarction.
    Stroke, 2019
    Co-Authors: Pongpat Vorasayan, Lauren A. Beslow, Matthew B Bevers, Holly E Hinson, Bradley J Molyneaux, Kevin N Sheth, J. Marc Simard, Gordon Sze, Rüdiger Von Kummer, W. Taylor Kimberly
    Abstract:

    Background and Purpose- Prior studies have shown a linear relationship between computed tomography (CT)-derived radiodensity and water uptake, or brain Edema, within stroke lesions. To test the hypothesis that intravenous glibenclamide (glyburide; BIIB093) reduces ischemic brain water uptake, we quantified the lesional net water uptake (NWU) on serial CT scans from patients enrolled in the phase 2 GAMES-RP Trial (Glyburide Advantage in Malignant Edema and Stroke). Methods- This was a post hoc exploratory analysis of the GAMES-RP study. Noncontrast CT scans performed between admission and day 7 (n=264) were analyzed in the GAMES-RP modified intention-to-treat sample. Quantitative change in CT radiodensity (ie, NWU) and midline shift (MLS) was measured. The gray and white matter NWU were also examined separately. Repeated-measures mixed-effects models were used to assess the effect of intravenous glibenclamide on MLS or NWU. Results- A median of 3 CT scans (interquartile range, 2-4) were performed per patient during the first 7 days after stroke. In a repeated-measures regression model, greater NWU was associated with increased MLS (β=0.23; 95% CI, 0.20-0.26; P

  • long term outcomes in patients aged 70 years with intravenous glyburide from the phase ii games rp study of large hemispheric infarction an exploratory analysis
    Stroke, 2018
    Co-Authors: Kevin N Sheth, Lauren A. Beslow, Holly E Hinson, Bradley J Molyneaux, Nils H. Petersen, Ken Cheung, Marc J Simard, Taylor W Kimberly
    Abstract:

    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 cm 3 ) 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 P 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.

  • games glyburide advantage in Malignant Edema and stroke rp a phase ii study toward preventing Edema after ischemia s7 004
    Neurology, 2016
    Co-Authors: Kevin N Sheth, Lauren A. Beslow, Holly E Hinson, Bradley J Molyneaux, Annchristin Ostwaldt, Gregory J Del Zoppo, J M Simard, Sven Jacobson, W. T Kimberly
    Abstract:

    Objective: The primary objective is to assess the safety and preliminary efficacy of intravenous glyburide (RP-1127) compared to placebo in ischemic stroke patients who are at high risk for developing Malignant Edema. Background: Patients with large territory ischemic stroke are at high risk for cerebral Edema and death. There is no available pharmacotherapy for the prevention of Edema after stroke. Methods: GAMES-RP was a double-blind, randomized, placebo controlled phase 2 study. Patients presenting to 18 centers were randomized 1:1 to drug or placebo. Eligible patients had a baseline lesion between 82 cm3 and 300 cm3, age 18-80 years, and time from symptom onset to drug infusion of ≤ 10 hours. Patients were treated with either RP-1127 (n=44) or placebo control (n=39) as a bolus followed by a continuous 72 hour infusion. The primary safety outcome was the frequency and severity of adverse events (SAE). The primary efficacy outcome was a composite of the modified Rankin Scale (mRS) and the incidence of decompressive craniectomy (DC), assessed at 90 days. We also analyzed outcomes up to 6 months. The primary analysis was per protocol. Results: There was no difference in the frequency of SAE between RP-1127 and placebo (68[percnt] versus 72[percnt], p= 0.72). There was no difference in the composite primary outcome achieving mRS 0-4 without DC at 90 days (p=0.77). Patients in the RP-1127 group had 61[percnt] decreased deaths at 30 days (14[percnt] versus 36[percnt], p=0.03) and decreased midline shift at 72-96 hours (4.4 ± 3.6 mm versus 8.8 ± 4.9 mm, p=0.0006). Six month mRS will be obtained and analyzed. Conclusions: RP-1127 was safe but the trial did not meet the primary efficacy outcome. Among patients with large hemispheric stroke at risk for cerebral Edema, RP-1127 may reduce mortality and midline shift. Further prospective study is warranted to confirm these findings. Disclosure: Dr. Sheth has nothing to disclose. Dr. Elm has received research support from Remedy. Dr. Hinson has nothing to disclose. Dr. Molyneaux has nothing to disclose. Dr. Beslow has nothing to disclose. Dr. Sze has received research support from Remedy. Dr. Ostwaldt has received research support from Remedy. Dr. Del Zoppo has received research support from Remedy. Dr. Simard has received royalty payments from Remedy. Dr. Jacobson holds stock and/or stock options in Remedy. Dr. Kimberly has received research support from Remedy Pharmaceuticals, Inc.

  • games glyburide advantage in Malignant Edema and stroke rp trial intermediate endpoint analysis as proof of concept s7 006
    Neurology, 2016
    Co-Authors: Taylor W Kimberly, Lauren A. Beslow, Holly E Hinson, Bradley J Molyneaux, Annchristin Ostwaldt, Gregory J Del Zoppo, Marc Simard, Kevin N Sheth
    Abstract:

    Registry: NCT01794182 Background: Patients with large territory ischemic stroke are at high risk for cerebral Edema and death but there is no available pharmacotherapy for its prevention. In the GAMES-RP trial, we evaluated pre-specified intermediate endpoints to evaluate proof-of-concept for intravenous glyburide (RP-1127). Objective: The objective of this pre-specified analysis was to evaluate the effect of intravenous glyburide treatment on imaging and plasma endpoints for brain Edema. Design: The GAMES-RP trial was a double blind, randomized, placebo controlled phase 2 study. Patients presenting to 18 U.S. centers with baseline stroke lesion volumes between 82 and 300 cm3 on magnetic resonance imaging were randomized 1:1 to study drug or placebo. Patients were treated with either RP-1127 (n=44) or placebo control (n=39) as a bolus followed by a continuous 72 hour infusion, administered within a target of 10 hours. Outcome measure: Imaging analysis included measurement of midline shift, hemispheric swelling and lesional swelling volume. Total plasma MMP-9 was measured by ELISA. Results: In subjects treated with RP-1127, there was decreased midline shift at 72-96 hours (4.4 ± 3.6 mm versus 8.8 ± 4.9 mm, p=0.0006). In those who did not undergo decompressive craniectomy, hemispheric swelling was 49mL in RP-1127 arm versus 77mL in placebo (p=0.032) and swelling volume was 41mL vs 75mL (p=0.14). MMP-9 was lower in the RP-1127 treatment arm compared to placebo (211 ng/mL versus 345 ng/mL, p=0.006). Conclusions: RP-1127 reduced neuroimaging markers of brain Edema and total MMP-9 level. Disclosure: Dr. Kimberly has received research support from Remedy Pharmaceuticals, Inc. Dr. Elm has received research support from Remedy. Dr. Hinson has nothing to disclose. Dr. Molyneaux has nothing to disclose. Dr. Beslow has nothing to disclose. Dr. Sze has received research support from Remedy. Dr. Ostwaldt has received research support from Remedy. Dr. Del Zoppo has received research support from Remedy. Dr. Simard has received royalty payments from Remedy. Dr. Sheth has nothing to disclose.

  • glyburide advantage in Malignant Edema and stroke games rp trial rationale and design
    Neurocritical Care, 2016
    Co-Authors: Kevin N Sheth, Lauren A. Beslow, William T Kimberly
    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.

Holly E Hinson - One of the best experts on this subject based on the ideXlab platform.

  • osmotherapy for Malignant cerebral Edema in a phase 2 prospective double blind randomized placebo controlled study of iv glibenclamide
    Journal of Stroke & Cerebrovascular Diseases, 2020
    Co-Authors: Holly E Hinson, Rüdiger Von Kummer, Bradley J Molyneaux, Taylor W Kimberly, ANDREW MICHAEL DEMCHUK, Javier Romero, Kevin N Sheth
    Abstract:

    Abstract Background/Objective Malignant Edema can be a life-threatening complication of large hemispheric infarction (LHI), and is often treated with osmotherapy. In this exploratory analysis of data from the GAMES-RP study, we hypothesized that patients receiving osmotherapy had symptomatic cerebral Edema, and that treatment with intravenous (IV) glibenclamide would modify osmotherapy use as compared with placebo. Methods GAMES-RP was a phase 2 multi-center prospective, double blind, randomized, placebo-controlled study in LHI. Patients were randomized to IV glibenclamide (e.g. IV glyburide) or placebo. Cerebral Edema therapies included osmotherapy and/or decompressive craniectomy at the discretion of the treating team. Total bolus osmotherapy dosing was quantified by “osmolar load”. Radiographic Edema was defined by dichotomizing midline shift at 24 h. Clinical changes were defined as any increase in NIHSS1a. Results Osmotherapy was administered to 40 of the 77 patients at a median of 39 [27–55] h after stroke onset. The median baseline DWI lesion volume was significantly larger in the osmotherapy treated group (167 [146–211] mL v. 139 [112–170] mL; P=0.046). Adjudicated Malignant Edema (75% v. 16%; P Conclusions In the GAMES-RP trial, osmolar therapies were most often administered in response to clinical symptoms of decreased consciousness. However, the optimal timing of administration and impact on outcome after LHI have yet to be defined.

  • Intravenous Glibenclamide Reduces Lesional Water Uptake in Large Hemispheric Infarction.
    Stroke, 2019
    Co-Authors: Pongpat Vorasayan, Lauren A. Beslow, Matthew B Bevers, Holly E Hinson, Bradley J Molyneaux, Kevin N Sheth, J. Marc Simard, Gordon Sze, Rüdiger Von Kummer, W. Taylor Kimberly
    Abstract:

    Background and Purpose- Prior studies have shown a linear relationship between computed tomography (CT)-derived radiodensity and water uptake, or brain Edema, within stroke lesions. To test the hypothesis that intravenous glibenclamide (glyburide; BIIB093) reduces ischemic brain water uptake, we quantified the lesional net water uptake (NWU) on serial CT scans from patients enrolled in the phase 2 GAMES-RP Trial (Glyburide Advantage in Malignant Edema and Stroke). Methods- This was a post hoc exploratory analysis of the GAMES-RP study. Noncontrast CT scans performed between admission and day 7 (n=264) were analyzed in the GAMES-RP modified intention-to-treat sample. Quantitative change in CT radiodensity (ie, NWU) and midline shift (MLS) was measured. The gray and white matter NWU were also examined separately. Repeated-measures mixed-effects models were used to assess the effect of intravenous glibenclamide on MLS or NWU. Results- A median of 3 CT scans (interquartile range, 2-4) were performed per patient during the first 7 days after stroke. In a repeated-measures regression model, greater NWU was associated with increased MLS (β=0.23; 95% CI, 0.20-0.26; P

  • effect of iv glyburide on adjudicated Edema endpoints in the games rp trial
    Neurology, 2018
    Co-Authors: Taylor W Kimberly, Rüdiger Von Kummer, Matthew B Bevers, Holly E Hinson, Bradley J Molyneaux, Marc J Simard, ANDREW MICHAEL DEMCHUK, Javier Romero, Kevin N Sheth
    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 p 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.

  • effect of iv glyburide on adjudicated Edema endpoints in the games rp trial
    Neurology, 2018
    Co-Authors: Taylor W Kimberly, Rüdiger Von Kummer, Matthew B Bevers, Holly E Hinson, Bradley J Molyneaux, Marc J Simard, ANDREW MICHAEL DEMCHUK, Javier Romero, Kevin N Sheth
    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 p 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.

  • long term outcomes in patients aged 70 years with intravenous glyburide from the phase ii games rp study of large hemispheric infarction an exploratory analysis
    Stroke, 2018
    Co-Authors: Kevin N Sheth, Lauren A. Beslow, Holly E Hinson, Bradley J Molyneaux, Nils H. Petersen, Ken Cheung, Marc J Simard, Taylor W Kimberly
    Abstract:

    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 cm 3 ) 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 P 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.