Format

Send to

Choose Destination
Lancet Neurol. 2016 Oct;15(11):1160-9. doi: 10.1016/S1474-4422(16)30196-X. Epub 2016 Aug 23.

Safety and efficacy of intravenous glyburide on brain swelling after large hemispheric infarction (GAMES-RP): a randomised, double-blind, placebo-controlled phase 2 trial.

Author information

1
Department of Neurology, Division of Neurocritical Care and Emergency Neurology, Yale University School of Medicine, New Haven, CT, USA. Electronic address: kevin.sheth@yale.edu.
2
Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, USA.
3
Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
4
Department of Neurology, Oregon Health Sciences University, Portland, OR, USA.
5
Department of Neurology, Division of Neurocritical Care and Emergency Neurology, Yale University School of Medicine, New Haven, CT, USA; Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA.
6
Department of Radiology, Yale University School of Medicine, New Haven, CT, USA.
7
Department of Neurology, Division of Neurocritical Care and Emergency Neurology, Massachusetts General Hospital, Boston, MA, USA.
8
Division of Hematology, Department of Medicine, and Department of Neurology, University of Washington, Seattle, WA, USA.
9
Department of Neurosurgery, University of Maryland, Baltimore, MD, USA.
10
Remedy Pharmaceuticals, New York, NY, USA.
11
Department of Neurology, Division of Neurocritical Care and Emergency Neurology, Massachusetts General Hospital, Boston, MA, USA. Electronic address: wtkimberly@mgh.harvard.edu.

Abstract

BACKGROUND:

Preclinical models of stroke have shown that intravenous glyburide reduces brain swelling and improves survival. We assessed whether intravenous glyburide (RP-1127; glibenclamide) would safely reduce brain swelling, decrease the need for decompressive craniectomy, and improve clinical outcomes in patients presenting with a large hemispheric infarction.

METHODS:

For this double-blind, randomised, placebo-controlled phase 2 trial, we enrolled patients (aged 18-80 years) with a clinical diagnosis of large anterior circulation hemispheric infarction for less than 10 h and baseline diffusion-weighted MRI image lesion volume of 82-300 cm(3) on MRI at 18 hospitals in the USA. We used web-based randomisation (1:1) to allocate patients to the placebo or intravenous glyburide group. Intravenous glyburide was given as a 0·13 mg bolus intravenous injection for the first 2 min, followed by an infusion of 0·16 mg/h for the first 6 h and then 0·11 mg/h for the remaining 66 h. The primary efficacy outcome was the proportion of patients who achieved a modified Rankin Scale (mRS) score of 0-4 at 90 days without undergoing decompressive craniectomy. Analysis was by per protocol. Safety analysis included all randomly assigned patients who received the study drug. This trial is registered with ClinicalTrials.gov, number NCT01794182.

FINDINGS:

Between May 3, 2013, and April 30, 2015, 86 patients were randomly assigned but enrolment was stopped because of funding reasons. The funder, principal investigators, site investigators, patients, imaging core, and outcomes personnel were masked to treatment. The per-protocol study population was 41 participants who received intravenous glyburide and 36 participants who received placebo. 17 (41%) patients in the intravenous glyburide group and 14 (39%) in the placebo group had an mRS score of 0-4 at 90 days without decompressive craniectomy (adjusted odds ratio 0·87, 95% CI 0·32-2·32; p=0·77). Ten (23%) of 44 participants in the intravenous glyburide group and ten (26%) of 39 participants in the placebo group had cardiac events (p=0·76), and four of 20 had serious adverse events (two in the intravenous glyburide group and two in the placebo group, p=1·00). One cardiac death occurred in each group (p=1·00).

INTERPRETATION:

Intravenous glyburide was well tolerated in patients with large hemispheric stroke at risk for cerebral oedema. There was no difference in the composite primary outcome. Further study is warranted to assess the potential clinical benefit of a reduction in swelling by intravenous glyburide.

FUNDING:

Remedy Pharmaceuticals.

PMID:
27567243
DOI:
10.1016/S1474-4422(16)30196-X
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center