Elsevier

The Lancet Neurology

Volume 15, Issue 11, October 2016, Pages 1160-1169
The Lancet Neurology

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

https://doi.org/10.1016/S1474-4422(16)30196-XGet rights and content

Summary

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 cm3 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.

Introduction

Malignant cerebral oedema can develop as a complication of large hemispheric infarction and leads to abrupt neurological deterioration within 24–48 h after stroke onset.1, 2 Brain swelling, which is the mass-occupying consequence of cerebral oedema, can cause further ischaemic damage and, if left untreated, can result in brain herniation. The horizontal tissue shifts that occur as a consequence of brain swelling manifest clinically as a reduction in the level of arousal.3 Medical treatment to reduce the brain volume includes supportive care and osmotic drugs. Nevertheless, herniation and death occur in up to 50% of patients with brain swelling.1, 4 Neurosurgical treatment with decompressive craniectomy can reduce mortality and might improve outcomes in patients younger than 60 years.5 However, decompressive craniectomy is associated with substantial morbidity.6 Moreover, surgery is done only after substantial tissue injury, brain shift, and neurological deterioration have already occurred.1, 3 Although treatment of oedema is reactive in clinical practice, no drug therapy has been assessed to prevent oedema.7

Results of preclinical studies8, 9 suggest that blockade of the inducible sulfonylurea receptor 1 (SUR1)-transient receptor potential melastatin 4 (TRPM4) channel in neurons, astrocytes, and endothelium substantially reduces cerebral oedema in rodent models of stroke. Further preclinical studies and retrospective studies in human beings have shown that a continuous parenteral infusion of the SUR1 inhibitor glyburide (glibenclamide) decreases water accumulation in the brain, improves survival, and facilitates neurological recovery in experimental settings.10 This evidence suggests that the SUR1–TRPM4 channel is a candidate target for prevention of cerebral oedema after large hemispheric stroke in patients.8 A phase 2A clinical trial showed the feasibility and safety of administering intravenous glyburide to critically ill stroke patients.11, 12

Research in context

Evidence before this study

We searched PubMed for randomised controlled trials published in only English between Jan 1, 2000, and March 4, 2016, with the search terms “ischemic stroke”, AND “brain edema”, AND “glyburide”, OR “glibenclamide”, OR “sulfonylurea”. We found 12 preclinical studies that showed that continuous glyburide administration led to a reduction in brain oedema and mortality in rodent models of stroke. A pilot trial of intravenous glyburide in patients with acute, large hemispheric stroke showed feasibility and initial safety of treatment of critically ill stroke patients at high risk for oedema. Interpretation of these retrospective and prospective pilot data is limited by the absence of double-blind, placebo controlled trials.

Added value of this study

To our knowledge, this is the first trial to assess the effect of early (within 10 h) and continuous administration of an intravenous glyburide for the prevention of brain oedema after a large hemispheric stroke in a randomised, double-blind, placebo-controlled trial. Treatment was well tolerated, hypoglycaemia was uncommon and successfully treated with a prespecified hypoglycaemia protocol. Although the percentage of people who had a modified Rankin Scale score of 0–4 at 90 days without decompressive craniectomy (primary endpoint) was not significantly different in the glyburide and placebo groups, and mortality was non-significantly reduced overall, functional outcome measured by the modified Rankin Scale was improved in patients treated with the active drug. There was an association with a reduction in midline shift of the brain and lower plasma matrix metalloproteinase-9 concentrations in patients treated with intravenous glyburide compared with placebo.

Implications of all the available evidence

Our findings suggest that the sulfonylurea receptor pathway is implicated in the formation of brain oedema after stroke in patients. Early and continuous intravenous administration of glyburide favourably affects markers of brain oedema and suggests that there might be a clinical effect on mortality and functional outcome at 90 days. These findings need to be replicated in a larger phase 3 trial in patients with large hemispheric infarction.

The Glyburide Advantage in Malignant Edema and Stroke (GAMES-RP) trial was designed to test the safety and efficacy of intravenous glyburide in a critically ill, acute ischaemic stroke population at high risk for brain swelling.13 On the basis of the GAMES-Pilot data,11, 12 we hypothesised that intravenous glyburide would safely diminish brain swelling, decrease the need for decompressive craniectomy, and improve clinical outcome.11, 12 An additional objective was to provide information for the design of a phase 3 trial of intravenous glyburide in patients at high risk for developing brain oedema.

Section snippets

Study design and participants

GAMES-RP was a double-blind randomised, phase 2 trial —done at 18 hospitals in the USA—of intravenous glyburide in patients with a large anterior circulation hemispheric infarction who were at risk to develop malignant oedema. The design of the GAMES-RP trial has been previously reported.13 The study was done under an Investigational New Drug Application from the US Food and Drug Administration. The study was approved by the institutional review boards at all participating centres. All

Results

86 participants with a large anterior circulation hemispheric infarction were enrolled between May 3, 2013, and April 30, 2015. 44 participants were randomly allocated to the intravenous glyburide group and 42 participants were randomly allocated to the placebo group. Three participants in the placebo group did not receive the study drug (two because of pharmacy delays and one because the lesion on the enrolling MRI was reassessed at the site before dosing and was >300 cm3), and were withdrawn

Discussion

The GAMES-RP trial showed that intravenous glyburide was safe in patients who are critically ill after an ischaemic stroke and have a large hemispheric infarction, but the trial was negative for the prespecified primary and secondary efficacy endpoints. However, intravenous glyburide administration resulted in a non-significant reduction in mortality and reduced brain swelling, as shown by the lower median midline shift compared with placebo, which is consistent with the preclinical effect of

References (31)

  • JM Simard et al.

    Glibenclamide is superior to decompressive craniectomy in a rat model of malignant stroke

    Stroke

    (2010)
  • JM Simard et al.

    Glibenclamide in cerebral ischemia and stroke

    Neurocrit Care

    (2014)
  • KN Sheth et al.

    Pilot study of intravenous glyburide in patients with a large ischemic stroke

    Stroke

    (2014)
  • KN Sheth et al.

    Exploratory analysis of glyburide as a novel therapy for preventing brain swelling

    Neurocrit Care

    (2014)
  • KN Sheth et al.

    Glyburide Advantage in Malignant Edema and Stroke (GAMES-RP) Trial: rationale and design

    Neurocrit Care

    (2016)
  • Cited by (180)

    View all citing articles on Scopus

    Contributed equally

    View full text