Pilot Study of Intravenous Glyburide in Patients With a Large Ischemic Stroke

Abstract

Background and Purpose

Preclinical and retrospective clinical data indicate that glyburide, a selective inhibitor of sulfonylurea receptor 1-transient receptor potential melastatin 4, is effective in preventing edema and improving outcome after focal ischemia. We assessed the feasibility of recruiting and treating patients with severe stroke while obtaining preliminary information on the safety and tolerability of RP-1127 (glyburide for injection).

Methods

We studied 10 patients with acute ischemic stroke, with baseline diffusion-weighted imaging lesion volumes of 82 to 210 cm³, whether treated with intravenous recombinant tissue-type plasminogen activator, age 18 to 80 years, and time to RP-1127 ≤10 hours.

Results

Recruitment was completed within 10 months. The mean age was 50.5 years, and baseline diffusion-weighted image lesion volume was 102±23 cm³. There were no serious adverse events related to drug and no symptomatic hypoglycemia. The increase in ipsilateral hemisphere volume was 50±33 cm³. The proportion of 90-day modified Rankin Scale ≤4 was 90% (40% modified Rankin Scale, ≤3).

Conclusions

RP-1127 at a dose of 3 mg/d was well tolerated and did not require any dose reductions. A clinical trial of RP-1127 is feasible.

The recently characterized ion channel composed of sulfonylurea receptor 1 and transient receptor potential melastatin 4¹ is a promising therapeutic target in stroke. The channel is upregulated in all cell types of the neurovascular unit after ischemia.¹ Excessive channel opening leads to the influx of sodium and water, oncotic cell swelling, and necrotic cell death.² Preclinical studies have shown that pharmacological blockade using a low dose of the selective sulfonylurea receptor 1 inhibitor, glyburide, reduces infarct volume, reduces mortality, and improves neurological outcomes.^1,3,4

Here, we report on a pilot study of RP-1127 (glyburide for injection) in patients with severe ischemic stroke who were at high risk for developing clinically significant brain swelling (Glyburide Advantage in Malignant Edema and Stroke-Pilot).

Methods

Approval for this study was obtained from local institutional review boards. Patient surrogates provided written informed consent. This study was a prospective, open-label, multicenter, phase IIa clinical trial of RP-1127. The primary outcomes of feasibility were (1) the rate of recruitment; (2) proportion of patients recruited versus screened; (3) the ability to manage blood glucose levels according to protocol. The secondary objectives were to obtain preliminary data on safety and tolerability of RP-1127 and to compare clinical and imaging outcome data with historical controls.⁵ The primary safety outcomes were all-cause deaths, hemorrhagic events, and hypoglycemia. The protocol included prespecified rules for reducing or discontinuing study drug because of hypoglycemia, hemolytic anemia, and liver or cardiac toxicity (additional details in the online-only Data Supplement).

Inclusion criteria were baseline diffusion-weighted image lesion volume, 82 to 210 cm³; age 18 to 80 years; time from symptom onset to start of study drug infusion ≤10 hours.

Results

Between February 2011 and May 2012, 10 subjects were enrolled and treated at University of Maryland and the Massachusetts General Hospital within 9.6 months, which was faster than the anticipated time of 14 months, based on an a priori review of the local stroke registries using the proposed inclusion/exclusion criteria. The baseline characteristics of enrolled subjects are presented in Table 1. Recombinant tissue-type plasminogen activator was administered to 5 subjects within 0 to 3 hours and to 4 subjects from 3 to 4.5 hours.

Table 1.

Baseline Demographic and Clinical Characteristics

	n=10
Age, mean±SD (min–max)	50.5±15.3 (25–73)
Men % (n)	30% (3)
Nonhispanic whites % (n)	30% (3)
Baseline NIHSS, median±IQR (min–max)	18±8 (11–31)
History % (n)
Arterial hypertension	50% (5)
Diabetes mellitus	20% (2)
Prior ischemic stroke	40% (4)
Atrial fibrillation	10% (1)
Intravenous thrombolysis	90% (9)
Left hemisphere	60% (6)
Laboratory values, mean±SD (min–max)
Hemoglobin, g/dL	12.5±3.7 (5.1–16.6)
Blood glucose, mg/dL	125.6±31 (98–207)
Creatinine, mg/dL	1.0±0.4 (0.6–1.7)
Time from onset to start of RP-1127 infusion, h; mean±SD (min–max)	8.7±1.2 (6.8–9.9)
Time to MRI, h; mean±SD (min–max)	5.3±1.9 (2.2–7.5)
Vessel occlusion
Cervical carotid occlusion	30% (3)
Middle cerebral artery (M1 segment)	70% (7)
Middle cerebral artery (M2 segment)	30% (3)
Anterior cerebral artery	0% (0)

All values expressed in % (n) except where otherwise indicated. IQR indicates interquartile range; and NIHSS, National Institutes of Health Stroke Scale.

Two subjects experienced serious adverse events during hospitalization. One patient required decompressive craniectomy and survived; another patient required decompressive craniectomy and died. In both cases, neurological deterioration was considered to be unrelated to the study drug.

Hypoglycemia was predefined as a blood glucose <70 mg/dL. There were no instances of hypoglycemia that triggered a reduction in dose or cessation of study drug infusion.

At 90 days, 90% of patients had modified Rankin Scale ≤4, and 40% had modified Rankin Scale ≤3. There were no PH1/PH2 hemorrhages. Baseline and follow-up neuroimaging metrics are shown in Table 2. The mean (±SD) increase in ipsilateral hemisphere volume (change from baseline to day 3 or last visit) was 50±33 cm³, and the mean diffusion-weighted image lesion volume increase was 60±41 cm³.

Table 2.

Centrally Determined Neuroimaging Lesion Volumes

	GAMES-Pilot (n=10)
	Mean (SD)	95% CI
Mean hemisphere volume, baseline, cm3 (SD)	468.2 (73.7)	(420.1, 516.3)
Mean hemisphere volume, final visit, cm3 (SD)	507.9 (59.2)	(469.2, 546.6)
Mean hemisphere volume increase, cm3 (SD)	49.9 (33.3)	(29.3, 70.5)
Mean DWI volume, baseline, cm3 (SD)	101.8 (22.6)	(87.0, 116.6)
Mean DWI volume, final visit, cm3 (SD)	160.4 (51.7)	(126.6, 194.2)
Mean DWI volume increase, cm3 (SD)	60.3 (41.4)	(34.6, 86.0)

CI indicates confidence interval; DWI, diffusion-weighted image; and GAMES, Glyburide Advantage in Malignant Edema and Stroke.

Discussion

The present study examined a potential pharmacotherapy for the prevention of edema after ischemia in humans. The main finding of this study is that our protocol for administering RP-1127 to critically ill patients with stroke is feasible. No safety concerns, hypoglycemia, or drug-related serious adverse events were observed. Declines in serum glucose were similar to those in prior natural history and glucose control studies.⁶

Because of the morbidity and mortality that are a direct consequence of brain swelling after stroke, there is an urgent need to identify novel treatments to ameliorate edema formation. Our inclusion criteria were developed to enroll patients to test the major potential therapeutic mechanism of glyburide, namely prevention of edema. The diffusion-weighted image cutpoint of 82 cm³ has been prospectively validated in an independent cohort.⁵ Because our approach aimed to establish proof of principle, we targeted subjects using this highly predictive marker of swelling.

The subjects in this pilot study had increases in hemisphere volumes >3 days of 50±33 cm³ compared with 72±27 cm³ in historical controls.⁷ The diffusion-weighted image lesion volume increase was 60±41 cm³ compared with 96±41 cm³ in historical controls.⁷ Even though 90% of subjects presented with high National Institutes of Health Stroke Scale scores and received intravenous recombinant tissue-type plasminogen activator, there were no PH1/PH2 hemorrhages, consistent with a retrospective study of stroke in patients with diabetes mellitus treated with oral sulfonylureas.⁸ The proportion of subjects with 90-day modified Rankin Scale ≤4 was 90% compared with 24% (at 12 months) in patients from a pooled analysis of decompressive craniectomy trials.⁹

This pilot study has shortcomings. It was open-label, had no placebo control arm, and the number of patients studied was small. Therefore, we cannot determine whether any seemingly favorable clinical outcome was because of RP-1127, enrollment of patients with milder stroke, or some other cause. However, the reduced hemispheric volume, hemorrhagic transformation, lesion growth, mortality, and improved neurological outcomes observed in this pilot study parallel findings in preclinical studies.^1,3,4

Further clinical investigation is warranted to determine whether RP-1127 can mitigate the devastating consequences associated with severe anterior circulation infarction and resulting edema.