Glyburide Advantage in Malignant Edema and Stroke - Remedy Pharmaceuticals (GAMES-RP)

A Randomized, Multi-Center, Prospective, Double Blind, Phase II Trial of RP- 1127 (Glyburide for Injection) in Patients With a Severe Anterior Circulation Ischemic Stroke Who Are Likely to Develop Malignant Edema

This is a randomized, multi-center, prospective, double blind study. The primary objective is to assess the efficacy and safety of glyburide (RP-1127) compared to placebo in participants with a severe anterior circulation ischemic stroke who are likely to develop malignant edema.This objective will be addressed by comparing the proportion of glyburide treated particpants and placebo treated participants with a Day 90 modified Rankin Scale (mRS) ≤ 4 without decompressive craniectomy (DC). The secondary objective is to assess the efficacy of RP-1127 compared to placebo in participants with a severe anterior circulation ischemic stroke who were likely to develop malignant edema.

Study Overview

• Status: Completed
• Conditions: Ischemic Stroke; Malignant Edema
• Intervention / Treatment: Drug: Placebo; Drug: Glyburide for Injection

Detailed Description

The study population consists of participants with a clinical diagnosis of acute severe anterior circulation ischemic stroke, a baseline diffusion weighted image (DWI) lesion between 82 and 300 cm3, age 18-80 years, and time from symptom onset to start of study infusion of ≤10 hours. The study will enroll both participants that do not receive intravenous (IV) recombinant tissue plasminogen activator (rtPA) and those that receive IV rtPA within 4.5 hours of stroke.

Enrollment will be randomized controlling for site, age ≤60 (yes/no), and IV rtPA treatment at baseline (yes/no). Participants will be randomized equally between glyburide and placebo.

This study was previously posted by Remedy Pharmaceuticals, Inc. and has since been acquired by Biogen.

• Study Type: Interventional
• Enrollment (Actual): 86
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85719
      • University of Arizona Medical Center
  • California
    • Stanford, California, United States, 94305
      • Stanford University Medical Center
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale University School Of Medicine
  • Florida
    • Jacksonville, Florida, United States, 32209
      • University of Florida, Jacksonville
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern Memorial Hospital
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville Hospital
  • Maine
    • Scarborough, Maine, United States, 04074
      • Maine Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland School of Medicine
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Worcester, Massachusetts, United States, 01655
      • UMass Memorial Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
    • Columbus, Ohio, United States, 43210
      • Ohio State University Wexner Medical Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University Hospital
  • Pennsylvania
    • Abington, Pennsylvania, United States, 19001
      • Abington Memorial Hospital
    • Pittsburgh, Pennsylvania, United States, 15213
      • UPMC Presbyterian Hospital
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah Healthcare

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• A clinical diagnosis of acute ischemic stroke in the MCA territory (PCA and/or ACA territory involvement in addition to primary MCA territory stroke is acceptable).
• Prior to stroke, no disability, or no significant disability despite symptoms (able to carry out all usual duties and activities).
• A baseline DWI lesion between 82 and 300 cm3 on MRI.
• Patients treated with IV rtPA should meet established criteria for IV rtPA administration in the 0-3 and 3-4.5 hr time periods at the time of rtPA administration (if rtPA is administered in the 3-4.5 hr time window, the NIHSS must be ≤ 25 at the time of rtPA administration).
• The time to the start of infusion of Study Drug must be ≤ 10 hours after time of symptom onset, if known, or the time last seen well [termed "time last known at neurologic baseline" (TLK@B)].
• Provision of written informed consent by a legally authorized representative according to institutional guidelines and national regulations.

Key Exclusion Criteria:

• Commitment to decompressive craniectomy (DC) prior to enrollment, or following enrollment and prior to start of Study Drug.
• Treatment with intra-arterial (IA) rtPA or by mechanical means for clot disruption.
• Patients unable to tolerate MRI scanning, e.g. those with pacemakers or automatic defibrillators.
• Evidence (clinical or imaging) of concurrent infarction in the contralateral hemisphere deemed by the investigator to be sufficiently serious so as to affect functional outcome.
• Clinical signs of herniation, e.g. one or two dilated, fixed pupils; unconsciousness (i.e., ≥ 2 on item 1a on the NIHSS); and/or loss of other brain stem reflexes attributable to edema or herniation according to the investigator's judgment.
• Hemorrhage (other than small petechial hemorrhages) on CT/MRI, or CT/MRI evidence of anteroseptal/pineal shift greater ≥2 mm prior to enrollment that is due to cerebral edema.
• Severe renal disorder from the patient's history (e.g. dialysis) or eGFR of < 30 mL/min/1.73 m2.
• Severe liver disease or ALT >3 times normal, or bilirubin >2 times normal.
• Blood glucose <55 mg/dL at enrollment or immediately prior to administration of Study Drug, or a clinically significant history of hypoglycemia.
• Acute ST elevation myocardial infarction, and/or acute decompensated HF, and/or QTc>520 ms, and/or known history of cardiac arrest (PEA, VT, VF, asystole), and/or admission for an ACS, MI, or coronary intervention (PCI or coronary artery surgery) within the past 3 months.
• Known sulfonylurea treatment within 7 days. Sulfonylureas include glyburide /glibenclamide (Diabeta, Glynase); glyburide plus metformin (Glucovance); glimepiride (Amaryl); repaglinide (Prandin); netaglinide (Starlix); glipizide (Glucotrol, GlibeneseR, MinodiabR); gliclazide (DiamicronR); tolbutamide (Orinase, Tolinase); glibornuride (Glutril).
• Known allergy to sulfa or specific allergy to sulfonylurea drugs.
• Known G6PD enzyme deficiency.
• Pregnant women. Women must be either post-menopausal (as confirmed by the LAR), permanently sterilized or, if ≤ 50 years old must have a negative test for pregnancy obtained before enrollment.
• Breast-feeding women who do not agree (or their LAR does not agree) to stop breast- feeding during Study Drug infusion and for 7 days following the end of Study Drug infusion.
• Patients already enrolled in a non-observation-only stroke study, or with life-expectancy <3 months not related to current stroke, or those unlikely to be compliant with follow up.
• Patients currently receiving an investigational drug.
• Patients in whom a peripheral IV line cannot be placed.
• Mentally incompetent (prior to qualifying stroke) patients and wards of the state.
• Patients who, in the opinion of the investigator, are not suitable for the study (reason to be documented).

NOTE: Other protocol defined inclusion/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Matching Placebo; Participants received a bolus dose of matching placebo over 2 minutes, followed by a continuous matching placebo infusion for 72 hours.	Drug: Placebo; Administered as specified in the treatment arm.
Experimental: Glyburide for Injection; Participants received a 0.13 mg bolus dose of glyburide over 2 minutes, followed by a 0.16 mg/hr continuous infusion for 6 hours and than a 0.11 mg/hr for 66 hours for a total dosing period of 72 hours.	Drug: Glyburide for Injection; Administered as specified in the treatment arm.; Other Names: RP-1127; glibenclamide; glybenclamide

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants with a Modified Rankin Scale (mRS) score of ≤ 4 Without Decompressive Craniectomy (DC)	The mRS scale runs from 0-6, the scoring is as follows: 0 - No symptoms, 1 - No significant disability, 2 - Slight disability, 3 - Moderate disability, 4 - Moderately severe disability, 5 - Severe disability, 6 - Dead	Day 90
Number of Participants with Adverse Events and Serious Adverse Events	An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity during the course of the study. A serious adverse event is any AE that is fatal, life-threatening, requires or prolongs hospital stay, results in persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event	Up to 1 Year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Undergoing DC or Dead		Baseline and Day 14
Change from Baseline in Ipsilateral Hemispheric Swelling	To be assessed using Magnetic Resonance Imaging (MRI).	Baseline up to 72-96 Hours
Change from Baseline in Lesional Swelling	To be assessed using MRI.	Baseline up to 72-96 Hours

Collaborators and Investigators

• Sponsor: Remedy Pharmaceuticals, Inc.
• Investigators: Study Director: Medical Director, Biogen

Publications and helpful links

General Publications

• Payabvash S, Falcone GJ, Sze GK, Jain A, Beslow LA, Petersen NH, Sheth KN, Kimberly WT. Poor Outcomes Related to Anterior Extension of Large Hemispheric Infarction: Topographic Analysis of GAMES-RP Trial MRI Scans. J Stroke Cerebrovasc Dis. 2020 Feb;29(2):104488. doi: 10.1016/j.jstrokecerebrovasdis.2019.104488. Epub 2019 Nov 29.
• Vorasayan P, Bevers MB, Beslow LA, Sze G, Molyneaux BJ, Hinson HE, Simard JM, von Kummer R, Sheth KN, Kimberly WT. Intravenous Glibenclamide Reduces Lesional Water Uptake in Large Hemispheric Infarction. Stroke. 2019 Nov;50(11):3021-3027. doi: 10.1161/STROKEAHA.119.026036. Epub 2019 Sep 20.
• Kimberly WT, Bevers MB, von Kummer R, Demchuk AM, Romero JM, Elm JJ, Hinson HE, Molyneaux BJ, Simard JM, Sheth KN. Effect of IV glyburide on adjudicated edema endpoints in the GAMES-RP Trial. Neurology. 2018 Dec 4;91(23):e2163-e2169. doi: 10.1212/WNL.0000000000006618. Epub 2018 Nov 16.
• Sheth KN, Petersen NH, Cheung K, Elm JJ, Hinson HE, Molyneaux BJ, Beslow LA, Sze GK, Simard JM, Kimberly WT. 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 Jun;49(6):1457-1463. doi: 10.1161/STROKEAHA.117.020365. Epub 2018 May 22.
• Sheth KN, Elm JJ, Molyneaux BJ, Hinson H, Beslow LA, Sze GK, Ostwaldt AC, Del Zoppo GJ, Simard JM, Jacobson S, Kimberly WT. Safety and efficacy of intravenous glyburide on brain swelling after large hemispheric infarction (GAMES-RP): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 2016 Oct;15(11):1160-9. doi: 10.1016/S1474-4422(16)30196-X. Epub 2016 Aug 23.

Study record dates

Study Major Dates

• Study Start (Actual): June 13, 2013
• Primary Completion (Actual): April 4, 2016
• Study Completion (Actual): April 4, 2016

Study Registration Dates

• First Submitted: February 14, 2013
• First Submitted That Met QC Criteria: February 15, 2013
• First Posted (Estimated): February 18, 2013

Study Record Updates

• Last Update Posted (Actual): April 30, 2024
• Last Update Submitted That Met QC Criteria: April 26, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Clostridium Infections; Bacillaceae Infections; Stroke; Ischemic Stroke; Edema; Anthrax; Gas Gangrene; Hypoglycemic Agents; Physiological Effects of Drugs; Glyburide
• Other Study ID Numbers: 252LH203; RPI 203 (Other Identifier: Remedy Pharmaceuticals, Inc.)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO