Glyburide Advantage in Malignant Edema and Stroke - Remedy Pharmaceuticals

NCT01794182 | Completed Phase 2 DMC

• 2 other identifiers: 252LH203RPI 203
• Study Type: interventional
• Target: 86
• Locations: 1 country
• Sites: 17

Brief Summary

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.

Conditions

Ischemic Stroke; Malignant Edema

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (3)

• Percentage of Participants Undergoing DC or Dead

  Baseline and Day 14

• Change from Baseline in Ipsilateral Hemispheric Swelling

  Baseline up to 72-96 Hours

• Change from Baseline in Lesional Swelling

  Baseline up to 72-96 Hours

Study Arms (2)

Matching Placebo

PLACEBO COMPARATOR

Participants received a bolus dose of matching placebo over 2 minutes, followed by a continuous matching placebo infusion for 72 hours.

Drug: Placebo

Glyburide for Injection

EXPERIMENTAL

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

Interventions

Glyburide for Injection DRUG

Administered as specified in the treatment arm.

Also known as: RP-1127, glibenclamide, glybenclamide

Glyburide for Injection

Placebo DRUG

Administered as specified in the treatment arm.

Matching Placebo

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Remedy Pharmaceuticals, Inc.: lead

Study Sites (17)

University of Arizona Medical Center

Tucson, Arizona, 85719, United States

Location

Stanford University Medical Center

Stanford, California, 94305, United States

Location

Yale University School of Medicine

New Haven, Connecticut, 06510, United States

Location

University of Florida, Jacksonville

Jacksonville, Florida, 32209, United States

Location

Northwestern Memorial Hospital

Chicago, Illinois, 60611, United States

Location

University of Louisville Hospital

Louisville, Kentucky, 40202, United States

Location

Maine Medical Center

Scarborough, Maine, 04074, United States

Location

University of Maryland School of Medicine

Baltimore, Maryland, 21201, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

UMASS Memorial Medical Center

Worcester, Massachusetts, 01655, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

Ohio State University Wexner Medical Center

Columbus, Ohio, 43210, United States

Location

Oregon Health & Science University Hospital

Portland, Oregon, 97239, United States

Location

Abington Memorial Hospital

Abington, Pennsylvania, 19001, United States

Location

UPMC Presbyterian Hospital

Pittsburgh, Pennsylvania, 15213, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

University of Utah Healthcare

Salt Lake City, Utah, 84132, United States

Location

Related Publications (5)

• 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.

  PMID: 31787498 DERIVED

• 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.

  PMID: 31537189 DERIVED

• 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.

  PMID: 30446594 DERIVED

• 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.

  PMID: 29789393 DERIVED

• 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.

  PMID: 27567243 DERIVED

MeSH Terms

Conditions

Ischemic Stroke; Anthrax

Interventions

Glyburide; Injections

Condition Hierarchy (Ancestors)

Stroke; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Bacillaceae Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Sulfonylurea Compounds; Urea; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Drug Administration Routes; Drug Therapy; Therapeutics

Study Officials

• Medical Director

  Remedy Pharmaceuticals

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 14, 2013
• First Posted: February 18, 2013
• Study Start: June 13, 2013
• Primary Completion: April 4, 2016
• Study Completion: April 4, 2016
• Last Updated: November 12, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (17)