Glyburide Advantage in Malignant Edema and Stroke - Remedy Pharmaceuticals

NCT ID: NCT01794182

Last Updated: 2024-11-12

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 86 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-06-13
• Study Completion Date: 2016-04-04

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.

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.

Conditions

Ischemic Stroke; Malignant Edema

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

Matching Placebo

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

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Administered as specified in the treatment arm.

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.

Group Type: EXPERIMENTAL

Glyburide for Injection

Intervention Type: DRUG

Administered as specified in the treatment arm.

Interventions

Glyburide for Injection

Administered as specified in the treatment arm.

Intervention Type: DRUG

Placebo

Administered as specified in the treatment arm.

Intervention Type: DRUG

Other Intervention Names

RP-1127; glibenclamide; glybenclamide

Eligibility Criteria

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.

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).

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Remedy Pharmaceuticals, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Director

Role: STUDY_DIRECTOR

Remedy Pharmaceuticals

Locations

University of Arizona Medical Center

Tucson, Arizona, United States

Stanford University Medical Center

Stanford, California, United States

Yale University School of Medicine

New Haven, Connecticut, United States

University of Florida, Jacksonville

Jacksonville, Florida, United States

Northwestern Memorial Hospital

Chicago, Illinois, United States

University of Louisville Hospital

Louisville, Kentucky, United States

Maine Medical Center

Scarborough, Maine, United States

University of Maryland School of Medicine

Baltimore, Maryland, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

UMASS Memorial Medical Center

Worcester, Massachusetts, United States

Cleveland Clinic

Cleveland, Ohio, United States

Ohio State University Wexner Medical Center

Columbus, Ohio, United States

Oregon Health & Science University Hospital

Portland, Oregon, United States

Abington Memorial Hospital

Abington, Pennsylvania, United States

UPMC Presbyterian Hospital

Pittsburgh, Pennsylvania, United States

Medical University of South Carolina

Charleston, South Carolina, United States

University of Utah Healthcare

Salt Lake City, Utah, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 31787498 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 31537189 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 30446594 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 29789393 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 27567243 (View on PubMed)

Other Identifiers

RPI 203

Identifier Type: OTHER

Identifier Source: secondary_id

252LH203

Identifier Type: -

Identifier Source: org_study_id