Safety and Efficacy of Glibenclamide Combined With Rt-PA in Acute Cerebral Embolism (SE-GRACE)

Safety and Efficacy of Glibenclamide Combined With Rt-PA in Treating Acute Ischemic Stroke: a Prospective, Randomized, Double-blind, Placebo-control, Multi-center Study

This study is designed to evaluate the safety and efficacy of oral glibenclamide in acute ischemic stroke patients who under intravenous rt-PA thrombolysis.

Study Overview

• Status: Completed
• Conditions: Acute Stroke
• Intervention / Treatment: Drug: Glibenclamide; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 306
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China
      • Nanfang Hospital of Southern Medical University
    • Guangzhou, Guangdong, China, 510515
      • Huadu District People's Hospital of Guangzhou
    • Heyuan, Guangdong, China
      • Heyuan People's Hospital
    • Maoming, Guangdong, China
      • Maoming People's Hospital
    • Maoming, Guangdong, China
      • Maoming Traditional Chinese Medical Hospital
  • Hainan
    • Haikou, Hainan, China, 570208
      • Haikou People's Hospital
    • Haikou, Hainan, China, 570100
      • Hainan Provincial Hospital of Traditional Chinese Medicine
  • Jiangsu
    • Wenzhou, Jiangsu, China, 325000
      • The First Affiliated Hospital of Wenzhou Medical University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 74 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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)
• Aged ≥18 and ≤74 years
• A baseline NIHSS score between 4 to 25
• Intravenous rt-PA thrombolysis conducted within 4.5 hours after stroke onset, if known, or the time last seen well [termed "time last known at neurologic baseline" (TLK@B)]
• The time to the start of administration of Study Drug must be ≤10 h after time of symptom onset or TLK@B
• Informed consent was signed by the subject or the legal representative

Exclusion Criteria:

• Prior to stroke, significant disability exists, with modified Rankin Scale >1 point
• With medical history or evidence of cerebral hemorrhage, subarachnoid hemorrhage, arteriovenous malformation, cerebral aneurysm or brain tumor
• With clinical or imaging evidence of contralateral cerebral infarction which is believed to have influence on the patient outcome by the investigators
• With clinical or imaging evidence of occlusion in vertebral or basilar artery
• With clinical evidence of brain herniation, e.g., one or two dilated, fixed pupils; unconsciousness (i.e., C2 on item 1a on the NIHSS); and/or loss of other brainstem reflexes, attributable to edema or herniation according to the investigator's judgment
• With gastrointestinal bleeding and instable hemodynamics or other causes that force the patient to stop nutritional support
• Renal disorder from the patient's history (e.g., dialysis) or eGFR of <60 mL/min/1.73 m2
• Severe liver disease, or ALT >3 times upper limit of normal or bilirubin >2 times normal (subjects may be randomized if liver function tests have been drawn but are not yet available and the subject has no known history of liver disease; however treatment with Study Drug cannot commence until liver function tests are available and indicate ALT >3 times upper limit of normal and bilirubin >2 times upper limit of normal)
• Blood glucose <3.0 mmol/L 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 heart failure, and/or Tc > 520 ms, and/or known history of cardiac arrest (PEA, VT, VF, asystole), and/or admission for an acute coronary syndrome, myocardial infarction, or coronary intervention within the past 3 months
• Known sulfonylurea treatment within 7 days. Sulfonylureas include glyburide/glibenclamide; glibenclamide plus metformin; Xiaoke Pill (a Chinese patent medicine with main effective constituent of glibenclamide); glimepiride; repaglinide; nateglinide; glipizide; gliclazide; tolbutamide; glibornuride
• Known treatment with bosentan within 7 days
• Known allergy to sulfa or specific allergy to sulfonylurea drugs
• Known G6PD enzyme deficiency
• Pregnant women. Women must be either postmenopausal (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 breastfeeding 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 <6 months not related to current stroke, or those unlikely to be compliant with follow up
• Patients currently receiving an investigational drug
• 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)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Glibenclamide; Glibenclamide Tablets	Drug: Glibenclamide; Glibenclamide is administered with a loading dose of 1.25 mg within 10 hours of stroke onset, orally or through gastric tube, followed by 0.625 mg every 8 hour for 5 days.
Placebo Comparator: Placebo; Placebo for Glibenclamide	Drug: Placebo; Placebo is administered with a loading dose of 1.25 mg within 10 hours of stroke onset, orally or through gastric tube, followed by 0.625 mg every 8 hour for 5 days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Functional outcome: The proportion of mordified Rankin Scale of 0 to 2 points	The proportion of mordified Rankin Scale of 0 to 2 points at 90 days	90 days after the stroke onset

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Early improvement: The proportion of NIHSS decreased ≥ 4 points	The proportion of NIHSS decreased ≥ 4 points at 7 days	7 days after the stroke onset
Hemorrhagic transformation: The proportion of parenchymal hemorrhagic transformation in cranial CT	The proportion of parenchymal hemorrhagic transformation in cranial CT within 96 hours	96 hours after the stroke onset
Midline shift: The proportion of midline shift ≥ 6 mm in cranial CT	The proportion of midline shift ≥ 6 mm in cranial CT within 96 hours	96 hours after the stroke onset
Functional outcome 2: The modified Rankin Scale distribution	The modified Rankin Scale distribution at 90 days	90 days after the stroke onset
Functional outcome 3: The proportion of Barthel Index of 60-100 points	The proportion of Barthel Index of 60-100 points	90 days after the stroke onset
Functional outcome 4: The proportion of IQCODE of ≤ 3.40	The proportion of Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) of ≤ 3.40 at 6 months and 1 year after the stroke onset	6 months and 1 year after the stroke onset
Blood-brain barrier: The serum concentration of MMP-9	The serum concentration of MMP-9 at baseline, and at 24, 48, and 72 h	Baseline, 24, 48, and 72 hours after the stroke onset

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality	The mortality at 90 days	90 days after the stroke onset
Early neurological deterioration	The ratio of neurological deterioration (NIHSS increased ≥ 4 points) within 24 hours after the onset	24 hours after the stroke onset
Hypoglycemia	The incidence of hypoglycemia (random blood glucose < 3.9 mmol/L)	5 days after the stroke onset
Cardiac events	The incidence of cardiac events in cardiac examination (ECG, echocardiography)	30 days after the stroke onset
Pulmonary infection	The incidence of pulmonary infection	7 days within the stroke onset
AEs and SAEs	The incidence of adverse event and serious adverse event	30 days after the stroke onset

Collaborators and Investigators

• Sponsor: Nanfang Hospital of Southern Medical University
• Investigators: Principal Investigator: Suyue Pan, M.D., Ph.D., Department of Neurology, Nanfang Hospital, Southern Medical University

Publications and helpful links

General Publications

• Huang K, Ji Z, Wu Y, Huang Y, Li G, Zhou S, Yang Z, Huang W, Yang G, Weng G, Chen P, Pan S. Safety and efficacy of glibenclamide combined with rtPA in acute cerebral ischemia with occlusion/stenosis of anterior circulation (SE-GRACE): study protocol for a randomized controlled trial. BMC Neurol. 2020 Jun 11;20(1):239. doi: 10.1186/s12883-020-01823-z.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2018
• Primary Completion (Actual): August 28, 2022
• Study Completion (Actual): May 28, 2023

Study Registration Dates

• First Submitted: September 14, 2017
• First Submitted That Met QC Criteria: September 14, 2017
• First Posted (Actual): September 15, 2017

Study Record Updates

• Last Update Posted (Actual): June 12, 2023
• Last Update Submitted That Met QC Criteria: June 9, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: acute ischemic stroke; rt-PA; brain edema; blood-brain barrier; glibenclamide
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Stroke; Hypoglycemic Agents; Physiological Effects of Drugs; Glyburide
• Other Study ID Numbers: NFEC-2017-130

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No