Glibenclamide Advantage in Treating Edema After Intracerebral Hemorrhage (GATE-ICH)

Glibenclamide Advantage in Treating Edema After Intracerebral Hemorrhage (GATE-ICH): a Multi-center Randomized, Controlled, Assessor-blinded Trial

The purpose of the present study is to explore the efficacy of small doses of oral glibenclamide on brain edema after acute primary intracerebral hemorrhage (ICH), and improving the prognosis of patients.

Study Overview

• Status: Completed
• Conditions: Intracerebral Hemorrhage
• Intervention / Treatment: Drug: Glibenclamide Tablets; Other: Standard management for ICH

Detailed Description

In order to explore the efficacy and safety of oral glibenclamide on brain edema after acute primary ICH, a web-based 1:1 randomization process will be employed to assign 220 subjects to Glibenclamide group (giving standard management for ICH plus glibenclamide) or Control group (giving standard management for ICH). The investigators will make a neurofunctional assessment at baseline, and 3 days, 7 days, 90 days after enrollment. The investigators also assess the midline shift, and the change in the volume of ICH and perihematomal edema (PHE) from the initial to follow-up (3 days and 7days after enrollment). The serious adverse events of all-cause mortality, cardiac-related and blood glucose-related adverse events will be collected to assess the safety of glibenclamide.

• Study Type: Interventional
• Enrollment (Actual): 220
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Shaanxi
    • Ankang, Shaanxi, China, 725000
      • Ankang Central Hospital
    • Hanzhong, Shaanxi, China, 723000
      • Hanzhong Central Hospital
    • Xi'an, Shaanxi, China, 710032
      • Xijing Hospital
    • Xi'an, Shaanxi, China, 710038
      • Tangdu Hospital
    • Xianyang, Shaanxi, China, 712000
      • Xianyang Central Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 68 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age 18-70 years with a primary ICH
2. A baseline CT with basal ganglia hemorrhage of 5 to 30 mL
3. Glasgow Coma Scale (GCS) score ≥ 6
4. Symptom onset less than 72 hours prior to admission
5. Informed consent

Exclusion Criteria:

1. Supratentorial ICH planned to evacuation of a large hematoma
2. Hemorrhage breaking into ventricles of brain
3. Prior significant disability (mRS ≥ 3)
4. Severe renal disease (i.e., renal disorder requiring dialysis ) or eGFR <30ml/min/1.73m2
5. Severe liver disorder, or ALT >3 times or bilirubin >2 times upper limit of normal
6. Blood glucose < 55 mg/dL (3.1 mmol/L）at enrollment, or with the history of hypoglycemia
7. With acute ST elevation infarction, or decompensated heart failure, or cardiac arrest, or acute coronary syndrome, or known history of admission for acute coronary syndrome, or acute myocardial infarction, or coronary intervention in the past 3 months
8. Treatment with sulfonylurea in the past 7 days, including glyburide, glyburide plus metformin, glimepiride, repaglinide, glipizide, gliclazide, tolbutamide and glibornuride
9. Treatment with bosentan in the past 7 days
10. Be allergic to sulfa or other sulfonylurea drugs
11. Known G6PD deficiency
12. Pregnant women
13. Breast-feeding women disagreeing to participate the study or stop breastfeeding during and after the study
14. Be enrolled in other non-observation-only study with receiving an investigational drug
15. Life expectancy <3 months due to other diseases rather than current ICH
16. Refusing to be enrolled, or having poor compliance, or tending to withdraw

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Glibenclamide group; Giving standard management for ICH plus glibenclamide tablets, 1.25 mg 3 times daily, orally or through gastric tube, for 7 consecutive days after enrollment.	Drug: Glibenclamide Tablets; Giving glibenclamide tablets, 1.25 mg 3 times daily, orally or through gastric tube, for 7 consecutive days after enrollment.; Other: Standard management for ICH; Usual care and drug in hospital
Placebo Comparator: Control group; Giving standard management for ICH	Other: Standard management for ICH; Usual care and drug in hospital

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The proportion of death or major disability	Unfavourable outcome including death and disability is defined as patients achieving modified Rankin Scale (mRS) ≥3. The mRS is used for measuring the degree of disability or dependence in the daily activities of patients with stroke or other neurological diseases. The total score of the scale runs from 0 (perfect health without symptoms) to 6 (death).	90 days after the onset

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The change in the volume of ICH from the initial to follow-up CT scans		3 days after onset
The change in the volume of PHE from the initial to follow-up CT scans		3 days after onset
The change in the volume of ICH from the initial to follow-up CT scans		7 days after onset
The change in the volume of PHE from the initial to follow-up CT scans		7 days after onset
The proportion of death or major disability	Unfavourable outcome including death and disability is defined as patients achieving modified Rankin Scale (mRS) ≥3. The mRS is used for measuring the degree of disability or dependence in the daily activities of patients with stroke or other neurological diseases. The total score of the scale runs from 0 (perfect health without symptoms) to 6 (death).	3 days after onset
National Institute of Health stroke scale	The National Institutes of Health Stroke Scale (NIHSS) is used by healthcare providers to evaluate the impairment caused by stroke. The total score of the scale runs from 0 to 42. The higher score is an indicative of more severe impairment.	3 days after onset
Glasgow Coma Scale	The Glasgow Coma Scale is a scale for measuring the conscious state of patients with neurological diseases. The total score of the scale runs from 3 (deep coma or death) to 15 (fully awake person).	3 days after onset
Barthel Index	The Barthel Index scale is used to measure performance in activities of daily living (ADL). The total score of the scale runs from 0 to 100. The high score of the scale represents favourable performance in activities of daily life.	3 days after onset
The proportion of death or major disability	Unfavourable outcome including death and disability is defined as patients achieving modified Rankin Scale (mRS) ≥3. The mRS is used for measuring the degree of disability or dependence in the daily activities of patients with stroke or other neurological diseases. The total score of the scale runs from 0 (perfect health without symptoms) to 6 (death).	7 days after onset
National Institute of Health stroke scale	The National Institutes of Health Stroke Scale (NIHSS) is used by healthcare providers to evaluate the impairment caused by stroke. The total score of the scale runs from 0 to 42. The higher score is an indicative of more severe impairment.	7 days after onset
Glasgow Coma Scale	The Glasgow Coma Scale is a scale for measuring the conscious state of patients with neurological diseases. The total score of the scale runs from 3 (deep coma or death) to 15 (fully awake person).	7 days after onset
Barthel Index	The Barthel Index scale is used to measure performance in activities of daily living (ADL). The total score of the scale runs from 0 to 100. The high score of the scale represents favourable performance in activities of daily life.	7 days after onset
Barthel Index	The Barthel Index scale is used to measure performance in activities of daily living (ADL). The total score of the scale runs from 0 to 100. The high score of the scale represents favourable performance in activities of daily life.	90 days after onset

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of hypoglycemia	Blood glucose <3.1 mmol/L	7 days after admission
Incidence of symptomatic hypoglycemia	Blood glucose <3.1 mmol/L with investigator-identified hypoglycemic symptoms	7 days after admission
Incidence of cardiac-related Adverse Events and Serious Adverse Events		7 days after admission
Incidence of all-cause mortality		90 days after onset
Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs)		During hospitalization

Collaborators and Investigators

• Sponsor: Xijing Hospital
• Investigators: Study Director: Wen Jiang, PhD, Department of Neurology, Xijing Hospital, Fourth Military Medical

Publications and helpful links

General Publications

• Keep RF, Hua Y, Xi G. Intracerebral haemorrhage: mechanisms of injury and therapeutic targets. Lancet Neurol. 2012 Aug;11(8):720-31. doi: 10.1016/S1474-4422(12)70104-7. Epub 2012 Jun 13.
• Gebel JM Jr, Jauch EC, Brott TG, Khoury J, Sauerbeck L, Salisbury S, Spilker J, Tomsick TA, Duldner J, Broderick JP. Natural history of perihematomal edema in patients with hyperacute spontaneous intracerebral hemorrhage. Stroke. 2002 Nov;33(11):2631-5. doi: 10.1161/01.str.0000035284.12699.84.
• Inaji M, Tomita H, Tone O, Tamaki M, Suzuki R, Ohno K. Chronological changes of perihematomal edema of human intracerebral hematoma. Acta Neurochir Suppl. 2003;86:445-8. doi: 10.1007/978-3-7091-0651-8_91.
• Butcher KS, Baird T, MacGregor L, Desmond P, Tress B, Davis S. Perihematomal edema in primary intracerebral hemorrhage is plasma derived. Stroke. 2004 Aug;35(8):1879-85. doi: 10.1161/01.STR.0000131807.54742.1a. Epub 2004 Jun 3.
• Xi G, Keep RF, Hoff JT. Mechanisms of brain injury after intracerebral haemorrhage. Lancet Neurol. 2006 Jan;5(1):53-63. doi: 10.1016/S1474-4422(05)70283-0.
• Shi Y, Leak RK, Keep RF, Chen J. Translational Stroke Research on Blood-Brain Barrier Damage: Challenges, Perspectives, and Goals. Transl Stroke Res. 2016 Apr;7(2):89-92. doi: 10.1007/s12975-016-0447-9. Epub 2016 Jan 13. No abstract available.
• Jiang B, Li L, Chen Q, Tao Y, Yang L, Zhang B, Zhang JH, Feng H, Chen Z, Tang J, Zhu G. Role of Glibenclamide in Brain Injury After Intracerebral Hemorrhage. Transl Stroke Res. 2017 Apr;8(2):183-193. doi: 10.1007/s12975-016-0506-2. Epub 2016 Nov 3.
• Zhao J, Song C, Li D, Yang X, Yu L, Wang K, Wu J, Wang X, Li D, Zhang B, Li B, Guo J, Feng W, Fu F, Gu X, Qian J, Li J, Yuan X, Liu Q, Chen J, Wang X, Liu Y, Wei D, Wang L, Shang L, Yang F, Jiang W; GATE-ICH Study Group. Efficacy and safety of glibenclamide therapy after intracerebral haemorrhage (GATE-ICH): A multicentre, prospective, randomised, controlled, open-label, blinded-endpoint, phase 2 clinical trial. EClinicalMedicine. 2022 Sep 23;53:101666. doi: 10.1016/j.eclinm.2022.101666. eCollection 2022 Nov.
• Zhao J, Yang F, Song C, Li L, Yang X, Wang X, Yu L, Guo J, Wang K, Fu F, Jiang W. Glibenclamide Advantage in Treating Edema After Intracerebral Hemorrhage (GATE-ICH): Study Protocol for a Multicenter Randomized, Controlled, Assessor-Blinded Trial. Front Neurol. 2021 Apr 27;12:656520. doi: 10.3389/fneur.2021.656520. eCollection 2021.

Study record dates

Study Major Dates

• Study Start (Actual): December 15, 2018
• Primary Completion (Actual): September 23, 2020
• Study Completion (Actual): September 23, 2020

Study Registration Dates

• First Submitted: November 8, 2018
• First Submitted That Met QC Criteria: November 11, 2018
• First Posted (Actual): November 15, 2018

Study Record Updates

• Last Update Posted (Actual): April 8, 2022
• Last Update Submitted That Met QC Criteria: April 7, 2022
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: Clinical trial; Disability; Intracerebral hemorrhage; Perihematomal edema
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Intracranial Hemorrhages; Hemorrhage; Cerebral Hemorrhage; Hypoglycemic Agents; Physiological Effects of Drugs; Glyburide
• Other Study ID Numbers: KY20182067-X-3

Drug and device information, study documents

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