Safety and Efficacy of Glibenclamide Combined With Rt-PA in Acute Cerebral Embolism

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

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

Conditions
-----------------
Acute Stroke

Intervention / Treatment
-----------------
* Drug: Glibenclamide
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 74 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Glibenclamide<br>Glibenclamide Tablets | Drug: Glibenclamide<br>* 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.<br>|
| Placebo Comparator: Placebo<br>Placebo for Glibenclamide | Drug: Placebo<br>* 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.<br>|

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
brain edema, acute ischemic stroke, glibenclamide, rt-PA, blood-brain barrier