Clinical trial NCT03284463: Safety and Efficacy of Glibenclamide Combined With Rt-PA in Acute Cerebral Embolism
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Acute Stroke
Keywords: acute ischemic stroke
glibenclamide
rt-PA
blood-brain barrier
brain edema
Lead sponsor: Nanfang Hospital, Southern Medical University
Sponsor class: OTHER
First posted: 2017-09-15
Enrollment: 306
Sex: ALL
Minimum age (years): 18
Maximum age (years): 74
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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)

Primary outcomes:
measure: Functional outcome: The proportion of mordified Rankin Scale of 0 to 2 points
timeFrame: 90 days after the stroke onset
Secondary outcomes:
measure: Early improvement: The proportion of NIHSS decreased ≥ 4 points
timeFrame: 7 days after the stroke onset
measure: Hemorrhagic transformation: The proportion of parenchymal hemorrhagic transformation in cranial CT
timeFrame: 96 hours after the stroke onset
measure: Midline shift: The proportion of midline shift ≥ 6 mm in cranial CT
timeFrame: 96 hours after the stroke onset
measure: Functional outcome 2: The modified Rankin Scale distribution
timeFrame: 90 days after the stroke onset
measure: Functional outcome 3: The proportion of Barthel Index of 60-100 points
timeFrame: 90 days after the stroke onset
measure: Functional outcome 4: The proportion of IQCODE of ≤ 3.40
timeFrame: 6 months and 1 year after the stroke onset
measure: Blood-brain barrier: The serum concentration of MMP-9
timeFrame: Baseline, 24, 48, and 72 hours after the stroke onset
Other outcomes:
measure: Mortality
timeFrame: 90 days after the stroke onset
measure: Early neurological deterioration
timeFrame: 24 hours after the stroke onset
measure: Hypoglycemia
timeFrame: 5 days after the stroke onset
measure: Cardiac events
timeFrame: 30 days after the stroke onset
measure: Pulmonary infection
timeFrame: 7 days within the stroke onset
measure: AEs and SAEs
timeFrame: 30 days after the stroke onset
Locations:
city: Guangzhou
country: China
facility: Huadu District People's Hospital of Guangzhou
state: Guangdong
city: Guangzhou
country: China
facility: Nanfang Hospital of Southern Medical University
state: Guangdong
city: Heyuan
country: China
facility: Heyuan People's Hospital
state: Guangdong
city: Maoming
country: China
facility: Maoming People's Hospital
state: Guangdong
city: Maoming
country: China
facility: Maoming Traditional Chinese Medical Hospital
state: Guangdong
city: Haikou
country: China
facility: Hainan Provincial Hospital of Traditional Chinese Medicine
state: Hainan
city: Haikou
country: China
facility: Haikou People's Hospital
state: Hainan
city: Wenzhou
country: China
facility: The First Affiliated Hospital of Wenzhou Medical University
state: Jiangsu
Study officials:
affiliation: Department of Neurology, Nanfang Hospital, Southern Medical University
name: Suyue Pan, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.