Stroke, Acute Ischemic
Conditions
Keywords
malignant middle cerebral artery infarction, Y-3, postsynaptic density protein 95 inhibitor, BBB-bypassing route, brain drug delivery, Intracalvaria bone marrow injection
Brief summary
The mortality of malignant middle cerebral artery infarction (mMCAI) is up to 80%, while current available treatment is limited. The purpose of this study is to explore the feasibility, safety and efficacy of Intracalvaria bone marrow injection of cytoprotective drug Y-3 in mMCAI patients with contradictions of reperfusion therapy or poor reperfusion outcome.
Detailed description
The mortality rate of malignant middle cerebral artery infarction (mMCAI) is up to 80%, while current available treatment is limited. Mainstream therapeutics include endovascular reperfusion therapy and decompressive craniectomy. But endovascular-reperfusion has limits such as short time window and hemorrhagic transformation risk, while decompressive craniectomy can reduce mortality but not infarct volume. Curative effect of intravenous injection of neuroprotective drugs is severely limited because of the blood-brain barrier. Microchannels connecting the skull bone marrow and dura may be effective drug delivery shortcuts bypassing the blood-brain barrier. Cytoprotective drug Y-3 affects dual aspects of ischemic cascade by disrupting both function of the synaptic folding post-synaptic density protein 95 (PSD-95), as well as α2-γ⁃Aminobutyric acid type A receptor （α2-GABAAR） agonist. Preclinical testing proved that intracalvaria bone marrow injection of Y-3 solution 24h post rat permanent middle cerebral artery infarction reduced rat infarction volume and improved neurological function. The purpose of this study is to explore the feasibility, safety and efficacy of Intracalvaria bone marrow injection of cytoprotective drug Y-3 in mMCAI patients with contradictions of reperfusion therapy or poor reperfusion outcome. This is a prospective, randomized, open-label, blinded endpoint (PROBE) clinical trial. The trial planned to enroll 20 patients with mMCAI, aged 18-85 years, within 24 hours of onset, with contradictions of reperfusion therapy or poor reperfusion outcome. Patients will be randomly assigned to one of the following 2 groups at 1:1 ratio. Intracalvaria bone marrow injection group: intracalvaria bone marrow injection Y-3 (dose was given as 32 ug/kg)once a day for 3 consecutive days, as well as standard treatment and management according to the related guidelines. Conventional treatment group: standard treatment and management according to related guidelines Face to face interviews will be made on baseline, 4±1 days after randomization, 7±2 days after randomization, 14±2 days after randomization or discharge day, and 90 days after randomization. The primary outcomes include feasibility outcomes and safety outcomes. Feasibility Outcomes include the internal plate of skull was drilled throughly, drug leakage during injection, the patient refused to continue, failure for other reasons during 3 days'treatment. Safety Outcomes includes Infection events (skin infection, osteomyelitis, or intracranial infection), symptomatic and non-symptomatic intracranial hemorrhage, moderate to severe bleeding(defined by the GUSTO), hepatic insufficiency, renal insufficiency during the treatment, severe or extremely severe anaemia (hemoglobin \<60g / L), mortality, incidence of other adverse events / serious adverse events reported. The secondary outcomes include change of the NIHSS scores from baseline to 14±2 days or at discharge, the NIHSS scores improved by 4 points from baseline at 7±2 days, the NIHSS limb score improved by 2 points from baseline at 7±2 days, change of core infarction volume from baseline to 7±2 days, change of Glasgow Coma Scale (GCS) scores from baseline values to 14±2 days or at discharge, the modified Rankin Scale（mRS） 0-3 points at 90±7 days, Rate of decompressive hemicraniectomy according to guidelines within 90±7 days, Rate of decompressive hemicraniectomy within 90±7 days, neurological intensive care unit (NICU) hospitalization days, cost of the NICU hospitalization Safety indicators will be compared using the Fisher exact probability method. Primary effectiveness measures will be tested by the t-test or the Wilcoxon rank-sum test. Secondary effectiveness measures will use the Fisher exact probability method, where the comparison of neurofunction scale or daily living energy scale will be performed using non-parametric analysis. NICU hospitalization days and NICU hospitalization costs differences will be compared using the t-test or Wilcoxon rank-sum test. All statistics will be two-sided, P \<0.05 is considered statistically significant.
Interventions
PROCEDUREIntracalvaria bone marrow injection
Intracalvaria bone marrow injection Y-3 (dose was given at 32 ug/kg), continuous medication for 3 days
OTHERConventional treatment
standard treatment and management according to related guidelines
Sponsors
Beijing Tiantan Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1.18-75 years old; 2.No gender limitation; 3.Pre-stroke mRS score \<2 4. Randomization can be finished within 24 hours of stroke onset (onset time is defined as last-seen-well time) 5. Ischemic stroke in the middle cerebral artery(MCA) territory meeting the following characteristics: A. 15\<NIHSS≤30 B. Imaging within 6h of onset indicated the core area of infarction (rCBF\<30% volume in CTP)\>1/2 MCA territory or ASPECTS score≤6 6.If endovascular-reperfusion therapy is performed, the treatment is not effective with one of the following conditions: A. The NIHSS score decreased≤4 and the total score was still\>15 B. The NIHSS score progressed immediately after the therapy and the total score≤30 7. Informed consent signed
Exclusion criteria
1. Concurrent with one of the other cerebrovascular diseases of the following conditions: A.Acute cerebral hemorrhage or subarachnoid hemorrhage B. Acute posterior circulation infarction C.Other types of TOAST classification such as intracranial artery dissection, vasculitis and moyamoya disease 2. Hemorrhagic transformation in the infarct area, over 30% of the infarct area, and significant occupancy effect 3. Bilateral pupil fixation / pupillary reflex disappeared 4. Decompressive craniectomy was planned before randomization 5. Resistant hypertension (systolic\> 200mmHg or diastolic\> 110mmHg) or hypotension (systolic \<70mmHg or diastolic \<50mmHg) 6. Abnormal blood glycemia before randomization (random venous blood glucose \<2.8 mmol/L or\> 23 mmol/L) 7. Severe hepatic or renal insufficiency (Note: severe hepatic insufficiency refers to the ALT\> 3 times the upper limit of normal or the AST \> 3 times the upper limit of normal; severe renal insufficiency means the creatinine value\> 1.5 times the upper limit of normal or GFR \<40 ml/min/1.73m2) 8. Severe cardiac insufficiency before randomization (compliance with New York College of Cardiology (NYHA) Cardiac Function Class III, IV) 9. Dual antiplatelet (aspirin plus clopidogrel or ticagrelor or cilostazol) within 24 hours or tirofiban within 4 hours 10. Combining with contraindications for intra-diplo administration, such as skull fracture, skull infection, subdural / external hematoma, subscalp hematoma, scalp skin or subcutaneous infection, etc 11. Bleeding tendency (including but not limited to): platelet count \<100×109 / L; received heparin within nearly 24h, APTT ≥35s; oral warfarin, INR\>1.7; new-oral-anticoagulant orally; with direct thrombin or factor Xa inhibitor; Combining with coagulopathy such as hemophilia 12. presence of severe or very severe anemia (hemoglobin \<60g / L) 13. Combining with respiratory failure, and still difficult to correct after endotracheal intubation or tracheotomy, requiring ventilator treatment 14. Combining with severe CNS degenerative disease, such as AD, PD and severe dementia from various causes 15. Combining with other organic diseases, such as malignancy, the patient's life expectancy is less than 3 months 16. Allergy to any component of the therapeutic drug 17. Other neuroprotective agents without guideline recommendations and with unknown mechanism of the most important component were used within 24 hours of onset 18. Patients with pregnancy, lactation, or a possible pregnancy and a planned pregnancy 19. Unable to comply with the trial protocol or follow-up requirements 20. Other circumstances deemed unsuitable by investigator 21. Also participate in other interventional clinical trials
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adverse events / serious adverse events | within 90±7 days after randomization | Incidence of other adverse events / serious adverse events reported |
| Number of drug-leakage events | during 3 days of treatment | Number of drug-leakage events |
| Patients' tolerance of therapy | during 3 days of treatment | The number of patient who refused to continue the treatment because of the intolerance |
| Failed for other reasons | during 3 days of treatment | Number of failed for other reasons |
| Rate of participants with infection events | within 90±7 days after randomization | Rate of participants with infection events (including skin infection, osteomyelitis of skull, or intracranial infection) |
| Rate of intracranial hemorrhage | within 90±7 days after randomization | Rate of symptomatic and non-symptomatic intracranial hemorrhage |
| Rate of bleeding | within 90±7 days after randomization | Rate of bleeding (moderate to severe bleeding, defined by the GUSTO) |
| Rate of hepatic insufficiency | within 90±7 days after randomization | Rate of hepatic insufficiency: Posttreatment retest alanine aminotransferase(ALT) or aspartate transaminase(AST) value exceeds 3 times the upper normal limit |
| Rate of renal insufficiency | within 90±7 days after randomization | Rate of renal insufficiency: glomerular filtration rate (GFR)\<40 ml/min/1.73m2 during the treatment |
| Anaemia | within 90±7 days after randomization | Severe or extremely severe anaemia (hemoglobin \<60g / L) |
| Mortality | within 90±7 days after randomization | Mortality |
| Failed of drilling | during 3 days of treatment | The rate of the internal plate of skull was drilled through |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change of core infarction volume from baseline | baseline，7±2 days after randomization | The core infarction volume is determined on CTP image with rCBF\<30% |
| Change of the NIHSS scores from baseline | 14±2 days after randomization or at discharge | Change of the NIHSS scores from baseline to 14±2 days or at discharge. The National Institutes of Health Stroke Scale (NIHSS) is a standardized neurological examination score that is a valid and reliable measure of disability and recovery after acute stroke. Scores range from 0 to 42, with higher scores indicating increasing severity. |
| Patients with symptoms improvement | baseline，7±2 days after randomization | The NIHSS scores improved by 4 points from baseline at 7±2 days |
| Change of GCS scores from baseline | baseline, 14±2 days after randomization or at discharge | The GCS is a validated and reliable scale to evaluate level of consciousness in patients. The scale assesses 3 functions: Eye Opening, Verbal Response, and Motor Response. GCS scores range from 15 (best) to 3 (worst). |
| 90 days Functional improvement | 90±7 days after randomization | The modified Rankin Scale 0-3 points at 90±7 days |
| Rate of decompressive hemicraniectomy according to guidelines | 90±7 days after randomization | Rate of decompressive hemicraniectomy according to guidelines within 90±7 days |
| Rate of decompressive hemicraniectomy | 90±7 days after randomization | Rate of decompressive hemicraniectomy |
| Days of NICU hospitalization | From date of randomization until the date of discharge or date of death from any cause, assessed up to 1 month | Days of NICU hospitalization |
| The cost of the NICU hospitalization | From date of randomization until the date of discharge or date of death from any cause, assessed up to 1 month | The cost of the NICU hospitalization |
| Patients with limbs' symptoms improvement | baseline，at 7±2 days after randomization | The NIHSS limb score improved by 2 points from baseline at 7±2 days |
Countries
China
Outcome results
None listed