Y-3 Injection Through Skull Bone Marrow in the Treatment of Acute Malignant Middle Cerebral Artery Infarction (SOLUTION)

Sponsor

Beijing Tiantan Hospital (Other)

Overall Status

Recruiting

CT.gov ID

NCT05849805

Collaborator

(none)

Enrollment

Location

Arms

9.9

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Stroke, Acute Ischemic	Procedure: Intracalvaria bone marrow injection Other: Conventional treatment	N/A

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

20 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

The Feasibility, Safety and Efficacy of Y-3 Injection Through Skull Bone Marrow Bypassing Blood-brain Barrier in the Treatment of Acute Malignant Middle Cerebral Artery Infarction(SOLUTION)

Actual Study Start Date :

Apr 17, 2023

Anticipated Primary Completion Date :

Sep 13, 2023

Anticipated Study Completion Date :

Feb 13, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Intracalvaria bone marrow injection group Y-3 ，Intracalvaria bone marrow injection , continuous medication for 3 days, with standard treatment and management according to the related guidelines.	Procedure: Intracalvaria bone marrow injection Intracalvaria bone marrow injection Y-3 (dose was given at 32 ug/kg), continuous medication for 3 days Other: Conventional treatment standard treatment and management according to related guidelines
Sham Comparator: Conventional treatment group standard treatment and management according to related guidelines	Other: Conventional treatment standard treatment and management according to related guidelines

Arm

Intervention/Treatment

Experimental: Intracalvaria bone marrow injection group

Y-3 ，Intracalvaria bone marrow injection , continuous medication for 3 days, with standard treatment and management according to the related guidelines.

Procedure: Intracalvaria bone marrow injection

Intracalvaria bone marrow injection Y-3 (dose was given at 32 ug/kg), continuous medication for 3 days

Other: Conventional treatment

standard treatment and management according to related guidelines

Sham Comparator: Conventional treatment group

standard treatment and management according to related guidelines

Other: Conventional treatment

standard treatment and management according to related guidelines

Outcome Measures

Primary Outcome Measures

Failed of drilling [during 3 days of treatment]
The rate of the internal plate of skull was drilled through
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
Adverse events / serious adverse events [within 90±7 days after randomization]
Incidence of other adverse events / serious adverse events reported

Secondary Outcome Measures

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
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
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 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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

The NIHSS score progressed immediately after the therapy and the total score≤30 7. Informed consent signed

Exclusion Criteria:

Concurrent with one of the following cerebrovascular events:

Acute cerebral hemorrhage or subarachnoid hemorrhage; B. Acute posterior-circulation ischemia; C. Other types of TOAST classified ischemic stroke such as intracranial artery dissection, vasculitis and moyamoya disease

Hemorrhagic transformation within the infarct area, over 30% of the infarct area, and significant mass effect
Bilateral pupil fixation / pupillary reflex disappeared
Decompressive craniectomy scheduled before randomization
Refractory hypertension (systolic>200mmHg or diastolic>110mmHg) or hypotension (systolic<70mmHg or diastolic <50mmHg)
Abnormal blood glycemia before randomization (random venous blood glucose <2.8 mmol/L or> 23 mmol/L)
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 was defined as the creatinine value> 1.5 times the upper limit of normal or GFR <40 ml/min/1.73m2)
Severe cardiac insufficiency before randomization (comply with New York College of Cardiology (NYHA) Cardiac Function Class III, IV)
Taken dual antiplatelet drugs(aspirin plus clopidogrel or ticagrelor or cilostazol) within 24 hours or tirofiban within 4 hours
Combining with contraindications for intracalvaria administration (such as skull fracture, skull infection, subdural / external hematoma, sub-scalp hematoma, scalp skin or subcutaneous infection, etc)
Known hemorrhagic tendency (including but not limited to: platelet count <100×109 / L; Heparin was administered within 48 hours with APTT≥35s; on therapy of warfarin, International Normalized Ratio (INR)>1.7; on therapy of novel oral anticoagulants (NOACs); with direct thrombin or factor Xa inhibitor; accompanied with coagulopathy such as hemophilia).
Presence of severe anemia (hemoglobin <60 g/L)
Combining with respiratory failure, and is difficult to correct after endotracheal intubation or tracheotomy, requiring mechanical ventilation
Combined with severe central nervous system(CNS) degenerative disease (such as Alzheimer's disease, Parkinson's disease and severe dementia)
Life expectancy is less than 3 months (such as combining with malignancy)
Allergy to any component of the therapeutic drug
Other neuroprotective agents without guideline recommendations or with unknown mechanism were used within 24 hours of onset
Patients with pregnancy, lactation, or possible pregnancy, or planned pregnancy
Unable to comply with the trial protocol or follow-up requirements
Other conditions deemed unsuitable by investigator
The patient participated in other interventional clinical trials