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)
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 发起方
- 入组人数
- 20
- 试验地点
- 1
- 主要终点
- Rate of renal insufficiency
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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\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
排除标准
- •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
- •Hemorrhagic transformation in the infarct area, over 30% of the infarct area, and significant occupancy effect
- •Bilateral pupil fixation / pupillary reflex disappeared
- •Decompressive craniectomy was planned before randomization
- •Resistant 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 means the creatinine value> 1.5 times the upper limit of normal or GFR <40 ml/min/1.73m2)
- •Severe cardiac insufficiency before randomization (compliance with New York College of Cardiology (NYHA) Cardiac Function Class III, IV)
- •Dual antiplatelet (aspirin plus clopidogrel or ticagrelor or cilostazol) within 24 hours or tirofiban within 4 hours
- •Combining with contraindications for intra-diplo administration, such as skull fracture, skull infection, subdural / external hematoma, subscalp hematoma, scalp skin or subcutaneous infection, etc
- •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
- •presence of severe or very severe anemia (hemoglobin <60g / L)
- •Combining with respiratory failure, and still difficult to correct after endotracheal intubation or tracheotomy, requiring ventilator treatment
- •Combining with severe CNS degenerative disease, such as AD, PD and severe dementia from various causes
- •Combining with other organic diseases, such as malignancy, the patient's life expectancy is less than 3 months
- •Allergy to any component of the therapeutic drug
- •Other neuroprotective agents without guideline recommendations and with unknown mechanism of the most important component were used within 24 hours of onset
- •Patients with pregnancy, lactation, or a possible pregnancy and a planned pregnancy
- •Unable to comply with the trial protocol or follow-up requirements
- •Other circumstances deemed unsuitable by investigator
- •Also participate in other interventional clinical trials
研究组 & 干预措施
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.
干预措施: Intracalvaria bone marrow injection (Procedure)
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.
干预措施: Conventional treatment (Other)
Conventional treatment group
standard treatment and management according to related guidelines
干预措施: Conventional treatment (Other)
结局指标
主要结局
Rate of renal insufficiency
时间窗: within 90±7 days after randomization
Rate of renal insufficiency: glomerular filtration rate (GFR)\<40 ml/min/1.73m2 during the treatment
Failed for other reasons
时间窗: during 3 days of treatment
Number of failed for other reasons
Number of drug-leakage events
时间窗: during 3 days of treatment
Number of drug-leakage events
Failed of drilling
时间窗: during 3 days of treatment
The rate of the internal plate of skull was drilled through
Rate of participants with infection events
时间窗: within 90±7 days after randomization
Rate of participants with infection events (including skin infection, osteomyelitis of skull, or intracranial infection)
Patients' tolerance of therapy
时间窗: during 3 days of treatment
The number of patient who refused to continue the treatment because of the intolerance
Rate of bleeding
时间窗: within 90±7 days after randomization
Rate of bleeding (moderate to severe bleeding, defined by the GUSTO)
Rate of hepatic insufficiency
时间窗: 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
Mortality
时间窗: within 90±7 days after randomization
Mortality
Rate of intracranial hemorrhage
时间窗: within 90±7 days after randomization
Rate of symptomatic and non-symptomatic intracranial hemorrhage
Anaemia
时间窗: within 90±7 days after randomization
Severe or extremely severe anaemia (hemoglobin \<60g / L)
Adverse events / serious adverse events
时间窗: within 90±7 days after randomization
Incidence of other adverse events / serious adverse events reported
次要结局
- Rate of decompressive hemicraniectomy(90±7 days after randomization)
- 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)
- Change of the NIHSS scores from baseline(14±2 days after randomization or at discharge)
- Patients with symptoms improvement(baseline，14±2 days after randomization)
- Change of GCS scores from baseline(baseline, 14±2 days after randomization or at discharge)
- Rate of decompressive hemicraniectomy according to guidelines(90±7 days after randomization)
- 90 days Functional improvement(90±7 days after randomization)
- 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)
- Patients with limbs' symptoms improvement(baseline，at 14±2 days after randomization)
- Change of core infarction volume from baseline(baseline，7±2 days after randomization)
- Patients with symptoms improvement(baseline，7±2 days after randomization)
- Patients with limbs' symptoms improvement(baseline，at 7±2 days after randomization)
研究者
yilong Wang
Vice President of Beijing Tiantan Hospital
Beijing Tiantan Hospital