Clinical Research on Umbilical Cord Mesenchymal Stem Cells Therapy for Patients with Subacute Intracerebral Hemorrhage
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 39
- 主要终点
- Hematoma volume
研究概览
简要总结
Intracerebral hemorrhage (ICH) is a common condition with high morbidity, mortality, and disability. The current treatments for ICH primarily include surgical and pharmacological interventions. For large hematomas, surgical options such as craniotomy, debridement, decompression, and minimally invasive hematoma aspiration may be performed. Pharmacological treatments are mainly symptomatic. Despite timely and standardized surgical or pharmacological interventions, many patients with ICH still experience significant sequelae, which severely affect their quality of life and place a substantial burden on both families and society. Currently, there are limited drugs available specifically for the treatment of ICH.
In recent years, stem cell therapy has gained attention as a promising treatment for neurological diseases. Human umbilical cord mesenchymal stem cells (UC-MSCs) are multifunctional stem cells with properties such as self-renewal, multidirectional differentiation potential, tissue repair, immunomodulation, and anti-inflammatory effects. Studies have shown that intravenous transplantation of UC-MSCs is safe, and their application in the treatment of ICH can reduce hematoma volume, attenuate cerebral edema and inflammation, and promote the recovery of neurological function. These findings offer a novel therapeutic strategy for ICH.
The purpose of this clinical trial is to evaluate the safety and efficacy of UC-MSCs transplantation in patients with subacute intracerebral hemorrhage, and providing a potential new therapeutic approach for this challenging condition.
详细描述
This clinical trial is divided into two phases: Phase I and Phase II. The Phase I clinical trial is a single-center, open-label, dose-escalation study. It follows a 3+3 dose-escalation design and includes the following phases: screening/baseline phase, stem cell treatment phase, safety and tolerability observation phase, and follow-up phase, with a total of 10 visits. The primary focus of Phase I is to assess the safety of stem cell treatment. There are three dose groups, with at least 3 subjects in each group. Each subject will receive a cell dose of 1×10^6 cells/kg, 2×10^6 cells/kg, or 4×10^6 cells/kg. Phase I will enroll patients with subacute intracerebral hemorrhage who meet all inclusion and exclusion criteria. In line with the 3+3 dose-escalation design, human umbilical cord mesenchymal stem cells (UC-MSCs) will be intravenously administered at the designated doses at specific time points. The study will then observe both the primary and secondary safety endpoints following transplantation.
The Phase II clinical trial is also a single-center, open-label study. It is an exploratory efficacy study, consisting of a screening/baseline phase, stem cell treatment phase, and follow-up phase, with 8 visits in total. The primary objective of Phase II is to evaluate the safety and efficacy of UC-MSCs in the treatment of subacute intracerebral hemorrhage. The Phase II trial will consist of two groups, each with 15 subjects, for a total of 30 participants. The specific number of cells to be transplanted will be determined based on the findings from Phase I. UC-MSCs or saline will be intravenously infused into the subjects at designated time points, and visits will be scheduled according to the study plan. The primary safety and efficacy endpoints, as well as secondary endpoints, will be closely monitored after transplantation.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age 18-65 years old, gender is not limited.
- •Clinically confirmed intracerebral hemorrhage during the subacute period (3 days-10 days after onset).
- •CT confirmed as cerebral parenchymal hemorrhage, ABC/2 method to calculate the episodic hemorrhage volume of 15-30 mL (ABC/2 method hematoma volume calculation formula V (cm3) =A×B×C×1/2, A is the longest diameter of the largest level of the hematoma in the horizontal position of the CT scan (cm), B is the widest diameter of the hematoma in this plane perpendicular to the A (cm), C is the thickness of the hematoma appearing in the CT film (cm)).
- •Blood biochemical indexes meet the following conditions: 1) good coagulation function, international normalized ratio (INR) <2; 2) alachlor aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 times the upper limit of the normal value, and total bilirubin <2 times the upper limit of the normal value; 3) creatinine clearance >50 mL/min; 4) hemoglobin >90 g/L; 5) absolute neutrophil value (ANC) ≥ 1.5×10^9/L, absolute lymphocyte count ≥0.4×10^9/L, platelet count ≥80×10^9/L, and albumin >25g/L; 6) procalcitonin (PCT) ≤2ng/mL.
- •National Institutes of Health Stroke Scale score (NIHSS) ≥5 and ≤
- •Pre-onset modified Ranking Scale score (mRS) ≤
- •Glasgow Coma Score (GCS) ≥9 points and ≥3 points on a single item.
- •Good compliance, signed informed consent by the person and/or legal guardian and able to receive follow-up visits at the specified time.
排除标准
- •Brain midline deviation >10 mm or brain hernia formation.
- •Patients who have undergone or intend to undergo surgical treatment to remove hematoma.
- •Secondary intracerebral hemorrhage caused by traumatic brain injury, arteriovenous malformation, intracranial aneurysm, coagulation disorders, hemorrhagic transformation after cerebral infarction, or tumors.
- •Suffering from malignant tumors, autoimmune diseases (including but not limited to systemic lupus erythematosus, systemic vasculitis, etc.), hemorrhagic predisposition diseases (including all kinds of hereditary hemorrhagic disorders and acquired hemorrhagic diseases), malignant cardiac arrhythmia, cardiac insufficiency (BNP ≥1000pg/mL or left ventricular ejection fraction ≤40%), acute myocardial infarction, acute or severe infectious diseases (such as intracranial infection, severe pneumonia, sepsis, etc.) and other serious diseases that may aggravate the condition and affect the assessment of efficacy.
- •Allergy or intolerance to stem cell preparations or related medicines that need to be used in the infusion process, such as saline preparations and hormone preparations.
- •Pregnant or lactating women.
- •History of stroke disease with sequelae in the last 1 year, NIHSS score ≥
- •Subarachnoid hemorrhage, primary ventricular hemorrhage, pharmacological hemorrhagic stroke.
- •Unstable vital signs, including combined respiratory abnormalities (respiratory rate <12 breaths/min or >24 breaths/min, oxygen saturation ≤90%), hyperthermia (axillary temperature >39 ℃), blood pressure ≥180/100 mmHg after antihypertensive treatment, blood glucose >20 mmol/L.
- •Those who are participating in other clinical trials.
- •Previous history of epilepsy or current use of antiepileptic drugs.
- •Unable to accept all laboratory tests and imaging tests designed by the program due to metal implants or pacemakers in the body.
- •Inability to complete the follow-up program as required.
- •Patients or their legal guardians are unwilling to sign the written informed consent.
研究组 & 干预措施
PhaseⅠclinical trial: 3+3 dose-escalation design
The Phase I clinical trial is a 3+3 dose-escalation trial, with three dose groups, each including at least 3 subjects. The trial begins with the low-dose group. If the dose-limiting toxicity (DLT) assessment during the observation period meets the criteria of the 3+3 dose-escalation design, enrollment will proceed to the next higher dose group. Each subject will receive one dose of human umbilical cord mesenchymal stem cells (UC-MSCs) therapy, in addition to the standard treatment for intracerebral hemorrhage.
干预措施: Device: Phase Ⅰ Dose Level 1 (Biological)
PhaseⅠclinical trial: 3+3 dose-escalation design
The Phase I clinical trial is a 3+3 dose-escalation trial, with three dose groups, each including at least 3 subjects. The trial begins with the low-dose group. If the dose-limiting toxicity (DLT) assessment during the observation period meets the criteria of the 3+3 dose-escalation design, enrollment will proceed to the next higher dose group. Each subject will receive one dose of human umbilical cord mesenchymal stem cells (UC-MSCs) therapy, in addition to the standard treatment for intracerebral hemorrhage.
干预措施: Device: Phase Ⅰ Dose Level 2 (Biological)
PhaseⅠclinical trial: 3+3 dose-escalation design
The Phase I clinical trial is a 3+3 dose-escalation trial, with three dose groups, each including at least 3 subjects. The trial begins with the low-dose group. If the dose-limiting toxicity (DLT) assessment during the observation period meets the criteria of the 3+3 dose-escalation design, enrollment will proceed to the next higher dose group. Each subject will receive one dose of human umbilical cord mesenchymal stem cells (UC-MSCs) therapy, in addition to the standard treatment for intracerebral hemorrhage.
干预措施: Device: Phase Ⅰ Dose Level 3 (Biological)
Phase Ⅱ clinical trial: MTD group
The Phase II clinical trial included two groups. The dose of UC-MSCs received in each group patients will be determined based on the phase I results. One of the two groups subjects received the MTD obtained in phase I, and the other group subjects received a dose lower than the MTD. Each subject in the Phase II clinical trial received three dose of stem cell therapies after enrollment.The second therapy is 7 days after the first therapy, and the third therapy is 7 days after the second therapy.
干预措施: Device: Phase II MTD in Phase I (Biological)
Phase Ⅱ clinical trial: lower than the MTD group
The Phase II clinical trial included two groups. The dose of UC-MSCs received in each group patients will be determined based on the phase I results. One of the two groups subjects received the MTD obtained in phase I, and the other group subjects received a dose lower than the MTD. Each subject in the Phase II clinical trial received three dose of stem cell therapies after enrollment.The second therapy is 7 days after the first therapy, and the third therapy is 7 days after the second therapy.
干预措施: Device: Phase II lower than the MTD in Phase I (Biological)
结局指标
主要结局
Hematoma volume
时间窗: Baseline and 7 days, 2 weeks, 1 month, 6 months post-transplantation for phase I; Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 6 months post-transplantation for phase Ⅱ.
Volume of intracerebral hemorrhage measured in cubic centimeters (cm³) as determined by quantitative analysis of head computed tomography scans.
Peri-hematomal edema volume
时间窗: Baseline and 7 days, 2 weeks, 1 month, 6 months post-transplantation for phase I; Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 6 months post-transplantation for phase Ⅱ.
Volume of edema surrounding the hematoma measured in cubic centimeters (cm³) as determined by quantitative analysis of head magnetic resonance imaging scans.
National Institutes of Health Stroke Scale (NIHSS) score
时间窗: Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 3 months, 6 months post-transplantation for phase Ⅱ.
The NIHSS is a neurological examination scale that provides a quantitative measure of stroke-related neurologic deficit. Scores range from 0 to 42 points, with higher scores indicating more severe neurological impairment.
Barthel Index scale score
时间窗: Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 3 months, 6 months post-transplantation for phase Ⅱ.
The Barthel Index assesses functional independence in activities of daily living across 10 items. Total scores range from 0 to 100, with higher scores indicating greater independence in activities of daily living.
Incidence of serious adverse events
时间窗: Up to 6 months post-transplantation
The incidence of serious adverse events (SAEs, such as recurrent bleeding, progressive stroke, brain death, respiratory failure, renal failure, circulatory failure, secondary epilepsy, sepsis, deep vein thrombosis, etc.) and treatment-related adverse events (TEAEs, such as fever or allergies after intravenous infusion of human umbilical cord mesenchymal stem cells(UC-MSCs)) occurring within 6 months of receiving UC-MSCs therapy.
The modified Rankin Scale (mRS) score
时间窗: Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 3 months, 6 months post-transplantation for phase Ⅱ.
The mRS measures the degree of disability or dependence in daily activities among individuals who have suffered a stroke. Scores range from 0 (no symptoms) to 6 (death), with higher scores indicating greater disability.
次要结局
- Electrocardiogram ST Segment Deviation(Baseline and 1 day, 2 days, 7 days, 2 weeks, 3 weeks, 1 month, 3 months, 6 months post-transplantation for phase I.; Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 6 months post-transplantation for phase Ⅱ.)
- Electrocardiogram QTc Prolongation(Baseline and 1 day, 2 days, 7 days, 2 weeks, 3 weeks, 1 month, 3 months, 6 months post-transplantation for phase I.; Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 6 months post-transplantation for phase Ⅱ.)
- Electrocardiogram Arrhythmia Assessment(Baseline and 1 day, 2 days, 7 days, 2 weeks, 3 weeks, 1 month, 3 months, 6 months post-transplantation for phase I.; Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 6 months post-transplantation for phase Ⅱ.)
- Electrocardiogram Pathological Q Waves(Baseline and 1 day, 2 days, 7 days, 2 weeks, 3 weeks, 1 month, 3 months, 6 months post-transplantation for phase I.; Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 6 months post-transplantation for phase Ⅱ.)
- Montreal Cognitive Assessment (MoCA) Score(Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 3 months, 6 months post-transplantation for phase Ⅱ.)
- Incidence of adverse events(Up to 6 months post-transplantation)
- Serum Interleukin-2 Receptor (IL-2R) Level(Baseline and 7 days, 2 weeks, 1 month, 6 months post-transplantation for phase I.; Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 6 months post-transplantation for phase Ⅱ.)
- Pulmonary Embolism(Baseline and 7 days, 2 weeks, 1 month, 6 months post-transplantation for phase I; Baseline and 3 weeks, 6 months post-transplantation for phase Ⅱ.)
- Mini-Mental State Examination (MMSE) Score(Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 3 months, 6 months post-transplantation for phase Ⅱ.)
- Hamilton Anxiety Scale (HAMA) Score(Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 3 months, 6 months post-transplantation for phase Ⅱ.)
- Hamilton Depression Scale (HAMD) Score(Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 3 months, 6 months post-transplantation for phase Ⅱ.)
- Serum Tumor Necrosis Factor-Alpha (TNF-alpha) Level(Baseline and 7 days, 2 weeks, 1 month, 6 months post-transplantation for phase I.; Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 6 months post-transplantation for phase Ⅱ.)
- Serum Interleukin-1 Beta (IL-1beta) Level(Baseline and 7 days, 2 weeks, 1 month, 6 months post-transplantation for phase I.; Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 6 months post-transplantation for phase Ⅱ.)
- Serum Interleukin-6 (IL-6) Level(Baseline and 7 days, 2 weeks, 1 month, 6 months post-transplantation for phase I.; Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 6 months post-transplantation for phase Ⅱ.)
- Serum Interleukin-8 (IL-8) Level(Baseline and 7 days, 2 weeks, 1 month, 6 months post-transplantation for phase I.; Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 6 months post-transplantation for phase Ⅱ.)
- Serum Interleukin-10 (IL-10) Level(Baseline and 7 days, 2 weeks, 1 month, 6 months post-transplantation for phase I.; Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 6 months post-transplantation for phase Ⅱ.)
- Hemoglobin Level(Baseline and 7 days, 2 weeks, 1 month, 6 months post-transplantation for phase I; Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 6 months post-transplantation for phase Ⅱ.)
- White Blood Cell Count(Baseline and 7 days, 2 weeks, 1 month, 6 months post-transplantation for phase I; Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 6 months post-transplantation for phase Ⅱ.)
- Platelet Count(Baseline and 7 days, 2 weeks, 1 month, 6 months post-transplantation for phase I; Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 6 months post-transplantation for phase Ⅱ.)
- Alanine Aminotransferase (ALT) Level(Baseline and 7 days, 2 weeks, 1 month, 6 months post-transplantation for phase I; Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 6 months post-transplantation for phase Ⅱ.)
- Aspartate Aminotransferase (AST) Level(Baseline and 7 days, 2 weeks, 1 month, 6 months post-transplantation for phase I; Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 6 months post-transplantation for phase Ⅱ.)
- Blood Urea Nitrogen (BUN) Level(Baseline and 7 days, 2 weeks, 1 month, 6 months post-transplantation for phase I; Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 6 months post-transplantation for phase Ⅱ.)
- Serum Creatinine Level(Baseline and 7 days, 2 weeks, 1 month, 6 months post-transplantation for phase I; Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 6 months post-transplantation for phase Ⅱ.)
- Urine Protein Level(Baseline and 7 days, 2 weeks, 1 month, 6 months post-transplantation for phase I; Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 6 months post-transplantation for phase Ⅱ.)
- Urine Red Blood Cell Count(Baseline and 7 days, 2 weeks, 1 month, 6 months post-transplantation for phase I; Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 6 months post-transplantation for phase Ⅱ.)
- Fecal Occult Blood Test(Baseline and 7 days, 2 weeks, 1 month, 6 months post-transplantation for phase I; Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 6 months post-transplantation for phase Ⅱ.)
- Serum Sodium Level(Baseline and 7 days, 2 weeks, 1 month, 6 months post-transplantation for phase I; Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 6 months post-transplantation for phase Ⅱ.)
- Serum Potassium Level(Baseline and 7 days, 2 weeks, 1 month, 6 months post-transplantation for phase I; Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 6 months post-transplantation for phase Ⅱ.)
- Prothrombin Time (PT)(Baseline and 7 days, 2 weeks, 1 month, 6 months post-transplantation for phase I; Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 6 months post-transplantation for phase Ⅱ.)
- Activated Partial Thromboplastin Time (aPTT)(Time required for plasma to clot after activation of intrinsic pathway, measured in seconds.)
- Total Cholesterol Level(Baseline and 7 days, 2 weeks, 1 month, 6 months post-transplantation for phase I; Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 6 months post-transplantation for phase Ⅱ.)
- High-Density Lipoprotein (HDL) Cholesterol Level(Baseline and 7 days, 2 weeks, 1 month, 6 months post-transplantation for phase I; Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 6 months post-transplantation for phase Ⅱ.)
- Low-Density Lipoprotein (LDL) Cholesterol Level(Baseline and 7 days, 2 weeks, 1 month, 6 months post-transplantation for phase I; Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 6 months post-transplantation for phase Ⅱ.)
- Fasting Blood Glucose Level(Baseline and 7 days, 2 weeks, 1 month, 6 months post-transplantation for phase I; Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 6 months post-transplantation for phase Ⅱ.)
- CD4+ T Lymphocyte Count(Baseline and 7 days, 2 weeks, 1 month, 6 months post-transplantation for phase I; Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 6 months post-transplantation for phase Ⅱ.)
- CD8+ T Lymphocyte Count(Baseline and 7 days, 2 weeks, 1 month, 6 months post-transplantation for phase I; Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 6 months post-transplantation for phase Ⅱ.)
- CD4+/CD8+ Ratio(Baseline and 7 days, 2 weeks, 1 month, 6 months post-transplantation for phase I; Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 6 months post-transplantation for phase Ⅱ.)
- High-Sensitivity C-Reactive Protein (hs-CRP) Level(Baseline and 7 days, 2 weeks, 1 month, 6 months post-transplantation for phase I; Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 6 months post-transplantation for phase Ⅱ.)
- Middle Cerebral Artery Blood Flow Velocity(Baseline and 7 days, 2 weeks, 1 month, 6 months post-transplantation for phase I; Baseline and 6 months post-transplantation for phase Ⅱ.)
- Pulsatility Index(Baseline and 7 days, 2 weeks, 1 month, 6 months post-transplantation for phase I; Baseline and 6 months post-transplantation for phase Ⅱ.)
- Carotid Artery Stenosis Percentage(Baseline and 7 days, 2 weeks, 1 month, 6 months post-transplantation for phase I; Baseline and 6 months post-transplantation for phase Ⅱ.)
- Electroencephalogram Delta Wave Activity(Baseline and 7 days, 2 weeks, 1 month, 6 months post-transplantation for phase I; Baseline and 3 weeks , 6 months post-transplantation for phase Ⅱ.)
- Electroencephalogram Epileptiform Discharges(Baseline and 7 days, 2 weeks, 1 month, 6 months post-transplantation for phase I; Baseline and 3 weeks , 6 months post-transplantation for phase Ⅱ.)
- Electroencephalogram Background Rhythm Analysis(Baseline and 7 days, 2 weeks, 1 month, 6 months post-transplantation for phase I; Baseline and 3 weeks , 6 months post-transplantation for phase Ⅱ.)
- Corticospinal Tract Integrity(Baseline and 7 days, 2 weeks, 1 month, 6 months post-transplantation for phase I; Baseline and 6 months post-transplantation for phase Ⅱ.)
- Electroencephalogram Hemispheric Asymmetry(Quantitative comparison of power spectral density between homologous regions of both cerebral hemispheres. Asymmetry of >50% in any frequency band will be classified as abnormal.)
研究者
Tang Zhouping
Professor
Tongji Hospital