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.
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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
39
Patients in the first dose level will receive a cell dose of 1×10\^6 cells/kg.
Patients in the second dose level will receive a cell dose of 2×10\^6 cells/kg.
Patients in the third dose level will receive a cell dose of 4×10\^6 cells/kg. Based on these findings, the maximum tolerated dose (MTD) will be determined.
This group subjects received the MTD obtained in phase I.
This group subjects received a dose lower than the MTD
Incidence of serious adverse events
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.
Time frame: Up to 6 months post-transplantation
Hematoma volume
Volume of intracerebral hemorrhage measured in cubic centimeters (cm³) as determined by quantitative analysis of head computed tomography scans.
Time frame: 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.
Peri-hematomal edema volume
Volume of edema surrounding the hematoma measured in cubic centimeters (cm³) as determined by quantitative analysis of head magnetic resonance imaging scans.
Time frame: 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.
National Institutes of Health Stroke Scale (NIHSS) score
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.
Time frame: Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 3 months, 6 months post-transplantation for phase Ⅱ.
The modified Rankin Scale (mRS) score
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.
Time frame: Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 3 months, 6 months post-transplantation for phase Ⅱ.
Barthel Index scale score
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.
Time frame: Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 3 months, 6 months post-transplantation for phase Ⅱ.
Incidence of adverse events
The incidence of all non-serious adverse events occurring from infusion date through end of follow-up, including stress ulcers, pneumonia, injection site infections, and fever.
Time frame: Up to 6 months post-transplantation
Pulmonary Embolism
Binary assessment (present/absent) of pulmonary embolism based on chest computed tomography with contrast enhancement.
Time frame: 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.
Electrocardiogram ST Segment Deviation
Measurement of ST segment elevation or depression in millimeters from baseline. ST elevation ≥1mm in two or more contiguous leads or ST depression ≥0.5mm will be classified as abnormal.
Time frame: 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
Assessment for presence of pathological Q waves, defined as Q waves ≥40ms in duration or ≥25% of the height of the following R wave in at least two contiguous leads.
Time frame: 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
Measurement of corrected QT interval in milliseconds. QTc intervals \>450ms in males or \>460ms in females will be classified as prolonged, indicating abnormal ventricular repolarization.
Time frame: 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
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Identification and quantification of cardiac arrhythmias including atrial fibrillation, atrial flutter, ventricular tachycardia, ventricular fibrillation, and heart blocks. Results will be reported as presence or absence of each arrhythmia type.
Time frame: 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.
Mini-Mental State Examination (MMSE) Score
The MMSE is a 30-point questionnaire used to measure cognitive impairment. Scores range from 0 to 30, with higher scores indicating better cognitive function.
Time frame: Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 3 months, 6 months post-transplantation for phase Ⅱ.
Montreal Cognitive Assessment (MoCA) Score
The MoCA is a cognitive screening test designed to detect mild cognitive impairment. Scores range from 0 to 30, with higher scores indicating better cognitive function.
Time frame: Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 3 months, 6 months post-transplantation for phase Ⅱ.
Hamilton Anxiety Scale (HAMA) Score
The HAMA is a 14-item scale that measures the severity of anxiety symptoms. Scores range from 0 to 56, with higher scores indicating more severe anxiety.
Time frame: Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 3 months, 6 months post-transplantation for phase Ⅱ.
Hamilton Depression Scale (HAMD) Score
The HAMD is a 17-item scale that measures the severity of depression symptoms. Scores range from 0 to 52, with higher scores indicating more severe depression.
Time frame: 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
Concentration of TNF-alpha in pg/mL measured in serum samples.
Time frame: 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
Concentration of IL-1beta in pg/mL measured in serum samples.
Time frame: 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-2 Receptor (IL-2R) Level
Concentration of IL-2R in pg/mL measured in serum samples.
Time frame: 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
Concentration of IL-6 in pg/mL measured in serum samples.
Time frame: 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
Concentration of IL-8 in pg/mL measured in serum samples.
Time frame: 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
Concentration of IL-10 in pg/mL measured in serum samples.
Time frame: 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
Concentration of hemoglobin in blood measured in grams per deciliter (g/dL).
Time frame: 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
Number of white blood cells per microliter (cells/μL) of blood.
Time frame: 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
Number of platelets per microliter (cells/μL) of blood.
Time frame: 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
Concentration of ALT enzyme in international units per liter (IU/L) as a measure of liver function.
Time frame: 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
Concentration of AST enzyme in international units per liter (IU/L) as a measure of liver function.
Time frame: 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
Concentration of BUN in milligrams per deciliter (mg/dL) as a measure of kidney function.
Time frame: 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
Concentration of creatinine in milligrams per deciliter (mg/dL) as a measure of kidney function.
Time frame: 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
Concentration of protein in urine measured in milligrams per deciliter (mg/dL).
Time frame: 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
Number of red blood cells per high-power field (HPF) in urine microscopy.
Time frame: 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
Qualitative assessment of occult blood in stool (positive or negative).
Time frame: 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
Concentration of sodium in serum measured in millimoles per liter (mmol/L).
Time frame: 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
Concentration of potassium in serum measured in millimoles per liter (mmol/L).
Time frame: 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)
Time required for plasma to clot after addition of tissue factor, measured in seconds.
Time frame: 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.
Time frame: Time required for plasma to clot after activation of intrinsic pathway, measured in seconds.
Total Cholesterol Level
Concentration of total cholesterol in serum measured in milligrams per deciliter (mg/dL).
Time frame: 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
Concentration of HDL cholesterol in serum measured in milligrams per deciliter (mg/dL).
Time frame: 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
Concentration of LDL cholesterol in serum measured in milligrams per deciliter (mg/dL).
Time frame: 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
Concentration of glucose in blood after overnight fasting, measured in milligrams per deciliter (mg/dL).
Time frame: 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
Number of CD4+ T lymphocytes per microliter (cells/μL) of blood as a measure of immune function.
Time frame: 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
Number of CD8+ T lymphocytes per microliter (cells/μL) of blood as a measure of immune function.
Time frame: 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
Ratio of CD4+ to CD8+ T lymphocytes as a measure of immune system balance.
Time frame: 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
Concentration of hs-CRP in milligrams per liter (mg/L) as a measure of inflammation.
Time frame: 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
Mean blood flow velocity in the middle cerebral artery measured in centimeters per second (cm/s) using transcranial Doppler ultrasonography.
Time frame: 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
Ratio of the difference between peak systolic and end-diastolic velocities to the mean velocity in cerebral arteries as measured by transcranial Doppler ultrasonography. Higher values indicate increased vascular resistance.
Time frame: 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
Degree of carotid artery stenosis expressed as percentage reduction in vessel diameter as measured by computed tomography angiography.
Time frame: 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
Quantitative measurement of delta wave (0.5-4 Hz) power in microvolts squared (μV²). Increased focal delta activity outside of sleep states indicates abnormal cerebral function.
Time frame: 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
Quantification of epileptiform discharges (spikes, sharp waves, spike-and-wave complexes) per hour of recording. Presence of ≥1 discharge per hour will be classified as abnormal.
Time frame: 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
Assessment of background rhythm frequency in Hertz (Hz) and amplitude in microvolts (μV). Normal adult awake posterior dominant rhythm is 8-13 Hz (alpha rhythm). Slowing below 8 Hz will be classified as abnormal.
Time frame: 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
Tractography-based assessment of corticospinal tract integrity expressed as percentage of fibers preserved compared to the unaffected hemisphere. Values range from 0% to 100%, with lower percentages indicating greater tract damage.
Time frame: 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
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.
Time frame: 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.