Stem Cell Therapy for Intracerebral Hemorrhage

Official title

Clinical Research on Umbilical Cord Mesenchymal Stem Cells Therapy for Patients With Subacute Intracerebral Hemorrhage

Overview

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.

Detailed description

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.

Interventions

• Biological Device: Phase Ⅰ Dose Level 1
  Patients in the first dose level will receive a cell dose of 1×10\^6 cells/kg.
• Biological Device: Phase Ⅰ Dose Level 2
  Patients in the second dose level will receive a cell dose of 2×10\^6 cells/kg.
• Biological Device: Phase Ⅰ Dose Level 3
  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.
• Biological Device: Phase II MTD in Phase I
  This group subjects received the MTD obtained in phase I.
• Biological Device: Phase II lower than the MTD in Phase I
  This group subjects received a dose lower than the MTD

Primary outcome measures

• Incidence of serious adverse events [Time frame: Up to 6 months post-transplantation]
• Hematoma volume [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 [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 [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 [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 [Time frame: Baseline and 7 days, 2 weeks, 3 weeks, 1 month, 3 months, 6 months post-transplantation for phase Ⅱ.]

Secondary outcome measures (12)

• Incidence of adverse events [Time frame: Up to 6 months post-transplantation]
• Pulmonary Embolism [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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.]

Eligibility criteria

Inclusion criteria

• 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 ≤20.
• Pre-onset modified Ranking Scale score (mRS) ≤1.
• 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.

Exclusion criteria

• 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 ≥ 6.
• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• Moise KJ Jr. Umbilical cord stem cells. Obstet Gynecol. 2005 Dec;106(6):1393-407. doi: 10.1097/01.AOG.0000188388.84901.e4. PMID 16319269
• Li T, Xia M, Gao Y, Chen Y, Xu Y. Human umbilical cord mesenchymal stem cells: an overview of their potential in cell-based therapy. Expert Opin Biol Ther. 2015;15(9):1293-306. doi: 10.1517/14712598.2015.1051528. Epub 2015 Jun 12. PMID 26067213
• Tsang KS, Ng CPS, Zhu XL, Wong GKC, Lu G, Ahuja AT, Wong KSL, Ng HK, Poon WS. Phase I/II randomized controlled trial of autologous bone marrow-derived mesenchymal stem cell therapy for chronic stroke. World J Stem Cells. 2017 Aug 26;9(8):133-143. doi: 10.4252/wjsc.v9.i8.133. PMID 28928910
• Chang Z, Mao G, Sun L, Ao Q, Gu Y, Liu Y. Cell therapy for cerebral hemorrhage: Five year follow-up report. Exp Ther Med. 2016 Dec;12(6):3535-3540. doi: 10.3892/etm.2016.3811. Epub 2016 Oct 18. PMID 28101148
• Hu Y, Liu N, Zhang P, Pan C, Zhang Y, Tang Y, Deng H, Aimaiti M, Zhang Y, Zhou H, Wu G, Tang Z. Preclinical Studies of Stem Cell Transplantation in Intracerebral Hemorrhage: a Systemic Review and Meta-Analysis. Mol Neurobiol. 2016 Oct;53(8):5269-77. doi: 10.1007/s12035-015-9441-6. Epub 2015 Sep 26. PMID 26409481
• Gao L, Xu W, Li T, Chen J, Shao A, Yan F, Chen G. Stem Cell Therapy: A Promising Therapeutic Method for Intracerebral Hemorrhage. Cell Transplant. 2018 Dec;27(12):1809-1824. doi: 10.1177/0963689718773363. Epub 2018 Jun 5. PMID 29871521
• Gong YH, Hao SL, Wang BC. Mesenchymal Stem Cells Transplantation in Intracerebral Hemorrhage: Application and Challenges. Front Cell Neurosci. 2021 Mar 24;15:653367. doi: 10.3389/fncel.2021.653367. eCollection 2021. PMID 33841103
• Zhou JF, Xiong Y, Kang X, Pan Z, Zhu Q, Goldbrunner R, Stavrinou L, Lin S, Hu W, Zheng F, Stavrinou P. Application of stem cells and exosomes in the treatment of intracerebral hemorrhage: an update. Stem Cell Res Ther. 2022 Jun 28;13(1):281. doi: 10.1186/s13287-022-02965-2. PMID 35765072

Identifiers

NCT: NCT06862388 · TJ-IRB202502088 · ChiCTR2500095990

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)
• ChiCTR ChiCTR2500095990 (Chinese Clinical Trial Registry)

View this study on ClinicalTrials.gov ↗