MSC-EVs in Acute/ Acute-on-Chronic Liver Failure After Liver Transplantation

Mesenchymal Stem Cells-Derived Extracellular Vesicles (MSC-EV) in Acute/Acute-on-Chronic Liver Failure After Liver Transplantationa：a Prospective, Randomized, Controlled Clinical Study

Acute liver failure (ALF) refers to a potentially reversible disorder that was the result of severe liver injury, with an onset of encephalopathy within 8 weeks of symptom appearance and in the absence of pre-existing liver disease. Acute-on-chronic liver failure refers to a liver failure syndrome in which some patients with chronic liver disease with relatively stable liver function suffer from acute liver decompensation and liver failure due to the effects of various acute injury factors. Liver transplantation is the only curative treatment for this type of end-stage liver disease. The potential of MSCs to repair or regenerate damaged tissue and suppress immune responses makes them promising in the treatment of liver diseases, especially in the field of liver transplantation. Many studies have shown that MSC-based therapies can reduce the symptoms of liver disease due to their paracrine effects. Therefore, compared to the cells they derive from, mesenchymal stem cells-derived extracellular vesicles (MSC-EV) are gradually gaining attention for their enhanced safety, as they do not replicate or cause microvascular embolism, and can be easily stored without losing their properties. It represents a novel and effective cell-free therapeutic agent as alternative to cell-based therapies for liver diseases, and liver failure was also concerned. This study was designed to evaluate the safety and tolerability of MSC-EV in acute-on-chronic liver failure after liver transplantation.

Study Overview

• Status: Not yet recruiting
• Conditions: Liver Failure; Extracellular Vesicles; Mesenchymal Stem Cell
• Intervention / Treatment: Biological: MSC-EVs

Detailed Description

In the MSC-EV group (experimental group), 15 patients will receive a single injection of MSC-EV after their first liver transplantation. In the non-MSC-EV group (control group), 15 patients will not receive MSC-EV therapy after their first liver transplantation.

The outcome of the experimental group will be compared with that of similar control patients undergoing liver transplantation but who will not receive MSC-EV. Both of the two groups will receive standard immunosuppressive therapy( a regimen based on tacrolimus (TAC), mycophenolate mofetyl (MMF) and steroids). Patients participated in the experimental cohort will be infused with a single dose of 10 E10 MSC-EV particles per 100ml, at an appropriate time during the first 1-5 days after transplantation.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Jun Zheng, PHD, MD; Phone Number: 020-85252113; Email: zhengj67@mail2.sysu.edu.cn

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510630
      • Third Affiliated Hospital, Sun Yat-Sen University
      • Contact: Yang Yang, PHD, MD; Phone Number: 020-85252113; Email: yysysu@163.com
      • Contact: Yang Yang, PHD, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• aged 18-70 years;
• Acute on chronic liver failure-which is characterized by acute hepatic insult manifesting as jaundice (serum total bilirubin [TBil] ≥ 10×ULN umol/L) and coagulopathy (international normalized ratio [INR] ≥ 1.5 or prothrombin activity < 40%), complicated within 4 weeks by ascites and/or encephalopathy as determined by physical examination, in patients with previously diagnosed or undiagnosed chronic liver disease; Requiring liver transplantation due to acute on chronic liver failure;
• Obtain the patients' consent after informing patients of the purpose and method of the clinical trial;

Exclusion Criteria:

• Past history of malignant disease
• Active uncontrolled infection;
• Combined transplantation
• EBV-negative;
• HIV or HCV positive;
• Retransplantation;

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MSC-EVs group; After liver transplantation, on the basis of postoperative standard treatment (anti-infection treatment, immunosuppressive treatment, nutritional support treatment, etc.), an additional injection of MSC-EV will be received between the 1st and 5th days after transplantation	Biological: MSC-EVs; 10 E10 MSC-EV particles per 100ml for a single dose. No prior HLA matching between MSC donors and recipients or liver donors
No Intervention: Non-MSC-EVs group; After liver transplantation, patients will receive postoperative standard treatment (anti-infection treatment, immunosuppressive treatment, nutritional support treatment, etc.)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with MSC-EV infusion-related toxicity as assessed by CTCAE v4.0.	Incidence, timing and severity of any clinical complication related to MSC-EV infusion, such as tympanic body temperature, heart rate, mean arterial blood pressure and allergy, as assessed by CTCAE v4.0 .	24 hours after injection
Aspartate aminotransferase (AST)	Collect clinical results reflecting liver function	6 months after transplantation
Alanine aminotransferase (ALT)	Collect clinical results reflecting liver function	6 months after transplantation
Bilirubin level	Collect clinical results reflecting liver function	6 months after transplantation
International normalized ratio (INR)	Collect clinical results reflecting liver function	6 months after transplantation
carbohydrate Compound antigen (GGT) level	Collect clinical results reflecting liver function	6 months after transplantation
Adverse events	Any adverse events which may related to MSC-EV infusion	6 months after transplantation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of survived patients at 1 year after liver transplantation, according to the follow-up results.	Patients who are surviving, as assessed by outpatient or telephone follow-up, at 1 year after liver transplantation	12 months
Number of survived grafts at 1 year after liver transplantation, according to the follow-up results.	Surviving patients with primary and functional grafts, as assessed by outpatient or telephone follow-up, at 1 year after liver transplantation.	12 months
Recipient's immune function, as assessed by analysis of immune cell subsets from biopsy or blood samples ,at months 1-6 after liver transplantation.	A series of immune cell subsets will be analyzed, including T cells (CD3+), CD4+ T cells (CD3+ CD4+ lymphocytes), CD8+ T cells (CD3+ CD8+ lymphocytes), naïve CD4+ T cells (CD4+ CD45RAhigh lymphocytes), memory CD4+ T cells (CD4+ CD45RO+ lymphocytes), natural killer (NK) cells (CD3- CD56+ lymphocytes), as well as B cells (CD19+ lymphocytes)	6 months after transplantation

Collaborators and Investigators

• Sponsor: Third Affiliated Hospital, Sun Yat-Sen University
• Investigators: Study Director: Yang Yang, PHD, MD, Third Affiliated Hospital, Sun Yat-Sen University, guangzhou, Guangdong, China

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2025
• Primary Completion (Estimated): March 30, 2026
• Study Completion (Estimated): September 30, 2026

Study Registration Dates

• First Submitted: February 9, 2025
• First Submitted That Met QC Criteria: February 9, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 9, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: Liver transplantation; Liver failure; MSC-EV
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Liver Failure, Acute; End Stage Liver Disease; Liver Failure; Hepatic Insufficiency; Acute-On-Chronic Liver Failure
• Other Study ID Numbers: MSC-EVs of ThirdSunYatSen

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No