MSC-EV in Acute-on-Chronic Liver Failure After Liver Transplantation

Liver Failure, Acute on Chronic Clinical Trial

Official title:

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

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT05881668
• Other study ID #: MSC-EV of ThirdSunYatSen
• Status: Withdrawn
• Phase: Phase 1
• Start date: September 30, 2023
• Est. completion date: April 30, 2025

Study information

• Verified date: October 2023
• Source: Third Affiliated Hospital, Sun Yat-Sen University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: April 30, 2025
• Est. primary completion date: September 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

Inclusion Criteria:

• aged 18-60 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;

Related Conditions & MeSH terms

• Acute-On-Chronic Liver Failure
• End Stage Liver Disease
• Hepatic Insufficiency
• Liver Failure
• Liver Failure, Acute
• Liver Failure, Acute on Chronic

Intervention

Biological:
• MSC-EV
10 E10 MSC-EV particles per 100ml for a single dose. No prior HLA matching between MSC donors and recipients or liver donors

Locations

Country	Name	City	State
China	Third Affiliated Hospital, Sun Yat-Sen University	Guangzhou	Guangdong

Sponsors (1)

Lead Sponsor	Collaborator
Third Affiliated Hospital, Sun Yat-Sen University

Country where clinical trial is conducted

China, 

References & Publications (3)

Detry O, Vandermeulen M, Delbouille MH, Somja J, Bletard N, Briquet A, Lechanteur C, Giet O, Baudoux E, Hannon M, Baron F, Beguin Y. Infusion of mesenchymal stromal cells after deceased liver transplantation: A phase I-II, open-label, clinical study. J Hepatol. 2017 Jul;67(1):47-55. doi: 10.1016/j.jhep.2017.03.001. Epub 2017 Mar 9. — View Citation

Lin BL, Chen JF, Qiu WH, Wang KW, Xie DY, Chen XY, Liu QL, Peng L, Li JG, Mei YY, Weng WZ, Peng YW, Cao HJ, Xie JQ, Xie SB, Xiang AP, Gao ZL. Allogeneic bone marrow-derived mesenchymal stromal cells for hepatitis B virus-related acute-on-chronic liver failure: A randomized controlled trial. Hepatology. 2017 Jul;66(1):209-219. doi: 10.1002/hep.29189. Epub 2017 May 27. — View Citation

Psaraki A, Ntari L, Karakostas C, Korrou-Karava D, Roubelakis MG. Extracellular vesicles derived from mesenchymal stem/stromal cells: The regenerative impact in liver diseases. Hepatology. 2022 Jun;75(6):1590-1603. doi: 10.1002/hep.32129. Epub 2021 Nov 27. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	Aspartate aminotransferase (AST)	Collect clinical results reflecting liver function	6 months after transplantation
Primary	Alanine aminotransferase (ALT)	Collect clinical results reflecting liver function	6 months after transplantation
Primary	Bilirubin level	Collect clinical results reflecting liver function	6 months after transplantation
Primary	International normalized ratio (INR)	Collect clinical results reflecting liver function	6 months after transplantation
Primary	carbohydrate Compound antigen (GGT) level	Collect clinical results reflecting liver function	6 months after transplantation
Primary	Adverse events	Any adverse events which may related to MSC-EV infusion	6 months
Secondary	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
Secondary	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
Secondary	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