Clinical trial NCT05881668: MSC-EV in Acute-on-Chronic Liver Failure After Liver Transplantation
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
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE1
Conditions: Liver Failure, Acute on Chronic
Keywords: MSC-EV
Acute-on-chronic liver failure
Liver transplantation
Lead sponsor: Third Affiliated Hospital, Sun Yat-Sen University
Sponsor class: OTHER
First posted: 2023-05-31
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility criteria: 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;

Primary outcomes:
measure: Number of participants with MSC-EV infusion-related toxicity as assessed by CTCAE v4.0.
timeFrame: 24 hours after injection
measure: Aspartate aminotransferase (AST)
timeFrame: 6 months after transplantation
measure: Alanine aminotransferase (ALT)
timeFrame: 6 months after transplantation
measure: Bilirubin level
timeFrame: 6 months after transplantation
measure: International normalized ratio (INR)
timeFrame: 6 months after transplantation
measure: carbohydrate Compound antigen (GGT) level
timeFrame: 6 months after transplantation
measure: Adverse events
timeFrame: 6 months
Secondary outcomes:
measure: Number of survived patients at 1 year after liver transplantation, according to the follow-up results.
timeFrame: 12 months
measure: Number of survived grafts at 1 year after liver transplantation, according to the follow-up results.
timeFrame: 12 months
measure: Recipient's immune function, as assessed by analysis of immune cell subsets from biopsy or blood samples ,at months 1-6 after liver transplantation.
timeFrame: 6 months
Other outcomes:
Locations:
city: Guangzhou
country: China
facility: Third Affiliated Hospital, Sun Yat-Sen University
state: Guangdong
Study officials:
affiliation: Third Affiliated Hospital, Sun Yat-Sen University, guangzhou, Guangdong, China
name: Yang Yang, PHD, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
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.
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.