The Safety and Efficacy of MSC-EVs in Acute/Acute-on-Chronic Liver Failure

Study Overview
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Brief Summary
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Acute-on-chronic liver failure (ACLF) 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，while 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. Liver transplantation is the only curative treatment for this type of end-stage liver disease, but the rapid disease progression and lack of donors limit its application. 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. It has been confirmed in previous studies that infusion of allogeneic MSCs is safe and convenient for patients with ACLF and improve liver function and decrease the incidence of severe infections. Compared to the cells they derive from, mesenchymal stem cells-derived extracellular vesicles (MSC-EVs) 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 efficacy of MSC-EVs in ACLF/ALF .

Detailed Description
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In the MSC-EV group (experimental group), onthe basis of standard medical treatment, 10 patients will receive a single injection of MSC-EV . In the non-MSC-EV group (control group), 10 patients will not receive MSC-EV therapy but standard medical treatment. The standard medical treatment iclude nutritional supplementation, administration of human serum albumin and fresh frozen plasma, anti-viral therapy (if hepatitis virus-related ACLF/ALF), liver protective treatment and other appropriate treatment for complications. The outcome of the experimental group will be compared with that of similar control patients who will not receive MSC-EV. Both of the two groups will receive standard medical treatment. Patients participated in the experimental cohort will be infused with a single dose of 10 E10 MSC-EV particles per 100ml, when they are inpatient.

Official Title
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The Safety and Efficacy of Mesenchymal Stem Cells-Derived Extracellular Vesicles (MSC-EV) in Acute/Acute-on-Chronic Liver Failure：a Prospective, Randomized, Controlled Clinical Study

Conditions
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Acute-On-Chronic Liver Failure, Acute Liver Failure

Intervention / Treatment
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* Biological: MSC-EVs


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: aged 18-65 years old; 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; Acute liver failure-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. Total bilirubin (TBil) ≥ 171umolL or daily increase ≥17.1umol/L; Prothrombin activity (PTA) between 20% and 40% (or INR between 1.5 and 2.6); No hepatic encephalopathy, or encephalopathy below grade II (including grade II); Exclusion Criteria: Patients with primary or metastatic liver cancer Severe active bleeding or diffuse intravascular coagulation Patients who are allergic to blood products or drugs used in treatment, such as plasma, heparin and protamine; MELD score >30 Other serious disease including heart disease, lung disease, blood disease, autoimmune disease, diabetes, active uncontrolled infection,etc.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MSC-EV group<br>On the basis of standard medical treatment, an additional injection of MSC-EVs will be received by participants once a week for 4 weeks while hospitalized. | Biological: MSC-EVs<br>* 10 E10 MSC-EV particles per 100ml for a single dose. Once a week for 4 weeks.<br>|
| No Intervention: Non-MSC-EV group<br>In the non-MSC-EV group, patients will receive standard medical treatment and 100ml saline as a control. | |

What is the study measuring?
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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 first rejection | 
| Alanine aminotransferase (ALT) | Collect clinical results reflecting liver function | 6 months after first rejection | 
| Bilirubin level | Collect clinical results reflecting liver function | 6 months after first rejection | 
| International normalized ratio (INR) | Collect clinical results reflecting liver function | 6 months after first rejection | 
| Carbohydrate Compound antigen (GGT) level | Collect clinical results reflecting liver function | 6 months after first rejection | 
| Adverse events | Any adverse events which may related to MSC-EV infusion | 6 months after first rejection | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of survived patients at 1 year, according to the follow-up results | Patients who are surviving, as assessed by outpatient or telephone follow-up, at 1 year after rejection | 12 months | 
| Proportion of immune cell subsets from biopsy or blood samples ,at months 1-6 after infusion. | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MSC-EVs, Acute-on-chronic liver failure, Acute liver failure, Liver transplantation