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

Primary Purpose

Acute-On-Chronic Liver Failure, Acute Liver Failure

Status
Withdrawn
Phase
Phase 1
Locations
China
Study Type
Interventional
Intervention
MSC-EVs
Sponsored by
Third Affiliated Hospital, Sun Yat-Sen University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute-On-Chronic Liver Failure focused on measuring MSC-EVs, Acute-on-chronic liver failure, Acute liver failure, Liver transplantation

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Third Affiliated Hospital, Sun Yat-Sen University

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

MSC-EV group

Non-MSC-EV group

Arm Description

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.

In the non-MSC-EV group, patients will receive standard medical treatment and 100ml saline as a control.

Outcomes

Primary Outcome Measures

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 .
Aspartate aminotransferase (AST)
Collect clinical results reflecting liver function
Alanine aminotransferase (ALT)
Collect clinical results reflecting liver function
Bilirubin level
Collect clinical results reflecting liver function
International normalized ratio (INR)
Collect clinical results reflecting liver function
Carbohydrate Compound antigen (GGT) level
Collect clinical results reflecting liver function
Adverse events
Any adverse events which may related to MSC-EV infusion

Secondary Outcome Measures

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
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)

Full Information

First Posted
July 2, 2023
Last Updated
October 10, 2023
Sponsor
Third Affiliated Hospital, Sun Yat-Sen University
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1. Study Identification

Unique Protocol Identification Number
NCT05940610
Brief Title
The Safety and Efficacy of MSC-EVs in Acute/Acute-on-Chronic Liver Failure
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Withdrawn
Why Stopped
The supply of msc-ev has been delayed and approval by the Ethics committee will take some time.
Study Start Date
September 1, 2023 (Anticipated)
Primary Completion Date
September 30, 2024 (Anticipated)
Study Completion Date
October 1, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Third Affiliated Hospital, Sun Yat-Sen University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute-On-Chronic Liver Failure, Acute Liver Failure
Keywords
MSC-EVs, Acute-on-chronic liver failure, Acute liver failure, Liver transplantation

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
0 (Actual)

8. Arms, Groups, and Interventions

Arm Title
MSC-EV group
Arm Type
Experimental
Arm Description
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.
Arm Title
Non-MSC-EV group
Arm Type
No Intervention
Arm Description
In the non-MSC-EV group, patients will receive standard medical treatment and 100ml saline as a control.
Intervention Type
Biological
Intervention Name(s)
MSC-EVs
Intervention Description
10 E10 MSC-EV particles per 100ml for a single dose. Once a week for 4 weeks.
Primary Outcome Measure Information:
Title
Number of participants with MSC-EV infusion-related toxicity as assessed by CTCAE v4.0.
Description
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 .
Time Frame
24 hours after injection
Title
Aspartate aminotransferase (AST)
Description
Collect clinical results reflecting liver function
Time Frame
6 months after first rejection
Title
Alanine aminotransferase (ALT)
Description
Collect clinical results reflecting liver function
Time Frame
6 months after first rejection
Title
Bilirubin level
Description
Collect clinical results reflecting liver function
Time Frame
6 months after first rejection
Title
International normalized ratio (INR)
Description
Collect clinical results reflecting liver function
Time Frame
6 months after first rejection
Title
Carbohydrate Compound antigen (GGT) level
Description
Collect clinical results reflecting liver function
Time Frame
6 months after first rejection
Title
Adverse events
Description
Any adverse events which may related to MSC-EV infusion
Time Frame
6 months after first rejection
Secondary Outcome Measure Information:
Title
Number of survived patients at 1 year, according to the follow-up results
Description
Patients who are surviving, as assessed by outpatient or telephone follow-up, at 1 year after rejection
Time Frame
12 months
Title
Proportion of immune cell subsets from biopsy or blood samples ,at months 1-6 after infusion.
Description
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)
Time Frame
6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Facility Information:
Facility Name
Third Affiliated Hospital, Sun Yat-Sen University
City
Guangzhou
State/Province
Guangdong
ZIP/Postal Code
510630
Country
China

12. IPD Sharing Statement

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

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