Safety of UC-MSC Transfusion for ACLF Patients

July 20, 2021 updated by: Hai Li

Safety of Human Umbilical Cord-derived Mesenchymal Stem Cell (UC-MSC) Transfusion for Acute-on-chronic Liver Failure Patients

Acute on chronic liver failure (ACLF) is a type of critically ill liver disease with high short-term mortality in liver disease. Liver transplantation is currently the only method to improve survival. Current clinical research evidence shows that mesenchymal stem cells can reduce the mortality of ACLF patients and are safe. This study aims to explore the safety of umbilical cord mesenchymal stem cells (UC-MSCs) in the treatment of ACLF. The study population is ACLF patients with 1-2 organ failures. To explore the safety of 3 doses of UC-MSCs, 16 patients need to be enrolled. The main observation indicators are the short-term and long-term safety of the treatment. All patients need to receive the standard medical treatment (SMT) at the same time. Stem cell treatment is given by intravenous infusion on the first, fourth, seventh, and tenth day. The occurrence of adverse events (AE) and serious adverse events(SAE) before and after the infusion will be observed. After the patient is discharged from the hospital, patients will be followed , the follow-up time is 5 years.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

Acute-on-chronic liver failure (acute-on-chronic liver failure, ACLF) is a special type of rapid deterioration of liver function that occurs on the basis of cirrhosis or non-cirrhosis, which is characterized by sequential multiple organ failure and high short-term (28 days) mortality (15%). ACLF was first proposed by Jalan R and Williams R. in 2002. It is a newly discovered type of critically ill liver disease characterized by high short-term mortality after hospitalization [1]. At present, the pathophysiological mechanism of ACLF is not clear, and its definition in Europe and Asia-Pacific is still controversial. However, severe systemic inflammatory response is often closely related to the cause, accompanied by single or multiple organ failure are three important characteristics of ACLF. In the past ten years, the prevalence of ACLF has increased. Due to the rapid progress of the disease and the close relationship between mortality and organ failure, there is no effective method to improve the survival rate of ACLF patients except liver transplantation. The latest literature review shows that the 28-day and 90-day mortality rates are as high as 27.8-37.6% and 40-, respectively. 51.2%[2].

In 2013, European Association for the Study of Chronic Acute Liver Failure（EASL-CLIF） conducted a prospective multi-center EASL-CLIF Chronic Acute Liver Failure (CANONIC) study in 29 liver disease treatment centers in eight European countries, and proposed chronic liver failure-sequential organ failure assessment（CLIF-SOFA）score is used as the clinical diagnostic criteria for alcoholic and hepatitis B virus（HBV）related ACLF. According to the CLIF-SOFA score, the 90-day mortality rate of ACLF patients is as high as 51%, while that of non-ACLF patients is 10% [3]. The European CANONIC study also shows that systemic inflammation is the main driving force of multiple organ failure, which is a typical pathogenesis of ACLF patients with western liver cirrhosis [4]. For another, the current Asian ACLF diagnostic criteria is the Asia Pacific Association for the Study of Liver Diseases (APASL) criteria, which reached a consensus in 2009, and the guidelines were improved in 2014, but there is still a lack of multi-center, prospective evidence-based medical evidence to support . In 2016, led by the person in charge of this project, an oriental ACLF prospective multi-center observation cohort was established in China, which included 3970 ACLF high-risk patients, filling the gap in the natural course and mortality of oriental ACLF patients, and established a 90-day oriental ACLF diagnostic criteria for mortality [5]. The person in charge of this project also explored the pathophysiological mechanism of ACLF patients in areas with high prevalence of oriental HBV. The study showed that submassive hepatic necrosis is an important histological feature in ACLF patients with HBV-related cirrhosis. The systemic inflammatory response of multiple organ failure caused by parenchymal liver cells has a similar mechanism to that of western alcoholic ACLF [6]. Although the causes of ACLF type are not the same in the East and the West, the cohorts from the East and the West have confirmed the short-term high mortality rate of ACLF. Systemic inflammation, sub-large necrosis, and aseptic inflammation may all important reasons that lead to multiple organ failure and eventual death of ACLF patients.

Due to the high short-term mortality of ACLF and the limited liver source for liver transplantation, exploring new methods for the treatment of ACLF is a major issue facing clinical research. Mesenchymal stem cells have great application prospects in regenerative medicine because of their strong self-renewal, low immunogenicity, non-tumorigenicity and strong immune regulation ability[7]. Many previous documents have confirmed that mesenchymal stem cells in animal models can promote liver cell regeneration, resist inflammation, regulate local microenvironment and anti-fibrosis [8-10]. Among them, umbilical cord mesenchymal stem cells (UC-MSC) have attracted attention of researchers because they are easily obtained from the medical waste-the umbilical cord, are not invasive, and have high expansion capabilities in vitro [11]. The possible mechanism of UC-MSC in the treatment of end-stage liver disease is that it can repair the liver. At present, there are the following opinions: ① Cell rehabilitation. In the case of liver failure, MSC can differentiate into hepatocytes and play an alternative therapeutic effect. A large number of studies have shown that MSC can be differentiated into functional hepatocytes in different inducing factors and culture systems in vitro, capable of storing glycogen and urea synthesis. Function; ②Immune regulation. Studies have shown that MSC can regulate immune cells by secreting a variety of cytokines in the body, and play an immunomodulatory effect; ③Anti-fibrosis. MSC can induce hepatic stellate cell apoptosis or inhibit its activation, and can secrete anti-fibrotic substances such as granulocyte colony stimulating factor and matrix metallopeptidase 9（MMP-9）to reduce the deposition of extracellular matrix and inhibit the formation of liver fibrosis.

According to the results of a single-center clinical trial published by the Third Affiliated Hospital of Sun Yat-sen University in the previous period, there were no serious adverse reactions at 6 hours and 72 weeks after intravenous infusion of MSCs. The dose was (1-6)*10^7 cells/time for 4 times, confirming the safety and effectiveness of both low-dose and high-dose treatments. Another open clinical trial of Beijing 302 Hospital used mesenchymal stem cells at a dose of 5*10^5 cells/kg (based on the patient's weight of 60kg, the dose was 3*10^7 cells/time), excluded severe ACLF patients accompanied by severe infections and other sever complications. In addition, previous pharmacokinetic tests showed that the half-life of mesenchymal stem cells in animals is 3 days.

Therefore, this research plans to carry out a single-center open clinical trial to confirm the safety of umbilical cord-derived mesenchymal stem cells in the treatment of ACLF, and provide stronger clinical evidence for the safety of UC-MSCs in the treatment of ACLF.

Study Type

Interventional

Enrollment (Anticipated)

16

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • China
    • Shanghai
      • Shanghai, Shanghai, China
        • Ren Ji Hospital, School of Medicine, Shanghai Jiao TongUniversity,
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 70 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. . Age 18-70 years old;
  2. . A history of chronic liver disease, chronic acute liver failure (ACLF) caused by various causes, 1-2 organ failure (ACLF diagnosis is based on the European EASL diagnostic criteria, and the organ failure criteria is based on CLIF-OF);
  3. . The patient or adult family members agree to participate in this study and sign an informed consent form;

Exclusion Criteria:

  • Those who meet any of the following conditions will not be included:

    1. Those who intend to undergo artificial liver treatment;
    2. Those who have received liver transplantation and any form of stem cell therapy;
    3. Malignant tumors in or outside the liver; or imaging findings suggest malignant mass in the liver or tuberculosis;
    4. Complicated with severe autoimmune diseases; combined with severe cardiopulmonary insufficiency; renal replacement therapy; Immunosuppressive therapy; HIV/tuberculosis infection; alcohol/drug addiction; participated in drug trials in the past 3 months;
    5. Gastrointestinal bleeding or serious infection occurred in the past one month;
    6. Pregnant and lactating women;
    7. Those who do not have the ability to make independent judgments and have no direct adult family members to sign the informed consent form.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: low dose
hUC-MSCs 4*10^5/kg/each time
Genetic: Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs)
The hUC-MSCs were injected intravenously on the 1, 4, 7 and 10 days after patients recruitment. The treatment doses include low dose: 4*10^5 cells/kg/each time, and medium dose: 8*10^5 cells/kg/each time, high dose 12*10^5 cells/kg/each time. After 3 groups of patients were enrolled, the group with appropriate safety and effectiveness was selected and the other 4 subjects were included.
Experimental: middle dose
hUC-MSCs 8*10^5/kg/each time
Genetic: Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs)
The hUC-MSCs were injected intravenously on the 1, 4, 7 and 10 days after patients recruitment. The treatment doses include low dose: 4*10^5 cells/kg/each time, and medium dose: 8*10^5 cells/kg/each time, high dose 12*10^5 cells/kg/each time. After 3 groups of patients were enrolled, the group with appropriate safety and effectiveness was selected and the other 4 subjects were included.
Experimental: high dose
hUC-MSCs 12*10^5/kg/each time
Genetic: Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs)
The hUC-MSCs were injected intravenously on the 1, 4, 7 and 10 days after patients recruitment. The treatment doses include low dose: 4*10^5 cells/kg/each time, and medium dose: 8*10^5 cells/kg/each time, high dose 12*10^5 cells/kg/each time. After 3 groups of patients were enrolled, the group with appropriate safety and effectiveness was selected and the other 4 subjects were included.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Safety of treatment
Time Frame: 1 month since intervention start
The purpose of this trial is to observe the short-term safety of low, medium and high doses of hUC-MSCs in the treatment of ACLF patients. The primary endpoint of the study was serious adverse events that occurred during the course of one month of treatment. If serious adverse reactions(SAE) occur during the treatment in hospital, the intervention will be stopped and the study will be terminated.
1 month since intervention start

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Short-time efficacy of treatment
Time Frame: 90 days
To assess the efficacy of hUC-MSCs in the treatment of ACLF patients, patients will be followed-up, and the prognosis at each time point will be collected as our schedule.
90 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Hai Li

Investigators

  • Study Director: Hai Li, Digestive Department of Renji Hospital,Shanghai Jiao Tong University School of Medicine

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Anticipated)

September 30, 2021

Primary Completion (Anticipated)

July 31, 2022

Study Completion (Anticipated)

July 21, 2024

Study Registration Dates

First Submitted

March 26, 2021

First Submitted That Met QC Criteria

March 26, 2021

First Posted (Actual)

March 30, 2021

Study Record Updates

Last Update Posted (Actual)

July 21, 2021

Last Update Submitted That Met QC Criteria

July 20, 2021

Last Verified

July 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • MSC-ACLF-1

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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