Human Umbilical Cord Mesenchymal Stem Cell Transplantation for The Treatment of Acute-on-Chronic Liver Failure

Sponsor

Beijing 302 Hospital (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05985863

Collaborator

Shulan (Hang Zhou) Hospital (Other), BeijingYouan Hospital (Other), Shenzhen Third People's Hospital (Other), Shen Zhen Wingor Biotechnology CO. LTD (Other)

150

Enrollment

Location

Arms

Anticipated Duration (Months)

2.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study is a randomized double-blind placebo-controlled multicenter clinical trial to evaluate the safety and efficacy of human umbilical cord mesenchymal stem cell (UC-MSC) transplantation for the treatment of acute-on-chronic liver failure (ACLF). UC-MSC therapy may improve the clinical outcomes of patients with ACLF. The trial would provide scientific evidence for UC-MSC transplantation as a potential treatment for ACLF.

Condition or Disease	Intervention/Treatment	Phase
Acute-On-Chronic Liver Failure	Drug: standard medical treatment Drug: hUC-MSC at week0 Drug: Placebo at week0 Drug: hUC-MSC at week1 Drug: Placebo at week1 Drug: hUC-MSC at week2 Drug: Placebo at week2 Drug: hUC-MSC at week4 Drug: Placebo at week4 Drug: hUC-MSC at week5 Drug: Placebo at week5	Phase 1/Phase 2

Detailed Description

Acute-on-chronic liver failure (ACLF) has been proposed to define a distinct syndrome which is characterized by an intense systemic inflammatory response, single- or multiple organ system failures, and high 28-day mortality. Current treatments for liver failure are still limited, and liver transplantation remains the only available approach to improve survival but is restricted by a shortage of organ resources, rejection after transplantation, and heavy financial costs. In the past decade, a series of new applications based on mesenchymal stem cell (MSC) therapy have been studied as an alternative interventional method for chronic liver diseases. This randomized double-blind placebo-controlled multicenter clinical trial is aimed at determining the safety and clinical efficacy of UC-MSC transfusions in ACLF patients.

A total of 150 ACLF patients would be enrolled,100patients would be assigned to the MSC intervention group and the other 50 patients would be assigned to the placebo control group. This trial is two-stage randomized designed. At the first stage, the patients would be randomized into two groups, the placebo short control group would receive standard medical treatment plus 3 times placebo (at week0, week1 and week2), while the MSC short treatment group would receive standard medical treatment plus 3 times hUC-MSC (1.5×10^{8, Peripheral IV,
at week0, week1 and week2). The two groups would be followed up for 2 weeks, and unblinding
would be conducted at week4. At the second stage, the survived patients of the MSC short
treatment group would be further randomized and blinded into another two groups. The MSC
Prolonged treatment group would receive another 2 times hUC-MSC (1.5×10}8, Peripheral IV, at week4 and week5), while the MSC Prolonged control group would receive 2 times placebo (at week4 and week5).

Transplantation free survival rate and incidence of treatment-emergent adverse events would be the primary outcomes, and other outcomes such as international normalized ratio (INR), total bilirubin (TBIL, mg/dL), serum albumin (ALB, g/L), blood urea nitrogen (BUN, mmol/l), the model for end-stage liver disease(MELD) score and child-turcotte-pugh(CTP) score would also be measured.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

150 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

Clinical Research of Human Umbilical Cord Mesenchymal Stem Cell Transplantation for The Treatment of Acute-on-Chronic Liver Failure

Anticipated Study Start Date :

Sep 30, 2023

Anticipated Primary Completion Date :

Dec 30, 2026

Anticipated Study Completion Date :

Dec 30, 2028

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo short control standard medical treatment+Placebo(5% human serum albumin in 0.9% saline, at week0, week1 and week2)	Drug: standard medical treatment standard medical treatment for ACLF Drug: Placebo at week0 5% human serum albumin in 0.9% saline Drug: Placebo at week1 5% human serum albumin in 0.9% saline Drug: Placebo at week2 5% human serum albumin in 0.9% saline
Experimental: MSC short treatment standard medical treatment+3 times hUC-MSC (1.5×10^8, Peripheral IV, at week0, week1 and week2)	Drug: standard medical treatment standard medical treatment for ACLF Drug: hUC-MSC at week0 hUC-MSC (1.5×10^8, Peripheral IV) at week0 Drug: hUC-MSC at week1 hUC-MSC (1.5×10^8, Peripheral IV) at week1 Drug: hUC-MSC at week2 hUC-MSC (1.5×10^8, Peripheral IV) at week2
Other: MSC Prolonged control At the first stage, standard medical treatment+3 times hUC-MSC (1.5×10^8, Peripheral IV, at week0, week1 and week2); At the second stage, standard medical treatment+2 times placebo (5% human serum albumin in 0.9% saline, at week4 and week5)	Drug: standard medical treatment standard medical treatment for ACLF Drug: hUC-MSC at week0 hUC-MSC (1.5×10^8, Peripheral IV) at week0 Drug: hUC-MSC at week1 hUC-MSC (1.5×10^8, Peripheral IV) at week1 Drug: hUC-MSC at week2 hUC-MSC (1.5×10^8, Peripheral IV) at week2 Drug: Placebo at week4 5% human serum albumin in 0.9% saline Drug: Placebo at week5 5% human serum albumin in 0.9% saline
Experimental: MSC Prolonged treatment At the first stage, standard medical treatment+3 times hUC-MSC (1.5×10^8, Peripheral IV, at week0, week1 and week2); At the second stage, standard medical treatment+2 times hUC-MSC (1.5×10^8, Peripheral IV, at week4 and week5);	Drug: standard medical treatment standard medical treatment for ACLF Drug: hUC-MSC at week0 hUC-MSC (1.5×10^8, Peripheral IV) at week0 Drug: hUC-MSC at week1 hUC-MSC (1.5×10^8, Peripheral IV) at week1 Drug: hUC-MSC at week2 hUC-MSC (1.5×10^8, Peripheral IV) at week2 Drug: hUC-MSC at week4 hUC-MSC (1.5×10^8, Peripheral IV) at week4 Drug: hUC-MSC at week5 hUC-MSC (1.5×10^8, Peripheral IV) at week5

Outcome Measures

Primary Outcome Measures

Transplantation free survival rate [week1, week2, week3, week4, week5, week8, week12, week24, week53]
Transplantation free survival rate of ACLF patients.
Incidence of Treatment-Emergent Adverse Events [day0, day3, week1, week2, week3, week4, week5, week8, week12, week24, week53]
Safety and Tolerability of UC-MSCs transplantation.

Secondary Outcome Measures

International Normalized Ratio (INR) [week-1, week0, day3, week1, week2, week3, week4, week5, week12, week24, week53]
INR was introduced as a standardized reporting mechanism allowing comparisons across laboratories and patients. Consensus guidelines recommend that INR ≥ 1.5 can be used as a threshold, and current recommendations for targeting an INR of < 1.5 were based on studies across all surgical disciplines.
Concentration of Total Bilirubin (TBIL, mg/dL) [week-1, week0, day3, week1, week2, week3, week4, week5, week12, week24, week53]
Total bilirubin refers to the concentration of bilirubin in a patient's blood sample, which is automatically measured by the laboratories in accordance with standard operating procedures. APASL defines ACLF as "an acute hepatic insult manifesting as jaundice (Serum Bilirubin ≥ 5 mg/dL) and coagulopathy (international normalized ratio [INR] ≥ 1.5) complicated within 4 weeks by clinical ascites and/or encephalopathy in a patient with previously diagnosed or undiagnosed chronic liver disease/cirrhosis, that is associated with a high 28-day mortality."
Concentration of Serum Albumin (ALB, g/L) [week-1, week0, day3, week1, week2, week3, week4, week5, week12, week24, week53]
Serum albumin refers to the concentration of albumin in a patient's serum, which is automatically measured by the laboratory in accordance with standard operating procedures. Serum albumin is an independent protective factor for 30-day prognosis in ACLF patients.
Concentration of Blood Urea Nitrogen (BUN, mmol/L) [week-1, week0, day3, week1, week2, week3, week4, week5, week12, week24, week53]
Blood urea nitrogen refers to the concentration of urea nitrogen in a patient's blood sample. Blood urea nitrogen is a commonly used indicator of renal function in clinic.
The Model for End-Stage Liver Disease(MELD) score [week-1, week1, week2, week4, week5, week12, week24, week53]
R = 3.8×ln [TBiL (mg/dl)] +11.2×ln (INR) +9.6×ln [Cr (mg/dl)] +6.4× (Cause: biliary or alcoholic is 0, other is 1), the result is taken as an integer. Studies have shown that the optimal critical value of MELD score to judge the short-term prognosis of ACLF patients is 30, and when MELD score is greater than 30, the case fatality rate of patients within 3 months is significantly increased.
Child-Turcotte-Pugh(CTP) score [week-1, week1, week2, week4, week5, week12, week24, week53]
CTP score is currently the most commonly used model to evaluate liver reserve function and prognosis in patients with cirrhosis. This model evaluates liver function based on HE grade, degree of abdominal fluid accumulation, bilirubin (TBiL), albumin (Alb) and prothrombin time (PT). The score ranges from 0 to 15, with the higher the score, the worse the prognosis.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

18 years old ≤ age ≤ 70 years old, gender is not limited.
Meet the APASL definition of ACLF: acute liver injury in patients with previously diagnosed or undiagnosed chronic liver disease or cirrhosis, manifested as jaundice (total bilirubin levels of 5 mg/dl or more) and coagulopathy (INR of 1.5 or more, or prothrombin activity of less than 40%） complicated within 4 weeks by clinical ascites, encephalopathy, or both.
Willing to sign the informed consent form.

Exclusion Criteria:

Patients with acute kidney injury, upper gastrointestinal hemorrhage, hepatic encephalopathy above grade II (inclusive) or uncontrolled infection at baseline;
Before the onset of liver failure, the previous indicators of the patient included PLT<50×10^9/L or Child-Pugh score>9;
Combined with liver cancer or other malignant tumors;
Patients with previous liver transplantation or planned liver transplantation within 3 months;
Severe organic disease of primary extrahepatic organs;
Those who have a history of venous thrombosis or pulmonary embolism are judged by the investigator to be ineligible to participate in this trial;
Pregnant, breastfeeding women or those who plan to have a baby in the near future;
Those who are highly allergic or have a history of severe allergies;
Those who have received immunosuppressant and immune enhancer treatment within 1 month;
Drug abuse in the past 5 years;
Alcohol withdrawal symptoms;
A history of severe mental disorders within 24 months before screening, including uncontrolled major depression or controlled or uncontrolled psychosis;
Those who have participated or are participating in other clinical trials within three months before screening, or have previously received stem cell therapy;
Other conditions that the investigator thinks that the patient is not suitable to participate in this study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	the Fifth Medical Center, Chinese PLA General Hospital	Beijing	Beijing	China	100039

Sponsors and Collaborators

Beijing 302 Hospital
Shulan (Hang Zhou) Hospital
BeijingYouan Hospital
Shenzhen Third People's Hospital
Shen Zhen Wingor Biotechnology CO. LTD

Investigators

Principal Investigator: Ming Shi, PhD, the Fifth Medical Center, Chinese PLA General Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

Responsible Party:

Shi Ming, Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing 302 Hospital

ClinicalTrials.gov Identifier:

NCT05985863

Other Study ID Numbers:

2022YFC2304402

First Posted:

Aug 14, 2023

Last Update Posted:

Aug 16, 2023

Last Verified:

Aug 1, 2023

Individual Participant Data (IPD) Sharing Statement:

Plan to Share IPD:

Studies a U.S. FDA-regulated Drug Product:

Studies a U.S. FDA-regulated Device Product:

Keywords provided by Shi Ming, Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing 302 Hospital

Mesenchymal Stem Cells

Acute-On-Chronic Liver Failure

Therapeutics

Additional relevant MeSH terms:

Liver Failure

Hepatic Insufficiency

End Stage Liver Disease

Acute-On-Chronic Liver Failure

Study Results

No Results Posted as of Aug 16, 2023