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

Phase 1

Recruiting

• Conditions: Acute-On-Chronic Liver Failure
• Interventions: Drug: standard medical treatment; Drug: Placebo; Drug: hUC-MSC; Drug: hUC-MSC_Prolonged

• Registration Number: NCT05985863
• Lead Sponsor: Beijing 302 Hospital

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.

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 Timeline

• Study First Submitted: 2023-07-24
• Study First Submitted QC: 2023-08-03
• Study First Posted: 2023-08-14
• Study Start: 2023-09-30
• Status Verified: 2024-05
• Last Update Submitted: 2024-05-06
• Last Update Posted: 2024-05-07
• Primary Completion: 2026-12-30
• Study Completion: 2028-12-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 150

Inclusion Criteria

1. 18 years old ≤ age ≤ 70 years old, gender is not limited.
2. 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.
3. Willing to sign the informed consent form.

Exclusion Criteria

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group Control	standard medical treatment	standard medical treatment+Placebo(5% human serum albumin in 0.9% saline, at week0, week1 and week2)
Group Control	Placebo	standard medical treatment+Placebo(5% human serum albumin in 0.9% saline, at week0, week1 and week2)
Group MSC-1	standard medical treatment	Patients received standard medical treatment and infusions of hUC-MSC(1.5×10\^8) via peripheral veins once a week for 3 timess(at week0, week1, and week2).
Group MSC-1	hUC-MSC	Patients received standard medical treatment and infusions of hUC-MSC(1.5×10\^8) via peripheral veins once a week for 3 timess(at week0, week1, and week2).
Group MSC-2	standard medical treatment	Patients in Group MSC-1 received standard medical treatment and infusions of hUC-MSC(1.5×10\^8) via peripheral veins once a week for another 2 timess(at week4 and week5).
Group MSC-2	hUC-MSC_Prolonged	Patients in Group MSC-1 received standard medical treatment and infusions of hUC-MSC(1.5×10\^8) via peripheral veins once a week for another 2 timess(at week4 and week5).
Group MSC-2	hUC-MSC	Patients in Group MSC-1 received standard medical treatment and infusions of hUC-MSC(1.5×10\^8) via peripheral veins once a week for another 2 timess(at week4 and week5).

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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 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.
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.
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.

Trial Locations

Locations (1)

the Fifth Medical Center, Chinese PLA General Hospital; 🇨🇳 Beijing, Beijing, China