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

Acute-On-Chronic Liver Failure Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05985863
• Other study ID #: 2022YFC2304402
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: September 30, 2023
• Est. completion date: December 30, 2028

Study information

• Verified date: May 2024
• Source: Beijing 302 Hospital
• Contact: Tao Yang, MD
• Phone: 86-010-66933333
• Email: y_t_0321[@]163.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 150
• Est. completion date: December 30, 2028
• Est. primary completion date: December 30, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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.

Related Conditions & MeSH terms

• Acute-On-Chronic Liver Failure
• End Stage Liver Disease
• Hepatic Insufficiency
• Liver Failure

Intervention

Drug:
• standard medical treatment
standard medical treatment for ACLF
• Placebo
5% human serum albumin in 0.9% saline (at week0, week1 and week2)
• hUC-MSC
hUC-MSC (1.5×10^8 cells/time, Peripheral IV, at week0, week1 and week2)
• hUC-MSC_Prolonged
hUC-MSC (1.5×10^8 cells/time, Peripheral IV, at week4 and week5)

Locations

Country	Name	City	State
China	the Fifth Medical Center, Chinese PLA General Hospital	Beijing	Beijing

Sponsors (5)

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

Country where clinical trial is conducted

China, 

References & Publications (10)

Gilsanz C, Aller MA, Fuentes-Julian S, Prieto I, Blazquez-Martinez A, Argudo S, Fernandez-Delgado J, Belena J, Arias J, De Miguel MP. Adipose-derived mesenchymal stem cells slow disease progression of acute-on-chronic liver failure. Biomed Pharmacother. 2017 Jul;91:776-787. doi: 10.1016/j.biopha.2017.04.117. Epub 2017 May 10. — View Citation

He Y, Guo X, Lan T, Xia J, Wang J, Li B, Peng C, Chen Y, Hu X, Meng Z. Human umbilical cord-derived mesenchymal stem cells improve the function of liver in rats with acute-on-chronic liver failure via downregulating Notch and Stat1/Stat3 signaling. Stem Cell Res Ther. 2021 Jul 13;12(1):396. doi: 10.1186/s13287-021-02468-6. Erratum In: Stem Cell Res Ther. 2022 Feb 7;13(1):65. — View Citation

Li YH, Xu Y, Wu HM, Yang J, Yang LH, Yue-Meng W. Umbilical Cord-Derived Mesenchymal Stem Cell Transplantation in Hepatitis B Virus Related Acute-on-Chronic Liver Failure Treated with Plasma Exchange and Entecavir: a 24-Month Prospective Study. Stem Cell Rev Rep. 2016 Dec;12(6):645-653. doi: 10.1007/s12015-016-9683-3. — View Citation

Lin BL, Chen JF, Qiu WH, Wang KW, Xie DY, Chen XY, Liu QL, Peng L, Li JG, Mei YY, Weng WZ, Peng YW, Cao HJ, Xie JQ, Xie SB, Xiang AP, Gao ZL. Allogeneic bone marrow-derived mesenchymal stromal cells for hepatitis B virus-related acute-on-chronic liver failure: A randomized controlled trial. Hepatology. 2017 Jul;66(1):209-219. doi: 10.1002/hep.29189. Epub 2017 May 27. — View Citation

Lin D, Chen H, Xiong J, Zhang J, Hu Z, Gao J, Gao B, Zhang S, Chen J, Cao H, Li Z, Lin B, Gao Z. Mesenchymal stem cells exosomal let-7a-5p improve autophagic flux and alleviate liver injury in acute-on-chronic liver failure by promoting nuclear expression of TFEB. Cell Death Dis. 2022 Oct 12;13(10):865. doi: 10.1038/s41419-022-05303-9. — View Citation

Maheshwari D, Kumar D, Jagdish RK, Nautiyal N, Hidam A, Kumari R, Sehgal R, Trehanpati N, Baweja S, Kumar G, Sinha S, Bajpai M, Pamecha V, Bihari C, Maiwall R, Sarin SK, Kumar A. Bioenergetic Failure Drives Functional Exhaustion of Monocytes in Acute-on-Chronic Liver Failure. Front Immunol. 2022 Jun 3;13:856587. doi: 10.3389/fimmu.2022.856587. eCollection 2022. — View Citation

Schacher FC, Martins Pezzi da Silva A, Silla LMDR, Alvares-da-Silva MR. Bone Marrow Mesenchymal Stem Cells in Acute-on-Chronic Liver Failure Grades 2 and 3: A Phase I-II Randomized Clinical Trial. Can J Gastroenterol Hepatol. 2021 Aug 4;2021:3662776. doi: 10.1155/2021/3662776. eCollection 2021. — View Citation

Shi M, Zhang Z, Xu R, Lin H, Fu J, Zou Z, Zhang A, Shi J, Chen L, Lv S, He W, Geng H, Jin L, Liu Z, Wang FS. Human mesenchymal stem cell transfusion is safe and improves liver function in acute-on-chronic liver failure patients. Stem Cells Transl Med. 2012 Oct;1(10):725-31. doi: 10.5966/sctm.2012-0034. Epub 2012 Oct 11. — View Citation

Xu WX, He HL, Pan SW, Chen YL, Zhang ML, Zhu S, Gao ZL, Peng L, Li JG. Combination Treatments of Plasma Exchange and Umbilical Cord-Derived Mesenchymal Stem Cell Transplantation for Patients with Hepatitis B Virus-Related Acute-on-Chronic Liver Failure: A Clinical Trial in China. Stem Cells Int. 2019 Feb 4;2019:4130757. doi: 10.1155/2019/4130757. eCollection 2019. — View Citation

Yu H, Feng Y, Du W, Zhao M, Jia H, Wei Z, Yan S, Han Z, Zhang L, Li Z, Han Z. Off-the-shelf GMP-grade UC-MSCs as therapeutic drugs for the amelioration of CCl4-induced acute-on-chronic liver failure in NOD-SCID mice. Int Immunopharmacol. 2022 Dec;113(Pt A):109408. doi: 10.1016/j.intimp.2022.109408. Epub 2022 Nov 9. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Transplantation free survival rate	Transplantation free survival rate of ACLF patients.	week1, week2, week3, week4, week5, week8, week12, week24, week53
Primary	Incidence of Treatment-Emergent Adverse Events	Safety and Tolerability of UC-MSCs transplantation.	day0, day3, week1, week2, week3, week4, week5, week8, week12, week24, week53
Secondary	International Normalized Ratio (INR)	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.	week-1, week0, day3, week1, week2, week3, week4, week5, week12, week24, week53
Secondary	Concentration of Total Bilirubin (TBIL, mg/dL)	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."	week-1, week0, day3, week1, week2, week3, week4, week5, week12, week24, week53
Secondary	Concentration of Serum Albumin (ALB, g/L)	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.	week-1, week0, day3, week1, week2, week3, week4, week5, week12, week24, week53
Secondary	Concentration of Blood Urea Nitrogen (BUN, mmol/L)	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.	week-1, week0, day3, week1, week2, week3, week4, week5, week12, week24, week53
Secondary	The Model for End-Stage Liver Disease(MELD) score	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.	week-1, week1, week2, week4, week5, week12, week24, week53
Secondary	Child-Turcotte-Pugh(CTP) score	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.	week-1, week1, week2, week4, week5, week12, week24, week53