Clinical trial NCT05224960: Human Umbilical Cord-derived Mesenchymal Stem Cells for Decompensated Cirrhosis (MSC-DLC-2)
Official title: A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy and Safety of Human Umbilical Cord-derived Mesenchymal Stem Cells in the Treatment of Decompensated Cirrhosis Patients(MSC-DLC-2)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Decompensated Cirrhosis
Lead sponsor: Beijing 302 Hospital
Sponsor class: OTHER
Collaborators: name: Chinese PLA General Hospital
name: Shanghai Changzheng Hospital
name: LanZhou University
name: Jin Yin-tan Hospital
name: Hainan Hospital of Chinese PLA General Hospital
name: Vcanbio Cell and Gene Engineering Corp., Ltd.
name: Third Affiliated Hospital, Sun Yat-Sen University
name: Xinjiang Kashi Area Number 1 Hospital
First posted: 2022-02-04
Enrollment: 140
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, double-blind, placebo-controlled, multicenter study
Primary purpose: TREATMENT

Brief summary: Decompensated cirrhosis has a high overall mortality rate. There is a large unmet need for safe and alternative therapeutic potions. This clinical trial is to inspect the efficiency and safety of mesenchymal stem cells (MSCs) therapy for decompensated cirrhosis.

Detailed description: Decompensated cirrhosis has a high overall mortality rate. Liver transplantation is still the most effective treatment for decompensated cirrhosis. However, the shortage of matched liver sources, high costs, and rejection after liver transplantation restrict the development of liver transplantation.

Mesenchymal stem cells (MSC) are a kind of pluripotent stem cells belonging to mesoderm, which mainly exist in connective tissue and organ interstitium. At present, MSC can be isolated and prepared from bone marrow, fat, synovium, bone, muscle, lung, liver, pancreas and amniotic fluid and umbilical cord blood . Due to its wide range of sources and self-proliferation and differentiation ability, MSCs have therapeutic potential for many diseases, including acute and chronic liver diseases.

In recent years, our team has carried out a series of clinical trials using umbilical cord-derived MSCs to treat patients with end-stage liver disease, decompensated cirrhosis, primary biliary cholangitis, and status after liver transplantation and found that MSCs therapy can significantly improve patient liver function, reduce post-transplantation rejection, reduce complications, improve quality of life, and improve survival. Other investigators have also found in clinical trials with MSCs from different sources that treatment with MSCs can improve MELD scores or liver function levels to varying degrees. However, some studies have found no significant difference between the treatment group and the control group, and MSCs may differentiate into hepatic stellate cells and have the risk of promoting liver fibrosis, it is believed that MSCs do not favor the improvement of liver function in these studies. Therefore, the therapeutic effects of MSCs need to be further validated by larger multicenter randomized controlled clinical trials.

The investigators will do a prospective, double-blind, muliticenter, randomised trial to assess treatment with three intravenous doses of MSCs compared with placebo. 140 decompensated cirrhosis patients will be recruited in China. 70 patients will receive i.v. transfusion 3 times of MSCs and the standard of care as the treated group. In addition, the 70 patients will receive placebo and standard of care as control group.

Eligibility criteria: Inclusion Criteria:

1. Willing to provide written informed consent;
2. Aged 18 to 75 years (including 18 and 75 years), male or female;
3. Patients diagnosed with decompensated liver cirrhosis based on clinical findings, laboratory tests, imaging findings and/or representative pathological findings (decompensated liver cirrhosis is defined as the occurrence of at least one serious complication, including esophageal and gastric varices bleeding, hepatic encephalopathy, ascites, spontaneous bacterial peritonitis and other serious complications);
4. The Model for End-stage Liver Disease (MELD) score 15 to 30 points.

Exclusion Criteria:

1. Appearance of active variceal bleeding, overt hepatic encephalopathy (HE), refractory ascites or hepatorenal syndrome within 1 month prior to screening visit.
2. Uncontrolled severe infection within 2 weeks of screening.
3. Patients with hepatitis B virus-related decompensated liver cirrhosis may discontinue antiviral therapy during the study, or those who with antiviral therapy for HBV for less than 12 months, or hepatitis B virus (HBV) DNA ≥ detection limit at the time of screening.
4. Patients with hepatitis C virus-related decompensated liver cirrhosis may discontinue antiviral therapy during the study, or those who with antiviral therapy for HCV for less than 12 months, or hepatitis C virus (HCV) RNA ≥ detection limit at the time of screening (except HCV RNA\< detection limit without any antiviral treatment).
5. Patients under treatment with corticosteroids for autoimmune hepatitis for less than 6 months.
6. Trans-jugular intrahepatic portosystemic shunts (TIPS) insertion within 6 months prior to study inclusion.
7. Active drinkers with alcohol-related decompensated cirrhosis are unwilling to stop alcohol abuse after inclusion.
8. Significant renal insufficiency (serum creatinine ≥ 1.2 times upper normal limit); Severe electrolyte abnormality (serum sodium level \< 125 mmol/L); Severe leukopenia (white blood cell count \< 1 × 10E9/L).
9. Patients with biliary obstruction, or portal vein spongiosis.
10. Patients with surgical history such as splenic cut-off flow.
11. Patients with malignant tumors within 5 years, except those with basal cell carcinoma, squamous cell carcinoma and/or carcinoma in situ who had received curative treatment and curative resection.
12. Patients with a prior history of major organ transplantation or complicated with significant disease of heart, lung, kidney, blood, endocrine and other systems.
13. Drug abuse, drug dependence and patients who receive methadone treatment or with psychosis.
14. Against the human immunodeficiency virus antibody (Anti - HIV) or syphilis antibody test results were positive.
15. Pregnancy, lactation or with recent fertility plan during the test and 6 months after the test.
16. Highly allergic, or have a history of severe allergies, known severe allergies to the investigational drug or any of the excipients.
17. History of pulmonary embolism.
18. Patients who had previously received stem cell therapy or were intolerant to cell therapy.
19. The proposed line of liver transplants within three months.
20. Participants in other clinical trials within the last 3 months.
21. Any other clinical condition which the investigator considers would make the patient unsuitable for the trial.

Primary outcomes:
measure: Change in Model for End-Stage Liver Disease (MELD) score from baseline to 28th day
timeFrame: Baseline, 28th day
Secondary outcomes:
measure: Change in MELD score from baseline to 24 months
timeFrame: up to 24 months
measure: Incidence of each complication associated with decompensated cirrhosis
timeFrame: up to 24 months
measure: Liver transplant-free survival
timeFrame: month 12 and 24
measure: Incidence of liver failure
timeFrame: month 12 and 24
measure: plasma albumin (ALB)
timeFrame: up to 24 months
measure: plasma prealbumin (PALB)
timeFrame: up to 24 months
measure: total bilirubin (TBIL)
timeFrame: up to 24 months
measure: serum cholinesterase (CHE)
timeFrame: up to 24 months
measure: prothrombin activity (PA)
timeFrame: up to 24 months
measure: Child-Turcotte-Pugh (CTP) score
timeFrame: up to 24 months
measure: EuroQol Group 5-Dimension Self-Report Questionnaire (EQ-5D)
timeFrame: up to 24 months
measure: ChronicLiver Disease Questionnaire (CLDQ)
timeFrame: up to 24 months
measure: Incidence of liver cancer
timeFrame: up to 24 months
measure: Incidence of Treatment-Emergent Adverse Events and Serious Adverse Events
timeFrame: up to 24 months
measure: Alanine Aminotransferase (ALT)
timeFrame: up to 24 months
measure: Aspartate Aminotransferase (AST)
timeFrame: up to 24 months
measure: Alkaline Phosphatase (ALP)
timeFrame: up to 24 months
measure: Gamma-Glutamyl transferase (GGT)
timeFrame: up to 24 months
measure: plasma ammonia
timeFrame: up to 24 months
measure: international normalized ratio (INR)
timeFrame: up to 24 months
measure: creatinine （Cr）
timeFrame: up to 24 months
measure: Prothrombin time (PT)
timeFrame: up to 24 months
measure: Liver transplant-free survival rate
timeFrame: month 12 and 24
Other outcomes:
Locations:
city: Lanzhou
country: China
facility: The First Hospital of Lanzhou University
state: Gansu
city: Guangzhou
country: China
facility: Third Affiliated Hospital, Sun Yat-Sen University
state: Guangdong
city: Sanya
country: China
facility: Hainan hospital of Chinese PLA General Hospital
state: Hainan
city: Wuhan
country: China
facility: Jin Yin-tan Hospital
state: Hubei
city: Shanghai
country: China
facility: Shanghai Changzheng Hospital
state: Shanghai
city: Kashi
country: China
facility: Xinjiang Kashi Area Number 1 Hospital
state: Xinjiang
city: Beijing
country: China
facility: Beijing 302 Hospital
Study officials:
affiliation: Beijing 302 Hospital
name: Fu-Sheng Wang, MD, PhD
role: STUDY_CHAIR
References: