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)
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 140
- 试验地点
- 7
- 主要终点
- Change in Model for End-Stage Liver Disease (MELD) score from baseline to 28th day
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Willing to provide written informed consent;
- •Aged 18 to 75 years (including 18 and 75 years), male or female;
- •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);
- •The Model for End-stage Liver Disease (MELD) score 15 to 30 points.
排除标准
- •Appearance of active variceal bleeding, overt hepatic encephalopathy (HE), refractory ascites or hepatorenal syndrome within 1 month prior to screening visit.
- •Uncontrolled severe infection within 2 weeks of screening.
- •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.
- •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).
- •Patients under treatment with corticosteroids for autoimmune hepatitis for less than 6 months.
- •Trans-jugular intrahepatic portosystemic shunts (TIPS) insertion within 6 months prior to study inclusion.
- •Active drinkers with alcohol-related decompensated cirrhosis are unwilling to stop alcohol abuse after inclusion.
- •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).
- •Patients with biliary obstruction, or portal vein spongiosis.
- •Patients with surgical history such as splenic cut-off flow.
- •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.
- •Patients with a prior history of major organ transplantation or complicated with significant disease of heart, lung, kidney, blood, endocrine and other systems.
- •Drug abuse, drug dependence and patients who receive methadone treatment or with psychosis.
- •Against the human immunodeficiency virus antibody (Anti - HIV) or syphilis antibody test results were positive.
- •Pregnancy, lactation or with recent fertility plan during the test and 6 months after the test.
- •Highly allergic, or have a history of severe allergies, known severe allergies to the investigational drug or any of the excipients.
- •History of pulmonary embolism.
- •Patients who had previously received stem cell therapy or were intolerant to cell therapy.
- •The proposed line of liver transplants within three months.
- •Participants in other clinical trials within the last 3 months.
- •Any other clinical condition which the investigator considers would make the patient unsuitable for the trial.
研究组 & 干预措施
Placebo
Placebo plus SOC.
干预措施: Placebo(solution without UC-MSCs) (Biological)
Human Umbilical Cord-Mesenchymal Stem Cells (UC-MSCs)
UC-MSCs plus standard of care (SOC).
干预措施: UC-MSCs (Biological)
结局指标
主要结局
Change in Model for End-Stage Liver Disease (MELD) score from baseline to 28th day
时间窗: Baseline, 28th day
The Model for End-stage Liver Disease (MELD) is a scoring system that evaluates the liver function reserve and prognosis of patients with chronic liver disease by creatinine, international normalized ratio (INR), and bilirubin-conjugated cirrhosis etiology.
次要结局
- ChronicLiver Disease Questionnaire (CLDQ)(up to 24 months)
- Incidence of liver cancer(up to 24 months)
- Incidence of Treatment-Emergent Adverse Events and Serious Adverse Events(up to 24 months)
- Change in MELD score from baseline to 24 months(up to 24 months)
- Incidence of each complication associated with decompensated cirrhosis(up to 24 months)
- Liver transplant-free survival(month 12 and 24)
- Incidence of liver failure(month 12 and 24)
- plasma albumin (ALB)(up to 24 months)
- plasma prealbumin (PALB)(up to 24 months)
- total bilirubin (TBIL)(up to 24 months)
- serum cholinesterase (CHE)(up to 24 months)
- prothrombin activity (PA)(up to 24 months)
- Alanine Aminotransferase (ALT)(up to 24 months)
- Aspartate Aminotransferase (AST)(up to 24 months)
- Alkaline Phosphatase (ALP)(up to 24 months)
- Gamma-Glutamyl transferase (GGT)(up to 24 months)
- plasma ammonia(up to 24 months)
- international normalized ratio (INR)(up to 24 months)
- creatinine （Cr）(up to 24 months)
- Prothrombin time (PT)(up to 24 months)
- Liver transplant-free survival rate(month 12 and 24)
- Child-Turcotte-Pugh (CTP) score(up to 24 months)
- EuroQol Group 5-Dimension Self-Report Questionnaire (EQ-5D)(up to 24 months)
研究者
Fu-Sheng Wang
Head of Treatment and Research Center for Infectious Diseases, Principle Investigator, Clinical Professor
Beijing 302 Hospital