National Collaborative Centre for Hepatic Regenerative Medicine (NC-CHRM): To Study the Safety and Efficacy of Mesenchymal Stem-Cell (MSC) Therapy in the Management of Non-viral ACLF Patients: Phase-II Clinical Study
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 100
- 试验地点
- 1
- 主要终点
- 90-day transplant-free survival
研究概览
简要总结
Liver disease deaths are rising, but transplants remain scarce in India. With over 100,000 needed annually and only ~2,500 performed, non-transplant options are urgently needed. Regenerative therapy, especially MSCs, shows promise but lacks validation, particularly for non-viral ACLF. The proposed NC-CHRM aims to develop and validate MSC-based therapy to promote native liver regeneration and offer a safe, effective, transplant-free treatment.
详细描述
The incidence of deaths from chronic liver diseases (CLD) and cirrhosis are rapidly increasing globally, including India. Liver transplant is the only curative option. Unfortunately, transplant is often not feasible. There is a need for nearly 100,000 liver transplants every year in India, though, only about 2,500 transplants are being done at present across the country. There is therefore, a huge unmet need of developing non-transplant options for chronic liver disease patients. In this regard emerging science of regenerative therapy holds great promises but therapeutic benefit of these therapies is limited due to lack of clinical validation.
Novelty: Liver failure is failure of regeneration hence, potentiating native liver repair and regeneration can serve as potential non-transplant approaches. Others and us have shown in experimental studies that mesenchymal stem cells (MSCs) can improve hepatic regeneration. MSC therapy trials in decompensated cirrhosis and viral ACLF in Korea, China and Japan have shown promise but their utility in non-viral ACLF is limited. In the proposed National Collaborative Centre for Hepatic Regenerative Medicine (NC-CHRM) we will use this novel regenerative medicine approaches MSC for management of acute liver failure in non-viral ACLF to develop safe and effective regenerative therapy clinical protocol for transplant free management of liver failure in cirrhosis. Using integrated cellular, molecular and functional analysis we will also establish their mechanism of action and identify biomarker to access therapeutic response.
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
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •ACLF patients with Model for End-Stage Liver Disease(MELD)>18 or APASL ACLF Research Consortium(AARC) grade 2 or more with (no or single extrahepatic organ dysfunction or failure having no option of liver transplant).
排除标准
- •Age <18 or >65 yrs
- •Patients with active sepsis
- •Patients with hepatic venous outflow tract obstruction (HVOTO) or Extrahepatic portal vein obstruction (EHPVO)
- •Hepatocellular carcinoma (beyond Milan) or any extrahepatic malignancy
- •Active bleed (mucosal or variceal) or severe coagulopathy (platelets <20,000 or INR>4)
- •Patients with refractory shock requiring norepinephrine >0.5ug/kg/min
- •Patients with severe Acute Respiratory Distress Syndrome (ARDS) with Pa02/Fi02 <150
- •Patients with retroviral infections
- •Autoimmune hepatitis
- •Viral etiology of liver disease
- •Co-existent Hepatitis B, Hepatitis C, HIV
- •Chronic kidney disease
- •Multiorgan failure or Disseminated Intravascular Coagulation (DIC)
- •Patients improving on standard medical treatment
- •Patients on immunosuppressive medications
- •Pregnancy or active breastfeeding
- •Known severe cardiopulmonary diseases (structural or valvular heart disease, coronary artery disease, coronary pulmonary disease, chronic kidney disease)
- •Lack of informed consent
研究组 & 干预措施
Umbilical cord mesenchymal stem cell (ucMSC) and Standard medical treatment (SMT)
Patient randomize for MSC therapy together with standard medical treatment, ucMSC 1 million/kg will be given once a week for 4 week . 250 ml normal saline will be infused 30 minutes prior to ucMSCs infusion. The fresh ucMSCs will then be infused through IV canula peripherally over 30 minutes followed by a further 250 ml normal saline over 20-30 minutes. A baseline early warning score (EWS) will be undertaken with continuous monitoring of pulse and with blood pressure checks every 5 minutes during the cell infusion and then every 15 minutes during the subsequent 2-hour observation period, then every hour for the remaining 10-hour observation period (minimum total of 12 hours observation) after cell infusion. All patients will receive the standard medical treatment.
干预措施: ucMSC and Standard medical treatment (Drug)
Umbilical cord mesenchymal stem cell (ucMSC) and Standard medical treatment (SMT)
Patient randomize for MSC therapy together with standard medical treatment, ucMSC 1 million/kg will be given once a week for 4 week . 250 ml normal saline will be infused 30 minutes prior to ucMSCs infusion. The fresh ucMSCs will then be infused through IV canula peripherally over 30 minutes followed by a further 250 ml normal saline over 20-30 minutes. A baseline early warning score (EWS) will be undertaken with continuous monitoring of pulse and with blood pressure checks every 5 minutes during the cell infusion and then every 15 minutes during the subsequent 2-hour observation period, then every hour for the remaining 10-hour observation period (minimum total of 12 hours observation) after cell infusion. All patients will receive the standard medical treatment.
干预措施: Standard medical treatment (Other)
Standard Medical Treatment
Patients in the SMT group will be managed as per requirement with nutrition, lactulose, intravenous albumin, fluids, blood transfusion or antibiotics as required. Patients with hepatorenal syndrome will be treated with intravenous terlipressin or noradrenaline. Renal replacement therapy will be done for standard indications in patients with severe volume overload, metabolic acidosis, or hyperkalemia unresponsive to goal-directed SMT as described above. Mechanical ventilation and routine intensive care management will be done in patients with multiorgan failure.
干预措施: Standard medical treatment (Other)
结局指标
主要结局
90-day transplant-free survival
时间窗: 90-day
次要结局
- 28-day and 6-month transplant free survival(28-day and 6-month)
- Cumulative incidence of AKI, sepsis and extrahepatic-extrarenal organ dysfunctions at day 28, day 60 and day 90.(Day 28, day 60 and day 90.)
- Proportion of patients achieving resolution of ACLF (complete and partial) at day 90.(Day 90)
- Improvement in liver severity indices MELD score by 4 points and improvement in AARC grade by 1 from baseline at 28 days, day 60 and day 90.(Day 28, Day 60 and Day 90.)
- Impact on liver injury and regeneration (serum and histology ) at day 28 and day 90.(Day 28 and day 90)
- Change in monocyte energy metabolism (glycolysis and OXPHOS test) and function from baseline at day 3, day 7, day 28 and day 90.(Day 3, 7,28 and 90)
- Change in peripheral blood level of cytokines (pro-inflammatory: TNF-α, IL-6, IL-1β; anti-inflammatory: IL-10, TGF-β), endotoxin and extracellular vesicles (EVs, number of EVs per mL of blood) at baseline, day 3, day14, day 28 and day 90.(Day 3,14, 28, 90)
- Proportion of patients completing treatment without major adverse effects(Day 90)