National Collaborative Centre for Hepatic Regenerative Medicine (NC-CHRM): Evaluating Mesenchymal Stem Cell Therapy in Non-viral Acute on Chronic Liver Failure (ACLF) Patient- Phase-II Trial

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.

• 28-day and 6-month transplant free survival [Time frame: 28-day and 6-month]
• Cumulative incidence of AKI, sepsis and extrahepatic-extrarenal organ dysfunctions at day 28, day 60 and day 90. [Time frame: Day 28, day 60 and day 90.]
• Proportion of patients achieving resolution of ACLF (complete and partial) at day 90. [Time frame: 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. [Time frame: Day 28, Day 60 and Day 90.]
• Impact on liver injury and regeneration (serum and histology ) at day 28 and day 90. [Time frame: 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. [Time frame: 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. [Time frame: Day 3,14, 28, 90]
• Proportion of patients completing treatment without major adverse effects [Time frame: Day 90]