National Collaborative Centre for Hepatic Regenerative Medicine (NC-CHRM): Single vs Repeated Cycle of Granulocyte Colony-Stimulating Factor (GCSF) & Darbepoetin in Early Decompensated Cirrhosis

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: Cirrhosis as a result of hepatitis B and C can regress with effective antiviral therapy. Therapeutic options for patients with cryptogenic or alcoholic cirrhosis are, however, limited. With limited options for transplant. Liver failure is failure of regeneration hence, potentiating native liver repair and regeneration can serve as potential non-transplant approaches. Growth factors {like GCSF, darbepoetin (EPO) have shown survival benefits with improve liver repair and regeneration in clinical trials by us (Gastroenterology 2012, 2015, Liver Int. 2019; Hepatology 2021) and others, however the effect is transient. In the proposed National Collaborative Centre for Hepatic Regenerative Medicine (NC-CHRM) we will use this novel regenerative medicine approaches GCSF therapy (for management of chronic liver failure) 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.

• Transplant-free survival [Time frame: 6-month, one year, 2 year and 3 year]
• Proportion of patient developed new-onset of Liver Related Event (such as ascites, hepatic encephalopathy , acute kidney injury, bleed and sepsis) or show mortality in both the groups [Time frame: 6-month, one year, 2 year and 3 year]
• Cumulative incidence of sepsis, acute kidney injury or secondary organ dysfunction in both groups [Time frame: 6-month, one year, 2 year and 3 year]
• Cumulative incidence of second decompensation [Time frame: 6-month, one year, 2 year and 3 year]
• Improvement in liver disease severity indices, including the Child-Turcotte-Pugh (CTP) score (ΔCTP). [Time frame: 6-month, one year, 2 year and 3 year]
• Improvement in liver disease severity indice like Model for End-Stage Liver Disease (MELD) score (ΔMELD). [Time frame: 6-month, one year, 2 year and 3 year]
• Proportion of patients completing treatment without major adverse effects [Time frame: 6-month, one year, 2 year and 3 year]
• Impact on liver injury (assessed by AST and ALT levels in blood). [Time frame: 6-month, one year, 2 year and 3 year]
• Impact on fibrosis (evaluated using Masson's Trichome stain and the Enhanced Liver Fibrosis [ELF] score). [Time frame: 6-month, one year, 2 year and 3 year]
• Impact on regeneration (measured by plasma Alpha-Fetoprotein levels). [Time frame: 6-month, one year, 2 year and 3 year]
• Impact on bone marrow stem cell reserve (CD34⁺ cell count in peripheral blood) [Time frame: One year, 2 year and 3 year]