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

Institute of Liver and Biliary Sciences, India

Status and phase: Begins enrollment in a year or more; Phase 3

Conditions: Acute-On-Chronic Liver Failure

Treatments: Drug: Steroid; Drug: Umbilical cord Mesenchymal stem cell; Other: Standard Medical Treatment

Study type: Interventional

Funder types: Other

Identifiers

NCT07075315

ILBS-ACLF-73

Details and patient eligibility

About

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 mesenchymal stem cells (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.

Full description

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.

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 Acute-on-Chronic Liver Failure (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.

Enrollment: 100 estimated patients

Sex: All

Ages: 18 to 65 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• ACLF patients with Model for End-Stage Liver Disease (MELD) score >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.

Exclusion criteria

• 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
• 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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100 participants in 2 patient groups

Umbilical cord Mesenchymal stem cell (ucMSC) and standard medical treatment (SMT)

Experimental group

Description:

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 (SMT).

Treatment:

Other: Standard Medical Treatment

Drug: Umbilical cord Mesenchymal stem cell

Steroid and Standard medical treatment

Active Comparator group

Description:

Patients in steroid group will be given prednisolone 40 mg once daily for 7 days as inpatients. After that Lille score will be calculated on day 7. Responders (Lille score \< 0.45) will be continued on steroids for a total of 4 weeks, followed by 2 weeks of tapering before stopping the therapy. In patients who were nonresponsive to steroids (Lille score \> 0.45) at day 7, steroids will be stopped at day 7 and will receive only SMT. Patients 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.

Treatment:

Other: Standard Medical Treatment

Drug: Steroid