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

Official title

National Collaborative Centre for Hepatic Regenerative Medicine (NC-CHRM): To Study the Safety and Efficacy of Mesenchymal Stem-Cell Therapy in the Management of Non-viral ACLF Patients: Phase-III Clinical Study

Overview

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.

Detailed 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.

Interventions

• Drug Umbilical cord Mesenchymal stem cell
  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.
• Drug Steroid
  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 oftapering before stopping the therapy. In patients who were non responsive to steroids (Lille score \> 0.45) at day 7, steroids will be stopped at day 7 and will receive only SMT.
• Other Standard Medical Treatment
  All patients will receive the standard medical treatment.

Primary outcome measures

• 90-day transplant-free survival [Time frame: Day 90]

Secondary outcome measures (5)

• 28-day and 6-month transplant free survival [Time frame: 28-day and 6-month]
• Cumulative incidence of acute kidney injury (AKI), sepsis and extrahepatic-extrarenal organ dysfunctions 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 model for End-stage liver disease (MELD) score by 4 points and improvement in APASL ACLF Research Consortium (AARC) grade by 1 from baseline at 28 days, day 60 and day 90. [Time frame: 28 days, day 60 and day 90]
• Proportion of patients completing treatment without major adverse effects [Time frame: 5 year]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

India · 3 centers

• Postgraduate Institute of Medical Education and Research (PGIMER) — Chandigarh
• All India Institutes of Medical Sciences (AIIMS) — New Delhi
• Institute of Liver & Biliary Sciences — New Delhi

Identifiers

NCT: NCT07075315 · ILBS-ACLF-73

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗