Acute-On-Chronic Liver Failure
Conditions
Keywords
Acute on Chronic Liver Failure, Mesenchymal Stem Cells, ACLF, Liver Regeneration
Brief summary
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.
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. 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.
Interventions
DRUGucMSC and Standard medical treatment
umbilical cord Mesenchymal stem cell1 million/kg will be given once a week for 4 week . 250 ml normal saline will be infused 30 minutes prior to ucMSCs infusion. All patients will receive the standard medical treatment.
OTHERStandard medical treatment
Standard medical treatment
Sponsors
Indian Council of Medical Research
Institute of Liver and Biliary Sciences, India
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* 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).
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 (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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 90-day transplant-free survival | 90-day |
Secondary
| Measure | Time frame |
|---|---|
| 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. |
| 28-day and 6-month transplant free survival | 28-day and 6-month |
| 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 |
| Impact on liver injury and regeneration (serum and histology ) at day 28 and day 90. | Day 28 and day 90 |
Countries
India
Contacts
Primary ContactDr. Anupam Kumar, PhD
Backup ContactFagun Sharma, M.Sc
Outcome results
None listed