Combination of Autologous MSC and HSC Infusion in Patients With Decompensated Cirrhosis

Study Overview
=================
Brief Summary
-----------------
Though the results of autologous CD34+ cell infusion and MSC in independent studies have shown promise, yet they are yet to reach the desired long term outcome. The possible postulation for this is possibly because when using autologous CD34+ cell infusion, the inflammatory milieu of the liver may not be conducive for sustained effects of the mobilized CD 34+ cells. MSC have immunomodulatory effect (ref) and may improve the liver environment making it more beneficial for the CD34+ cells to function and survive. In addition, MSC has ben shown to produce hepatocyte growth factor which is protective against liver injury and beneficial for liver regeneration (shown in above tables). However, it remains to be understood how MSCs promote liver stem stem cells to differentiate into hepatocytes or expand the residual hepatocyte population. MSC can also directly inhibit the activation of hepatic stellate cells, the main source of extracellular matrix via MSC derived IL 10 and TNF-αand may also induce hepatic stellate cell apoptosis. Current lacunae in cell based therapy is based on the poor consensus and understanding on the best type of cells to be used, the ideal number of cells, the most appropriate route of administration and the need for repeat dosing . The concept that combination of autologous hematopoietic and mesenchymal stem cells infusion may be more beneficial than infusing any one of them alone has been discussed in many scientific forums but there are no study till date to either see the safety as well as the efficacy of this proof of concept . With this above background data, we propose a study design which will be a safety study for combination use of autologous CD34+ and MSC

Official Title
-----------------
Combination of Autologous Mesenchymal and Hematopoietic Stem Cell Infusion in Patients With Decompensated Cirrhosis: A Pilot Study

Conditions
-----------------
Cirrhosis, Liver

Intervention / Treatment
-----------------
* Combination Product: CD 34 and MSC infusion
* Drug: Standard of care for Cirrhosis management


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age between 20-70 years Clinically diagnosed for hepatic cirrhosis having a Child Pugh score of B or MELD >10 but below 20 Not willing for immediate liver transplantation either due to lack of donor tissue or financial issues Platelet count of > 80,000 and INR <1.6 Life expectancy of at least 3 months based on MELD score and Child Pugh Score Ability to give informed consent Exclusion Criteria: Age less than 20 or more than 70 years Have liver tumors or history of any other cancer Pregnant or lactating women Patients with hepato-renal syndrome and acute kidney injury (Any creatinine > 1.6 will be excluded) Evidence of ongoing sepsis - as per Surviving sepsis guideline Recent gastrointestinal bleeding or spontaneous bacterial peritonitis (within last one month) Any HIV positive patients Co-morbid conditions such as severe cardiac and/or pulmonary disease Inability to give informed consent

Ages Eligible for Study
-----------------
Minimum Age: 20 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Combination MSC and HSC<br>Patient will receive a combination of mesenchymal and Hematopoetic stem cell through hepatic artery under fluroscopic guidance | Combination Product: CD 34 and MSC infusion<br>* Combination of stem cells<br>* Other names: Stem cell infusion;|
| Active Comparator: Standard of care for Cirrhosis management<br>Diuretics, Hepatoprotective agents and Lactulose | Drug: Standard of care for Cirrhosis management<br>* Drugs used for Cirrhosis management such as Diuretics, Hepatoprotective agents and Lactulose<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the safety of combination of hematopoetic and mesenchymal stem cell in patients of liver cirrhosis. | Any adverse events after the use of combination stem cell treatment would be recorded: Bone marrow aspiration related complications such as pain (>6 on VAS) and bleeding from the site. Leukapheresis related complications such as hypotension and hypocalcemia. Hepatic artery catheterization related complications such as pain or discomfort at the catheter insertion site, bleeding and infection. Post MSC and CD34 infusion related adverse reactions would be recorded using CDSCO form. | Up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in MELD (Model for End stage Liver disease) score. | Difference in MELD score from baseline to follow-up period. | Up to 6 months | 
| Change in Child Pugh score. | Difference in Child Pugh score from baseline to follow-up period. | Up to 6 months | 
| Change in the percentage of CD 34 cells in liver. | To assess improvement in the percentage of CD 34 cells in liver by performing a paired liver biopsy- before and after infusion. | Up to 6 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Mesenchymal Stem Cell, Hematopoetic Stem cell, Autologous transfusion