GCSF Therapy in Decompensated Cirrhosis - A Double Blinded RCT

Study Overview
=================
Brief Summary
-----------------
Cirrhosis of liver is a leading cause of morbidity and mortality worldwide. Complications like ascites, spontaneous bacterial peritonitis, variceal bleed, hepatic encephalopathy, hepatorenal syndrome (HRS) and hepatocellular carcinoma (HCC) portend a poor prognosis and further decreases survival in these patients. The major causes of cirrhosis include excessive alcohol consumption, viral hepatitis and non- alcoholic fatty liver disease. Currently the only definitive treatment option for cirrhosis is liver transplantation which is limited in its applicability due to donor shortage, exorbitant costs and lack of widespread availability. Moreover, it requires lifelong immunosuppression and has considerable long term side effects including chronic renal failure, post-transplant lymphoproliferative disease and cardiovascular complications. The ability of stem cells to differentiate into multiple cellular lineages makes one speculate that stem cells can be used for tissue repair and regeneration when tissue-resident stem cells become overwhelmed. It has been shown that in response to acute or chronic liver damage, bone marrow derived stem cells can spontaneously populate the liver and differentiate into hepatic cells, thereby contributing to hepatic regeneration. Thus, apart from hepatocytes and intrahepatic stem cells, bone marrow derived stem cells also participate in the liver regeneration process. Currently, there are two methods to mobilize stem cells from the bone marrow to the liver. One is administration of cytokines like granulocyte-colony stimulating factor (G-CSF) and the other is the isolation of stem cells from the marrow and their injection into the hepatic artery or portal vein after purification. The latter is probably more cumbersome and may be potentially risky due to the underlying coagulation abnormalities in cirrhotic patients. Improved liver histology and survival has been noted in patients with cirrhosis following mobilization of bone marrow stem cells by granulocyte-colony stimulating factor (G-CSF). Three recent studies have demonstrated G-CSF induced mobilization of bone marrow stem cells (CD34 cells) in peripheral blood and their subsequent increase in liver tissue and improved survival in patients with alcoholic hepatitis and ACLF. However, there is a paucity of data on whether G-CSF improves survival and prognosis in patients with decompensated cirrhosis. Verma, Singh et al have shown in an open label trial that there was significantly better 12 month transplant free survival in ( GCSF+ Growth hormone + standard medical therapy group ) and ( G CSF + standard medical therapy group ) as compared to standard medical therapy group alone. CD 34+ cells at day 6 of therapy increased as compared to baseline. There was also a significant decrease of clinical scores, improvement in nutrition, better control of ascites, reduction in liver stiffness, lesser episodes of infection as well as improvement in QOL scores in the treatment groups having G CSF as compared to baseline. In a recent study by Newsome et al, a multicentre, open label randomized phase 2 trial, patients were randomized to standard care, treatment with subcutaneous G CSF or treatment with G CSF for 5 days followed by leukaphersis and IV infusion of CD 133 positive haematopoietic stem cells. They did not find any difference in MELD score over time in all 3 treatment groups. Serious adverse effects were more common in the G CSF groups than in standard treatment group. In a study by Kedarisetty CK et al. a significantly larger proportion of patients with decompensated cirrhosis given a combination of G-CSF & Darbopoietin α survived for 12 months more than patients given only placebo ( 68% vs. 26.9%; P = 0.001 ). The combination therapy also reduced liver severity scores and sepsis to a greater extent than placebo. In view of the conflicting results of the above studies and no studies on the use of multiple courses of GCSF in patients with decompensated cirrhosis in a double blind manner, the present study was undertaken to assess the safety and efficacy of G-CSF in patients with decompensated cirrhosis in the form of a double blinded RCT.

Official Title
-----------------
Granulocyte Colony Stimulating Factor Therapy In Decompensated Cirrhosis Of Liver: A Double Blinded Single Centre Randomised Controlled Trial

Conditions
-----------------
Decompensated Cirrhosis of Liver

Intervention / Treatment
-----------------
* Drug: G-CSF
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: • Decompensated Cirrhosis of liver irrespective of etiology Exclusion Criteria: Acute on chronic liver failure (fulfilling either APASL or CANONIC criteria of ACLF) Splenic diameter of more than 18 cm Concomitant HCC or other active malignancy Upper gastrointestinal bleeding in the previous 7 days Portal vein thrombosis Severe renal dysfunction as defined by creatnine > 1.5mg/dl Severe cardiac dysfunction Uncontrolled diabetes (HbA1c ≥ 9) or diabetic retinopathy Acute infection or disseminate intravascular coagulation Active alcohol abuse in last 3 months Known hypersensitivity to G-CSF HIV co-infection Pregnancy Refusal to give informed consent Those opting for liver transplant

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

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

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

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard Medical Therapy + G CSF Therapy<br>Standard medical therapy will include nutritional support, rifaximin, lactulose, bowel wash, albumin, diuretics, multivitamins, antibiotics. fresh frozen plasma and packed red-cell transfusions (as required). G-CSF ( prefilled syringe) at the dosage of 5 μg/Kg subcutaneously every 12 hr will be administered for five consecutive days. Four such cycles at 3 monthly intervals will be administered. | Drug: G-CSF<br>* G-CSF will be administered as prefilled syringes at a dosage of 5 μg/Kg subcutaneously every 12 hr for five consecutive days. Four such cycles will be administered at three monthly intervals.<br>|
| Placebo Comparator: Standard Medical Therapy + Placebo<br>Standard medical therapy will include nutritional support, rifaximin, lactulose, bowel wash, albumin, diuretics, multivitamins, antibiotics. fresh frozen plasma and packed red-cell transfusions (as required). Placebo ( prefilled syringe) filled with normal saline subcutaneously every 12 hr will be administered for five consecutive days. Four such cycles at 3 monthly intervals will be administered. | Drug: Placebo<br>* Placebo ( prefilled syringe) filled with normal saline subcutaneously every 12 hr will be administered for five consecutive days. Four such cycles at 3 monthly intervals will be administered.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall Survival at 1 year from the onset of therapy | One year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hemopoietic stem cell mobilisation | Mobilisation of CD 34+ cells in peripheral blood | One Year | 
| Clinical improvement in liver functions | Occurrence of decompensations namely ascites, hepatic encephalopathy and variceal bleed | One Year | 
| Biochemical improvement in liver functions | Improvement in model for end-stage liver disease (MELD) score. MELD score includes serum bilirubin, serum creatinine and international normalized ratio (INR). The score ranges from 6 to 40 with higher score indicating more severe liver disease. | One Year | 
| Improvement in nutritional status | Nutritional status will be assessed by skeletal muscle index (SMI) measurement using CT scan measurements at L3 level | One Year | 
| Improvement in quality of life | Quality of life will be assessed using SF-36V2 Health Survey questionnaire | One year | 
| Depression | Improvement in Depression as assessed by Patient Health Questionnaire (PHQ-9). The questionnaire score ranges from 1 to 27 with 1 indicating minimal depression and 27 indicating severe depression. | One year | 
| Demoralisation scale | Change in demoralisation scale will be noted at baseline and at the end of one year. The demoralisation scale is a questionnaire comprising of 24 items each being scored from 0 to 4. The total score ranges from 0 to 96 with higher score indicating more severe demoralisation. | One year | 
| Immunological profile | Change in the immunological profile of patients. Immunological profile will be assessed using various interleukins (IL) including IL-6, IL-10, TNF-alpha, IL-17, IL-4, IL-13 and IFN-gamma which will be measured in pg/ml at baseline and at the end of one year. | One year | 
| Safety of G-CSF as assessed by its adverse effects | Safety of G-CSF as assessed by its adverse effects | One year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Regenerative medicine