Decompensated Cirrhosis of Liver Clinical Trial
Official title:
Granulocyte Colony Stimulating Factor Therapy In Decompensated Cirrhosis Of Liver: A Double Blinded Single Centre Randomised Controlled Trial
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.
n/a