Clinical trial NCT03911037: GCSF Therapy in Decompensated Cirrhosis - A Double Blinded RCT
Official title: Granulocyte Colony Stimulating Factor Therapy In Decompensated Cirrhosis Of Liver: A Double Blinded Single Centre Randomised Controlled Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
PHASE3
Conditions: Decompensated Cirrhosis of Liver
Keywords: Regenerative medicine
Lead sponsor: PGIMER
Sponsor class: UNKNOWN
Collaborators: name: Society for the Study of Liver Diseases, Chandigarh ( India )
First posted: 2019-04-10
Enrollment: 70
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Overall Survival
timeFrame: One year
Secondary outcomes:
measure: Hemopoietic stem cell mobilisation
timeFrame: One Year
measure: Clinical improvement in liver functions
timeFrame: One Year
measure: Biochemical improvement in liver functions
timeFrame: One Year
measure: Improvement in nutritional status
timeFrame: One Year
measure: Improvement in quality of life
timeFrame: One year
measure: Depression
timeFrame: One year
measure: Demoralisation scale
timeFrame: One year
measure: Immunological profile
timeFrame: One year
measure: Safety of G-CSF as assessed by its adverse effects
timeFrame: One year
Other outcomes:
Locations:
city: Chandigarh
country: India
facility: Post Graduate Institute of Medical Education and Research
Study officials:
References:
citation: Venkitaraman A, De A, Verma N, Kumari S, Leishangthem B, Sharma RR, Kalra N, Grover S, Singh V. Multiple cycles of granulocyte colony-stimulating factor in decompensated cirrhosis: a double-blind RCT. Hepatol Int. 2022 Oct;16(5):1127-1136. doi: 10.1007/s12072-022-10314-x. Epub 2022 Mar 23.