GCSF Therapy in Decompensated Cirrhosis - A Double Blinded RCT

NCT03911037 | Unknown Phase 2 DMC

• 1 other identifier: GCSF in DC
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 1

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.

Conditions

Decompensated Cirrhosis of Liver

Keywords

Regenerative medicine

Outcome Measures

Primary Outcomes (1)

• Overall Survival

  Overall Survival at 1 year from the onset of therapy

  One year

Secondary Outcomes (9)

• Hemopoietic stem cell mobilisation

  One Year

• Clinical improvement in liver functions

  One Year

• Biochemical improvement in liver functions

  One Year

• Improvement in nutritional status

  One Year

• Improvement in quality of life

  One year

Study Arms (2)

Standard Medical Therapy + G CSF Therapy

ACTIVE COMPARATOR

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

Standard Medical Therapy + Placebo

PLACEBO COMPARATOR

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

Interventions

G-CSF DRUG

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.

Standard Medical Therapy + G CSF Therapy

Placebo DRUG

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.

Standard Medical Therapy + Placebo

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Decompensated Cirrhosis of liver irrespective of etiology

You may not qualify if:

• 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

Sponsors & Collaborators

• Post Graduate Institute of Medical Education and Research, Chandigarh: lead
• Society for the Study of Liver Diseases, Chandigarh ( India ): collaborator

Study Sites (1)

Post Graduate Institute of Medical Education and Research

Chandigarh, 160012, India

RECRUITING

Related Publications (1)

• 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.

  PMID: 35322373 DERIVED

MeSH Terms

Interventions

Granulocyte Colony-Stimulating Factor

Intervention Hierarchy (Ancestors)

Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Central Study Contacts

Virendra Singh, DM

CONTACT

7087009338; virendrasingh100@hotmail.com

Aswath Venkitaraman, MD

CONTACT

9597517036; av3280@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Hepatology

Study Record Dates

• First Submitted: April 6, 2019
• First Posted: April 10, 2019
• Study Start: May 4, 2019
• Primary Completion: June 30, 2020
• Study Completion: June 30, 2020
• Last Updated: July 19, 2019

Record last verified: 2019-07

Data Sharing

• IPD Sharing: Will not share

Locations

IN (1)