G-CSF in Decompensated Cirrhosis: an Open Label Trial

Granulocyte Colony Stimulating Factor in Decompensated Cirrhosis: an Open Label Study

Globally, cirrhosis is the fifth commonest cause of mortality. Its natural history is typified by an initial, largely asymptomatic, "compensated" phase followed by "decompensation" due to complications of raised portal pressures and hepatocellular dysfunction.

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. The need for long term immunosuppression and its attendant complications are a further drawback. The ability of stem cells to differentiate into multiple cellular lineages makes one speculate that they can be used for tissue repair and regeneration when tissue-resident stem cells become overwhelmed. Bone marrow derived stem cells have amazing plasticity. They can "home" to the liver in response to injury and help in liver regeneration by trans-differentiation, cell fusion and augmentation of tissue- resident stem cell mediated repair. Two methods are available for the mobilisation of stem cells from the bone marrow to the liver. One involves the administration of cytokines like granulocyte-colony stimulating factor (G-CSF) and the other is the isolation of stem cells from the marrow followed by 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 .

G-CSF has been shown to mobilise bone marrow stem cells and even increase survival in patients of severe alcoholic steatohepatitis and ACLF. There is conflicting evidence on the role of G-CSF in decompensated cirrhosis with some studies showing improved survival while others have shown a lack of clinical or biochemical benefit. Many of these studies have used a single course of G-CSF. Verma et al, in a recent study published in 2018, elegantly demonstrated the beneficial effect of multiple courses of G-CSF in improving mortality and transplant free survival in decompensated cirrhotics.

The investigators too speculate that multiple cycles of G-CSF could result in better outcomes in decompensated cirrhosis by causing more prolonged and sustained stem cell homing to the liver. Thus, this study is being undertaken to further evaluate the safety and efficacy of multiple cycles of G-CSF in decompensated cirrhotics.

Study Overview

• Status: Unknown
• Conditions: Cirrhosis, Liver
• Intervention / Treatment: Drug: Standard Medical Therapy; Drug: G-CSF

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Arka De, MD; Phone Number: 9999816539; Email: arkascore@gmail.com

Study Locations

• India
  • Chandigarh, India, 160012
    • Recruiting
    • Post Graduate Institute of Medical Education and Research
    • Contact: Arka De, MD; Phone Number: 9999816539; Email: arkascore@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 (Hb A 1c ≥ 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Standard Medical Therapy; 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)	Drug: Standard Medical Therapy; Nutritional support, rifaximin, lactulose, bowel wash, albumin, diuretics, multivitamins and antibiotics.
ACTIVE_COMPARATOR: G-CSF + Standard Medical Therapy; G-CSF 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: Standard Medical Therapy; Nutritional support, rifaximin, lactulose, bowel wash, albumin, diuretics, multivitamins and antibiotics.; Drug: G-CSF; G-CSF will be administered at the dosage of 5 µg/Kg subcutaneously every 12 hr for five consecutive days. four such cycles will be administered at three monthly intervals.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival	Survival at 1 year after start of therapy	One year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical improvement in liver functions	Occurrence of decompensations namely ascites, hepatic encephalopathy and variceal bleed	One Year
Improvement in quality of life	Quality of life will be assessed using SF-36V2 Health Survey questionnaire	One year
Hemopoieticstem cell mobilisation	Mobilisation of CD 34+ cells in peripheral blood	One Year
Biochemical improvement in liver functions	Improvment in MELD score	One year
Improvement in nutritional status	Nutritional status will be assesses by skeletal muscle index measurement using CT scan measurements at L3 level	One Year
Safety of G-CSF as assessed by its adverse effects		One Year

Collaborators and Investigators

• Sponsor: Postgraduate Institute of Medical Education and Research
• Investigators: Principal Investigator: Virendra Singh, DM, Professor, Department of Hepatology, PGIMER, Chandigarh

Publications and helpful links

General Publications

• De A, Kumari S, Singh A, Kaur A, Sharma R, Bhalla A, Sharma N, Kalra N, Singh V. Multiple Cycles of Granulocyte Colony-Stimulating Factor Increase Survival Times of Patients With Decompensated Cirrhosis in a Randomized Trial. Clin Gastroenterol Hepatol. 2021 Feb;19(2):375-383.e5. doi: 10.1016/j.cgh.2020.02.022. Epub 2020 Feb 21.

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 1, 2016
• Primary Completion (ANTICIPATED): July 1, 2018
• Study Completion (ANTICIPATED): December 1, 2018

Study Registration Dates

• First Submitted: January 11, 2018
• First Submitted That Met QC Criteria: January 23, 2018
• First Posted (ACTUAL): January 30, 2018

Study Record Updates

• Last Update Posted (ACTUAL): January 30, 2018
• Last Update Submitted That Met QC Criteria: January 23, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Keywords: Regenerative medicine
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Liver Diseases; Fibrosis; Liver Cirrhosis
• Other Study ID Numbers: GCSF in cirrhosis

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No