G-CSF in Decompensated Cirrhosis: an Open Label Trial

Study Overview
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Brief Summary
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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.

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

Conditions
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Cirrhosis, Liver

Intervention / Treatment
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* Drug: G-CSF
* Drug: Standard Medical Therapy


Participation Criteria
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Eligibility Criteria
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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

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard Medical 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) | Drug: Standard Medical Therapy<br>* Nutritional support, rifaximin, lactulose, bowel wash, albumin, diuretics, multivitamins and antibiotics.<br>|
| Active Comparator: G-CSF + Standard Medical Therapy<br>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: G-CSF<br>* 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.<br>Drug: Standard Medical Therapy<br>* Nutritional support, rifaximin, lactulose, bowel wash, albumin, diuretics, multivitamins and antibiotics.<br>|

What is the study measuring?
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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 |
| --- | --- | --- |
| Hemopoieticstem 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 | 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 | 
| Improvement in quality of life | Quality of life will be assessed using SF-36V2 Health Survey questionnaire | One year | 
| Safety of G-CSF as assessed by its adverse effects |  | One Year | 

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