Effect of Single vs Repeated Cycles of a Combination of Granulocyte Colony Stimulating Factor and Darbepoetin vs Standard Medical Treatment on Immunometabolic Profile in Patient With Early Decompensated Cirrhosis.

Aim: To study the efficacy of single vs repeated cycle of Granulocyte Colony Stimulating Factor+ darbopoetin vs standard medical treatmenton immunometabolic profile in patient with early decompensated cirrhosis

Study population:

* Age 18-70 years
* Early decompensated cirrhosis MELD < 16 , CTP < 9B
* Uncomplicated ascites
* A Prospective Randomized Controlled Trial.
* Single Centre.
* Open label.
* Block Randomization will be done , it will be implemented by IWRS method.
* The study will be conducted in Department of Hepatology, ILBS.

• Darbepoetin (Drug): Darbepoetin will be given s/c at dose of 40 mcg once a week (total 4 doses) for 1 month
• G-CSF (Drug): G-CSF will be given at a dose of 5 µg/kg s/c at days 1, 2, 3, 4, 5 and then every third and 7th day till day 30
• Lactulose (Drug): Standard Medical Tretament part
• Albumin (Biological): Standard Medical Tretament part

Primary outcomes

• Change in innate immunity between the groups. [6 months]: Innate immunity -Monocyte, neutrophils -distribution , function and bioenergetic adaptation

Secondary outcomes

• Proportion of participants developed new-onset of LRE (such as ascites, HE, AKI, bleed and sepsis) or show mortality in all the groups. [6 months]
• Cumulative incidence of second decompensation in all the groups. [6 months & 1 year]
• Transplant-free survival. [6 months & 1 year]
• Number of participants with improvement in liver disease severity indices (CTP). [6 months]
• Number of participants with improvement in liver disease severity indices (MELD). [6 months]
• Number of participants with change in adaptive immunity(T-cell, B-cell and NK cells distribution only ) [6 months]
• Number of participants with change in inflammation (a panel of pro and anti-inflammatory cytokines). [6 months]
• Change in gcsf levels and EPO levels at baseline and completion of each cycle. [6 months]
• Proportion of participants completing treatment without major adverse effects; [6 months]
• Number of participants with change in peripheral blood CD34+ Hematopoietic Stem Cells count at 6months. [6 months]

Sex: All, ages: 18 Years to 70 Years

Inclusion Criteria:

1. Age 18-70 years
2. Decompensated cirrhosis patients
3. Uncomplicated ascites,
4. CTP ≤ 9B and MELD <16
5. BM Hematopoietic stem cell reserve > 0.4
6. Given informed consent

Exclusion Criteria:

1. Patients with age less than 18 years or more than 65 years
2. Lack of informed consent
3. Patients with a history of serious allergic reactions to the active component, filgrastim, other human granulocyte colony-stimulating factors, or any of the ingredients
4. Evidence of alcoholic hepatitis/active alcohol abuse last intake ≤ 3 months
5. Suspected autoimmune hepatitis (ANA/ASMA-positive in titers 1:80 and/ or IgG 1.5 times upper limit of normal),
6. Hemolytic anaemia -Sickle cell disease or thalassemia
7. Patients with Grade III ascites /complicated ascites
8. Patients with large spleen (size ≥ 15cm)
9. Recent variceal bleeding in less than 42 days
10. Patients with any focus of sepsis as proven by culture positivity or presence of spontaneous Bacterial Peritonitis (SBP)
11. H/o Seizures
12. Hepatocellular Carcinoma (HCC) or other malignancy
13. Acute Kidney Injury (AKI) with serum Creatinine >1.5 mg/ dl,
14. Multi-organ failure,
15. Hepatic Encephalopathy or prior history of HE in less than 6months
16. HIV seropositivity,
17. Uncontrolled essential hypertension, CAD /Stroke
18. Massive hydrothorax
19. Pregnancy
20. Viral etiology of liver disease
21. Chronic kidney disease
22. Portal vein thrombosis
23. Planned for LT
24. Bone marrow hematopoietic stem cells < 0.4

• Dr Manoj Kumar Sharma, DM, Study director, Institute of Liver and Biliary Sciences, India