Efficacy of Granulocyte Colony-stimulating Factor and Erythropoetin for Patients With Acute-on-chronic Liver Failure
Condition: Acute on Chronic Hepatic Failure
MeSH terms: Liver Failure; Hepatic Insufficiency; End Stage Liver Disease; Acute-On-Chronic Liver Failure
Study type: Interventional
Phase: Phase 3

Summary: 
      50 patients of Acute-on-chronic liver failure (ACLF) will be enrolled and randomized into
      G-CSF+EPO or Placebo arms

      Treatment protocol To administer G-CSF (in prefilled syringe) at a dose of 5 µg/kg s/c at
      days 1, 2, 3, 4, 5 and then every 3rd day till day 28 (total 12 doses), along with
      Darbopoetin alpha 100 mcg/ week (in prefilled syringe) for 4 weeks (total 4 doses).

      Standard medical therapy included as per requirement lactulose, bowel wash, albumin,
      terlipressin, antibiotics (if indicated) will be continued and recorded. Pentoxiphylline in
      alcoholic hepatitis and Tenofovir in Hep B reactivation Controls: Standard medical therapy
      will be given along with placebo in similar prefilled syringes.

      Follow up Physical examination will be done daily, after 1 week and at 4 weeks, at 2 months,
      at 3 months and at 6 months CBC on alternate day for 1 week, at end of 1 week and then at end
      of 4 weeks , at 2 months, at 3 months and at 6 months

      KFT on alternate day for 1 week, at end of 1 week and then at end of 4 weeks, at 2 months, at
      3 months and at 6 months LFT along with PT/INR on alternate day for 1 week, at end of 1 week
      and then at end of 4 weeks, at 2 months, at 3 months and at 6 months AFP at baseline, after 4
      weeks, at 3 months and at 6 months Liver regenerative potential efficacy testing at baseline
      and after 4 weeks
    

Detailed description: 
      50 patients of ACLF will be enrolled and randomized into G-CSF+EPO or Placebo arms

      Baseline investigations:

        -  Hematology

             -  CBC, Prothrombin time and INR

             -  Peripheral smear, Retics

        -  Biochemistry

             -  Liver function testing, AFP

             -  Kidney function test

        -  Etiology of acute event:

             -  Infectious etiology: IgM anti HAV, IgM anti HEV, IgM anti HBc ( If HBsAg +ve), IgM
                anti HDV ( If HBsAg +ve), HEV RNA

             -  Non Infectious etiology: Alcohol binging in last 4 weeks, hepatotoxic drugs, ANA
                (>1: 80), IgG , surgeries in past 4 weeks, acute variceal bleed within 4 weeks

        -  Etiology of underlying chronic liver disease :

             -  Infectious etiology: total antiHBc, anti HCV, HCV RNA, HBV DNA

             -  Non infectious etiology: Autoimmune markers, copper studies, iron studies, HOMA IR,
                FBS Ascitic fluid analysis ( wherever its possible) UGI endoscopy Imaging USG
                abdomen with Doppler for spleno-portal axis CECT- Triple phase upper abdomen Liver
                regenerative potential efficacy testing (wherever it is possible) Histology ( by
                transjugular liver biopsy) Liver Dendritic cells ( CD11c, CD40, CD 54, CD 123, BDCA
                2 staining) by flow cytometry CD 34+ cells and CD 133+ cells measurement in hepatic
                venous blood, peripheral blood and liver biopsy by flow cytometry Markers of
                proliferation like ki- 67, proliferating cell nuclear antigen (PCNA) in hepatic
                venous blood and liver biopsy Markers of angiogenesis like VEGF, v WF in hepatic
                venous blood Measurement of Hepatic venous pressure gradient ( HVPG)

      Treatment protocol To administer G-CSF (in prefilled syringe) at a dose of 5 µg/kg s/c at
      days 1, 2, 3, 4, 5 and then every 3rd day till day 28 (total 12 doses), along with
      Darbopoetin alpha 100 mcg/ week (in prefilled syringe) for 4 weeks (total 4 doses).

      Standard medical therapy included as per requirement lactulose, bowel wash, albumin,
      terlipressin, antibiotics (if indicated) will be continued and recorded. Pentoxiphylline in
      alcoholic hepatitis and Tenofovir in Hep B reactivation Controls: Standard medical therapy
      will be given along with placebo in similar prefilled syringes.

      Follow up Physical examination will be done daily, after 1 week and at 4 weeks, at 2 months,
      at 3 months and at 6 months CBC on alternate day for 1 week, at end of 1 week and then at end
      of 4 weeks , at 2 months, at 3 months and at 6 months

      KFT on alternate day for 1 week, at end of 1 week and then at end of 4 weeks, at 2 months, at
      3 months and at 6 months LFT along with PT/INR on alternate day for 1 week, at end of 1 week
      and then at end of 4 weeks, at 2 months, at 3 months and at 6 months AFP at baseline, after 4
      weeks, at 3 months and at 6 months Liver regenerative potential efficacy testing at baseline
      and after 4 weeks
    

Intervention name(s): Granulocyte Colony-stimulating Factor (G-CSF) and Erythropoetin (EPO); Placebo
Intervention type(s): Drug; Drug
Intervention description(s): G-CSF (in prefilled syringe) at a dose of 5 µg/kg s/c at days 1, 2, 3, 4, 5 and then every 3rd day till day 28 (total 12 doses), along with Darbopoetin alpha 100 mcg/ week (in prefilled syringe) for 4 weeks (total 4 doses).; Placebo 1 (in prefilled syringe) s/c at days 1, 2, 3, 4, 5 and then every 3rd day till day 28 (total 12 doses), along with Placebo 2 every week (in prefilled syringe) for 4 weeks (total 4 doses).
Intervention MeSH terms: Epoetin Alfa; Lenograstim
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Primary purpose: Treatment
Keywords: Acute-on-chronic liver failure; ACLF; cirrhosis; acute hepatitis