Efficacy and Safety of G-CSF in Patients With Severe Alcoholic Hepatitis With Null or Partial Response to Steroid (GraCiAH)

Chuncheon Sacred Heart Hospital

Status and phase: Terminated; Phase 3

Conditions: Alcoholic Hepatitis

Treatments: Drug: placebo; Drug: steroid; Drug: G-CSF (Filgrastim injection)

Study type: Interventional

Funder types: Other

Identifiers

NCT02442180

2014-6

Details and patient eligibility

About

Steroid is the treatment of choice in patients with severe alcoholic hepatitis. However, null- or partial responder of steroid treatment is recommended to consider liver transplantation. The yearly demand for liver transplants far exceeds the supply of available organs and alcoholic liver disease has been a controversial indication for transplantation. Granulocyte-Colony Stimulating Factor (G-CSF) has been reported to have effect of proliferation of hepatic progenitors in alcoholic steatohepatitis. The aim of this study is to investigate the efficacy of G-CSF in patients with severe alcoholic hepatitis with null or partial response to steroid.

Full description

Severe alcoholic hepatitis is defined as alcoholic hepatitis patients having discriminant function (DF) score over 32 or accompanying hepatic encephalopathy. These patients have shown poor prognosis of 28 day mortality as 30 to 50% without treatment. Steroid (prednisolone 40mg/day for 28 days) is the treatment of choice in patients with severe alcoholic hepatitis. Alcoholic hepatitis with modified DF score greater than or equal to 32 or model for end-stage liver disease (MELD) score over 21 or with hepatic encephalopathy are indications. However, null- or partial responder of steroid treatment is recommended to consider liver transplantation. The yearly demand for liver transplants far exceeds the supply of available organs and alcoholic liver disease has been a controversial indication for transplantation. Even in the responders of steroid treatment, the mortality is still 20% (from 40% without treatment to 20% with steroid treatment). There is a need for development of new treatment for this catastrophic disease. Granulocyte-Colony Stimulating Factor (G-CSF) has been reported to have effect of proliferation of hepatic progenitors in alcoholic steatohepatitis. The aim of this study is to investigate the efficacy of G-CSF in patients with severe alcoholic hepatitis with null or partial response to steroid.

Enrollment: 64 patients

Sex: All

Ages: 21 to 79 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria: Patients with

• Clinical significant alcohol intake history (men over 50g within 3 months, women over 40g within 3 months)
• modified DF score greater than or equal to 32
• Transjugular liver biopsy shows typical feature of alcoholic hepatitis or meet the clinical diagnosis (total serum bilirubin level over 5 mg/dL, aspartate aminotransferase/alanine aminotransferase ratio >2, aspartate aminotransferase < 300 IU/L)
• Included patients should meet the all above criteria and Lille score > 0.16 at the day 7 of prednisolone 40mg (or 32 mg of methylprednisolone) daily treatment.

Exclusion Criteria: Patients with

• hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (anti-HCV), or anti-human immunodeficiency virus (HIV) (+)
• Malignancy including hepatocellular carcinoma
• Portal vein thrombosis, hemochromatosis, autoimmune hepatitis, Wilson's disease, alpha-1-antitrypsin deficiency
• Pregnancy, breast feeding, or who refuses contraception, or who cannot do contraception
• History of adverse event including allergic response, hypersensitivity to G-CSF
• Hypovolemic shock due to gastrointestinal hemorrhage or who need packed red blood cell (RBC) transfusion more than 3 units or increased modified discriminant factor (DF) score greater or equal to 32 from below 32 due to gastrointestinal hemorrhage
• Sepsis or uncontrolled acute infection
• Hepatic encephalopathy grade 3-4
• History of steroid or pentoxifylline treatment within 3 months
• Myeloblast on peripheral blood smear test
• Critical comorbidities (type I hepatorenal syndrome, serum creatinine >2.5mg/dL, heart failure, pulmonary disease, psychiatric disease, acute pancreatitis etc.)
• Who refuses to participate in clinical trial

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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64 participants in 4 patient groups, including a placebo group

G-CSF + steroid in partial responder

Experimental group

Description:

Patients who are randomized to prednisolone plus G-CSF treatment group in patients with partial responder to prednisolone therapy.

Treatment:

Drug: G-CSF (Filgrastim injection)

Drug: steroid

Placebo + steroid in partial responder

Placebo Comparator group

Description:

Patients who are randomized to prednisolone plus placebo treatment group in patients with partial responder to prednisolone therapy.

Treatment:

Drug: steroid

Drug: placebo

G-CSF in null responder to steroid

Experimental group

Description:

Patients who are randomized to G-CSF treatment group in patients with null responder to prednisolone therapy.

Treatment:

Drug: G-CSF (Filgrastim injection)

Placebo in null responder to steroid

Placebo Comparator group

Description:

Patients who are randomized to placebo treatment group in patients with null responder to prednisolone therapy.

Treatment:

Drug: placebo