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

August 4, 2022 updated by: Dong Joon Kim, Chuncheon Sacred Heart Hospital

Efficacy and Safety of Granulocyte-colony Stimulating Factor in Patients With Severe Alcoholic Hepatitis With Null or Partial Response to Steroid: A Randomized, Double-blind, Placebo-controlled, Nationwide Multi-center Study

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.

Study Overview

Detailed 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.

Study Type

Interventional

Enrollment (Actual)

64

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

19 years to 77 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: G-CSF + steroid in partial responder
Patients who are randomized to prednisolone plus G-CSF treatment group in patients with partial responder to prednisolone therapy.
G-CSF (Filgrastim injection) 5ug/kg subcutaneous injection daily for 5 days and every 3 days (total 12 doses)
Other Names:
  • Filgrastim (brand name), Recombinant Filgrastim
oral prednisolone 40mg qd or iv methylprednisolone 32 mg if oral medication is not tolerable
Other Names:
  • prednisolone or methylprednisolone
Placebo Comparator: Placebo + steroid in partial responder
Patients who are randomized to prednisolone plus placebo treatment group in patients with partial responder to prednisolone therapy.
oral prednisolone 40mg qd or iv methylprednisolone 32 mg if oral medication is not tolerable
Other Names:
  • prednisolone or methylprednisolone
equivalent to G-CSF doses
Other Names:
  • normal saline
Experimental: G-CSF in null responder to steroid
Patients who are randomized to G-CSF treatment group in patients with null responder to prednisolone therapy.
G-CSF (Filgrastim injection) 5ug/kg subcutaneous injection daily for 5 days and every 3 days (total 12 doses)
Other Names:
  • Filgrastim (brand name), Recombinant Filgrastim
Placebo Comparator: Placebo in null responder to steroid
Patients who are randomized to placebo treatment group in patients with null responder to prednisolone therapy.
equivalent to G-CSF doses
Other Names:
  • normal saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
2-month survival rate of null responder to steroid treatment and 6-month survival rate of partial responder to steroid treatment
Time Frame: After 2 months of G-CSF or placebo treatment in patients with null responder to steroid treatment and after 6 months of G-CSF+steroid or only steroid treatment in patients with partial responder to steroid treatment
Survival status can be determined by the occurrence of mortality regardless of any cause of death.
After 2 months of G-CSF or placebo treatment in patients with null responder to steroid treatment and after 6 months of G-CSF+steroid or only steroid treatment in patients with partial responder to steroid treatment

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Hepatic function improvement as assessed by the Child-Pugh score
Time Frame: day 0,1,3,7,9,11,14,17,20,23,26,29,32,35,60,90,120,150,180
Hepatic function is defined as the Child-Pugh score.
day 0,1,3,7,9,11,14,17,20,23,26,29,32,35,60,90,120,150,180
Hepatic function improvement as assessed by the MELD score
Time Frame: day 0,1,3,7,9,11,14,17,20,23,26,29,32,35,60,90,120,150,180
Hepatic function is defined as the MELD score.
day 0,1,3,7,9,11,14,17,20,23,26,29,32,35,60,90,120,150,180
Hepatic function improvement as assessed by the Chronic Liver Failure (CLIF)-Sequential Organ Failure Assessment (SOFA) score
Time Frame: day 0,1,3,7,9,11,14,17,20,23,26,29,32,35,60,90,120,150,180
Hepatic function is defined as the CLIF-SOFA score.
day 0,1,3,7,9,11,14,17,20,23,26,29,32,35,60,90,120,150,180
Hepatic function improvement as assessed by the Fraction of Cluster of differentiation (CD34)+ cell in peripheral blood
Time Frame: day0,7,35
Hepatic function is defined as the CD34+ cell count percentage in circulating blood.
day0,7,35
Hepatic function improvement as assessed by the Alcoholic Hepatitis Histology score
Time Frame: day0,35
Hepatic function is defined as histological scoring system of alcoholic hepatitis (AHHS).
day0,35

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Dong Joon Kim, M.D., Ph.D., Hallym Universitiy College of Medicine, Chuncheon Sacred Heart hospital, Chuncheon, South Korea

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 1, 2015

Primary Completion (Actual)

July 1, 2022

Study Completion (Actual)

July 1, 2022

Study Registration Dates

First Submitted

May 2, 2015

First Submitted That Met QC Criteria

May 8, 2015

First Posted (Estimate)

May 13, 2015

Study Record Updates

Last Update Posted (Actual)

August 8, 2022

Last Update Submitted That Met QC Criteria

August 4, 2022

Last Verified

August 1, 2022

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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