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

Primary Purpose

Alcoholic Hepatitis

Status
Terminated
Phase
Phase 3
Locations
Korea, Republic of
Study Type
Interventional
Intervention
G-CSF (Filgrastim injection)
steroid
placebo
Sponsored by
Chuncheon Sacred Heart Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Alcoholic Hepatitis

Eligibility Criteria

21 Years - 79 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Chuncheon Sacred Heart hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Placebo Comparator

Experimental

Placebo Comparator

Arm Label

G-CSF + steroid in partial responder

Placebo + steroid in partial responder

G-CSF in null responder to steroid

Placebo in null responder to steroid

Arm Description

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

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

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

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

Outcomes

Primary Outcome Measures

2-month survival rate of null responder to steroid treatment and 6-month survival rate of partial responder to steroid treatment
Survival status can be determined by the occurrence of mortality regardless of any cause of death.

Secondary Outcome Measures

Hepatic function improvement as assessed by the Child-Pugh score
Hepatic function is defined as the Child-Pugh score.
Hepatic function improvement as assessed by the MELD score
Hepatic function is defined as the MELD score.
Hepatic function improvement as assessed by the Chronic Liver Failure (CLIF)-Sequential Organ Failure Assessment (SOFA) score
Hepatic function is defined as the CLIF-SOFA score.
Hepatic function improvement as assessed by the Fraction of Cluster of differentiation (CD34)+ cell in peripheral blood
Hepatic function is defined as the CD34+ cell count percentage in circulating blood.
Hepatic function improvement as assessed by the Alcoholic Hepatitis Histology score
Hepatic function is defined as histological scoring system of alcoholic hepatitis (AHHS).

Full Information

First Posted
May 2, 2015
Last Updated
August 4, 2022
Sponsor
Chuncheon Sacred Heart Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT02442180
Brief Title
Efficacy and Safety of G-CSF in Patients With Severe Alcoholic Hepatitis With Null or Partial Response to Steroid
Acronym
GraCiAH
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
August 2022
Overall Recruitment Status
Terminated
Why Stopped
failure to recruit eligible patients
Study Start Date
July 2015 (Actual)
Primary Completion Date
July 2022 (Actual)
Study Completion Date
July 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Chuncheon Sacred Heart Hospital

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Alcoholic Hepatitis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
64 (Actual)

8. Arms, Groups, and Interventions

Arm Title
G-CSF + steroid in partial responder
Arm Type
Experimental
Arm Description
Patients who are randomized to prednisolone plus G-CSF treatment group in patients with partial responder to prednisolone therapy.
Arm Title
Placebo + steroid in partial responder
Arm Type
Placebo Comparator
Arm Description
Patients who are randomized to prednisolone plus placebo treatment group in patients with partial responder to prednisolone therapy.
Arm Title
G-CSF in null responder to steroid
Arm Type
Experimental
Arm Description
Patients who are randomized to G-CSF treatment group in patients with null responder to prednisolone therapy.
Arm Title
Placebo in null responder to steroid
Arm Type
Placebo Comparator
Arm Description
Patients who are randomized to placebo treatment group in patients with null responder to prednisolone therapy.
Intervention Type
Drug
Intervention Name(s)
G-CSF (Filgrastim injection)
Other Intervention Name(s)
Filgrastim (brand name), Recombinant Filgrastim
Intervention Description
G-CSF (Filgrastim injection) 5ug/kg subcutaneous injection daily for 5 days and every 3 days (total 12 doses)
Intervention Type
Drug
Intervention Name(s)
steroid
Other Intervention Name(s)
prednisolone or methylprednisolone
Intervention Description
oral prednisolone 40mg qd or iv methylprednisolone 32 mg if oral medication is not tolerable
Intervention Type
Drug
Intervention Name(s)
placebo
Other Intervention Name(s)
normal saline
Intervention Description
equivalent to G-CSF doses
Primary Outcome Measure Information:
Title
2-month survival rate of null responder to steroid treatment and 6-month survival rate of partial responder to steroid treatment
Description
Survival status can be determined by the occurrence of mortality regardless of any cause of death.
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
Secondary Outcome Measure Information:
Title
Hepatic function improvement as assessed by the Child-Pugh score
Description
Hepatic function is defined as 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
Title
Hepatic function improvement as assessed by the MELD score
Description
Hepatic function is defined as 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
Title
Hepatic function improvement as assessed by the Chronic Liver Failure (CLIF)-Sequential Organ Failure Assessment (SOFA) score
Description
Hepatic function is defined as the CLIF-SOFA score.
Time Frame
day 0,1,3,7,9,11,14,17,20,23,26,29,32,35,60,90,120,150,180
Title
Hepatic function improvement as assessed by the Fraction of Cluster of differentiation (CD34)+ cell in peripheral blood
Description
Hepatic function is defined as the CD34+ cell count percentage in circulating blood.
Time Frame
day0,7,35
Title
Hepatic function improvement as assessed by the Alcoholic Hepatitis Histology score
Description
Hepatic function is defined as histological scoring system of alcoholic hepatitis (AHHS).
Time Frame
day0,35

10. Eligibility

Sex
All
Minimum Age & Unit of Time
21 Years
Maximum Age & Unit of Time
79 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Dong Joon Kim, M.D., Ph.D.
Organizational Affiliation
Hallym Universitiy College of Medicine, Chuncheon Sacred Heart hospital, Chuncheon, South Korea
Official's Role
Principal Investigator
Facility Information:
Facility Name
Chuncheon Sacred Heart hospital
City
Chuncheon
Country
Korea, Republic of

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
30577864
Citation
Cho Y, Park YS, Kim HY, Kim W, Lee HJ, Kim DJ. Efficacy of granulocyte colony stimulating factor in patients with severe alcoholic hepatitis with partial or null response to steroid (GRACIAH trial): study protocol for a randomized controlled trial. Trials. 2018 Dec 22;19(1):696. doi: 10.1186/s13063-018-3092-7.
Results Reference
derived

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

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