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

Status

Status

Indicates the current recruitment status or the expanded access status.
Terminated

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
64

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • 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

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

17 years to 75 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

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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.
Drug: G-CSF (Filgrastim injection)
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
Drug: steroid
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.
Drug: steroid
oral prednisolone 40mg qd or iv methylprednisolone 32 mg if oral medication is not tolerable
Other Names:
  • prednisolone or methylprednisolone
Drug: placebo
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.
Drug: G-CSF (Filgrastim injection)
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.
Drug: placebo
equivalent to G-CSF doses
Other Names:
  • normal saline

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
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

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
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.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Chuncheon Sacred Heart Hospital

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • 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.

General Publications

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)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
July 1, 2015

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
July 1, 2022

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
July 1, 2022

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
May 2, 2015

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 8, 2015

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
May 13, 2015

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
August 8, 2022

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 4, 2022

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
August 1, 2022

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 2014-6

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

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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