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

NCT02442180 | Terminated Phase 3 DMC

• 1 other identifier: 2014-6
• Study Type: interventional
• Target: 64
• Locations: 1 country
• Sites: 1

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.

Conditions

Alcoholic Hepatitis

Outcome Measures

Primary Outcomes (1)

• 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.

  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 Outcomes (5)

• Hepatic function improvement as assessed by 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

  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

  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

  day0,7,35

• Hepatic function improvement as assessed by the Alcoholic Hepatitis Histology score

  day0,35

Study Arms (4)

G-CSF + steroid in partial responder

EXPERIMENTAL

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

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

Placebo + steroid in partial responder

PLACEBO COMPARATOR

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

Drug: steroid; Drug: placebo

G-CSF in null responder to steroid

EXPERIMENTAL

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

Drug: G-CSF (Filgrastim injection)

Placebo in null responder to steroid

PLACEBO COMPARATOR

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

Drug: placebo

Interventions

G-CSF (Filgrastim injection) DRUG

G-CSF (Filgrastim injection) 5ug/kg subcutaneous injection daily for 5 days and every 3 days (total 12 doses)

Also known as: Filgrastim (brand name), Recombinant Filgrastim

G-CSF + steroid in partial responder; G-CSF in null responder to steroid

steroid DRUG

oral prednisolone 40mg qd or iv methylprednisolone 32 mg if oral medication is not tolerable

Also known as: prednisolone or methylprednisolone

G-CSF + steroid in partial responder; Placebo + steroid in partial responder

placebo DRUG

equivalent to G-CSF doses

Also known as: normal saline

Placebo + steroid in partial responder; Placebo in null responder to steroid

Eligibility Criteria

• Age: 21 Years - 79 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Chuncheon Sacred Heart Hospital: lead

Study Sites (1)

Chuncheon Sacred Heart hospital

Chuncheon, South Korea

Location

Related Publications (1)

• 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.

  PMID: 30577864 DERIVED

MeSH Terms

Conditions

Hepatitis, Alcoholic

Interventions

Granulocyte Colony-Stimulating Factor; Filgrastim; Steroids; Prednisolone; Methylprednisolone; Saline Solution

Condition Hierarchy (Ancestors)

Hepatitis; Liver Diseases; Digestive System Diseases; Liver Diseases, Alcoholic; Alcohol-Induced Disorders; Alcohol-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders

Intervention Hierarchy (Ancestors)

Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Fused-Ring Compounds; Polycyclic Compounds; Pregnadienetriols; Pregnadienes; Pregnanes; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Study Officials

• Dong Joon Kim, M.D., Ph.D.

  Hallym Universitiy College of Medicine, Chuncheon Sacred Heart hospital, Chuncheon, South Korea

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: professor Dong Joon Kim

Study Record Dates

• First Submitted: May 2, 2015
• First Posted: May 13, 2015
• Study Start: July 1, 2015
• Primary Completion: July 1, 2022
• Study Completion: July 1, 2022
• Last Updated: August 8, 2022

Record last verified: 2022-08

Data Sharing

• IPD Sharing: Will not share

Locations

KR (1)