Clinical trial NCT02442180: Efficacy and Safety of G-CSF in Patients With Severe Alcoholic Hepatitis With Null or Partial Response to Steroid
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
Overall status: TERMINATED
Phase: PHASE3
Conditions: Alcoholic Hepatitis
Lead sponsor: Chuncheon Sacred Heart Hospital
Sponsor class: OTHER
First posted: 2015-05-13
Enrollment: 64
Sex: ALL
Minimum age (years): 21
Maximum age (years): 79
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: 2-month survival rate of null responder to steroid treatment and 6-month survival rate of partial responder to steroid treatment
timeFrame: 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:
measure: Hepatic function improvement as assessed by the Child-Pugh score
timeFrame: day 0,1,3,7,9,11,14,17,20,23,26,29,32,35,60,90,120,150,180
measure: Hepatic function improvement as assessed by the MELD score
timeFrame: day 0,1,3,7,9,11,14,17,20,23,26,29,32,35,60,90,120,150,180
measure: Hepatic function improvement as assessed by the Chronic Liver Failure (CLIF)-Sequential Organ Failure Assessment (SOFA) score
timeFrame: day 0,1,3,7,9,11,14,17,20,23,26,29,32,35,60,90,120,150,180
measure: Hepatic function improvement as assessed by the Fraction of Cluster of differentiation (CD34)+ cell in peripheral blood
timeFrame: day0,7,35
measure: Hepatic function improvement as assessed by the Alcoholic Hepatitis Histology score
timeFrame: day0,35
Other outcomes:
Locations:
city: Chuncheon
country: Korea, Republic of
facility: Chuncheon Sacred Heart hospital
Study officials:
affiliation: Hallym Universitiy College of Medicine, Chuncheon Sacred Heart hospital, Chuncheon, South Korea
name: Dong Joon Kim, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
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.