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
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 发起方
- 入组人数
- 64
- 试验地点
- 1
- 主要终点
- 2-month survival rate of null responder to steroid treatment and 6-month survival rate of partial responder to steroid treatment
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 21 Years 至 79 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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
研究组 & 干预措施
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.
干预措施: G-CSF (Filgrastim injection) (Drug)
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.
干预措施: steroid (Drug)
Placebo + steroid in partial responder
Patients who are randomized to prednisolone plus placebo treatment group in patients with partial responder to prednisolone therapy.
干预措施: steroid (Drug)
Placebo + steroid in partial responder
Patients who are randomized to prednisolone plus placebo treatment group in patients with partial responder to prednisolone therapy.
干预措施: placebo (Drug)
G-CSF in null responder to steroid
Patients who are randomized to G-CSF treatment group in patients with null responder to prednisolone therapy.
干预措施: G-CSF (Filgrastim injection) (Drug)
Placebo in null responder to steroid
Patients who are randomized to placebo treatment group in patients with null responder to prednisolone therapy.
干预措施: placebo (Drug)
结局指标
主要结局
2-month survival rate of null responder to steroid treatment and 6-month survival rate of partial responder to steroid treatment
时间窗: 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.
次要结局
- 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 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 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 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)
研究者
Dong Joon Kim
professor Dong Joon Kim
Chuncheon Sacred Heart Hospital