Granulocyte Colony Stimulating Factor (G-CSF) to Treat Acute-on-chronic Liver Failure

The acute on chronic liver failure (ACLF) is characterised by a severe deterioration of liver function due to a precipitating event on top of an underlying chronic liver disease. As therapeutic options are limited the mortality rate lies between 40 and 80% at 3 months. The granulocyte colony-stimulating factor (G-CSF) mobilized stem- as well as immune cells and improved liver function in preclinical trials. G-CSF treatment reduced the rate of infectious complications and significantly improved patients´ survival in acute on chronic liver failure, shown recently in small randomised studies. Thus, G-CSF is a promising treatment option that needs to be evaluated in a multi-centre controlled trial. The GRAFT trial will randomise patients with ACLF between standard of care with and without G-CSF. All participants will be followed for 12 months in order to evaluate safety and efficacy of G-CSF. If successful, the GRAFT trial has the potential to change clinical practice in acute on chronic liver failure.

Inclusion criteria

• Acute-on-chronic liver failure (ACLF) according to the consensus criteria recently defined by the CANONIC study group [Moreau 2013]. Patients with acute decompensation of cirrhosis [defined as acute development of one or more of the following: ascites (onset and/or worsening), hepatic encephalopathy (onset and/or worsening), gastrointestinal haemorrhage, bacterial infection] are classified as ACLF if one of the following applies:

• single kidney failure (serum creatinine level ≥ 2 mg/dl) or
• single failure of one of the following organ systems: liver, coagulation, circulation, or respiration, together with a serum creatinine level ranging from 1.5 to < 2.0 mg/dl and/or mild to moderate hepatic encephalopathy or
• single cerebral failure together with serum creatinine level ranging from 1.5 to < 2.0 mg/dl or
• two or more organ failures. Organ failures are defined according to the CLIF-C OFs [Jalan 2014].
• Age ≥ 18 years, male or female
• Written informed consent from patient, legal or authorized representative or a confirmation of justification of trial participation by an independent medical consultant PLEASE NOTE: In case of confirmation by the independent medical consultant a deferred informed consent from patient, legal or authorized representative has to be given

Exclusion criteria

• Prior not curatively treated or active malignancies
• Sickle cell disease
• septic shock, defined by the following symptom complex: bacteraemia AND SIRS AND shock
• WBC-count of > 50 x 109/L
• Known HIV infection
• Known intolerance to filgrastim
• Suspected lack of compliance
• Pregnant or nursing women
• Fertile women (within two years of their last menstruation) without appropriate contraceptive measures (implanon, injections, oral contraceptives, intrauterine devices, partner with vasectomy) while participating in the trial (participants using a hormone-based method have to be informed of possible effects from the trial medication on contraception).
• Participation in other interventional trials