Clinical trial NCT02669680: Granulocyte Colony Stimulating Factor (G-CSF) to Treat Acute-on-chronic Liver Failure
Official title: Granulocyte Colony Stimulating Factor (G-CSF) to Treat Acute-on-chronic Liver Failure: A Multicentre Randomized Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Acute-On-Chronic Liver Failure
Lead sponsor: University of Leipzig
Sponsor class: OTHER
First posted: 2016-02-01
Enrollment: 176
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Multicentre, open, randomised, and controlled trial conducted in patients diagnosed with acute on chronic liver failure (ACLF) who meet inclusion/exclusion criteria.The objective of GRAFT-trial is to evaluate efficacy and safety of subcutaneously administered granulocyte colony-stimulating factor (G-CSF) in patients with ACLF. All patients will receive standard medical care for ACLF according to the guidelines. Patients in the experimental arm additional receive subcutaneous injections of G-CSF.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

1. 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 \[Jalan 2014\].
2. Age ≥ 18 years, male or female
3. 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:

1. Prior not curatively treated or active malignancies
2. Sickle cell disease
3. septic shock, defined by the following symptom complex: bacteraemia AND SIRS AND shock
4. WBC-count of \> 50 x 109/L
5. Known HIV infection
6. Known intolerance to filgrastim
7. Suspected lack of compliance
8. Pregnant or nursing women
9. 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).
10. Participation in other interventional trials

Primary outcomes:
measure: Transplant-free survival up to 90 days (death or transplant count as events)
timeFrame: 90 days
Secondary outcomes:
measure: Overall survival time until the end of follow-up
timeFrame: 360 days
measure: Transplant-free survival time until the end of follow-up
timeFrame: 360 days
measure: Complications of ACLF (hepatorenal syndrome (HRS), variceal bleeding, ascites, hepatic encephalopathy (HE))
timeFrame: 90 days/360 days
measure: Infections (proven infection necessitating systemic use of antibiotics)
timeFrame: 90 days/360 days
measure: Liver function - assessed by MELD-Score - during the course of treatment and follow-up
timeFrame: 360 days
measure: Liver function - assessed by Child-Pugh-Score - during the course of treatment and follow-up
timeFrame: 360 days
measure: Duration of the initial hospital stay
timeFrame: up to 360 days
Other outcomes:
Locations:
city: Leipzig
country: Germany
facility: University Hospital of Leipzig
state: Sachsen
city: Aachen
country: Germany
facility: Universitätsklinikum Aachen
city: Berlin
country: Germany
facility: Charité-Campus Virchow-Klinikum
city: Bonn
country: Germany
facility: Universitätsklinikum Bonn
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Frankfurt
country: Germany
facility: Klinikum der J.W. Goethe- Universität
city: Freiburg
country: Germany
facility: Universitätsklinik Freiburg
city: Halle
country: Germany
facility: Universitätsklinikum Halle (Saale)
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
city: Homburg
country: Germany
facility: Universitätsklinikum des Saarlandes
city: Jena
country: Germany
facility: Universitätsklinikum Jena
city: Kiel
country: Germany
facility: Universitätsklinikum Schleswig-Holstein
city: Köln
country: Germany
facility: Universitätsklinikum KÖLN
city: Leipzig
country: Germany
facility: HELIOS Park-Klinikum Leipzig
city: Leipzig
country: Germany
facility: Klinikum St. Georg gGmbH
city: Magdeburg
country: Germany
facility: Universitätsklinikum Magdeburg AöR
city: Mainz
country: Germany
facility: Universitätsmedizin Mainz
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen
city: Wiesbaden
country: Germany
facility: St. Josefs-Hospital
Study officials:
affiliation: University Hospital of Leipzig;
name: Thomas Berg, Prof.
role: STUDY_DIRECTOR
References:
citation: Engelmann C, Herber A, Franke A, Bruns T, Reuken P, Schiefke I, Zipprich A, Zeuzem S, Goeser T, Canbay A, Berg C, Trebicka J, Uschner FE, Chang J, Mueller T, Aehling N, Schmelzle M, Splith K, Lammert F, Lange CM, Sarrazin C, Trautwein C, Manns M, Haussinger D, Pfeiffenberger J, Galle PR, Schmiedeknecht A, Berg T. Granulocyte-colony stimulating factor (G-CSF) to treat acute-on-chronic liver failure: A multicenter randomized trial (GRAFT study). J Hepatol. 2021 Dec;75(6):1346-1354. doi: 10.1016/j.jhep.2021.07.033. Epub 2021 Aug 5.