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

Not Applicable

Completed

• Conditions: Acute-On-Chronic Liver Failure
• Interventions: Other: Standard therapy; Drug: G-CSF

• Registration Number: NCT02669680
• Lead Sponsor: University of Leipzig

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.

Study Timeline

• Study First Submitted: 2016-01-22
• Study First Submitted QC: 2016-01-29
• Study Start: 2016-02
• Study First Posted: 2016-02-01
• Primary Completion: 2020-03
• Study Completion: 2020-03
• Status Verified: 2022-06
• Last Update Submitted: 2022-06-14
• Last Update Posted: 2022-06-28

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 176

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Standard therapy	Standard therapy	Standard care of acute-on-chronic liver failure
G-CSF + Standard therapy	Standard therapy	Standard care of acute-on-chronic liver failure and application of G-CSF
G-CSF + Standard therapy	G-CSF	Standard care of acute-on-chronic liver failure and application of G-CSF

Primary Outcome Measures

Name	Time	Method
Transplant-free survival up to 90 days (death or transplant count as events)	90 days

Secondary Outcome Measures

Name	Time	Method
Infections (proven infection necessitating systemic use of antibiotics)	90 days/360 days
Liver function - assessed by MELD-Score - during the course of treatment and follow-up	360 days
Transplant-free survival time until the end of follow-up	360 days
Liver function - assessed by Child-Pugh-Score - during the course of treatment and follow-up	360 days
Duration of the initial hospital stay	up to 360 days
Overall survival time until the end of follow-up	360 days
Complications of ACLF (hepatorenal syndrome (HRS), variceal bleeding, ascites, hepatic encephalopathy (HE))	90 days/360 days

Trial Locations

Locations (21)

Universitätsklinikum Essen; 🇩🇪 Essen, Germany

Klinikum der J.W. Goethe- Universität; 🇩🇪 Frankfurt, Germany

Charité-Campus Virchow-Klinikum; 🇩🇪 Berlin, Germany

Universitätsklinikum Bonn; 🇩🇪 Bonn, Germany

Medizinische Hochschule Hannover; 🇩🇪 Hannover, Germany

HELIOS Park-Klinikum Leipzig; 🇩🇪 Leipzig, Germany

Universitätsklinikum Heidelberg; 🇩🇪 Heidelberg, Germany

Klinikum St. Georg gGmbH; 🇩🇪 Leipzig, Germany

Universitätsklinikum Düsseldorf; 🇩🇪 Düsseldorf, Germany

Universitätsklinikum Schleswig-Holstein; 🇩🇪 Kiel, Germany

Universitätsklinikum KÖLN; 🇩🇪 Köln, Germany

University Hospital of Leipzig; 🇩🇪 Leipzig, Sachsen, Germany

Universitätsklinikum Aachen; 🇩🇪 Aachen, Germany

Universitätsklinik Freiburg; 🇩🇪 Freiburg, Germany

Universitätsklinikum des Saarlandes; 🇩🇪 Homburg, Germany

Universitätsklinikum Halle (Saale); 🇩🇪 Halle, Germany

Universitätsklinikum Magdeburg AöR; 🇩🇪 Magdeburg, Germany

Universitätsklinikum Tübingen; 🇩🇪 Tübingen, Germany

St. Josefs-Hospital; 🇩🇪 Wiesbaden, Germany

Universitätsklinikum Jena; 🇩🇪 Jena, Germany

Universitätsmedizin Mainz; 🇩🇪 Mainz, Germany