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

Acute-On-Chronic Liver Failure Clinical Trial

Official title:

Granulocyte Colony Stimulating Factor (G-CSF) to Treat Acute-on-chronic Liver Failure: A Multicentre Randomized Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02669680
• Other study ID #: GRAFT
• Status: Completed
• Phase: N/A
• Start date: February 2016
• Est. completion date: March 2020

Study information

• Verified date: June 2022
• Source: University of Leipzig
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 176
• Est. completion date: March 2020
• Est. primary completion date: March 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acute-On-Chronic Liver Failure
• End Stage Liver Disease
• Hepatic Insufficiency
• Liver Failure

Intervention

Drug:
• G-CSF
G-CSF subcutaneously, 5 µg/kg daily on day 0-4, then every 3rd day over 26 days (days 7, 10, 13, 16, 19, 22, 25) = 12 doses

Other:
• Standard therapy

Locations

Country	Name	City	State
Germany	Universitätsklinikum Aachen	Aachen
Germany	Charité-Campus Virchow-Klinikum	Berlin
Germany	Universitätsklinikum Bonn	Bonn
Germany	Universitätsklinikum Düsseldorf	Düsseldorf
Germany	Universitätsklinikum Essen	Essen
Germany	Klinikum der J.W. Goethe- Universität	Frankfurt
Germany	Universitätsklinik Freiburg	Freiburg
Germany	Universitätsklinikum Halle (Saale)	Halle
Germany	Medizinische Hochschule Hannover	Hannover
Germany	Universitätsklinikum Heidelberg	Heidelberg
Germany	Universitätsklinikum des Saarlandes	Homburg
Germany	Universitätsklinikum Jena	Jena
Germany	Universitätsklinikum Schleswig-Holstein	Kiel
Germany	Universitätsklinikum KÖLN	Köln
Germany	HELIOS Park-Klinikum Leipzig	Leipzig
Germany	Klinikum St. Georg gGmbH	Leipzig
Germany	University Hospital of Leipzig	Leipzig	Sachsen
Germany	Universitätsklinikum Magdeburg AöR	Magdeburg
Germany	Universitätsmedizin Mainz	Mainz
Germany	Universitätsklinikum Tübingen	Tübingen
Germany	St. Josefs-Hospital	Wiesbaden

Sponsors (1)

Lead Sponsor	Collaborator
University of Leipzig

Country where clinical trial is conducted

Germany, 

References & Publications (1)

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, Häussing — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Transplant-free survival up to 90 days (death or transplant count as events)		90 days
Secondary	Overall survival time until the end of follow-up		360 days
Secondary	Transplant-free survival time until the end of follow-up		360 days
Secondary	Complications of ACLF (hepatorenal syndrome (HRS), variceal bleeding, ascites, hepatic encephalopathy (HE))		90 days/360 days
Secondary	Infections (proven infection necessitating systemic use of antibiotics)		90 days/360 days
Secondary	Liver function - assessed by MELD-Score - during the course of treatment and follow-up		360 days
Secondary	Liver function - assessed by Child-Pugh-Score - during the course of treatment and follow-up		360 days
Secondary	Duration of the initial hospital stay		up to 360 days

External Links

•   Link to the EU trials register to the GRAFT results