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

Primary Purpose

Acute-On-Chronic Liver Failure

Status
Completed
Phase
Not Applicable
Locations
Germany
Study Type
Interventional
Intervention
G-CSF
Standard therapy
Sponsored by
University of Leipzig
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute-On-Chronic Liver Failure

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University Hospital of Leipzig
  • Universitätsklinikum Aachen
  • Charité-Campus Virchow-Klinikum
  • Universitätsklinikum Bonn
  • Universitätsklinikum Düsseldorf
  • Universitätsklinikum Essen
  • Klinikum der J.W. Goethe- Universität
  • Universitätsklinik Freiburg
  • Universitätsklinikum Halle (Saale)
  • Medizinische Hochschule Hannover
  • Universitätsklinikum Heidelberg
  • Universitätsklinikum des Saarlandes
  • Universitätsklinikum Jena
  • Universitätsklinikum Schleswig-Holstein
  • Universitätsklinikum KÖLN
  • HELIOS Park-Klinikum Leipzig
  • Klinikum St. Georg gGmbH
  • Universitätsklinikum Magdeburg AöR
  • Universitätsmedizin Mainz
  • Universitätsklinikum Tübingen
  • St. Josefs-Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

G-CSF + Standard therapy

Standard therapy

Arm Description

Standard care of acute-on-chronic liver failure and application of G-CSF

Standard care of acute-on-chronic liver failure

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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

Full Information

First Posted
January 22, 2016
Last Updated
June 14, 2022
Sponsor
University of Leipzig
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1. Study Identification

Unique Protocol Identification Number
NCT02669680
Brief Title
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

2. Study Status

Record Verification Date
June 2022
Overall Recruitment Status
Completed
Study Start Date
February 2016 (Actual)
Primary Completion Date
March 2020 (Actual)
Study Completion Date
March 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Leipzig

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute-On-Chronic Liver Failure

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
176 (Actual)

8. Arms, Groups, and Interventions

Arm Title
G-CSF + Standard therapy
Arm Type
Experimental
Arm Description
Standard care of acute-on-chronic liver failure and application of G-CSF
Arm Title
Standard therapy
Arm Type
Active Comparator
Arm Description
Standard care of acute-on-chronic liver failure
Intervention Type
Drug
Intervention Name(s)
G-CSF
Other Intervention Name(s)
Filgrastim
Intervention Description
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
Intervention Type
Other
Intervention Name(s)
Standard therapy
Primary Outcome Measure Information:
Title
Transplant-free survival up to 90 days (death or transplant count as events)
Time Frame
90 days
Secondary Outcome Measure Information:
Title
Overall survival time until the end of follow-up
Time Frame
360 days
Title
Transplant-free survival time until the end of follow-up
Time Frame
360 days
Title
Complications of ACLF (hepatorenal syndrome (HRS), variceal bleeding, ascites, hepatic encephalopathy (HE))
Time Frame
90 days/360 days
Title
Infections (proven infection necessitating systemic use of antibiotics)
Time Frame
90 days/360 days
Title
Liver function - assessed by MELD-Score - during the course of treatment and follow-up
Time Frame
360 days
Title
Liver function - assessed by Child-Pugh-Score - during the course of treatment and follow-up
Time Frame
360 days
Title
Duration of the initial hospital stay
Time Frame
up to 360 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Thomas Berg, Prof.
Organizational Affiliation
University Hospital of Leipzig;
Official's Role
Study Director
Facility Information:
Facility Name
University Hospital of Leipzig
City
Leipzig
State/Province
Sachsen
ZIP/Postal Code
04103
Country
Germany
Facility Name
Universitätsklinikum Aachen
City
Aachen
Country
Germany
Facility Name
Charité-Campus Virchow-Klinikum
City
Berlin
Country
Germany
Facility Name
Universitätsklinikum Bonn
City
Bonn
Country
Germany
Facility Name
Universitätsklinikum Düsseldorf
City
Düsseldorf
Country
Germany
Facility Name
Universitätsklinikum Essen
City
Essen
Country
Germany
Facility Name
Klinikum der J.W. Goethe- Universität
City
Frankfurt
Country
Germany
Facility Name
Universitätsklinik Freiburg
City
Freiburg
Country
Germany
Facility Name
Universitätsklinikum Halle (Saale)
City
Halle
Country
Germany
Facility Name
Medizinische Hochschule Hannover
City
Hannover
Country
Germany
Facility Name
Universitätsklinikum Heidelberg
City
Heidelberg
Country
Germany
Facility Name
Universitätsklinikum des Saarlandes
City
Homburg
Country
Germany
Facility Name
Universitätsklinikum Jena
City
Jena
Country
Germany
Facility Name
Universitätsklinikum Schleswig-Holstein
City
Kiel
Country
Germany
Facility Name
Universitätsklinikum KÖLN
City
Köln
Country
Germany
Facility Name
HELIOS Park-Klinikum Leipzig
City
Leipzig
Country
Germany
Facility Name
Klinikum St. Georg gGmbH
City
Leipzig
Country
Germany
Facility Name
Universitätsklinikum Magdeburg AöR
City
Magdeburg
Country
Germany
Facility Name
Universitätsmedizin Mainz
City
Mainz
Country
Germany
Facility Name
Universitätsklinikum Tübingen
City
Tübingen
Country
Germany
Facility Name
St. Josefs-Hospital
City
Wiesbaden
Country
Germany

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
34364917
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.
Results Reference
result
Links:
URL
https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-002212-32/results
Description
Link to the EU trials register to the GRAFT results

Learn more about this trial

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

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