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

Study Description

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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.

Condition or disease	Intervention/treatment	Phase
Acute-On-Chronic Liver Failure	Drug: G-CSF; Other: Standard therapy	Not Applicable

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 Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	292 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Granulocyte Colony Stimulating Factor (G-CSF) to Treat Acute-on-chronic Liver Failure: A Multicentre Randomized Trial
Study Start Date :	February 2016
Estimated Primary Completion Date :	January 2019
Estimated Study Completion Date :	January 2019

Arms and Interventions

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Arm	Intervention/treatment
Experimental: G-CSF + Standard therapy; Standard care of acute-on-chronic liver failure and application of G-CSF	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 Name: Filgrastim Other: Standard therapy
Active Comparator: Standard therapy; Standard care of acute-on-chronic liver failure	Other: Standard therapy

Outcome Measures

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Primary Outcome Measures :

1. Transplant-free survival up to 90 days (death or transplant count as events) [ Time Frame: 90 days ]

Secondary Outcome Measures :

1. Overall survival time until the end of follow-up [ Time Frame: 360 days ]
2. Transplant-free survival time until the end of follow-up [ Time Frame: 360 days ]
3. Complications of ACLF (hepatorenal syndrome (HRS), variceal bleeding, ascites, hepatic encephalopathy (HE)) [ Time Frame: 90 days/360 days ]
4. Infections (proven infection necessitating systemic use of antibiotics) [ Time Frame: 90 days/360 days ]
5. Liver function - assessed by MELD-Score - during the course of treatment and follow-up [ Time Frame: 360 days ]
6. Liver function - assessed by Child-Pugh-Score - during the course of treatment and follow-up [ Time Frame: 360 days ]
7. Duration of the initial hospital stay [ Time Frame: up to 360 days ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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 as defined by ACCP/SCCM consensus [Bone 1992]
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

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Contacts

Contact: Cornelius Engelmann, MD	0049 34197 ext 12330	Cornelius.Engelmann@medizin.uni-leipzig.de
Contact: Anett Schmiedeknecht, PhD	0049 34197 ext 16256	anett.schmiedeknecht@zks.uni-leipzig.de

Locations

Germany
University Hospital of Leipzig;	Recruiting
Leipzig, Sachsen, Germany, 04103
Contact: Cornelius Engelmann, MD
Klinikum St. Georg gGmbH	Recruiting
Leipzig, Sachsen, Germany, 04129
Contact: Ingolf Schiefke, Prof. MD

Sponsors and Collaborators

University of Leipzig

Investigators

Principal Investigator:	Cornelius Engelmann, MD	University Hospital of Leipzig;

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Cornelius Engelmann, MD, University of Leipzig
ClinicalTrials.gov Identifier:	NCT02669680 History of Changes
Other Study ID Numbers:	GRAFT
First Posted:	February 1, 2016
Last Update Posted:	September 7, 2016
Last Verified:	September 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Additional relevant MeSH terms:

Liver Failure; End Stage Liver Disease; Acute-On-Chronic Liver Failure; Hepatic Insufficiency; Liver Diseases; Digestive System Diseases	Liver Failure, Acute; Lenograstim; Adjuvants, Immunologic; Immunologic Factors; Physiological Effects of Drugs