Early Liver Support With MARS in Post-hepatectomy Liver Failure (ELISH)

Early Liver Support With MARS in Post-hepatectomy Liver Failure: a Randomized, Multicentre Trial

This is a prospective, randomized, open-label, multicentre study involving European centers with experience in the management of PHLF to assess the impact of early liver support with MARS on survival in patients with post-hepatectomy liver failure (PHLF).

Study Overview

• Status: Unknown
• Conditions: Liver Failure as A Complication of Care
• Intervention / Treatment: Device: Molecular Adsorbent Recirculating System; Other: Standard medical treatment (SMT)

Detailed Description

PHLF is a major risk factor for mortality in patients who underwent major hepatectomy. A specific treatment is yet not available. In a primary proof-of-concept study, it was shown that it is safe and feasible to use MARS in patients with PHLF early after hepatectomy. Survival was superior to a historical control group.

This study will include patients with early, primary PHLF (based on the 50:50 criteria) after major liver surgery. Patients will be randomized 1:1 to receive standard treatment alone or standard treatment + liver dialysis using the Molecular Adsorbent Recirculating System (MARS). Relevant outcome along with several physiological parameters will be assessed.

• Study Type: Interventional
• Enrollment (Anticipated): 44
• Phase: Not Applicable

Contacts and Locations

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients subjected for major liver surgery (4 or more Couinaud segments) or patients undergoing a 2nd, 3rd or 4th hepatic resection. Pre-operative chemotherapy and/or biological agents are allowed.
• Primary PHLF occurring early after surgery defined by the 50:50 criteria (from PO day 5 to day 14) or by the presence of hepatic encephalopathy grade 2 or more and the 50:50 criteria (from PO day 3 to 4).
• Written informed consent.

Exclusion Criteria:

• ALPPS (Associating Liver Partition and Portal vein Ligation for Staged hepatectomy) procedure.
• In patients with chronic liver disease presence of significant portal hypertension (hepatic venous pressure gradient ≥ 10 mmHg and/or Fibroscan ≥ 21kPa) prior to surgical intervention.
• Any contraindication for MARS therapy such as uncontrolled active bleeding, platelet counts <20.000 /µl or uncontrolled infection (presence of fever or adequate antibiotic therapy for less than 48h), septic shock, haemodynamic instability requiring inotropic support (noradrenaline > 1mg/h).
• PHLF occurring after post operative day 14.
• Secondary PHLF: post-operative liver failure secondary to vascular (outflow or inflow thrombosis) or septic problems.
• Persistant biliary complications (infected biloma, main biliary tree damage).
• Inability or unwilling of the patient or family to give informed consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Standard medical treatment + MARS; Patients assigned to the control arm will receive standard medical treatment (SMT) and liver dialysis using Molecular Adsorbent Recirculating System (MARS).	Device: Molecular Adsorbent Recirculating System; MARS therapy will start within 24-48 h after randomization and be given on 3 consecutive days in sessions of 8-12 h. The patients are observed for 2 days following the last session, with focus on bilirubin INR and signs of encephalopathy, and can thereafter receive 3 additional sessions in case of no or partial response to treatment.; Other Names: MARS 1116/1 - X-MARS
ACTIVE_COMPARATOR: Standard medical treatment; Patients assigned to the control arm will receive standard medical treatment (SMT) as specified in the study protocol.	Other: Standard medical treatment (SMT); Patient management and standard medical treatment (SMT) as specified in the study protocol.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
60 day survival	Overall survival rate from time of randomization to death from any cause	From randomization to death from any cause, assessed up to 60 days postop

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
28 day survival	Overall survival rate from time of randomization to death from any cause.	From randomization to death from any cause, assessed up to 28 days post-op
90 day survival	Overall survival rate from time of randomization to death from any cause.	From randomization to death from any cause, assessed up to 90 days postop
6 month survival	Overall survival rate from time of randomization to death from any cause.	From randomization to death from any cause, assessed up to 6 months postop
1 year survival	Overall survival rate from time of randomization to death from any cause.	From randomization to death from any cause, assessed up to 1 year.
Impact of MARS therapy on liver function	Impact of MARS therapy on liver function according to Child Pugh score (grade A, B and C)	From randomization up to 1 year.
Impact of MARS therapy on liver function	Impact of MARS therapy on liver function according to the Model for End-stage Liver Disease (MELD) score (5 groups: < 9, 10-19, 20-29, 30-39 and >40 points, lower points indicate improvement of liver function).	From randomization up to 1 year.
Impact of MARS therapy on extra-hepatic function (APACHE-II scoring)	Impact of MARS therapy on extra-hepatic function assessed by the Acute Physiology And Chronic Health Evaluation II (APACHE II) scoring system (range 0-71 points, lower points indicate less severe disease).	From randomization up to 1 year.
Impact of MARS therapy on extra-hepatic function (SOFA scoring)	Impact of MARS therapy on extra-hepatic function assessed by the Sequential Organ Failure Assessment (SOFA) scoring system (0-24 points, higher points indicate more severe disease).	From randomization up to 1 year.
Impact of MARS therapy on extra-hepatic function (CLIF-SOFA scoring)	Impact of MARS therapy on extra-hepatic function assessed by the Chronic Liver Failure-Sequential Organ Failure Assessment (CLIF-SOFA) scoring system (0-24 points, higher points indicate more severe disease).	From randomization up to 1 year.
Impact of MARS therapy on splanchnic hemodynamics assessed by direct estimation of portal blood flow.	Impact of MARS therapy on splanchnic hemodynamics assessed by direct estimation of portal blood flow (ml/min).	At randomization (day 0) and on day 10.
Impact of MARS therapy on splanchnic hemodynamics assessed by indirect estimation of portal blood flow using ultrasonography.	Impact of MARS therapy on splanchnic hemodynamics assessed by indirect estimation of portal blood flow using ultrasonography (ml/min).	At randomization (day 0) and on day 10.
Impact of MARS therapy on splanchnic hemodynamics assessed by portal pressure measuring.	Impact of MARS therapy on splanchnic hemodynamics assessed by portal pressure measuring.	At randomization (day 0) and on day 10.
Impact of MARS therapy on liver regeneration assessed by volumetric liver analysis using combined Computed Tomography (CT) and Magnetic Resonance Imaging (MR).	Impact of MARS therapy on liver regeneration assessed by volumetric liver analysis using combined Computed Tomography (CT) and Magnetic Resonance Imaging (MR).	At randomization (day 0) and on days 5, 10 and 30 .
Impact of MARS therapy on liver regeneration assessed by serum levels of phosphate.	Impact of MARS therapy on liver regeneration assessed by serum levels of phosphate.	At randomization (day 0) and on days 5 and 10.
Impact of MARS therapy on liver regeneration assessed by serum levels of alphafetoprotein.	Impact of MARS therapy on liver regeneration assessed by serum levels of alphafetoprotein.	At randomization (day 0) and on days 5 and 10.
Impact of MARS therapy on liver regeneration assessed by serum levels of hepatocyte growth factor.	Impact of MARS therapy on liver regeneration assessed by serum levels of hepatocyte growth factor.	At randomization (day 0) and on days 5 and 10.
Impact of MARS therapy on liver performance status.	Impact of MARS therapy on liver performance status estimated using indocyanine green (ICG) clearance.	At randomization (day 0) and on days 5 and 10.
Impact of MARS therapy on liver toxins (bile acids) in serum and dialysate.	impact of MARS therapy on liver toxins (ammonia, bile acids and cytokines (IL-6 and TNF-alpha)). Determinations in serum and in the dialysate.	At randomization (day 0) and on days 5 and 10.
Impact of MARS therapy on liver toxins (ammonia) in serum and dialysate.	impact of MARS therapy on liver toxins (ammonia). Determinations in serum and in the dialysate.	At randomization (day 0) and on days 5 and 10.
Impact of MARS therapy on liver toxins (IL-6) in serum and dialysate.	impact of MARS therapy on liver toxins (IL-6). Determinations in serum and in the dialysate.	At randomization (day 0) and on days 5 and 10.
Impact of MARS therapy on liver toxins (TNF-alpha) in serum and dialysate.	impact of MARS therapy on liver toxins (TNF-alpha). Determinations in serum and in the dialysate.	At randomization (day 0) and on days 5 and 10.

Collaborators and Investigators

• Sponsor: Stefan Gilg, MD, PhD
• Investigators: Principal Investigator: Stefan Gilg, MD PhD, Karolinska Institutet

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): March 15, 2019
• Primary Completion (ANTICIPATED): September 15, 2021
• Study Completion (ANTICIPATED): September 15, 2022

Study Registration Dates

• First Submitted: November 20, 2018
• First Submitted That Met QC Criteria: November 29, 2018
• First Posted (ACTUAL): December 3, 2018

Study Record Updates

• Last Update Posted (ACTUAL): December 3, 2018
• Last Update Submitted That Met QC Criteria: November 29, 2018
• Last Verified: November 1, 2018

More Information

Terms related to this study

• Keywords: liver dialysis; Molecular Adsorbent Recirculating System; post-hepatectomy liver failure; post-hepatectomy liver dysfunction
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Liver Failure; Hepatic Insufficiency
• Other Study ID Numbers: ELISH

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: Yes