Early Liver Support With MARS in Post-hepatectomy Liver Failure

Not Applicable

• Conditions: Liver Failure as A Complication of Care
• Interventions: Other: Standard medical treatment (SMT); Device: Molecular Adsorbent Recirculating System

• Registration Number: NCT03761238
• Lead Sponsor: Stefan Gilg, MD, PhD

Brief Summary

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).

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 Timeline

• Status Verified: 2018-11
• Study First Submitted: 2018-11-20
• Study First Submitted QC: 2018-11-29
• Last Update Submitted: 2018-11-29
• Study First Posted: 2018-12-03
• Last Update Posted: 2018-12-03
• Study Start: 2019-03-15
• Primary Completion: 2021-09-15
• Study Completion: 2022-09-15

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 44

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Standard medical treatment	Standard medical treatment (SMT)	Patients assigned to the control arm will receive standard medical treatment (SMT) as specified in the study protocol.
Standard medical treatment + MARS	Molecular Adsorbent Recirculating System	Patients assigned to the control arm will receive standard medical treatment (SMT) and liver dialysis using Molecular Adsorbent Recirculating System (MARS).

Primary Outcome Measures

Name	Time	Method
60 day survival	From randomization to death from any cause, assessed up to 60 days postop	Overall survival rate from time of randomization to death from any cause

Secondary Outcome Measures

Name	Time	Method
28 day survival	From randomization to death from any cause, assessed up to 28 days post-op	Overall survival rate from time of randomization to death from any cause.
6 month survival	From randomization to death from any cause, assessed up to 6 months postop	Overall survival rate from time of randomization to death from any cause.
1 year survival	From randomization to death from any cause, assessed up to 1 year.	Overall survival rate from time of randomization to death from any cause.
Impact of MARS therapy on liver function	From randomization up to 1 year.	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).
90 day survival	From randomization to death from any cause, assessed up to 90 days postop	Overall survival rate from time of randomization to death from any cause.
Impact of MARS therapy on extra-hepatic function (APACHE-II scoring)	From randomization up to 1 year.	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).
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 regeneration assessed by serum levels of hepatocyte growth factor.
Impact of MARS therapy on liver toxins (bile acids) in serum and dialysate.	At randomization (day 0) and on days 5 and 10.	impact of MARS therapy on liver toxins (ammonia, bile acids and cytokines (IL-6 and TNF-alpha)). Determinations in serum and in the dialysate.
Impact of MARS therapy on liver toxins (ammonia) in serum and dialysate.	At randomization (day 0) and on days 5 and 10.	impact of MARS therapy on liver toxins (ammonia). Determinations in serum and in the dialysate.
Impact of MARS therapy on liver toxins (IL-6) in serum and dialysate.	At randomization (day 0) and on days 5 and 10.	impact of MARS therapy on liver toxins (IL-6). Determinations in serum and in the dialysate.
Impact of MARS therapy on extra-hepatic function (CLIF-SOFA scoring)	From randomization up to 1 year.	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).
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 alphafetoprotein.
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 volumetric liver analysis using combined Computed Tomography (CT) and Magnetic Resonance Imaging (MR).
Impact of MARS therapy on extra-hepatic function (SOFA scoring)	From randomization up to 1 year.	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).
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 phosphate.
Impact of MARS therapy on liver performance status.	At randomization (day 0) and on days 5 and 10.	Impact of MARS therapy on liver performance status estimated using indocyanine green (ICG) clearance.
Impact of MARS therapy on liver toxins (TNF-alpha) in serum and dialysate.	At randomization (day 0) and on days 5 and 10.	impact of MARS therapy on liver toxins (TNF-alpha). Determinations in serum and in the dialysate.
Impact of MARS therapy on splanchnic hemodynamics assessed by direct estimation of portal blood flow.	At randomization (day 0) and on day 10.	Impact of MARS therapy on splanchnic hemodynamics assessed by direct estimation of portal blood flow (ml/min).
Impact of MARS therapy on splanchnic hemodynamics assessed by indirect estimation of portal blood flow using ultrasonography.	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 (ml/min).
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 splanchnic hemodynamics assessed by portal pressure measuring.