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

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ClinicalTrials.gov Identifier: NCT03761238
Recruitment Status : Not yet recruiting
First Posted : December 3, 2018
Last Update Posted : December 3, 2018
Sponsor:
Information provided by (Responsible Party):
Stefan Gilg, MD, PhD, Karolinska University Hospital

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).

Condition or disease Intervention/treatment Phase
Liver Failure as A Complication of Care Device: Molecular Adsorbent Recirculating System Other: Standard medical treatment (SMT) Not Applicable

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  (Clinical Trial)
Estimated Enrollment : 44 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Early Liver Support With MARS in Post-hepatectomy Liver Failure: a Randomized, Multicentre Trial
Estimated Study Start Date : March 15, 2019
Estimated Primary Completion Date : September 15, 2021
Estimated Study Completion Date : September 15, 2022

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 Name: 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.




Primary Outcome Measures :
  1. 60 day survival [ Time Frame: 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 :
  1. 28 day survival [ Time Frame: 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.

  2. 90 day survival [ Time Frame: 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.

  3. 6 month survival [ Time Frame: 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.

  4. 1 year survival [ Time Frame: From randomization to death from any cause, assessed up to 1 year. ]
    Overall survival rate from time of randomization to death from any cause.

  5. Impact of MARS therapy on liver function [ Time Frame: From randomization up to 1 year. ]
    Impact of MARS therapy on liver function according to Child Pugh score (grade A, B and C)

  6. Impact of MARS therapy on liver function [ Time Frame: 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).

  7. Impact of MARS therapy on extra-hepatic function (APACHE-II scoring) [ Time Frame: 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).

  8. Impact of MARS therapy on extra-hepatic function (SOFA scoring) [ Time Frame: 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).

  9. Impact of MARS therapy on extra-hepatic function (CLIF-SOFA scoring) [ Time Frame: 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).

  10. Impact of MARS therapy on splanchnic hemodynamics assessed by direct estimation of portal blood flow. [ Time Frame: 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).

  11. Impact of MARS therapy on splanchnic hemodynamics assessed by indirect estimation of portal blood flow using ultrasonography. [ Time Frame: 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).

  12. Impact of MARS therapy on splanchnic hemodynamics assessed by portal pressure measuring. [ Time Frame: At randomization (day 0) and on day 10. ]
    Impact of MARS therapy on splanchnic hemodynamics assessed by portal pressure measuring.

  13. Impact of MARS therapy on liver regeneration assessed by volumetric liver analysis using combined Computed Tomography (CT) and Magnetic Resonance Imaging (MR). [ Time Frame: 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).

  14. Impact of MARS therapy on liver regeneration assessed by serum levels of phosphate. [ Time Frame: At randomization (day 0) and on days 5 and 10. ]
    Impact of MARS therapy on liver regeneration assessed by serum levels of phosphate.

  15. Impact of MARS therapy on liver regeneration assessed by serum levels of alphafetoprotein. [ Time Frame: At randomization (day 0) and on days 5 and 10. ]
    Impact of MARS therapy on liver regeneration assessed by serum levels of alphafetoprotein.

  16. Impact of MARS therapy on liver regeneration assessed by serum levels of hepatocyte growth factor. [ Time Frame: 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.

  17. Impact of MARS therapy on liver performance status. [ Time Frame: At randomization (day 0) and on days 5 and 10. ]
    Impact of MARS therapy on liver performance status estimated using indocyanine green (ICG) clearance.

  18. Impact of MARS therapy on liver toxins (bile acids) in serum and dialysate. [ Time Frame: 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.

  19. Impact of MARS therapy on liver toxins (ammonia) in serum and dialysate. [ Time Frame: 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.

  20. Impact of MARS therapy on liver toxins (IL-6) in serum and dialysate. [ Time Frame: 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.

  21. Impact of MARS therapy on liver toxins (TNF-alpha) in serum and dialysate. [ Time Frame: 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.



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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03761238


Contacts
Contact: Stefan Gilg, MD PhD 0702677722 ext 46 stefan.gilg@ki.se

Sponsors and Collaborators
Stefan Gilg, MD, PhD
Investigators
Principal Investigator: Stefan Gilg, MD PhD Karolinska Institutet

Responsible Party: Stefan Gilg, MD, PhD, Principal Investigator, Karolinska University Hospital
ClinicalTrials.gov Identifier: NCT03761238     History of Changes
Other Study ID Numbers: ELISH
First Posted: December 3, 2018    Key Record Dates
Last Update Posted: December 3, 2018
Last Verified: November 2018

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: Yes
Device Product Not Approved or Cleared by U.S. FDA: No
Pediatric Postmarket Surveillance of a Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Stefan Gilg, MD, PhD, Karolinska University Hospital:
Molecular Adsorbent Recirculating System
post-hepatectomy liver failure
liver dialysis
post-hepatectomy liver dysfunction

Additional relevant MeSH terms:
Liver Failure
Hepatic Insufficiency
Liver Diseases
Digestive System Diseases
Liver Extracts
Hematinics