<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03761238</url>
  </required_header>
  <id_info>
    <org_study_id>ELISH</org_study_id>
    <nct_id>NCT03761238</nct_id>
  </id_info>
  <brief_title>Early Liver Support With MARS in Post-hepatectomy Liver Failure</brief_title>
  <acronym>ELISH</acronym>
  <official_title>Early Liver Support With MARS in Post-hepatectomy Liver Failure: a Randomized, Multicentre Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Stefan Gilg, MD, PhD</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Karolinska University Hospital</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a prospective, randomized, open-label, multicentre study involving European centers&#xD;
      with experience in the management of PHLF to assess the impact of early liver support with&#xD;
      MARS on survival in patients with post-hepatectomy liver failure (PHLF).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PHLF is a major risk factor for mortality in patients who underwent major hepatectomy. A&#xD;
      specific treatment is yet not available. In a primary proof-of-concept study, it was shown&#xD;
      that it is safe and feasible to use MARS in patients with PHLF early after hepatectomy.&#xD;
      Survival was superior to a historical control group.&#xD;
&#xD;
      This study will include patients with early, primary PHLF (based on the 50:50 criteria) after&#xD;
      major liver surgery. Patients will be randomized 1:1 to receive standard treatment alone or&#xD;
      standard treatment + liver dialysis using the Molecular Adsorbent Recirculating System&#xD;
      (MARS). Relevant outcome along with several physiological parameters will be assessed.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">March 15, 2019</start_date>
  <completion_date type="Anticipated">September 15, 2022</completion_date>
  <primary_completion_date type="Anticipated">September 15, 2021</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>60 day survival</measure>
    <time_frame>From randomization to death from any cause, assessed up to 60 days postop</time_frame>
    <description>Overall survival rate from time of randomization to death from any cause</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>28 day survival</measure>
    <time_frame>From randomization to death from any cause, assessed up to 28 days post-op</time_frame>
    <description>Overall survival rate from time of randomization to death from any cause.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>90 day survival</measure>
    <time_frame>From randomization to death from any cause, assessed up to 90 days postop</time_frame>
    <description>Overall survival rate from time of randomization to death from any cause.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>6 month survival</measure>
    <time_frame>From randomization to death from any cause, assessed up to 6 months postop</time_frame>
    <description>Overall survival rate from time of randomization to death from any cause.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>1 year survival</measure>
    <time_frame>From randomization to death from any cause, assessed up to 1 year.</time_frame>
    <description>Overall survival rate from time of randomization to death from any cause.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Impact of MARS therapy on liver function</measure>
    <time_frame>From randomization up to 1 year.</time_frame>
    <description>Impact of MARS therapy on liver function according to Child Pugh score (grade A, B and C)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Impact of MARS therapy on liver function</measure>
    <time_frame>From randomization up to 1 year.</time_frame>
    <description>Impact of MARS therapy on liver function according to the Model for End-stage Liver Disease (MELD) score (5 groups: &lt; 9, 10-19, 20-29, 30-39 and &gt;40 points, lower points indicate improvement of liver function).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Impact of MARS therapy on extra-hepatic function (APACHE-II scoring)</measure>
    <time_frame>From randomization up to 1 year.</time_frame>
    <description>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).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Impact of MARS therapy on extra-hepatic function (SOFA scoring)</measure>
    <time_frame>From randomization up to 1 year.</time_frame>
    <description>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).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Impact of MARS therapy on extra-hepatic function (CLIF-SOFA scoring)</measure>
    <time_frame>From randomization up to 1 year.</time_frame>
    <description>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).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Impact of MARS therapy on splanchnic hemodynamics assessed by direct estimation of portal blood flow.</measure>
    <time_frame>At randomization (day 0) and on day 10.</time_frame>
    <description>Impact of MARS therapy on splanchnic hemodynamics assessed by direct estimation of portal blood flow (ml/min).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Impact of MARS therapy on splanchnic hemodynamics assessed by indirect estimation of portal blood flow using ultrasonography.</measure>
    <time_frame>At randomization (day 0) and on day 10.</time_frame>
    <description>Impact of MARS therapy on splanchnic hemodynamics assessed by indirect estimation of portal blood flow using ultrasonography (ml/min).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Impact of MARS therapy on splanchnic hemodynamics assessed by portal pressure measuring.</measure>
    <time_frame>At randomization (day 0) and on day 10.</time_frame>
    <description>Impact of MARS therapy on splanchnic hemodynamics assessed by portal pressure measuring.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Impact of MARS therapy on liver regeneration assessed by volumetric liver analysis using combined Computed Tomography (CT) and Magnetic Resonance Imaging (MR).</measure>
    <time_frame>At randomization (day 0) and on days 5, 10 and 30 .</time_frame>
    <description>Impact of MARS therapy on liver regeneration assessed by volumetric liver analysis using combined Computed Tomography (CT) and Magnetic Resonance Imaging (MR).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Impact of MARS therapy on liver regeneration assessed by serum levels of phosphate.</measure>
    <time_frame>At randomization (day 0) and on days 5 and 10.</time_frame>
    <description>Impact of MARS therapy on liver regeneration assessed by serum levels of phosphate.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Impact of MARS therapy on liver regeneration assessed by serum levels of alphafetoprotein.</measure>
    <time_frame>At randomization (day 0) and on days 5 and 10.</time_frame>
    <description>Impact of MARS therapy on liver regeneration assessed by serum levels of alphafetoprotein.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Impact of MARS therapy on liver regeneration assessed by serum levels of hepatocyte growth factor.</measure>
    <time_frame>At randomization (day 0) and on days 5 and 10.</time_frame>
    <description>Impact of MARS therapy on liver regeneration assessed by serum levels of hepatocyte growth factor.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Impact of MARS therapy on liver performance status.</measure>
    <time_frame>At randomization (day 0) and on days 5 and 10.</time_frame>
    <description>Impact of MARS therapy on liver performance status estimated using indocyanine green (ICG) clearance.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Impact of MARS therapy on liver toxins (bile acids) in serum and dialysate.</measure>
    <time_frame>At randomization (day 0) and on days 5 and 10.</time_frame>
    <description>impact of MARS therapy on liver toxins (ammonia, bile acids and cytokines (IL-6 and TNF-alpha)). Determinations in serum and in the dialysate.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Impact of MARS therapy on liver toxins (ammonia) in serum and dialysate.</measure>
    <time_frame>At randomization (day 0) and on days 5 and 10.</time_frame>
    <description>impact of MARS therapy on liver toxins (ammonia). Determinations in serum and in the dialysate.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Impact of MARS therapy on liver toxins (IL-6) in serum and dialysate.</measure>
    <time_frame>At randomization (day 0) and on days 5 and 10.</time_frame>
    <description>impact of MARS therapy on liver toxins (IL-6). Determinations in serum and in the dialysate.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Impact of MARS therapy on liver toxins (TNF-alpha) in serum and dialysate.</measure>
    <time_frame>At randomization (day 0) and on days 5 and 10.</time_frame>
    <description>impact of MARS therapy on liver toxins (TNF-alpha). Determinations in serum and in the dialysate.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">44</enrollment>
  <condition>Liver Failure as A Complication of Care</condition>
  <arm_group>
    <arm_group_label>Standard medical treatment + MARS</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients assigned to the control arm will receive standard medical treatment (SMT) and liver dialysis using Molecular Adsorbent Recirculating System (MARS).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Standard medical treatment</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients assigned to the control arm will receive standard medical treatment (SMT) as specified in the study protocol.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Molecular Adsorbent Recirculating System</intervention_name>
    <description>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.</description>
    <arm_group_label>Standard medical treatment + MARS</arm_group_label>
    <other_name>MARS 1116/1 - X-MARS</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Standard medical treatment (SMT)</intervention_name>
    <description>Patient management and standard medical treatment (SMT) as specified in the study protocol.</description>
    <arm_group_label>Standard medical treatment</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients subjected for major liver surgery (4 or more Couinaud segments) or patients&#xD;
             undergoing a 2nd, 3rd or 4th hepatic resection. Pre-operative chemotherapy and/or&#xD;
             biological agents are allowed.&#xD;
&#xD;
          -  Primary PHLF occurring early after surgery defined by the 50:50 criteria (from PO day&#xD;
             5 to day 14) or by the presence of hepatic encephalopathy grade 2 or more and the&#xD;
             50:50 criteria (from PO day 3 to 4).&#xD;
&#xD;
          -  Written informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  ALPPS (Associating Liver Partition and Portal vein Ligation for Staged hepatectomy)&#xD;
             procedure.&#xD;
&#xD;
          -  In patients with chronic liver disease presence of significant portal hypertension&#xD;
             (hepatic venous pressure gradient ≥ 10 mmHg and/or Fibroscan ≥ 21kPa) prior to&#xD;
             surgical intervention.&#xD;
&#xD;
          -  Any contraindication for MARS therapy such as uncontrolled active bleeding, platelet&#xD;
             counts &lt;20.000 /µl or uncontrolled infection (presence of fever or adequate antibiotic&#xD;
             therapy for less than 48h), septic shock, haemodynamic instability requiring inotropic&#xD;
             support (noradrenaline &gt; 1mg/h).&#xD;
&#xD;
          -  PHLF occurring after post operative day 14.&#xD;
&#xD;
          -  Secondary PHLF: post-operative liver failure secondary to vascular (outflow or inflow&#xD;
             thrombosis) or septic problems.&#xD;
&#xD;
          -  Persistant biliary complications (infected biloma, main biliary tree damage).&#xD;
&#xD;
          -  Inability or unwilling of the patient or family to give informed consent.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Stefan Gilg, MD PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Karolinska Institutet</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Stefan Gilg, MD PhD</last_name>
    <phone>0702677722</phone>
    <phone_ext>46</phone_ext>
    <email>stefan.gilg@ki.se</email>
  </overall_contact>
  <verification_date>November 2018</verification_date>
  <study_first_submitted>November 20, 2018</study_first_submitted>
  <study_first_submitted_qc>November 29, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 3, 2018</study_first_posted>
  <last_update_submitted>November 29, 2018</last_update_submitted>
  <last_update_submitted_qc>November 29, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">December 3, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Karolinska University Hospital</investigator_affiliation>
    <investigator_full_name>Stefan Gilg, MD, PhD</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Molecular Adsorbent Recirculating System</keyword>
  <keyword>post-hepatectomy liver failure</keyword>
  <keyword>liver dialysis</keyword>
  <keyword>post-hepatectomy liver dysfunction</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Liver Failure</mesh_term>
    <mesh_term>Hepatic Insufficiency</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03761238
org study id: ELISH
nct id: NCT03761238
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: Yes
is us export: Yes
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).
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: 60 day survival
time frame: From randomization to death from any cause, assessed up to 60 days postop
description: Overall survival rate from time of randomization to death from any cause
measure: 28 day survival
time frame: From randomization to death from any cause, assessed up to 28 days post-op
description: Overall survival rate from time of randomization to death from any cause.
measure: 90 day survival
time frame: From randomization to death from any cause, assessed up to 90 days postop
description: Overall survival rate from time of randomization to death from any cause.
measure: 6 month survival
time frame: From randomization to death from any cause, assessed up to 6 months postop
description: Overall survival rate from time of randomization to death from any cause.
measure: 1 year survival
time frame: From randomization to death from any cause, assessed up to 1 year.
description: Overall survival rate from time of randomization to death from any cause.
measure: Impact of MARS therapy on liver function
time frame: From randomization up to 1 year.
description: Impact of MARS therapy on liver function according to Child Pugh score (grade A, B and C)
measure: Impact of MARS therapy on liver function
time frame: From randomization up to 1 year.
description: 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).
measure: Impact of MARS therapy on extra-hepatic function (APACHE-II scoring)
time frame: From randomization up to 1 year.
description: 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).
measure: Impact of MARS therapy on extra-hepatic function (SOFA scoring)
time frame: From randomization up to 1 year.
description: 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).
measure: Impact of MARS therapy on extra-hepatic function (CLIF-SOFA scoring)
time frame: From randomization up to 1 year.
description: 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).
measure: 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.
description: Impact of MARS therapy on splanchnic hemodynamics assessed by direct estimation of portal blood flow (ml/min).
measure: 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.
description: Impact of MARS therapy on splanchnic hemodynamics assessed by indirect estimation of portal blood flow using ultrasonography (ml/min).
measure: Impact of MARS therapy on splanchnic hemodynamics assessed by portal pressure measuring.
time frame: At randomization (day 0) and on day 10.
description: Impact of MARS therapy on splanchnic hemodynamics assessed by portal pressure measuring.
measure: 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 .
description: Impact of MARS therapy on liver regeneration assessed by volumetric liver analysis using combined Computed Tomography (CT) and Magnetic Resonance Imaging (MR).
measure: 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.
description: Impact of MARS therapy on liver regeneration assessed by serum levels of phosphate.
measure: 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.
description: Impact of MARS therapy on liver regeneration assessed by serum levels of alphafetoprotein.
measure: 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.
description: Impact of MARS therapy on liver regeneration assessed by serum levels of hepatocyte growth factor.
measure: Impact of MARS therapy on liver performance status.
time frame: At randomization (day 0) and on days 5 and 10.
description: Impact of MARS therapy on liver performance status estimated using indocyanine green (ICG) clearance.
measure: 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.
description: impact of MARS therapy on liver toxins (ammonia, bile acids and cytokines (IL-6 and TNF-alpha)). Determinations in serum and in the dialysate.
measure: Impact of MARS therapy on liver toxins (ammonia) in serum and dialysate.
time frame: At randomization (day 0) and on days 5 and 10.
description: impact of MARS therapy on liver toxins (ammonia). Determinations in serum and in the dialysate.
measure: 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.
description: impact of MARS therapy on liver toxins (IL-6). Determinations in serum and in the dialysate.
measure: 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.
description: impact of MARS therapy on liver toxins (TNF-alpha). Determinations in serum and in the dialysate.
arm group label: Standard medical treatment + MARS
arm group type: Experimental
description: Patients assigned to the control arm will receive standard medical treatment (SMT) and liver dialysis using Molecular Adsorbent Recirculating System (MARS).
arm group label: Standard medical treatment
arm group type: Active Comparator
description: Patients assigned to the control arm will receive standard medical treatment (SMT) as specified in the study protocol.
intervention type: Device
intervention name: Molecular Adsorbent Recirculating System
description: 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.
arm group label: Standard medical treatment + MARS
other name: MARS 1116/1 - X-MARS
intervention type: Other
intervention name: Standard medical treatment (SMT)
description: Patient management and standard medical treatment (SMT) as specified in the study protocol.
arm group label: Standard medical treatment
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Stefan Gilg, MD PhD
role: Principal Investigator
affiliation: Karolinska Institutet
last name: Stefan Gilg, MD PhD
phone: 0702677722
phone ext: 46
email: stefan.gilg@ki.se
responsible party type: Sponsor-Investigator
investigator affiliation: Karolinska University Hospital
investigator full name: Stefan Gilg, MD, PhD
investigator title: Principal Investigator
mesh term: Liver Failure
mesh term: Hepatic Insufficiency