<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/NCT01690845</url>
  </required_header>
  <id_info>
    <org_study_id>10712010</org_study_id>
    <nct_id>NCT01690845</nct_id>
  </id_info>
  <brief_title>Molecular Adsorbent Recirculating System (MARS®) in Hypoxic Hepatitis</brief_title>
  <acronym>MARS in HH</acronym>
  <official_title>Molecular Adsorbent Recirculating System (MARS®) for the Treatment of Patients With Hypoxic Hepatitis - a Prospective Randomized Controlled Clinical Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Medical University of Vienna</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Medical University of Vienna</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Hypoxic hepatitis (HH) is reported to be the most frequent cause of elevated aminotransferase&#xD;
      levels in hospital. Up to 10 % of critically ill patients develop HH during the course of&#xD;
      their intensive care unit (ICU) stay. Occurrence of HH is a life threatening event and&#xD;
      ICU-mortality is reported to be up to 60%. Early therapeutic intervention is of central&#xD;
      prognostic importance in patients with HH to improve the hemodynamic impairment as early as&#xD;
      possible, to reduce hyperammonemia and hepatic encephalopathy, to avoid progression of organ&#xD;
      failure and to improve outcome. Studies reported that Molecular Adsorbent Recirculating&#xD;
      System (MARS®) therapy improved the hemodynamic situation in patients with acute and acute on&#xD;
      chronic liver failure. The study hypothesis is that MARS® therapy in critically ill patients&#xD;
      with severe HH improves hepatic hemodynamics and function and consecutively the course of the&#xD;
      disease. 40 patients with suffering of severe HH with aminotransferase levels &gt; 40 times the&#xD;
      upper limit of normal of more than 12 hours will be randomized 1:1 to MARS® therapy (n=20) or&#xD;
      conventional therapy (n=20). 4 MARS®-sessions will be performed on three consecutive days,&#xD;
      each for at least 12 hours. Treatment will be continued under special circumstances. The&#xD;
      maximum duration of the treatment phase is 7 days. The primary endpoint is the difference of&#xD;
      the indocyanine plasma disappearance rate at day 7. The expected duration of the study is 2&#xD;
      years.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>June 2012</start_date>
  <primary_completion_date type="Anticipated">June 2017</primary_completion_date>
  <phase>Phase 2</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>difference of the indocyanine plasma disappearance rate (ICG-PDR)</measure>
    <time_frame>Days 1-7</time_frame>
    <description>The primary endpoint will be the difference of the indocyanine plasma disappearance rate (ICG-PDR) at day 7. Only in case of major differences in baseline values of ICG-PDR we will use the change from baseline to day 7 of ICG-PDR (delta ICG-PDR) as outcome. Assuming normal distribution of ICG-PDR, we will formally test the null-hypothesis of no difference between intervention group and control using an independent sample t-test. The assumption of a normal distribution will be founded on visually inspecting a histogram and using the Shapiro Wilks test for normal distribution. If the assumption of normality does not hold data will be compared using the Mann-Whitney U-test. A p-level of &lt; 0.05 will be considered statistically significant. Furthermore a linear random coefficient model will be used to incorporate daily measurements of ICG-PDR during the course of the study in terms of a repeated measures design.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>duration of vasopressor support</measure>
    <time_frame>1-28</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ICU - length of stay</measure>
    <time_frame>1-28</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>hospital - length of stay</measure>
    <time_frame>1-90</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>7-day mortality</measure>
    <time_frame>7 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>28 day mortality</measure>
    <time_frame>28 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>number of organ failure on day 7</measure>
    <time_frame>7 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>number of organ failure on day 28</measure>
    <time_frame>28 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>markers of liver function</measure>
    <time_frame>1-28</time_frame>
    <description>especially occurrence of jaundice (defined as total bilirubin levels &gt; 3 mg/dL) will be documented</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>number of vasopressor free days</measure>
    <time_frame>28 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>systemic hemodynamics</measure>
    <time_frame>7 days</time_frame>
    <description>systemic blood pressure, heart rate, cardiac index, central venous oxygen saturation, systemic vascular resistance index, global enddiastolic volume index, stroke volume variation, extravascular lung water index, pulse pressure variation, intrathoracic blood volume index, cardiac function index, central venous pressure</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>number of complications of HH</measure>
    <time_frame>1-28</time_frame>
    <description>following complications will be encountered: cholestasis, secondary sclerosing cholangitis, hepatic encephalopathy grade 3 &amp; 4, hypoglycemia, intraabdominal hypertension, new onset of infections, renal failure, hepatopulmonary syndrome</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>biomarkers</measure>
    <time_frame>0-28</time_frame>
    <description>blood samples will be collected the assess markers of inflammation, markers of endothelial function, markers of cardiac function, markers of cholestasis, markers of liver cell necrosis etc</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>duration of mechanical ventilation</measure>
    <time_frame>1-28</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>necessity of renal replacement therapy</measure>
    <time_frame>1-28</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>duration of renal replacement therapy</measure>
    <time_frame>1-28</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>90 days mortality</measure>
    <time_frame>90 days</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">40</enrollment>
  <condition>Hypoxic Hepatitis</condition>
  <condition>Ischemic Hepatitis</condition>
  <condition>Shock Liver</condition>
  <condition>Hypoxic Liver Injury</condition>
  <condition>Acute Liver Failure</condition>
  <arm_group>
    <arm_group_label>Control</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Patients with severe HH will be treated with standard medical therapy (i.e. vasopressor support with norepinephrine in refractory hypotension = RR mean &lt; 65 mmHg, positive inotropic support with dobutamine if the central venous oxygen saturation &lt; 70%, renal replacement therapy in case of severe metabolic acidosis and/or renal failure, antibiotic treatment in case of suspected or proven infection, mechanical ventilation in case of severe hypoxemia or hypercapnia and/or GCS &lt;= 8.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>MARS-Group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>20 patients will be allocated by randomization to the MARS arm. Additionally to standard medical therapy they will receive 4 MARS sessions on three consecutive days, MARS® therapy will be applied for at least 12 hours per session. Thereafter, MARS® treatment will be continued if the patient still has increasing aminotransferase levels, requires vasopressor support or suffers from cholestasis (defined as serum bilirubin levels &gt; 5 mg/dL) for 3 sessions again. There will be a maximum of 7 MARS ® sessions per patient.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>MARS</intervention_name>
    <description>Molecular adsorbent recirculating system (MARS®) can be used in patients with acute liver failure for bridging to liver transplantation. Studies reported that MARS® therapy improved the hemodynamic situation in patients with acute and acute on chronic liver failure. Several groups observed an increase in arterial pressure, systemic vascular resistance index, a decrease in portal pressure and improvement of renal blood flow. Furthermore, studies demonstrated that MARS therapy reduces ammonia levels and improves hepatic encephalopathy.</description>
    <arm_group_label>MARS-Group</arm_group_label>
    <other_name>Molecular adsorbent recirculating system (MARS®)</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  presence of severe hypoxic hepatitis with aminotransferase levels &gt; 40 times the upper&#xD;
             limit of normal&#xD;
&#xD;
          -  duration of hypoxic hepatitis more than 12 hours&#xD;
&#xD;
          -  age &gt;/= 18 years&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  age &lt; 18 years&#xD;
&#xD;
          -  pregnancy&#xD;
&#xD;
          -  DNR - order&#xD;
&#xD;
          -  liver cirrhosis&#xD;
&#xD;
          -  Cardiopulmonary resuscitation with unknown neurological outcome and/or hypoxic brain&#xD;
             damage&#xD;
&#xD;
          -  Expected survival of less than 24 hours&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Valentin Fuhrmann, Prof</last_name>
    <role>Principal Investigator</role>
    <affiliation>Medical University Vienna</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Valentin Fuhrmann, Prof</last_name>
    <phone>0043140400</phone>
    <phone_ext>4741</phone_ext>
    <email>valentin.fuhrmann@meduniwien.ac.at</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Thomas Horvatits, MD</last_name>
    <phone>0043140400</phone>
    <phone_ext>4741</phone_ext>
    <email>thomas.horvatits@meduniwien.ac.at</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Medical University Vienna, Dpt. of Internal Medicine 3, Div. of Gastroenterology and Hepatology</name>
      <address>
        <city>Vienna</city>
        <zip>1090</zip>
        <country>Austria</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Valentin Fuhrmann, Prof</last_name>
      <phone>0043140400</phone>
      <phone_ext>4741</phone_ext>
      <email>valentin.fuhrmann@meduniwien.ac.at</email>
    </contact>
    <contact_backup>
      <last_name>Thomas Horvatitis, MD</last_name>
      <phone>0043140400</phone>
      <phone_ext>4741</phone_ext>
      <email>thomas.horvatitis@meduniwien.ac.at</email>
    </contact_backup>
    <investigator>
      <last_name>Valentin Fuhrmann, Prof</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University Medical Center Hamburg-Eppendorf</name>
      <address>
        <city>Hamburg</city>
        <zip>20246</zip>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Stefan Kluge, Prof</last_name>
    </contact>
  </location>
  <location_countries>
    <country>Austria</country>
    <country>Germany</country>
  </location_countries>
  <verification_date>September 2016</verification_date>
  <study_first_submitted>September 16, 2012</study_first_submitted>
  <study_first_submitted_qc>September 19, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 24, 2012</study_first_posted>
  <last_update_submitted>September 21, 2016</last_update_submitted>
  <last_update_submitted_qc>September 21, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">September 22, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Medical University of Vienna</investigator_affiliation>
    <investigator_full_name>Valentin Fuhrmann</investigator_full_name>
    <investigator_title>Associate Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hepatitis A</mesh_term>
    <mesh_term>Hepatitis</mesh_term>
    <mesh_term>Liver Failure</mesh_term>
    <mesh_term>Liver Failure, Acute</mesh_term>
    <mesh_term>Hypoxia</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/NCT01690845
org study id: 10712010
nct id: NCT01690845
lead sponsor: 
has dmc: Yes
Hypoxic hepatitis (HH) is reported to be the most frequent cause of elevated aminotransferase
      levels in hospital. Up to 10 % of critically ill patients develop HH during the course of
      their intensive care unit (ICU) stay. Occurrence of HH is a life threatening event and
      ICU-mortality is reported to be up to 60%. Early therapeutic intervention is of central
      prognostic importance in patients with HH to improve the hemodynamic impairment as early as
      possible, to reduce hyperammonemia and hepatic encephalopathy, to avoid progression of organ
      failure and to improve outcome. Studies reported that Molecular Adsorbent Recirculating
      System (MARS®) therapy improved the hemodynamic situation in patients with acute and acute on
      chronic liver failure. The study hypothesis is that MARS® therapy in critically ill patients
      with severe HH improves hepatic hemodynamics and function and consecutively the course of the
      disease. 40 patients with suffering of severe HH with aminotransferase levels > 40 times the
      upper limit of normal of more than 12 hours will be randomized 1:1 to MARS® therapy (n=20) or
      conventional therapy (n=20). 4 MARS®-sessions will be performed on three consecutive days,
      each for at least 12 hours. Treatment will be continued under special circumstances. The
      maximum duration of the treatment phase is 7 days. The primary endpoint is the difference of
      the indocyanine plasma disappearance rate at day 7. The expected duration of the study is 2
      years.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: difference of the indocyanine plasma disappearance rate (ICG-PDR)
time frame: Days 1-7
description: The primary endpoint will be the difference of the indocyanine plasma disappearance rate (ICG-PDR) at day 7. Only in case of major differences in baseline values of ICG-PDR we will use the change from baseline to day 7 of ICG-PDR (delta ICG-PDR) as outcome. Assuming normal distribution of ICG-PDR, we will formally test the null-hypothesis of no difference between intervention group and control using an independent sample t-test. The assumption of a normal distribution will be founded on visually inspecting a histogram and using the Shapiro Wilks test for normal distribution. If the assumption of normality does not hold data will be compared using the Mann-Whitney U-test. A p-level of < 0.05 will be considered statistically significant. Furthermore a linear random coefficient model will be used to incorporate daily measurements of ICG-PDR during the course of the study in terms of a repeated measures design.
measure: duration of vasopressor support
time frame: 1-28
measure: ICU - length of stay
time frame: 1-28
measure: hospital - length of stay
time frame: 1-90
measure: 7-day mortality
time frame: 7 days
measure: 28 day mortality
time frame: 28 days
measure: number of organ failure on day 7
time frame: 7 days
measure: number of organ failure on day 28
time frame: 28 days
measure: markers of liver function
time frame: 1-28
description: especially occurrence of jaundice (defined as total bilirubin levels > 3 mg/dL) will be documented
measure: number of vasopressor free days
time frame: 28 days
measure: systemic hemodynamics
time frame: 7 days
description: systemic blood pressure, heart rate, cardiac index, central venous oxygen saturation, systemic vascular resistance index, global enddiastolic volume index, stroke volume variation, extravascular lung water index, pulse pressure variation, intrathoracic blood volume index, cardiac function index, central venous pressure
measure: number of complications of HH
time frame: 1-28
description: following complications will be encountered: cholestasis, secondary sclerosing cholangitis, hepatic encephalopathy grade 3 & 4, hypoglycemia, intraabdominal hypertension, new onset of infections, renal failure, hepatopulmonary syndrome
measure: biomarkers
time frame: 0-28
description: blood samples will be collected the assess markers of inflammation, markers of endothelial function, markers of cardiac function, markers of cholestasis, markers of liver cell necrosis etc
measure: duration of mechanical ventilation
time frame: 1-28
measure: necessity of renal replacement therapy
time frame: 1-28
measure: duration of renal replacement therapy
time frame: 1-28
measure: 90 days mortality
time frame: 90 days
arm group label: Control
arm group type: No Intervention
description: Patients with severe HH will be treated with standard medical therapy (i.e. vasopressor support with norepinephrine in refractory hypotension = RR mean < 65 mmHg, positive inotropic support with dobutamine if the central venous oxygen saturation < 70%, renal replacement therapy in case of severe metabolic acidosis and/or renal failure, antibiotic treatment in case of suspected or proven infection, mechanical ventilation in case of severe hypoxemia or hypercapnia and/or GCS <= 8.
arm group label: MARS-Group
arm group type: Experimental
description: 20 patients will be allocated by randomization to the MARS arm. Additionally to standard medical therapy they will receive 4 MARS sessions on three consecutive days, MARS® therapy will be applied for at least 12 hours per session. Thereafter, MARS® treatment will be continued if the patient still has increasing aminotransferase levels, requires vasopressor support or suffers from cholestasis (defined as serum bilirubin levels > 5 mg/dL) for 3 sessions again. There will be a maximum of 7 MARS ® sessions per patient.
intervention type: Device
intervention name: MARS
description: Molecular adsorbent recirculating system (MARS®) can be used in patients with acute liver failure for bridging to liver transplantation. Studies reported that MARS® therapy improved the hemodynamic situation in patients with acute and acute on chronic liver failure. Several groups observed an increase in arterial pressure, systemic vascular resistance index, a decrease in portal pressure and improvement of renal blood flow. Furthermore, studies demonstrated that MARS therapy reduces ammonia levels and improves hepatic encephalopathy.
arm group label: MARS-Group
other name: Molecular adsorbent recirculating system (MARS®)
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Valentin Fuhrmann, Prof
role: Principal Investigator
affiliation: Medical University Vienna
last name: Valentin Fuhrmann, Prof
phone: 0043140400
phone ext: 4741
email: valentin.fuhrmann@meduniwien.ac.at
last name: Thomas Horvatits, MD
phone: 0043140400
phone ext: 4741
email: thomas.horvatits@meduniwien.ac.at
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
facility: 
status: Recruiting
contact: 
country: Austria
country: Germany
responsible party type: Principal Investigator
investigator affiliation: Medical University of Vienna
investigator full name: Valentin Fuhrmann
investigator title: Associate Professor
mesh term: Hepatitis A
mesh term: Hepatitis
mesh term: Liver Failure
mesh term: Liver Failure, Acute
mesh term: Hypoxia