<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/NCT01700660</url>
  </required_header>
  <id_info>
    <org_study_id>2012_238</org_study_id>
    <secondary_id>NL41737.018.12</secondary_id>
    <nct_id>NCT01700660</nct_id>
  </id_info>
  <brief_title>Reperfusion-induced Self-antigen Excretion Following Major Liver Surgery</brief_title>
  <acronym>RISE</acronym>
  <official_title>Reperfusion-induced Self-antigen Excretion Following Major Liver Surgery</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Major liver surgery often requires the surgeon to temporarily halt the afferent blood flow in&#xD;
      order to prevent excessive blood loss. However, this predisposes the liver to a detrimental&#xD;
      inflammatory response once the circulation is restored. Altogether, the effects that result&#xD;
      from this temporary withdrawal of blood are known as ischemia and reperfusion (I/R) injury,&#xD;
      and the extent to which this occurs determines the functional outcome of the liver after&#xD;
      surgery.&#xD;
&#xD;
      Recently, it has become clear that (over)activation of the immune system forms the mainstay&#xD;
      of I/R injury in the liver. More importantly, it has been shown in animal models that&#xD;
      self-antigens, which are normal cellular constituents that become immunogenic mediators&#xD;
      following their release from dying cells, are involved in the earliest stages of I/R injury&#xD;
      of the liver. Clinical data on the release self-antigens in I/R injury are however scarce to&#xD;
      date. Therefore, the aim of this study is to investigate the release of self-antigens in&#xD;
      patients that undergo a major liver resection with or without withdrawal of the liver's blood&#xD;
      flow. Also, the results will be correlated to genes involved in the inflammatory response as&#xD;
      well as clinical parameters for liver damage and function.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Rationale&#xD;
&#xD;
      Major liver surgery often requires the surgeon to temporarily halt the afferent blood flow in&#xD;
      order to prevent excessive blood loss. Vascular inflow occlusion (VIO) however predisposes&#xD;
      the liver to a detrimental inflammatory response once the circulation is restored.&#xD;
      Altogether, the ramifications that result from this temporary withdrawal of oxygen supply are&#xD;
      known as ischemia and reperfusion (I/R) injury, and the extent to which this occurs&#xD;
      determines the functional outcome of the liver after surgery. Recently, it has become clear&#xD;
      that (over)activation of the immune system forms the mainstay of hepatic I/R injury. More&#xD;
      importantly, it has been shown in animal models that endogenous self-antigens, known as&#xD;
      damage-associated molecular patterns (DAMPs), are released from stressed liver cells in the&#xD;
      earliest stages of reperfusion and, as such, form the most proximal triggers of hepatic I/R&#xD;
      injury. Clinical data on DAMP release following hepatic I/R are however scarce to date.&#xD;
      Therefore, the aim of this study is to investigate DAMP release in patients that undergo a&#xD;
      major liver resection with or without VIO and to correlate the results to the expression of&#xD;
      acute- phase inflammatory response genes and routine clinical parameters for hepatocellular&#xD;
      damage.&#xD;
&#xD;
      Objective&#xD;
&#xD;
      To investigate the release of damage-associated molecular patterns (DAMPs) following major&#xD;
      hepatic resection with or without VIO and to correlate the outcomes to the acute inflammatory&#xD;
      response and clinical parameters for hepatocellular damage.&#xD;
&#xD;
      Study design&#xD;
&#xD;
      The study is designed as an observational study. Because the decision to apply VIO is often&#xD;
      made during surgery, patients will be allocated to a group postoperatively. Therefore, the&#xD;
      inclusion of subjects in this study will continue until the calculated sample size of 15&#xD;
      patients has been reached in each group.&#xD;
&#xD;
      Study population&#xD;
&#xD;
      Eligible patients for participation in this study are those diagnosed with a malignant or&#xD;
      benign hepatic tumor that are scheduled to undergo major hepatectomy (resection of ≥3&#xD;
      segments).&#xD;
&#xD;
      Main study parameters/endpoints&#xD;
&#xD;
      The primary endpoint of this study is defined as the effect of I/R on the release of DAMPs,&#xD;
      measured in the systemic circulation. Secondary parameters constitute the expression of acute&#xD;
      inflammatory response genes, AST, ALT, total bilirubin, and INR.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>October 2012</start_date>
  <completion_date type="Actual">December 2014</completion_date>
  <primary_completion_date type="Actual">December 2014</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Control</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>DAMPs in systemic circulation</measure>
    <time_frame>8 hours</time_frame>
    <description>Plasma DAMP levels will be determined perioperatively.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Up regulation of acute inflammatory response genes</measure>
    <time_frame>1 hour</time_frame>
    <description>Up regulation of acute inflammatory response genes will be determined in liver biopsy tissue (acquired intraoperatively) by means of qPCR.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Parenchymal damage</measure>
    <time_frame>8 hours</time_frame>
    <description>Measured as plasma ALT and AST.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Liver function</measure>
    <time_frame>8 hours</time_frame>
    <description>Assessed by means of total bilirubin levels and prothrombin time.</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Actual">40</enrollment>
  <condition>Warm Hepatic Ischemia-reperfusion Injury</condition>
  <arm_group>
    <arm_group_label>VIO</arm_group_label>
    <description>Patients operated under VIO.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control</arm_group_label>
    <description>Patients operated without VIO.</description>
  </arm_group>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      2 liver biopsies&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Patients diagnosed with a malignant or benign hepatic tumor that are scheduled for a liver&#xD;
        resection.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients scheduled to undergo a major liver resection for a benign or malignant&#xD;
             hepatic tumor&#xD;
&#xD;
          -  Signed informed consent obtained prior to any study-specific procedure&#xD;
&#xD;
          -  ASA classification I-III&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  VIO &lt;20 min&#xD;
&#xD;
          -  ASA classification IV/V&#xD;
&#xD;
          -  Emergency operations&#xD;
&#xD;
          -  Pregnancy or breast feeding&#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>Thomas M. van Gulik, MD, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Megan J. Reiniers, MSc</last_name>
    <role>Principal Investigator</role>
    <affiliation>Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Academic Medical Center</name>
      <address>
        <city>Amsterdam</city>
        <state>Noord Holland</state>
        <zip>1105 AZ</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <reference>
    <citation>van Golen RF, van Gulik TM, Heger M. The sterile immune response during hepatic ischemia/reperfusion. Cytokine Growth Factor Rev. 2012 Jun;23(3):69-84. doi: 10.1016/j.cytogfr.2012.04.006. Epub 2012 May 17.</citation>
    <PMID>22609105</PMID>
  </reference>
  <verification_date>January 2016</verification_date>
  <study_first_submitted>October 3, 2012</study_first_submitted>
  <study_first_submitted_qc>October 3, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 4, 2012</study_first_posted>
  <last_update_submitted>January 25, 2016</last_update_submitted>
  <last_update_submitted_qc>January 25, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">January 26, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)</investigator_affiliation>
    <investigator_full_name>Megan J. Reiniers</investigator_full_name>
    <investigator_title>PhD student at the Department of Surgery</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Reperfusion Injury</mesh_term>
    <mesh_term>Ischemia</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- 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/NCT01700660
org study id: 2012_238
secondary id: NL41737.018.12
nct id: NCT01700660
lead sponsor: 
has dmc: No
Major liver surgery often requires the surgeon to temporarily halt the afferent blood flow in
      order to prevent excessive blood loss. However, this predisposes the liver to a detrimental
      inflammatory response once the circulation is restored. Altogether, the effects that result
      from this temporary withdrawal of blood are known as ischemia and reperfusion (I/R) injury,
      and the extent to which this occurs determines the functional outcome of the liver after
      surgery.

      Recently, it has become clear that (over)activation of the immune system forms the mainstay
      of I/R injury in the liver. More importantly, it has been shown in animal models that
      self-antigens, which are normal cellular constituents that become immunogenic mediators
      following their release from dying cells, are involved in the earliest stages of I/R injury
      of the liver. Clinical data on the release self-antigens in I/R injury are however scarce to
      date. Therefore, the aim of this study is to investigate the release of self-antigens in
      patients that undergo a major liver resection with or without withdrawal of the liver's blood
      flow. Also, the results will be correlated to genes involved in the inflammatory response as
      well as clinical parameters for liver damage and function.
Rationale

      Major liver surgery often requires the surgeon to temporarily halt the afferent blood flow in
      order to prevent excessive blood loss. Vascular inflow occlusion (VIO) however predisposes
      the liver to a detrimental inflammatory response once the circulation is restored.
      Altogether, the ramifications that result from this temporary withdrawal of oxygen supply are
      known as ischemia and reperfusion (I/R) injury, and the extent to which this occurs
      determines the functional outcome of the liver after surgery. Recently, it has become clear
      that (over)activation of the immune system forms the mainstay of hepatic I/R injury. More
      importantly, it has been shown in animal models that endogenous self-antigens, known as
      damage-associated molecular patterns (DAMPs), are released from stressed liver cells in the
      earliest stages of reperfusion and, as such, form the most proximal triggers of hepatic I/R
      injury. Clinical data on DAMP release following hepatic I/R are however scarce to date.
      Therefore, the aim of this study is to investigate DAMP release in patients that undergo a
      major liver resection with or without VIO and to correlate the results to the expression of
      acute- phase inflammatory response genes and routine clinical parameters for hepatocellular
      damage.

      Objective

      To investigate the release of damage-associated molecular patterns (DAMPs) following major
      hepatic resection with or without VIO and to correlate the outcomes to the acute inflammatory
      response and clinical parameters for hepatocellular damage.

      Study design

      The study is designed as an observational study. Because the decision to apply VIO is often
      made during surgery, patients will be allocated to a group postoperatively. Therefore, the
      inclusion of subjects in this study will continue until the calculated sample size of 15
      patients has been reached in each group.

      Study population

      Eligible patients for participation in this study are those diagnosed with a malignant or
      benign hepatic tumor that are scheduled to undergo major hepatectomy (resection of ≥3
      segments).

      Main study parameters/endpoints

      The primary endpoint of this study is defined as the effect of I/R on the release of DAMPs,
      measured in the systemic circulation. Secondary parameters constitute the expression of acute
      inflammatory response genes, AST, ALT, total bilirubin, and INR.
observational model: Case-Control
time perspective: Prospective
measure: DAMPs in systemic circulation
time frame: 8 hours
description: Plasma DAMP levels will be determined perioperatively.
measure: Up regulation of acute inflammatory response genes
time frame: 1 hour
description: Up regulation of acute inflammatory response genes will be determined in liver biopsy tissue (acquired intraoperatively) by means of qPCR.
measure: Parenchymal damage
time frame: 8 hours
description: Measured as plasma ALT and AST.
measure: Liver function
time frame: 8 hours
description: Assessed by means of total bilirubin levels and prothrombin time.
arm group label: VIO
description: Patients operated under VIO.
arm group label: Control
description: Patients operated without VIO.
2 liver biopsies
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Thomas M. van Gulik, MD, PhD
role: Study Director
affiliation: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
last name: Megan J. Reiniers, MSc
role: Principal Investigator
affiliation: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
facility: 
country: Netherlands
citation: van Golen RF, van Gulik TM, Heger M. The sterile immune response during hepatic ischemia/reperfusion. Cytokine Growth Factor Rev. 2012 Jun;23(3):69-84. doi: 10.1016/j.cytogfr.2012.04.006. Epub 2012 May 17.
PMID: 22609105
responsible party type: Principal Investigator
investigator affiliation: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
investigator full name: Megan J. Reiniers
investigator title: PhD student at the Department of Surgery
mesh term: Reperfusion Injury
mesh term: Ischemia
sharing ipd: Undecided