<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/NCT03266302</url>
  </required_header>
  <id_info>
    <org_study_id>ZKSJ0108</org_study_id>
    <nct_id>NCT03266302</nct_id>
  </id_info>
  <brief_title>Hemoadsorption for Prevention of Vasodilatory Shock in Cardiac Surgery Patients With Infective Endocarditis</brief_title>
  <acronym>REMOVE</acronym>
  <official_title>Revealing Mechanisms and Investigating Efficacy of Hemoadsorption for Prevention of Vasodilatory Shock in Cardiac Surgery Patients With Infective Endocarditis - a Multicentric Randomized Controlled Group Sequential Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Jena University Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>CytoSorbents, Inc</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Thermo Fisher Scientific, Inc</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Fraunhofer Institute for Interfacial Engineering and Biotechnology</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>German Federal Ministry of Education and Research</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Jena University Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Infective endocarditis (IE) is associated with high hospital mortality for various reasons;&#xD;
      one of them is circulatory failure in patients who undergo cardiac surgery for IE. One&#xD;
      discussed reason underlying circulatory failure during surgery is the release of&#xD;
      vasodilatatory mediators and cytokines. This study examines the efficacy and safety of a&#xD;
      hemoadsorption filter which is approved for the reduction of the concentration of cytokines&#xD;
      in the bloodstream.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The investigators assume a common standard deviation of 3.8 points and that a 1.4-point lower&#xD;
      SOFA score in the Intervention Group is of clinical relevance.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 17, 2018</start_date>
  <completion_date type="Actual">December 31, 2020</completion_date>
  <primary_completion_date type="Actual">February 28, 2020</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>Sequential Assignment</intervention_model>
    <intervention_model_description>two-arm randomized-controlled group sequential (Pocock) design for assessing superiority and safety</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Single (Participant)</masking>
    <masking_description>Participant will not be informed about group allocation</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>SOFA Score</measure>
    <time_frame>24 hours before until day 9 post-surgery</time_frame>
    <description>The investigators will test if mean SOFA scores are different for the experimental and control group.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall mortality rate</measure>
    <time_frame>until day 30 post surgery</time_frame>
    <description>Overall mortality rate until day 30 post-surgery</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in cytokine and cfDNA levels</measure>
    <time_frame>24 hours before, during cardiac surgery and 24 hours after surgery</time_frame>
    <description>changes in cytokine and cfDNA levels will be measured at different time points before, during and after surgery in both groups; only for the first 2x25 patients</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>SOFA subscores</measure>
    <time_frame>24 hours before surgery until day 9 post-surgery</time_frame>
    <description>single SOFA subscores will be analyzed</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Days on ventilator, vasopressor and renal replacement therapy</measure>
    <time_frame>until day 30 post-surgery</time_frame>
    <description>Total days on ventilator, vasopressor and renal replacement therapy within 30 days post-surgery will be assessed</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>incidence of stroke</measure>
    <time_frame>until day 30 post-surgery</time_frame>
    <description>incidence of stroke within 30 days post-surgery will be assessed</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>length of ICU and in-hospital stay</measure>
    <time_frame>until day 30 post-surgery</time_frame>
    <description>total length of ICU and in-hospital stay until day 30 post-surgery</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">288</enrollment>
  <condition>Infective Endocarditis</condition>
  <arm_group>
    <arm_group_label>Interventional group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Use of hemoadsorber for removal of cytokines. Participants undergoing cardiac surgery due to infective endocarditis will be treated using a hemoadsorption device (CytoSorb) within the cardiopulmonary Bypass circuit (=Intervention)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control group</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Participants undergoing cardiac surgery due to infective endocarditis will be treated according to Standard of care (no hemoadsorption advice installed in the CPB circuit)</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>hemoadsorber for removal of cytokines</intervention_name>
    <description>Use of the hemoadsorber during cardiac surgery with CPB. Hemoadsorber is integrated into the CPB circuit according to manufacturer's recommendation.</description>
    <arm_group_label>Interventional group</arm_group_label>
    <other_name>CytoSorb(R)</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  patients with infective endocarditis (according to DUKE criteria) undergoing cardiac&#xD;
             surgery&#xD;
&#xD;
          -  informed consent&#xD;
&#xD;
          -  age ≥18 years&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  EuroScoreII ≤ 3&#xD;
&#xD;
          -  current participation in another interventional Trial&#xD;
&#xD;
          -  pregnancy&#xD;
&#xD;
          -  current immunosuppressive or immunomodulatory therapy (with dosing of glucocorticoids&#xD;
             over Cushing threshold)&#xD;
&#xD;
          -  previous participation in the REMOVE study&#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>Mahmoud Diab, Dr.</last_name>
    <role>Study Director</role>
    <affiliation>Jena University Hospital, Department of Cardiac and Thoracic Surgery</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University Heart Center Bad Krozingen</name>
      <address>
        <city>Bad Krozingen</city>
        <state>Baden-Württemberg</state>
        <zip>D-79189</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Heart Center Freiburg</name>
      <address>
        <city>Freiburg</city>
        <state>Baden-Württemberg</state>
        <zip>D-79106</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Ulm, Clinics of Heart-, Thoracic and Cardiovascular Surgery</name>
      <address>
        <city>Ulm</city>
        <state>Baden-Württemberg</state>
        <zip>D-89081</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Cologne, Clinic and Policlinics for Heart and Thoracic Surgery</name>
      <address>
        <city>Cologne</city>
        <state>North Rhine-Westphalia</state>
        <zip>D-50937</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Essen, Clinic of Thoracic and Cardiovascular Surgery</name>
      <address>
        <city>Essen</city>
        <state>North Rhine-Westphalia</state>
        <zip>D-45147</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Jena University Hospital, Dept. of Cardiac and Thoracic Surgery</name>
      <address>
        <city>Jena</city>
        <state>Thuringia</state>
        <zip>07747</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Herz- und Diabeteszentrum NRW, Klinik für Thorax- und Kardiovaskularchirurgie</name>
      <address>
        <city>Bad Oeynhausen</city>
        <zip>32545</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Herzzentrum Brandenburg, Immanuel Klinikum Bernau</name>
      <address>
        <city>Bernau bei Berlin</city>
        <zip>16321</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil gGmbH, Klinik für Herz- und Thoraxchirurgie</name>
      <address>
        <city>Bochum</city>
        <zip>44789</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Bonn, Klinik und Poliklinik für Herzchirurgie</name>
      <address>
        <city>Bonn</city>
        <zip>53127</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Herzzentrum Dresden GmbH, Universitätsklinik an der TU Dresden, Klinik für Herzchirurgie</name>
      <address>
        <city>Dresden</city>
        <zip>01307</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Düsseldorf, Klinik für Kardiovaskuläre Chirurgie</name>
      <address>
        <city>Düsseldorf</city>
        <zip>40225</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mitteldeutsches Herzzentrum, Universitätsklinikum Halle (Saale), Universitätsklinik und Poliklinik für Herzchirurgie</name>
      <address>
        <city>Halle (Saale)</city>
        <zip>06120</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Herzzentrum Leipzig, Universitätsklinik für Herzchirurgie</name>
      <address>
        <city>Leipzig</city>
        <zip>04289</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <reference>
    <citation>Bernardi MH, Rinoesl H, Dragosits K, Ristl R, Hoffelner F, Opfermann P, Lamm C, Preissing F, Wiedemann D, Hiesmayr MJ, Spittler A. Effect of hemoadsorption during cardiopulmonary bypass surgery - a blinded, randomized, controlled pilot study using a novel adsorbent. Crit Care. 2016 Apr 9;20:96. doi: 10.1186/s13054-016-1270-0.</citation>
    <PMID>27059056</PMID>
  </reference>
  <reference>
    <citation>Brunkhorst FM, Oppert M, Marx G, Bloos F, Ludewig K, Putensen C, Nierhaus A, Jaschinski U, Meier-Hellmann A, Weyland A, Grundling M, Moerer O, Riessen R, Seibel A, Ragaller M, Buchler MW, John S, Bach F, Spies C, Reill L, Fritz H, Kiehntopf M, Kuhnt E, Bogatsch H, Engel C, Loeffler M, Kollef MH, Reinhart K, Welte T; German Study Group Competence Network Sepsis (SepNet). Effect of empirical treatment with moxifloxacin and meropenem vs meropenem on sepsis-related organ dysfunction in patients with severe sepsis: a randomized trial. JAMA. 2012 Jun 13;307(22):2390-9. doi: 10.1001/jama.2012.5833.</citation>
    <PMID>22692171</PMID>
  </reference>
  <reference>
    <citation>Bustamante J, Arevalo A, Tamayo E, Sarria C, Aguilar-Blanco EM, Heredia M, Almansa R, Rico L, Iglesias V, Bermejo-Martin JF. Cytokine profiles linked to fatal outcome in infective prosthetic valve endocarditis. APMIS. 2014 Jun;122(6):526-9. doi: 10.1111/apm.12189. Epub 2013 Sep 30.</citation>
    <PMID>24106887</PMID>
  </reference>
  <reference>
    <citation>Boyle EM Jr, Pohlman TH, Johnson MC, Verrier ED. Endothelial cell injury in cardiovascular surgery: the systemic inflammatory response. Ann Thorac Surg. 1997 Jan;63(1):277-84. doi: 10.1016/s0003-4975(96)01061-2.</citation>
    <PMID>8993292</PMID>
  </reference>
  <reference>
    <citation>Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med. 2003 Jan 9;348(2):138-50. doi: 10.1056/NEJMra021333. No abstract available.</citation>
    <PMID>12519925</PMID>
  </reference>
  <reference>
    <citation>Minne L, Abu-Hanna A, de Jonge E. Evaluation of SOFA-based models for predicting mortality in the ICU: A systematic review. Crit Care. 2008;12(6):R161. doi: 10.1186/cc7160. Epub 2008 Dec 17.</citation>
    <PMID>19091120</PMID>
  </reference>
  <reference>
    <citation>Prendergast BD, Tornos P. Surgery for infective endocarditis: who and when? Circulation. 2010 Mar 9;121(9):1141-52. doi: 10.1161/CIRCULATIONAHA.108.773598. No abstract available.</citation>
    <PMID>20212293</PMID>
  </reference>
  <verification_date>March 2020</verification_date>
  <study_first_submitted>August 28, 2017</study_first_submitted>
  <study_first_submitted_qc>August 29, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 30, 2017</study_first_posted>
  <last_update_submitted>April 7, 2022</last_update_submitted>
  <last_update_submitted_qc>April 7, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">April 8, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>vasodilatory shock</keyword>
  <keyword>hemoadsorption</keyword>
  <keyword>cardiac surgery</keyword>
  <keyword>cytokines</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Endocarditis, Bacterial</mesh_term>
    <mesh_term>Endocarditis</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</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/NCT03266302
org study id: ZKSJ0108
nct id: NCT03266302
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Infective endocarditis (IE) is associated with high hospital mortality for various reasons;
      one of them is circulatory failure in patients who undergo cardiac surgery for IE. One
      discussed reason underlying circulatory failure during surgery is the release of
      vasodilatatory mediators and cytokines. This study examines the efficacy and safety of a
      hemoadsorption filter which is approved for the reduction of the concentration of cytokines
      in the bloodstream.
The investigators assume a common standard deviation of 3.8 points and that a 1.4-point lower
      SOFA score in the Intervention Group is of clinical relevance.
allocation: Randomized
intervention model: Sequential Assignment
intervention model description: two-arm randomized-controlled group sequential (Pocock) design for assessing superiority and safety
primary purpose: Prevention
masking: Single (Participant)
masking description: Participant will not be informed about group allocation
measure: SOFA Score
time frame: 24 hours before until day 9 post-surgery
description: The investigators will test if mean SOFA scores are different for the experimental and control group.
measure: Overall mortality rate
time frame: until day 30 post surgery
description: Overall mortality rate until day 30 post-surgery
measure: Changes in cytokine and cfDNA levels
time frame: 24 hours before, during cardiac surgery and 24 hours after surgery
description: changes in cytokine and cfDNA levels will be measured at different time points before, during and after surgery in both groups; only for the first 2x25 patients
measure: SOFA subscores
time frame: 24 hours before surgery until day 9 post-surgery
description: single SOFA subscores will be analyzed
measure: Days on ventilator, vasopressor and renal replacement therapy
time frame: until day 30 post-surgery
description: Total days on ventilator, vasopressor and renal replacement therapy within 30 days post-surgery will be assessed
measure: incidence of stroke
time frame: until day 30 post-surgery
description: incidence of stroke within 30 days post-surgery will be assessed
measure: length of ICU and in-hospital stay
time frame: until day 30 post-surgery
description: total length of ICU and in-hospital stay until day 30 post-surgery
arm group label: Interventional group
arm group type: Experimental
description: Use of hemoadsorber for removal of cytokines. Participants undergoing cardiac surgery due to infective endocarditis will be treated using a hemoadsorption device (CytoSorb) within the cardiopulmonary Bypass circuit (=Intervention)
arm group label: Control group
arm group type: No Intervention
description: Participants undergoing cardiac surgery due to infective endocarditis will be treated according to Standard of care (no hemoadsorption advice installed in the CPB circuit)
intervention type: Device
intervention name: hemoadsorber for removal of cytokines
description: Use of the hemoadsorber during cardiac surgery with CPB. Hemoadsorber is integrated into the CPB circuit according to manufacturer's recommendation.
arm group label: Interventional group
other name: CytoSorb(R)
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Mahmoud Diab, Dr.
role: Study Director
affiliation: Jena University Hospital, Department of Cardiac and Thoracic Surgery
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Germany
citation: Bernardi MH, Rinoesl H, Dragosits K, Ristl R, Hoffelner F, Opfermann P, Lamm C, Preissing F, Wiedemann D, Hiesmayr MJ, Spittler A. Effect of hemoadsorption during cardiopulmonary bypass surgery - a blinded, randomized, controlled pilot study using a novel adsorbent. Crit Care. 2016 Apr 9;20:96. doi: 10.1186/s13054-016-1270-0.
PMID: 27059056
citation: Brunkhorst FM, Oppert M, Marx G, Bloos F, Ludewig K, Putensen C, Nierhaus A, Jaschinski U, Meier-Hellmann A, Weyland A, Grundling M, Moerer O, Riessen R, Seibel A, Ragaller M, Buchler MW, John S, Bach F, Spies C, Reill L, Fritz H, Kiehntopf M, Kuhnt E, Bogatsch H, Engel C, Loeffler M, Kollef MH, Reinhart K, Welte T; German Study Group Competence Network Sepsis (SepNet). Effect of empirical treatment with moxifloxacin and meropenem vs meropenem on sepsis-related organ dysfunction in patients with severe sepsis: a randomized trial. JAMA. 2012 Jun 13;307(22):2390-9. doi: 10.1001/jama.2012.5833.
PMID: 22692171
citation: Bustamante J, Arevalo A, Tamayo E, Sarria C, Aguilar-Blanco EM, Heredia M, Almansa R, Rico L, Iglesias V, Bermejo-Martin JF. Cytokine profiles linked to fatal outcome in infective prosthetic valve endocarditis. APMIS. 2014 Jun;122(6):526-9. doi: 10.1111/apm.12189. Epub 2013 Sep 30.
PMID: 24106887
citation: Boyle EM Jr, Pohlman TH, Johnson MC, Verrier ED. Endothelial cell injury in cardiovascular surgery: the systemic inflammatory response. Ann Thorac Surg. 1997 Jan;63(1):277-84. doi: 10.1016/s0003-4975(96)01061-2.
PMID: 8993292
citation: Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med. 2003 Jan 9;348(2):138-50. doi: 10.1056/NEJMra021333. No abstract available.
PMID: 12519925
citation: Minne L, Abu-Hanna A, de Jonge E. Evaluation of SOFA-based models for predicting mortality in the ICU: A systematic review. Crit Care. 2008;12(6):R161. doi: 10.1186/cc7160. Epub 2008 Dec 17.
PMID: 19091120
citation: Prendergast BD, Tornos P. Surgery for infective endocarditis: who and when? Circulation. 2010 Mar 9;121(9):1141-52. doi: 10.1161/CIRCULATIONAHA.108.773598. No abstract available.
PMID: 20212293
responsible party type: Sponsor
mesh term: Endocarditis, Bacterial
mesh term: Endocarditis
sharing ipd: No