<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/NCT02204852</url>
  </required_header>
  <id_info>
    <org_study_id>CO-ILEPSS</org_study_id>
    <nct_id>NCT02204852</nct_id>
  </id_info>
  <brief_title>Co-administration of Iloprost and Eptifibatide in Septic Shock Patients</brief_title>
  <acronym>CO-ILEPSS</acronym>
  <official_title>Safety and Efficacy of Iloprost and Eptifibatide Co-administration Compared to Standard Therapy in Patients With Septic Shock - a Randomized, Controlled, Double-blind Investigator-initiated Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sisse R. Ostrowski, MD PhD DMSc</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Rigshospitalet, Denmark</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Objective Evaluating the safety and efficacy of iloprost and eptifibatide co-administration&#xD;
      compared to placebo as an addition to standard care in septic shock patients.&#xD;
&#xD;
      Trial rationale Iloprost and eptifibatide combination therapy in septic shock patients is&#xD;
      expected to deactivate the endothelium and restore vascular integrity, reduce formation of&#xD;
      microvascular thrombosis and dissolve existing clots in the microcirculation and maintain&#xD;
      platelet counts, thereby improving platelet-mediated immune function and reducing the risk of&#xD;
      bleeding. Together this is expected to translate into reduced organ failure and improved&#xD;
      outcome in patients with septic shock.&#xD;
&#xD;
      Trial population The trial population is patients &gt;18 years admitted to the ICU with septic&#xD;
      shock within the last 24h. Eighteen evaluable septic shock patients will be included.&#xD;
&#xD;
      Trial design This is a single center, randomized (2:1, active:placebo), placebo controlled,&#xD;
      double-blind investigator-initiated phase IIa trial in patients with septic shock,&#xD;
      investigating the safety and efficacy of co-administration of Iloprost and Eptifibatide as a&#xD;
      48h continuous i.v infusion in totally 18 patients.&#xD;
&#xD;
      All patients will receive standard ICU care including LMWH thrombosis prophylaxis.&#xD;
&#xD;
      As all patients present at the trial site in an acute, critical condition, scientific&#xD;
      guardians will co-sign the informed consent form before inclusion. Next-of-kin and the&#xD;
      patients' general practitioner will co-sign as soon as possible and the patient will provide&#xD;
      informed consent whenever possible. The active treatment is expected to improve the clinical&#xD;
      condition of the individual patient and to provide information that may translate into&#xD;
      improved therapy of future sepsis patients.&#xD;
&#xD;
      During the study, blood samples will be taken at different time points. Patients will be&#xD;
      observed and assessed continuously with regards to complications including bleeding. Patients&#xD;
      will be actively assessed as long as the patient is in the ICU. During the extended follow up&#xD;
      period at day 30 and 90, contact will be made with the patients to follow up on safety events&#xD;
      and vital status.&#xD;
&#xD;
      The trial is conducted in accordance with the protocol and the current regulatory&#xD;
      requirements and legislation in Denmark.&#xD;
&#xD;
      Investigational product The active treatment in the trial comprises co-administration of 1&#xD;
      ng/kg/min Ilomedin® and 0.5 µg/kg/min Integrilin® as 48h continuous i.v infusions. The drugs&#xD;
      will be purchased and administered according to the product specifications.&#xD;
&#xD;
      Placebo The placebo in the trial is 0.9% saline as 48h continuous i.v infusion, which will be&#xD;
      used as placebo for both study drugs. The i.v volume of placebo saline to be administered is&#xD;
      equal to the administered volume of diluted (in 0.9% saline) active drug.&#xD;
&#xD;
      Data protection In compliance with the Danish data protection law, the trial will be approved&#xD;
      by the Danish Data Protection Agency.&#xD;
&#xD;
      Sponsor of study and financial support This research project is investigator-initiated by the&#xD;
      trial sponsor and co-investigator Sisse R. Ostrowski and co-investigator Pär I. Johansson in&#xD;
      collaboration with the principal investigator Morten Bestle.&#xD;
&#xD;
      It has not received funding from any commercial sponsors.&#xD;
&#xD;
      Time line Patient recruitment period runs from September 2014 to August 2015. Follow-up data&#xD;
      on 30-day and 90-day outcome and adverse events will be collected. Initial data analyses will&#xD;
      be done after completion of 30-day follow-up for all patients. Secondary data analyses will&#xD;
      be done after completion of 90-day follow-up for all patients.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>September 2014</start_date>
  <completion_date type="Actual">August 2016</completion_date>
  <primary_completion_date type="Actual">August 2016</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>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Mean change i plasma biomarkers reflecting endothelial damage</measure>
    <time_frame>48 hours</time_frame>
    <description>Change in biomarkers indicative of endothelial activation and damage (sE-selectin, syndecan-1, thrombomodulin, sVE-cadherin, nucleosomes) from baseline to 48 hours post-randomization</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Mean change in platelet count reflecting platelet consumption</measure>
    <time_frame>48 hours</time_frame>
    <description>Change in platelet count from baseline to 48 hours post-randomization</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Mean change in biomarkers reflecting fibrinolysis</measure>
    <time_frame>48 hours</time_frame>
    <description>Change in D-dimer and fibrin split products indicative of fibrinolysis (fibrinogen degradation Bβ15-42; fibrin degradation Fragments X, Y, D and E) from baseline to 48 hours post-randomization</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of patients with severe bleeding</measure>
    <time_frame>24 hours to 90 days</time_frame>
    <description>Severe bleeding (intracranial or clinical bleeding with the use of 3 RBC units or more/24 hours)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients with transfusion requirements</measure>
    <time_frame>24 hours to 90 days</time_frame>
    <description>Use of blood products (in ICU) post-randomization</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mortality</measure>
    <time_frame>7 to 90 days</time_frame>
    <description>Difference in day 7, 30 and 90 day mortality between patients receiving active treatment (eptifibatide and iloprost) and placebo</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean change in disease severity score</measure>
    <time_frame>48 hours to 7 days</time_frame>
    <description>Changes in SOFA score from baseline to 48 h and day 5 and 7 post-randomization</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients requiring organ support</measure>
    <time_frame>48 hours to 90 days</time_frame>
    <description>Days of vasopressor, ventilator and renal replacement therapy post-randomization</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">18</enrollment>
  <condition>Septic Shock</condition>
  <arm_group>
    <arm_group_label>Iloprost+eptifibatide</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Co-administration of 1 ng/kg/min Ilomedin® and 0.5 µg/kg/min Integrilin® as 48h continuous i.v infusions</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Saline</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Double dummy 0.9% saline as 48h continuous i.v infusion</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Iloprost+eptifibatide</intervention_name>
    <arm_group_label>Iloprost+eptifibatide</arm_group_label>
    <other_name>Ilomedin(R)</other_name>
    <other_name>Integrilin(R)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <arm_group_label>Saline</arm_group_label>
    <other_name>0.9% saline, double dummy</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Adult intensive care patients (age ≥18 years) AND&#xD;
&#xD;
          2. Sepsis, defined as suspected or confirmed site of infection or positive blood culture&#xD;
             and ≥2 of 4 systemic inflammatory response syndrome (SIRS) criteria fulfilled within&#xD;
             the last 24h:&#xD;
&#xD;
               -  Temperature ≤ 36˚ C or ≥ 38˚C&#xD;
&#xD;
               -  Heart rate ≥ 90 beats per minute&#xD;
&#xD;
               -  Mechanical ventilation for acute respiratory process or respiratory rate ≥ 20&#xD;
                  breaths per minute or PaCO2 &lt; 4.2 kPa&#xD;
&#xD;
               -  WBC ≥ 12,000/mm³ OR ≤ 4,000/mm³ OR &gt; 10% bands AND&#xD;
&#xD;
          3. Septic shock within the last 24h, defined as:&#xD;
&#xD;
               -  Hypotension (MAP &lt;70 mmHg, Lactate 4 mmol/L) despite ongoing resuscitation with&#xD;
                  fluids (crystalloids, colloids, blood products) within the last 24h OR&#xD;
&#xD;
               -  ≥30 ml/kg ideal body weight (IBW) fluid (crystalloids, colloids, blood products)&#xD;
                  given in the last 24h AND&#xD;
&#xD;
               -  Need for vasopressor/inotropic agents (noradrenaline, adrenaline, dopamine)&#xD;
                  within the last 24h AND&#xD;
&#xD;
          4. Can be randomized into trial and dosed &lt; 24h after septic shock diagnosis (the&#xD;
             time-point for the septic shock diagnosis corresponds to the time-point where the&#xD;
             vasopressor/inotropic therapy (3c) is initiated) AND&#xD;
&#xD;
          5. Consent is obtainable&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patient is pregnant or breast-feeding&#xD;
&#xD;
          2. Patient weights more than 125 kg&#xD;
&#xD;
          3. Patients with known allergy towards any of the investigational products or&#xD;
             contraindications which should be excluded according to the investigational product&#xD;
             specifications&#xD;
&#xD;
          4. Patients in whom the clinician finds antithrombotic therapy contraindicated -&#xD;
             prophylaxis included&#xD;
&#xD;
          5. Patients at increased risk of bleeding:&#xD;
&#xD;
               -  Surgery in the previous 48h and expected surgery within 48 h&#xD;
&#xD;
               -  Epidural or spinal puncture in the previous 12h&#xD;
&#xD;
               -  Platelet count less than 10,000/mm3 in the previous 24h&#xD;
&#xD;
               -  Need of blood products for bleeding in the previous 24h (3 or more RBC/24 h)&#xD;
&#xD;
               -  Treatment with any antithrombotics within 12h (profylaxis excepted)&#xD;
&#xD;
               -  Current intracranial bleeding&#xD;
&#xD;
               -  Traumatic brain or spinal injury within the last month&#xD;
&#xD;
          6. Patients requiring any form of antithrombotics (beyond profylaxis) in therapeutic&#xD;
             doses or prothrombotics in any dose, including:&#xD;
&#xD;
               -  Unfractionated heparin within 8h before the infusion (prophylactic heparin up to&#xD;
                  15,000 U/day permitted)&#xD;
&#xD;
               -  LMWH within 12h before the infusion (prophylactic doses permitted)&#xD;
&#xD;
               -  Warfarin within 1 day before the infusion&#xD;
&#xD;
               -  Acetylsalicylic acid more than 650 mg/day within 3 days before the study&#xD;
&#xD;
               -  Thrombolytic therapy within 3 days before the study (catheter clearance doses&#xD;
                  permitted)&#xD;
&#xD;
               -  GPIIb/IIIa receptor inhibitors within 4 days before the study&#xD;
&#xD;
               -  Antithrombin III with dose greater than 10,000 U within 12h before the study&#xD;
&#xD;
          7. Patients with a do-not-resuscitate order (expected not to survive more than few days&#xD;
             because of uncorrectable medical or surgical condition other than sepsis)&#xD;
&#xD;
          8. Patient with chronic renal failure requiring dialysis (renal failure without need for&#xD;
             dialysis permitted)&#xD;
&#xD;
          9. Patients who have undergone transplantation of bone marrow, liver, pancreas, heart,&#xD;
             lung, or bowel (kidney transplant permitted)&#xD;
&#xD;
         10. Patient with known hypercoagulable condition:&#xD;
&#xD;
               -  Activated protein C resistance&#xD;
&#xD;
               -  Hereditary protein C, protein S, or antithrombin III deficiency&#xD;
&#xD;
               -  Anticardiolipin or antiphospholipid antibody&#xD;
&#xD;
               -  Lupus anticoagulant&#xD;
&#xD;
               -  Homocysteinemia&#xD;
&#xD;
               -  Recent or highly suspected pulmonary embolism or deep venous thrombosis (within 3&#xD;
                  months)&#xD;
&#xD;
         11. Patients with known congenital hypocoagulable diseases&#xD;
&#xD;
         12. Patient with known primary pulmonary hypertension&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>99 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Sisse R Ostrowski, MD, PhD, DMSc</last_name>
    <role>Study Chair</role>
    <affiliation>Copenhagen University Hospital, Rigshospitalet, Denmark</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Pär I Johansson, MD, DMSc, MPA</last_name>
    <role>Study Director</role>
    <affiliation>Copenhagen University Hospital, Rigshospitalet, Denmark</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Department of Anesthesia and Intensive Care, Nordsjællands Hospital</name>
      <address>
        <city>Hillerød</city>
        <state>Capital Region</state>
        <zip>DK-3400</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Denmark</country>
  </location_countries>
  <verification_date>April 2017</verification_date>
  <study_first_submitted>July 24, 2014</study_first_submitted>
  <study_first_submitted_qc>July 29, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 30, 2014</study_first_posted>
  <last_update_submitted>April 21, 2017</last_update_submitted>
  <last_update_submitted_qc>April 21, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">April 24, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Rigshospitalet, Denmark</investigator_affiliation>
    <investigator_full_name>Sisse R. Ostrowski, MD PhD DMSc</investigator_full_name>
    <investigator_title>MD, PhD, DMSc</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Shock, Septic</mesh_term>
    <mesh_term>Shock</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Iloprost</mesh_term>
    <mesh_term>Eptifibatide</mesh_term>
  </intervention_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/NCT02204852
org study id: CO-ILEPSS
nct id: NCT02204852
lead sponsor: 
has dmc: Yes
Objective Evaluating the safety and efficacy of iloprost and eptifibatide co-administration
      compared to placebo as an addition to standard care in septic shock patients.

      Trial rationale Iloprost and eptifibatide combination therapy in septic shock patients is
      expected to deactivate the endothelium and restore vascular integrity, reduce formation of
      microvascular thrombosis and dissolve existing clots in the microcirculation and maintain
      platelet counts, thereby improving platelet-mediated immune function and reducing the risk of
      bleeding. Together this is expected to translate into reduced organ failure and improved
      outcome in patients with septic shock.

      Trial population The trial population is patients >18 years admitted to the ICU with septic
      shock within the last 24h. Eighteen evaluable septic shock patients will be included.

      Trial design This is a single center, randomized (2:1, active:placebo), placebo controlled,
      double-blind investigator-initiated phase IIa trial in patients with septic shock,
      investigating the safety and efficacy of co-administration of Iloprost and Eptifibatide as a
      48h continuous i.v infusion in totally 18 patients.

      All patients will receive standard ICU care including LMWH thrombosis prophylaxis.

      As all patients present at the trial site in an acute, critical condition, scientific
      guardians will co-sign the informed consent form before inclusion. Next-of-kin and the
      patients' general practitioner will co-sign as soon as possible and the patient will provide
      informed consent whenever possible. The active treatment is expected to improve the clinical
      condition of the individual patient and to provide information that may translate into
      improved therapy of future sepsis patients.

      During the study, blood samples will be taken at different time points. Patients will be
      observed and assessed continuously with regards to complications including bleeding. Patients
      will be actively assessed as long as the patient is in the ICU. During the extended follow up
      period at day 30 and 90, contact will be made with the patients to follow up on safety events
      and vital status.

      The trial is conducted in accordance with the protocol and the current regulatory
      requirements and legislation in Denmark.

      Investigational product The active treatment in the trial comprises co-administration of 1
      ng/kg/min Ilomedin® and 0.5 µg/kg/min Integrilin® as 48h continuous i.v infusions. The drugs
      will be purchased and administered according to the product specifications.

      Placebo The placebo in the trial is 0.9% saline as 48h continuous i.v infusion, which will be
      used as placebo for both study drugs. The i.v volume of placebo saline to be administered is
      equal to the administered volume of diluted (in 0.9% saline) active drug.

      Data protection In compliance with the Danish data protection law, the trial will be approved
      by the Danish Data Protection Agency.

      Sponsor of study and financial support This research project is investigator-initiated by the
      trial sponsor and co-investigator Sisse R. Ostrowski and co-investigator Pär I. Johansson in
      collaboration with the principal investigator Morten Bestle.

      It has not received funding from any commercial sponsors.

      Time line Patient recruitment period runs from September 2014 to August 2015. Follow-up data
      on 30-day and 90-day outcome and adverse events will be collected. Initial data analyses will
      be done after completion of 30-day follow-up for all patients. Secondary data analyses will
      be done after completion of 90-day follow-up for all patients.
allocation: Randomized
intervention model: Single Group Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Mean change i plasma biomarkers reflecting endothelial damage
time frame: 48 hours
description: Change in biomarkers indicative of endothelial activation and damage (sE-selectin, syndecan-1, thrombomodulin, sVE-cadherin, nucleosomes) from baseline to 48 hours post-randomization
measure: Mean change in platelet count reflecting platelet consumption
time frame: 48 hours
description: Change in platelet count from baseline to 48 hours post-randomization
measure: Mean change in biomarkers reflecting fibrinolysis
time frame: 48 hours
description: Change in D-dimer and fibrin split products indicative of fibrinolysis (fibrinogen degradation Bβ15-42; fibrin degradation Fragments X, Y, D and E) from baseline to 48 hours post-randomization
measure: Number of patients with severe bleeding
time frame: 24 hours to 90 days
description: Severe bleeding (intracranial or clinical bleeding with the use of 3 RBC units or more/24 hours)
measure: Number of patients with transfusion requirements
time frame: 24 hours to 90 days
description: Use of blood products (in ICU) post-randomization
measure: Mortality
time frame: 7 to 90 days
description: Difference in day 7, 30 and 90 day mortality between patients receiving active treatment (eptifibatide and iloprost) and placebo
measure: Mean change in disease severity score
time frame: 48 hours to 7 days
description: Changes in SOFA score from baseline to 48 h and day 5 and 7 post-randomization
measure: Number of patients requiring organ support
time frame: 48 hours to 90 days
description: Days of vasopressor, ventilator and renal replacement therapy post-randomization
arm group label: Iloprost+eptifibatide
arm group type: Experimental
description: Co-administration of 1 ng/kg/min Ilomedin® and 0.5 µg/kg/min Integrilin® as 48h continuous i.v infusions
arm group label: Saline
arm group type: Placebo Comparator
description: Double dummy 0.9% saline as 48h continuous i.v infusion
intervention type: Drug
intervention name: Iloprost+eptifibatide
arm group label: Iloprost+eptifibatide
other name: Ilomedin(R)
other name: Integrilin(R)
intervention type: Drug
intervention name: Placebo
arm group label: Saline
other name: 0.9% saline, double dummy
criteria: 
gender: All
minimum age: 18 Years
maximum age: 99 Years
healthy volunteers: No
last name: Sisse R Ostrowski, MD, PhD, DMSc
role: Study Chair
affiliation: Copenhagen University Hospital, Rigshospitalet, Denmark
last name: Pär I Johansson, MD, DMSc, MPA
role: Study Director
affiliation: Copenhagen University Hospital, Rigshospitalet, Denmark
facility: 
country: Denmark
responsible party type: Sponsor-Investigator
investigator affiliation: Rigshospitalet, Denmark
investigator full name: Sisse R. Ostrowski, MD PhD DMSc
investigator title: MD, PhD, DMSc
mesh term: Shock, Septic
mesh term: Shock
mesh term: Iloprost
mesh term: Eptifibatide