<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/NCT04420741</url>
  </required_header>
  <id_info>
    <org_study_id>COMBAT-COVID-19</org_study_id>
    <secondary_id>2020-001296-33</secondary_id>
    <nct_id>NCT04420741</nct_id>
  </id_info>
  <brief_title>Infusion of Prostacyclin (Iloprost) vs Placebo for 72-hours in COVID-19 Patients With Respiratory Failure</brief_title>
  <acronym>COMBAT-COVID</acronym>
  <official_title>Efficacy and Safety of 72-hour Infusion of Prostacyclin (1 Nanogram(ng)/ Kilo(kg)/Minute(Min)) in Patients With COVID-19 Induced Pulmonary Endotheliopathy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Pär Johansson</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Rigshospitalet, Denmark</source>
  <oversight_info>
    <has_dmc>No</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>
      The purpose of this trial is to investigate the efficacy and safety of continuous intravenous&#xD;
      administration of low dose iloprost versus placebo for 72-hours, in 80 patients with COVID-19&#xD;
      suffering from respiratory failure. The study hypothesis is that iloprost may be beneficial&#xD;
      as an endothelial rescue treatment as it is anticipated to deactivate the endothelium and&#xD;
      restore vascular integrity in COVID-19 patients suffering from respiratory failure caused by&#xD;
      endothelial breakdown, ultimately improving survival. Given that the pulmonary system, apart&#xD;
      from the brain, is the most highly vascularized vital organ in the body, extensive&#xD;
      endothelial damage is a central feature of acute respiratory distress syndrome (ARDS) with&#xD;
      respiratory failure being the rationale for the current study COMBAT-COVID-19.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Patients with the most severe type of sepsis, those with septic shock have a mortality rate&#xD;
      between 30% to 45% due to multiple organ failure. The poor outcome of shocked patients, and&#xD;
      especially those with sepsis, may by related to microvascular endothelial dysfunction.&#xD;
&#xD;
      Coronavirus disease 2019 (COVID-19) is an infectious disease caused by coronavirus 2&#xD;
      (SARS-CoV-2) and, thus, being a novel cause of sepsis. The disease was first identified in&#xD;
      2019 in Wuhan, the capital of Hubei, China, and has since spread globally, resulting in the&#xD;
      2019-20 coronavirus pandemic. Common symptoms include fever, cough and shortness of breath,&#xD;
      muscle pain and sputum production. While many cases result in mild symptoms, some progress to&#xD;
      pneumonia and multi-organ failure. In particular COVID-19 is associated with ARDS with&#xD;
      respiratory failure and high mortality.&#xD;
&#xD;
      Evidence support that iloprost infusion significantly improved endothelial function and&#xD;
      integrity, The main objective in this trial is to investigate whether continuous infusion of&#xD;
      lov dose iloprost at a dose of 1 ng/kg/min for 72-hours is safe and significantly reduce the&#xD;
      need of respiratory support in the intensive care unit (ICU) compared to infusion of placebo&#xD;
      in patients with COVID-19 induced pulmonary endotheliopathy (SHINE).&#xD;
&#xD;
      Patients that are eligible for this trial will be temporarily incompetent due to acute severe&#xD;
      illness relating to respiratory failure, therefore informed consent will be obtained from a&#xD;
      scientific guardian. Next-of kin and subsequently the patient will co-sign as soon as&#xD;
      possible hereafter. During the trial, patient will be given continuous infusion of low dose&#xD;
      iloprost or placebo for 72 hours and additional blood samples will be obtained at baseline&#xD;
      and at 24 hours. Follow up on respiratory failure and mortality will be performed on dag 28&#xD;
      and 90.&#xD;
&#xD;
      This trial is conducted in accordance with the Helsinki 2 Declaration and International&#xD;
      Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use,&#xD;
      Guideline for Good Clinical Practice (ICH-GCP) and in compliance with the protocol. As part&#xD;
      of the quality assurance on-site monitoring visit will be performed by the an independent&#xD;
      GCP-unit including source data verification. Standard Operation Procedure (SOP) to address&#xD;
      protocol specific procedures such as data collection and adverse event reporting are&#xD;
      developed.&#xD;
&#xD;
      The number of patients participating is based on a power calculation using the data on days&#xD;
      alive and free from mechanical ventilation in the ICU within 28 days from a randomized,&#xD;
      double blind, placebo controlled clinical trial in patients with acute respiratory distress&#xD;
      syndrome ARDS (NTC 02622724).&#xD;
&#xD;
      The number of patients may be increased if required for regulatory approval for this&#xD;
      indication.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 15, 2020</start_date>
  <completion_date type="Actual">April 23, 2021</completion_date>
  <primary_completion_date type="Actual">February 23, 2021</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>
    <intervention_model_description>Randomization active/placebo (1:1) parallel arms</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>The preparation will be done by an unblinded study nurse at the respective ICU´s, who will be responsible for preparing the investigational drug so that it can be administered in blinded fashion. Iloprost is a colorless fluid that is to be diluted in 0.9% saline. The infusion pump containing diluted active drug and placebo will be identical on how the fluid looks and behaves.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Mechanical ventilation free days</measure>
    <time_frame>Until ICU discharge, maximun 28 days after randomization</time_frame>
    <description>Days alive without mechanical ventilation in the ICU within 28 days</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>28 and 90-day mortality</measure>
    <time_frame>Day 28 and 90 after randomization</time_frame>
    <description>Vital status of the patient at day 28 and day 90</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Modified Sequential Organ Failure Assessment (SOFA)</measure>
    <time_frame>Until ICU discharge, maximun 90 days after randomization</time_frame>
    <description>Mean daily modified SOFA score in the intensive care unit (scores for each of five systems range from 0 to 4, with higher scores indicating more severe dysfunction; range score 0-20).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Vasopressor free days</measure>
    <time_frame>Until ICU discharge, maximun 90 days after randomization</time_frame>
    <description>Days alive without vasopressor in the ICU within 28-and 90 days</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Renal replacement free days</measure>
    <time_frame>Until ICU discharge, maximun 90 days after randomization</time_frame>
    <description>Days without renal replacement in the ICU within 28 -and 90 days</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mechanical ventilation free days</measure>
    <time_frame>Until ICU discharge, maximun 90 days after randomization</time_frame>
    <description>Days alive without mechanical ventilation in the ICU within 90 days</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serious adverse reactions (SARs)</measure>
    <time_frame>Until day 7 after randomization</time_frame>
    <description>Numbers of serious adverse reactions within the first 7 days</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serious adverse events (SAEs)</measure>
    <time_frame>Until day 7 after randomization</time_frame>
    <description>Numbers of serious adverse events within the first 7 days</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">80</enrollment>
  <condition>COVID-19</condition>
  <condition>Respiratory Failure</condition>
  <arm_group>
    <arm_group_label>Iloprost</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients randomized to active treatment (n=40 patients) will receive continuous infusion of iloprost for 72 hours after inclusion or until discharge to ward or death, whichever comes first.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Isotonic saline</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Patients randomized to placebo treatment (n=40 patients) will receive continuous infusion of placebo for 72 hours after inclusion or until discharge to ward or death, whichever comes first.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Iloprost</intervention_name>
    <description>Continuously infusion for 72 hours at 3 ml/hours. Treatment dose 1 ng/kg/min</description>
    <arm_group_label>Iloprost</arm_group_label>
    <other_name>Ilomedin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Isotonic saline</intervention_name>
    <description>Continuously infusion for 72 hours at 3 ml/hours</description>
    <arm_group_label>Isotonic saline</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Adult intensive care patients (aged 18 years or above)&#xD;
&#xD;
          -  Confirmed COVID-19 infection&#xD;
&#xD;
          -  Need for mechanical ventilation (&lt; 72 hours at time of screening)&#xD;
&#xD;
          -  Soluble thrombomodulin (sTM) ≥ 4 ng/mL&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Withdrawal from active therapy&#xD;
&#xD;
          -  Pregnancy (non-pregnancy confirmed by patient being postmenopausal (age 60 or above)&#xD;
             or having a negative urine- or plasma-hCG)&#xD;
&#xD;
          -  Known hypersensitivity to iloprost or to any of the other ingredients.&#xD;
&#xD;
          -  Previously included in this trial or a prostacyclin trial within 30 days&#xD;
&#xD;
          -  Consent cannot be obtained&#xD;
&#xD;
          -  Life-threatening bleeding defined by the treating physician&#xD;
&#xD;
          -  Known severe heart failure (NYHA class IV)&#xD;
&#xD;
          -  Suspected acute coronary syndrome&#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>Anders Perner, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Copenhagen University Hospital, Intensive care Unit 4131</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Pär I Johansson, MD, DMSc</last_name>
    <role>Study Director</role>
    <affiliation>Copenhagen University Hospital, Capital Blood Bank 2034</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Dept. of Anaesthesia and Intensive Care, Bispebjerg Hospital</name>
      <address>
        <city>Copenhagen</city>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dept. of Intensive Care, Copenhagen University Hospital, Rigshospitalet</name>
      <address>
        <city>Copenhagen</city>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dept. of Intensive Care, Copenhagen University Hospital Herlev</name>
      <address>
        <city>Herlev</city>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dept. of Anaesthesia and Intensive Care, Nordsjaelands Hospital</name>
      <address>
        <city>Hillerød</city>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dept. of Anaesthesia and Intensive Care, Hvidovre Hospital</name>
      <address>
        <city>Hvidovre</city>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Denmark</country>
  </location_countries>
  <reference>
    <citation>Johansson PI, Soe-Jensen P, Bestle MH, Clausen NE, Kristiansen KT, Lange T, Stensballe J, Perner A. Prostacyclin in Intubated Patients with COVID-19 and Severe Endotheliopathy: A Multicenter, Randomized Clinical Trial. Am J Respir Crit Care Med. 2022 Feb 1;205(3):324-329. doi: 10.1164/rccm.202108-1855OC.</citation>
    <PMID>34813414</PMID>
  </reference>
  <results_reference>
    <citation>Johansson PI, Bestle M, Soe-Jensen P, Kristiansen KT, Stensballe J, Clausen NE, Perner A. The effect of prostacyclin (Iloprost) infusion at a dose of 1 ng/kg/min for 72 hours compared to placebo in mechanically ventilated patients with COVID-19: A structured summary of a study protocol for a randomized controlled trial. Trials. 2020 Aug 26;21(1):746. doi: 10.1186/s13063-020-04696-2.</citation>
    <PMID>32847626</PMID>
  </results_reference>
  <verification_date>December 2021</verification_date>
  <study_first_submitted>June 4, 2020</study_first_submitted>
  <study_first_submitted_qc>June 5, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 9, 2020</study_first_posted>
  <last_update_submitted>December 8, 2021</last_update_submitted>
  <last_update_submitted_qc>December 8, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">December 29, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Rigshospitalet, Denmark</investigator_affiliation>
    <investigator_full_name>Pär Johansson</investigator_full_name>
    <investigator_title>Sponsor</investigator_title>
  </responsible_party>
  <keyword>COVID-19</keyword>
  <keyword>SHINE</keyword>
  <keyword>Endotheliopathy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>COVID-19</mesh_term>
    <mesh_term>Respiratory Insufficiency</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Iloprost</mesh_term>
  </intervention_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/NCT04420741
org study id: COMBAT-COVID-19
secondary id: 2020-001296-33
nct id: NCT04420741
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The purpose of this trial is to investigate the efficacy and safety of continuous intravenous
      administration of low dose iloprost versus placebo for 72-hours, in 80 patients with COVID-19
      suffering from respiratory failure. The study hypothesis is that iloprost may be beneficial
      as an endothelial rescue treatment as it is anticipated to deactivate the endothelium and
      restore vascular integrity in COVID-19 patients suffering from respiratory failure caused by
      endothelial breakdown, ultimately improving survival. Given that the pulmonary system, apart
      from the brain, is the most highly vascularized vital organ in the body, extensive
      endothelial damage is a central feature of acute respiratory distress syndrome (ARDS) with
      respiratory failure being the rationale for the current study COMBAT-COVID-19.
Patients with the most severe type of sepsis, those with septic shock have a mortality rate
      between 30% to 45% due to multiple organ failure. The poor outcome of shocked patients, and
      especially those with sepsis, may by related to microvascular endothelial dysfunction.

      Coronavirus disease 2019 (COVID-19) is an infectious disease caused by coronavirus 2
      (SARS-CoV-2) and, thus, being a novel cause of sepsis. The disease was first identified in
      2019 in Wuhan, the capital of Hubei, China, and has since spread globally, resulting in the
      2019-20 coronavirus pandemic. Common symptoms include fever, cough and shortness of breath,
      muscle pain and sputum production. While many cases result in mild symptoms, some progress to
      pneumonia and multi-organ failure. In particular COVID-19 is associated with ARDS with
      respiratory failure and high mortality.

      Evidence support that iloprost infusion significantly improved endothelial function and
      integrity, The main objective in this trial is to investigate whether continuous infusion of
      lov dose iloprost at a dose of 1 ng/kg/min for 72-hours is safe and significantly reduce the
      need of respiratory support in the intensive care unit (ICU) compared to infusion of placebo
      in patients with COVID-19 induced pulmonary endotheliopathy (SHINE).

      Patients that are eligible for this trial will be temporarily incompetent due to acute severe
      illness relating to respiratory failure, therefore informed consent will be obtained from a
      scientific guardian. Next-of kin and subsequently the patient will co-sign as soon as
      possible hereafter. During the trial, patient will be given continuous infusion of low dose
      iloprost or placebo for 72 hours and additional blood samples will be obtained at baseline
      and at 24 hours. Follow up on respiratory failure and mortality will be performed on dag 28
      and 90.

      This trial is conducted in accordance with the Helsinki 2 Declaration and International
      Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use,
      Guideline for Good Clinical Practice (ICH-GCP) and in compliance with the protocol. As part
      of the quality assurance on-site monitoring visit will be performed by the an independent
      GCP-unit including source data verification. Standard Operation Procedure (SOP) to address
      protocol specific procedures such as data collection and adverse event reporting are
      developed.

      The number of patients participating is based on a power calculation using the data on days
      alive and free from mechanical ventilation in the ICU within 28 days from a randomized,
      double blind, placebo controlled clinical trial in patients with acute respiratory distress
      syndrome ARDS (NTC 02622724).

      The number of patients may be increased if required for regulatory approval for this
      indication.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Randomization active/placebo (1:1) parallel arms
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: The preparation will be done by an unblinded study nurse at the respective ICU´s, who will be responsible for preparing the investigational drug so that it can be administered in blinded fashion. Iloprost is a colorless fluid that is to be diluted in 0.9% saline. The infusion pump containing diluted active drug and placebo will be identical on how the fluid looks and behaves.
measure: Mechanical ventilation free days
time frame: Until ICU discharge, maximun 28 days after randomization
description: Days alive without mechanical ventilation in the ICU within 28 days
measure: 28 and 90-day mortality
time frame: Day 28 and 90 after randomization
description: Vital status of the patient at day 28 and day 90
measure: Modified Sequential Organ Failure Assessment (SOFA)
time frame: Until ICU discharge, maximun 90 days after randomization
description: Mean daily modified SOFA score in the intensive care unit (scores for each of five systems range from 0 to 4, with higher scores indicating more severe dysfunction; range score 0-20).
measure: Vasopressor free days
time frame: Until ICU discharge, maximun 90 days after randomization
description: Days alive without vasopressor in the ICU within 28-and 90 days
measure: Renal replacement free days
time frame: Until ICU discharge, maximun 90 days after randomization
description: Days without renal replacement in the ICU within 28 -and 90 days
measure: Mechanical ventilation free days
time frame: Until ICU discharge, maximun 90 days after randomization
description: Days alive without mechanical ventilation in the ICU within 90 days
measure: Serious adverse reactions (SARs)
time frame: Until day 7 after randomization
description: Numbers of serious adverse reactions within the first 7 days
measure: Serious adverse events (SAEs)
time frame: Until day 7 after randomization
description: Numbers of serious adverse events within the first 7 days
arm group label: Iloprost
arm group type: Experimental
description: Patients randomized to active treatment (n=40 patients) will receive continuous infusion of iloprost for 72 hours after inclusion or until discharge to ward or death, whichever comes first.
arm group label: Isotonic saline
arm group type: Placebo Comparator
description: Patients randomized to placebo treatment (n=40 patients) will receive continuous infusion of placebo for 72 hours after inclusion or until discharge to ward or death, whichever comes first.
intervention type: Drug
intervention name: Iloprost
description: Continuously infusion for 72 hours at 3 ml/hours. Treatment dose 1 ng/kg/min
arm group label: Iloprost
other name: Ilomedin
intervention type: Drug
intervention name: Isotonic saline
description: Continuously infusion for 72 hours at 3 ml/hours
arm group label: Isotonic saline
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Anders Perner, MD, PhD
role: Principal Investigator
affiliation: Copenhagen University Hospital, Intensive care Unit 4131
last name: Pär I Johansson, MD, DMSc
role: Study Director
affiliation: Copenhagen University Hospital, Capital Blood Bank 2034
facility: 
facility: 
facility: 
facility: 
facility: 
country: Denmark
citation: Johansson PI, Soe-Jensen P, Bestle MH, Clausen NE, Kristiansen KT, Lange T, Stensballe J, Perner A. Prostacyclin in Intubated Patients with COVID-19 and Severe Endotheliopathy: A Multicenter, Randomized Clinical Trial. Am J Respir Crit Care Med. 2022 Feb 1;205(3):324-329. doi: 10.1164/rccm.202108-1855OC.
PMID: 34813414
citation: Johansson PI, Bestle M, Soe-Jensen P, Kristiansen KT, Stensballe J, Clausen NE, Perner A. The effect of prostacyclin (Iloprost) infusion at a dose of 1 ng/kg/min for 72 hours compared to placebo in mechanically ventilated patients with COVID-19: A structured summary of a study protocol for a randomized controlled trial. Trials. 2020 Aug 26;21(1):746. doi: 10.1186/s13063-020-04696-2.
PMID: 32847626
responsible party type: Sponsor-Investigator
investigator affiliation: Rigshospitalet, Denmark
investigator full name: Pär Johansson
investigator title: Sponsor
mesh term: COVID-19
mesh term: Respiratory Insufficiency
mesh term: Iloprost
sharing ipd: No