<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/NCT04478539</url>
  </required_header>
  <id_info>
    <org_study_id>EBPZ.357</org_study_id>
    <nct_id>NCT04478539</nct_id>
  </id_info>
  <brief_title>Extracorporeal Blood Purification as a Treatment Modality for COVID-19</brief_title>
  <official_title>Clinical Efficacy and Safety of Extracorporeal Blood Purification to Control Hyperinflammation and Hypercoagulability in COVID-19 Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Zan Mitrev Clinic</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Zan Mitrev Clinic</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Several studies have suggested a potential clinical benefit of controlling hyper inflammation&#xD;
      triggered by SARS-CoV-2/COVID-19. Blood purification, the removal of excessive&#xD;
      proinflammatory mediators may control disease progression and support clinical recovery.&#xD;
&#xD;
      For this purpose, COVID-19 patients might benefit from treatment with AN69ST hemofilter based&#xD;
      extracorporeal blood purification.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      COVID-19 disease progression is associated with dysregulated immunity, commonly referred to&#xD;
      as cytokine storm, in particular, aberrant Interleukin (IL) 6 levels that promote numerous&#xD;
      pathological downstream effects. Hyperinflammation is a well-established trigger of&#xD;
      multiorgan failure, for example, acute kidney injury. Moreover, recent reports point to a&#xD;
      link between hyper inflammation and COVID-19 induced coagulopathy as a result of increased&#xD;
      production of clotting factors by the liver.&#xD;
&#xD;
      Despite several lines of evidence pointing to a potential clinical benefit of controlling&#xD;
      hyperinflammation triggered by COVID-19, management of COVID-19 remains mostly supportive&#xD;
      built around continuous respiratory support.&#xD;
&#xD;
      To this end, considering the underlying immunological character of COVID-19 disease and the&#xD;
      high risk of SARS-CoV-2 hyperinflammation to trigger ARDS, hypercoagulability and Acute&#xD;
      Kidney Injury (AKI) this study aims to monitor selected biochemical, immunological and&#xD;
      coagulation parameters in combination with radiological imaging to guide clinical practice&#xD;
      and to tailor therapy consisting of 1) early initiation of blood purification using the&#xD;
      oXiris® (AN69ST) filter, 2) systemic heparinisation and 3) respiratory support&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 1, 2020</start_date>
  <completion_date type="Actual">July 1, 2021</completion_date>
  <primary_completion_date type="Actual">July 1, 2021</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Retrospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Changes in cytokine levels of Interleukin (IL) 6, IL-8 and Tumor Necrosis Factor-α (pg/mL)</measure>
    <time_frame>Hospitalisation window, day 0 until day 14 or until hospital discharge (whichever comes first)</time_frame>
    <description>Systemic levels of IL-6, IL-8 and TNF-α are evaluated to assess the effect of blood purification.&#xD;
Measurement points: at admission, &quot;before and after a blood purification cycle&quot; and before discharge</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Changes in inflammatory markers; C-Reactive Protein (CRP) (mg/L)</measure>
    <time_frame>Hospitalisation window, day 0 until day 14 or until hospital discharge (whichever comes first)</time_frame>
    <description>Systemic levels of proinflammatory mediators are measured as a marker for disease severity.&#xD;
Measurement points: at admission, &quot;before and after a blood purification cycle&quot; and before discharge.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Changes in thrombocyte counts (10^3 counts/microL)</measure>
    <time_frame>Hospitalisation window, day 0 until day 14 or until hospital discharge (whichever comes first)</time_frame>
    <description>Systemic levels of thrombocytes are measured as a marker for disease severity.&#xD;
Measurement points: at admission, &quot;before and after a blood purification cycle&quot; and before discharge.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Changes in the coagulation marker Fibrinogen (g/L)</measure>
    <time_frame>Hospitalisation window, day 0 until day 14 or until hospital discharge (whichever comes first)</time_frame>
    <description>Coagulation markers will be followed to assess the effect of systemic heparinisation,&#xD;
Measurement points, at admission, &quot;before and after a blood purification cycle&quot; and before discharge</description>
  </primary_outcome>
  <primary_outcome>
    <measure>ICU length of stay after admission (days)</measure>
    <time_frame>An expected average of 4 - 14 hospitalisation days or until hospital discharge (whichever comes first)</time_frame>
    <description>Duration of intensive care will be determined in relation to the number of blood purification cycles&#xD;
Patients will be followed for the duration of ICU stay.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Changes in Neutrophil-to-Lymphocyte Ratio</measure>
    <time_frame>Hospitalisation window, day 0 until day 14 or until hospital discharge (whichever comes first)</time_frame>
    <description>Systemic levels of proinflammatory mediators are measured as a marker for disease severity.&#xD;
Measurement points: at admission, &quot;before and after a blood purification cycle&quot; and before discharge.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in the coagulation marker D-Dimers (ng/mL)</measure>
    <time_frame>Hospitalisation window, day 0 until day 14 or until hospital discharge (whichever comes first)</time_frame>
    <description>Coagulation markers will be followed to assess the effect of systemic heparinisation,&#xD;
Measurement points, at admission, &quot;before and after a blood purification cycle&quot; and before discharge</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in the Activation Clotting Time (seconds).</measure>
    <time_frame>Hospitalisation window, day 0 until day 14 or until hospital discharge (whichever comes first)</time_frame>
    <description>Coagulation markers will be followed to assess the effect of systemic heparinisation,&#xD;
Measurement points, at admission, &quot;before and after a blood purification cycle&quot; and before discharge</description>
  </secondary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Actual">35</enrollment>
  <condition>Covid19</condition>
  <arm_group>
    <arm_group_label>COVID-19 patients admitted to the ICU</arm_group_label>
    <description>COVID-19 patients will be treated with the Prismaflex® oXiris® system in the ICU.&#xD;
Treatment will be initiated within 4 - 12 hours after admission upon establishing control of the haemostasis, ACT = Activated Coagulation Time of 180 seconds</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Extracorporeal blood purification using the oXiris® (AN69ST) hemofilter</intervention_name>
    <description>Admitted patients will receive at least 1 cycle of extracorporeal blood purification using the oXiris® (AN69ST) hemofilter (Baxter, IL, USA). The number of cycles of blood purification is determined based on multiple biochemical, immunological, coagulation parameters, radiological imaging and overall clinical condition.&#xD;
The patient is connected to the Prismaflex® oXiris® system via a double lumen catheter placed in the femoral vein or vena subclavia.&#xD;
Flow rates will be maintained as follow; effluent dose 35 mL/Kg/h, dialysate 14 - 16 mL/Kg/h, blood 150 mL/min, replacement 16 -18 mL/Kg/h; patient fluid removal is tailored to the individual's volume status, ≈ 100 - 250 mL/h.&#xD;
The oXiris® extracorporeal and organ support modality will be chosen according to the patient's kidney function; continuous venovenous hemofiltration (CVVH), continuous venovenous hemodiafiltration (CVVHDF) or slow continuous ultrafiltration (SCUF).</description>
    <arm_group_label>COVID-19 patients admitted to the ICU</arm_group_label>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        COVID positive patients admitted to ICU&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Confirmed COVID-19 disease:&#xD;
&#xD;
          -  RT-PCR&#xD;
&#xD;
          -  Atypical Pneumonia; X-Ray and/or Computed Tomography&#xD;
&#xD;
          -  ≥ 1 oXiris® blood purification cycle&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Heart failure; severe systolic dysfunction, left ventricular ejection fraction &lt; 25%&#xD;
             requiring urgent surgery&#xD;
&#xD;
          -  Aortic Aneurysms, dissection or rupture requiring urgent surgery&#xD;
&#xD;
          -  Recent Myocardial Infarction; cardiovascular disease patients requiring urgent surgery&#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>Zan K Mitrev, MD</last_name>
    <role>Study Director</role>
    <affiliation>Zan Mitrev Clinic</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Rodney A Rosalia, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Zan Mitrev Clinic</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Zan Mitrev Clinic</name>
      <address>
        <city>Skopje</city>
        <zip>1000</zip>
        <country>North Macedonia</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>North Macedonia</country>
  </location_countries>
  <link>
    <url>https://www.baxter.com/baxter-newsroom/baxter-obtains-us-fda-emergency-use-authorization-oxiris-blood-purification-filter</url>
    <description>FDA Emergency Use Authorization for Oxiris Blood Purification Filter for COVID-19 Treatment</description>
  </link>
  <reference>
    <citation>Malard B, Lambert C, Kellum JA. In vitro comparison of the adsorption of inflammatory mediators by blood purification devices. Intensive Care Med Exp. 2018 May 4;6(1):12. doi: 10.1186/s40635-018-0177-2.</citation>
    <PMID>29728790</PMID>
  </reference>
  <reference>
    <citation>Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ; HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020 Mar 28;395(10229):1033-1034. doi: 10.1016/S0140-6736(20)30628-0. Epub 2020 Mar 16. No abstract available.</citation>
    <PMID>32192578</PMID>
  </reference>
  <reference>
    <citation>The Lancet Haematology. COVID-19 coagulopathy: an evolving story. Lancet Haematol. 2020 Jun;7(6):e425. doi: 10.1016/S2352-3026(20)30151-4. No abstract available.</citation>
    <PMID>32470428</PMID>
  </reference>
  <reference>
    <citation>Herold T, Jurinovic V, Arnreich C, Lipworth BJ, Hellmuth JC, von Bergwelt-Baildon M, Klein M, Weinberger T. Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19. J Allergy Clin Immunol. 2020 Jul;146(1):128-136.e4. doi: 10.1016/j.jaci.2020.05.008. Epub 2020 May 18.</citation>
    <PMID>32425269</PMID>
  </reference>
  <reference>
    <citation>Zhang Y, Yu L, Tang L, Zhu M, Jin Y, Wang Z, Li L. A Promising Anti-Cytokine-Storm Targeted Therapy for COVID-19: The Artificial-Liver Blood-Purification System. Engineering (Beijing). 2021 Jan;7(1):11-13. doi: 10.1016/j.eng.2020.03.006. Epub 2020 Mar 20. No abstract available.</citation>
    <PMID>32292628</PMID>
  </reference>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>July 14, 2020</study_first_submitted>
  <study_first_submitted_qc>July 17, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 20, 2020</study_first_posted>
  <last_update_submitted>November 28, 2022</last_update_submitted>
  <last_update_submitted_qc>November 28, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">December 1, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>SARS-CoV-2</keyword>
  <keyword>cytokine storm</keyword>
  <keyword>Interleukin 6</keyword>
  <keyword>hypercoagulability</keyword>
  <keyword>Fibrinogen</keyword>
  <keyword>D-dimer</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>COVID-19</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/NCT04478539
org study id: EBPZ.357
nct id: NCT04478539
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: Yes
is us export: Yes
Several studies have suggested a potential clinical benefit of controlling hyper inflammation
      triggered by SARS-CoV-2/COVID-19. Blood purification, the removal of excessive
      proinflammatory mediators may control disease progression and support clinical recovery.

      For this purpose, COVID-19 patients might benefit from treatment with AN69ST hemofilter based
      extracorporeal blood purification.
COVID-19 disease progression is associated with dysregulated immunity, commonly referred to
      as cytokine storm, in particular, aberrant Interleukin (IL) 6 levels that promote numerous
      pathological downstream effects. Hyperinflammation is a well-established trigger of
      multiorgan failure, for example, acute kidney injury. Moreover, recent reports point to a
      link between hyper inflammation and COVID-19 induced coagulopathy as a result of increased
      production of clotting factors by the liver.

      Despite several lines of evidence pointing to a potential clinical benefit of controlling
      hyperinflammation triggered by COVID-19, management of COVID-19 remains mostly supportive
      built around continuous respiratory support.

      To this end, considering the underlying immunological character of COVID-19 disease and the
      high risk of SARS-CoV-2 hyperinflammation to trigger ARDS, hypercoagulability and Acute
      Kidney Injury (AKI) this study aims to monitor selected biochemical, immunological and
      coagulation parameters in combination with radiological imaging to guide clinical practice
      and to tailor therapy consisting of 1) early initiation of blood purification using the
      oXiris® (AN69ST) filter, 2) systemic heparinisation and 3) respiratory support
observational model: Cohort
time perspective: Retrospective
measure: Changes in cytokine levels of Interleukin (IL) 6, IL-8 and Tumor Necrosis Factor-α (pg/mL)
time frame: Hospitalisation window, day 0 until day 14 or until hospital discharge (whichever comes first)
description: Systemic levels of IL-6, IL-8 and TNF-α are evaluated to assess the effect of blood purification.
Measurement points: at admission, "before and after a blood purification cycle" and before discharge
measure: Changes in inflammatory markers; C-Reactive Protein (CRP) (mg/L)
time frame: Hospitalisation window, day 0 until day 14 or until hospital discharge (whichever comes first)
description: Systemic levels of proinflammatory mediators are measured as a marker for disease severity.
Measurement points: at admission, "before and after a blood purification cycle" and before discharge.
measure: Changes in thrombocyte counts (10^3 counts/microL)
time frame: Hospitalisation window, day 0 until day 14 or until hospital discharge (whichever comes first)
description: Systemic levels of thrombocytes are measured as a marker for disease severity.
Measurement points: at admission, "before and after a blood purification cycle" and before discharge.
measure: Changes in the coagulation marker Fibrinogen (g/L)
time frame: Hospitalisation window, day 0 until day 14 or until hospital discharge (whichever comes first)
description: Coagulation markers will be followed to assess the effect of systemic heparinisation,
Measurement points, at admission, "before and after a blood purification cycle" and before discharge
measure: ICU length of stay after admission (days)
time frame: An expected average of 4 - 14 hospitalisation days or until hospital discharge (whichever comes first)
description: Duration of intensive care will be determined in relation to the number of blood purification cycles
Patients will be followed for the duration of ICU stay.
measure: Changes in Neutrophil-to-Lymphocyte Ratio
time frame: Hospitalisation window, day 0 until day 14 or until hospital discharge (whichever comes first)
description: Systemic levels of proinflammatory mediators are measured as a marker for disease severity.
Measurement points: at admission, "before and after a blood purification cycle" and before discharge.
measure: Changes in the coagulation marker D-Dimers (ng/mL)
time frame: Hospitalisation window, day 0 until day 14 or until hospital discharge (whichever comes first)
description: Coagulation markers will be followed to assess the effect of systemic heparinisation,
Measurement points, at admission, "before and after a blood purification cycle" and before discharge
measure: Changes in the Activation Clotting Time (seconds).
time frame: Hospitalisation window, day 0 until day 14 or until hospital discharge (whichever comes first)
description: Coagulation markers will be followed to assess the effect of systemic heparinisation,
Measurement points, at admission, "before and after a blood purification cycle" and before discharge
arm group label: COVID-19 patients admitted to the ICU
description: COVID-19 patients will be treated with the Prismaflex® oXiris® system in the ICU.
Treatment will be initiated within 4 - 12 hours after admission upon establishing control of the haemostasis, ACT = Activated Coagulation Time of 180 seconds
intervention type: Device
intervention name: Extracorporeal blood purification using the oXiris® (AN69ST) hemofilter
description: Admitted patients will receive at least 1 cycle of extracorporeal blood purification using the oXiris® (AN69ST) hemofilter (Baxter, IL, USA). The number of cycles of blood purification is determined based on multiple biochemical, immunological, coagulation parameters, radiological imaging and overall clinical condition.
The patient is connected to the Prismaflex® oXiris® system via a double lumen catheter placed in the femoral vein or vena subclavia.
Flow rates will be maintained as follow; effluent dose 35 mL/Kg/h, dialysate 14 - 16 mL/Kg/h, blood 150 mL/min, replacement 16 -18 mL/Kg/h; patient fluid removal is tailored to the individual's volume status, ≈ 100 - 250 mL/h.
The oXiris® extracorporeal and organ support modality will be chosen according to the patient's kidney function; continuous venovenous hemofiltration (CVVH), continuous venovenous hemodiafiltration (CVVHDF) or slow continuous ultrafiltration (SCUF).
arm group label: COVID-19 patients admitted to the ICU
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Zan K Mitrev, MD
role: Study Director
affiliation: Zan Mitrev Clinic
last name: Rodney A Rosalia, PhD
role: Principal Investigator
affiliation: Zan Mitrev Clinic
facility: 
country: North Macedonia
url: https://www.baxter.com/baxter-newsroom/baxter-obtains-us-fda-emergency-use-authorization-oxiris-blood-purification-filter
description: FDA Emergency Use Authorization for Oxiris Blood Purification Filter for COVID-19 Treatment
citation: Malard B, Lambert C, Kellum JA. In vitro comparison of the adsorption of inflammatory mediators by blood purification devices. Intensive Care Med Exp. 2018 May 4;6(1):12. doi: 10.1186/s40635-018-0177-2.
PMID: 29728790
citation: Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ; HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020 Mar 28;395(10229):1033-1034. doi: 10.1016/S0140-6736(20)30628-0. Epub 2020 Mar 16. No abstract available.
PMID: 32192578
citation: The Lancet Haematology. COVID-19 coagulopathy: an evolving story. Lancet Haematol. 2020 Jun;7(6):e425. doi: 10.1016/S2352-3026(20)30151-4. No abstract available.
PMID: 32470428
citation: Herold T, Jurinovic V, Arnreich C, Lipworth BJ, Hellmuth JC, von Bergwelt-Baildon M, Klein M, Weinberger T. Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19. J Allergy Clin Immunol. 2020 Jul;146(1):128-136.e4. doi: 10.1016/j.jaci.2020.05.008. Epub 2020 May 18.
PMID: 32425269
citation: Zhang Y, Yu L, Tang L, Zhu M, Jin Y, Wang Z, Li L. A Promising Anti-Cytokine-Storm Targeted Therapy for COVID-19: The Artificial-Liver Blood-Purification System. Engineering (Beijing). 2021 Jan;7(1):11-13. doi: 10.1016/j.eng.2020.03.006. Epub 2020 Mar 20. No abstract available.
PMID: 32292628
responsible party type: Sponsor
mesh term: COVID-19
sharing ipd: No