<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/NCT04445454</url>
  </required_header>
  <id_info>
    <org_study_id>TJT2012</org_study_id>
    <nct_id>NCT04445454</nct_id>
  </id_info>
  <brief_title>Mesenchymal Stromal Cell Therapy for Severe Covid-19 Infection</brief_title>
  <official_title>Mesenchymal Stromal Cell Therapy for Severe Covid-19 Infection</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Liege</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Liege</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 overall objective of the study is to evaluate the safety and efficacy of MSC therapy&#xD;
      combined with best supportive care in hospitalized patients with COVID-19.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This study is a monocentric prospective phase I/II clinical trial, aiming at evaluating the&#xD;
      safety and efficacy of 3 intravenous administrations of BM-MSC in 20 patients with severe to&#xD;
      critical COVID-19 pneumonia.&#xD;
&#xD;
      After signed informed consent, patients will receive 3 infusions of (1.5)-3.0 x106/kg BM-MSC&#xD;
      (from the same donor) at 3-4 days interval, in addition to the standard of care for COVID-19&#xD;
      disease.&#xD;
&#xD;
      The trial will be open for inclusion for 2 years after initiation. Each patient will be&#xD;
      followed for 90 days after inclusion. The total study duration will thus be 2 years and 90&#xD;
      days.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">June 12, 2020</start_date>
  <completion_date type="Anticipated">September 30, 2024</completion_date>
  <primary_completion_date type="Anticipated">September 30, 2024</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>This study is a monocentric prospective phase I/II clinical trial, aiming at evaluating the safety and efficacy of 3 intravenous administrations of BM-MSC in 20 patients with severe to critical COVID-19 pneumonia.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>To evaluate the safety of intravenous infusion of MSC in patients with severe to critical COVID-19 pneumonia</measure>
    <time_frame>Day 28</time_frame>
    <description>To assess the infusional toxicity</description>
  </primary_outcome>
  <primary_outcome>
    <measure>To evaluate the safety of intravenous infusion of MSC in patients with severe to critical COVID-19 pneumonia</measure>
    <time_frame>Day 28</time_frame>
    <description>To assess the number of Adverse events of special interest : Incidence of infections (bacterial, viral, fungal, parasitic) and thrombo-embolic events.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>To evaluate the efficacy of intravenous infusion of MSC in patients with severe to critical COVID-19 pneumonia</measure>
    <time_frame>Day 28</time_frame>
    <description>Group A (patients not under mechanical ventilation): to determine the pourcentage of patients requiring mechanical ventilation</description>
  </primary_outcome>
  <primary_outcome>
    <measure>To evaluate the efficacy of intravenous infusion of MSC in patients with severe to critical COVID-19 pneumonia</measure>
    <time_frame>Day 28</time_frame>
    <description>Group B (patients under mechanical ventilation): to determine the vital status (dead/alive)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>To evaluate the effect of MSC administration associated with the standard of care (SOC including anti-viral therapy)</measure>
    <time_frame>Day 28</time_frame>
    <description>To assess the clinical status (on a 7-point WHO ordinal scale)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To evaluate the effect of MSC administration associated with the standard of care (SOC including anti-viral therapy)</measure>
    <time_frame>Day 28</time_frame>
    <description>To assess the duration of oxygen therapy and/or mechanical ventilation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To evaluate the effect of MSC administration associated with the standard of care (SOC including anti-viral therapy)</measure>
    <time_frame>Day 90</time_frame>
    <description>To assess the length of stay at the intensive care unit and of hospitalization</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To evaluate the effect of MSC administration associated with the standard of care (SOC including anti-viral therapy)</measure>
    <time_frame>Day 28</time_frame>
    <description>To assess the number of organ failures</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To evaluate the effect of MSC administration associated with the standard of care (SOC including anti-viral therapy)</measure>
    <time_frame>Day 28</time_frame>
    <description>To assess the intensity of the inflammatory response</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To evaluate the effect of MSC administration associated with the standard of care (SOC including anti-viral therapy)</measure>
    <time_frame>Day 28</time_frame>
    <description>To assess the evolution of coagulation parameter</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To evaluate the effect of MSC administration associated with the standard of care (SOC including anti-viral therapy)</measure>
    <time_frame>Day 28</time_frame>
    <description>To assess the presence of Biomarker of lung lesion, repair and scarring</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To evaluate the effect of MSC administration associated with the standard of care (SOC including anti-viral therapy)</measure>
    <time_frame>Day 90</time_frame>
    <description>To assess the v iral load over the 28 days after inclusion and seroconversion to COVID-19 over the 90 days after inclusion</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To evaluate the effect of MSC administration associated with the standard of care (SOC including anti-viral therapy)</measure>
    <time_frame>Day 90</time_frame>
    <description>To assess the pulmonary function</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To evaluate the effect of MSC administration associated with the standard of care (SOC including anti-viral therapy)</measure>
    <time_frame>Day 90</time_frame>
    <description>To assess the number of adverse reactions (ARs), ARs grade &gt; 3, serious adverse events (SAEs), serious ARs (SARs), suspected expected and unexpected SARs (SESARs and SUSARs).</description>
  </secondary_outcome>
  <other_outcome>
    <measure>To investigate immune modulation</measure>
    <time_frame>Day 28</time_frame>
    <description>To determine the FACS analysis of regulatory T-cell (Treg) levels and Treg and Tconv sub-populations</description>
  </other_outcome>
  <other_outcome>
    <measure>To compare the cytotoxic activity of PBMCs from healthy control and COVID-19 patients (divided in responders / non-responders to MSC therapy) against MSCs in vitro</measure>
    <time_frame>Day 28</time_frame>
    <description>To assess the cytotoxic activity by MLR</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">20</enrollment>
  <condition>Coronavirus Infection</condition>
  <arm_group>
    <arm_group_label>MSC therapy for severe COVID-19 infection</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>After signed informed consent, patients will receive 3 infusions of (1.5)-3.0 x106/kg BM-MSC (from the same donor) at 3-4 days interval, in addition to the standard of care for COVID-19 disease.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Mesenchymal stromal cells</intervention_name>
    <description>Bone marrow collection and MSC expansion cultures will be carried out at the Laboratory of Cell and Gene Therapy (LTCG) at the University of Liège as described in IMPD and its SOPs.</description>
    <arm_group_label>MSC therapy for severe COVID-19 infection</arm_group_label>
    <other_name>MSC</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        COVID-19 patients Inclusion criteria&#xD;
&#xD;
          -  Male or female patients aged at least 18 years and up to 70 years&#xD;
&#xD;
          -  Diagnosed with microbiologically or radiologically confirmed COVID-19 pneumonia as&#xD;
             defined by:&#xD;
&#xD;
          -  Extensive interstitial pneumonia on CT scan, consistent with viral pneumonia, within&#xD;
             10 days prior to randomization&#xD;
&#xD;
          -  And either positive result of COVID-19 PCR test within 14 days prior to inclusion or&#xD;
             positive result of SARS-CoV2 PCR or serology within 14 days after inclusion.&#xD;
&#xD;
          -  Requiring oxygen administration (SpO2 ≤ 93% on room air):&#xD;
&#xD;
               -  Group A: in standard or intensive care unit requiring supplemental oxygen&#xD;
&#xD;
               -  Group B: in intensive care unit under mechanical ventilation administered through&#xD;
                  a tracheal tube, either:&#xD;
&#xD;
          -  for less than or equal to 7 days&#xD;
&#xD;
          -  for 7 to 14 days, with persisting high inflammation (ferritin &gt; 2,000 µg/L; ferritin &gt;&#xD;
             1,000 µg/L and rising; lymphocytes &lt; 800 with CRP &gt; 70 mg/L and rising or ferritin &gt;&#xD;
             700 µg/L and rising or LDH &gt; 300 UI/L or D-Dimers &gt; 1000 ng/ml), not explained by&#xD;
             superinfection. Rising = compared to previous 24H.&#xD;
&#xD;
          -  Written consent of the patient, or - if impossible (clinical condition precluding&#xD;
             capacity to consent) - of his/her legal representative, or - if impossible - of an&#xD;
             impartial witness such as a physician from a non-participating department or member of&#xD;
             the Ethics Committee. Any consent obtained this way shall be documented and confirmed&#xD;
             by way of normal consent procedures at the earliest opportunity when the patient has&#xD;
             recovered&#xD;
&#xD;
        Exclusion criteria&#xD;
&#xD;
          -  Ongoing pregnancy. Women of childbearing potential (WOCBP, defined as a premenopausal&#xD;
             female capable of becoming pregnant) should use an appropriate method of contraception&#xD;
             (oral, injectable, or mechanical contraception; women whose partners have been&#xD;
             vasectomized or have received or are utilizing mechanical contraceptive devices).&#xD;
&#xD;
          -  Extracorporeal membrane oxygenation&#xD;
&#xD;
          -  Limitations to intensity of care&#xD;
&#xD;
          -  Life expectancy &lt; 24 hours&#xD;
&#xD;
          -  Known allergy to IMP component&#xD;
&#xD;
          -  Active secondary infection&#xD;
&#xD;
          -  Any malignancy (except non-melanoma skin carcinoma) within 2 years before inclusion&#xD;
&#xD;
          -  Pre-existing thrombo-embolic pathology&#xD;
&#xD;
          -  Signs of an active drug or alcohol dependence, serious current illness, mental illness&#xD;
             or any factors which, in the opinion of the Investigator, may interfere with subject's&#xD;
             ability to understand and comply with study requirements&#xD;
&#xD;
          -  Patients with any serious medical condition or abnormality of clinical laboratory&#xD;
             tests that, in the Investigator's judgment, precludes the patient's safe participation&#xD;
             in and completion of the study.&#xD;
&#xD;
          -  Participation in another clinical trial(use of anti-viral/supportive drugs for&#xD;
             COVID-19 infection on a compassionate use basis is not an exclusion criterion).&#xD;
&#xD;
        MSC donors Inclusion criteria&#xD;
&#xD;
          -  Unrelated to the patient&#xD;
&#xD;
          -  Male or female&#xD;
&#xD;
          -  Age &gt; 18 yrs&#xD;
&#xD;
          -  No HLA matching required&#xD;
&#xD;
          -  Fulfills generally accepted criteria for allogeneic HSC donation&#xD;
&#xD;
          -  Informed consent given by donor&#xD;
&#xD;
        Exclusion criteria&#xD;
&#xD;
          -  Any condition not fulfilling inclusion criteria&#xD;
&#xD;
          -  Known allergy to lidocaine&#xD;
&#xD;
          -  Any risk factor for transmissible infectious diseases, in particular HIV&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Yves Beguin, MD,PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>CHU de Liège</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Yves Beguin, MD,PhD</last_name>
    <phone>(0032)43667201</phone>
    <email>yves.beguin@chuliege.be</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Audrey Janssen</last_name>
    <phone>(0032)43667470</phone>
    <email>audrey.janssen@chuliege.be</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>CHU de Liège</name>
      <address>
        <city>Liège</city>
        <zip>4000</zip>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Yves Beguin, MD,PhD</last_name>
      <phone>(0032)43667201</phone>
      <email>yves.beguin@chuliege.be</email>
    </contact>
    <investigator>
      <last_name>Benoit Misset, MD,PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Nathalie Layios, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Bernard Lambermont, MD,PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Michel Moutschen, MD,PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Gilles Darcis, MD,PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Belgium</country>
  </location_countries>
  <verification_date>September 2022</verification_date>
  <study_first_submitted>June 19, 2020</study_first_submitted>
  <study_first_submitted_qc>June 22, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 24, 2020</study_first_posted>
  <last_update_submitted>September 19, 2022</last_update_submitted>
  <last_update_submitted_qc>September 19, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">September 21, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Liege</investigator_affiliation>
    <investigator_full_name>Yves Beguin</investigator_full_name>
    <investigator_title>MD,PhD</investigator_title>
  </responsible_party>
  <keyword>mesenchymal stromal cells</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Infections</mesh_term>
    <mesh_term>Communicable Diseases</mesh_term>
    <mesh_term>Coronavirus Infections</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/NCT04445454
org study id: TJT2012
nct id: NCT04445454
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The overall objective of the study is to evaluate the safety and efficacy of MSC therapy
      combined with best supportive care in hospitalized patients with COVID-19.
This study is a monocentric prospective phase I/II clinical trial, aiming at evaluating the
      safety and efficacy of 3 intravenous administrations of BM-MSC in 20 patients with severe to
      critical COVID-19 pneumonia.

      After signed informed consent, patients will receive 3 infusions of (1.5)-3.0 x106/kg BM-MSC
      (from the same donor) at 3-4 days interval, in addition to the standard of care for COVID-19
      disease.

      The trial will be open for inclusion for 2 years after initiation. Each patient will be
      followed for 90 days after inclusion. The total study duration will thus be 2 years and 90
      days.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: This study is a monocentric prospective phase I/II clinical trial, aiming at evaluating the safety and efficacy of 3 intravenous administrations of BM-MSC in 20 patients with severe to critical COVID-19 pneumonia.
primary purpose: Treatment
masking: None (Open Label)
measure: To evaluate the safety of intravenous infusion of MSC in patients with severe to critical COVID-19 pneumonia
time frame: Day 28
description: To assess the infusional toxicity
measure: To evaluate the safety of intravenous infusion of MSC in patients with severe to critical COVID-19 pneumonia
time frame: Day 28
description: To assess the number of Adverse events of special interest : Incidence of infections (bacterial, viral, fungal, parasitic) and thrombo-embolic events.
measure: To evaluate the efficacy of intravenous infusion of MSC in patients with severe to critical COVID-19 pneumonia
time frame: Day 28
description: Group A (patients not under mechanical ventilation): to determine the pourcentage of patients requiring mechanical ventilation
measure: To evaluate the efficacy of intravenous infusion of MSC in patients with severe to critical COVID-19 pneumonia
time frame: Day 28
description: Group B (patients under mechanical ventilation): to determine the vital status (dead/alive)
measure: To evaluate the effect of MSC administration associated with the standard of care (SOC including anti-viral therapy)
time frame: Day 28
description: To assess the clinical status (on a 7-point WHO ordinal scale)
measure: To evaluate the effect of MSC administration associated with the standard of care (SOC including anti-viral therapy)
time frame: Day 28
description: To assess the duration of oxygen therapy and/or mechanical ventilation
measure: To evaluate the effect of MSC administration associated with the standard of care (SOC including anti-viral therapy)
time frame: Day 90
description: To assess the length of stay at the intensive care unit and of hospitalization
measure: To evaluate the effect of MSC administration associated with the standard of care (SOC including anti-viral therapy)
time frame: Day 28
description: To assess the number of organ failures
measure: To evaluate the effect of MSC administration associated with the standard of care (SOC including anti-viral therapy)
time frame: Day 28
description: To assess the intensity of the inflammatory response
measure: To evaluate the effect of MSC administration associated with the standard of care (SOC including anti-viral therapy)
time frame: Day 28
description: To assess the evolution of coagulation parameter
measure: To evaluate the effect of MSC administration associated with the standard of care (SOC including anti-viral therapy)
time frame: Day 28
description: To assess the presence of Biomarker of lung lesion, repair and scarring
measure: To evaluate the effect of MSC administration associated with the standard of care (SOC including anti-viral therapy)
time frame: Day 90
description: To assess the v iral load over the 28 days after inclusion and seroconversion to COVID-19 over the 90 days after inclusion
measure: To evaluate the effect of MSC administration associated with the standard of care (SOC including anti-viral therapy)
time frame: Day 90
description: To assess the pulmonary function
measure: To evaluate the effect of MSC administration associated with the standard of care (SOC including anti-viral therapy)
time frame: Day 90
description: To assess the number of adverse reactions (ARs), ARs grade > 3, serious adverse events (SAEs), serious ARs (SARs), suspected expected and unexpected SARs (SESARs and SUSARs).
measure: To investigate immune modulation
time frame: Day 28
description: To determine the FACS analysis of regulatory T-cell (Treg) levels and Treg and Tconv sub-populations
measure: To compare the cytotoxic activity of PBMCs from healthy control and COVID-19 patients (divided in responders / non-responders to MSC therapy) against MSCs in vitro
time frame: Day 28
description: To assess the cytotoxic activity by MLR
arm group label: MSC therapy for severe COVID-19 infection
arm group type: Experimental
description: After signed informed consent, patients will receive 3 infusions of (1.5)-3.0 x106/kg BM-MSC (from the same donor) at 3-4 days interval, in addition to the standard of care for COVID-19 disease.
intervention type: Biological
intervention name: Mesenchymal stromal cells
description: Bone marrow collection and MSC expansion cultures will be carried out at the Laboratory of Cell and Gene Therapy (LTCG) at the University of Liège as described in IMPD and its SOPs.
arm group label: MSC therapy for severe COVID-19 infection
other name: MSC
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Yves Beguin, MD,PhD
role: Principal Investigator
affiliation: CHU de Liège
last name: Yves Beguin, MD,PhD
phone: (0032)43667201
email: yves.beguin@chuliege.be
last name: Audrey Janssen
phone: (0032)43667470
email: audrey.janssen@chuliege.be
facility: 
status: Recruiting
contact: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
country: Belgium
responsible party type: Principal Investigator
investigator affiliation: University of Liege
investigator full name: Yves Beguin
investigator title: MD,PhD
mesh term: Infections
mesh term: Communicable Diseases
mesh term: Coronavirus Infections
sharing ipd: No