<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/NCT04466098</url>
  </required_header>
  <id_info>
    <org_study_id>2020LS075</org_study_id>
    <secondary_id>MT2020-12</secondary_id>
    <nct_id>NCT04466098</nct_id>
  </id_info>
  <brief_title>Multiple Dosing of Mesenchymal Stromal Cells in Patients With ARDS (COVID-19)</brief_title>
  <official_title>Multi-center, Randomized, Placebo Controlled, Interventional Phase 2A Clinical Trial Evaluating the Safety and Potential Efficacy of Multiple Dosing of Mesenchymal Stromal Cells in Patients With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-Cov-2)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Masonic Cancer Center, University of Minnesota</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Masonic Cancer Center, University of Minnesota</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a multi-center, randomized, placebo controlled, interventional phase 2A trial to&#xD;
      evaluate the safety profile and potential efficacy of multi-dosing of mesenchymal stromal&#xD;
      cells (MSC) for patients with SARS-CoV-2 associated Acute Respiratory Distress Syndrome&#xD;
      (ARDS). After informed consent, treatment assignment will be made by computer-generated&#xD;
      randomization to administer either MSC or vehicle placebo control with a 2:1 allocation to&#xD;
      the MSC: placebo arm.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      MSCs are adult, non-hematopoietic precursor cells derived from a variety of tissues (e.g.,&#xD;
      bone marrow, adipose tissue, and placenta) and have been used as therapy in multiple&#xD;
      conditions, especially in immune-mediated inflammatory diseases, such as graft versus-host&#xD;
      disease (GVHD) and systemic lupus erythematosus (SLE) with evidence of benefit.&#xD;
&#xD;
      In preclinical models, MSC are effective in ameliorating acute lung injury due to their&#xD;
      ability to secrete paracrine factors that regulate lung endothelial and epithelial&#xD;
      permeability, including growth factors, anti-inflammatory cytokines, and antimicrobial&#xD;
      peptides. Based on the promising pre-clinical preliminary data and intriguing results in&#xD;
      patients with COVID-19 associated pneumonia and ARDS as well as an established safety profile&#xD;
      of MSC generally and in ARDS in particular, the researchers propose multiple dosing of MSCs&#xD;
      as a study treatment to ameliorate the severity and duration of SARS-CoV-2 associated&#xD;
      pneumonia and ARDS potentially improve survival.&#xD;
&#xD;
      Patients will receive study agent (MSC or placebo) within 48 hours of enrollment. Three doses&#xD;
      will be administered unless a severe infusion adverse event occurs that is related to the MSC&#xD;
      infusion. Doses will be repeated approximately every 48-72 hours with the aim of completing 3&#xD;
      doses within 7 days of the first dose. All patients will receive standard of care treatments&#xD;
      for ARDS.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">July 30, 2020</start_date>
  <completion_date type="Anticipated">December 2023</completion_date>
  <primary_completion_date type="Actual">February 25, 2022</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>This is a randomized (2:1 ratio) placebo controlled trial.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
    <masking_description>Patients will be randomly assigned (2:1) to receive either 300 × 10^6 MSC or vehicle placebo control. Randomization will be stratified by risk (high versus standard risk based on the presence of preexisting co-morbidities), using permuted block sizes of 3. The allocation sequence will be accessed by each cell processing laboratory through ONCORE. Personnel in the cell processing laboratories are not masked to the treatment group, but patients, clinical staff, and investigators will be unaware of treatment assignment. To maintain masking of the investigators and clinicians, bags containing the study products and intravenous tubing had opaque coverings applied in the cell laboratories.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Incidence of grade 3-5 infusional toxicities and predefined hemodynamic or respiratory adverse events related to the infusion of MSC</measure>
    <time_frame>Within 6 hours of the start of the infusion</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence of a reduction in one or more biomarkers of inflammation by day 7</measure>
    <time_frame>Day 7 after first infusion</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Trend changes in PaO2:FiO2 ratio</measure>
    <time_frame>On the day of screening and on days 3, 7 and 14 after first infusion</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Trend changes in Mean Airway Pressure</measure>
    <time_frame>On the day of screening and on days 3, 7 and 14 after first infusion</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Trend changes in peak pressure</measure>
    <time_frame>On the day of screening and on days 3, 7 and 14 after first infusion</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Trend changes in plateau pressure</measure>
    <time_frame>On the day of screening (baseline) and on days 3, 7 and 14 after first infusion</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Trend changes in Positive end-expiratory airway pressure (PEEP)</measure>
    <time_frame>On the day of screening and on days 3, 7 and 14 after first infusion</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of mortality</measure>
    <time_frame>28 days after first infusion</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of mortality</measure>
    <time_frame>100 days after first infusion</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of ICU-free days</measure>
    <time_frame>28 days after first infusion</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of days alive and ventilator free composite score 3</measure>
    <time_frame>28 days after first infusion</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in acute lung injury (ALI) score 2</measure>
    <time_frame>Baseline and Day 28 after first infusion</time_frame>
    <description>Acute Lung Injury Score is a composite 4 point scoring system validated by the NHLBI ARDS Network that considers PaO2/FiO2, the level of positive end-expiratory airway pressure, respiratory compliance, and the extent of pulmonary infiltrates on the chest radiograph</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of serious adverse events</measure>
    <time_frame>28 days after first infusion</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of days alive off supplemental oxygen</measure>
    <time_frame>100 days after first infusion</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">9</enrollment>
  <condition>Acute Respiratory Distress Syndrome</condition>
  <condition>ARDS (Moderate or Severe)</condition>
  <condition>COVID-19 Pneumonia</condition>
  <arm_group>
    <arm_group_label>Mesenchymal Stromal Cells</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Three fixed doses of MSC approximately 48 hours apart.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Three fixed doses of placebo control approximately 48 hours apart.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Mesenchymal stromal cells</intervention_name>
    <description>Thawed product containing MSC(300x10^6) in DMSO resuspended 1:1 with Dextran 40 + 5% human serum albumin [total volume 60 mL]</description>
    <arm_group_label>Mesenchymal Stromal Cells</arm_group_label>
    <other_name>MSC</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Dextran 40 + 5% human serum albumin [total volume 60 mL]</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age 18-80 years&#xD;
&#xD;
          -  Meets 'Berlin Criteria' for diagnosis of moderate to severe ARDS for a minimum of 4&#xD;
             hours&#xD;
&#xD;
          -  Less than 48 hours on a ventilator after meeting criteria for diagnosis of ARDS&#xD;
&#xD;
          -  SARS-CoV-2 (proven by RT-PCR assay) with radiographic infiltrates&#xD;
&#xD;
          -  PaO2/FiO2 &lt; 250&#xD;
&#xD;
          -  Positive end-expiratory airway pressure (PEEP) &gt;5 cm H20&#xD;
&#xD;
          -  Elevated C-reactive protein (above laboratory upper limit of normal)&#xD;
&#xD;
          -  Meets organ function requirements, including left ventricular ejection fraction (LVEF)&#xD;
             &gt;35% ( as defined below)&#xD;
&#xD;
          -  Off other investigational agents directed against inflammatory cytokines 48 hours&#xD;
             prior to enrollment; agents directed against the replication of SARS-CoV-2 [e.g.,&#xD;
             Remdesivir] are permitted&#xD;
&#xD;
          -  Voluntary informed consent in person or virtually by the patient or patient surrogate&#xD;
             considering the face to face limitations during the COVID-19 pandemic and, given the&#xD;
             nature of the study population, which frequently requires mechanical ventilation with&#xD;
             sedation, surrogate consent will likely occur in a substantial proportion of the study&#xD;
             population (this will remain a valid consent until the patient is fully alert, and&#xD;
             aware, and can provide a second consent to continue participation in the study).&#xD;
&#xD;
          -  Adequate organ function is defined as:&#xD;
&#xD;
               -  Renal: Calculated estimated glomerular filtration rate &gt;30 mL/min/1.73 m2 (on&#xD;
                  chemistry panel)&#xD;
&#xD;
               -  Hepatic: Bilirubin &lt;3x upper limit of normal (ULN) and AST, ALT and alkaline&#xD;
                  phosphatase &lt;5x ULN&#xD;
&#xD;
               -  Cardiac: Absence of uncontrolled arrhythmia and LVEF &gt;35%&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Ventilator support of FiO2 &gt;0·8 or PEEP &gt;20 cm H2O and ongoing use of more than two&#xD;
             vasopressors for 2 or more hours with any agent at doses shown below in the supine&#xD;
             position.&#xD;
&#xD;
               -  Norepinephrine &gt;12 μg/min or 0.2 μg/kg per min&#xD;
&#xD;
               -  Phenylephrine &gt;150 μg/min or 3 μg/kg per min&#xD;
&#xD;
               -  Epinephrine &gt;10 ug/min or 0.2 μg/kg per min&#xD;
&#xD;
               -  Vasopressin &gt;0.04 units/min&#xD;
&#xD;
          -  Concurrent use of other investigational agents specifically for treatment of ARDS or&#xD;
             inflammatory cytokines. (Note: Agents established to be efficacious and/or those used&#xD;
             outside of formal trials are permitted as supportive data emerge)&#xD;
&#xD;
          -  Known ineligibility for use of a ventilator for a minimum of 7 days, as judged by the&#xD;
             institution's Triage Team&#xD;
&#xD;
          -  Known allergy to MSC components: fetal calf serum, human albumin or DMSO&#xD;
&#xD;
          -  Active invasive malignant disease requiring chemotherapy/radiation&#xD;
&#xD;
          -  Other concurrent life-threatening disease (life expectancy &lt;6 months) or eligible for&#xD;
             hospice care&#xD;
&#xD;
          -  Known history of HIV infection on active treatment&#xD;
&#xD;
          -  Females who are pregnant or breastfeeding&#xD;
&#xD;
          -  Current mean arterial pressure (MAP) &lt;60 mmHg while on 2 or more vasopressors at above&#xD;
             doses for more than 2 hours&#xD;
&#xD;
          -  History of any significant cardiac (myocardial infarction within 12 months of&#xD;
             screening visit or unstable angina), chronic ongoing hepatic, or renal disease (grade&#xD;
             3 or higher); diagnosis of congestive heart failure with hypoxemia primarily due to&#xD;
             decompensated heart failure; diagnosis of severe chronic obstructive pulmonary disease&#xD;
             (COPD) or interstitial lung disease requiring supplemental oxygen at home&#xD;
&#xD;
          -  Concurrent diagnosis of diffuse alveolar hemorrhage&#xD;
&#xD;
          -  Requiring continuous dialysis (unable to stop dialysis during study agent infusion)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>David Ingbar, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Masonic Cancer Center, University of Minnesota</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Minnesota</name>
      <address>
        <city>Minneapolis</city>
        <state>Minnesota</state>
        <zip>55455</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Pittsburgh</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15261</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>January 2023</verification_date>
  <study_first_submitted>July 8, 2020</study_first_submitted>
  <study_first_submitted_qc>July 8, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 10, 2020</study_first_posted>
  <last_update_submitted>January 31, 2023</last_update_submitted>
  <last_update_submitted_qc>January 31, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 1, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>cytokine storm</keyword>
  <keyword>Mesenchymal Stem Cells</keyword>
  <keyword>SARS-CoV-2</keyword>
  <keyword>COVID-19</keyword>
  <keyword>Mesenchymal Stromal Cells</keyword>
  <keyword>MSC</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>COVID-19</mesh_term>
    <mesh_term>Respiratory Distress Syndrome</mesh_term>
    <mesh_term>Respiratory Distress Syndrome, Newborn</mesh_term>
    <mesh_term>Acute Lung Injury</mesh_term>
    <mesh_term>Syndrome</mesh_term>
  </condition_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/NCT04466098
org study id: 2020LS075
secondary id: MT2020-12
nct id: NCT04466098
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This is a multi-center, randomized, placebo controlled, interventional phase 2A trial to
      evaluate the safety profile and potential efficacy of multi-dosing of mesenchymal stromal
      cells (MSC) for patients with SARS-CoV-2 associated Acute Respiratory Distress Syndrome
      (ARDS). After informed consent, treatment assignment will be made by computer-generated
      randomization to administer either MSC or vehicle placebo control with a 2:1 allocation to
      the MSC: placebo arm.
MSCs are adult, non-hematopoietic precursor cells derived from a variety of tissues (e.g.,
      bone marrow, adipose tissue, and placenta) and have been used as therapy in multiple
      conditions, especially in immune-mediated inflammatory diseases, such as graft versus-host
      disease (GVHD) and systemic lupus erythematosus (SLE) with evidence of benefit.

      In preclinical models, MSC are effective in ameliorating acute lung injury due to their
      ability to secrete paracrine factors that regulate lung endothelial and epithelial
      permeability, including growth factors, anti-inflammatory cytokines, and antimicrobial
      peptides. Based on the promising pre-clinical preliminary data and intriguing results in
      patients with COVID-19 associated pneumonia and ARDS as well as an established safety profile
      of MSC generally and in ARDS in particular, the researchers propose multiple dosing of MSCs
      as a study treatment to ameliorate the severity and duration of SARS-CoV-2 associated
      pneumonia and ARDS potentially improve survival.

      Patients will receive study agent (MSC or placebo) within 48 hours of enrollment. Three doses
      will be administered unless a severe infusion adverse event occurs that is related to the MSC
      infusion. Doses will be repeated approximately every 48-72 hours with the aim of completing 3
      doses within 7 days of the first dose. All patients will receive standard of care treatments
      for ARDS.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: This is a randomized (2:1 ratio) placebo controlled trial.
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
masking description: Patients will be randomly assigned (2:1) to receive either 300 × 10^6 MSC or vehicle placebo control. Randomization will be stratified by risk (high versus standard risk based on the presence of preexisting co-morbidities), using permuted block sizes of 3. The allocation sequence will be accessed by each cell processing laboratory through ONCORE. Personnel in the cell processing laboratories are not masked to the treatment group, but patients, clinical staff, and investigators will be unaware of treatment assignment. To maintain masking of the investigators and clinicians, bags containing the study products and intravenous tubing had opaque coverings applied in the cell laboratories.
measure: Incidence of grade 3-5 infusional toxicities and predefined hemodynamic or respiratory adverse events related to the infusion of MSC
time frame: Within 6 hours of the start of the infusion
measure: Incidence of a reduction in one or more biomarkers of inflammation by day 7
time frame: Day 7 after first infusion
measure: Trend changes in PaO2:FiO2 ratio
time frame: On the day of screening and on days 3, 7 and 14 after first infusion
measure: Trend changes in Mean Airway Pressure
time frame: On the day of screening and on days 3, 7 and 14 after first infusion
measure: Trend changes in peak pressure
time frame: On the day of screening and on days 3, 7 and 14 after first infusion
measure: Trend changes in plateau pressure
time frame: On the day of screening (baseline) and on days 3, 7 and 14 after first infusion
measure: Trend changes in Positive end-expiratory airway pressure (PEEP)
time frame: On the day of screening and on days 3, 7 and 14 after first infusion
measure: Incidence of mortality
time frame: 28 days after first infusion
measure: Incidence of mortality
time frame: 100 days after first infusion
measure: Number of ICU-free days
time frame: 28 days after first infusion
measure: Number of days alive and ventilator free composite score 3
time frame: 28 days after first infusion
measure: Change in acute lung injury (ALI) score 2
time frame: Baseline and Day 28 after first infusion
description: Acute Lung Injury Score is a composite 4 point scoring system validated by the NHLBI ARDS Network that considers PaO2/FiO2, the level of positive end-expiratory airway pressure, respiratory compliance, and the extent of pulmonary infiltrates on the chest radiograph
measure: Incidence of serious adverse events
time frame: 28 days after first infusion
measure: Number of days alive off supplemental oxygen
time frame: 100 days after first infusion
arm group label: Mesenchymal Stromal Cells
arm group type: Experimental
description: Three fixed doses of MSC approximately 48 hours apart.
arm group label: Placebo
arm group type: Placebo Comparator
description: Three fixed doses of placebo control approximately 48 hours apart.
intervention type: Biological
intervention name: Mesenchymal stromal cells
description: Thawed product containing MSC(300x10^6) in DMSO resuspended 1:1 with Dextran 40 + 5% human serum albumin [total volume 60 mL]
arm group label: Mesenchymal Stromal Cells
other name: MSC
intervention type: Other
intervention name: Placebo
description: Dextran 40 + 5% human serum albumin [total volume 60 mL]
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: David Ingbar, MD
role: Principal Investigator
affiliation: Masonic Cancer Center, University of Minnesota
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: COVID-19
mesh term: Respiratory Distress Syndrome
mesh term: Respiratory Distress Syndrome, Newborn
mesh term: Acute Lung Injury
mesh term: Syndrome