<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/NCT04400032</url>
  </required_header>
  <id_info>
    <org_study_id>20200243-01H</org_study_id>
    <nct_id>NCT04400032</nct_id>
  </id_info>
  <brief_title>Cellular Immuno-Therapy for COVID-19 Acute Respiratory Distress Syndrome</brief_title>
  <acronym>CIRCA-19</acronym>
  <official_title>Cellular Immuno-Therapy for COVID-19 ARDS (CIRCA-19)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Ottawa Hospital Research Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Stem Cell Network</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Ontario Research Fund</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Ottawa Hospital Research Institute</source>
  <oversight_info>
    <has_dmc>Yes</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 clinical picture of the novel corona virus 2 (SARS-CoV-2) disease (COVID-19) is rapidly&#xD;
      evolving. Although infections may be mild, up to 25% of all patients admitted to hospital&#xD;
      require admission to the intensive care unit, and as many as 40% will progress to develop&#xD;
      severe problems breathing due to the acute respiratory distress syndrome (ARDS). ARDS often&#xD;
      requires mechanical ventilation, with a 50% risk of mortality. Researchers at the Ottawa&#xD;
      Hospital Research Institute (OHRI) have been studying the potential therapeutic role of&#xD;
      mesenchymal stromal/stem cells, or MSCs, for the treatment of ARDS for over a decade. This&#xD;
      has led to the world's first clinical trial using MSC therapy for patients with severe&#xD;
      infections (sepsis) which is often associated with ARDS (NCT02421484). This trial&#xD;
      demonstrated tolerability, and potential signs of efficacy. In addition, the investigators&#xD;
      have established expertise in producing clinical-grade MSCs and have received approval from&#xD;
      Health Canada for the use of MSCs in three different clinical studies.&#xD;
&#xD;
      This protocol consists of 2 sequential trials using the same trial infrastructure, noted as&#xD;
      the Phase 1 trial 'CIRCA-1901' and the Phase 2a trial 'CIRCA-1902'. CIRCA-1901 is an&#xD;
      open-label, dose-escalating and safety trial using a 3+3+3 design to determine the safety,&#xD;
      and maximum feasible tolerated dose of repeated delivery of Umbilical Cord Mesenchymal&#xD;
      Stromal Cells (UC-MSC) intravenously. The investigators will enroll up to 9 patients; each&#xD;
      receiving repeated unit doses of UC-MSCs delivered by IV infusion on each of 3 consecutive&#xD;
      days (24±4 hours apart) according to the following dose-escalation schedule (3 patients per&#xD;
      dose panel): (i) Panel 1: 25 million cells/unit dose (cumulative dose: 75 million MSCs), (ii)&#xD;
      Panel 2: 50 million cells/unit dose (cumulative dose: 150 million MSCs), (iii) Panel 3: up to&#xD;
      90 million cells/unit dose (cumulative dose: up to 270 million MSCs). If no safety issues are&#xD;
      identified, we will continue to the Phase 2a trial.&#xD;
&#xD;
      CIRCA-1902 is a single-arm, open-label extension of the CIRCA-1901 trial to assess early&#xD;
      signs of efficacy (major morbidity and mortality). The Phase 2a trial (CIRCA-1902) will&#xD;
      enroll 12 patients to assess early signals of benefit on mortality and major morbidity in a&#xD;
      high risk, high mortality population.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 15, 2020</start_date>
  <completion_date type="Actual">April 22, 2021</completion_date>
  <primary_completion_date type="Actual">April 22, 2021</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>Non-Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <intervention_model_description>CIRCA-1901 is is a dose-escalating and safety trial using a 3+3+3 design to determine the safety, and maximum feasible tolerated dose (MFTD) of intravenously (IV) delivered umbilical cord derived MSCs (UC-MSCs). If no safety issues are identified, we will continue to the Phase 2a trial.&#xD;
CIRCA-1902 is a single-arm, open-label extension of the CIRCA-1901 trial to assess early signs of efficacy (major morbidity and mortality). The Phase 2a trial (CIRCA-1902) will enroll 12 patients to assess early signals of benefit on mortality and major morbidity in a high risk, high mortality population.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v4.0</measure>
    <time_frame>At time of infusion until one year post-infusion</time_frame>
    <description>Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v4.0 to determine the maximum feasible tolerated dose (MFTD) of UC-MSCs given to patients with COVID-19</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of Participants alive by Day 28</measure>
    <time_frame>Day 28</time_frame>
    <description>Number of Participants alive by Day 28</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants with ventilator-free Days by Day 28</measure>
    <time_frame>Day 28</time_frame>
    <description>Number of Participants with ventilator-free Days by Day 28</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">15</enrollment>
  <condition>Acute Respiratory Distress Syndrome</condition>
  <condition>Covid19</condition>
  <arm_group>
    <arm_group_label>Panel 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>25 million cells/unit dose (cumulative dose: 75 million MSCs)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Panel 2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>50 million cells/unit dose (cumulative dose: 150 million MSCs)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Panel 3</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>up to 90 million cells/unit dose (cumulative dose: up to 270 million MSCs)</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Mesenchymal Stromal Cells</intervention_name>
    <description>The Mesenchymal Stromal Cells will be administered intravenously</description>
    <arm_group_label>Panel 1</arm_group_label>
    <arm_group_label>Panel 2</arm_group_label>
    <arm_group_label>Panel 3</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age of ≥18 years&#xD;
&#xD;
          -  Laboratory-confirmed SARS-CoV-2 infection during the current admission&#xD;
&#xD;
          -  On invasive, non-invasive mechanical ventilation (NIV) (PEEP≥5 cmH20) or high-flow&#xD;
             nasal canula (HFNC) oxygen therapy (minimum total flow rate of 40 lpm)&#xD;
&#xD;
          -  ARDS (onset &lt;96h) as per the international consensus definition (P/F) ratio &lt; 300 on&#xD;
             fraction of inspired oxygen (FiO2)≥0.5, with PEEP ≥5cm H2O or on HFNC), not due to&#xD;
             cardiac causes.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        An individual who meets any of the following criteria will be excluded from participation&#xD;
        in this trial:&#xD;
&#xD;
          -  No consent/inability to obtain consent&#xD;
&#xD;
          -  Moribund patient not expected to survive 24 hours&#xD;
&#xD;
          -  Any other irreversible disease or condition for which 6-month mortality is estimated&#xD;
             to be greater than 50%&#xD;
&#xD;
          -  Currently receiving extracorporeal life support&#xD;
&#xD;
          -  Pregnant or lactating&#xD;
&#xD;
          -  Patients with a prior or concurrent malignancy whose natural history or treatment does&#xD;
             not have the potential to interfere with the safety or efficacy assessment of the&#xD;
             investigational regimen are eligible for this trial&#xD;
&#xD;
          -  Moderate to severe chronic liver disease (Childs-Pugh Score &gt; 12)&#xD;
&#xD;
          -  Severe chronic respiratory disease with a baseline PaCO2 &gt; 50 mm Hg or the use of home&#xD;
             oxygen&#xD;
&#xD;
          -  Lung transplant patient&#xD;
&#xD;
          -  Documented deep venous thrombosis or pulmonary embolism within the past 3 months&#xD;
&#xD;
          -  Inability/contra-indications to receiving local standard of care thromboprophylaxis&#xD;
&#xD;
          -  Chronic immunosuppression (any chronic immunotherapy including daily oral steroid use&#xD;
             &gt;6months)&#xD;
&#xD;
          -  Known HIV, Hep B/C positive, or active Tuberculosis&#xD;
&#xD;
          -  Multisystem shock (SOFA score of &gt;2 in &gt;2 systems)&#xD;
&#xD;
          -  Patient, surrogate, or physician not committed to full support including intubation&#xD;
             (exception: a patient will not be excluded if he/she would receive all supportive care&#xD;
             except for attempts at resuscitation from cardiac arrest)&#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>Duncan J Stewart, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Ottawa Hospital Research Institute</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>The Ottawa Hospital</name>
      <address>
        <city>Ottawa</city>
        <state>Ontario</state>
        <zip>K1H 8L6</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>April 2021</verification_date>
  <study_first_submitted>April 27, 2020</study_first_submitted>
  <study_first_submitted_qc>May 20, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 22, 2020</study_first_posted>
  <last_update_submitted>April 23, 2021</last_update_submitted>
  <last_update_submitted_qc>April 23, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">April 26, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>ARDS</keyword>
  <keyword>COVID-19</keyword>
  <keyword>Mesenchymal Stromal Cells</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>
  <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/NCT04400032
org study id: 20200243-01H
nct id: NCT04400032
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The clinical picture of the novel corona virus 2 (SARS-CoV-2) disease (COVID-19) is rapidly
      evolving. Although infections may be mild, up to 25% of all patients admitted to hospital
      require admission to the intensive care unit, and as many as 40% will progress to develop
      severe problems breathing due to the acute respiratory distress syndrome (ARDS). ARDS often
      requires mechanical ventilation, with a 50% risk of mortality. Researchers at the Ottawa
      Hospital Research Institute (OHRI) have been studying the potential therapeutic role of
      mesenchymal stromal/stem cells, or MSCs, for the treatment of ARDS for over a decade. This
      has led to the world's first clinical trial using MSC therapy for patients with severe
      infections (sepsis) which is often associated with ARDS (NCT02421484). This trial
      demonstrated tolerability, and potential signs of efficacy. In addition, the investigators
      have established expertise in producing clinical-grade MSCs and have received approval from
      Health Canada for the use of MSCs in three different clinical studies.

      This protocol consists of 2 sequential trials using the same trial infrastructure, noted as
      the Phase 1 trial 'CIRCA-1901' and the Phase 2a trial 'CIRCA-1902'. CIRCA-1901 is an
      open-label, dose-escalating and safety trial using a 3+3+3 design to determine the safety,
      and maximum feasible tolerated dose of repeated delivery of Umbilical Cord Mesenchymal
      Stromal Cells (UC-MSC) intravenously. The investigators will enroll up to 9 patients; each
      receiving repeated unit doses of UC-MSCs delivered by IV infusion on each of 3 consecutive
      days (24±4 hours apart) according to the following dose-escalation schedule (3 patients per
      dose panel): (i) Panel 1: 25 million cells/unit dose (cumulative dose: 75 million MSCs), (ii)
      Panel 2: 50 million cells/unit dose (cumulative dose: 150 million MSCs), (iii) Panel 3: up to
      90 million cells/unit dose (cumulative dose: up to 270 million MSCs). If no safety issues are
      identified, we will continue to the Phase 2a trial.

      CIRCA-1902 is a single-arm, open-label extension of the CIRCA-1901 trial to assess early
      signs of efficacy (major morbidity and mortality). The Phase 2a trial (CIRCA-1902) will
      enroll 12 patients to assess early signals of benefit on mortality and major morbidity in a
      high risk, high mortality population.
allocation: Non-Randomized
intervention model: Sequential Assignment
intervention model description: CIRCA-1901 is is a dose-escalating and safety trial using a 3+3+3 design to determine the safety, and maximum feasible tolerated dose (MFTD) of intravenously (IV) delivered umbilical cord derived MSCs (UC-MSCs). If no safety issues are identified, we will continue to the Phase 2a trial.
CIRCA-1902 is a single-arm, open-label extension of the CIRCA-1901 trial to assess early signs of efficacy (major morbidity and mortality). The Phase 2a trial (CIRCA-1902) will enroll 12 patients to assess early signals of benefit on mortality and major morbidity in a high risk, high mortality population.
primary purpose: Treatment
masking: None (Open Label)
measure: Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v4.0
time frame: At time of infusion until one year post-infusion
description: Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v4.0 to determine the maximum feasible tolerated dose (MFTD) of UC-MSCs given to patients with COVID-19
measure: Number of Participants alive by Day 28
time frame: Day 28
description: Number of Participants alive by Day 28
measure: Number of Participants with ventilator-free Days by Day 28
time frame: Day 28
description: Number of Participants with ventilator-free Days by Day 28
arm group label: Panel 1
arm group type: Experimental
description: 25 million cells/unit dose (cumulative dose: 75 million MSCs)
arm group label: Panel 2
arm group type: Experimental
description: 50 million cells/unit dose (cumulative dose: 150 million MSCs)
arm group label: Panel 3
arm group type: Experimental
description: up to 90 million cells/unit dose (cumulative dose: up to 270 million MSCs)
intervention type: Biological
intervention name: Mesenchymal Stromal Cells
description: The Mesenchymal Stromal Cells will be administered intravenously
arm group label: Panel 1
arm group label: Panel 2
arm group label: Panel 3
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Duncan J Stewart, MD
role: Principal Investigator
affiliation: Ottawa Hospital Research Institute
facility: 
country: Canada
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
sharing ipd: No