<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/NCT04416139</url>
  </required_header>
  <id_info>
    <org_study_id>SCI-3354-20-21-1</org_study_id>
    <nct_id>NCT04416139</nct_id>
  </id_info>
  <brief_title>Mesenchymal Stem Cell for Acute Respiratory Distress Syndrome Due for COVID-19</brief_title>
  <acronym>COVID-19</acronym>
  <official_title>Mesenchymal Stem Cells for the Treatment of Severe Acute Respiratory Distress Syndrome Due to COVID-19. Pilot Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran</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>
      Acute Respiratory Distress Syndrome (ARDS) is the main cause of death from COVID-19. One of&#xD;
      the main mechanisms for ARDS is the violent storm of cytokines and chemokines, which cause&#xD;
      uncontrolled fatal systemic inflammation by the immune system on the body, with additional&#xD;
      multiple organ failure. Mortality in cases of severe ARDS caused by COVID 19 varies&#xD;
      significantly between 50 and 90%, basically depending on the age of the patient and the&#xD;
      presence of comorbidities.&#xD;
&#xD;
      The plasticity of Mesenchymal Stem Cells (MSC) regulates inflammation and immunity. MSC can&#xD;
      promote and inhibit an immune response, depending on the dynamics of inflammation and&#xD;
      depending on the activation force of the immune system, the types of inflammatory cytokines&#xD;
      present, and the effects of immunosuppressants. Essentially, the state of inflammation&#xD;
      determines the immunoregulatory fate of MSC. Thus, IV application of AMSCa has been shown to&#xD;
      control the inflammatory response in various diseases, such as the graft-versus-host reaction&#xD;
      and the ARDS caused by H5NI.&#xD;
&#xD;
      The objective of this study is to describe the clinical changes secondary to IV&#xD;
      administration of MSC allogenic, in patients with bilateral COVID-19 pneumonia complicated by&#xD;
      severe ARDS, with the evaluation of the PaO2 / FiO2 ratio, heart and respiratory rates, and&#xD;
      the fever curve.&#xD;
&#xD;
      Five patients, of either sex, over 18 years of age, with bilateral pneumonia caused by&#xD;
      COVID-19 and severe SIRA that has not improved with the standard management measures used at&#xD;
      that time in the care center, will be included in the study. This treatment will be&#xD;
      administered after discussing it with the relatives that it is a procedure considered as&#xD;
      rescue and will be carried out with informed consent. 1x10(6) xKg will be applied IV.&#xD;
&#xD;
      The follow-up of the patient will be for three weeks. PaO2 / FiO2 data, fever, inflammatory&#xD;
      markers and immunity will be evaluated. The results will be compared with the historical&#xD;
      controls attended at INCMNSZ.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Acute Respiratory Distress Syndrome (ARDS) is the main cause of death from COVID-19. One of&#xD;
      the main mechanisms for ARDS is the storm of cytokines and chemokines, which cause&#xD;
      uncontrolled fatal systemic inflammation. The SARS-CoV-2 virus infects cells that express the&#xD;
      angiotensin II converting enzyme receptor (ACE2). This receptor is widely distributed on the&#xD;
      surface of type II alveolar cells (AT2) and on the capillary endothelium. This is why the&#xD;
      cytokine storm will trigger a violent attack by the immune system on the body, cause ARDS and&#xD;
      multiple organ failure, and can ultimately lead to death. Mortality in cases of severe SIRA&#xD;
      caused by COVID 19 varies significantly between 50 and 90%, basically depending on the age of&#xD;
      the patient and the presence of comorbidities.&#xD;
&#xD;
      The plasticity of Mesenchymal Stem Cell (MSC) regulates inflammation and immunity. MSC can&#xD;
      promote and inhibit an immune response, depending on the dynamics of inflammation and&#xD;
      depending on the activation force of the immune system, the types of inflammatory cytokines&#xD;
      present, and the effects of immunosuppressants. Essentially, the state of inflammation&#xD;
      determines the immunoregulatory fate of MSC. Thus, IV application of MSC has been shown to&#xD;
      control the inflammatory response in various diseases, such as the graft-versus-host reaction&#xD;
      and the ARDS caused by H5NI.&#xD;
&#xD;
      MSC are negative for ACE2, therefore they have been used to decrease the cytokine storm&#xD;
      present in COVID-19.&#xD;
&#xD;
      Two recent studies in China have used human allogeneic MSC to treat COVID-19 pneumonia. Both&#xD;
      studies reveal a marked reversal of symptoms, even in critically serious cases. Lung function&#xD;
      improved two days after MSC application and 10 days later they were discharged. Lymphocytes&#xD;
      increased, PCR decreased, and cytokine-producing immune cells disappeared within 3 to 6 days.&#xD;
      Regulatory immune cells increased. TNF alpha factor decreased and IL10 increased.&#xD;
&#xD;
      Taking into account the previous concepts together with the current global pandemic, and the&#xD;
      high mortality existing among patients with bilateral pneumonia caused by COVID-19 and severe&#xD;
      ARDS, the investigators propose intravenous infusion of mesenchymal stem cells from bank&#xD;
      laboratory, with the purpose partially proven to decrease the systemic inflammatory process,&#xD;
      offering it as a salvage treatment.&#xD;
&#xD;
      Five patients, of either sex, over 18 years of age, with bilateral pneumonia caused by&#xD;
      COVID-19 and severe ARDS that has not improved in relation to the following parameters: a)&#xD;
      Persistent PaO2 / FiO2 less than 150, b) persistent fever, c ) D-dimer increase of at least&#xD;
      50% of baseline and / or ferritin greater than 1000, after 48 h of hospital stay receiving&#xD;
      the standard management measures used at that time in the care center, will be included in&#xD;
      the study. Covid pneumonia should be confirmed by chest CT and RNA detection by positive&#xD;
      SARS-Cov2 PCR. This treatment will be administered after discussing it with the relatives&#xD;
      that it is a procedure considered as rescue and will be carried out with informed consent.&#xD;
&#xD;
      Their follow-up will be daily while they are hospitalized in the Intensive Care Unit and / or&#xD;
      hospitalized, until their discharge from the hospital or until the third week after surgery.&#xD;
      If the patient has already been discharged from the hospital, his last evaluation will be in&#xD;
      the third week.&#xD;
&#xD;
      The main objective of this protocol is: To describe the clinical changes secondary to IV&#xD;
      administration of MSC, in patients with bilateral COVID-19 pneumonia complicated by severe&#xD;
      ARDS, with the evaluation of the PaO2 / FiO2 ratio, heart rate and respiratory rate, as well&#xD;
      as of the fever curve daily.&#xD;
&#xD;
      The secondary objectives are:&#xD;
&#xD;
      a) To assess the effect of the proposed treatment on the general biochemical indicators&#xD;
      (Leukocytes, absolute lymphocytes, absolute neutrophils, absolute monocytes, absolute&#xD;
      eosinophils, absolute basophils, erythrocytes, hemoglobin, platelets, total bilirubin,&#xD;
      albumin, amino-aspartate transferase, fibrinogen, procalcitonin, glomerular filtration,&#xD;
      myoglobin, troponin, ferritin and D-dimer. Daily.&#xD;
&#xD;
      b. To assess the anti-inflammatory effect of the proposed treatment with assessment of the&#xD;
      levels of cytokines, and C-reactive protein, TNFa, IL10, IL1, IL6, IL17, VEGF in plasma.&#xD;
      These variables will be evaluated before treatment, upon discharge from the ICU, and / or&#xD;
      from the Hospital.&#xD;
&#xD;
      c. Assess the radiological evolution of the proposed treatment through simple chest CT. These&#xD;
      variables will be evaluated before treatment, upon discharge from the ICU, and / or from the&#xD;
      Hospital.&#xD;
&#xD;
      d. Evaluate immune system improvement with mass cytometry to analyze patients' immune cells:&#xD;
      regulatory T cells (CXCR3-), dendritic cells (DC, CXCR3-), CXCR3 + CD4 + T, CXCR3 + CD + T,&#xD;
      and CXCRT3 + NK. These variables will be evaluated before treatment, upon discharge from the&#xD;
      ICU, and / or from the Hospital.&#xD;
&#xD;
      e) Assess the safety of the proposed treatment (allergic reactions and / or infection) F. To&#xD;
      assess the negativization of the RNA detection test by SARS-Cov2 PCR. These variables will be&#xD;
      evaluated before treatment, upon discharge from the ICU, and / or from the Hospital.&#xD;
&#xD;
      The inclusion criteria are:&#xD;
&#xD;
        1. Comply with the informed consent procedure and sign the informed consent form.&#xD;
&#xD;
        2. Over 18 years&#xD;
&#xD;
        3. Of any gender&#xD;
&#xD;
        4. With SARS-Cov2 PCR RNA detection test, positive&#xD;
&#xD;
        5. With bilateral pneumonia caused by COVID-19&#xD;
&#xD;
        6. Severe ARDS with PaO2 / FiO2 less than 150&#xD;
&#xD;
        7. That it has not improved in relation to: a) Persistent PaO2 / FiO2 less than 150, b)&#xD;
           persistent fever, c) increase in D-dimer at least 50% of the baseline and / or ferritin&#xD;
           greater than 1000, after 48 hrs hospital stay receiving the standard management measures&#xD;
           used at that time in the care center.&#xD;
&#xD;
        8. Lymphopenia less than 800 total lymphocytes&#xD;
&#xD;
        9. Increased D-dimer (&gt; 1200 mg / dl)&#xD;
&#xD;
       10. CT compatible with bilateral pneumonia&#xD;
&#xD;
       11. SOFA under 11 With knowledge of the patient and / or their responsible relatives that it&#xD;
           is a rescue treatment, in an experimental phase.&#xD;
&#xD;
      The bank mesenchymal cells will be donated by the CBCells Bio Technology Laboratory, at no&#xD;
      cost to the patient or INCMNSZ.&#xD;
&#xD;
      1x106 x Kg of weight, diluted in 100 ml of saline, will be infused intravenously, to pass in&#xD;
      40 minutes. It will be monitored with monitors, Pao2 / Fio2, FC, FR, ECG. Additionally, fever&#xD;
      and muscle contractures will be monitored, which will be recorded every hour for 24 hours and&#xD;
      every 24 hours thereafter, up to three weeks after the application of MSC. The patient should&#xD;
      continue with their indicated medical treatments, such as antibiotics and specific treatments&#xD;
      in case of comorbidities.&#xD;
&#xD;
      The results will be compared with the historical controls attended at INCMNSZ Thus, the&#xD;
      results obtained will give information to calculate the sample size in subsequent studies in&#xD;
      which the usefulness of the procedure will be evaluated.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">May 1, 2020</start_date>
  <completion_date type="Anticipated">May 1, 2021</completion_date>
  <primary_completion_date type="Anticipated">April 30, 2021</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Mesenchymal Stem Cell from umbilical cord allogenic from de bank laboratory, will be applied IV to 5 patients con pneumonia bilateral due to COVID 19, complicated with acute respiratory distress syndrome. The clinical, biochemical, inflammatory and immune changes will be described and compare against historical cases treated in the Instituto Nacional de Ciencias Medicas y Nutrición Salvador Zubirán</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Functional Respiratory changes: PaO2 / FiO2 ratio</measure>
    <time_frame>Three weeks</time_frame>
    <description>To describe the clinical changes secondary to IV administration of AMSCa, in patients with bilateral COVID-19 pneumonia complicated by severe SIRA, with the evaluation of the PaO2 / FiO2 ratio.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Clinical cardiac changes: Heart rate per minute</measure>
    <time_frame>Three weeks</time_frame>
    <description>To describe the clinical changes secondary to IV administration of AMSCa, in patients with bilateral COVID-19 pneumonia complicated by severe SIRA, with the evaluation of the heart rate per minute.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Clinical Respiratory Changes: Respiratory rate per minute</measure>
    <time_frame>Three weeks</time_frame>
    <description>To describe the clinical changes secondary to IV administration of AMSCa, in patients with bilateral COVID-19 pneumonia complicated by severe SIRA, with the evaluation of the respiratory rate per minute.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Changes in body temperature</measure>
    <time_frame>Three weeks</time_frame>
    <description>To describe the clinical changes secondary to IV administration of AMSCa, in patients with bilateral COVID-19 pneumonia complicated by severe SIRA, with the evaluation of the fever curve in degrees centigrade.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>General biochemical changes in Leukocytes</measure>
    <time_frame>Three weeks</time_frame>
    <description>To assess the effect of the proposed treatment on the total Leukocytes</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>General biochemical changes on lymphocytes</measure>
    <time_frame>Three weeks</time_frame>
    <description>To assess the effect of the proposed treatment on absolute lymphocytes</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>General biochemical changes on platelets</measure>
    <time_frame>Three weeks</time_frame>
    <description>To assess the effect of the proposed treatment on total platelets</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>General biochemical changes on fibrinogen</measure>
    <time_frame>Three weeks</time_frame>
    <description>To assess the effect of the proposed treatment on serum fibrinogen</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>General biochemical changes on pocalcitonin</measure>
    <time_frame>Three weeks</time_frame>
    <description>To assess the effect of the proposed treatment on procalcitonin</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>General biochemical changes on ferritin</measure>
    <time_frame>Three weeks</time_frame>
    <description>To assess the effect of the proposed treatment on ferritin</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>General biochemical changes on D-dimer</measure>
    <time_frame>Three weeks</time_frame>
    <description>To assess the effect of the proposed treatment on D-dimer</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes on inflammatory C-reactive protein</measure>
    <time_frame>Three weeks</time_frame>
    <description>To assess the anti-inflammatory effect of the proposed treatment with assessment of the levels of C-reactive protein</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cahnges on Inflammatory cytokine TNFa</measure>
    <time_frame>Three weeks</time_frame>
    <description>To assess the anti-inflammatory effect of the proposed treatment with assessment of the levels of TNFa in plasma.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes on Inflammatory cytokine IL10</measure>
    <time_frame>Three weeks</time_frame>
    <description>To assess the anti-inflammatory effect of the proposed treatment with assessment of the levels of IL10 in plasma.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes on Inflammatory cytokine IL1</measure>
    <time_frame>Three weeks</time_frame>
    <description>To assess the anti-inflammatory effect of the proposed treatment with assessment of the levels of IL1 in plasma.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes on Inflammatory cytokine IL6</measure>
    <time_frame>Three weeks</time_frame>
    <description>To assess the anti-inflammatory effect of the proposed treatment with assessment of the levels of IL6 in plasma.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes on Inflammatory cytokine IL 17</measure>
    <time_frame>Three weeks</time_frame>
    <description>To assess the anti-inflammatory effect of the proposed treatment with assessment of the levels of IL17 in plasma</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes on VEGF</measure>
    <time_frame>Three weeks</time_frame>
    <description>To assess the anti-inflammatory effect of the proposed treatment with assessment of the levels of VEGF in plasma</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Radiological Changes</measure>
    <time_frame>Three weeks</time_frame>
    <description>Assess the radiological evolution of the proposed treatment through simple chest CT</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immunological changes on T cell</measure>
    <time_frame>Three weeks</time_frame>
    <description>Evaluate immune system improvement with mass cytometry to analyze patients' immune cells: regulatory T cells</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immunological changes on Dendritic cells</measure>
    <time_frame>Three weeks</time_frame>
    <description>Evaluate immune system improvement with mass cytometry to analyze patients' immune cells: dendritic cells</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immunological changes on CD4+ T</measure>
    <time_frame>Three weeks</time_frame>
    <description>Evaluate immune system improvement with mass cytometry to analyze patients' immune cells: CD4 + T</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immunological changes on CD8+ T</measure>
    <time_frame>Three weeks</time_frame>
    <description>Evaluate immune system improvement with mass cytometry to analyze patients' immune cells: CD8 + T</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immunological changes on NK cell</measure>
    <time_frame>Three weeks</time_frame>
    <description>Evaluate immune system improvement with mass cytometry to analyze patients' immune cells: NK cells</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse events</measure>
    <time_frame>Three weeks</time_frame>
    <description>Evaluate the safety of the proposed treatment (allergic reactions and / or infection)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>RNA detection by SARS-Cov2 PCR</measure>
    <time_frame>Three weeks</time_frame>
    <description>To assess the negativization of the SARS-Cov2 PCR RNA detection test</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">10</enrollment>
  <condition>Covid 19</condition>
  <arm_group>
    <arm_group_label>Treated group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Five patients, of any sex and age, with bilateral COVID-19 pneumonia, severe SIRA with PaO2 / FiO2 less than 150, lymphopenia less than 800 total lymphocytes, CT with bilateral pneumonia, SOFA less than 11 and that has not improved in relation to the following parameters: a) persistent PaO2 / FiO2 less than 150; b) persistent fever, c) increase in D-dimer of at least 50% of the baseline and / or ferritin greater than 1000, after 48 h of hospital stay receiving the standard management measures used at that time in the Care Center, will be included in the study. This treatment will be administered after discussing it with the relatives that it is a procedure considered as rescue and will be carried out with informed consent.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control Group</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>The results obtained in the treated group will be compared against the historical controls treated in INCMNSZ, evaluating the same variables.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Infusion IV of Mesenchymal Stem cells</intervention_name>
    <description>Mesenchymal Stem cells from bank will be applied IV, at dose 1 million xKg in a single dose</description>
    <arm_group_label>Treated group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Bilateral pneumonia due to COVID-19&#xD;
&#xD;
          -  With SARS-Cov2 PCR RNA detection test, positive&#xD;
&#xD;
          -  Severe ARDS&#xD;
&#xD;
          -  PaO2/FiO2 &lt;150&#xD;
&#xD;
          -  Leukocytes &lt; 800&#xD;
&#xD;
          -  Chest TAC with pneumonia bilateral&#xD;
&#xD;
          -  persistant fever&#xD;
&#xD;
          -  increase 50% D-Dimer, respect to basal value&#xD;
&#xD;
          -  Ferritin &gt; 1000&#xD;
&#xD;
          -  SOFA &lt; 11&#xD;
&#xD;
          -  Medical treatment during 48 hr according to de Institutional Medical center&#xD;
&#xD;
          -  With knowledge of the patient and / or his relatives responsible that it is a rescue&#xD;
             treatment, in experimental phase.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pneumonia or ARDS caused by COVID-19, mild and moderate.&#xD;
&#xD;
          -  More than three organic failures&#xD;
&#xD;
          -  Expectations of survival less than 48 hr in the opinion of the treating service&#xD;
&#xD;
          -  Pneumonia or SIRA not caused by COVID-19&#xD;
&#xD;
          -  Advance will of the patient to refuse rescue or experimental treatment.&#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_contact>
    <last_name>Martin Iglesias, MD</last_name>
    <phone>+1 52 55 5580097509</phone>
    <email>iglesias@drmartiniglesias.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Carlos A Aguilar-Salinas, MD</last_name>
    <phone>+1 52 55 54870900</phone>
    <phone_ext>6321</phone_ext>
    <email>caguilarsalinas@yahoo.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán</name>
      <address>
        <city>Mexico City</city>
        <zip>14080</zip>
        <country>Mexico</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Martin Iglesias, MD</last_name>
      <phone>+1 52 555580097509</phone>
      <email>iglesias@drmartiniglesias.com</email>
    </contact>
    <contact_backup>
      <last_name>Carlos Aguilar-Salinas, MD</last_name>
      <phone>*1 52 55 54870900</phone>
      <phone_ext>6321</phone_ext>
      <email>caguilarsalinas@yahoo.com</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Mexico</country>
  </location_countries>
  <verification_date>June 2020</verification_date>
  <study_first_submitted>May 30, 2020</study_first_submitted>
  <study_first_submitted_qc>June 3, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 4, 2020</study_first_posted>
  <last_update_submitted>June 3, 2020</last_update_submitted>
  <last_update_submitted_qc>June 3, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">June 4, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran</investigator_affiliation>
    <investigator_full_name>Martín Iglesias</investigator_full_name>
    <investigator_title>Plastic surgeon</investigator_title>
  </responsible_party>
  <keyword>Mesenchymal Stem Cell</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>
  </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/NCT04416139
org study id: SCI-3354-20-21-1
nct id: NCT04416139
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Acute Respiratory Distress Syndrome (ARDS) is the main cause of death from COVID-19. One of
      the main mechanisms for ARDS is the violent storm of cytokines and chemokines, which cause
      uncontrolled fatal systemic inflammation by the immune system on the body, with additional
      multiple organ failure. Mortality in cases of severe ARDS caused by COVID 19 varies
      significantly between 50 and 90%, basically depending on the age of the patient and the
      presence of comorbidities.

      The plasticity of Mesenchymal Stem Cells (MSC) regulates inflammation and immunity. MSC can
      promote and inhibit an immune response, depending on the dynamics of inflammation and
      depending on the activation force of the immune system, the types of inflammatory cytokines
      present, and the effects of immunosuppressants. Essentially, the state of inflammation
      determines the immunoregulatory fate of MSC. Thus, IV application of AMSCa has been shown to
      control the inflammatory response in various diseases, such as the graft-versus-host reaction
      and the ARDS caused by H5NI.

      The objective of this study is to describe the clinical changes secondary to IV
      administration of MSC allogenic, in patients with bilateral COVID-19 pneumonia complicated by
      severe ARDS, with the evaluation of the PaO2 / FiO2 ratio, heart and respiratory rates, and
      the fever curve.

      Five patients, of either sex, over 18 years of age, with bilateral pneumonia caused by
      COVID-19 and severe SIRA that has not improved with the standard management measures used at
      that time in the care center, will be included in the study. This treatment will be
      administered after discussing it with the relatives that it is a procedure considered as
      rescue and will be carried out with informed consent. 1x10(6) xKg will be applied IV.

      The follow-up of the patient will be for three weeks. PaO2 / FiO2 data, fever, inflammatory
      markers and immunity will be evaluated. The results will be compared with the historical
      controls attended at INCMNSZ.
Acute Respiratory Distress Syndrome (ARDS) is the main cause of death from COVID-19. One of
      the main mechanisms for ARDS is the storm of cytokines and chemokines, which cause
      uncontrolled fatal systemic inflammation. The SARS-CoV-2 virus infects cells that express the
      angiotensin II converting enzyme receptor (ACE2). This receptor is widely distributed on the
      surface of type II alveolar cells (AT2) and on the capillary endothelium. This is why the
      cytokine storm will trigger a violent attack by the immune system on the body, cause ARDS and
      multiple organ failure, and can ultimately lead to death. Mortality in cases of severe SIRA
      caused by COVID 19 varies significantly between 50 and 90%, basically depending on the age of
      the patient and the presence of comorbidities.

      The plasticity of Mesenchymal Stem Cell (MSC) regulates inflammation and immunity. MSC can
      promote and inhibit an immune response, depending on the dynamics of inflammation and
      depending on the activation force of the immune system, the types of inflammatory cytokines
      present, and the effects of immunosuppressants. Essentially, the state of inflammation
      determines the immunoregulatory fate of MSC. Thus, IV application of MSC has been shown to
      control the inflammatory response in various diseases, such as the graft-versus-host reaction
      and the ARDS caused by H5NI.

      MSC are negative for ACE2, therefore they have been used to decrease the cytokine storm
      present in COVID-19.

      Two recent studies in China have used human allogeneic MSC to treat COVID-19 pneumonia. Both
      studies reveal a marked reversal of symptoms, even in critically serious cases. Lung function
      improved two days after MSC application and 10 days later they were discharged. Lymphocytes
      increased, PCR decreased, and cytokine-producing immune cells disappeared within 3 to 6 days.
      Regulatory immune cells increased. TNF alpha factor decreased and IL10 increased.

      Taking into account the previous concepts together with the current global pandemic, and the
      high mortality existing among patients with bilateral pneumonia caused by COVID-19 and severe
      ARDS, the investigators propose intravenous infusion of mesenchymal stem cells from bank
      laboratory, with the purpose partially proven to decrease the systemic inflammatory process,
      offering it as a salvage treatment.

      Five patients, of either sex, over 18 years of age, with bilateral pneumonia caused by
      COVID-19 and severe ARDS that has not improved in relation to the following parameters: a)
      Persistent PaO2 / FiO2 less than 150, b) persistent fever, c ) D-dimer increase of at least
      50% of baseline and / or ferritin greater than 1000, after 48 h of hospital stay receiving
      the standard management measures used at that time in the care center, will be included in
      the study. Covid pneumonia should be confirmed by chest CT and RNA detection by positive
      SARS-Cov2 PCR. This treatment will be administered after discussing it with the relatives
      that it is a procedure considered as rescue and will be carried out with informed consent.

      Their follow-up will be daily while they are hospitalized in the Intensive Care Unit and / or
      hospitalized, until their discharge from the hospital or until the third week after surgery.
      If the patient has already been discharged from the hospital, his last evaluation will be in
      the third week.

      The main objective of this protocol is: To describe the clinical changes secondary to IV
      administration of MSC, in patients with bilateral COVID-19 pneumonia complicated by severe
      ARDS, with the evaluation of the PaO2 / FiO2 ratio, heart rate and respiratory rate, as well
      as of the fever curve daily.

      The secondary objectives are:

      a) To assess the effect of the proposed treatment on the general biochemical indicators
      (Leukocytes, absolute lymphocytes, absolute neutrophils, absolute monocytes, absolute
      eosinophils, absolute basophils, erythrocytes, hemoglobin, platelets, total bilirubin,
      albumin, amino-aspartate transferase, fibrinogen, procalcitonin, glomerular filtration,
      myoglobin, troponin, ferritin and D-dimer. Daily.

      b. To assess the anti-inflammatory effect of the proposed treatment with assessment of the
      levels of cytokines, and C-reactive protein, TNFa, IL10, IL1, IL6, IL17, VEGF in plasma.
      These variables will be evaluated before treatment, upon discharge from the ICU, and / or
      from the Hospital.

      c. Assess the radiological evolution of the proposed treatment through simple chest CT. These
      variables will be evaluated before treatment, upon discharge from the ICU, and / or from the
      Hospital.

      d. Evaluate immune system improvement with mass cytometry to analyze patients' immune cells:
      regulatory T cells (CXCR3-), dendritic cells (DC, CXCR3-), CXCR3 + CD4 + T, CXCR3 + CD + T,
      and CXCRT3 + NK. These variables will be evaluated before treatment, upon discharge from the
      ICU, and / or from the Hospital.

      e) Assess the safety of the proposed treatment (allergic reactions and / or infection) F. To
      assess the negativization of the RNA detection test by SARS-Cov2 PCR. These variables will be
      evaluated before treatment, upon discharge from the ICU, and / or from the Hospital.

      The inclusion criteria are:

        1. Comply with the informed consent procedure and sign the informed consent form.

        2. Over 18 years

        3. Of any gender

        4. With SARS-Cov2 PCR RNA detection test, positive

        5. With bilateral pneumonia caused by COVID-19

        6. Severe ARDS with PaO2 / FiO2 less than 150

        7. That it has not improved in relation to: a) Persistent PaO2 / FiO2 less than 150, b)
           persistent fever, c) increase in D-dimer at least 50% of the baseline and / or ferritin
           greater than 1000, after 48 hrs hospital stay receiving the standard management measures
           used at that time in the care center.

        8. Lymphopenia less than 800 total lymphocytes

        9. Increased D-dimer (> 1200 mg / dl)

       10. CT compatible with bilateral pneumonia

       11. SOFA under 11 With knowledge of the patient and / or their responsible relatives that it
           is a rescue treatment, in an experimental phase.

      The bank mesenchymal cells will be donated by the CBCells Bio Technology Laboratory, at no
      cost to the patient or INCMNSZ.

      1x106 x Kg of weight, diluted in 100 ml of saline, will be infused intravenously, to pass in
      40 minutes. It will be monitored with monitors, Pao2 / Fio2, FC, FR, ECG. Additionally, fever
      and muscle contractures will be monitored, which will be recorded every hour for 24 hours and
      every 24 hours thereafter, up to three weeks after the application of MSC. The patient should
      continue with their indicated medical treatments, such as antibiotics and specific treatments
      in case of comorbidities.

      The results will be compared with the historical controls attended at INCMNSZ Thus, the
      results obtained will give information to calculate the sample size in subsequent studies in
      which the usefulness of the procedure will be evaluated.
allocation: Non-Randomized
intervention model: Parallel Assignment
intervention model description: Mesenchymal Stem Cell from umbilical cord allogenic from de bank laboratory, will be applied IV to 5 patients con pneumonia bilateral due to COVID 19, complicated with acute respiratory distress syndrome. The clinical, biochemical, inflammatory and immune changes will be described and compare against historical cases treated in the Instituto Nacional de Ciencias Medicas y Nutrición Salvador Zubirán
primary purpose: Treatment
masking: None (Open Label)
measure: Functional Respiratory changes: PaO2 / FiO2 ratio
time frame: Three weeks
description: To describe the clinical changes secondary to IV administration of AMSCa, in patients with bilateral COVID-19 pneumonia complicated by severe SIRA, with the evaluation of the PaO2 / FiO2 ratio.
measure: Clinical cardiac changes: Heart rate per minute
time frame: Three weeks
description: To describe the clinical changes secondary to IV administration of AMSCa, in patients with bilateral COVID-19 pneumonia complicated by severe SIRA, with the evaluation of the heart rate per minute.
measure: Clinical Respiratory Changes: Respiratory rate per minute
time frame: Three weeks
description: To describe the clinical changes secondary to IV administration of AMSCa, in patients with bilateral COVID-19 pneumonia complicated by severe SIRA, with the evaluation of the respiratory rate per minute.
measure: Changes in body temperature
time frame: Three weeks
description: To describe the clinical changes secondary to IV administration of AMSCa, in patients with bilateral COVID-19 pneumonia complicated by severe SIRA, with the evaluation of the fever curve in degrees centigrade.
measure: General biochemical changes in Leukocytes
time frame: Three weeks
description: To assess the effect of the proposed treatment on the total Leukocytes
measure: General biochemical changes on lymphocytes
time frame: Three weeks
description: To assess the effect of the proposed treatment on absolute lymphocytes
measure: General biochemical changes on platelets
time frame: Three weeks
description: To assess the effect of the proposed treatment on total platelets
measure: General biochemical changes on fibrinogen
time frame: Three weeks
description: To assess the effect of the proposed treatment on serum fibrinogen
measure: General biochemical changes on pocalcitonin
time frame: Three weeks
description: To assess the effect of the proposed treatment on procalcitonin
measure: General biochemical changes on ferritin
time frame: Three weeks
description: To assess the effect of the proposed treatment on ferritin
measure: General biochemical changes on D-dimer
time frame: Three weeks
description: To assess the effect of the proposed treatment on D-dimer
measure: Changes on inflammatory C-reactive protein
time frame: Three weeks
description: To assess the anti-inflammatory effect of the proposed treatment with assessment of the levels of C-reactive protein
measure: Cahnges on Inflammatory cytokine TNFa
time frame: Three weeks
description: To assess the anti-inflammatory effect of the proposed treatment with assessment of the levels of TNFa in plasma.
measure: Changes on Inflammatory cytokine IL10
time frame: Three weeks
description: To assess the anti-inflammatory effect of the proposed treatment with assessment of the levels of IL10 in plasma.
measure: Changes on Inflammatory cytokine IL1
time frame: Three weeks
description: To assess the anti-inflammatory effect of the proposed treatment with assessment of the levels of IL1 in plasma.
measure: Changes on Inflammatory cytokine IL6
time frame: Three weeks
description: To assess the anti-inflammatory effect of the proposed treatment with assessment of the levels of IL6 in plasma.
measure: Changes on Inflammatory cytokine IL 17
time frame: Three weeks
description: To assess the anti-inflammatory effect of the proposed treatment with assessment of the levels of IL17 in plasma
measure: Changes on VEGF
time frame: Three weeks
description: To assess the anti-inflammatory effect of the proposed treatment with assessment of the levels of VEGF in plasma
measure: Radiological Changes
time frame: Three weeks
description: Assess the radiological evolution of the proposed treatment through simple chest CT
measure: Immunological changes on T cell
time frame: Three weeks
description: Evaluate immune system improvement with mass cytometry to analyze patients' immune cells: regulatory T cells
measure: Immunological changes on Dendritic cells
time frame: Three weeks
description: Evaluate immune system improvement with mass cytometry to analyze patients' immune cells: dendritic cells
measure: Immunological changes on CD4+ T
time frame: Three weeks
description: Evaluate immune system improvement with mass cytometry to analyze patients' immune cells: CD4 + T
measure: Immunological changes on CD8+ T
time frame: Three weeks
description: Evaluate immune system improvement with mass cytometry to analyze patients' immune cells: CD8 + T
measure: Immunological changes on NK cell
time frame: Three weeks
description: Evaluate immune system improvement with mass cytometry to analyze patients' immune cells: NK cells
measure: Adverse events
time frame: Three weeks
description: Evaluate the safety of the proposed treatment (allergic reactions and / or infection)
measure: RNA detection by SARS-Cov2 PCR
time frame: Three weeks
description: To assess the negativization of the SARS-Cov2 PCR RNA detection test
arm group label: Treated group
arm group type: Active Comparator
description: Five patients, of any sex and age, with bilateral COVID-19 pneumonia, severe SIRA with PaO2 / FiO2 less than 150, lymphopenia less than 800 total lymphocytes, CT with bilateral pneumonia, SOFA less than 11 and that has not improved in relation to the following parameters: a) persistent PaO2 / FiO2 less than 150; b) persistent fever, c) increase in D-dimer of at least 50% of the baseline and / or ferritin greater than 1000, after 48 h of hospital stay receiving the standard management measures used at that time in the Care Center, will be included in the study. This treatment will be administered after discussing it with the relatives that it is a procedure considered as rescue and will be carried out with informed consent.
arm group label: Control Group
arm group type: No Intervention
description: The results obtained in the treated group will be compared against the historical controls treated in INCMNSZ, evaluating the same variables.
intervention type: Biological
intervention name: Infusion IV of Mesenchymal Stem cells
description: Mesenchymal Stem cells from bank will be applied IV, at dose 1 million xKg in a single dose
arm group label: Treated group
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Martin Iglesias, MD
phone: +1 52 55 5580097509
email: iglesias@drmartiniglesias.com
last name: Carlos A Aguilar-Salinas, MD
phone: +1 52 55 54870900
phone ext: 6321
email: caguilarsalinas@yahoo.com
facility: 
status: Recruiting
contact: 
contact backup: 
country: Mexico
responsible party type: Principal Investigator
investigator affiliation: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
investigator full name: Martín Iglesias
investigator title: Plastic surgeon
mesh term: COVID-19
mesh term: Respiratory Distress Syndrome
mesh term: Respiratory Distress Syndrome, Newborn
mesh term: Acute Lung Injury
sharing ipd: No