<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/NCT04456361</url>
  </required_header>
  <id_info>
    <org_study_id>MSC-ARDS-001</org_study_id>
    <nct_id>NCT04456361</nct_id>
  </id_info>
  <brief_title>Use of Mesenchymal Stem Cells in Acute Respiratory Distress Syndrome Caused by COVID-19</brief_title>
  <official_title>A Study of Mesenchymal Stem Cells as a Treatment in Patients With Acute Respiratory Distress Syndrome Caused by COVID-19</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Instituto de Medicina Regenerativa</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Instituto de Medicina Regenerativa</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>
      This is a pilot phase, open label, non-randomized study for the treatment of ARDS in patients&#xD;
      infected with COVID-19. Subjects will be enrolled and treated with one dose of mesenchymal&#xD;
      stem cells and follow-up will occur 90 days post-treatment.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      A Study of Mesenchymal Stem Cells as a treatment in Patients with Acute Respiratory Distress&#xD;
      Syndrome caused by COVID-19 is a pilot phase, open label, non-randomized study, with a single&#xD;
      study center.&#xD;
&#xD;
      The current pandemic caused by the novel virus SARS-CoV-2 has lead to a health care crisis&#xD;
      affecting hospitals, hospital workers and health care structure globally. Many countries are&#xD;
      dealing with a disrupted infrastructure in health care and imminent economic downfall to an&#xD;
      extent that has not been seen in recent years. COVID-19 has lead to a large number of deaths&#xD;
      in several countries, and Mexico has not been an exception. Availability of supplies,&#xD;
      hospital space and equipment for mechanical ventilation are running critically low, and it&#xD;
      has been a challenge for hospitals coping with severe clinical symptoms in COVID-19. This&#xD;
      disease is characterized by pneumonia, fever, cough and occasional diarrhea, and the severity&#xD;
      has been largely attributed to the high affinity of the virus to Angiotensin-Converting&#xD;
      Enzyme 2 (ACE2) as the main receptor, and the Type II Transmembrane Serine Protease TMPRSS2&#xD;
      as the main host protease that mediates S protein activation on primary target cells in the&#xD;
      lung and small intestine.&#xD;
&#xD;
      Many agencies and professional societies are working worldwide in developing treatment&#xD;
      guidelines to care for patients with COVID-19, since the present treatments are supportive&#xD;
      but not yet curative, therefore these guidelines are based on scientific evidence and expert&#xD;
      opinion, the use of an array of drugs approved for other indications, as well as multiple&#xD;
      investigational agents that are being studied. Lately, Remdesivir, a novel small-molecule&#xD;
      adenine nucleotide analogue antiviral drug that has shown efficacy against Ebola virus in&#xD;
      rhesus monkeys has shown improvement in patients with oxygen support. The focus of the&#xD;
      research for a cure of COVID-19 has been centered on the individual's response in an&#xD;
      immunological context, where an over activation of the immune response can cause a production&#xD;
      of a large quantity of inflammatory molecules resulting in a cytokine storm with severe&#xD;
      physiological consequences. The cytokine storm induces an increase in inflammatory proteins&#xD;
      that results in edema, improper oxygen exchange, acute respiratory distress syndrome (ARDS),&#xD;
      other organ damage and secondary infection. In recent studies, mesenchymal stem cells (MSCs)&#xD;
      have proven to decrease the hyper inflammatory response in the lungs, leading to a steady&#xD;
      recovery in patients with ARDS. The use of umbilical cord mesenchymal stem cells (UC-MSCs)&#xD;
      may prove a potential effective measure for the treatment of the cytokine storm induced by&#xD;
      COVID-19.&#xD;
&#xD;
      A step forward in a treatment strategy for the novel virus infection in humans would be&#xD;
      critical for treating COVID-19 and especially ARDS-induced severe pneumonia, which is&#xD;
      currently depleting resources around the world. Because efforts to control lung injury via&#xD;
      pharmacological agents have been unsuccessful, mesenchymal stem cell (MSC)-based therapy is&#xD;
      being investigated, based on the characteristics of MSCs to self-renew in a limitless manner&#xD;
      and their multipotency.&#xD;
&#xD;
      Furthermore, MSC-based therapies have demonstrated in the past of having sufficient promising&#xD;
      effects in experimental treatment of ARDS via inhibition of alveolar collapse, collagen&#xD;
      accumulation, and cell apoptosis in lung tissue. Recent studies found that administrating&#xD;
      allogeneic MSCs in patients with ARDS resulted in no pre-specified adverse events, including&#xD;
      hypoxemia, cardiac arrhythmia, and ventricular tachycardia. MSCs are currently attracting&#xD;
      interest due to source potential, a high proliferation rate, and a painless procedure that is&#xD;
      free of ethical issues. Selection of a starting dose of approximately 100 million cells has&#xD;
      been chosen to approximate the standard dosage of cells employed in prior clinical studies.&#xD;
      This dosage may be adjusted depending on the data generated during the conduction of the&#xD;
      study.&#xD;
&#xD;
      MSCs play a positive role mainly in two ways, namely immunomodulatory effects and&#xD;
      differentiation abilities. MSCs can secrete many types of cytokines by paracrine secretion or&#xD;
      make direct interactions with immune cells, leading to immunomodulation. The immunomodulatory&#xD;
      effects of MSCs are triggered further by the activation of TLR receptor in MSCs, which is&#xD;
      stimulated by pathogen-associated molecules such as LPS or double-stranded RNA from virus,&#xD;
      like the HCoV-19.&#xD;
&#xD;
      There are many pilot studies conducted with MSC transplantation to explore their therapeutic&#xD;
      potential for HCoV-19 infected patients, in many of them the pulmonary function and symptoms&#xD;
      of patients were significantly improved days after MSC transplantation. Thus, in this study&#xD;
      we intend to prove the intravenous transplantation of MSCs as safe and effective for&#xD;
      treatment in patients with COVID-19 pneumonia, especially for patients in severe condition.&#xD;
&#xD;
      Primary Objective: To determine the feasibility and safety of intravenously administered MSCs&#xD;
      in patients with Acute Respiratory Distress Syndrome.&#xD;
&#xD;
      Secondary Objectives:&#xD;
&#xD;
      To assess preliminary response in respiratory performance in patients with ARDS.&#xD;
&#xD;
      To assess overall survival of patients. To determine mortality rate at 14 days post&#xD;
      treatment. To assess clinical and radiological improvements in patients.&#xD;
&#xD;
      Number of Subjects to be studied: 10&#xD;
&#xD;
      Endpoints&#xD;
&#xD;
      Primary Endpoint:&#xD;
&#xD;
      Evaluate Respiratory distress symptoms based on Berlin definition (RR; Oxygen saturation at&#xD;
      rest; Arterial partial pressure of oxygen (PaO2) / Fraction of inspiration O2 (FiO2)).&#xD;
&#xD;
      Determine the degree of ground-glass opacity and pneumonia infiltration in imaging studies&#xD;
      (X-ray or CT).&#xD;
&#xD;
      Evaluate clinical improvement based on APACHE II Score. Determine mortality rate at 2 weeks&#xD;
      post treatment.&#xD;
&#xD;
      Secondary Endpoints:&#xD;
&#xD;
      Adverse events related to MSC infusion (description, timing, grade, seriousness, and&#xD;
      relatedness) Hematological decompensation (based on CBC, SQ and metabolic panels) Objective&#xD;
      response rate Progression free survival, overall survival, and best overall response rate&#xD;
      Determine if any infusion reactions/toxicity occurs&#xD;
&#xD;
      Clinical and radiological parameters will be assessed at Baseline, 2, 4 and 14 day&#xD;
      post-treatment, and there will be a 3 month follow-up by telephone contact.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">April 16, 2020</start_date>
  <completion_date type="Anticipated">December 15, 2022</completion_date>
  <primary_completion_date type="Anticipated">October 15, 2022</primary_completion_date>
  <phase>Early Phase 1</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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Oxygen saturation</measure>
    <time_frame>Baseline, and at days 2, 4 and 14 post-treatment</time_frame>
    <description>Number of patients with changes in percentage of resting Oxygen saturation (%O2)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Oxygen pressure in inspiration</measure>
    <time_frame>Baseline, and at days 2, 4 and 14 post-treatment</time_frame>
    <description>Changes in mmHg of Arterial partial pressure of oxygen / Fraction of inspiration O2 (PaO2/FiO2) in all participants</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ground-glass opacity</measure>
    <time_frame>Baseline, and at day 14 post-treatment</time_frame>
    <description>Changes in percentage of participants with reduction in bilateral ground-glass opacities</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pneumonia infiltration</measure>
    <time_frame>Baseline, and at day 14 post-treatment</time_frame>
    <description>Changes in percentage of participants with reduction of pneumonia bilateral infiltration</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Lactate dehydrogenase</measure>
    <time_frame>Baseline, and at days 4 and 14 post-treatment</time_frame>
    <description>Number of participants with a reduction in Lactate dehydrogenase (mg/dL)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>C-reactive protein</measure>
    <time_frame>Baseline, and at days 4 and 14 post-treatment</time_frame>
    <description>Number of participants with a reduction in C-reactive protein (mg/dL)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>D-dimer</measure>
    <time_frame>Baseline, and at days 4 and 14 post-treatment</time_frame>
    <description>Number of participants with a reduction in D-dimer (mg/dL)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ferritine</measure>
    <time_frame>Baseline, and at days 4 and 14 post-treatment</time_frame>
    <description>Number of participants with a reduction in Ferritine (mg/dL)</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">9</enrollment>
  <condition>ARDS, Human</condition>
  <condition>Covid-19</condition>
  <arm_group>
    <arm_group_label>COVID-19 patients</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Treatment consistsof Mesenchymal Stem Cells administered as a one-time, single-dose therapy via IV infusion at a dose of 1 X 10 8 cells.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Mesenchymal Stem Cells derived from Wharton Jelly of Umbilical cords</intervention_name>
    <description>Mesenchymal Stem Cells as a single-dose therapy via IV infusion at a dose of 1 X 10 8 cells.</description>
    <arm_group_label>COVID-19 patients</arm_group_label>
    <other_name>UCMSC</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Ability to understand and the willingness to provide informed consent or a legally&#xD;
             authorized representative.&#xD;
&#xD;
          -  Diagnosis of Acute Respiratory Distress Syndrome according to the Berlin Definition&#xD;
             following the failing of prior standard therapy, and other available therapies.&#xD;
&#xD;
        Mild: 200 mm Hg &lt; PaO2/FIO2 ≤ 300 mm Hg with PEEP or CPAP ≥ 5 cm H2Oc Moderate: 100 mm Hg &lt;&#xD;
        PaO2/FIO2 ≤ 200 mm Hg with PEEP ≥ 5 cm H2O Severe: PaO2/FIO2 ≤ 100 mm Hg with PEEP ≥ 5 cm&#xD;
        H2O&#xD;
&#xD;
          -  Diagnostic test positive for SARS-CoV-2&#xD;
&#xD;
          -  Age ≥ 18 years&#xD;
&#xD;
          -  Any man with a partner of child-bearing potential agrees to use adequate contraception&#xD;
             which will include two of the following: hormonal or barrier method of birth control,&#xD;
             or abstinence prior to study entry, for the duration of study participation, and for&#xD;
             30 days following completion of therapy.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Current or anticipated use of other investigational agents.&#xD;
&#xD;
          -  History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
             composition to MSC infusion plus any patently atopic patients who have a history of&#xD;
             having experienced an episode of allergic anaphylaxis.&#xD;
&#xD;
          -  Severe or uncontrolled medical disorder that would, in the investigator's opinion,&#xD;
             impair ability to receive study treatment (i.e., uncontrolled diabetes, chronic renal&#xD;
             disease).&#xD;
&#xD;
          -  Known diagnosis of human immunodeficiency virus (HIV) infection.&#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>Jesus Perez</last_name>
    <role>Principal Investigator</role>
    <affiliation>Instituto de Medicina Regenerativa</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Juan Parcero</last_name>
    <role>Study Chair</role>
    <affiliation>Instituto de Medicina Regenerativa</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Instituto de Medicina Regenerativa</name>
      <address>
        <city>Tijuana</city>
        <state>Baja California</state>
        <zip>22100</zip>
        <country>Mexico</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Mexico</country>
  </location_countries>
  <verification_date>July 2022</verification_date>
  <study_first_submitted>June 23, 2020</study_first_submitted>
  <study_first_submitted_qc>June 30, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 2, 2020</study_first_posted>
  <last_update_submitted>August 2, 2022</last_update_submitted>
  <last_update_submitted_qc>August 2, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">August 4, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <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>
  <!-- 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/NCT04456361
org study id: MSC-ARDS-001
nct id: NCT04456361
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This is a pilot phase, open label, non-randomized study for the treatment of ARDS in patients
      infected with COVID-19. Subjects will be enrolled and treated with one dose of mesenchymal
      stem cells and follow-up will occur 90 days post-treatment.
A Study of Mesenchymal Stem Cells as a treatment in Patients with Acute Respiratory Distress
      Syndrome caused by COVID-19 is a pilot phase, open label, non-randomized study, with a single
      study center.

      The current pandemic caused by the novel virus SARS-CoV-2 has lead to a health care crisis
      affecting hospitals, hospital workers and health care structure globally. Many countries are
      dealing with a disrupted infrastructure in health care and imminent economic downfall to an
      extent that has not been seen in recent years. COVID-19 has lead to a large number of deaths
      in several countries, and Mexico has not been an exception. Availability of supplies,
      hospital space and equipment for mechanical ventilation are running critically low, and it
      has been a challenge for hospitals coping with severe clinical symptoms in COVID-19. This
      disease is characterized by pneumonia, fever, cough and occasional diarrhea, and the severity
      has been largely attributed to the high affinity of the virus to Angiotensin-Converting
      Enzyme 2 (ACE2) as the main receptor, and the Type II Transmembrane Serine Protease TMPRSS2
      as the main host protease that mediates S protein activation on primary target cells in the
      lung and small intestine.

      Many agencies and professional societies are working worldwide in developing treatment
      guidelines to care for patients with COVID-19, since the present treatments are supportive
      but not yet curative, therefore these guidelines are based on scientific evidence and expert
      opinion, the use of an array of drugs approved for other indications, as well as multiple
      investigational agents that are being studied. Lately, Remdesivir, a novel small-molecule
      adenine nucleotide analogue antiviral drug that has shown efficacy against Ebola virus in
      rhesus monkeys has shown improvement in patients with oxygen support. The focus of the
      research for a cure of COVID-19 has been centered on the individual's response in an
      immunological context, where an over activation of the immune response can cause a production
      of a large quantity of inflammatory molecules resulting in a cytokine storm with severe
      physiological consequences. The cytokine storm induces an increase in inflammatory proteins
      that results in edema, improper oxygen exchange, acute respiratory distress syndrome (ARDS),
      other organ damage and secondary infection. In recent studies, mesenchymal stem cells (MSCs)
      have proven to decrease the hyper inflammatory response in the lungs, leading to a steady
      recovery in patients with ARDS. The use of umbilical cord mesenchymal stem cells (UC-MSCs)
      may prove a potential effective measure for the treatment of the cytokine storm induced by
      COVID-19.

      A step forward in a treatment strategy for the novel virus infection in humans would be
      critical for treating COVID-19 and especially ARDS-induced severe pneumonia, which is
      currently depleting resources around the world. Because efforts to control lung injury via
      pharmacological agents have been unsuccessful, mesenchymal stem cell (MSC)-based therapy is
      being investigated, based on the characteristics of MSCs to self-renew in a limitless manner
      and their multipotency.

      Furthermore, MSC-based therapies have demonstrated in the past of having sufficient promising
      effects in experimental treatment of ARDS via inhibition of alveolar collapse, collagen
      accumulation, and cell apoptosis in lung tissue. Recent studies found that administrating
      allogeneic MSCs in patients with ARDS resulted in no pre-specified adverse events, including
      hypoxemia, cardiac arrhythmia, and ventricular tachycardia. MSCs are currently attracting
      interest due to source potential, a high proliferation rate, and a painless procedure that is
      free of ethical issues. Selection of a starting dose of approximately 100 million cells has
      been chosen to approximate the standard dosage of cells employed in prior clinical studies.
      This dosage may be adjusted depending on the data generated during the conduction of the
      study.

      MSCs play a positive role mainly in two ways, namely immunomodulatory effects and
      differentiation abilities. MSCs can secrete many types of cytokines by paracrine secretion or
      make direct interactions with immune cells, leading to immunomodulation. The immunomodulatory
      effects of MSCs are triggered further by the activation of TLR receptor in MSCs, which is
      stimulated by pathogen-associated molecules such as LPS or double-stranded RNA from virus,
      like the HCoV-19.

      There are many pilot studies conducted with MSC transplantation to explore their therapeutic
      potential for HCoV-19 infected patients, in many of them the pulmonary function and symptoms
      of patients were significantly improved days after MSC transplantation. Thus, in this study
      we intend to prove the intravenous transplantation of MSCs as safe and effective for
      treatment in patients with COVID-19 pneumonia, especially for patients in severe condition.

      Primary Objective: To determine the feasibility and safety of intravenously administered MSCs
      in patients with Acute Respiratory Distress Syndrome.

      Secondary Objectives:

      To assess preliminary response in respiratory performance in patients with ARDS.

      To assess overall survival of patients. To determine mortality rate at 14 days post
      treatment. To assess clinical and radiological improvements in patients.

      Number of Subjects to be studied: 10

      Endpoints

      Primary Endpoint:

      Evaluate Respiratory distress symptoms based on Berlin definition (RR; Oxygen saturation at
      rest; Arterial partial pressure of oxygen (PaO2) / Fraction of inspiration O2 (FiO2)).

      Determine the degree of ground-glass opacity and pneumonia infiltration in imaging studies
      (X-ray or CT).

      Evaluate clinical improvement based on APACHE II Score. Determine mortality rate at 2 weeks
      post treatment.

      Secondary Endpoints:

      Adverse events related to MSC infusion (description, timing, grade, seriousness, and
      relatedness) Hematological decompensation (based on CBC, SQ and metabolic panels) Objective
      response rate Progression free survival, overall survival, and best overall response rate
      Determine if any infusion reactions/toxicity occurs

      Clinical and radiological parameters will be assessed at Baseline, 2, 4 and 14 day
      post-treatment, and there will be a 3 month follow-up by telephone contact.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Oxygen saturation
time frame: Baseline, and at days 2, 4 and 14 post-treatment
description: Number of patients with changes in percentage of resting Oxygen saturation (%O2)
measure: Oxygen pressure in inspiration
time frame: Baseline, and at days 2, 4 and 14 post-treatment
description: Changes in mmHg of Arterial partial pressure of oxygen / Fraction of inspiration O2 (PaO2/FiO2) in all participants
measure: ground-glass opacity
time frame: Baseline, and at day 14 post-treatment
description: Changes in percentage of participants with reduction in bilateral ground-glass opacities
measure: Pneumonia infiltration
time frame: Baseline, and at day 14 post-treatment
description: Changes in percentage of participants with reduction of pneumonia bilateral infiltration
measure: Lactate dehydrogenase
time frame: Baseline, and at days 4 and 14 post-treatment
description: Number of participants with a reduction in Lactate dehydrogenase (mg/dL)
measure: C-reactive protein
time frame: Baseline, and at days 4 and 14 post-treatment
description: Number of participants with a reduction in C-reactive protein (mg/dL)
measure: D-dimer
time frame: Baseline, and at days 4 and 14 post-treatment
description: Number of participants with a reduction in D-dimer (mg/dL)
measure: Ferritine
time frame: Baseline, and at days 4 and 14 post-treatment
description: Number of participants with a reduction in Ferritine (mg/dL)
arm group label: COVID-19 patients
arm group type: Experimental
description: Treatment consistsof Mesenchymal Stem Cells administered as a one-time, single-dose therapy via IV infusion at a dose of 1 X 10 8 cells.
intervention type: Biological
intervention name: Mesenchymal Stem Cells derived from Wharton Jelly of Umbilical cords
description: Mesenchymal Stem Cells as a single-dose therapy via IV infusion at a dose of 1 X 10 8 cells.
arm group label: COVID-19 patients
other name: UCMSC
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Jesus Perez
role: Principal Investigator
affiliation: Instituto de Medicina Regenerativa
last name: Juan Parcero
role: Study Chair
affiliation: Instituto de Medicina Regenerativa
facility: 
country: Mexico
responsible party type: Sponsor
mesh term: COVID-19
mesh term: Respiratory Distress Syndrome
mesh term: Respiratory Distress Syndrome, Newborn
mesh term: Acute Lung Injury