<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/NCT04494386</url>
  </required_header>
  <id_info>
    <org_study_id>ULSC-CV-01</org_study_id>
    <nct_id>NCT04494386</nct_id>
  </id_info>
  <brief_title>Umbilical Cord Lining Stem Cells (ULSC) in Patients With COVID-19 ARDS</brief_title>
  <acronym>ULSC</acronym>
  <official_title>Phase 1/2a Study of Umbilical Cord Lining Stem Cells (ULSC) in Patients With ARDS Due to COVID-19</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Restem, LLC.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Restem, LLC.</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>
      ULSC-CV-01 is a clinical trial that comprises both Phase 1 and Phase 2a, which will be&#xD;
      conducted sequentially. This trial will evaluate the safety and potential efficacy of&#xD;
      allogeneic Umbilical Cord Lining Stem Cells (ULSC), which are a type of umbilical cord tissue&#xD;
      derived mesenchymal stem cells (MSC), with intravenous (IV) administration in hospitalized&#xD;
      patients with acute respiratory distress syndrome (ARDS) due to COVID-19.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The Phase 1, open-label, non-controlled trial in this study will investigate the safety of&#xD;
      intravenous (IV) infusion of ULSC in a total of 20 patients with COVID-19-related ARDS that&#xD;
      will include patients that are not intubated and not on a ventilator (NV) and patients that&#xD;
      are intubated and on a ventilator (V) for respiratory support. Separate cohorts of each group&#xD;
      (NV and V) will receive either a single dose (one infusion) or repeat dose (two infusions&#xD;
      separated by 48-hour interval).&#xD;
&#xD;
      The Phase 2a randomized and placebo-controlled trial in this study will investigate the&#xD;
      potential efficacy of IV infusion of ULSC in a total of 40 patients with COVID-19-related&#xD;
      ARDS that will all be EITHER NV or V; the determination of that eligibility criterion and the&#xD;
      ULSC dosing regimen will be based on Phase 1 data of safety and tolerability. Phase 2a will&#xD;
      evaluate EITHER single dose (one infusion) or repeat dose (two infusions separated by 48-hour&#xD;
      interval). The randomization will be 3:1 with 30 patients receiving investigational product&#xD;
      (ULSC) and 10 patients receiving placebo (carrier control).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">July 23, 2020</start_date>
  <completion_date type="Anticipated">July 31, 2023</completion_date>
  <primary_completion_date type="Anticipated">April 30, 2023</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>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Incidence of Dose Limiting Toxicity (DLT)</measure>
    <time_frame>24 hours</time_frame>
    <description>Number of subjects with a DLT event during or within 24 hours after ULSC infusion&#xD;
[Dose Limiting Toxicities are treatment-emergent suspected adverse reactions graded as severe, such as severe infusion-related hypersensitivity toxicities of grade ≥3, and any treatment-emergent serious adverse event (SAE) will be investigated to determine if DLT.]</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of Dose Limiting Toxicity (DLT), suspected adverse reaction (SAR), or serious adverse event (SAE)</measure>
    <time_frame>1 week</time_frame>
    <description>Number of subjects with a DLT event, suspected adverse reaction, or any serious adverse event (SAE) within 1 week of each ULSC infusion</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Treatment-emergent adverse events (AE) and serious adverse events (SAE)</measure>
    <time_frame>1 month</time_frame>
    <description>Treatment-emergent adverse events (AE; incidence, grade, and assessment of relatedness or causality) and serious adverse events (SAE) during the study up to 1-month follow-up</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Treatment-emergent adverse events (AE) and serious adverse events (SAE)</measure>
    <time_frame>12 months</time_frame>
    <description>Treatment-emergent adverse events (AE; incidence, grade, and assessment of relatedness or causality) and serious adverse events (SAE) during the study and up to the 12-month follow-up</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Levels of COVID-19 related ARDS as defined by the Berlin Definition of ARDS</measure>
    <time_frame>1 month</time_frame>
    <description>Times to transitions between levels of COVID-19 related ARDS as defined by the Berlin Definition of ARDS</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes from baseline pulse oximetric saturation SpO2/FiO2 ratio or arterial oxygen pressure pAO2/FiO2 ratio</measure>
    <time_frame>1 month</time_frame>
    <description>Changes in SpO2/FiO2 ratio or pAO2/FiO2 ratio compared to baseline, measured daily at a minimum; oxygenation index daily when on ventilator</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of ventilator-free days (VFD)</measure>
    <time_frame>1 month</time_frame>
    <description>Number of ventilator-free days (VFD) in period of 1 month from study treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in Complete Blood Count (CBC) with differential from baseline</measure>
    <time_frame>1 month, 2 months, 3 months, 6 months, and 12 months</time_frame>
    <description>Changes in CBC with differential from baseline to 1 month, 2 months, 3 months, 6 months, and 12 months after study treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in levels of blood glucose (mg/dL) from baseline</measure>
    <time_frame>1 month, 2 months, 3 months, 6 months, and 12 months</time_frame>
    <description>Changes in blood glucose (mg/dL) from baseline to 1 month, 2 months, 3 months, 6 months, and 12 months after study treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in levels of sodium (mEq/L) from baseline</measure>
    <time_frame>1 month, 2 months, 3 months, 6 months, and 12 months</time_frame>
    <description>Changes in levels of sodium (mEq/L) from baseline to 1 month, 2 months, 3 months, 6 months, and 12 months after study treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in levels of potassium (mEq/L) from baseline</measure>
    <time_frame>1 month, 2 months, 3 months, 6 months, and 12 months</time_frame>
    <description>Changes in levels of potassium (mEq/L) from baseline to 1 month, 2 months, 3 months, 6 months, and 12 months after study treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in levels of blood urea nitrogen (BUN; mg/dL) from baseline</measure>
    <time_frame>1 month, 2 months, 3 months, 6 months, and 12 months</time_frame>
    <description>Changes in levels of blood urea nitrogen (BUN; mg/dL) from baseline to 1 month, 2 months, 3 months, 6 months, and 12 months after study treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in levels of alanine transaminase (ALT; U/L) from baseline</measure>
    <time_frame>1 month, 2 months, 3 months, 6 months, and 12 months</time_frame>
    <description>Changes in levels of alanine transaminase (ALT; U/L) from baseline to 1 month, 2 months, 3 months, 6 months, and 12 months after study treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Urinalysis (UA) from baseline</measure>
    <time_frame>1 month</time_frame>
    <description>Change in Urinalysis (UA) at baseline and 1 month after study treatment to assess for presence and qualitative proteinuria</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">17</enrollment>
  <condition>Covid19</condition>
  <condition>Corona Virus Infection</condition>
  <condition>SARS-CoV Infection</condition>
  <condition>ARDS</condition>
  <condition>Coronavirus</condition>
  <arm_group>
    <arm_group_label>ULSC in Phase 1 Open Label</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Intravenous (IV) infusion of ULSC in 20 patients with COVID-19 ARDS:&#xD;
In Phase 1, two separate cohorts per group will receive either a single dose (one infusion) or repeat dose regimen (two infusions separated by 48-hour interval). The first cohort enrolled will receive the single dose; the next cohort enrolled will be administered the repeat dose regimen.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>ULSC in Phase 2a Randomized</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Intravenous (IV) infusion of ULSC in 30 patients with COVID-19 ARDS:&#xD;
In Phase 2a, 30 patients assigned ULSC will receive either a single dose (one infusion) or repeat dose regimen (two infusions separated by 48-hour interval). The ULSC dosing regimen will be chosen based on Phase 1 data of safety and tolerability.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo in Phase 2a Randomized</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Intravenous (IV) infusion of carrier control in 10 patients with COVID-19 ARDS:&#xD;
In Phase 2a, 10 patients assigned Placebo will receive either single dose (one infusion) or repeat dose (two infusions separated by 48-hour interval) of carrier control; the dosing regimen will correspond to that of the experimental arm.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Umbilical Cord Lining Stem Cells (ULSC)</intervention_name>
    <description>IV infusion of allogeneic ULSC (100 million cells per dose) in sterile saline for injection</description>
    <arm_group_label>ULSC in Phase 1 Open Label</arm_group_label>
    <arm_group_label>ULSC in Phase 2a Randomized</arm_group_label>
    <other_name>Umbilical Cord Lining Stem Cells (ULSC), type of mesenchymal stem cells (MSC) derived from single donor umbilical cord tissue for allogeneic use</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo (carrier control)</intervention_name>
    <description>IV infusion of carrier control consisting of sterile saline for injection</description>
    <arm_group_label>Placebo in Phase 2a Randomized</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Adult, male or female, age ≥18 years old&#xD;
&#xD;
          2. Diagnosis of the presence of the COVID-19 agent with confirmation of COVID-19 by&#xD;
             standard reverse transcriptase polymerase chain reaction (RT-PCR) or equivalent test.&#xD;
&#xD;
          3. Patient with diagnosis of COVID-related ARDS, classified as either:&#xD;
&#xD;
               -  Not requiring mechanical ventilation (NV) or&#xD;
&#xD;
               -  Requiring mechanical ventilation (V).&#xD;
&#xD;
             According to Berlin Definition of Acute Respiratory Distress Syndrome (ARDS), patients&#xD;
             will be categorized based on degrees of hypoxemia [arterial partial pressure of oxygen&#xD;
             (PaO2)/oxygen concentration (FiO2)]:&#xD;
&#xD;
               -  Mild ARDS: 200 mm Hg &lt; PaO2/FIO2 ≤ 300 mm Hg&#xD;
&#xD;
               -  Moderate ARDS: 100 mm Hg &lt; PaO2/FIO2 ≤ 200 mm Hg&#xD;
&#xD;
               -  Severe ARDS: PaO2/FIO2 ≤ 100 mm Hg&#xD;
&#xD;
          4. Patient who has exhibited deterioration in condition during the past 72 hours prior to&#xD;
             the informed consent.&#xD;
&#xD;
          5. Patient receiving standard of care in-hospital therapy, including appropriate critical&#xD;
             oxygenation, fluid, and hemodynamic support as indicated clinically.&#xD;
&#xD;
          6. Patient or responsible family member or surrogate signs informed consent.&#xD;
&#xD;
        Exclusion Criteria&#xD;
&#xD;
          1. Hypersensitivity to study product components. History of hypersensitivity to dimethyl&#xD;
             sulfoxide (DMSO).&#xD;
&#xD;
          2. Active cancer or prior diagnosis of cancer within the past year; however, patients&#xD;
             with basal and squamous cell cancer of skin will not be excluded.&#xD;
&#xD;
          3. Organ transplant recipient.&#xD;
&#xD;
          4. Chronic renal failure being treated by renal replacement therapy (dialysis) before&#xD;
             development of COVID-19.&#xD;
&#xD;
          5. Any other condition that, in the judgment of the Investigator or Sponsor, would be a&#xD;
             contraindication to enrollment, study product administration, or follow-up.&#xD;
&#xD;
          6. Pregnancy or lactation; a negative pregnancy test between screening and day 1 (before&#xD;
             administration of treatment) will be required of women with childbearing potential,&#xD;
             and they will be advised of the requirement to use an effective means of&#xD;
             contraception. A woman is considered to be of childbearing potential unless she is&#xD;
             postmenopausal and without menses for 12 months or without a uterus and/or both&#xD;
             ovaries.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Miami Baptist Hospital</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33176</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sanford Research</name>
      <address>
        <city>Sioux Falls</city>
        <state>South Dakota</state>
        <zip>57105</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>July 24, 2020</study_first_submitted>
  <study_first_submitted_qc>July 29, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 31, 2020</study_first_posted>
  <last_update_submitted>March 27, 2023</last_update_submitted>
  <last_update_submitted_qc>March 27, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 29, 2023</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>Infections</mesh_term>
    <mesh_term>Communicable Diseases</mesh_term>
    <mesh_term>COVID-19</mesh_term>
    <mesh_term>Coronavirus Infections</mesh_term>
    <mesh_term>Severe Acute Respiratory 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/NCT04494386
org study id: ULSC-CV-01
nct id: NCT04494386
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
ULSC-CV-01 is a clinical trial that comprises both Phase 1 and Phase 2a, which will be
      conducted sequentially. This trial will evaluate the safety and potential efficacy of
      allogeneic Umbilical Cord Lining Stem Cells (ULSC), which are a type of umbilical cord tissue
      derived mesenchymal stem cells (MSC), with intravenous (IV) administration in hospitalized
      patients with acute respiratory distress syndrome (ARDS) due to COVID-19.
The Phase 1, open-label, non-controlled trial in this study will investigate the safety of
      intravenous (IV) infusion of ULSC in a total of 20 patients with COVID-19-related ARDS that
      will include patients that are not intubated and not on a ventilator (NV) and patients that
      are intubated and on a ventilator (V) for respiratory support. Separate cohorts of each group
      (NV and V) will receive either a single dose (one infusion) or repeat dose (two infusions
      separated by 48-hour interval).

      The Phase 2a randomized and placebo-controlled trial in this study will investigate the
      potential efficacy of IV infusion of ULSC in a total of 40 patients with COVID-19-related
      ARDS that will all be EITHER NV or V; the determination of that eligibility criterion and the
      ULSC dosing regimen will be based on Phase 1 data of safety and tolerability. Phase 2a will
      evaluate EITHER single dose (one infusion) or repeat dose (two infusions separated by 48-hour
      interval). The randomization will be 3:1 with 30 patients receiving investigational product
      (ULSC) and 10 patients receiving placebo (carrier control).
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: Incidence of Dose Limiting Toxicity (DLT)
time frame: 24 hours
description: Number of subjects with a DLT event during or within 24 hours after ULSC infusion
[Dose Limiting Toxicities are treatment-emergent suspected adverse reactions graded as severe, such as severe infusion-related hypersensitivity toxicities of grade ≥3, and any treatment-emergent serious adverse event (SAE) will be investigated to determine if DLT.]
measure: Incidence of Dose Limiting Toxicity (DLT), suspected adverse reaction (SAR), or serious adverse event (SAE)
time frame: 1 week
description: Number of subjects with a DLT event, suspected adverse reaction, or any serious adverse event (SAE) within 1 week of each ULSC infusion
measure: Treatment-emergent adverse events (AE) and serious adverse events (SAE)
time frame: 1 month
description: Treatment-emergent adverse events (AE; incidence, grade, and assessment of relatedness or causality) and serious adverse events (SAE) during the study up to 1-month follow-up
measure: Treatment-emergent adverse events (AE) and serious adverse events (SAE)
time frame: 12 months
description: Treatment-emergent adverse events (AE; incidence, grade, and assessment of relatedness or causality) and serious adverse events (SAE) during the study and up to the 12-month follow-up
measure: Levels of COVID-19 related ARDS as defined by the Berlin Definition of ARDS
time frame: 1 month
description: Times to transitions between levels of COVID-19 related ARDS as defined by the Berlin Definition of ARDS
measure: Changes from baseline pulse oximetric saturation SpO2/FiO2 ratio or arterial oxygen pressure pAO2/FiO2 ratio
time frame: 1 month
description: Changes in SpO2/FiO2 ratio or pAO2/FiO2 ratio compared to baseline, measured daily at a minimum; oxygenation index daily when on ventilator
measure: Number of ventilator-free days (VFD)
time frame: 1 month
description: Number of ventilator-free days (VFD) in period of 1 month from study treatment
measure: Changes in Complete Blood Count (CBC) with differential from baseline
time frame: 1 month, 2 months, 3 months, 6 months, and 12 months
description: Changes in CBC with differential from baseline to 1 month, 2 months, 3 months, 6 months, and 12 months after study treatment
measure: Changes in levels of blood glucose (mg/dL) from baseline
time frame: 1 month, 2 months, 3 months, 6 months, and 12 months
description: Changes in blood glucose (mg/dL) from baseline to 1 month, 2 months, 3 months, 6 months, and 12 months after study treatment
measure: Changes in levels of sodium (mEq/L) from baseline
time frame: 1 month, 2 months, 3 months, 6 months, and 12 months
description: Changes in levels of sodium (mEq/L) from baseline to 1 month, 2 months, 3 months, 6 months, and 12 months after study treatment
measure: Changes in levels of potassium (mEq/L) from baseline
time frame: 1 month, 2 months, 3 months, 6 months, and 12 months
description: Changes in levels of potassium (mEq/L) from baseline to 1 month, 2 months, 3 months, 6 months, and 12 months after study treatment
measure: Changes in levels of blood urea nitrogen (BUN; mg/dL) from baseline
time frame: 1 month, 2 months, 3 months, 6 months, and 12 months
description: Changes in levels of blood urea nitrogen (BUN; mg/dL) from baseline to 1 month, 2 months, 3 months, 6 months, and 12 months after study treatment
measure: Changes in levels of alanine transaminase (ALT; U/L) from baseline
time frame: 1 month, 2 months, 3 months, 6 months, and 12 months
description: Changes in levels of alanine transaminase (ALT; U/L) from baseline to 1 month, 2 months, 3 months, 6 months, and 12 months after study treatment
measure: Change in Urinalysis (UA) from baseline
time frame: 1 month
description: Change in Urinalysis (UA) at baseline and 1 month after study treatment to assess for presence and qualitative proteinuria
arm group label: ULSC in Phase 1 Open Label
arm group type: Experimental
description: Intravenous (IV) infusion of ULSC in 20 patients with COVID-19 ARDS:
In Phase 1, two separate cohorts per group will receive either a single dose (one infusion) or repeat dose regimen (two infusions separated by 48-hour interval). The first cohort enrolled will receive the single dose; the next cohort enrolled will be administered the repeat dose regimen.
arm group label: ULSC in Phase 2a Randomized
arm group type: Experimental
description: Intravenous (IV) infusion of ULSC in 30 patients with COVID-19 ARDS:
In Phase 2a, 30 patients assigned ULSC will receive either a single dose (one infusion) or repeat dose regimen (two infusions separated by 48-hour interval). The ULSC dosing regimen will be chosen based on Phase 1 data of safety and tolerability.
arm group label: Placebo in Phase 2a Randomized
arm group type: Placebo Comparator
description: Intravenous (IV) infusion of carrier control in 10 patients with COVID-19 ARDS:
In Phase 2a, 10 patients assigned Placebo will receive either single dose (one infusion) or repeat dose (two infusions separated by 48-hour interval) of carrier control; the dosing regimen will correspond to that of the experimental arm.
intervention type: Biological
intervention name: Umbilical Cord Lining Stem Cells (ULSC)
description: IV infusion of allogeneic ULSC (100 million cells per dose) in sterile saline for injection
arm group label: ULSC in Phase 1 Open Label
arm group label: ULSC in Phase 2a Randomized
other name: Umbilical Cord Lining Stem Cells (ULSC), type of mesenchymal stem cells (MSC) derived from single donor umbilical cord tissue for allogeneic use
intervention type: Other
intervention name: Placebo (carrier control)
description: IV infusion of carrier control consisting of sterile saline for injection
arm group label: Placebo in Phase 2a Randomized
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Infections
mesh term: Communicable Diseases
mesh term: COVID-19
mesh term: Coronavirus Infections
mesh term: Severe Acute Respiratory Syndrome
sharing ipd: No