Use of UC-MSCs for COVID-19 Patients

• ClinicalTrials.gov Identifier: NCT04355728
• Recruitment Status: Completed
• First Posted: April 21, 2020
• Results First Posted: December 6, 2021
• Last Update Posted: December 6, 2021
• Sponsor: Camillo Ricordi
• Information provided by (Responsible Party): Camillo Ricordi, University of Miami

Study Description

Brief Summary:

The purpose of this research study is to learn about the safety and efficacy of human umbilical cord derived Mesenchymal Stem Cells (UC-MSC) for treatment of COVID-19 Patients with Severe Complications of Acute Lung Injury/Acute Respiratory Distress Syndrome (ALI/ARDS).

Condition or disease	Intervention/treatment	Phase
Corona Virus Infection; ARDS; ARDS, Human; Acute Respiratory Distress Syndrome; COVID-19	Biological: Umbilical Cord Mesenchymal Stem Cells + Heparin along with best supportive care.; Other: Vehicle + Heparin along with best supportive care	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: The trial has two groups, each with 12 subjects (n=24). All eligible subjects will be randomized to either the treatment group or standard of care, and randomization will be stratified by ARDS severity.
• Masking: Triple (Participant, Care Provider, Investigator)
• Masking Description: Double-Blinding Trial
• Primary Purpose: Treatment
• Official Title: Umbilical Cord-derived Mesenchymal Stem Cells for COVID-19 Patients With Acute Respiratory Distress Syndrome (ARDS)
• Actual Study Start Date: April 25, 2020
• Actual Primary Completion Date: October 31, 2020
• Actual Study Completion Date: October 31, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: UC-MSCs Group; Participants in this group will be treated with two infusions of UC-MCSs along with heparin (blood thinner) in addition to standard of care treatment. The first infusion will be administered within 24 hours of study enrollment and the second infusion will be administered within 72 hours of study enrollment.	Biological: Umbilical Cord Mesenchymal Stem Cells + Heparin along with best supportive care.; UC-MSC will be administered at 100x10^6 cells/infusion administered intravenously in addition to the standard of care treatment.
Placebo Comparator: Control Group; Participants in this group will be treated with two infusions of vehicle along with heparin (blood thinner) in addition to standard of care treatment. The first infusion will be administered within 24 hours of study enrollment and the second infusion will be administered within 72 hours of study enrollment.	Other: Vehicle + Heparin along with best supportive care; Best supportive care treatment per the treating hospital protocol.

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Pre-Specified Infusion Associated Adverse Events [ Time Frame: 6 and 24 hours ]

   Safety as defined by the number of pre-specified infusion associated adverse events as assessed by treating physician. Any of the following occurring within 6 h post each infusion:

   1. An increase in vasopressor dose greater than or equal to the following:

      • Norepinephrine: 10 μg/min
      • Phenylephrine: 100 μg/min
      • Dopamine: 10 μg/kg/min
      • Epinephrine: 10 μg/min
   2. In patients receiving mechanical ventilation: worsening hypoxemia, as assessed by a requirement for an increase of PEEP by 5 cm H2O over baseline, or requirement to increase FiO2 of >20%.
   3. In patients receiving high flow oxygen therapy: worsening hypoxemia, as indicated by requirement of intubation and mechanical ventilation.
   4. New cardiac arrhythmia requiring cardioversion
   5. New ventricular tachycardia, ventricular fibrillation, or asystole
   6. A clinical scenario consistent with transfusion incompatibility or transfusion-related infection
   7. Cardiac arrest or death within 24h post infusion
2. Number of Subjects With Serious Adverse Events by 31 Days After First Infusion [ Time Frame: 31 days ]
   The number of subjects experiencing serious adverse events by 31 days after the first infusion (corresponding to 28 days after the last infusion).
3. Percentage of Participants Experiencing Serious Adverse Events (SAEs) Through Study Day 90 [ Time Frame: 90 days ]
   Safety will be reported as the percentage of participants experiencing serious adverse events through Day 90 as assessed by treating physician.
4. Number of Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: 90 days ]
   Total number of adverse events and serious adverse events as assessed by treating physician
5. Number of Adverse Events (AEs) and Serious Adverse Events (SAEs) by Severity [ Time Frame: 90 days ]
   Total number of adverse events plus serious adverse events categorized by severity.
6. Subjects With Adverse Events and Serious Adverse Events by Severity [ Time Frame: 90 days ]
   Total number of subjects with adverse events and serious adverse events categorized by severity.
7. Number of Adverse Events and Serious Adverse Events by Relatedness to Treatment [ Time Frame: 90 days ]
   Total number of adverse events and serious adverse events categorized by relatedness to treatment defined by a medical professional.
8. Subjects With Adverse Events by Relatedness to Treatment [ Time Frame: 90 days ]
   Total number of subjects with adverse events categorized by relatedness to treatment by a medical professional

Secondary Outcome Measures :

1. Survival at 31 Days Post First Infusion [ Time Frame: 31 Days ]
   Number of participants that are alive at 31 days post first infusion follow up corresponding to 28 day post second infusion.
2. Survival at 60 Days Post First Infusion [ Time Frame: 60 days ]
   Number of participants alive at 60 days post first infusion follow up.
3. Time to Recovery [ Time Frame: 31 days ]
   Time to discharge or, if the subject was hospitalized, no longer requiring supplemental oxygen and no longer requiring COVID-19-related medical care by 31 days. The numbers represent days at which 25%, 50%, 75% subjects within the treatment group had recovered.
4. Ventilator-Free Days Throughout 28 Days Post Second Infusion [ Time Frame: 28 days post second infusion ]
   Number of days participants were off ventilators during 28 days post second infusion.
5. Ventilator-Free Days Throughout 90 Days [ Time Frame: 90 days or hospital discharge, whichever is earlier ]
   Number of days participants were off ventilators within up to 90 days of hospitalization.
6. Respiratory Rate and Oxygenation Index (ROX Index) [ Time Frame: day 6 ]
   Respiratory Rate-Oxygenation (ROX) index is defined as the ratio of oxygen saturation as measured by pulse oximetry (SpO2)/ Fraction of inspired oxygen (FiO2) to respiratory rate. This index can be used in the assessment of disease progression and the risk of intubation in COVID-19 patients with pneumonia.
7. Oxygenation Index (OI) [ Time Frame: day 6 ]
   Measure of the fraction of inspired oxygen (FiO2) and its usage within the body during intensive care, measured using fNIRS (Functional Near Infrared Spectroscopy). The calculation for Oxygenation index is ((FIO2 * Mean airway pressure)/partial pressure of oxygen).
8. Positive End-Expiratory Pressure (PEEP) and Plateau Pressure (Pplat) [ Time Frame: day 6 ]
   Measuring the respiratory mechanics; positive end-expiratory pressure (PEEP) and plateau pressure (Pplat) in ventilated patients visit 8 (day 6)
9. Sequential Organ Failure Assessment (SOFA) Scores [ Time Frame: Day 6 ]
   Sequential Organ Failure Assessment (SOFA) Scores is used to track a person's risk status during stay in the Intensive Care Unit (ICU). The score is based on six different scores, one each for the respiratory, cardiovascular, hepatic, coagulation, renal, and neurological systems. Each organ system is assigned a point value from a minimum of 0 (normal) to a maximum of 4 (high degree of dysfunction/failure). The total score corresponds to the sum of the six different scores of the organ systems. In total, the minimum SOFA score is 0 (normal) and the maximum SOFA score is 24 (highest degree dysfunction/failure).
10. Smell Identification Test (SIT) Scores [ Time Frame: 90 days ]
    SIT measures the participant's sense of smell. SIT has a total score ranging from 0 to 40 with the higher the score indicating a more normal sense of smell
11. White Blood Cell Count (WBC) [ Time Frame: day 6 ]
    As assessed via serum blood samples.
12. Platelets Count [ Time Frame: day 6 ]
    As assessed via serum blood samples.
13. Hemogoblin [ Time Frame: day 6 ]
    Measures the total amount of the oxygen-carrying protein in the blood as assessed via serum blood samples.
14. Hematocrit [ Time Frame: day 6 ]
    The percentage by volume of red cells in your blood as assessed via serum blood samples.
15. Neutrophils [ Time Frame: day 6 ]
    the amount of immune cells (that is one of the first cell types to travel to the site of an infection) as assessed via serum blood samples
16. Lymphocytes [ Time Frame: day 6 ]
    Lymphocyte count as assessed via serum blood samples
17. Glomerular Filtration Rate [ Time Frame: day 6 ]
    Glomerular filtration rate (GFR) as assessed via serum blood samples to check how well the kidneys are working. It estimates how much blood passes through the glomeruli each minute.
18. Total Protein [ Time Frame: Day 6 ]
    Total protein as assessed via serum blood samples as a part of the comprehensive metabolic panel (CMP). It is a measurement of the sum of albumin and globulins.
19. Sodium [ Time Frame: day 6 ]
    Sodium levels as assessed by serum blood samples.
20. Potassium [ Time Frame: day 6 ]
    Potassium levels as assessed via serum blood samples.
21. Creatinine [ Time Frame: day 6 ]
    Creatinine levels as assessed via serum blood samples
22. Glucose [ Time Frame: day 6 ]
    Glucose levels as assessed via serum blood samples
23. Albumin [ Time Frame: day 6 ]
    Albumin levels as assessed via serum blood samples
24. Alkaline Phosphatase [ Time Frame: day 6 ]
    Alkaline phosphatase levels as assessed via serum blood samples for the Comprehensive Metabolic Panel.
25. Alanine Aminotransferase or Serum Glutamate-pyruvate Transaminase (ALT or SGPT) [ Time Frame: day 6 ]
    The alanine aminotransferase or serum glutamate-pyruvate transaminase (ALT or SGPT) test as assessed via serum blood samples
26. Aspartate Aminotransferase or Serum Glutamic Oxaloacetic Transaminase (AST or SGOT) [ Time Frame: day 6 ]
    The aspartate aminotransferase or serum glutamic oxaloacetic transaminase (AST or SGOT) test as assessed via serum blood samples
27. Total Bilirubin [ Time Frame: day 6 ]
    Bilirubin levels as assessed via serum blood samples for the comprehensive metabolic panel.
28. Blood Urea Nitrogen (BUN) [ Time Frame: day 6 ]
    Blood urea nitrogen (BUN) levels as assessed via serum blood samples for the comprehensive metabolic panel.
29. Calcium [ Time Frame: day 6 ]
    Calcium levels as assessed via serum blood samples for the comprehensive metabolic panel.
30. Chloride [ Time Frame: day 6 ]
    Chloride levels as assessed via serum blood samples for the comprehensive metabolic panel.
31. Carbon Dioxide (CO2) [ Time Frame: day 6 ]
    Carbon Dioxide (CO2) levels as assessed via serum blood samples for the comprehensive metabolic panel.
32. C-Reactive Protein Levels [ Time Frame: day 6 ]
    As assessed via serum blood samples.
33. Arachidonic Acid/Eicosapentaenoic Acid (AA/EPA) Ratio [ Time Frame: day 6 ]
    As assessed via serum blood samples on day 6 (visit 8).
34. D-dimer Levels [ Time Frame: day 6 ]
    As assessed via serum blood samples.
35. 25-Hydroxy Vitamin D Levels [ Time Frame: day 6 ]
    As assessed via serum blood samples.
36. Tumor Necrosis Factor-alpha (TNFα) [ Time Frame: day 6 ]
    Analysis of TNFα in peripheral blood plasma
37. Tumor Necrosis Factor-beta (TNFβ) [ Time Frame: day 6 ]
    Analysis of TNFβ in peripheral blood plasma
38. Soluble Tumor Necrosis Factor Receptor 2 (sTNFR2) [ Time Frame: day 6 ]
    Analysis of soluble tumor necrosis factor receptor 2 (sTNFR2) in peripheral blood plasma
39. Viral Load by SARS-CoV-2 RT-PCR [ Time Frame: day 6 ]
    Viral load as assessed in blood plasma for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) via Reverse Transcriptase Polymerase Chain Reaction (RT-PCR).
40. Number of Participants Reporting Panel Reactive Antibody (PRA) Positivity at Day 3 Post First Infusion [ Time Frame: day 3 post first infusion ]
    Number of participants reporting panel reactive antibody (PRA) positivity at Day 3 post first infusion for class I and class II as assessed via serum blood samples. These antibodies can develop following a transplant. Recipients can become sensitized to certain molecules (Human Leukocyte Antigen Class I or Class II), which can affect immune responses to and rejection of potential future transplants.
41. Number of Participants Reporting Panel Reactive Antibody (PRA) Positivity at Day 6 Post First Infusion [ Time Frame: day 6 ]
    Number of participants reporting panel reactive antibody (PRA) positivity at Day 6 post first infusion for class I and class II as assessed via serum blood samples. These antibodies can develop following a transplant. Recipients can become sensitized to certain molecules (Human Leukocyte Antigen Class I or Class II), which can affect immune responses to and rejection of potential future transplants.
42. Number of Participants Reporting Panel Reactive Antibody (PRA) Positivity at Day 14 Post First Infusion [ Time Frame: day 14 ]
    Number of participants reporting panel reactive antibody (PRA) positivity at Day 14 post first infusion for class I and class II as assessed via serum blood samples. These antibodies can develop following a transplant. Recipients can become sensitized to certain molecules (Human Leukocyte Antigen Class I or Class II), which can affect immune responses to and rejection of potential future transplants.
43. Number of Participants With Positive, Negative, or Borderline Serology Testing for SARS-CoV-2 IgM/IgG [ Time Frame: day 14 post first infusion ]
    Number of participants with positive, negative, or borderline SARS-CoV-2 Immunoglobulin M (IgM)/Immunoglobulin G (IgG) serology from serum blood samples.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

Patients >/= 18 years old diagnosed with COVID-19 (as evaluated by PCR test confirming infection with SARS-CoV-2) will be eligible for inclusion if they meet all of the below criteria. Inclusion criteria must all be present within a 24-hour time period at the time of enrollment:

1. Patient currently hospitalized
2. Aged ≥ 18 years
3. Willing and able to provide written informed consent, or with a legal representative who can provide informed consent
4. Peripheral capillary oxygen saturation (SpO2) ≤ 94% at room air, or requiring supplemental oxygen at screening
5. PaO2/FiO2 ratio < 300 mmHg
6. Bilateral infiltrates on frontal chest radiograph or bilateral ground glass opacities on a chest CT scan
7. Hypoxemia requiring an increase in the fraction of inspired oxygen (FiO2) of ≥ 20% AND an increase in positive end-expiratory airway pressure (PEEP) level of 5 cm H2O or more to maintain transcutaneous oxygen saturations in the target range of 88-95%, or requirement for escalation from oxygen therapy to invasive mechanical ventilation

Exclusion Criteria:

1. PaO2/FiO2 ≥ 300 at the time of enrollment
2. A previous MSC infusion not related to this trial
3. History of Pulmonary Hypertension (WHO Class III/IV)
4. History of left atrial hypertension or decompensated left heart failure.
5. Pregnant or lactating patient
6. Unstable arrhythmia
7. Patients with previous lung transplant
8. Patients currently receiving chronic dialysis
9. Patients currently receiving Extracorporeal Membrane Oxygenation (ECMO)
10. Presence of any active malignancy (except non-melanoma skin cancer)
11. Any other irreversible disease or condition for which 6-month mortality is estimated to be greater than 50%
12. Moderate to severe liver disease (AST and ALT >5 X ULN)
13. Severe chronic respiratory disease with a PaCO2 > 50 mm Hg or the use of home oxygen
14. Baseline QT prolongation
15. Moribund patient not expected to survive > 24 hours

Contacts and Locations

Locations

United States, Florida

Diabetes Research Institute, University of Miami Miller School of Medicine

Miami, Florida, United States, 33136

Sponsors and Collaborators

Camillo Ricordi

Investigators

• Principal Investigator: Camillo Ricordi, MD; University of Miami

  Study Documents (Full-Text)

Documents provided by Camillo Ricordi, University of Miami:

Study Protocol and Statistical Analysis Plan  [PDF] February 12, 2021

More Information

• Responsible Party: Camillo Ricordi, Professor of Surgery and Chief, Division of Cellular Transplantation, University of Miami
• ClinicalTrials.gov Identifier: NCT04355728
• Other Study ID Numbers: 20200671; 20200370 ( Other Identifier: Secondary Protocol ID )
• First Posted: April 21, 2020
• Results First Posted: December 6, 2021
• Last Update Posted: December 6, 2021
• Last Verified: December 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Camillo Ricordi, University of Miami:

COVID-19

Additional relevant MeSH terms:

COVID-19; Coronavirus Infections; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury; Syndrome; Disease; Pathologic Processes; Respiratory Tract Infections; Infections; Pneumonia, Viral; Pneumonia; Virus Diseases; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Respiration Disorders; Infant, Premature, Diseases; Infant, Newborn, Diseases; Lung Injury; Heparin; Calcium heparin; Anticoagulants; Fibrinolytic Agents; Fibrin Modulating Agents; Molecular Mechanisms of Pharmacological Action