Acute Respiratory Distress Syndrome, ARDS (Moderate or Severe), COVID-19 Pneumonia
Conditions
Keywords
cytokine storm, Mesenchymal Stem Cells, SARS-CoV-2, COVID-19, Mesenchymal Stromal Cells, MSC
Brief summary
This is a multi-center, randomized, placebo controlled, interventional phase 2A trial to evaluate the safety profile and potential efficacy of multi-dosing of mesenchymal stromal cells (MSC) for patients with SARS-CoV-2 associated Acute Respiratory Distress Syndrome (ARDS). After informed consent, treatment assignment will be made by computer-generated randomization to administer either MSC or vehicle placebo control with a 2:1 allocation to the MSC: placebo arm.
Detailed description
MSCs are adult, non-hematopoietic precursor cells derived from a variety of tissues (e.g., bone marrow, adipose tissue, and placenta) and have been used as therapy in multiple conditions, especially in immune-mediated inflammatory diseases, such as graft versus-host disease (GVHD) and systemic lupus erythematosus (SLE) with evidence of benefit. In preclinical models, MSC are effective in ameliorating acute lung injury due to their ability to secrete paracrine factors that regulate lung endothelial and epithelial permeability, including growth factors, anti-inflammatory cytokines, and antimicrobial peptides. Based on the promising pre-clinical preliminary data and intriguing results in patients with COVID-19 associated pneumonia and ARDS as well as an established safety profile of MSC generally and in ARDS in particular, the researchers propose multiple dosing of MSCs as a study treatment to ameliorate the severity and duration of SARS-CoV-2 associated pneumonia and ARDS potentially improve survival. Patients will receive study agent (MSC or placebo) within 48 hours of enrollment. Three doses will be administered unless a severe infusion adverse event occurs that is related to the MSC infusion. Doses will be repeated approximately every 48-72 hours with the aim of completing 3 doses within 7 days of the first dose. All patients will receive standard of care treatments for ARDS.
Interventions
BIOLOGICALMesenchymal stromal cells
Thawed product containing MSC(300x10\^6) in DMSO resuspended 1:1 with Dextran 40 + 5% human serum albumin \[total volume 60 mL\]
OTHERPlacebo
Dextran 40 + 5% human serum albumin \[total volume 60 mL\]
Sponsors
Masonic Cancer Center, University of Minnesota
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Patients will be randomly assigned (2:1) to receive either 300 × 10\^6 MSC or vehicle placebo control. Randomization will be stratified by risk (high versus standard risk based on the presence of preexisting co-morbidities), using permuted block sizes of 3. The allocation sequence will be accessed by each cell processing laboratory through ONCORE. Personnel in the cell processing laboratories are not masked to the treatment group, but patients, clinical staff, and investigators will be unaware of treatment assignment. To maintain masking of the investigators and clinicians, bags containing the study products and intravenous tubing had opaque coverings applied in the cell laboratories.
Intervention model description
This is a randomized (2:1 ratio) placebo controlled trial.
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Age 18-80 years * Meets 'Berlin Criteria' for diagnosis of moderate to severe ARDS for a minimum of 4 hours * Less than 48 hours on a ventilator after meeting criteria for diagnosis of ARDS * SARS-CoV-2 (proven by RT-PCR assay) with radiographic infiltrates * PaO2/FiO2 \< 250 * Positive end-expiratory airway pressure (PEEP) \>5 cm H20 * Elevated C-reactive protein (above laboratory upper limit of normal) * Meets organ function requirements, including left ventricular ejection fraction (LVEF) \>35% ( as defined below) * Off other investigational agents directed against inflammatory cytokines 48 hours prior to enrollment; agents directed against the replication of SARS-CoV-2 \[e.g., Remdesivir\] are permitted * Voluntary informed consent in person or virtually by the patient or patient surrogate considering the face to face limitations during the COVID-19 pandemic and, given the nature of the study population, which frequently requires mechanical ventilation with sedation, surrogate consent will likely occur in a substantial proportion of the study population (this will remain a valid consent until the patient is fully alert, and aware, and can provide a second consent to continue participation in the study). * Adequate organ function is defined as: * Renal: Calculated estimated glomerular filtration rate \>30 mL/min/1.73 m2 (on chemistry panel) * Hepatic: Bilirubin \<3x upper limit of normal (ULN) and AST, ALT and alkaline phosphatase \<5x ULN * Cardiac: Absence of uncontrolled arrhythmia and LVEF \>35%
Exclusion criteria
* Ventilator support of FiO2 \>0·8 or PEEP \>20 cm H2O and ongoing use of more than two vasopressors for 2 or more hours with any agent at doses shown below in the supine position. * Norepinephrine \>12 μg/min or 0.2 μg/kg per min * Phenylephrine \>150 μg/min or 3 μg/kg per min * Epinephrine \>10 ug/min or 0.2 μg/kg per min * Vasopressin \>0.04 units/min * Concurrent use of other investigational agents specifically for treatment of ARDS or inflammatory cytokines. (Note: Agents established to be efficacious and/or those used outside of formal trials are permitted as supportive data emerge) * Known ineligibility for use of a ventilator for a minimum of 7 days, as judged by the institution's Triage Team * Known allergy to MSC components: fetal calf serum, human albumin or DMSO * Active invasive malignant disease requiring chemotherapy/radiation * Other concurrent life-threatening disease (life expectancy \<6 months) or eligible for hospice care * Known history of HIV infection on active treatment * Females who are pregnant or breastfeeding * Current mean arterial pressure (MAP) \<60 mmHg while on 2 or more vasopressors at above doses for more than 2 hours * History of any significant cardiac (myocardial infarction within 12 months of screening visit or unstable angina), chronic ongoing hepatic, or renal disease (grade 3 or higher); diagnosis of congestive heart failure with hypoxemia primarily due to decompensated heart failure; diagnosis of severe chronic obstructive pulmonary disease (COPD) or interstitial lung disease requiring supplemental oxygen at home * Concurrent diagnosis of diffuse alveolar hemorrhage * Requiring continuous dialysis (unable to stop dialysis during study agent infusion)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Incidence of Grade 3-5 Infusional Toxicities and Predefined Hemodynamic or Respiratory Adverse Events Related to the Infusion of MSC | Within 6 hours of the start of the infusion |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Trend Changes in PaO2:FiO2 Ratio | On the day of screening and on days 3, 7 and 14 after first infusion | Trend change was determined by evaluating PaO2:FiO2 ratios at prespecified time points and determining the slope of the line of best fit across data points for each patient, followed by taking the mean and SD across patients in each treatment group. Negative and positive slopes indicating decreasing or increasing values over time, respectively. |
| Trend Changes in Mean Airway Pressure | On the day of screening and on days 3, 7 and 14 after first infusion | Trend change was determined by evaluating mean airway pressure values at prespecified time points and determining the slope of the line of best fit across data points for each patient, followed by taking the mean and SD across patients in each treatment group. Negative and positive slopes indicating decreasing or increasing values over time, respectively. |
| Trend Changes in Peak Pressure | On the day of screening and on days 3, 7 and 14 after first infusion | Trend change was determined by evaluating peak pressure values at prespecified time points and determining the slope of the line of best fit across data points for each patient, followed by taking the mean and SD across patients in each treatment group. Negative and positive slopes indicating decreasing or increasing values over time, respectively. |
| Trend Changes in Plateau Pressure | On the day of screening (baseline) and on days 3, 7 and 14 after first infusion | Trend change was determined by evaluating plateau pressure values at prespecified time points and determining the slope of the line of best fit across data points for each patient, followed by taking the mean and SD across patients in each treatment group. Negative and positive slopes indicating decreasing or increasing values over time, respectively. |
| Trend Changes in Positive End-expiratory Airway Pressure (PEEP) | On the day of screening and on days 3, 7 and 14 after first infusion | Trend change was determined by evaluating Positive end-expiratory airway pressure (PEEP) values at prespecified time points and determining the slope of the line of best fit across data points for each patient, followed by taking the mean and SD across patients in each treatment group. Negative and positive slopes indicating decreasing or increasing values over time, respectively. |
| Change in Biomarkers of Inflammation From Day 0 to Day 7 | Day 7 after first infusion | Mean (SD) represents the change on day 7 after treatment compared to pretreatment value for each biomarker of inflammation. (IL-1, IL-6, IL-8 and TNFa) Measured in pg/mL. |
| Number of ICU-free Days | 28 days after first infusion | — |
| Number of Days Alive and Ventilator Free | 28 days after first infusion | — |
| Change in Acute Lung Injury (ALI) Score 2 | Baseline and Day 28 after first infusion | Acute Lung Injury Score is a composite 4 point scoring system validated by the NHLBI ARDS Network that considers PaO2/FiO2, the level of positive end-expiratory airway pressure, respiratory compliance, and the extent of pulmonary infiltrates on the chest radiograph. Each criterion is scored from 0-4 based on the severity of the condition. The final score is calculated by dividing the total score by the number of criteria used. A score of 0 indicates no lung injury, and a score over 2.5 indicates Acute respiratory distress syndrome (ARDS). The scoring ranges from 0 to a maximum score of 3. |
| Incidence of Serious Adverse Events | 28 days after first infusion | — |
| Number of Days Alive Off Supplemental Oxygen | 100 days after first infusion | — |
| Incidence of Mortality | 50 days after first infusion | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Mesenchymal Stromal Cells Three fixed doses of MSC approximately 48 hours apart.
Mesenchymal stromal cells: Thawed product containing MSC(300x10\^6) in DMSO resuspended 1:1 with Dextran 40 + 5% human serum albumin \[total volume 60 mL\] | 6 |
| Placebo Three fixed doses of placebo control approximately 48 hours apart.
Placebo: Dextran 40 + 5% human serum albumin \[total volume 60 mL\] | 2 |
| Total | 8 |
Baseline characteristics
| Characteristic | Total | Placebo | Mesenchymal Stromal Cells |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 1 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 2 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 1 Participants | 5 Participants |
| Region of Enrollment United States | 8 participants | 2 participants | 6 participants |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 6 Participants | 1 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 6 | 1 / 2 |
| other Total, other adverse events | 6 / 6 | 2 / 2 |
| serious Total, serious adverse events | 2 / 6 | 1 / 2 |
Outcome results
Primary
Incidence of Grade 3-5 Infusional Toxicities and Predefined Hemodynamic or Respiratory Adverse Events Related to the Infusion of MSC
Time frame: Within 6 hours of the start of the infusion
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Mesenchymal Stromal Cells | Incidence of Grade 3-5 Infusional Toxicities and Predefined Hemodynamic or Respiratory Adverse Events Related to the Infusion of MSC | 0 Participants |
| Placebo | Incidence of Grade 3-5 Infusional Toxicities and Predefined Hemodynamic or Respiratory Adverse Events Related to the Infusion of MSC | 0 Participants |
Secondary
Change in Acute Lung Injury (ALI) Score 2
Acute Lung Injury Score is a composite 4 point scoring system validated by the NHLBI ARDS Network that considers PaO2/FiO2, the level of positive end-expiratory airway pressure, respiratory compliance, and the extent of pulmonary infiltrates on the chest radiograph. Each criterion is scored from 0-4 based on the severity of the condition. The final score is calculated by dividing the total score by the number of criteria used. A score of 0 indicates no lung injury, and a score over 2.5 indicates Acute respiratory distress syndrome (ARDS). The scoring ranges from 0 to a maximum score of 3.
Time frame: Baseline and Day 28 after first infusion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mesenchymal Stromal Cells | Change in Acute Lung Injury (ALI) Score 2 | -0.25 Scores on a scale | Standard Deviation 0.43 |
| Placebo | Change in Acute Lung Injury (ALI) Score 2 | -1.5 Scores on a scale | Standard Deviation 0 |
Secondary
Change in Biomarkers of Inflammation From Day 0 to Day 7
Mean (SD) represents the change on day 7 after treatment compared to pretreatment value for each biomarker of inflammation. (IL-1, IL-6, IL-8 and TNFa) Measured in pg/mL.
Time frame: Day 7 after first infusion
Population: One participant in 'Mesenchymal Stromal Cells' arm unable to be evaluated.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Mesenchymal Stromal Cells | Change in Biomarkers of Inflammation From Day 0 to Day 7 | Change in IL-1 | 0 pg/mL | Standard Deviation 0.55 |
| Mesenchymal Stromal Cells | Change in Biomarkers of Inflammation From Day 0 to Day 7 | Change in IL-6 | -61 pg/mL | Standard Deviation 190 |
| Mesenchymal Stromal Cells | Change in Biomarkers of Inflammation From Day 0 to Day 7 | Change in TNFa | 0 pg/mL | Standard Deviation 12 |
| Mesenchymal Stromal Cells | Change in Biomarkers of Inflammation From Day 0 to Day 7 | Change in IL-8 | 6 pg/mL | Standard Deviation 53 |
| Placebo | Change in Biomarkers of Inflammation From Day 0 to Day 7 | Change in IL-8 | 145 pg/mL | Standard Deviation 33 |
| Placebo | Change in Biomarkers of Inflammation From Day 0 to Day 7 | Change in IL-1 | 0.4 pg/mL | Standard Deviation 0.99 |
| Placebo | Change in Biomarkers of Inflammation From Day 0 to Day 7 | Change in TNFa | 2 pg/mL | Standard Deviation 2 |
| Placebo | Change in Biomarkers of Inflammation From Day 0 to Day 7 | Change in IL-6 | 102 pg/mL | Standard Deviation 75 |
Secondary
Incidence of Mortality
Time frame: 50 days after first infusion
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Mesenchymal Stromal Cells | Incidence of Mortality | 2 Participants |
| Placebo | Incidence of Mortality | 1 Participants |
Secondary
Incidence of Serious Adverse Events
Time frame: 28 days after first infusion
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mesenchymal Stromal Cells | Incidence of Serious Adverse Events | 2 Participants |
| Placebo | Incidence of Serious Adverse Events | 1 Participants |
Secondary
Number of Days Alive and Ventilator Free
Time frame: 28 days after first infusion
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Mesenchymal Stromal Cells | Number of Days Alive and Ventilator Free | 0 days | 3 Participants |
| Mesenchymal Stromal Cells | Number of Days Alive and Ventilator Free | 1 day | 0 Participants |
| Mesenchymal Stromal Cells | Number of Days Alive and Ventilator Free | 4 days | 1 Participants |
| Mesenchymal Stromal Cells | Number of Days Alive and Ventilator Free | 23 days | 1 Participants |
| Mesenchymal Stromal Cells | Number of Days Alive and Ventilator Free | 24 days | 1 Participants |
| Placebo | Number of Days Alive and Ventilator Free | 24 days | 0 Participants |
| Placebo | Number of Days Alive and Ventilator Free | 0 days | 1 Participants |
| Placebo | Number of Days Alive and Ventilator Free | 23 days | 0 Participants |
| Placebo | Number of Days Alive and Ventilator Free | 1 day | 1 Participants |
| Placebo | Number of Days Alive and Ventilator Free | 4 days | 0 Participants |
Secondary
Number of Days Alive Off Supplemental Oxygen
Time frame: 100 days after first infusion
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Mesenchymal Stromal Cells | Number of Days Alive Off Supplemental Oxygen | 0 days | 2 Participants |
| Mesenchymal Stromal Cells | Number of Days Alive Off Supplemental Oxygen | 10 days | 1 Participants |
| Mesenchymal Stromal Cells | Number of Days Alive Off Supplemental Oxygen | 53 days | 0 Participants |
| Mesenchymal Stromal Cells | Number of Days Alive Off Supplemental Oxygen | 61 days | 1 Participants |
| Mesenchymal Stromal Cells | Number of Days Alive Off Supplemental Oxygen | 87 days | 1 Participants |
| Mesenchymal Stromal Cells | Number of Days Alive Off Supplemental Oxygen | 88 days | 1 Participants |
| Placebo | Number of Days Alive Off Supplemental Oxygen | 87 days | 0 Participants |
| Placebo | Number of Days Alive Off Supplemental Oxygen | 0 days | 1 Participants |
| Placebo | Number of Days Alive Off Supplemental Oxygen | 61 days | 0 Participants |
| Placebo | Number of Days Alive Off Supplemental Oxygen | 10 days | 0 Participants |
| Placebo | Number of Days Alive Off Supplemental Oxygen | 88 days | 0 Participants |
| Placebo | Number of Days Alive Off Supplemental Oxygen | 53 days | 1 Participants |
Secondary
Number of ICU-free Days
Time frame: 28 days after first infusion
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Mesenchymal Stromal Cells | Number of ICU-free Days | 0 days | 3 Participants |
| Mesenchymal Stromal Cells | Number of ICU-free Days | 7 days | 1 Participants |
| Mesenchymal Stromal Cells | Number of ICU-free Days | 18 days | 1 Participants |
| Mesenchymal Stromal Cells | Number of ICU-free Days | 22 days | 1 Participants |
| Placebo | Number of ICU-free Days | 22 days | 0 Participants |
| Placebo | Number of ICU-free Days | 0 days | 2 Participants |
| Placebo | Number of ICU-free Days | 18 days | 0 Participants |
| Placebo | Number of ICU-free Days | 7 days | 0 Participants |
Secondary
Trend Changes in Mean Airway Pressure
Trend change was determined by evaluating mean airway pressure values at prespecified time points and determining the slope of the line of best fit across data points for each patient, followed by taking the mean and SD across patients in each treatment group. Negative and positive slopes indicating decreasing or increasing values over time, respectively.
Time frame: On the day of screening and on days 3, 7 and 14 after first infusion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mesenchymal Stromal Cells | Trend Changes in Mean Airway Pressure | -2.7 ratio/day | Standard Deviation 6 |
| Placebo | Trend Changes in Mean Airway Pressure | 0.3 ratio/day | Standard Deviation 0.4 |
Secondary
Trend Changes in PaO2:FiO2 Ratio
Trend change was determined by evaluating PaO2:FiO2 ratios at prespecified time points and determining the slope of the line of best fit across data points for each patient, followed by taking the mean and SD across patients in each treatment group. Negative and positive slopes indicating decreasing or increasing values over time, respectively.
Time frame: On the day of screening and on days 3, 7 and 14 after first infusion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mesenchymal Stromal Cells | Trend Changes in PaO2:FiO2 Ratio | -7 ratio/day | Standard Deviation 8 |
| Placebo | Trend Changes in PaO2:FiO2 Ratio | 8 ratio/day | Standard Deviation 7 |
Secondary
Trend Changes in Peak Pressure
Trend change was determined by evaluating peak pressure values at prespecified time points and determining the slope of the line of best fit across data points for each patient, followed by taking the mean and SD across patients in each treatment group. Negative and positive slopes indicating decreasing or increasing values over time, respectively.
Time frame: On the day of screening and on days 3, 7 and 14 after first infusion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mesenchymal Stromal Cells | Trend Changes in Peak Pressure | -0.28 ratio/day | Standard Deviation 1.51 |
| Placebo | Trend Changes in Peak Pressure | 0.19 ratio/day | Standard Deviation 0.45 |
Secondary
Trend Changes in Plateau Pressure
Trend change was determined by evaluating plateau pressure values at prespecified time points and determining the slope of the line of best fit across data points for each patient, followed by taking the mean and SD across patients in each treatment group. Negative and positive slopes indicating decreasing or increasing values over time, respectively.
Time frame: On the day of screening (baseline) and on days 3, 7 and 14 after first infusion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mesenchymal Stromal Cells | Trend Changes in Plateau Pressure | 0.08 ratio/day | Standard Deviation 2.91 |
| Placebo | Trend Changes in Plateau Pressure | 0.38 ratio/day | Standard Deviation 0.71 |
Secondary
Trend Changes in Positive End-expiratory Airway Pressure (PEEP)
Trend change was determined by evaluating Positive end-expiratory airway pressure (PEEP) values at prespecified time points and determining the slope of the line of best fit across data points for each patient, followed by taking the mean and SD across patients in each treatment group. Negative and positive slopes indicating decreasing or increasing values over time, respectively.
Time frame: On the day of screening and on days 3, 7 and 14 after first infusion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mesenchymal Stromal Cells | Trend Changes in Positive End-expiratory Airway Pressure (PEEP) | -0.68 ratio/day | Standard Deviation 0.9 |
| Placebo | Trend Changes in Positive End-expiratory Airway Pressure (PEEP) | 0.14 ratio/day | Standard Deviation 0.28 |