Respiratory Distress Syndrome, Adult
Conditions
Keywords
Human Mesenchymal Stromal Cells, Acute Respiratory Distress Syndrome
Brief summary
This is a Phase 2b, randomized, double-blind, placebo-controlled, multi-center study to assess the safety and efficacy of a single dose of Allogeneic Bone Marrow-derived Human Mesenchymal Stromal Cells (hMSCs) infusion in patients with Acute Respiratory Distress Syndrome (ARDS). This study is the extension of the Phase 1 pilot study (NCT01775774) and Phase 2a study (NCT02097641).
Detailed description
This clinical study design is a randomized, double-blinded, placebo-controlled Phase 2b clinical trial using a 10 million cell/kg dose of human Mesenchymal Stromal Cells (hMSCs). Subjects will be randomized in a 1:1 randomization scheme to receive hMSCs or cell reconstitution media (1:1 mix of 5% human serum albumin and 10% Dextran 40) as the placebo; the study will enroll 120 patients who achieve a stable clinical baseline and receive study product (either hMSCs or the placebo). The Data and Safety Monitoring Board (DSMB) will review adverse outcomes and protocol compliance. A pre-specified interim review will occur after 60 subjects have been enrolled and received study product; enrollment will continue during the DSMB review. All pre-specified clinically important events and unexpected serious adverse events including death during hospitalization up to 60 days will be reported to the DSMB on an ongoing basis; the study will be stopped for a safety evaluation by the DSMB if they have any concerns or if three subjects have pre-specified clinically important events or unexpected serious adverse events except death since death will be common in this critically ill population due the nature of the underlying illness (e.g., ARDS).
Interventions
BIOLOGICALHuman Mesenchymal Stromal Cells
Immediately prior to administration, the study product will be thawed and diluted 1:1 with reconstitution media (1:1 mix of 5% human serum albumin and 10% Dextran 40). Additional reconstitution media is added to a final product volume of 300 mL.
BIOLOGICALCell Reconstitution Media
300 mL of reconstitution media (1:1 mix of 5% human serum albumin and 10% Dextran 40)
Sponsors
United States Department of Defense
Harborview Injury Prevention and Research Center
Oregon Health and Science University
Vanderbilt University Medical Center
The University of Texas Health Science Center, Houston
University of Minnesota
Michael A. Matthay
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Intervention model description
For this Phase 2b trial, after informed consent is given, an assignment will be made by computer-generated randomization to administer either hMSCs therapy or placebo with a 1:1 allocation to the hMSCs:placebo arms.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Patients will be eligible for inclusion if they meet all of the below criteria within 14 days of initial ICU admission. Criteria 1-3 must all be present within a 24-hour time period and at the time of enrollment: Acute onset (defined below) of: 1. A need for positive pressure ventilation by an endotracheal or tracheal tube with a PaO2/FiO2 ratio \<250 mmHg and ≥5 cm H2O positive end-expiratory airway pressure (PEEP), as per the Berlin Criteria. 2. Bilateral infiltrates consistent with pulmonary edema (defined below) on the frontal chest radiograph, or bilateral ground glass opacities on a chest CT scan. 3. No clinical evidence of left atrial hypertension as a primary explanation for the bilateral pulmonary infiltrates. 4. If the cause of ARDS is trauma, additional inclusion criteria will include ONE of the following relevant risk factors for developing ARDS: 1. Hypotension (systolic blood pressure\[SBP\] \< 90 mmHg) in the field or in the first 24 h after injury, or 2. Transfusion of 3 units of blood products in the first 24 hours following injury, or 3. Meets the new Critical Administration Threshold (CAT) criteria with at least 3 units of blood in one hour, or 4. Blunt or penetrating torso trauma, or 5. Long bone fractures, or 6. The highest level of institutional trauma activation
Exclusion criteria
1. Age less than 18 years 2. Greater than 72 hours since first meeting ARDS criteria per the Berlin definition of ARDS 3. Greater than 14 days since initial ICU admission 4. Inability to administer study product within 14 days of ICU admission 5. PaO2/FiO2 ≥ 250 mmHg after consent obtained and before study product is administered 6. Unable to obtain informed consent/no surrogate available 7. Pregnant or lactating 8. In custody of law enforcement officials 9. Burns \> 20% of total body surface area 10. WHO Class III or IV pulmonary hypertension 11. History of cancer treatment in the last 2 years except for non-melanotic skin cancers 12. Underlying medical condition for which 6-month mortality is estimated to be \> 50% 13. Moribund patient not expected to survive 24 hours 14. Advanced chronic liver disease (Child-Pugh Score \> 12) 15. Severe chronic respiratory disease with the use of home oxygen 16. Severe traumatic brain injury - defined as: 1. A patient who has undergone intracranial neurosurgical intervention for monitoring or therapy (intracranial pressure monitoring, external ventricular drain, craniotomy), or 2. Intracranial injury by head CT (does not include patients with minimal subarachnoid injury and/or minor skull fracture), or 3. Post-resuscitation Glasgow Coma Score (GCS) \< 9 assessed after sedation interruption, or 4. Non-survivable head injury as assessed by neurosurgery 17. Evidence of anoxic brain injury 18. History of stroke within the last 3 years 19. No intent/unwillingness to follow lung protective ventilation strategy 20. Currently receiving extracorporeal life support (ECLS) or high-frequency oscillatory ventilation (HFOV) 21. Anticipated extubation within 24 hours of enrollment 22. Clinical evidence of left atrial hypertension as measured by a pulmonary arterial wedge pressure \> 18mmHg or left ventricular failure measured by an echocardiogram with a left ventricular ejection fraction less than 40%. Clinical judgement will determine if either of these measurements needs to be carried out.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Oxygenation Index (OI) | 36 hours | Change in OI from baseline over the 36 hours (6, 12, 18, 24, 30, 36 hours) following the initiation of the study product infusion. Lower values are considered better. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Acute Lung Injury Score (LIS) | 7 days | Changes in the 4-point acute lung injury (LIS) score from the baseline to days 1, 2, 3 and 7, or on the last day of positive pressure ventilation prior to day 7. The LIS is a composite 4-point scoring system including the PaO2/FiO2, PEEP, lung compliance, and the extent of infiltrates on the chest X-ray. Each of the four components is categorized from 0 to 4, where a higher number is worse. The total Lung Injury Score is obtained by dividing the aggregate sum by the number of components used. |
| Change of Chest Radiograph Assessment of Pulmonary Edema (RALE Score) | 7 days | Changes of RALE score at day 1, 2, 3 and 7 from baseline RALE score. To calculate RALE, each radiographic quadrant is scored for extent of consolidation (0-4) and density of opacification (1-3). The product of the consolidation and density scores for each of the four quadrants is summed. The RALE score ranges from 0 (best) to 48 (worst). |
| Ventilator Free-days (VFD) Over 14 Days | 14 days | Ventilator free-days over 14 days. Defined as the number of days from the time of initiating unassisted breathing to day 14 after study product administration, assuming survival for at least two consecutive calendar days after initiating unassisted breathing and continued unassisted breathing to day 14. If a patient returns to assisted breathing and subsequently achieves unassisted breathing to day 14, VFDs will be counted from the end of the last period of assisted breathing to day 14. |
| Ventilator Free-days (VFD) Over 28 Days. | 28 days | Defined as the number of days from the time of initiating unassisted breathing to day 28 after study product administration, assuming survival for at least two consecutive calendar days after initiating unassisted breathing and continued unassisted breathing to day 28. If a patient returns to assisted breathing and subsequently achieves unassisted breathing to day 28, VFDs will be counted from the end of the last period of assisted breathing to day 28. |
| Duration of Assisted Ventilation Over 28 Days | 28 days | Duration of assisted ventilation over 28 days in the survivors |
| Percentage of Patients Achieving Pressure Support Ventilation for 2 Hours | 28 days | Percentage of patients achieving pressure support ventilation equal to 5 cm H2O with positive end-expiratory pressure (PEEP) equal to 5 cm H2O for 2 hours |
| Occurrence of Infection | 14 days | Superficial incisional/wound infections, deep incisional wound infections, and organ/space infections, and ventilator associated pneumonia (all during the 14 days after enrollment) |
| Occurrence of Thromboembolic Events | 60 days | Thromboembolic events are measured by ultrasound of the deep venous system or CT-angiography of the chest ordered for clinical purposes/by treating clinicians |
| Sequential Organ Failure Assessment (SOFA) Over 7 Days | 7 days | SOFA score at 3 and 7 days. The score is based on six different scores, one each for the respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems which are added up. Each score ranges from 0 to 4. SOFA score ranges from 0 (best) to 24 (worst). |
| Non-pulmonary Sequential Organ Failure Assessment (SOFA) Over 7 Days | 7 days | Non-pulmonary SOFA score at 3 and 7 days. The score is based on 5 different scores, one each for the cardiovascular, hepatic, coagulation, renal and neurological systems which are added up. Each score ranges from 0 to 4. SOFA score ranges from 0 (best) to 20 (worst). |
| All-cause Mortality | 60 days | All-cause mortality at 14, 28 and 60 days |
| Glasgow Outcome Score (GCS) | 60 days | Glasgow Outcome Score at hospital discharge. The GCS is a scale to evaluate level of consciousness in patients with acute brain injury. The scale assesses 3 functions: Eye Opening, Verbal Response, and Motor Response. GCS scores range from 15 (best) to 3 (worst) |
| Pulmonary Dead Space Fraction | 7 days | Pulmonary Dead Space at day 1, 2, 3 and 7. The dead-space fraction is calculated as: (PaCO2 - PeCO2) ÷ PaCO2 |
| Plasma Receptor for Advanced Glycation Endproducts (RAGE) | 72 hours | Change in levels of plasma RAGE from baseline at 6, 24, 48 and 72 hours since the initiation of the study product infusion. |
| Plasma Interleukin-6 (IL-6) | 72 hours | Change in levels of plasma interleukin-6 from baseline compared to 6, 24, 48 and 72 hours |
| Plasma Interleukin-8 (IL-8) | 72 hours | Change in levels of plasma interleukin-8 from baseline at 6, 24, 48 and 72 hours since the initiation of study product infusion. |
| Plasma Tumor Necrosis Factor Receptor 1 (TNFR-1) | 72 hours | Change in levels of plasma TNFR-1 from baseline at 6, 24, 48 and 72 hours since the initiation of study product infusion. |
| Plasma Protein C | 72 hours | Change in levels of plasma protein C from baseline at 6, 24, 48 and 72 hours since the initiation of study product infusion. |
| Plasma Angiopoietin-1 (ANG-1) | 72 hours | Change in levels of plasma angiopoietin-1 from the baseline to 6, 24, 48 and 72 hours since the initiation of study product infusion. |
| Plasma Lipoxin A4 | 72 hours | Change in levels of plasma lipoxin A4 from baseline compared to 6, 24, 48 and 72 hours |
| Plasma Resolvin D1 | 72 hours | Change in levels of plasma Resolvin D1 from baseline compared to 6, 24, 48 and 72 hours |
| Plasma Keratinocyte Growth Factor (KGF) | 72 hours | Change in levels of plasma KGF from baseline at 6, 24, 48 and 72 hours since the initiation of study product infusion. |
| Urine Microalbumin | 48 hours | Change in levels of urine microalbumin from baseline compared to 24 and 48 hours |
| Total Protein in Min-bronchoalveolar Lavage (mBAL) | 2 days | Change in total protein levels in from baseline to day 2 |
| Tolerability of the hMSCs - Incidence of Pre-specified Infusion-associated Events and Unexpected Severe Adverse Events | 24 hours | Tolerability of the hMSCs, defined as the incidence of pre-specified infusion-associated events and unexpected severe adverse events in ARDS patients treated with human MSCs |
| Plasma Angiopoietin-2 | 72 hours | Change in levels of plasma angiopoietin-2 from baseline at 6, 24, 48 and 72 hours since the initiation of the study product infusion. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Human Mesenchymal Stromal Cells A single dose of 10 million cells/kg predicted body weight (PBW) Allogeneic Bone Marrow-Derived Human Mesenchymal Stromal Cells will administered intravenously over approximately 60-80 minutes.
Human Mesenchymal Stromal Cells: Immediately prior to administration, the study product will be thawed and diluted 1:1 with reconstitution media (1:1 mix of 5% human serum albumin and 10% Dextran 40). Additional reconstitution media is added to a final product volume of 300 mL. | 59 |
| Cell Reconstitution Media A single dose of cell reconstitution media (1:1 mix of 5% human serum albumin and 10% Dextran 40) will administered intravenously over approximately 60-80 minutes.
Cell Reconstitution Media: 300 mL of reconstitution media (1:1 mix of 5% human serum albumin and 10% Dextran 40) | 61 |
| Total | 120 |
Baseline characteristics
| Characteristic | Human Mesenchymal Stromal Cells | Total | Cell Reconstitution Media |
|---|---|---|---|
| Acute Physiology, Age, Chronic Health Evaluation (APACHE) III | 100.8 units on a scale STANDARD_DEVIATION 26 | 97.1 units on a scale STANDARD_DEVIATION 26.1 | 93.6 units on a scale STANDARD_DEVIATION 26 |
| Age, Continuous | 54.0 years STANDARD_DEVIATION 14.4 | 55.5 years STANDARD_DEVIATION 14.8 | 57.0 years STANDARD_DEVIATION 15.1 |
| Angiopoietin 2 (ANG-2) | 3519 pg/mL | 3593 pg/mL | 3755 pg/mL |
| COVID positive No | 3 Participants | 19 Participants | 16 Participants |
| COVID positive Yes | 56 Participants | 101 Participants | 45 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 21 Participants | 47 Participants | 26 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 30 Participants | 61 Participants | 31 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 8 Participants | 12 Participants | 4 Participants |
| Interleukin 6 (IL-6) | 56.3 pg/mL | 37.1 pg/mL | 23.2 pg/mL |
| Interleukin 8 (IL-8) | 14.8 pg/mL | 14.2 pg/mL | 12.8 pg/mL |
| Lung Injury Score | 3.2 units on a scale STANDARD_DEVIATION 0.4 | 3.1 units on a scale STANDARD_DEVIATION 0.4 | 3.0 units on a scale STANDARD_DEVIATION 0.4 |
| Minute Ventilation | 10.0 liter/min STANDARD_DEVIATION 2.8 | 9.7 liter/min STANDARD_DEVIATION 2.6 | 9.4 liter/min STANDARD_DEVIATION 2.4 |
| Non-pulmonary Sequential Organ Failure Assessment (SOFA) Score | 6.9 units on a scale STANDARD_DEVIATION 3.3 | 6.7 units on a scale STANDARD_DEVIATION 3 | 6.5 units on a scale STANDARD_DEVIATION 2.6 |
| Oxygenation Index | 13.6 cmH20/mmHg STANDARD_DEVIATION 6.6 | 12.8 cmH20/mmHg STANDARD_DEVIATION 5.6 | 12.1 cmH20/mmHg STANDARD_DEVIATION 4.4 |
| PaO2:FiO2 | 152 mmHg STANDARD_DEVIATION 44 | 153 mmHg STANDARD_DEVIATION 42 | 154 mmHg STANDARD_DEVIATION 39 |
| Primary Cause of ARDS Aspiration | 0 Participants | 3 Participants | 3 Participants |
| Primary Cause of ARDS COVID-19 Pneumonia | 56 Participants | 100 Participants | 44 Participants |
| Primary Cause of ARDS Non COVID-19 Pneumonia | 0 Participants | 5 Participants | 5 Participants |
| Primary Cause of ARDS Other | 0 Participants | 1 Participants | 1 Participants |
| Primary Cause of ARDS Sepsis | 1 Participants | 4 Participants | 3 Participants |
| Primary Cause of ARDS Trauma | 2 Participants | 7 Participants | 5 Participants |
| Protein C | 104.3 pg/mL | 102.2 pg/mL | 99.7 pg/mL |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 9 Participants | 14 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 8 Participants | 2 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 | 21 Participants | 43 Participants | 22 Participants |
| Race (NIH/OMB) White | 22 Participants | 54 Participants | 32 Participants |
| Receptor for Advanced Glycation Endproducts (RAGE) | 5736 pg/mL | 6229 pg/mL | 6373 pg/mL |
| Region of Enrollment United States | 59 participants | 120 participants | 61 participants |
| Sex: Female, Male Female | 20 Participants | 49 Participants | 29 Participants |
| Sex: Female, Male Male | 39 Participants | 71 Participants | 32 Participants |
| Tumor Necrosis Factor Receptor 1 (TNFR-1) | 3492 pg/mL | 3758 pg/mL | 3919 pg/mL |
| Ventilatory Ratio | 2.0 ratio STANDARD_DEVIATION 0.8 | 1.9 ratio STANDARD_DEVIATION 0.7 | 1.9 ratio STANDARD_DEVIATION 0.6 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 24 / 59 | 21 / 61 |
| other Total, other adverse events | 9 / 59 | 6 / 61 |
| serious Total, serious adverse events | 3 / 59 | 2 / 61 |
Outcome results
Primary
Change in Oxygenation Index (OI)
Change in OI from baseline over the 36 hours (6, 12, 18, 24, 30, 36 hours) following the initiation of the study product infusion. Lower values are considered better.
Time frame: 36 hours
Population: Missing data are due to various causes: ventilated by PSV mode, not recorded, or expired.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Human Mesenchymal Stromal Cells | Change in Oxygenation Index (OI) | 6 Hour | -0.7 cmH20/mmHg |
| Human Mesenchymal Stromal Cells | Change in Oxygenation Index (OI) | 12 Hour | 0.8 cmH20/mmHg |
| Human Mesenchymal Stromal Cells | Change in Oxygenation Index (OI) | 18 Hour | 0.3 cmH20/mmHg |
| Human Mesenchymal Stromal Cells | Change in Oxygenation Index (OI) | 24 Hour | 0.3 cmH20/mmHg |
| Human Mesenchymal Stromal Cells | Change in Oxygenation Index (OI) | 30 Hour | 0.8 cmH20/mmHg |
| Human Mesenchymal Stromal Cells | Change in Oxygenation Index (OI) | 36 Hour | 0.8 cmH20/mmHg |
| Cell Reconstitution Media | Change in Oxygenation Index (OI) | 30 Hour | -0.7 cmH20/mmHg |
| Cell Reconstitution Media | Change in Oxygenation Index (OI) | 6 Hour | -1.5 cmH20/mmHg |
| Cell Reconstitution Media | Change in Oxygenation Index (OI) | 24 Hour | -1.1 cmH20/mmHg |
| Cell Reconstitution Media | Change in Oxygenation Index (OI) | 12 Hour | -1.1 cmH20/mmHg |
| Cell Reconstitution Media | Change in Oxygenation Index (OI) | 36 Hour | -1.5 cmH20/mmHg |
| Cell Reconstitution Media | Change in Oxygenation Index (OI) | 18 Hour | -1.0 cmH20/mmHg |
p-value: 0.34Mixed Models Analysis
Secondary
Acute Lung Injury Score (LIS)
Changes in the 4-point acute lung injury (LIS) score from the baseline to days 1, 2, 3 and 7, or on the last day of positive pressure ventilation prior to day 7. The LIS is a composite 4-point scoring system including the PaO2/FiO2, PEEP, lung compliance, and the extent of infiltrates on the chest X-ray. Each of the four components is categorized from 0 to 4, where a higher number is worse. The total Lung Injury Score is obtained by dividing the aggregate sum by the number of components used.
Time frame: 7 days
Population: LIS were calculated for patients who were intubated.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Human Mesenchymal Stromal Cells | Acute Lung Injury Score (LIS) | Day 1 | -0.10 score on a scale | Standard Deviation 0.41 |
| Human Mesenchymal Stromal Cells | Acute Lung Injury Score (LIS) | Day 2 | -0.07 score on a scale | Standard Deviation 0.41 |
| Human Mesenchymal Stromal Cells | Acute Lung Injury Score (LIS) | Day 3 | -0.15 score on a scale | Standard Deviation 0.53 |
| Human Mesenchymal Stromal Cells | Acute Lung Injury Score (LIS) | Day 7 | -0.39 score on a scale | Standard Deviation 0.69 |
| Cell Reconstitution Media | Acute Lung Injury Score (LIS) | Day 7 | -0.21 score on a scale | Standard Deviation 0.63 |
| Cell Reconstitution Media | Acute Lung Injury Score (LIS) | Day 1 | -0.10 score on a scale | Standard Deviation 0.48 |
| Cell Reconstitution Media | Acute Lung Injury Score (LIS) | Day 3 | -0.09 score on a scale | Standard Deviation 0.57 |
| Cell Reconstitution Media | Acute Lung Injury Score (LIS) | Day 2 | -0.15 score on a scale | Standard Deviation 0.62 |
Comparison: The analysis is for the change of LIS from the baseline to day 1.p-value: 0.92t-test, 2 sided
Comparison: The analysis is for the change of LIS from the baseline to day 2.p-value: 0.37t-test, 2 sided
Comparison: The analysis is for the change of LIS from the baseline to day 3.p-value: 0.54t-test, 2 sided
Comparison: The analysis is for the change of LIS from the baseline to day 7.p-value: 0.19t-test, 2 sided
Secondary
All-cause Mortality
All-cause mortality at 14, 28 and 60 days
Time frame: 60 days
Population: 4 patients were lost of followup up to 60 days.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Human Mesenchymal Stromal Cells | All-cause Mortality | 14-day mortality | 12 Participants |
| Human Mesenchymal Stromal Cells | All-cause Mortality | 28-day mortality | 16 Participants |
| Human Mesenchymal Stromal Cells | All-cause Mortality | 60-day mortality | 21 Participants |
| Cell Reconstitution Media | All-cause Mortality | 14-day mortality | 8 Participants |
| Cell Reconstitution Media | All-cause Mortality | 28-day mortality | 15 Participants |
| Cell Reconstitution Media | All-cause Mortality | 60-day mortality | 18 Participants |
Comparison: The analysis is for the mortality between two arms at Day 14.p-value: 0.29Chi-squared
Comparison: The analysis is for the mortality between the two arms at Day 28.p-value: 0.83Chi-squared
Comparison: The analysis is for the mortality between the two arms at Day 60.p-value: 0.56Chi-squared
Secondary
Change of Chest Radiograph Assessment of Pulmonary Edema (RALE Score)
Changes of RALE score at day 1, 2, 3 and 7 from baseline RALE score. To calculate RALE, each radiographic quadrant is scored for extent of consolidation (0-4) and density of opacification (1-3). The product of the consolidation and density scores for each of the four quadrants is summed. The RALE score ranges from 0 (best) to 48 (worst).
Time frame: 7 days
Population: RALE scores are calculated by the available Chest X-ray photographs.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Human Mesenchymal Stromal Cells | Change of Chest Radiograph Assessment of Pulmonary Edema (RALE Score) | Day 1 | -0.7 score on a scale |
| Human Mesenchymal Stromal Cells | Change of Chest Radiograph Assessment of Pulmonary Edema (RALE Score) | Day 2 | -1.1 score on a scale |
| Human Mesenchymal Stromal Cells | Change of Chest Radiograph Assessment of Pulmonary Edema (RALE Score) | Day 3 | -0.5 score on a scale |
| Human Mesenchymal Stromal Cells | Change of Chest Radiograph Assessment of Pulmonary Edema (RALE Score) | Day 7 | -2.3 score on a scale |
| Cell Reconstitution Media | Change of Chest Radiograph Assessment of Pulmonary Edema (RALE Score) | Day 7 | 2.4 score on a scale |
| Cell Reconstitution Media | Change of Chest Radiograph Assessment of Pulmonary Edema (RALE Score) | Day 1 | 1.0 score on a scale |
| Cell Reconstitution Media | Change of Chest Radiograph Assessment of Pulmonary Edema (RALE Score) | Day 3 | 0.0 score on a scale |
| Cell Reconstitution Media | Change of Chest Radiograph Assessment of Pulmonary Edema (RALE Score) | Day 2 | 1.7 score on a scale |
Comparison: The analysis is for the change in RALE scores from the baseline to day 1.p-value: 0.35Wilcoxon (Mann-Whitney)
Comparison: The analysis is for the change in RALE scores from the baseline to day 2.p-value: 0.25Wilcoxon (Mann-Whitney)
Comparison: The analysis is for the change in RALE scores from the baseline to day 3.p-value: 0.69Wilcoxon (Mann-Whitney)
Comparison: The analysis is for the change in RALE scores from the baseline to day 7.p-value: 0.08Wilcoxon (Mann-Whitney)
Secondary
Duration of Assisted Ventilation Over 28 Days
Duration of assisted ventilation over 28 days in the survivors
Time frame: 28 days
Population: The analysis was conducted in the subgroup of patients who survived by 6 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Human Mesenchymal Stromal Cells | Duration of Assisted Ventilation Over 28 Days | 22 days |
| Cell Reconstitution Media | Duration of Assisted Ventilation Over 28 Days | 10 days |
p-value: 0.01Wilcoxon (Mann-Whitney)
Secondary
Glasgow Outcome Score (GCS)
Glasgow Outcome Score at hospital discharge. The GCS is a scale to evaluate level of consciousness in patients with acute brain injury. The scale assesses 3 functions: Eye Opening, Verbal Response, and Motor Response. GCS scores range from 15 (best) to 3 (worst)
Time frame: 60 days
Population: 11 patients did not have recorded Glasgow Coma Scores at hospital discharge, all of them were expired.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Human Mesenchymal Stromal Cells | Glasgow Outcome Score (GCS) | 10.6 score on a scale | Standard Deviation 5.6 |
| Cell Reconstitution Media | Glasgow Outcome Score (GCS) | 11.5 score on a scale | Standard Deviation 5.3 |
p-value: 0.41t-test, 2 sided
Secondary
Non-pulmonary Sequential Organ Failure Assessment (SOFA) Over 7 Days
Non-pulmonary SOFA score at 3 and 7 days. The score is based on 5 different scores, one each for the cardiovascular, hepatic, coagulation, renal and neurological systems which are added up. Each score ranges from 0 to 4. SOFA score ranges from 0 (best) to 20 (worst).
Time frame: 7 days
Population: Data were collected in the patients who were still in hospital alive.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Human Mesenchymal Stromal Cells | Non-pulmonary Sequential Organ Failure Assessment (SOFA) Over 7 Days | Day 3 | 6.0 score on a scale | Standard Deviation 3.2 |
| Human Mesenchymal Stromal Cells | Non-pulmonary Sequential Organ Failure Assessment (SOFA) Over 7 Days | Day 7 | 5.6 score on a scale | Standard Deviation 3.5 |
| Cell Reconstitution Media | Non-pulmonary Sequential Organ Failure Assessment (SOFA) Over 7 Days | Day 3 | 5.5 score on a scale | Standard Deviation 2.9 |
| Cell Reconstitution Media | Non-pulmonary Sequential Organ Failure Assessment (SOFA) Over 7 Days | Day 7 | 4.8 score on a scale | Standard Deviation 3.8 |
Comparison: The analysis is for non-pulmonary SOFA scores between the two arms at Day 3.p-value: 0.39t-test, 2 sided
Comparison: The analysis is for non-pulmonary SOFA scores between the two arms at Day 7.p-value: 0.26t-test, 2 sided
Secondary
Occurrence of Infection
Superficial incisional/wound infections, deep incisional wound infections, and organ/space infections, and ventilator associated pneumonia (all during the 14 days after enrollment)
Time frame: 14 days
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Human Mesenchymal Stromal Cells | Occurrence of Infection | Incisional/wound infection | 3 Participants |
| Human Mesenchymal Stromal Cells | Occurrence of Infection | Organ/space infection | 1 Participants |
| Human Mesenchymal Stromal Cells | Occurrence of Infection | Ventilator associated pneumonia | 20 Participants |
| Cell Reconstitution Media | Occurrence of Infection | Incisional/wound infection | 1 Participants |
| Cell Reconstitution Media | Occurrence of Infection | Organ/space infection | 0 Participants |
| Cell Reconstitution Media | Occurrence of Infection | Ventilator associated pneumonia | 14 Participants |
Comparison: The analysis is for the percentages of patients who developed incision/wound infection events by day 14.p-value: 0.36Fisher Exact
Comparison: The analysis is for the percentages of patients who developed organ/space infection events by day 14.p-value: 0.5Fisher Exact
Comparison: The analysis is for the percentages of patients who developed ventilator-associated pneumonia by day 14.p-value: 0.2Fisher Exact
Secondary
Occurrence of Thromboembolic Events
Thromboembolic events are measured by ultrasound of the deep venous system or CT-angiography of the chest ordered for clinical purposes/by treating clinicians
Time frame: 60 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Human Mesenchymal Stromal Cells | Occurrence of Thromboembolic Events | 10 Participants |
| Cell Reconstitution Media | Occurrence of Thromboembolic Events | 8 Participants |
p-value: 0.56Chi-squared
Secondary
Percentage of Patients Achieving Pressure Support Ventilation for 2 Hours
Percentage of patients achieving pressure support ventilation equal to 5 cm H2O with positive end-expiratory pressure (PEEP) equal to 5 cm H2O for 2 hours
Time frame: 28 days
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Human Mesenchymal Stromal Cells | Percentage of Patients Achieving Pressure Support Ventilation for 2 Hours | Yes | 25 Participants |
| Human Mesenchymal Stromal Cells | Percentage of Patients Achieving Pressure Support Ventilation for 2 Hours | No | 34 Participants |
| Cell Reconstitution Media | Percentage of Patients Achieving Pressure Support Ventilation for 2 Hours | Yes | 31 Participants |
| Cell Reconstitution Media | Percentage of Patients Achieving Pressure Support Ventilation for 2 Hours | No | 30 Participants |
p-value: 0.35Chi-squared
Secondary
Plasma Angiopoietin-1 (ANG-1)
Change in levels of plasma angiopoietin-1 from the baseline to 6, 24, 48 and 72 hours since the initiation of study product infusion.
Time frame: 72 hours
Population: Samples were not collected due to the intuitional policies regarding the biospecimen collection during COVID-19 pandemic, or not available at the required timepoint of collection (e.g. hospital discharge, death).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Human Mesenchymal Stromal Cells | Plasma Angiopoietin-1 (ANG-1) | 6 Hour | -224 pg/mL |
| Human Mesenchymal Stromal Cells | Plasma Angiopoietin-1 (ANG-1) | 24 Hour | 786 pg/mL |
| Human Mesenchymal Stromal Cells | Plasma Angiopoietin-1 (ANG-1) | 48 Hour | 612 pg/mL |
| Human Mesenchymal Stromal Cells | Plasma Angiopoietin-1 (ANG-1) | 72 Hour | 148 pg/mL |
| Cell Reconstitution Media | Plasma Angiopoietin-1 (ANG-1) | 72 Hour | 59 pg/mL |
| Cell Reconstitution Media | Plasma Angiopoietin-1 (ANG-1) | 6 Hour | -292 pg/mL |
| Cell Reconstitution Media | Plasma Angiopoietin-1 (ANG-1) | 48 Hour | 661 pg/mL |
| Cell Reconstitution Media | Plasma Angiopoietin-1 (ANG-1) | 24 Hour | 582 pg/mL |
Comparison: The analysis for the changes of ANG-1 at 6 hours since the initiation of study product infusion from the baseline.p-value: 0.85Wilcoxon (Mann-Whitney)
Comparison: The analysis for the changes of ANG-1 at 24 hours since the initiation of study product infusion from the baseline.p-value: 0.22Wilcoxon (Mann-Whitney)
Comparison: The analysis for the changes of ANG-1 at 48 hours since the initiation of study product infusion from the baseline.p-value: 0.61Wilcoxon (Mann-Whitney)
Comparison: The analysis for the changes of ANG-1 at 72 hours since the initiation of study product infusion from the baseline.p-value: 0.98Wilcoxon (Mann-Whitney)
Secondary
Plasma Angiopoietin-2
Change in levels of plasma angiopoietin-2 from baseline at 6, 24, 48 and 72 hours since the initiation of the study product infusion.
Time frame: 72 hours
Population: Plasma samples were not collected due to institutional policies during COVID-19 pandemic, or not available at the required timepoints (e.g. discharged from hospital or death).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Human Mesenchymal Stromal Cells | Plasma Angiopoietin-2 | 6 hour | 125 pg/mL |
| Human Mesenchymal Stromal Cells | Plasma Angiopoietin-2 | 24 hour | 407 pg/mL |
| Human Mesenchymal Stromal Cells | Plasma Angiopoietin-2 | 48 hour | 879 pg/mL |
| Human Mesenchymal Stromal Cells | Plasma Angiopoietin-2 | 72 hour | 594 pg/mL |
| Cell Reconstitution Media | Plasma Angiopoietin-2 | 72 hour | 544 pg/mL |
| Cell Reconstitution Media | Plasma Angiopoietin-2 | 6 hour | 184 pg/mL |
| Cell Reconstitution Media | Plasma Angiopoietin-2 | 48 hour | 343 pg/mL |
| Cell Reconstitution Media | Plasma Angiopoietin-2 | 24 hour | 288 pg/mL |
Comparison: Plasma angiopoietin-2 changes from the baseline between two arms at 6 hours since the initiation of the study product infusion.p-value: 0.56Wilcoxon (Mann-Whitney)
Comparison: Plasma angiopoietin-2 changes from the baseline between two arms at 24 hours since the initiation of the study product infusion.p-value: 0.79Wilcoxon (Mann-Whitney)
Comparison: Plasma angiopoietin-2 changes from the baseline between two arms at 48 hours since the initiation of the study product infusion.p-value: 0.62Wilcoxon (Mann-Whitney)
Comparison: Plasma angiopoietin-2 changes from the baseline between two arms at 72 hours since the initiation of the study product infusion.p-value: 0.67Wilcoxon (Mann-Whitney)
Secondary
Plasma Interleukin-6 (IL-6)
Change in levels of plasma interleukin-6 from baseline compared to 6, 24, 48 and 72 hours
Time frame: 72 hours
Population: Samples were not collected due to the intuitional policies regarding the biospecimen collection during COVID-19 pandemic, or not available at the required timepoint of collection (e.g. hospital discharge, death).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Human Mesenchymal Stromal Cells | Plasma Interleukin-6 (IL-6) | 6 Hour | -10.1 pg/mL |
| Human Mesenchymal Stromal Cells | Plasma Interleukin-6 (IL-6) | 24 Hour | -9.1 pg/mL |
| Human Mesenchymal Stromal Cells | Plasma Interleukin-6 (IL-6) | 48 Hour | -10.7 pg/mL |
| Human Mesenchymal Stromal Cells | Plasma Interleukin-6 (IL-6) | 72 Hour | -11.7 pg/mL |
| Cell Reconstitution Media | Plasma Interleukin-6 (IL-6) | 72 Hour | 2.8 pg/mL |
| Cell Reconstitution Media | Plasma Interleukin-6 (IL-6) | 6 Hour | -3.3 pg/mL |
| Cell Reconstitution Media | Plasma Interleukin-6 (IL-6) | 48 Hour | 4.1 pg/mL |
| Cell Reconstitution Media | Plasma Interleukin-6 (IL-6) | 24 Hour | 5.2 pg/mL |
Comparison: Plasma IL-6 changes from the baseline between two arms at 6 hours since the initiation of the study product infusion.p-value: 0.28Wilcoxon (Mann-Whitney)
Comparison: Plasma IL-6 changes from the baseline between two arms at 24 hours since the initiation of the study product infusion.p-value: 0.1Wilcoxon (Mann-Whitney)
Comparison: Plasma IL-6 changes from the baseline between two arms at 48 hours since the initiation of the study product infusion.p-value: 0.15Wilcoxon (Mann-Whitney)
Comparison: Plasma IL-6 changes from the baseline between two arms at 72 hours since the initiation of the study product infusion.p-value: 0.34Wilcoxon (Mann-Whitney)
Secondary
Plasma Interleukin-8 (IL-8)
Change in levels of plasma interleukin-8 from baseline at 6, 24, 48 and 72 hours since the initiation of study product infusion.
Time frame: 72 hours
Population: Samples were not collected due to the intuitional policies regarding the biospecimen collection during COVID-19 pandemic, or not available at the required timepoint of collection (e.g. hospital discharge, death).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Human Mesenchymal Stromal Cells | Plasma Interleukin-8 (IL-8) | 6 Hour | -1.0 pg/mL |
| Human Mesenchymal Stromal Cells | Plasma Interleukin-8 (IL-8) | 24 Hour | -0.3 pg/mL |
| Human Mesenchymal Stromal Cells | Plasma Interleukin-8 (IL-8) | 48 Hour | -2.5 pg/mL |
| Human Mesenchymal Stromal Cells | Plasma Interleukin-8 (IL-8) | 72 Hour | 0.4 pg/mL |
| Cell Reconstitution Media | Plasma Interleukin-8 (IL-8) | 72 Hour | 1.4 pg/mL |
| Cell Reconstitution Media | Plasma Interleukin-8 (IL-8) | 6 Hour | -0.4 pg/mL |
| Cell Reconstitution Media | Plasma Interleukin-8 (IL-8) | 48 Hour | -0.7 pg/mL |
| Cell Reconstitution Media | Plasma Interleukin-8 (IL-8) | 24 Hour | 0.3 pg/mL |
Comparison: Plasma IL-8 changes from the baseline between two arms at 6 hours since the initiation of the study product infusion.p-value: 0.85Wilcoxon (Mann-Whitney)
Comparison: Plasma IL-8 changes from the baseline between two arms at 24 hours since the initiation of the study product infusion.p-value: 0.5Wilcoxon (Mann-Whitney)
Comparison: Plasma IL-8 changes from the baseline between two arms at 48 hours since the initiation of the study product infusion.p-value: 0.64Wilcoxon (Mann-Whitney)
Comparison: Plasma IL-8 changes from the baseline between two arms at 72 hours since the initiation of the study product infusion.p-value: 0.7Wilcoxon (Mann-Whitney)
Secondary
Plasma Keratinocyte Growth Factor (KGF)
Change in levels of plasma KGF from baseline at 6, 24, 48 and 72 hours since the initiation of study product infusion.
Time frame: 72 hours
Population: Most plasma samples were collected but some were not due to institutional restriction during the COVID-19 pandemic or patient unavailable (e.g. discharge, death). KGF doesn't accurately reflect biological activity of the mesenchymal stromal cell (MSC) treatment, and KGF assay is unreliable for determining the quantity released by MSCs (the therapeutic product) versus the release from endogenous cells within the patient. Thus, KGF levels have not been analyzed and will not analyzed in the future.
Secondary
Plasma Lipoxin A4
Change in levels of plasma lipoxin A4 from baseline compared to 6, 24, 48 and 72 hours
Time frame: 72 hours
Population: The majority of plasma samples were collected but some were not due to institutional policies on biospecimen collection during COVID-19 pandemic or because patients were no longer available (e.g. discharge, death). Plasma lipoxin A4 levels were not tested because the method depends on a complicated assay that is not validated for human use and is therefore unreliable. As a result, these samples have not been analyzed and will not be analyzed in the future.
Secondary
Plasma Protein C
Change in levels of plasma protein C from baseline at 6, 24, 48 and 72 hours since the initiation of study product infusion.
Time frame: 72 hours
Population: Samples were not collected due to the intuitional policies regarding the biospecimen collection during COVID-19 pandemic, or not available at the required timepoint of collection (e.g. hospital discharge, death).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Human Mesenchymal Stromal Cells | Plasma Protein C | 6 Hour | 7.3 pg/mL |
| Human Mesenchymal Stromal Cells | Plasma Protein C | 24 Hour | 8.5 pg/mL |
| Human Mesenchymal Stromal Cells | Plasma Protein C | 72 Hour | 26.7 pg/mL |
| Human Mesenchymal Stromal Cells | Plasma Protein C | 48 Hour | 14.0 pg/mL |
| Cell Reconstitution Media | Plasma Protein C | 72 Hour | 8.3 pg/mL |
| Cell Reconstitution Media | Plasma Protein C | 6 Hour | -2.9 pg/mL |
| Cell Reconstitution Media | Plasma Protein C | 24 Hour | 6.8 pg/mL |
| Cell Reconstitution Media | Plasma Protein C | 48 Hour | 12.7 pg/mL |
Comparison: The analysis for the changes of Protein C at 6 hours since the initiation of study product infusion from the baseline.p-value: 0.16Wilcoxon (Mann-Whitney)
Comparison: The analysis for the changes of Protein C at 24 hours since the initiation of study product infusion from the baseline.p-value: 0.64Wilcoxon (Mann-Whitney)
Comparison: The analysis for the changes of Protein C at 48 hours since the initiation of study product infusion from the baseline.p-value: 0.8Wilcoxon (Mann-Whitney)
Comparison: The analysis for the changes of Protein C at 72 hours since the initiation of study product infusion from the baseline.p-value: 0.4Wilcoxon (Mann-Whitney)
Secondary
Plasma Receptor for Advanced Glycation Endproducts (RAGE)
Change in levels of plasma RAGE from baseline at 6, 24, 48 and 72 hours since the initiation of the study product infusion.
Time frame: 72 hours
Population: Samples were not collected due to the intuitional policies regarding the biospecimen collection during COVID-19 pandemic, or not available at the required timepoint of collection (e.g. hospital discharge, death).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Human Mesenchymal Stromal Cells | Plasma Receptor for Advanced Glycation Endproducts (RAGE) | 6 Hour | 62 pg/mL |
| Human Mesenchymal Stromal Cells | Plasma Receptor for Advanced Glycation Endproducts (RAGE) | 24 Hour | -1249 pg/mL |
| Human Mesenchymal Stromal Cells | Plasma Receptor for Advanced Glycation Endproducts (RAGE) | 48 Hour | -1603 pg/mL |
| Human Mesenchymal Stromal Cells | Plasma Receptor for Advanced Glycation Endproducts (RAGE) | 72 Hour | -2619 pg/mL |
| Cell Reconstitution Media | Plasma Receptor for Advanced Glycation Endproducts (RAGE) | 72 Hour | -2054 pg/mL |
| Cell Reconstitution Media | Plasma Receptor for Advanced Glycation Endproducts (RAGE) | 6 Hour | -137 pg/mL |
| Cell Reconstitution Media | Plasma Receptor for Advanced Glycation Endproducts (RAGE) | 48 Hour | -906 pg/mL |
| Cell Reconstitution Media | Plasma Receptor for Advanced Glycation Endproducts (RAGE) | 24 Hour | 100 pg/mL |
Comparison: Plasma RAGE changes from the baseline between two arms at 6 hours since the initiation of the study product infusion.p-value: 0.6Wilcoxon (Mann-Whitney)
Comparison: Plasma RAGE changes from the baseline between two arms at 24 hours since the initiation of the study product infusion.p-value: 0.04Wilcoxon (Mann-Whitney)
Comparison: Plasma RAGE changes from the baseline between two arms at 48 hours since the initiation of the study product infusion.p-value: 0.09Wilcoxon (Mann-Whitney)
Comparison: Plasma RAGE changes from the baseline between two arms at 72 hours since the initiation of the study product infusion.p-value: 0.38Wilcoxon (Mann-Whitney)
Secondary
Plasma Resolvin D1
Change in levels of plasma Resolvin D1 from baseline compared to 6, 24, 48 and 72 hours
Time frame: 72 hours
Population: The majority of plasma samples were collected but some were not due to institutional policies on biospecimen collection during COVID-19 pandemic or because patients were no longer available (e.g. discharge, death). Plasma resolvin D1 levels were not tested because the method depends on a complicated assay that is not validated for human use and is therefore unreliable. As a result, these samples have not been analyzed and will not be analyzed in the future.
Secondary
Plasma Tumor Necrosis Factor Receptor 1 (TNFR-1)
Change in levels of plasma TNFR-1 from baseline at 6, 24, 48 and 72 hours since the initiation of study product infusion.
Time frame: 72 hours
Population: Samples were not collected due to the intuitional policies regarding the biospecimen collection during COVID-19 pandemic, or not available at the required timepoint of collection (e.g. hospital discharge, death).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Human Mesenchymal Stromal Cells | Plasma Tumor Necrosis Factor Receptor 1 (TNFR-1) | 6 Hour | -1 pg/mL |
| Human Mesenchymal Stromal Cells | Plasma Tumor Necrosis Factor Receptor 1 (TNFR-1) | 24 Hour | 231 pg/mL |
| Human Mesenchymal Stromal Cells | Plasma Tumor Necrosis Factor Receptor 1 (TNFR-1) | 48 Hour | 721 pg/mL |
| Human Mesenchymal Stromal Cells | Plasma Tumor Necrosis Factor Receptor 1 (TNFR-1) | 72 Hour | 382 pg/mL |
| Cell Reconstitution Media | Plasma Tumor Necrosis Factor Receptor 1 (TNFR-1) | 72 Hour | 985 pg/mL |
| Cell Reconstitution Media | Plasma Tumor Necrosis Factor Receptor 1 (TNFR-1) | 6 Hour | 271 pg/mL |
| Cell Reconstitution Media | Plasma Tumor Necrosis Factor Receptor 1 (TNFR-1) | 48 Hour | 1596 pg/mL |
| Cell Reconstitution Media | Plasma Tumor Necrosis Factor Receptor 1 (TNFR-1) | 24 Hour | 1047 pg/mL |
Comparison: The analysis for the changes of TNFR-1 at 6 hours since the initiation of study product infusion from the baseline.p-value: 0.32Wilcoxon (Mann-Whitney)
Comparison: The analysis for the changes of TNFR-1 at 24 hours since the initiation of study product infusion from the baseline.p-value: 0.02Wilcoxon (Mann-Whitney)
Comparison: The analysis for the changes of TNFR-1 at 48 hours since the initiation of study product infusion from the baseline.p-value: 0.02Wilcoxon (Mann-Whitney)
Comparison: The analysis for the changes of TNFR-1 at 72 hours since the initiation of study product infusion from the baseline.p-value: 0.19Wilcoxon (Mann-Whitney)
Secondary
Pulmonary Dead Space Fraction
Pulmonary Dead Space at day 1, 2, 3 and 7. The dead-space fraction is calculated as: (PaCO2 - PeCO2) ÷ PaCO2
Time frame: 7 days
Population: Due to the COVID-19 pandemic, the master majority of the enrolled patients had COVID-19, and it was not feasible to conduct the pulmonary dead space measurement because if would have increased the risk of spreading the COVID-19 virus to the health care workers, especially the respiratory therapists. Thus, this analysis is not available.
Secondary
Sequential Organ Failure Assessment (SOFA) Over 7 Days
SOFA score at 3 and 7 days. The score is based on six different scores, one each for the respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems which are added up. Each score ranges from 0 to 4. SOFA score ranges from 0 (best) to 24 (worst).
Time frame: 7 days
Population: Data were collected in the patients who were still in hospital alive.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Human Mesenchymal Stromal Cells | Sequential Organ Failure Assessment (SOFA) Over 7 Days | Day 3 | 9.2 score on a scale | Standard Deviation 3.1 |
| Human Mesenchymal Stromal Cells | Sequential Organ Failure Assessment (SOFA) Over 7 Days | Day 7 | 8.5 score on a scale | Standard Deviation 3.8 |
| Cell Reconstitution Media | Sequential Organ Failure Assessment (SOFA) Over 7 Days | Day 3 | 8.6 score on a scale | Standard Deviation 3.1 |
| Cell Reconstitution Media | Sequential Organ Failure Assessment (SOFA) Over 7 Days | Day 7 | 7.7 score on a scale | Standard Deviation 4.8 |
Comparison: The analysis for the SOFA score between two arms at Day 3.p-value: 0.32t-test, 2 sided
Comparison: The analysis for the SOFA score between two arms at Day 7.p-value: 0.33t-test, 2 sided
Secondary
Tolerability of the hMSCs - Incidence of Pre-specified Infusion-associated Events and Unexpected Severe Adverse Events
Tolerability of the hMSCs, defined as the incidence of pre-specified infusion-associated events and unexpected severe adverse events in ARDS patients treated with human MSCs
Time frame: 24 hours
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Human Mesenchymal Stromal Cells | Tolerability of the hMSCs - Incidence of Pre-specified Infusion-associated Events and Unexpected Severe Adverse Events | 2 Participants |
| Cell Reconstitution Media | Tolerability of the hMSCs - Incidence of Pre-specified Infusion-associated Events and Unexpected Severe Adverse Events | 2 Participants |
p-value: >0.99Fisher Exact
Secondary
Total Protein in Min-bronchoalveolar Lavage (mBAL)
Change in total protein levels in from baseline to day 2
Time frame: 2 days
Population: The mini-BAL samples were not able to be collected during the COVID-19 pandemic due to local COVID policies and safety concerns. Collecting bronchoalveolar (BAL) samples would have been a major risk for spreading the COVID-19 virus to health care workers.
Secondary
Urine Microalbumin
Change in levels of urine microalbumin from baseline compared to 24 and 48 hours
Time frame: 48 hours
Population: The majority of urine samples were collected, but some were not due to institutional policies on biospecimen collection during the COVID-19 pandemic or because patients were no longer available (e.g., discharge, death). However, this measurement isn't reliable, as it doesn't accurately reflect kidney function or correlate intelligently with the effects of MSC therapy on kidney function. As a result, urine microalbumin levels were not analyzed and will not analyzed in the future.
Secondary
Ventilator Free-days (VFD) Over 14 Days
Ventilator free-days over 14 days. Defined as the number of days from the time of initiating unassisted breathing to day 14 after study product administration, assuming survival for at least two consecutive calendar days after initiating unassisted breathing and continued unassisted breathing to day 14. If a patient returns to assisted breathing and subsequently achieves unassisted breathing to day 14, VFDs will be counted from the end of the last period of assisted breathing to day 14.
Time frame: 14 days
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Human Mesenchymal Stromal Cells | Ventilator Free-days (VFD) Over 14 Days | 5 - 9 days | 7 Participants |
| Human Mesenchymal Stromal Cells | Ventilator Free-days (VFD) Over 14 Days | 0 day | 44 Participants |
| Human Mesenchymal Stromal Cells | Ventilator Free-days (VFD) Over 14 Days | 10 - 13 days | 4 Participants |
| Human Mesenchymal Stromal Cells | Ventilator Free-days (VFD) Over 14 Days | 1 - 4 days | 4 Participants |
| Cell Reconstitution Media | Ventilator Free-days (VFD) Over 14 Days | 10 - 13 days | 10 Participants |
| Cell Reconstitution Media | Ventilator Free-days (VFD) Over 14 Days | 0 day | 32 Participants |
| Cell Reconstitution Media | Ventilator Free-days (VFD) Over 14 Days | 5 - 9 days | 12 Participants |
| Cell Reconstitution Media | Ventilator Free-days (VFD) Over 14 Days | 1 - 4 days | 7 Participants |
p-value: 0.01Regression, Logistic
Secondary
Ventilator Free-days (VFD) Over 28 Days.
Defined as the number of days from the time of initiating unassisted breathing to day 28 after study product administration, assuming survival for at least two consecutive calendar days after initiating unassisted breathing and continued unassisted breathing to day 28. If a patient returns to assisted breathing and subsequently achieves unassisted breathing to day 28, VFDs will be counted from the end of the last period of assisted breathing to day 28.
Time frame: 28 days
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Human Mesenchymal Stromal Cells | Ventilator Free-days (VFD) Over 28 Days. | 0 day | 36 Participants |
| Human Mesenchymal Stromal Cells | Ventilator Free-days (VFD) Over 28 Days. | 1-9 days | 6 Participants |
| Human Mesenchymal Stromal Cells | Ventilator Free-days (VFD) Over 28 Days. | 10-15 days | 3 Participants |
| Human Mesenchymal Stromal Cells | Ventilator Free-days (VFD) Over 28 Days. | 15-19 days | 6 Participants |
| Human Mesenchymal Stromal Cells | Ventilator Free-days (VFD) Over 28 Days. | 20-24 days | 6 Participants |
| Human Mesenchymal Stromal Cells | Ventilator Free-days (VFD) Over 28 Days. | 25-27 days | 2 Participants |
| Cell Reconstitution Media | Ventilator Free-days (VFD) Over 28 Days. | 20-24 days | 10 Participants |
| Cell Reconstitution Media | Ventilator Free-days (VFD) Over 28 Days. | 0 day | 27 Participants |
| Cell Reconstitution Media | Ventilator Free-days (VFD) Over 28 Days. | 15-19 days | 12 Participants |
| Cell Reconstitution Media | Ventilator Free-days (VFD) Over 28 Days. | 1-9 days | 4 Participants |
| Cell Reconstitution Media | Ventilator Free-days (VFD) Over 28 Days. | 25-27 days | 7 Participants |
| Cell Reconstitution Media | Ventilator Free-days (VFD) Over 28 Days. | 10-15 days | 1 Participants |
p-value: 0.02Regression, Logistic