Primary Outcomes

Description: Hospital mortality will be death in the ICU during the same hospital admission

Measure: Hospital mortality

Time: Death in the Hospital (ICU or ward) before or at 6 months after enrollment

---

Secondary Outcomes

Description: Death in the ICU during the same hospital admission.

Measure: ICU mortality

Time: Death in the ICU at or after 90 days of enrollment

---

Description: Number of calendar days between admission and final discharge from ICU.

Measure: ICU Length of Stay

Time: Number of days in ICU with an average expected duration of 10 days.

---

Description: Number of calendar days between start and final liberation from mechanical ventilation.

Measure: Duration of Mechanical Ventilation

Time: Number of days of mechanical ventilation with an expected average duration of 8 days

---

Description: viral clearance from all sampled sites by day 3 after administration of CP

Measure: Viral load in tracheal aspirate

Time: Serial levels in the first 28 days of enrollment

---

Description: Epidermal Growth Factor (EGF), Eotaxin, Granulocyte colony-stimulating factor (G-CSF), Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF), Interferon(IFN)-γ, IFN-a2, Interleukin (IL)-10, IL-12(p40), IL-12(p70), IL-13, IL-15, IL-17, IL-1ra, IL-1a, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, Interferon gamma-induced protein (IP)-10, Monocyte Chemotactic Protein (MCP)-1, Macrophage Inflammatory Protein (MIP)-1a, MIP-1β, Tumor Necrosis Factor-α (TNF-a), TNF-β, Vascular Endothelial Growth Factor (VEGF)

Measure: Inflammatory markers,

Time: Serial levels in the first 28 days of enrollment

---

Description: anti-MERS-CoV antibody level before and after administration of CP.

Measure: Anti-MERS-CoV antibodies

Time: Serial levels in the first 28 days of enrollment

---

Other Outcomes

Description: X ray changes at day 0, 1, 3, 7, 14, 21 and 28

Measure: Chest X ray

Time: Serial changes in the X ray till day 28

---

Primary Outcomes

Description: OI is a physiological index of the severity of ARDS and measures both impaired oxygenation and the amount of mechanical ventilation delivered

Measure: Oxygenation index (OI)

Time: Day 7

---

Description: Incidence of SAEs

Measure: Incidence of Serious Adverse Events (SAEs)

Time: 28 days

---

Secondary Outcomes

Measure: Oxygenation index

Time: Days 4 and 14

---

Description: SOFA score is a measure of organ failure

Measure: Sequential Organ Failure Assessment (SOFA) score

Time: Days 4, 7 and 14

---

Description: Crs is a physiological measure of pulmonary function in ARDS

Measure: Respiratory compliance (Crs)

Time: Days 4, 7 and 14

---

Description: P/F ratio is a physiological measure of pulmonary function in ARDS

Measure: Partial pressure of arterial oxygen to the fraction of inspired oxygen ratio (P/F ratio)

Time: Days 4, 7 and 14

---

Measure: Driving Pressure

Time: Days 4, 7 and 14

---

Measure: Extubation and reintubation

Time: Up to day 14 or until the patient is discharged from ICU or the patient dies

---

Measure: Ventilation free days at day 28

Time: Day 28

---

Measure: Length of ICU and hospital stay

Time: Until the patient is discharged or the patient dies

---

Measure: 28-day and 90-day mortality

Time: Up to 28 and 90 days

---

Primary Outcomes

Measure: Ventilator free days to day 28

Time: 28 days

---

Secondary Outcomes

Measure: 30 day mortality

Time: 30 days

---

Measure: 90 day mortality

Time: 90 days

---

Measure: Hospital discharge disposition

Time: 30 days

---

Measure: Hospital mortality

Time: 1 week

---

Measure: Time to first ICU activity

Time: 24 hours

---

Primary Outcomes

Description: The total time in hours from beginning of cooling to beginning of rewarming during which the patient's core temperature was within the target range of 34-35°C.

Measure: Targeted temperature compliance

Time: Randomization through day 3

---

Secondary Outcomes

Description: Adverse events expected during cooling, including hemorrhage, bradycardia, and hypotension.

Measure: Adverse event

Time: Randomization through study day 3

---

Description: Total number of days alive and not admitted to the ICU in the first 28 days after

Measure: 28-day ICU-free days

Time: Calculated at study day 28 or death (whichever occurs first)

---

Description: 28-day, 60-day, and 90-day mortality

Measure: Survival

Time: calculated at 28, 60, and 90 days

---

Description: SOFA score excluding neurologic component - based on PaO2/FiO2 (0-4), BP and pressor requirement (0-4), bilirubin level (0-4), platelet count (0-4), and creatinine (0-14) with total composite score 0-20

Measure: non neurologic Sequential Organ Failure (SOFA) scores

Time: At enrollment and study days 1, 2, 3, 4, 7, and 28

---

Description: Pulse ox reading

Measure: Oxygen saturation (SpO2)

Time: Measured at enrollment, every 4 hours on enrollment day, then once on day 2, 3, 4, 7 and 28

---

Description: On machine initiated breath

Measure: Plateau airway pressure

Time: Measured at enrollment, every 4 hours on enrollment day, then once on day 2, 3, 4, and 7 or until extubation whichever occurs first

---

Description: Direct ventilator measurement on machine initiated breath

Measure: Mean airway pressure

Time: Measured at enrollment, every 4 hours on enrollment day, then once on day 2, 3, 4, and 7 or until extubation whichever occurs first

---

Description: Plateau pressure - PEEP (machine initiated breath)

Measure: Airway driving pressure

Time: Measured at enrollment, every 4 hours on enrollment day, then once on day 2, 3, 4, and 7 or until extubation whichever occurs first

---

Description: Mean airway pressure x 100 x FiO2/SpO2

Measure: Oxygen saturation index

Time: Measured at enrollment, every 4 hours on enrollment day, then once on day 2, 3, 4, and 7 or until extubation whichever occurs first

---

Description: Measured continuously from iv catheter, urinary catheter, or esophageal probe.

Measure: Core temperature

Time: Measured continuously and recorded at enrollment, every 2 hours on the day of enrollment, and mornings on study day 2, 3, 4, and 7

---

Description: 24 hour urine volume

Measure: Urine output

Time: Daily on study day 1, 2, 3, 4, and 7

---

Description: performed in clinical lab

Measure: comprehensive metabolic panel

Time: Daily on study day 1, 2, 3, 4, and 7

---

Description: preformed in clinical lab

Measure: Complete blood count with differential count and platelet count

Time: Daily on study day 1, 2, 3, 4, and 7

---

Description: 10 ml blood draw

Measure: Biomarkers

Time: Daily on study day 1, 2, 3, 4, and 7

---

Description: performed in clinical lab

Measure: Serum electrolytes

Time: Every 8 hours until study hour 60

---

Description: Beside blood glucose testing

Measure: Blood glucose

Time: Every 4 hours until study hour 60

---

Description: Total number of days alive and not on a ventilator in the first 28 days after enrollment

Measure: 28-day ventilator-free days

Time: Calculated at study day 28 or death (whichever occurs first)

---

Primary Outcomes

Description: Change in the ratio of arterial oxygen tension to fraction of inspired oxygen from the baseline (day 0, before randomization and or the start of intervention) to day 1 to day 8 after the randomization and or start of intervention.

Measure: Change in PaO2/FiO2 ratio

Time: daily over eight days

---

Secondary Outcomes

Description: Change in the plateau airway pressure during ventilation from the baseline (day 0, before randomization and or the start of intervention) to day 1 to day 8 after the randomization and or start of intervention.

Measure: Change in the plateau pressure

Time: daily over eight days

---

Description: change in volume of the lungs per change in pressure during ventilation from the baseline (day 0, before randomization and or the start of intervention) to day 1 to day 8 after the randomization and or start of intervention.

Measure: Change in the pulmonary compliance

Time: daily over eight days

---

Description: Number of patients who are discharged alive

Measure: ICU survival rate

Time: At the end of ICU stay up to one year after the start of recruitment

---

Description: the total duration the patient stays in ICU

Measure: ICU length of stay

Time: At the end of ICU stay up to one year after the start of recruitment

---

Description: number of patients who required tracheostomy

Measure: Tracheostomy rate

Time: During ICU stay up to one month after the start of recruitment

---

Primary Outcomes

Description: VFD for 28 days after administration of the investigational product

Measure: Ventilator-free days (VFD)(ARDS caused by pneumonia cohort)

Time: 28 days after administration of the investigational product

---

Description: The number and rate of adverse events

Measure: Adverse events(ARDS caused by COVID-19 cohort)

Time: From informed consent to 180 days after administration of the investigational product

---

Description: Change from baseline in systolic blood pressure(mmHg)

Measure: Change from baseline in systolic blood pressure(ARDS caused by COVID-19 cohort)

Time: From screening to 180 days after administration of the investigational product

---

Description: Change from baseline in diastolic blood pressure(mmHg)

Measure: Change from baseline in diastolic blood pressure(ARDS caused by COVID-19 cohort)

Time: From screening to 180 days after administration of the investigational product

---

Description: Change from baseline in pulse rate(beats/min)

Measure: Change from baseline in pulse rate(ARDS caused by COVID-19 cohort)

Time: From screening to 180 days after administration of the investigational product

---

Description: Change from baseline in respiration(breath/min)

Measure: Change from baseline in respiration(ARDS caused by COVID-19 cohort)

Time: From screening to 180 days after administration of the investigational product

---

Description: Change from baseline in oxygen saturation(%)

Measure: Change from baseline in oxygen saturation(ARDS caused by COVID-19 cohort)

Time: From screening to 180 days after administration of the investigational product

---

Description: Change from baseline in body temperature(C)

Measure: Change from baseline in body temperature(ARDS caused by COVID-19 cohort)

Time: From screening to 180 days after administration of the investigational product

---

Description: Change from baseline in red blood cell count(/uL)

Measure: Change from baseline in red blood cell count(ARDS caused by COVID-19 cohort)

Time: From screening to 180 days after administration of the investigational product

---

Description: Change from baseline in hemoglobin(g/dL)

Measure: Change from baseline in hemoglobin(ARDS caused by COVID-19 cohort)

Time: From screening to 180 days after administration of the investigational product

---

Description: Change from baseline in hematocrit(%)

Measure: Change from baseline in hematocrit(ARDS caused by COVID-19 cohort)

Time: From screening to 180 days after administration of the investigational product

---

Description: Change from baseline in leukocyte count(/uL)

Measure: Change from baseline in leukocyte count(ARDS caused by COVID-19 cohort)

Time: From screening to 180 days after administration of the investigational product

---

Description: Change from baseline in neutrophils(%)

Measure: Change from baseline in neutrophils(ARDS caused by COVID-19 cohort)

Time: From screening to 180 days after administration of the investigational product

---

Description: Change from baseline in eosinophils(%)

Measure: Change from baseline in eosinophils(ARDS caused by COVID-19 cohort)

Time: From screening to 180 days after administration of the investigational product

---

Description: Change from baseline in basophils(%)

Measure: Change from baseline in basophils(ARDS caused by COVID-19 cohort)

Time: From screening to 180 days after administration of the investigational product

---

Description: Change from baseline in lymphocytes(%)

Measure: Change from baseline in lymphocytes(ARDS caused by COVID-19 cohort)

Time: From screening to 180 days after administration of the investigational product

---

Description: Change from baseline in monocytes(%)

Measure: Change from baseline in monocytes(ARDS caused by COVID-19 cohort)

Time: From screening to 180 days after administration of the investigational product

---

Description: Change from baseline in platelet count(/uL)

Measure: Change from baseline in platelet count(ARDS caused by COVID-19 cohort)

Time: From screening to 180 days after administration of the investigational product

---

Description: Change from baseline in asparate aminotransferase(AST)(IU/L)

Measure: Change from baseline in asparate aminotransferase(AST)(ARDS caused by COVID-19 cohort)

Time: From screening to 180 days after administration of the investigational product

---

Description: Change from baseline in alanine aminotransferase(ALT)(IU/L)

Measure: Change from baseline in alanine aminotransferase(ALT)(ARDS caused by COVID-19 cohort)

Time: From screening to 180 days after administration of the investigational product

---

Description: Change from baseline in alkaline phosphatase(ALP)(IU/L)

Measure: Change from baseline in alkaline phosphatase(ALP)(ARDS caused by COVID-19 cohort)

Time: From screening to 180 days after administration of the investigational product

---

Description: Change from baseline in total bilirubin(mg/dL)

Measure: Change from baseline in total bilirubin(ARDS caused by COVID-19 cohort)

Time: From screening to 180 days after administration of the investigational product

---

Description: Change from baseline in blood urea nitrogen(BUN)(mg/dL)

Measure: Change from baseline in blood urea nitrogen(BUN)(ARDS caused by COVID-19 cohort)

Time: From screening to 180 days after administration of the investigational product

---

Description: Change from baseline in creatinine(mg/dL)

Measure: Change from baseline in creatinine(ARDS caused by COVID-19 cohort)

Time: From screening to 180 days after administration of the investigational product

---

Description: Change from baseline in sodium(Na)(mmol/L)

Measure: Change from baseline in sodium(Na)(ARDS caused by COVID-19 cohort)

Time: From screening to 180 days after administration of the investigational product

---

Description: Change from baseline in potassium(K)(mmol/L)

Measure: Change from baseline in potassium(K)(ARDS caused by COVID-19 cohort)

Time: From screening to 180 days after administration of the investigational product

---

Description: Change from baseline in chloride(Cl)(mmol/L)

Measure: Change from baseline in chloride(Cl)(ARDS caused by COVID-19 cohort)

Time: From screening to 180 days after administration of the investigational product

---

Description: Change from baseline in calcium(Ca)(mg/dL)

Measure: Change from baseline in calcium(Ca)(ARDS caused by COVID-19 cohort)

Time: From screening to 180 days after administration of the investigational product

---

Description: Change from baseline in blood sugar(mg/dL)

Measure: Change from baseline in blood sugar(ARDS caused by COVID-19 cohort)

Time: From screening to 180 days after administration of the investigational product

---

Description: Change from baseline in urinary protein(- to >= 4+)

Measure: Change from baseline in urinary protein(ARDS caused by COVID-19 cohort)

Time: From screening to 180 days after administration of the investigational product

---

Description: Change from baseline in urinary sugar(- to >= 4+)

Measure: Change from baseline in urinary sugar(ARDS caused by COVID-19 cohort)

Time: From screening to 180 days after administration of the investigational product

---

Description: Change from baseline in uric blood(- to >= 4+)

Measure: Change from baseline in uric blood(ARDS caused by COVID-19 cohort)

Time: From screening to 180 days after administration of the investigational product

---

Description: Change from baseline in urinary sediment(RBC)(/HPF)

Measure: Change from baseline in urinary sediment(RBC)(ARDS caused by COVID-19 cohort)

Time: From screening to 180 days after administration of the investigational product

---

Description: Change from baseline in urinary sediment(WBC)(/HPF)

Measure: Change from baseline in urinary sediment(WBC)(ARDS caused by COVID-19 cohort)

Time: From screening to 180 days after administration of the investigational product

---

Description: Change from baseline in urinary sediment(Other)(/HPF)

Measure: Change from baseline in urinary sediment(Other)(ARDS caused by COVID-19 cohort)

Time: From screening to 180 days after administration of the investigational product

---

Primary Outcomes

Description: The lack of an appropriate surrogate endpoint, and the high baseline mortality rate mandate a multicentre RCT to determine the mortality effects of setting the ventilator based on recruitability and effort compared with conventional ventilation.

Measure: All-cause 60-day mortality

Time: 60 days

---

Secondary Outcomes

Measure: Duration of ventilation

Time: Duration of ventilation in days, which may exceed 60 days

---

Measure: Duration of ICU and hospital stay

Time: Duration of ICU and hospital stay in days, which may exceed 60 days

---

Description: Organ dysfunction as per the SOFA score

Measure: Number of patients with organ dysfunction

Time: Day 1-7, 14, 21, 28

---

Description: Barotrauma defined as new onset of pneumothorax

Measure: Number of patients with barotrauma

Time: Up to 60 days

---

Measure: Mortality at ICU discharge, 28 days, and hospital discharge

Time: Up to date of ICU discharge, 28 days, and hospital discharge

---

Other Outcomes

Description: Biomarkers include interleukin 6 (IL-6), interleukin 8 (IL-8), tumor necrosis factor receptor 1 (TNFr1), soluble receptor of the advanced glycation end products (sRAGE), and surfactant protein D (SPD). All measured in pg/ml

Measure: The change in biomarker expression

Time: Baseline, 24 and 72 hours

---

Primary Outcomes

Description: The primary outcome will be the reduction in the incidence of patients requiring intubation and mechanical ventilation, as a marker of deterioration from a mild to a severe form of COVID-19. Patients with indication to intubation and mechanical ventilation but concomitant DNI (Do Not Intubate) or not intubated for any other reason external to the clinical judgment of the attending physician will be considered as meeting the criteria for the primary endpoint.

Measure: Reduction in the incidence of patients with mild/moderate COVID-19 requiring intubation and mechanical ventilation

Time: 28 days

---

Secondary Outcomes

Description: Proportion of deaths from all causes

Measure: Mortality

Time: 28 days

---

Description: Time from initiation of the study to discharge or to normalization of fever (defined as <36.6°C from axillary site, or < 37.2°C from oral site or < 37.8°C from rectal or tympanic site), respiratory rate (< 24 bpm while breathing room air), alleviation of cough (defined as mild or absent in a patient reported scale of severe >>moderate>>mild>>absent) and resolution of hypoxia (defined as SpO2 ≥ 93% in room air or P/F ≥ 300 mmHg). All these improvements must be sustained for 72 hours.

Measure: Time to clinical recovery

Time: 28 days

---

Other Outcomes

Description: Proportion of patients with a negative conversion of RT-PCR from an oropharyngeal or oropharyngeal swab.

Measure: Negative conversion of COVID-19 RT-PCR from upper respiratory tract

Time: 7 days

---

Primary Outcomes

Description: Number of participants at 14 days post enrollment with active COVID19 disease.

Measure: Incidence of COVID19 Disease among those who are asymptomatic at baseline

Time: 14 days

---

Description: Repeated Measure mixed regression model of change in: Visual Analog Scale 0-10 score of rating overall symptom severity (0 = no symptoms; 10 = most severe)

Measure: Overall change in disease severity over 14 days among those who are symptomatic at baseline

Time: 14 days

---

Secondary Outcomes

Description: Outcome reported as the number of participants in each arm who require hospitalization for COVID19-related disease.

Measure: Incidence of Hospitalization

Time: 14 days

---

Description: Outcome reported as the number of participants in each arm who expire due to COVID-19-related disease.

Measure: Incidence of Death

Time: 90 days

---

Description: Outcome reported as the number of participants in each arm who have confirmed SARS-CoV-2 infection.

Measure: Incidence of Confirmed SARS-CoV-2 Detection

Time: 14 days

---

Description: Outcome reported as the number of participants in each arm who self-report symptoms compatible with COVID19 infection.

Measure: Incidence of Symptoms Compatible with COVID19 (possible disease)

Time: 90 days

---

Description: Outcome reported as the number of participants in each arm who discontinue or withdraw medication use for any reason.

Measure: Incidence of All-Cause Study Medicine Discontinuation or Withdrawal

Time: 14 days

---

Description: Visual Analog Scale 0-10 score of rating overall symptom severity (0 = no symptoms; 10 = most severe)

Measure: Overall symptom severity at 5 and 14 days

Time: 5 and 14 days

---

Description: Participants will self-report disease severity status as one of the following 3 options; no COVID19 illness (score of 1), COVID19 illness with no hospitalization (score of 2), or COVID19 illness with hospitalization or death (score of 3). Increased scale score indicates greater disease severity. Outcome is reported as the percent of participants who fall into each category per arm.

Measure: Ordinal Scale of COVID19 Disease Severity at 14 days among those who are symptomatic at trial entry

Time: 14 days

---

Primary Outcomes

Description: Outcome reported as the number of participants per arm admitted to inpatient hospital care due to COVID-19-related disease within 15 days of randomization. Currently, there is a pre-planned pooled analysis with a national trial network under development.

Measure: Hospital Admission

Time: 15 days

---

Secondary Outcomes

Description: The PROMIS Dyspnea (shortness of breath) item banks and pools assess self-reported Functional Limitations, Severity, Activity Motivation, Activity Requirements, Airborne Exposure, Assistant Devices Resources, Characteristics, Emotional Response, Task Avoidance and Time Extension as they related to dyspnea. In the 33-item Functional Limitations bank, 33 daily activities are rated in terms of degree of difficulty while engaging in the activity over the past 7 days (0 = no difficulty, 1 = a little difficulty, 2 = some difficulty, 3 = much difficulty). Total scores range from 0 to 99, with higher scores reflecting greater functional limitations.

Measure: Change in PROMIS Dyspnea Functional Limitations

Time: baseline, 10 days

---

Description: The PROMIS Dyspnea (shortness of breath) item banks and pools assess self-reported Functional Limitations, Severity, Activity Motivation, Activity Requirements, Airborne Exposure, Assistant Devices Resources, Characteristics, Emotional Response, Task Avoidance and Time Extension as they related to dyspnea. The 33-item Severity bank assesses the severity of difficulty breathing during various specific activities (the same 33 activities assessed in Dyspnea Functional Limitations). Each activity is rated in terms of degree of dyspnea (0 = no shortness of breath, 1 = mildly short of breath, 2 = moderately short of breath, 3 = severely short of breath) while engaging in the activity over the past 7 days. Total scores range from 0 to 99 with higher scores reflecting greater levels of dyspnea during daily activity.

Measure: Change in PROMIS Dyspnea Severity

Time: baseline, 10 days

---

Description: Participants will report their maximum daily oral temperature to the study team. Outcome is reported as the mean maximum daily body temperature (in degrees Celsius) over 10 days.

Measure: Daily Maximum Temperature

Time: 10 days

---

Description: Outcome is reported as the mean number of emergency department and clinic presentations combined per participant in each arm.

Measure: Emergency Department/Clinic Presentations

Time: 28 days

---

Description: Outcome reported as the number of participants in each arm who fall into each of 7 categories. Lower scores indicate greater condition severity. The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen; 6) Not hospitalized, limitation on activities; 7) Not hospitalized, no limitations on activities.

Measure: Disease Severity Rating Day 7

Time: 7 days

---

Description: Outcome reported as the number of participants in each arm who fall into each of 7 categories. Lower scores indicate greater condition severity. The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen; 6) Not hospitalized, limitation on activities; 7) Not hospitalized, no limitations on activities.

Measure: Disease Severity Rating Day 15

Time: 15 days

---

Description: Outcome reported as the number of participants in each arm who fall into each of 7 categories. Lower scores indicate greater condition severity. The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen; 6) Not hospitalized, limitation on activities; 7) Not hospitalized, no limitations on activities.

Measure: Disease Severity Rating Day 28

Time: 28 days

---

Description: Participants will collect oropharyngeal swabs every third day for the duration of study participation. Viral load is measured as number of viral genetic copies per mL.

Measure: Viral Load by Oropharyngeal Swab Day 9

Time: 9 days

---

Description: Participants will collect oropharyngeal swabs every third day for the duration of study participation. Viral load is measured as number of viral genetic copies per mL.

Measure: Viral Load by Oropharyngeal Swab Day 15

Time: 15 days

---

Description: Outcome reported as the mean number of days participants in each arm did not require ventilator use.

Measure: Ventilator-Free Days

Time: 28 days

---

Description: Outcome reported as the mean number of days participants in each arm did not require therapeutic oxygen use.

Measure: Therapeutic Oxygen-Free Days

Time: 28 days

---

Description: Outcome reported as the percent of participants in each arm who require hospital admission by day 15 following randomization.

Measure: Need for Hospital Admission at 15 Days

Time: 15 days

---

Description: Outcome reported as the percent of participants in each arm who require oxygen therapy by day 15 following randomization.

Measure: Need for Oxygen Therapy at 15 Days

Time: 15 days

---

Primary Outcomes

Description: Mortality

Measure: Mortality

Time: 5 Days with followup through 30 days

---

Description: Index of Respiratory Distress

Measure: PaO2:FiO2 ratio

Time: 5 Days with followup through the end of telemetry monitoring

---

Secondary Outcomes

Description: TNF alpha levels as measured in hospital laboratory

Measure: TNF alpha

Time: 5 Days

---

Description: Multi-system organ failure free days

Measure: Multi-system organ failure free days

Time: 5 days with followup through 30 days

---

Description: Days free of Respiratory Failure

Measure: Days free of Respiratory Failure

Time: 14 days

---

Primary Outcomes

Description: Outcome calculated from the partial pressure of oxygen or peripheral saturation of oxygen by pulse oximetry divided by the fraction of inspired oxygen (PaO2 or SaO2 : FiO2 ratio). PaO2 is preferentially used if available. A correction is applied for endotracheal intubation and/or positive end-expiratory pressure. Patients discharged prior to day 7 will have a home pulse oximeter send home for measurement of the day 7 value, and will be adjusted for home O2 use, if applicable. Patients who died will be applied a penalty with a P/F ratio of 0.

Measure: Difference in Estimated (PEEP adjusted) P/F Ratio at 7 days

Time: 7 days

---

Secondary Outcomes

Description: Outcome reported as the mean number of daily hypotensive episodes (MAP < 65 mmHg) prompting intervention (indicated by a fluid bolus >=500 mL) per participant in each arm.

Measure: Daily Hypotensive Episodes

Time: 10 days

---

Description: Outcome reported as the number of participants in each arm requiring the use of vasopressors for hypotension.

Measure: Hypotension Requiring Vasopressors

Time: 10 days

---

Description: Outcome reported as the number of participants in each arm who experience acute kidney injury as defined by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines: Increase in serum creatinine by 0.3mg/dL or more within 48 hours OR Increase in serum creatinine to 1.5 times baseline or more within the last 7 days OR Urine output less than 0.5 mL/kg/h for 6 hours.

Measure: Acute Kidney Injury

Time: 10 days

---

Description: The SOFA assessment 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 0 (normal) to 4 (high degree of dysfunction/failure). Total score is calculated by entering patient data into a SOFA calculator, a widely-available software. Total scores range from 0-24, with higher scores indicating greater chance of mortality.

Measure: Sequential Organ Failure Assessment (SOFA) Total Score

Time: 10 days

---

Description: Oxygen saturation (percent) is measured by pulse oximeter. Fraction of inspired oxygen (FiO2) (unitless) is the volumetric fraction of oxygen to other gases in respiratory support. The F/S ratio is unitless.

Measure: Oxygen Saturation / Fractional Inhaled Oxygen (F/S)

Time: 10 days

---

Description: Outcome reported as the number of participants who have expired at 28 days post enrollment.

Measure: 28-Day Mortality

Time: 28 days

---

Description: Outcome reported as the number of participants who have expired at 90 days post enrollment.

Measure: 90-Day Mortality

Time: 90 days

---

Description: Outcome reported as the number of participants in each arm who require admission to the Intensive Care Unit (ICU).

Measure: ICU Admission

Time: 10 days

---

Description: Outcome reported as the mean number of days participants in each arm did not require mechanical ventilation during an in-patient hospital admission.

Measure: Number of Ventilator-Free Days

Time: 10 days

---

Description: Outcome reported as the mean number of days participants in each arm did not require therapeutic oxygen usage during an in-patient hospital admission.

Measure: Number of Therapeutic Oxygen-Free Days

Time: 10 days

---

Description: Outcome reported as the mean number of days participants in each arm did not require vasopressor usage during an in-patient hospital admission.

Measure: Number of Vasopressor-Free Days

Time: 10 days

---

Description: Outcome reported as the mean length of stay (in days) in the Intensive Care Unit (ICU) for participants in each arm.

Measure: Length of ICU Stay

Time: 10 days

---

Description: Outcome reported as the mean length of in-patient hospital stay (in days) for participants in each arm.

Measure: Length of Hospital Stay

Time: 10 days

---

Description: Outcome reported as the number of participants requiring BiPAP OR high flow nasal cannula OR mechanical ventilation OR extracorporeal membranous oxygenation (ECMO) utilization during in-patient hospital care in each arm.

Measure: Incidence of Respiratory Failure

Time: 10 days

---

Description: The PROMIS Dyspnea (shortness of breath) item banks and pools assess self-reported Functional Limitations, Severity, Activity Motivation, Activity Requirements, Airborne Exposure, Assistant Devices Resources, Characteristics, Emotional Response, Task Avoidance and Time Extension as they related to dyspnea. In the 33-item Functional Limitations bank, 33 daily activities are rated in terms of degree of difficulty while engaging in the activity over the past 7 days (0 = no difficulty, 1 = a little difficulty, 2 = some difficulty, 3 = much difficulty). Total scores range from 0 to 99, with higher scores reflecting greater functional limitations.

Measure: Change in PROMIS Dyspnea Functional Limitations

Time: 10 days

---

Description: The PROMIS Dyspnea (shortness of breath) item banks and pools assess self-reported Functional Limitations, Severity, Activity Motivation, Activity Requirements, Airborne Exposure, Assistant Devices Resources, Characteristics, Emotional Response, Task Avoidance and Time Extension as they related to dyspnea. The 33-item Severity bank assesses the severity of difficulty breathing during various specific activities (the same 33 activities assessed in Dyspnea Functional Limitations). Each activity is rated in terms of degree of dyspnea (0 = no shortness of breath, 1 = mildly short of breath, 2 = moderately short of breath, 3 = severely short of breath) while engaging in the activity over the past 7 days. Total scores range from 0 to 99 with higher scores reflecting greater levels of dyspnea during daily activity.

Measure: Change in PROMIS Dyspnea Severity

Time: 10 days

---

Description: Outcome reported as the number of participants in each arm who fall into each of 7 categories. Lower scores indicate greater condition severity. The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen; 6) Not hospitalized, limitation on activities; 7) Not hospitalized, no limitations on activities.

Measure: Disease Severity Rating

Time: 10 days

---

Description: Nasopharyngeal swabs will be collected every third day for the duration of study participation. Viral load is measured as number of viral genetic copies per mL.

Measure: Viral Load by Nasopharyngeal Swab Day 9

Time: 9 days

---

Description: Nasopharyngeal swabs will be collected every third day for the duration of study participation. Viral load is measured as number of viral genetic copies per mL.

Measure: Viral Load by Nasopharyngeal Swab Day 15

Time: 15 days

---

Description: Blood will be collected every third day for viral load assessment for the duration of study participation. Viral load is measured as number of viral genetic copies per mL.

Measure: Viral Load by Blood Day 9

Time: 9 days

---

Description: Blood will be collected every third day for viral load assessment for the duration of study participation. Viral load is measured as number of viral genetic copies per mL.

Measure: Viral Load by Blood Day 15

Time: 15 days

---

Primary Outcomes

Description: KDIGO AKI score

Measure: Acute Kidney Injury

Time: During Intensive Care, an estimated average of 10 days.

---

Secondary Outcomes

Description: Acute Respiratory Distress Syndrome yes/no

Measure: ARDS

Time: During intensive care, an estimated average of 10 days.

---

Description: Death within 30 days of ICU admission

Measure: 30 day mortality

Time: 30 days

---

Description: Death within 1 year of ICU admission

Measure: 1 year mortality

Time: 1 year

---

Description: Development of Chronic Kidney Disease

Measure: Chronic Kidney Disease

Time: 60 days and 1 year after ICU admission

---

Description: Sequential Organ Failure Score as a continuous variable

Measure: SOFA-score

Time: During Intensive Care, an estimated average of 10 days.

---

Primary Outcomes

Description: All cause in-hospital mortality

Measure: In-hospital mortality

Time: 3 weeks

---

Secondary Outcomes

Measure: Occurrence and duration of mechanical ventilation

Time: 3 weeks

---

Measure: Occurrence and duration of intensive care unit (ICU) treatment

Time: 3 weeks

---

Measure: Duration of hospital admittance

Time: 1 month

---

Measure: 28 Day mortality

Time: 3 weeks

---

Measure: Viral clearance as assessed by SARS-CoV-2 PCR in peripheral blood and nasopharyngeal airway speciemen

Time: 3 weeks

---

Measure: Occurrence of co-infections

Time: 3 weeks

---

Measure: Occurrence of organ dysfunction

Time: 3 months

---

Other Outcomes

Measure: Inflammatory and anti-inflammatory mediators as assessed in serum and plasma

Time: Throughout hospitalization

---

Measure: Markers of extracellular matrix remodeling

Time: Throughout hospitalization and 3 months after remission

---

Measure: Markers of endothelial activation

Time: Throughout hospitalization

---

Measure: Markers of platelet activation

Time: Throughout hospitalization

---

Primary Outcomes

Description: All-cause mortality at 60 days after enrollment

Measure: 60-day mortality

Time: 60 days

---

Secondary Outcomes

Description: Number of ventilator-free days (VFDs) at Day 28 (defined as days being alive and free from mechanical ventilation at day 28 after enrollment, For patients ventilated 28 days or longer and for subjects who die, VFD is 0.

Measure: Ventilator-free days

Time: 28 days

---

Primary Outcomes

Description: the treatment failure rate of HFNC/HFNC+PP support and clinical requirement for advanced respiratory support

Measure: Treatment failure

Time: 28 days

---

Measure: Intubation rate

Time: 28 days

---

Secondary Outcomes

Description: the improvement of SpO2/FIO2 or PaO2/FiO2 from HFNC alone to HFNC+PP

Measure: Efficacy of PP

Time: 28 days

---

Primary Outcomes

Description: Ventilator-free days, defined as alive and free from mechanical ventilation, at 28 days after randomization.

Measure: Ventilator-free days

Time: 28 days after randomization

---

Secondary Outcomes

Description: Evaluation of the clinical status of patients on the 15th day after randomization defined by the 6-point Ordinal Scale, this scale ranges from 1 (Not hospitalized) to 6 (Death) with higher scores meaning worse outcomes.

Measure: Evaluation of the clinical status

Time: 15 days after randomization

---

Description: All-cause mortality rates at 28 days after randomization.

Measure: All-cause mortality

Time: 28 days after randomization

---

Description: Number of days of mechanical ventilation from randomization to day 28.

Measure: Mechanical ventilation duration

Time: 28 days after randomization

---

Description: Sequential Organ Failure Assessment (SOFA) Score 48 hours, 72 hours and 7 days after randomization

Measure: Sequential Organ Failure Assessment (SOFA) Score

Time: Score at 48 hours, 72 hours and 7 days after randomization

---

Other Outcomes

Description: Intensive Care Unit free days, defined as alive and discharged from the intensive care unit, at 28 days after randomization.

Measure: Intensive Care Unit free days

Time: 28 days after randomization

---

Primary Outcomes

Description: Outcome reported as the percent of participants in each arm who are COVID-19-free at the end of study treatment.

Measure: COVID-19-free survival

Time: up to 12 weeks

---

Secondary Outcomes

Description: Outcome reported as the percent of participants in each arm who have a confirmed SARS-CoV-2 infection during study treatment.

Measure: Incidence of confirmed SARS-CoV-2 detection

Time: up to 12 weeks

---

Description: Outcome reported as the percent of participants in each arm who report COVID-19-related symptoms during study treatment.

Measure: Incidence of possible COVID-19 symptoms

Time: up to 12 weeks

---

Description: Outcome reported as the percent of participants in each arm who discontinue study medication use for any reason during treatment.

Measure: Incidence of all-cause study medicine discontinuation

Time: up to 12 weeks

---

Description: Participants will self-report COVID-19 status on an ordinal scale as follows: No illness (score=1), Illness with outpatient observation (score=2), Hospitalization (or post-hospital discharge) (score=3), or Hospitalization with ICU stay or death (score=4). Possible scores range from 1-4 with higher scores indicating greater disease severity.

Measure: Ordinal Scale of COVID-19 Disease maximum severity if COVID-19 diagnosed at study end

Time: up to 12 weeks

---

Description: Outcome reported as the percent of participants in each arm who are hospitalized or expire due to COVID-19 during study treatment.

Measure: Incidence of Hospitalization for COVID-19 or death

Time: up to 12 weeks

---

Description: Outcome reported as the percent of participants in each arm who experience medication-related side effects during study treatment.

Measure: Incidence of study medication-related side effects

Time: up to 12 weeks

---

Primary Outcomes

Description: Frequency of adverse reaction (AE) and severe adverse reaction (SAE) within 28 days after treatment

Measure: Adverse reaction (AE) and severe adverse reaction (SAE)

Time: Within 28 days after treatment

---

Description: Evaluation by chest CT

Measure: Changes of lung imaging examinations

Time: Within 28 days after treatment

---

Secondary Outcomes

Description: Marker for SARS-CoV-2

Measure: Time to SARS-CoV-2 RT-PCR negative

Time: Within 28 days after treatment

---

Description: The duration of a fever above 37.3 degrees Celsius

Measure: Duration of fever (Celsius)

Time: Within 28 days after treatment

---

Description: Marker for efficacy

Measure: Changes of blood oxygen (%)

Time: Within 28 days after treatment

---

Description: Marker for efficacy

Measure: Rate of all-cause mortality within 28 days

Time: Within 28 days after treatment

---

Description: Counts of lymphocyte in a litre (L) of blood

Measure: Lymphocyte count (*10^9/L)

Time: Within 28 days after treatment

---

Description: Alanine aminotransferase in unit (U)/litre(L)

Measure: Alanine aminotransferase (U/L)

Time: Within 28 days after treatment

---

Description: Creatinine in micromole (umol)/litre(L)

Measure: Creatinine (umol/L)

Time: Within 28 days after treatment

---

Description: Creatine kinase in U/L

Measure: Creatine kinase (U/L)

Time: Within 28 days after treatment

---

Description: C-reactive in microgram (mg)/litre(L)

Measure: C-reactive protein (mg/L)

Time: Within 28 days after treatment

---

Description: Procalcitonin in nanogram (ng)/litre(L)

Measure: Procalcitonin (ng/L)

Time: Within 28 days after treatment

---

Description: Lactate in millimole(mmol)/litre(L)

Measure: Lactate (mmol/L)

Time: Within 28 days after treatment

---

Description: IL-1beta in picogram(pg)/millilitre(mL)

Measure: IL-1beta (pg/mL)

Time: Within 28 days after treatment

---

Description: IL-2 in pg/mL

Measure: IL-2 (pg/mL)

Time: Within 28 days after treatment

---

Description: IL-6 in pg/mL

Measure: IL-6 (pg/mL)

Time: Within 28 days after treatment

---

Description: IL-8 in pg/mL

Measure: IL-8 (pg/mL)

Time: Within 28 days after treatment

---

Primary Outcomes

Measure: Respiratory efficacy evaluated by the increase in PaO2/FiO2 ratio from baseline to day 7 in the experimental group compared with the placebo group

Time: From baseline to day 7

---

Secondary Outcomes

Measure: Lung injury score

Time: From baseline to day 28

---

Measure: Oxygenation index

Time: From baseline to day 28

---

Measure: In-hospital mortality

Time: From baseline to day 28

---

Measure: Mortality

Time: At day 28

---

Measure: Ventilator-free days

Time: From baseline to day 28

---

Measure: Number of days between randomization and the first day the patient meets weaning criteria o Number of days between randomization and the first day the patient meets PaO2/FiO2 > 200 (out of a prone positioning session)

Time: From baseline to day 28

---

Measure: Cumulative use of sedatives

Time: From baseline to day 28

---

Measure: Cumulative duration of use of sedatives

Time: From baseline to day 28

---

Measure: Cumulative duration of use of neuromuscular blocking agents (other than used for intubation)

Time: From baseline to day 28

---

Measure: Cumulative use of neuromuscular blocking agents (other than used for intubation)

Time: From baseline to day 28

---

Measure: ICU-acquired weakness and delirium

Time: From baseline to day 28

---

Measure: Treatment-induced toxicity rate and adverse events up to day 28

Time: From baseline to day 28

---

Measure: Quality of life at one year (EQ5D-3L quality of life questionnaire)

Time: At 6 months and 12 months

---

Measure: Measurements of plasmatic cytokines (IL1, IL6, IL8, TNF-alpha, IL10, TGF-beta, sRAGE, Ang2) level

Time: At day 1, 3, 5, 7 and 14

---

Measure: Anti-HLA antibodies plasmatic dosage

Time: From baseline to day 14, and at 6 months

---

Primary Outcomes

Description: Worsening respiratory failure; defined using severity of hypoxaemia using [PaO2/FiO2 ratio OR SpO2/FiO2 ratio]

Measure: Disease progression

Time: 14 days

---

Description: Time to mechanical ventilation (or need of)

Measure: Time to mechanical ventilation

Time: 14 days

---

Secondary Outcomes

Measure: Overall survival

Time: 28 days

---

Measure: Reduction in proportion of patients who require ventilation

Time: 28 days

---

Measure: Reduction in length of Critical Care stay

Time: 28 days

---

Measure: Reduction in length of Hospital stay

Time: 28 days

---

Measure: Modulation of serum pro- and anti-inflammatory cytokines

Time: 28 days

---

Measure: Reduction in duration of ventilation

Time: 28 days

---

Measure: Increase in ventilator-free days

Time: 28 days

---

Primary Outcomes

Description: Death is defined as all-cause mortality

Measure: first occurrence of intensive care unit admission, mechanical ventilation or death

Time: within 14 days

---

Secondary Outcomes

Description: All-cause mortality; and time to all-cause mortality

Measure: Death

Time: Within 14 days, 30 days, 90 days and at 1 year

---

Description: Occurrence of mechanical ventilation and time to ventilation

Measure: Mechanical ventilation

Time: within 14 days

---

Description: Occurrence of ICU admission and time to admission

Measure: Intensive care unit admission

Time: within 14 days

---

Description: Defined as a 50% decline in estimated glomerular filtration rate relative to baseline, or decrease of >30 ml/min/1.73m2 and to a value below 60 ml/min/1.73m2

Measure: Occurrence of acute kidney injury

Time: Within 14 days

---

Primary Outcomes

Description: ELISA test (Higher the ACE2 level, higher the virus penetrate cells)

Measure: ACE2 level change over time

Time: at the day of admission, day 3 and day 7

---

Secondary Outcomes

Description: Ratio angiotensin (1-7)/angiotensin(1/10) (Higher Ratio angiotensin (1-7)/angiotensin(1/10), higher is ACE2 activity)

Measure: ACE2 activity over time

Time: at the day of admission, day 3 and day 7

---

Description: Mortality at day 28

Measure: Mortality at day 28

Time: day 28

---

Description: PaO2/FiO2 ratio (ARDS is severe when <100, moderate when between 100 and 200, mild when >200)

Measure: ARDS severity

Time: from the day of admission to day 7

---

Description: Day under mechanical ventilation

Measure: Duration of mechanical ventilation

Time: from the day of admission to day 28

---

Description: Need for prone positionning

Measure: Need for prone positionning

Time: from the day of admission to day 28

---

Description: Need for extracorporeal membran oxygenation

Measure: Need for extracorporeal membran oxygenation

Time: from the day of admission to day 28

---

Description: Need for use of paralytic agents

Measure: Use of paralytic agents

Time: from the day of admission to day 28

---

Description: Need for renal replacement therapy

Measure: Need for renal replacement therapy

Time: from the day of admission to day 28

---

Description: Need for vasoactive drugs

Measure: Need for vasoactive drugs (norepinephrine, dobutamine,epinephrine)

Time: from the day of admission to day 28

---

Description: The SOFA score evaluates the severity of patients through 6 items: respiration (PaO2/FiO2 ratio); coagulation (platelets count); liver (bilirubin); Cardiovascular (hypotension); Central nervous system (coma glasgow score) and Renal (creatinine serum level). Score ranges from 0 to 24, a higher score indicates higher severity and probability of death

Measure: Sequential Organ Failure Assessment (SOFA) score

Time: from the day of admission to day 7

---

Description: Number of session(s) of prone positionning

Measure: Number of session(s) of prone positionning

Time: from the day of admission to day 28

---

Description: Duration of extracorporeal membran oxygenation treatment

Measure: Duration of extracorporeal membran oxygenation treatment

Time: from the day of admission to day 28

---

Description: Several vasoactive agents may be used: norepinephrine, dobutamine, epinephrine, vasopressin analogues...

Measure: Type of vasoactive drugs

Time: from the day of admission to day 28

---

Description: Duration of vasoactive treatment

Measure: Duration of vasoactive treatment

Time: from the day of admission to day 28

---

Primary Outcomes

Description: Body temperature(°C)

Measure: Body temperature

Time: Through study completion, an estimation of 6 months

---

Description: Blood pressure in mmHg

Measure: Blood pressure

Time: Through study completion, an estimation of 6 months

---

Description: Pulse (heart rate) in times/minute

Measure: Pulse (heart rate)

Time: Through study completion, an estimation of 6 months

---

Description: Respiratory rate in times/minute

Measure: Respiratory rate

Time: Through study completion, an estimation of 6 months

---

Description: Cardiac index (L/min/m2)

Measure: Data provided by transpulmonary thermodilution-CI

Time: Through study completion, an estimation of 6 months

---

Description: Global end-diastolic volume(mL/m2)

Measure: Data provided by transpulmonary thermodilution-GEDV

Time: Through study completion, an estimation of 6 months

---

Description: Extravascular lung water (mL/kg)

Measure: Data provided by transpulmonary thermodilution-EVLW

Time: Through study completion, an estimation of 6 months

---

Description: Pulmonary vascular permeability index

Measure: Data provided by transpulmonary thermodilution-PVPI

Time: Through study completion, an estimation of 6 months

---

Measure: Incidence of abnormal laboratory test results

Time: Through study completion, an estimation of 6 months

---

Secondary Outcomes

Description: Left ventricle ejection fraction, Segmental left ventricle contractility, Speckle tracking data of the left and right ventricles, Dimensions of right and left cavities and Diastolic function of left ventricle

Measure: Incidence of new-onset or reversible systolic left ventricular dysfunction

Time: Through study completion, an estimation of 6 months

---

Description: The worst extravascular lung water

Measure: Changes of extravascular lung water measured by transpulmonary thermodilution

Time: Change from baseline extravascular lung water at 6 months

---

Description: The worst pulmonary vascular permeability index

Measure: Changes of pulmonary vascular permeability index measured by transpulmonary thermodilution

Time: Change from baseline extravascular lung water at 6 months

---

Measure: Correlation between the hemodynamic characteristics and 90-day mortality

Time: Up to 90th day after inclusion

---

Primary Outcomes

Measure: Retrospective description of COVID-19 patients receiving respiratory ECMO-VV supplementation and what happens to them

Time: Files analysed retrospectily from March 1st, 2020 to April 15, 2020 will be examined

---

Primary Outcomes

Description: Treatment-related serious adverse events (tSAE) will be considered as those directly related to the investigational infusion product per protocol defined criteria.

Measure: Treatment-related serious adverse events (tSAEs)

Time: 28 days post cell infusion

---

Description: Change by at least two categories on a six category ordinal scale at day 14 post randomization per protocol defined criteria. The six-category ordinal scale ranges from 6 to 1 with a higher score indicates worse clinical outcome

Measure: Change in clinical status at day 14

Time: 14 days post cell infusion

---

Primary Outcomes

Description: improvement in oxygenation

Measure: p/f ratio

Time: 5 days

---

Secondary Outcomes

Description: improvement in SOFA Score

Measure: SOFA

Time: 5 days

---

Primary Outcomes

Description: Mortality rate evaluated 28 days after randomization

Measure: Day-28 mortality

Time: 28 days after randomization

---

Secondary Outcomes

Description: Ventilator-free days (VFDs) at 28 days are one of several organ failure-free outcome measures to quantify the efficacy of therapies and interventions. VFDs are typically defined as follows: VFDs = 0 if subject dies within 28 days of mechanical ventilation. VFDs = 28 - x if successfully liberated from ventilation x days after initiation. VFDs = 0 if the subject is mechanically ventilated for >28 days.

Measure: Ventilator-free days

Time: 28 days after randomization

---

Description: Mortality rate evaluated during Intensive care unit stay

Measure: Intensive Care Unit mortality

Time: Up to 60 days after randomization

---

Description: Mortality rate evaluated 60 days after randomization

Measure: Day-60 mortality

Time: 60 days after randomization

---

Description: Number of patients with pneumonia diagnosed during intensive care unit stay

Measure: Nosocomial pneumonia

Time: Up to 60 days after randomization

---

Description: Number of patients with bacteremia diagnosed during intensive care unit

Measure: Bacteremia

Time: Up to 60 days after randomization

---

Other Outcomes

Description: Placement of ECMO during intensive care unit stay

Measure: Extra corporeal membrane oxygenation (ECMO)

Time: Up to 60days after randomization

---

Description: Number of patients who underwent tracheostomy during intensive care unit stay

Measure: Tracheostomy

Time: Up to 60 days after randomization

---

Description: Number of Prone position session

Measure: Prone Position

Time: Up to 60 days after randomization

---

Primary Outcomes

Measure: Efficacy of the administration of allogeneic mesenchymal stem cells derived from adipose tissue assessed by Survival Rate)

Time: 28 days

---

Measure: Safety of the administration of allogeneic mesenchymal stem cells derived from adipose tissue assessed by Adverse Event Rate

Time: 6 months

---

Primary Outcomes

Description: For an alive patient at day 90, the score will be built as follow: a value +1 will be given for comparisons to dead patients and alive patients with a lower number of VFD. For comparisons to alive patients with a higher number of VFD a value -1 will be given and in case of identical number of VFD a value 0 will be given. For a dead patient a value -1 will be given for comparisons to alive patients and 0 for comparisons to dead patients. For a given patients the score will correspond to the sum of values resulting to the comparison to all patients of the other group. A higher score indicates a more favorable result.

Measure: A composite score based on all-cause mortality and the number of ventilator free-days (VFD)

Time: Day 90

---

Secondary Outcomes

Description: All-cause mortality with analysis in intention to treat, i.e. each patient will be analyzed in his initial randomization group regardless of whether the allocated strategy was effectively applied or not.

Measure: All-cause mortality (intention to treat)

Time: 90-day after inclusion

---

Description: VFD will be computed as follows from the day of inclusion: VFD= 0 if the patient dies between inclusion and day 60 VFD = 60-x if the patient is successfully weaned from invasive mechanical ventilation x days after inclusion. Successful weaning from mechanical ventilation is defined by extubation without reintubation within at least 48 hours (or weaning from mechanical ventilation for at least 48 hours in patients with tracheostomy) VFD= 0 if the patient is mechanically ventilated for more than 60 days after inclusion

Measure: Ventilator-free days (VFD)

Time: day 60 after inclusion

---

Description: Per protocol analysis will be carried out by comparing the group of patients in whom median daily tidal volume from inclusion to weaning of deep sedation will be lower of equal to 4.2 ml/kg of predicted body weight to the group of patients in whom median tidal volume from inclusion to weaning of deep sedation will be greater than 4.2 ml/kg of predicted body weight, whatever the patients' initial randomization group. Weaning of deep sedation is defined by a Richmond Agitation Sedation (RASS) score greater than -3 for at least 48 hours.

Measure: All-cause mortality with per protocol analysis

Time: 90-day

---

Description: Successful extubation is defined by extubation without reintubation within at least 48 hours (or weaning from mechanical ventilation for at least 48 hours in patients with tracheostomy) Data will be right censored at 60 days and death will be taken into account as a competing risk.

Measure: Time to successful extubation

Time: 60 days

---

Description: Data will be right censored at 90 days and death will be taken into account as a competing risk.

Measure: Length of hospital stay

Time: 90 days

---

Description: Weaning of deep sedation is defined by a Richmond Agitation Sedation (RASS) score greater than -3 for at least 48 hours.

Measure: Respiratory parameters assessed daily from inclusion to weaning of deep sedation or 14 days whichever comes first

Time: 14 days

---

Description: Doses of the following drugs used for deep sedation will be assessed daily: midazolam, propofol and opioid. Opioid dose will be expressed as morphine equivalent with the following conversion factor: 1µg of sufentanil = 10 µg of fentanyl = 1 mg of morphine

Measure: Daily sedation dose during the first 14 days of the study

Time: 14 days

---

Description: Rescue therapies are any therapy among the following ones: neuromuscular blocking agents, prone position, nitric oxide, recruitment maneuvers, ECMO

Measure: Rate of use of rescue therapies

Time: 14 days

---

Description: Severe mixed acidosis is defined by the association of pH<7.15 and PaCO2>45 mm Hg.

Measure: Incidence density rate of severe mixed acidosis

Time: ICU stay

---

Description: Ventilator associated pneumonia will be defined as any pneumonia acquired under mechanical ventilation after inclusion.

Measure: Incidence density rate of ventilator associated pneumonia

Time: ICU stay

---

Description: Acute cor pulmonale is defined by the association of right ventricle dilatation (right ventricle surface / left ventricle surface >0,6) and septal dyskinesia assessed by echocardiography

Measure: Incidence density rate of acute cor pulmonale

Time: ICU stay

---

Description: Barotrauma is defined by any pneumothorax OR pneumomediastinum OR subcutaneous emphysema, OR pneumatocele of more than 2 cm detected on image examinations.

Measure: Incidence density rate of barotrauma

Time: ICU stay

---

Description: Serious adverse event is any life threatening event OR any event resulting in death.

Measure: Incidence density rate of any serious adverse events

Time: ICU stay

---

Description: The Telephone Montreal Cognitive Assessment score will be assessed by phone call. The total score ranges from 0 to 30; higher scores being associated to a better outcome.

Measure: Cognitive impairment assessed by phone call using the Telephone Montreal Cognitive Assessment (T-MoCA) test

Time: Day 365 after inclusion

---

Description: The RAND 36-Item Health Survey (SF-36) score will be assessed by phone call. The score ranges from 0 to 100; higher scores being associated to a better outcome.

Measure: Quality of life assessed by the RAND 36-Item Health Survey (SF-36) score

Time: Day 365 after inclusion

---

Description: The Impact of Event Scale - revised (IES-R) score will be assessed by phone call. The total score ranges from 0 to 88; higher scores being associated to a worse outcome.

Measure: Post-traumatic stress disorder assessed by the Impact of Event Scale - revised (IES-R) score by phone call

Time: Day 365 after inclusion

---

Description: The cost-efficacy ratio will be computed as the ratio of cost difference on efficacy difference between the intervention arm and the reference arm. The costs taken into account will be the direct hospitalized costs. The efficacy will be assessed as the number of days alive free from mechanical ventilation.

Measure: Cost-efficacy ratio of the innovative strategy compared to the reference strategy

Time: Day 90 after inclusion

---

Primary Outcomes

Description: Sum of the days the patient did not receive VM, but if death occurs before D28, the score is zero

Measure: Ventilator-free days

Time: 28 days

---

Secondary Outcomes

Description: Vital status at 28 and 90 days

Measure: Mortality

Time: 28 and 90 days

---

Description: Used to determine the extent of a person's organ function or rate of failure, from 0 to 24, with severity increasing the higher the score

Measure: Sequential Organ Failure Assessment Score

Time: Days 1, 3, 7, 14, 21 and 28

---

Description: Ratio of arterial oxygen partial pressure (PaO2 in mmHg) to fractional inspired oxygen (FiO2 expressed as a fraction, not a percentage)

Measure: P/F ratio

Time: Days 1, 3, 7, 14, 21 and 28

---

Description: Measure of lung compliance

Measure: Lung compliance

Time: Days 1, 3, 7, 14, 21 and 28

---

Description: Severity scoring of lung oedema on the chest radiograph

Measure: Radiological score

Time: Days 1, 3, 7, 14, 21 and 28

---

Description: Concentration in mg/L

Measure: Biological efficacy endpoints - C-reactive protein

Time: Days 1, 3, 7, 14, 21 and 28

---

Description: Concentration in microgram/L

Measure: Biological efficacy endpoints - Procalcitonin

Time: Days 1, 3, 7, 14, 21 and 28

---

Description: Number of CD4 HLA-DR+ and CD38+, CD8 lymphocytes

Measure: Immunological profile

Time: Up to 28 days

---

Description: Use of corticosteroids, antiretroviral, chloroquine

Measure: Number of patients using other treatments for COVID-19 related ARDS

Time: Up to 28 days

---

Description: Diagnosis of deep vein thrombosis or pulmonary embolism through imaging exam (eg ultrasound and CT scan)

Measure: Occurrence of deep vein thrombosis or pulmonary embolism

Time: 28 days

---

Description: Total time of mechanical ventilation, weaning and use of neuromuscular blockade

Measure: Total duration of mechanical ventilation, ventilatory weaning and curarisation

Time: 28 days

---

Description: Divided in 3 stages, with higher severity of kidney injury in higher stages

Measure: Kidney Disease: Improving Global Outcomes (KDIGO) score and need for dialysis

Time: 28 days

---

Description: Kidney failure, hypersensitivity with cutaneous or hemodynamic manifestations, aseptic meningitis, hemolytic anemia, leuko-neutropenia, transfusion related acute lung injury (TRALI)

Measure: Occurrence of adverse event related to immunoglobulins

Time: 28 days

---

Description: Medical research council sum score on awakening

Measure: Occurrence of critical illness neuromyopathy

Time: Up to 28 days

---

Description: Radiological and clinical context associated with a bacteriological sampling in culture of tracheal secretions, bronchiolar-alveolar lavage or a protected distal sampling

Measure: Occurrence of ventilator-acquired pneumonia

Time: Up to 28 days

---

Primary Outcomes

Description: no unit

Measure: Recruitment-to Inflation ratio (R/I ratio)

Time: Day 1

---

Description: no unit

Measure: Recruitment-to Inflation ratio (R/I ratio)

Time: Day 5

---

Description: no unit

Measure: Recruitment-to Inflation ratio (R/I ratio)

Time: Day 10

---

Secondary Outcomes

Description: Arterial blood gases

Measure: PaO2/FiO2 (mmHg)

Time: Day 1

---

Description: Arterial blood gases

Measure: PaO2/FiO2 (mmHg)

Time: Day 5

---

Description: Arterial blood gases

Measure: PaO2/FiO2 (mmHg)

Time: Day 10

---

Description: mL

Measure: Lung volume recruited (VRec)

Time: Day 1

---

Description: mL

Measure: Lung volume recruited (VRec)

Time: Day 5

---

Description: mL

Measure: Lung volume recruited (VRec)

Time: Day 10

---

Description: Obtained by inspiratory pause of 5 seconds

Measure: Plateau pressure (cm H2O)

Time: Day 1

---

Description: Obtained by inspiratory pause of 5 seconds

Measure: Plateau pressure (cm H2O)

Time: Day 5

---

Description: Obtained by inspiratory pause of 5 seconds

Measure: Plateau pressure (cm H2O)

Time: Day 10

---

Measure: Oesophagal pressure (cm H2O)

Time: Day 1

---

Measure: Oesophagal pressure (cm H2O)

Time: Day 5

---

Measure: Oesophagal pressure (cm H2O)

Time: Day 10

---

Measure: weight (Kg)

Time: Day 1

---

Measure: weight (Kg)

Time: Day 5

---

Measure: weight (Kg)

Time: Day 10

---

Measure: urine output (mL)

Time: day 1

---

Measure: urine output (mL)

Time: day 5

---

Measure: urine output (mL)

Time: day 10

---

Measure: serum creatinine (Umo/L)

Time: day 1

---

Measure: serum creatinine (Umo/L)

Time: day 5

---

Measure: serum creatinine (Umo/L)

Time: day 10

---

Measure: Mean arterial pressure (mmHg)

Time: day 1

---

Measure: Mean arterial pressure (mmHg)

Time: day 5

---

Measure: Mean arterial pressure (mmHg)

Time: day 10

---

Measure: Peak Pressure (cm H2O)

Time: Day 1

---

Measure: Peak Pressure (cm H2O)

Time: Day 5

---

Measure: Peak Pressure (cm H2O)

Time: Day 10

---

Description: Obtained by expiratory pause of 5 seconds

Measure: PEEP total (cm H2O)

Time: Day 1

---

Description: Obtained by expiratory pause of 5 seconds

Measure: PEEP total (cm H2O)

Time: Day 5

---

Description: Obtained by expiratory pause of 5 seconds

Measure: PEEP total (cm H2O)

Time: Day 10

---

Measure: PEP Set (cm H2O)

Time: Day 1

---

Measure: PEP Set (cm H2O)

Time: Day 5

---

Measure: PEP Set (cm H2O)

Time: Day 10

---

Measure: Height (cm)

Time: Day 1

---

Measure: Airway pening pressure (cm H2O)

Time: day 1

---

Measure: Airway pening pressure (cm H2O)

Time: day 5

---

Measure: Airway pening pressure (cm H2O)

Time: day 10

---

Description: respiratory rate decreased to 10 /min, expired tidal volume displayed by the ventilator is noted

Measure: Expired volume in PEEP setted at 15 cmH2O (mL)

Time: Day 1

---

Description: respiratory rate decreased to 10 /min, expired tidal volume displayed by the ventilator is noted

Measure: Expired volume in PEEP setted at 15 cmH2O (mL)

Time: Day 5

---

Description: respiratory rate decreased to 10 /min, expired tidal volume displayed by the ventilator is noted

Measure: Expired volume in PEEP setted at 15 cmH2O (mL)

Time: Day 10

---

Description: respiratory rate decreased to 10 /min, expired tidal volume displayed by the ventilator is noted

Measure: Expired volume in PEEP setted at 5 cmH2O (mL)

Time: Day 1

---

Description: respiratory rate decreased to 10 /min, expired tidal volume displayed by the ventilator is noted

Measure: Expired volume in PEEP setted at 5 cmH2O (mL)

Time: Day 5

---

Description: respiratory rate decreased to 10 /min, expired tidal volume displayed by the ventilator is noted

Measure: Expired volume in PEEP setted at 5 cmH2O (mL)

Time: Day 10

---

Primary Outcomes

Measure: Incidence of mortality

Time: Day 43

---

Secondary Outcomes

Measure: Incidence of subjects who are alive and not on mechanical ventilation

Time: Day 29

---

Description: Subjects who die will be assigned "0" ventilator-free days

Measure: Number of ventilator-free days

Time: Baseline to Day 29

---

Measure: Time to hospital discharge

Time: Baseline to Day 43

---

Primary Outcomes

Description: Delta partial pressure of carbon dioxide change during ECCO2R treatment

Measure: Delta change in arterial partial pressure of carbon dioxide during ECCO2R treatment

Time: Up to 72 hours

---

Secondary Outcomes

Description: Epinephrine and norepinephrine dose, mcg/kg/min

Measure: Change in vasopressor use during ECCO2R

Time: Up to 72 hours

---

Description: Assessment of changes in tidal volume

Measure: Assessment of changes in tidal volume during ECCO2R

Time: Up to 72 hours

---

Description: Assessment of changes in pH

Measure: Assessment of changes in pH during ECCO2R

Time: Up to 72 hours

---

Description: Assessment of changes in Positive End-Expiratory Pressure

Measure: Assessment of changes in Positive End-Expiratory Pressure during ECCO2R

Time: Up to 72 hours

---

Description: Adverse events directly related to ECCO2R are infection at the catheter site, hemorrhage at the cannulation site, air entry in the circuit.

Measure: Number of participants with adverse events directly related to ECCO2R

Time: Up to 72 hours

---

Description: Adverse events directly related to ECCO2R are clotting of the circuit.

Measure: Rate of technical adverse events related to ECCO2R

Time: Up to 72 hours

---

Description: Delta change in delta venous partial pressure of carbon dioxide before and after ECCO2R membrane

Measure: Delta change in venous partial pressure of carbon dioxide before and after ECCO2R membrane

Time: Up to 72 hours

---

Primary Outcomes

Description: The primary endpoint is the occurrence of at least one grade improvement between D0 (inclusion) and D7 in the ARDS scale severity (Berlin criteria). For instance from severe to moderate or from moderate to mild

Measure: Efficacy of intratracheal administration: occurrence of at least one grade improvement

Time: Day 7

---

Primary Outcomes

Description: Safety will be defined by the incidence of pre-specified infusion associated adverse events as assessed by treating physician

Measure: Incidence of pre-specified infusion associated adverse events

Time: Day 5

---

Description: Safety will be defined by the incidence of severe adverse events as assessed by treating physician

Measure: Incidence of Severe Adverse Events

Time: 90 days

---

Secondary Outcomes

Description: Number of participants that are alive at 90 days post first infusion follow up.

Measure: Survival rate after 90 days post first infusion

Time: 90 days

---

Description: Number of days participants were off ventilators within up to 28 days of hospitalization

Measure: Ventilator-Free Days

Time: 28 days or hospital discharge, whichever is earlier

---

Description: Measure the fraction of inspired oxygen (FiO2) and its usage within the body during intensive care, measured using fNIRS (Functional Near Infrared Spectroscopy).

Measure: Change in Oxygenation Index (OI)

Time: 28 days

---

Description: Measuring respiratory mechanics in ventilated patients [plateau pressure (Pplat)-positive end-expiratory pressure]

Measure: Plat-PEEP

Time: 28 days

---

Description: The SOFA assessment 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 0 (normal) to 4 (high degree of dysfunction/failure)

Measure: Sequential Organ Failure Assessment (SOFA) Scores

Time: 28 days

---

Description: The SIT is a self-administered 40-item test involving microencapsulated (scratch-and-sniff) odors with a forced-choice design. The test has a total score ranging from 0-40 Follows scoring key for evaluation. The higher score indicates better outcome.

Measure: Small Identification Test (SIT) scores

Time: At baseline, day 18 and day 28.

---

Description: As assessed via serum blood samples.

Measure: Troponin I levels

Time: Baseline, 28 days

---

Description: As assessed via serum blood samples.

Measure: C-Reactive Protein levels

Time: Baseline, 28 days

---

Description: As assessed via serum blood samples.

Measure: Arachidonic Acid (AA)/Eicosapentaenoic Acid (EPA) Ratio

Time: Baseline, 28 days

---

Description: As assessed via serum blood samples.

Measure: D-dimer levels

Time: Baseline, 28 days

---

Description: As assessed via serum blood samples.

Measure: 25-Hydroxy Vitamin D levels

Time: Baseline, 28 days

---

Description: As assessed via serum blood samples.

Measure: Alloantibodies levels

Time: Baseline, 28 days

---

Description: As assessed via serum blood samples.

Measure: Blood white cell count

Time: Baseline, 28 days

---

Description: As assessed via serum blood samples.

Measure: Platelets count

Time: Baseline, 28 days

---

Primary Outcomes

Measure: The PaO2/FiO2 ratio at D11

Time: at Day11

---

Secondary Outcomes

Measure: Changes in Tregs between Baseline and Day 7 (expressed in %)

Time: at Day0 and Day7

---

Measure: Number of days alive with oxygen therapy within 28 days

Time: at Day28

---

Measure: Maximal oxygen rate within 28 days

Time: at Day28

---

Measure: Number of days alive free of invasive or non-invasive ventilation within 28 days

Time: At Day28

---

Measure: Number of days alive outside ICU within 28 days

Time: at Day28

---

Measure: Number of days alive outside hospital within 28 days

Time: at Day28

---

Measure: Time (in days) from randomization to death

Time: through study completion at day 28

---

Measure: Mortality rate at D28

Time: at Day28

---

Measure: Difference between CRP levels at randomization and at Day 7 (or at the time of discharge if occurs before Day 7)

Time: at Day0 and Day7 or at the time of discharge

---

Measure: Use of antibiotics for respiratory (proved or suspected) infection within 28 days

Time: at Day28

---

Measure: Number of prone positioning sessions

Time: throughout the follow up period at day 28

---

Measure: Changes in Tregs during the different visits between baseline and day 28

Time: at Day0, 5, 7, 11, 14 and Day28

---

Description: To evaluate selected immune and inflammatory markers: Serum concentrations of cytokines and soluble factors related to the immune response and inflammatory processes will be evaluated and compare to baseline by multiplex immunoprofiling to analyse a larger number of molecules including at least IFNα2, IFNγ, IL-1α, IL-1β, IL-1RA, IL-2, IL-6, IL-8, IL-10, IL-17, TNFα, TNFβ, VEGF-A, TGF-beta, S-RAGE, SP-A, SP-D, Angiopoétine 1 and KGF.

Measure: Cytokines analysis on plasma samples at Day 0, 7 and 14

Time: at Day 0, 7 and 14

---

Measure: Tregs numbers during induction period and throughout the follow up period at day 5, 7, 11, 14 and 28 compared to baseline before the first IL-2 injection.

Time: at Day0, 5, 7, 11, 14 and Day28

---

Measure: Tregs percentages during induction period and throughout the follow up period at day 5, 7, 11, 14 and 28 compared to baseline before the first IL-2 injection.

Time: at Day0, 5, 7, 11, 14 and Day28

---

Description: Cellular components will be analysed by flow cytometry covering (i) most of the innate and adaptive immune cells including Tregs, T helper cell subsets including follicular helper cells, B cell subsets, NK cell subsets, (ii) the associated relevant markers of activation/function/differentiation, tissue migration, as well as (iii) unconventional lymphoid cells (NKT/MAIT, innate lymphoid cells), myeloid-derived suppressor cells, classical and non-classical monocytes and dendritic cells (mDC1/2, pDC).

Measure: Deep Immunophenotyping of Cellular components in blood samples at Day 0, 7, and 14

Time: at Day0, 7 and Day14

---

Measure: T cell repertoire on Treg, after sorting from blood at Day 7 and Day 14 and compared to baseline

Time: at Day0, 7 and Day14

---

Measure: T cell repertoire on Teff (CD4 and CD8) after sorting from blood at Day 7 and Day 14 and compared to baseline

Time: at Day0, 7 and Day14

---

Measure: Single cells sequencing will be performed in BAL at Day 7 and Day 14 and compared to baseline.

Time: at Day0, 7 and Day14

---

Primary Outcomes

Description: Ideally, the PaO2/FiO2 will be measured with the patient in the same prone/supine position as in baseline, as change in positions may artificially reduce the improvement attributable to the study drug. However, given the pragmatic nature of the trial, the prone/supine position will be determined by the attending physician, in which case, we will use as an outcome the PaO2/FiO2 closest to the 48 hours obtained prior to the change in position as the outcome.

Measure: PaO2/FiO2 improvement from pre-to-post intervention

Time: at 48 hours post randomization

---

Secondary Outcomes

Description: Achievement of PaO2/FiO2 ≥ 200 or 50% increase in PaO2/FiO2 (whatever is lower)

Measure: Achievement of PaO2/FiO2 ≥ 200 or 50% increase in PaO2/FiO2

Time: at 48 hours post randomization

---

Description: This score is based on seven clinical features (respiration rate, hypercapnic respiratory failure, any supplemental oxygen, temperature, systolic blood pressure, heart rate and level of consciousness) and determines the degree of illness of a patient and prompts critical care intervention.

Measure: National Early Warning Score 2 (NEWS2)

Time: at 48 hours post randomization

---

Description: The ordinal scale is an assessment of the clinical status as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7) Not hospitalized, limitation on activities and/or requiring home oxygen; 8) Not hospitalized, no limitations on activities. (combined items 7 and 8 as our study is limited to hospital).

Measure: National Institute of Allergy and Infectious Diseases (NIAID) ordinal scale

Time: at 48 hours post randomization

---

Description: 48 hour mortality for hospitalized patients

Measure: 48 hour in-hospital mortality

Time: at 48 hours post randomization

---

Description: 14 days mortality for hospitalized patients

Measure: 14 days in-hospital mortality

Time: 14 days post randomization

---

Description: 28 days mortality for hospitalized patients

Measure: 28 days in-hospital mortality

Time: 28 days post randomization

---

Description: ICU-free days will be calculated based on (28 - number of days spent in the ICU) formula

Measure: ICU-free days

Time: 28 days of hospital stay or until hospital discharge (whichever comes first)

---

Description: In-hospital coagulation-related events include bleeding, stroke, myocardial infarction and venous thromboembolism (VTE). In-hospital coagulation-related event-free (arterial and venous) days will be calculated based on (28 - number of days without coagulation-related event) formula.

Measure: In-hospital coagulation-related event-free (arterial and venous) days

Time: 28 days of hospital stay or until hospital discharge (whichever comes first)

---

Description: Ventilator-free days will be calculated based on (28 - number of days on mechanical ventilation) formula.

Measure: Ventilator-free days

Time: 28 days of hospital stay or until hospital discharge (whichever comes first)

---

Description: Calculated for patients who was on a mechanical ventilation any period of time during hospitalization. The extubation will be considered successful if no re-intubation occurred for more than 3 days have passed after the initial extubation.

Measure: Successful extubation

Time: Day 4 after initial extubation

---

Description: Calculated for patients who was on paralytics at the time of randomization. The weaning will be considered successful if no paralytics were used for more than 3 days have passed after termination of paralytics.

Measure: Successful weaning from paralysis

Time: Day 4 after initial termination of paralytics

---

Description: Is counted for the patients who was alive at the time of discharge.

Measure: Survival to discharge

Time: 28 days of hospital stay or until hospital discharge (whichever comes first)

---

Primary Outcomes

Description: (Presence/Absence) requirement of mechanical ventilation

Measure: Mechanical ventilation

Time: expected within first three days (non conclusive due to lack of evidence yet)

---

Secondary Outcomes

Description: Duration of mechanical ventilation if it is required (hours from the start)

Measure: Duration of mechanical ventilation

Time: expected within first seven days (non conclusive due to lack of evidence yet)

---

Description: Delirium criteria as defined in DSM-4

Measure: Delirium on recovery from sedation

Time: First 24 hours after retiring dexmedetomidine sedation

---

Primary Outcomes

Description: Therapeutic failure is defined by death or intubation or use of non-invasive ventilation at two pressure levels.

Measure: Therapeutic failure within 14 days of randomization

Time: From randomization to day 14

---

Secondary Outcomes

Description: Therapeutic failure is defined by death or intubation or use of non-invasive ventilation at two pressure levels.

Measure: Therapeutic failure within 28 days of randomization

Time: From randomization to day 28

---

Measure: Timeframe of intubation or death

Time: From randomization to day 28

---

Measure: Timeframe of therapeutic escalation (in case of non-invasive ventilation at two pressure levels)

Time: From randomization to day 28

---

Measure: Evolution of oxygenation (PaO2/FiO2 ratio or SpO2/FiO2 surrogate) over the 14 days following randomization

Time: From randomization to day 14

---

Measure: Evolution of the SpO2/FiO2 ratio during the first prone session

Time: From randomization to day 1

---

Description: ROX index is the ratio of pulse oximetry (SpO2)/fraction of inspired oxygen (FiO2) to respiratory rate.

Measure: Evolution of the ROX index during the first prone session

Time: From randomization to day 1

---

Description: Score reaches from 1 to 7, 7 indicates worse outcome

Measure: Evolution of the World Health Organization disease severity score of COVID

Time: From randomization to day 28

---

Description: Comfort evaluted by the patient through a visual analogical scale

Measure: Patient comfort before, during and after the first prone position session

Time: From randomization to day 1

---

Measure: Occurrence of skin lesions on the anterior surface of the body

Time: From randomization to day 28

---

Description: Invasive devices include : central and peripheric vascular catheters, tracheal tube, urinary catheter, chest tubes.

Measure: Displacement of invasive devices during reversals

Time: From randomization to day 28

---

Measure: Days of nasal High-Flow therapy use in the general population, in non-intubated patients and in intubated patients

Time: From randomization to day 28

---

Measure: Days spent in the intensive care unit and in the hospital

Time: From randomization to day 28

---

Measure: Mortality in the intensive care unit and in the hospital

Time: From randomization to day 28

---

Measure: Ventilator-free-days within 28 days of randomization

Time: From randomization to day 28

---

Primary Outcomes

Description: the respiratory system compliance was compared among three groups

Measure: Respiratory system compliance improvement

Time: 20 minutes

---

Secondary Outcomes

Description: P/Fwere compared among three groups

Measure: Gas echanges improvement

Time: 20 minutes

---

Other Outcomes

Description: MAP were compared among three groups

Measure: hemodynamics improvement

Time: 20 minutes

---

Primary Outcomes

Description: Progression to ARDS is defined as the need for mechanical ventilation

Measure: Progression to ARDS

Time: 28 days

---

Secondary Outcomes

Description: Blood PO2 as measured by pulse oximetry

Measure: Blood oxygenation

Time: 28 days

---

Description: 0 = no shortness of breath at all 0.5 = very, very slight shortness of breath = very mild shortness of breath = mild shortness of breath = moderate shortness of breath or breathing difficulty = somewhat severe shortness of breath = strong or hard breathing 7 = severe shortness of breath or very hard breathing 8 9 = extremely severe shortness of breath 10 = shortness of breath so severe you need to stop the exercise or activity

Measure: RDP Dsypnea Scale

Time: 28 days

---

Description: Distance walked in six minutes

Measure: Distance walked in six minutes

Time: 28 days

---

Primary Outcomes

Description: Number of ventilator-free days (VFDs) at day 28 (defined as days being alive and free from mechanical ventilation at day 28 after enrollment. For patients ventilated 28 days or longer and for ventilated subjects who die, VFD is 0

Measure: Mechanical ventilation-free days

Time: up to 28days

---

Secondary Outcomes

Measure: 30-day mortality

Time: up to 30 days

---

Measure: length of ICU stay (days)

Time: up to 30 days

---

Measure: length of hospital stay

Time: up to 30 days

---

Measure: Duration of renal replacement and cathecolamines therapies

Time: up to 30 days

---

Measure: Need for extracorporeal membrane oxygenation (ECMO) support

Time: up to 30 days

---

Measure: multi-organ failure measured by the Sequential Organ Failure Assessment (SOFA) score

Time: up to 30 days (measured on days 0, 1, 2, 3, 4, 5, 6, and the last day of mechanical ventilation)

---

Primary Outcomes

Description: Number of patients who avoid mechanical assisted ventilation in acute respiratory distress syndrome in patients with SARS-CoV-2 COVID-19 with rapid deterioration of respiratory parameters in the last 12 hours

Measure: Number of patients who avoid mechanical assisted ventilation in acute respiratory distress syndrome in patients with SARS-CoV-2 COVID-19

Time: 15 days

---

Secondary Outcomes

Description: ABG (arterial Blood Gas): pH as SI Unit, every 12 hours and in any case in the presence of significant clinical variations.

Measure: Improvement of respiratory performance - Arterial Blood Gas Analisys - pH

Time: 15 days

---

Description: ABG (arterial Blood Gas): pO2 in mm Hg, every 12 hours and in any case in the presence of significant clinical variations.

Measure: Improvement of respiratory performance - Arterial Blood Gas Analisys - pO2

Time: 15 days

---

Description: ABG (arterial Blood Gas): pCO2 in mm Hg, every 12 hours and in any case in the presence of significant clinical variations.

Measure: Improvement of respiratory performance - Arterial Blood Gas Analisys - pCO2

Time: 15 days

---

Description: PaO2 / FiO2, SatO2 ratio. Vital parameters and respiratory function every 12 hours and in any case in the presence of significant clinical variations.

Measure: Improvement of respiratory performance - ratio values

Time: 15 days

---

Description: every 24 hours D-Dimer value in mgr/ml

Measure: Evaluation of known adverse events related to the use of the drug - D-Dimer

Time: 15 days

---

Description: every 24 hours fibrinogen value in mg/dl

Measure: Evaluation of known adverse events related to the use of the drug - fibrinogen

Time: 15 days

---

Description: every 24 hours transaminases value in U/L

Measure: Evaluation of known adverse events related to the use of the drug - transaminases

Time: 15 days

---

Description: every 24 hours aPTT value in seconds

Measure: Evaluation of known adverse events related to the use of the drug - aPTT

Time: 15 days

---

Description: every 24 hours INR value in %

Measure: Evaluation of known adverse events related to the use of the drug - INR

Time: 15 days

---

Description: every 24 hours glycemia value in mg/dl

Measure: Evaluation of known adverse events related to the use of the drug - glycemia

Time: 15 days

---

Description: every 24 hours creatinine serum value in mg/dl

Measure: Evaluation of known adverse events related to the use of the drug - creatinine

Time: 15 days

---

Description: Total leucocyte as CBC x10e)/L

Measure: Evaluation of known adverse events related to the use of the drug - Leucocytes count

Time: 15 days

---

Description: formula % on total leucocyte

Measure: Evaluation of known adverse events related to the use of the drug - Leucocytes formula

Time: 15 days

---

Description: Thoracic imaging, every 48 h: presence, extension and dimension on lung thickening - Chest CT at start and end of treatment, Time elapsed between the onset of clinical symptoms and hospitalization.

Measure: Evaluation of the epidemiological parameters: Chest CT

Time: 15 days

---

Description: Thoracic imaging: every day: presence and number of line B every 48 hours.Time elapsed between the onset of clinical symptoms and hospitalization.

Measure: Evaluation of the epidemiological parameters: Eco Chest

Time: 15 days

---

Description: Thoracic imaging: presence, extension and dimension on lung thickening - Chest X-ray, Time elapsed between the onset of clinical symptoms and hospitalization.

Measure: Evaluation of the epidemiological parameters: CHEST X-ray

Time: 15 days

---

Description: Monitoring of serum cytokines (IL-6 in pgr/dL, TNF in pgr/dL) every 48 h

Measure: Monitoring of Serum levels of cytokines before and every 48 h from start to to end of treatment

Time: 15 days

---

Description: Number of AE grade 1 to 4

Measure: Monitoring incidence of treatment Emergent Adverse Events of ruxolitinib therapy

Time: 15 days

---

Primary Outcomes

Description: To show that PP in spontaneously ventilation patients could reduce the risk of acquiring the following event (composite endpoint): Endotracheal intubation Or non-invasive ventilation (NIV) with two pressure levels And/or death

Measure: Percent age of patients who will have endotracheal intubation or non-invasive ventilation at two pressure levels and/or die, in each of the 2 randomization groups.

Time: Day 28

---

Secondary Outcomes

Description: Show that the use of prone position improves the WHO ordinal scale score by 2 points faster (after randomization)

Measure: Duration in days for the change of 2 points on the WHO ordinal scale

Time: Day 28

---

Description: Show that prone position with spontaneous ventilation reduces the need for endotracheal intubation and invasive mechanical ventilation

Measure: Rate (%) of intubation and invasive ventilation in the 2 randomization groups.

Time: Day 28

---

Description: Show that prone position with spontaneous ventilation reduces the use of non-invasive ventilation at two pressure levels

Measure: Rate (%) of non-invasive ventilation at two pressure levels in the 2 randomization groups

Time: Day 28

---

Description: Show that prone position in spontaneous ventilation reduces the time under oxygen therapy.

Measure: Duration of oxygen therapy in the 2 randomization groups.

Time: Day 28

---

Description: Show that prone position reduces the length of hospitalization.

Measure: Duration of hospitalization in the 2 randomization groups.

Time: Day 28

---

Description: Compare the hospital mortality of the 2 groups

Measure: Hospital mortality and mortality at D28 in the 2 randomization groups

Time: Day 28

---

Description: Compare the incidence of the need for resuscitation transfer between the two groups.

Measure: Rate (%) of need for transfer to intensive care unit

Time: Day 28

---

Description: Compare the impact of the use of non-invasive ventilation and intubation on the entire hospital stay when the hospital stay is longer than 28 days between the two groups.

Measure: Rate (%) of use of non-invasive ventilation at two pressure levels, intubation throughout the entire stay when the stay is longer than 28 days.

Time: 1 year

---

Primary Outcomes

Description: Count of participants initially presenting with mild/moderate disease who progress to requiring advanced oxygenation (high flow nasal canula, non-rebreather, continuous positive airway pressure (CPAP), bilevel positive airway pressure (BIPAP), or intubation)

Measure: Progression of oxygenation needs

Time: up to 1 month

---

Secondary Outcomes

Description: Count of participants who develop or experience worsened renal failure as defined by RIFLE criteria, a 5-point scale where the categories are labeled: Risk-Injury-Failure-Loss-End stage renal disease, with Risk being the least severe and End stage renal disease being the most severe. The criteria for determination of stage are factors of serum creatinine and urine output. Numbers of participants worsening one or more RIFLE stages will be reported.

Measure: Renal failure

Time: up to 1 month

---

Description: Count of participants who develop or experience worsened liver failure as defined by serum transaminases five times normal limits

Measure: Liver failure

Time: up to 1 month

---

Description: Count of participants who develop cytokine storm as measured by elevated markers of inflammation (elevated D-dimer, hypofibrinogenemia, hyperferritinemia), evidence of acute respiratory distress syndrome (ARDS) measured by imaging findings and mechanical ventilator requirements, and/or continuous fever (≥ 38.1 ° Celsius unremitting)

Measure: Cytokine Storm

Time: up to 1 month

---

Description: Count of participants who die from COVID-19

Measure: Mortality

Time: up to 1 month post hospital discharge

---

Description: Length of hospital stay in days

Measure: Length of hospital stay

Time: up to 1 month

---

Description: Count of patients admitted to the ICU at any time during index hospitalization

Measure: Intensive Care Unit (ICU) admission

Time: up to 1 month

---

Description: Length of ICU stay in days

Measure: Intensive Care Unit (ICU) duration

Time: up to 1 month

---

Description: Count of participants requiring intubation

Measure: Intubation

Time: up to 1 month

---

Description: Length of intubation, measured in days

Measure: Intubation duration

Time: up to 1 month

---

Description: Time measured in days from hospital admission to determination patient is stable for discharge

Measure: Time until recovery

Time: up to 1 month

---

Primary Outcomes

Description: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

Measure: Adverse events assessment

Time: From baseline to day 28

---

Description: Evaluation of Pneumonia Improvement

Measure: Blood oxygen saturation

Time: From baseline to day 14

---

Secondary Outcomes

Description: Number of days

Measure: Intensive care unit-free days

Time: Up to day 8

---

Description: Improvement of clinical symptoms including duration of fever, respiratory distress, pneumonia, cough, sneezing

Measure: Clinical symptoms

Time: From baseline to day 14

---

Description: increase in PaO2/FiO2 ratio from baseline to day 7

Measure: Respiratory efficacy

Time: From baseline to day 7

---

Description: Biochemical examination

Measure: Biomarkers concentrations in plasma

Time: At baseline, 7, 14, 28 days after the first intervention

---

Primary Outcomes

Description: The primary endpoint of the Phase 1 portion of the study is to evaluate the safety of AVM0703 in subjects with severe or life-threatening COVID-19 infection, and to identify the RP2D.

Measure: Dose-Limiting Toxicities

Time: 0-12 months

---

Description: The primary endpoint of the Phase 1/2 portion of the study is to evaluate the efficacy of AVM0703 in subjects with severe or life-threatening COVID-19 infection.

Measure: 28 day all-cause mortality will be a primary end point for Phase 1 and 2

Time: 0-12 months

---