ARDS, Human, Coronavirus Infections, Severe Acute Respiratory Syndrome (SARS) Pneumonia
Conditions
Keywords
SARS-CoV-2,, SARS, ARDS, Methylprednisolone
Brief summary
COVID-19 infection is overwhelming Italian healthcare. There is an urgent need for a solution to the lack of ICU beds and increasing deaths day after day. A recent retrospective Chinese paper (JAMA Intern Med, online March 13, 2020) showed impressive positive effect of methylprednisolone (MP) on survival of SARS-CoV-2 critically ill patients. Moreover, the Italian Infectious Disease leading institution guidelines for COVID-19 clinical management included as an option for patients with incipient worsening of respiratory functions methylprednisolone treatment at an approximate dose of 80mg. The main objective of this multi-centre observational trial is to analyse the association of low dose prolonged infusion of methylprednisolone (MP) for patients with severe acute respiratory syndrome with composite primary end-point (ICU referral, need for intubation, in-hospital death at day 28).
Detailed description
Comparison of two groups of patients SARS-CoV-2 positive with severe acute respiratory syndrome: 1. Exposed to low prolonged doses of Methylprednisolone 2. Not exposed to corticosteroids (standard of care alone) The two group will be weighted by means of a propensity score according to: 1. Sex 2. Age 3. C-reactive protein (CRP) at baseline 4. Sequential Organ Failure Assessment (SOFA) score at baseline 5. PaO2/FiO2 ratio at baseline (ratio of arterial oxygen partial pressure to fractional inspired oxygen) Anti-viral agents, chloroquine, respiratory support (any), and antibiotics (any) are allowed in each study group. Corticosteroids use, other than per-protocol Methylprednisolone in the exposed group is a reason for dropout. 1. The exposed group is treated with Methylprednisolone at study entry (baseline) according to a protocol based on the Italian national recommendations for COVID-19 management: a loading dose of 80 mg IV, followed by an infusion of 80 mg/day in 240 mL normal saline at 10 mL/h. The infusion is continued for at least eight days and until achieving either a PaO2:FiO2 \> 350 mmHg or a CRP \< 20 mg/L. Treatment is then switched to oral administration of Methylprednisolone 16 mg or 20 mg IV twice daily until CRP returns to \< 20% of normal range and/or PaO2:FiO2 \> 400 or SatHbO2 ≥ 95%. The decision to apply the protocol to Covid-19 is left to the discretion of the treating team for each individual patient. 2. Unexposed patients will be selected from concurrent consecutive COVID-19 patients with the same inclusion and exclusion criteria and blinded to outcome data.
Interventions
DRUGMethylprednisolone
Usual standard of care plus Methylprednisolone (MP) 80 mg/kg IV bolus, followed by MP infusion of 80 mg/day in 240 mL normal saline at 10 mL/h. The infusion is continued for at least eight days and until achieving either a PaO2:FiO2 \> 350 mmHg or a CRP \< 20 mg/L. Treatment is then switched to oral administration of Methylprednisolone 16 mg or 20 mg IV twice daily until CRP returns to \< 20% of normal range and/or PaO2:FiO2 \> 400 or SatHbO2 ≥ 95%. The decision to apply the protocol to Covid-19 is left to the discretion of the treating team for each individual patient.
OTHERstandard care
usual standard of care: * oxygen therapy (regular or high-flow) and monitoring * empiric antibiotic therapy * mechanical ventilation (invasive or noninvasive) * ECMO when needed and available * pronation when possible * other treatment which can be used are: antivirals, chloroquine, vitamins
Sponsors
University of Trieste
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. SARS-CoV-2 positive 2. Age \>17 years and \< 80 years 3. P/F \< 250 mmHg 4. Bilateral pneumonia (infiltrates/interstitial) 5. CRP \>10mg/dL (or \>100mg/L) 6. Alternatively to 4-5-6 criteria a diagnosis of ARDS according to the Berlin definition (Ranieri M, et al. JAMA 2012)
Exclusion criteria
* Heart failure as predominant cause of acute respiratory failure * Decompensated liver cirrhosis * Cancer * Organ transplantation * HIV+ * dialysis * long-term oxygen therapy, home mechanical ventilation * Idiopathic pulmonary fibrosis * Progressive neuromuscular disorders (e.g. Duchenne, Pompe, ALS) * Dementia or decompensated psychiatric diseases * immunosuppressive treatments * Chronic use of corticosteroids * Use of Tocilizumab * pregnancy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite Primary End-point: Admission to ICU, Need for Invasive Mechanical Ventilation (MV), or All-cause Death by Day 28 | 28 days | We reported below the number of participants meeting at least one of three among death or ICU admission or Invasive mechanical ventilation. |
| In-hospital Death Within 28 Days | 28 days | We reported below the number of participants who died within 28 days, during the hospital stay. |
| Admission to Intensive Care Unit (ICU) | 28 days | We reported below the number of participants admitted to ICU within 28 days. |
| Endotracheal Intubation (Invasive Mechanical Ventilation) | 28 days | We reported below the number of participants who needed endotracheal intubation during ICU admission |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in C-reactive Protein (CRP) | 7 days | Change in C-reactive protein after 7 days from baseline. A reduction of CRP reveals a laboratory improvement. |
| Number of Days Free From Mechanical Ventilation | 28 days | number of days free from mechanical ventilation (both invasive and non-invasive) by day 28 |
Countries
Italy
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Exposed to Methylprednisolone SARS-CoV-2 positive patients with severe acute respiratory syndrome consecutively treated with methylprednisolone (MP) at low prolonged dose.
At admission, inclusion criteria checked, the patient undergo 80mg iv bolus of MP followed by infusion (10cc/h) of MP in 240cc 0.9% saline every day until PaO2/FiO2 increase over 350 and/or CRP decrease below 20mg/L, then MP is administered PO tapering until normal CRP values (+20%) are reached.
Methylprednisolone: Methylprednisolone given at low prolonged dose infusion after initial 80mg iv bolus at admission followed by 80mg in 240cc 0.9% saline administered iv at 10cc/h speed for at least 7 day or more. Duration of Methylprednisolone treatment depends from CRP and P/F values already described in arm/group description
standard care: usual standard of care:
* oxygen therapy (regular or high-flow) and monitoring
* empiric antibiotic therapy
* mechanical ventilation (invasive or noninvasive)
* ECMO when needed and available
* pronati | 83 |
| Non-exposed to Methylprednisolone Concurrent patients with the same inclusion/section exclusion criteria never treated with steroids, strictly matched according to gender and age (+/-10 years) and other three parameters:
CRP, SOFA score, PaO2:FiO2 -\> each parameter must be \<20% difference between case and control.
standard care: usual standard of care:
* oxygen therapy (regular or high-flow) and monitoring
* empiric antibiotic therapy
* mechanical ventilation (invasive or noninvasive)
* ECMO when needed and available
* pronation when possible
* other treatment which can be used are: antivirals, chloroquine, vitamins | 90 |
| Total | 173 |
Baseline characteristics
| Characteristic | Exposed to Methylprednisolone | Non-exposed to Methylprednisolone | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 48 Participants | 56 Participants | 104 Participants |
| Age, Categorical Between 18 and 65 years | 35 Participants | 34 Participants | 69 Participants |
| Age, Continuous | 64.39 years STANDARD_DEVIATION 10.73 | 67.08 years STANDARD_DEVIATION 8.24 | 65.79 years STANDARD_DEVIATION 9.58 |
| C-reactive Protein | 136.92 mg/L STANDARD_DEVIATION 72.57 | 148.64 mg/L STANDARD_DEVIATION 75.59 | 143.01 mg/L STANDARD_DEVIATION 74.17 |
| D-dimer | 780 ug/L Fibrinogen Equivalent Units (FEU) | 890 ug/L Fibrinogen Equivalent Units (FEU) | 813 ug/L Fibrinogen Equivalent Units (FEU) |
| lactate dehydrogenase (LDH) | 380 U/L STANDARD_DEVIATION 132.93 | 413.06 U/L STANDARD_DEVIATION 143.83 | 396.41 U/L STANDARD_DEVIATION 138.96 |
| Lactates | 1.76 mmol/L STANDARD_DEVIATION 1.97 | 1.34 mmol/L STANDARD_DEVIATION 0.51 | 1.52 mmol/L STANDARD_DEVIATION 1.32 |
| Lymphocytes | 622.28 cells/uL STANDARD_DEVIATION 650.62 | 954.5 cells/uL STANDARD_DEVIATION 914.7 | 938.94 cells/uL STANDARD_DEVIATION 797.81 |
| PaO2/FiO2 | 152.02 ratio STANDARD_DEVIATION 49.84 | 151.01 ratio STANDARD_DEVIATION 60.26 | 151.50 ratio STANDARD_DEVIATION 55.35 |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Region of Enrollment Italy | 83 Participants | 90 Participants | 173 Participants |
| Respiratory rate | 23.74 Breaths per minute STANDARD_DEVIATION 5.95 | 25.27 Breaths per minute STANDARD_DEVIATION 6.76 | 24.55 Breaths per minute STANDARD_DEVIATION 6.41 |
| Sequential Organ Failure Assessment (SOFA) Score | 3 score | 3 score | 3 score |
| Sex: Female, Male Female | 29 Participants | 24 Participants | 53 Participants |
| Sex: Female, Male Male | 54 Participants | 66 Participants | 120 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 9 / 83 | 24 / 90 |
| other Total, other adverse events | 23 / 83 | 21 / 90 |
| serious Total, serious adverse events | 6 / 83 | 9 / 90 |
Outcome results
Primary
Admission to Intensive Care Unit (ICU)
We reported below the number of participants admitted to ICU within 28 days.
Time frame: 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Exposed to Methylprednisolone | Admission to Intensive Care Unit (ICU) | 15 Participants |
| Non-exposed to Methylprednisolone | Admission to Intensive Care Unit (ICU) | 27 Participants |
Primary
Composite Primary End-point: Admission to ICU, Need for Invasive Mechanical Ventilation (MV), or All-cause Death by Day 28
We reported below the number of participants meeting at least one of three among death or ICU admission or Invasive mechanical ventilation.
Time frame: 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Exposed to Methylprednisolone | Composite Primary End-point: Admission to ICU, Need for Invasive Mechanical Ventilation (MV), or All-cause Death by Day 28 | 19 Participants |
| Non-exposed to Methylprednisolone | Composite Primary End-point: Admission to ICU, Need for Invasive Mechanical Ventilation (MV), or All-cause Death by Day 28 | 40 Participants |
Primary
Endotracheal Intubation (Invasive Mechanical Ventilation)
We reported below the number of participants who needed endotracheal intubation during ICU admission
Time frame: 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Exposed to Methylprednisolone | Endotracheal Intubation (Invasive Mechanical Ventilation) | 15 Participants |
| Non-exposed to Methylprednisolone | Endotracheal Intubation (Invasive Mechanical Ventilation) | 26 Participants |
Primary
In-hospital Death Within 28 Days
We reported below the number of participants who died within 28 days, during the hospital stay.
Time frame: 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Exposed to Methylprednisolone | In-hospital Death Within 28 Days | 6 Participants |
| Non-exposed to Methylprednisolone | In-hospital Death Within 28 Days | 21 Participants |
Secondary
Change in C-reactive Protein (CRP)
Change in C-reactive protein after 7 days from baseline. A reduction of CRP reveals a laboratory improvement.
Time frame: 7 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exposed to Methylprednisolone | Change in C-reactive Protein (CRP) | -82.08 mg/L | Standard Deviation 28.24 |
| Non-exposed to Methylprednisolone | Change in C-reactive Protein (CRP) | -34.34 mg/L | Standard Deviation 66.64 |
Secondary
Number of Days Free From Mechanical Ventilation
number of days free from mechanical ventilation (both invasive and non-invasive) by day 28
Time frame: 28 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exposed to Methylprednisolone | Number of Days Free From Mechanical Ventilation | 19.11 days | Standard Deviation 8.73 |
| Non-exposed to Methylprednisolone | Number of Days Free From Mechanical Ventilation | 14.34 days | Standard Deviation 11.65 |