Methylprednisolone for Patients With COVID-19 Severe Acute Respiratory Syndrome

Study Overview
=================
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: Exposed to low prolonged doses of Methylprednisolone Not exposed to corticosteroids (standard of care alone) The two group will be weighted by means of a propensity score according to: Sex Age C-reactive protein (CRP) at baseline Sequential Organ Failure Assessment (SOFA) score at baseline 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. 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. Unexposed patients will be selected from concurrent consecutive COVID-19 patients with the same inclusion and exclusion criteria and blinded to outcome data.

Official Title
-----------------
Prolonged Low Doses of Methylprednisolone for Patients With COVID-19 Severe Acute Respiratory Syndrome

Conditions
-----------------
Severe Acute Respiratory Syndrome (SARS) Pneumonia, Coronavirus Infections, ARDS, Human

Intervention / Treatment
-----------------
* Drug: Methylprednisolone
* Other: standard care


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: SARS-CoV-2 positive Age >17 years and < 80 years P/F < 250 mmHg Bilateral pneumonia (infiltrates/interstitial) CRP >10mg/dL (or >100mg/L) 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Exposed to Methylprednisolone<br>Consecutive SARS-CoV-2 positive patients with severe acute respiratory syndrome treated with methylprednisolone (MP) at low prolonged dose, fulfilling inclusion and exclusion criteria. | Drug: Methylprednisolone<br>* 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.<br>Other: standard care<br>* 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<br>|
| Non-exposed to Methylprednisolone<br>Concurrent patients fulfilling the same inclusion and exclusion criteria, never treated with steroids. | Other: standard care<br>* 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<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 28 days | 
| In-hospital Death Within 28 Days | We reported below the number of participants who died within 28 days, during the hospital stay. | 28 days | 
| Admission to Intensive Care Unit (ICU) | We reported below the number of participants admitted to ICU within 28 days. | 28 days | 
| Endotracheal Intubation (Invasive Mechanical Ventilation) | We reported below the number of participants who needed endotracheal intubation during ICU admission | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in C-reactive Protein (CRP) | Change in C-reactive protein after 7 days from baseline. A reduction of CRP reveals a laboratory improvement. | 7 days | 
| Number of Days Free From Mechanical Ventilation | number of days free from mechanical ventilation (both invasive and non-invasive) by day 28 | 28 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
SARS-CoV-2,, SARS, ARDS, Methylprednisolone