Clinical trial NCT04323592: Methylprednisolone for Patients With COVID-19 Severe Acute Respiratory Syndrome
Official title: Prolonged Low Doses of Methylprednisolone for Patients With COVID-19 Severe Acute Respiratory Syndrome
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Severe Acute Respiratory Syndrome (SARS) Pneumonia
Coronavirus Infections
ARDS, Human
Keywords: SARS-CoV-2,
SARS
ARDS
Methylprednisolone
Lead sponsor: University of Trieste
Sponsor class: OTHER
First posted: 2020-03-26
Enrollment: 173
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Consecutive patients admitted to Respiratory High dependency units for severe acute respiratory syndrome associated to COVID-19

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.

Eligibility criteria: 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

Primary outcomes:
measure: Composite Primary End-point: Admission to ICU, Need for Invasive Mechanical Ventilation (MV), or All-cause Death by Day 28
timeFrame: 28 days
measure: In-hospital Death Within 28 Days
timeFrame: 28 days
measure: Admission to Intensive Care Unit (ICU)
timeFrame: 28 days
measure: Endotracheal Intubation (Invasive Mechanical Ventilation)
timeFrame: 28 days
Secondary outcomes:
measure: Change in C-reactive Protein (CRP)
timeFrame: 7 days
measure: Number of Days Free From Mechanical Ventilation
timeFrame: 28 days
Other outcomes:
Locations:
city: Trieste
country: Italy
facility: Marco Confalonieri
state: TS
Study officials:
affiliation: University of Trieste
name: Marco Confalonieri, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Nicastri E, Petrosillo N, Ascoli Bartoli T, Lepore L, Mondi A, Palmieri F, D'Offizi G, Marchioni L, Murachelli S, Ippolito G, Antinori A. National Institute for the Infectious Diseases "L. Spallanzani", IRCCS. Recommendations for COVID-19 clinical management. Infect Dis Rep. 2020 Mar 16;12(1):8543. doi: 10.4081/idr.2020.8543. eCollection 2020 Feb 25.
citation: Salton F, Confalonieri P, Meduri GU, Santus P, Harari S, Scala R, Lanini S, Vertui V, Oggionni T, Caminati A, Patruno V, Tamburrini M, Scartabellati A, Parati M, Villani M, Radovanovic D, Tomassetti S, Ravaglia C, Poletti V, Vianello A, Gaccione AT, Guidelli L, Raccanelli R, Lucernoni P, Lacedonia D, Foschino Barbaro MP, Centanni S, Mondoni M, Davi M, Fantin A, Cao X, Torelli L, Zucchetto A, Montico M, Casarin A, Romagnoli M, Gasparini S, Bonifazi M, D'Agaro P, Marcello A, Licastro D, Ruaro B, Volpe MC, Umberger R, Confalonieri M. Prolonged Low-Dose Methylprednisolone in Patients With Severe COVID-19 Pneumonia. Open Forum Infect Dis. 2020 Sep 12;7(10):ofaa421. doi: 10.1093/ofid/ofaa421. eCollection 2020 Oct.