Methylprednisolone for Patients With COVID-19 Severe Acute Respiratory Syndrome (MP-C19)

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

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).

Study Overview

• Status: Completed
• Conditions: Coronavirus Infections; ARDS, Human; Severe Acute Respiratory Syndrome (SARS) Pneumonia
• Intervention / Treatment: Drug: Methylprednisolone; Other: standard care

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.

• Study Type: Observational
• Enrollment (Actual): 173

Contacts and Locations

Study Locations

• Italy
  • TS
    • Trieste, TS, Italy, 34149
      • Marco Confalonieri

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Consecutive patients admitted to Respiratory High dependency units for severe acute respiratory syndrome associated to COVID-19

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Exposed to Methylprednisolone; 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; 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.; Other: 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
Non-exposed to Methylprednisolone; Concurrent patients fulfilling the same inclusion and exclusion criteria, never treated with steroids.	Other: 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

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

Collaborators and Investigators

• Sponsor: University of Trieste
• Investigators: Principal Investigator: Marco Confalonieri, MD, University of Trieste

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): March 23, 2020
• Primary Completion (Actual): May 10, 2020
• Study Completion (Actual): May 10, 2020

Study Registration Dates

• First Submitted: March 19, 2020
• First Submitted That Met QC Criteria: March 24, 2020
• First Posted (Actual): March 26, 2020

Study Record Updates

• Last Update Posted (Actual): June 24, 2020
• Last Update Submitted That Met QC Criteria: June 23, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: ARDS; Methylprednisolone; SARS; SARS-CoV-2,
• Additional Relevant MeSH Terms: Pathologic Processes; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Disease; Severe Acute Respiratory Syndrome; Coronavirus Infections; Syndrome; Respiratory Distress Syndrome; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Neuroprotective Agents; Protective Agents; Prednisolone; Methylprednisolone Acetate; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate
• Other Study ID Numbers: MP-19 023_2020

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: Anonymised data will be available only to data manager who can visualise clinical chart anytime when is needed

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No