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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).
Comparison of two groups of patients SARS-CoV-2 positive with severe acute respiratory syndrome:
The two group will be weighted by means of a propensity score according to:
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
| |
| Non-exposed to Methylprednisolone | Concurrent patients fulfilling the same inclusion and exclusion criteria, never treated with steroids. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Methylprednisolone | Drug | 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. |
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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Consecutive patients admitted to Respiratory High dependency units for severe acute respiratory syndrome associated to COVID-19
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| Name | Affiliation | Role |
|---|---|---|
| Marco Confalonieri, MD | University of Trieste | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Marco Confalonieri | Trieste | TS | 34149 | Italy |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32218915 | Background | 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. | |
| 33072814 |
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Anonymised data will be available only to data manager who can visualise clinical chart anytime when is needed
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| ID | Title | Description |
|---|---|---|
| FG000 | Exposed to Methylprednisolone | SARS-CoV-2 positive patients with severe acute respiratory syndrome consecutively treated with methylprednisolone (MP) at prolonged dose. 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 slowly until normal CRP values (+20%) are reached. Methylprednisolone: after initial 80mg iv bolus 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:
|
| FG001 | 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:
|
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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:
|
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Posted | Count of Participants | Participants | 28 days |
|
28 days
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Exposed to Methylprednisolone | SARS-CoV-2 positive patients with severe acute respiratory syndrome consecutively treated with methylprednisolone (MP) at prolonged dose. 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 slowly until normal CRP values (+20%) are reached. Methylprednisolone: after initial 80mg iv bolus 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:
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Shock | General disorders | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Bacterial superinfection | General disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Prof. Marco Confalonieri | University of Trieste | +393356895168 | 4667 | mconfalonieri@units.it |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| ICF | No | No | Yes | Informed Consent Form | Mar 23, 2020 | May 27, 2020 | ICF_003.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Mar 23, 2020 | May 27, 2020 | SAP_004.pdf |
| Prot | Yes | No | No | Study Protocol | Mar 23, 2020 | Jun 17, 2020 | Prot_006.pdf |
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| ID | Term |
|---|---|
| D045169 | Severe Acute Respiratory Syndrome |
| D011014 | Pneumonia |
| D018352 | Coronavirus Infections |
| D012128 | Respiratory Distress Syndrome |
| ID | Term |
|---|---|
| D012141 | Respiratory Tract Infections |
| D007239 | Infections |
| D003333 | Coronaviridae Infections |
| D030341 | Nidovirales Infections |
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| ID | Term |
|---|---|
| D008775 | Methylprednisolone |
| D059039 | Standard of Care |
| ID | Term |
|---|---|
| D011239 | Prednisolone |
| D011246 | Pregnadienetriols |
| D011245 | Pregnadienes |
| D011278 | Pregnanes |
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Previous specific informed consent, blood samples of some patients treated with methylprednisolone were collected, in order to have the possibility to do
|
| standard care | Other | usual standard of care:
|
|
number of days free from mechanical ventilation (both invasive and non-invasive) by day 28
| 28 days |
| 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. |
| BG001 | 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:
|
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| C-reactive Protein | Mean | Standard Deviation | mg/L |
|
| PaO2/FiO2 | Mean | Standard Deviation | ratio |
|
| Sequential Organ Failure Assessment (SOFA) Score | Sum of subscales scoring the function of: nervous system, kidneys, coagulation, respiratory system, cardiovascular system, liver. Values ranging 0-24; higher values represent worse outcome. | Median | Inter-Quartile Range | score |
|
| Lactates | Mean | Standard Deviation | mmol/L |
|
| Lymphocytes | Mean | Standard Deviation | cells/uL |
|
| D-dimer | Median | Inter-Quartile Range | ug/L Fibrinogen Equivalent Units (FEU) |
|
| lactate dehydrogenase (LDH) | Mean | Standard Deviation | U/L |
|
| Respiratory rate | Mean | Standard Deviation | Breaths per minute |
|
| OG001 | 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:
|
|
|
| Primary | In-hospital Death Within 28 Days | We reported below the number of participants who died within 28 days, during the hospital stay. | Posted | Count of Participants | Participants | 28 days |
|
|
|
| Primary | Admission to Intensive Care Unit (ICU) | We reported below the number of participants admitted to ICU within 28 days. | Posted | Count of Participants | Participants | 28 days |
|
|
|
| Primary | Endotracheal Intubation (Invasive Mechanical Ventilation) | We reported below the number of participants who needed endotracheal intubation during ICU admission | Posted | Count of Participants | Participants | 28 days |
|
|
|
| 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. | Posted | Mean | Standard Deviation | mg/L | 7 days |
|
|
|
| Secondary | Number of Days Free From Mechanical Ventilation | number of days free from mechanical ventilation (both invasive and non-invasive) by day 28 | Posted | Mean | Standard Deviation | days | 28 days |
|
|
|
| 9 |
| 83 |
| 6 |
| 83 |
| 23 |
| 83 |
| EG001 | 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:
| 24 | 90 | 9 | 90 | 21 | 90 |
| Acute renal failure | Renal and urinary disorders | Non-systematic Assessment |
|
| Disseminated intravascular coagulation | Vascular disorders | Non-systematic Assessment |
|
| Acute myocardial infarction | Cardiac disorders | Non-systematic Assessment |
|
| Stroke | Nervous system disorders | Non-systematic Assessment |
|
| Pulmonary embolism | Vascular disorders | Non-systematic Assessment |
|
| Agitation | Psychiatric disorders | Non-systematic Assessment |
|
| Hyperglycemia | Endocrine disorders | Non-systematic Assessment |
|
| Hypokalemia | General disorders | Non-systematic Assessment |
|
| Pneumothorax | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Transaminase elevation | Hepatobiliary disorders | Non-systematic Assessment |
|
| QT elongation | Cardiac disorders | Non-systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | Non-systematic Assessment |
|
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| D012327 | RNA Virus Infections |
| D014777 | Virus Diseases |
| D012140 | Respiratory Tract Diseases |
| D008171 | Lung Diseases |
| D012120 | Respiration Disorders |
| D013256 |
| Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D019984 | Quality Indicators, Health Care |
| D011787 | Quality of Health Care |
| D006298 | Health Services Administration |
| D017530 | Health Care Quality, Access, and Evaluation |