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
Sponsor: University of Trieste

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Prolonged Low Doses of 
Methylprednisolone for Patients With 
COVID-19 Severe Acute Respiratory 
Syndrome  
NCT04323592
March 23rd, 2020

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MP-C19 – Study protocol
Background and rationale
The COVID-19 pandemic caused by the new coronavirus called SARS-CoV-2 is associated 
in about 20% of hospitalized cases in Italy with a severe acute respiratory syndrome with 
dramatic impact on the system organization and health of the population due to the high 
need for mechanical ventilation (MV), frequent hospitalization in the General Intensive Care 
Unit (ICU) and significant increase in mortality [1,2].
It is precisely the high concomitant number of cases of severe acute respiratory syndromes 
in very short times that is having an extraordinary impact on the health system with high 
consumption of precious resources such as beds of intensive care units and the need to 
quickly commit huge economic and human resources.
Due to the exceptional nature of the current situation that is being experienced in Italy, there 
is a desperate need for evidence to improve the therapeutic management of COVID-19 
patients with severe acute respiratory syndrome.
A very recent Chinese report published on 13.March.2020 in JAMA Internal Medicine 
describes favourable data on the treatment with methylprednisolone (MP) in a series of 201 
patients with COVID193 acute respiratory distress syndrome (ARDS) stating that the use of 
corticosteroids, in particular methylprednisolone, can have a beneficial effect on mortality.
The World Health Organization (WHO) advises against the use of steroids in COVID-19 
based on retrospective MERS studies that have shown prolongation of viral clearance 
without however influencing the clinical outcome [5].
On the other hand, WHO itself through the Blueprint process has prioritized studies on 
steroids as an additional therapy that can improve outcomes in order to identify actions that 
can save lives throughout the COVID-19 pandemic [6].
In Italy, the use of corticosteroids is currently not recommended by official guidelines, but is 
routinely practiced in some respiratory centers with Semi-Intensive Respiratory Therapy Unit
(UTIR) on the basis of positive results of randomized controlled trials on patients with severe
community pneumonia [7] .
Corticosteroids, like any other drug, can have different effects based on the dosage 
schedule used, the timing of intervention and indications. Previous controversial studies on 
cortisone do not indicate the dosage regimen [5] or use a reduced time with rebound effect 
[8] and / or too high doses [9] and immunosuppressive effect, or are used in patients who 
are not too sick [10]. Here we want to propose the use of prolonged low para-physiological 
doses of MP as suggested several times in the studies of Prof. Umberto Meduri of Memphis 
in patients with ARDS [11]. Indeed, prolonged glucocorticoid treatment is a highly effective 
treatment in ARDS caused by severe bacterial pneumonia [7].
Acute respiratory distress syndrome (ARDS) is a catastrophic disease of multifactorial 
etiology characterized by severe and diffuse inflammatory exudate of the lung leading to 
hypoxemic respiratory failure (ARF) that requires mechanical ventilation (MV) [12,13]. Lung 
infections, including COVID-19, are the main cause of ARDS.
Translational research has established a strong association between dysregulated 
inflammation, pulmonary and systemic, and progression (maladaptive repair) or delayed 
resolution of ARDS. Randomized controlled trials (RCTs) have shown that prolonged 

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treatment of glucocorticoids (GCs) mediated by downregulation of systemic and pulmonary 
inflammation is essential to accelerate disease resolution and restore tissue homeostasis 
and can be significantly improved with a prolonged moderate dose of GC [15,16]. Since 
1998, ten RCTs have studied prolonged GC treatment (methylprednisolone, hydrocortisone, 
dexamethasone) in ARDS for a total of 1093 patients. Compared to placebo, GC treatment 
was associated with statistically significant improvements (among those reported) in (i) 
markers of systemic inflammation (7 of 7), (ii) oxygenation (10 of 10), (iii) duration of MV (7 
of 9) and length of stay in intensive care (7 of 7). Overall, cortisone treatment was effective 
despite disease-related heterogeneity (precipitating conditions, disease severity, ARDS 
timing, mechanical ventilation mode) and treatment (type of GC, start timing, dose, mode of 
administration, duration of treatment and titration). Importantly, with the exception of 
transient hyperglycaemia related to initial bolus administration, corticosteroid treatment was 
not associated with an increased risk of complications, and hyperglycaemia didn’t affect the 
outcome. Table 1 shows the data of the ten RCTs [7, 17-25] conducted on the prolonged 
treatment with glucocorticoids started before the 14th day of ARDS (treatment vs. control) 
with the following outcome of interest: overall mortality, treatment mortality, improvement of 
the markers of systemic inflammation, oxygenation, duration of mechanical ventilation and 
stay in intensive care, and infection rate after entering the study.
Table 1 (see below) also shows the median increase in free days from MV to day 28 in the 
aggregated data of patients randomized to three cortisone compounds (methylprednisolone, 
hydrocortisone and dexamethasone) and the effective reduction in the duration of MV for 
methylprednisolone and dexamethasone. The significant reduction in the duration of MV 
reported in the last RCT by Villar et al.  [22] (14.1 ± 1.7 vs. 23.6 ± 2.9; p = 0.006) is similar to
the one reported in the other RCT [26] (From -8.7 to - 10.6 days) on methylprednisolone 
(median 8 days in each group).
Table 1. Prolonged glucocorticoid treatment in ARDS (treated vs. control): overall mortality, mortality for treatment 
initiated before day 14 of ARDS, improvement in markers of systemic inflammation, oxygenation, duration of 
mechanical ventilation and ICU stay, and infection rate after study entry.
Hospital 
mortality*
for treatment 
started before
ARDS day 14
Study
RCTs = 10
N = 1043
Comparisons 
are reported as 
glucocorticoid-
treated vs. 
control.
Reduction in 
inflammation
Improvement 
in PaO2:FiO2
Reduction 
in MV 
duration
Reduction
in ICU 
stay
Rate of 
infection
Early ALI-ARDS 
(< 3 d; n=899)
31.4% vs. 
44.3%
5 of 5
8 of 8
5 of 7
5 of 5
22% vs. 
27%
Confalonieri, 2005
(n=34)† ‡ ADDIN 
EN.CITE [7]
0% vs. 36.8%
Yes
Yes
Yes
Yes
0% vs. 
21%
Annane, 2006 
(n=177) ADDIN 
EN.CITE [25]
63.5% vs. 
72.8%
Yes
Yes
No
NR
14% vs. 
13%
Yes
Yes
Yes
Yes

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Meduri, 2007  
(n=91)†  ADDIN 
EN.CITE [17]
23.8% vs. 
42.9%
63% vs. 
143%
Sabry, 2011 
(n=60) ‡ [18]
7.7% vs. 
17.6%
Yes
Yes
Yes
NR
0% vs 
10%
Liu, 2012 (n=26)  
ADDIN EN.CITE 
[19]
16.7% vs 
50.0%
NR
Yes
NR
Yes
7% vs. 
9%
Rezk, 2013 
(n=27)[20]
0% vs. 33.3%
Yes
Yes
Yes
Yes
0% vs 
33%
Tongyoo, 2016 
(n=197)  ADDIN 
EN.CITE [21]
22.4% vs. 
27.3%
NR
Yes
No
NR
17% vs. 
19%
Villar, 2020 
(n=277)  ADDIN 
EN.CITE [22]
23.7% vs. 
36.2%
NR
Yes
Yes
Yes
24% vs. 
25%
Late ARDS (> 5 
d; n=154)
21.3% vs. 
37.8%
2 of 2
2 of 2
2 of 2
2 of 2
42 vs. 
40%
Meduri, 1998 
(n=22) ADDIN 
EN.CITE [24]
14.3% vs. 
62.5%
Yes
Yes
Yes
Yes
150% vs.
125%
Steinberg, 2006 
(n=132) ADDIN 
EN.CITE [23]
22.7% vs. 
34.8%
Yes
Yes
Yes
Yes
22.5 vs. 
33%
Early and Late 
ARDS
35% vs. 54%
7 of 7
10 of 10
7 of 9
7 of 7
26% vs. 
30% 
Legend: NA = not available or not applicable; NR = not reported; d = days; MV = mechanical ventilation; ICU = intensive care unit.
Rate of infection = number of infections divided by number of patients.
* Mortality data for Liu et al  ADDIN EN.CITE [19] are reported as 28-day mortality.
† In two positive trials  ADDIN EN.CITE [7, 17] improvement in lung function (PaO2:FiO2 or lung injury score) was the primary
outcome variable.
‡   Data for the Confalonieri et al.  ADDIN EN.CITE [7] and Sabry et al.[18] are limited to patients receiving mechanical ventilation.
Figure 1 shows the median increase in free days from the MV to the 28th day in the 
aggregated data of all the clinical trials described above (Reproduced with permission from 
reference [15]).
Figure 1. Impact of long-dose cortisone treatment on ventilation dependence.

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The Faculty of Intensive Care Medicine (FICM) and the Intensive Care Society (ICS) have 
recently published [26] their "Guidelines on the management of acute respiratory distress 
syndrome (ARDS)". These guidelines used the GRADE methodology in developing evidence
-based recommendations for the management of ARDS in adult ICU patients. The task force
suggested that methylprednisolone should be administered to patients with moderate to 
severe early ARDS (1 mg / kg / day) (recommendation based on moderate quality of 
evidence). The treatment protocol recommended by the guidelines is the one adopted in this
proposal. Importantly, the task force suggested that methylprednisolone should be weaned 
slowly (6-14 days) and not stopped quickly (2-4 days) or abruptly since deterioration may 
occur from the development of a reconstituted inflammatory response [26]. The 
methylprednisolone dose of 1 mg / kg / day in the first ARDS is similar to that commonly 
used in other forms of interstitial lung disease and in the individual patient data the 
metanalysis (IPDMA) was associated - compared to placebo - with a triple increase rate of 
extubation by day 28 (HR 3.48, 95% CI 2.07-5.85; p <0.0001) [26].
Prolonged treatment with methylprednisolone in ARDS caused by COVID19: a 
desperate need for evidence.
Given the SARS-CoV-2 virus pandemic and the dramatic Italian situation, we think that the 
efficacy of cortisone for patients with ARDS from COVID-19 should be urgently clarified, as 
WHO requires.
The dramatic rate of progression of the infection in Italy and the high simultaneous number 
of hospitalizations for severe pneumonia from COVID-19 provides the opportunity and the 
need to start quickly to collect important public health data in a short time.
Particular concern raises the high number in Italy of COVID-19 subjects suffering from 
severe acute respiratory failure with extensive need for hospitalization in general intensive 
care (16% of all hospitalized in Italy) with very frequent (79%) need for mechanical 
ventilation invasive (IMV) and high mortality (in Italy it was estimated to be 5.8% in mid-
March 20), sometimes even in young adults and without serious co-morbidities [1, 30].

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Many RCTs have shown evidence of the use of low prolonged corticosteroids in bacterial 
community-acquired pneumonia as the main cause of ARDS [7,25]. Evidence and studies 
are lacking in patients with ARDS from viral pneumonia. ARDS caused by bacteria or 
COVID-19 viruses is associated with a massive inflammatory response and is potentially 
responsive to cortisone-type anti-inflammatory treatment. It is therefore not surprising that 
many Chinese researchers have suggested the use of corticosteroids in patients with ARDS 
from viral pneumonia due to COVID-19 virus.
In the absence of RCT, WHO [4] does not recommend treatment with glucocorticoids in 
ARDS associated with COVID-19 partly based on concern about the risk of decreased viral 
clearance from a single study [5]. There are no quality data indicating an increase in 
morbidity or mortality with prolonged low to moderate dose glucocorticoid therapy in severe 
viral pneumonia. Furthermore, there are multiple factors that influence the interpretation of 
observational studies conducted without a standard protocol, that create conflicting results 
and confusion [27]. However, WHO believes that promoting RCT is a priority to study the 
anti-inflammatory treatment of glucocorticoids in COVID-19 pneumonia [4]. Preliminary 
Italian data in some patients indicate improvement with the use of a new selective interleukin
-6 blocker, tocilizumab, indicating that anti-inflammatory interventions could be of benefit 
[unpublished].
Due to the methodological limitations in previous studies, the Chinese Thoracic Society 
developed an expert consensus statement [28] on the use of corticosteroids in pneumonia 
2019-nCoV. According to this experts consensus statement, the following basic principles 
must be followed when using corticosteroids: (1) the benefits and harms must be carefully 
weighed before using corticosteroids; (2) corticosteroids should be used with caution in 
critically ill patients with pneumonia 2019-nCoV; (3) for patients with hypoxemia due to 
underlying diseases or who regularly use corticosteroids for chronic diseases, further use of 
corticosteroids should be prudent; and (4) the dosage should be low to moderate (≤0.5–1 
mg / kg per day of methylprednisolone or equivalent) and the duration should be short (≤7 
days) [28].
The organization, supervision and conduct of RCTs add further levels of complexity and 
commitment by institutions that are in extreme conditions. In today's reality, our intensive 
care units do not have the ability to administer complex RCT in patients with highly lethal 
disease. Support for our proposal is provided by a new observational study of 201 patients 
with confirmed COVID-19 pneumonia admitted to Wuhan Jinyintan hospital in China 
[December 25, 2019 and January 26, 2020] [3]. In this study, among ARDS patients, of 
those who received methylprednisolone treatment, 23 of 50 (46.0%) patients died, while of 
those who did not receive methylprednisolone treatment, 21 of 34 (61.8%) died. 
Methylprednisolone administration appears to have reduced the risk of death in patients with
ARDS (HR, 0.38; 95% CI, 0.20-0.72; P = 0.003) (Figure 2) [3]. The protocol used during the 
study was not reported. Further observational studies reported that the sickest patients 
received "high-dose" glucocorticoid treatment (without specific details) with higher mortality 
(48% vs. 23%), while two other observational studies found a reduction in mortality with 
glucocorticoid treatment [29].
Figure 2 - Progression from hospital entry to development of ARDS from COVID-19 [32]

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Study acronym: MP-C19
Primary aim:
Evaluate the efficacy of methylprednisolone (MP) at prolonged low doses in severe acute 
respiratory syndrome (SARS) with ARDS from COVID-19.
Primary outcome: proportion of patients experiencing one or more of the following events: 
admission to a General Intensive Care Unit (ICU), need of invasive mechanical ventilation 
(intubation), death.
Based on data from the recent study by Wu C, et al. [3] on MP in the ARDS COVID-19 
related and from the studies on ARDS secondary to community pneumonia, we expect a 
strong difference in the proportion of patients who will encounter at least one of the events 
included in the primary outcome mentioned above in the group treated with MP compared to
the controls (no MP treatment).
Secondary objectives:
- Assess the impact of the MP in terms of changing the values of the reactive Protein C 
(PCR) and PaO2/FiO2 ratio
- Assess the impact of the MP on intra-hospital mortality 
- Assess the impact of the MP on the use of intubation and on days free from mechanical 
ventilation (VM)

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Study design: multi centers, observational prospective cohort study in patients with severe 
acute respiratory syndrome due to COVID-19.
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:
a.
Sex
b.
Age
c.
C-reactive Protein (CRP) at baseline
d.
SOFA score at baseline
e.
PaO2/FiO2 ratio at baseline
Study population: patients admitted to respiratory/UTIR departments of the centers 
participating in the study who meet the following inclusion criteria.
Inclusion criteria:
1. SARS-CoV-2 positive (on swab or bronchial wash)
2. Age >18 years and <80 years
3. PaO2/FiO2 <250 mmHg
4. Diffuse interstitial pneumonia or bilateral infiltrates
5. CRP (C-reactive protein) > 10mg / dL (or> 100mg / L)
6. As an alternative to criteria 4.-5.-6. diagnosis of ARDS according to the Berlin definition 
[31]
Exclusion criteria:
- Left heart failure as the main cause of acute respiratory failure
- Decompensated liver cirrhosis
- Cancer in progress
- Organ transplantation
- HIV
- Dialysis
- Home oxygen therapy
- Idiopathic Pulmonary Fibrosis
- Progressive neuromuscular diseases (e.g. ALS, Duchenne dystrophy, etc.)
- Dementia or decompensated psychiatric diseases
- Immunosuppressant drugs in use

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- Chronically used oral steroid
- Use of tocilizumab
- Known pregnancy
Groups/Cohorts
Interventions
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.
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.
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

 pg. 10 - low dose MP in ARDS – v1.0
•
pronation when possible
•
other treatment which can be used are:
antivirals, chloroquine, vitamins
Study variables and timing of data collection
Outcome measures:
- PaO2/FiO2, mmHg
- PCR, mg / L (or mg / dL)
- Platelets, n / mm3
- Total bilirubin, mg / dL
- Blood pressure (Max / Min mmHg)
- Creatinine mg / dL
- Glasgow Come Scale (score)
- SOFA score (https://www.mdcalc.com/sequential-organ-failure-assessment-sofa-score)
- Number of days free from VM of any type (CPAP, NIV, IMV, number of days until the 28th 
day of admission to Respiratory Unit / UTIR)
- Number of days free from invasive VM (number of days until the 28th day of admission to 
Respiratory Unit / UTIR)
Follow up: 28 days from hospital admission
Measures timepoints: 
UTIR = Semi-Intensive Respiratory Therapy Unit
- Day 0-1 from entry into UTIR / Respiratory Unit
- Day 3 from entry into UTIR / Respiratory Unit
- Day 7 from entry into UTIR / Respiratory Unit
- Day 14 from entry into UTIR / Respiratory Unit
- Day 28 from entry into UTIR / Respiratory Unit
Additional data to be collected:
- Intra-hospital Medications, type and dosages
- Pre-hospital Medications, type and dosages
- Pre-hospital co-morbidity
- In-hospital adverse events

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- Date of death
- ICU Admission date 
- ICU and Hospital dates of discharge
- COVID-19 test negative date
EXPECTED RESULTS:
In the group treated with MP compared to the group without MP:
•
Reduction of the proportion of patients who undergo ICU admission, intubation, or 
death within 28 days of admission to Respiratory Unit / UTIR
•
Increase in days free from VM of all types on day 28 of admission to Respiratory Unit
/ UTIR
•
Increase in days free from invasive VM on day 28 of admission to Respiratory Unit / 
UTIR
•
In-hospital mortality reduction
•
Reduction of PCR values on day 7 and 14 of admission to Respiratory Unit / UTIR
•
Improvement of PaO2/FiO2 on day 7 and 14 of admission to Respiratory Unit / UTIR
Primary Outcome:
Difference between the two study groups in the proportion of patients experiencing one or 
more of the following events within 28 days of admission to Respiratory Unit / UTIR:
a) hospitalization in Intensive Care Unit
b) intubation and use of invasive mechanical ventilation
c) death in hospital for any reason.
Patients who on day 0 fall into one of the 3 previous conditions or leave the study on day 0 
are excluded from the primary outcome analysis.
Secondary Outcomes:
Difference between the two groups compared to:
-
Proportion of patients with PCR reduction on day 7 and day 14 of admission to 
Respiratory Unit / UTIR
-
Proportion of patients with PaO2/FiO2 improvement (> 350 mmHg) on 
​day 7 and on 
day 14 of admission to Respiratory Unit / UTIR
-
Proportion of intubated patients with invasive VM on day 28 of admission to 
Respiratory Unit / UTIR
-
Total number of days free from VM or non-invasive CPAP (helmet, mask) on day 28 
of admission to Respiratory Unit / UTIR
-
Total number of days free from invasive VM on day 28 of admission to Respiratory 
Unit / UTIR
-
In-hospital mortality, expressed both in terms of the proportion of patients with death 
within 28 days of admission to Respiratory Unit / UTIR, both in terms of survival 
(calculated as time from the date of admission to Respiratory Unit / UTIR until the 

 pg. 12 - low dose MP in ARDS – v1.0
first of the following dates: date of death, date of hospital discharge or end of study 
follow-up).
SAMPLE SIZE
The Chinese observational study published on 13/3/2020 in JAMA Intern Med3 showed that 
the use of MP leads to a reduction of about 15% percentage points of mortality (30-day 
mortality: 46.0% in 50 treated patients vs. 61.8 % in 34 untreated patients; survival median: 
25 days vs. 10 days, HR 0.4, 95% CI: 0.2-0.7). Furthermore, the same study shows a 
proportion of ICU admissions of patients with ARDS of 63% and use of intubation and 
invasive VM in 79% of ARDS cases.
Given a study power (1-beta) of 80% and a probability of type 1 error (alpha) of 0.05, we 
calculated a sample size of 98 patients (49 for each group) using a proportional test, Z-test 
(pooled), 2-code. Considering the primary outcome, from the literature data it is expected for 
ARDS patients a proportion equal to about 70% of patients intubated and / or hospitalized in 
ICU and / or deceased that would be reduced by at least 40% (i.e. from 70% to 42%) with 
the MP-based intervention in Respiratory Unit / UTIR.
Considering a 5% drop-out, a total of at least 104 patients will need to be enrolled (52 per 
group).
Statistical analysis plan
See statistical analysis plan document.
ETHICAL CONSIDERATIONS FOR THE MP-C19 STUDY:
1.
The highly virulent epidemic Covid19 is reaping victims in Italy even among people 
without particular co-morbidities despite every type of respiratory support.
2.
The results of the most recent Chinese study published on March 13, 2020 in JAMA 
Intern Med suggests testing of methylprednisolone as a possible therapy in patients 
with severe COVID-19 pneumonia is needed.
3.
The Chinese observational study shows an important 30-day mortality change with 
methylprednisolone. In addition, the impact on the health system with high number of
simultaneous accesses to the hospital by patients with ARDS requires the need to 
find feasible solutions in a short time.
4.
The size of the problem does not allow us to think of a randomized study, so we 
opted for a prospective case-control study with a control group selected from 
"contemporary" and not "historical" cases
5.
Written informed consent is not necessary in these clinical situations according to the
law.
6.
There are robust justifications for a well-designed controlled study based on strong 
pharmacological and physiological principles.
7.
A multicenter study is proposed that includes several centers directly involved in 
patient care in geographical areas with a high incidence of cases with acute 
respiratory failure and severe COVID-19 pneumonia in order to enroll large numbers 
of patients in a short time.

 pg. 13 - low dose MP in ARDS – v1.0
8.
The study will be conducted in accordance with the Good Clinical Practice 
guidelines, the ethical principles deriving from the Helsinki declaration and the 
current legislation on observational studies.
9.
The study follows the guidance of AIFA regarding "Management of clinical studies in 
Italy during an emergency COVID-19 (coronavirus disease 19)" (see 
https://www.aifa.gov.it/web/guest / - / management-of-clinical-studies-in-italy-in-
course-of-emergency-covid-19-coronavirus-disease-19-)
CONSENT AND PRIVACY STATEMENT
Consistent with the need to inform the subjects to be included in the research, and the 
applicable right of patients to receive personalized information, it is believed that the 
conditions of extreme clinical severity and urgent care foreseen in the protocol could, for the 
most part, be incompatible with the application of the procedures required for the formulation
of an informed consent prior to the start of the Study. This issue also applies to the 
presumed possibility of being able to appoint and have any legal representatives available.
In the logic outlined above, ad hoc forms (Information on Data Processing and Informed 
Consent for participation in the Study) are attached to this protocol which will also be 
presented to those patients who survive, after resuming the cognitive, functional and 
emotional functions to validly participate in the information process.
Therefore this clinical study will be conducted in compliance with the provisions of the 
Privacy Guarantor n. 146 of 5 June 2019, which recalls the previous authorization n. 9/2016 
- general authorization for the processing of personal data carried out for scientific research 
purposes - 15 December 2016, which allows the processing of data suitable for revealing the
state of health, sexual life and racial and ethnic origin, even in the absence of the consent of 
the interested parties, for scientific research purposes in the medical, biomedical or 
epidemiological field in compliance with the limits and conditions set out in the authorization 
itself.
The a’forementioned authorization, in fact, also allows Healthcare Companies to process the
data of subjects to be included in the research, if it is not possible to contact them, in order 
to provide the information, if there is, among others, the following exceptional circumstance, 
documented in the protocol:
the intervention is necessary for the conduct of studies carried out with data referring to 
people who, due to the seriousness of their clinical status, are unable to understand the 
indications given in the information and to give valid consent.
The obligation to collect consent to the participation and processing of data [*] [**] of the 
interested parties enrolled in the research remains valid in all cases in which, during the 
study, it is possible to provide them with adequate information, as in the case in which the 
patient initially in critical or unconscious conditions, recovers the ability to validly give his 
consent to the participation to the study and gathering/usage/disclosure of data already 
collected and / or to the continuation of the study.

 pg. 14 - low dose MP in ARDS – v1.0
[*] for the prospective part of the study: "After adequate information and signing of the 
informed consent form and the ICF form, in accordance with the current legislation on data 
processing (Regulation (EU) 2016/679 of 27 April 2016 , Legislative Decree 10.08.18 No. 
101 GU 205-18) and subsequent amendments, and to comply with the provisions of the 
Guidelines for the treatment of personal data in the context of clinical trials of medicines, 
adopted on 24 July 2008 of Guarantor for the protection of personal data, or to comply with 
the provisions of Resolution no. 85 of 01 March 2012, OJ General Series n.72 of 26-3-2012),
the patient data that will be affiliated with our Center, will be collected anonymously at the 
source and will be kept until the conclusion of the study ".
[**]
for the part of the controls: "(...) it should be noted that in the condition of samples / 
retrospective data of patients found to be deceased or unavailable, the right enshrined in art.
110, paragraph 1, and 41 of the Code, to process the data and carry out the operations 
strictly indispensable and pertinent to the conduct of the study, even in the absence of their 
informed consent. Data will be collected for all patients relating to the diagnosis, the therapy 
they underwent and the clinical course. Biological samples and clinical data will be 
immediately anonymised, before proceeding with the subsequent analysis ".
RETENTION OF DOCUMENTS
The documentation will be available, for inspection, for at least 7 years from the formal 
closure of the study
SCIENTIFIC DATA OWNER
The owner of the collected data will be the promoter of the study
PUBLICATION POLICIES AND COMMUNICATION OF RESULTS
The scientific director of the study will undertake to write a final report and a scientific article 
and to publish the results at the end of the study. The data will be anonymous and presented
in aggregate mode.
The study is promoted by ASUGI (Giuliano Isontina University Health Authority)
COORDINATING CENTER
Struttura complessa Pneumologia, ASUGI - Ospedale di Cattinara, strada di Fiume 447, 
34149 Trieste 
Director: Prof Marco Confalonieri, phone 040/3994667, email  mconfalonieri@units.it)
 
For information: 
Dr Francesco Salton (email: francesco.salton@gmail.com), 

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Prof Marco Confalonieri (email mconfalonieri@units.it, ph 0403994667)
Ethic committee: CEUR F.V.G. – C/o C.R.O. di  Aviano (PN)- Italy
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