Trial protocol and summary of changes for Continuous Infusion versus Intermittent Administration of

MERopenem in CriticallY Ill Patients (MERCY) trial

Title: Continuous infusion versus intermittent administration of meropenem in critically ill
patients. A multicenter randomized double blind trial.
MERCY – Version n° 1.1 October 20th 2017
EUDRACT N° 2016-002052-24
Principal Investigator: Prof. Alberto Zangrillo
Firma:

AREA TEMATICA
· Area: A - Confronto fra farmaci e fra strategie terapeutiche per patologie e condizioni
cliniche ad elevato impatto per la salute pubblica e per il SSN
· Topic; number: 3 - Studi randomizzati per valutare se specifiche modalità di
somministrazione (per es., somministrazione infusionale continua vs discontinua o in bolo)
hanno un diverso impatto sugli outcomes clinici più rilevanti

PROPOSAL TITLE
· Title in Italian: Meropenem in infusione continua o a boli nel paziente ricoverato in terapia
intensiva. Uno studio multicentrico randomizzato in doppio cieco.
· Title: Continuous infusion versus intermittent administration of meropenem in critically ill
patients. A multicenter randomized double blind trial.
· Running title (max 50 chars): Bolus versus continuous infusion of meropenem.
· Key words (max 5) 1. Drug Administration Schedule ; 2. meropenem; 3. critical illness 4
mortality 5 drug resistance, microbial

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PHARMACOLOGICAL TREATMENT
(Please list every drugs used both in the treatment and in the control groups)
Drug Marketed Not marketed
(in Italy or abroad ) (neither in
Active Reimburs Drug for treatment
Italy nor
ingredient ement group (T) Can be all clicked abroad)
(50 chars) class drug for standard
within
group (C)
the NHS
(A, C, H) Can be clicked both
1 Meropenem H T Off patent Approved
indications

STUDY DESIGN (please, specify “experimental” or “observational” or “systematic review”)

• Experimental
Phase IV
- Randomised Controlled Trial: Yes

- If Yes, the trial is

active controlled

- Blinding / Masking Yes

- If Yes, please select:
double

- The study is designed as:

parallel groups

- The active treatment is administered add-on over standard care? Yes

- Number of the study arms:_______2________
- Estimation of number of patients to be recruited: ________600_______
* Please indicate only Clinical Centres directly involved in patients recruitment.

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ESTIMATION OF THE STUDY DURATION:
• Estimation of the complete duration of the study*: ____24____ (months)
• Duration of recruitment (if applicable): ____23____ (months)
• Treatment duration (if applicable): _few days during intensive care unit
stay_(months)
• Duration of follow up (if applicable): _1 month for the primary endpoint_(months)

* intended as the time from the protocol approval by the Ethics Committee to the
submission of the final study report.

OUTCOME(S)
Please describe the primary end point(s):
A composite endpoint of 28-day mortality and/or new extensive or pan drug resistant pathogen.

B.1. ABSTRACT
Background
Hospital-acquired infections are a major challenge: in intensive care units, gram-negative
bacteria account for about 70% of these infections, and similar data are reported from other
parts of the world. Infections caused by gram-negative bacteria have features that are of
particular concern. These organisms are highly efficient at up-regulating or acquiring genes
that code for mechanisms of antibiotic drug resistance, especially in the presence of
antibiotic selection pressure.
Meropenem is a β-lactam, carbapenem antibacterial agent that has antimicrobial activity
against gram-negative, gram-positive and anaerobic micro-organisms. In the last several
years, a progressive increase in resistance among Gram-negative pathogens has continued
unabated. The emergence of multi-drug resistant GN organisms (MDRs) coupled with an
alarming scarcity of new antibiotic classes in the pipelines of the pharmaceutical industry has
forced the healthcare community to optimize the therapeutic potential of available
antibiotics. Patent of meropenem has recently expired: reduction in costs of the drug could
lead to an increase of the drug. Developing strategies to reinforce efficacy and maintain
pathogens' sensitivity to drug is of paramount importance.
The primary determinant of a β-lactam efficacy is the duration of time in which the non-
protein bound drug concentration (fT) exceeds the minimum inhibitory concentration (MIC)
of the organism (fT>MIC) (Drusano). β-lactam antibiotics have traditionally been
administered by intermittent infusion. With intermittent dosing, β-lactams attain a high peak
concentration, but short half-lives can lead to precipitous drops in serum drug levels.
Pharmacokinetic studies have shown that prolonging the infusion time provides more
consistent serum levels and maximizes fT>MIC.
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A meta-analysis concludes that prolonged infusion β-lactam antibiotics may have value in a
specific subsets of patients, such as those with highly-resistant GN infections and in patients
with a higher degree of severity of illness, nevertheless definitive high quality, randomized
controlled trials are needed to confirm this hypothesis. Another important issue is that
exposing patients to a certain degree of variation of antibiotics concentration, can cause
resistance emergence and therefore, treatment inefficacy: continuous infusion of β-lactam
could minimize this risk.
Objectives
We are planning a large multicentre randomized controlled study to confirm the beneficial
effect of continuous infusion of meropenem against bolus administration as indicated by a
composite outcome of reducing death, and emergence of extensive or pan drug resistant
pathogens in a population of severely ill patients. Secondary endpoints will be reducing long-
term mortality, days under mechanical ventilation, intensive care unit length of stay,
fastening reduction of severity of disease.
Methods
Patients enrolled will receive 1 g of meropenem bolus in both randomization arm. After that,
subjects will be randomized to receive a continuous infusion of study drug 3 g/day or a bolus
administration of the same amount of drugs. Correction for renal function will be applied.
Study will last up 28 days after first bolus of study drug. Subjects will be strictly monitored for
efficacy and safety of the treatment.
Principal outcome is a composite outcome of mortality and emergence of new multidrug
pathogens at 28 days from first bolus of study drug. Secondary outcome are: mortality at day
90, ICU-, antibiotics- and SOFA-free days.
Expected result
We expect a primary outcome reduction from 52 to 40% in the continuous infusion group.
Applying a 80% power and a 5% alpha errors, with continuity correction and a two-tails test,
a total of 287 subjects for group will be necessary, rounded to 300 for possible protocol
deviations, with a total of 600 patients included in the study.

B.2. BACKGROUND AND RATIONALE

Definition
Multidrug, extensive drug, pandrug resistance.
The terms “multidrug resistance (MDR)”, “extensive drug resistance (XDR)” and “pandrug
resistance (PDR)” are increasingly frequently used in the biomedical literature to describe
various degrees of antimicrobial resistance among bacteria.
Unfortunately, there are currently no internationally accepted definitions for these terms for
bacteria other than Mycobacterium tuberculosis. As a result, these terms are used arbitrarily
creating great confusion among researchers, health care professionals and the public. For the
purpose of this study “MDR” will be used to denote isolates resistant to representatives
three or more classes of antimicrobial agents, “XDR” those resistant to all but one or two

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classes and “PDR” as those resistant to all classes of antimicrobial agents available and
intrinsically active against the respective species.( Pauli)
Bolus administration
Bolus administration refers to an infusion of drugs lasting less than 30 minutes.
Continuous infusion
Continuous administration refers to an infusion of drugs that proceed over the whole day.
Inotropic Score
Vasoactive or inotropic drugs have relatively different power.
To the purpose of this study, 1 point of inotropic score will be assigned each 0.01
mcg/kg/min infusion of epinephrine or nor-epinephrine and 1 point each 1 mcg/kg/min of
dopamine or dobutamine.

Introduction
Hospital-acquired infections are a major challenge to patient safety. It is estimated that in
2002, a total of 1.7 million hospital-acquired infections occurred (4.5 per 100 admissions) (1),
and almost 99,000 deaths resulted from or were associated with a hospital-acquired
infection (1) making hospital-acquired infections the sixth leading cause of death in the
United States; similar data have been reported from Europe (2) .
Infections caused by gram-negative bacteria have features that are of particular concern.
These organisms are highly efficient at up-regulating or acquiring genes that code for
mechanisms of antibiotic drug resistance, especially in the presence of antibiotic selection
pressure. Furthermore, they have available to them a plethora of resistance mechanisms,
often using multiple mechanisms against the same antibiotic or using a single mechanism to
affect multiple antibiotics. (3)

Pneumonia
Recent data from the U.S. National Healthcare Safety Network indicate that gram-negative
bacteria are responsible for more than 30% of hospital-acquired infections, and these
bacteria predominate in cases of ventilator-associated pneumonia (47%) and urinary tract
infections (45%) (Hildron) In intensive care units (ICUs) in the United States, gram-negative
bacteria account for about 70% of these types of infections, and similar data are reported
from other parts of the world. (Gates)
Ventilator-associated pneumonia occurs in approximately 10 to 20% of patients who are on
ventilators for longer than 48 hours and is associated with significant increases in length of
hospital stay, mortality, and costs (Jarby). Gram-negative organisms predominate in hospital-
acquired pneumonia, particularly P. aeruginosa, A. baumannii, and the Enterobacteriaceae.
(Gaynes)
A more recent clinical entity that physicians need to be aware of is health care–associated
pneumonia — that is, cases of pneumonia acquired in the community by patients who have
had direct or indirect contact with a health care or long-term care facility and are
subsequently hospitalized. Such patients are more likely to have a coexisting illness and to
receive inactive empirical antibiotic therapy and are at greater risk for death than patients
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who have true community-acquired pneumonia. (carratala collef) As a consequence,
antibiotics with a broader spectrum of coverage — particularly those with activity against P.
aeruginosa, other multidrug-resistant gram-negative bacilli, should be considered for
patients who have defined risk factors and who present to the emergency room with
pneumonia (ATS, Mandell).

Bloodstream Infection
Infection of the bloodstream remains a life-threatening occurrence and is most commonly
associated with the presence of a central vascular catheter but may also be associated with a
gram-negative infection in other areas of the body, such as the lung, genitourinary tract, or
abdomen. Approximately 30% of hospital-acquired bloodstream infections in ICUs in the
United States are due to gram-negative organisms (Gaynes).
Given an adequate portal of entry, almost any gram-negative organism can cause
bloodstream infection; however, the most common organisms include klebsiella species,
Escherichia coli, enterobacter species, and P. aeruginosa. As described above for organisms
that cause hospital-acquired pneumonia, resistance is an emerging problem, particularly
resistance against extended-spectrum cephalosporins and carbapenems. For example, of
bloodstream isolates of Klebsiella pneumoniae from hospitals throughout the United States,
27.1% (from 483 isolates tested) were resistant to third-generation cephalosporins and 10.8%
(from 452 isolates tested) were resistant to carbapenems. (Gaynes) Higher rates of resistance
are reported from parts of Europe. (Souli)

Urinary Tract Infection

Gram-negative organisms predominate in hospital-acquired urinary tract infections, almost
all of which are associated with urethral catheterization. After the second day of
catheterization, it is estimated that the risk of bacteriuria increases by 5 to 10% per day. The
majority of cases of bacteriuria are asymptomatic, and the most effective management is
removal of the catheter rather than antibiotic treatment. In rare cases, local and systemic
complications ensue, and antibiotic treatment should be initiated for asymptomatic
bacteriuria in patients who are about to undergo urologic surgery or implantation of a
prosthesis.(Tenke) Such therapy should also be considered in immunocompromised patients.
Bloodstream infection appears to be a well-defined but rare complication of catheter-
associated urinary tract infection.(Tambyah)
Recent U.S. data indicate that E. coli is the most common etiologic gram-negative organism,
followed in descending order of frequency by P. aeruginosa, Klebsiella species, Enterobacter
species, and A. baumannii. (Hildron). The emergence of resistance to quinolones and
extended-spectrum cephalosporins remains a considerable challenge, since these agents are
often used as first-line therapy. Traditionally, the SHV-type and TEM-type ESBLs have
predominated among hospital-acquired organisms, and this is still the case in the United
States. The epidemiology of ESBLs is changing, however, and CTX-M–type ESBLs are
becoming more common worldwide. In particular, CTX-M-15 is the most widespread, and
this β-lactamase has frequently been associated with a uropathogenic E. coli clone known as
sequence type 131.(Nicolas-Chanoine) Unfortunately, the plasmids carrying these ESBL genes
often carry resistance determinants targeting fluoroquinolones as well. To reduce the
morbidity associated with hospital-acquired urinary tract infections and prevent the
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dissemination of drug-resistant gram-negative organisms, adherence to evidence-based
prevention guidelines is strongly recommended.

Meropenem
Meropenem is a β-lactam, carbapenem antibacterial agent that has antimicrobial activity
against gram-negative, gram-positive and anaerobic micro-organisms. Meropenem is well
tolerated as either a bolus or an infusion, and clinical trials have shown similar incidences of
adverse events to those observed with cephalosporin-based treatments. It is well tolerated
by the central nervous system, with seizures reported infrequently, and can therefore be
used at high doses and in patients with meningitis. Meropenem has an important role in the
empirical treatment of serious infections in adults and children in ICUs.
Meropenem license has recently expired, with an immediate impact of costs of the drug.
This could cause an increasing in usage, but meropenem is a well established strong weapon
against severe infections caused by gram negative bacteria that need to be reserved for most
aggressive and resistant pathogens. Therefore, developing strategies able to maintain
efficacy of the drug are very useful.
Multi drug resistant Gram Negative organism
In the last several years, a progressive increase in resistance among Gram-negative
pathogens has continued unabated. The emergence of multi-drug resistant Gram-negative
organisms (MDRs) coupled with an alarming scarcity of new antibiotic classes in the pipelines
of the pharmaceutical industry has forced the healthcare community to optimize the
therapeutic potential of currently available antibiotics (Rice).

Β-lactam administration
The primary determinant of β-lactam efficacy is the duration of time in which the non-
protein bound drug concentration (fT) exceeds the minimum inhibitory concentration (MIC)
of the organism (fT>MIC) (4).
β-lactam antibiotics have traditionally been administered by intermittent infusion. With
intermittent dosing, β-lactams attain a high peak concentration, but short half-lives can lead
to precipitous drops in serum drug levels. Pharmacokinetic studies have shown that
prolonging the infusion time provides more consistent serum levels and maximizes fT>MIC
(4, 5, 6 ).
It is unclear, however, if this translates into improved patient outcomes because the
interpretation of these studies remains controversial as most trials were conducted with
small numbers of patients.
A systematic review and meta-analysis of randomized controlled trials (RCTs) investigating
the efficacy of prolonged infusion β-lactam therapy compared with intermittent infusion β-
lactam therapy with regards to mortality, clinical cure, and adverse effects has been recently
performed, with the primary objective to determine whether prolonged infusion of β-lactam
antibiotics resulted in improved patient survival and clinical cure compared to intermittent
dosing of β-lactam antibiotics. (5).
After carefull selection, 14 study were included in the meta-analysis.
(http://www.biomedcentral.com/1471-2334/11/181/table/T1)
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Eight studies reported mortality as an outcome. Among the 487 patients enrolled in the
prolonged infusion β-lactam arm, there were 53 deaths, compared to 56 deaths among the
495 patients in the intermittent infusion arm. These differences were not statistically
significant with an RR of 0.92 (95% CI 0.61 - 1.37). The overall I2 statistic was 9% suggesting
relatively low heterogeneity between the studies. Similarly, the Chi-square statistic was 7.66,
p = 0.36. All studies except one crossed the null value. Mortality ranged from 2% in a trial
consisting of a relatively young population with low severity of illness to 57% in a severely ill
population infected with a highly pathogenic organism, Burkholderia pseudomallei. Only one
study demonstrated a mortality advantage to prolonged infusion β-lactams ( 6 ). This was the
only study in which all included subjects were in critical condition and had bacterial cultures
confirming infection with a resistant Gram-negative organism.
This meta-analysis concludes that prolonged infusion β-lactam antibiotics may have value in
a specific subsets of patients, such as those with highly-resistant Gram-negative infections
because of exploitation of their property of fT>MIC. Unfortunately, the very limited number
of patients in the included RCTs with MDRGNs precluded evaluation of this subgroup in the
present meta-analysis. Methodologically rigorous studies analyzing prolonged infusion β-
lactams for critically ill patients with MDRGN infections are necessary to substantiate this
potential benefit.

Therapy efficacy and Resistance Emergence

Another important issue is that exposing patients to a certain degree of variation of
antibiotics concentration, can cause resistance emergence and therefore, treatment
inefficacy (4).
When large populations of organisms exist at the primary infection site, as is often the case
in patients with nosocomial pneumonia, for example, the size of the population often
exceeds the inverse of the mutational frequency to resistance. This means that the total
population consists of a large population of wild-type organisms combined with a smaller
population of mutant organisms, the MIC of which is increased relative to the wild-type
parent strain. The presence of this smaller, more resistant bacterial population has important
implications for chemotherapy. When a fixed dose of drug is administered, the resultant drug
exposure will frequently have a differential effect on the two populations. The wild-type
population will often be readily killed by the drug exposure. The mutant population, even
when the MIC is only slightly increased (for example, 2–4-fold), is often not killed by the drug
exposure, allowing this population to amplify over time. With time, the total population
decreases the number of wild-type clones and increases the mutant clones, thereby
increasing the level of resistant isolates in the population. The wild-type (sensitive)
population is efficiently killed, whereas the mutant (resistant) population is often amplified.
The change in profile of the total population is explained by the differential effects of the
drug exposure on the two populations.
The probability of developing MDR pathogens and, moreover, clinical failure, could be
related to species of pathogen and initial MIC.
Krueger et al. (7) demonstrates that K. pneumoniae and E. cloacae both have MIC
distributions in which over 90% of the isolates examined have meropenem MICs less than
0.25 mg/liter. P. aeruginosa, on the other hand, is a much more challenging pathogen for this
(or any other) agent, and less than 30% of the isolates have meropenem MICs under 0.25
mg/liter. In their work, the target attainment rates for the continuous-infusion mode of
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administration demonstrate more than 99% probability of target attainment for both high
(3g/day) and low (1.5 g/day) doses of meropenem for both Klebsiella and Enterobacter
species. For P. aeruginosa, the probability of target attainment is still quite good at 83% for
the high dose and 76% for the low dose. For this mode of administration, the probability of
target attainment falls precipitously from over 99% to about 50% and then to almost 0%.
The MIC with circa 50% probability of target attainment represents most clearly the impact
of between patient variability in drug clearance, as at a twofold higher MIC, approximately
half the patients will have a drug clearance that drops their steady-state drug concentration
to below (if only barely) the MIC.
Intermittent administration as a short infusion demonstrates that the probability of target
attainment declines more slowly, but the probability of target attainment for maximal
bacterial cell killing decreased below 90% earlier, at 0.5 mg/liter for the 3-g/day group and at
0.25 mg/liter for the low-dose (1.5-g/day) group.
Given the expected organism distributions, it is demonstrated that the continuous-infusion
mode of administration has advantages over the intermittent mode of administration. Every
contrast by dose and organism shows that the continuous-infusion mode is superior.
However, determination of where the superiority is most important is also important. For K.
pneumoniae and E. cloacae, even the low-dose intermittent administration group had
probabilities of target attainment that exceeded 93%.
While the continuous-infusion groups had target attainments that were higher, it should be
recognized that continuous (or even prolonged) infusions are not without a price. The need
to use a line continuously means that drug incompatibilities may surface, necessitating the
placement of a separate line, with all the implications for infection attendant to the
placement of an intravenous access.
It is in P. aeruginosa where the advantage of continuous infusion is most clearly made
manifest. Here, the probabilities of target attainment are 83% and 76% for the high- and low-
dose continuous-infusion regimens, respectively; but they are 64% and 52% for the high- and
low-dose intermittent administration regimens, respectively.
In the empirical therapy situation, the infective pathogen is, by definition, unknown.
Therefore, when starting a new antibiotics, continuous infusion could offer the advantage to
be more confident of obtaining a more effective bacterial killing and a less probable
emergence of new resistant pathogens.

The importance for the regulatory activity of the Italian medicines agency (AIFA) and the
clinical relevance for the Italian national health service (SSN)
International and local surveillance networks as well as numerous reports in the biomedical
literature provide evidence that the prevalence of antibiotic resistant Gram-negative bacteria
is escalating in many European countries. Among 33 European countries participating in the
European Antimicrobial Resistance Surveillance System (EARSS) in 2007, six countries
reported carbapenem resistance rates of more than 25% among P. aeruginosa isolates, the
highest rate reported from Greece (51%).
Among Italy the situation is also very severe.
The MYSTIC (Meropenem Yearly Susceptibility Test Information Collection) program reported
the antimicrobial susceptibility of 490 A. baumannii strains collected in 37 centres in 11
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European countries from 1997 to 2000. Against A. baumannii, imipenem and meropenem
were the most active agents with resistance rates of 16% and 18% respectively (Table 1) but
ampicillin/sulbactam and colistin were not tested. There was important geographic variability
in resistance rates in different countries. Among 11 participating countries (Belgium, Bulgaria,
The Czech Republic, Germany, Italy, Poland, Russia, Sweden, Switzerland, Turkey and the
United Kingdom), Turkey showed the highest resistance rates for almost all of the tested
antimicrobials, followed by Italy and the UK (8).
More recent data (2004 – 2008) shown a general increase in resistance rates, with Italy at 4th
places after Greece, Turkey and Spain. (9)
Similar condition can be documented for P. Aeruginosa.
According to the most 2007 data of EARSS database [http://www.rivm.nl/earss/database/],
in Enterobacteriaceae family, K. pneumoniae is the species with the highest rates of
carbapenem resistance. In Italy, carbapenems resistance of K. Pneumoniae was reported to
be 2.7% in 2007.
More recently, different outbreaks of aggressive, resistant gram negatives have been
reported. The table 1 in annexes summarize publication about Italian outbreaks of MDR
gram negatives after 2007. As shown, many outbreaks involves bacteria with a high degree of
resistance, most of them with extensive drug or pan drug resistance.
Therefore, strategies to enforce carbapenem efficacy should be addressed, especially in
Mediterranean-see area, as Italy, where gram negative resistance to antibiotics looks to be
more alarming.

Major outbreaks of gram negatives reported in Italy after 2007.

Author Pathogens Number Study time Place Main resistance to
of antibiotics
isolates
Carretto et Acinetobacter 277 1 february - 17 mixed Not available
al. baumannii 31 July hospital
2007
Cristina ML Acinetobacter 22 August Galliera Resistant to AGS, FQL,
et al. baumannii 2009 - Hospital, 3CFS CPN, pip/tazo,
February Genoa. Tmp/Smx. Susceptible to
2010 colistin and tigecycline.
Ansaldi F. Acinetobacter 53 January San Resistant to Amp/sulbactam,
et al. Baumanii 2007 - May Martino Pip/tazo, 3CFS, FQL.
2010 Hospital, Susceptible to colistin.
Genoa.
Gaibani P. Klebsiella 52 March 2010 St.Orsola- Resistant CPN, 3-4CFS,
et al. Pneumoniae – Malpighi Pip/tazo, FQL, Tmp/Smx
September University Susceptible to gentamicin,
2010 Hospital, tigecycline and colistin was
Bologna. retained in 47 of these KPC.

Mammina Klebsiella 13 April 2009 Civico and Resistant to CPN, AGS,

C.et al Pneumoniae – Benfratelli Amoxi/clavulate, 3CFS,
September Hospital FQL, Pip/Tazo, Tmp-Smx
2009 Palermo. Susceptible to gentamicin

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 and colistin; full or
intermediate susceptibility to
tigecycline.

Mezzatesta Acinetobacter 82 Two 22 Italian Resistant to Pip/tazo, 3CFS,

et al. Baumanii different hospitals FQL, AGS.
surveillance from 14
periods different
(2004–2005 cities
and 2008–
2009)

Mammina Acinetobacter 45 3-month ICU of All isolates were resistant to

C. et al Baumanii period in three at least three classes of
2010 different antibiotics, but susceptible to
hospitals in colistin and tygecycline.
Palermo. Forty isolates were non-
susceptible to CPN.

Abbreviation. AGS: Aminoglycoside; 3-4 CFS: 3rd or 4th generation cephalosporins; CPN:
carbapenem, FQL: fluoroquinolones, Pip/Tazo: piperacillina/tazobactam; AMP/Sulbactam:
Ampicillin sulbactam; Amoxi/clavulate: Amoxicillin clavulanate; Tmp/Smx:
Trimetoprim/Sulfametazol; KPC: Klebsiella pneumoniae carbapenemase.

B.3. OBJECTIVES OF THE STUDY

Primary outcome is a composite outcome of reducing death and emergence of extensive or
pan drug resistant pathogens in the study population. Secondary endpoints are reducing
long-term mortality, days under mechanical ventilation, intensive care unit length of stay,
fastening reduction of severity of disease. Statistical hypothesis is that experimental
treatment is superior to standard treatment.
In brief: what is already known on this subject

Gram-negative bacteria account for about 70% of hospital acquired infections and these
organisms are highly efficient at develop antibiotic drug resistance. Meropenem is a β-
lactam, carbapenem antibacterial agent that has antimicrobial activity against gram-negative
pathogens.
The primary determinant of a β-lactam efficacy is the duration of time in which the non-
protein bound drug concentration (fT) exceeds the minimum inhibitory concentration (MIC)
of the organism (fT>MIC). Many pharmacokinetic studies have shown that prolonging the
infusion time provides more consistent serum levels and maximizes fT>MIC. It is unclear,
however, if this translates to improved patient outcomes because the interpretation of these
studies remains controversial as most trials were conducted with small numbers of patients.
A recent meta-analysis concludes that prolonged infusion β-lactam antibiotics may have
value in a specific subsets of patients, such as those with highly-resistant Gram-negative
infections or a higher burden of disease, but failed to demonstrate an advantage on clinically
important outcomes. Large, randomized RCT are therefore needed.
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What this study adds
Our study could suggest if a continuous administration of meropenem add any advantages
against bolus administration regarding mortality and emergence of new multidrug resistant
pathogens.

B.4.a. METHODS
Study design
Randomized, controlled, double-blinded, multicentric study.

Study population
Inclusion criteria
Will be enrolled patients that:
1. Are at least 18 years old
2. Need a new antibiotic treatment, by clinical judgment, with meropenem
3. Are admitted to ICU
4. Have Sepsis or septic shock
1. Sepsis
1. SIRS (Systemic Inflammatory Response Syndrome) plus;
2. suspected or documented infection plus;
3. a SOFA score ≥ 2
2. Septic shock
1.Sepsis plus
2.persisting hypotension requiring vasopressors to maintain MAP ≥65mmHg
and having a serum lactate level >2 mmol/L (18mg/dL) despite adequate
volume resuscitation.
5. Are able to express informed consent or by him/her next of kin or as requested by Ethical
Committee.

Rationale for Inclusion Criteria

#1 Pediatric septic population can't be studied in a mixed population, due to excessive
difference in expected outcome, vital signs variation, reference value of laboratory samples.
Also drug dosing should be more accurately addressed.
#2 Meropenem way of administration in object of the study, therefore clinical decision of
necessity of study drug is not object of the study and fundamental criteria for enrollment.

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#3-4 These criteria select more severely ill patients. It is expected that this special kind of
patients can benefit more of study intervention than general infected population.

Exclusion criteria
Will be excluded patients that:
1. Are able to express informed consent and denying it
2. Are already receiving study drug or other carbapenem both as a bolus or continuous
infusion
3. Have a known allergy or intolerance to study drug, to other carbapenem antibacterial
agents or severe allergic reaction to β-lactam antibacterial agents or to anhydrous sodium
carbonate (study drug excipient)
4. Have a little chance of survival, as defined by a SAPS II score more than 65 point
5. Have concomitant acquired immunodeficiency syndrome (stage 3 according to CDC)
6. Have received immunosuppressant or long-term corticosteroid therapy (more than 0.5
mg/kg/day for over 30 days)

Rationale for exclusion criteria

# 1, 3: Rationale is self-evident.
# 2: Already receiving study drug in any way of administration can impair subsequent
analysis, because it can have already caused a significative amount of time f time in which
the non-protein bound drug concentration (fT) is less the minimum inhibitory concentration
(MIC) of the organism (fT<MIC).
# 4-5: In this subset of patients, the relative effect of way of administration of study drugs is
likely very little in front of the severity of disease. Excluding these patients could help to
identify severe ill but not moribund patients that can get beneficial effect from treatment
object of study.
# 6: This subset of patients have other than way of administration of the study drug known
reason to develop sovrainfection or MDR infection. They have also different outcome
regarding mortality and ICU stay than general population.

Intervention / exposure
Initiation of the study
Every patient, independently of renal function, will receive 1 g bolus of meropenem
immediately after clinician decision to use carbapenem to immediately achieve, with the
greatest probability, a bactericide concentration of study drug.
Immediately before, if not already performed in the preceding 48 hours, blood, respiratory
and urine culture will be performed. When possible, respiratory culture will be a distal,
protected sample (broncoalveolar lavage or similar). Blood culture will be performed with 3
samples (each sample doubled, for aerobic and anaerobic pathogens) with at least one not
drawn from an indwelling catheter.
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This will be done prior to informed consent expression and randomization. It is well known
that every hour without proper antibiotic treatment could increase patient mortality and this
immediate administration will minimize the risk that the study can slow down first dose of
antibiotic administration.
Retrieval of informed consent (if requested by Ethical Committee) and randomization will be
done simultaneously or immediately after (less than 1 hour) after start of bolus
administration

Bolus group
Patient randomized to bolus group, will receive a bolus infusion of meropenem according to
their renal function (creatinine clearance -ClCr- estimated by Cockcroft-Gault formula):
1. for Cl-Cr > 50 ml/min 1 g every 6 hours on first 24 hours, every 8 hours after
2. for Cl-Cr < 50 ml/min 1 g every 8 hours on first 24 hours, every 12 hours after

Continuous infusion group

Patient randomized to continuous infusion group, will receive a continuous infusion of
meropenem according to their renal function and study day
1. for ClCrea > 50 ml/min: 3 g / day
2. for ClCrea < 50 ml/min: 2 g / day

Rationale for dosage scheme

With this schedule, patient randomized in any arms, will receive the same total study
drug/day in first and subsequent day.

Special circumstances
In special circumstances, by physician judgment, total amount of study drug can be doubled
(example: evidence of high MIC at culture results or meningitis). In this circumstances the
dosage will be doubled exactly in both groups. Doubling will not affect drug final
concentration but just speed of infusion, to not alter stability of diluted solution of study
drug.

Stopping of study drugs

Stopping of study drugs will be primarily by physician judgment.
As a general rule, the following rules will be applied. Causes for divergences from following
rules will be registered and object of result analysis.

For patient with microbiologically confirmed diagnosis, the following rules can be apply:
• for P. Aeruginosa, consider at least 15 day of antibiotics

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• for any pathogens with 1 <= MIC <=2, consider at least 15 days of antibiotics
• for other pathogen with mic < 1 consider to stop treatment after 8-10 days of treatment

For patient without microbiologically confirmed diagnosis, the following rules can be apply:
• consider at least 8 days of treatment
• consider to stop antibiotics after:
48-72 hours with core temperature less than 38,4°C
neutrophile leukocitosys resolved
for pneumonia, inspired FiO2 < 40%

Study drug administration

For continuous administration of study drug some important issue of drug stability after
reconstitution should be addressed. IMP - Meropenem must not be mixed with other
medicinal products except those mentioned in section 6.6. of reference SmPCTo comply with
the European Pharmacopoeia, b-lactam solutions should always contain at least 90% of
intact molecule. Viaene (10) showed that carbapenems are quite unstable in concentrated
(6.4 g/100 mL) aqueous solutions (>10% degradation in <5-6 h at 25°C).

Berthoin (11) recently shown that meropenem solution degradation is affected both by
temperature and concentration and that solution kept at 25°C with concentration less than
4% (40 mg/ml) are stable (less than 10% degradation) for 6-12 hours.

However, we acknowledge that different commercial preparations may have different

stability and different stability in use.
In each center we will use the stability in use according to relevant sections of the
“Summary of product characteristic (SmPC) (Italian: “RCP: Riassunto caratteristiche del
prodotto” ). When cooling is described by the producer, in the SmPC, as a way to extend the
stability in use of the drug, this technique can be used.

Study drug will be prepared as follows for the continuous infusion group:
1. for ClCrea > 50 ml/min: 3 g/day
1. 500 mg of meropenem in 50 ml (10 mg/ml) of NaCl 0.9% at 12,5 ml/h. This solution will
be replaced every time its duration exceeds the stability in use stated by the producer in the
relevant sections of the SmPC.

2. for ClCrea < 50 ml/min: 2 g/day

1. 500 mg of meropenem in 50 ml (10 mg/ml) of NaCl 0.9% at 8,3 ml/h. This solution will be
replaced every time its duration exceeds the stability in use stated by the producer in the
relevant sections of the SmPC.

According to currently available SmPC and to the chosen dilution of the study drug (10
mg/ml solution in NaCl 0.9%) only two commercial available meropenem will be used:
1. Merrem (or Meronem) by Astrazeneca:
2. Meropenem by Aurobindo:
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Primary and secondary outcomes
Primary outcome
The primary outcome measures is a composite outcome:
1. death from any cause at day 28
2. emergence of new XDR or PDR bacteria at day 28

Secondary outcomes
1. Death from any cause at day 90
2. Antibiotic-free days all of which were assessed 28 days after randomization
Proportion of day from randomization to day 28 or death in which subject didn't receive any
antibiotics (excluding anti-fungal anti-viral drugs)
3. ICU – free day (ICU-fd) at day 28
Number of day in from randomization to day 28 (or death) in which the subject is outside the
ICU. For any discharge lasting less than 48h, no ICU-fd will be computed. Re-admission lasting
less than 24 hours will no reduce ICU-fd. Patients that will not survive outside ICU for at least
48 hours, will have a ICU-fd of zero.
4. Cumulative SOFA-free point from randomization to day 28
SOFA score will be evaluated every day up to day 28. SOFA-free daily score is 24 (maximum
SOFA) minus actual SOFA. Cumulative SOFA-free is the sum of SOFA-free daily from
randomization to date 28. Patients dead before day 28 can't ameliorate their SOFA-free
score. In this way, higher the cumulative SOFA-free is, higher is the amelioration of the
patient and his probability of survival.

Rationale for outcomes

Mortality is a patient - centred clearly important outcome.
Emergence of new MDR- XDR or PDR pathogens is important to patients (that will not have
to fight against a new and probably more aggressive pathogens), to other patients (reducing
possibility of outbreaks of antibiotics resistant pathogens), to national health system
(reducing cost for third of fourth line treatments).
Mid – term morality (90 days) is again a patient clearly important outcome. Antibiotics- ICU-
free days are important outcomes for health care systems because both increase costs and
reduces resources for other patients. SOFA – free days outcome is a clinician important
outcome because it can help to identify better ameliorating and worsening patients to
correctly adress resources.

Randomization
Subjects will be allocated according to a web based centralized randomization derived from a
computer-generated list of random number that will be available only shortly before
meropenem administration. Data will be collected by trained observers who will not
participate in patient care and will be blinded to the administration scheme. The
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randomization, performed at the last available moment, will reduce most biases together
with the double blindness of the study. All study personnel, including those involved in the
ICU management will be blinded to treatment assignment for the duration of the study.

Blinding (masking)
Each patient will receive both continuous infusion and bolus. According to randomization
arms, one of administration will be placebo and the other study drug (“double dummy”
procedure).

Information retrieval
Day of the study
Day 0 is the day of first administration of study drug.
Day 1 begin at 8.00 AM of day after first bolus of study drug and last 24 hours. Similarly for
successive study days.

Peri-randomization data and sample (day 0)

Following information will be recorded in day 0 preferably before first administration of study
drugs, however, little modification could be expected if the same sample will be drowned at
a maximum of 2 hours after first study drug administration, therefore also sampling after first
study drug administration will be considered acceptable. When available more than one
measurement, the nearest to first bolus administration (in a 2 hours pre-and-after window)
with preference to pre-bolus values, will be considered. For SAPS II score, the worse value in
24 hours preceding first bolus administration will be recorded, or, if unavailable, the peri-
bolus samples will be considered.
• Pregnancy test (blood or urine) for women in fertile – years and without a previously
recorded data.
• Demographic and administrative data
• Height and weight (measured or estimated)
• Ventilatory status (ventilated or not, invasive ventilation or not) and ventilatory settings
(mode, inspired fraction of oxygen -FiO2-, positive end-expiratory pressure (peep),
plateau or maximum inspiratory pressure -Pmax-, mean airway pressure -MAP-
respiratory rate -RR-, dynamic complication -Cdyn-, tidal volume – TV-)
• Story of previously administered antibiotics in the 3 months before (time, way of
administration, dosage)
• Vital signs (heart rate – HR, arterial blood pressure: systolic, diastolic and mean -SBP, DBP,
MBP- core temperature -°C-, central venous pressure -CVP- when available)
• Arterial blood gas sample and, when available, central venous or mixed venous blood gas
sample
• Serum electrolytes, dosage of serum albumin and total protein

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• Complete blood count, clotting tests (PT, aPTT), liver (bilirubin, AST, ALT) and kidney
(creatinine) profile, lactates
• Urine output 24 hours and diuretic administration (drug and quantity)
• C-reactive protein (CPR) and, where available, procalcitonin (PCT )
• Glasgow coma scale evaluation
• Source of infection (documented or presumed) according to specific criteria
• ALI/ARDS presence and severity (according to Murray's score)
• Inotropic / vasopressors drugs presence (according to Inotropic score)
• Evaluation after study drug bolus and randomization

The following evaluation will be performed daily, form study day 1 up to study day 8
• Ventilatory status (ventilated or not, invasive ventilation or not) and ventilatory settings
(mode, inspired fraction of oxygen -FiO2-, positive end-expiratory pressure (peep),
plateau or maximum inspiratory pressure -Pmax-, mean airway pressure -MAP-
respiratory rate -RR-, dynamic complication-Cdyn-, tidal volume – TV-)
• Vital signs (heart rate – HR, arterial blood pressure: systolic, diastolic and mean -SBP, DBP,
MBP- core temperature -°C-, central venous pressure -CVP- when available)
• Arterial blood gas sample and, when available central venous or mixed venous blood gas
sample
• Serum electrolytes, dosage of serum albumin and total protein
• Complete blood count, clotting tests (PT, aPTT), liver (bilirubin, AST, ALT) and kidney
(creatinine) profile, lactate
• Urine output 24 hours and diuretic administration (drug and quantity)
• C-reactive protein (CPR) and, where available, procalcitonin (PCT ))
• Glasgow coma scale evaluation
• ALI/ARDS presence and severity (according to Murray's score)
• Inotropic / vasopressors drugs presence (according to Inotropic score)

Microbiological sample (blood, respiratory sample and urine) will be collected:

• In every patient after 48 hours at study day 3, 8 and 28
• Every time physician judges to be necessary or patient develops at least one of the
following in absence of microbiological sample in the 48 hours before:
- a core temperature higher than 38.3°C for at least 1 hour
- a new worsening of vasopressor / inotropic drugs requirement evaluated by inotropic score
more than 30% of the day before
- a new worsening of ventilatory requirement, evaluated by a worsening of Murray score
more than 30% of the day before
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- a new worsening of CRP or PCT, increased of 1.5 of the day before

Sample size estimation

Sample size estimation is largely based on two sets of published data. The first is the
mortality of septic shock patients, as reported by European Medicines Agency with the end
of the Prowess-Shock Study, notably the largest and more recent trial on severe sepsis,
published at 25th Oct 2011 (EMA/856472/2011 ), that estimates a 28 days mortality rate of
about 25%. The second source is a very recent paper published by Kim in 2012 in the setting
of hospital acquired pneumonia patients randomized to different antibiotics treatment.
Overall 28 days mortality in this paper is 32.7%, little higher in patient randomized to
carbapenem treatment (39.6%). On this specific arm, the rate of emergence of a new MDR
pathogens was 37.9%. To our best knowledge, this is the most recent, reliable and accurate
estimation of MDR rates and mortality. The higher mortality rate in Kim's work is explained
by different case mix against Prowess-Shock that has included sepsis with different primary
infection sites.
Overall, 52% of the subjects will reach primary endpoint of the proposed study. These data
are confirmed also by American Thoracic Society guidelines (13,14), that report an overall
mortality of 30-50% and a MDR rate up to 50%.
From these data, we expect a primary outcome reduction from 52 to 40% in the continuous
infusion group. Applying a 80% power and a 5% alpha errors, with continuity correction and
a two-tails test, a total of 287 subjects for group will be necessary, rounded to 300 for
possible protocol deviations, with a total of 600 patients included in the study.

Statistical analysis
Primary data analysis will be based on intention to treat (ITT) analysis.
Data will be analyzed also on a modified ITT approach (mITT). Will be included in this analysis
only patient with evidence of a MDR bacteria on culture performed immediately before first
study drug dose or in the 48 hours before.
Sub Groups analysis
Some pre-defined sub groups analysis will be performed
1. Patients with identified pathogens with a high MIC to carbapenems
2. Patients with identified pathogens, known to develop carbapenem resistance more easily
3. Patient with established renal failure (I of Rifle) at day 0
4. Patients with more severe disease presentation at day 0. They will be identified by a
higher SOFA and SAPS II score or by being on inotropic / vasopressors drugs.

Interim analysis
Interim analyses will consider the defined study endpoints, after enrolment of 150, 300 and
450 patients, adjusted according to the O'Brien and Fleming method.

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N pts % P value
150 25 0,000015
300 50 0,00301
450 75 0,019
600 100 0,05

Organizational characteristics

The coordinating center.

Scientific Institute San Raffaele is based in Milan and is the largest biomedical science park in
Italy. It coordinates and carries out research into clinical and molecular medicine with
dramatic impact on the National Health Service: new therapeutic approaches have been
adopted for the treatment of hard-to-cure pathologies and procedures have become more
efficient, faster, less-invasive as well as cheaper for the diagnosis and the treatment of more
traditional diseases. The clinical scientific structure of the Institute consists of: 24 medical
units, 16 special services for diagnosis and medical care, 32 general and specialistic
ambulatory services, 28 clinical research units, 46 basic research units and 5 support
laboratories. The Hospital staff includes 1062 graduated employee, 1742 nurses and health
technicians, 686 administrative staff. The clinical activities include 1068 beds, 44.042
ordinary admissions, 13.978 day hospital admissions. At present, the Institute collaborates, in
various way, with more than 120 public and private Research Bodies and Institutes all over
the world.

With 27 publications in 2010, 34 in 2011, 36 in 2012 and over 20 in the first months of 2013,
the Department of Anesthesia and Intensive Care of San Raffaele is the most prolific group in
the field of anesthesia and intensive care in Italy and the most prolific in the world in the
field of cardiac anesthesia and intensive care. This is an assurance for the donor that the
project will be finalized in due time and published in an international peer reviewed Journal
within a short time.

The other centers.

All the ICUs of the other centers have already the organizational structure, knowledge,
experience and equipment to perform such a study and have a long lasting experience in
performing rigorous, high quality studies. They all have already secretariat and statistical
personnel. Nevertheless, this personnel will be insufficient to manage the present study and
will need to be temporarily increased. All these centers have the structure and equipment to
conduct the research. It should be underlined that the study has a very simple design and
that the administration of the antibiotic in a double dummy double blind way will be the only
non-routinely part of the management of the enrolled patients (on top of the best available
treatment for every patient). All the patients included in the study will be strictly assisted by
qualified personnel evaluating all the possible clinical variations. All of them will be routinely
and invasively monitored. Invasive monitoring, blood chemistry and other technology are
routinely available in the centers involved in the RCT. Even if the design of the study is simple,
there is need for study personnel, especially in the data collection and data entry. The
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centers have been collaborating for many years at academic, research and clinical levels.
Researchers are already familiar each others. However, the present study will require initial
and periodical meetings.

The randomization will be computer generated and web based and will be organized by a
specialized society. A dedicated blinded team will perform the randomization through the
web randomization site, will prepare and administer the study drug in a double-blind fashion.
Trained, blinded and skilled independent data manager will collect and analyze study data.

Feasibility
The principal investigator is Full Professor in Anesthesiology and Intensive Care and Head of
Department of Anesthesia and Intensive Care. He’s author of more than 200 papers
published in indexed international journals (Hindex 26; H index 5 years 16) including
randomized trials in Circulation and British Medical Journal. He was principal investigator in
27 randomized controlled trials. He is Vice-Chairman of the National Research Committee
(CNR), Member of the Bioethics Committee of the Ministry of Health and Chairman of the II
Committee of the Supreme Public Health Council. He has extensive GCP training and already
won 8 research grants in the field of critical care, advanced heart support and anesthesiology
fields.
The Scientific Institute San Raffaele is the largest biomedical science park in Italy. It
coordinates and carries out research into clinical and molecular medicine with dramatic
impact on the National Health Service.
All the hospitals have the technology needed to conduct this study.
There is no need for centralized laboratories for this study.

Timing
Overall study duration will be of 2 years.
Patients included in the present study will receive treatment for at least 15 days.
Study follow up will be conducted at 28 days at 90 days after randomization.
Evaluation of the work in progress will be provided every month after randomization of the
first patient.
An independent safety board composed by epidemiologists and clinical scientists will
conduct the ad-interim analyses at 25%, 50% and 75% of enrolled patients.
Good clinical practices
The Investigators will conduct the study according to the procedures specified in the study
protocol, and in accordance with ICH GCP notes for Guidance on Good Clinical Practice
(CPMP/ICH/135/95) Annotated with TGA comments and NH&MRC National Statement on
Ethical Conduct in Research Involving Humans.
The monitoring of the study will be performed according to international standards and GCP
by an independent CRO.
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It is recognized that patients with sepsis or septic shock and admitted in the ICU will
experience a number of aberrations in laboratory values, signs and symptoms due to the
severity of the undergoing disease and the impact of standard critical medicine therapies. For
example, the data listed in the CRF are “expected” to occur and will be considered “disease
progression”. These will not necessarily constitute an adverse event or serious adverse event
unless they are considered to be related to study treatment or a concern in the principal
investigator’s clinical judgement.

Ethical aspects
There aren’t any major expected ethical issues.

B5. REFERENCES (max 5,000 chars or max 20/25 references)

(1) Klevens RM, Edwards JR, Richards CL Jr, et al. Estimating health care-associated infections
and deaths in U.S. hospitals, 2002. Public Health Rep. 2007, 122: 160-6.
(2) Chopra I, Schofield C, Everett M, et al. Treatment of health-care-associated infections
caused by Gram-negative bacteria: a consensus statement. Lancet Infect Dis. 2008, 8: 133-9.
(3) Peleg AY, Hooper DC. Hospital-acquired infections due to gram-negative bacteria. N Engl J
Med. 2010, 362: 1804-13.
(4) Drusano GL. Antimicrobial pharmacodynamics: critical interactions of 'bug and drug'. Nat
Rev Microbiol. 2004, 2: 289-300.
(5) Tamma PD, Putcha N, Suh YD,et al. Does prolonged β-lactam infusions improve clinical
outcomes compared to intermittent infusions? A meta-analysis and systematic review of
randomized, controlled trials. BMC Infect Dis. 2011, 11: 181.
(6) Angus BJ, Smith MD, Suputtamongkol Y, et al. Pharmacokinetic-pharmacodynamic
evaluation of ceftazidime continuous infusion vs intermittent bolus injection in septicaemic
melioidosis. Br J Clin Pharmacol. 2000, 50: 184-91
(7) Krueger WA, Bulitta J, Kinzig-Schippers M, et al. Evaluation by Monte Carlo Simulation of
the phhamacokinetics of two doses of meropenem administered intermittently or as a
continuous infusion in healty volunteers. Antimicrob Agents Chemother. 2005, 49: 1881-9.
(8) Turner PJ, Greenhalgh JM; MYSTIC Study Group (Europe). The activity of meropenem and
comparators against Acinetobacter strains isolated from European hospitals, 1997-2000. Clin
Microbiol Infect. 2003, 9: 563-7.
(9) Turner PJ. Meropenem activity against European isolates: report on the MYSTIC
(Meropenem Yearly Susceptibility Test Information Collection) 2006 results. Diagn Microbiol
Infect Dis. 2008, 60: 185-92.
(10) Viaene E, Chanteux H, Servais H et al. Comparative stability studies of antipseudomonal
b-lactams for potential administration through portable elastomeric pumps (home therapy
for cystic fibrosis patients) and motor-operated syringes (intensive care units). Antimicrob
Agents Chemother. 2002, 46: 2327–32.

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(11) Berthoin K, Le Duff CS, Marchand-Brynaert J, et al. Stability of meropenem and
doripenem solutions for administration by continuous infusion. J Antimicrob Chemother.
2010, 65: 1073-5.
(12) Kim JW, Chung J, SH Choi SH, et al. Early Use of Imipenem/cilastatin and Vancomycin
Followed by De-escalation Versus Conventional Antimicrobials Without De-escalation for
Patients with Hospital-acquired Pneumonia in a Medical ICU: a Randomized Clinical Trial.
Critical Care. 2012, 16: R28.
(13) American Thoracic Society. Infectious Diseases Society of America. Guidelines for the
management of adults with hospital-acquired, ventilator-associated, and healthcare-
associated pneumonia. Am J Respir Crit Care Med. 2005, 171: 388-416.
(14) Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of
America/American Thoracic Society consensus guidelines on the management of community-
acquired pneumonia in adults. Clin Infect Dis. 2007, 44 Suppl 2:S27-72.
(15) Carlier M, Stove V, Verstraete AG, De Waele JJ. Stability of generic brands of meropenem
reconstituted in isotonic saline. Minerva Anestesiol. 2015 Mar;81(3):283-7.

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Summary of changes
There were no changes thereafter the initial approval of the protocol by the ethical committee of the coordinating center of this trial (IRCCS San
Raffaele Scientific Institute, Milan, Italy), except adding new participating centers and changing the name of the local principal investigator in few
of these centers. 25 participating centers were added to this trial for a total of 26 including the coordinating center (full list below). All the
participating centers got approval from their own ethical committee.

Country City Site PI

Alberto Zangrillo
Italy Milano IRCCS Ospedale San Raffaele - Milano
Giovanni Landoni
Italy San Donà di Piave Azienda ULSS 4 Veneto Orientale - Ospedale di San Donà di Piave (VE) Fabio Toffoletto
Italy Cremona ASST Cremona - Presidio Ospedaliero di Cremona (POC) Daniele Cristadoro
Maria Caterina Pace
Italy Napoli Azienda Ospedaliera Universitaria - Università degli Studi della Campania "Luigi Vanvitelli"
Fausto Ferraro
Italy Potenza Azienda Ospedaliera Regionale "San Carlo" - Potenza Gianluca Paternoster
Italy Genova Ente Ospedaliero "Ospedali Galliera" - Genova Mariano Ballestra
Italy Foggia Policlinico Riuniti - Azienda Ospedaliera Universitaria di Foggia - Terapia Intensiva Antonella Cotoia
Italy Alba Azienda Sanitaria Locale CN2 - Ospedale "San Lazzaro" - Alba (CN) Andrea Della Selva
Azienda Sanitaria Universitaria Friuli Centrale - Presidio Ospedaliero Universitario "Santa
Italy Udine Luigi Vetrugno
Maria della Misericordia" - Udine
Rosetta Lobreglio
Italy Torino Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino
Giorgia Montrucchio
Italy Castel Volturno Pineta Grande Hospital - Castel Volturno (CE) Antonio De Sio
Italy Rozzano Humanitas Research Hospital - Rozzano (MI) Maurizio Cecconi
Italy Catanzaro Azienda Ospedaliera Universitaria "Mater Domini" - Catanzaro Federico Longhini
Italy Roma Policlinico Universitario Campus Bio-Medico - Roma Felice Eugenio Agrò
Italy Cagliari Azienda Ospedaliera Universitaria di Cagliari - Presidio Ospedaliero Duilio Casula Mario Musu
Italy Reggio Calabria Grande Ospedale Metropolitano "Bianchi-Melacrino-Morelli" - Reggio Calabria Eugenio Vadalà
Russia Moscow Federal Clinical & Research Center for Reanimatology and Rehabilitation Valery Likhvantsev
Italy Lecce Città di Lecce Hospital - GVM Care & Research - Lecce Giuseppe Santarpino
Russia Moscow I.M. Sechenov First Moscow State Medical Andrey Yavorovsky
Italy Merano Azienda Sanitaria dell'Alto Adige - Ospedale di Merano Simon Rauch
Francesco Corradi
Italy Pisa Azienda Ospedaliera Universitaria Pisana - Pisa
Fabio Guarracino
Kazakhstan Astana Astana Medical University Aidos Konkayev
Croatia Dubrava University North - Croazia Nikola Bradic
Italy Firenze Azienda Ospedaliero Universitaria Careggi - Firenze Fulvio Pinelli
Italy Campobasso ASREM - Ospedale "A. Cardarelli" di Campobasso (HUB) Torrente Sergio
Italy Padova Azienda Ospedale - Università Padova - Ospedale "Sant'Antonio" - Padova Sabrina Boraso