Impact of Totally Transdermal Sedation in the Weaning From Remifentanil Infusion Among Critically Ill Patients Undergoing Mechanical Ventilation: a Pilot Randomized-controlled Study (The TOES Trial)
Phase: PHASE2
Conditions: Respiratory Insufficiency, Ventilator Weaning, Analgesics, Opioid
Sponsor: Fondazione Policlinico Universitario Agostino Gemelli IRCCS

1 
 
 
 
Impact of TOtally transdErmal Sedation in the weaning from 
remifentanil infusion among critically ill patients undergoing 
mechanical ventilation: a pilot randomized-controlled Study (The 
TOES Trial) 
NCT04204967 
24/02/2020 versione n°3 
Abstract 
Rationale and Background: The choice of the sedation protocol has a massive impact on the duration of 
mechanical ventilation and the timing of extubation. Many sedation protocols are described in the literature. 
No data are available about the possibility of using TTS-fentanyl as an alternative to intravenous opioids 
during the weaning phase from mechanical ventilation and the post-extubation period until the discharge 
from ICU to the ward. Objective: We aim to assess if a TTS fentanyl-based sedation protocol can have an 
impact on the global Work of Breathing (WOB). Secondary endpoints of the study are the duration of 
mechanical ventilation, the duration of continuous infusion of opioids, the length of stay in ICU and in 
hospital. Methods: We will perform a 2-arm, single-center, prospective randomized controlled trial. The 
duration of the study will be approximately one year, for a total of 24 patients. Patients ventilated in 
pressure support ventilation (PSV) receiving continuous intravenous remifentanil for more than 5 days will 
be considered eligible. Eligible patients will be randomized in 2 groups: Group 1 will receive remifentanil; 
Group 2 will receive TTS-fentanyl and remifentanil. Patients will be selected from the population admitted 
to the adult ICU (a 20-beds unit), the post-operative ICU (a 13-beds unit), and the NeuroICU (a 10-beds 
unit). An Edi Catheter for diaphragm electrical activity monitoring will be put in place for each patient. 
Outcomes: The primary endpoint is to demonstrate that the area under the curve (AUC) of the work of 
breathing per minute in the intervention group is not higher than the control group. Secondary endpoints 
are differences respiratory rate, tidal volume, arterial blood pressure, heart rate, global duration of 
mechanical ventilation and opioids infusion, length of stay in ICU and in hospital. Statistical Analysis: 
Distribution normality will be assessed with the Kolmogorov-Smirnov test. Continuous variables will be 
reported expressed as medians (interquartile ranges). Qualitative variables will be reported as frequencies. 
Analysis on the primary efficacy criterion and other quantitative variables will be assessed with the 
Wilcoxon-Mann-Whitney test. Categorical outcomes will be compared with the chi-square test, or Fisher’s 
exact test, as appropriate. Cochran–Mantel–Haenszel statistics will be reported for all these results. Two-
way analysis of variance (ANOVA) for repeated measures with Bonferroni correction will be used to 
determine the differences in secondary endpoints. Comparisons between groups regarding these variables 
at each study time point were performed with the Student’s t-test or Mann-Whitney test, as appropriate. 
Mean difference and 95% confidence interval [CI95%] are reported for most significant results. Two-tail p 
values≤0.05 Will be considered significant.  

2 
 
 
 
 
AUTHORS 
Dott. Anselmo Caricato1 (PI) 
Dott. Daniele Natalini1 (Responsabile Scientifico) 
Dott. Domenico Luca Grieco1 
Prof. Massimo Antonelli1 
 
1Department of Anesthesiology, Intensive Care Medicine and Pain Management, Fondazione 
Policlinico Universitario A. Gemelli, Rome, Italy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

3 
 
 
Title 
Impact of totally transdermal sedation in the weaning from 
remifentanil infusion among critically ill patients undergoing 
mechanical ventilation: a pilot randomized-controlled Study 
Protocol ID 
2687 
Clinical Trials number  
NCT04204967 
Date 
24/02/2020 
Center 
Fondazione Policlinico Universitario A. Gemelli  IRCCS, Roma 
PI 
Dott. Anselmo Caricato 
Collaborators 
Dott. Daniele Natalini, Dott. Domenico Luca Grieco, Prof. 
Massimo Antonelli 
Type of financing 
internal funding for Interventional Pharmacological Studies 
Study type and phase 
Monocentric, phase II 
Study setting 
Neurosurgical intensive care (10 Beds), Adult ICU (20 Beds), 
Post-operative intensive care (13 Beds) 
Length of the study 
12 months 
Study design 
Randomized Controlled Trial. Interventional with drug 
GROUP 1 : Remifentanil continuous iv infusion 
GROUP 2:Transdermal fentanyl plus remifentanil 
Inclusion criteria 
 
Age > 18 yo 
 
On Pressure Support Ventilation 
 
Negative pregnancy test prior to inclusion in the study 
 
The informed consent form needs to be signed and dated 
by the patient or a relative/legal guardian before of any 
procedure related to the study 
 
A patient with prolonged weaning from the mechanical 
ventilator will be considered eligible  
 
Analgesia provided by continuous infusion of remifentanil 
lasting five days or more and an  intolerance to a dose 
reduction of 0.025 mcg/kg/min  

4 
 
Exclusion criteria 
 
Hypoxemic respiratory failure (P/F < 200 mmHg); 
 
Haemodynamic instability requiring high doses of 
inotropes or vasopressors; 
 
Current enrollment or plan to enroll in any interventional 
clinical study in which an investigational treatment or 
approved therapy for investigational use is administered 
within 30 days or 5 half-lives of the agent, prior to the 
baseline visit; 
 
Any condition that may contraindicate the use of 
remifentanil or transdermal fentanyl; 
 
Patient admitted for post-operative monitoring after 
elective surgery; 
 
EAdi catheter contraindicated. 
 
Hypersensitivity to the active substance or any of the 
excipients;  
 
Hepatic or renal impairment; 
 
Fever (body temperature ≥ 38 °C) or septic shock, 
hypothermia (body temperature < 35 °C) or presence 
of active surface cooling systems; 
 
Hypercapnic patients with a PaCO2 > 45 mmHg; 
 
Delirium state defined as RASS ≥ 3 and CAM-ICU 
positive; 
 
Patients with a BMI ≥ 35. 
Primary Objective 
To assess if a transdermal fentanyl-based sedation protocol is at 
least non-inferior when compared to a totally intravenous 
remifentanil infusion protocol. we will compare the global work 
of breathing (WOB) of the patients randomized to receive 
transdermal fentanyl vs. remifentanil alone. We will calculate the 
area under the curve (AUC) of the work of breathing per minute 
in the intervention group vs the control group 
Secondary Objectives 
Main secondary endpoints include differences in respiratory 
rate, tidal volume, arterial blood pressure, heart rate, global 
duration of mechanical ventilation, length of stay in ICU and in 
hospital. 
Number of Patients 
N = 24 

5 
 
 
 
 
 
 
 
 
 
 
Statistical Analysis 
Distribution normality will be assessed with the Kolmogorov- 
Smirnov test. Continuous variables will be reported expressed as
medians (interquartile ranges). Qualitative variables will be 
reported as frequencies. Analysis on the primary efficacy 
criterion (AUC of the work of breathing) and other quantitative 
variables will be assessed with the Wilcoxon-Mann-Whitney sum
of rank test. Categorical outcomes will be compared with the 
chisquare 
test, or Fisher’s exact test, as appropriate: Cochran– 
Mantel–Haenszel statistics will be reported for all these results. 
Two-way analysis of variance (ANOVA) for repeated measures 
with Bonferroni correction will be used to determine the 
differences in work of breathing per breath, inspiratory effort, 
delta EAdi, plateau pressure, P 0.1 respiratory rate, tidal volume,
arterial blood pressure, heart rate in the two groups. 
Comparisons between groups regarding these variables at each 
study timepoint were performed with the Student’s t test or 
Mann-Whitney test, as appropriate. Mean difference and 95% 
confidence interval [CI95%] are reported for most significant 
results. Two-tail p values≤0.05 Will be considered significant. 
Statistical analysis will be performed with SPSS software 
package (SPSS Inc. Released 2009. PASW Statistics for Windows, 
Version 18.0. Chicago: SPSS Inc.). 

6 
 
1. Rationale and Background 
Invasive mechanical ventilation is a lifesaving intervention among critically ill patients. However, 
prolonged ventilation is associated with increased morbidity and mortality. Optimal processes 
for weaning from ventilation have been studied for many years and have led to evidence-based 
clinical practice guidelines to facilitate early liberation from invasive mechanical ventilation. It is 
crucial to avoid prolonged MV, and weaning from the mechanical ventilator should not be 
delayed to avoid complications as VAP, weakness and atrophy of respiratory muscles, and the 
need for a tracheostomy (Jeong et al. 2015; Béduneau et al. 2017; Girard et al. 2017; Peñuelas et 
al. 2011; Perkins et al. 2018). 
The choice of the sedation protocol has certainly a massive impact on the duration of MV and the 
timing of extubation. Many different sedation protocols are described in the literature and adopted 
in every day clinical practice. A hypnotic agent, propofol or midazolam, is commonly used in 
combination with an opioid in infusion, typically remifentanil, fentanyl or sufentanil. However, 
analgesia-based sedation techniques, which focus on patient comfort rather than on patient 
sedation by catering to the analgesic needs of the patient and adding a sedative only if necessary, 
are well established in the ICU setting.  
1.1 Remifentanil 
Remifentanil is a selective μ opioid receptor agonist indicated for use during anesthesia and for the 
provision of analgesia in mechanically ventilated critically patients. Remifentanil has an onset of 1 
min and quickly achieves a steady state. Differently, from other opioids, it is metabolized by non-
specific blood and tissue esterases into a clinically inactive metabolite, resulting in an elimination 
half-life of fewer than 10 minutes and not correlated at all with the infusion duration. The unique 
pharmacological profile of remifentanil has proved particularly advantageous in ICU 
patients(Muellejans et al. 2004). Muellejans et al. randomly compared remifentanil versus 
propofol-fentanyl sedation regimen in ICU, showing that remifentanil alone allowed the adequate 
provision of optimal sedation and rapid extubation without the need for propofol in the majority 
of patients. Remifentanil was associated with less between-patient variability in the mean 
percentage of time with optimal sedation than was fentanyl. Using conventional opioids such as 
fentanyl, however, would require constant patient monitoring to avoid over-sedation caused by 
drug accumulation, resulting in delayed extubation(Muellejans et al. 2004). An RCT published by 
Akinci et al. comparing remifentanil to fentanyl infusion in postoperative children confirmed the 
advantages given by the use of remifentanil, but the authors suggested that the short elimination 
time of remifentanil may also cause some disadvantages. The elevated heart rates, blood pressures, 
and the increased sedation scores after cessation of remifentanil probably reflected the short 
elimination time of remifentanil. Moreover, a higher incidence of pain was noticed after end of the 
remifentanil infusion and probably this could beneficiate of long-acting analgesic administration 
before the cessation(Akinci et al. 2005). 23 RCTs with a total of 1905 patients were included in a 
recent systematic review and meta-analysis comparing remifentanil infusion with other opioids in 
mechanically ventilated patients. The results of this meta-analysis suggested that the use of 
remifentanil was associated with a reduction in the duration of mechanical ventilation when 
compared with other opioids, specifically with fentanyl infusion, probably related to the 
pharmacokinetics and pharmacodynamics of remifentanil, its rapid onset and offset. Remifentanil 

7 
 
was associated with reductions in time to extubation after sedation cessation and ICU length of 
stay but not reductions in hospital length of stay or costs.  
Moreover, neurologic assessment is essential for neurosurgical and neurotrauma patients, and the 
association between remifentanil and rapid and predictable awakening may be more meaningful 
in these patients(Zhu et al. 2017). Futier et al. in a retrospective study comparing remifentanil to 
sufentanil suggested that using a short-acting opiate with short context-sensitive half-life in an 
analgesia-based sedation protocol may significantly decrease the duration of mechanical 
ventilation and the ICU length of stay even though not significantly in long term sedation, while 
improving the achievement of sedation goals despite a lower requirement for adjunctive hypnotic 
agents (Futier et al. 2012). Moreover, remifentanil is demonstrated to reduce inspiratory muscle 
effort and improve ventilatory patterns in mechanically ventilated patients with tachypnoea or 
rapid shallow breathing resulting in an effective choice for patients who remain tachypnoeic 
during weaning from mechanical ventilation(Natalini et al. 2011). 
1.2 TTS-fentanyl 
Fentanyl was the first in a class of potent synthetic opioid analgesics developed in the 1960s. 
Restricted to anesthesia until the 1990s when the development of non-injectable fentanyl 
formulations was intensively pursued. Nowadays, transdermal fentanyl patches are among the 
most frequently prescribed strong opioid analgesics. As for remifentanil, fentanyl is another pure 
μ opioid receptor agonist. Fentanyl is extensively metabolized, and renal excretion accounts for 
only 10 % of the dose. Passive Transdermal Therapeutic Systems (TTS) use the matrix technique 
with the drug dissolved in an inert polymer matrix that controls drug release. Delivery results from 
the concentration gradient between fentanyl in the patch and the skin. Transdermal fentanyl 
patches constantly deliver 12.5, 25, 50, 75 or 100 mcg/h over 72 h. The amount delivered is 
proportional to the surface of the resorption area, fentanyl can be detected in plasma after 1–2 h, 
but the onset of the full analgesic effect is obtained between 12 and 24 h after patch application 
and may vary with local conditions such as skin temperature. For example, during fever, fentanyl 
plasma concentrations can increase by approximately 33 % at body temperatures of 40 C. 
Transdermally delivered fentanyl is not subject to first-pass metabolism and providing a great 
bioavailability, near 92%(Newshan 1998; Carter 2003; Lötsch et al. 2013). High doses of TTS-
fentanyl is documented to have an effect on the respiratory drive, causing respiratory depression, 
as a potential danger of any technique maintaining constant blood opioid concentrations, as 
described in an old study performed on post-operative patients comparing high doses of TTS-
fentanyl vs. placebo(Bülow et al. 1995). 
1.3 IMP-dose rationale 
Different patches delivering different doses of fentanyl are available (12,5 mcg/hr, 25 mcg/hr, 50 
mcg/hr, 75 mcg/hr, 100 mcg/hr). Because we had to choose only one, we decided a priori to adopt 
a TTS-fentanyl patch delivering 25/hr of the active principle. The reason for this choice was that it 
is more practical for us to titrate the dose. The starting dose will be 50 mcg/hr (two patches) and, 
based on the PaCO2 values, can be increased or decreased every 24 hours, adding or removing two 
(50 mcg/hr) or three patches (75 mcg/hr). According to the study protocol, the maximum 
achievable dose of fentanyl is 300 mcg/hr. Due to the completely new usage that we are proposing 
for this drug, there is a lack of information in the literature about which is the maximum dose 
administrable to patients. In the Summary of Product Characteristics of TTS-fentanyl is specified 

8 
 
that: “Some patients may require additional or alternative methods of opioid administration when 
the TTS-fentanyl dose exceeds 300 mcg/hr”. The conclusion is that we decided not to exceed 300 
mcg/hr of transdermal fentanyl. 
Moreover, more considerations need to be done: 
 We use TTS-fentanyl to wean the patient from remifentanil, a much more stronger opioid 
routinely used in Intensive Care Unit (ICU); 
 Patients in ICU are strictly monitored 24 hours a day and mechanically ventilated, so the 
risks for respiratory depression is minimum; 
 Remifentanil is traditionally infused at rates that may vary from 0.0125 to 0.25 
mcg/kg/min. Using tables available for opioid conversion, we can estimate that 300 mcg/hr 
of transdermal fentanyl corresponds to 180 mg/day of intravenous (IV) morphine and so 
1,80 mg of remifentanil. In a subject of 70 kg, 1,80 mg/day of remifentanil correspond to 
0,0178 mcg/kg/min of infusion rate, a very low dose for ICU standards (see APPENDIX 3). 
 
1.4 EAdi and monitoring of the electrical activity of the diaphragm 
Diaphragm dysfunction frequently develops in mechanically ventilated ICU patients and is 
associated with adverse clinical outcomes, including prolonged mechanical ventilation and 
mortality. Diaphragm electromyography (EMG) is a technique used to quantify breathing effort in 
ICU patients. A correlation has been reported between the electrical activity of the diaphragm 
(EAdi) and trans-diaphragmatic pressure (Pdi) or esophageal pressure (Pes). The Pmusc/EAdi 
index (PEI), also known as neuromechanical efficiency, defined as the ratio of the change in airway 
pressure (ΔPaw) to ΔEAdi during an end-expiratory occlusion (PEIoccl,paw), has been used to 
estimate the inspiratory effort breath by breath. This ratio describes how much pressure can be 
generated for each microvolt of EAdi signal, in other words, how efficient the diaphragm is in 
generating pressure for a certain amount of electrical activity (BECK et al. 2001; Bellani et al. 2013; 
Liu et al. 2010; Jansen et al. 2018). The proportionality between EAdi and the pressure developed 
by respiratory muscles (Pmusc) is well described:                 
𝑃𝑚𝑢𝑠ா஺ௗ௜ =  𝐸𝐴𝑑𝑖 •  𝑃𝐸𝐼௢௖௖௟,௣௔௪ 
Bellani and coworkers demonstrated that PEIoccl,paw is a good surrogate of the PEI measured during 
regular tidal ventilation (PEIdyn), thus allowing a clinically valuable estimate of inspiratory effort 
without the need for Pes monitoring. Moreover, Bellani showed that PEIoccl,paw is a good estimate 
of PEIdyn but slightly overestimated probably because of the more favorable condition of the 
diaphragm in the absence of flow. They deduced that PEIoccl,paw needs to be corrected by a factor of 
1.25(Bellani et al. 2013). It is, therefore, possible to obtain a continuous calculation of Pmusc based 
on EAdi and PEIoccl,paw without knowing the Pes value. From PmuscEAdi two commonly accepted 
indexes of inspiratory effort can be obtained: the maximal Pmusc of the respiratory cycle and the 
pressure-time product (PTPEAdi, the integral of PmuscEAdi during inspiration). 
 
No data are available in the literature about the possibility of using TTS-fentanyl as an alternative 

9 
 
to intravenous opioids during the weaning phase from mechanical ventilation and the post-
extubation period until the discharge from ICU to the ward. There is only a case-report 
documenting the use with success of TTS-fentanyl for a patient who developed central 
hyperventilation(Adachi et al. 2007).  
Our hypothesis is that, due to the intrinsic pharmacokinetics and pharmacodynamic 
characteristics of TTS formulation of fentanyl, it can have a role in weaning the patient from 
intravenous opioids, such as remifentanil, and mechanical ventilation, reducing the duration of MV 
itself. It can have also an impact on costs allowing the discharge to the ward of patients with an 
ongoing patch. 
2. Study Objectives and Endpoints 
2.1 Primary Objective 
We aim to assess if a TTS fentanyl-based sedation protocol is at least non-inferior when compared 
to a totally intravenous remifentanil infusion protocol. To do that, we will compare the global work 
of breathing (WOB) of the patients randomized to receive TTS-fentanyl vs. remifentanil alone. 
2.2 Primary Endpoint 
To demonstrate that the area under the curve (AUC) of the work of breathing per minute (assessed 
at 1, 6, 12, 24 hours for the first day after randomization, and every 24 hours for the following 
days) in the intervention group is not higher than the control group. We will also analyze 
differences in work of breathing per breath, inspiratory effort, delta EAdi, plateau pressure, driving 
pressure, transpulmonary driving pressure, pulmonary compliance, P0.1, P/F ratio. 
2.3 Secondary Objectives 
Secondly, we will assess if a TTS fentanyl-based sedation protocol can have an impact on the 
duration of mechanical ventilation, as well the duration of continuous infusion of opioids, the 
length of stay in ICU and hospital compared to a totally intravenous remifentanil infusion protocol. 
2.4 Secondary Endpoints 
We will analyze differences in respiratory rate, tidal volume, arterial blood pressure, heart rate, 
global duration of mechanical ventilation and intravenous remifentanil infusion, length of stay in 
ICU and in hospital. 
2.5 Safety Endpoints 
Main safety endpoints will be hypercapnia (PaCO2 >45 mmHg), acidosis (pH<7.35), hypotension 
(SBP< 90 mmHg), need for NMBA (neuromuscular blockade agents), need for vasopressors, 
episodes of ICP>20 mmHg in neurological patients, need for a tracheostomy, infections. 
 
 

10 
 
3. Methods 
3.1 Study Design 
 
The aim is to perform a 2-arm, single-center, prospective randomized controlled trial. The duration 
of the study will be approximately one year, aiming to enroll 12 patients for each arm. An informed 
consent form will be obtained before randomization. 
3.2 Study Population 
Eligible patients will be selected from the population admitted to the adult ICU (a 20-beds unit), the post-
operative ICU (a 13-beds unit), and the NeuroICU (a 10-beds unit). 
3.3 Inclusion and Exclusion Criteria 
3.3.1 Criteria for inclusion are: 
• 
Age > 18 yo; 
• 
Negative pregnancy test prior to inclusion in the study; 
• 
The informed consent form needs to be signed and dated by the patient or a relative/legal 
guardian before of any procedure related to the study; if the patient is initially unable to sign 
the informed consent form, but later regains the ability to sign it, a new informed consent form 
will be given to the patient and must be signed and dated; 
 
• 
Mechanically ventilated in Pressure Support Ventilation, according to the decision to the 
attending physician; 
 
• 
A patient with prolonged weaning from the mechanical ventilator will be considered eligible. 
Prolonged weaning is defined as weaning that is still not terminated 7 days after the first 
separation attempt from the ventilator (by success or death).                                                                                   
 
A successful weaning is defined as: 
 
1. 
For intubated patients: extubation without death or reintubation within 7 days after 
extubation (whether post-extubation noninvasive ventilation was used or not), or ICU 
discharge without invasive mechanical ventilation within 7 days, whichever comes 
first; 
2. 
For tracheostomized patients: spontaneous ventilation through tracheostomy without 
any mechanical ventilation during 7 consecutive days or ICU discharge with 
spontaneous breathing, whichever comes first (Béduneau et al. 2017); 
• 
Analgesia provided by continuous infusion of remifentanil lasting five days or more and an  
intolerance to a dose reduction of 0.025 mcg/kg/min defined as the presence of at least one 
of the following criteria: RASS ≥ 2, a respiratory rate ≥ 35 breaths/minute, a PaCO2 < 30 mmHg, 

11 
 
a heart rate > 120 bpm, a systolic blood pressure value > 160 mmHg or an increase of Visual 
Analogue Scale for pain assessment of ≥ 2 points. 
3.3.2 Criteria for exclusion are: 
• 
Hypersensitivity to the active substance or any of the excipients; 
• 
Hepatic or renal impairment;  
• 
Fever (body temperature ≥ 38 °C) or septic shock, hypothermia (body temperature < 35 °C) 
or presence of active surface cooling systems; 
• 
Hypoxemic respiratory failure (P/F < 200 mmHg); 
• 
Hypercapnic patients with a PaCO2 > 45 mmHg; 
• 
Hemodynamic instability requiring high doses of inotropes or vasopressors; 
• 
Delirium state defined as RASS ≥ 3 and CAM-ICU positive; 
• 
Any condition that may contraindicate the use of remifentanil or TTS-fentanyl; 
• 
Patient admitted for postoperative monitoring after elective surgery; 
• 
Patients with a BMI ≥ 35; 
• 
Current enrollment or plan to enroll in any interventional clinical study in which an 
investigational treatment or approved therapy for investigational use is administered within 
30 days or 5 half-lives of the agent, prior to the baseline visit;  
• 
EAdi catheter contraindicated. 
4. Study Periods, Visits and Assessments 
An overview of the study periods and “visits” is provided below.  
4.1 Screening Period 
The subject will be evaluated for eligibility for the study based on the inclusion and exclusion 
criteria. A pregnancy test for females in fertile age and an informed consent will be obtained from 
the subject or proxy, and/or a third party and signed by the investigator, prior to performing any 
assessment that is considered to be specifically mandated by the study.  
Patients considered eligible for the study will be randomized in two arms. An EAdi Catheter, which 
is a standard nasogastric tube for enteral nutrition, will be positioned and connected to a 
mechanical ventilator provided with an EAdi module (Servo-U ventilator, Maquet). EAdi, flow, and 
Paw waveforms will be acquired from the Servo-U ventilator via a RS232 serial port connected to 
a laptop with dedicated software (SERVO Tracker SCI, version 1.0, Maquet Critical Care 2017). 
Baseline data will be collected before randomization.  

12 
 
4.2 Treatment Period 
The treatment period starts immediately with the baseline assessments. 
In Group 1, in which remifentanil infusion is administered alone, the infusion rate will be increased 
or decreased according to the study protocol based on PaCO2 value resulting from the Arterial 
Blood Gases sample (ABG) collected at each visit.  
In Group 2, TTS-fentanyl will be administered with a starting dose of 50 mcg/hr simultaneously 
with the preexistent remifentanil continue infusion. Remifentanil infusion rate will be increased 
or decreased based on PaCO2 value resulting from the Arterial Blood Gases sample (ABG) collected 
at each visit. After randomization, the TTS-fentanyl dose can be modified every 24 hours according 
to the study protocol to achieve the desired effect in terms of PaCO2 value resulting from the 
Arterial Blood Gases sample (ABG) collected. 
A priori we will no exceed 0,2 mcg/kg/min for remifentanil infusion in both arms. 
4.3.1 Visits 
Visits will be performed at the baseline and every 4 hours for the first 24 hours, every 6 hours for 
day 2 and day 3. 
At each visit we will record: 
• 
An Arterial Blood Gases (ABG) sample will be collected and ABG parameters recorded (pH, 
PaCO2, PaO2, HCO3-, Lactates, SaO2); 
• 
Glasgow Coma Scale, RASS (see APPENDIX 1-2), the dosage of remifentanil and TTS-fentanyl; 
• 
Respiratory parameters: Ventilation mode, Pressure Support, Respiratory Rate (RR), Tidal 
Volume(Vt), peep, FiO2, EtCO2, SpO2; if patient is spontaneously breathing: FiO2, RR, SpO2. 
• 
Hemodynamic parameters (Heart Rate, SBP/DBP/MAP, need for vasopressors, inotropes). 
A baseline 1-hour recording of EAdi, flow, and Paw waveforms will be performed, as well as after 
1, 6, 12, 24 for the first day from the time of randomization and every 24 hours for the following 
days until the end of the observation period for the primary endpoint. Each recording will last one 
hour for patients mechanically ventilated, 10 minutes for patients weaned from the mechanical 
ventilator. 
Four different situations are possible: 
• 
For patients connected to the mechanical ventilator in pressure support ventilation (PSV), we 
will perform an expiratory pause maneuver and an inspiratory pause maneuver (both lasting 
enough to have 2 or 3 spontaneous breaths) with an interval of one minute between each 
maneuver. The maneuvers will be performed after 30 and 60 minutes from the start of 
recording.  
• 
If in the meantime the patient is weaned from the mechanical ventilator and spontaneously 
breathing through a tracheostomy, we will temporarily reconnect the patient to the 
mechanical ventilator, in PSV mode, with zero peep (ZEEP), we will perform an expiratory 

13 
 
pause maneuver and an inspiratory pause maneuver (both lasting enough to have 2 or 3 
spontaneous breaths) with an interval of one minute between each maneuver. In these 
weaned patients, the maneuvers will be performed after 5 and 10 minutes from the start of 
recording that will last only 10 minutes; 
• 
If in the meantime the patient is weaned from the mechanical ventilator, extubated, 
spontaneously breathing and able to cooperate, the patient will be asked to inspire in a close 
system connected to a pneumotachograph to estimate Paw. The maneuver will be performed 
after 5 and 10 minutes from the start of recording that will last only 10 minutes; 
• 
If in the meantime, the patient is weaned from the mechanical ventilator, extubated, 
spontaneously breathing, and unable to cooperate we will use as a surrogate the 
neuromechanical efficiency calculated when the patient was connected to the ventilator. The 
recording will last only 10 minutes. 
We will calculate PEIoccl,paw, the PmusEAdi waveform, and the two most validated indexes of 
inspiratory effort: Δ Pmus and the PTPEAdi (a good indicator of the metabolic work of breathing). 
We will analyze the dynamic transpulmonary driving pressure, corresponding to the sum of the 
pressure support level and Pmusdyn, and representing a surrogate of dynamic stress that takes into 
account the chest wall elastance. Moreover we will measure the plateau pressure, the positive end-
expiratory pressure (PEEP), and we will calculate the driving pressure and the static compliance 
of the respiratory system.  
4.3.2 Spontaneous Breathing Trial (SBT) and Extubation/Deconnection 
When PaO2/FiO2 is no lower than 200 mm Hg at PEEP ≤ 8 cmH2O, the patient will be considered 
to have an acceptable gas exchange on 8-5 cmH2O of PEEP and will be deemed capable to tolerate 
this setting. 
A 30-120 minute spontaneous breathing trial  (SBT) will be initiated as the following criteria are 
met and whether a patient tolerated fully assist ventilation with PEEP ≤ 8 cmH2O for at least 4 
hours without experiencing hypoxemia (SpO2 < 88% ora PaO2/FiO2 < 150mmHg): 
• 
improvement or resolution of the underlying cause of acute respiratory failure; 
• 
correction of arterial hypoxemia (PaO2 ≥ 60 mmHg at a FiO2 ≤ 0.4 with PEEP ≤ 8 cmH2O); 
• 
absence of fever ( ≥ 38 °C) or sepsis; 
• 
blood hemoglobin concentration of 7 g/dL or more; 
• 
hemodynamic stability without cardiac ischemia or arrhythmias (norepinephrine < 0.1 
gamma/kg/min). 
Success of the spontaneous breathing trial will be defined as presence of the following criteria:   
• 
respiratory rate < 35/min; 
• 
arterial oxygen saturation ≥ 90%; 
• 
heart rate < 120/min; 

14 
 
• 
systolic blood pressure > 90 and < 160 mmHg; 
• 
adequate cough. 
If the spontaneous breathing trial is successful, the patient will be extubated or deconnected from 
the mechanical ventilator if tracheostomized. In case of SBT failure, mechanical ventilation will be 
resumed (with any PEEP levels accepted, according to the strategies described above   
Data about extubation/deconnection will be collected immediately before extubation and 20 
minutes following extubation. The need for a tracheostomy will be recorded in the CRF as well as 
the incidence of adverse events, i.e., the need for reintubation, infection rate, death. After the 
discharge from ICU, the enrolled patients will be followed until discharge from the hospital. 
4.4 Observation period for the primary endpoint     
This period covers the interval over which the subject may qualify for the primary endpoint of the 
study. It starts with the randomization and ends 72 hours after randomization. After this period 
the treatment duration will be dependent on the subject’s clinical course and the investigator's 
judgment on the perceived need to continue the study drug. The use of TTS-fentany will not be 
allowed in remifentanil alone group even after the end of the observation period for the primary 
outcome. 
4.5 24-hour safety follow-up period 
This period starts with the permanent discontinuation of the study drug (TTS-fentanyl) and ends 
24 hours later. Subjects must not be discharged from the hospital until the end of this period. 
New Adverse Events occurring in this period are recorded in the case report form (CRF). 
 
4.6 End of Study (EOS) visit (individual subject) 
This visit occurs at the discharge from the intensive care unit or in case of death after the 
observation period for the primary endpoint and is defined as the last visit performed by an 
individual subject for the study. This visit may occur earlier for subjects who prematurely 
withdraw from the study. 
 In this visit we will record: 
• 
An Arterial Blood Gases (ABG) sample will be collected and ABG parameters recorded (pH, 
PaCO2, PaO2, HCO3-, Lactates, SaO2); 
• 
Glasgow Coma Scale, RASS; 
• 
Respiratory parameters: Ventilation mode, Pressure Support, Respiratory Rate, Tidal Volume, 
peep, FiO2, EtCO2; if patient is spontaneously breathing: FiO2, RR, SpO2; 
• 
Hemodynamic parameters (Heart Rate, SBP/DBP/MAP); 
• 
Data on the global duration of opioid therapy/length of stay (LOS) in hospital and ICU. 

15 
 
4.7 Last Visit Last Patient (LVLP) 
This visit or time point occurs when the last subject randomized into the study completes his/her 
last visit 
The overall study design is depicted in Figures 1, 2, 3, 4, and table 1. 
5. Previous and Concomitant therapy 
5.1 Definitions 
For this study, a previous therapy is defined as any treatment for which the end date is prior to the 
signature of the informed consent form. A study-concomitant therapy is defined as any treatment 
that is ongoing or initiated after the signature of the informed consent form or initiated up to 24 
hours post-study drug discontinuation. A therapy that is study treatment-concomitant is any 
treatment that is either ongoing at the start of study treatment or is initiated during the treatment 
period until the time of permanent study drug discontinuation. 
5.2 Allowed concomitant therapy 
The usual standard of care for each patient is allowed except for those therapies listed in the 
“forbidden concomitant therapy” section and must be documented in the medical chart. 
5.3 Forbidden concomitant therapy 
The following medications/therapies are forbidden due to their potential to interfere with the 
evaluation of efficacy or safety, or due to the potential for a drug to drug interaction with study 
drug (TTS-fentanyl): 
 Monoamine Oxidase Inhibitors (MAOI): TTS-fentanyl is not recommended for use in patients 
who require the concomitant administration of an MAOI. Severe and unpredictable interactions 
with MAOIs, involving the potentiation of opiate effects or the potentiation of serotoninergic 
effects, have been reported. Therefore, TTS-fentanyl should not be used within 14 days after 
discontinuation of treatment with MAOIs; 
 Serotonergic medicinal products: Co-administration of fentanyl with serotonergic medicinal 
products, such as a Selective Serotonin Re-uptake Inhibitor (SSRI) or a Serotonin Norepinephrine 
Re-uptake Inhibitor (SNRI) or a Monoamine Oxidase Inhibitor (MAOI), may increase the risk of 
serotonin syndrome, a potentially life-threatening condition; 
 Concomitant use of mixed opioid agonists/antagonists: The concomitant use of buprenorphine, 
nalbuphine, or pentazocine is not recommended. They have high affinity to opioid receptors with 
relatively low intrinsic activity and therefore partially antagonize the analgesic effect of fentanyl 
and may induce withdrawal symptoms in opioid-dependent patients;  
 The concomitant use of CYP3A4 inhibitors and inducers and TTS-fentanyl is not 
recommended because it can interfere with the drug concentrations and with the 
evaluation of efficacy or safety. The following substances may increase fentanyl 
concentrations and should be avoided: amiodarone, cimetidine, clarithromycin, diltiazem, 
erythromycin, fluconazole, itraconazole, ketoconazole, nefazodone, ritonavir, verapamil, 

16 
 
and voriconazole. The following substances may decrease fentanyl concentrations and 
should be avoided: carbamazepine, phenobarbital, phenytoin, and rifampicin; 
 Techniques of haemofiltration and haemodiafiltration can interfere with fentanyl serum 
concentrations causing a potential bias in the study; 
 Techniques of extracorporeal circulation can interfere with fentanyl serum concentrations 
causing a potential bias in the study; 
 Noradrenaline infusion rates more or equal than 0.1 mcg/kg/min or Inotropes should be 
avoided as they can have an impact on fentanyl transdermal absorption altering 
microcirculation resulting in unpredictable fentanyl serum concentrations causing a 
potential bias in the study. 
5.4 Reporting of previous/concomitant therapy in the CRF 
All previous and study-concomitant therapies taken/administered less than or equal to 24 hours 
prior to randomization into the study will be recorded in the CRF. All medications administered 
randomization and up to 24 hours post-study drug discontinuation will also be recorded in the 
CRF. The generic name, start/end dates and times of administration, route, dose regimen, and 
indication will be recorded. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

17 
 
 
 
 
 
 
 
 
 
 
 
BASELINE VISIT  
• 
ABG (pH, PaCO2, PaO2, HCO3-, Lactates, SaO2); 
• 
GCS, RASS, the dosage of remifentanil; 
• 
Respiratory parameters; 
• 
Haemodynamic parameters; 
• 
1-hour recording of EAdi, flow and Paw 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fig 1. Screening Period 

Age > 18 yo 

Pregnancy test ( - ) if female in fertile age 

Obtain Informed Consent 

Remifentanil infusion lasting > or = 5 days  

On Pressure Support Ventilation 
Patient Considered 
Eligible 
Place EAdi catheter
RANDOMIZATION 
GROUP 2 
Starts TTS fentanyl 50 
mcg/hr  
GROUP 1 
Continuous infusion of 
Remifentanil alone 

18 
 
 
 
 
                                                                                                 
 
 
 
                                                                                                                           
                                                                                                                                            
 
 
                                             
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GROUP 1 
Remifentanil iv alone 
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10 
Day 1 
Visits every 4 
hours 
Day 2 and 3 
Visits every 6 hours 
If PaCO2>45 mmHg ↓0.025 mcg/kg/min 
If PaCO2 40-45 mmHg ↓0.0125 mcg/kg/min 
If PaCO2 35-40 mmHg ≈ no changes 
If PaCO2 30-35 mmHg ↑0.0125 mcg/kg/min 
If PaCO2 <30 mmHg ↑0.025 mcg/kg/min 
If PaCO2>45 mmHg ↓0.025 mcg/kg/min
If PaCO2 30-45 mmHg ↓0.0125 mcg/kg/min 
If PaCO2 <30 mmHg ↑0.0125 mcg/kg/min 
At each visit  we will record: 
•
An Arterial Blood Gases (ABG) sample will be 
collected  
•
Glasgow Coma Scale, RASS, the dosage of 
remifentanil; 
•
Respiratory parameters: Ventilation mode, 
Pressure Support, Respiratory Rate, Tidal Volume, 
peep, FiO2, EtCO2, SpO2; if spontaneously 
breathing: FiO2, RR, SpO2 
•
Haemodynamic parameters 
EAdi, flow and Paw waveforms will be 
recorded 1, 6, 12, 24 hours from the 
time of randomization for day 1 and 
every 24 hours for the following days. 

19 
 
Figure 2. Treatment Period Group 1 
 
                                                                                                  
                                                                                                 
 
 
 
                                                                                                                           
                                                                                                                                            
 
 
                                             
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GROUP 2 
Starts TTS fentanyl 50 mcg/hr and maintain remifentanil iv  
V1
V2
V3
V4
V5
V6
Day 1 
Visits every 4 
hours 
If PaCO2>45 mmHg ↓0.025 mcg/kg/min 
If PaCO2 40-45 mmHg ↓0.0125 mcg/kg/min 
If PaCO2 35-40 mmHg ≈ no changes 
If PaCO2 30-35 mmHg ↑0.0125 mcg/kg/min 
If PaCO2 <30 mmHg ↑0.025 mcg/kg/min 
V7
V8
V9
V10 
Day 2 and 3 
Visits every 6 
hours 
If PaCO2>45 mmHg ↓0.025 mcg/kg/min
If PaCO2 30-45 mmHg ↓0.0125 mcg/kg/min 
If PaCO2 <30 mmHg ↑0.0125 mcg/kg/min 
         EVERY 24 HOURS 
If PaCO2 >45 mmHg remove TTS-fentanyl 25 mcg/hr 
If PaCO235-45 mmHg don’t add or remove tts fentanyl 
If PaCO230-35 mmHg add TTS-fentanyl 50 mcg/hr 
If PaCO2 <30 mmHg add TTS-fentanyl 75 mcg/hr 
 
At each visit we will record: 
•
An Arterial Blood Gases (ABG) sample will be 
collected  
•
Glasgow Coma Scale, RASS, the dosage of 
remifentanil and TTS-fentanyl; 
•
Respiratory parameters: Ventilation mode, 
Pressure Support, Respiratory Rate, Tidal Volume, 
peep, FiO2, EtCO2, SpO2; if spontaneously 
breathing: FiO2, RR, SpO2 
•
Haemodynamic parameters  
EAdi, flow and Paw waveforms will be 
recorded 1, 6, 12, 24 hours from the 
time of randomization for day 1 and 
every 24 hours for the following days.  

20 
 
  Figure 3. Treatment Period Group 2                                
 
 
 
 
                                                    
 
 
 
 
Figure 4. Study Design 
 
Screening Period 
Verify inclusion/exclusion Criteria, Obtain Pregnancy test and 
Informed consent 
Patient Enrolled 
Baseline: ABG sample, respiratory and hemodynamic parameters, 
GCS, RASS, dosage of remifentanil at inclusion, 1-hour recording of 
EAdi, flow, and Paw 
Treatment period 
Randomization (group 1 remifentanil alone, group 2 remifentanil + 
TTS-fentanyl) 
1 hour* 
Recording of EAdi, flow, and Paw 
4 hours* (Visit 1) 
ABG sample, respiratory and hemodynamic parameters, GCS, RASS, 
dosage of remifentanil and TTS-fentanyl 
6 hours* 
Recording of EAdi, flow, and Paw 
8 hours* (visit 2) 
ABG sample, respiratory and hemodynamic parameters, GCS, RASS, 
dosage of remifentanil and TTS-fentanyl 
12 hours* (visit 3) 
ABG sample, respiratory and hemodynamic parameters, GCS, RASS, 
dosage of remifentanil and TTS-fentanyl, Recording of EAdi, flow, 
and Paw 
ICU admission
Negative 
Pregnancy test  
screening 
randomization 
Observation period for 
primary endpoint  
Treatment 
suspended 
(End of 
Treatment)
24hrs safety 
FU period 
24 hours 
after 
suspension 
of 
remifentanil 
Start of treatment 
End of 
24 hrs 
FU 
End of Study 
(Discharge 
from hospital, 
Death)  

21 
 
16 hours* (visit 4) 
ABG sample, respiratory and hemodynamic parameters, GCS, RASS, 
dosage of remifentanil and TTS-fentanyl 
20 hours* (visit 5) 
ABG sample, respiratory and hemodynamic parameters, GCS, RASS, 
dosage of remifentanil and TTS-fentanyl 
24 hours* (visit 6) 
ABG sample, respiratory and hemodynamic parameters, GCS, RASS, 
dosage of remifentanil and TTS-fentanyl, Recording of EAdi, flow, 
and Paw 
30 hours* (visit 7) 
ABG sample, respiratory and hemodynamic parameters, GCS, RASS, 
dosage of remifentanil and TTS-fentanyl 
36 hours* (visit 8) 
ABG sample, respiratory and hemodynamic parameters, GCS, RASS, 
dosage of remifentanil and TTS-fentanyl 
42 hours* (visit 9) 
ABG sample, respiratory and hemodynamic parameters, GCS, RASS, 
dosage of remifentanil and TTS-fentanyl 
48 hours* (visit 10) 
ABG sample, respiratory and hemodynamic parameters, GCS, RASS, 
dosage of remifentanil and TTS-fentanyl, Recording of EAdi, flow, 
and Paw 
54 hours* (visit 11) 
ABG sample, respiratory and hemodynamic parameters, GCS, RASS, 
dosage of remifentanil and TTS-fentanyl 
60 hours* (visit 12) 
ABG sample, respiratory and hemodynamic parameters, GCS, RASS, 
dosage of remifentanil and TTS-fentanyl 
66 hours* (visit 13) 
ABG sample, respiratory and hemodynamic parameters, GCS, RASS, 
dosage of remifentanil and TTS-fentanyl 
72 hours* (visit 14) 
ABG sample, respiratory and hemodynamic parameters, GCS, RASS, 
dosage of remifentanil and TTS-fentanyl, Recording of EAdi, flow, 
and Paw 
End of observation 
period for the primary 
endpoint 
72 hours after randomization 

22 
 
Treatment suspended 
The treatment duration will be dependent on the subject’s clinical 
course and the investigator’s judgment on the perceived need to 
continue the study drug 
Safety FU period 
Permanent discontinuation of TTS-fentanyl: start of 24 hours of 
Safety Follow up Period (any adverse event will be recorded on the 
CRF) 
End of Study Visit 
This visit occurs at the discharge from the ICU or in case of death 
after the observation period for the primary endpoint 
ABG sample, respiratory and hemodynamic parameters, GCS, RASS, 
Data on the global duration of opioid therapy/length of stay (LOS) in 
hospital and ICU 
*Hours from randomization 
Table 1. Study visits and assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

23 
 
6. Statistical analysis 
Distribution normality will be assessed with the Kolmogorov-Smirnov test. Continuous variables 
will be reported expressed as medians (interquartile ranges). Qualitative variables will be 
reported as frequencies.  
Analysis of the primary efficacy criterion (AUC of the work of breathing) and other quantitative 
variables will be assessed with the Wilcoxon-Mann-Whitney sum of rank test. Categorical 
outcomes will be compared with the chi-square test, or Fisher’s exact test, as appropriate: 
Cochran–Mantel–Haenszel statistics will be reported for all these results. Two-way analysis of 
variance (ANOVA) for repeated measures with Bonferroni correction will be used to determine the 
differences in work of breathing per breath, inspiratory effort, delta EAdi, plateau pressure, P 0.1 
respiratory rate, tidal volume, arterial blood pressure, heart rate in the two groups. Comparisons 
between groups regarding these variables at each study time point will be performed with the 
Student’s t-test or Mann-Whitney test, as appropriate. Mean difference and 95% confidence 
interval [CI95%] are reported for most significant results.  
Two-tail p values≤0.05 Will be considered significant. Statistical analysis will be performed with 
SPSS software package (SPSS Inc. Released 2009. PASW Statistics for Windows, Version 18.0. 
Chicago: SPSS Inc.). 
6.1 Sample size calculation 
As said previously, the primary endpoint is to demonstrate that the area under the curve (AUC) of 
the work of breathing per minute (assessed at 1, 6, 12, 24, 48, and 72 hours) in the intervention 
group is not higher than the control group. Data on the work of breathing of ICU patients 
undergoing mechanical ventilation while on remifentanil continuous infusion are lacking. 
However, there are studies suggesting that a sample of 10 patients is adequate to draw significant 
conclusions on the physiological endpoints related to respiratory mechanics and work of breathing 
among patients with respiratory failure (Delorme et al. 2017; Lellouche et al. 2002; Prat et al. 2003; 
LHer et al. 2005). Thus, for this phase II, pilot, randomized trial, using a conservative approach and 
considering an attrition rate lower than 10%, we planned to enroll 12 patients per group, for a 
total sample of 24 patients in 12 months. Julius et al., in their study published on pharmaceutical 
statistics in 2005 confirmed that a minimum 12 subjects per group are enough for a pilot 
randomized trial (Julious et al. 2005). 
7. Premature withdrawal from the study 
Subjects may voluntarily withdraw from the study without justification for any reason at any time. 
Subjects are considered withdrawn if they state an intention to withdraw further participation in 
all components of the study (i.e., withdrawal of consent), die within the observation period for the 
primary endpoint, or are lost to follow up. If a subject withdraws consent, no further data will be 
collected in the CRF from the date of withdrawal onward. The investigator may withdraw a subject 
from the study (without regard to the subject’s consent) if he/she believes that continued 
participation in the study would be contrary to the best interests of the subject. 

24 
 
The reason for premature withdrawal from the study must be recorded in the CRF. 
7.1 Premature termination or suspension of the study 
The Sponsor has the right to close the study (or, if applicable, individual segments (e.g. treatment 
arms; dose steps; centers)) at any time, which may be due, but not limited to, the following reasons: 
-If risk-benefit ratio becomes unacceptable owing to, for example: Safety findings from this study 
(e.g. SAEs) 
-If the study conduct (recruitment rate; drop-out rate; data quality; protocol compliance) does not 
suggest a proper completion of the trial within a reasonable time frame and a proper quality status. 
7.2 Medical care of subjects after withdrawal from the study 
After the subject’s study completion or premature withdrawal from the study, whichever applies, 
the investigator/delegate will explain to subjects what treatment(s)/medical care is necessary and 
available according to local regulations. Such care may include the use of drugs that were forbidden 
during concomitant study treatment administration. 
8. Safety definitions and reporting requirements 
8.1 Safety definitions 
8.1.1 Definition of adverse events 
An AE is any untoward medical occurrence, i.e., any unfavorable and unintended sign, including 
an abnormal laboratory finding, symptom, or disease that occurs in a subject during the study, 
whether or not considered by the investigator as related to the study treatment. 
 
AEs include 
 Exacerbation of a pre-existing disease if considered medically relevant; 
 Increase in frequency or intensity of a pre-existing episodic disease or medical condition; 
 Disease or medical condition detected or diagnosed during the study even though it may 
have been present before the start of the study; 
 Continuous persistent disease or symptoms present at study start that worsen following 
the signing of the informed consent form; 
 Laboratory test abnormalities if they represent a clinically significant finding (symptomatic 
or not), which was not present at study start or worsened during the course of the study as 
per investigator’s judgment, or led to interruption or permanent discontinuation of study 
treatment. 
8.1.2 Definition of adverse drug reaction (ADR) 
Considering the new usage that is proposed in this study for TTS-fentanyl and that the therapeutic 
dose is not well established, all noxious and unintended responses to TTS-fentanyl related to any 
dose should be considered adverse drug reactions. 

25 
 
8.1.3 Definition of serious adverse events  
An SAE is defined by the ICH guidelines as any AE fulfilling at least 1 of the following criteria: 
 Fatal; 
 Life-threatening: refers to an event in which the subject was at risk of death at the time of 
the event. It does not refer to an event that hypothetically might have caused death had it 
been more severe; 
 Requiring prolongation of hospitalization; 
 Resulting in persistent or significant disability or incapacity; 
 Congenital anomaly or birth defect; 
 Medically significant: refers to important medical events that may not immediately result 
in death, be life-threatening, or require hospitalization but may be considered medically 
significant based upon appropriate medical judgment, as they may jeopardize the subject, 
and/or may require medical or surgical intervention to prevent one of the outcomes listed 
in the definition above. 
8.2 Reporting of adverse events  
All AEs with an onset date and time from study drug initiation up to 24 hours after study treatment 
discontinuation (i.e., the 24-hour safety follow-up period) must be recorded on specific AE forms 
of the CRF. Those AEs occurring from the signature of the informed consent form until End of Study 
will also be recorded on an AE form in the CRF if they are believed to be related to a protocol-
mandated procedure. 
Information to be collected in an AE form in the CRF includes date and time of onset, action taken 
with the study treatment, outcome of AE, date of resolution (if applicable) and PI’s assessment of 
seriousness and intensity, and relationship to study treatment, study design or protocol mandated 
procedures. For AEs related to cardiac rhythm abnormalities, additional ECG parameters may be 
collected.  
If the intensity of an AE worsens during study treatment administration, only the worst intensity 
should be reported on the AE form. If the AE lessens in intensity, no change in the severity is 
required to be reported. 
For AEs ongoing at the start of study treatment, the worsening of the AE after the start of study 
treatment will be recorded as a separate AE with the new intensity. 
Follow-up information on any ongoing AEs obtained after the subject’s EOS visit will not be 
collected in the CRF.  
 
9. Risk-Benefit Assessment 
In an ICU setting, in which patients are continuously monitored 24 hours a day and mechanically 
ventilated, it can be stated that the risks related to the use of TTS-fentanyl are few. There is 
obviously a consistent risk of developing an opioid addiction, already present using remifentanil, 
that compared to fentanyl is stronger and short-acting. Respiratory depression is easily and early 
detected. On the other hand, an alternative and “needle-free” route of administration of an opioid, 

26 
 
fentanyl, that is different from a pharmacokinetic point of view if compared to remifentanil, could 
help in IV opioids weaning, it can reduce the length of mechanical ventilation, and length of stay 
in ICU, decreasing the risks related to the stay in an ICU setting as infections rate and increases in 
costs. Moreover, TTS-fentanyl could theoretically be exported out from the ICU to the medical 
wards, allowing more gradual and physiological weaning from opioids. 
10. Data handling 
The investigator is responsible for ensuring the accuracy, completeness, and timely reporting of 
subject data. All source documents should be completed in a neat, legible manner to ensure 
accurate interpretation and traceability of the data. Data reported in the CRF derived from source 
documents must be consistent with the source documents. 
The investigator must ensure that data confidentiality is maintained. On CRF or other documents, 
subjects must be identified only by a number and never by their name or initials, date of birth, 
hospital numbers, or any other personal identifier. The investigator must keep a subject 
identification code list at the site, showing the subject number, the subject’s name, date of birth, 
and address or any other accepted identifiers. Documents identifying the subjects (e.g., signed 
informed consents) must be kept in strict confidence by the investigator. 
10.1 Archiving 
The Principal Investigator must ensure the archiving of the essential documents of the study as 
specified by the GCP and in compliance with the applicable legislation. The Principal Investigator 
or his/her delegates must adopt all the necessary measures to avoid accidental or premature 
destruction. Patient (hospital) files will be archived according to local regulations and in 
accordance with the maximum period of time permitted by the hospital (25 years). Where the 
archiving procedures do not meet the minimum timelines required by the sponsor, alternative 
arrangements must be made to ensure the availability of the source documents for the required 
period.  
10.2 Direct access to original documents 
The Principal Investigator and/or his delegates must allow the Regulatory Authorities and 
individuals delegated by the Independent Ethics Committee to have free access to and to conduct 
the relevant verification of all the original documentation of the study, including the informed 
consent forms signed by the patients enrolled into the study, the relevant patient files and/or out-
patient files. Those individuals who are given free access to the documentation must take every 
reasonable precaution to keep the identity of the patients as reserved information, in accordance 
with applicable legislation. 
 
10.3 Data Protection 
 
We will follow Art. 13 GDPR (UE/2016/679) about normative regarding data protection. 
 
 
 

27 
 
11. Publication policies and communication of results 
The scientific director of the study will undertake to draw up a final report and a scientific article and 
to make the results public at the end of the study. The data will be made public anonymously and 
presented as requested in an aggregate manner. 
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APPENDIX 1. RASS SCORE 
 
 
 
 
 
 
 
 
 
 

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APPENDIX 2. GLASGOW COMA SCALE
 
 
APPENDIX 3. TABLES OF OPIOID CONVERSION 
 
 https://opioidcalculator.practicalpainmanagement.com/conversion.php 
 Arnold R, Weissman DE. Calculating Opioid Dose Conversions, 2nd Edition. Fast Facts and 
Concepts. July 2005; 36. Available at: 
http://www.eperc.mcw.edu/EPERC/FastFactsIndex/ff_036.htm.