Efficacy and Safety of Dexmedetomidine During Weaning From Analgesia and Sedation in Pediatric Intensive Care Unit. A Multicenter, Double-blind, Randomized Controlled Trial.
Phase: PHASE2
Conditions: Withdrawal Syndrome
Sponsor: IRCCS Azienda Ospedaliero-Universitaria di Bologna

 
Study code: TIP-15-01 
 
Efficacy and safety of Dexmedetomidine 
during analgesic and sedative drugs weaning 
in Pediatric Intensive Care Unit 
Multicenter, Randomized, Double-Blind, Placebo-Controlled, Spontaneous 
Clinical Trial 
 
Author: 
Maria Cristina Mondardini 
Study phase: 
II b 
Document 
EudraCT 
Protocol 
2015-002114-80 
Version: 
Final 2.0 
Date of issue: 
18/09/2016 
Number of pages: 
23 
 
 
 
 
 

 
 
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SCIENTIFIC COMMITTEE  
 
Study code: TIP-15-01 
 
MARIA CRISTINA MONDARDINI 
PICU University-Hospital, S.Orsola-Malpighi, Bologna, Italy 
mariacristina.mondardini@aosp.bo.it 
 
FABIO CARAMELLI 
PICU University-Hospital, S.Orsola-Malpighi, Bologna, Italy 
fabio.caramelli@aosp.bo.it 
 
ANGELA AMIGONI 
PICU University-Hospital, Padova, Italy 
angela.amigoni@aopd.veneto.it 
 
GIORGIO CONTI 
PICU Catholic University of Rome, Roma, Italy 
Giorgio.Conti@unicatt.it 
 
 
 
 
 
 
 
 

 
 
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PROTOCOL SIGNATURE PAGE 
 
Study code: TIP-15-01 
 
The study protocol was developed according to the Guidelines of Good Clinical Practice and 
in accordance with the Helsinki Declaration.  
I state that I will conduct the Trial according to all the above requirements. 
 
                                18/09/2016 
 
 
 
 
 
 
 
 
TABLE OF CONTENTS  
Chief Investigator:  
Maria Cristina Mondardini 
AOU di Bologna  
Policlinico S.Orsola-Malpighi,  
Bologna, 
Italy 
 
firma 
 
Data 

 
 
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1. Background .......................................................................................................................... 6 
2. Trial Objectives ................................................................................................................... 7 
3. Study plan ............................................................................................................................ 8 
3.1 
Study design ............................................................................................................. 8 
3.2 
Studty population ..................................................................................................... 8 
3.3 
Assignment to treatment .......................................................................................... 9 
3.4. 
Treatments ............................................................................................................. 10 
3.5. 
Evaluations and visits ............................................................................................ 11 
3.6. 
Assessment of the efficacy .................................................................................... 13 
3.7.     Assessment of the safety ........................................................................................ 13 
3.8.     Evaluation of risk-benefit ratio  .............................................................................. 16  
4. Data management and Statistical analysis ......................................................................... 16 
4.1.Data management plan ................................................................................................ 16 
4.2 
Statistical analysis .................................................................................................. 17 
!  
Characteristics, treatments and comorbidities ....................................... 17 
!  
Efficacy evaluation: primary outcome assessment ............................... 17 
!  
Efficacy evaluation: secondary outcomes ............................................. 18 
!  
Safety evaluation ................................................................................... 19 
!  
Sample size ............................................................................................ 19 
5. Administrative proceedings ............................................................................................... 19 
6. Bibliography ...................................................................................................................... 22 
 
 
 

 
 
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ACRONYMS and ABBREVIATIONS 
 
 
AE 
Adverse Event 
AR 
Adverse Reaction 
CRF 
Case Report Form 
GCP 
Good Clinical Practice 
HR 
Heart rate 
MBP 
Mean Blood Pressure 
PICU 
Pediatric Intensive Care Unit 
PIM3 
Paediatric Index of  Mortality 3 
PMA 
Postmenstrual age 
SBP/DBP Systolic Blood Pressure/Diastolic Blood Pressure 
SOS 
Sophia Observational withdrawal Symptoms-scale 
SPC 
Summary of Product Characteristics 
WAT-1 
Withdrawal Assessment Tool-Version 1 
 
 
 
 
 
 

 
 
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1. 
Background 
 
Children admitted to the Pediatric Intensive Care Unit (PICU) often need of analgosedation as 
an essential part of their treatment. However, exposure to analgosedation drugs can lead to 
undesirable effects like dependence, tolerance and withdrawal syndrome 1,2.  
The withdrawal syndrome may occur during the drug weaning process in patients that have 
developed dependence to both opioids and benzodiazepines. Withdrawal symptoms are due to 
central  nervous  system  excitement,  gastrointestinal  disturbance,  and  sympathetic  system 
activation.  The  resulting  tremors,  agitation,  sleeplessness,  inconsolable  crying,  sweating, 
yawning, sneezing, diarrhea, vomiting, that are among the most frequent signs, affect patients 
with intense suffering, increased morbidity and lengthen PICU stay 3. Recently, two pediatric 
assessment tools have been validated to evaluate the degree of severity of the withdrawal: the 
withdrawal assessment tool version 1 (WAT-1) 
4, and the Sophia Observational withdrawal 
Symptoms-scale (SOS) 5.  
The cumulative dose and length of treatment are predictive risk factors for withdrawal as well 
as the overly rapid reduction or abrupt withholding of analgosedation drugs 6.  
Therefore, withdrawal syndrome prevention strategies are addressed both to the restriction of 
drug  exposure  (dose  and  length)  and  to  the  gradual  tapering  of  infusion.  However,  these 
strategies have weak evidence of effectiveness, clinical signs of abstinence frequently occur 
requiring  targeted  treatment.  To  simplify  weaning  management,  the  drug  switch  is  also 
proposed:  the  drug  has  changed  with  one  of  the  same  pharmacological  class  with  a  longer 
half-life, at an equipotent dose. Although at present no drug seems to have more advantage 
than another, methadone is the most commonly prescribed one 
7. Sometimes, in very critical 
children admitted to PICU, the most appropriate level of analgosedation is more challenging 
to  achieve.  Increase  the  dosage  or  replace  the  drug  with  a  more  potency  one  or  even  add 
adjuvants  cannot  always  reach  the  goal  while  it  may  instead  increase  the  risk  of  highest 
cumulative doses. From the literature data, the incidence of withdrawal syndrome in PICU is 
variable  between  17  and  57%.  In  a  multicenter  study  conducted  at  Italian  PICUs,  in  the 

 
 
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process of being published, this incidence reaches 64.6% in patients undergoing five days or 
more of treatment.  
In this study, we hypothesize that dexmedetomidine may be useful and effective during the 
weaning  of  analgosedation  drugs  in  PICU,  in  preventing  the  withdrawal  syndrome 
8,9. 
Dexmedetomidine is a selective α2-receptor agonist. The binding to the receptors at the locus 
ceruleus  level,  blocking  the  release  of  noradrenaline  inducing  the  sedative  and  anxiolytic 
effects. The analgesic effects come from the inhibition of the release of the substance P at the 
dorsal horns level of the spinal cord 
10,11,12. The most common side effects are hypotension 
and  bradycardia,  due  to  sympatholytic  action 13.  The  dexmedetomidine  used  as  adjuvant 
improves patient comfort and may contribute to containing the cumulative dose of sedative 
and analgesic drugs 14. 
The possible cellular mechanisms of dexmedetomidine withdrawal-preventing effect may be, 
at least partly, related to the interaction among to G protein-coupled receptors (GPCRs); both 
the  adrenergic  receptors  and  the  opioid  receptors,  belong  to  this  large  family,  as  well  as 
dopaminergic, serotonergic, and others again 1. Up to now the off-label drug condition of the 
dexmedetomidine in pediatrics has limited the clinical research to retrospective observational 
studies  or  case  series.  Additional  studies  have  been  advocated  to  better  define  the  role  of 
dexmedetomidine  in  PICU,  particularly  in  the  management  of  weaning  from  analgesic  and 
sedative 
drugs. 
 
2. 
Trial Objectives  
Primary objective:  
To evaluate the efficacy of dexmedetomidine in reducing the occurrence of the withdrawal 
syndrome during the weaning of analgesic and sedative drugs. 
Secondary objectives:  
1. To  evaluate  the  safety  of  dexmedetomidine  during  the  weaning  of  analgesic  and 
sedative drugs. 

 
 
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2. To  evaluate  the  efficacy  of  dexmedetomidine  in  reducing  the  duration  (days)  of  the 
weaning of analgesic and sedative drugs. 
3. To  evaluate  the  efficacy  of  dexmedetomidine  in  reducing  the  duration  (days)  of 
mechanical ventilation.  
4. To  evaluate  the  efficacy  of  dexmedetomidine  in  reducing  the  PICU  length  of  stay 
(days).  
5. To  compare  the  efficacy  of  dexmedetomidine  among  pediatric  age  groups,  gender, 
race,  Pediatric  Index  of  Mortality  (PIM3)  score,  and  length  of  the  analgosedation 
treatment. 
6. To evaluate the effective dose range of dexmedetomidine in reducing the occurrence 
of the withdrawal syndrome. 
3. 
Study plan 
An outline of the trial plan is given in the protocol flow chart.  
3.1. 
Study design 
Multicenter, randomized, double blind, placebo-controlled, spontaneous clinical trial.  
3.2. 
Study population 
The  study  population  will  include  patients  admitted  to  the  PICU  that  meets  the  inclusion 
criteria: 
Inclusion Criteria 
– Continuous analgesic and sedative endovenous treatment for at least five days 
– Invasive or non-invasive mechanical ventilation 
– Clinical conditions that allow by clinical judgment the start of analgosedation weaning  
– Age between 0 to18 years 
– Post-natal age ≥ 7 days and PMA beyond the 37 weeks 
Count of the PMA = gestational age at birth + age in number of weeks since birth 

 
 
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– Written informed consent obtained 
For the childbearing girls (at least one menstrual cycle) the beta HCG test is scheduled 
and enrollment is subject to the negative result of the test 
Exclusion Criteria 
– Hemodynamic instability   
– Inotropic or antihypertensive treatments (ß-blockers, calcium antagonists, ACE 
inhibitors, digoxin, nicardipine, nitroglycerin) 
– Cardiac bundle-branch block of 2 or 3 degree 
– Hypersensitivity to the alpha-agonists 
– Persistent fever of unknown origin or sensitivity to malignant hyperthermia 
– Use of alpha-agonist (clonidine or dexmedetomidine) in the last 30 days 
3.3. 
Assignment to treatment 
An  identification  code  will  individually  assigned  to  each  enrolled  patient.  The  code  cannot 
longer be re-used even if the patient for any reason interrupts the study. 
Each patient will be randomly assigned to one of the two treatment groups: 
– Treatment A: dexmedetomidine 
– Treatment B: placebo (physiological saline solution) 
The  Investigational  Drug  Service  (IDS)  of  the  Coordinating  Center  generated  a  single 
randomization list for all the centers. This confidential document will be only available to the 
not  blinded  staff  involved.  The  concealment  of  the  randomization  list  implies  that  the 
allocation  sequence  is  unknown  by  the  blinded  researchers,  included  the  promoter  of  the 
study. The non-blind staff of each center one will carry out the preparation of the 
experimental drug. 

 
 
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3.4. 
Treatments 
Twenty-four hours before the start of the weaning from analgosedation treatment, intravenous 
infusion of dexmedetomidine/placebo will start according to the below schedule. 
The  start  dose  is  0.4  mcg/kg/h,  without  a  loading  dose.  The  dose  will  increase,  if  well 
tolerated, of 0.2 mcg/kg per hour, until it reaches 0.8 mcg/kg/h. Given the pharmacological 
differences 15,  the  start  dose  in  newborn  is  0.2mcg  /  kg  /  h  without  the  loading  dose,  the 
hourly increase is 0.1mcg / Kg / h up to 0.4mcg / Kg / h. 
After 24 hours of dexmedetomidine infusion, the weaning regimen will begin following the 
subsequent indications: 
– 10% reduction of the dose every 12 hours 
The Protocol allows the switch of opioids and/or benzodiazepines to an equipotent dose of 
drugs of the same pharmacological class with a longer half-life. The scheme of conversion 
refers 
to 
the 
National 
recommendations 
for 
analgosedation 
in 
PICU 
(http://www.sarnepi.it/wp-content/uploads/2012/05/linee-guida-ANALG-SED-baroncini-
2012-.pdf).  The  optional  switch  to  enteral  drugs  (methadone,  morphine,  lorazepam)  may 
facilitate patient’s management even without venous access. Enteral drugs, in the same way 
as iv drugs, are subsequently reduced by 10% every 12 hours. 
The dose of 0.8 mcg/Kg/h (0.4 mcg/Kg/h for the neonate) of dexmedetomidine/placebo does 
not change unless the WAT-1 score detects symptoms of withdrawal (see 3.5.); in this case 
the dose will be increased. Every single increase equal to 0.2 mcg/Kg/h (0.1 mcg/Kg/h for the 
neonate) is kept unchanged until the next WAT-1 measurement (see details in WAT-1 score). 
The dose of dexmedetomidine/placebo, titrated to the needs, can be increased to a maximum 
of 1.4 mcg/Kg/h.  
'Acute Withdrawal Crisis'  
If the patient shows clinically significant iatrogenic withdrawal: 
- 
Clinician  administers  a  rescue  dose  of  the  opioid  and/or  benzodiazepine  in  use, 
repeatable until resolution of the crisis (see diagram below) 

 
 
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Drug 
Rescue Dose (iv)  
Methadone 
0,05 – 0,1 mg/Kg 
Morphine 
0,05 -0,1 mg/Kg 
Fentanyl 
0,5 – 2 mcg/kg 
Midazolam 
0,05 – 0,2 mg/Kg 
 
- Clinician evaluates a temporary suspension of the weaning regimen (see details in 
WAT-1 score). 
Once  analgesics  and  sedatives  weaning  is  complete,  dexmedetomidine  will  discontinue.  A 
gradual  reduction  of  the  dexmedetomidine  dose  is  strongly  recommended  to  prevent  the 
documented  risk  of  dexmedetomidine  withdrawal 16,17.  Since  dexmedetomidine  weaning  is 
not a specific analysis topic in this study no specific protocol need to be followed. 
Treatment Interruption 
The study can be interrupted at any time in case of:  
– drug sensitivity  
– intolerance 
– hemodynamic instability (see safety assessment)  
– changes in therapeutic needs  
– withdrawal of consent 
Adherence to the Treatment 
Since study treatment consists of an intravenous drug administration in patients admitted to 
PICU, the clinician investigator assumes the responsibility of adherence to the treatment. 
3.5. 
Evaluations and visits 
For each enrolled patient, continuous observation time varies from a minimum of 5 days to a 
maximum of 7 days.  

 
 
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The  indicated  daily  dose  reduction  allows  the  completion  of  analgosedation  weaning  in  5 
days. If, as hypothesized, dexmedetomidine is effective in reducing the occurrence of 
withdrawal  its  administration  will  allow  the  perfect  adherence  to  this  regime.  In  case  of 
extended weaning, further 48-hour of observation (7 days) will allow to evaluate the clinical 
trend.  
WAT-1 Assessment Tool  
The Withdrawal Assessment Tool Version 1 (WAT-1) was chosen for the following reasons: 
• it is validated in the pediatric age 
• it is reliable and has shown high sensitivity (0.87) and specificity (0.88) 
• it is easy and quick to use 
The  Italian  version  of  WAT-1  scale  will  be  administered  every  12  hours  from  the  start  of 
weaning.  
The  score  ranges  from  0  to  12.  A  WAT-1  score  <3  indicates  no  withdrawal  symptoms.  A 
score ≥3 indicates the presence of signs/symptoms of withdrawal. The severity of withdrawal 
is grading from mild to severe, proportionally to the value of the score. 
WAT-1 score 
Patients with a score of WAT-1 <3 continue the weaning regimen. 
Patients with a score ≥3 increase the dose of dexmedetomidine / placebo of 0.2 mcg / kg / h 
(neonates 0.1 mcg/Kg/h) until the subsequent WAT-1 score control and temporarily stop the 
planned 10% dose reduction. 
If the next WAT-1 score decreased by at least 1 point from the previous score, the weaning 
program restarted (10% reduction) without further changes in the dose of dexmedetomidine / 
placebo until the subsequent score. 
The 'acute withdrawal crisis' will be treated as previously indicated. 
Follow-up Visit 
Five days after discharge from PICU, a follow-up visit will be performed.  

 
 
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The following data are collected during the visit: 
- 
duration (days) of the analgosedation weaning when longer than 5 days 
- 
WAT-1 scores until 72 hours after the stop of the analgesics and sedatives  
- 
dexmedetomidine weaning (% of daily reduction) 
- 
duration (hours) of dexmedetomidine weaning 
- 
occurrence of dexmedetomidine withdrawal 
- 
signs/symptoms of dexmedetomidine withdrawal  
- 
WAT-1 scores until 72 hours after dexmedetomidine stop 
3.6. 
Assessment of the Efficacy  
The  assessment  of  the  efficacy  of  dexmedetomidine  in  reducing  the  occurrence  of  the 
withdrawal syndrome results from the evaluation of the following variables: 
- 
WAT-1 score <3 is recorded more frequently in the dexmedetomidine group 
compared to the placebo group. 
- 
in the case of a WAT-1 score ≥3, after the increase of dexmedetomidine /placebo, a 
reduction  of  1  or  more  points  at  the  next  score  is  recorded  more  frequently  in  the 
dexmedetomidine group compared to the placebo group. 
- 
number  of  rescue  doses  is  lower  in  the  dexmedetomidine  group  compared  to  the 
placebo group. 
- 
number  of  temporary  stop  of  drug  dose  reduction  is  lower  in  the  dexmedetomidine 
group compared to the placebo group. 
3.7. 
 Assessment of the Safety  
In  the  dexmedetomidine  Summary  of  Product  Characteristics  (SPC)  the  most  frequently 
reported Adverse Reactions are hypotension, hypertension, and bradycardia. Patients enrolled 
in the study are admitted to the Pediatric Intensive Care Unit, as part of routine care they are 
usually  continuous  monitored  and  vital  parameters  as  cardiac  frequency,  blood  pressure, 
oxygen saturation, respiration rate, body temperature and glycemia are regularly recorded.  

 
 
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For the purposes of the study changes in heart rate and blood pressure will be recorded when 
their value differs more than 20% by the patient's baseline values.  
All Adverse Reactions listed in the SPC (hyperglycemia, hypoglycemia, metabolic acidosis, 
hypoalbuminemia,  dyspnea,  hypothermia,  hyperthermia)  will  be  carefully  monitored  and 
reported. 
Adverse Reactions (AR) are all those adverse events for which there is reasonable suspicion 
that a causal relationship may exist with the investigational medicinal product in the opinion 
of the investigators or of the clinical trial promoter. 
Safety  will  also  be  assessed  through  monitoring  and  recording  in  the  appropriate  CRF  of 
Adverse Events, Serious Adverse Events and Suspected Unexpected Serious Adverse 
Reactions (SUSARs). 
An  Adverse  Event  (AE)  is  any  sign,  symptom,  damaging  reaction  or  undesirable  clinical 
condition  occurring  after  the  start  of  the  experimental  treatment,  during  any  phase  of  the 
study, AE does not entail a causal relationship with the study drug. 
Investigators  are  responsible  for  the  collection  and  notification  of  all  adverse  events  and 
adverse reactions to the Promoter. 
The  Promoter  will  evaluate  the  severity  of  the  event,  the  causal  relationship  between  the 
experimental medicinal product and the event considered, and whether the event is expected 
or not expected with respect to the information contained in the SPC of the product. 
 Evaluation of severity 
An adverse event or an adverse reaction is serious when it meets one or more of the following 
criteria: 
– it is fatal;  
– it is life-threatening;  
– it lengthens hospital stay;  
– it entails important and persistent disability, although not necessarily permanent;  

 
 
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– it requires medical or surgical intervention. 
Evaluation of causality 
The assessment of causality aims to establish whether there is a reasonable possibility that the 
experimental product has caused or contributed to an event. 
In particular, the Promoter will have to define whether the event is related to the 
investigational medicinal product: 
– unrelated 
– probably unrelated 
– possibly related 
– probably related. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
It  is  defined  as  Suspected  Unexpected  Serious  Adverse  Reaction  (SUSAR)  an  Adverse 
Reaction to the experimental drug when it is serious and unexpected. 
All SUSARs that occurred during the clinical trial will be registered by the Promoter in the 
EudraVigilance Clinical Trial Module database and transmitted to the Ethics Committee as 
follows: 
– within 7 days SUSAR fatal or life threatening 
– within 15 days all the others. 
Reference Safety Information (RSI) 
Reference Safety Information (RSI) for the purpose of reporting SUSARs is contained in the 
SPC. 
Development Safety Update Report (DSUR) 
The annual review of the Reference Safety Information related to the investigational 
medicinal  product,  will  be  transmitted  by  the  Promoter  to  the  Italian  Medicines  Agency 
(AIFA) and to the Ethics Committees involved once a year. 

 
 
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3.8. Evaluation of Risk-Benefit Ratio 
The potential and known risks associated with study participation include: 
– risks associated with the investigational medicinal product illustrated in the SPC of the 
dexmedetomidine 
– risk of withdrawal syndrome during dexmedetomidine weaning 
Diagnostic procedures do not constitute an additional risk, as they do not differ from the usual 
ones within the care path in the PICU.  
There is no risk of worsening of the withdrawal syndrome because the use of the drug/placebo 
in the study does not replace the recommended treatment, but is added to it. 
The potential benefits associated with participation in the study will depend on the 
demonstration of the study hypothesis and may include: 
- prevention and/or control of the withdrawal syndrome 
- reduction of duration of analgosedation weaning  
- reduction of length of PICU stay  
- improvement of neurocognitive outcomes. 
4. 
Data Management and Statistical Analysis 
4.1. Data management plan 
The Investigators and blinded staff of the PICU collect and record data on paper case report 
forms (CRFs). Paper CRFs will be stored within a locked cabinet/office in accordance with 
local and national regulations. Paper CRFs will have an identifiable patient data page in order 
to  allow  follow-up  of  clinical  outcomes  and  data  possibly  monitoring  visits  by  national 
coordinators or regulatory committees. Investigators onto an electronic CRF using the 
identification  code  will  transcribe  these  data.  No  patient  identifiable  data  will  be  directly 
accessible from the electronic CRF. 
The  data  recorded  on  the  CRF  will  be  entered  in  a  dedicated  database,  checked  and 
subsequently processed. 

 
 
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4.2 
Statistical analysis 
!  Characteristics, treatments and comorbidities  
The data collected by all participating centers will be grouped and summarized in relation to 
the demographic and clinical variables considered and to the efficacy and safety assessments. 
Descriptive data analysis will be performed using: means and standard or median deviations 
and range for continuous variables, frequencies, and percentages for categorical variables. 
The population who completed the study without any major protocol violations will be the 
one used for the analysis of primary and secondary efficacy variables and safety variables. 
Furthermore, analytical lists will be produced that show detailed information regarding: 
– patients who discontinued the study and related reasons 
– patients who discontinued the study due to adverse events or adverse reactions 
A two-sided P-value of less than 0.05 indicates statistical difference. 
!  Efficacy evaluation: primary outcome assessment 
The main variable is the WAT-1 score recorded every 12 hours during the observation period. 
In particular patients with a WAT-1 score <3 do not have withdrawal symptoms, patients with 
a score ≥ 3 show mild to severe withdrawal symptoms in proportion to the score value. 
Patients with a score of ≥3 that decreased by at least 1 point at the next measurement can be 
considered with controlled or improving symptoms and can continue the weaning program.  
Considering  the  WAT-1  score  patients  will  be  divided  into  two  outcomes  groups  (yes  /  no 
efficacy). 
The group "yes efficacy" will include both patients who maintain score <3 by administering 
the treatment (dexmedetomidine/placebo) at initial dose without variation, and those patients 
who respond to the increase in treatment dosage (dexmedetomidine/placebo) with the 
decrease in WAT -1 score of at least 1 point. 
For each treatment the % of efficacy cases will be calculated and association with outcome 
will be investigated through the Pearson’s χ2 test or the Fisher’s Exact test.  

 
 
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The  two  outcomes  groups  will  also  compared  on  the  basis  of  the  other  variables  collected, 
using Pearson’s χ2 test or Fisher’s Exact test for categorical variables, the t-test for 
parametric  variables  with  normal  distribution,  and  the  Wilcoxon  test  or  Mann-Whitney 
nonparametric test for continuous variables. 
Furthermore, a Univariate Logistic Regression model will be estimated to quantify the effect 
of treatment on outcome and a Multivariate model to see if the association between treatment 
and outcome remains while considering possible confounding factors. 
!  Efficacy evaluation: secondary outcomes 
Considering 
the 
treatment 
patients 
were 
divided 
into 
two 
treatment 
groups 
(dexmedetomidine/placebo) and compared evaluating the following variables: 
– number of rescue doses for acute withdrawal symptoms  
– number of temporary stops of the drugs weaning  
– duration (days) of the drugs weaning  
– duration (days) of the mechanical ventilation  
– PICU length of stay (days)  
– comparison of efficacy between age groups, sex, race, PIM3 score, length (hours) 
of analgesia and sedation 
– effective dose range  
– adverse events/reactions 
For continuous variables, the central trends (mean or median) will be compared, using t-test in 
the event of normal distribution or non-parametric test of Wilcoxon Mann-Whitney otherwise. 
For categorical variables, the Pearson χ2 test or the Fisher Exact test will be used.  
In the presence of a significant difference between the two treatment groups, the association 
will be further investigated using regression models, as with the primary variable.  

 
 
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!  Safety Evaluation 
The  safety  evaluation  will  be  established  on  the  frequency  of  adverse  events  and  reported 
adverse reactions.  
Patients who have had adverse events/reactions and have discontinued the study will be listed; 
furthermore,  information  on  severity,  unpredictability  and  a  causal  relationship  will  be 
collected and listed.  
In the two treatment groups, the frequencies of the adverse events/reaction will be compared.  
Changes in heart rate and blood pressure will be recorded in the CRF when their value differs 
by more than 20% of the patient's baseline value. 
!  Sample size 
The study was designed to demonstrate the effectiveness of dexmedetomidine during weaning 
from analgesic and sedative drugs in reducing the occurrence of withdrawal syndrome.  
A recent multicenter national study reported an incidence of 64.6% of withdrawal syndrome 
in Italian PICUs.  
Sample size was calculated considering this incidence and estimating that dexmedetomidine 
could reduce the withdrawal syndrome by 29%. Assuming a confidence interval of 95% and a 
potency of 95% a number equal to 77 patients was calculated for each of the 2 groups for a 
total population of the study of 154 patients. To ensure correct balancing of the randomization 
160 patients will be enrolled.  
5. 
Administrative proceedings 
Standards of Good Clinical Practice 
This study will be conducted in accordance with the principles of Good Clinical Practice, the 
Helsinki Declaration and national regulations on the conduct of clinical trials. By signing the 
protocol, the Promoter agrees to adhere to the procedures and instructions contained therein 
and  to  carry  out  the  study  according  to  GCP,  the  Helsinki  Declaration  and  the  national 
regulations governing clinical trials. 

 
 
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Amendments or any other modification to the protocol of the study 
Any  changes  to  the  study  protocol  will  be  made  by  amendment.  During  the  study  period, 
modifications to the protocol are not permitted. Any unexpected changes in the conduct of the 
study will be recorded in the "Clinical Study Report". 
Ethics committees and Informed Consent 
The Ethics Committee of each Center must approve the study protocol, any protocol 
amendment, informed consent, and any other information for patients. 
The  Investigator  can  immediately  apply  an  amendment  upon  written  communication  to  the 
Ethics Committee without waiting for the approval of the Ethics Committee if the patient’s 
safety  is  at  risk.  Furthermore,  if  the  Investigator  believes  that  for  safety  it  is  necessary  to 
immediately  change  the  protocol,  he  must  inform  the  Promoter  and  the  Ethics  Committee 
within 10 working days. 
To participate in the study each patient must provide written informed consent. 
Archive of the study documents  
The Investigator is responsible for archiving and storing the essential documents of the study, 
before,  during  the  conduction  and  after  the  completion  or  the  interruption  of  the  study,  as 
defined by the current legislation and by the Good Clinical Practice. 
The data collected on the CRF will be strictly anonymous and each patient enrolled will only 
be identified with a number and with the initials. 
The Investigator must retain the patient's original data (demographic and medical information, 
laboratory data etc.) and a copy of the signed informed consent.  

 
 
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Emergency procedures for the suspension of blindness 
During the study, two sealed copies of the list of randomization codes will be available for 
emergencies: a sealed list will be kept in the archive of the Investigational Drug Service of the 
Coordinating Center and the other at the archive of the Principal Investigator of participating 
centers. 
The  list  of  randomization  codes  clearly  shows  the  treatment  attributed  to  the  patient.  The 
Investigator must document the reason for opening the sealed copy of the list of 
randomization codes, the date/time and sign the code that was opened. 
The Investigator must also immediately notify the Promoter of the study. 
Inspection 
Regulatory Authorities may conduct inspections during the study to ensure that it is 
conducted in accordance with the protocol and applicable regulatory provisions. 
If  a  Regulatory  Authority  requires  an  inspection,  the  Investigator  must  immediately  inform 
the  Promoter  of  the  study.  By  signing  the  protocol,  the  Investigator  consents  both  to  the 
verification by the Promoter of the study and to the Regulatory Authority. 
Investigational medicinal product management 
The  investigational  medical  product  will  be  provided  as  packaged  on  market.  The  solution 
that contains the drug will be prepared and managed by non-blinded staff. 
The Investigator must ensure that the study drug is used in accordance with the protocol.  
The storage conditions indicated on the packaging of the drug must be respected. 
Publication of results 
Any formal presentation or publication of data derived from this study should be understood 
as  a  joint  publication  by  the  Promoter  of  the  study  and  by  Investigators.  For  multicenter 
studies, it is mandatory that the first publication is based on data from all the centers, analyzed 
according  to  protocol.  Experimenters  who  participate  in  multicenter  studies  agree  not  to 
submit data from a single center or a small group of centers unless there is a formal consent 
from the other Investigators and the Promoter. 

 
 
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The  Promoter  of  the  study  must  receive  a  copy  of  any  communication  in  advance  on  the 
publication itself. 
Confidentiality and Privacy 
The  documents  of  the  study  must  be  kept  in  a  safe  place  to  ensure  the  maintenance  of 
confidentiality and privacy, cannot be disclosed to others without written permission of the 
Promoter of the study except to the extent necessary to obtain the consent of the patient to 
participate in the study. 
Investigators and co-Investigator 
Investigators and co-Investigator are listed in the List of Centers document. 
 
6. 
Bibliography  
1. Anand  KJ,  Wilson  DF,  Berger  J  et  al.  Tolerance  and  withdrawal  from  prolonged 
opioid use in critically ill children. Pediatrics. 2010 May;125(5):e1208-25. 
2. Tobias JD. Tolerance, withdrawal, and physical dependency after long-term sedation 
and  analgesia  of  children  in  the  pediatric  intensive  care  unit.  Crit  Care  Med.  2000 
Jun;28(6):2122-32. 
3. Birchley  G.  Opioid  and  benzodiazepine  withdrawal  syndromes  in  the  paediatric 
intensive care unit: a review of recent literature. NursCrit Care. 2009 Jan-
Feb;14(1):26-37. 
4. Franck LS, Scoppettuolo LA, Wypij D, Curley MA. Validity and generalizability of 
the  Withdrawal  Assessment  Tool-1  (WAT-1)  for  monitoring  iatrogenic  withdrawal 
syndrome in pediatric patients. Pain. 2012 Jan;153(1):142-8. 
5. Ista E, van Dijk M, de Hoog M, Tibboel D, Duivenvoorden HJ. Construction of the 
Sophia  Observation  withdrawal  Symptoms-scale  (SOS)  for  critically  ill  children. 
Intensive Care Med. 2009 Jun;35(6):1075-81. 
6. Amigoni  A,  Vettore  E,  Brugnolaro  V  et  al  .High  doses  of  benzodiazepine  predict 
analgesic and sedative drug withdrawal syndrome in paediatric intensive care patients. 
ActaPaediatr. 2014 Dec; 103(12):e538-43. 

 
 
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7. Johnson PN, Boyles KA, Miller JL. Selection of the initial methadone regimen for the 
management of iatrogenic opioid abstinence syndrome in critically ill children. 
Pharmacotherapy. 2012 Feb;32(2):148-57. 
8. Honey BL, Benefield RJ, Miller JL, Johnson PN. Alpha2-receptor agonists for 
treatment  and  prevention  of  iatrogenic  opioid  abstinence  syndrome  in  critically  ill 
patients. Ann Pharmacother. 2009 Sep;43(9):1506-11. 
9. Oschman A, McCabe T, Kuhn RJ. Dexmedetomidine for opioid and benzodiazepine 
withdrawal in pediatric patients. Am J Health Syst Pharm. 2011 Jul 1;68(13):1233-8. 
10. Su  F,  Hammer  GB.  Dexmedetomidine:  pediatric  pharmacology,  clinical  uses  and 
safety. Expert Opin Drug Saf .2011 Jan;10(1):56-66. 
11. Mason KP, Lerman J. Review article: Dexmedetomidine in children: current 
knowledge and future applications. Anesth Analg. 2011 Nov;113(5):1129-42. 
12. Plambech MZ, Afshari A. Dexmedetomidine in the pediatric population : A review. 
Minerva Anestesiol. 2014 May 14. Epub ahead of print. 
13. Cummings BM, Cowl AS, Yager PH, Saleeby CM, Shank ES, Noviski N. 
Cardiovascular Effects of Continuous Dexmedetomidine Infusion Without a Loading 
Dose in the Pediatric Intensive Care Unit J Intensive Care Med. 2014 Jun 12. 
14. Whalen LD, Di Gennaro JL, Irby GA, Yanay O, Zimmerman JJ. Long-term 
dexmedetomidine  use  and  safety  profile  among  critically  ill  children  and  neonates. 
Pediatr Crit Care Med. 2014 Oct;15(8):706-14. 
15. Chrysostomou C, Schulman SR, Herrera Castellanos M et al. A phase II/III, 
multicenter, safety, efficacy and pharmacokineticstudy of dexmedetomidine in 
preterm and termneonates. J Pediatr. 2014 Feb;164(2):276-82. 
16. CarneyL,  Kendrick  J,  Carr  R.  Safety  and  effectiveness  of  dexmedetomidine  in  the 
Pediatric Intensive Care Unit (SAD-PICU). Can J Hosp Pharm. 2013 Jan;66(1):21-7. 
17. Tobias JD.  Dexmedetomidine: are there going to be issues with prolonged 
administration? J Pediatr Pharmacol Ther. 2010 Jan;15(1):4-9.