Clinical trial NCT02757625
Conditions: ICU Sedation
Sponsor: Pfizer
Start date: 2016-07-20; Completion date: 2017-05-24
Enrollment: 63 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
To evaluate the efficacy, safety, and pharmacokinetics of dexmedetomidine given as continuous IV infusion in pediatric subjects \[≥ 45 weeks CGA (corrected gestational age) to \<17 years old\] requiring sedation under intensive care unit

Detailed description:

Arms: arm 1: A single vial contains an injection solution with 2 mL of dexmedetomidine hydrochloride solution (100 µg/mL as dexmedetomidine) dissolved in physiological saline
Interventions: intervention 1: Dexmedetomidine hydrochloride
Intervention descriptions: intervention 1: * 45 weeks CGA to \< 6 years old: Maintenance infusion will be started at 0.2 µg/kg/h. The infusion rate will be adjusted within a range of 0.2 to 1.4 µg/kg/h according to the pediatric subject's sedative state
* 6 years old to \< 17 years old: Maintenance infusion will be started at 0.2 µg/kg/h. The infusion rate will be adjusted within a range of 0.2 to 1.0 µg/kg/h according to the pediatric subject's sedative state

Protocol documents:
Prot_000.pdf: 
DA-9501
C0801017 (ZIN-DEX-1506)
Protocol Amendment 2, 24-Mar-2016 (English translation version, 21-Dec-2016)
Page 1
CLINICAL STUDY PROTOCOL
PHASE 3, MULTI-CENTER, SINGLE-ARM, OPEN-LABEL STUDY EVALUATING 
THE EFFICACY, SAFETY, AND PHARMACOKINETICS OF DA-9501 
(DEXMEDETOMIDINE HYDROCHLORIDE) IN PEDIATRIC SUBJECTS
IN THE INTENSIVE CARE UNIT
Compound:
DA-9501
Compound Name:
Dexmedetomidine hydrochloride
United States (US) Investigational 
New Drug (IND) Number:
N/A
European Clinical Trials 
Database (EudraCT) Number:
N/A
Protocol Number:
C0801017
Phase:
Phase 3
This protocol (English translation version, 21-Dec-2016) is intended to assist understanding of the 
original version of the protocol (Japanese version, 24-Mar-2016), and all implementation procedures 
and judgment standards should be in accordance with the descriptions in the original version.
Pfizer Japan Inc.
Maruishi Pharmaceutical Co., Ltd.


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Document History
Document
Version Date
Summary of Changes
Amendment 2
24-Mar-2016

Primary analysis population for 
efficacy endpoints was changed from 
efficacy evaluation population to full 
analysis set.

Data collection of non-drug treatment 
was added.
Amendment 1
10-Feb-2016

The clinical study protocol template 
was changed from the Hospira 
version to the Pfizer version.

Laboratory tests were all changed to 
in-hospital tests.

Other administrative changes were 
made.
Original protocol
27-Jan-2016
Not applicable (N/A)


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TABLE OF CONTENTS
TABLE OF CONTENTS.......................................................................................................... 3
LIST OF TABLES.................................................................................................................... 6
LIST OF FIGURES .................................................................................................................. 7
1. INTRODUCTION .............................................................................................................. 16
1.1. Mechanism of Action/Indication............................................................................ 16
1.2. Background ............................................................................................................ 16
1.3. Non-Clinical Studies .............................................................................................. 17
1.4. Clinical Studies (from the Investigator’s Brochure) .............................................. 18
1.5. Rationale for This Study......................................................................................... 21
1.5.1. Study Population........................................................................................ 22
1.5.2. Dose Levels and Infusion Rates ................................................................ 22
1.6. Risks/Benefits......................................................................................................... 23
2. STUDY OBJECTIVES AND ENDPOINTS...................................................................... 24
2.1. Objectives............................................................................................................... 24
2.2. Endpoints................................................................................................................ 24
2.2.1. Primary Efficacy Endpoint ........................................................................ 24
2.2.2. Secondary Efficacy Endpoints................................................................... 24
2.2.3. Safety Endpoints........................................................................................ 26
27
3. STUDY DESIGN................................................................................................................ 27
4. SUBJECT SELECTION..................................................................................................... 27
4.1. Inclusion Criteria.................................................................................................... 28
4.2. Exclusion Criteria................................................................................................... 29
4.3. Criteria Lifestyle Guidelines .................................................................................. 30
4.4. Sponsor’s Appropriately Qualified Medical Personnel.......................................... 32
5. STUDY TREATMENTS.................................................................................................... 32
5.1. Allocation to Investigational Product..................................................................... 32
5.2. Medication Compliance ......................................................................................... 32
5.3. Investigational Product........................................................................................... 32
5.3.1. Dosage Form and Packaging Form of Investigational Product................. 33
5.3.2. Preparation and Dispensing ....................................................................... 33
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5.4. Administration of Investigational Product ............................................................. 33
5.5. How to Deal With Overdose .................................................................................. 34
5.6. Investigational Product Storage.............................................................................. 34
5.7. Investigational Product Accountability.................................................................. 35
5.7.1. Destruction of Investigational Product Supplies ....................................... 35
5.8. Concomitant Therapies........................................................................................... 35
5.8.1. Prohibited Concomitant Drugs .................................................................. 35
5.8.2. Restricted Concomitant Drugs................................................................... 36
5.9. Rescue Sedatives and Rescue Analgesics .............................................................. 36
6. STUDY PROCEDURES .................................................................................................... 37
6.1. Screening (1 to 7 Days Before Start Date of Treatment With Investigational 
Product) .................................................................................................................... 37
6.2. Treatment Period.................................................................................................... 39
6.2.1. Baseline (Start Date of Treatment With Investigational Product)............. 39
6.2.2. From Start of Dosing to 24 Hours After Dosing or End of Mechanical 
Ventilation....................................................................................................... 39
6.2.3. From 24 Hours After Dosing to End of Mechanical Ventilation .............. 40
6.2.4. From End of Mechanical Ventilation to End of Dosing of 
Investigational Product ................................................................................... 41
6.2.5. 24 Hours (± 5 min) After End of Dosing of Investigational product ........ 41
6.2.6. At Early Discontinuation of Study ............................................................ 42
6.3. Follow-up Period.................................................................................................... 42
6.4. Criteria and Procedure for Subject Withdrawal From Study................................. 42
7. ASSESSMENTS................................................................................................................. 44
7.1. Efficacy Evaluation................................................................................................ 44
7.1.1. Rescue Sedatives and Rescue Analgesics.................................................. 44
7.1.2. Sedation Assessment ................................................................................. 44
7.1.3. Ventilator Setting....................................................................................... 46
7.2. Safety Evaluation ................................................................................................... 47
7.2.1. Physical Examination ................................................................................ 47
7.2.2. Core Body Temperature ............................................................................ 47
7.2.3. Body Weight.............................................................................................. 47
7.2.4. Vital Signs (BP, HR, RR), SpO2, and ETCO2........................................... 47


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7.2.5. 12-Lead ECG and ECG Monitoring.......................................................... 48
7.2.6. Laboratory Tests; Pregnancy Test ............................................................. 48
7.2.7. Total Input/Output Fluid Volume.............................................................. 49
7.2.8. Adverse Events; Serious Adverse Events.................................................. 49
49
49
8. ADVERSE EVENT REPORTING..................................................................................... 50
8.1. Adverse Events....................................................................................................... 50
8.2. Reporting Period..................................................................................................... 50
8.3. Definition of an Adverse Event.............................................................................. 51
8.4. Medication Error .................................................................................................... 52
8.5. Abnormal Test Findings......................................................................................... 53
8.6. Serious Adverse Events.......................................................................................... 53
8.6.1. Protocol-Specified Serious Adverse Events .............................................. 54
8.6.2. Potential Cases of Drug-Induced Liver Injury........................................... 54
8.7. Hospitalization........................................................................................................ 55
8.8. Severity Assessment............................................................................................... 56
8.9. Causality Assessment............................................................................................. 56
8.10. Exposure During Pregnancy (EDP) ..................................................................... 57
8.11. Occupational Exposure......................................................................................... 58
8.12. Withdrawal Due to Adverse Events (See Also the Section on Subject 
Withdrawal).............................................................................................................. 58
8.13. Eliciting Adverse Event Information ................................................................... 58
8.14. Reporting Requirements....................................................................................... 58
8.14.1. Serious Adverse Event Reporting Requirements .................................... 58
8.14.2. Nonserious Adverse Event Reporting Requirements .............................. 59
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities ............... 59
9. STATISTICAL ANALYSES ............................................................................................. 59
9.1. Analysis Populations.............................................................................................. 59
9.1.1. Efficacy Evaluation Population................................................................. 60
9.1.2. Safety Analysis Population (Full Analysis Set)......................................... 60
60
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9.2. Sample Size Setting................................................................................................ 60
9.3. Efficacy Analysis ................................................................................................... 62
9.3.1. Analysis of Primary Endpoint ................................................................... 62
9.3.2. Analysis of Secondary Endpoints.............................................................. 63
9.4. Safety Analysis....................................................................................................... 63
9.5. Pharmacokinetics.................................................................................................... 63
9.6. Interim Analysis ..................................................................................................... 63
9.7. Data Monitoring Committee (DMC)...................................................................... 63
9.8. Early Discontinuation of Study.............................................................................. 63
10. QUALITY CONTROL AND QUALITY ASSURANCE................................................ 63
11. DATA HANDLING AND RECORD KEEPING ............................................................ 64
11.1. Case Report Forms/Electronic Data Record ........................................................ 64
11.2. Record Retention.................................................................................................. 65
12. ETHICS............................................................................................................................. 65
12.1. Institutional Review Board/Ethics Committee..................................................... 65
12.2. Ethical Conduct of the Study................................................................................ 65
12.3. Subject Information and Consent......................................................................... 66
12.4. Subject Recruitment ............................................................................................. 67
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
.................................................................................................................................. 67
13. DEFINITION OF END OF TRIAL.................................................................................. 67
14. SPONSOR DISCONTINUATION CRITERIA ............................................................... 67
15. PUBLICATION OF STUDY RESULTS ......................................................................... 67
15.1. Publications by Sponsor....................................................................................... 67
15.2. Publications by Investigators................................................................................ 68
16. REFERENCES ................................................................................................................. 70
LIST OF TABLES
Table 1.
Schedule of Study Activities ............................................................................... 11
Table 2.
ASA Classification .............................................................................................. 28
Table 3.
Centiles of Heart Rate (HR) in Children ............................................................. 29
Table 4.
Centiles of Respiratory Rate (RR) in Children25 ................................................. 43


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Table 5.
State Behavioral Scale (SBS) .............................................................................. 46
Table 6.
Measurement Items for Laboratory Tests............................................................ 49
60
. 61
Table 9.
Efficacy Percentages in U.S. Pediatric Dose-Response Study............................ 62
LIST OF FIGURES
Figure 1.
Elective Surgical Subjects ................................................................................... 27
Figure 2.
Medical ICU Subjects.......................................................................................... 27
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PROTOCOL SUMMARY
Study Objectives: To evaluate the efficacy, safety, and pharmacokinetics (PK) of DA-9501 
(dexmedetomidine hydrochloride; hereinafter referred to as “dexmedetomidine”) administered as continuous 
intravenous injection (IV) infusion in pediatric subjects (45 weeks CGA [corrected gestational age] to <17 
years old) who require sedation in the intensive care unit.  
Study Design: Phase 3, multi-center, single-arm, open-label study evaluating the efficacy, safety, and PK of 
dexmedetomidine administered as continuous IV infusion in pediatric subjects aged 45 weeks CGA to <17 
years old
Study Patients: Target number of subjects: 60 subjects
Of these subjects, at least 32 subjects aged 45 weeks CGA to <17 years old will be included in the PK 
evaluation. The target numbers of subjects included in the efficacy/safety evaluation and in the PK evaluation
by age group are shown in the table below. 
Age group
Efficacy/safety 
evaluation:
Target number of 
subjects
PK evaluation:
Target number of 
subjects*
I
45 weeks CGA,<12 months
8
8
II
12 months, <24 months
16
8
III
2 years, <6 years
16
8
IV
6 years, <17 years
8
8
Target number of subjects
60
32
* Of enrolled subjects, those from whom informed consent for blood sampling for PK evaluation is obtained 
Investigational Product and Dosage/Administration:
Investigational product: DA-9501 (dexmedetomidine hydrochloride)
Dosage/administration:
≥45 weeks CGA to <6 years old: Start maintenance administration at 0.2 µg/kg/h. The infusion rate will 
be adjusted within a range of 0.2 to 1.4 µg/kg/h according to the pediatric subject’s sedative state.
≥6 years to <17 years old: Start maintenance administration at 0.2 µg/kg/h. The infusion rate will be 
adjusted within a range of 0.2 to 1.0 µg/kg/h according to the pediatric subject’s sedative state.
<Target Sedation Depth>
During mechanical ventilation: SBS −2 to 0; After extubation: SBS −1 to 0
Duration of Treatment with Investigational Product: The duration of treatment will be up to 28 days.
Efficacy Endpoints: 

Primary Efficacy Endpoint: 
The following item for the period from the start of dosing of the investigational product to 24 hours of 
dosing or to the end of mechanical ventilation (when mechanical ventilation ends within 24 hours of 
dosing of the investigational product):
-
Percentage of subjects who did not use a rescue sedative (midazolam) during mechanical 
ventilation to achieve/maintain adequate sedation (efficacy percentage)

Secondary Efficacy Endpoints: 
The following item for the period from the start of dosing of the investigational product to 24 hours of 
dosing or to the end of mechanical ventilation (when mechanical ventilation ends within 24 hours of 
dosing of the investigational product):
-
Percentage of subjects who did not require administration of a rescue analgesic (fentanyl) 


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during mechanical ventilation in addition to administration of the investigational product
-
Total amount and weight adjusted total amount of rescue sedative/analgesic during 
mechanical ventilation
-
Absolute time and its percentage that subject was in the target sedation level during 
mechanical ventilation
The following items for the period from 24 hours of dosing of the investigational product to the end of 
mechanical ventilation (in subjects whose period of dosing of the investigational product exceeds 24 
hours):
-
Percentage of subjects who did not use a rescue sedative during mechanical ventilation to 
maintain/achieve adequate sedation 
-
Percentage of subjects who did not require dosing of a rescue analgesic during mechanical 
ventilation in addition to dosing of the investigational product
-
Total amount and weight adjusted total amount of rescue sedative/analgesic during 
mechanical ventilation 
-
Absolute time and its percentage that subject was in the target sedation level during 
mechanical ventilation
The following items for the period from extubation to the end of dosing of the investigational product:
-
Absolute time and its percentage that subject was in the target sedation level after extubation
-
Total amount of rescue sedative/analgesic
The following item for the period from the start of dosing of the investigational product to the end of 
mechanical ventilation:
-
Time until the end of mechanical ventilation
The evaluation will be performed by age group in addition to all subjects.
Safety Endpoints: 
-
Adverse events
-
Vital signs (blood pressure, heart rate, respiratory rate), SpO2, ETCO2, core body temperature, and 
body weight 
-
Laboratory test values
-
Total Input/Output Fluid Volume 
-
Occurrence of withdrawal symptoms (presence/absence of hypertension, tachycardia, or agitation 
symptoms after the end of dosing of the investigational product)
-
Electrocardiogram (ECG)
The evaluation will be performed by age group in addition to all subjects.
Statistical Methods: 
Analysis for Primary Efficacy Endpoints:
Efficacy percentage of dexmedetomidine (percentage of subjects who did not use a rescue sedative 
(midazolam) during mechanical ventilation to achieve/maintain adequate sedation) and its 95% confidence 
interval will be calculated, and the 95% lower confidence limit will be compared to the threshold value (40%).
Primary efficacy analysis will be performed for full analysis set. As secondary analysis, a similar analysis will 
be performed for the efficacy evaluation population.  Efficacy percentages will be calculated by age group as 
well..
Analysis for Secondary Efficacy Endpoints:
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Continuous variables will be summarized by using basic statistics such as mean, median, standard deviation
and range. For categorical variables, the number of subjects and its percentage will be summarized.  The 
analyses will be performed for whole subjects as well as for age groups.
Analysis for Safety Endpoints:
Safety evaluation will be performed for items such as changes from baseline. Also, the evaluation will be 
summarized based on “Pfizer Data Standards (PDS)” and  investigated clinically. The analyses will be 
performed for whole subjects as well as for age groups.


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SCHEDULE OF ACTIVITIES
The schedule of activities table provides an overview of the protocol visits and procedures.  
Refer to the Study Procedures and Assessments sections of the protocol for detailed 
information on each procedure and assessment required for compliance with the protocol.
The investigator may schedule visits (unplanned visits) in addition to those listed on the 
schedule of activities, in order to conduct evaluations or assessments required to protect the 
well-being of the subject.
Table 1.
Schedule of Study Activities
Item
Screening 
(1 to 7 days 
before BL)
Baseline
(BL)*
From start of 
dosing to 24 
hours after 
dosing or end 
of mechanical 
ventilation**
From 24 
hours after 
dosing to end 
of mechanical 
ventilation***
From end of 
mechanical 
ventilation to 
end of dosing 
of 
investigational 
product****
24 hours (±5 
min) after end 
of dosing of 
investigational 
product
Follow-up 
period (28 
days after end 
of dosing of 
investigational 
product)
Informed consent1
X
Subject registration
X
Inclusion/exclusion 
criteria
X
Subject 
demographics/medical 
history
X
Surgery/actions, primary 
disease name, etc.
X
X
Physical examination
X
X
X
Height
X
Body weight2
X
X
X
Core body temperature3
X
X
→
→
→
X
Vital signs (BP, HR, 
RR), SpO2, ETCO2
4
X
X
→
→
→
X
12-lead ECG
X
X5
X
ECG monitoring
→
→
→
→
→
Laboratory tests 
(hematology test, blood 
biochemistry tests, 
urinalysis)
X
X6
(X): To be performed as needed.
X
Pregnancy test7
X
Ventilator setting8
→
→
Total input/output fluid 
volume
X
Sedation assessment9
X
→
→
→
X
Administration of 
investigational product
→
→
→
Rescue sedative 
assessment
→
→
→
Rescue analgesic 
assessment
→
→
→
Concomitant 
medications, Non-drug 
treatment10
X
→
→
→
→
X
Adverse events
→
→
→
X
Serious adverse events
→
→
→
→
→
→


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Item
Screening 
(1 to 7 days 
before BL)
Baseline
(BL)*
From start of 
dosing to 24 
hours after 
dosing or end 
of mechanical 
ventilation**
From 24 
hours after 
dosing to end 
of mechanical 
ventilation***
From end of 
mechanical 
ventilation to 
end of dosing 
of 
investigational 
product****
24 hours (±5 
min) after end 
of dosing of 
investigational 
product
Follow-up 
period (28 
days after end 
of dosing of 
investigational 
product)
Blood sampling for 
plasma drug 
concentration11
→
→
→
→
*: In medical ICU subjects, the items for baseline will be performed before dosing of the investigational product on the start 
date of treatment with the investigational product.  In elective surgical subjects, the items will be performed after surgery.
**: If mechanical ventilation management ended within 24 hours of dosing of the investigational product.
***: If dosing of dexmedetomidine continued for 24 hours or longer and mechanical ventilation management was done.
****: If dexmedetomidine was continuously used after the end of mechanical ventilation management.  
1.
Prior to the study, written consent will be obtained from a guardian of the subject.  For subjects 7 years and older, it is 
desirable that an informed assent is also obtained from the pediatric subject him/herself when possible. 
2.
The dose level of the investigational product will be calculated based on the baseline body weight. 
3.
Core body temperature will be measured at screening, at baseline, and subsequently, every 12 hours (5 min) during 
dosing of the investigational product, at the end of dosing of the investigational product, and at 24 hours (±5 min) after the 
end of dosing of the investigational product. 
4.
Vital signs, SpO2, and ETCO2 will be measured at screening, at baseline, at 102 minutes, 202 minutes, 302 minutes, 
1 hour5 minutes, 2 hours5 minutes, 4 hours5 minutes after dosing of the investigational product, and every 4 hours5 
minutes later than 4 hours after the start of dosing. These items will be measured every 4 hours5 minutes from Day 2 of 
treatment to extubation. If the investigational product is continuously dosed after extubation, the items will be measured 
every 4 hours5 minutes until the end of dosing of the investigational product. When extubation is done, the items will be 
measured at 52 minutes before extubation, and 52 minutes, 152 minutes, 302 minutes, 1 hour5 minutes, 2 hours5 
minutes, 4 hours5 minutes, and 12 hours5 minutes after extubation. When dosing of the investigational product ends, 
the items will be measured at the end of dosing of the investigational product (+5 min), at 1 hour ± 5 minutes, 2 hours5 
minutes, and 4 hours5 minutes after the end of dosing of the investigational product, and every 4 hours5 minutes later 
than 4 hours after the end of dosing of the investigational product. In addition, the items will be measured at 52 minutes 
immediately before changing the infusion rate of the investigational product, at 52 minutes after changing the rate, and 
at 52 minutes immediately before and after dosing of the rescue sedative (midazolam) and the rescue analgesic 
(fentanyl).
5.
Baseline 12-lead ECG will be performed only in elective surgical subjects.  The item should be performed after surgery.
However, in subjects undergoing heart surgery, the item should be performed after surgery and within 90 minutes before 
the start of dosing of the investigational product. 
6.
Laboratory tests at baseline will be performed only in elective surgical subjects.  The item should be performed after 
surgery.  However, in subjects undergoing heart surgery, the item should be performed after surgery and within 90 
minutes before the start of dosing of the investigational product.  
7.
Urinalysis or blood test will be performed only in female subjects of childbearing potential.  
8.
If the mode of the ventilator was changed, the date/time of the change and the mode will be recorded.
9.
For sedation assessment, the level will be measured at baseline, at 102 minutes, 202 minutes, 302 minutes, 1 hour5 
minutes, 2 hours5 minutes, and 4 hours5 minutes after dosing of the investigational product, and every 4 hours5 
minutes later than 4 hours after the start of dosing. These levels will be measured every 4 hours5 minutes from Day 2 of 
treatment to extubation. If the investigational product is continuously dosed after extubation, the levels will be measured 
every 4 hours5 minutes until the end of dosing of the investigational product. When extubation is done, the levels will 
be measured at 52 minutes before extubation, and 52 minutes, 152 minutes, 302 minutes, 1 hour5 minutes, 2 
hours5 minutes, 4 hours5 minutes, and 12 hours5 minutes after extubation. When dosing of the investigational 
product ends, the level will be measured at the end of dosing of the investigational product (+5 min), at 1 hour5 minutes, 
2 hours5 minutes, and 4 hours5 minutes after the end of dosing of the investigational product, and every 4 hours5 
minutes later than 4 hours after the end of dosing of the investigational product. In addition, the level will be measured at 
52 minutes immediately before changing the infusion rate of the investigational product, at 52 minutes after changing 
the rate, and the level will be measured at 52 minutes immediately before administration of the rescue sedative 
(midazolam) or rescue analgesic (fentanyl) and at 52 minutes after administration.
10. All concomitant medications from 48 hours before the start of dosing of the investigational product to 24 hours after the 
end of dosing of the investigational product will be recorded. In addition, non-drug treatment from 48 hours before the 
start of dosing of the investigational product to 24 hours after the end of dosing of the investigational product will be 
recorded.


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11. Blood sampling for plasma drug concentration will be performed 1-2 hours before the end of dosing of the investigational 
product, immediately before the end of dosing of the investigational product, and at 10 minutes, 30 minutes, 2 hours, 4 
hours, and 6-8 hours after the end of dosing of the investigational product. When the dose of dexmedetomidine is tapered, 
blood sampling will be performed immediately before the start of tapering, immediately before the end of tapering, and at 
10 minutes, 30 minutes, 2 hours, 4 hours, and 6-8 hours after the end of tapering. 


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List of Abbreviations
The following is a list of abbreviations used in the protocol.
Abbreviation
Term
AE
adverse event
ALT
alanine aminotransferase
ASA
American Society of Anesthesiologists
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUCinf
area under the concentration-time curve from time zero to infinity
AUClast
area under the concentration-time curve from zero to time of last measurable 
concentration
CL
clearance
CLw
weight adjusted clearance
Cmax
maximum observed concentration
CRF
case report form
CSA
clinical study agreement
DMC
data monitoring committee
EC
ethics committee
ECG
electrocardiogram
EDP
exposure during pregnancy
ETCO2
end-tidal CO2
ETT
endotracheal tube
EudraCT
European Clinical Trials Database
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
ICH
International Conference on Harmonisation
ICU
intensive care unit
IND
investigational new drug application
INR
international normalized ratio
IRB
institutional review board
IRC
internal review committee
IUD
intrauterine device
LFT
liver function test
N/A
not applicable
PCD
primary completion date 
PD
pharmacodynamics
PK
pharmacokinetic(s)
PT
prothrombin time
SAE
serious adverse event
SBS
State Behavioral Scale
SC
subcutaneous
SIB
suicidal ideation and behavior


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Abbreviation
Term
SOP
standard operating procedure
SpO2
percutaneous oxygen saturation
SRSD
single reference safety document
t½
elimination half-life
UMSS
University of Michigan Sedation Scale
US
United States
USPI
United States package insert
Vss
steady-state volume of distribution
Vss,w
weight adjusted steady-state volume of distribution
Vd
volume of distribution


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1. INTRODUCTION
1.1. Mechanism of Action/Indication
DA-9501 (dexmedetomidine hydrochloride; hereinafter referred to as “dexmedetomidine”) is 
a potent and highly selective central 2 adrenergic receptor agonist. It is currently under 
development as a sedative for pediatric patients under intensive care.
1.2. Background
Dexmedetomidine, which is the active ingredient of this drug, is an active dextro rotatory form 
(D form) of medetomidine with an imidazole skeleton. It was discovered by the Farmos Group 
in 1986. Dexmedetomidine is a potent and highly selective central 2 adrenergic receptor 
agonist. In addition to the sedative action, the drug is known to show a wide range of 
pharmacological actions, including inhibitory action on pain or anxiety and stabilizing action 
on the circulatory dynamics through alleviation of stress-induced hyperactivity of the 
sympathetic nervous system.1, 2, 3. Also, research conducted after that time indicated that the 
dosing of this drug could result in near natural sleep4, 5 that it would be possible to ensure 
recovery of the consciousness level as necessary even when sufficient sedation was achieved 
through continuous infusion of this drug, and that it would be possible to maintain a state free 
of anxiety and pain.5, 6
Ideally, sedative drugs used in intensive care should show “good quality of sedation”, “mild 
respiratory/circulatory inhibition”, “easy adjustment of the sedation level and the ability to
awaken the patient in a short period of time following the discontinuation of dosing”, and “the 
ability to maintain analgesic activity at the same time”. 5 7, 8, 9, 10, 11
This drug shows almost none of the respiratory depression that is an issue with conventional 
sedatives,12, 13, 14 and it was first approved in the United States (US) in December 1999 for 
“Sedation of initially intubated and mechanically ventilated patients during treatment in an 
intensive care setting. Administer Precedex by continuous infusion not to exceed 24 hours 
mechanical ventilation” as a sedative that can be administered continuously not only during 
mechanical ventilation, but even after disconnection of the mechanical ventilation.15 In Japan, 
a bridging study was started in March 2000 in order to investigate the “possibility of 
extrapolating foreign clinical data to Japanese patients”, and the drug was first approved in 
January 2004 for “sedation during mechanical ventilation and following extubation in patients 
capable of early extubation and managed in the intensive care unit (ICU)”.
However, in actual clinical settings, there are many patients requiring sedation for more than 
24 hours while in the ICU, and in order to address the need for continuous dosing exceeding 24 
hours in intensive care in Japan, a long-term dosing study (phase 3 study) was started in 
October 2007 with the objective of expanding the indications to sedation in intensive care 
exceeding 24 hours. As a result, the safety and efficacy of this drug during long term dosing 
were confirmed, leading to approval of the drug in August 2010 for “Sedation during and after 
mechanical ventilation in the intensive care setting”.


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No particular issues were observed in terms of efficacy or safety in the post marketing 
surveillance, and the reexamination results on March 24, 2014 indicated that “none of the 
matters listed in Article 14, Paragraph 2, Item 3 of the Pharmaceuticals and Medical Devices 
Law (reasons for denial of approval) were applicable”.
Also, this drug causes milder respiratory depression compared with other sedatives16, 17, 18 and 
communication is possible with the patient under appropriate depth of sedation.7, 16, 17 Because 
of these characteristics, requests started to emerge from medical settings to use this drug in 
sedation during surgery or other procedures without intubation and with a local anesthetic. In 
the US, the drug has already been approved in 2008 for the indication of use in sedation during 
surgery and procedures without intubation under local anesthesia. In order to obtain approval 
for this indication in Japan, a study targeting subjects undergoing surgery or procedures
without intubation under local anesthesia such as local infiltration or conduction anesthesia as 
well as a study on subjects undergoing surgery without intubation under epidural or spinal 
subarachnoid anesthesia were started in 2011 (each study was a phase 3, randomized, 
placebo-controlled, double-blind comparative study). As a result, the efficacy and safety of 
this drug were confirmed, leading to the approval of the drug in June 2013 for “sedation of 
non-intubated patients at surgical or other procedures under local anesthesia”.
This drug is used in clinical practice to treat children as well, and the use of this drug as a 
sedative is described in guidelines such as the “Guidelines for Drug Therapy in Pediatric 
Patients with Cardiovascular Diseases” 18 and the “Guidelines for the use of Anesthesia and 
Anesthesia-related Drugs”. 19 Further, there was a request for pediatric indications for this 
drug from academic societies at the start of the “Council for Paediatric Pharmacotherapy”20, 
and in consideration of these academic society requests as well as current medical practice in 
Japan, the study is planned to obtain approval of pediatric indication in Japan.
Dexmedetomidine has been approved as a sedative in intensive care treatment of adults in 70 
countries across the world, and it has been approved for use as a sedative during surgery or 
procedures without intubation under local anesthesia in 26 countries. No approval for use of 
this drug in children has been obtained in any country.
1.3. Non-Clinical Studies
Prior to the conduct of a study in children, the following non-clinical studies in juvenile 
animals were conducted.
Dexmedetomidine was subcutaneously administered to adult and juvenile rats to determine the 
effect of age on the plasma concentration of dexmedetomidine. Dexmedetomidine was rapidly 
absorbed and eliminated. Differences in the maximum observed concentration (Cmax) and 
elimination half-life (t½) between two age groups were expected due to the metabolism rate. 
Cmax values in adult and juvenile rats were 23.816.05 ng/mL and 10.790.99 ng/mL, 
respectively, and the area under the concentration-time curve (AUC) values were
53.5 ngh/mL and 19.9 ngh/mL, respectively.  Plasma clearance (CL) values were 1.9 L/hkg 
and 5.0 L/hkg, respectively.


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Dexmedetomidine was rapidly eliminated following intravenously administration to adult and 
juvenile dogs. Differences in t½ were expected due to the metabolism rate in the 2 age groups. 
AUCs were 118.037.4 ngh/mL and 36.62.2 ng･h/mL for adult and juvenile dogs, 
respectively, and plasma CLs were 0.40.1 L/hkg and 1.20.1 L/hkg, respectively.
A repeated-dose toxicity study in juvenile beagle dogs was conducted to investigate the 
potential effects of dexmedetomidine on juvenile animals and to determine if effects were 
produced in juvenile dogs that were not found in adults. Administration of 15, 25, or 50 
g/kg/day dexmedetomidine over a 6-hour infusion period daily for 2 weeks was well tolerated 
by juvenile beagle dogs. Extending the dosing period to a 6-hour infusion had no effect on the 
tolerability or toxicity of dexmedetomidine, and these findings concur with those of the study 
in adult dogs, in which dexmedetomidine was intravenously administered as a bolus each day 
for 28-day.  The finding of increased bile acids in individual dogs receiving 15 or 25 g/kg/day
dexmedetomidine was not considered as toxicological significant, since there was no 
histopathologic evidence of hepatotoxicity, and none of the dogs in the 50 g/kg/day group
had increased bile acids.
In a neurotoxicity study in juvenile rats, dexmedetomidine administrations, at 3, 10, or 
30 g/kg, did not produce any increase in neurodegeneration, and the numbers of degenerating
cells were equivalent to saline.
Regarding other non-clinical study data, see the Investigator’s Brochure.
1.4. Clinical Studies (from the Investigator’s Brochure)
Overseas, phase 1 studies [Study W98-266 and Study CHOP] and 5 phase 2 or 3 studies 
[Studies DEX-08-01, DEX-11-01, DEX-09-08, DEX-11-06, and DEX-08-05] in pediatric 
subjects under intensive care have been completed.
A summary of a pharmacokinetic (PK) study is described below.  A phase 1, multi-center, 
open-label study to evaluate the PK and pharmacodynamics (PD) of dexmedetomidine when 
administered as a single dose preoperatively to 36 pediatric subjects aged 2 to 12 years was 
conducted (Study W98-266).  As loading doses, dexmedetomidine was intravenously infused 
at 0.33 g/kg, 0.66 g/kg, and 1 g/kg over 10 minutes.  In adults, the mean body weight 
adjusted clearance (CLw) and mean volume of distribution (Vd) for dexmedetomidine were 
0.53 L/h/kg and 1.31 L/kg, respectively, but the mean CLw and the mean volume of 
distribution at steady state (Vss) in children in this study were 0.848 L/h/kg and 1.65 L/kg, 
respectively.  Plasma protein binding ratio in the pediatric population was comparable to that 
in adults.  The ratios were 92.64% and 93.72%, respectively.  All of the children treated with 
dexmedetomidine became drowsy or sedated, and well tolerated to dexmedetomidine.  
Between the start of treatment and the start of surgery, adverse events (AEs) were observed in 
three subjects: hypertension in 1 subject and oxygen saturation <95% in 2 subjects.  
A phase 2, open-label, multi-center, dose-escalation pediatric study (Study DEX-08-01) to 
clarify the PK and PD profiles of dexmedetomidine was conducted in 2 age groups: 2 years to 
<6 years old (26 subjects) and 6 years to <17 years old (33 subjects).  Within each age group, 


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the following 4 escalating dose levels were set up: 0.25 g/kg loading dose, 0.2 g/kg/h
maintenance dose (Dose 1); 0.5 g/kg loading dose, 0.4 g/kg/h maintenance dose (Dose 2); 1 
g/kg loading dose, 0.7 g/kg/h  maintenance dose (Dose 3); and 1 g/kg loading dose,
2 g/kg/h maintenance dose (Dose 4).  A loading dose of the investigational product was to be 
given over 10 minutes, and a maintenance dose was to be given over 6 to 24 hours.  The PK 
profile demonstrated linearity and dose-proportionality among the Dose 1, Dose 2, Dose 3, and 
Dose 4 groups.  The AUC and Cmax increased in proportion to increasing dose.  The t½ in the 
Dose 1, Dose 2, Dose 3, and Dose 4 groups were 1.546 hours, 1.743 hours, 2.045 hours, and 
2.145 hours, respectively.  The overall level of sedation was higher in the Dose 4 group in 
subjects aged 6 to <17 years old compared to other treatment groups.  The most frequently 
occurring AEs in both age groups were hypokalemia, pyrexia, vomiting, and hypertension.  
One subject experienced a serious adverse event (SAE), but the event was judged to be 
“Unrelated” to the investigational product.  The 4 dose levels of dexmedetomidine studied 
were generally well-tolerated, and there were no clinically meaningful differences observed 
among dose levels in the safety profile of dexmedetomidine.
In a phase 2, randomized, open-label, single-center study (Study DEX-11-01), the PK, PD, and 
safety of dexmedetomidine were evaluated in intubated and mechanically ventilated pediatric 
subjects aged 12 months to <24 months by using 2 doses of dexmedetomidine (a loading dose 
of 0.7 g/kg immediately followed by a maintenance dose of 0.5 g/kg/h and a loading dose of 
1 g/kg immediately followed by a maintenance dose of 0.75 g/kg/h).  A loading dose was to 
be given over 10 minutes and a maintenance dose was to be given over 6 to 24 hours.  The 
exposure to dexmedetomidine (Cmax and AUC) was considered to be related to the dose, 
whereas the t½, CL, and Vd were not dependent of the dose.  Observed time to reach maximum 
plasma concentration (Tmax) was generally 0.08 hours before the end of the loading dose, and 
was fairly consistent across all subjects and dose groups.  The maintenance doses of 
dexmedetomidine used in this study were moderately effective for sedating and keeping 
subjects comfortable.  Compared to Dose level 2 subjects, Dose level 1 subjects spent 
considerably less time in the target University of Michigan Sedation Scale (UMSS) range of 2 
to 4, but had lower total Faces, Legs, Activity, Cry and Consolability (FLACC) scores.  
Dexmedetomidine was safe and well tolerated at both dose levels.  One of the 5 enrolled 
subjects experienced mild AEs of pyrexia and atelectasis, but both were assessed as 
“Unrelated” to dexmedetomidine.
In a Phase 2/3 open-label, multicenter, safety, efficacy and PK study, dexmedetomidine were 
administered as an intravenous injection (IV) loading dose followed by a continuous IV
infusion, in initially intubated and mechanically ventilated neonates ages 28 weeks to 44 
weeks gestational age (GA), in a neonatal, cardiac, or pediatric intensive care unit (CICU or 
PICU) (Study DEX-09-08).  Subjects were divided into 2 age groups (premature neonates 28 
weeks to <36 weeks GA and term neonates 36 weeks to 44 weeks GA). Within each group, 
there were 3 escalating dose levels (consisting of a loading dose immediately followed by a 
maintenance dose up to 24 hours).  The results of the PK analysis suggested that the body 
weight adjusted volume of distribution at steady state (Vss,w) and t½ were comparable across 
dose levels and age groups.  In addition, the exposure of dexmedetomidine appeared to be 
dose-proportional in preterm neonates and term neonates.  Dose-proportionality in younger 


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subjects could not be assessed.  Premature neonates appeared to have lower CLw compared to 
term neonates, which resulted in higher exposure adjusted for dose.  The lower CL and higher 
concentrations in this age group were consistent with the greater efficacy observed in the 
premature neonates (no subjects required rescue administration of midazolam for sedation and 
1 subject required rescue administration of a medication for analgesia) compared to the term 
neonates (4 subjects required rescue administration of midazolam for sedation and 14 subjects 
required rescue administration of a medication for analgesia).  Dexmedetomidine was safe and 
well tolerated in both age groups and at all dose levels used in the study.  Three subjects 
experienced 4 AEs assessed as related to treatment, namely diastolic hypotension, respiratory 
acidosis, hypertension, and anger.
In a phase 2/3 open-label, multicenter, safety and efficacy study, dexmedetomidine were 
administered as an IV loading dose followed by a continuous IV infusion in initially intubated 
and mechanically ventilated preterm subjects, 28 weeks through <36 weeks, GA, having a 
weight of >1000 g, in an intensive care setting anticipated to require at least 6 hours of 
continuous IV sedation (Study DEX-11-06).  All of the 6 enrolled subjects received 
dexmedetomidine at 0.2 g/kg  as a loading dose over 10 or 20 minutes followed by 
continuous maintenance infusion of dexmedetomidine at a rate of 0.2 g/kg/h over 6 to 24 
hours.  The efficacy evaluation was performed by assessing the sedation level with the use of 
the Neonatal Pain, Agitation, and Sedation Scale (N-PASS) developed to assess sedation and 
pain/agitation in neonates.  From the results of the study, it was concluded that 
dexmedetomidine at the doses used in the study was an effective sedative and was safe and 
well tolerated in premature neonates aged 28 weeks to <36 weeks GA who were 
mechanically ventilated with intubation at the start of treatment.  Most premature neonates (5 
out of 6) did not require additional medication for pain while on dexmedetomidine infusion.  
One subject received rescue administration of a medication for analgesia during infusion of the 
investigational product.  Subjects spent a short period of time with a total N-PASS score >3, 
indicating that most subjects were adequately sedated and did not manifest signs of 
pain/agitation.  There were no deaths, SAEs, AEs leading to dexmedetomidine 
discontinuation, or dose-limiting toxicities that led to dexmedetomidine discontinuation.
In a phase 3, randomized, double-blind, dose-comparative, multi-center study (Study 
DEX-08-05), the safety and efficacy of dexmedetomidine were evaluated in pediatric ICU 
subjects aged 1 month to <17 years who were mechanically ventilated with intubation.  
Enrolled subjects were randomized to receive either high dose or low dose of 
dexmedetomidine and were stratified according to the presence or absence of cardiopulmonary 
bypass (CPB).  Dexmedetomidine was effective for sedating critically ill infants and children 
who were mechanically ventilated with intubation at the start of treatment, following major 
cardiac surgery with CPB or noncardiac surgery.  Although not significant, a dose-response 
effect was observed in the high dose group (54.3%), with more subjects who did not require 
rescue administration of midazolam to maintain the target sedation level than in the low dose 
group (44.6%).  High dose dexmedetomidine showed the highest level of efficacy in subjects 
who underwent cardiac surgery, with more subjects who did not require rescue administration 
of midazolam for sedation.  Dexmedetomidine was well tolerated at all doses used in the study 
in both cardiac and noncardiac critically ill subjects.  The AE profile is typical of this critically 


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ill high risk pediatric population following major cardiac and noncardiac surgery.  The most 
frequently reported AEs were hypotension, agitation, and bradycardia.  Hypotension and 
bradycardia are considered to have been influences of 2 agonists.  Two SAEs that occurred 
under study treatment (myocarditis and apnea) were reported in 2 subjects and were judged to 
be “Possibly related” or “Probably related” to dexmedetomidine.
Diaz et al. reported the PK of  dexmedetomidine when given at a loading dose of 1 g/kg over 
10 minutes followed by titrated infusion at a dose of 0.2 to 0.7 g/kg/h over  an average of 18.8 
hours in 10 subjects who underwent cardiac surgery (aged 4 months to 7.9 years)21.  Mean CL 
was 0.580.14 L/kg/h, (correspond to approximately 40 L/h in a 70 kg adult), Vss was 
1.530.37 L/kg, and t½ was 2.650.88 hours.  No treatment-related SAEs were reported.
A phase 1, single-center, dose-escalation study regarding PK and PD (Study CHOP) was 
conducted in infants (aged 1 month to 2 years) requiring postoperative mechanical ventilation 
with tracheal intubation immediately after cardiac surgery.  Subjects were randomized to one 
of the following 3 dose levels: low dose (0.35 g/kg bolus, 0.25 g/kg/h infusion), 
intermediate dose (0.7 g/kg bolus, 0.5 g/kg/h infusion), or high dose (1 g/kg bolus, 0.75 
g/kg/h infusion).  Both area under plasma concentration-time curve from time zero to infinity 
(AUCinf) and Cmax of dexmedetomidine were dose-proportional in a dose range of 0.25 to 
0.75 g/kg/h.  In the 3 dexmedetomidine dose groups, dose-dependent increases were 
observed in mean plasma concentration, area under plasma concentration-time curve from zero 
to time of last measurable concentration (AUClast), and AUCinf.  No notable differences in CL 
or CLW by age were observed in all dose groups.  In all of 38 subjects who received at least 1 
dose of the investigational product experienced at least 1 AE, and 33 subjects experienced at 
least 1 AE that was judged to be “Related” to treatment.
Zuppa et al. investigated the PK of dexmedetomidine in infants aged 1 month to 2 years old, 
following cardiac surgery with CPB22.  In open-label settings, dexmedetomidine was 
administered at the following 3 dose levels: 0.35 g/kg bolus over 20 minutes followed by 
0.25 g/kg/h, 0.7 g/kg bolus over 20 minutes followed by 0.5 g/kg/h, or 1 g/kg bolus over 
20 minutes followed by 0.75 g/kg/h.  The dose levels were titrated for 24 hours based on a 
target sedation level according to the UMSS.  PK data were obtained from 36 subjects.  Vss
were 4.0 L/kg, 3.7 L/kg, and 5.3 L/kg in the high dose, medium dose, and low dose groups, 
respectively, which were higher than in older children and adults.  Mean CLs were 1.4 L/h/kg, 
1.2 L/h/kg, and 1.1 L/h/kg in the low dose, medium dose, and high dose groups, respectively, 
which were also higher than in older children.  t½ was 2.12 to 3.05 hours, comparable to that 
seen in the Diaz study.21 One SAE possibly related to treatment was reported.
1.5. Rationale for This Study
Sedation is an important factor in the management of critically ill subjects.  Sedation control is 
an essential element not only for adult patients, but also for infants and children.  In current 
medical care, it is common to combine midazolam with morphine or fentanyl for sedation and 
analgesia in pediatric patients, but this can induce respiratory depression and make it difficult 
to manage the patient.


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In adults, the efficacy and safety of dexmedetomidine hydrochloride have been established, 
and it is widely used as a drug for “Sedation during and after mechanical ventilation in the 
intensive care setting”.  Although no indications have been approved, DA-9501 is used for 
sedation in pediatric intensive care, and indications for the drug and its dosage and 
administration are also described in the Japanese guidelines.  Further, although having not 
approved as indications in the U.S., the pharmacology, PK, and safety studies in juvenile 
animals, and PK studies and efficacy/safety studies  in infants/children have been conducted.
Also, taking into account the data of pediatric PK studies in the U.S., the maximum 
maintenance dose for pediatric subjects in this study was set to be a dose at which the predicted 
steady-state plasma concentration of dexmedetomidine in children does not exceed the 
steady-state plasma drug concentration at the maximum maintenance dose for adults.
Taking into account the above-mentioned situations, it was considered appropriate to plan a 
study to obtain approval of pediatric indications for dexmedetomidine in Japan.
1.5.1. Study Population
Based on the indications for this drug in adults, the subject population was set to be “pediatric 
subjects requiring sedation during and after mechanical ventilation in intensive care.” Also, 
according to a questionnaire survey in pediatric intensive care physicians, there are some cases 
of the use of dexmedetomidine in patients aged <45 weeks CGA, but in these ages, usual 
sedative is not used or this drug is not the first choice even when sedation is required and the 
main target subjects were considered to be patients aged 45 weeks CGA; and therefore, the 
target age was set to be 45 weeks CGA to <17 years old.
It was considered that there would be patients requiring sedation in both surgical subjects and 
medical ICU subjects, and therefore it was made possible to enroll both patient populations, 
and the target study population was set to be “pediatric subjects undergoing mechanical 
ventilation management under intensive care and requiring sedation (age 45 weeks GGA to 
<17 years old)”.
1.5.2. Dose Levels and Infusion Rates
Initial loading dose
It is assumed that dexmedetomidine would have an influence on circulation dynamics when an 
initial loading dose is given.  It was considered not always necessary to promptly increase the 
plasma drug concentration by giving an initial loading dose in sedation management in the 
ICU.
Starting dose for maintenance infusion
In a survey in pediatric intensive care specialists, it was recommended to start maintenance 
infusion from a low dose in children.  Taking into account this survey, the starting dose for 
maintenance infusion was set to be 0.2 µg/kg/h.


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Maximum maintenance dose
In a clinical study conducted in pediatric subjects in the U.S., no clear relationship was 
demonstrated between the plasma drug concentration and sedative effect, but the efficacy and 
safety of dexmedetomidine were demonstrated at a plasma concentration of 0.3 to 1.25 ng/mL 
(0.2 to 0.7 µg/kg/h) in healthy adults.  For setting the dosage and administration of this drug for 
pediatric subjects, effective plasma concentrations in adults were referred to on the assumption 
that there would be no much difference in response to dexmedetomidine between children and 
adults.  Also, the maximum maintenance dose for pediatric subjects in this study was set to be 
a dose at which the predicted steady-state plasma concentration of dexmedetomidine in 
children does not exceed the steady-state plasma drug concentration at the maximum 
maintenance dose for adults (0.7 µg/kg/h).
The dexmedetomidine CLw obtained in a U.S. study showed that the predicted steady-state 
plasma drug concentration at a maintenance dose of 1.4 µg/kg/h in children aged 1 month to <6 
years old corresponded to that at a dose of 0.7 µg/kg/h in adults and that the predicted plasma 
drug concentration at a maintenance dose of 1.0 µg/kg/h in children aged 6 years old
corresponded to that at a dose of 0.7 µg/kg/h in adults.
The dosage and administration in this study are within the range of dosage and administration 
in the clinical study conducted in the U.S. In these studies, there have been no reports of SAEs 
attributable to dexmedetomidine.  Also, in the literature on sedation under pediatric intensive 
care, it was reported that dexmedetomidine was used safely at 1.0 µg/kg/h, 1.4 µg/kg/h or 
higher as an adjustment range of maintenance dose levels.  But it was decided that the dose 
level would be increased in consideration of tolerability when using a dose level exceeding 
1.0 µg/kg/h described in the Japanese guidelines.
1.6. Risks/Benefits
This study is a multi-center, single-arm, open-label study with the objective of evaluating the 
efficacy, safety, and PK of this drug when given as continuous infusion of up to 1.4 µg/kg/h in 
pediatric ICU patients  45 weeks CGA to <17 years old. Based on the data of the pediatric PK 
study in the U.S. and the safety data that have been obtained to date, no specific risks to 
infant/pediatric patients have been identified compared to adults.  In clinical practice in Japan, 
this drug has been used in children as well.  The use of this drug as a sedative is described in 
guidelines such as the “Guidelines for Drug Therapy in Pediatric Patients with Cardiovascular 
Diseases” and the “Guidelines for the use of Anesthesia and Anesthesia related Drugs”.  
Further, there was a request for pediatric indications for dexmedetomidine hydrochloride from 
academic societies at the start of the “Council for Pediatric Pharmacotherapy”, and in 
consideration of these academic society requests as well as current medical practice in Japan, it 
is considered appropriate to conduct this study.
Complete information for this compound may be found in the single reference safety document 
(SRSD), which for this study is the Investigator’s brochure.


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2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
To evaluate the efficacy, safety, and PK of dexmedetomidine given as continuous IV infusion 
in pediatric subjects (45 weeks GGA to <17 years old) requiring sedation under intensive 
care.
2.2. Endpoints
2.2.1. Primary Efficacy Endpoint
The following item for the period from the start of dosing of the investigational product to 24 
hours of dosing or to the end of mechanical ventilation (when mechanical ventilation ends
within 24 hours of dosing of the investigational product):

Percentage of subjects who did not use a rescue sedative (midazolam) during mechanical 
ventilation to achieve/maintain adequate sedation (efficacy percentage)
[Rationale for setting of primary efficacy endpoint]
This efficacy endpoint was set up to judge whether sedation management can be performed 
with this drug alone without additional administration of other sedative (midazolam) in the 
subjects of the study.15 Also, in adult clinical studies in Japan and overseas that investigated the 
efficacy of dexmedetomidine within 24 hours of dosing under intensive care, a significant 
difference was seen between the dexmedetomidine dosing group and placebo dosing group 
when this primary efficacy endpoint was used.15 And in a U.S. pediatric dose-comparative 
study of dexmedetomidine within 24 hours of dosing (DEX-08-05), this primary efficacy 
endpoint was also used, and although no significant difference was seen, a difference was seen 
in efficacy percentage between the low dose group and high dose group.  Therefore, the 
endpoint was judged appropriate as the primary endpoint for this study.
2.2.2. Secondary Efficacy Endpoints
The following items for the period from the start of dosing of the investigational product to 24 
hours of dosing or to the end of mechanical ventilation (when mechanical ventilation ends
within 24 hours of dosing of the investigational product):
1. Percentage of subjects who did not require administration of a rescue analgesic (fentanyl) 
during mechanical ventilation in addition to administration of the investigational product
2. Total amount and weight adjusted total amount of rescue sedative/analgesic during 
mechanical ventilation
3. Absolute time and its percentage that subject was in the target sedation level during 
mechanical ventilation


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The following items for the period from 24 hours of dosing of the investigational product to the 
end of mechanical ventilation in subjects whose period of dosing of the investigational product 
exceeds 24 hours:
4. Percentage of subjects who did not use a rescue sedative during mechanical ventilation to 
achieve/maintain adequate sedation 
5. Percentage of subjects who did not require dosing of a rescue analgesic during mechanical 
ventilation in addition to dosing of the investigational product
6. Total amount and weight adjusted total amount of rescue sedative/analgesic during 
mechanical ventilation
7. Absolute time and its percentage that subject was in the target sedation level during 
mechanical ventilation
The following items for the period from extubation to the end of dosing of the investigational 
product:
8. Absolute time and its percentage that subject was in the target sedation level after 
extubation
9. Total amount of rescue sedative/analgesic
The following item for the period from the start of dosing of the investigational product to the 
end of mechanical ventilation:
10. Time until the end of mechanical ventilation
[Rationale for setting of secondary efficacy endpoints]
1. This efficacy endpoint was set up to investigate the analgesic effect of dexmedetomidine 
for the period from the start of dosing of the investigational product to 24 hours of dosing 
or to the end of mechanical ventilation.
2. This efficacy endpoint was set up to investigate the sedative/analgesic effects of 
dexmedetomidine for the period from the start of dosing of the investigational product to 
24 hours of dosing or to the end of mechanical ventilation.
3. This efficacy endpoint was set up to investigate the sedative effect of dexmedetomidine for 
the period from the start of dosing of the investigational product to 24 hours of dosing or to 
the end of mechanical ventilation.
4. This efficacy endpoint was set up to investigate the sedative effect of dexmedetomidine in 
subjects whose period of dosing of the investigational product exceeds 24 hours.


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5. This efficacy endpoint was set up to investigate the analgesic effect of dexmedetomidine in 
subjects whose period of dosing of the investigational product exceeds 24 hours.
6. This efficacy endpoint was set up to investigate the sedative/analgesic effect of 
dexmedetomidine in subjects whose period of dosing of the investigational product 
exceeds 24 hours.
7. This efficacy endpoint was set up to investigate the sedative effect of dexmedetomidine in 
subjects whose period of dosing of the investigational product exceeds 24 hours.
8. This efficacy endpoint was set up to investigate the sedative effect of dexmedetomidine 
after the end of mechanical ventilation.
9. This efficacy endpoint was set up to investigate drugs that seem to affect the 
sedative/analgesic effects.
10. This efficacy endpoint was set up to investigate the sedative effect of dexmedetomidine for 
the period from the start of dosing of the investigational product to 24 hours of dosing or to 
the end of mechanical ventilation.
2.2.3. Safety Endpoints

Adverse eventsa

Vital signs (blood pressure, heart rate, respiratory rate), percutaneous oxygen saturation 
(SpO2), end-tidal carbon dioxide (ETCO2), core body temperature, and body weight

Laboratory test values

Total Input/Output Fluid Volume 

Occurrence of withdrawal symptoms (presence/absence of hypertension, tachycardia, or 
agitation symptoms after the end of dosing of the investigational product)

Electrocardiogram (ECG)
                                                
a The following symptoms at the surgery site are considered common surgically-related events and are not to be 
reported as AEs:
Bleeding, bruising, itching, redness, swelling, numbness, tingling, burning sensation, pain, infection and 
rupturing of incision stitches.
Changes in laboratory test values that are normally observed after surgery do not need to be evaluated as AEs 
based on the physician’s judgment, even if the values are outside the reference range.
Bradycardia, hypotension, and respiratory depression are to be reported as AEs if the pulse rate, blood pressure 
level, and respiratory rate are below the range specified for each age.
b Not approved in Japan


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3. STUDY DESIGN
This study is a phase 3, multi-center, single-arm, open-label study with the objective of 
evaluating the efficacy, safety, and PK of dexmedetomidine when given as continuous IV 
infusion in pediatric subjects 45 weeks CGA to <17 years old.
Figure 1.
Elective Surgical Subjects
Figure 2.
Medical ICU Subjects
4. SUBJECT SELECTION
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular subject is suitable for this protocol.
CCI
C
C


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4.1. Inclusion Criteria
Subject eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before subjects are included in the study.
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Subjects whose consent is obtained in writing prior to the clinical trial from a guardian after 
a full explanation.  For subjects 7 years and older, it is desirable that an informed assent is 
also obtained from the pediatric subject him/herself when possible.
2. Subjects aged 45 weeks CGA to <17 years old at time of consent.  No restriction on sex of 
subject.
3. [Elective surgical subjects] Subjects classified as American Society of Anesthesiologists 
(ASA) (ASA physical status classification) Class I to III by preoperative diagnosis.
Table 2.
ASA Classification23
I
A normal healthy patient
II
A patient with mild systemic disease
Moderate obesity, elderly, diabetes mellitus with dietary 
restrictions, mild hypertension, chronic lung disease
III
A patient with severe systemic disease that interferes with activities
Morbid obesity, highly restrictive heart disease, angina pectoris, 
old myocardial infarction, insulin-dependent diabetes mellitus, 
moderate to severe lung disease
IV
An almost bedridden patient with severe systemic disease that is a 
constant threat to life
Organic heart disease associated with heart failure, unstable 
angina pectoris, refractory arrhythmia, severe 
lung/kidney/liver/endocrine disease
V
A moribund patient who is not expected to survive for 24 hours without 
the operation
Ruptured aortic aneurysm associated with shock, severe lung 
infarction, head injury associated with brain hypertension
4. [Elective surgical subjects] Subjects who require at least 6 hours of respiratory 
management with intubation under intensive care from immediately after surgery and are 
anticipated to require sedation.
5. [Medical ICU subjects] Subjects who require at least 24 hours of respiratory management 
with intubation under intensive care and are anticipated to require sedation.  For medical 
ICU subjects, sedatives used prior to treatment with the investigational product should be 
discontinued before the start of treatment with the investigational product.
6. If a subject is a female of childbearing potential, she should not be pregnant or possibly 
pregnant, or lactating.


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4.2. Exclusion Criteria
Subjects with any of the following patient characteristics/conditions must not be included in 
the study:
1. Subjects who are judged by investigator or sub-investigator to have a neurological disease 
that will make sedation assessment difficult, such as:

Subjects with brain damage which is expected to increase intracranial pressure due to 
trauma or central nervous system disease.

Subjects with cerebral palsy, autism, severe mental retardation, etc.

Subjects with paralysis due to continuous administration of a muscle relaxant or due to a 
spinal injury of class T5 or higher.
2. Subjects with 2nd or 3rd degree heart block in the tests at the screening period (excluding 
subjects using a pacemaker).
3. Subjects with any of the following low blood pressure levels24 in the tests at the screening 
period:

Age 45 weeks CGA to <1 year old: Systolic Blood Pressure (SBP) <70 mmHg

Age 1 year to <10 years old: SBP <70 + (2 x age in years) mmHg

Age 10 years to <17 years old: SBP <90 mmHg
4. Subjects with bradycardia (10th centile of heart rate for healthy children) in the physical 
examination at screening period shown in Table 3.
Table 3.
Centiles of Heart Rate (HR) in Children25
Range of ages
1st centile
10th centile
25th centile
Median
75th centile
90th centile
99th centile
0-3 mos.
107
123
133
143
154
164
181
3-6 mos.
104
120
129
140
150
159
175
6-9 mos.
98
114
123
134
143
152
168
9-12 mos.
93
109
118
128
137
145
161
12-18 mos.
88
103
112
123
132
140
156
18-24 mos.
82
98
106
116
126
135
149
2-3 yrs.
76
92
100
110
119
128
142
3-4 yrs.
70
86
94
104
113
123
136
4-6 yrs.
65
81
89
98
108
117
131
6-8 yrs.
59
74
82
91
101
111
123
8-12 yrs.
52
67
75
84
93
103
115
12-15 yrs.
47
62
69
78
87
96
108
15-18 yrs.
43
58
65
73
83
92
104


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5. Subjects with ALT 100 U/L in the laboratory tests at the screening period.
6. Subjects in whom dexmedetomidine or other 2 receptor agonists, 2 receptor antagonists 
and drug that may be used in this study are contraindicated.
7. Subjects who may need a sedative or analgesic (including narcotics) other than 
dexmedetomidine, midazolam or fentanyl during treatment with the investigational 
product.
8. Subjects who have acute febrile illness (with a temperature [core or tympanic]
38Centigrade) at the screening period.
9. Subjects who received other investigational product within 30 days before baseline or 
subjects who will participate in other study that uses an investigational product during the 
study period.
10. Subjects who received dexmedetomidine within 48 hours before baseline
11. Subjects who, in the opinion of the investigator or sub-investigator, may be at increased 
risk due to the conduct of the study or may have a disease or factor which will probably 
preclude the obtainment of sufficient study data.
12. Subjects for whom, in the opinion of the investigator or sub-investigator, risks involved 
with administration of dexmedetomidine outweigh its benefits (e.g., >2 doses of 
vasopressor due to cardiogenic shock).
13. Subjects who are investigational site staff members directly involved in the conduct of the 
study and their family members, site staff members otherwise supervised by the 
investigator, or subjects who are Sponsor’s employees directly involved in the conduct of 
the study.
4.3. Criteria Lifestyle Guidelines
All fertile male subjects and female subjects of pregnancy potential who are sexually active 
and at risk for pregnancy must agree to use a highly effective contraceptive method 
consistently and properly during the period of treatment with the investigational product and 
for at least 28 days after the last dose of the investigational product.  The investigator or his or 
her designee, in consultation with the subject, will confirm that the subject has selected a 
contraceptive method appropriate for the individual subject or subject’s male or female partner 
from among permitted contraceptive methods (See below), and also instruct the subject to use 
the method consistently and properly.  Subjects need to affirm that they meet the criteria for 
correct use of at least 1 of the selected methods of contraception.  The investigator or his/her 
designee will discuss with the subject the need to use highly effective contraception 
consistently and correctly according to the schedule of activities and document such 
conversation in the subject’s chart.  In addition, the investigator or his or her designee will 
instruct the subject to call immediately if the selected contraception method is discontinued or 
if pregnancy is known or suspected in the subject or the subject’s partner.


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Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:
1. Established use of oral, inserted, injected, implanted or transdermal hormonal methods 
of contraception is allowed provided the subject plans to remain on the same treatment 
throughout the entire study and has been using that hormonal contraceptive for an 
adequate period of time to ensure effectiveness.
2. Correctly placed copper-containing intrauterine device (IUD).
3. Male condom or female condom used WITH a spermicideb (ie, foam, gel, film, cream, 
or suppository).  For countries where spermicide is not available or condom plus 
spermicide is not accepted as highly effective contraception, this option is not 
appropriate.
4. Male sterilization with absence of sperm in the postvasectomy ejaculate.
5. Bilateral tubal ligation / bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
6. Female partner who meets the criteria for non-childbearing potential, as described 
below:
Female subjects of non childbearing potential must meet at least one of the following 
criteria:

Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure; or

Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or physiological 
cause; a serum follicle stimulating hormone (FSH) level confirming the post 
menopausal state.

Women who have not yet had her first menstrual period
All other female subjects (including females with tubal ligations) will be considered to be of
childbearing potential.
                                                
b Not approved in Japan


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All sexually active male subjects must agree to prevent potential transfer of and exposure to 
drug through semen to their partners by using a condom consistently and correctly, beginning 
with the first dose of investigational product and continuing for at least 28 days after the last 
dose.
4.4. Sponsor’s Appropriately Qualified Medical Personnel
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, subjects are provided with a contact card.  The contact card contains, at 
a minimum, protocol and investigational compound identifiers, subject study numbers, contact 
information for the investigational site, and contact details for a contact center in the event that 
the investigational site staff cannot be reached to provide advice on a medical question or 
problem originating from another healthcare professional not involved in the subject’s 
participation in the study.  The contact number can also be used by investigational staff if they 
are seeking advice on medical questions or problems; however, it should be used only in the 
event that the established communication pathways between the investigational site and the 
study team are not available.  It is therefore intended to augment, but not replace, the 
established communication pathways between the investigational site and the study team for 
advice on medical questions or problems that may arise during the study.  The contact number 
is not intended for use by the subject directly, and if a subject calls that number, he or she will 
be directed back to the investigational site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonization (ICH) 
guidelines investigational product is defined as a pharmaceutical form of an active ingredient 
or placebo being tested or used as a reference in a clinical trial, including a product with a 
marketing authorization when used or assembled (formulated or packaged) in a way different 
from the approved form, or when used for an unapproved indication, or when used to gain 
further information about an approved use (ICH E6 1.33).
5.1. Allocation to Investigational Product
As this study is a single-arm study, no allocation will be performed.  
5.2. Medication Compliance
Administration of the investigational product will be performed by persons who are 
appropriately designated at the investigational site.
5.3. Investigational Product
Name: DA-9501
Generic name: Dexmedetomidine hydrochloride (JAN)
Chemical name: (+)-(S)-4-[1-(2, 3-dimethylphenyl) ethyl]-1H-imidazole monohydrochloride


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5.3.1. Dosage Form and Packaging Form of Investigational Product
Content/Dosage Form: A single vial contains an injection solution with 2 mL of 
dexmedetomidine hydrochloride solution (100 g/mL as dexmedetomidine) dissolved in 
physiological saline.
5.3.2. Preparation and Dispensing
For instructions on how to prepare the investigational product for administration, see the IP 
manual (Investigational Product Manual).  Investigational product should be prepared and 
dispensed by an appropriately qualified and experienced member of the study staff (eg, 
physician, nurse, physician’s assistant, practitioner, or pharmacist) as allowed by local, state, 
and institutional guidance.
5.4. Administration of Investigational Product
No initial loading dose will be given.  Baseline body weight will be used to determine the dose 
of the investigational product.
45 weeks CGA to <6 years old
Maintenance infusion will be started at 0.2 µg/kg/h.  The infusion rate will be adjusted within 
a range of 0.2 to 1.4 µg/kg/h according to the pediatric subject’s sedative state.
6 years to <17 years old
Maintenance infusion will be started at 0.2 µg/kg/h.  The infusion rate will be adjusted within 
a range of 0.2 to 1.0 µg/kg/h according to the pediatric subject’s sedative state.
[Dosing Duration]
Dosing of dexmedetomidine will be started after the patient is admitted to the intensive care 
unit.  Dosing of dexmedetomidine may be continued after extubation as needed.  The dosing 
duration will be at least 6 hours in elective surgical subjects and at least 24 hours in medical 
ICU subjects for up to 28 days.
[Points to note when increasing the infusion rate of the investigational product]
If the investigator or sub-investigator deems that the subject has not reached an adequate 
sedative state or the SBS score specified in the protocol is +1 or +2, the investigator or 
sub-investigator will increase the infusion rate of the investigational product.  While an 
increase of 0.1 µg/kg/h or more is possible when increasing the infusion rate, the infusion rate 
should be gradually increased over 3 to 4 minutes or longer per 0.1 µg/kg/h.
[Points to note at end of dosing of the investigational product]
If dosing of dexmedetomidine lasts longer than 24 hours at the end of dosing of the 
investigational product, gradual reduction of the infusion rate of dexmedetomidine will be 


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considered at the discretion of the investigator or sub-investigator.  An example of gradual 
reduction is gradually reducing the infusion rate of dexmedetomidine over about 4 hours or 
longer.  Withdrawal symptoms may occur following sudden discontinuation of dosing after 
long-term treatment (See the package insert of this drug).  Tachycardia, hypertension, 
agitation, and vomiting after discontinuation of this drug are likely to be such withdrawal 
symptoms.  A publication reported that these symptoms can occur easily in patients for whom 
the total dose of this drug is 8.5 µg/kg or more, and therefore it is necessary to reduce the dose 
slowly (by 0.1 µg/kg/h, every 12 hours when the drug is used for a long period)26.  For 
example, it is said that the infusion rate of this drug should be gradually reduced over 4 hours 
or longer, but if dosing of the drug is to be discontinued, the treatment period for the subject 
should be considered, and according to the circumstances, the dose reduction period should be 
carefully considered.
[Target Sedation Depth]
The target sedation depths during mechanical ventilation and after extubation are shown 
below.

During mechanical ventilation: SBS −2 to 0

After extubation: SBS −1 to 0
5.5. How to Deal With Overdose
Overdose will be dealt with according to the Investigator’s Brochure and/or package insert of 
dexmedetomidine.27
5.6. Investigational Product Storage
The investigator, or an approved representative, eg, pharmacist, will ensure that all 
investigational products are stored in a secured area with controlled access under required 
storage conditions and in accordance with applicable regulatory requirements.  Investigational 
product should be stored in its original container and in accordance with the label.  Regarding 
the storage conditions of the investigational product which is once diluted, see the written 
procedures for the management of investigational products and the IP manual.
Storage conditions stated in the SRSD (Investigator’s Brochure in the case of this study) will 
be superseded by the storage conditions stated in the label of the investigational product.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated and/or room temperature products).  This should be 
captured from the time of investigational product receipt throughout the study.  Even for 
continuous monitoring systems, a log or site procedure that ensures active daily evaluation for 
excursions should be available. The operation of the temperature monitoring device and 
storage unit (for example, refrigerator), as applicable, should be regularly inspected to ensure it 
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Any excursions from the product label storage conditions should be reported upon discovery.  
The site should actively pursue options for returning the product to the storage conditions as 
described in the labeling, as soon as possible.  Deviations from the storage requirements, 
including any actions taken, must be documented and reported to the sponsor.  Once an 
excursion is identified, the investigational product must be quarantined and not used until the 
sponsor provides documentation of permission to use the investigational product.  It will not be 
considered a protocol deviation if the sponsor approves the use of the investigational product 
after the temperature excursion.  Use of the investigational product prior to sponsor approval 
will be considered a protocol deviation.
Specific details regarding information the site should report for each excursion will be 
provided to the site.
5.7. Investigational Product Accountability
The investigative site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.
5.7.1. Destruction of Investigational Product Supplies
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site).  If destruction is authorized to take place at the study site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Sponsor, and all destruction must be adequately documented.
5.8. Concomitant Therapies
All concomitant medications used between 48 hours before the start of infusion of the 
investigational product and 24 hours after the end of infusion of the investigational product 
(date and time of administration, dosage/administration, route of administration, and reason for 
administration) will be recorded in the case report form (CRF).  Drugs used during surgery 
may be described as the total dose given during surgery.  In addition, non-drug treatment from 
48 hours before the start of dosing of the investigational product to 24 hours after the end of 
dosing of the investigational product will be recorded.
Any other sedatives used prior to the start of infusion of the investigational product should be 
discontinued.
5.8.1. Prohibited Concomitant Drugs
Between the start of infusion of the investigational product (for dexmedetomidine, 48 hours 
before the start of infusion of the investigational product) and the end of dosing of the 
investigational product, concomitant uses of the following drugs will be prohibited.  When 
continuing dosing of dexmedetomidine after withdrawal from mechanical ventilation, it is 
acceptable to use standard analgesics at each medical institution if necessary.


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1. Sedatives/analgesics (including narcotics) other than dexmedetomidine, midazolam, and 
fentanyl.  Use of non-steroidal anti-inflammatory drugs for the management of patient 
ductus arteriosus will be allowed but should be appropriately described in the CRF.
2. Continuous infusion of muscle relaxants
3. Drugs contraindicated for coadministration with dexmedetomidine, midazolam, and 
fentanyl
4. 2 receptor agonists other than dexmedetomidine and 2 receptor antagonists
[Rationale for setting of prohibited concomitant drugs]
These criteria were set up to avoid any influence on the sedation/analgesia assessment.
1. Concomitant uses are prohibited because of influence on the sedation/analgesia 
assessment.
2. Concomitant uses are prohibited because of possible influence on the sedation assessment.
3. Prohibition of concomitant uses was set up in consideration of the subject’s safety.
4. Concomitant uses are prohibited because of possible influence on the sedation assessment.
5.8.2. Restricted Concomitant Drugs
Between the start of infusion of the investigational product and 24 hours after the end of 
infusion of the investigational drug, the following drugs will be restricted.
Continuous infusion of fentanyl
If discontinuation of continuous infusion of fentanyl is considered likely to cause disadvantage 
to the subject, fentanyl may be continuously used.  It is desirable not to change the infusion rate 
of fentanyl during administration of dexmedetomidine.
Muscle relaxants
Temporary use of muscle relaxants will be allowed at the time of painful or irritative 
procedures, but they will not be used at the time of sedation assessment.
5.9. Rescue Sedatives and Rescue Analgesics
If the investigator or sub-investigator deems that the subject has not reached an adequate 
sedative state or the SBS score specified in the protocol is +1 or +2, the investigator or 
sub-investigator will increase the infusion rate of the investigational product.  While an 
increase of 0.1 µg/kg/h or more is possible when increasing the infusion rate, the infusion rate 
should be gradually increased over 3 to 4 minutes or longer per 0.1 µg/kg/h.


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If sedation is needed, it is possible to administer a rescue sedative (midazolam) based on the 
data of SBS and the investigator or sub-investigator’s judgment, but it is desirable to judge the 
necessity of a rescue sedative after increasing the infusion rate of dexmedetomidine (maximum 
maintenance dose: 1.4 µg/kg/h for 45 weeks GA to <6 years old; 1.0 µg/kg/h for 6 years to 
<17 years old) and performing the sedation assessment again.
A rescue analgesic (fentanyl) will be used at the time of painful or irritative procedures based 
on the investigator or sub-investigator’s judgment.  Continuous infusion of fentanyl may be 
used for the treatment of pain or irritation (See 5.8.2 restricted concomitant drugs).  Bolus 
infusion of fentanyl should not be performed at the time of sedation assessment.
If the SBS score is <−2, the infusion rate may be deceased to the lower limit maintenance 
infusion rate (0.2 µg/kg/h).  If judged necessary by the investigator or sub-investigator, the 
infusion rate can be decreased below the lower limit maintenance infusion rate or the infusion 
can be stopped.
If a rescue sedative or rescue analgesic is used between the start of infusion of the 
investigational product and 24 hours after the completion of infusion of the investigational 
product, this should be appropriately described in the CRF.
Rescue Sedative: Midazolam
Midazolam will be intravenously administered at a dose of 0.05 to 0.2 mg/kg over 2 to 3 
minutes according to the package insert based on the investigator or sub-investigator’s 
judgment.  Sedation assessment will be performed immediately before infusion of the rescue 
sedative and at 52 minutes after infusion.
In subjects who need 5 or more doses of the rescue sedative per hour despite an increase of the 
infusion rate up to the maximum maintenance infusion rate of dexmedetomidine, the study will 
be discontinued and other sedation management method will be used.
Rescue Analgesic: Fentanyl
Pain/discomfort will be dealt with by increasing the infusion rate not exceeding the upper limit 
for dexmedetomidine, based on the investigator or sub-investigator’s judgment.  Bolus 
infusion of fentanyl will be based on the investigator or sub-investigator’s judgment (1 to 
2 µg/kg).  Sedation assessment will be performed immediately before infusion of the rescue 
analgesic and at 52 minutes after infusion.
6. STUDY PROCEDURES
6.1. Screening (1 to 7 Days Before Start Date of Treatment With Investigational Product)
Screening will be performed 1 to 7 days before the start date of treatment with the 
investigational product for the following items:

Informed consent


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Prior to the study, a written consent will be obtained from the guardian of the subject after
a full explanation.  For subjects 7 years and older, it is desirable that an informed assent is
also obtained from the pediatric subject him/herself when possible.  If the signature of the
subjects cannot be obtained or if an assent was obtained orally without using a document, it
should be described, in the consent form signed by the guardian, that an assent was
obtained from the subject.  

Subject registration
The investigator or sub-investigator will confirm that the subject matches the subject
background and inclusion criteria and does not meet the exclusion criteria at the start of the
study, and then promptly register the subject via FAX with the center designated by the
sponsor.

Checking of inclusion/exclusion criteria

Subject background (date of birth, weeks of CGA [only when <1 year old], gender, race, 
etc. )

Checking of noteworthy medical history/complications

Checking of surgery/actions, primary disease name, etc.
-
Elective surgical subjects: Checking of primary disease name and ASA classification
-
Medial ICU subjects: Checking of primary disease name, status of intubation during 
sedation and reason for intubation, start date/time and mode of ventilator, and 
date/time of ICU admission

Physical examination

Height, body weight, core body temperature (All of them will be measured to first decimal 
place)

Vital signs (BP, HR, RR), percutaneous oxygen saturation (SpO2), and end-tidal carbon 
dioxide (ETCO2)

12-lead ECG

Laboratory tests

Pregnancy test (to be performed only in women of childbearing potential)

Checking of concomitant drugs and non-drug treatment


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6.2. Treatment Period
6.2.1. Baseline (Start Date of Treatment With Investigational Product)
Baseline will be the start date of treatment with the investigational product, and the following 
items will be performed before the start of treatment with the investigational product.  In 
elective surgical subjects, the items will be performed after surgery unless otherwise 
particularly described.

Checking of surgery/actions, primary disease name, etc.
-
Elective surgical subjects: Checking of date of surgery, type of procedure, start and 
end date/time of surgery, status of intubation during sedation and reason for 
intubation, anesthetics and analgesics used for surgery, start date/time and mode of 
ventilator, and date/time of ICU admission

Physical examination

Body weight and core body temperature (All of them will be measured to first decimal 
place)
Baseline body weight will be used to determine the dose of the investigational product.

Vital signs (BP, HR, RR), SpO2, and ETCO2

12-lead ECG and laboratory tests (to be performed only in elective surgical subjects)
In patients undergoing heart surgery, these items will be performed after surgery and 
within 90 minutes before the start of dosing of the investigational product.

Sedation assessment

Checking of concomitant drugs and non-drug treatment

Checking of SAEs

Start of ECG monitoring (to be continued until 24 hours after the end of dosing of the 
investigational product)
6.2.2. From Start of Dosing to 24 Hours After Dosing or End of Mechanical Ventilation

Core body temperature (See section 7.2.2; To be measured to first decimal place)

Vital signs (BP, HR, RR), SpO2, and ETCO2 (See section 7.2.4)

Checking of setting of ventilator (If the mode of the ventilator was changed, the mode will 
be recorded)


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
Sedation assessment (See section 7.1.2)

Dosing of investigational product (See section 5.4)

Checking of dosing of rescue sedative

Checking of dosing of rescue analgesic

Checking of concomitant drugs and non-drug treatment

Checking of AEs/SAEs

Blood sampling for plasma drug concentration (See section 7.3)

Laboratory tests (to be performed as needed)

ECG monitoring (to be continued from before the start of dosing of the investigational 
product to 24 hours after the end of dosing of the investigational product)
6.2.3. From 24 Hours After Dosing to End of Mechanical Ventilation

Core body temperature (See section 7.2.2; To be measured to first decimal place)

Vital signs (BP, HR, RR), SpO2, and ETCO2 (See section 7.2.4)

Checking of setting of ventilator (If the mode of the ventilator was changed, the mode will 
be recorded)

Checking of end date/time of ventilator

Sedation assessment (See section 7.1.2)

Dosing of investigational product (See section 5.4)

Checking of dosing of rescue sedative

Checking of dosing of rescue analgesic

Checking of concomitant drugs and non-drug treatment

Checking of AEs/SAEs

Blood sampling for plasma drug concentration (See section 7.3)

Laboratory tests (to be performed as needed)


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
ECG monitoring (to be continued from before the start of dosing of the investigational 
product to 24 hours after the end of dosing of the investigational product)
6.2.4. From End of Mechanical Ventilation to End of Dosing of Investigational Product

Core body temperature (See section 7.2.2; To be measured to first decimal place)

Vital signs (BP, HR, RR), SpO2, and ETCO2 (See section 7.2.4)

Checking of Total Input/Output Fluid Volume (from the start to end of dosing of the 
investigational product)

Sedation assessment (See section 7.1.2)

Dosing of investigational product (See section 5.4)

Checking of dosing of rescue sedative

Checking of dosing of rescue analgesic

Checking of concomitant drugs and non-drug treatment

Checking of AEs/SAEs

Blood sampling for plasma drug concentration (See section 7.3)

Laboratory tests (to be performed as needed)

ECG monitoring (to be continued from before the start of dosing of the investigational 
product to 24 hours after the end of dosing of the investigational product)
6.2.5. 24 Hours (± 5 min) After End of Dosing of Investigational product

Checking of date/time of ICU discharge (if the subject was discharged)

Physical examination

Body weight and core body temperature (to be measured to first decimal place)

Vital signs (BP, HR, RR), SpO2, and ETCO2

12-lead ECG and laboratory tests

End of ECG monitoring

Sedation assessment

Checking of concomitant drugs and non-drug treatment


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
Checking of AEs/SAEs

Blood sampling for plasma drug concentration (See section 7.3)
6.2.6. At Early Discontinuation of Study
For subjects who have discontinued the study after the start of dosing of the investigational 
product, all of the tests planned to be performed at 24 hours after the end of dosing of the 
investigational product will be performed at the time of the early discontinuation in principle 
and those will be evaluated.  Also, all of the observation items up to that time point will be 
recorded, and the reason for the discontinuation will be clearly stated in the CRF.  
6.3. Follow-up Period
The follow-up period will be from the observation at 24 hours after the end of dosing of the 
investigational product to 28 days after the end of dosing.  SAEs that occur during this period 
will be reported to the sponsor according to the procedure described in section 8.
6.4. Criteria and Procedure for Subject Withdrawal From Study
The investigator or sub-investigator will withdraw a subject from the study if the subject meets 
any of the following criteria.
1. If any of the following AEs occurred.
Bradycardia
Bradycardia (Table 3: 10th percentile or less of heart rate) does not respond to treatments, 
including administration of atropine, which are usually done in the intensive care unit or 
bradycardia is clinically relevant.
Hypotension
Any of the following hypotension levels does not respond to treatments, including infusion 
solution, and vasopressors/inotropic agents, that are usually done in the intensive care unit or 
hypotension is clinically relevant.

Age 45 weeks CGA to <1 year old: SBP <70 mmHg

Age 1 year to <10 years old: SBP <70 + (2x age in years) mmHg

Age 10 years to <17 years old: SBP <90 mmHg
Respiratory Depression
If respiratory depression persists at the 10th percentile or less of respiratory rate (Table 4) and 
does not respond to treatments that are usually done in the intensive care unit or respiratory 
depression is clinically relevant.


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Table 4.
Centiles of Respiratory Rate (RR) in Children25
Range of ages
1st centile
10th centile 25th centile
Median
75th centile 90th centile 99th centile
0-3 mos.
25
34
40
43
52
57
66
3-6 mos.
24
33
38
41
49
55
64
6-9 mos.
23
31
36
39
47
52
61
9-12 mos.
22
30
35
37
45
50
58
12-18 mos.
21
28
32
35
42
46
53
18-24 mos.
19
25
29
31
36
40
46
2-3 yrs.
18
22
25
28
31
34
38
3-4 yrs.
17
21
23
25
27
29
33
4-6 yrs.
17
20
21
23
25
27
29
6-8 yrs.
16
18
20
21
23
24
27
8-12 yrs.
14
16
18
19
21
22
25
12-15 yrs.
12
15
16
18
19
21
23
15-18 yrs.
11
13
15
16
18
19
22
Paradoxical Reactions
If any of the following paradoxical reactions occurred.
[45 weeks CGA to <8 years old]
It is not possible to explain the subject’s medical condition as other than a paradoxical reaction, 
and there is agitation or crying out loud to the extent that cannot be controlled through normal 
intervention.
[8 years to <17 years old]
It is not possible to explain the subject’s medical condition as other than a paradoxical reaction, 
and there is severe emotional volatility or aggressive behavior to the extent that cannot be 
controlled through normal intervention.  Examples include violence by the subject or 
obstruction of medical professionals, etc.
2. It is necessary to give 5 doses or more of a rescue sedative (midazolam) per hour in order to 
maintain an adequate sedation level despite an increase of the infusion rate up to the 
maximum maintenance infusion rate of investigational product.
3. The subject or his/her guardian requests withdrawal from the study.
4. The investigator or sub-investigator judges that withdrawal from the study is the best 
interest of the subject (e.g. due to occurrence of an AE).
5. The subject’s medical condition changes and a deeper sedation level or continuous 
administration of muscle relaxant is required.


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6. The subject no longer requires sedation by continuous IV and dosing of dexmedetomidine 
is less than 6 hours.
7. Any other reason for which the investigator or sub-investigator judges continuation of the 
study to be difficult.
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety or behavioral 
reasons, or the inability of the subject to comply with the protocol-required schedule of study 
visits or procedures at a given study site.
If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator that may make it unfeasible to perform 
the test.  In these cases the investigator will take all steps necessary to ensure the safety and 
well-being of the subject.  When a protocol-required test cannot be performed, the investigator 
will document the reason for this and any corrective and preventive actions that he or she has 
taken to ensure that normal processes are adhered to as soon as possible.  The study team will 
be informed of these incidents in a timely fashion.
7.1. Efficacy Evaluation
7.1.1. Rescue Sedatives and Rescue Analgesics
See section 5.9.
7.1.2. Sedation Assessment
Assessment Scale of Sedation Depth
Sedation depth will be assessed by using the State Behavioral Scale (SBS) (Table 5).
Sedation Assessment and Target Sedation Level
The investigator, sub-investigator, or clinical research collaborator who has attended the SBS
training provided by the sponsor will assess sedation depth by using SBS.  The target sedation 
depth by SBS is –2 to 0 during mechanical ventilation and −1 to 0 after extubation.  The 
assessment points will be as follows.
[Prior to dosing to end of dosing of investigational product]


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The level will be measured at baseline, at 102 minutes, 202 minutes, 302 minutes, 1 
hour5 minutes, 2 hours5 minutes, and 4 hours5 minutes after dosing of the investigational 
product, and every 4 hours5 minutes later than 4 hours after the start of dosing.  The level will 
be measured every 4 hours5 minutes from Day 2 of treatment to extubation.  If the 
investigational product is continuously dosed after extubation, the level will be measured 
every 4 hours5 minutes until the end of dosing of the investigational product.
[At the time of extubation]
The level will be measured at 52 minutes before extubation, and at 52 minutes, 152 
minutes, 302 minutes, 1 hour5 minutes, 2 hours5 minutes, 4 hours5 minutes, and 12 
hours5 minutes after extubation.
[End of dosing of investigational product to 24 hours after end of dosing of investigational 
product]
The level will be measured at the end of dosing of the investigational product (+5 minutes), at 
1 hour5 minutes, 2 hours5 minutes and 4 hours5 minutes after the end of dosing of the 
investigational product, and every 4 hours5 minutes later than 4 hours after the end of dosing 
of the investigational product.
[At the time of changing the infusion rate of investigational product]
The level will be measured at 52 minutes immediately before changing the infusion rate of 
the investigational product and at 52 minutes after changing the rate.  
[When administering a rescue sedative/analgesic]
The level will be measured at 52 minutes immediately before administration of the rescue 
sedative (midazolam) or rescue analgesic (fentanyl) and at 52 minutes after administration.


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Table 5.
State Behavioral Scale (SBS)28
-3
Unresponsive
No spontaneous respiratory effort
No cough or coughs only with suctioning
No response to noxious stimuli
Unable to pay attention to care provider
Does not distress with any procedures [including noxious]
Does not move
-2
Responsive to 
noxious stimuli
Spontaneous yet supported breathing
Coughs with suctioning/repositioning
Responds to noxious stimuli
Unable to pay attention to care provider
Will distress with a noxious procedures
Does not move/occasional movement of limbs or shifting of position
-1
Responsive to gentle 
touch or voice
Spontaneous but ineffective nonsupported breaths
Coughs with suctioning/repositioning
Responds to touch/voice
Able to pay attention but drifts off after stimulation
Distresses with procedures
Able to calm with comforting touch or voice when stimulus is removed
Occasional movement of limbs or shifting of position
0
Awake and able to 
calm
Spontaneous and effective breathing
Coughs when repositioned/occasional spontaneous cough
Responds to voice/no external stimulus is required to elicit response
Spontaneously pays attention to care provider
Distresses with procedures
Able to calm with comforting touch or voice when stimulus is removed
Occasional movement of extremities or shifting of position/increased 
movement (restless, squirming)
1
Restless and 
difficult to calm
Spontaneous effective breathing/having difficulty breathing with ventilator
Occasional spontaneous cough
Responds to voice/no external stimulus is required to elicit response
Drifts off/Spontaneously pays attention to care provider
Intermittently unsafe
Does not consistently calm, despite 5-min attempt/unable to be console
Increased movement (restless, squirming)
2
Agitated
May have difficulty breathing with ventilator
Coughing spontaneously
No external stimulus required to elicit response
Spontaneously pays attention to care provider
Unsafe (biting the endotracheal tube [ETT], pulling at catheters, cannot be 
left alone)
Unable to console
Increased movement (restless, squirming, or thrashing side-to-side, kicking 
legs)
7.1.3. Ventilator Setting
The start date/time and end date/time of the ventilator will be recorded.  Also, if the mode of 
the ventilator was changed, the mode and the date/time of the change will be recorded.


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7.2. Safety Evaluation
7.2.1. Physical Examination
Physical examination (medical examination) including auscultation, percussion, visual 
examination, palpation, etc. will be performed at screening, at baseline, and at 24 hours (30 
minutes) after dosing of the investigational product.  If any change (worsening) from baseline 
is observed in physical findings, it will be reported as an AE.
7.2.2. Core Body Temperature
It will be measured at screening, at baseline, and subsequently, every 12 hours (5 min) during 
dosing of the investigational product, at the end of dosing of the investigational product, and at 
24 hours (5 min) after the end of dosing of the investigational product.
7.2.3. Body Weight
It will be measured at screening, at baseline, and at 24 hours (5 min) after the end of dosing of 
the investigational product.
7.2.4. Vital Signs (BP, HR, RR), SpO2, and ETCO2
Blood pressure (SBP and DBP), HR, RR, SpO2, and ETCO2 will be measured.  The 
measurement points will be as follows.
[Prior to dosing to end of dosing of investigational product]
The items will be measured at screening, at baseline, at 102 minutes, 202 minutes, 302 
minutes, 1 hour5 minutes, 2 hours5 minutes, and 4 hours5 minutes after dosing of the 
investigational product, and every 4 hours5 minutes later than 4 hours after the start of 
dosing.  The items will be measured every 4 hours5 minutes from Day 2 of treatment to 
extubation.  If the investigational product is continuously dosed after extubation, the items will 
be measured every 4 hours5 minutes until the end of dosing of the investigational product.
[At the time of extubation]
The items will be measured at 52 minutes before extubation, and at 52 minutes, 152 
minutes, 302 minutes, 1 hour5 minutes, 2 hours5 minutes, 4 hours5 minutes, and 12 
hours5 minutes after extubation.
[End of dosing of investigational product to 24 hours after end of dosing of investigational 
product]
The items will be measured at the end of dosing of the investigational product (+5 minutes), at 
1 hour5 minutes, 2 hours5 minutes and 4 hours5 minutes after the end of dosing of the 
investigational product, and every 4 hours5 minutes later than 4 hours after the end of dosing 
of the investigational product.


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[At the time of changing the infusion rate of investigational product]
The items will be measured at 52 minutes immediately before changing the infusion rate of 
the investigational product and at 52 minutes after changing the rate.  
[When administering a rescue sedative/analgesic]
The items will be measured at 52 minutes immediately before and after dosing of the rescue 
sedative (midazolam) and rescue analgesic (fentanyl).
7.2.5. 12-Lead ECG and ECG Monitoring
12-lead ECG will be measured at screening and at 24 hours (30 min) after the end of dosing of 
the investigational product.
In elective surgical subjects, it will be performed at baseline (after surgery) as well.  In patients 
undergoing heart surgery, it will be performed after surgery and within 90 minutes before the 
start of dosing of the investigational product.
Also, continuous ECG monitoring will be started prior to dosing of the investigational product, 
and continue until 24 hours after the end of dosing of the investigational product.  All clinically 
significant changes observed in the ECG (e.g. arrhythmia) will be recorded as AEs.
7.2.6. Laboratory Tests; Pregnancy Test
The laboratory tests described in the table below will be performed at screening and at 24 hours 
(30 min) after the end of dosing of the investigational product at the investigational site.  
Also, the laboratory tests during the period of treatment with the investigational product will be 
performed as needed.
In elective surgical subjects, it will be performed at baseline (after surgery) as well.  In patients 
undergoing heart surgery, they will be performed after surgery and within 90 minutes before 
the start of dosing of the investigational product.
For female subjects of childbearing potential, a serum or urine pregnancy test with sensitivity 
of at least 25 mIU/mL will be performed at screening at the investigational site.  A negative 
pregnancy test result is required before the subject may receive the investigational product.
If there occurred any laboratory test value outside the reference range in laboratory tests 
performed after the end of dosing of the investigational product, follow-up will be performed if 
the investigator or sub-investigator judges it necessary.


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Table 6.
Measurement Items for Laboratory Tests
Laboratory tests
Test items
Hematology test
Red blood cell count, hemoglobin content, hematocrit level, white blood cell 
count, neutrophil, eosinophil, basophil, lymphocyte, monocyte, stab cell, and 
platelet count
Blood chemistry test
Glucose, total protein, albumin, creatinine, BUN, uric acid, total bilirubin, 
AST/SGOT, ALT/SGPT, -GTP, alkaline phosphatase, sodium, potassium, 
magnesium, calcium, and inorganic phosphorus
Urinalysis
Specific gravity, pH, glucose, protein, occult blood, and ketone body
Pregnancy testa
Serum hCG test or urinary hCG test
a To be performed only in women of childbearing potential at screening.
7.2.7. Total Input/Output Fluid Volume
From the start to end of dosing of the investigational product, total input fluid volume and total 
output fluid volume will be recorded.
7.2.8. Adverse Events; Serious Adverse Events
AEs and SAEs will be recorded according to the procedure described in Chapter 8.
 
 
 
 
 
 
 
 
 
  
 
, 
CCI


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8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs regardless of treatment group or suspected causal relationship 
to the investigational product(s) will be reported as described in the following sections.
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as an SAE 
requiring immediate notification to sponsor or its designated representative.  For all AEs, 
sufficient information should be obtained by the investigator to determine the causality of the 
AE.  The investigator is required to assess causality.  Follow up by the investigator may be 
required until the event or its sequelae resolve or stabilize at a level acceptable to the 
investigator, and sponsor concurs with that assessment.
As part of ongoing safety reviews conducted by the sponsor, any nonserious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist in 
the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.2. Reporting Period
For SAEs, the active reporting period to Sponsor or its designated representative begins from 
the time that the subject provides informed consent, which is obtained prior to the subject’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or receiving 
investigational product, through and including 28 calendar days after the last administration of 
the investigational product.  SAEs occurring to a subject after the active reporting period has 
ended should be reported to the sponsor if the investigator becomes aware of them; at a 
minimum, all SAEs that the investigator believes have at least a reasonable possibility of being 
related to investigational product are to be reported to the sponsor.
AEs (serious or non-serious) should be recorded on the CRF from the time the subject has 
taken at least 1 dose of investigational product through the subject’s last visit (24 hours after 
the end of dosing of the investigational product in the case of this study).
CCI


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8.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to:

Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease ;

Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse;

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
AEs peculiar to this study are defined as follows.
[AEs at the surgery site]
The following symptoms at the surgery site are considered common surgically-related events 
and are not to be reported as AEs: Other postoperative symptoms are to be reported as AEs.


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
Bleeding, bruising, itching, redness, swelling, numbness, tingling, burning sensation, 
pain, infection and rupturing of incision stitches.
[Changes in clinical laboratory test values associated with surgery]
Changes in laboratory test values that are normally observed in elective surgical subjects or 
medical ICU subjects do not need to be evaluated as AEs based on the investigator’s judgment, 
even if the values are outside the reference range.
[Bradycardia, hypotension and respiratory depression]
Bradycardia
If a heart rate at the 10th percentile or less of heart rate (Table 3), this will be handled as an AE.  
Hypotension
If blood pressure levels below the following reference blood pressure ranges are observed, they 
shall be handled as AEs.

Age 45 weeks CGA to <1 year old: SBP <70 mmHg

Age 1 year to <10 years old: SBP < 70+ (2x age in years) mmHg

Age 10 years to <17 years old: SBP < 90 mmHg
Respiratory Depression
If a respiratory rate at the 10 percentile or less of respiratory rate (Table 4), this will be handled 
as an AE.
8.4. Medication Error
Medication errors may result, in this study, from the administration or consumption of the 
wrong product, by the wrong subject, at the wrong time, or at the wrong dosage strength.  Such 
medication errors occurring to a study participant are to be captured on the medication error 
CRF, which is a specific version of the AE page, and on the SAE form when appropriate.  In 
the event of medication dosing error, the sponsor should be notified immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving subject exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do or 
do not involve the participating subject.


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Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the AE page 
and, if applicable, any associated AE(s) are captured on an AE CRF page.
8.5. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows:

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or

Test result leads to a change in study dosing (outside of protocol-stipulated dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
8.6. Serious Adverse Events
An SAE is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other AE outcomes, the important 
medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or 
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8.6.1. Protocol-Specified Serious Adverse Events
There are no protocol-specified SAEs in this study.  All SAEs will be reported by the 
investigator as described in previous sections, and will be handled as SAEs in the safety 
database (see the section on Serious Adverse Event Reporting Requirements).
8.6.2. Potential Cases of Drug-Induced Liver Injury
Abnormal values in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
levels concurrent with abnormal elevations in total bilirubin level that meet the criteria 
outlined below in the absence of other causes of liver injury are considered potential cases of
drug-induced liver injury (potential Hy’s law cases) and should always be considered 
important medical events.
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the subject’s individual baseline values and underlying conditions.  Subjects who 
present with the following laboratory abnormalities should be evaluated further to definitively 
determine the etiology of the abnormal laboratory values:

Subjects with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT values 3 times the upper limit of normal 
(×ULN) concurrent with a total bilirubin value 2×ULN with no evidence of hemolysis 
and an alkaline phosphatase value 2×ULN or not available; 

For subjects with preexisting ALT OR AST OR total bilirubin values above the ULN, 
the following threshold values should be used in the definition mentioned above:

For subjects with preexisting AST or ALT baseline values above the normal range: 
AST or ALT values 2 times the baseline values and 3×ULN, or 8 ULN 
(whichever is smaller).
Concurrent with

For subjects with preexisting values of total bilirubin above the normal range: Total 
bilirubin level increased from baseline by an amount of at least 1×ULN or if the 
value reaches 3×ULN (whichever is smaller).
The subject should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.
In addition to repeating measurements of AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl 
transferase, prothrombin time (PT)/international normalized ratio (INR), and alkaline 
phosphatase.  A detailed history, including relevant information, such as review of ethanol, 
acetaminophen, recreational drug, and supplement consumption, family history, occupational 
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blood transfusion, history of liver or allergic disease, and work exposure, should be collected.  
Further testing for acute hepatitis A, B, or C infection and liver imaging (eg, biliary tract) may 
be warranted.  All cases confirmed on repeat testing as meeting the laboratory criteria defined 
above, with no other cause for LFT abnormalities identified at the time, should be considered 
potential Hy’s law cases irrespective of availability of all the results of the investigations 
performed to determine etiology of the abnormal LFTs.  Such potential Hy’s law cases should 
be reported as SAEs.
8.7. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit should be assessed for medical 
importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical AE 
is not in itself an SAE.  Examples include:

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of persistent pretreatment laboratory abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
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
Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject;
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis that 
begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.
8.8. Severity Assessment
If required on the AE CRFs, the investigator will use the adjectives MILD, MODERATE, or SEVERE to describe 
the maximum intensity of the AE.  For purposes of consistency, these intensity grades are defined as follows:
MILD
Does not interfere with subject's usual function.
MODERATE
Interferes to some extent with subject's usual function.
SEVERE
Interferes significantly with subject's usual function.
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with the 
subject's usual function) but would not be classified as serious unless it met one of the criteria 
for SAEs, listed above.
8.9. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the SAE reporting requirements if 
applicable.  An investigator’s causality assessment is the determination of whether there exists 
a reasonable possibility that the investigational product caused or contributed to an AE; 
generally the facts (evidence) or arguments to suggest a causal relationship should be provided.  
If the investigator does not know whether or not the investigational product caused the event, 
then the event will be handled as “related to investigational product” for reporting purposes, as 
defined by the sponsor (see the section on Reporting Requirements).  If the investigator's 
causality assessment is "unknown but not related to investigational product," this should be 
clearly documented on CRFs.
In addition, if the investigator determines that an SAE is associated with study procedures, the 
investigator must record this causal relationship in the source documents and CRF, as 


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appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.
8.10. Exposure During Pregnancy (EDP)
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;
2. An example of environmental exposure would be a case involving direct contact with a 
Sponsor product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).
3. A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a study subject or study subject’s partner becomes or is found to be pregnant during the study 
subject’s treatment with the investigational product, the investigator must submit this 
information to the Sponsor’s drug safety unit on an SAE report form and an EDP supplemental 
form, regardless of whether an SAE has occurred.  In addition, the investigator must submit 
information regarding environmental exposure to a Sponsor’s product in a pregnant woman 
(eg, a subject reports that she is pregnant and has been exposed to a cytotoxic product by 
inhalation or spillage) using the EDP supplemental form.  This must be done irrespective of 
whether an AE has occurred and within 24 hours of awareness of the exposure.  The 
information submitted should include the anticipated date of delivery (see below for 
information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for all 
EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Sponsor of the outcome as a follow-up 
to the initial EDP supplemental form.  In the case of a live birth, the structural integrity of the 
neonate can be assessed at the time of birth.  In the event of a termination, the reason(s) for 
termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless pre-procedure test 
findings are conclusive for a congenital anomaly and the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
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
Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product.
Additional information regarding the EDP may be requested by the investigator.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on preterm 
infants to identify developmental delays).  In the case of paternal exposure, the investigator 
will provide the study subject with the Pregnant Partner Release of Information Form to deliver 
to his partner.  The investigator must document in the source documents that the subject was 
given the Pregnant Partner Release of Information Form to provide to his partner.
8.11. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to the drug safety unit within 24 hours of the 
investigator’s awareness, using the SAE report form, regardless of whether there is an 
associated AE/SAE.  Since the information does not pertain to a subject enrolled in the study, 
the information is not reported on a CRF; however, a copy of the completed SAE report form is 
maintained in the investigator site file.
8.12. Withdrawal Due to Adverse Events (See Also the Section on Subject Withdrawal)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF page.
When a subject withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.13. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study subject/legal guardian.  In addition, each study subject/legal guardian will be 
questioned about AEs.
8.14. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
8.14.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Sponsor is to be notified within 24 hours of investigator awareness of the 
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In particular, if the SAE is fatal or life-threatening, notification to Sponsor must be made 
immediately, irrespective of the extent of available AE information.  This time frame also 
applies to additional new information (follow-up) on previously forwarded SAE reports as 
well as to the initial and follow-up reporting of EDP, exposure via breastfeeding, and 
occupational exposure cases.
In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (eg, if an outpatient study subject initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time of 
his or her first awareness of the AE.
For all SAEs, the investigator is obligated to pursue and provide information to Sponsor in 
accordance with the time frames for reporting specified above.  In addition, an investigator 
may be requested by Sponsor to obtain specific additional follow-up information in an 
expedited fashion.  This information collected for SAEs is more detailed than that captured on 
the AE CRF.  In general, this will include a description of the AE in sufficient detail to allow 
for a complete medical assessment of the case and independent determination of possible 
causality.  Information on other possible causes of the event, such as concomitant medications, 
vaccines, and/or illnesses, must be provided.  In the case of a subject death, a summary of 
available autopsy findings must be submitted as soon as possible to Sponsor or its designated 
representative.
8.14.2. Nonserious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE 
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out in 
accordance with applicable local regulations.
9. STATISTICAL ANALYSES
Detailed methods of summarization and statistical analyses of data collected in this study will 
be described in the statistical analysis plan retained by the sponsor.  In the statistical analysis 
plan, the plan outlined in the protocol may be modified, but for important changes related to 
the definition of the primary endpoint and/or its analysis, the protocol will be also revised.
9.1. Analysis Populations
Efficacy evaluation population, safety analysis population (full analysis set), and PK analysis 
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9.1.1. Efficacy Evaluation Population
Subjects meeting all of the following criteria will be handled as the efficacy evaluation 
population: 
1. Subjects who did not receive any prohibited concomitant drug.  
2. Subjects who received continuous IV infusion of the investigational product over at least 6 
hours.  
Note that time of receiving study drug excludes time of interruptions if subjects experience 
interruptions of study drug.
In the efficacy evaluation, this analysis population will be used for the secondary analysis, and 
the full analysis set will be used for the primary analysis.
9.1.2. Safety Analysis Population (Full Analysis Set)
The safety analysis population (full analysis set) will be composed of all subjects who have 
received at least one dose of the investigational product.
Safety evaluation will use this analysis population.
 
  
 
 
 
 
 
 
 
 
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9.3. Efficacy Analysis
9.3.1. Analysis of Primary Endpoint
In the primary efficacy analysis, the efficacy percentage of dexmedetomidine defined in 
section 2.2.1 and its 95% confidence interval will be calculated for all subjects in full analysis 
set, and the 95% lower confidence limit will be compared to the threshold value (40%). A 
similar analysis will be also performed for the efficacy evaluation population as a secondary 
efficacy analysis. In addition, the efficacy percentage and the number of subjects will be 
summarized by age group.
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9.3.2. Analysis of Secondary Endpoints
For the secondary endpoints defined in section 2.2.2, continuous variables will be summarized 
by using basic statistics such as mean, median, standard deviation and range. For categorical 
variables, the number of subjects and its percentage will be summarized. The analyses will be 
performed for whole subjects as well as for age groups.
9.4. Safety Analysis
Safety evaluation will be performed for items such as changes from baseline. Also, the 
evaluation will be summarized based on “Pfizer Data Standards (PDS)” and investigated 
clinically. The analyses will be performed for whole subjects as well as for age groups.
9.5. Pharmacokinetics
A population PK analysis will be performed by using data obtained in this study.  The details of 
this analysis will be described in the population PK analysis plan, and the results of the analysis 
will be described in a report which will be separately prepared.
9.6. Interim Analysis
Interim analyses will be performed for the purpose of protecting the subject’s safety.  The 
details of the interim analyses will be described in statistical analysis plan and internal review 
committee (IRC) charter specified separately.
9.7. Data Monitoring Committee (DMC)
In this study, an IRC will be established.  The IRC will be composed of 3 or more members 
who are not directly related to this study and will perform safety monitoring based on the 
internal review committee charter which are separately specified for the purpose of protecting 
the subject’s safety.  The IRC will provide advices to the sponsor regarding modifications of 
the protocol, temporary suspension of the study, or early discontinuation of the study from the 
viewpoint of safety.
9.8. Early Discontinuation of Study
The sponsor may discontinue the study either entirely or at an applicable medical institution 
after giving written notice at an appropriate timing in advance if there is a reasonable cause.
The investigator may discontinue the study after giving a written notice to the sponsor at an 
appropriate timing in advance if there is a reasonable cause.
An advance written notice is not required if the study is discontinued for safety related reasons.
10. QUALITY CONTROL AND QUALITY ASSURANCE
Sponsor or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
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regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.
During study conduct and/or after study completion, the study site may be subject to review by 
the institutional review board (IRB)/ethics committee (EC), and/or to quality assurance audits 
performed by Sponsor, or companies working with or on behalf of Sponsor, and/or to 
inspection by appropriate regulatory authorities.
The investigator(s) will notify Sponsor or its agents immediately of any regulatory inspection 
notification in relation to the study.  Furthermore, the investigator will cooperate with Sponsor 
or its agents to prepare the study site for the inspection and will allow Sponsor or its agent, 
whenever feasible, to be present during the inspection.  The investigator will promptly provide 
copies of the inspection findings to Sponsor or its agent.  Before response submission to the 
regulatory authorities, the investigator will provide Sponsor or its agents with an opportunity to 
review and comment on responses to any such findings.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.  
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included subject.  The completed original 
CRFs are the sole property of Sponsor and should not be made available in any form to third 
parties, except for authorized representatives of Sponsor or appropriate regulatory authorities, 
without written permission from Sponsor.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the data 
contained on the CRFs are true.  Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry.
In most cases, the source documents are the hospital's or the physician's subject chart.  In these 
cases, data collected on the CRFs must match the data in those charts.
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigative site as well as at Sponsor and clearly 


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identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Sponsor, the investigator 
agrees to keep records, including the identity of all participating subjects (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent documents or assent document, copies of all CRFs, safety reporting forms, source 
documents, and detailed records of treatment disposition, and adequate documentation of 
relevant correspondence (eg, letters, meeting minutes, and telephone call reports).  The records 
should be retained by the investigator according to the ICH guidelines, according to local 
regulations, or as specified in the clinical study agreement (CSA), whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Sponsor should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Sponsor, such as another 
investigator, another institution, or an independent third party arranged by Sponsor.  
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
The investigator must obtain Sponsor's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board/Ethics Committee
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents/assent documents, and other relevant 
documents, eg, recruitment advertisements, if applicable, from the IRB/EC.  All 
correspondence with the IRB/EC should be retained in the investigator file.  Copies of IRB/EC 
approvals should be forwarded to Sponsor.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In that 
event, the investigator must notify the IRB/EC and Sponsor in writing immediately after the 
implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical Research 
Involving Human Subjects (Council for International Organizations of Medical Sciences 
2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World Medical 
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In addition, the study will be conducted in accordance with the protocol, the ICH guideline on 
GCP, and applicable local regulatory requirements and laws.
12.3. Subject Information and Consent
All parties will ensure protection of subject personal data and will not include subject names or 
other identifiable data in any reports, publications, or other disclosures, except where required 
by law.
When study data are compiled for transfer to Sponsor and other authorized parties, subject 
names, addresses, and other identifiable data will be replaced by a numerical code based on a 
numbering system provided by Sponsor in order to de-identify study subjects.  The study site 
will maintain a confidential list of subjects who participated in the study, linking each subject’s 
numerical code to his or her actual identity.  In case of data transfer, Sponsor will maintain high 
standards of confidentiality and protection of subjects’ personal data consistent with applicable 
privacy laws.
The informed consent documents/assent documents must be in compliance with ICH GCP, 
local regulatory requirements, and legal requirements, including applicable privacy laws.
The informed consent/assent documents used during the informed consent process must be 
reviewed and approved by the sponsor, approved by the IRB/EC before use, and available for 
inspection.
The investigator must ensure that each study subject or his or her legally acceptable 
representative, or parent(s) or legal guardian if a minor, is fully informed about the nature and 
objectives of the study and possible risks associated with participation.
Whenever consent is obtained from a subject’s parent(s) or legal guardian, the subject’s assent 
(affirmative agreement) must subsequently be obtained when the subject has the capacity to 
provide assent, as determined by the IRB/EC.  If the investigator determines that a subject’s 
decisional capacity is so limited he/she cannot reasonably be consulted, then, as permitted by 
the IRB/EC and consistent with local regulatory and legal requirements, the subject’s assent 
may be waived with source documentation of the reason assent was not obtained.  If the study 
subject does not provide his or her own consent, the source documents must record why the 
subject did not provide consent (eg, minor, decisional impaired adult), how the investigator 
determined that the person signing the consent was the subject’s legally acceptable 
representative, the consent signer’s relationship to the study subject (eg, parent, spouse), and 
that the subject’s assent was obtained, or waived.  If assent is obtained verbally it must be 
documented in the source documents.
If the study includes minor subjects who reach the age of majority during the study, as 
recognized under local law, they must re-consent as adults to remain in the study.  If the 
enrollment of ‘emancipated minors’ is permitted by the study age criteria, the IRB/EC, and 
local law, they must provide documentation of legal status to give consent without the 
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The investigator or a person designated by the investigator will obtain written informed 
consent from each subject or his/her guardian, or subject’s assent if applicable, before any 
study-specific activity is performed.  The investigator will retain the original of each subject's 
signed consent document/assent document.
12.4. Subject Recruitment
Advertisements approved by IRBs/ECs and investigator databases may be used as recruitment 
procedures.  Sponsor will have an opportunity to review and approve the content of any study 
recruitment materials directed to potential study subjects before such materials are used.
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Sponsor should be informed immediately.
In addition, the investigator will inform Sponsor immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of any 
serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
Completion of this study is defined as the time of the final observation of the final subject (24 
hours after dosing of the investigational product).
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Sponsor.  In addition, the sponsor retains the right to discontinue the development 
of dexmedetomidine at any time.
If a study is prematurely terminated or discontinued, Sponsor will promptly notify the 
investigator.  After notification, the investigator must contact all participating subjects and the 
hospital pharmacy (if applicable) within 1 week.  As directed by Sponsor, all study materials 
must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Publications by Sponsor
Sponsor fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.Sponsor.com, and other public registries in accordance with 
applicable local laws/regulations.


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In all cases, study results are reported by Sponsor in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Sponsor posts clinical trial US Basic Results on www.clinicaltrials.gov for Sponsor-sponsored 
interventional studies conducted in patients that evaluate the safety and/or efficacy of a 
Sponsor product, regardless of the geographical location in which the study is conducted.  US 
Basic Results are submitted for posting within 1 year of the primary completion date for 
studies in adult populations or within 6 months of the primary completion date for studies in 
pediatric populations.
Primary completion date is defined as the date that the final subject was examined or received 
an intervention for the purposes of final collection of data for the primary outcome, whether 
the clinical study concluded according to the prespecified protocol or was terminated.
EudraCT
Sponsor posts EU Basic Results on EudraCT for all Sponsor-sponsored interventional studies 
that are in scope of EU requirements.  EU Basic Results are submitted for posting within 1 year 
of the primary completion date for studies in adult populations or within 6 months of the 
primary completion date for studies in pediatric populations.
www.pfizer.com
Sponsor posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
sponsored interventional studies at the same time the US Basic Results document is posted to 
www.clinicaltrials.gov.
15.2. Publications by Investigators
Sponsor supports the exercise of academic freedom and has no objection to publication by 
principal investigator of the results of the study based on information collected or generated by 
principal investigator, whether or not the results are favorable to the Sponsor product.  
However, to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Sponsor an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “Publication”) 
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Sponsor at least 30 days before they are 
submitted for publication or otherwise disclosed.  If any patent action is required to protect 
intellectual property rights, the investigator agrees to delay the disclosure for a period not to 
exceed an additional 60 days.


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Protocol Amendment 2, 24-Mar-2016 (English translation version, 21-Dec-2016)
Page 69
The investigator will, on request, remove any previously undisclosed confidential information 
before disclosure, except for any study- or Sponsor product-related information necessary to 
the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is to 
be a joint publication covering all study sites, and that any subsequent publications by the 
principal investigator will reference that primary publication. However, if a joint manuscript 
has not been submitted for publication within 12 months of completion or termination of the 
study at all participating sites, the investigator is free to publish separately, subject to the other 
requirements of this section.
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Sponsor and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any Attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control as 
to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues.


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Page 70
16. REFERENCES
1 Sakura S, Saito Y. Role of α2 adrenoceptor agonists in clinical anesthesia. 
Anesthesia 21 Century 2001;3:490-6.
2 Kamibayashi T, Maze M. Clinical uses of alpha2 -adrenergic agonists. 
Anesthesiology 2000;93:1345-9.
3 Bloor BC. General pharmacology of α2-adrenoceptors. Anaesthetic 
Pharmacology Review 1993:221-32.
4 Nelson LE, Lu J, Guo T, et al. The alpha2-adrenoceptor agonist 
dexmedetomidine converges on an endogenous sleep-promoting pathway to 
exert its sedative effects. Anesthesiology 2003;98:428-36.
5 Huupponen E, Maksimow A, Lapinlampi P, et al. Electroencephalogram 
spindle activity during dexmedetomidine sedation and physiological sleep. 
Acta anaesthesiologica Scandinavica 2008;52:289-94.
6 Hall JE, Uhrich TD, Barney JA, et al. Sedative, amnestic, and analgesic 
properties of small-dose dexmedetomidine infusions. Anesthesia and 
analgesia 2000;90:699-705.
7 Aitkenhead AR. Analgesia and sedation in intensive care. British journal of 
anaesthesia 1989;63:196-206.
8 Yoshiya I, Nishimura S, Taenaka N. Sedation in Intensive Care Anesthesia 21
Century 2000;2:333-7.
9 Katsanoulas C. Concluding Remarks: Redefining Intensive Care Unit 
Sedation. International Congress and Symposium Series 1998;221:83-8.
10 Mantz J, Singer M. Importance of Patient Orientation and Rousability as 
Components of Intensive Care Unit Sedation. International Congress and 
Symposium Series 1998;221:23-9.
11 Kumon K TS, Hanaoka K, Yoshiya I, Nomura M, Adachi T, et al. Usage of 
Dexmedetomidine. The Japanese Journal of Respiratory Care 2004;21:29-37.
12 Venn RM, Hell J, Grounds RM. Respiratory effects of dexmedetomidine in 
the surgical patient requiring intensive care. Critical care 2000;4:302-8.
13 Hsu YW, Cortinez LI, Robertson KM, et al. Dexmedetomidine 
pharmacodynamics: part I: crossover comparison of the respiratory effects of 


DA-9501
C0801017 (ZIN-DEX-1506)
Protocol Amendment 2, 24-Mar-2016 (English translation version, 21-Dec-2016)
Page 71
dexmedetomidine and remifentanil in healthy volunteers. Anesthesiology 
2004;101:1066-76.
14 Ebert TJ, Hall JE, Barney JA, et al. The effects of increasing plasma 
concentrations of dexmedetomidine in humans. Anesthesiology 
2000;93:382-94.
15 Precedex Interview Form (revised in April 2014, revised version 4)
16 Internal material: Results of a Phase I study on Japanese expatriates living 
abroad (continuous dosing study)
17 Jakob SM, Ruokonen E, Grounds RM, et al. Dexmedetomidine vs 
midazolam or propofol for sedation during prolonged mechanical ventilation: 
two randomized controlled trials. Jama 2012;307:1151-60.
18 Guidelines for Drug Therapy in Pediatric Patients with Cardiovascular 
Diseases (JCS2012), 2012, 213-20.
19 Guidelines for the Use of Anesthesia and Anesthesia-related Drugs, Version 
3, X Pediatric Anesthesia, Japanese Society of Anesthesiologists 2012;
414-5.
20 Candidate drug therapies (proposed) to be reviewed at the “1st Meeting of 
Council for Paediatric Pharmacotherapy (held on March 30, 2006); 
Document 7 “Council for Paediatric Pharmacotherapy”
21 Diaz SM, Rodarte A, Foley J, et al. Pharmacokinetics of dexmedetomidine in 
postsurgical pediatric intensive care unit patients: preliminary study. Pediatr 
Crit Care Med 2007; 8(5): 419-424.
22 Zuppa AF. The pharmacokinetics and pharmacodynamics of 
dexmedetomidine in infants following open heart surgery. Society of Critical 
Care Medicine presentation#23; January 8, 2006
23 Guidelines for perioperative cardiovascular evaluation and management for 
noncardiac surgery (revised version 2014)
24 Haque IU, Zaritsky AL. Analysis of the evidence for the lower limit of 
systolic and mean arterial pressure in children. Pediatric critical care 
medicine : a journal of the Society of Critical Care Medicine and the World 
Federation of Pediatric Intensive and Critical Care Societies 2007;8:138-44.


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Protocol Amendment 2, 24-Mar-2016 (English translation version, 21-Dec-2016)
Page 72
25 Fleming S, Thompson M, Stevens R, et al. Normal ranges of heart rate and 
respiratory rate in children from birth to 18 years of age: a systematic review 
of observational studies. Lancet 2011;377:1011-8.
26 Kazuya Tachibana, Muneyuki Takeuchi: Dexmedetomidine and Sedation; 
Methods of Using DEX in Children; Methods of Perioperative 
Administration and Points to Note [in Japanese]:LiSA 2014; 21(03): 224-8
2014
27 PrecedexTM United States package insert (USPI)
28 Curley, MA, Harris, SK, Fraser, KA, et al. State Behavioral Scale: A sedation 
assessment instrument for infants and young children supported on 
mechanical ventilation. Pediatric Critical Care Medicine, 2006; 7(2):
107-114. (PMID: 16446601) 
http://www.marthaaqcurley.com/uploads/8/9/8/6/8986925/sbs_japanese.pdf

SAP_001.pdf: 
Protocol C0801017(ZIN-DEX-1506) Statistical Analysis Plan
Page 1
Protocol C0801017
Phase 3, Multi-center, Single-arm, Open-label Study Evaluating the Efficacy, Safety, and 
Pharmacokinetics of DA-9501 (Dexmedetomidine Hydrochloride) in Pediatric Subjects
in the Intensive Care Unit
Statistical Analysis Plan 
(SAP)
Version:
4.0
Date:
27-June-2017
Author:
(Clinical Statistics), 
(Clinical Pharmacology)
PPD
PPD


Protocol C0801017(ZIN-DEX-1506) Statistical Analysis Plan
Page 2
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................3
LIST OF FIGURES ...................................................................................................................3
APPENDICES ...........................................................................................................................4
1. VERSION HISTORY............................................................................................................5
2. INTRODUCTION .................................................................................................................8
2.1. Study Objectives .......................................................................................................8
2.2. Study Design .............................................................................................................8
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................10
3.1. Primary Endpoint(s) ................................................................................................10
3.2. Secondary Endpoint(s) ............................................................................................10
3.3. PK Endpoints...........................................................................................................11
3.4. Baseline Variables...................................................................................................11
3.5. Safety Endpoints .....................................................................................................11
3.5.1. Adverse Events...........................................................................................11
3.5.2. Baseline values ...........................................................................................12
4. ANALYSIS SETS ...............................................................................................................12
4.1. Full Analysis Set .....................................................................................................12
4.2. Per Protocol Analysis Set........................................................................................13
4.3. Safety Analysis Set..................................................................................................13
4.4. PK Analysis Sets .....................................................................................................13
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................13
5.1. Hypotheses and Decision Rules ..............................................................................13
5.2. General Methods .....................................................................................................13
5.2.1. Analyses for Binary Data............................................................................13
5.2.2. Analyses for Continuous Data....................................................................14
5.2.3. Analyses for Categorical Data....................................................................14
5.2.4. Analyses for Time to Event Data................................................................14
5.2.5. Linear Interpolation ....................................................................................14
5.3. Methods to Manage Missing Data ..........................................................................15
5.4. Concentrations below the Limit of Quantification..................................................15


Protocol C0801017(ZIN-DEX-1506) Statistical Analysis Plan
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5.5. Deviations, Missing Concentrations and Anomalous Values .................................15
6. ANALYSES AND SUMMARIES ......................................................................................15
6.1. Primary Endpoint(s) ................................................................................................15
6.1.1. Percentage of Subjects who did not Use a Rescue Sedative 
(midazolam) during Mechanical Ventilation to Achieve/maintain 
Adequate Sedation (efficacy percentage) ........................................................15
6.1.1.1. Primary Analysis.......................................................................15
6.1.1.2. Sensitivity/Robustness Analyses...............................................16
6.2. Secondary Endpoint(s) ............................................................................................16
6.2.1. Endpoint for Responder..............................................................................16
6.2.2. Endpoint for Dosage...................................................................................17
6.2.3. Endpoint for Maintenance Time of Target Sedation..................................18
6.2.4. Endpoint of Time to Event .........................................................................19
6.3. Other Endpoint(s)....................................................................................................19
6.3.1. PK Endpoints..............................................................................................19
6.3.2. Longitudinal SBS Score .............................................................................21
6.4. Subset Analyses.......................................................................................................21
6.5. Summaries for Baseline Characteristics..................................................................22
6.6. Safety Summaries and Analyses .............................................................................22
7. INTERIM ANALYSES/INTERNAL REVIEW COMMITTEE.........................................25
8. REFERENCES ....................................................................................................................25
LIST OF TABLES
Table 1.
Summary of Major Changes in SAP Amendments ................................................5
Table 2.
Target number of subjects ....................................................................................10
Table 3.
Summary of Efficacy Analyses ............................................................................26
LIST OF FIGURES
Figure 1.
Elective Surgical Cases...........................................................................................9
Figure 2.
Medical ICU Cases.................................................................................................9
Figure 3.
Example for a Linear Interpolation.......................................................................14
Figure 4.
Rescue Medication Dosage Record......................................................................17


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APPENDICES
Appendix 1. SUMMARY OF EFFICACY ANALYSES........................................................26
Appendix 2. DATA DERIVATION DETAILS ......................................................................31
Appendix 2.1. Definition of Protocol Deviations that Relate to Statistical 
Analyses/Populations............................................................................................31


Protocol C0801017(ZIN-DEX-1506) Statistical Analysis Plan
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1. VERSION HISTORY
This Statistical Analysis Plan (SAP) for study C0801017 is based on the protocol dated 24 March, 
2016.  
Table 1.
Summary of Major Changes in SAP Amendments
SAP 
Version
Change
Rationale
1
Not Applicable
Not Applicable
2
Section 4.2: Add [Prohibited concomitant drug 
before the start of dexmedetomidine administration 
and after the end of dexmedetomidine administration 
is outside the scope of the criterion 1].
- Clarify the period of 
prohibited concomitant drug for 
per protocol set
Section 5.2.4: Add [be the last observed time which 
may represent time of subject’s withdrawal from the 
study, time of the end of the period, time of death, 
time of the last recorded observation during the 
period, whichever happened first].
- Add explanations of censoring
Section 6.2.2: Add a detail analysis method for a 
case where rescue medication will be used 
continuously over an analysis time point.
- Add the analysis method in the 
case of unexpected cases occur
Section 6.2.4: Add and change [There are two 
analysis points. One is at 24 hours after initial 
administration of dexmedetomidine or at the 
conclusion of mechanical ventilation, whichever is 
earlier. The other is at the conclusion of mechanical 
ventilation].
- Add a different analysis point
based on rationale of this 
endpoint
- Correct an explanation of 
previous written analysis point
Section 6.3.1: Plots of mean concentration-time 
profile by age group, mean dose-normalized 
concentration-time profile by age group and 
individual concentration-time profiles by age group 
were added. In addition, a list of concentration, 
actual time points and SBS scores was added.
- Add plots for mean 
concentration-time profile by 
age group
- Add plots for mean dose-
normalized concentration-time 
profile by age group
- Add individual plots for 
concentration-time profle by 
age group
- Add a list of concentration 
with actual time points and SBS 
scores
Section 6.3.2: Add [In addition, individual SBS 
scores will be listed].
- Add a list of SBS scores
Section 6.5: Add [CGA will be listed and only used 
to evaluate whether a subject’s age is equal to or 
higher than a lower limit of age group 1 described in 
Section 6.4 when categorizing age. Otherwise age 
calculated using birthday records will be used for 
summary of age and evaluation of the age category].
- Add detail descriptions of age 
for under 1 year old subjects
Section 6.5:Add [ASA classification will be 
summarized according to Section 5.2.3 and listed].
- Add a summary and a list of 
ASA classification


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Section 6.5: Change [Drugs administered druing 
surgery for anesthesia will be summarized with total 
dosage given over the time period. -> Prior and 
concomitant medications will be listed with total 
dosage].
- A list of prior and concomitant 
medications which includes
drug information for anesthesia 
during surgery will be 
generated.
Section 6.6: Add [(eg, vital signs)].
- Add an example of safety 
evaluation using major time 
points
Section 6.6: Add [Incidence of laboratory test 
abnormalities will be summarized. All laboratory 
data, laboratory test abnormalities by subject and 
laboratory test abnormalities by test will be listed 
separately].
- Add a burette of laboratory 
test values and its evaluation 
details
Section 6.6: Change [maintenance-> exposure].
- Change a word in summary of 
exposure to study drug
Section 6.6: Change [summarized -> listed].
- Change summary to list of 
adverse event occurred after end 
of administration of 
dexmedetomidine for incident 
of withdroawal symptoms
Section 6.6: Add [Medication error will be listed].
- Add a list of medication error
Appendix table 3: Remove [or the last observation,
whichever is earlier. (#18)].
- Correct an explanation 
according to change of 
corresponding section
Appendix table 3: Add [The analysis point will be at 
24 hours after initial administration of 
dexmedetomidine or at the conclusion of mechanical 
ventilation, whichever is earlier. The start point of 
this evaluation is initiation of administration. (#19)].
- Add an analysis using a 
different analysis point
Appendix table 3: Change [#19 -> #20].
- Shift the number one line
3
Section 3.2 Endpoint # 9: Add [and weight adjusted 
total dose]
- Add based on protocol 
administrative change letter on 
December 16, 2016.
Section 5.2.1: Change descriptions and add 95% 
confidence interval
- Considering consistency with 
outputs for the analysis
Section 5.2.2: Change [quantiles -> quartiles]
- Minor modification to make 
the derection more correctly
Section 5.2.4: Delete descriptions regarding subjects 
at risk.
- It was difficult technically to 
display subjects at risk on KM-
plot.
Section 6.1.1.1, 6.2.1, 6.2.2, 6.2.3: Add definition 
for the analysis point for the patients who
discontinue the study drug earlier than the previous 
defined analysis points as an exception
- To deal with unexpected cases 
in the protocol.
Section 6.3.2 Add analysis population for the 
analysis
- Add a missing point
Section 6.6 Add detailed explanations in the 
descriptions of continuous variables and categorical 
- Described in detail


Protocol C0801017(ZIN-DEX-1506) Statistical Analysis Plan
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variables.
Section 6.6 Add analysis for exclusions from 
primary evaluation
- Add a missing analysis
Section 6.6 Add a list for administration recodes
- Add a missing analysis
Section 6.6 Add detailed explanations for the 
summary of vital signs
- Add a missing analysis
Section 6.6 Add a list of hospitalization details and 
detailed explanation of ICU discharge time for the 
summary
- Add a missing analysis
Section 6.6 Add a list for the surgery details, fluid 
volume and gradually reducing of administration 
rate to complete treatment with dexmedetomidine
- Add a missing analysis
Section 6.6 Add summary and a list for previous 
and/or concomitant drug/non-drug
- Add a missing analysis
Appendix 1, Table 3: Change descriptions according 
the newly defined analysis points in Section 6.1.1.1, 
6.2.1, 6.2.2, 6.2.3
- To deal with unexpected cases 
in the protocol.
4
Section 5.5: Add a condition for exclusion of 
analysis
- Applied this for all figures 
- Add plasma samples may have
incomplete or inaccurate sample 
collection
-Change of expression
Section 6.2.1: Add an additional analysis point of 
the responder analysis for rescue medications.
- Exploratory analyses
Section 6.2.3: Add detail explanations for analysis 
points for calculating evaluated values as endpoint 
3,7 and 8
- To make the calculation clear 
for those endpoints
Section 6.2.3: Change the analysis time point of 
endpoint 8
- Correct typo
Section 6.2.3: Delete a term of “the” in analysis 
methodology paragraph due to confusing
- To avoid misunderstanding
Section 6.3.1: Add a descriptive summary of the 
plasma dexmedetomidine concentrations based on 
nominal time points  by age group
-Add a descriptive summary by 
age group
Section 6.4: Delete terms of "Group" described for 
exposure to study drug and modify categories.
- To avoid misunderstanding
- Exposure categories were 
reviewed and needed to modify.
Section 6.6: Add a description of all adverse events 
in addition to TEAE
- Summary of events which 
occurred both before and after 
initial administration of a study 
drug was needed considering 
with this protocol design.
Section 6.6: Add evaluation time points for vital 
signs and name of the time points (major time point) 
was changed to analysis time point.
- More time points were needed 
to assess longitudinal transition.
Section 6.6: Summary was added for Incident of 
withdrawal symptoms.
- Summary was needed besides 
to a listing
Section 6.6: Add descriptions of adverse events of 
subjects dosed over 24 hours
- Summary was needed for the 
specific adverse events


Protocol C0801017(ZIN-DEX-1506) Statistical Analysis Plan
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Section 6.6: Add descriptions for the Intubation 
summary
- Add descriptions how to deal 
with too long intubation time or 
not applicable records
Section 6.6: Add descriptions for the hospitalization 
summary
- Add descriptions how to deal 
with too long hospitalization 
time or not applicable records
Appendix 1 (Table 3): Add exploratory analyses 
regarding rescue medications
- Add two rows in 
correspondence with the 
exploratory responder analyses
2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study C0801017.  This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint definition or its analysis will also 
be reflected in a protocol amendment.
2.1. Study Objectives
To evaluate the efficacy, safety, and pharmacokinetics (PK) of DA-9501 (dexmedetomidine 
hydrochloride; hereinafter referred to as “dexmedetomidine”) administered as continuous IV 
infusion in pediatric subjects (45 weeks CGA [corrected gestational age] to <17 years old) 
who require sedation in the intensive care unit.
2.2. Study Design
This study is a phase 3, multi-center, single-arm, open-label study evaluating the efficacy, 
safety, and pharmacokinetics (PK) of dexmedetomidine administered as continuous IV 
infusion in pediatric subjects aged 45 weeks CGA to <17 years old. 


Protocol C0801017(ZIN-DEX-1506) Statistical Analysis Plan
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In this study, there are two types of cases described in following figures.
Figure 1.
Elective Surgical Cases
Figure 2.
Medical ICU Cases
Target sample size is 60 subjects.  Of these subjects, at least 32 subjects aged 45 weeks 
CGA to <17 years old will be included in the PK evaluation.  The target number of subjects 
for efficacy/safety evaluation and the target number of subjects for PK evaluation by age 
group are as follows. 


Protocol C0801017(ZIN-DEX-1506) Statistical Analysis Plan
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Table 2.
Target number of subjects
Age group
Efficacy/safety evaluation:
Target number of subjects
Number of subjects for PK 
evaluationa
I
45 weeks CGA, <12 months
8
8
II
12 months, <24 months
16
8
III
2 years, <6 years
16
8
IV
6 years, <17 years
8
8
Target number of subjects
60
32
a Of enrolled subjects, those from whom informed consent for blood sampling for PK measurement is obtained
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint(s)
Percentage of subjects who did not use a rescue sedative (midazolam) during mechanical 
ventilation to achieve/maintain adequate sedation (efficacy percentage) from the start of 
dexmedetomidine administration to 24 hours after the initial administration or conclusion of 
mechanical ventilation.  If the mechanical ventilation is concluded within 24 hours of 
dexmedetomidine administration, the record at conclusion of mechanical ventilation will be 
used for the primary endpoint.
3.2. Secondary Endpoint(s)
i.
From the start of dexmedetomidine administration to 24 hours after the initial 
administration or conclusion of mechanical ventilation when mechanical ventilation 
is concluded within 24 hours of dexmedetomidine administration,
1. Percentage of subjects who did not require administration of a rescue analgesic 
(fentanyl) during mechanical ventilation in addition to administration of the 
investigational product.
2. Dose level corrected for total dose of rescue sedative/analgesic during mechanical 
ventilation and for body weight.
3. Duration and percentage of maintenance of target sedation level during 
mechanical ventilation.
ii.
From 24 hours of dexmedetomidine administration to conclusion of mechanical 
ventilation when dexmedetomidine administration exceeds 24 hours,
4. Percentage of subjects who did not use a rescue sedative(midazolam) during 
mechanical ventilation to maintain/achieve adequate sedation.
5. Percentage of subjects who did not require dosing of a rescue analgesic(fentanyl)
during mechanical ventilation in addition to dosing of the investigational product.


Protocol C0801017(ZIN-DEX-1506) Statistical Analysis Plan
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6. Dose level corrected for total dose of rescue sedative/analgesic during mechanical 
ventilation and for body weight. 
7. Duration and percentage of maintenance of target sedation level during 
mechanical ventilation.
iii.
From after extubation to conclusion of dexmedetomidine administration,
8. Duration and percentage of maintenance of target sedation level after extubation.
9. Total dose and weight adjusted total dose of rescue sedative/analgesic.
iv.
From the start of dexmedetomidine administration to conclusion of mechanical 
ventilation,
10. Time until the end of mechanical ventilation.
3.3. PK Endpoints
Plasma dexmedetomidine concentration.
3.4. Baseline Variables
There is no model based on analysis using a baseline value as a variable.
3.5. Safety Endpoints

Adverse events.

Vital signs (blood pressure, heart rate, respiratory rate), SpO2, ETCO2, core body 
temperature, and body weight.

Laboratory test values.

Total Input/output Fluid Volume.

Occurrence of withdrawal (abstinence) symptoms (presence/absence of hypertension, 
tachycardia, or agitation symptoms after the end of dosing of the investigational 
product).

Electrocardiogram (ECG).
3.5.1. Adverse Events
AEs (regardless of seriousness) will be recorded in the case report form (CRF) between the 
time when the subject has taken at least 1 dose of the investigational product and the last visit 
(24 hours after the end of dosing of the investigational product in the case of this study).


Protocol C0801017(ZIN-DEX-1506) Statistical Analysis Plan
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For SAEs, the active reporting period to Sponsor or its designated representative begins from 
the time that the subject provides informed consent, which is obtained prior to the subject’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 28 calendar days after the last 
administration of investigational product.  SAEs occurring to a subject after the active 
reporting period has ended should be reported to the sponsor if the investigator becomes 
aware of them; at a minimum, all SAEs that the investigator believes have at least a 
reasonable possibility of being related to investigational product are to be reported to the 
sponsor.
The following symptoms at the surgery site are considered common surgically-related events 
and are not to be reported as AEs: Bleeding, bruising, itching, redness, swelling, numbness, 
tingling, burning sensation, pain, infection and rupturing of incision stitches.  Other 
postoperative symptoms are to be reported as AEs.
Changes in laboratory test values that are normally observed in elective surgical cases or 
medical ICU cases do not need to be evaluated as AEs based on the physician’s judgment, 
even if the values are outside the reference range.
Bradycardia, hypotension, and respiratory depression are to be reported as AEs if the pulse 
rate, blood pressure level, and respiratory rate are below the range specified for each age.
3.5.2. Baseline values
The baseline assessment is defined as the last assessment recorded before study drug 
administration.  If baseline data is recorded at both screening visit and baseline visit, data at 
baseline visit will be used as baseline data for the safety endpoint.  If baseline data is 
recorded at either screening visit or baseline visit, the existing data at screening visit or 
baseline visit will be used as baseline data for the safety endpoint.  If baseline data is 
recorded at neither screening visit nor baseline visit, baseline data for the safety endpoint will 
be missing.  This algorism will be applied to endpoints which are observed at both screening 
visit and baseline visit.
4. ANALYSIS SETS
Data for all subjects will be assessed to determine if subjects meet the criteria for inclusion in 
each analysis population prior to releasing the database and classifications will be 
documented per standard operating procedures.
4.1. Full Analysis Set
The Full Analysis Set (FAS) is composed of all subjects who have received at least one dose 
of the investigational product. FAS is the primary analysis population for efficacy 
evaluation.


Protocol C0801017(ZIN-DEX-1506) Statistical Analysis Plan
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4.2. Per Protocol Analysis Set 
The Efficacy Evaluation analysis set (EE) will be a subset of the FAS dataset and include
subjects that satisfy both of the following criteria:
Subjects who did not receive any prohibited concomitant drug. 
Subjects who received continuous IV infusion of the investigational product over at least 
6 hours.
Note that receiving study drug excludes interruptions.
Prohibited concomitant drug before the start of dexmedetomidine administration and after the
end of dexmedetomidine administration is outside the scope of the criterion 1.  The definition 
of prohibited concomitant drugs is described in Section 5.8.1 “Prohibited Concomitant 
Drugs” in the protocol amendment 2.
EE is the secondary analysis population for efficacy evaluation.
4.3. Safety Analysis Set
The definition of safety analysis set (SS) is the same as that of FAS.  SS is the primary 
population for safety evaluation.
4.4. PK Analysis Sets
The PK analysis population is defined as all subjects treated with dexmedetomidine over at 
least 6 hours and measured at least 1 plasma concentration.
5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
The lower limit of 95% confidence interval of primary endpoint described in Section 3.1 will 
be compared with threshold value (40%) set as an intermediary efficacy rate between the 
placebo (20%) and dexmedetomidine(60%). 
5.2. General Methods 
5.2.1. Analyses for Binary Data
Estimation
For a single binominal proportion, 95% confidence interval will be calculated as a two-sided, 
2.5% upper and lower intervals, based on Agresti-Coull’s method (Agresti and Coull, 1998, 
Lawrence D. Brown et al, 2001). 
Descriptive summary
Following statistics will be used: number of subjects, number of subjects with the response, 
percentage of the responses and its 95% confindence interval.


Protocol C0801017(ZIN-DEX-1506) Statistical Analysis Plan
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5.2.2. Analyses for Continuous Data
Descriptive summary 
Following statistics will be used: number of subjects, mean, standard deviation, median, 
minimum, maximum, and quartiles. 
5.2.3. Analyses for Categorical Data
Descriptive summary 
Following statistics will be used: number and percentage of subjects in each category.
5.2.4. Analyses for Time to Event Data
Time-to-event endpoints will be summarized using the Kaplan-Meier method and estimated 
survival curves will be displayed graphically when appropriate.  The time of median and 
quartiles (hours) will be estimated by the Kaplan-Meier method.  Confidence interval for 
median and quartiles are based on the Brookmeyer-Crowley method. 
The subjects who did not have the event of interest during the corresponding evaluation 
period that starts at the time of first study drug infusion will be considered censored.  The
time of censoring will be the last observed time which may represent time of subject’s 
withdrawal from the study, time of the end of the period, time of death, time of the last 
recorded observation during the period, whichever happened first.
5.2.5. Linear Interpolation
The two coordinates are given as (t1,y1) and (t2,y2).  If y are given in the interval [y1, y2], the 
value t along the straight line between these coordinates is calculated from the following 
equation;
An example figure for a linear interpolation in the above situation is as follows:
Figure 3.
Example for a Linear Interpolation


Protocol C0801017(ZIN-DEX-1506) Statistical Analysis Plan
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5.3. Methods to Manage Missing Data
No imputation rule will be applied to missing data in efficacy evaluation, while a standard 
algorithm for imputation will be applied to safety evaluation if needed.
5.4. Concentrations below the Limit of Quantification
In all data presentations (except listings), concentrations below the limit of quantification
(BLQ) will be set to zero.
5.5. Deviations, Missing Concentrations and Anomalous Values
In summary tables, figures (including individual plots), concentration value will be treated
as missing if 1 of the following cases is true:
A concentration has been collected as ND (ie, not done) or NS (ie, no sample);
A gap in sampling time between prescribed and actual time is of sufficient concern or a 
concentration has been flagged anomalous;
Plasma samples may have incomplete or inaccurate sample collection.
Note that summary statistics will not be presented at a particular time point if more than
50% of the data are missing.
6. ANALYSES AND SUMMARIES
6.1. Primary Endpoint(s)
6.1.1. Percentage of Subjects who did not Use a Rescue Sedative (midazolam) during 
Mechanical Ventilation to Achieve/maintain Adequate Sedation (efficacy percentage)
6.1.1.1. Primary Analysis

Analysis time points: The analysis point will be at 24 hours from administration of 
dexmedetomidine or at the conclusion of mechanical ventilation, whichever is earlier.  
The start point of this evaluation is initiation of administration. If administration of 
dexmedetomidine is discontinued earlier than both time points of 24 hours from 
administration and the conclusion of mechanical ventilation, the analysis point will be
at the end of administration of dexmedetomeidine.

Analysis population: FAS.

Analysis methodology: Estimation described in Section 5.2.1.
Reporting results:

The total number of FAS, the number of subjects with no additional 
sedative(midazolam), the percentage and its 95% confidence interval will be 
presented.


Protocol C0801017(ZIN-DEX-1506) Statistical Analysis Plan
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6.1.1.2. Sensitivity/Robustness Analyses
The same analysis as the primary analysis will be conducted in EE.  The reporting results 
will be also the same as Section 6.1.1.1.
In addition, total number, the number of subjects with no additional sedative(midazolam) and 
its percentage in each age group (see Section 6.4) will be reported by FAS and EE according 
to descriptive summary described in Section 5.2.1.
6.2. Secondary Endpoint(s)
6.2.1. Endpoint for Responder
Responder is defined as a subject who did not require administration of a rescue 
medication(midazolam/fentanyl) during mechanical ventilation in addition to administration 
of the investigational product .  The endpoints for responder are 1, 4 and 5 described at 
Section 3.2.

Analysis time points: If the endpoint is 1, the analysis point will be at 24 hours after
initial administration of dexmedetomidine or at the conclusion of mechanical 
ventilation, whichever is earlier.  The start point of this evaluation is initiation of 
administration of dexmedetomidine. If the endpoint is 4 or 5, the analysis point will 
be at the conclusion of mechanical ventilation.  The start point of this evaluation is at 
24 hours after initial administration of dexmedetomidine. If administration of 
dexmedetomidine is discontinued earlier than both time points of 24 hours from 
administration and the conclusion of mechanical ventilation for the endpoint 1 or than
the conclusion of mechanical ventilation for the endpoints of 4 and 5, the analysis
point will be at the end of administration of dexmedetomeidine.

Analysis population: FAS, EE.

Analysis methodology: Descriptive summary described in Section 5.2.1.
Reporting results:

All calculated descriptive summaries based on Section 5.2.1 for each endpoint will be 
reported.

In addition, the percentage of subjects who did not use a rescue medication
(midazolam/fentanyl) will be calculated during the period from after extubation to 
conclusion of dexmedetomidine administration as exploratory analyses in the same 
manner as above.


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6.2.2. Endpoint for Dosage
The endpoints for dosage are 2, 6 and 9 described at Section 3.2. 

Analysis time points: If the endpoint is 2, the analysis point will be at 24 hours after
initial administration of dexmedetomidine or at the conclusion of mechanical 
ventilation, whichever is earlier.  The start point of this evaluation is initiation of 
administration.  If the endpoint is 6, the analysis point will be at the conclusion of 
mechanical ventilation. The start point of this evaluation is at 24 hours after initial 
administration of dexmedetomidine. If administration of dexmedetomidine is
discontinued earlier than both time points of 24 hours from administration and the
conclusion of mechanical ventilation for the endpoint 2 or than the conclusion of 
mechanical ventilation for the endpoint 6, the analysis point will be at the end of 
administration of dexmedetomeidine.   If the endpoint is 9, the analysis point will be 
at the conclusion of mechanical ventilation.  The start point of this evaluation is at the 
point of extubation.

Analysis population: FAS, EE.

Analysis methodology: Descriptive summaries described in Section 5.2.2 for total 
dosage and dosage compensation based on weight of rescue medication will be 
calculated separately for only rescued subjects and all subjects by each rescue 
medication (midazolam/ fentanyl).  In this analysis, the rescued subject is defined as a 
subject who received any amount of rescue medication in the target evaluation period 
for each endpoint.  The dose of the subjects who did not receive rescue medication 
will be treated as zero in the calculation for the descriptive summaries of all subjects.
If rescue medication is used continuously over the analysis time point (Figure 4 shows an 
example case), total dosage up to the analysis time point will be calculated as follows:
Figure 4.
Rescue Medication Dosage Record
.


Protocol C0801017(ZIN-DEX-1506) Statistical Analysis Plan
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Reporting results:

The summary tables will be generated by the type of the endpoints (total 
dosage/weight adjusted dosage), the type of the subjects (rescued/all), and the type of 
the rescue medication(midazolam/fentanyl) according to Section 5.2.2, respectively. 
6.2.3. Endpoint for Maintenance Time of Target Sedation
The endpoints for maintenance time of target sedation are 3, 7 and 8 described at Section 3.2. 

Time that the target sedation is maintained/achieved.
The target sedation scores by state behavioral scale (SBS) are −2 to 0 while intubated and 
−1 to 0 after extubation (See table 5 in the protocol amendment 2 for the details).  If the 
subjects meet the target sedation score at the analysis point for the evaluation period, the 
subjects will be regarded as maintain/achieve target sedation. 
If one of the consecutive SBS scores is out of the target range (-2 to 0 while intubated/-1 
to 0 after extubation), a linear interpolation described in Section 5.2.5 will be used 
between them to estimate the time within the SBS target range and above or below the 
range.  If there are several SBS scores at one time, then the average of these scores will 
be used.  Then the absolute time that the subject in the SBS target range will be 
calculated for each subject as the total amount of time where the estimated SBS scores 
are in the SBS target range.  The percentage of the time will be derived then as a ratio of 
the time in SBS target range while the evaluation period for the endpoint.

Analysis time points: If the endpoint is 3, the analysis point will be at 24 hours after 
initial administration of dexmedetomidine or at the conclusion of mechanical 
ventilation, whichever is earlier.  The start point of this evaluation is initiation of 
administration.  If the endpoint is 7, the analysis point will be at the conclusion of 
mechanical ventilation.  The start point of this evaluation is at 24 hours after initial
administration of dexmedetomidine. If the analysis point is at the conclusion of 
mechanical ventilation, values measured at designated allowance intervals of before 
extubation visit will be used for both numerator and denominator in endpoint 3 and 7.
In addition, if administration of dexmedetomidine is discontinued earlier than both 
time points of 24 hours from administration and the conclusion of mechanical 
ventilation for the endpoint 3 or than the conclusion of mechanical ventilation for the 
endpoint 7, the analysis point will be at the end of administration of 
dexmedetomeidine. If the endpoint is 8, the analysis point will be the end of 
administration of dexmedetomidine. Evaluated duration will be the same between 
numerator and denominator. The start point of this evaluation is at the point of 
extubation.

Analysis population: FAS, EE.

Analysis methodology: Number of subjects that spent any amount of time in SBS 
target range and its percentage will be summarized according to Section 5.2.1.  


Protocol C0801017(ZIN-DEX-1506) Statistical Analysis Plan
Page 19
Descriptive summaries for absolute time in hours and its percentage regarding the 
maintained interval of the target sedation will be calculated according to
Section 5.2.2.  In the same table, total absolute time in hours of the analysis 
population will be also summarized according to Section 5.2.2.
As a sensitivity analysis, the endpoint 3 will be also analysed using an analysis point 
which is the earliest point among 24 hours after initial administration of 
dexmedetomidine, the conclusion of mechanical ventilation, the end of administration 
of dexmedetomidine and initiation of gradually reducing of administration rate to 
complete treatment with dexmedetomidine.  The start point of this evaluation is 
initiation of administration.
Reporting results:

All calculated descriptive summaries based on Section 5.2.1 and Section 5.2.2 for 
each endpoint will be reported.
6.2.4. Endpoint of Time to Event
The endpoint of time to event is the endpoint 10 described at Section 3.2.  The event in this 
analysis is conclusion of mechanical ventilation.

Analysis time points: There are two analysis points.  One is at 24 hours after initial 
administration of dexmedetomidine or at the conclusion of mechanical ventilation, 
whichever is earlier.  The other is at the conclusion of mechanical ventilation.  The 
start point of this evaluation is initiation of administration.

Analysis population: FAS, EE.

Analysis methodology: Descriptive summary and figures described in Section 5.2.4
will be generated. 
The same analysis without figures will be also conducted by age group.
6.3. Other Endpoint(s)
6.3.1. PK Endpoints
The following reporting of PK data will be done: 

A descriptive summary of the plasma dexmedetomidine concentrations based on 
nominal time points.

A descriptive summary of the plasma dexmedetomidine concentrations based on 
nominal time points by age group.

Plots of mean plasma dexmedetomidine concentrations against nominal time post 
dose (on both linear and semi-log scales) by age group in one graph for all age group.


Protocol C0801017(ZIN-DEX-1506) Statistical Analysis Plan
Page 20

A descriptive summary of the plasma dexmedetomidine concentrations based on 
nominal time points by age group and presence or absence of taper.

Plots of mean plasma dexmedetomidine concentrations against nominal time points 
(on both linear and semi-log scales) by age group and presence or absence of taper in 
one graph for all age groups.

A descriptive summary of the plasma dexmedetomidine concentrations based on 
nominal time points by age group, presence or absence of taper and presence or 
absence of additional sedative (midazolam).

Plots of mean plasma dexmedetomidine concentrations against nominal time post 
dose by age group, presence or absence of taper and presence or absence of additional 
sedative (midazolam) in one graph for same combination of age group and taper 
condition.

A descriptive summary of the dose-normalized plasma dexmedetomidine 
concentrations based on nominal time points.

Plots of mean dose-normalized plasma dexmedetomidine concentrations against 
nominal time post dose (on both linear and semi-log scales) by age group in one 
graph for all age group.

A descriptive summary of the dose-normalized plasma dexmedetomidine 
concentrations based on nominal time points by age group and presence or absence of 
taper.

Plots of mean dose-normalized plasma dexmedetomidine concentrations against 
nominal time points (on both linear and semi-log scales) by age group and presence 
or absence of taper in one graph for all age groups.

Box plots of plasma dexmedetomidine concentrations at 1-2 hours before the end of 
dosing or before the start of tapering represented by age group.

Box plots of plasma dexmedetomidine concentrations at 1-2 hours before the end of 
dosing or before the start of tapering represented by age group and presence or 
absence of additional sedative (midazolam) in one graph for each age group.

A listing of all plasma dexmedetomidine concentrations sorted by subject, age group 
and nominal time points.  The listing of concentrations will also include the actual 
time points.

Individual plots of plasma dexmedetomidine concentrations against actual time post 
dose (on both linear and semi-log scales) represented by age group.

Individual plots of plasma dexmedetomidine concentrations against actual time points 
(on both linear and semi-log scales) represented by age group and presence or 
absence of taper.


Protocol C0801017(ZIN-DEX-1506) Statistical Analysis Plan
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
A listing of all plasma dexmedetomidine concentrations sorted by subject, age group 
and nominal time points.  The listing of concentrations will also include the actual 
time points and SBS scores.  SBS scores at closest time points to each blood 
collection time will be used.

Individual plots for SBS scores versus the dexmedetomidine plasma concentration at 
the time to end of dosing by age group in one graph for all subjects.  SBS scores at 
closest time points to each blood collection time will be used.

Individual plots for SBS scores versus the dexmedetomidine plasma concentration at 
the time from end of dosing to last PK sample by age group in one graph for all 
subjects.  SBS scores at closest time points to each blood collection time will be used.
The set of statistics will include n, geometric mean, arithmetric mean, median, standard
deviation, cv, geometric cv, minimum, maximum and the number of concentrations above 
the lower limit of quantification.
6.3.2. Longitudinal SBS Score 

Longitudinal individual plots of all recorded SBS scores will be generated by 
subjects.  These plots include information of initiation and conclusion time points 
about both dexmedetomidine administration and intubation.  These figures will be 
reviewed by internal review committee.  In addition, individual SBS scores will be 
listed. Analysis population of these analyses will be FAS.
6.4. Subset Analyses 
For safety and efficacy analyses
Subset analyses regarding age group will be conducted for all efficacy and safety analyses 
unless otherwise specified.
Age group is defined as follows:
Age group
I
45 weeks CGA, <12 months
II
12 months, <24 months
III
2 years, <6 years
IV
6 years, <17 years
Patient type (Elective surgery or Medical ICU) can be specified with records of surgery and 
ASA classification.  If patient type is Elective surgery, the patient has records of surgery
details and ASA classification.
If number of patients in one of patient types is more than 20 subjects, following subgroup 
analyses will be conducted:  For efficacy evaluation, endpoints which are the same definition 
of a primary endpoint described in Section 3.1 and secondary endpoints of 1, 2 and 3


Protocol C0801017(ZIN-DEX-1506) Statistical Analysis Plan
Page 22
described in Section 3.2 will be analyzed using FAS by patient type.  For safety evaluation, 
frequency of adverse events will be summarized with severity by patient types.
Exposure to study drug
Exposure to study drug will be summarized by subgroups of time of exposure to the study 
drug defined as follows:

Exposure time <6 hours.

Exposure time >= 6 hours.

Exposure time > 12 hours.

Exposure time > 24 hours.

6 =< Exposure time <=12 hours.

12 < Exposure time <=24 hours.
6.5. Summaries for Baseline Characteristics
The analyses regarding baseline characteristics will be conducted according to Pfizer data 
standard (PDS) by FAS and EE for both total subjects and each age group unless otherwise 
specified.
The summary which may be non-PDS is described as follows:
Summary for demography: Age will be summarized with both units of years and months
as a continuous variable.  Also age will be treated as a category variable described in
Section 6.4 for the summary of total subjects.  CGA will be listed and only used to 
evaluate whether a subject’s age is equal to or higher than a lower limit of age group 1
described in Section 6.4 when categorizing age.  Otherwise age calculated using birthday 
records will be used for summary of age and evaluation of the age category.  Body mass 
index will not be calculated and summarized.  Weight will be summarized as a continuous 
variable.  Patient types (Elective surgery or Medical ICU) will be summarized according to 
Section 5.2.3.  ASA classification will be summarized according to Section 5.2.3 and listed.
List for prior and concomitant medications: Prior and concomitant medications will be 
listed with total dosage.
6.6. Safety Summaries and Analyses
All safety analyses will be conducted according to PDS by both total subjects and each age 
group in SS unless otherwise specified.
Adverse events will be summarized by treatement emergent adverse events and all adverse 
events recorded in CRF, respectively.
Following analysis time points will be used for longitudinal summaries for safety evaluation
of vital signs; Baseline (Day1/Pre-dose), Day 1 visits (Day 1/10 minutes, Day 1/20 minutes, 
…, Day 1/24 hours), End of mechanical ventilation (Extubation/-5 minutes, Extubation/5


Protocol C0801017(ZIN-DEX-1506) Statistical Analysis Plan
Page 23
minutes), End of dosing (End of treatment/0 minute), 24 hours after end of dosing (End of 
treatment/24 hours), Visits for rescue medications (Rescue Medications [Fentanyl or 
Midazolam]/-5 minutes, Rescue Medications [Fentanyl or Midazolam]/5 minutes), 
Unplanned visits (Change Infusion rate/-5 minutes, Change Infusion Rate/5 minutes) and 
Discontinuation. Subjects may be duplicated in the summaries of Visits for rescue 
medications and Unplanned visits. Continuous variables of vital signs will be summarized for 
actual values and change from baseline by descriptive statistics at each analysis time point.  
Categorical variables for ECG at each analysis time point [Baseline (Day1/Pre-dose), 24 
hours after initial dosing(Day1/24H),  End of mechanical ventilation (Extubation/5MIN), 
End of dosing(End of treatment/0MIN) and 24 hours after end of dosing (End of 
treatment/24H)] will be summarized by number and its percentage.  In addition, change from 
baseline of them will be summarized by cross table. For evaluation of 24 hours after end of 
dosing (End of treatment/24H), only subjects who complete the study treatment will be 
summarized.
In terms of fluctuation, the following variables are of interest in particular:
Vital signs (Systolic Blood Pressure[SBP], Diastolic Blood Pressure [DBP], Heart 
Rate[HR], Respiratory Rate[RR]), Oxygen Saturation of Arterial Blood [SpO2], End 
Tidal CO2[ETCO2], core body temperature, and body weight.
Laboratory test values.
The following may be study-specific summaries:

Exclusions from primary evaluation
The number of subjects in per protocol set out of full analysis set and it’s percentage 
will be calculated.

Summary of exposure to study drug
Total exposure dose, average exposure dose and total esposure time of the study drug 
will be summarized in the same table.  The subgroup analysis using exposure time 
group will be also conducted in the same manner, respectively. In addition, 
administration recodes including variables used in summary of exposure to study 
drug will be listed.

Vital sign
Actual values and change from baseline of vital signs, SpO2, ETCO2 and body weight
will be summarized by descriptive statistics at each analysis time point. In terms of 
records for 24 hours after end of dosing (End of treatment/24H), summaries will be 
made separately for subjects who completed the study treatment as “End of 
treatment/24H” and subjects who experienced early discontinuation before the study 
treatment completion as “Discontinulation”.


Protocol C0801017(ZIN-DEX-1506) Statistical Analysis Plan
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Longitudinal records for vital signs, SpO2,ETCO2 and body weight with information
of subject ID, administration rate(μg/kg/hour) and actual time will be generated as a 
list format.

Laboratory test values
Incidence of laboratory test abnormalities will be summarized.  All laboratory data, 
laboratory test abnormalities by subject and laboratory test abnormalities by test will 
be listed separately.

Incident of withdrawal symptoms
Adverse event occurred after end of administration of dexmedetomidine will be 
summarized and listed in order to evaluate occurrence of withdrawal (abstinence) 
symptoms (eg, presence/absence of hypertension, tachycardia, or agitation symptoms 
after the end of dosing of the investigational product).

Adverse events of subjects dosed over 24 hours
Incidence of adverse events (all causality, treatment related) occurred after 24 hours
of dosing will be summarized for subjects dosed over 24 hours by severity, 
respectively. 

Intubation details
Duration (hour) of intubation will be summarized according to Section 5.2.2. If time 
of extubation is over 24 hours after the end of dosing in subjects who completed the 
study, time of 24 hours after the end of dosing will be used in the summary. In 
addition, time of end of dosing will be used in the summary if extubation time is later 
than the end of dosing or not reported for subjects who discontinued from the study.
In addition,  reasons for intubation will be summarized according to Section 5.2.3.  
Other reasons recorded by text descriptions will be summarized as a list format 
separately.

Ventilator settings
Records of ventilator setting will be summarized as a list format.

Hospitalization details
Duration from ICU admission to ICU discharge will be summarized according to 
Section 5.2.2 and listed. If ICU discharge time is over 24 hours after the last 
administration, it is regarded as 24 hours after the last administration in the summary.
In addition, time of end of dosing will be used in the summary if discharge time is 
later than the end of dosing or not reported for subjects who discontinued from the 
study.


Protocol C0801017(ZIN-DEX-1506) Statistical Analysis Plan
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
Surgery details
Duration of surgery will be summarized according to Section 5.2.2. Data used in the 
summary will be also listed.

Fluid Volume
Total input and output fluid volume will be summarized separately according to 
Section 5.2.2. Data used in the summary will be also listed.

Gradually reducing of administration rate to complete treatment with 
dexmedetomidine
Number of patients who experienced gradually reducing of administration rate to 
complete treatment with dexmedetomidine and its percentage will be summarized 
according to Section 5.2.3. Data used in the summary will be also listed.

Medication error
Medication error will be listed.

Previous and/or concomitant drug/non-drug
Previous and concomitant drug/nondrug will be summarized by number of subject for 
each drug/nondrug and listed. In addition, concomitant rescue medications 
(Midazolam and Fentanyl) will be listed respectively.
7. INTERIM ANALYSES/INTERNAL REVIEW COMMITTEE
Interim analyses for internal review committee (IRC) will be conducted from the view of
safety monitoring. The committee meetings will be scheduled when all data of 24 hours after 
end of administration are available on the first 10 and 20 subjects for the first and second 
meetings.  After the second meeting, additional meetings may be conducted if needed.  The 
detailed procedures of IRC will be documented in internal review committee charter.
8. REFERENCES 
1.
Agresti, A., and Coull, B.A. (1998).  Approximate is better than ‘exact’ for interval 
estimation of binomial proportions.  The American Statistician 52, 119-126.
2.
Lawrence D. Brown, T. Tony Cai, and Anirban DasGupta (2001). Interval Estimation 
for a Binomial Proportion. Statistical Science 16(2), 101-133.


Protocol C0801017(ZIN-DEX-1506) Statistical Analysis Plan
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APPENDICES 
Appendix 1. SUMMARY OF EFFICACY ANALYSES
Table 3.
Summary of Efficacy Analyses
#
Description of 
Endpoint
Analysis Time Point
End 
point 
#
Summary
Analysis
Set
Analysis 
Section #
Reporting 
Results
Subset
Primary/
Secondary
1
Percentage of 
subjects who did 
not use a rescue 
sedative 
(midazolam) 
during 
mechanical 
ventilation to 
achieve/maintai
n adequate 
sedation 
(efficacy 
percentage)
The analysis point will be 
at 24 hours after initial 
administration of 
dexmedetomidine or at the 
conclusion of mechanical 
ventilation or the end of 
administration of 
dexmedetomidine, 
whichever is earliest. The 
start point of this 
evaluation is initiation of 
administration.
§ 3.1
95% confidence 
interval will be 
calculated as a 
two-sided, 2.5% 
upper and lower 
intervals, based 
on 
Agresti-Coull’s 
method
FAS
§ 6.1.1.1
Total number, 
the number of 
subjects with 
no additional 
sedative
(midazolam), 
the percentage 
and its 95% 
confidence 
interval
-
Primary
2
EE
§ 6.1.1.2
Sensitivity
analysis for 
primary 
analysis
3
Descriptive 
summary
FAS/EE
§ 6.1.1.2, 
§ 6.4
§ 5.2.1
by age group
Secondary
4
FAS
by patient type
Secondary
5
The analysis point will be 
at the conclusion of 
mechanical ventilation or 
the end of administration 
of dexmedetomidine, 
whichever is earlier.  The 
start point of this 
evaluation is at 24 hours 
after initial administration.
4 in
§ 3.2
Descriptive 
summary
FAS/EE
§ 6.2.1,
§ 6.4
§5.2.1
In addition to 
whole 
population, 
subgroup 
analysis for each 
age group will 
be conducted.
Secondary
-
The analysis point will be 
at the end of administration 
of dexmedetomidine.  The 
start point is at the 
conclusion of mechanical 
ventilation.
-
Descriptive 
summary
FAS/EE
§5.2.1
Exploratory


Protocol C0801017(ZIN-DEX-1506) Statistical Analysis Plan
Page 27
#
Description of 
Endpoint
Analysis Time Point
End 
point 
#
Summary
Analysis
Set
Analysis 
Section #
Reporting 
Results
Subset
Primary/
Secondary
6
Percentage of 
subjects who did 
not require 
administration 
of a rescue 
analgesic 
(fentanyl) during 
mechanical 
ventilation in 
addition to 
administration 
of the 
investigational 
product.
The analysis point will be 
at 24 hours after initial 
administration of 
dexmedetomidine or at the 
conclusion of mechanical 
ventilation or the end of 
administration of 
dexmedetomidine, 
whichever is earliest.  The 
start point of this 
evaluation is initiation of
administration.
1 in
§ 3.2
Descriptive 
summary
FAS/EE
§5.2.1
In addition to 
whole 
population, 
subgroup 
analysis for each 
age group will 
be conducted.
Secondary
7
FAS
by patient type
Secondary
8
The analysis point will be 
at the conclusion of 
mechanical ventilation or 
the end of administration 
of dexmedetomidine, 
whichever is earlier.  The 
start point of this 
evaluation is at 24 hours 
after initial administration.
5 in
§ 3.2
Descriptive 
summary
FAS/EE
§ 5.2.1
In addition to 
whole 
population, 
subgroup 
analysis for each 
age group will 
be conducted.
Secondary
-
The analysis point will be 
at the end of administration 
of dexmedetomidine.  The 
start point is at the 
conclusion of mechanical 
ventilation.
-
Descriptive 
summary
FAS/EE
§ 5.2.1
Exploratory
9
Dose level 
corrected for 
total dose of 
rescue 
sedative/analges
ic during 
mechanical 
The analysis point will be 
at 24 hours after initial 
administration of 
dexmedetomidine or at the 
conclusion of mechanical 
ventilation or the end of 
administration of 
2 in
§ 3.2
Descriptive 
summaries of 
both total 
dosage and 
weight adjusted 
dosage by each
rescue 
FAS/EE
§ 6.2.2,
§ 6.4
§ 5.2.2
In addition to 
whole 
population, 
subgroup 
analysis for each 
age group will 
be conducted.
Secondary


Protocol C0801017(ZIN-DEX-1506) Statistical Analysis Plan
Page 28
#
Description of 
Endpoint
Analysis Time Point
End 
point 
#
Summary
Analysis
Set
Analysis 
Section #
Reporting 
Results
Subset
Primary/
Secondary
10
ventilation and 
for body weight
dexmedetomidine, 
whichever is earliest. The 
start point of this 
evaluation is initiation of 
administration.
medication(mida
zolam/ fentanyl) 
for rescued 
subjects and all 
subjects, 
respectively
FAS
by patient type
Secondary
11
The analysis point will be 
at the conclusion of 
mechanical ventilation or
the end of administration 
of dexmedetomidine, 
whichever is earlier.  The 
start point of this 
evaluation is at 24 hours 
after initial administration 
of dexmedetomidine.
6 in
§ 3.2
FAS/EE
§ 5.2.2
In addition to 
whole 
population, 
subgroup 
analysis for each 
age group will 
be conducted.
Secondary
12
The analysis point will be 
at the conclusion of 
mechanical ventilation.  
The start point of this 
evaluation is at the point of 
extubation.
9 in
§ 3.2
FAS/EE
§ 5.2.2
In addition to 
whole 
population, 
subgroup 
analysis for each 
age group will 
be conducted.
Secondary
13
Duration and 
percentage of 
maintenance of 
target sedation 
level during 
mechanical 
ventilation
The analysis point will be 
at 24 hours after initial 
administration of 
dexmedetomidine or at the 
conclusion of mechanical 
ventilation or the end of 
administration of 
dexmedetomidine, 
whichever is earliest. The 
start point of this 
evaluation is initiation of 
administration.
3 in
§ 3.2
Descriptive 
summary
FAS/EE
§ 6.2.3,
§ 6.4
§ 5.2.1 for 
percentage.
§ 5.2.2 for 
absolute time
(sedation time 
and total 
observation 
time)
In addition to 
whole 
population, 
subgroup 
analysis for each 
age group will 
be conducted.
Secondary
14
FAS
by patient type
Secondary


Protocol C0801017(ZIN-DEX-1506) Statistical Analysis Plan
Page 29
#
Description of 
Endpoint
Analysis Time Point
End 
point 
#
Summary
Analysis
Set
Analysis 
Section #
Reporting 
Results
Subset
Primary/
Secondary
15
The analysis point will be 
the earliest point among 24 
hours after initial 
administration of 
dexmedetomidine, the 
conclusion of mechanical 
ventilation, the end of 
administration of 
dexmedetomidine and 
initiation of gradually 
reducing of administration 
rate to complete treatment 
with dexmedetomidine .  
The start point of this 
evaluation is initiation of 
administration.
Descriptive
summary 
FAS/EE
§ 5.2.1 for 
percentage.
§ 5.2.2 for 
absolute 
time(sedation 
time and total 
observation 
time)
In addition to 
whole 
population, 
subgroup 
analysis for each 
age group will 
be conducted.
Sensitivity
analysis for 
secondary 
analysis
16
The analysis point will be 
at the conclusion of 
mechanical ventilation or
the end of administration 
of dexmedetomidine, 
whichever is earlier.  The 
start point of this 
evaluation is at 24 hours 
after initial administration.
7 in
§ 3.2
Descriptive 
summary
FAS/EE
§ 5.2.1 for 
percentage.
§ 5.2.2 for 
absolute 
time(sedation 
time and total 
observation 
time)
In addition to 
whole 
population, 
subgroup 
analysis for each 
age group will 
be conducted.
Secondary
17
The analysis point will be 
at the conclusion of 
mechanical ventilation. 
The start point of this 
evaluation is at the point of 
extubation.
8 in
§ 3.2
Descriptive 
summary
FAS/EE
§ 5.2.1 for 
percentage.
§ 5.2.2 for 
absolute 
time(sedation 
time and total 
observation 
time)
In addition to 
whole 
population, 
subgroup 
analysis for each 
age group will 
be conducted.
Secondary


Protocol C0801017(ZIN-DEX-1506) Statistical Analysis Plan
Page 30
#
Description of 
Endpoint
Analysis Time Point
End 
point 
#
Summary
Analysis
Set
Analysis 
Section #
Reporting 
Results
Subset
Primary/
Secondary
18
Time until the 
end of 
mechanical 
ventilation
The analysis point will be 
at the conclusion of 
mechanical ventilation.  
The start point of this 
evaluation is initiation of 
administration.
10 in
§ 3.2
Descriptive 
summary,
Figure
FAS/EE
§ 6.2.4,
§ 6.4
§ 5.2.4
In addition to 
whole 
population, 
subgroup 
analysis for each 
age group will 
be conducted 
except for 
figures.
Secondary
19
The analysis point will be 
at 24 hours after initial 
administration of 
dexmedetomidine or at the 
conclusion of mechanical 
ventilation, whichever is 
earlier.  The start point of 
this evaluation is initiation 
of administration.
20
Longitudinal 
SBS score
whole study period
-
Figure
FAS
§ 6.3.2
§ 6.3.2
-
Other


Protocol C0801017(ZIN-DEX-1506) Statistical Analysis Plan
Page 31
Appendix 2. DATA DERIVATION DETAILS
Appendix 2.1. Definition of Protocol Deviations that Relate to Statistical 
Analyses/Populations
If prohibited concomitant drugs are administrated, it will be impact on analysis population 
(See Section 4.2).  The details are described in Section 5.8.1 “Prohibited Concomitant 
Drugs” of the protocol amendment 2.