Clinical trial NCT04237792
Conditions: MRI Sedation
Keywords: procedural sedation dexmedetomidine propofol MRI
Sponsor: Pfizer
Start date: 2020-02-18; Completion date: 2021-11-30
Enrollment: 128 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, double-blind, dose-ranging study of the efficacy and safety of dexmedetomidine (DEX) when used with propofol as needed, for procedural sedation of pediatric subjects ≥1 month to \<17 years of age undergoing MRI scans in the US and Japan.

Detailed description:

Arms: arm 1: low dose of dexmedetomidine to be given arm 2: middle dose of dexmedetomidine to be given arm 3: high dose of dexmedetomidine to be given
Interventions: intervention 1: dexmedetomidine intervention 2: propofol
Intervention descriptions: intervention 1: dexmedetomidine low, middle and high doses are provided as an intravenous bolus loading dose followed by an intravenous maintenance dose infusion throughout the MRI scan intervention 2: propofol IV administration will be given if needed to maintain sedation

Protocol documents:
Prot_000.pdf: 
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A PHASE 3/4 RANDOMIZED, DOUBLE-BLIND, DOSE-RANGING STUDY OF THE 
SAFETY AND EFFICACY OF DEXMEDETOMIDINE (DEX) USED WITH 
PROPOFOL (PRO) AS NEEDED FOR PROCEDURAL SEDATION OF PEDIATRIC 
SUBJECTS ≥1 MONTH TO <17 YEARS OF AGE UNDERGOING MRI SCANS
Investigational Product Number:
PF-00914730
Investigational Product Name:
Dexmedetomidine hydrochloride
United States (US) Investigational New 
Drug (IND) Number:
32,934
European Clinical Trials Database 
(EudraCT) Number:
N/A
Protocol Number:
C0801039
Phase:
3 / 4
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this information in 
confidence and not copy or disclose it to others (except where required by applicable law) or use it for 
unauthorized purposes.  In the event of any actual or suspected breach of this obligation, Pfizer must be 
promptly notified.


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Document History
Document
Version Date
Summary of Changes and 
Rationale
Original protocol
27 August 2019
Not applicable (N/A)
Amendment 1
21 April 2020
General grammatical and 
formatting revisions & 
typographical error 
corrections
Protocol Summary section: 
updated as appropriate to be 
consistent with the revisions 
described below
Schedule of Activities (SOA) 
section: updated as 
appropriate to be consistent 
with the revisions described 
below.
Section 1. Introduction: 
revised to provide
clarification around propofol 
approval in the US vs Japan.
Section 1.2.1. Study DEX 
10-16: revised to remove
trailing zeroes related to 
DEX dosing.
Section 1.2.2.2. Dose 
Selection: revised to: clarify
that age cohorts are based on 
age on Day 1; remove
trailing zeroes related to 
DEX dosing.
Section 1.3.1.1. Safety Data 
from Pediatric ICU Sedation 
Studies: revised to remove 
trailing zeroes related to
DEX dosing.
Section 2. Study Objectives 


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and Endpoints: revised to: 
remove safety endpoint for 
clinically significant 
hemodynamic changes from 
Baseline; add safety endpoint 
for time outside of the stable 
range for hemodynamic 
parameters; clarify that 
incidences of listed adverse
events are for protocol-
specified events; add
paradoxical agitation reaction 
as a safety endpoint.
Section 3. Study Design:
revised to provide allowance 
for Screening and Day 1 
Visits to occur on different 
days.
Section 3.2. Approximate 
Number of Subjects: revised 
to: remove the number of 
sites; clarify that age cohorts 
are based on age on Day 1.
Section 4.1. Inclusion 
Criteria at Screening: revised 
to: provide separate 
Screening and Day 1 
Inclusion Criteria; clarify
that age is based on age on 
Day 1; require that ASA 
assessment is performed by
medically qualified personnel 
and reviewed by PI; permit 
conditional use of a pre-
existing IV for study drug 
administration.
Section 4.2. Inclusion 
Criteria on Day 1: revised to 
add this section to confirm 
subject continued to meet 
Screening inclusion criteria.


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Section 4.3. Exclusion 
Criteria at Screening, revised 
to: separate the exclusion 
criteria into separate
Screening and Day 1 
Exclusion Criteria; modify
weight criterion for global 
details to be done at 
Screening; clarify non-
interventional/observational 
procedures are permitted 
during MRI; change 
“allergy” to
“hypersensitivity” to DEX,
PRO or components; remove
the acute MI exclusion; add 
medication as a factor that 
may increase subject risk.
Section 4.4. Exclusion 
Criteria on Day 1: revised to 
add this section and move 
selected Screening exclusion 
criteria here.
Section 5.1. Allocation to 
Treatment: revised to add
DEX total loading dose in 
mLs to the unblinded IRT 
confirmation report.
Section 5.4.2. Preparation 
and Dispensing: revised to 
clarify the study drug 
preparation and dispensation 
responsibilities of the
unblinded site pharmacist.
Section 5.5. Investigational 
Product Administration: 
revised to: remove the
requirement for a new IV to 
be placed; clarify age cohorts 
are based on age on Day 1; 
remove trailing zeroes from 


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the dosing tables.
Section 5.6. Rescue Propofol 
Medication: revised to: 
clarify the propofol 
maintenance dosing 
requirements; provide
clarification around propofol 
approval in the US vs Japan.
Section 5.10.2. Permitted 
Concomitant Treatments: 
revised to clarify gas 
induction procedure
requirements.
Section 5.10.3. Prohibited 
Concomitant Treatments: 
revised to: clarify other 
alpha-2 agonist/antagonist 
use; clarify 
interventional/non-
interventional/observational 
procedures during scan and 
post-scan recovery.
Section 6.1. Screening: 
revised to: provide separate 
Screening Visit
requirements; allow 12-lead
ECG to be performed in lieu 
of rhythm strip; remove 
pregnancy test from 
Screening.
Section 6.2. Day 1 Period 1 
(MRI scan): revised to: 
separate Day 1 assessments 
into pre- and post-
randomization timeframes; 
add caveat regarding weight 
and temperature if 
Screening/Day 1 are the 
same day; allow for urine or 
whole-blood pregnancy test; 
clarify Baseline values are 


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those obtained within
approximately 5 minutes 
before the DEX loading 
dose; remove requirement for 
placement of a new IV.
Section 6.3. Day 1 Period 2
(Post-MRI Recovery): 
revised to: clarify Baseline 
values are those obtained 
within approximately 5 
minutes before the DEX 
loading dose; remove the 
PSSS assessments from this 
period; modify the PAED
collection timepoint
requirements.
Section 6.5. Subject
Withdrawal/Early 
Termination:  revised to add
a discontinuation
requirement for subjects who 
have a medical procedure 
performed during the MRI 
scan.
Section 6.5.1. Adverse 
Events Requiring Subject 
Withdrawal from Treatment: 
revised to add
discontinuation requirement 
for subjects who have a 
medical procedure performed 
during the MRI scan.
Section 7. Assessments: 
revised to: add “as 
appropriate” to assent 
collection; remove
requirement for placement of 
a new IV; allow for urine or 
whole-blood pregnancy test; 
clarify the 12-lead ECG and 
blood pressure at Screening


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requirements.
Section 7.1. Pregnancy 
Testing: revised to clarify
that urine or whole blood 
pregnancy test will be done 
on Day 1.
Section 8.4.1.1. Changes in 
Blood Pressure and Heart 
Rate: revised to clarify 
Baseline values are those 
obtained within
approximately 5 minutes 
before the DEX loading 
dose.
Section 8.5. Medical Device 
Complaint Reporting 
Requirements: revised to 
limit medical device 
reporting to sites in Japan
using propofol pre-filled 
syringes.
Section 9.1. Sample Size 
Determination: revised to
remove trailing zeroes 
related to DEX dosing.
Section 9.2.5. Japanese 
Population Set: revised to 
add a new analysis 
population set for Japanese 
subjects.
Section 9.5. Safety Analysis: 
revised to: clarify Baseline 
values are those obtained 
within approximately 5 
minutes before the DEX 
loading dose; add 
paradoxical agitation reaction
and clarify text regarding
protocol-specified adverse 
events summarized for each 


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age cohort and each dose 
level; remove text regarding 
separate tabulations of 
specific AEs.
Appendix 1. Abbreviations: 
revised to update per 
protocol text revisions.
Appendix 4. Modified 
Aldrete Score: revised to add
reference.
Appendix 5. Pediatric 
Anesthesia Emergence 
Delirium Scale (PAED): 
revised to add reference.
Appendix 6. Pediatric 
Sedation State Scale (PSSS): 
revised to add reference.
Appendix 9. Propofol Pre-
filled Syringe Medical 
Device Reporting in Japan; 
revised to add appendix.
Amendment 2
11 March 2021
Protocol Summary section: 
updated as appropriate to be 
consistent with the revisions 
described below.
Schedule of Activities:
updated as appropriate to be 
consistent with the revisions 
described below.
Section 1. Introduction: 
revised to remove text 
identifying the US and Japan 
as participating countries; 
clarify PRO is not approved
for procedural sedation in the 
pediatric population and is


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investigational in this study.
Section 1.4 Safety Summary: 
updated the SRSD language
and clarified that the 
propofol USPI may be 
referenced for additional 
safety information and 
countries may also reference 
their local package insert for 
country-specific information.
Section 2 Study Objectives
and Endpoints: revised the 
primary efficacy endpoint to
clarify the comparison is in 
the combined age cohorts;
corrected the safety endpoint
to include subjects who 
require intervention to 
complete the MRI; changed 
the protocol-specified AE
term “systolic hypotension”
to “hypotension”.
Section 3.2 Approximate 
Number of Subjects: revised 
to remove text identifying
participating countries.
Section 4.3 Exclusion 
Criteria at Screening:
modified exclusion criterion 
#2 to clarify that medications 
or vaccines approved for 
emergency authorization are
not considered 
investigational and are not
included in the 30-day 
restriction; revised exclusion
criterion #22 to include ECG 
findings diagnostic of AV 
conduction block or 
sustained cardiac arrhythmia; 
eliminated “acute febrile 
illness” from exclusion


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criterion #26 to limit the
exclusion to fever.
Section 5.6 Rescue Propofol 
Medications: clarified
requirements for propofol 
bolus dosing and 
maintenance dose increases
and decreases; clarify PRO is 
not approved for procedural 
sedation in the pediatric 
population and is
investigational in this study.
Section 5.10 Concomitant 
Treatments: revised to
extend collection of
concomitant treatments 
through the Day 29 Long-
term Follow-up Visit.
Section 5.10.1 Required 
Treatments: revised the 
maintenance IV fluid 
requirements to require a
minimum mL/hr rate per
formula but also permitting a
maximum rate of 100 mL/hr.
Section 6.2 Day 1 Period 1 
(MRI scan): added 
clarification that serum 
qualitative or quantitative 
hCG pregnancy tests are not 
permitted; clarified vital 
signs collection and
timepoint capture.
Section 6.3 Day 1 Period 2 
(Post-MRI Recovery): 
clarified vital signs collection 
and timepoint capture.
Section 6.4.2 Day 29 Long-
term Follow-up Visit: added
collection of concomitant 


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treatments.
Section 6.5.1 Adverse Events
Requiring Subject 
Withdrawal from Treatment: 
changed the AE term
“systolic hypotension” to
“hypotension”.
Section 7 Assessments: 
revised to extend collection 
of concomitant treatments
through the Day 29 Long-
term Follow-up Visit; added 
clarification that serum 
qualitative or quantitative 
hCG pregnancy tests are not 
permitted; clarified
requirement for 12-lead ECG 
vs rhythm strip including 
changes suggestive of AV 
conduction block or 
sustained cardiac arrhythmia;
added instruction on
rounding height/weight 
values to 1 decimal place; 
clarified BP cuff size must be 
appropriate for arm or leg
girth.
Section 7.1 Pregnancy 
Testing: added clarification 
that serum qualitative or 
quantitative hCG pregnancy 
tests are not permitted.
Section 8.1 Requirements: 
updated the requirements for 
recording safety events on 
the CRF to be consistent with 
the current Pfizer protocol 
template.
Section 8.1.4 Time Period for
Collecting AE/SAE
Information: added 


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concomitant treatment data 
to be collected at the Day 29 
Long-term Follow-up visit.
Section 8.4.1.1 Changes in 
Blood Pressure and Heart 
Rate: clarified text to specify
AE criteria refer to
measurements exceeding the 
specified limits within the 
indicated time periods;
clarified bradycardia AE
definition based on 2
consecutive measurements at 
least 1 minute apart to ensure
a minimum duration of 
decreased HR; changed the 
AE term “systolic 
hypotension” to 
“hypotension”; clarified 
hypotension AE definition 
based on 2 consecutive 
measurements at least 5 
minutes apart to ensure a 
minimum duration of 
decreased SBP and/or 
requires intervention;
clarified hypertension AE
definition based on 
measurements at least 5 
minutes apart.
Section 8.4.1.3 Changes in 
Respiratory Rate, EtCO2 and 
SpO2: clarified bradypnea
AE definition based on 
measurements at least 1
minutes apart.
Section 8.4.5.1: Medication 
Errors: modified the sponsor 
notification timeframe 
requirement to 24 hours.
Section 9.3.3 Analysis of 
Other Secondary Endpoints:


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added text when censored
time would be used to 
calculate emergence time.
 
 
Section 9.5 Safety Analysis: 
corrected the safety endpoint
to include subjects who 
require intervention to 
complete the MRI; changed 
the AE term “systolic
hypotension” to 
“hypotension”.
Appendix 5: Pediatric
Anesthesia Emergence 
Delirium Scale (PAED): 
additional reference added.
General grammatical and 
formatting revisions & 
typographical error 
corrections.
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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................18
LIST OF FIGURES .................................................................................................................18
APPENDICES .........................................................................................................................19
PROTOCOL SUMMARY.......................................................................................................20
SCHEDULE OF ACTIVITIES................................................................................................29
1. INTRODUCTION ...............................................................................................................33
1.1. Mechanism of Action and Indication......................................................................33
1.2. Approval History and PREA...................................................................................33
1.2.1. Study DEX 10-16 .......................................................................................34
1.2.1.1. Study DEX 10-16 Study Results...............................................35
1.2.2. DEX Expert Advisory Committee..............................................................35
1.2.2.1. Imaging Procedures...................................................................36
1.2.2.2. Dose Selection...........................................................................36
1.2.2.3. Concomitant Sedative Drugs.....................................................39
1.2.2.4. Summary of Study Design ........................................................39
1.3. Safety Data ..............................................................................................................39
1.3.1. Clinical Trial Safety Data Base ..................................................................39
1.3.1.1. Safety Data from Pediatric ICU Sedation Studies ....................39
1.3.1.2. Safety Data from Pediatric Procedural Sedation Study 
DEX 10-16.........................................................................................41
1.4. Safety Summary......................................................................................................42
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................43
3. STUDY DESIGN.................................................................................................................44
3.1. Approximate Duration of Subject Participation......................................................45
3.2. Approximate Number of Subjects...........................................................................45
4. SUBJECT ELIGIBILITY CRITERIA.................................................................................46
4.1. Inclusion Criteria at Screening................................................................................47
4.2. Inclusion Criteria on Day 1 .....................................................................................48
4.3. Exclusion Criteria at Screening...............................................................................48
4.4. Exclusion Criteria on Day 1....................................................................................51
4.5. Lifestyle Requirements ...........................................................................................51


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4.5.1. Contraception..............................................................................................51
4.6. Sponsor’s Qualified Medical Personnel..................................................................52
5. STUDY TREATMENTS.....................................................................................................53
5.1. Allocation to Treatment ..........................................................................................53
5.2. Breaking the Blind ..................................................................................................54
5.3. Subject Compliance.................................................................................................54
5.4. Investigational Product Supplies.............................................................................54
5.4.1. Dosage Form(s) and Packaging..................................................................54
5.4.2. Preparation and Dispensing........................................................................55
5.5. Investigational Product Administration ..................................................................55
5.6. Rescue Propofol Medication ...................................................................................56
5.7. Investigational Product Storage ..............................................................................57
5.8. Investigational Product Accountability...................................................................58
5.8.1. Destruction of Investigational Product Supplies ........................................58
5.9. Prior Treatments......................................................................................................58
5.10. Concomitant Treatments .......................................................................................58
5.10.1. Required Treatments.................................................................................58
5.10.2. Permitted Concomitant Treatments..........................................................59
5.10.3. Prohibited Concomitant Treatments.........................................................59
6. STUDY PROCEDURES .....................................................................................................60
6.1. Screening.................................................................................................................60
6.1.1. Screen Fail Subject .....................................................................................62
6.2. Day 1 Period 1 (MRI scan) .....................................................................................62
6.3. Day 1 Period 2 (Post-MRI Recovery).....................................................................64
6.4. Follow-up ................................................................................................................65
6.4.1. Day 2 Follow-up.........................................................................................65
6.4.2. Day 29 Long-term Follow-up.....................................................................65
6.5. Subject Withdrawal / Early Termination ................................................................66
6.5.1. Adverse Events Requiring Subject Withdrawal from Treatment...............67
6.5.2. Adverse Events Requiring Assessment for Subject Withdrawal from 
Treatment .........................................................................................................68
7. ASSESSMENTS..................................................................................................................68


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7.1. Pregnancy Testing...................................................................................................72
7.2. Rater Qualifications.................................................................................................72
8. ADVERSE EVENT REPORTING......................................................................................72
8.1. Requirements...........................................................................................................72
8.1.1. Additional Details On Recording Adverse Events on the CRF..................74
8.1.2. Eliciting Adverse Event Information..........................................................74
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the 
Subject Withdrawal / Early Termination section) ...........................................74
8.1.4. Time Period for Collecting AE/SAE Information......................................74
8.1.4.1. Reporting SAEs to Pfizer Safety...............................................75
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF .................75
8.1.5. Causality Assessment .................................................................................75
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ..................75
8.2. Definitions...............................................................................................................76
8.2.1. Adverse Events ...........................................................................................76
8.2.2. Abnormal Test Findings .............................................................................76
8.2.3. Serious Adverse Events..............................................................................77
8.2.4. Hospitalization............................................................................................78
8.3. Severity Assessment................................................................................................79
8.4. Special Situations ....................................................................................................80
8.4.1. Protocol-Specified Adverse Events ............................................................80
8.4.1.1. Changes in Blood Pressure and Heart Rate...............................80
8.4.1.2. Paradoxical Agitation Reactions ...............................................82
8.4.1.3. Changes in Respiratory Rate, EtCO2 and SpO2 ........................82
8.4.2. Protocol-Specified Serious Adverse Events...............................................83
8.4.3. Potential Cases of Drug-Induced Liver Injury............................................83
8.4.4. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................85
8.4.4.1. Exposure During Pregnancy......................................................85
8.4.4.2. Exposure During Breastfeeding ................................................87
8.4.4.3. Occupational Exposure .............................................................87
8.4.5. Medication Errors .......................................................................................87


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8.4.5.1. Medication Errors......................................................................87
8.5. Medical Device Complaint Reporting Requirements .............................................88
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................88
9.1. Sample Size Determination.....................................................................................88
9.2. Analysis Populations...............................................................................................89
9.2.1. Safety Analysis Set.....................................................................................89
9.2.2. Full Analysis Set (FAS)..............................................................................89
9.2.3. Efficacy Evaluable Population (EEP).........................................................89
9.2.4. Per Protocol Population (PPP)....................................................................90
9.2.5. Japanese Population Set (JPS)....................................................................90
9.3. Efficacy Analysis ....................................................................................................90
9.3.1. Analysis of the Primary Endpoint...............................................................90
9.3.2. Analysis of the Key Secondary Endpoint...................................................90
9.3.3. Analysis of Other Secondary Endpoints.....................................................90
9.5. Safety Analysis........................................................................................................91
9.6. Interim Analysis ......................................................................................................92
9.7. Data Monitoring Committee ...................................................................................92
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................93
11. DATA HANDLING AND RECORD KEEPING .............................................................93
11.1. Case Report Forms/Electronic Data Record .........................................................93
11.2. Record Retention...................................................................................................94
12. ETHICS..............................................................................................................................94
12.1. Institutional Review Board/Ethics Committee......................................................94
12.2. Ethical Conduct of the Study ................................................................................95
12.3. Subject Information and Consent..........................................................................95
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................96
13. DEFINITION OF END OF TRIAL...................................................................................97
14. SPONSOR DISCONTINUATION CRITERIA ................................................................97
15. PUBLICATION OF STUDY RESULTS..........................................................................97
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15.1. Communication of Results by Pfizer ....................................................................97
15.2. Publications by Investigators ................................................................................98
16. REFERENCES ................................................................................................................100
LIST OF TABLES
Table 1.
Reported DEX PK Parameters in Pediatric ICU Patients and Pediatric 
Procedural Sedation Patients ..............................................................................107
Table 2.
Demographics of Input Dataset by Age Group ..................................................108
Table 3.
Dose levels for Subjects >2 years of age............................................................108
Table 4.
Dose levels for Subjects ≥1 month to ≤2 years of age........................................108
Table 5.
Dexmedetomidine PK Parameters for Simulated Data by Dose and Age 
Group..................................................................................................................112
LIST OF FIGURES
Figure 1.
Simulated Plasma Dexmedetomidine Concentration vs Time Profiles in 
Different Age Groups following Low Dose Infusion.........................................109
Figure 2.
Simulated Plasma Dexmedetomidine Concentration vs Time Profiles in 
Different Age Groups following Medium Dose Infusion...................................110
Figure 3.
Simulated Plasma Dexmedetomidine Concentration vs Time Profiles in 
Different Age Groups following High Dose Infusion........................................111


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APPENDICES
Appendix 1. Abbreviations....................................................................................................103
Appendix 2. Simulated Pharmacokinetic Profiles of Dexmedetomidine in Pediatric 
Subjects Undergoing Procedural Sedation .........................................................106
Appendix 4. Modified Aldrete Score.....................................................................................114
Appendix 5. Pediatric Anesthesia Emergence Delirium Scale (PAED)................................115
Appendix 6. Pediatric Sedation State Scale (PSSS) ..............................................................116
Appendix 7. HR and RR Centile Chart Cut-offs for Children from Birth to 18 Years of 
Age......................................................................................................................117
Appendix 8. Normal Vital Signs According to Age..............................................................118
Appendix 9. Propofol Pre-filled Syringe Medical Device Reporting in Japan......................119
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PROTOCOL SUMMARY
Background & Rationale
Dexmedetomidine (DEX) is a highly selective α2-adrenergic agonist that is being 
investigated for use in procedural sedation in pediatric subjects undergoing magnetic 
resonance imaging (MRI) requiring moderate to deep sedation.  DEX is currently approved 
for sedation of initially intubated and mechanically ventilated adults during treatment in an 
intensive care setting and for procedural sedation of adults.
The present study is being conducted by Pfizer, Inc under the Pediatric Research Equity Act 
(PREA) and is a Phase 3/4 randomized, double-blind, dose-ranging study of the safety and 
efficacy of DEX used with propofol (PRO) for procedural sedation of pediatric subjects 
≥1 month to <17 years of age undergoing MRI scans.
Objectives
•
The primary efficacy objective is to assess the efficacy of DEX for pediatric 
procedural sedation as measured by the percent of subjects at the high dose level 
versus the low dose level in the combined age cohorts who do not require 
concomitant PRO to achieve adequate sedation.
•
The key secondary objective is to assess the efficacy of DEX for pediatric procedural 
sedation as measured by the percent of subjects at the high dose level versus the low 
dose level in each age cohort who do not require concomitant PRO to achieve 
adequate sedation.
•
Other secondary efficacy objectives include:
•
Explore the efficacy of DEX at the middle dose level compared to the high dose 
level and the low dose level in both the overall sample and in each age cohort as 
measured by the percent of subjects who do not require concomitant PRO to 
achieve adequate sedation.
•
Explore the efficacy of DEX by examining the percent of time at the target 
sedation score, time to first PRO use, emergence time from sedation, proportion 
of subjects at each dose level receiving PRO and amount of PRO required.
 
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•
The safety objective is to assess the safety of DEX used for procedural sedation of 
pediatric subjects undergoing an MRI scan.
Endpoints
•
Primary Efficacy: Percent of subjects at the DEX high dose level versus the low dose 
level in the combined age cohorts who do not require concomitant PRO to complete 
the MRI.
•
Key Secondary Efficacy: Percent of subjects at the DEX high dose level versus the 
low dose level in each age cohort who do not require concomitant PRO to complete 
the MRI.
•
Secondary Efficacy: 
•
Percent of subjects at the DEX middle dose level compared to the high dose level 
and the low dose level in both the overall sample and in each age cohort who do 
not require concomitant PRO to complete the MRI.
•
Percent of time at the target sedation rating scale score (Pediatric Sedation State 
Scale [PSSS] rating of 2) after the administration of the DEX loading dose and 
during the DEX maintenance infusion. 
•
The amount of time from the start of the DEX loading dose infusion to the time of 
the first PRO bolus administration.
•
Emergence time (defined as the time from the end of the MRI scan to when the 
subject meets a Modified Aldrete Score ≥9).
•
The proportion of subjects at each dose level who receive PRO.
•
Total amount (mg/kg) and weight and time adjusted amount (per kg per minute 
basis) of concomitant PRO required to successfully complete the MRI scan.
 
•
Safety:
•
Incidence, seriousness, causality and severity of treatment-emergent adverse 
events.
C
C
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
Percent of subjects who completed the MRI scan and required artificial 
ventilation or intervention to restore baseline or normal hemodynamic status.

Mean change from baseline in systolic blood pressure (SBP), diastolic blood 
pressure (DBP), mean arterial pressure (MAP), heart rate (HR) and respiratory 
rate (RR).

Time outside of the stable range for hemodynamic parameters of SBP and HR.

Incidence of protocol-specified respiratory adverse events of bradypnea, hypoxia 
and apnea.

Incidence of protocol-specified cardiac adverse events of hypotension, 
hypertension and bradycardia.

Incidence of protocol-specified adverse event of paradoxical agitation reaction.

Incidence of protocol-specified adverse events of bradypnea, hypoxia, apnea, 
hypotension, hypertension, bradycardia and paradoxical agitation reaction 
requiring intervention.

Incidence of DEX withdrawal-related adverse events after discontinuation of 
DEX infusion.
Study Design
This is a randomized, double-blind, dose-ranging study of the efficacy and safety of DEX
when used with PRO as needed, for procedural sedation of pediatric subjects ≥1 month to 
<17 years of age undergoing MRI scans.  The sponsor, subject and investigator will be
blinded to the dose of DEX.
This study includes a Screening, Day 1, Day 2 Follow-up and Day 29 Long-term Follow-up 
Visit.  The Day 1 Visit is comprised of a Period 1 (MRI scan) Phase and Period 2 (Post-MRI 
Recovery) Phase.  The Day 2 Visit is a 24-hour Follow-up, and the Day 29 Visit is a 28-day 
Follow-up. 
A sufficient number of subjects will be screened to randomize approximately 120 subjects 
(40 subjects per dose level):
Age Cohort
Low Dose Group
Middle Dose Group
High Dose Group
≥1 month to <2 years
20
20
20
≥2 years to <17 years
20
20
20


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All eligible subjects will receive double-blind treatment where one of 3 dose levels of DEX 
will be administered.  Following completion of required procedures before randomization at 
the Day 1 Visit, subjects meeting entry criteria will be randomly assigned to a Low, Middle 
or High dose level group (actual dose dependent on age) in a 1:1:1 ratio.  
Treatment will be initiated just prior to the start of the MRI scan and will continue during 
Period 1 (MRI scan). Subjects will first receive a DEX loading dose administered over 
10 minutes.  Following completion of the loading dose, the maintenance infusion of DEX 
will be started. The subject’s level of sedation will be assessed using the PSSS at 5-minute
intervals throughout the drug infusion.  If an adequate level of sedation is not achieved as 
assessed by the investigator (eg, if the subject moves) within 5 minutes after the DEX 
maintenance infusion has been started, concomitant PRO may be given to ensure that an
adequate sedation level is achieved and maintained for completion of the scan.  Sedation with 
DEX and if required, concomitant PRO, shall continue through completion of the MRI scan, 
to maintain the subject at an adequate sedation level per principal investigator (PI) clinical 
judgment.  The target sedation level is indicated by a PSSS score of 2.  Subjects will also be 
administered supplemental intravenous (IV) fluids throughout the DEX infusion at a 
maintenance rate per Section 5.10.1 Required Treatments.  The use, type and rate of 
maintenance fluid administration following discontinuation of the DEX infusion will be at 
site discretion.
The investigational product infusion(s) should not be discontinued until confirmation that the 
MRI is complete has been received and DEX must be discontinued prior to the subject being 
transferred to the post-procedural recovery area.  Period 2 (post-MRI recovery) begins at the 
conclusion of the MRI scan.
Investigational Product Administration
The study will be conducted using the manufactured strength of DEX 200 mcg/2 mL, diluted 
to a concentration directed by the Investigational Product Manual (IP Manual) based on each 
subject’s treatment group assignment.
Subjects enrolled into the study will be randomized to receive one of three DEX dosing 
regimens (Low, Middle, or High), each consisting of an IV loading dose that is immediately 
followed by an IV maintenance infusion that will continue for the duration of the MRI scan.
The loading and maintenance infusion doses will be given at the stable, pre-defined doses as 
described below and may not be modified, but the infusion may be discontinued if clinically 
indicated.  The loading dose will be administered over 10 minutes:
Blinded dose levels for subjects ≥1 month to <2 years of age on Day 1:
Dose Level
DEX Loading Dose
DEX Maintenance Infusion Dose
Low dose level
0.5 mcg/kg
0.5 mcg/kg/hour
Middle dose level
1 mcg/kg
1 mcg/kg/hour
High dose level
1.5 mcg/kg
1.5 mcg/kg/hour


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Blinded dose levels for subjects ≥2 years to <17 years of age on Day 1:
Dose Level
DEX Loading Dose
DEX Maintenance Infusion Dose
Low dose level
0.5 mcg/kg
0.5 mcg/kg/hour
Middle dose level
1.2 mcg/kg
1 mcg/kg/hour
High dose level
2 mcg/kg
1.5 mcg/kg/hour
Rescue Propofol Administration
Once the DEX loading dose has been administered and the maintenance dose started, if an 
adequate level of sedation is not achieved within 5 minutes after the start of the DEX 
maintenance infusion, concomitant PRO may be given per clinical judgment to ensure that an 
adequate level of sedation is achieved to start the scan.  The target sedation level is indicated 
by a PSSS score of 2. 
Concomitant PRO should be administered as needed through completion of the scan to 
maintain adequate subject sedation per PI clinical judgment.  If it is needed, concomitant 
PRO should be administered first as a bolus of 0.5 mg/kg (500 mcg/kg) over approximately 
1 minute followed by the start of a PRO maintenance infusion at 50 mcg/kg/min.  Additional 
bolus doses of PRO 0.5 mg/kg may be given as needed for subject movement/wakening.  
Following each additional PRO bolus, there must be a simultaneous increase in the PRO 
maintenance infusion rate in a 25 or 50 mcg/kg/min increment.  However, subsequent 
increases in the PRO maintenance infusion rate may be made in 25 or 50 mcg/kg/min 
increments without a corresponding PRO bolus.  The PRO maintenance infusion may also be 
decreased in 25 or 50 mcg/kg/min increments as needed to maintain adequate subject 
sedation, or it may be discontinued if clinically indicated.  
PRO is not approved for procedural sedation in the pediatric population, so in this study the 
use of PRO is considered investigational.
Statistical Methods: 
Sample Size
The primary comparison will be the percent of subjects who do not require supplemental 
PRO in the high dose group vs. the low dose group in both age cohorts combined.  The 
younger age cohort will be comprised of subjects aged ≥1 month to <2 years of age and the 
older age cohort will include subjects ≥2 to <17 years of age.  The primary efficacy analysis 
population is the Full Analysis Set (FAS) defined as all randomized subjects who receive any 
amount of DEX, and for the primary and key secondary analyses, subjects who do not 
complete the MRI scan will be considered failures, ie, will be counted as receiving 
supplemental PRO.  Assuming that the percent of subjects not requiring PRO are 15% and 
60% in the low and high dose groups respectively, a sample size of 40 per dose group would 
provide a 99% power for a 2-sided test with alpha=0.05.  The key secondary comparison is 
the percent of subjects who do not require supplemental PRO in each of the 2 age cohorts.  
Assuming that the percentage of subjects not requiring supplemental PRO in the older age 
cohort is 17% and 63% for the low and high dose groups respectively, and the percent of 


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subjects not requiring PRO in the younger age cohort is 13% and 57% for the low and high 
dose groups respectively, and assuming that equal number of subjects will be enrolled in 
each age cohort, the power = 87% for the older age cohort and 86% for the younger age 
cohort.  Within the older age cohort, it is planned to enroll approximately 4 subjects per dose 
group for subjects ≥12 to <17 years of age, since it is expected that these subjects would 
require minimum sedation.  Forty subjects will be enrolled per each dose level, and 
20 subjects for each dose group for age cohorts ≥1 month to <2 years and ≥2 years to 
<17 years.
Analysis Populations:
Safety Analysis Set
The safety analysis set consists of all randomized subjects who received any amount of DEX.  
Participants will be analyzed according to the intervention they received.  In the event a 
subject receives a loading and/or maintenance dose that is different from the dose group to 
which they were randomized, the subject will be analyzed in the dose level group that 
corresponds to the lowest dose received.  All safety analyses will be performed on the safety 
analysis set.
Full Analysis Set (FAS)
All randomized subjects who receive any amount of DEX will form the FAS.  Participants
will be analyzed according to the intervention to which they were randomized.  This will be 
the primary population for efficacy analysis.
Efficacy Evaluable Population (EEP)
All randomized subjects who receive any amount of DEX and complete the MRI scan will 
form the EEP.
Per Protocol Population (PPP)
All subjects included in the FAS and have no major protocol deviations will form the PPP.  
The details of the major protocol violation criteria will be documented in a separate 
document prior to the end of the study.
Japanese Population Set (JPS)
All randomized Japanese subjects who receive any amount of DEX will form the JPS.  The
JPS will be used for efficacy endpoints, demographic and baseline characteristic and safety 
endpoints.  Participants will be analyzed according to the intervention to which they are 
randomized for efficacy and will be analyzed according to the intervention they receive for 
safety.


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Endpoint Analyses:
Primary Efficacy Endpoint Analysis
The DEX high vs low dose group will be compared by Mantel-Haenszel test, and by 
calculating the odds ratio and 95% confidence intervals on the percent of subjects not 
requiring supplemental PRO.  All age cohorts will be combined.  The primary analysis will 
be performed based on the FAS.  The same analysis will be repeated on the EEP and PPP.
Analysis of Key Secondary Efficacy Endpoint
The method of analysis for the primary endpoint will be repeated for the key secondary 
endpoint for each age cohort based on the FAS.  The same analysis will be repeated on the 
EEP and PPP.
Analyses of Other Secondary Efficacy Endpoints
The method of analysis for the primary endpoint will be repeated for the secondary endpoints 
comparing the low dose to the medium dose and the medium dose to the high dose, overall 
and within each age cohort based on the FAS, EEP and PPP. 
The total amount and the weight and time adjusted amount (per kg per minute) of PRO use 
will be summarized for each dose group with descriptive statistics (N, mean, standard 
deviation [SD], median, minimum, Q1, Q3, and maximum). The weight- and time-adjusted 
difference between treatment groups (high dose and low dose, and medium dose and low 
dose and high dose versus medium dose) will be assessed using two-way analysis of variance 
(ANOVA) when assumption of normal distribution is reasonable or by nonparametric tests 
when this assumption is not met.  
Emergence time (defined as the time from the end of the MRI scan to when the subject meets 
a Modified Aldrete Score ≥9) will be summarized and compared between dose groups using 
Kaplan Meier methodology. Subjects who are withdrawn or discharged from the recovery 
area without reaching an Aldrete score ≥9, will be considered as having censored time
computed from the end of the MRI scan to the time of the last vital signs assessment.  Zero 
minute will be used as the censored time if no vital signs are taken during the post-MRI
recovery period.
Additionally, the difference between dose levels in percent of time at the target sedation 
rating scale score (PSSS rating of 2) following the administration of the DEX loading dose 
and during the DEX maintenance infusion will be assessed using the Wilcoxon test.  
Time (minutes) from the onset of the DEX infusion to the first dose of PRO will be 
summarized using the Kaplan-Meier method.  Subjects that do not receive any additional 
PRO will be considered as having a censored time.  The censored time to the first dose of 
PRO for additional sedation will be computed as the length of time from the onset of the 
DEX infusion up to the time the DEX infusion is stopped.


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Efficacy analyses will be conducted for all age cohorts combined and by each age cohort.
 
 
 
 
Analysis of Safety Endpoints
All safety analyses will be performed on the safety analysis set.
Descriptive statistics (quantitative variables: arithmetic mean, SD, median, minimum, and 
maximum, categorical and ordinal variables: proportion of subjects) will be calculated for 
quantitative safety data as well as for the change from baseline, when appropriate.  Data 
analyses will be presented by dose level, overall and within each age cohort.
TEAEs will be analyzed by dose level, overall, and for each age cohort according to the 
Medical Dictionary for Regulatory Activities system organ class and preferred term.  
Additionally, the proportion of subjects with protocol-specified adverse events of bradypnea, 
hypoxia, apnea, hypotension, hypertension, bradycardia and paradoxical agitation reaction
and the proportion of subjects with such events requiring intervention will be summarized for 
each age cohort and each dose level.  Pre-specified criteria will be used to identify the 
protocol-defined adverse events mentioned above.
The proportion of subjects who completed the MRI scan and required artificial ventilation or 
intervention to restore baseline or normal hemodynamic status will also be summarized.  The 
incidence of individual adverse events during MRI sedation will be descriptively summarized 
for each dose level, including the total adverse events.
The types of individual interventions and the total number of interventions will be
descriptively summarized at each dose level and for each age cohort (ie, airway
repositioning, bag-mask intervention, deepening of sedation, fluid bolus, jaw thrust,
continuous positive airway pressure (CPAP), increased oxygen, intubation, etc). 
Vital sign measurements and hemodynamic and respiratory parameters will be summarized 
descriptively by dose level and age cohort.
Prior and concomitant medications will be summarized according to WHODRUG 
Dictionary.  The number and percentage of subjects who used prior medications (by 
preferred term) will be tabulated by dose level and age cohort.  The number and percentage 
of subjects who used concomitant medications will be similarly tabulated.  
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DEX withdrawal symptoms, such as agitation/anxiety, rebound tachycardia and rebound 
hypertension will be summarized by each dose level and age cohort.  A descriptive summary 
will be performed for the incidence of DEX withdrawal-related AEs after discontinuation of 
the DEX infusion.
Descriptive analyses will be performed for the Pediatric Anesthesia Emergence Delirium 
Scale (PAED) total score for dose level and by age cohort.


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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 table, to in 
order to conduct evaluations or assessments required to protect the well-being of the subject.  
Study Visit Identifier
Screen
Day 1 (Day of MRI scan)
Day 2 Follow-up
Day 29 Long-term Follow-up
Study Visit Scheduling/Window
Screening 
(up to 3 days before-
randomization)a
Period 1  
(MRI scan) 
Period 2 
(Post-MRI Recovery)b
24-Hour
(±2 hours)c
28-Day 
(+3 days)
Informed consent
X
Subject Number assigned
X
Demography
X
Medical history 
X
Inclusion/Exclusion criteria
X
X
Physical examinationd
X
Contraception checke
X
X
Vital signsf
X
X
X
EtCO2g
X
Rhythm strip (12-lead ECG if needed)h
X
Laboratory: Pregnancy testi
X
Randomization
X
Peripheral IV placementj
X
MRI scanj
X
Cardiac telemetryh
X
X
PSSSk
X
Study treatmentl
X
Propofol (as needed)l
X
Supplemental IV fluidsl
X
Modified Aldrete Score and PAEDm
X
AEs/SAEsn
X
→
→
→
X
Prior/Concomitant Treatmentso
X
→
→
→
X
Abbreviations: → = continues; AE = adverse event; ECG = electrocardiogram; EtCO2 = end-tidal carbon dioxide; IV = intravenous; MRI = magnetic 
resonance imaging; PAED = Pediatric Anesthesia Emergence Delirium Scale; PSSS = Pediatric Sedation State Scale; SAE = serious adverse event
a.
Signed informed consent and age-appropriate assent must be obtained prior to conducting any tests, assessments or procedures.  All Screening tests, 
assessments and procedure results must be received and reviewed by study site personnel prior to randomization.  All inclusion criteria must be met and 
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Study Visit Identifier
Screen
Day 1 (Day of MRI scan)
Day 2 Follow-up
Day 29 Long-term Follow-up
Study Visit Scheduling/Window
Screening 
(up to 3 days before-
randomization)a
Period 1  
(MRI scan) 
Period 2 
(Post-MRI Recovery)b
24-Hour
(2 hours)c
28-Day 
(+3 days)
all exclusion criteria must not be met. The Screening Visit may occur on or up to 3 days before Day 1.
b.
Subjects must be monitored per protocol requirements for a minimum of 1 hour; this must occur in a post-procedure recovery area such as a post-
anesthesia care unit (PACU), recovery room or other hospital area where the required monitoring can be achieved.  After 1 hour, subjects will meet 
criteria to leave this area when the subject attains a minimum Modified Aldrete Score of 9, is tolerating oral fluids and if applicable, any institution-
specific discharge criteria have been met.
c.
The Day 2 Follow-up visit will be completed 24 hours (±2 hours) after discontinuation of dexmedetomidine (DEX).  Contact with the subject or 
parent/legal guardian may be done via a phone call.
d.
Physical examination will include evaluation of general appearance, head, ears, eyes, nose, mouth, throat, neck, lungs, heart, abdomen, musculoskeletal, 
extremities, skin, lymph node and a neurological assessment.  
e.
The investigator must assess and document in the source if the subject is biologically capable of having/fathering children and if the subject is sexually 
active, continues to be sexually active or has become sexually active.  If yes, their method of contraception and confirmation of its consistent and correct 
use must also be documented in the source documents.
f.
Vital signs will include height (or length), weight, temperature, heart rate, respiratory rate, saturation of peripheral oxygen (SpO2) and blood pressure 
including mean arterial pressure (MAP).  Measurements should be obtained with the subject in a supine position as much as possible.  

Height will only be measured at Screening.  

Weight will only be measured at Screening and Day 1 Period 1 before randomization. If Screening and Day 1 occur on the same day, the weight does 
not need to be repeated. 

Height and weight values will be rounded to 1 decimal place (the nearest tenth) for calculations and documentation. If the second number to the right 
of the decimal point (the hundredths) is 4 or less, remove all numbers to the right of the tenths place. If the hundredths number is 5 or greater, add 1 
to the number in the tenths place, and then remove all numbers to the right of the tenths place.

Body temperature will be measured at Screening, at Day 1 Period 1 prior to randomization and during Day 1 Period 2 both when the subject arrives 
in the post-procedure recovery area and when they meet the criteria to leave this area.  If Screening and Day 1 occur on the same day, the 
temperature does not need to be repeated at Day 1 Period 1 prior to randomization but would need to be obtained on Day 1 Period 2 in addition to 
Screening.

Blood pressure, MAP, heart rate, respiratory rate and SpO2 will be measured at Screening, within approximately 5 minutes before the loading dose 
and then every 5 (±1) minutes once the loading dose has started until the end of the MRI scan.  The measurements obtained just before the loading 
dose will be considered the Baseline values for analysis purposes.

On Day 1 Period 2, blood pressure including MAP, heart rate, respiratory rate and SpO2 will be measured upon arrival in the post-procedure recovery 
area and then every 5 (±1) minutes for the first 15 minutes, and every 15 (±5) minutes for at least 1 hour until the subject attains a minimum 


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Study Visit Identifier
Screen
Day 1 (Day of MRI scan)
Day 2 Follow-up
Day 29 Long-term Follow-up
Study Visit Scheduling/Window
Screening 
(up to 3 days before-
randomization)a
Period 1  
(MRI scan) 
Period 2 
(Post-MRI Recovery)b
24-Hour
(2 hours)c
28-Day 
(+3 days)
Modified Aldrete Score of 9, is tolerating oral fluids and any institution-specific discharge criteria as applicable have been met.  

Heart rate, respiratory rate and SpO2, as well as blood pressure where available, will also be monitored between scheduled readings either per site
equipment monitoring standards or more frequently as deemed clinically necessary from the start of the study treatment loading dose through the 
post-MRI recovery period.  If heart rate decreases >20% from Baseline and is outside the normal range, a blood pressure measurement including 
MAP should be repeated at approximately 2-minute intervals until the heart rate returns to the normal range.  If systolic blood pressure decreases 
≥30% from Baseline and is outside the normal range, a blood pressure measurement including MAP should be checked approximately 1 minute later. 
If the systolic blood pressure remains outside the normal range, measurements should be repeated at approximately 2-minute intervals until the 
systolic blood pressure returns to the normal range.  Normal ranges are provided in Appendix 8, Normal Ranges by Age (Nelson Textbook of 
Pediatrics, 20th Ed, 2016).  Baseline values are those obtained at Day 1 Period 1 within approximately 5 minutes prior to the start of the DEX loading 
dose.
g.
Nasal cannula capnography will be used to monitor EtCO2 concentrations from the start of the study treatment loading dose through the MRI scan.  
EtCO2 data will not be collected on a CRF.
h.
A 2-minute rhythm strip will be obtained at Screening, and a 12-lead ECG will be performed if clinically significant abnormalities are noted.  If a site 
does not have the capability to obtain a hard copy rhythm strip, the 12-lead ECG may be performed in lieu of the rhythm strip. Subjects with a known 
history of cardiac disease will be required to have a 12-lead ECG performed at Screening.  Cardiac telemetry monitoring is required beginning just prior
to the start of the study treatment loading dose and continuing through the post-MRI recovery period.  
i.
For all female subjects of child-bearing potential, a urine dipstick or whole-blood qualitative human chorionic gonadotropin (hCG) pregnancy test that 
can be performed at the bedside will be performed on Day 1 Period 1.  Serum qualitative or quantitative hCG pregnancy tests are not permitted. A 
negative pregnancy result is required before the subject may be randomized. Subjects with an indeterminate or positive test result may not randomize in 
the study.  Please refer to Section 7.1 Pregnancy Testing for details.
j.
DEX must be administered through a peripheral IV line that is not a central catheter such as a subclavian or peripherally inserted central catheter (PICC) 
line.  The MRI scan may commence once the subject has achieved an adequate sedation level in the investigator’s clinical judgment.  The target sedation 
level is indicated by a Pediatric Sedation State Scale (PSSS) score of 2.  During subject sedation, facilities for maintenance of a patent airway, provision 
of artificial ventilation, administration of supplemental oxygen and cardiovascular resuscitation must be immediately available.  Site personnel trained in 
the use of resuscitative drugs and emergency equipment and skilled in airway management must be available at all times during subject sedation.
k.
The PSSS sedation ratings will be recorded as part of the anesthesia log on Day 1 Period 1 within approximately 5 minutes prior to the start of the study 
treatment loading dose infusion, immediately following completion of the loading dose infusion, and at 5 (±1) minute intervals throughout the duration of 
the study treatment infusion and MRI scan.    
l.
After all Screening and Day 1 assessments have been completed and reviewed, subject has been confirmed as meeting entry criteria and has been 
randomized, study treatment will be administered as a 2-stage intravenous infusion to be started just prior to the start of the MRI scan.  Immediately prior 
to the scan, a loading dose of dexmedetomidine (DEX) will be administered over a period of 10 minutes.  Then a continuous maintenance dose infusion 


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Study Visit Identifier
Screen
Day 1 (Day of MRI scan)
Day 2 Follow-up
Day 29 Long-term Follow-up
Study Visit Scheduling/Window
Screening 
(up to 3 days before-
randomization)a
Period 1  
(MRI scan) 
Period 2 
(Post-MRI Recovery)b
24-Hour
(±2 hours)c
28-Day 
(+3 days)
of DEX will be started that will continue for the duration of the scan.  Concomitant PRO may be administered starting 5 minutes following the start of the
DEX maintenance infusion to ensure that an adequate level of sedation is achieved prior to and throughout the scan.  Subjects will also be required to
receive supplemental IV fluids during the administration of DEX.  The use, type and rate of maintenance fluid administration following discontinuation 
of DEX will be at site discretion.  Please refer to Section 5, Study Treatment, for details.
m. The Modified Aldrete Score will be performed on arrival at the post-procedure recovery area and every 15 (±5) minutes until the subject meets criteria to 
leave that area.  The PAED will be performed after the subject awakens following arrival at the post-procedure recovery area and every 15 (±5) minutes 
until the subject meets criteria to leave that area. If any total score on the PAED is 10 or greater, the subject should be evaluated for emergence delirium, 
treated as appropriate and the PAED assessment frequency should be increased to every 5 (±1) minutes until the PAED score is below 10 or the subject 
leaves that area. 
 
n.
Adverse events (AEs) and serious adverse events (SAEs) will be collected from the time the informed consent is obtained through the Day 29 Long-term 
Follow-up Visit or final visit prior to the Day 29 Long-term Follow-up Visit as appropriate. See Section 8.1.4, Time Period for Collecting AE/SAE 
Information, for further details.  The Day 29 Long-term Follow-up Visit is a telephone contact visit to elicit contraception and AE/SAE information only.  
SAE information must be reported to Pfizer per Section 8.1.4.1 Reporting SAEs to Pfizer Safety.  
o.
Prior medications and non-pharmacologic therapies will be collected for the 4-week period before randomization.  Concomitant treatments and 
non-pharmacologic therapies will be collected from randomization through the Day 29 Long-term Follow-up Visit as described in Section 5, Study 
Treatments.
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1. INTRODUCTION
The present study is being conducted by Pfizer, Inc under the Pediatric Research Equity Act 
(PREA) and is a Phase 3/4 randomized, double-blind, dose-ranging study of the safety and 
efficacy of dexmedetomidine (DEX) used with propofol (PRO) for procedural sedation of 
pediatric subjects ≥1 month to <17 years of age undergoing magnetic resonance imaging 
(MRI) scans.
  PRO is not approved for procedural sedation in the pediatric population, so in this study the 
use of PRO is considered investigational.
1.1. Mechanism of Action and Indication
DEX is a highly selective α2-adrenergic agonist that is being investigated for use in 
procedural sedation in pediatric subjects undergoing MRI requiring moderate to deep 
sedation.  DEX is currently approved for sedation of initially intubated and mechanically
ventilated adults during treatment in an intensive care setting and for procedural sedation of 
adults.
The effects of DEX are mediated via adrenoreceptors in both the central and peripheral 
nervous systems.  Owing to the wide distribution of adrenergic receptors, DEX has effects 
across multiple organ systems and in some cases, multiple effects on a single organ system.  
For example, DEX has a dual effect on the cardiovascular system.  Upon administration DEX 
has a transient peripheral effect mediated through its stimulation of α2- receptors on vascular 
smooth muscle causing an increase in blood pressure and a reflex decrease in heart rate.  In 
the heart, the dominant effect of DEX is to induce bradycardia─ mediated through vagal 
stimulation and a decrease in tachycardia as DEX blocks the cardio accelerator nerves.  In 
children, large doses of dexmedetomidine have been shown to cause peripheral 
vasoconstriction, leading to transient systemic hypertension, whereas low doses can cause 
central sympatholysis, leading to systemic hypotension.1-4
The sedative and anxiolytic effects result primarily from activity in the locus ceruleus of the 
brain stem where stimulation of the α2-adrenergic receptors inhibits norepinephrine release, 
resulting in increased firing of inhibitory neurons.  In the dorsal horn of the spinal cord, DEX 
modulates the release of substance P which produces its analgesic effects.5  The 
α2-adrenergic agonist action of DEX results in mild to moderate analgesia, sedation, 
anxiolysis, diuresis, peripheral and central effects on the cardiovascular system, and mild 
inhibition of insulin release and platelet aggregation.6
In healthy subjects, DEX caused dose-dependent decreases in systolic blood pressure (SBP) 
and diastolic blood pressure (DBP) and a slowed heart rate but did not alter respiratory rate 
or oxygen saturation at recommended dosages.6,7,8
1.2. Approval History and PREA
In December 1999, Precedex (developed by Hospira Inc.) received regulatory approval in the 
United States for sedation of initially intubated and mechanically ventilated adults in an 
intensive care unit (ICU) setting for up to 24 hours.  In October 2008 DEX was approved for 


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use in non-intubated adults requiring sedation prior to and/or during surgical and other 
procedures.  
In 2007 the FDA issued a PediatricWritten Request (PWR) in ICU sedation.  In response, 
6 studies were conducted, and the results submitted to the FDA.  In March 2013, following 
2 amendments (December 2010 and August 2011), the FDA granted Pediatric Exclusivity for 
Precedex, based on the fulfillment of the requirements of the PWR.  However, based on the 
FDA’s assessment of insufficient proof of efficacy and safety, they did not accept the results 
of the PWR studies as adequate to support the approval of an indication for Precedex in 
pediatric ICU sedation.
In 2008 following the approval of DEX for procedural sedation in adults, a PREA request 
was issued to conduct a clinical study in pediatric subjects receiving DEX for procedural 
sedation.  In response, study DEX 10-16, entitled Phase IV, Open Label, Safety Study 
Evaluating the Use of Dexmedetomidine in Pediatric Subjects Undergoing Procedure-Type 
Sedation was conducted to fulfill the PREA requirement.  The objective of the DEX 
10-16 study was to evaluate safety; this study was not intended to support an indication for 
the use of DEX in pediatric procedural sedation (PPS).  The DEX 10-16 study ultimately did 
not fulfill the PREA requirement, and FDA advised consultation with clinical experts in PPS to 
inform the design of a new study and ensure that the study reflected the way DEX was used in
clinical practice (ie, with regard to dose selection and rationale, types of procedures, and use of 
concomitant sedative drugs).
1.2.1. Study DEX 10-16
DEX 10-16 was an open-labeled, single-arm, multi-center study designed to evaluate the 
safety of DEX in pediatric subjects ages ≥28 weeks to <17 years old who required 
non-intubated moderate to deep sedation (NI-MDS) for procedures lasting at least 30 minutes 
and falling into 1 of the following 3 procedural groups:

Non-invasive diagnostic/therapeutic procedures including ultrasound (U/S),
computed tomography (CT) scans, MRI, cardiac catheterization or transthoracic 
echocardiogram (TTE).

Minimally invasive diagnostic/therapeutic procedures such as procedures performed 
under U/S or CT guidance (eg, U/S or CT-guided solid organ biopsy), and routine 
myocardial biopsies in cardiac transplant recipients.

Surgical procedures including small surgical procedures (eg, excisions, biopsies) and 
dental procedures (eg, extractions, pulpectomy, pediatric rehabilitation dental 
procedures, fillings, and crowns).
Dosing of DEX was based on age: subjects aged ≥28 weeks’ gestational age to <1 month 
postnatal (n=1) received a 0.1 microgram/kilogram (mcg/kg) loading dose over 10 minutes and a 
0.05 - 0.2 mcg/kg/hour infusion; subjects aged 1 month to <17 years (n=90) received a 1 mcg/kg 
loading dose over 10 minutes and a 0.2 - 2 mcg/kg/hour infusion.


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Although DEX 10-16 was initially designed to assess safety only, based on feedback from the 
FDA, the study was revised to incorporate assessments of efficacy.
The primary efficacy endpoint of DEX 10-16 was the rate of successful sedation.  This was a 
composite endpoint consisting of the following 3 criteria, all of which had to be satisfied for a 
sedation to be considered a success:

Subject had adequate level of sedation (University of Michigan Sedation Scale 
[UMSS] score of 1 to 3 or a Neonatal Pain, Agitation and Sedation Scale [N-PASS] 
score of -5 to -2) at least 80% of the time the subject was given the study drug.

Subject successfully completed the procedure without rescue medication 
(midazolam).

Subject did not need artificial ventilation or intervention to restore baseline or normal 
hemodynamic status.
The primary safety endpoint of DEX 10-16 was the incidence of treatment-emergent adverse 
events (TEAEs).
The study enrolled 91 subjects, of whom 90 subjects were included in the safety evaluable 
population and 78 in the efficacy evaluable population.
1.2.1.1. Study DEX 10-16 Study Results
DEX 10-16 demonstrated that DEX was generally safe and well tolerated in pediatric
subjects who were undergoing procedural sedation.  The most common TEAE was 
respiratory depression (62%) which was pre-defined in the protocol as the presence of either 
absolute or relative thresholds for respiratory rate and saturation of peripheral oxygen (SpO2) 
changes.  None of the events of respiratory depression required medical intervention or 
resulted in a subject discontinuing from the study.  The other common TEAEs were 
hypotension (37%) and bradycardia (4.4%).9
Based on the 3 criteria comprising the primary efficacy endpoint, the study failed to 
demonstrate efficacy.  The majority of subjects in all 3 procedural groups required rescue 
midazolam for adequate sedation.  Only 2 subjects met the criteria for successful sedation; 
both were in the non-invasive procedure group.  Notably, the need for rescue sedation and 
incidence of AEs increased with increasingly invasive/painful procedures.  More subjects in 
the non-invasive procedures group (primarily subjects undergoing imaging studies) were 
adequately sedated compared to subjects in the minimally invasive or surgical procedures 
groups.
1.2.2. DEX Expert Advisory Committee
In preparation for the current protocol, Pfizer assembled a team of 5 nationally and 
internationally recognized Clinical Experts in the field of pediatric sedation and met with 
them for advice in designing a study based on current clinical practice for the use of DEX for 
PPS.  As a result of that meeting and subsequent communication with the Advisory 


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Committee, the procedures for study, dose range and concomitant sedation drugs for this 
study were determined.
1.2.2.1. Imaging Procedures 
The Clinical Experts recommended that Pfizer include only MRI/non-invasive imaging 
procedures for this study because approximately 80% of DEX used in pediatric procedural 
sedation is for imaging procedures.  The predominant use of DEX for sedation for imaging 
procedures (MRI in particular) is also strongly supported by the the literature.10,11,12
1.2.2.2. Dose Selection
Pharmacokinetic (PK) data from adults undergoing procedural sedation with DEX is not 
available and only limited PK data is available for pediatric subjects.13  Additionally, no 
PK/Pharmacodynamic (PD) model has been established to guide dose selection in pediatric 
subjects undergoing procedural sedation with DEX. In the absence of PK and modeling data 
to guide dose selection for this study, the selection of the DEX dosing regimens was based on 
consideration of the following:
1. The recommended DEX dose for procedural sedation in adults.
2. The dosing experience and results of the previous pediatric procedural sedation
study DEX 10-16.
3. The available PK data in adult and pediatric ICU subjects, as well as simulated 
PK profiles of DEX at the projected doses in pediatric procedural sedation subjects 
based on a population PK model developed from the ICU pediatric subjects 
(Appendix 2).
4. The published literature in similar patient populations undergoing similar non-
invasive imaging procedures.
5. Reports of dose-related effects of DEX on required concomitant anesthesia.
6. Clinical expert advisor recommendations.
The doses selected for this study are shown below:
Blinded dosing for subjects ≥1 month to <2 years of age on Day 1
Dose Level
DEX Loading Dose
DEX Maintenance Infusion Dose
Low dose level
0.5 mcg/kg
0.5 mcg/kg/hour
Middle dose level
1 mcg/kg
1 mcg/kg/hour 
High dose level
1.5 mcg/kg
1.5 mcg/kg/hour


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Blinded dosing for subjects ≥2 years to <17 years of age on Day 1
Dose Level
DEX Loading Dose
DEX Maintenance Infusion Dose
Low dose level
0.5 mcg/kg
0.5 mcg/kg/hour
Middle dose level
1.2 mcg/kg
1 mcg/kg/hour   
High dose level
2 mcg/kg
1.5 mcg/kg/hour
Lower loading doses were selected for subjects <2 years old compared to subjects from 2 to 
<17 years of age because of a potential increased risk of respiratory insufficiency leading to 
hypoxia and bradycardia in newborns and infants treated with high doses of DEX.14
The clinical expert advisory board unanimously agreed that the dosing regimen used in the 
DEX 10-16 study does not reflect current clinical usage.  The DEX doses used in children in 
practice today are higher than the doses administered in the DEX 10-16 study and higher than 
the doses specified for adults in the current label.
Since the approval of DEX for adult procedural sedation in 2008, there have been numerous 
publications on the use of DEX for PPS, chiefly for non-invasive procedures such as MRI, 
CT, nuclear medicine studies, and electroencephalograms (EEG).  A review of this literature 
reveals that the range of loading and maintenance doses used in pediatric subjects is 
frequently higher than the recommended adult dose.  In addition, there has been a progressive 
increase in the doses used over time.
Mason et al. reported on 747 consecutive pediatric patients who received DEX for MRI 
sedation.15  Between April 2005 and April 2007 the loading dose of DEX was increased from 
2 to 3 mcg/kg, and the maintenance infusion rate increased from 1 mcg/kg/hour to 1.5 to 
2 mcg/kg/hour.  During this time the success rate of sedation with DEX alone increased from 
91.8% to 97.6% of patients being able to complete the imaging study.  Similarly, Siddappa et 
al reported on the successful use of high-dose DEX (2 mcg/kg loading dose followed by 
1 mcg/kg/hour infusion) for sedation during MRI.11  The safety profile of DEX at these 
higher doses was found to be acceptable and was characterized in multiple studies by a 
modest decrease in heart rate and blood pressure that typically did not require intervention.14
Co-administration of DEX with other sedatives such as ketamine, midazolam, or PRO is also 
common; about 67% of cases in the recent analysis of the DEX database by Sulton et al. 
utilized concomitant sedatives such as midazolam or ketamine.10  In addition, DEX has been 
reported to exert a dose-sparing effect on the requirement for concomitant opioids and 
sedatives.16,17  The reduced need for concomitant sedatives is significant, given increasing 
concerns regarding potential neurotoxic effects of anesthetics in developing children.18,19
The doses selected for this study were based on the combined information from the above 
sources and input from clinical experts.  The selected doses range from a minimally effective 
low dose to maximum doses, which are representative of current clinical usage. 


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It is anticipated that the proportion of subjects adequately sedated at the lowest dose level 
(0.5 mcg/kg loading dose and 0.5 mcg/kg/hour maintenance dose) will be low.  As reported by 
Berkenbosch et al., initial use of a 0.5 mcg/kg induction and 0.5 mcg/kg/hour maintenance dose 
regimen failed to achieve adequate sedation and prevent patient movement in most children 
undergoing MRI scans, leading subsequently to the use of higher DEX doses.20  The middle 
dose level chosen for this study is comparable to the approved dose for adult procedural 
sedation and the dose utilized in the original Hospira pediatric trial (DEX 10-16), in which 
approximately 30% of subjects undergoing MRI did not require supplemental midazolam.  The 
high doses were chosen to be more representative of current practice, and it is expected that up 
to 70-80% of subjects who receive this dose level will not require supplemental anesthetic to 
achieve adequate sedation.15  Across the dose range to be studied, it is anticipated that 
increasing dose levels of DEX will be associated with a decreasing requirement for a
concomitant sedative, and with an increasing proportion of subjects who are able to complete 
the procedure with DEX alone.
Although there are very limited PK data available for DEX used for procedural sedation, the 
PK of DEX has been well characterized in adults and in pediatric ICU subjects.  DEX 
undergoes extensive hepatic metabolism to inactive metabolites, with 85% undergoing 
glucuronidation by UDP-glucuronyltransferase (UGT) and 15% by cytochrome P450 2A6.  
In adults, following intravenous (IV) administration, DEX exhibits a rapid distribution phase 
with a distribution half-life (t½) of approximately 6 minutes; a terminal elimination t½ of 
approximately 2 hours; a steady-state volume of distribution (Vdss) of approximately 118 L, 
and an estimated clearance of approximately 39 L/hour.  In adults, DEX exhibits linear PK in 
the dosage range of 0.2 to 0.7 mcg/kg/hour when administered by IV infusion for up to 
24 hours.21,22
Based on the results from 5 clinical studies (W98-266, CHOP, DEX 08-01, DEX 08-09, and 
DEX 11-01) in pediatric ICU subjects ranging in age from 1 month to 17 years, the median 
weight-adjusted DEX clearance values were between 0.79 and 1.32 L/hour/kg and the 
median weight-adjusted volume of distribution (Vd) values, between 2.09 and 3.64 L/kg.  
DEX exhibits linear PK across the dosage range of 0.2 to 2 mcg/kg/hour studied in pediatric 
ICU subjects when administered by IV infusion for up to 24 hours.  Hence, the exposure of 
DEX in this study is expected to be dose-proportional within the proposed DEX dosage range
of 0.5 to 2 mcg/kg/hour in PPS subjects.
1.2.2.2.1. Loading Dose Infusion Duration
The Precedex United States Package Insert (USPI) recommends a loading dose of 1 mcg/kg 
infused over 10 minutes for adults (DEX is not approved for pediatric use).  The pediatric 
ICU sedation studies used a 10-minute interval for infusion of the DEX loading dose.  
However, there are some literature reports of PPS studies that infused the DEX loading dose 
over ≤5 minutes.  Some members of our clinical expert advisory committee also use an 
infusion rate of ≤5 minutes for PPS.  This practice of shortening the duration of the loading 
dose infusion is employed primarily at tertiary care hospitals and by very experienced 
providers with specialized interest and/or training in using DEX for PPS.  However, while 
there is little published data on the safety and tolerability of different infusion duration times, 


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a shorter duration may be associated with increased AEs.  Therefore, this study will use the 
more conservative 10-minute infusion interval for the DEX loading dose, which is consistent 
with the current USPI as recommended for adults.  
1.2.2.3. Concomitant Sedative Drugs
The Clinical Experts emphasized that in practice, DEX is usually used in combination with 
other sedatives and analgesics (ie, midazolam, PRO, ketamine, morphine, or fentanyl).10
For an MRI to be successful the subject must remain motionless during image capture and 
therefore in young children deep sedation is necessary.  While multiple sedative drug 
regimens have been used to achieve deep sedation for MRI studies, PRO has become a
commonly used drug because it has a short induction and recovery time and can be titrated 
easily to the required sedation level.23,24  In this study, PRO will be used as a rescue sedative 
in subjects who are not sufficiently sedated by DEX alone.
1.2.2.4. Summary of Study Design
This study design is based on the comments received in the FDA’s complete response letter 
(CRL) of August 2016 and the recommendations of the Clinical Expert advisory committee.  
The study is designed to meet the post-marketing study requirements (PMR 1772-1) to fulfill 
the PREA requirements and to investigate the safety and efficacy of DEX for pediatric 
procedural sedation.
This clinical trial will be a randomized, double-blind, fixed dose-ranging study of the 
efficacy and safety of DEX, when used with PRO administered as needed, for procedural 
sedation of pediatric subjects ≥1 month to <17 years of age undergoing diagnostic magnetic 
resonance imaging (MRI) scans.
1.3. Safety Data
1.3.1. Clinical Trial Safety Data Base
The legacy Hospira clinical safety data base for DEX pediatric studies contains safety 
information on 319 pediatric subjects participating in 6 studies conducted on the use of DEX 
for ICU pediatric sedation and 90 subjects receiving DEX for PPS in DEX 10-16.
1.3.1.1. Safety Data from Pediatric ICU Sedation Studies
In support of the Pediatric Written Request for DEX for the indication of sedation in initially 
intubated and mechanically ventilated pediatric ICU (PICU) subjects, Hospira completed 
6 pediatric clinical studies with a total of 319 subjects aged 28 weeks to <17 yr.  In these 
studies, the loading dose was given over 10 minutes and the maintenance doses were as 
follows: 

28 weeks gestational age to <1 month chronological age: loading dose of 
0.05 - 0.2 mcg/kg and maintenance dose of 0.05 - 0.2 mcg/kg/hour.


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
1 month to ≤16 years of age: loading dose of 0.25 - 0.5 mcg/kg and maintenance dose 
of 0.2 - 0.5 mcg/kg/hour.

1 month to ≤16 years of age: loading dose 0.5 - 1 mcg/kg and maintenance dose of 
0.5 - 2 mcg/kg/hour.
Adverse events occurring between the start of the DEX infusion and up to 24 hours after its 
discontinuation (study end) were considered TEAEs.  Among the 319 pediatric subjects in 
the integrated safety population, 203(63.3%) had 1 or more TEAEs, 2.5% had severe TEAEs, 
and 50 subjects (15.7%) had one or more drug-related TEAEs.  Nine subjects (2.8%) had 1 or 
more treatment emergent serious adverse events (SAEs); 4 subjects had treatment-emergent 
SAEs that were considered drug-related.  Thirteen subjects (4.1%) had TEAEs leading to 
discontinuation; the incidence of any single TEAE leading to discontinuation was low, 
ranging from 0.3 to 0.6%.  No single TEAE led to discontinuation in more than two subjects, 
and no subjects died as a result of a TEAE.
Most TEAEs in the PICU sedation studies were mild in severity (2.5% were considered 
severe). No subject had a TEAE resulting in death.  The incidences of discontinuations due to 
TEAEs was low (4.1%), and no single TEAE leading to discontinuation occurred in more 
than two subjects.  The incidence of treatment-emergent SAEs leading to discontinuation was 
also low (1.3%), and none of the treatment-emergent SAE leading to discontinuation 
occurred in more than one subject.
The most common TEAEs were hypertension (43 subjects, 13.5%), hyperglycemia 
(36 subjects, 11.6%, with no hyperglycemia considered related to drug), hypotension 
(32 subjects, 10.1%), hypokalemia (28 subjects, 8.8%), pyrexia (26 subjects 8.2%), and 
vomiting (16 subjects, 5.0%). 
Based on the known mechanism of action of DEX and its adverse event profile in adults, 
certain adverse events were considered “adverse events of special interest”.  These adverse 
events included bradycardia, tachycardia, hypotension, diastolic hypotension, and systolic 
hypertension.  The majority of AEs of special interest did not require medical intervention, 
which was defined as any action taken in response to the AE and included decreasing the 
infusion rate of DEX, re-positioning the patient and/or treatment with fluids, medications, or 
procedures.  The Incidence of AEs of Special Interest and the incidence of these events 
requiring medical intervention are shown below:
The Incidence of AEs of Special Interest vs. Incidence of AEs of Special Interest 
Receiving Medical Attention in an Integrated Pediatric Population During ICU 
Sedation <24 Hours
Adverse event
Subjects with AEs of 
special interest 
N=319
n (%)
Subjects receiving medical 
intervention
N=319
n (%)
Bradycardia
11 (3.4)
3 (0.9)


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Adverse event
Subjects with AEs of 
special interest 
N=319
n (%)
Subjects receiving medical 
intervention
N=319
n (%)
Tachycardia
12 (3.8)
1 (0.3)
Hypertension
43 (13.5)
14 (4.4)
Hypotension
34 (10.7)
11 (3.4)
The changes in vital signs (blood pressure [BP] and heart rate [HR]) across the PICU 
sedation studies were predictable given DEX’s mechanism of action and were generally 
manageable.  Additionally, DEX had no clinically meaningful effect on hematology or serum 
chemistry analytes.
Overall, considering the underlying medical condition of the pediatric subjects upon 
enrollment (subjects had to be intubated and mechanically ventilated to qualify for the 
studies), DEX appeared to be generally safe and well-tolerated in the sedation of initially 
intubated and mechanically ventilated PICU subjects.  The TEAEs that occurred were 
generally consistent with the known AE profile of DEX in the adult population.25  
1.3.1.2. Safety Data from Pediatric Procedural Sedation Study DEX 10-16
As discussed in Section 1.2.1.1, study DEX 10-16 demonstrated that DEX was generally safe 
and consistent with the known safety profile of DEX in adults.26  Adverse events of special 
interest were AEs of bradycardia, tachycardia, hypotension, hypertension, hypoxia and 
respiratory depression based on protocol-defined vital signs limits.  The frequency of 
subjects experiencing a TEAE and TEAE of special interest in subjects undergoing 
non-invasive diagnostic/therapeutic procedures were 32 (69.6%) and 30 (65.2%).  With few 
exceptions, all TEAEs were TEAEs of special interest.  The commonly reported treatment-
related TEAEs (reported in ≥2 subjects) were hypotension in 30 subjects (33.3%), respiratory 
depression in 19 subjects (21.1%), bradycardia in 3 subjects (3.3%), and vomiting, BP 
systolic decreased, headache and hypoxia in 2 subjects each (2.2%).
The increased frequency of TEAEs of bradypnea and hypotension was noted with more 
invasive procedures, and with increased use of rescue sedation and analgesia.  As noted by 
Jooste et al, the high incidence (62%) of the protocol-defined decrease in respiratory rate of 
>30% from baseline, was not viewed as being clinically significant and represents a normal 
decrease in the respiratory rate of a child who is well-sedated in pediatric subjects 
undergoing procedural sedation.  All of the AEs reported were in calmly sedated children 
compared with that of a child in a relatively anxious pre-sedation state.9  There were 2 events 
of a >10% decrease in the saturation of peripheral oxygen (SpO2) from baseline that resolved 
quickly, and none of the subjects in DEX 10-16 required mechanical ventilation either during 
or post study drug infusion.  
There was 1 treatment-emergent SAE of syncope reported in this study.  This event was 
reported.  The SAE of syncope was assessed as probably not related to DEX and resolved 
without treatment.


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1.4. Safety Summary
Based on the safety data from the pediatric ICU sedation studies, the DEX 10-16 study in 
PPS, and the published literature, DEX is generally safe and well tolerated in pediatric 
subjects.  The most common TEAEs - hypotension, respiratory depression, and bradycardia, 
are well understood based on the drugs mechanism of action, are generally mild, and 
generally resolve without medical intervention. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of DEX may be found in the Investigator Brochure (IB), which is the single
reference safety document (SRSD) for this study.
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of PRO may be found in the United States package insert [(USPI], which is the 
SRSD for this study. Individual countries may also reference their local package insert for 
additional country-specific information on PRO.  


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2. STUDY OBJECTIVES AND ENDPOINTS
Primary Efficacy Objective:
Primary Efficacy Endpoint:
•
Assess efficacy of DEX for pediatric procedural 
sedation as measured by the percent of subjects at the 
high dose level versus the low dose level in the 
combined age cohorts who do not require concomitant 
PRO to achieve adequate sedation.
•
Percent of subjects at the DEX high dose level versus 
the low dose level in the combined age cohorts who 
do not require concomitant PRO to complete the 
MRI.
Key Secondary Efficacy Objective:
Key Secondary Efficacy Endpoint:
•
Assess the efficacy of DEX for pediatric procedural 
sedation as measured by the percent of subjects at the 
high dose level versus the low dose level in each age 
cohort who do not require concomitant PRO to achieve 
adequate sedation.
•
Percent of subjects at the DEX high dose level versus 
the low dose level in each age cohort who do not 
require concomitant PRO to complete the MRI.  
Secondary Efficacy Objective(s):
Secondary Efficacy Endpoint(s):
•
Explore the efficacy of DEX at the middle dose level 
compared to the high dose level and the low dose level 
in both the overall sample and in each age cohort as 
measured by the percent of subjects who do not require 
concomitant PRO to achieve adequate sedation.
•
Explore the efficacy of DEX by examining the percent 
of time at the target sedation score, time to first PRO 
use, emergence time from sedation, proportion of 
subjects at each dose level receiving PRO and amount 
of PRO required.
•
Percent of subjects at the DEX middle dose level 
compared to the high dose level and the low dose 
level in both the overall sample and in each age 
cohort who do not require concomitant PRO to 
complete the MRI.
•
Percent of time at the target sedation rating scale 
score (Pediatric Sedation State Scale [PSSS] rating of 
2) after the administration of the DEX loading dose 
and during the DEX maintenance infusion. 
•
The amount of time from the start of the DEX 
loading dose infusion to the time of the first PRO 
bolus administration.
•
Emergence time (defined as the time from the end of 
the MRI scan to when the subject meets a Modified 
Aldrete Score ≥9).
•
The proportion of subjects at each DEX dose level 
who receive PRO.
•
Total amount (mg/kg) and weight and time adjusted 
amount (per kg per minute basis) of concomitant 
PRO required to successfully complete the MRI scan.
 
 
 
Safety Objective:
Safety Endpoints:
•
Assess the safety of DEX used for procedural sedation 
of pediatric subjects undergoing an MRI scan.
•
Incidence, seriousness, causality and severity of 
treatment-emergent adverse events.
•
Percent of subjects who completed the MRI scan and 
required artificial ventilation or intervention to 
restore baseline or normal hemodynamic status.
CCI


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
Mean change from baseline in SBP, DBP, mean 
arterial pressure (MAP), HR and respiratory rate 
(RR).

Time outside of the stable range for hemodynamic 
parameters of SBP and HR.

Incidence of protocol-specified respiratory adverse 
events of bradypnea, hypoxia and apnea.

Incidence of protocol-specified cardiac adverse 
events of hypotension, hypertension and bradycardia.

Incidence of protocol-specified adverse event of 
paradoxical agitation reaction.

Incidence of protocol-specified adverse events of 
bradypnea, hypoxia, apnea, hypotension, 
hypertension, bradycardia and paradoxical agitation 
reaction requiring intervention.

Incidence of DEX withdrawal-related adverse events 
after discontinuation of DEX infusion.
Safety Assessments

Exposure to study drug (total dose of study drug 
received and the duration of study drug infusion).

Adverse Events (AEs).

Cardiac telemetry.

Vital signs (HR, blood pressure [DBP, SBP and 
MAP], RR, temperature, SpO2), end-tidal carbon 
dioxide (EtCO2) and body weight.

Prior and concomitant medications.

Pediatric Anesthesia Emergence Delirium Scale 
(PAED).
3. STUDY DESIGN
This is a randomized, double-blind, dose-ranging study of the efficacy and safety of DEX, 
when used with PRO as needed, for procedural sedation of pediatric subjects ≥1 month to 
<17 years of age undergoing MRI scans.  The sponsor, subject and investigator will be
blinded to the dose of DEX.
This study includes a Screening, Day 1, Day 2 Follow-up and Day 29 Long-term Follow-up 
Visit.  The Day 1 Visit is comprised of a Period 1(MRI scan) Phase and a Period 2 (Post-
MRI Recovery) Phase.  The Day 2 Visit is a 24-hour Follow-up, and the Day 29 Visit is a 28-
day Follow-up.  
All eligible subjects will receive double-blind treatment where one of 3 dose levels of DEX 
will be administered.  Following completion of required procedures before randomization at 
the Day 1 Visit, subjects meeting entry criteria will be randomly assigned to a Low, Middle 
or High dose level group (actual dose dependent on age) in a 1:1:1 ratio.  


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Treatment will be initiated just prior to the start of the MRI scan and will continue during 
Period 1 (MRI scan). Subjects will first receive a DEX loading dose administered over 
10 minutes.  Following completion of the loading dose, the maintenance infusion of DEX 
will be started. The subject’s level of sedation will be assessed using the Pediatric Sedation 
State Scale (PSSS) at 5-minute intervals throughout the drug infusion and MRI scan.  If an 
adequate level of sedation is not achieved as assessed by the investigator (eg, if the subject 
moves) within 5 minutes after the DEX maintenance infusion has been started, concomitant 
PRO may be given to ensure that an adequate sedation level is achieved and maintained for 
completion of the scan.  The target sedation level is indicated by a PSSS score of 2 (ie, 
patient is quiet [asleep or awake], not moving during procedure, has no frown [or brow 
furrow] indicating pain or anxiety and no verbalization of any complaint).27  
Once the subject has achieved an adequate sedation level per principal investigator (PI)
clinical judgment, the MRI scan can commence.  Sedation with DEX and if required, 
concomitant PRO, shall continue through completion of the MRI scan to maintain the subject 
at an adequate sedation level per PI clinical judgment.
Subjects will also be administered supplemental IV fluids throughout the DEX infusion at a 
maintenance rate per Section 5.10.1 Required Treatments.  Please refer to the Investigational 
Product Manual (IP Manual) for the list of permitted IV fluids that may be used.  The use, 
type and rate of maintenance fluid administration following discontinuation of the DEX 
infusion will be at the site’s discretion.
During subject sedation, facilities for maintenance of a patent airway, provision of artificial 
ventilation, administration of supplemental oxygen and cardiovascular resuscitation must be 
immediately available.  Site personnel trained in the use of resuscitative drugs and 
emergency equipment and skilled in airway management must be available at all times 
during subject sedation.
The DEX infusion should not be discontinued until confirmation that the MRI is complete 
has been received and DEX must be discontinued prior to the subject being transferred to the 
post-procedural recovery area.  Period 2 (post-MRI recovery) begins at the conclusion of the 
MRI scan.
The study will be conducted using the manufactured strength of DEX 200 mcg/2 mL, diluted 
to a concentration directed by the Investigational Product Manual (IP Manual) based on each 
subject’s treatment group assignment. 
3.1. Approximate Duration of Subject Participation
Subjects will participate in the study for ~4 weeks.  
3.2. Approximate Number of Subjects
A sufficient number of subjects will be screened to randomize approximately 120 subjects 
(40 subjects per dose level) who will participate in the study.  The numbers of enrolled 
subjects are not pre-specified for each participating country.  Enrollment is competitive and 


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will depend on the capabilities of each site.  Subjects who withdraw from the study will not 
be replaced. 
Age Cohort
Low Dose Group
Middle Dose Group
High Dose Group
≥1 month to <2 years
20
20
20
≥2 years to <17 years
20
20
20

Age Cohort ≥1 month to <2 years:
This age cohort should have an even distribution of subjects between the ages of 
1 month to <2 years on Day 1 within each dose group: 

Approximately 10 subjects aged ≥1 month to <1 year in each dose group.   

Approximately 10 subjects aged ≥1 year to <2 years in each dose group.  

Age Cohort ≥2 years to <17 years:
This age cohort should have an even distribution of subjects between the ages of 
2 years to <12 years on Day 1 within each dose group:  

Approximately 8 subjects aged ≥2 years to <6 years in each dose group.

Approximately 8 subjects aged ≥6 years to <12 years in each dose group.

Approximately 4, but no more than 5 subjects aged ≥12 years to <17 years in
each dose group.

All age cohorts can be enrolled in parallel. 
4. SUBJECT ELIGIBILITY CRITERIA
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.  
Female subjects of non-childbearing potential must meet at least 1 of the following criteria:
a.
Are pre-menarche;
b. Achieved postmenopausal status, defined as follows: cessation of regular menses for 
at least 12 consecutive months with no alternative pathological or physiological 


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cause; status may be confirmed with a serum follicle-stimulating hormone (FSH) 
level confirming the postmenopausal state;
c.
Have undergone a documented hysterectomy and/or bilateral oophorectomy; 
d. Have medically confirmed ovarian failure. 
All other female subjects who have experienced menarche (including female subjects with 
tubal ligations) are considered to be of childbearing potential.
Subject eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before subjects are included in the study.  
4.1. Inclusion Criteria at Screening
Subjects must meet all the following inclusion criteria to be eligible for enrollment into the 
study:
1. Evidence of a personally signed and dated informed consent document indicating 
that the subject or a parent(s)/legal guardian has been informed of all pertinent 
aspects of the study.  Assent will also be obtained where age-appropriate and 
according to state regulations.
2. Willing and able to comply with scheduled visits, treatment plan, laboratory 
tests, and other study procedures.
3. Male or female subject ≥1 month and <17 years of age on Day 1.
4. American Society of Anesthesiologists (ASA) Physical Status I, II or III. This 
assessment is to be performed by a medically qualified person and reviewed by 
the PI.
5. Requires non-intubated, spontaneous breathing, moderate to deep sedation 
(NI-MDS) for a magnetic resonance imaging (MRI) study with an intensivist, 
anesthesiologist or other proceduralist in attendance.
6. Duration of the MRI scan is expected to take at least 20 minutes but no more 
than 3 hours to complete.
7. Subjects must be willing and able to undergo placement of a peripheral IV 
catheter inserted specifically for this study. Existing IV catheters being used for 
another purpose (eg, administration of fluids, IV antibiotics etc.) must be used
with the Sponsor provided Y-connector and 3-port connector. Existing IV tubing 
must not be used.


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4.2. Inclusion Criteria on Day 1
Subjects must meet all the following inclusion criteria to be eligible for enrollment into the 
study:
1. All Screening inclusion criteria continue to apply as appropriate.
4.3. Exclusion Criteria at Screening
Subjects with any of the following characteristics/conditions will not be included in the 
study:
1. Investigator 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 Pfizer employees, including their family 
members, directly involved in the conduct of the study.
2. Participation in other studies involving investigational drug(s) within 30 days
prior to study entry and/or during study participation.  This includes 
investigational medicinal products and investigational vaccines received outside 
of a clinical study such as coronavirus disease 2019 (COVID-19) vaccines that 
do not have emergency use authorization. Approved or Emergency Use 
Authorized medicinal products and vaccines are not considered investigational 
and do not fall into this category.
3. Other acute or chronic medical or psychiatric condition including recent (within 
the past year) or active suicidal ideation or behavior or laboratory abnormality 
that may increase the risk associated with study participation or investigational 
product administration or may interfere with the interpretation of study results 
and, in the judgment of the investigator, would make the subject inappropriate 
for entry into this study.
4. Female subjects of childbearing potential who are sexually active who have not
been using a highly effective method of contraception as outlined in this protocol 
during the 2 weeks prior to randomization.
5. Fertile male subjects and female subjects of childbearing potential who are 
sexually active and are unwilling or unable to use a highly effective method of 
contraception as outlined in this protocol for the duration of the study and for at 
least 28 days after the last dose of investigational product. 
6. Weight at Screening is less than the 10th percentile of weight for age and sex or 
is greater than the 95th percentile of weight for age and sex (97th percentile in 
Japan) based on sponsor-provided growth charts.
7. Previous participation in this study or concurrent participation in any other 
interventional non-observational study.


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8. Planned medical procedure during the MRI scan or post-MRI recovery period.
Non-interventional/observational procedures are not exclusionary.
9. Craniofacial anomaly that could make it difficult to effectively establish a mask 
airway for positive pressure ventilation if needed.
10. Requires endotracheal intubation or laryngeal mask airway (LMA).
11. Neurological or psychiatric condition that in the opinion of the Investigator could 
confound reliable assessment of sedation score.  Examples include but are not 
limited to cerebral palsy, autism, severe mental retardation, etc.
12. Other central nervous system (CNS) disease including an uncontrolled seizure 
disorder, any seizure activity within 1 week of Day 1, known history of or 
anticipated potential for increased intracranial pressure, and/or known 
psychiatric illness that could confound a normal response to sedatives.  History 
of single childhood febrile seizure is not exclusionary.
13. Known Type I diabetes mellitus (DM), or insulin dependent Type II DM.
14. Known history of significant renal or liver disease.
15. Uncorrected hypothyroidism or hyperthyroidism or subjects whose thyroid 
function and medication regimen have been stable less than 1 month prior to 
Day 1.
16. Known hypersensitivity to DEX or PRO or any of the Diprivan® Injectable 
emulsion components.
17. Known allergy to eggs, egg products, soybeans or soybean products.
18. Subjects for whom PRO, opiates, benzodiazepines, DEX or other alpha-2 
agonists are contraindicated.
19. Received general anesthesia within 7 days prior to the planned start of the
investigational product administration.
20. Received treatment with an alpha-2 agonist or antagonist within 14 days prior to 
the planned start of the investigational product administration.
21. Received digoxin in the month prior to the planned start of the investigational
product administration.
22. Known second- or third-degree heart block or clinically significant abnormal 
findings on the Screening rhythm strip or electrocardiogram (ECG) diagnostic of 
atrioventricular (AV) conduction block or sustained cardiac arrhythmia.


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23. Symptomatic cardiac or respiratory disease that, in the Investigator’s opinion, 
might increase the risk to the subject.
24. Requirement for an apnea monitor within the past 3 months, or moderate to 
severe Sleep Apnea Syndrome based on clinical history or sleep study.
25. SpO2 <93 % on room air.
26. A temperature (core or tympanic) ≥38.0° Centigrade.
27. Any other medication, condition or factor that, in the Investigator’s opinion,
might increase the risk to the subject.
28. Any subject that, in the Investigator’s opinion, is exhibiting any behavior(s) or 
indication(s) that they may be under the influence of alcohol or drugs of abuse.
29. Heart rate values at Screening according to the respective age groups below 
based on the 10th centile data from the HR table in Appendix 7, HR and RR 
Centile Chart Cut-offs for Children from Birth to 18 Years of Age (Fleming et al, 
Lancet 2011).  Subject can be reassessed after 5 minutes and can be considered 
for randomization if their heart rate increases above the criteria.
Exclusion Criteria for Heart Rate
Age
Heart Rate
≥1 month to <3 months
<123 beats per minute (bpm)
≥3 months to <6 months
<120 bpm
≥6 months to <9 months
<114 bpm
≥9 months to <12 months
<109 bpm
≥12 months to <18 months
<103 bpm
≥18 months to <24 months
<98 bpm
≥2 year to <3 years 
<92 bpm
≥3 years to <4 years
<86 bpm
≥4 years to <6 years
<81 bpm
≥6 years to <8 years
<74 bpm
≥8 years to <12 years
<67 bpm
≥12 years to <15 years
<62 bpm
≥15 years to <18 years
<58 bpm
30. Systolic blood pressure values at Screening according to the respective age 
groups below based on the BP data from the table in Appendix 8, Normal Vital 
Signs According to Age (Nelson Textbook of Pediatrics 20th Ed, 2016).  Subject 
can be reassessed after 5 minutes and can be considered for randomization if 
their blood pressure does not meet the below criteria.


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Exclusion Criteria for Systolic Blood Pressure
Age
SBP
≥1 month to <3 months
<65 or >85 millimeters of mercury (mm Hg)
≥3 months to <6 months
<70 or >90 mm Hg
≥6 months to <1 year
<80 or >100 mm Hg
≥1 year to <3 years
<90 or >105 mm Hg
≥3 years to <6 years 
<95 or >110 mm Hg
≥6 years to <12 years
<100 or >120 mm Hg
≥12 years to <17 years
<110 or >135 mm Hg
4.4. Exclusion Criteria on Day 1
Subjects with any of the following characteristics/conditions will not be included in the 
study:
1. All Screening exclusion criteria continue to apply as appropriate.
2. Pregnant female subjects (including those with an indeterminate or positive 
pregnancy test); breastfeeding female subjects.
3. Weight on Day 1 before randomization is less than the 10th percentile of weight for 
age and sex or is greater than the 95th percentile of weight for age and sex (97th 
percentile in Japan) based on sponsor-provided growth charts.
4. Exposed to DEX within 48 hours prior to the planned start of the investigational 
product administration.
5. Received an IV opioid within one hour, or oral/intra-muscular (PO/IM) opioid within 
4 hours prior to the planned start of the investigational product administration.
6. Received any medication that has sedative or hypnotic properties within 4 hours prior 
to the planned start of the investigational product administration.
7. Received any pre-induction medication (ie, ketamine, chloral hydrate, 
benzodiazepines) within 4 hours prior to the planned start of the investigational 
product administration, other than planned gas induction to be administered via mask 
for placement of IV access as described in Section 5.10.2 Permitted Concomitant 
Treatments.
8. Received anti-depressant agents (eg, fluoxetine) during the 48-hour period prior to the 
planned start of the investigational product administration.
4.5. Lifestyle Requirements
4.5.1. Contraception
All fertile male subjects and female subjects who are of childbearing potential who are, in the 
opinion of the investigator, sexually active and at risk for pregnancy with their partner(s),


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must have been using a highly effective method of contraception consistently and correctly 
for at least 2 weeks prior to Day 1 and must agree to use a highly effective method of 
contraception consistently and correctly for the duration of the active treatment period and 
for at least 28 days after the last dose of investigational product.  The investigator or his or 
her designee will confirm that the subject has selected an appropriate method of 
contraception from the list of permitted contraception methods (see below).  At time points 
indicated in the Schedule of Activities, the investigator or designee will instruct the subject 
of the need to use highly effective contraception consistently and correctly and document the 
conversation, and the subject’s affirmation, in the subject’s chart.  In addition, the 
investigator or 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 
partner.
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 hormonal methods of contraception associated with inhibition of 
ovulation (eg, oral, inserted, injected, implanted, transdermal), 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 separate spermicide product (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. 
NOTE: Sexual abstinence, defined as completely and persistently refraining from all 
heterosexual intercourse (including during the entire period of risk associated with the study 
treatments) may obviate the need for contraception ONLY if this is the preferred and usual 
lifestyle of the subject. 
All sexually active male subjects must agree to prevent potential transfer to and exposure of 
partner(s) to drug through ejaculate 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 of investigational product.
4.6. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the supporting study documentation.
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 product identifiers, subject study numbers, 


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contact information for the investigator site, and contact details for a contact center in the 
event that the investigator 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 investigator 
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 investigator site 
and the study team are not available.  It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator 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 investigator site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonisation (ICH) 
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference/comparator 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). 
For this study, the investigational product is Dexmedetomidine hydrochloride injection, US 
approved PRECEDEX™. 
5.1. Allocation to Treatment
Within the appropriate age stratum, subjects will be randomized in a 1:1:1 ratio on Study 
Day 1 to the DEX low dose, middle dose or high dose group.  Allocation of subjects to dose
groups will proceed through the use of an interactive response technology (IRT) system 
(interactive Web-based response [IWR]).
Once the signed informed consent has been provided by the parent/legal guardian and assent 
(as required by the Institutional Review Board [IRB]/Independent Ethics Committee [IEC]) 
has been provided by the subject, the blinded site staff will screen the subject in the IRT 
system and obtain a single subject identification number (SSID) which will be used to 
identify the subject throughout the study.  Subjects will be numbered sequentially.  The 
subject must keep that number throughout the study even if he or she transfers to another site.  
A subject who discontinues or is withdrawn from the study prior to randomization and who 
re-screens at a later time must be assigned a new subject number.  A subject number must 
never be reassigned or reused for any reason.  The investigator must maintain a log linking 
the subject number to the subject’s name.  The investigator must follow all applicable 
privacy laws in order to protect a subject’s privacy and confidentiality.  Information that 
could identify a subject will be masked on material received by the sponsor.
To randomize an eligible subject, the blinded personnel will be required to enter or select 
information including but not limited to the user’s identification (ID) and password, the 
protocol number, the subject number, subject date of birth and the subject’s weight. The 


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blinded personnel will only be provided with a randomization number which must be 
recorded on the case report form (CRF).  The IRT system will provide them a confirmation 
report containing the above information, which must be retained in the blinded site file.
The designated unblinded dispenser(s) will receive notification that a subject has been 
randomized into the study and will be provided with the subject number, weight, date of birth 
with age, randomization number, dose group assignment, loading dose per kg in mcg/kg, 
total loading dose in mcg, total loading dose in mLs, loading dose concentration in mcg/mL, 
loading dose IV rate in mL/hr to be given over 10 minutes, maintenance dose per kg in 
mcg/kg/hr, maintenance dose in mcg/hr, maintenance dose concentration in mcg/mL, 
maintenance dose IV rate in mL/hr (ie, all values used in determining the infusion rates), 
number of vials needed and the dispensable unit(s) (DU) or container number(s) to be 
used.  Once subject numbers, randomization numbers and DU or container number(s) have
been assigned, they cannot be reassigned. This notification must be retained by the 
unblinded dispenser in the unblinded site files.
A study specific IRT manual will be provided that will include IRT contact information and 
details on the use of the IRT system for this study.
A study specific IP manual will provide dosing and administration instructions and 
investigational product dilution instructions for this study.
All manuals will be provided separately.
5.2. Breaking the Blind
The investigational product dose is blinded to the sponsor, investigator and subject.
At the initiation of the study, the investigator site will be instructed on the method for 
breaking the blind.  The method will be an electronic process.  Sites must not contact the 
unblinded dispenser for this information.  Blinding codes should be broken only in 
exceptional circumstances when knowledge of the actual treatment code is absolutely 
essential for further management of the subject.  Investigators are encouraged to discuss with 
a member of the study team if they believe that breaking the blind is necessary. When the 
blinding code is broken, the reason must be fully documented in the source documents and 
entered on the CRF.
5.3. Subject Compliance
The investigational product will be administered as a single loading dose infusion followed 
by a maintenance dose infusion by the appropriately designated study staff at the investigator 
site. Subjects will not be assessed for dosing compliance.
5.4. Investigational Product Supplies
5.4.1. Dosage Form(s) and Packaging
Precedex™ (dexmedetomidine hydrochloride) Injection, Concentrate, will be provided by
Pfizer Inc. as vials for IV infusion following dilution of the concentrate.  Precedex Injection, 


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Concentrate, 200 mcg/2 mL (100 mcg/mL) vials will be supplied in a 2 mL clear glass flip-
top vial and sealed with a coated stopper and an aluminum overseal with an aqua flip-off cap. 
Each vial will be packaged in an individual carton and labeled according to local regulatory 
requirements. 
Each carton will contain a single vial of study medication, and each carton will be identified 
with a unique DU or container number. Each carton will be packaged with a tamper-resistant
seal. The sponsor must be notified of any investigational product in which the 
tamper-resistant seal has been broken and this medication should not be used. Further details 
will be detailed in the Investigational Product Manual (IP Manual).  The IP is presented as a 
sterile, clear, colorless concentrate solution for IV administration.  Each vial contains 200 
mcg of Dexmedetomidine in 2 mL of 0.9% sodium chloride solution.  Each mL contains 100 
mcg of dexmedetomidine and 9000 mcg of sodium chloride in water and must be diluted 
before use.  The solution is preservative-free and contains no additives or chemical 
stabilizers.  Each vial is for single-use only.  
The intended dose will be diluted to a concentration not to exceed 4 mcg/mL.  Each vial must 
be diluted as described in the IP Manual to achieve the appropriate concentration for each 
subject’s treatment group assignment prior to administration.  Specific instructions for
dilution will be provided separately in the IP Manual.  
5.4.2. Preparation and Dispensing
The unblinded dispenser will prepare the investigational product from the carton(s) with the 
unique DU or container number(s) assigned by the IRT.  The IP will be dispensed on Day 1 
by the unblinded dispenser to the blinded study staff who will administer the blinded loading 
and maintenance doses to the subject.
The site should be instructed to maintain the product in the cartons provided, and the cartons 
should not be opened until the investigational product is to be diluted for administration.
The number of vials dispensed will be sufficient for preparing the subject’s dose based on the 
randomization to the low, middle, or high dose level. See the IP Manual for instructions on 
how to prepare the IP for administration.  The IP preparation and dispensation is the 
responsibility of and requires oversight by an appropriately qualified and experienced 
unblinded site pharmacist as allowed by local, state, and institutional guidance who must sign 
the Preparation Records.  For this study, third-party blind will be used to ensure the integrity 
of the blind.  The IP dose will be administered blinded to the subject by site staff.  The 
blinded study medication must be administered by a site physician experienced in delivering 
sedation and either the PI, or a sub-investigator (subI) who meets the criteria for PI and is 
listed on the 1572, must be present. The sponsor, subject and investigator will be blinded to 
the dose of DEX.
5.5. Investigational Product Administration
Subjects enrolled into the study will be randomized to receive one of three DEX dosing 
regimens (Low, Middle, or High), each consisting of an IV loading dose that is immediately 


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followed by an IV maintenance infusion that will continue for the duration of the MRI scan.  
DEX must be administered through a peripheral IV line that is not a subclavian line, 
peripherally inserted (or percutaneous indwelling) central catheter (PICC) line or other type 
of central catheter.
The loading and maintenance infusion doses will be given at the stable, pre-defined doses as 
described below and may not be modified, but the infusion may be discontinued if clinically 
indicated.  The loading dose will be administered over 10 minutes:
Blinded dose levels for subjects ≥1 month to <2 years of age on Day 1:
Dose Level
DEX Loading Dose
DEX Maintenance Infusion Dose
Low dose level
0.5 mcg/kg
0.5 mcg/kg/hour
Middle dose level
1 mcg/kg
1 mcg/kg/hour   
High dose level
1.5 mcg/kg
1.5 mcg/kg/hour
Blinded dose levels for subjects ≥2 years to <17 years of age on Day 1:
Dose Level
DEX Loading Dose
DEX Maintenance Infusion Dose
Low dose level
0.5 mcg/kg
0.5 mcg/kg/hour
Middle dose level
1.2 mcg/kg
1 mcg/kg/hour   
High dose level
2 mcg/kg
1.5 mcg/kg/hour
Refer to the IP Manual for instructions on how to administer the investigational product. 
Investigational product administration details including start time, stop time and IV rate in 
mL/hour will be recorded on the CRF.
5.6. Rescue Propofol Medication
Once the DEX loading dose has been administered and the maintenance dose started, if an 
adequate level of sedation is not achieved within 5 minutes after the start of the DEX 
maintenance infusion, concomitant PRO may be given per clinical judgment to ensure that an 
adequate sedation level is achieved to start the scan.  The target sedation level is indicated by 
a PSSS score of 2 (ie, “Quiet [asleep or awake], not moving during procedure, and no frown 
[or brow furrow] indicating pain or anxiety.  No verbalization of any complaint.”).27
Concomitant PRO should be administered as needed through completion of the scan to 
maintain adequate subject sedation per PI clinical judgment.  If it is needed, PRO should be 
administered first as a bolus of 0.5 mg/kg (500 mcg/kg) over approximately 1 minute 
followed by the start of a PRO maintenance infusion at 50 mcg/kg/min.  Additional bolus 
doses of PRO 0.5 mg/kg may be given as needed for subject movement/wakening. Following 
each additional PRO bolus, there must be a simultaneous increase in the PRO maintenance 
infusion rate in a 25 or 50 mcg/kg/min increment.  However, subsequent increases in the 
PRO maintenance infusion rate may be made in 25 or 50 mcg/kg/min increments without a 
corresponding PRO bolus.  The PRO maintenance infusion may also be decreased in 25 or 50 


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mcg/kg/min increments as needed to maintain adequate subject sedation, or it may be 
discontinued if clinically indicated.  
PRO administration details including start time, stop time, bolus doses in mg/kg and 
maintenance dose rates in mcg/kg/min will be recorded on the CRF.
PRO will be supplied by each individual study site.
PRO is not approved for procedural sedation in the pediatric population, so in this study the 
use of PRO is considered investigational.
5.7. Investigational Product Storage 
The investigator or an approved representative, eg, pharmacist, will ensure that all 
investigational products including PRO are stored in a secured area with controlled access 
under required storage conditions and in accordance with applicable regulatory requirements.
Investigational products should be stored in their original containers and in accordance with 
the labels.  
See the IP manual for storage conditions of the product.
Any storage conditions stated in the SRSD will be superseded by the storage conditions 
stated on the product label.
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 evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all non-working days upon return to normal operations.  The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order.  
Any excursions from the product label storage conditions should be reported to Pfizer upon 
discovery.  The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer.  
Once an excursion is identified, the investigational product must be quarantined and not used 
until Pfizer provides permission to use the investigational product.  It will not be considered a 
protocol deviation if Pfizer approves the use of the investigational product after the 
temperature excursion. Use of the investigational product prior to Pfizer approval will be 
considered a protocol deviation. Specific details regarding information the site should report 
for each excursion will be provided to the site.


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Receipt of materials, door opening and closing, and other routine handling operations where 
the products are briefly out of the temperature range described in the labeling are not 
considered excursions.
5.8. Investigational Product Accountability 
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All investigational products will be 
accounted for using a drug accountability form/record.  
5.8.1. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site).  All used and unused supplies must be inventoried and accounted for 
by the study monitor.  When notified by the Sponsor that it is appropriate, all used, partially 
used, or unused vials may be destroyed according to site-specific standard operating 
procedure (SOP) for clinical supply destruction after accountability has been completed by 
the study monitor.  If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.
5.9. Prior Treatments
The start and stop dates of administration for all medications and non-pharmacologic 
therapies received by the subject for the 4-week period before randomization will be 
recorded on the subject’s CRF.
5.10. Concomitant Treatments
All medications and non-pharmacologic therapies that the subject receives from 
randomization through the Day 29 Long-term Follow-up Visit will be recorded on the 
appropriate CRF along with the dates of administration and dosages.  Time will also be 
collected for concomitant treatments with a start date on Day 1.  Any questions about 
whether use of a concomitant medication or treatment is prohibited or permitted during a 
subject’s study participation should be discussed with the Pfizer medical representative.
5.10.1. Required Treatments
The following treatments are concomitant treatments or procedures that are required during 
the DEX administration.
Subjects will be administered supplemental IV fluids during the DEX infusion that will be 
administered at a minimum maintenance rate in mL/hr per the following formula:  

4 mL/kg/hr for the first 10 kg of weight; and

2 mL/kg/hr for the next 10 kg of weight; and

1 mL/kg/hr for every additional 1 kg of weight.


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However, sites may limit the IV rate to a maximum of 100 mL/hr for subjects weighing ≥60 
kg if appropriate per PI judgment/local practice. Please refer to the IP Manual for the list of 
permitted IV fluids that may be used.  The use, type and rate of maintenance fluid 
administration following discontinuation of the DEX infusion will be at site discretion.
5.10.2. Permitted Concomitant Treatments
The following treatments are concomitant treatments or procedures that are permitted
throughout study participation.

Supplemental oxygen (O2) is permitted, but if used as prophylaxis, it should be 
administered via nasal cannula at a rate of 1-3 L/min or via face mask at a rate of at 
least 6 L/min and must not interfere with EtCO2 concentration monitoring throughout 
the MRI scan.  Oxygen may also be administered as interventional treatment if 
needed.  See Section 8.4.1.3.

Contrast solution is permitted but must be administered while the DEX and/or PRO 
infusion is paused.  Site-specific standard procedures for contrast solution infusion 
should be followed.

If the Investigator believes that placement of IV access could provoke anxiety or 
added discomfort to the subject, they may utilize one of the following options below 
in an effort to allay subject anxiety:

Topical or local anesthetic; 

Gas induction that is administered via mask with either sevoflurane-oxygen, 
sevoflurane-nitrous oxide-oxygen mixtures or nitrous oxide-oxygen. As soon as 
the patient becomes compliant, intravenous cannulation should occur.  Following 
intravenous cannulation, the inhalation agents should be turned off and the patient 
should be administered 100% oxygen.  To wash out these agents as fast as 
possible, a high fresh gas flow of 100% oxygen should be administered.  The 
Fractional Inspiratory Oxygen (FIO2), Fractional Inspiratory (FI), End Tidal (ET) 
sevoflurane/nitrous oxide should be monitored during this induction process.  
When the ET sevoflurane/nitrous oxide is below 0.1% and the subject is awake 
and not agitated the infusion of the DEX loading dose may commence.
5.10.3. Prohibited Concomitant Treatments
The following treatments are concomitant treatments or procedures that are prohibited from 
randomization through the Day 2 Follow-up Visit (24-Hour Post-Treatment Period) or as 
otherwise specified below.  Subjects requiring a prohibited treatment, procedure or 
medication to control a medical condition should not be enrolled.

Drugs administered during the study drug infusion that may affect the sedation 
assessment such as anesthetics (other than topical/local), sedatives, hypnotics and 
opioids other than DEX or PRO.


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
Prophylactic use of atropine or other medications to prevent bradycardia are 
prohibited, but they may be used as interventional treatment if needed.  See 
Section 8.4.1.3.

Current or recent use of digoxin within the past month.

Subjects receiving anti-depressants (eg, fluoxetine) for chronic therapy prior to 
enrollment in the study may be enrolled and continue the use of the prior 
antidepressant(s); however, these agents are not to be introduced during the 48-hour
period prior to study drug infusion through the Day 2 Follow-up Visit (24-Hour 
Post-Treatment Period). 

Any neuromuscular blocking agents.

Any drugs contraindicated with the use of DEX or PRO.

Alpha-2 agonists/antagonists other than DEX within 14 days prior to study drug start 
or during study drug infusion. (eg, clonidine, guanfacine, etc).

Agents to induce sleep (eg, triazolam, diphenhydramine, etc) during the study drug 
infusion other than those listed in Section 5.10.2 Permitted Concomitant Treatments.

Insulin administered for Type I or Type II DM.

Planned medical procedure during the MRI scan or post-MRI recovery period. Non-
interventional/observational procedures are not exclusionary.
6. STUDY PROCEDURES 
6.1. Screening
All subjects must complete the procedures listed below during a Screening Visit on or up to 3 
days before Day 1.
The study will be thoroughly explained to the subject and the subject’s legal guardian(s) as 
appropriate. The investigator must ensure that each trial subject, or his/her legal guardian(s), 
is fully informed about the nature and objectives of the trial and possible risks associated 
with participation.  If the subject wishes to participate in the study and the legal guardian(s) 
desires the subject to participate in the study, an IRB/IEC-approved informed consent form 
will be signed and dated by the subject or legal guardian(s) as appropriate, before any 
procedures are performed that are specific to this study. The informed consent form must be 
agreed to by Pfizer and the IRB/IEC and must be in compliance with ICH Good Clinical
Practice (GCP), local regulatory requirements, and legal requirements. 
The signed documents will be retained at the site and the investigator or person designated by 
the investigator must document in the source documents that informed consent was obtained. 
Each subject will be assigned a unique subject number via the IRT system.  The Day 1 Visit
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The following information/assessments will be collected.  
1. Informed consent/assent.  Signed informed consent/assent must be obtained prior to 
conducting any tests, assessments or procedures.
2.
Subject Number assignment via IRT.
3. Subject demography: date of birth, sex, race, and ethnicity.
4. Presence of chronic conditions and general medical history of relevance including 
surgical procedures.  Start and stop dates should be included if known.
5. Eligibility assessment.
6. Physical examination including the following body systems: general appearance, 
head, ears, eyes, nose, mouth, throat, neck, lungs, heart, abdomen, musculoskeletal, 
extremities, skin, lymph nodes, neurological.  The physical examination (PE) will be 
conducted by a physician, trained physician’s assistant or nurse practitioner as 
acceptable according to local regulation.
7. Contraception check.  The investigator must assess and document in the source if the 
subject is biologically capable of having/fathering children and if the subject 
continues to be or has become sexually active. If yes, their method of contraception 
and confirmation of its consistent and correct use must also be documented in the 
source documents.
8. Vital signs measurements, including height (or length as appropriate), weight, 
temperature, heart rate, respiratory rate, SpO2 and blood pressure including MAP.  
Vital signs measurements should be taken in a supine position as much as possible.
9. Two-minute rhythm strip and/or 12-lead ECG as required.  A 12-lead ECG will be 
performed if clinically significant abnormalities are noted on the rhythm strip. If a site 
does not have the capability to obtain a hard copy rhythm strip, the 12-lead ECG may 
be performed in lieu of the rhythm strip. Subjects with a known history of cardiac
disease will be required to have a 12-lead ECG performed.  Rhythm strips and 12-
lead ECGs must be evaluated for abnormalities by a physician experienced in 
pediatric rhythm interpretation and hard copies retained.  The investigator is 
responsible for reviewing, signing and dating the interpretations.  If a clinically 
significant observation is noted, please contact the Pfizer Medical Representative 
prior to randomization.
10. Adverse events (AEs)/serious adverse events (SAEs) will be collected from the time 
the informed consent is obtained.
11. Collection of prior treatment information. 
The presence of all required inclusion criteria and the absence of all exclusion criteria must 
be recorded in the source documents.  Subjects meeting all of the inclusion criteria and none 
of the exclusion criteria will be eligible to randomize in the study.  


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6.1.1. Screen Fail Subject
A subject who does not meet one or more inclusion criteria or meets one or more exclusion 
criteria will be considered a screen failure and they should not be randomized.
Screen failure subjects may re-screen at a later date.  If a subject chooses to re-screen, a 
second informed consent must be obtained and documented, a new subject number must be 
assigned, and all screening tests and procedures must be repeated.  All results must be 
obtained and reviewed before the subject may be randomized.  Subjects needing to be 
re-screened more than once must first be discussed with the Pfizer Medical Representative.
6.2. Day 1 Period 1 (MRI scan)
All tests and procedures described in Section 6.1 and those prior to randomization listed 
below must be completed and all results reviewed before the subject may be evaluated for 
eligibility to randomize.  Subjects who meet all inclusion criteria and do not meet any 
exclusion criteria will be randomly assigned by age to one of three dose groups.  The 
following will be completed before randomization: 
1. Eligibility assessment.
2. Temperature and weight. If Screening and Day 1 occur on the same day, the 
temperature and weight do not need to be repeated before randomization.
3. Laboratory evaluation: Urine dipstick or whole-blood qualitative hCG pregnancy test 
that can be performed at the bedside for all female subjects of child-bearing potential.
Serum qualitative or quantitative hCG pregnancy tests are not permitted.
The following will be completed after randomization:
1. Vital signs measurements, including heart rate, respiratory rate, SpO2 and blood
pressure including MAP should be obtained with the subject in a supine position as 
much as possible.  Heart rate, respiratory rate, SpO2, blood pressure and MAP will be 
measured within approximately 5 minutes before the loading dose to obtain Baseline 
values and those values will be documented on the CRF. Heart rate, respiratory rate, 
SpO2, blood pressure and MAP will be measured every 5 (±1) minutes once the 
loading dose has started until the end of the MRI scan and the values documented on 
the CRF.  Heart rate, respiratory rate and SpO2, as well as blood pressure where 
available, will also be monitored between scheduled readings either per site
equipment monitoring standards or more frequently as deemed clinically necessary 
from the start of the study treatment loading dose through the post-MRI recovery 
period.  All vital sign values obtained from a monitoring equipment download need to
be reviewed for adverse events regardless of their collection frequency. If any vital 
sign values between the required scheduled readings meet the criteria for a protocol-
specified adverse event, the AE needs to be reported. Nadir values for HR, RR and 
SpO2 vital sign measurements during the course of the sedation will also be obtained 
from the telemetry monitor data and documented on the CRFs.  Nadir values for 
systolic BP and MAP during the course of the sedation will be identified 
programmatically from the data entered on the CRF.  


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If heart rate decreases >20% from Baseline and is outside the normal range, a blood 
pressure measurement including MAP should be repeated at approximately 2-minute 
intervals until the heart rate returns to the normal range.  If systolic blood pressure 
decreases ≥30% from Baseline and is outside the normal range, a blood pressure 
measurement including MAP should be checked approximately 1 minute later. If the 
systolic blood pressure remains outside the normal range, measurements should be 
repeated at approximately 2-minute intervals until the systolic blood pressure returns 
to the normal range.  Normal ranges are provided in Appendix 8, Normal Ranges by 
Age (Nelson Textbook of Pediatrics, 20th Ed, 2016).  Baseline values are those 
obtained at Day 1 Period 1 within approximately 5 minutes before the start of the 
DEX loading dose.
2. EtCO2 will be monitored from the start of the study treatment loading dose through 
the MRI scan. EtCO2 data will not be collected on a CRF.
3. Continuous cardiac telemetry monitoring is required beginning just prior to the start 
of the study treatment loading dose and continuing through the post-MRI recovery 
period.  New or worsening clinically significant abnormalities not already defined in 
Section 8.4.1, Protocol-Specified Adverse Events, will also be documented as adverse 
events on the CRF.  
4. Peripheral IV line insertion if needed.  DEX must be administered through a 
peripheral IV line that is not a subclavian line, PICC line or other central catheter.
5. PSSS sedation ratings will be obtained prior to the study treatment loading dose, 
immediately following administration of the loading dose, and at 5 (±1) minute 
intervals throughout the duration of the study treatment infusion and MRI scan. 
6. Administration of DEX.  Subjects will receive a single blinded IV Loading Dose of 
DEX over 10 minutes followed by a blinded IV Maintenance Infusion Dose of DEX
per their age and dose group assignment described in Section 5.5 Investigational 
Product Administration.  The infusion rate of the loading and maintenance dose IV 
infusions in mL/hour will be provided by the third-party unblinded dispenser.  The 
sponsor, subject and investigator will remain blinded to the dose assignment. Dose 
adjustments of DEX are not permitted. 
7. Open-label PRO may be administered if needed per Section 5.6 Rescue Propofol 
Medication to achieve and maintain an adequate level of sedation in the clinical 
judgment of the PI.  The target sedation level is indicated by a PSSS score of 2.
8. Supplemental IV fluids will be administered during the DEX infusion at a 
maintenance rate per Section 5.10.1.  Please refer to the IP Manual for the list of 
permitted IV fluids that may be used.
9. The MRI scan may commence once the subject has achieved an adequate level of 
sedation.  Any necessary contrast solution must be administered while the DEX 


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and/or PRO infusion is paused. Site-specific standard procedures for contrast 
solution infusion should be followed.
10. AE/SAE monitoring.
11. Collection of concomitant treatment information.
6.3. Day 1 Period 2 (Post-MRI Recovery)
Subjects must be monitored per protocol requirements for a minimum of 1 hour; this must 
occur in a post-procedure recovery area such as a post-anesthesia care unit (PACU), recovery 
room or other hospital area where the required monitoring can be achieved.  After 1 hour, 
subjects will meet criteria to leave this area when the subject attains a minimum Modified 
Aldrete Score of 9, is tolerating oral fluids and if applicable, any institution-specific 
discharge criteria have also been met.
1. Vital signs measurements, including temperature, heart rate, respiratory rate, SpO2
and blood pressure including MAP should be obtained with the subject in a supine 
position as much as possible. Body temperature will be measured when the subject 
arrives in the post-procedure recovery area and when they meet the criteria to leave 
this area. Heart rate, respiratory rate, SpO2, blood pressure and MAP will be
measured upon arrival in the post-procedure recovery area and every 5 (±1) minutes 
for the first 15 minutes, and every 15 (±5) minutes until the subject meets the criteria 
to leave this area described above. These values will be documented on the CRF.  
Heart rate, respiratory rate and SpO2, as well as blood pressure where available, will 
also be monitored between scheduled readings either per site equipment monitoring
standards or more frequently as deemed clinically necessary from the start of the 
study treatment loading dose through the post-MRI recovery period.  All vital sign 
values obtained from a monitoring equipment download need to be reviewed for 
adverse events regardless of their collection frequency. If any vital sign values 
between the required scheduled readings meet the criteria for a protocol-specified 
adverse event, the AE needs to be reported. If heart rate decreases >20% from 
Baseline and is outside the normal range, a blood pressure measurement including 
MAP should be repeated at approximately 2-minute intervals until the heart rate 
returns to the normal range.  If systolic blood pressure decreases ≥30% from Baseline 
and is outside the normal range, a blood pressure measurement including MAP 
should be checked approximately 1 minute later.  If the systolic blood pressure 
remains outside the normal range, measurements should be repeated at approximately 
2-minute intervals until the systolic blood pressure returns to the normal range.  
Normal ranges are provided in Appendix 8, Normal Ranges by Age (Nelson 
Textbook of Pediatrics, 20th Ed, 2016). Baseline values are those obtained at Day 1 
Period 1 within approximately 5 minutes before the start of the DEX loading dose.
2. Continuous cardiac telemetry monitoring is required beginning just prior to the start 
of the study treatment loading dose and continuing through the post-MRI recovery 
period.  New or worsening clinically significant abnormalities not already defined in 


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Section 8.4.1, Protocol-Specified Adverse Events, will also be documented as adverse 
events on the CRF. 
3. Modified Aldrete Score will be performed on arrival at the post-procedure recovery 
area and every 15 (±5) minutes until the subject is deemed suitable for discharge from 
that area.  Every attempt should be made to collect Modified Aldrete Scores for 
subjects less than 1 year of age.
4. PAED score will be performed after the subject awakens following arrival at the post-
procedure recovery area and every 15 (±5) minutes until the subject is deemed 
suitable for discharge from that area.  If any total score on the PAED is 10 or greater, 
subjects should be evaluated for emergence delirium, treated as appropriate and the 
PAED assessment frequency should be increased to every 5 (±1) minutes until the
PAED score is below 10 or the subject leaves that area.
 
6. AE/SAE monitoring.
7. Collection of concomitant treatment information.
6.4. Follow-up
6.4.1. Day 2 Follow-up
The Day 2 Follow-up visit will be completed 24 hours (±2 hours) following discontinuation 
of DEX.  Contact with the subject or parent/legal guardian may be done via a phone call.
1. AE/SAE monitoring (see the Time Period for Collecting AE/SAE Information 
Section 8.1.4).
2. Collection of concomitant treatment information.
6.4.2. Day 29 Long-term Follow-up
The Day 29 Long-term Follow-up contact will be completed at least 28 calendar days, and up 
to 31 calendar days after the last administration of the investigational product.  Contact with 
the subject or parent/legal guardian will be done via a phone call.
1. AE/SAE monitoring (see the Time Period for Collecting AE/SAE Information 
Section 8.1.4).
2. Contraception check (see the Contraception Section 4.5.1).
3. Collection of concomitant treatment information.
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6.5. Subject Withdrawal / Early Termination
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 (see also the 
Withdrawal From the Study Due to Adverse Events (see also the Subject Withdrawal / Early 
Termination section)) 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. 
Subjects who do not complete the MRI scan will be considered discontinued subjects.  
Subjects who have a medical procedure performed during the MRI scan must be 
discontinued. The Day 1 Period 1 assessments described in Section 6.2 and the Day 1 Period 
2 assessments described in Section 6.3 should be completed as appropriate.  The Follow-up 
Visits should be completed whenever possible.
Withdrawal of consent:
Subjects/parents/legal guardians who request to discontinue receipt of study treatment will 
remain in the study and must continue to be followed for protocol specified follow-up 
procedures.  The only exception to this is when a subject/parent/legal guardian specifically 
withdraws consent for any further contact with him or her or persons previously authorized 
by the subject to provide this information.  Subjects/parents/legal guardians should notify the 
investigator in writing of the decision to withdraw consent from future follow-up, whenever 
possible.  The withdrawal of consent should be explained in detail in the medical records by 
the investigator, as to whether the withdrawal is only from further receipt of investigational 
product or also from study procedures and/or post-treatment study follow-up and entered on 
the appropriate CRF page.  In the event that vital status (whether the subject is alive or dead) 
is being measured, publicly available information should be used to determine vital status 
only as appropriately directed in accordance with local law.
Lost to follow-up: 
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status.  This includes follow-up with persons authorized by the subject as noted above.  Lost 
to follow-up is defined by the inability to reach the subject/parent/legal guardian after a 
minimum of 2 documented phone calls, faxes, or e-mails as well as lack of response by the 
subject to 1 registered mail letter.  All attempts should be documented in the subject’s 
medical records.  If it is determined that the subject has died, the site will use locally 
permissible methods to obtain the date and cause of death.  If the investigator’s use of a third-
party representative to assist in the follow-up portion of the study has been included in the 
subject’s informed consent, then the investigator may use a sponsor-retained third-party 
representative to assist site staff with obtaining the subject’s contact information or other 
public vital status data necessary to complete the follow-up portion of the study.  The site 
staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information.  If, after all attempts, 
the subject remains lost to follow-up, then the last-known-alive date as determined by the 
investigator should be reported and documented in the subject’s medical records.


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If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  Study sites should document 3 attempts to contact subjects and/or parent(s)/legal 
guardian(s) as appropriate.  All attempts to contact the subject and information received 
during contact attempts must be documented in the subject’s medical record.  The final 
attempt should be a certified letter or use of a courier to the subject and/or parent(s)/legal 
guardian(s) to attempt contact.  In any circumstance, every effort should be made to 
document subject outcome, if possible.  The investigator should inquire about the reason for 
withdrawal, and request that the subject return for a final visit, if applicable, and follow up 
with the subject regarding any unresolved adverse events (AEs).
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.
Subjects who withdraw from the study will not be replaced. 
6.5.1. Adverse Events Requiring Subject Withdrawal from Treatment
The following adverse events should be assessed as described below to determine if the event 
requires discontinuation of treatment.  Refer to Section 8.4.1.1 for definitions of bradycardia, 
hypotension, hypertension and paradoxical agitation reaction.  Subjects experiencing an AE 
that requires a medical procedure be performed during the MRI scan must be discontinued.

Bradycardia that is not responsive to standard treatment (including glycopyrrolate or 
atropine).  The DEX infusion will be discontinued and the subject treated as clinically 
indicated.  This adverse event should be reported as an SAE.

Hypotension that is not responsive to standard treatment (including fluid 
resuscitation and vasopressor/inotropic support).  The DEX infusion will be 
discontinued and the subject treated as clinically indicated.  This adverse event should 
be reported as an SAE.

Hypertension that is not responsive to standard treatment.  The DEX infusion will be 
discontinued and the subject treated as clinically indicated.  This adverse event should 
be reported as an SAE.

Paradoxical agitation reaction occurring during the study drug infusion period. The 
DEX infusion will be discontinued and the subject treated as clinically indicated.  
This adverse event should be reported as an SAE.

Adverse event requiring intubation or LMA (laryngeal mask airway).  The DEX 
infusion will be discontinued and the subject treated as clinically indicated.  This 
adverse event should be reported as an SAE.

Second- or third-degree heart block.  The DEX infusion will be discontinued and 
the subject treated as clinically indicated.  Second-degree block adverse events should 


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be reported as an SAE if appropriate. All third-degree block adverse events should be 
reported as an SAE. 
6.5.2. Adverse Events Requiring Assessment for Subject Withdrawal from Treatment
The following adverse events should be assessed as described below for the Investigator to 
determine if the event warrants discontinuation of treatment: 
•
Decreased respiratory rate in a subject unresponsive to commands.  The 
Investigator should determine if the DEX infusion should be discontinued and if 
further intervention is needed.  
•
Other cardiac events should be assessed and the Investigator should determine if the 
DEX infusion should be discontinued and if further intervention is needed.
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 manner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
1. AE/SAE Reporting: adverse events and serious adverse events will be collected 
from the time the informed consent and assent (as appropriate) is obtained 
through the Day 29 Long-term Follow-up visit or final visit prior to the Day 29 
Long-term Follow-up visit as appropriate and will be recorded on the CRF and 
source documents.  There are 2 Adverse Event CRF pages used in this study: the 
Adverse Event Report CRF page and the Medication Error Record CRF page.  
See Section 8 for further information regarding adverse event reporting.
 
 
 
 
  
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3. Concomitant treatment recording: concomitant medications and 
non-pharmacologic therapies will be collected from randomization through the 
Day 29 Long-term Follow-up Visit and will be recorded on the CRF and source 
documents.
4. Contraception Check: The investigator must assess and document in the source 
if the subject is biologically capable of having/fathering children and if the 
subject continues to be or has become sexually active.  If yes, their method of 
contraception and confirmation of its consistent and correct use must also be 
documented in the source documents.
5. EtCO2: end tidal carbon dioxide to be monitored through nasal cannula 
capnography.
6. IV line access: peripheral IV access is required for the study drug infusion.  
DEX must be administered through a peripheral IV line that is not a subclavian 
line, PICC line or other central catheter.  Existing IV catheters being used for 
another purpose (eg, administration of fluids, IV antibiotics etc.) must be used
with the Sponsor provided Y-connector and 3-port connector. Existing IV tubing 
must not be used. Topical or local anesthetics may be used as needed for IV 
placement. 
7.
Laboratory whole-blood qualitative hCG pregnancy test:  a whole-blood 
test may be performed if it can be done at the bedside. Serum qualitative or 
quantitative hCG pregnancy tests are not permitted. The test must be conducted 
on Day 1 and a negative pregnancy result is required before the subject may be 
randomized prior to the MRI scan. Sites are expected to provide their own 
supplies.  Subjects with an indeterminate or positive test result may not 
randomize in the study.
8. Laboratory urine qualitative hCG pregnancy test: dipstick test kits will be 
provided by each individual site and only kits that have a sensitivity of at least 25 
milli-international units per milliliter (mIU/mL) will be approved for use in this 
study. A negative pregnancy result is required before the subject may be 
randomized.  Subjects with an indeterminate or positive test result may not 
randomize in the study.
9. Modified Aldrete Score: a validated observational medical scoring system that 
allows verbal prompts for the measurement of recovery after anesthesia (post 
anesthesia) which includes activity, respiration, circulation, consciousness and 
oxygenation.  The scores of each item are summed to obtain a total score.  
Information on qualification, training and approval to rate this scale will be 
provided separately.  Refer to Appendix 4.
10. PAED (Pediatric Anesthesia Emergence Delirium Scale): A validated 5-item 
rating scale to measure emergence delirium (ED) in children where each item is 


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scored along a range of “not at all” to “extremely”.  The scores of each item are 
summed to obtain a total PAED score where the degree of ED increases directly 
with the total score.  Information on qualification, training and approval to rate 
this scale will be provided separately.  Refer to Appendix 5.
11. PE: includes the following body systems: general appearance, head, ears, eyes, 
nose, mouth, throat, neck, lungs, heart, abdomen, musculoskeletal, extremities, 
skin, lymph nodes, neurological.  The PE will be conducted by a physician,
trained physician’s assistant or nurse practitioner as acceptable according to local 
regulation.  Results must be recorded in the source documents and any 
significant findings documented on the appropriate CRF pages. 
12. Prior treatment recording: prior medications and non-pharmacologic therapies 
will be collected for the 4-week period before randomization and will be 
recorded on the CRF and source documents.
13. PSSS (Pediatric Sedation State Scale): A validated 6-point scale that is a 
measurement of the effectiveness and quality of procedural sedation in children.  
It is specifically designed for evaluating pediatric patients undergoing sedation 
for diagnostic and therapeutic procedures, and measures aspects of procedural 
sedation relating to the quality of sedation provided, including the control of 
pain, anxiety, movement, and adverse side effects.  Information on qualification, 
training and approval to rate this scale will be provided separately.  Refer to
Appendix 6. 
14. Rhythm strip/12-lead ECG/cardiac telemetry monitoring: The 2-minute 
rhythm strip and/or 12-lead ECG at Screening should be obtained and hard 
copies retained after the subject has been calm for at least five (5) minutes and 
should be obtained prior to vital signs collection.  A physician experienced in 
pediatric rhythm interpretation will read and evaluate the tracing for 
abnormalities, which will be documented on the appropriate CRF.  Clinically 
significant abnormalities on the rhythm strip suggestive of AV conduction block 
or sustained cardiac arrhythmia will require that a 12-lead ECG be performed.  A 
12-lead ECG will be required at Screening for subjects with known history of 
cardiac disease.  If a site does not have the capability to obtain a hard copy 
rhythm strip, the 12-lead ECG may be performed in lieu of the rhythm strip. The 
investigator is responsible for reviewing, signing and dating the interpretations.  
Cardiac telemetry monitoring is required beginning just prior to the start of the 
study treatment loading dose and continuing through the post-MRI recovery 
period.  Clinically significant abnormalities noted on cardiac telemetry will be 
documented as adverse events.


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15. Vital signs: includes height (or length as appropriate), weight, temperature, heart 
rate, respiratory rate, SpO2, blood pressure including MAP.  Measurements 
should be obtained with the subject in a supine position as much as possible. 

Height (or Length): in inches or centimeters, recorded to one decimal place. 
The height (or length) should be measured with the subject not wearing shoes.  

Weight: in pounds or kilograms, recorded to one decimal place will be 
obtained using an electronic scale.  The weight should be measured with the
subject not wearing shoes.

Height and weight values will be rounded to 1 decimal place (the nearest 
tenth) for calculations and documentation. To round a number to the nearest 
tenth (ie, 1 decimal place), look at the second number to the right of the 
decimal point (the hundredths place). If that hundredths number is 4 or less, 
remove all numbers to the right of the tenths place. If that hundredths number 
is 5 or greater, add 1 to the number in the tenths place, and then remove all 
the numbers to the right of the tenths place.

Heart rate: whenever possible, the subject should refrain from products 
containing nicotine or caffeine 2 hours before taking heart rate measurements 
and should rest at least 2 minutes before heart rate is measured.  Once the 
loading dose is started, heart rate must be measured using the cardiac monitor.  

Blood pressure (SBP, DBP and includes MAP): whenever possible, the 
subject should refrain from products containing nicotine or caffeine 2 hours 
before taking blood pressure measurements and should rest at least 2 minutes 
before blood pressure readings are taken.  The Screening blood pressure may 
be measured using a manual aneroid or mercury sphygmomanometer or by an 
automated method (such as a Dinamap) with a cuff appropriate to the 
subject’s arm or leg girth as appropriate.  Once the DEX loading dose is 
started, blood pressure must be measured using an MRI compatible automated 
method that will provide BP monitoring throughout the MRI scan.  The site 
will need to retain documentation of machine calibration per the 
manufacturer’s suggested calibration schedule.   

Temperature: using oral, axillary, temporal scan or tympanic method 
measured in degrees Fahrenheit or Centigrade.

Respiratory rate: respirations per minute.

SpO2: saturation of peripheral oxygen to be measured as a percentage using 
pulse oximetry.


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7.1. Pregnancy Testing
For female subjects of childbearing potential, a urine pregnancy test with sensitivity of at 
least 25 mIU/mL, or a whole-blood pregnancy test that can be done at the bedside will be 
performed on Day 1 Period 1 (Pre-Randomization).  Serum qualitative or quantitative hCG 
pregnancy tests are not permitted. 
A negative pregnancy test result is required before the subject may receive the investigational
product.  Pregnancy tests may also be repeated if requested by institutional review boards 
(IRBs)/ethics committees (ECs) or if required by local regulations. 
Urine pregnancy tests must be sensitive to at least 25 mIU/mL and will be conducted with the 
test kit approved by the sponsor in accordance with instructions provided in its package 
insert.  Subjects who show an indeterminate or positive result on the urine test may not 
further progress in the study.   
7.2. Rater Qualifications
For specific rating assessments, only qualified raters will be allowed to evaluate and/or rate 
subjects in this study.  The minimum qualifications a rater must meet for each study rating 
assessment will be outlined in the Rater Assessment Manual provided to each participating 
site.  The level of experience with the target population (or equivalent), specific scale 
experience (or equivalent), and certification required (if applicable) will be listed and used to
determine whether a rater is approved for a given assessment.  Proposed raters who do not 
meet specific criteria but who may be qualified based on unique circumstances may be 
individually reviewed by the study clinical team to determine whether or not a waiver may be 
issued.  The rater must become certified to perform selected study assessments before he or
she can participate in the conduct of the study.  For specifically defined assessments, rater 
training and standardization exercises may be conducted, and written and signed
documentation will be provided by the site for each rater’s certification.  In return, each site 
will be provided written and signed documentation outlining each rater’s certification for 
specific study assessments.  Recertification may be required at periodic intervals during the 
study.  The raters who administer specific study assessments will be documented in a 
centralized location and all site staff who administer ratings will be verified in the site study 
documentation during the conduct of the study.
8. ADVERSE EVENT REPORTING
8.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial Serious Adverse Event (CT SAE) Report Form 
to Pfizer Safety. These requirements are delineated for 3 types of events: (1) SAEs; (2)
non-serious adverse events (AEs); and (3) exposure to the investigational product under 
study during pregnancy or breastfeeding, and occupational exposure.  


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Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the 
investigational product 
under study during 
pregnancy or 
breastfeeding, and
occupational exposure.
All AEs/SAEs associated 
with exposure during 
pregnancy or breastfeeding.  
Occupational exposure is not 
recorded.
All (and EDP supplemental 
form for EDP).
Note: Include all SAEs 
associated with exposure 
during pregnancy or 
breastfeeding.  Include all 
AEs/SAEs associated with 
occupational exposure.
All observed or volunteered events regardless of dose group or suspected causal relationship 
to the investigational product(s) will be reported as described in the following paragraphs.
Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report 
Form within 24 hours of awareness of the event by the investigator are to be reported 
regardless of whether the event is determined by the investigator to be related to an 
investigational product under study.  In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, irrespective of the extent of available
event information.  This time frame also applies to additional new (follow-up) information on 
previously forwarded reports.  In the rare situation that the investigator does not become 
immediately aware of the occurrence of an event, the investigator must report the event 
within 24 hours after learning of it and document the time of his/her first awareness of the 
event.
For each event, the investigator must pursue and obtain adequate information both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(see the Serious Adverse Events section below). In addition, the investigator may be 
requested by Pfizer Safety to obtain specific follow-up information in an expedited fashion.  
This information is more detailed than that recorded on the CRF.  In general, this will include 
a description of the event in sufficient detail to allow for a complete medical assessment of 
the case and independent determination of possible causality.  Any information relevant to 
the event, such as concomitant medications and 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 Pfizer Safety.  Any pertinent additional information must be reported on the CT SAE
Report Form; additional source documents (eg, medical records, CRF, laboratory data) are to 
be sent to Pfizer Safety ONLY upon request.
As part of ongoing safety reviews conducted by the sponsor, any non-serious 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 


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investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.1.1. Additional Details On Recording Adverse Events on the CRF
All events detailed in the table above will be recorded on the AE page(s) of the CRF.  It 
should be noted that the CT SAE Report Form for reporting of SAE information is not the 
same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE Report 
Form for reporting of SAE information.
8.1.2. Eliciting Adverse Event Information
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study subject/parent(s)/legal guardian/legally acceptable representative.  In 
addition, each study subject/parent(s)/legal guardian/legally acceptable representative will be 
questioned about the occurrence of AEs in a non-leading manner.
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the Subject 
Withdrawal / Early Termination section)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes,
according to the definition of AE noted below, and recorded on the CRF.  See Section 6.4.1
for adverse events requiring assessment for subject withdrawal. 
When a subject withdraws from the study because of an SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the 
Requirements section above.
8.1.4. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each subject begins from the time the subject/parent(s)/legal guardian/legally
acceptable representative provides informed consent, which is obtained before the subject’s 
participation in the study (ie, before undergoing any study-related procedure and/or receiving 
investigational product), through and including a minimum of 28 calendar days after the last 
administration of the investigational product.  At the Day 29 Long-term Follow-up visit (final 
telephone contact), the subject/parent(s)/legal guardian/legally acceptable representative will 
be contacted by telephone to inquire about SAEs, including hospitalizations, newly 
diagnosed chronic medical conditions and concomitant treatments since the previous study 
Visit.
For subjects who are screen failures, the active collection period ends when screen failure 
status is determined.


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8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a subject during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a subject after the active collection period has ended are reported to Pfizer 
Safety 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 must be reported to Pfizer Safety.
Follow up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF.
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 Pfizer concurs with that assessment.
8.1.5. 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 on the CRF, 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.  If the investigator's causality assessment is “unknown but not 
related” to investigational product, this should be clearly documented on study records.  
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, and 
report such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions (SUSAR), will be 
carried out in accordance with applicable local regulations.


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8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a study 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 signs and symptoms;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease;

Drug abuse;

Drug dependency.
Additionally, AEs may include signs and symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse;

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
8.2.2. Abnormal Test Findings
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met: 

Test result is associated with accompanying symptoms; and/or


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
Test result requires additional diagnostic testing or medical/surgical intervention;
and/or

Test result leads to a change in study dosing (outside of any protocol-specified 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 
recording as an AE.
8.2.3. Serious Adverse Events
A serious adverse event 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.
Or that is considered to be:

An important medical event.
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 development of drug dependency or drug abuse.
Medical device complaints may meet the SAE reporting requirement criteria (see the Medical 
Device Complaint Reporting Requirements section). An incident is any malfunction (ie, the 
failure of a device to meet its performance specifications or to perform as intended; 
performance specifications include all claims made in the labeling for the device) that, 


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directly or indirectly, might lead to or might have led to the death of a subject, or user, or of
other persons, or to a serious deterioration in their state of health.
A serious injury that can cause a serious deterioration in state of health can include:

A life-threatening illness, even if temporary in nature;

A permanent impairment of a body function or permanent damage to a body 
structure;

A condition necessitating medical or surgical intervention to prevent the above 
2 bulleted items;

Examples: clinically relevant increase in the duration of a surgical procedure; a 
condition that requires hospitalization or significant prolongation of existing 
hospitalization;

Any indirect harm as a consequence of an incorrect diagnostic or in vitro diagnostic 
device test results when used within the manufacturer’s instructions for use;

Fetal distress, fetal death, or any congenital abnormality or birth defects.
8.2.4. 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 is 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).


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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 a 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 
protocol);

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 SAEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an SAE.  For example, an acute 
appendicitis that begins during the reporting period should be reported if the SAE 
requirements are met, and the resulting appendectomy should be recorded as treatment of the 
AE.
8.3. Severity Assessment
If required on the AE page of the CRF, 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.


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8.4. Special Situations
8.4.1. Protocol-Specified Adverse Events
8.4.1.1. Changes in Blood Pressure and Heart Rate
The Investigator will assess changes in supine blood pressure and supine heart rate 
throughout the study. Blood pressure and/or heart rate measurements exceeding the specified 
limits as below will be recorded as adverse events, regardless of whether or not they result in 
discontinuation from the study or necessitate therapeutic medical intervention.  
Vital sign (HR or BP) measurements exceeding the specified limits within the indicated time 
periods below are considered AEs:  

Bradycardia: A decrease in HR of ≥30% from Baseline and/or meets the criteria 
below. HR must be sustained for ≥2 consecutive measurements that are separated by 
at least 1 minute. If available HR values between the scheduled readings meet the 
criteria for bradycardia, the AE should be reported. A decrease in HR that requires 
intervention should also be reported as an AE (or SAE as appropriate) of bradycardia.  
Baseline values are those obtained at Day 1 Period 1 within approximately 5 minutes
before the start of the DEX loading dose.
Study Criteria for AE of Bradycardia*
Age
HR
≥1 month to <3 months
<107 bpm
≥3 months to <6 months
<104 bpm
≥6 months to <9 months
<98 bpm
≥9 months to <12 months 
<93 bpm
≥12 months to <18 months
<88 bpm
≥18 months to <24 months
<82 bpm
≥2 years to <3 years
<76 bpm
≥3 years to <4 years
<70 bpm
≥4 years to <6 years
<65 bpm
≥6 years to <8 years
<59 bpm
≥8 years to <12 years
<52 bpm
≥12 years to <15 years
<47 bpm
≥15 years to <18 years
<43 bpm
*Based on 1st centile data from the HR table in Appendix 7, HR and RR Centile 
Chart Cut-offs for Children from Birth to 18 Years of Age (Fleming et al, Lancet 
2011). 


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
If bradycardia is not responsive to standard treatment (including glycopyrrolate or
atropine), the DEX infusion should be discontinued and the subject treated as
clinically indicated.  This adverse event should be reported as an SAE.  

Hypotension: A decrease in SBP of ≥30% from Baseline should be reported as an
AE of hypotension.  A decrease in SBP of ≥50% from Baseline should be reported as 
a severe AE.  SBP values must be sustained for ≥2 consecutive measurements at least 
5 (±1) minutes apart.  If available SBP values between the scheduled readings meet 
the criteria for hypotension, the AE should be reported. A decrease in SBP that
requires intervention should also be reported as an AE (or SAE as appropriate) of 
hypotension. Baseline values are those obtained at Day 1 Period 1 within 
approximately 5 minutes before the start of the DEX loading dose.

If hypotension is not responsive to standard treatment (including fluid 
resuscitation and vasopressor/inotropic support), the DEX infusion should be 
discontinued and the subject treated as clinically indicated.  This adverse event 
should be reported as an SAE. 

Hypertension: The criteria for the definition of an adverse event of hypertension 
were based on the National High Blood Pressure Education Program Working Group 
on High Blood Pressure in Children and Adolescents,28 the Pediatric Vital Signs 
Reference Chart (pediatric advanced life support [PALS] normal blood pressure by 
age guidelines)29 and the advice of clinical expert consultants. 

For subjects ages ≥1 month to <1 year: Hypertension is defined as supine SBP 
≥104 mm Hg and/or DBP ≥56 mm Hg measurements on ≥2 consecutive 
occasions taken at least 5 (±1) minutes apart and/or requires intervention.  This 
event should be reported as an AE.

For subjects ages ≥1 year to <17 years: Hypertension is defined as supine SBP 
and/or DBP measurements that are ≥95th percentile for gender, age, and height 
(stature) on ≥2 consecutive occasions taken at least 5 (±1) minutes apart and/or 
requires intervention.  The tables for hypertension assessment for this age group 
will be provided separately.  This event should be reported as an AE.  

If hypertension is not responsive to standard treatment, the DEX infusion will be 
discontinued and the subject treated as clinically indicated.  This adverse event 
should be reported as an SAE.


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8.4.1.2. Paradoxical Agitation Reactions 
Throughout the Study Drug Infusion Period and extending into the 24-hour post-infusion 
observation period, the Investigator should monitor for the onset of paradoxical agitation 
reactions (eg, rage).  The clinical features may vary with age of the subject, but the following 
should be used as a guide:

Age ≥1 month to <8 years: Inconsolable crying and/or irritability that are otherwise 
unexplained by the subjects’ current medical condition and are unable to be 
controlled with conventional interventions.

Age ≥8 years to ≤17 years: Aggressive behavior and/or excessive emotional outbursts
that are otherwise unexplained by the subjects’ current medical condition and are 
unable to be controlled with conventional interventions.  An example of this may 
include a subject that becomes physically violent that may expose healthcare 
personnel or themselves to harm.  
In the event a paradoxical agitation reaction occurs during the study drug infusion period, the 
study drug will be discontinued and the subject treated as clinically indicated.  The event 
should be reported as an AE and an SAE.
8.4.1.3. Changes in Respiratory Rate, EtCO2 and SpO2
The Investigator will assess changes in respiratory rate, changes in measurement of carbon 
dioxide (CO2) concentration and oxygen saturation throughout the study.  Respiratory rates, 
EtCO2 and/or SpO2 measurements below the thresholds outlined in the tables below will be 
recorded as adverse events, regardless of whether or not they result in discontinuation from 
the study or necessitate therapeutic medical intervention.
Thresholds for Respiratory Rate Adverse Events
Age
Respiratory Rate*
(breaths per minute)
Adverse Event Term**
≥1 month to <3 months
<25
Bradypnea
≥3 months to <6 months
<24
≥6 months to <9 months
<23
≥9 months to <12 
months
<22
≥12 months to <18 
months
<21
≥18 months to <24 
months
<19
≥2 years to <3 years
<18
≥3 years to <4 years
<17
≥4 years to <6 years
<17
≥6 years to <8 years
<16
≥8 years to <12 years
<14


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Age
Respiratory Rate*
(breaths per minute)
Adverse Event Term**
≥12 years to <15 years
<12
≥15 years to <17 years
<11
*Rate must be sustained for at least 2 consecutive measurements that are separated by at least one minute 
and/or requires intervention in order to meet the criteria for AE.  If available RR values between the 
scheduled readings meet the criteria for bradypnea, the AE should be reported. Based on the 1st centile 
data from the RR table in Appendix 7, HR and RR Centile Chart Cut-offs for Children from Birth to 18 
Years of Age (Fleming et al, Lancet 2011).
**This term should be used unless the decreased respiratory rate is part of a larger constellation of signs 
and symptoms documented as another adverse event.
Thresholds for EtO2 and SpO2 Change Adverse Events
Value
Adverse Event Term*
SpO2
<90% for any duration
Hypoxia
Capnography
EtCO2 = 0 for ≥30 seconds
Apnea
*These terms should be used unless the EtCO2 and/or SpO2 finding(s) are part of a larger constellation of 
signs and symptoms documented as another adverse event.  In determining whether an apnea or 
hypoxia AE has occurred the clinician should verify the nasal capnograph or SpO2 monitor is in the 
right location and functioning properly.
Respiratory rate, SpO2 and/or EtCO2 measurements that do not meet or exceed these values 
will also be recorded as adverse events if they necessitate therapeutic medical intervention or 
the Investigator considers them to be adverse events.  The date and time of occurrence and 
any treatment or intervention for all adverse events are to be recorded on the appropriate 
eCRF.  Examples of interventions that should be recorded to bradypnea/hypoxia/apnea are 
airway repositioning, bag-mask intervention, deepening of sedation, fluid bolus, jaw thrust, 
CPAP, initiation of or increased oxygen, intubation, etc.
For a decrease in respiratory rate in a subject unresponsive to commands, the Investigator 
will determine if study drug should be discontinued and will treat the subject as clinically 
indicated.  All interventions will be recorded in the appropriate section of the eCRF.
8.4.2. Protocol-Specified Serious Adverse Events
There are no protocol-specified SAEs in this study.  All SAEs will be reported to Pfizer 
Safety by the investigator as described in previous sections, and will be handled as SAEs in 
the safety database. 
8.4.3. Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some subjects, transaminase elevations are a harbinger of a more 
serious potential outcome.  These subjects fail to adapt and therefore are "susceptible" to 


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progressive and serious liver injury, commonly referred to as drug-induced liver injury 
(DILI).  Subjects who experience a transaminase elevation above 3 times the upper limit of 
normal (× ULN) should be monitored more frequently to determine if they are an “adaptor” 
or are “susceptible.”
Liver function tests (LFTs) are not required as a routine safety monitoring procedure in this 
study.  However, should an investigator deem it necessary to assess LFTs because a subject 
presents with clinical signs/symptoms, such LFT results should be managed and followed as 
described below.
In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (TBili) elevations (>2 × ULN) by several 
days or weeks.  The increase in TBili typically occurs while AST/ALT is/are still elevated 
above 3 × ULN (ie, AST/ALT and TBili values will be elevated within the same lab sample).  
In rare instances, by the time TBili elevations are detected, AST/ALT values might have 
decreased.  This occurrence is still regarded as a potential DILI.  Therefore, abnormal 
elevations in either AST OR ALT in addition to TBili that meet the criteria outlined below 
are considered potential DILI (assessed per Hy’s law criteria) cases and should always be 
considered important medical events, even before all other possible causes of liver injury 
have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the subject’s 
individual baseline values and underlying conditions.  Subjects who present with the 
following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values:

Subjects with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available;

For subjects with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

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).

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches >3 × ULN 
(whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor.  


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The subject should return to the investigator 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 and TBili, laboratory tests should 
include albumin, creatine kinase (CK), direct and indirect bilirubin, gamma-glutamyl 
transferase (GGT), prothrombin time (PT)/international normalized ratio (INR), total bile 
acids, alkaline phosphatase and acetaminophen drug and/or protein adduct levels.  
Consideration should also be given to drawing a separate tube of clotted blood and an 
anticoagulated tube of blood for further testing, as needed, for further contemporaneous 
analyses at the time of the recognized initial abnormalities to determine etiology.  A detailed 
history, including relevant information, such as review of ethanol, acetaminophen (either by 
itself or as a coformulated product in prescription or over-the-counter medications), 
recreational drug, supplement (herbal) use and consumption, family history, sexual history, 
travel history, history of contact with a jaundiced person, surgery, blood transfusion, history 
of liver or allergic disease, and potential occupational exposure to chemicals, should be 
collected.  Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging 
(eg, biliary tract) may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found.  Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.  
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
8.4.4. Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.4.4.1. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:

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 
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
An example of environmental exposure would be a case involving direct contact 
with a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant 
and has been exposed to chemotherapeutic products).

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 subject or subject’s partner becomes or is found to be pregnant during the subject’s 
treatment with the investigational product, the investigator must report this information to 
Pfizer Safety on the CT 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 Pfizer 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) to Pfizer Safety 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 Pfizer Safety 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.
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 

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 sponsor.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on


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preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the 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.
8.4.4.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in
accord with authorized use.  However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding.
8.4.4.3. 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 Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a subject enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.4.5. Medication Errors 
Other exposures to the investigational product under study may occur in clinical trial settings, 
such as medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
Medication errors
All (regardless of whether 
associated with an AE)
Only if associated with an 
SAE
8.4.5.1. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong subject, or at the wrong time, or at the wrong dosage strength.   
Medication errors include:

Medication errors involving subject exposure to the investigational product;


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
Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.5. Medical Device Complaint Reporting Requirements
This section applies only to sites in Japan using propofol pre-filled syringes.  Please refer to 
Appendix 9, Propofol Pre-filled Syringe Medical Device Reporting in Japan for details.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study
is outlined here and further detailed in a statistical analysis plan (SAP), which will be 
maintained by the sponsor.  The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the primary endpoint definitions or their 
analyses will also be reflected in a protocol amendment.
9.1. Sample Size Determination
The primary comparison will be the percent of subjects who do not require supplemental 
PRO in the high dose group vs. the low dose group in both age cohorts combined.  The 
younger age cohort will be comprised of subjects aged ≥1 month to <2 years of age and the 
older age cohort will include subjects ≥2 to <17 years of age.  The primary efficacy analysis 
population is the Full Analysis Set (FAS) defined as all randomized subjects who receive any 
amount of DEX, and for the primary and key secondary analyses, subjects who do not 
complete the MRI scan will be considered failures, ie, will be counted as receiving 
supplemental PRO.  Assuming that the percent of subjects not requiring PRO are 15% and 
60% in the low and high dose groups respectively, a sample size of 40 per dose group would 
provide a 99% power for a 2-sided test with alpha=0.05.  The key secondary comparison is 
the percent of subjects who do not require supplemental PRO in each of the 2 age cohorts.  
Assuming that the percentage of subjects not requiring supplemental PRO in the older age 
cohort is 17% and 63% for the low and high dose groups respectively, and the percent of 
subjects not requiring PRO in the younger age cohort is 13% and 57% for the low and high 
dose groups respectively, and assuming that equal number of subjects will be enrolled in 
each age cohort, the power = 87% for the older age cohort and 86% for the younger age 
cohort. Within the older age cohort, it is planned to enroll approximately 4 subjects per dose 


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group for subjects ≥12 to <17 years of age, since it is expected that these subjects would 
require minimum sedation.  Forty subjects will be enrolled per each dose level, and 20 
subjects for each dose group for age cohorts ≥1 month to <2 years and ≥2 years to <17 years.  
The table below shows the planned enrollment in this study.
Sample Size 
Age Group for Enrollment
Low Dose
Medium Dose
High Dose
≥1 month to <2 year
20
20
20
≥2 years to <12 years
16
16
16
≥12 years to <17 years
4
4
4
These assumptions were obtained from study DEX 10-16 and Mason et al publication in 
Pediatric Anesthesia 2008.  In DEX 10-16 approximately 30% of subjects who had MRIs did
not require rescue medication; the dose in study 10-16 is comparable to the middle dose in 
this study.  In the Mason et al publication, approximately 80-90% of patients treated with 2-3
mcg/kg loading dose of DEX for MRI scans did not require supplemental anesthesia, 
therefore a conservative estimate of 65% was assumed.  Additionally, in the DEX 
10-16 study, 6% of subjects did not complete the MRI scan, so a failure rate of 
approximately 5% was incorporated into the assumptions of patients requiring supplemental 
PRO.
9.2. Analysis Populations
9.2.1. Safety Analysis Set
The safety analysis set consists of all randomized subjects who received any amount of DEX.  
Participants will be analyzed according to the intervention they received.  In the event a 
subject receives a loading and/or maintenance dose that is different from the dose group to 
which they were randomized, the subject will be analyzed in the dose level group that 
corresponds to the lowest dose received.  All safety analyses will be performed on the safety 
analysis set.
9.2.2. Full Analysis Set (FAS)
All randomized subjects who receive any amount of DEX will form the FAS.  Participants 
will be analyzed according to the intervention to which they were randomized.  This will be 
the primary population for efficacy analysis.
9.2.3. Efficacy Evaluable Population (EEP)
All randomized subjects who receive any amount of DEX and complete the MRI scan will 
form the EEP.  


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9.2.4. Per Protocol Population (PPP)
All subjects included in the FAS and have no major protocol deviations will form the PPP.  
The details of the major protocol violation criteria will be documented in a separate 
document prior to the end of the study.
9.2.5. Japanese Population Set (JPS)
All randomized Japanese subjects who receive any amount of DEX will form the JPS.
The JPS will be used for efficacy endpoints, demographic and baseline characteristic and 
safety endpoints.  Participants will be analyzed according to the intervention to which they 
are randomized for efficacy and will be analyzed according to the intervention they receive 
for safety.
9.3. Efficacy Analysis
A randomized subject who received any amount of DEX but does not complete the MRI scan 
will be considered a treatment failure for the primary and key secondary endpoint analyses; 
ie, they will be counted as receiving PRO.
9.3.1. Analysis of the Primary Endpoint
The DEX high vs low dose group will be compared by Mantel-Haenszel test, and by 
calculating the odds ratio and 95% confidence intervals on the percent of subjects not 
requiring supplemental PRO.  All age cohorts will be combined.  The primary analysis will 
be performed based on the FAS.  The same analysis will be repeated on the EEP and PPP. 
9.3.2. Analysis of the Key Secondary Endpoint
The method of analysis for the primary endpoint will be repeated for the key secondary 
endpoint for each age cohort based on the FAS. The same analysis will be repeated on the 
EEP and PPP.
9.3.3. Analysis of Other Secondary Endpoints
The method of analysis for the primary endpoint will be repeated for the secondary endpoints 
comparing the low dose to the medium dose and the medium dose to the high dose, overall 
and within each age cohort based on the FAS, EEP and PPP. 
The total amount and the weight and time adjusted amount (per kg per minute) of PRO use 
will be summarized for each dose group with descriptive statistics (N, mean, standard 
deviation [SD], median, minimum, Q1, Q3, and maximum).  The weight- and time-adjusted 
difference between treatment groups (high dose and low dose, and medium dose and low 
dose and high dose versus medium dose) will be assessed using two-way analysis of variance 
(ANOVA) when assumption of normal distribution is reasonable or by nonparametric tests 
when this assumption is not met.  
Emergence time (defined as the time from the end of the MRI scan to when the subject meets 
a Modified Aldrete Score ≥9) will be summarized and compared between dose groups using


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Kaplan Meier methodology. Subjects who are withdrawn or discharged from the recovery 
area without reaching an Aldrete score ≥9, will be considered as having censored time
computed from the end of the MRI scan to the time of the last vital signs assessment.  Zero 
minute will be used as the censored time if no vital signs are taken during the post-MRI
recovery period.
Additionally, the difference between dose levels in percent of time at the target sedation 
rating scale score (PSSS rating of 2) following the administration of the DEX loading dose 
and during the DEX maintenance infusion will be assessed using the Wilcoxon test.  
Time (in minutes) from the onset of the DEX infusion to the first dose of PRO will be 
summarized using the Kaplan-Meier method.  Subjects that do not receive any additional 
PRO will be considered as having a censored time.  The censored time to the first dose of 
PRO for additional sedation will be computed as the length of time from the onset of the 
DEX infusion up to the time the DEX infusion is stopped.
Efficacy analyses will be conducted for all age cohorts combined and by each age cohort.
  
 
9.5. Safety Analysis
All safety analyses will be performed on the safety analysis set.
Descriptive statistics (quantitative variables: arithmetic mean, SD, median, minimum, and 
maximum, categorical and ordinal variables: proportion of subjects) will be calculated for 
quantitative safety data as well as for the change from baseline, when appropriate.  Data 
analyses will be presented by dose level, overall and within each age cohort.  Baseline values 
are those obtained at Day 1 Period 1 within approximately 5 minutes before the start of the 
DEX loading dose.
TEAEs will be analyzed by dose level, overall, and for each age cohort according to the 
Medical Dictionary for Regulatory Activities system organ class and preferred term.  
Additionally, the proportion of subjects with protocol-specified adverse events of bradypnea, 
hypoxia, apnea, hypotension, hypertension, bradycardia and paradoxical agitation reaction 
and the proportion of subjects with such events requiring intervention will be summarized for 
each age cohort and each dose level.  Pre-specified criteria will be used to identify the 
protocol-defined adverse events mentioned above.  
CCI


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The proportion of subjects who completed the MRI scan and required artificial ventilation or 
intervention to restore baseline or normal hemodynamic status will also be summarized.  The 
incidence of individual adverse events during MRI sedation will be descriptively summarized 
for each dose level, including the total adverse events.
The types of individual interventions and the total number of interventions will be 
descriptively summarized at each dose level and for each age cohort (ie, airway 
repositioning, bag-mask intervention, deepening of sedation, fluid bolus, jaw thrust, CPAP, 
initiation of or increased oxygen, intubation, etc). 
Vital sign measurements and hemodynamic and respiratory parameters will be summarized 
descriptively by dose level and age cohort.
Prior and concomitant medications will be summarized according to WHODRUG
Dictionary.  The number and percentage of subjects who used prior medications (by 
preferred term) will be tabulated by dose level and age cohort.  The number and percentage 
of subjects who used concomitant medications will be similarly tabulated. 
DEX withdrawal symptoms, such as agitation/anxiety, rebound tachycardia and rebound 
hypertension will be summarized by each dose level and age cohort.  A descriptive summary 
will be performed for the incidence of DEX withdrawal-related AEs after discontinuation of
the DEX infusion.
Descriptive analyses will be performed for the PAED total score for dose level and by age 
cohort.
9.6. Interim Analysis 
No formal interim analysis will be conducted for this study.
9.7. Data Monitoring Committee 
This study will use an external data monitoring committee (E-DMC). 
The E-DMC will be responsible for ongoing monitoring of the safety of subjects in the study 
according to the charter.  
The E-DMC will be comprised of a group of experts external to Pfizer who will review 
accumulated safety data from this study on an ongoing basis.  The E-DMC may at any time, 
request additional information from the Sponsor including any information they feel is 
relevant.  Based on these reviews, the E-DMC will have the capacity to make 
recommendations to Pfizer that might impact the future conduct of the trial.  These may 
include amending safety-monitoring procedures, modifying the protocol or consent/assent, 
terminating the study, or continuing the study as designed.
The recommendations made by the E-DMC to alter the conduct of the study will be 
forwarded to Pfizer for final decision.  Pfizer will forward such decisions, which may include 


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summaries of aggregate analyses of endpoint events and of safety data that are not endpoints, 
to regulatory authorities, as appropriate.  
The Pfizer study team and site personnel involved in the conduct of the study will remain 
blinded to any unblinded study data communicated to the E-DMC.  
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer 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 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
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 investigator site may be subject to 
review by the IRB/EC, and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study.  Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the investigator site for the inspection and will allow Pfizer or its 
agent, whenever feasible, to be present during the inspection.  The investigator site and 
investigator will promptly resolve any discrepancies that are identified between the study 
data and the subject's medical records.  The investigator will promptly provide copies of the 
inspection findings to Pfizer or its agent.  Before response submission to the regulatory 
authorities, the investigator will provide Pfizer 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 Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.  The investigator shall ensure that the 
CRFs are securely stored at the study site in encrypted electronic form and will be password 
protected to prevent access by unauthorized third parties.


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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 or the physician subject chart.  In these 
cases, data collected on the CRFs must match the data in those charts. 
In some cases, the CRF may also serve as the source document.  In these cases, a document 
should be available at the investigator site and at Pfizer that clearly identifies those data that 
will be recorded on the CRF, and for which the CRF will stand as the source document.
11.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, 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/assent documents, 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.  
The investigator must ensure that the records continue to be stored securely for so long as 
they are retained.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or an independent third party arranged by Pfizer.  
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 Pfizer'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/assent documents, and other relevant documents, eg, 
recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 


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IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
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 Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, legal and regulatory 
requirements and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organizations of 
Medical Sciences 2002), ICH Guideline for Good Clinical Practice, and the Declaration of 
Helsinki.
12.3. Subject Information and Consent
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of subject personal data.  Such 
measures will include omitting subject names or other directly identifiable data in any 
reports, publications, or other disclosures, except where required by applicable laws. 
The personal data will be stored at the study site in encrypted electronic and/or paper form 
and will be password protected or secured in a locked room to ensure that only authorized 
study staff have access.  The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster.  In the event of a potential personal data breach, the study site shall be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, when study data are compiled for transfer to Pfizer and other authorized 
parties, subject names will be removed and will be replaced by a single specific numerical 
code based on a numbering system defined by Pfizer.  All other identifiable data transferred 
to Pfizer or other authorized parties will be identified by this single, subject-specific code.
The investigator 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, Pfizer will maintain high standards of confidentiality and protection of subjects’ 
personal data consistent with the Clinical Study Agreement and applicable privacy laws.
The informed consent/assent documents and any subject recruitment materials must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements, including 
applicable privacy laws.


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The informed consent/assent documents used during the informed consent process and any 
subject recruitment materials must be reviewed and approved by Pfizer, 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, the sharing of data relating to the study and possible risks
associated with participation, including the risks associated with the processing of the 
subject’s personal data. The investigator further 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 his or her right to access and correct his or her personal data and to withdraw 
consent for the processing of his or her personal data.  
Whenever consent is obtained from a subject’s legally acceptable representative/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, decisionally 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 reconsent 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 
permission of a parent or legal guardian.  
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject or the subject's legally acceptable representative, parent(s) or legal 
guardian and the subject’s assent, when applicable, before any study-specific activity is 
performed, unless a waiver of informed consent has been granted by an IRB/EC.  The 
investigator will retain the original of each subject's signed consent/assent document.
Precedex is commercially available, however it is not approved for use in pediatrics.
12.4. 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 
regulatory 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, Pfizer should be informed immediately.  


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In addition, the investigator will inform Pfizer 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
End of trial in all participating countries is defined as last subject last visit (LSLV).
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 Pfizer.  In addition, Pfizer retains the right to discontinue development of
investigational product at any time.
If a study is prematurely terminated, Pfizer will promptly notify the investigator.  After 
notification, the investigator must contact all participating subjects and the hospital pharmacy 
(if applicable) within 7 days.  As directed by Pfizer, all study materials must be collected and 
all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer 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.pfizer.com, and other public registries in accordance with
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer 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
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
Pfizer 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 (PCD) 
for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.
PCD 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.


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EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.
www.pfizer.com
Pfizer 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 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by the 
PI of the results of the study based on information collected or generated by the PI, whether 
or not the results are favorable to the Pfizer product.  However, to ensure against inadvertent 
disclosure of confidential information or unprotected inventions, the investigator will provide 
Pfizer 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 Pfizer at least 30 days before it is 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.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer 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 investigator sites, and that any subsequent publications 
by the PI 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.


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Publication of study results is also provided for in the CSA between Pfizer 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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16. REFERENCES
1.
Petroz GC, Sikich N, James M, van Dyk H, Shafer SL, et al. A phase I, two-center 
study of the pharmacokinetics and pharmacodynamics of dexmedetomidine in children. 
Anesthesiology. 12 2006; 105:1098–1110.
2.
Potts AL, Anderson BJ, Holford NH, Vu TC, Warman GR. Dexmedetomidine 
hemodynamics in children after cardiac surgery. Pediatr Anesth. 2010; 20:425–33.
3.
Mason KP, Lerman J. Dexmedetomidine in Children: Current Knowledge and Future 
Applications. Anesth & Analg. 2011 Nov; 113:1129-1142.
4.
Mason KP, Zurakowski D, Zgleszewski S, Prescilla R, Fontaine PJ, Dinardo JA. 
Incidence and predictors of hypertension during high-dose dexmedetomidine sedation 
for pediatric MRI. Pediatr Anesth. 2010; 20:516–523.
5.
Venn RM, Hell J, Grounds RM. Respiratory effects of dexmedetomidine in the surgical 
patient requiring intensive care. Critical Care. 2000 Jul; 4:302-308.
6.
Sandler AN. The role of clonidine and alpha2-agonists for postoperative analgesia. Can 
J Anaesth. 1996 Dec; 43(12):1191-1194.
7.
Kamibayashi T, Maze M. Clinical uses of alpha2-adrenergic agonists. Anesthesiology.
2000 Nov; 93(5):1345-1349.
8.
Ebert TJ, Hall JE, Barney JA, et al. The effects of increasing plasma concentrations of 
dexmedetomidine in humans. Anesthesiology. 2000 Aug; 93(2):382-394.
9.
Jooste EH, Hammer GB, Reyes CR, Katkade V, Szmuk P. Phase IV, Open-Label, 
Safety Study Evaluating the Use of Dexmedetomidine in Pediatric Patients Undergoing 
Procedure-Type Sedation. Front Pharmacol. 2017; 8:529.
10.
Sulton C, McCracken C, Simon HK, et al. Pediatric Procedural Sedation Using 
Dexmedetomidine: A Report from the Pediatric Sedation Research Consortium. 
Hospital Pediatrics. 2016; 6(9):536-44.
11.
Siddappa R, Riggins J, Kariyanna S, et al. High-dose dexmedetomidine sedation for 
pediatric MRI. Pediatr Anesth. 2011; 21(2):153-158.
12.
Schulte-Uentrop L, Goepfert MS. Anaesthesia or sedation for MRI in children. Current 
Opinion in Anaesthesiology. 2010; 23(4):513-517.
13.
Vilo S, Rautianinen P, Kaisti K et al. Pharmacokinetics of intravenous 
dexmedetomidine in children under 11 yr of age. Br J Anaesth. 2008; 100(5):697-700.
14.
Farag E, Argalious M, Abd-Elsayed A, et al. The use of dexmedetomidine in anesthesia 
and intensive care: a review. Current Pharmaceutical Design. 2012;18(38):6257-65.


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15.
Mason KP, Zurakowski D, Zgleszewski SE, et al. High dose dexmedetomidine as the 
sole sedative for pediatric MRI. Pediatr Anesth. 2008; 18(5):403-411.
16.
Pestieau SR, Quezado ZMN, Johnson YJ, et al. High-dose dexmedetomidine increases 
the opioid-free interval and decreases opioid requirement after tonsillectomy in 
children. Can J Anesth. 2011; 58(6):540-550.
17.
Tirotta CF, Nguyen T, Fishberger S, et al. Dexmedetomidine use in patients undergoing 
electrophysiological study for supraventricular tachyarrhythmias. Pediatr Anesth. 2017; 
27(1):45-51.
18.
Degos V, Le charpentier T, Chhor V, et al. Neuroprotective effects of dexmedetomidine 
against glutamate agonist-induced neuronal cell death are related to increased astrocyte 
brain-derived neurotrophic factor expression. Anesthesiology. 2013; 118(5):1123-1132.
19.
Janke EL, Samra S. Dexmedetomidine and neuroprotection. Seminars in Anesthesia, 
Perioperative Medicine and Pain. 2006; 25(2):71-76.
20.
Berkenbosch JW, Wankum PC, Tobias JD. Prospective evaluation of dexmedetomidine 
for noninvasive procedural sedation in children. Pediatr Crit Care Med. 2005; 6(4):435-
439.
21.
Välitalo, PA, Ahtola-Sätilä T, Wighton A, et al. Population pharmacokinetics of 
dexmedetomidine in critically ill patients. Clin Drug Investig. 2013; 33(8):579-587.
22.
Potts, AL, Anderson BJ, Warman GR, et al. Dexmedetomidine pharmacokinetics in
pediatric intensive care - a pooled analysis. Pediatr Anesth. 2009; 19(11):1119-1129.
23.
Koroglu A, Teksan H, Sagr O, et al. A comparison of the sedative, hemodynamic, and 
respiratory effects of dexmedetomidine and propofol in children undergoing magnetic 
resonance imaging. Anesth & Analg. 2006; 103(1): 63-67.
24.
Boriosi JP, Eickhoff JC, Klein KB, Hollman GA. A retrospective comparison of 
propofol alone to propofol in combination with dexmedetomidine for pediatric 3T MRI 
sedation. Pediatr Anesth. 2017; 27(1):52-59.
25.
Precedex™ [Package Insert]. Hospira Inc., Lake Forest, IL; May 2016.
26.
Constantin JM, Momon A, Mantz J, Payen JF, De Jonghe B, Perbet S, et al. Efficacy 
and safety of sedation with dexmedetomidine in critical care patients: a meta-analysis of 
randomized controlled trials.  Anaesth Crit Care & Pain Med. 2016; 35(1):7–15.
27.
Cravero JP, Askins N, Sriswasdi P, et al. Validation of the Pediatric Sedation State 
Scale. Pediatrics. 2017; 139(5): e20162897.


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28.
National High Blood Pressure Education Program Working Group on High Blood 
Pressure in Children and Adolescents.  The Fourth Report on the Diagnosis, Evaluation, 
and Treatment of High Blood Pressure in Children and Adolescents.  Pediatrics. 2004; 
114: 555-578.
29.
Pediatric Vital Signs Reference Chart. http://www.pedscases.com/pediatric-vital-signs-
reference-chart; April 2016.


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Appendix 1. Abbreviations 
This following is a list of abbreviations that may be used in the protocol.  
Abbreviation
Term
AE
adverse event
ALT
alanine aminotransferase
ANOVA
analysis of variance
ASA
American Society of Anesthesiologists
AST
aspartate aminotransferase
AV
atrioventricular
BP
blood pressure
BPM
beats per minute
CHOP
Children’s Hospital of Philadelphia
CK
creatine kinase
CNS
Central nervous system
CO2
carbon dioxide
COVID-19
coronavirus disease 2019
CPAP
continuous positive airway pressure
CRF
case report form
CRL
complete response letter
CSA
clinical study agreement
CT
computed tomography
CT SAE
clinical trial serious adverse event
DBP
diastolic blood pressure
DEX
dexmedetomidine
DILI
drug-induced liver injury
DM
diabetes mellitus
DMC
data monitoring committee
DU
dispensable unit(s)
EC
ethics committee
ECG
electrocardiogram
ED
emergence delirium
E-DMC
external data monitoring committee 
EDP
exposure during pregnancy
EEG
electroencephalogram
EEP
Efficacy evaluable population
ET
End tidal
EtCO2
end-tidal carbon dioxide
EU
European Union
EudraCT
European Clinical Trials Database
FAS
Full analysis set
FI
Fractional Inspiratory
FIO2
Fractional Inspiratory Oxygen


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Abbreviation
Term
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
hCG
Human chorionic gonadotropin
HR
heart rate
HTN
hypertension
ICH
International Conference on Harmonisation
IB
Investigator brochure
ICU
intensive care unit
ID
identification
IEC
Independent Ethics Committee
IM
intramuscular
IND
investigational new drug application
INR
international normalized ratio
IP
investigational product
IRB
Institutional Review Board
IRT
interactive response technology
IUD
intrauterine device
IV
intravenous
IWR
interactive web response
J-PI
Japan Package Insert
JPS
Japan population set
KG
kilogram
LFT
liver function test
LMA
laryngeal mask airway
LSLV
last subject last visit 
MAP
mean arterial pressure
MCG
microgram
mIU/mL
milli international units per milliliter
mL
milliliter
MM HG
millimeters of mercury
MRI
magnetic resonance imaging
N/A
not applicable
NI-MDS
non-intubated, spontaneous breathing, moderate to deep sedation
N-PASS
Neonatal Pain, Agitation and Sedation Scale
O2
oxygen
PACU
post-anesthesia care unit
PAED
Pediatric Anesthesia Emergence Delirium Scale
PCD
primary completion date
PD
Pharmacodynamics(s)
PE
physical examination
PI
principal investigator
PICC
peripherally inserted (or percutaneous indwelling) central catheter


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Abbreviation
Term
PICU
pediatric intensive care unit
PK
pharmacokinetic
PO
per orum (oral)
PPP
Per protocol population
PPS
pediatric procedural sedation
PT
prothrombin time
PREA
Pediatric Research Equity Act
PRO
propofol
PSSS
Pediatric Sedation State Scale
PWR
Pediatric Written Request
RR
respiratory rate
SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
SD
standard deviation
SOP
standard operating procedure
SpO2
saturation of peripheral oxygen
SRSD
single reference safety document
SubI
sub-investigator
SUSAR
suspected unexpected serious adverse reaction
TBili
total bilirubin
TEAE
treatment-emergent adverse event
TTE
transthoracic echocardiogram
UGT
Uridine 5'-diphospho-glucuronosyltransferase
ULN
upper limit of normal
UMSS
University of Michigan Sedation Scale
US
United States
U/S
ultrasound
USPI
United States Package Insert
Vd
volume of distribution
Vdss
Steady-state volume of distribution


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Appendix 2. Simulated Pharmacokinetic Profiles of Dexmedetomidine in Pediatric 
Subjects Undergoing Procedural Sedation
Background
The pharmacokinetics (PK) of dexmedetomidine (DEX) has been well characterized in adult 
intensive care unit (ICU) patients.  In adults, following intravenous (IV) administration, DEX 
exhibits a rapid distribution phase with a distribution half-life (t½) of approximately 
6 minutes; a terminal elimination t½ of approximately 2 hours; a steady-state volume of 
distribution (Vdss) of approximately 118 L, and an estimated clearance of approximately 
39 L/hour.  DEX exhibits linear PK in adults in the dosage range of 0.2 to 0.7 µg/kg/hour
when administered by IV infusion for up to 24 hours. DEX undergoes extensive hepatic 
metabolism to inactive metabolites, with 85% undergoing glucuronidation by 
UDP-glucuronyltransferase (UGT) and 15% by cytochrome P450 2A6.
The PK of DEX has also been characterized in 5 clinical studies in pediatric population 
mainly in ICU patients.  Linear PK was observed in these studies within the dosage ranges
(0.2 to 2 µg/kg/hour) evaluated.  A population PK (Pop PK) model has been developed to 
characterize the PK and disposition of DEX in pediatric ICU patients.  In this model, a total 
of 1372 plasma DEX concentration records from 131 pediatric ICU patients of age range 
0.01 to 17 years enrolled in 4 studies (Study DEX-09-08, CHOP study, Study DEX-08-01, 
and Study DEX-11-01) were used for the analyses. The final population PK model was a 
2-compartment model with inter individual variability estimated on clearance (CL), 
inter-compartmental clearance (Q), volume of the central compartment (Vc), and volume of
the peripheral compartment (Vp) using exponential error models, fixed allometric exponents 
on the clearance (0.75 for CL and Q) and volume of distribution (1.0 for Vc and Vp) 
parameters.  
Limited information is available about the PK of DEX in pediatric procedural sedation (PPS) 
patients.  However, based on the known clearance pathways of DEX, the disposition of DEX 
in PPS patients is assumed to be similar to that in pediatric ICU patients, which seems to be 
supported by the reported PK parameters of DEX by Vilo et al (2008)13 in PPS patients 
compared to the PK parameters (CL and Vdss) obtained from pediatric ICU population PK 
model, as shown in Table 1 below.  As such, the PK profiles of DEX in PPS patients at the 
proposed doses in this study are simulated by using the pediatric ICU population PK model 
(Cognigen Corporation.  Population Pharmacokinetic Evaluation of Dexmedetomidine 
Infusion in Mechanically Ventilated Pediatric Subjects. June 6, 2012, Report on file).  These 
simulation results are provided for information purposes only.


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Table 1.
Reported DEX PK Parameters in Pediatric ICU Patients and Pediatric 
Procedural Sedation Patients
Pediatric Patients
Median Age (years)
CL (L/h/kg)
Vdss (L/kg)
ICU*
1.31
1.11
2.42
Procedural Sedation13
0.6
1.04
3.8
4.2
1.04
2.2
Source: *Cognigen Pop-PK model 
Abbreviations: CL = Clearance; DEX = Precedex; ICU = Intensive Care Unit; Vdss = Volume of 
Distribution at Steady State
Methods
Assumptions

Similar PK profiles of DEX between PICU patients and PPS patients.

Linear PK of DEX in the dose range from 0.5 to 2.0 µg/kg when administered via 
IV infusion.
Software
The PopPK simulations were conducted using the software packages NONMEM, version 7.2
(ICON Development Solutions, Hanover, MD).  A statistical software package R version 
3.2.2 (R Development Core Team) and R studio (RStudio, Inc.) was used for generation of 
simulation input datasets, statistical analysis and creation of simulation output graphs for this 
protocol.  Non-compartmental analysis to estimate the PK parameters were conducted using 
Phoenix WinNonlin, version 6.4 (Certara USA, Inc., Princeton, NJ).  
Input Datasets
Individual PK parameter and demographic information (age, body weight and sex) from the 
pediatric ICU population PK model were used as input parameters for the simulations.  There 
were total 124 pediatric subjects in the final ICU population PK model.  Out of those 
124 subjects, 28 subjects were less than 1 month old and were thus excluded from simulation 
input file.  Age and body weight distribution for the remaining 96 subjects based on age 
category proposed in protocol C0801039 are provided in Table 2 below.  The proposed 
loading and maintenance doses for each age group (Table 3 and Table 4 below) were used as 
dose level inputs for the simulations employing the final pediatric ICU population PK model. 


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Table 2.
Demographics of Input Dataset by Age Group
Demographics
Group-1 (1 month to < 
2 years)
Group-2 (2 to ≤ 12 
years)
Group-3 (12 to ≤ 17 
years)
N
42
44
10
Age Range (Years)
0.099 – 1.766
2.07 - 11.63
12.07 - 16.97
Mean Body Weight (Kg)
7.78
19.95
45.63
Body Weight Range (Kg)
3.15 – 13.5
9.98 - 61.6
23.59 - 72.3
Source: ePharm Artifact ID: 14554510
Table 3.
Dose levels for Subjects >2 years of age
Loading Dose (µg/kg)
Maintenance Infusion Dose 
(µg/kg/hour)
Low dose
0.5
0.5
Middle dose
1.2
1.0
High dose
2.0
1.5
Table 4.
Dose levels for Subjects ≥1 month to ≤2 years of age
Loading Dose (g/kg)
Maintenance Infusion Dose 
(g/kg/hour)
Low dose
0.5
0.5
Middle dose
1.0
1.0
High dose
1.5
1.5
Results 
Simulation Outputs
The simulated plasma DEX concentration-time profiles for each age group at low, mid and 
high dose levels are presented in Figure 1, Figure 2, and Figure 3, respectively.  The PK 
profiles of DEX via either a 5-minute or 10-minute loading dose infusion are also graphically 
presented side-by-side in the same graph for comparison.  The PK profiles of DEX via 5 min 
and 10 min infusion are generally similar within each age group at same dose except that the 
peak levels of DEX are slightly higher via 5 min loading infusion than that via 10 min 
loading infusion.


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Figure 1.
Simulated Plasma Dexmedetomidine Concentration vs Time Profiles in 
Different Age Groups following Low Dose Infusion
Red line: Mean concentration 
Shaded gray area: 90 % confidence interval.
Source data: ePharm Artifact ID: 14067909


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Figure 2.
Simulated Plasma Dexmedetomidine Concentration vs Time Profiles in 
Different Age Groups following Medium Dose Infusion
Red line: Mean concentration 
Shaded gray area: 90 % confidence interval.
Source data: ePharm Artifact ID: 14068066


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Figure 3.
Simulated Plasma Dexmedetomidine Concentration vs Time Profiles in 
Different Age Groups following High Dose Infusion
Red line: Mean concentration 
Shaded gray area: 90 % confidence interval.
Source data: ePharm Artifact ID: 14068080
Simulated PK Parameters
PK parameters including area under plasma concentration time curve (AUC) and maximum
plasma concentrations (Cmax) for simulated DEX data were estimated by noncompartmental 
PK analysis of simulation output.  Summary of PK parameters for each age group at low, 
medium and high dose levels are presented in Table 5.


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Table 5.
Dexmedetomidine PK Parameters for Simulated Data by Dose and Age 
Group
Dose 
Level
Age Group
PK Parameters
5 Minute Loading 
Infusion
10 Minute Loading 
Infusion
N
Mean (SD)
N
Mean (SD)
Low Dose
1 Month to ≤2 
Years
AUC0-t (ng*h/mL)
42
0.381(0.154)
42
0.352 (0.142)
Cmax (ng/mL)
42
0.453 (0.259)
42
0.408 (0.242)
2 to ≤12 Years
AUC0-t (ng*h/mL)
44
0.513 (0.285)
44
0.475 (0.264)
Cmax (ng/mL)
44
0.517 (0.291)
44
0.496 (0.292)
12 to ≤17 Years
AUC0-t (ng*h/mL)
10
0.621 (0.223)
10
0.574 (0.206)
Cmax (ng/mL)
10
0.603 (0.248)
10
0.595 (0.248)
Medium 
Dose
1 Month to ≤2 
Years
AUC0-t (ng*h/mL)
42
0.761 (0.309)
42
0.704 (0.283)
Cmax (ng/mL)
42
0.906 (0.517)
42
0.816 (0.484)
2 to ≤12 Years
AUC0-t (ng*h/mL)
44
1.14 (0.631)
44
1.05 (0.584)
Cmax (ng/mL)
44
1.22 (0.703)
44
1.17 (0.711)
12 to ≤17 Years
AUC0-t (ng*h/mL)
10
1.38 (0.491)
10
1.27 (0.454)
Cmax (ng/mL)
10
1.43 (0.607)
10
1.41 (0.614)
High 
Dose
1 Month to ≤2 
Years
AUC0-t (ng*h/mL)
42
1.14 (0.463)
42
1.06 (0.425)
Cmax (ng/mL)
42
1.36 (0.776)
42
1.22 (0.726)
2 to ≤12 Years
AUC0-t (ng*h/mL)
44
1.82 (1.01)
44
1.69 (0.932)
Cmax (ng/mL)
44
2.01 (1.18)
44
1.94 (1.20)
12 to ≤17 Years
AUC0-t (ng*h/mL)
10
2.20 (0.783)
10
2.04 (0.724)
Cmax (ng/mL)
10
2.37 (1.02)
10
2.35 (1.04)
Abbreviations: N = Number of subjects; SD = Standard deviation; Cmax = Maximum plasma concentration; 
AUC0-t = Area under plasma concentration time curve from time zero to time t where t= 1.5 hr.
Source: ePharm Artifact ID: 14067888


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Final Protocol Amendment 2, 11 March 2021
PFIZER CONFIDENTIAL
Page 113
 
 
 
 
 
 
 
CCI


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PFIZER CONFIDENTIAL
Page 114
Appendix 4. Modified Aldrete Score
The Modified Aldrete Score is an observational scale allowing verbal prompts.  The total 
score is the sum of all values.
Modified Aldrete Score
ACTIVITY
Able to move 4 extremities voluntarily or on command
2
Able to move 2 extremities voluntarily or on command
1
Unable to move extremities voluntarily or on command
0
RESPIRATION
Able to breathe deeply and cough freely
2
Dyspnea or limited breathing
1
Apneic
0
CIRCULATION
BP ± 20% of pre-anesthetic level
2
BP ± 20% to 49% of pre-anesthetic level
1
BP ± 50% of pre-anesthetic level
0
CONSCIOUSNESS
Fully awake
2
Arousable on calling
1
Not responding
0
O2 SATURATION
Able to maintain O2 saturation >92 % on room air
2
Needs O2 inhalation to maintain O2 saturation >90% 
1
O2 saturation <90 % even with O2 supplement
0
Reference: Aldrete JA. The post-anesthesia recovery score revisited. Journal of Clinical Anesthesia. 1995;7:89-
91


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Final Protocol Amendment 2, 11 March 2021
PFIZER CONFIDENTIAL
Page 115
Appendix 5. Pediatric Anesthesia Emergence Delirium Scale (PAED)
The total PAED score is the sum of all values.
Behavior
Not at 
all
Just a 
little
Quite 
a bit
Very 
much
Extremely
The child makes eye contact with the 
caregiver
4
3
2
1
0
The child’s actions are purposeful
4
3
2
1
0
The child is aware of his/her 
surroundings
4
3
2
1
0
The child is restless
0
1
2
3
4
The child is inconsolable
0
1
2
3
4
References: Sikich N, Lerman J. Development and Psychometric Evaluation of the Pediatric Anesthesia 
Emergence Delirium Scale. Anesthesiology 2004; 100:1138–45 and Bajwa S, Fanzca D, Cyna A. A 
Comparison of Emergence Delirium Scales Following General Anesthesia in Children. Pediatric
Anesthesia. 2010; 20(8): 704-711.


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Final Protocol Amendment 2, 11 March 2021
PFIZER CONFIDENTIAL
Page 116
Appendix 6. Pediatric Sedation State Scale (PSSS)
State
Behavior
5
Patient is moving (purposefully or nonpurposefully) in a manner that impedes the proceduralist and 
requires forceful immobilization.  This includes crying or shouting during the procedure, but 
vocalization is not required.  Score is based on movement.
4
Moving during the procedure (awake or sedated) that requires gentle immobilization for 
positioning.  May verbalize some discomfort or stress, but there is no crying or shouting that 
expresses stress or objection.
3
Expression of pain or anxiety on face (may verbalize discomfort), but not moving or impeding 
completion of the procedure.  May require help positioning (as with a lumbar puncture) but does 
not require restraint to stop movement during the procedure.
2
Quiet (asleep or awake), not moving during procedure, and no frown (or brow furrow) indicating 
pain or anxiety. No verbalization of any complaint.
1
Deeply asleep with normal vital signs, but requiring airway intervention and/or assistance (eg, 
central or obstructive apnea, etc).
0
Sedation associated with abnormal physiologic parameters that require acute intervention (ie,
oxygen saturation <90%, blood pressure is 30% lower than baseline, bradycardia receiving 
therapy).
Reference: Cravero JP, Askins N, Sriswasdi P, et al. Validation of the Pediatric Sedation State Scale. 
Pediatrics. 2017; 139(5):e20162897


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Final Protocol Amendment 2, 11 March 2021
PFIZER CONFIDENTIAL
Page 117
Appendix 7. HR and RR Centile Chart Cut-offs for Children from Birth to 18 Years of 
Age
Source: Fleming S, Thompson M, Stevens R, et al. Normal ranges of HR and RR in children 
from birth to 18 years of age: a systematic review of observational studies. Lancet.  2011; 
377:1011-18, Web appendix.


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Final Protocol Amendment 2, 11 March 2021
PFIZER CONFIDENTIAL
Page 118
Appendix 8. Normal Vital Signs According to Age
    Table 67-1, Nelson Textbook of Pediatrics
AGE
HEART RATE 
(beats/min)
BLOOD PRESSURE 
(mm Hg)
RESPIRATORY RATE 
(breaths/min)
Premature
120 – 170*
55-75 / 35-45†
40-70‡
0-3 months
100-150*
65-85 / 45-55
35-55
3-6 months
90-120
70-90 / 50-65
30-45
6-12 months
80-120
80-100 / 55-65
25-40
1-3 years
70-110
90-105 / 55-70
20-30
3-6 years
65-110
95-110 / 60-75
20-25
6-12 years
60-95
100-120 / 60-75
14-22
12+ years
55-85
110-135 / 65-85
12-18
Source: Nelson Textbook of Pediatrics, 20th Ed, 2016
*
In sleep, infant heart rates may drop significantly lower, but if perfusion is 
maintained, no intervention is required.
†
A blood pressure cuff should cover approximately two-thirds of the arm; too small a 
cuff yields spuriously high blood pressure readings, and too large a cuff yields 
spuriously low pressure readings.
‡
Many premature infants require mechanical ventilatory support, making their 
spontaneous respiratory rate less relevant.


PF-00914730
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Final Protocol Amendment 2, 11 March 2021
PFIZER CONFIDENTIAL
Page 119
Appendix 9. Propofol Pre-filled Syringe Medical Device Reporting in Japan
Propofol pre-filled syringe medical device incidents in Japan including those resulting from 
malfunctions of the device, must be detected, documented, and reported by the investigator to 
the Sponsor throughout the study.
The detection and documentation procedures described in this protocol apply only to sites in 
Japan using Propofol pre-filled syringes in the study.  
The specific reporting procedure process for medical device incidents will be provided to the 
sites in Japan under separate cover.
Definitions of a Medical Device Incident
Medical Device Incident Definition

A medical device incident is any malfunction or deterioration in the characteristics and/or 
performance of a device as well as any inadequacy in the labeling or the instructions for
use which, directly or indirectly, might lead to or might have led to the death of a 
participant/user/other person or to a serious deterioration in his/her state of health.

Not all incidents lead to death or serious deterioration in health.  The nonoccurrence of 
such a result might have been due to other fortunate circumstances or to the intervention 
of healthcare personnel.
It is sufficient that:

An incident associated with a device happened.
AND

The incident was such that, if it occurred again, might lead to death or a serious 
deterioration in health.
A serious deterioration in state of health can include any of the following:

Life-threatening illness;

Permanent impairment of body function or permanent damage to body structure;

Condition necessitating medical or surgical intervention to prevent one of the above;

Fetal distress, fetal death, or any congenital abnormality or birth defects.


PF-00914730
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Final Protocol Amendment 2, 11 March 2021
PFIZER CONFIDENTIAL
Page 120
Examples of Incidents

A participant, user, caregiver, or healthcare professional is injured as a result of a 
medical device failure or its misuse.

A participant’s study intervention is interrupted or compromised by a medical device 
failure.

A misdiagnosis due to medical device failure leads to inappropriate treatment.

A participant’s health deteriorates due to medical device failure.
Documenting Medical Device Incidents
Medical Device Incident Documentation

Any medical device incident occurring during the study will be documented in the 
participant’s medical records, in accordance with the investigator’s normal clinical
practice.

For medical device incidents meeting the definition of an AE or an SAE, the appropriate 
AE CRF page will be completed. An SAE will also require completion of the CT SAE 
form which will be forwarded to Pfizer Safety as per Section 8.1 of the protocol.

All medical device incidents must be reported to the manufacturer by the site.

The results from the manufacturer’s investigation of the medical device incident must 
also be reported to the sponsor as an appendix to the original report, as appropriate.

It is very important that the investigator provides his/her assessment of causality 
(relationship to the medical device provided by the sponsor) at the time of the initial AE 
or SAE report and describes any corrective or remedial actions taken to prevent 
recurrence of the incident.

A remedial action is any action other than routine maintenance or servicing of a medical 
device where such action is necessary to prevent recurrence of an incident.  This 
includes any amendment to the device design to prevent recurrence.

SAP_001.pdf: 
 PF-00914730 
 Protocol: C0801039   
 Statistical Analysis Plan 
 
 
PFIZER CONFIDENTIAL  
Page 1 
  
 
 
 
 
Protocol: C0801039 
  Protocol Date: 11MAR2021 
Protocol version: Amendment 2 
 
 
A PHASE 3/4 RANDOMIZED, DOUBLE-BLIND, DOSE-RANGING STUDY OF THE 
SAFETY AND EFFICACY OF DEXMEDETOMIDINE (DEX) USED WITH 
PROPOFOL (PRO) AS NEEDED FOR PROCEDURAL SEDATION OF PEDIATRIC 
SUBJECTS ≥1 MONTH TO <17 YEARS OF AGE UNDERGOING MRI SCANS 
 
 
 
Statistical Analysis Plan  
(SAP) 
 
 
 
 
 
 
 
Version: 2 
  
Date: 09June2021 
  


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1. Mason KP, Zurakowski D, Zgleszewski SE, et al. High dose 
dexmedetomidine as the sole sedative for pediatric MRI. Pediatr Anesth. 
2008; 18(5):403-411. .................................................................................................27 
9. SAS CODES FOR PRIMARY EFFICACY ENDPOINTS ................................................27 
 
LIST OF TABLES 
Table 1     Schedule of Clinical Activities ...............................................................................11 
Table 2      Sample Size ............................................................................................................14 
Table 3      Pediatric Sedation State Scale (PSSS) ...................................................................15 
 
APPENDICES 
Appendix 1. List of Abbreviations...........................................................................................28 
 
 
 


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1. AMENDMENTS FROM PREVIOUS VERSION(S)  
 
• Status of study when amendment (version 2) made: Study Ongoing 
• Descriptions of and rationale for the changes: 
Details of the Changes 
Rationale for the Changes 
Section 2.1. Study Objectives and Endpoints: 
revised to: remove safety endpoint for clinically 
significant hemodynamic changes from Baseline; 
add safety endpoint for time outside of the stable 
range for hemodynamic parameters; clarify that 
incidences of listed adverse events are for 
protocol specified events; add paradoxical 
agitation reaction as a safety endpoint. 
Updates are made to be consistent 
with protocol amendment 1. 
Section 2.1 Primary Endpoint: revised the 
primary efficacy endpoint to clarify the 
comparison is in the combined age cohorts 
 
Updates are made to be consistent 
with protocol amendment 2. 
Section 2.1 Endpoint: Secondary Efficacy: 
Percent of time at the target sedation rating 
scale score revised to: 
Percent of time at the target sedation rating 
scale score (Pediatric Sedation State Scale 
[PSSS] rating of 2) during the DEX 
maintenance infusion.   
Clarified the percent of time at the 
target sedation during DEX 
maintenance infusion to be analyzed. 
Section 2.1 Endpoint: Safety: 
corrected the safety endpoint to include subjects 
who require intervention to complete the MRI; 
changed the protocol-specified AE term “systolic 
hypotension”to “hypotension” 
 
Updates are made to be consistent 
with protocol amendment 2. 
Section 2.2. Study Design Table 1 Schedule of 
Clinical Activities  updated as appropriate to be 
consistent with the protocol amendment 2. 
 
Updates are made to be consistent 
with protocol amendment 2. 
Section 2.3. Sample Size Determination: revised 
to remove trailing zeroes related to DEX dosing. 
Updates are made to be consistent 
with protocol amendment 1. 
Section 3.2. Secondary Efficacy Endpoint(s) – 
Emergence Time: revised to: 
Subjects who are withdrawn or discharged without 
reaching an Aldrete score ≥9, will be considered 
as having censored time computed from end of 
The censored time for emergence time 
is clarified.    


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MRI scan to time of the last clinical assessment 
(vital signs).  Zero minute will be used as the 
censored time if no vital signs are taken during the 
post-MRI recovery period. 
Section 3.5.4 Other Safety Endpoints revised to: 
corrected a safety endpoint and revised to : 
Percent of subjects who completed the MRI scan 
and required artificial ventilation or intervention 
to restore baseline or normal hemodynamic 
status. 
Corrected to include subjects who 
require intervention to 
complete the MRI per protocol 
amendment 2. 
Section 3.5.4. Other Safety Endpoints: revised to: 
remove safety endpoint for clinically significant 
hemodynamic changes from Baseline; add safety 
endpoint for time outside of the stable range for 
hemodynamic. 
Updates are made to be consistent 
with protocol amendment 1. 
Section 3.5.4. Other Safety Endpoints: revised to: 
remove “All interventions used by the 
anesthesiologist to preserve hemodynamic 
stability will be compiled.  Treatments for 
hypertension, tachycardia, hypotension, 
bradycardia, and respiratory depression will be 
descriptively summarized by each dose level and 
age cohort.” 
The hemodynamic stability is 
removed from the protocol 
amendment 1. 
Section 6.2.2 Percentage of Time at the Target 
Sedation Scale, ADD: 
In addition, the difference between dose levels in 
the percentage of time at Pediatric Sedation State 
Scale [PSSS] rating of 2 or 3 during the DEX 
maintenance infusion will be assessed.  
 
The percentage of time at target Pediatric 
Sedation State Scale [PSSS] rating of 2  during 
the DEX maintenance infusion with/ without 
PRO will be summarized as well. 
Additional analyses are added. 
Section 6.2.3 Amount of Time to First PRO 
ADD: 
Kaplan Meier plot of time from the start of DEX 
loading dose infusion to the time of first PRO 
bolus Infusion will be performed by dose level 
and age cohort. 
Kaplan Meier Plots are added. 
 
 


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Section 6.2.4 Emergence Time, ADD: 
Kaplan Meier plot of emergence time by dose 
level and age cohort will be performed. 
Kaplan Meier Plots are added. 
Section 6.6.5. Electrocardiograms: revised to 
Electrocardiograms and MRI scan; add “Duration 
of MRI will be summarized descriptively by dose 
level and age cohort.” 
The duration of MRI will be reported 
in the CSR. 
 
2. INTRODUCTION 
Dexmedetomidine (DEX) is a highly selective α2-adrenergic agonist that is being 
investigated for use in procedural sedation in pediatric subjects undergoing magnetic 
resonance imaging (MRI) requiring moderate to deep sedation.  DEX is currently approved 
for sedation of initially intubated and mechanically ventilated adults during treatment in an 
intensive care setting and for procedural sedation of adults. 
 
The present study is being conducted by Pfizer, Inc under the Pediatric Research Equity Act 
(PREA) and is a Phase 3/4 randomized, double-blind, dose-ranging study of the safety and 
efficacy of DEX used with propofol (PRO) for procedural sedation of pediatric subjects ≥1 
month to <17 years of age undergoing MRI scans in the United States (US) and Japan. 
 
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study C0801039.  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 and Endpoints 
Objectives 
 
• The primary efficacy objective is to assess the efficacy of DEX for pediatric 
procedural sedation as measured by the percent of subjects at the high dose level 
versus the low dose level in the combined age cohorts who do not require 
concomitant PRO to achieve adequate sedation. 
 
• The key secondary objective is to assess the efficacy of DEX for pediatric 
procedural sedation as measured by the percent of subjects at the high dose level 
versus the low dose level in each age cohort who do not require concomitant PRO 
to achieve adequate sedation. 
 
• Other secondary efficacy objectives include: 
 
• 
Explore the efficacy of DEX at the middle dose level compared to the high 
dose level and the low dose level in both the overall sample and in each age 










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b. 
Subjects must be monitored per protocol requirements for a minimum of 1 hour; this must occur in a post-procedure recovery area 
such as a post-anesthesia care unit (PACU), recovery room or other hospital area where the required monitoring can be achieved. After 
1 hour, subjects will meet criteria to leave this area when the subject attains a minimum Modified Aldrete Score of 9, is tolerating oral 
fluids and if applicable, any institution-specific discharge criteria have been met. 
c. 
The Day 2 Follow-up visit will be completed 24 hours (±2 hours) after discontinuation of dexmedetomidine (DEX). Contact with the 
subject or parent/legal guardian may be done via a phone call. 
d. 
Physical examination will include evaluation of general appearance, head, ears, eyes, nose, mouth, throat, neck, lungs, heart, abdomen, 
musculoskeletal, extremities, skin, lymph node and a neurological assessment. 
e. 
The investigator must assess and document in the source if the subject is biologically capable of having/fathering children and if the 
subject is sexually active, continues to be sexually active or has become sexually active. If yes, their method of contraception and 
confirmation of its consistent and correct use must also be documented in the source documents. 
f. 
Vital signs will include height (or length), weight, temperature, heart rate, respiratory rate, saturation of peripheral oxygen (SpO2) and 
blood pressure including mean arterial pressure (MAP). Measurements should be obtained with the subject in a supine position as 
much as possible. 
• 
Height will only be measured at Screening. 
• 
Weight will only be measured at Screening and Day 1 Period 1 before randomization. If Screening and Day 1 occur on the same 
day, the weight does not need to be repeated. 
• 
Height and weight values will be rounded to 1 decimal place (the nearest tenth) for calculations and documentation. If the second  
number to the right of the decimal point (the hundredths) is 4 or less, remove all numbers to the right of the tenths place. If the  
hundredths number is 5 or greater, add 1 to the number in the tenths place, and then remove all numbers to the right of the tenths 
place. 
 
• 
Body temperature will be measured at Screening, at Day 1 Period 1 prior to randomization and during Day 1 Period 2 both when 
the subject arrives in the post-procedure recovery area and when they meet the criteria to leave this area. If Screening and Day 1 
occur on the same day, the temperature does not need to be repeated at Day 1 Period 1 prior to randomization but would need to 
be obtained on Day 1 Period 2 in addition to Screening. 
• 
Blood pressure, MAP, heart rate, respiratory rate and SpO2 will be measured at Screening, within approximately 5 minutes before 
the loading dose and then every 5 (±1) minutes once the loading dose has started until the end of the MRI scan. The measurements 
obtained just before the loading dose will be considered the Baseline values for analysis purposes. 
• 
On Day 1 Period 2, blood pressure including MAP, heart rate, respiratory rate and SpO2 will be measured upon arrival in the post-
procedure recovery area and then every 5 (±1) minutes for the first 15 minutes, and every 15 (±5) minutes for at least 1 hour until 
the subject attains a minimum Modified Aldrete Score of 9, is tolerating oral fluids and any institution-specific discharge criteria 
as applicable have been met. 
• 
Heart rate, respiratory rate and SpO2, as well as blood pressure where available,  will also be monitored between scheduled readings 
either per site equipment monitoring standards  or more frequently as deemed clinically necessary from the start of the study 
treatment loading dose through the post-MRI recovery period. If heart rate decreases >20% from Baseline and is outside the normal 
range, a blood pressure measurement including MAP should be repeated at approximately 2-minute intervals until the heart rate 
returns to the normal range. If systolic blood pressure decreases ≥30% from Baseline and is outside the normal range, a blood 
pressure measurement including MAP should be checked approximately 1 minute later. If the systolic blood pressure remains 
outside the normal range, measurements should be repeated at approximately 2-minute intervals until the systolic blood pressure 
returns to the normal range. Normal ranges are provided in the Protocol Appendix 8, Normal Ranges by Age (Nelson Textbook of 
Pediatrics, 20th Ed, 2016). Baseline values are those obtained at Day 1 Period 1 within approximately 5 minutes prior to the start 
of the DEX loading dose. 
g. 
Nasal cannula capnography will be used to monitor EtCO2 concentrations from the start of the study treatment loading dose through 
the MRI scan. EtCO2 data will not be collected on a CRF. 
h. 
A 2-minute rhythm strip will be obtained at Screening, and a 12-lead ECG will be performed if clinically significant abnormalities are 
noted. If a site does not have the capability to obtain a hard copy rhythm strip, the 12-lead ECG may be performed in lieu of the 
rhythm strip. Subjects with a known history of cardiac disease will be required to have a 12-lead ECG performed at Screening. 
Cardiac telemetry monitoring is required beginning just prior to the start of the study treatment loading dose and continuing through 
the post-MRI recovery period. 
i. 
For all female subjects of child-bearing potential, a urine dipstick or whole-blood qualitative human chorionic gonadotropin (hCG) 
pregnancy test that can be performed at the bedside will be performed on Day 1 Period 1. Serum qualitative or quantitative hCG 
pregnancy tests are not permitted. A negative pregnancy result is required before the subject may be randomized. Subjects with an 
indeterminate or positive test result may not randomize in the study. Please refer to the Protocol Section 7.1 Pregnancy Testing for 
details. 
j. 
DEX must be administered through a peripheral IV line that is not a central catheter such as a subclavian or peripherally inserted 




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group for subjects ≥12 to <17 years of age, since it is expected that these subjects would 
require minimum sedation.  Forty subjects will be enrolled per each dose level, and 20 
subjects for each dose group for age cohorts ≥1 month to <2 year and ≥2 years to <17 year.  
The table below shows the planned enrollment in this study. 
      Table 2      Sample Size  
 
Age Group for Enrollment 
Low Dose 
Medium Dose 
High Dose 
≥1 month to <2 year 
20 
20 
20 
≥2 years to <12 years 
16 
16 
16 
≥12 years to <17 years 
4 
4 
4 
 
These assumptions were obtained from study DEX 10-16 and Mason et al  publication in 
Pediatric Anesthesia 2008 (1).  In DEX 10-16 approximately 30% of subjects who had MRIs 
did not require rescue medication; the dose in study 10-16 is comparable to the middle dose 
in this study.  In the Mason et al publication, approximately 80-90% of patients treated with  
2-3 mcg/kg loading dose of DEX for MRI scans did not require supplemental anesthesia, 
therefore a conservative estimate of 65% was assumed.  Additionally, in the DEX 10-16 
study, 6% of subjects did not complete the MRI scan, so a failure rate of approximately 5% 
was incorporated into the assumptions of patients requiring supplemental PRO. 
 
3. ENDPOINTS AND BASELINE VARIABLES     
3.1. Primary and Key Secondary Efficacy Endpoint(s) 
• Primary Efficacy: Percent of subjects at the DEX high dose level versus the low dose 
level in the combined age cohorts who do not require concomitant PRO to complete 
the MRI. 
• Key Secondary Efficacy: Percent of subjects at the DEX high dose level versus the 
low dose level in each age cohort who do not require concomitant PRO to complete 
the MRI. 
A subject who does not complete the MRI scan will be considered a treatment failure, i.e., 
the subject will be counted as receiving PRO and will not be counted as a successful 
responder for the percentage of subjects who do not require concomitant PRO.  An indicator 
variable for the use of PRO after the first dose of DEX or during MRI scan is defined as 
follows: 
= 1, if the subject does not require PRO during DEX administration or during the 
MRI scan  
 






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3.4. Baseline Variables 
The baseline assessment is defined as the last assessment recorded before study drug 
administration.  The following baseline assessments will be summarized.  
• Vital signs (HR, BP, MAP, RR)  
• Body Temperature 
• PSSS 
• Prior Medications 
3.5. Safety Endpoints 
The main safety endpoints are incidence, seriousness, causality and severity of TEAEs.  
General adverse event (AE) summaries are described in Section 3.5.1, protocol-specified 
AEs are presented in Section 3.5.2 and other safety endpoints are listed in Section 3.5.4. 
3.5.1. Adverse Events 
The MedDRA adverse event dictionary (most recent, available version at the time of study 
initiation) will be used to map AEs to preferred terms and system organ classes.  A TEAE is 
defined as an AE that emerges or worsens relative to the pre-treatment state during the time 
from the start of study treatment on DAY 1 through DAY 2.  Only TEAEs will be analyzed.  
However, all AEs will be presented in data listings. 
An overall summary of TEAEs across the study drug period and up to the end of Day 2 will 
be generated.  TEAEs will be summarized separately for 3 different periods (loading dose, 
maintenance dose infusion, post study treatment).  An AE occurring during a study treatment 
period (loading dose period and/ or maintenance period), is defined as any AE with new 
onset during that period or worsening relative to the period prior to start of DEX treatment.  
An AE occurring post study drug is defined as any AE with new onset or worsening relative 
to the period prior to DEX treatment, any time after study drug discontinuation through Day 
2. 
 
For summaries by severity, if a subject has multiple events occurring in the same system 
organ class (SOC) or same preferred term, then the event with the highest severity will be 
summarized.  Any AE with a missing severity will be summarized as severe.   
Relationship to study drug will be summarized as follows: 
• Related (includes definitely related, probably related and possibly related) 
• Not Related (includes probably not related and not related)  


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3.5.2. Protocol-Specified Adverse Events 
3.5.2.1. Changes in Blood Pressure and Heart Rate 
Blood pressure and heart rate will be assessed throughout the study, and blood pressure and 
heart rate measurements exceeding specified limits defined in Section 8.4.1.1 of the 
C0801039 protocol will be recorded as AEs.  These AEs include: bradycardia, hypotension, 
and hypertension.  Since the study has pre-specified absolute and relative thresholds for these 
AEs, the AE data will be used to determine the incidence of cardiac AEs.  Further analysis 
will be applied to those cardiac AEs that require intervention, where the number and 
percentage of subjects who received interventions to preserve cardiac function will be 
summarized as well as the interventions that were received. 
 
3.5.2.2. Paradoxical Agitation Reactions 
Throughout the Study Drug Infusion Period and extending into the 24-hour post-infusion 
observation period, the Investigator should monitor for the onset of paradoxical agitation 
reactions (e.g., rage).  The clinical features may vary with age of the subject, but the 
following should be used as a guide: 
• Age ≥1 month to <8 years: Inconsolable crying and/or irritability that are 
otherwise unexplained by the subjects’ current medical condition and are 
unable to be controlled with conventional interventions. 
 
• Age ≥8 years to ≤17 years: Aggressive behavior and/or excessive emotional 
outbursts that are otherwise unexplained by the subjects’ current medical 
condition and are unable to be controlled with conventional interventions. An 
example of this may include a subject that becomes physically violent that may 
expose healthcare personnel or themselves to harm. 
 
In the event a paradoxical agitation reaction occurs during the study drug infusion period, the 
study drug will be discontinued and the subject treated as clinically indicated.  The event 
should be reported as an AE and an SAE and will be summarized. 
3.5.2.3. Changes in Respiratory Rate, EtCO2, and SpO2 
The Investigator will assess changes in respiratory rate, changes in measurement of carbon 
dioxide (CO2) concentration and oxygen saturation throughout the study.  Respiratory rates, 
EtCO2 and/or SpO2 measurements below the thresholds outlined in Section 8.4.1.3 of the 
protocol will be recorded as adverse events.  These adverse events include bradypnea, 
hypoxia and apnea.  Since the study has pre-specified absolute and relative thresholds for 
these AEs, the AE data will be used to determine the incidence of respiratory depression.  
Further analysis will be applied to respiratory depression that requires intervention, where the 
number and percentage of subjects who received interventions to preserve respiratory 
function will be summarized as well as the interventions received. 


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3.5.3. Protocol-Specified Serious Adverse Events 
There are no protocol-specified SAEs in this study.  All SAEs will be reported to Pfizer 
Safety by the investigator as described in the protocol and will be handled as SAEs in the 
safety database.   
3.5.4. Other safety endpoints  
• Mean change from baseline in systolic blood pressure (SBP), diastolic blood pressure 
(DBP), mean arterial pressure (MAP), heart rate (HR) and respiratory rate (RR). 
 
The post baseline value will be at the timepoint closest to the time for the planned 
time period. 
 
• Percent of subjects who complete the MRI scan and required artificial ventilation or 
intervention to restore baseline or normal hemodynamic status. 
An indicator variable for subjects who complete the MRI scan with or without the 
need for artificial ventilation or intervention is defined as follows: 
= 1, if the subject did not need artificial ventilation or intervention  
= 0, if the subject did need artificial ventilation or intervention. 
 
 
All interventions used by the anesthesiologist to preserve hemodynamic stability will 
be compiled.  Treatments for hypertension, tachycardia, hypotension, bradycardia, 
and respiratory depression will be descriptively summarized by each dose level and 
age cohort. 
 
• Time outside of the stable range for hemodynamic parameters of SBP and HR. 
 
The time outside of the stable range for hemodynamic parameters will be assessed as 
defined below: 
 
Hemodynamic stability is characterized by maintenance of (1) the SBP within + 30% 
of pre-study drug baseline, and (2) HR within + 30% of pre-study drug baseline. A 
composite endpoint of the time outside of the hemodynamically stable range will be 
constructed as such: 


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The numerator will be the time outside of the stable range for each hemodynamic 
parameter during the time period of evaluation.  The time outside of the stable range 
will be summed for each parameter and divided by the denominator.  The 
denominator will be the time from onset of study drug infusion to the time study 
drug is discontinued.  Theoretically, values for this endpoint could range from 0 (the 
subject remains within range during the time period of evaluation on all parameters 
assessed) to 2.0 (subject was out of range for the time period of evaluation for both 
SBP and HR).  Linear extrapolation will be used to estimate the parameter values 
between observation points. 
• Incidence of DEX withdrawal-related adverse events after discontinuation of the 
DEX infusion through Day 2.  
 
The number and percent of subjects who have withdrawal symptoms reported as 
AEs, such as agitation/anxiety, nausea, (rebound) tachycardia and (rebound) 
hypertension will be tabulated.  These are defined as AEs with new onset after 
study treatment discontinuation or worsening relative to the treatment period. 
  
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS) 
Data for all participants will be assessed to determine if participants meet the criteria for 
inclusion in each analysis population prior to unblinding and releasing the database and 
classifications will be documented per standard operating procedures.  
4.1. Enrolled Population (EP) 
All participants who sign the informed consent document. 
4.2. Safety Analysis Set 
The safety analysis set consists of all randomized subjects who receive any amount of DEX.  
Participants will be analyzed according to the intervention they received.  In the event a 
subject receives a loading and/or maintenance dose that is different from the dose group to 
which they are randomized, the subject will be analyzed in the dose level group that 
corresponds to the lowest dose received.  All safety analyses will be performed on the safety 
analysis set. 


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4.3. Full Analysis Set (FAS) 
All randomized subjects who receive any amount of DEX will form the FAS.  Participants 
will be analyzed according to the intervention to which they are randomized.  This will be the 
primary population for efficacy analysis. 
4.4. Efficacy Evaluable Population (EEP) 
All randomized subjects who receive any amount of DEX and complete the MRI scan will 
form the EEP. 
4.5. Per Protocol Population (PPP) 
All subjects included in the FAS and have no major protocol deviations will form the PPP.  
4.6. Japanese Population Set (JPS) 
All randomized Japanese subjects who receive any amount of DEX. 
The JPS will be used for efficacy endpoints, demographic and baseline characteristic and 
safety endpoints.  Participants will be analyzed according to the intervention to which they 
are randomized for efficacy and will be analyzed according to the intervention they receive 
for safety. 
5. GENERAL METHODOLOGY AND CONVENTIONS  
5.1. Hypotheses and Decision Rules 
The hypothesis that will be tested in this study is  
 
H0: p1 – p2  = 0 
 
 
           H1: p1 – p2  ≠ 0 
 
where p1 and p2  are the proportion of subjects who do not require concomitant PRO to 
complete the MRI for the high and low dose respectively. 
 
The high dose level will be considered superior to the low dose level with respect to the 
proportion of subjects who do not require concomitant PRO to complete the MRI if the 
difference is statistically significant in favor of the high dose level at the 2-sided 0.05 level.   
 
5.2. General Methods 
The statistical analyses will be performed using SAS, version 9.2 or later.  All statistical tests 
will be two-sided and p-values ≤0.0500, after rounding to four decimal places, will be 
considered statistically significant unless otherwise specified. 


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For continuous variables, N, mean, median, SD, minimum, Q1, Q3 and maximum will be 
presented.  The mean and median will be displayed to one decimal place more than the raw 
value.  The standard deviation will be displayed to two decimal places more than the raw 
value. 
For categorical variables, N and percent will be shown.  All percentages will be reported to 
one decimal place. 
Subject listings of all data from the CRFs will be presented.   
5.3. Methods to Manage Missing Data 
In general, missing data will not be imputed, exceptions will be described in the SAP.  
5.4. Time points 
Screening/Pre-Study Drug Administration Period: The period before randomization. 
Baseline: The last non-missing data prior to study drug administration. 
Study Drug Administration Period: Treatment Period (DEX loading dose and continuous 
infusion). 
 
Day 1: The visit is comprised of 3 phases: a Screening (pre-randomization) Phase, a Period 1 
(MRI scan) Phase and a Period 2 (Post-MRI Recovery) Phase.   
Day 2: The visit is a 24-hour (±2 hours) follow-up after discontinuing the study drug 
infusion. 
 
Day 29: The visit is a 28 day (+3 days) long term follow-up visit.   
Post-Study Drug Administration Period: time after discontinuing the study drug infusion.  
 
6. ANALYSES AND SUMMARIES  
6.1. Primary and Key Secondary Endpoint(s) 
6.1.1. Primary Endpoint 
The DEX high vs low dose group will be compared by Mantel-Haenszel test in PROC 
FREQ.  The difference between high and low dose groups will be assessed using odds ratios 
and 95% confidence intervals on the odds ratio.  Additionally, 95% confidence interval on 
the percent of subjects not requiring supplemental PRO will be provided by dose level using 
exact 95% confidence intervals.  All age cohorts will be combined.  The primary analysis 
will be performed based on the FAS.  The same analysis will be repeated on the EEP, PPP 
and JPS. 


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6.1.2. Key Secondary Endpoint 
The method of analysis for the primary endpoint will be repeated for the key secondary 
endpoint for each age cohort based on the FAS.  The same analysis will be repeated on the 
EEP, PPP, and JPS. 
6.2. Secondary Endpoint(s) 
All secondary endpoints will be summarized overall and by age cohort for the FAS and JPS. 
6.2.1. Percentage of Subjects Not Required PRO at the middle dose level   
The method of analysis for the primary endpoint will be repeated for the secondary endpoints 
comparing the low dose to the medium dose and the medium dose to the high dose. 
6.2.2. Percentage of Time at the Target Sedation Scale 
The difference between dose levels in percent of time at the target sedation rating scale score 
(PSSS rating of 2) during the DEX maintenance infusion will be assessed using the Wilcoxon 
test.   
 
In addition, the difference between dose levels in the percent of time at the PSSS rating of 2 
or 3 during the DEX maintenance infusion will be assessed using the Wilcoxon test.  
 
The percent of time at the target PSSS rating of 2 during the DEX maintenance infusion with/ 
without PRO will be summarized by dose level and age cohort as well. 
 
6.2.3. Amount of Time to First PRO 
The time to first dose of concomitant PRO will be summarized with Kaplan-Meier estimates.  
Between dose groups comparisons will be made with log-rank tests.   
Kaplan Meier plot of time from the start of DEX loading dose infusion to the time of first 
PRO bolus Infusion will be performed by dose level and age cohort. 
 
6.2.4. Emergence Time 
Time (minutes) from completion of MRI to time a subject first receives an Aldrete score of 9 
or greater will be summarized using the Kaplan-Meier method.  Between dose groups 
comparisons will be made with log-rank test.   
Kaplan Meier plot of emergence time  by dose Level and age cohort will be performed. 
 




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dose, maintenance dose, and total duration.  Total duration of exposure to study drug (min), 
is equal to total duration of loading dose plus total duration of maintenance dosing. 
 
Exposure to study drug will not be adjusted for dose interruptions.  Loading dose will be 
summarized using actual dose received. 
Maintenance dose will be summarized through the following parameters: 
• Total dose infused (mcg/kg) which is equal to the sum of all maintenance dose 
infusion rate (mcg/kg/min) times duration of the maintenance dose infusion (min) 
• Average dose (mcg/kg/min) which is equal to total dose of study drug infused 
(mcg/kg) divided by total duration of dosing (min) 
Total dose received (mcg), which is equal to total dose of study drug received (mcg/kg) 
multiplied by baseline weight (kg);  
Total duration of the exposure to study drug (min), which is equal to total duration of loading 
dose plus total duration of maintenance dosing. 
Study treatment exposure will be analyzed for overall subjects and subjects who complete the 
MRI scan without PRO, and for subjects who complete the MRI scan with PRO use.   
6.5.4. Concomitant Medications and Nondrug Treatments 
Prior and concomitant medications will be summarized according to WHODRUG 
Dictionary.  The number and percentage of subjects who use prior medications (by preferred 
term) will be tabulated by dose level/underlying condition/age.  The number and percentage 
of subjects who use concomitant medications will be similarly tabulated.  Summaries will be 
provided overall and by age cohort. 
6.6. Safety Summaries and Analyses 
All safety analyses will be performed on the safety analysis set and JPS. 
Descriptive statistics (quantitative variables: arithmetic mean, SD, median, minimum, and 
maximum, categorical and ordinal variables: proportion of subjects) will be calculated for 
quantitative safety data as well as for the change from baseline, when appropriate.  Data 
analyses will be presented by dose level, overall and within each age cohort. 
6.6.1. Adverse Events 
AEs will be analyzed by dose level, overall and by age cohort.  Only TEAEs will be 
analyzed.  However, all AEs will be presented in data listings. 
TEAEs will be analyzed overall and within each period (loading dose period, maintenance 
dose period, post study treatment through Day 2) according to the Medical Dictionary for 


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Regulatory Activities (MedDRA) system organ class (SOC) and preferred term.  AEs by 
severity and relationship to study drug will also be summarized, as well as SAEs.   
Separate tabulations will be displayed for protocol-specified events of bradycardia, hypoxia, 
apnea, hypotension, hypertension, bradycardia and paradoxical agitation reaction.  
Additionally, the above AEs, which require medical intervention will also be summarized.  
Relative risk of high dose level vs low dose level and medium dose level vs low dose level, 
and the 95% confidence interval associated with relative risk will be calculated. 
The types of individual interventions will be descriptively summarized at each dose level and 
for each age cohort.  
Listings will be presented by subject for all AEs as well as for SAEs, AEs associated with 
death, and AEs leading to discontinuation of DEX. 
 
6.6.2. Withdrawal Symptoms 
Withdrawal symptoms, such as agitation/anxiety, nausea, rebound tachycardia and rebound 
hypertension will be summarized by each dose level and age cohort.  Descriptive summaries 
will be performed for the incidence of DEX withdrawal-related adverse events after 
discontinuation of the DEX infusion. 
6.6.3. Laboratory Data 
Laboratory data at screening will be listed.  
6.6.4. Vital Signs 
The vital signs included in the safety assessments are SBP, DBP, MAP, HR, RR, and SpO2.   
The absolute value and change from baseline will be summarized descriptively at each 
timepoint by dose level and age cohort. 
 
Hemodynamic Status 
 
The proportion of subjects who completed the MRI scan without the need for artificial 
ventilation or intervention to restore baseline or normal hemodynamic status will also be 
summarized.   
 
Vital sign measurements and hemodynamic and respiratory parameters will be summarized 
descriptively by dose level and age cohort. 
 
In addition, descriptive summary statistics will be compiled for the composite endpoint of the 
time outside of the hemodynamically stable range.  Also, the number and percentage of 
subjects who receive interventions to preserve hemodynamic stability will be summarized for 
the study drug infusion period and for the post-infusion period, respectively.  


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6.6.5. Electrocardiograms  
ECG data will be listed.   
 
6.6.6. MRI scan 
Duration of MRI will be summarized descriptively by dose level and age cohort. 
 
6.6.7. Physical Examination 
Physical examination at screening will be listed. 
6.6.8. Pediatric Anesthesia Emergence Delirium Scale (PAED). 
Descriptive analyses will be performed for the PAED total score for dose level and by age 
cohort. 
7. INTERIM ANALYSES 
No interim analysis is planned.  
8. REFERENCES 
1. Mason KP, Zurakowski D, Zgleszewski SE, et al. High dose dexmedetomidine 
as the sole sedative for pediatric MRI. Pediatr Anesth. 2008; 18(5):403-411. 
9. SAS CODES FOR PRIMARY EFFICACY ENDPOINTS 
proc freq data= efficacy;  
tables dose_level*Response /cmh relrisk; 
run; 
  
 
 


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Appendix 1. List of Abbreviations 
Abbreviation 
Term 
AE 
adverse event 
ANOVA 
analysis of variance 
BPM 
beats per minute 
BP 
blood pressure 
CRF 
case report form 
CSR 
clinical study report 
DBP 
diastolic blood pressure 
DEX 
dexmedetomidine 
ECG 
electrocardiogram 
EtCO2 
end-tidal carbon dioxide 
EP 
enrolled population 
FAS 
full analysis set 
FDA 
Food and Drug Administration (United States) 
ITT 
intent-to-treat 
KG 
kilogram 
MAP 
mean arterial pressure 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
PAED 
Pediatric Anesthesia Emergence Delirium Scale 
PE 
Physical examination 
PI 
principal investigator 
PPP 
per-protocol Population 
PSSS 
Pediatric Sedation State Scale 
PT 
preferred term 
PREA 
Pediatric Research Equity Act 
PRO 
propofol 
RR 
respiratory rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
SOC 
system organ class 
SOP 
standard operating procedure 
SpO2 
saturation of peripheral oxygen 
TEAE 
treatment-emergent adverse event 
WHO  
World Health Organization 
WHODD 
World Health Organization Drug Dictionary