Final Clinical Study Report
Protocol C0801039

CLINICAL STUDY REPORT SYNOPSIS
Sponsor: Pfizer Inc
Investigational Product: PF-00914730
Clinical Study Report Synopsis: Protocol C0801039
Protocol Title: A Phase 3/4 Randomized, Double-Blind, Dose-Ranging Study of the Safety
and Efficacy of Dexmedetomidine (DEX) Used With Propofol (PRO) as Needed forProcedural Sedation of Pediatric Subjects ≥1 Month to <17 Years of age Undergoing MRI
Scans
Investigators: Refer to Appendix 16.1.4.1 for a list of investigators involved in this study.
Study Center(s): A total of 21 study sites in the United States and Japan randomized
participants in this study. Refer to Appendix 16.1.4.1 for a list of sites involved in this study.
Publications Based on the Study: None
Study Initiation Date: 18 February 2020 (First Participant First Visit)
Study Completion Date: 30 November 2021 (Last Participant Last Visit)
Report Date: 1 March 2022
Previous Report Date(s): Not applicable
Phase of Development: Phase 3/4
Study Objectives and Endpoints:
Table S1. Study Objectives and Endpoints
Objective
Primary Efficacy Objective:
Assess efficacy of DEX for pediatric procedural sedation
as measured by the percent of subjects at the high doselevel versus the low dose level in the combined age cohorts
who did not require concomitant PRO to achieve adequate
sedation.
Key Secondary Efficacy Objective:
Assess the efficacy of DEX for pediatric procedural
sedation as measured by the percent of subjects at the highdose level versus the low dose level in each age cohort
who did not require concomitant PRO to achieve adequate
sedation.

Endpoint
Primary Efficacy Endpoint:
Percent of subjects at the DEX high dose level versus the
low dose level in the combined age cohorts who did not
require concomitant PRO to complete the magnetic
resonance imaging (MRI).
Key Secondary Efficacy Endpoint:
Percent of subjects at the DEX high dose level versus the
low dose level in each age cohort who did not requireconcomitant PRO to complete the MRI.

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CLINICAL STUDY REPORT SYNOPSIS
Table S1. Study Objectives and Endpoints
Objective
Secondary Efficacy Objective(s):Explore the efficacy of DEX at the middle dose levelcompared to the high dose level and the low doselevel in both the overall sample and in each age
cohort as measured by the percent of subjects who did
not require concomitant PRO to achieve adequate
sedation.

Explore the efficacy of DEX by examining thepercent 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.

Exploratory Objective:
Examine the ease of maintenance of overall intraprocedural sedation using DEX.
Safety Objective:
Assess the safety of DEX used for procedural sedation ofpediatric subjects undergoing an MRI scan.

Endpoint
Secondary Efficacy Endpoint(s):Percent of subjects at the DEX middle dose levelcompared to the high dose level and the low doselevel in both the overall sample and in each age
cohort who did not require concomitant PRO tocomplete the MRI.
Percent of time at the target sedation rating scalescore (Pediatric Sedation State Scale [PSSS] rating of2) after the administration of the DEX loading doseand during the DEX maintenance infusion.
The amount of time from the start of the DEX loadingdose 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 received 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.
Exploratory Endpoint:
Anesthesiologist Assessment (a scoring of ease ofmaintenance of appropriate intra-procedural sedation level,
respiratory stability, hemodynamic stability, and subject
cooperation).
Safety Endpoints:
Incidence, seriousness, causality and severity oftreatment-emergent adverse events (TEAEs).

Percent of subjects who completed the MRI scan andrequired 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 arterialpressure (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 (AEs) of bradypnea, hypoxia and apnea.
Incidence of protocol-specified cardiac AEs ofhypotension, hypertension and bradycardia.
Incidence of protocol-specified AE of paradoxicalagitation reaction.

Incidence of protocol-specified AEs of bradypnea,
hypoxia, apnea, hypotension, hypertension,bradycardia and paradoxical agitation reaction
requiring intervention.

Incidence of DEX withdrawal-related AEs after
discontinuation of DEX infusion.

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Protocol C0801039

CLINICAL STUDY REPORT SYNOPSISMETHODS
Study Design: This was a randomized, double-blind, dose-ranging study of the efficacy andsafety of DEX when used with PRO as needed, for procedural sedation of pediatricparticipants ≥1 month to <17 years of age undergoing MRI scans.
This study included Screening, Day 1, Day 2 Follow-up, and Day 29 Long-term Follow-up
Visits. The Day 1 Visit comprised a Period 1 (MRI scan) Phase and Period 2 (Post-MRI
Recovery) Phase. The Day 2 Visit was a 24-hour follow-up, and the Day 29 Visit was a28-day follow-up.
A sufficient number of participants were planned to be screened to randomize approximately
120 participants (40 participants per dose level):
Age Cohort≥1 month to <2 years≥2 years to <17 years

Low Dose Group
20
20

Middle Dose Group20
20High Dose Group20
20

All eligible participants received double-blind treatment where one of 3 dose levels of DEX
were administered. Following completion of required procedures before randomization at the
Day 1 Visit, participants meeting entry criteria were randomly assigned to a low, middle orhigh dose level group (actual dose dependent on age) in a 1:1:1 ratio. Treatment was initiatedjust prior to the start of the MRI scan and continued through completion of the MRI scan.
Concomitant PRO may have been given to ensure adequate sedation.
Diagnosis and Main Criteria for Inclusion: The study population consisted of participants
aged ≥1 month and <17 years on Day 1, with American Society of Anesthesiologists
Physical Status I, II, or III, who required non-intubated, spontaneous breathing, moderate todeep sedation (NI-MDS) for an MRI study not expected to last >3 hours with an intensivist,
anesthesiologist, or other proceduralist in attendance. Participants whose weight at Screening
was less than the 10th percentile of weight for age and sex or was greater than the 95th
percentile of weight for age and sex (97th percentile in Japan), participants who had aplanned medical procedure during the MRI scan or post-MRI recovery period, andparticipants who required endotracheal intubation or laryngeal mask airway were excluded.
Study Treatment: Participants enrolled into the study were randomized to receive one of
3 DEX dosing regimens (Low, Middle, or High), each consisting of an intravenous (IV)loading dose that was immediately followed by an IV maintenance infusion that continued
for the duration of the MRI scan.
The loading and maintenance infusion doses were given at the stable, pre-defined doses as
described in Table S2 and Table S3 and were not modified, but the infusion may have been
discontinued if clinically indicated. The loading dose was administered over 10 minutes.

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CLINICAL STUDY REPORT SYNOPSIS
Table S2. Blinded Dose Levels for Participants ≥1 month to <2 years of age on Day 1
Dose Level
Low dose level
Middle dose level
High dose level

DEX Loading Dose
0.5 mcg/kg
1 mcg/kg
1.5 mcg/kg

DEX Maintenance Infusion Dose
0.5 mcg/kg/hour
1 mcg/kg/hour
1.5 mcg/kg/hour

Table S3. Blinded Dose Levels for Participants ≥2 years to <17 years of age on Day 1
Dose Level
Low dose level
Middle dose level
High dose level

DEX Loading Dose
0.5 mcg/kg
1.2 mcg/kg
2 mcg/kg

DEX Maintenance Infusion Dose
0.5 mcg/kg/hour
1 mcg/kg/hour
1.5 mcg/kg/hour

Once the DEX loading dose was administered and the maintenance dose started, if anadequate level of sedation was not achieved within 5 minutes after the start of the DEX
maintenance infusion, concomitant PRO may have been given per clinical judgment toensure that an adequate sedation level was achieved to start the scan. The target sedationlevel was 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.”).
Concomitant PRO was to be administered as needed through completion of the scan tomaintain adequate participant sedation per investigator clinical judgment. If it was needed,
PRO was to 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 have been given as needed for participant
movement/wakening. Following each additional PRO bolus, there must have been asimultaneous 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 havebeen made in 25 or 50 mcg/kg/min increments without a corresponding PRO bolus. The PRO
maintenance infusion may have also been decreased in 25 or 50 mcg/kg/min increments asneeded to maintain adequate participant sedation, or it may have been discontinued if
clinically indicated.
PRO is not approved for procedural sedation in the pediatric population, so in this study theuse of PRO was considered investigational.

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CLINICAL STUDY REPORT SYNOPSIS
Table S4. Investigational Product Description
Investigational Product
Description
Dexmedetomidinehydrochloride injection
200 mcg/2 mL (100mcg/mL) vial

Vendor Lot
Number17-202-DK
88-105-DK
06-098-DK
88-105-DK

Pfizer Lot Number

Strength/Potency

Dosage Form

20-003225
18-003179
19-003920
18-003376

100 mcg/mL

Solution

Efficacy Evaluations:
Investigational product administration details including start time, stop time and IV rate in
mL/hour were recorded on the case report form (CRF).
Concomitant medications and nonpharmacologic therapies were collected fromrandomization through the Day 29 Long-term Follow-up Visit and were recorded on the CRF
and source documents. PRO administration details including start time, stop time, bolus
doses in mg/kg and maintenance dose rates in mcg/kg/min were recorded on the CRF.
The PSSS sedation ratings were 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. The PSSS is a validated 6-point scale that is a measurement of the effectiveness andquality of procedural sedation in children. It is specifically designed for evaluating pediatricpatients undergoing sedation for diagnostic and therapeutic procedures, and measures aspects
of procedural sedation relating to the quality of sedation provided, including the control ofpain, anxiety, movement, and adverse side effects.
The Modified Aldrete Score was performed on arrival at the post-procedure recovery area
(Day 1, Period 2) and every 15 (±5) minutes until the subject met criteria to leave that area.
The Modified Aldrete Score is 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.
The Anesthesiologist Assessment was completed once the subject was in the post-procedure
recovery area (Day 1, Period 2). It is a 4-item rating where each item is scored along a rangeof “not difficult at all”, “very stable” or “very cooperative” to “extremely difficult”,“extremely unstable” or “extremely uncooperative”. It includes the ease of maintenance ofsedation level, hemodynamic stability, respiratory stability and subject cooperation during
the MRI scan.
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and/or Other Evaluations:
No pharmacokinetic, pharmacodynamic, pharmacogenomic, or other evaluations were donein this study.
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CLINICAL STUDY REPORT SYNOPSIS
Safety Evaluations: Safety evaluations included serious AEs (SAEs), protocol-specified
AEs (changes in BP and HR, paradoxical agitation reactions, and changes in respiratory rate,
end-tidal carbon dioxide [EtCO2], and saturation of peripheral oxygen [SpO2]), prior andconcomitant treatments, Pediatric Anesthesia Emergence Delirium Scale (PAED), physicalexamination, cardiac telemetry, vital signs, and pregnancy test.
The PAED was used to measure emergence delirium in participants post-MRI. It is a 5-item
rating scale where each item is scored along a range of “not at all” to “extremely”. The scoresof each item are summed to obtain a total PAED score where the degree of emergencedelirium increases directly with the total score.
Statistical Methods:
The statistical analyses were performed using SAS, version 9.2 or later. All statistical tests
were two-sided and p-values ≤0.0500, after rounding to 4 decimal places, were considered
statistically significant unless otherwise specified.
Efficacy
Primary Endpoint: The DEX high versus low dose group was compared byMantel-Haenszel test in PROC FREQ. The difference between high and low dose groups wasassessed using odds ratios and 95% confidence intervals (CIs) on the odds ratio.
Additionally, 95% CIs on the percent of subjects not requiring supplemental PRO were
provided by dose level using exact 95% CIs. All age cohorts were combined. The primary
analysis was performed based on the Full Analysis Set (FAS). The same analysis was
repeated on the Efficacy Evaluable Population (EEP), the Per Protocol Population (PPP), andthe Japanese Population Set (JPS).
Key Secondary Endpoint: The method of analysis for the primary endpoint was repeated
for the key secondary endpoint for each age cohort based on the FAS. The same analysis was
repeated on the EEP, PPP, and JPS.
Secondary Endpoints: All secondary endpoints were summarized overall and by age cohort
for the FAS and JPS.


Percentage of subjects at the middle dose level who did not require propofol tocomplete the MRI: The method of analysis for the primary endpoint was repeated for thesecondary endpoints comparing the low dose to the medium dose and the medium dose to
the high dose.

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CLINICAL STUDY REPORT SYNOPSIS

Percentage of time at the target sedation scale: The difference between dose levels inpercent of time at the target sedation rating scale score (PSSS rating of 2) during the DEX
maintenance infusion was assessed using the Wilcoxon test. In addition, the difference
between dose levels in the percentage of time at PSSS rating of 2 or 3 during the DEX
maintenance infusion was assessed using the Wilcoxon test. The percentage of time at thetarget PSSS rating of 2 during the DEX maintenance infusion with/without PRO wassummarized by dose level and age cohort.

Time to first propofol bolus administration: The time to first dose of concomitant PRO
was summarized with Kaplan-Meier estimates. Between dose group comparisons weremade with log-rank tests. Kaplan-Meier plots of time from the start of DEX loading dose
infusion to the time of first PRO bolus infusion were performed by dose level and age
cohort.



Emergence time: Time (minutes) from completion of MRI to time a participant firstreceives an Aldrete score of 9 or greater was summarized using the Kaplan-Meiermethod. Between dose group comparisons were made with log-rank test. Kaplan-Meierplots of emergence time by dose level and age cohort were performed.



Total amount of concomitant propofol: The total amount (mcg/kg) and the averageinfusion rate (mcg/kg/min), number of boluses and duration of PRO given for sedation
were summarized for each dose level with descriptive statistics. The difference between
dose groups (high dose and low dose, and medium dose and low dose and high doseversus medium dose) was assessed using analysis of variance (ANOVA) whenassumption of normal distribution is reasonable or by nonparametric tests when thisassumption is not met.

Exploratory Endpoint: The Anesthesiologist Assessment was summarized descriptively foreach of the 4 items overall and by age cohort.
SafetyAnalysis of safety endpoints included TEAEs, DEX withdrawal symptoms, laboratory data,
vital signs, MRI scan, and PAED.
All safety analyses were performed on the safety analysis set and JPS.
Descriptive statistics were calculated for quantitative safety data as well as for the change
from baseline, when appropriate. Data analyses were presented by dose level, overall andwithin each age cohort.
TEAEs were analyzed by dose level, overall and by age cohort. However, all AEs were
presented in data listings.

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CLINICAL STUDY REPORT SYNOPSISRESULTS
Subject Disposition and Demography:
Of 141 participants screened, 12 participants did not continue to randomization, 1 participant
was randomized but not enrolled, and the remaining 128 were randomized and enrolled:
44 to the low dose group, 43 to the middle dose group, and 41 to the high dose group.
Six participants were randomized and enrolled but not treated: 2 in the low dose group, 1 in
the middle dose group, and 3 in the high dose group. Five participants discontinued study
treatment: 3 due to AEs and 2 due to other reasons. All 122 treated participants completed
the Day 29 Follow-up Phase.
In the ≥1 month to <2 years age cohort, 59 participants were randomized and treated with
DEX: 20 to the low dose group, 21 to the middle dose group, and 18 to the high dose group.
Four participants were randomized but not treated: 1 in the low dose group, 1 in the middle
dose group, and 2 in the high dose group. Two of 59 participants (3.4%) discontinued study
treatment: 1 participant in the low dose group due to an AE and 1 participant in the high dosegroup due to other (protocol deviation). All 59 treated participants completed Day 1(Period 1 [MRI scan]) through the Day 29 (Follow-up) Phase.
In the ≥2 years to <17 years age cohort, 63 participants were randomized and treated with
DEX: 22 to the low dose group, 21 to the middle dose group, and 20 to the high dose group.
Two participants were randomized but not treated: 1 in the low dose group and 1 in the highdose group. Three of 63 participants (4.8%) discontinued study treatment: 2 participants due
to AEs (1 each in the middle and high dose groups) and 1 participant in the high dose groupdue to other (medication error). All 63 treated participants completed Day 1 (Period 1 [MRI
scan]) through the Day 29 (Follow-up) Phase.
Note: All 63 treated participants in the ≥2 years to <17 years age cohort completed Day 1(Period 1); however, 62 participants are reported as completed in the study database.
One participant was incorrectly reported as having discontinued Day 1, Period 1.
No participant discontinued from the study due to a COVID-19-related AE.
In the ≥1 month to <2 years age cohort, mean age was similar across dose groups. There wasa higher proportion of female participants (60.0%) in the low dose group compared with the
middle and high dose groups (42.9% and 44.4%, respectively). Additionally, the proportionof White participants was lower in the middle dose group than in the high and low dosegroups, and the proportion of Asian participants was higher in the middle dose group than in
the high and low dose groups. Overall, mean age was 0.95 years, and the majority ofparticipants were White or Asian (29 participants [49.2%] and 15 participants [25.4%],
respectively).

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CLINICAL STUDY REPORT SYNOPSIS
In the ≥2 years to <17 years age cohort, demographic characteristics (age, gender, and race)
were generally balanced across treatment groups. Overall, mean age was 6.90 years, and the
majority of participants were White or Asian (28 participants [44.4%] and 26 participants[41.3%], respectively).
Baseline characteristics (height/body length, weight, temperature) were generally balanced
across dose groups in both age cohorts.
Efficacy Results:
Primary Endpoint
A significantly higher percentage of participants at the DEX high dose level completed the
MRI without concomitant PRO compared with the DEX low dose level (p<0.001; Table S5).
In the combined age cohorts, an increase in the percentage of participants who did not requireconcomitant PRO to complete the MRI was observed with increasing DEX dose: 14.3% in
the low dose group, 35.7% in the middle dose group, and 63.2% in the high dose group.

Table S5. Percent of Participants who do not Require Concomitant PRO to
Complete MRI (High Dose vs Low Dose)- Mantel-Haenszel Test - Full
Analysis Set

Total

N=122

High Dosen (%) 95% CI*

Low Dosen (%)95% CI*

Odds ratio
95% CI**

p-value**

24/38(63.2%)(0.46,0.78)

6/42(14.3%)(0.05,0.29)

0.10(0.03,0.29)<0.001

Participants that did not require Propofol for sedation based upon achieving target sedation.
Odds ratio was assessed for the difference between treatment groups in percentage of Participants that did not require
Propofol for sedation* Exact 95% CI of proportion of not requiring PRO in each dose level.
**p-values are from PROC FREQ CMH statistics.CI is confidence interval of odds ratio.
PFIZER CONFIDENTIAL SDTM Creation: 21DEC2021 (06:07) Source Data: adpr Table Generation: 07FEB2022(07:26)(Database snapshot date : 17DEC2021) Output File: ./cdisc_csr/C0801039/adcm_s011
Table 14.2.1.1 Dexmedetomidine is for Pfizer internal use.

Key Secondary Endpoint
In both age cohorts, a significantly higher percentage of participants at the DEX high doselevel completed the MRI without concomitant PRO compared with the DEX low dose level(p≤0.022; Table S6).
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CLINICAL STUDY REPORT SYNOPSIS
In the ≥2 years to <17 years age cohort, an increase in the percentage of participants who did
not require concomitant PRO to complete the MRI was observed with increasing DEX dose:
13.6% in the low dose group, 61.9% in the middle dose group, and 75.0% in the high dosegroup. In the ≥1 month to <2 years age cohort, there was a higher percentage of participants
not requiring PRO in the high dose group (50.0%) compared with the middle and low dosegroups (9.5% and 15.0%, respectively).

Table S6. Percent of Participants who do not Require Concomitant PRO to
Complete MRI (High Dose vs Low Dose) by Age Cohort - MantelHaenszel Test - Full Analysis Set
High Dosen (%) 95% CI*>=1mn-<2yr

N=59>=2yr-<17yr

N=63

Low Dosen (%)95% CI*

9/18 (50.0%) (0.26,0.74) 3/20 (15.0%) (0.03,0.38)
15/20 (75.0%)(0.51,0.91)

3/22 (13.6%) (0.03,0.35)

Odds ratio
95% CI**

p-value**0.18(0.04,0.82)

0.022

0.05(0.01,0.26)<0.001

Participants that did not require Propofol for sedation within age group based upon achieving target sedation.
Odds ratio was assessed the difference between treatment groups in Percent of Participants that did not require Propofol
for sedation.
* Exact 95% CI of proportion of not requiring PRO in each dose level.
**p-values are from PROC FREQ CMH statistics.CI is confidence interval of odds ratio.
PFIZER CONFIDENTIAL SDTM Creation: 21DEC2021 (06:08) Source Data: adpr Table Generation: 07FEB2022(07:29)(Database snapshot date : 17DEC2021) Output File: ./cdisc_csr/C0801039/adcm_s0221
Table 14.2.1.2 Dexmedetomidine is for Pfizer internal use.

Secondary EndpointsPercentage of Participants at the DEX Middle Dose Level Not Requiring Propofol:In the combined age cohorts, a significantly higher percentage of participants completed
the MRI without concomitant PRO at the DEX middle dose level compared with the
DEX low dose level (p=0.024), and at the DEX high dose level compared with the DEX
middle dose level (p=0.015).
In the ≥2 years to <17 years age cohort, a significantly higher percentage of participantsat the DEX middle dose level completed the MRI without concomitant PRO comparedwith the DEX low dose level (p=0.001). A higher percentage of participants at the DEX
high dose level completed the MRI without concomitant PRO compared with the DEX
middle dose level (p=0.374).

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CLINICAL STUDY REPORT SYNOPSIS
In the ≥1 month to <2 years age cohort, a significantly higher percentage of participantsat the DEX high dose level completed the MRI without concomitant PRO compared with
the DEX middle dose level (p=0.006). A similar percentage of participants at the DEX
middle and low dose levels completed the MRI without concomitant PRO (p=0.597).


Pediatric Sedation State Scale: In the DEX high dose group, participants in both the
combined and individual age cohorts were at the target sedation rating scale score (PSSSof 2) for a mean >87% of the time during the DEX maintenance infusion. In both the
combined and individual age cohorts, an increase in the percentage of time at the target
sedation rating scale score (PSSS of 2) was observed with increasing DEX dose. The
percentage of time at the target sedation rating scale score was significantly higher forparticipants randomized to the DEX high dose level compared with the DEX low doselevel in both the combined and individual age cohorts, supportive of the primary and key
secondary endpoint results.

Amount of Time to First Propofol Bolus: In the combined age cohorts, an increase in
the time to the first PRO bolus infusion was observed with increasing DEX dose. In boththe combined and individual age cohorts, the time to the first PRO bolus infusion was
significantly longer for participants randomized to the DEX high dose level comparedwith the DEX low dose level (p≤0.005), supportive of the primary and key secondary
endpoint results.

Emergence Time: No meaningful differences in emergence time (time from completionof MRI to Modified Aldrete score ≥9) were observed between dose levels for the
combined age cohorts or either individual age cohort (p≥0.051). In the combined age
cohorts, the median emergence time increased with increasing DEX dose: 35.0 minutes(95% CI: 21.0, 41.0) for the low dose, 42.5 minutes (95% CI: 35.0, 52.0) for the middle
dose, and 45.5 minutes (95% CI: 35.0, 54.0) for the high dose. A similar pattern wasobserved for the individual age cohorts.

Proportion of Participants who Received Propofol: In the combined age cohorts andthe ≥2 years to <17 years age cohort, a decrease in the proportion of participantsreceiving PRO was observed with increasing DEX dose.

Amount of Propofol Required to Complete the MRI: Analysis of the amount of PRO
required to complete the MRI did not show any notable or significant differences
between dose levels for the combined age cohorts or either individual age cohort. In the
combined age cohorts, the mean total cumulative PRO dose per kg was lower for the
DEX high dose level (3426.4 mcg/kg) compared with the DEX middle or low dose levels(4810.7 and 4828.6 mcg/kg, respectively). Similar results were observed for each age
cohort.

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CLINICAL STUDY REPORT SYNOPSIS
Exploratory Endpoint
Anesthesiologist Assessment: In general, mean anesthesiologist assessment scores (ease ofmaintenance of sedation level, hemodynamic stability, respiratory stability, and subject
cooperation) were low, ranging from 0.7 to 4.6 on a scale from 0 to 10, where 0 equals notdifficult at all, very stable, or very cooperative. In each dose group, mean scores were higher
for the ≥1 month to <2 years age cohort compared with the ≥2 years to <17 years age cohort.
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, Immunogenicity and/or
Other Results: No pharmacokinetic, pharmacodynamic, pharmacogenomic, or otherevaluations were done in this study.
Safety Results: The proportion of participants with all-causality TEAEs was similar acrossdose groups (Table S7).
All TEAEs were mild or moderate; none were severe.

One participant experienced a treatment-emergent SAE of hypertension. The event wasconsidered moderate in severity and study treatment was withdrawn. In addition,
1 participant experienced severe SAEs of acute respiratory failure and sepsis on Day 30
following planned
surgery on Day 24, and 1 participant (who underwent an
MRI for assessment of an underlying) experienced 2 mild SAEs of
seizure on Days 2 and 21 that were reported as non-serious by the investigator but
upgraded to serious by the sponsor.

Three participants, 1 in each dose group, discontinued study treatment due to TEAEs(bradycardia, bradypnea, and hypertension)

No participant discontinued the study due to an AE.



No deaths were reported during this study.

No participant reported any AE related to COVID-19.

The proportion of participants with treatment-related TEAEs was higher for the DEX middle
dose group (37 participants [88.1%]) than the high and low dose groups (29 participants[76.3%] and 32 participants [76.2%], respectively).

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Table S7. Treatment-Emergent Adverse Events (All Causalities) - Safety Population
Low Dose Middle Dose High Dose

Total

Number (%) of Participants

n (%)

n (%)

n (%)

n (%)

Participants evaluable for adverse events

42

42

38

122

Number of adverse events

102

96

91

289

Participants with adverse events

38 (90.5)

39 (92.9)

36 (94.7)

113 (92.6)

Participants with serious adverse events00

1 (2.6)

1 (0.8)

Participants with severe adverse events

0

0

0

0

Participants discontinued from study due to adverse eventsa

0

0

0

0

Participants discontinued study drug due to AE and continue
Studyb1 (2.4)1 (2.4)1 (2.6)3 (2.5)

Includes all data collected since the first dose of study drug.
Except for the Number of Adverse Events participants are counted only once per treatment in each row.
Serious Adverse Events - according to the investigator's assessment.
a. Participants who have an AE record that indicates that the AE caused the participant to be discontinued from the study
b. Participants who have an AE record that indicates that Action Taken with Study Treatment was Drug Withdrawn but
AE did not Cause the Participant to be discontinued from Study
MedDRA v24.1 coding dictionary applied.
PFIZER CONFIDENTIAL SDTM Creation: 21DEC2021 (06:07) Source Data: adae Table Generation: 08FEB2022(14:39)(Database snapshot date : 17DEC2021) Output File: ./cdisc_csr/C0801039/adae_s010
Table 14.3.1.2.1 Dexmedetomidine is for Pfizer internal use.



Incidence of TEAEs: The most commonly reported all-causality TEAEs by PT (≥5%
participants in any dose group) were bradypnea, bradycardia, hypertension, hypotension,
hypoxia, diastolic hypertension, systolic hypertension, tachycardia. In the combined age
cohorts and each age cohort, decreases in bradypnea, hypoxia, and hypotension andincreases in bradycardia and hypertension were observed with increasing DEX dose.
The majority of all-causality TEAEs were mild, except for 4 participants who reported
moderate all-causality TEAEs: 2 participants in the DEX low dose group (1 participant
each with hypoxia and hypotension) and 2 participants in the DEX high dose group(1 participant with bradycardia, and 1 participant with bradycardia, tachycardia, andhypertension). No participant reported a severe all-causality TEAE.

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Protocol-Specified Respiratory TEAEs: Overall, in the combined age cohorts, the mostfrequently reported protocol-specified respiratory TEAE was bradypnea (82 participants[67.2%]). A decrease in the proportion of participants with bradypnea was observed withincreasing DEX dose: DEX low dose level (33 participants [78.6%]), DEX middle doselevel (27 participants [64.3%]), and DEX high dose level (22 participants [57.9%]). A
similar decrease in hypoxia was observed with increasing DEX dose: DEX low doselevel (6 participants [14.3%]), DEX middle dose level (3 participants [7.1%]), and DEX
high dose level (1 participant [2.6%]).

Protocol-Specified Cardiac TEAEs: Overall, in the combined age cohorts, the mostfrequently reported protocol-specified cardiac TEAE was bradycardia (75 participants[61.5%]). A higher proportion of participants at the DEX high dose level (27 participants[71.1%]) reported bradycardia compared with the low and middle dose levels(24 participants [57.1%] each). Increases in bradycardia and, hypertension, and decreases
in hypotension were observed with increasing DEX dose, consistent with the known
pharmacology of DEX.



Protocol-Specified TEAEs Requiring Intervention: Overall, in the combined age
cohorts, 5 participants (4.1%) experienced protocol-specified TEAEs requiring
intervention: 2 participants (4.8%) in the low dose group, 1 participant (2.4%) in the
middle dose group, and 2 participants (5.3%) in the high dose group. Events ofbradycardia requiring intervention were reported by 2 participants, both in the high dosegroup. All other protocol-specified TEAEs requiring intervention (bradypnea, hypoxia,
hypertension, and hypotension) were reported by 1 participant each. Two additional
participants experienced TEAEs that required intervention: 1 participant experienced a
TEAE of diastolic hypertension that required intervention, but the event was notconsidered a protocol-specific TEAE, and 1 participant experienced protocol-specified
TEAEs of bradypnea and hypoxia that required intervention, but the interventions forthese events were reported incorrectly in the CRF; therefore, these events were notincluded as TEAEs requiring intervention. No participant required artificial ventilation.

Withdrawal-Related Adverse Events: Overall, 3 participants experienced
withdrawal-related AEs (1 event of agitation and 2 events of anesthetic complicationneurological [investigator entry: emergence delirium]) after discontinuation of the DEX
infusion. All the events were considered mild, related to study treatment, and resolved.



Vital Signs: Baseline mean vital sign parameters (HR, blood pressure, respiratory rate,
and oxygen saturation) were generally similar within each age cohort for each of the doselevels. Decreases in mean HR, SBP, DBP, and MAP were observed within each age
cohort and across dose levels, consistent with the known pharmacology of DEX. At theparticipant level, decreases that met the protocol-specified threshold for reporting as
TEAEs were mild to moderate in severity. Of participants with protocol-specified
TEAEs, few required intervention to restore hemodynamic stability and no participant
required artificial ventilation.
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Hemodynamic Stability: Overall (total DEX), in both the combined and individual age
cohorts, the ratio for the time outside of the hemodynamically stable range was 0.5 orlower, indicating that on average, the time outside of the hemodynamically stable range
was less than or equal to half of the time period of evaluation. There were no apparent
dose-related effects in the combined age cohorts or in either age cohort.



Artificial Ventilation or Intervention: No participant required artificial ventilation to
restore baseline or normal hemodynamic status. Overall, 7 of 122 participants (5.7%)
required intervention to restore baseline or normal hemodynamic status. Interventions
included atropine, lactated ringer fluids, oxygen supplementation, hydralazine, andglycopyrronium bromide.



Pediatric Anesthesia Emergence Delirium Scale: The mean total PAED score was
generally similar across dose groups and age cohorts at the timepoints assessed, with the
exception of the ≥1 month to <2 years age cohort at the high dose level. At the time
participants first awoke in the recovery area (0 minutes), a total of 11 of 122 participants
had a PAED score ≥10: 5 in the high dose group, 2 in the middle dose group, and 4 in the
low dose group. With the exception of 2 participants in the ≥1 month to <2 years age
cohort at the high dose level, no participant had a PAED score ≥10 within 45 minutes of
waking in the recovery area.

Conclusion(s):Efficacy
The primary objective of the study was met. The DEX high dose level demonstrated
clinically meaningful efficacy and was superior to the low dose level to obtain sufficient
sedative effect by a single agent for procedural sedation of pediatric participants undergoing
MRI scan.


The DEX high dose level was superior to the low dose level for the primary efficacy
endpoint, percent of participants in the combined age cohorts who did not requireconcomitant PRO to complete the MRI.

The results for the key secondary efficacy endpoint, percent of participants in each age
cohort who did not require concomitant PRO to complete the MRI, were consistent withthe overall study population.

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The secondary objectives were met and supported the primary and key secondary endpoint
results.
An increase in the percentage of participants who did not require concomitant PRO tocomplete the MRI was observed with increasing DEX dose in the combined age cohorts
and the ≥2 years to <17 years age cohort. In the ≥1 month to <2 years age cohort, there
was a higher percentage of participants not requiring PRO in the high dose groupcompared with the middle and low dose groups.

The secondary endpoints of percentage of time at the target sedation rating scale score
and the amount of time to first PRO bolus support the results of the primary and key
secondary efficacy endpoints.



In general, mean anesthesiologist assessment scores (ease of maintenance of sedationlevel, hemodynamic stability, respiratory stability, and subject cooperation) were low.

SafetyThe doses of DEX administered in this study for procedural sedation were well tolerated inpediatric participants undergoing an MRI scan and the safety profile is consistent with the
known safety profile in adults. All reported TEAEs were mild to moderate in severity and no
unexpected TEAEs were reported. Few participants required intervention and no participant
required artificial ventilation.

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