Dose Escalation Pharmacokinetic Study of Intranasal Atomized Dexmedetomidine in Pediatric Patients With Congenital Heart Disease
Phase: PHASE1
Conditions: Dexmedetomidine, Congenital Heart Disease
Sponsor: Children's Hospital of Philadelphia

 
Protocol Version 6March2020 
 
 
Title: 
Dose Escalation Pharmacokinetic Study of Intranasal 
Atomized Dexmedetomidine in Pediatric Patients with 
Congenital Heart Disease  
Short Title 
Pediatric Pharmacokinetics of Intranasal Dexmedetomidine  
Drug or Device 
Name(s): 
Dexmedetomidine 
FDA IND 
 
Regulatory Sponsor: 
Dr. Athena Zuppa 
eIRB Number 
17-014084 
Protocol Date: 
March 6, 2020 
Amendment 1 Date:  
Amendment 3 Date:  
Amendment 2 Date: 
Amendment 4 Date: 
Sponsor: Athena Zuppa, MD, MSCE 
The Children’s Hospital of Philadelphia 
CRTB 4008 
Philadelphia, PA, 19104 
Phone: 609-760-4354 
email: zuppa@chop.edu 
 
Study and Site Principal Investigator: Kelly Grogan, MD 
The Children’s Hospital of Philadelphia 
3401 Civic Center Blvd, Suite 12NW40 
Philadelphia, PA, 19104 
Phone: 410-279-6994 
email: grogank@chop.edu 
 
Co-Investigator:  Susan Nicolson, MD 
The Children’s Hospital of Philadelphia 
3401 Civic Center Blvd, Suite 12NW40 
Philadelphia, PA, 19104 
Phone: 609-410-2892 
email: Nicolson@chop.edu 
  

 
 
 
 
 
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TABLE OF CONTENTS 
Table of Contents ................................................................................................................. iii 
Abbreviations and Definitions of Terms .............................................................................. v 
Abstract .................................................................................................................................. vi 
Protocol Synopsis ................................................................................................................ viii 
Table 1: Schedule of Study Procedures ............................................................................ xiii 
Figure 1: Study Diagram .................................................................................................... xiv 
1 
BACKGROUND INFORMATION AND RATIONALE ......................................................................... 1 
1.1 
INTRODUCTION ......................................................................................................................................... 1 
1.2 
NAME AND DESCRIPTION OF INVESTIGATIONAL PRODUCT OR INTERVENTION ........................................ 2 
1.3 
FINDINGS FROM NON-CLINICAL AND CLINICAL STUDIES ........................................................................ 3 
1.3.1 
Non-Clinical Studies ........................................................................................................................ 3 
1.3.2 
Clinical Studies ................................................................................................................................ 3 
1.4 
SELECTION OF DRUGS AND DOSAGES…………………………………………………………………...6 
1.5   RELEVANT LITERATUREA AND DATA ....................................................................................................... 8 
1.6 
COMPLIANCE STATEMENT ....................................................................................................................... 8 
2 
STUDY OBJECTIVES ................................................................................................................................. 8 
2.1 
PRIMARY OBJECTIVE (OR AIM) ................................................................................................................ 8 
2.2 
SECONDARY OBJECTIVES (OR AIM) ......................................................................................................... 8 
3 
INVESTIGATIONAL PLAN ...................................................................................................................... 9 
3.1 
GENERAL SCHEMA OF STUDY DESIGN ..................................................................................................... 9 
3.1.1 
Screening Phase ............................................................................................................................... 9 
3.1.2 
Study Treatment Phase (start of the study intervention) .................................................................. 9 
3.2 
ALLOCATION TO TREATMENT GROUPS AND BLINDING .......................................................................... 10 
3.3 
STUDY DURATION, ENROLLMENT AND NUMBER OF SITES .................................................................... 10 
3.3.1 
Duration of Study Participation ..................................................................................................... 10 
3.3.2 
Total Number of Study Sites/Total Number of Subjects Projected ................................................ 10 
3.4 
STUDY POPULATION ............................................................................................................................... 11 
3.4.1 
Inclusion Criteria ........................................................................................................................... 11 
3.4.2 
Exclusion Criteria .......................................................................................................................... 12 
4 
STUDY PROCEDURES ............................................................................................................................ 12 
4.1 
SCREENING VISIT ................................................................................................................................... 12 
4.2 
STUDY TREATMENT PHASE .................................................................................................................... 13 
4.2.1 
Visit 1 ............................................................................................................................................. 13 
4.3 
CONCOMITANT MEDICATION ................................................................................................................. 13 
4.4 
RESCUE MEDICATION ADMINISTRATION ............................................................................................... 13 
4.5 
SUBJECT COMPLETION/WITHDRAWAL ................................................................................................... 13 
4.5.1 
Early Termination Study Visit ........................................................................................................ 14 
5 
STUDY EVALUATIONS AND MEASUREMENTS .............................................................................. 14 
5.1 
SCREENING AND MONITORING EVALUATIONS AND MEASUREMENTS .................................................... 14 
5.1.1 
Medical Record Review ................................................................................................................. 14 
5.1.2 
Vital Signs ...................................................................................................................................... 14 
5.2 
PHARMACOKINETIC EVALUATION .......................................................................................................... 14 
5.3 
SAFETY EVALUATION ............................................................................................................................ 15 
6 
STATISTICAL CONSIDERATIONS ...................................................................................................... 17 
6.1 
PRIMARY ENDPOINT ............................................................................................................................... 17 
6.2 
SECONDARY ENDPOINTS ........................................................................................................................ 17 

 
 
 
 
 
 
 
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6.3 
STATISTICAL METHODS ......................................................................................................................... 17 
6.3.1 
Baseline Data ................................................................................................................................. 17 
6.3.2 
Pharmacokinetic Analysis .............................................................................................................. 17 
6.3.3 
Safety Analysis ............................................................................................................................... 18 
6.4 
SAMPLE SIZE AND POWER ...................................................................................................................... 18 
6.5 
INTERIM ANALYSIS ................................................................................................................................ 19 
7 
STUDY MEDICATION (STUDY DEVICE OR OTHER STUDY INTERVENTION) ...................... 19 
7.1 
DESCRIPTION .......................................................................................................................................... 19 
7.1.1 
Packaging ....................................................................................................................................... 19 
7.1.2 
Labeling ......................................................................................................................................... 20 
7.1.3 
Dosing ............................................................................................................................................ 20 
7.1.4 
Treatment Compliance and Adherence .......................................................................................... 20 
7.1.5 
Drug Accountability ....................................................................................................................... 21 
8 
SAFETY MANAGEMENT ....................................................................................................................... 21 
8.1 
CLINICAL ADVERSE EVENTS .................................................................................................................. 21 
8.2 
ADVERSE EVENT REPORTING ................................................................................................................. 21 
8.3 
DEFINITION OF AN ADVERSE EVENT ...................................................................................................... 21 
8.4 
DEFINITION OF A SERIOUS ADVERSE EVENT (SAE) ............................................................................... 22 
8.4.1 
Relationship of SAE to study drug or other intervention ............................................................... 22 
8.5 
IRB/IEC NOTIFICATION OF SAES AND OTHER UNANTICIPATED PROBLEMS ......................................... 23 
8.5.1 FOLLOW-UP REPORT ............................................................................................................................... 23 
8.6 
INVESTIGATOR REPORTING REQUIREMENTS TO SPONSOR ..................................................................... 23 
8.7 
FDA NOTIFICATIONS OF SAES/IND SAFETY REPORTS TO THE FDA .................................................... 24 
8.8 
STUDY STOPPING CRITERIA ................................................................................................................... 24 
9 
STUDY ADMINISTRATION ................................................................................................................... 24 
9.1 
TREATMENT ASSIGNMENT METHODS .................................................................................................... 24 
9.2 
DATA COLLECTION AND MANAGEMENT ................................................................................................ 25 
9.3 
CONFIDENTIALITY .................................................................................................................................. 25 
9.4 
REGULATORY AND ETHICAL CONSIDERATIONS ..................................................................................... 25 
9.4.1 
Data and Safety Monitoring Plan .................................................................................................. 25 
9.4.2 
Risk Assessment .............................................................................................................................. 26 
9.4.3 
Potential Benefits of Trial Participation ........................................................................................ 26 
9.4.4 
Risk-Benefit Assessment ................................................................................................................. 26 
9.5 
RECRUITMENT STRATEGY ...................................................................................................................... 26 
9.6 
INFORMED CONSENT/ASSENT AND HIPAA AUTHORIZATION ................................................................ 27 
9.6.1 
Waiver of Assent ............................................................................................................................. 27 
9.7 
PAYMENT TO SUBJECTS/FAMILIES ......................................................................................................... 27 
10 
PUBLICATION ........................................................................................................................................ 27 
11 
REFERENCES .......................................................................................................................................... 28 
Appendix I ............................................................................................................................. 30 
 
 
 
 
 
 

 
 
 
 
 
 
 
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ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
AE 
 
Adverse Events 
ALT 
 
Alanine Aminotransferase 
ASA 
 
American Society of Anesthesiology 
BPM 
 
Beats per minute 
CHOP  
Children’s Hospital of Philadelphia 
CICU              Cardiac Intensive Care Unit 
CPRU  
Cardiac Prep and Recovery Unit 
DBP 
 
Diastolic Blood Pressure 
DLT 
 
Dose Limiting Toxicities 
FDA 
 
Federal Drug Administration 
HR 
 
Heart Rate 
ICU 
 
Intensive Care Unit 
IDS 
 
Investigational Drug Services 
IN 
 
Intranasal 
IV 
 
Intravenous 
MAP 
 
Mean Arterial Pressure 
mL 
 
Milliliter 
MTD  
Maximum tolerated dose 
NIH 
 
National Institutes of Health 
ORC 
 
Office of Research Compliance 
PACU  
Post Anesthesia Care Unit 
PD 
 
Pharmacodynamics 
PG 
 
Picograms 
PK 
 
Pharmacokinetics 
SAE 
 
Significant adverse events 
SBP 
 
Systolic Blood Pressure 
UMSS  
University of Michigan Sedation Scale 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
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ABSTRACT 
Context:   
The main goals of premedication in children are to facilitate a smooth separation from the 
parents and to ease the induction of anesthesia.  Dexmedetomidine is a highly selective a2-
adrenergic receptor agonist with sedative, anxiolytic, and analgesic properties.  While off-
label in its use, intranasal dexmedetomidine is becoming a popular premedication and 
sedative in children because it is easily administered and well tolerated. Although it appears 
that intranasal dexmedetomidine is a safe, effective premedication in children, little data 
have been published regarding its onset time, duration of action, and optimal dose.  
 
Objectives: 
Primary  
• 
To determine peak plasma drug concentration level of dexmedetomidine following 
intranasal administration. 
• 
To determine time of peak drug concentration level of dexmedetomidine following 
intranasal administration. 
• 
To perform inter-subject cohort dose escalation of intranasal dexmedetomidine guided 
by associated dose-limiting adverse events and/or maximum plasma level not to exceed 
1000 pg/mL. 
Secondary 
• 
To determine if dexmedetomidine pharmacokinetics are age dependent. 
• 
To determine if dexmedetomidine pharmacokinetics are different when administered 
intranasally to patients who are spontaneously ventilating versus those that are 
mechanically ventilated via an oral endotracheal tube. 
Study Design:  
Prospective open-label inter-subject cohort dose-escalation pharmacokinetic and 
pharmacodynamic study 
Setting/Participants: 
Children’s Hospital of Philadelphia 
Single Center 
Pediatric cardiac catheterization laboratory 
Children age ≥1 mo to ≤ 6 yr undergoing an elective diagnostic or interventional cardiac 
catheterization procedure estimated to last greater than 2 or 3 hours depending on the cohort 
Study Interventions and Measures:  
Intranasal dexmedetomidine 

 
 
 
 
 
 
 
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Dexmedetomidine plasma concentration will be determined using a validated high-
performance liquid chromatography-tandem mass spectrometry assay at times: 0, 10, 15, 20, 
30, 45, 60, 90, 120, 180, 240, and 300 minutes post drug administration.  
 
 

 
 
 
 
 
 
 
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PROTOCOL SYNOPSIS 
Study Title 
Dose Escalation Pharmacokinetic Study of Atomized Intranasal 
Dexmedetomidine in Pediatric Patients with Congenital Heart 
Disease 
Funder 
J.J Templeton Endowed Chair Funds 
Clinical Phase 
Phase I 
Study Rationale 
The high anxiety levels that children may experience during the 
preoperative period may be associated with negative medical, 
psychological, and social consequences. To reduce this stress, and 
to facilitate separation from parents and the induction of anesthesia, 
children are often given a sedative prior to undergoing a procedure.  
Dexmedetomidine is a highly selective a2-adrenergic receptor 
agonist with sedative, anxiolytic, and analgesic properties.  While 
off-label in its use, the administration of dexmedetomidine by the 
intranasal route has become a popular and effective technique for 
sedation in children because it is non-invasive, easy to administer, 
well tolerated, and relatively fast in onset.  Despite this, little 
consistent data have been published on its onset time, duration of 
action, or optimal dose. The only available PK data on 
dexmedetomidine in pediatric patients is in children who were 
administered IV dexmedetomidine.  We are proposing a prospective 
open-label inter-subject cohort dose-escalation pharmacokinetic 
study to obtain peak dexmedetomidine drug concentration level in 
plasma and the corresponding time point following intranasal 
administration in the pediatric patient with cardiac disease. 
Study Objective(s) 
Primary  
• 
To obtain peak drug concentration level of dexmedetomidine 
following intranasal administration.  
• 
To determine time of peak drug concentration level of 
dexmedetomidine following intranasal administration. 
• 
To perform inter-subject cohort dose escalation of intranasal 
dexmedetomidine guided by associated dose-limiting adverse 
events and maximum plasma concentration. 
Secondary 
• 
To determine if dexmedetomidine pharmacokinetics are age 
dependent. 
• 
To determine if dexmedetomidine pharmacokinetics are 
different in patients who are spontaneously ventilating with a 
natural airway versus those that are mechanically ventilated via 
an oral endotracheal tube at the time of intranasal drug 
administration. 

 
 
 
 
 
 
 
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Test Article(s) 
(If Applicable) 
Study Interventions: 
Intranasal dexmedetomidine 2 μg/kg 
Intranasal dexmedetomidine 4 μg/kg  
 
Interim PK and safety analysis will be performed at the completion 
of each dosing cohort before enrollment in the next higher dose.  
Subsequent doses will be determined by the defined maximum 
tolerated dose (MTD). 
Study Design 
Prospective open-label inter-subject cohort dose-escalation 
pharmacokinetic study 
Subject Population 
key criteria for 
Inclusion and 
Exclusion: 
Inclusion Criteria 
1. Male or female subjects age ≥1 mo to ≤6 yo. 
2. Subjects must have congenital heart disease. 
3. ASA Physical Status 1-3. 
4. Subjects mechanically ventilated via an oral endotracheal 
tube scheduled for elective cardiac interventional or 
diagnostic catheterization anticipated to last ≥ 3hours. 
5. Subjects spontaneously ventilating with a natural airway 
scheduled for elective cardiac interventional or diagnostic 
catheterization anticipated to last ≥ 2hours. 
6. Subjects must have reliable intravascular access from which 
to draw blood samples. 
Exclusion Criteria 
1. History of allergic reaction or sensitivity to 
dexmedetomidine. 
2. Nasal pathology preventing the administration of drug. 
3. Patients that are on maintenance medications that could 
inhibit or induce the CYP2A6 enzyme (See Appendix I for 
full list of CYP2A6 inhibitors and inducers.) 
4. Cardiac conduction abnormalities defined as second or third 
degree heart block or pacemaker dependence. 
5. Bradycardia, defined by age, upon arrival in the preoperative 
care area. 
6. Hepatic dysfunction defined as a history of hepatic 
dysfunction AND an ALT value greater than 2 times normal 
in the 6 months prior to study drug administration. 
7. The subject has received dexmedetomidine or clonidine 
within 1 week of the study date. 
8. BMI >30. 

 
 
 
 
 
 
 
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9. Patients previously enrolled in this study. 
10. Any investigational drug use within 30 days prior to 
enrollment. 
11. Wards will not be eligible. 
Number of Subjects  
 
It is expected that approximately 65 subjects will be enrolled to 
produce 42 evaluable subjects. 
Additional subjects may be required: 
• 
If there is a statistically significant difference (>30%) 
between patients who are under general anesthesia versus 
those under sedation with a natural airway. 
• 
For additional dosing cohorts based on defined MTD.  
Study Duration 
Each subject’s participation will last for up to 6 hours from the time 
of drug administration.  
The entire study is expected to last for 15 months. 
Study Phases 
Screening 
Study Treatment 
Follow-Up   
 Screening 
• 
Subjects who satisfy the screening evaluation and selection 
criteria as outlined in Section 3.1.1 may be enrolled the study. 
Study Treatment 
• 
Preoperative management 
o 
The preoperative evaluation and care will be performed 
in accordance with CHOP CPRU protocol. 
o 
The study investigator will confirm that the subject’s 
preoperative vital signs are within the age appropriate 
normal range. 
o 
A rhythm strip will be performed and reviewed by the 
study team for any exclusion criteria. 
• 
Intraoperative management: 
o 
Following induction of anesthesia/ sedation, 
intravascular access necessary for the heart 
catheterization will be placed by the interventional 
cardiologist.  This access will be used for serum 
sampling. 
o 
The study drug will be obtained from the IDS pharmacy 
and will be administered via atomizer (Teleflex® LMA® 
MAD Nasal™ Intranasal Mucosal Atomization Device, 
MAD300) (See Attachment)  intranasally by 1 of 2  
physician members of the study team.   
o 
Serum dexmedetomidine levels will be drawn at 
approximately 0, 10, 15, 20, 30, 45, 60, 90, 120, 180, 
240, and 300 minutes post drug administration.  

 
 
 
 
 
 
 
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o 
Intraoperative heart rate, rhythm, blood pressure and 
pulse oximetry will be monitored continuously by the 
anesthesia team for the duration of the heart 
catheterization. 
o 
At the completion of the procedure, the patient will be 
transported to the PACU or ICU for recovery.  The 
patient will undergo normal postoperative monitoring 
and care per standard CHOP CPRU or CICU 
management. 
o 
The total duration of monitoring will be for 
approximately 6 hours from the time of study drug 
administration. 
o 
If the invasive monitoring lines are removed prior to the 
completion of the sampling period, no additional 
samples will be collected unless the patient has vascular 
access that permits blood draws OR a scheduled 
phlebotomy is performed for clinical indications AND 
the subject has not received IV dexmedetomidine as part 
of their normal anesthesia care. 
Follow-Up 
O 
The subject will be continuously monitored for 
approximately 6 hours from the time of drug 
administration. There is no additional follow-up. 
Efficacy Evaluations 
None 
Pharmacokinetic 
Evaluations 
Dexmedetomidine plasma concentration will be determined using a 
validated high-performance liquid chromatography-tandem mass 
spectrometry assay.  Samples will be drawn at approximately 0, 10, 
15, 20, 30, 45, 60, 90, 120, 180, 240, and 300 minutes post drug 
administration.  
Safety Evaluations 
Heart rate, rhythm, pulse oximetry, blood pressure and ECG 
monitoring will be performed throughout the study period. 
Dose-limiting toxicities (DLT) include bradycardia, hypotension, 
new intraventricular conduction delay, or any serious adverse event 
possibly, probably, or definitely related to dexmedetomidine 
administration.  
The maximum tolerated dose (MTD) is defined as the highest dose 
at which no more than 1 of 7 subjects in a cohort experiences a 
dose-limiting toxicity OR no more than 1 of 7 subjects in a cohort 
has a blood level in excess of 1000 pg/mL. 
Statistical And 
Analytic Plan 
Baseline and demographic characteristics will be summarized by 
standard descriptive summaries (e.g. means and standard deviations 

 
 
 
 
 
 
 
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for continuous variables such as age and percentages for categorical 
variables such as gender). 
Description of pharmacokinetic parameters to be assessed and 
methods to be employed to calculate those parameters are further 
discussed in section 6.3. 
Plasma concentration will be assessed for correlation with anesthetic 
method at the time of drug administration (ie, sedation in the 
spontaneously ventilating patient versus general oral endotracheal 
intubation) in the first dosing cohort.  If a greater than 30% 
difference in plasma concentration is seen between these 2 
populations, subsequent dosing cohorts will expand to include 
patients who are both spontaneously ventilating versus those 
receiving general oral endotracheal intubation after IRB and FDA 
approval. 
DATA AND SAFETY 
MONITORING PLAN 
Data will be abstracted from the electronic medical record and 
entered into the database.  Data quality will be assessed by regular 
review of completed Case Report Forms (CRFs) by the Principal 
Investigator throughout the course of the study. 
Interim PK and safety analysis will be performed at the completion 
of each dosing cohort before enrollment in the next higher dose.  
An independent Medical Monitor who is an anesthesiologist that is 
not an investigator on the study will be responsible for assessing and 
monitoring study safety.  

 
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TABLE 1: SCHEDULE OF STUDY PROCEDURES 
Study Phase 
Screening 
Open-Label Treatment 
Visit Number 
 
1: Day of Surgery 
Preoperative Period 
1: Day of Surgery 
Intraoperative Period 
Study Days 
-14 to -1 
0 
0 
Informed Consent/Assent 
X 
 
 
Review Inclusion/Exclusion Criteria 
X 
X 
 
Demographics/Medical History 
X 
 
 
EKG Rhythm Strip 
 
X 
 
Prior/Concomitant Medications 
X 
X 
 
Dispense Study Drug 
 
 
X 
Drug Compliance 
 
 
X 
Drug Administration 
 
 
X 
Serum Sample Acquisition 
 
 
X 
Adverse Event Assessment 
 
 
X 
 
 
 
 
 
 
 
 

 
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BACKGROUND INFORMATION AND RATIONALE 
1.1 
Introduction 
One of the challenges for pediatric anesthesiologists is to minimize distress for children 
undergoing procedures requiring anesthesia by facilitating separation from their parents 
and enabling a smooth induction of anesthesia.  These difficulties are especially prevalent 
in patients who require multiple repeat procedures.  Midazolam, a γ-amino-butyric acid 
(GABA) receptor inhibitor, is the most commonly used sedative drug for premedication 
in children.  It has been demonstrated that midazolam administered orally at 0.5 mg/kg is 
efficacious in producing sedation, reducing anxiety and improving the conditions for 
induction of anesthesia. However the acceptability of oral midazolam by pediatric 
patients is only 70% and it has been associated with adverse effects such as agitation, 
paradoxical hyperactive reaction, and negative postoperative behavioral changes.   
 
Dexmedetomidine is a highly selective a2-adrenergic receptor agonist with sedative, 
anxiolytic, and analgesic properties. Since 1999, it has been approved by the FDA for use 
in adult patients as a short-term (<24 hour) sedative and analgesic in intensive care units 
and for procedural sedation of non-intubated adult patients. While off-label in its use, the 
administration of intranasal dexmedetomidine has become a popular technique for 
sedation in children because it is non-invasive, well tolerated, easily administered, and 
relatively fast in onset.  Although it is established that intranasal dexmedetomidine is an 
effective sedative for premedication in children, little data have been published on its 
onset time, duration of action, or optimal dosing.  In healthy adult males, peak plasma 
concentrations of intranasally administered dexmedetomidine were reached in 38 (15-60) 
minutes and its absolute bioavailability was 65% (35-93%)(median and ranges)(1-2). 
Yuen et al (3), in a randomized, crossover evaluation of healthy adult volunteers, 
demonstrated that intranasal dexmedetomidine 1 and 1.5 μg/kg produced sedation in 45-
60 min and peaked in 90-105 min.  In the pediatric population, studies (4-7) have 
reported the time to adequate sedation anywhere from 5 to 60 minutes.  Variations in 
these studies include patient age, dosage, route of administration (atomizer vs dropper), 
indication, clinical endpoint, and sedation scoring scales. 
 
The optimal dose of intranasal dexmedetomidine for pre-operative sedation is unknown.  
Clinical trials have demonstrated that intranasal dexmedetomidine in a dose of 1 μg/kg 
produces satisfactory sedation in between 53% and 77% of children at anesthetic 
induction (6-8).  When intranasal dexmedetomidine was administered in doses of 1 μg/kg 
and 2 μg/kg for premedication in children aged 1-8 years approximately 53% and 66% of 
children, respectively, were satisfactorily sedated at the time of anesthetic induction (9). 
When intranasal dexmedetomidine was used as a primary sedative for transthoracic echo, 
87% of children had satisfactory sedation with intranasal dexmedetomidine 3 μg/kg (4).  
The highest published dose of intranasal dexmedetomidine used for procedural sedation 
is 4 μg/kg for cerebral MRI with no reported negative outcomes (10). 
 
In order to obtain peak plasma levels and the corresponding time after the administration 
of intranasal dexmedetomidine, an intravenous line of adequate size to allow frequent 
blood sampling must be placed prior to the administration of the study drug. This is an 

 
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unlikely expectation in a pediatric patient.  Therefore, we propose administering the drug 
to the patient already under general anesthesia. We chose the cardiac catheterization 
population for the following reasons: they require reliable blood drawing access for the 
procedure that they are undergoing; there is minimal fluid administration, minimal fluid 
shifts, and the procedures are of adequate duration to obtain several serum samples; and 
the patients are often administered intravenous dexmedetomidine as part of their 
anesthetic.  Since all patients in the available literature were awake and spontaneously 
ventilating at the time of intranasal administration of dexmedetomidine and there is no 
data available which compares the pharmacokinetics of intranasally administered drugs in 
patients who are spontaneously ventilating with a natural airway versus those that are 
under general anesthesia with an oral endotracheal tube, we will add additional subjects 
to our first dosing cohort who are undergoing heart catheterization under sedation with a 
natural airway and spontaneous ventilation.  This additional sub-cohort should allow us 
to compare the Cmax and Tmax between the 2 populations to ensure that our data in the 
general anesthesia population can be extrapolated to the awake population. 
 
We are proposing a prospective open-label inter-subject cohort dose-escalation 
pharmacokinetic study to obtain peak dexmedetomidine drug concentration level in 
plasma and the corresponding time point following atomized intranasal administration. 
 
1.2 
Name and Description of Investigational Product or Intervention 
 
Dexmedetomidine, a selective alpha-2 adrenergic agonist, is indicated for intravenous 
sedation in the perioperative and intensive care setting. It is currently FDA approved for 
use as an intensive care unit (ICU) sedative in ventilated adults, and for procedural 
sedation in spontaneously ventilating adults. Dexmedetomidine is currently not FDA 
approved in pediatric patients, however based on the literature (11-13), dexmedetomidine 
0.5-1 mcg/kg can be administered as a bolus, followed by a continuous infusion at 0.25-2 
mcg/kg/hour. After IV administration, the elimination half-life is approximately 2 hours. 
The intravenous formulation of dexmedetomidine 100 mg/mL will be administered 
intranasally (non-FDA approved route) to pediatric patients under general anesthesia or 
sedation undergoing diagnostic or interventional cardiac catheterization. We will be 

 
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obtaining serum samples in order to obtain pharmacokinetic data, including maximum 
concentration, time to maximum concentration, half-life and AUC. 
1.3 
Findings from Non-Clinical and Clinical Studies  
1.3.1 
Non-Clinical Studies 
Not applicable 
1.3.2 
Clinical Studies 
1.3.2.1 
Human Pharmacokinetics 
To date, there are only 2 studies that evaluate the pharmacokinetics and 
pharmacodynamics of intranasal dexmedetomidine and both use data from the same six 
adult male subjects.  Iirola and colleagues (1-2) performed a proof-of-concept study to 
characterize the pharmacokinetics and pharmacodynamics of intranasal dexmedetomidine 
compared with its intravenous administration in a small number of healthy volunteers.  
They gave six healthy male volunteers a dose of 84 μg of dexmedetomidine once 
intravenously and once intranasally via atomizer in a two-period, cross-over design with 
balanced randomization. The peak plasma concentrations of dexmedetomidine were 
reached in 38 (15-60) minutes and its absolute bioavailability was 65% (35-93%)(median 
and range).  Pharmacological effects were similar in both routes of administration, but 
their onset was more rapid after intravenous administration.  The authors suggest that 
dexmedetomidine should be administered intranasally 45-60 minutes prior to the desired 
moment of maximal effect. 
There are no pharmacokinetic studies of intranasal dexmedetomidine in the pediatric 
patient population.  However, the population pharmacokinetics of intravenous 
dexmedetomine in neonates and infants after open heart surgery has been evaluated by a 
team at CHOP (14).  They performed a prospective dose-escalation trial using 3 cohorts 
of 12 infants who were enrolled sequentially to 1 of the 3 initial loading dose – 
continuous IV infusion (CIVI) regimens: 0.35-0.25, 0.7-0.5, and 1-0.75 μg/kg-μg/kg/h.  
Using the same validated high-performance liquid chromatography-tandem mass 
spectrometry assay we plan to use, they found that dexmedetomidine clearance increased 
with weight, age, and single-ventricle physiology, whereas total bypass time was 
associated with a trend toward decreasing clearance.  All dosing regimens were well 
tolerated in this infant population.  They also found in the same dosing cohort that the 
dexmedetomidine administration provided improved sedation with reduction in 
supplemental medication requirements, leading to successful extubation (15).  This team 
subsequently looked at cohorts of 9 neonates who similarly received dexmedetomidine 
administered as a loading dose over 10 minutes followed by a continuous IV infusion for 
up to 24 hours.  The loading doses were the same as in the infant study, however, the 
infusion doses were 0.2, 0.3, or 0.4 μg/kg/h dexmedetomidine, respectively.  They found 
that dexmedetomidine clearance is significantly diminished in full-team newborns and 
increases rapidly in the first few weeks of life.  In addition to age, they found that 
dexmedetomidine pharmacokinetics were influenced by weight, total bypass time, and 
presence of intracardiac shunt (similar to earlier study in infants).  They concluded that 

 
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continuous infusions of up to 0.3 μg/kg/h in neonates and 0.75 μg/kg/h in infants were 
well tolerated after open heart surgery (16). 
1.3.2.2  Clinical Studies in Adults 
The clinical use of intranasal dexmedetomidine is quite limited in the adult patient 
population.  Yuen et al (3) used a Koch’s design for double-blind crossover trial to 
evaluate the sedative, anxiolytic, and analgesic effects of dexmedetomine when 
administered via the nasal route in 18 healthy volunteers between the age of 18 and 38 
years.  The interventions included a placebo group (A), intranasal dexmedetomidine 1 
μg/kg administered via drops from a syringe (B), and intranasal dexmedetomidine 1.5 
μg/kg administered via drops from a syringe (C).  Intranasal dexmedetomidine was well 
tolerated and both doses equally produced significant sedation and decreases in bispectral 
index, systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate when 
compared to placebo (P <0.05).  The maximum decreases in SBP were 6, 23, and 21% 
and in HR were 16, 22, and 26% for Groups A, B, and C respectively.  The onset of 
sedation occurred at 45 minutes with a peak effect at 90-150 minutes.  There was no 
effect on pain threshold, oxygen saturation, or respiratory rate. 
1.3.2.3 
Clinical Studies in Children 
The majority of clinical studies looking at intranasal dexmedetomidine in the pediatric 
patient population are designed to compare its effectiveness to oral midazolam as a 
premedication for surgery.  Yuen (8) performed the first prospective, randomized, double 
blind, controlled trial to test the hypothesis that intranasal dexmedetomidine is as 
effective as oral midazolam for preoperative anxiolysis and sedation in children before 
induction of anesthesia.  They looked at 96 children, aged 2 to 12, scheduled for elective 
minor surgery. Group M received midazolam 0.5 mg/kg (up to a maximum dose of 15 
mg) in acetaminophen syrup and intranasal placebo; Group D0.5 and Group D1 received 
intranasal dexmedetomidine 0.5 or 1 μg/kg, respectively, and acetaminophen syrup. 
There were no significant differences in parental separation acceptance, behavior score at 
induction and wake-up behavior score.  When compared with group M, patients in Group 
D0.5 and D1 were significantly more sedated when they were separated from their 
parents (P <0.001).  Patients from group D1 were significantly more sedated at induction 
of anesthesia when compared with group M (P = 0.009).  At the induction of anesthesia, 
18.8%, 40.6%, and 53.1% of the children from groups M, D0.5, and D1, respectively, 
were satisfactorily sedated.   
There are 2 additional groups that have performed prospective, randomized, double-blind 
controlled trials to compare oral midazolam versus intranasal dexmedetomidine for 
preoperative sedation.  Ghali (17) evaluated the preoperative sedative effects, anxiety 
level changes, and the ease of child-parent separation in 120 children, aged 4 to 12 years, 
undergoing adenotonsillectomy.  For their intervention, the subjects in Group D received 
intranasal dexmedetomidine 1 μg/kg via drops from a syringe and those in Group M 
received oral midazolam 0.5 mg/kg (max dose 15 mg) at approximately 60 and 30 
minutes, respectively, before induction of anesthesia.  Patients premedicated with 
intranasal dexmedetomidine achieved significantly better sedation levels  (P = 0.042), 
lower anxiety levels (P = 0.036) and easier child-parent separation (P =0.029) than 

 
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children who received oral midazolam. At the time of transferring patients to the OR, the 
HR was significantly less in the dexmedetomidine group compared to the midazolam 
group (P = 0.036) and the SBP was significantly less in the dexmedetomidine group 
compared to the midazolam group (P = 0.032).  However, there were no episodes of 
clinically significant bradycardia, hypotension, hypertension, or desaturation in either 
group.  Segovia and colleagues (5) looked at 108 subjects, aged 2 to 12 years, scheduled 
for elective surgery.  They similarly compared  premedication with oral midazolam, 0.05 
mg/kg (Group A) versus intranasal dexmedetomidine 1 μg/kg (Group B) .  Both 
interventions occurred 60 minutes prior to the induction of anesthesia.  Anxiety was less 
frequent in the dexmedetomidine group at 60 minutes (p = 0.001), induction (p = 0.04), 
and recovery (p = 0.0001).  Risk assessment showed that dexmedetomidine reduced the 
risk of anxiety by 28% (RAR = 0.28, 95% CI: 0.12-0.43).  Changes in heart rate, mean 
arterial pressure, and oxygen saturation were statistically significant in the 
dexmedetomidine group, with no clinical consequences.  There were no cases of 
bradycardia, hypotension or oxygen desaturation.   
Two groups have performed prospective, randomized, double-blind controlled trials 
comparing intranasal dexmedetomidine versus intranasal midazolam as a premedication.  
Akin and colleagues (18) compared the effects of intranasal dexmedetomidine and 
midazolam on mask induction and preoperative sedation in 99 children scheduled to 
undergo adenotonsillectomy.  Subjects in Group M received 0.2 mg/kg of intranasal 
midazolam and subjects in Group D received 1μg/kg of intranasal dexmedetomidine, 
both via drops from a syringe.  They found that satisfactory mask induction was achieved 
by 82.2% of Group M and 60% of group D (P = 0.01) and that there was no difference 
between the groups in sedation score (P = 0.36) or anxiety score (P = 0.56) upon 
separation from parents.  Satisfactory sedation was achieved upon separation from 
parents in 95.5% and 79.9% of patients in the midazolam and dexmedetomidine groups, 
respectively.  Sheta (6) looked at 72 uncooperative children, aged 3-6, undergoing 
complete dental rehabilitation using the same intervention as Akin but with significantly 
different results.  The median onset of sedation was significantly shorter in group M than 
in group D [15 (10-25) min vs 25 (20-40) min (P = 0.001)].  Subjects in group D were 
significantly more sedated than those in group M when they were separated from their 
parents (77.8% vs 44%, respectively)(P = 0.002).  Satisfactory compliance with mask 
application was 58.3% in group M vs 80.6% in group D (P = 0.035).   There were no 
incidences of bradycardia, conduction abnormalities, hypotension, or respiratory 
depression in either group. 
Two prospective, randomized, double blind, controlled trials have attempted to compare 
the effects of different doses of intranasal dexmedetomidine to see if the higher dose 
increased the adequacy of sedation. Yuen (9) compared  Dexmedetomidine 1 μg/kg 
intranasally (group 1)  versus Dexmedetomidine 2 μg/kg intranasally (group 2) in 116 
children, aged 1 to 8 years, scheduled for elective surgery.  53% of patients in Group 1 
and 66% of patients in group 2 were satisfactorily sedated at the time of anesthetic 
induction.  There were no differences in sedation onset time or duration of sedation 
between the different age groups or the two drug groups.  Both doses produced a similar 
level of satisfactory sedation in children aged 1-4 years, whereas the 2 μg/kg dosing 
resulted in a higher proportion of satisfactory sedation in children aged 5-8 years.  There 

 
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were no adverse hemodynamic effects.  In 2015, Tug (10) looked at Dexmedetomidine as 
a sedative for 60 patients, age 1 to 10 years, scheduled for cranial MRI examinations.  
They used higher doses than any of the other studies: Group 1 received intranasal 
Dexmedetomidine 3 μg/kg and Group 2 received intranasal Dexdemedetomidine 4 μg/kg.  
They compared onset time of sedation, mood at separation from parents, imaging quality, 
MRI duration, rescue anesthetic requirement, total duration of sedation, recovery 
duration, parents’ satisfaction and adverse effects.  Rescue anesthetic included placing an 
intravenous cannula and giving intravenous propofol for the procedure. The parental 
separation score was significantly higher in Group 2 (P = 0.03).  Rescue anesthetic 
requirement was significantly higher in Group 1 compared to group 2 (70 vs 30%, 
respectively)(P = 0.002).  Neither bradycardia nor oxygen desaturation were observed. 
Another study using a higher dose of dexmedetomidine (4) looked at its utility in sedating 
children for transthoracic echocardiography examination.  They gave 115 children under 
the age of 3 intranasal dexmedetomidine 3 μg/kg administered via atomizer.  87% of 
children had satisfactory sedation and the mean onset of drug effect was 16.7 ± 7 min 
(range 5-50 minutes) and the mean wake up time was 44.3 ± 15.1 min (range 12-123 
min).  The mean age of children who had successful sedation was significantly younger 
than those who had failed sedation (P <0.001).  Four patients had heart rates fall below 
the age-specific normal ranges.  Fifteen children had a systolic blood pressure below the 
age-specific normal ranges.  No intervention was required.  This same team  (19) looked 
at an even larger group of children (279 subjects) undergoing transthoracic 
echocardiography to see if there were any differences in effect when dexmedetomidine 
was given by an atomizer versus drops from a syringe. To help address the observation 
they noted in their earlier study that there appeared to be a difference in sedation level 
based on the age of the subjects, randomization was stratified by age: infants (2-12 
months old) and toddlers (>12 months old).  They again used intranasal delivery of 
dexmedetomidine in a dose of 3 μg/kg by either atomizer or drops from a syringe.  The 
successful sedation rate was 82.5% (95% CI 75.3-87.9%) and 84.5% (95% CI 77.7-
89.5%) for atomizer and drops, respectively (p = 0.569).  Sedation tended to be less 
successful in older children (p = 0.028, OR 0.949, 95% CI 0.916-0.983). The median 
sedation onset times, times from onset of sedation until the procedure commenced, 
duration of procedure, wake-up times and discharge times were no different between the 
two groups.  There were no significant complications. 
 
1.4 
Selection of Drugs and Dosages 
Dexmedetomidine is a selective alpha-2 adrenergic agonist that is indicated for sedation 
in the perioperative and intensive care setting, as it has sedative, anxiolytic and analgesic 
properties.  It is available in 4 μg/ml and 100 μg/ml concentrations.  For intranasal use, 
the 100 μg/ml concentration will be used.   
Dosing Plan: 
Inter-subject cohort dose escalation: 
Intranasal Dexmedetomidine 2 μg/kg  

 
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Intranasal Dexmedetomidine 4 μg/kg 
The dosing of intranasal dexmedetomidine was based on the available clinical data in the 
pediatric patient population as outlined above. Clinical trials have demonstrated that 
intranasal dexmedetomidine in a dose of 1 μg/kg and 2 μg/kg produced safe and 
satisfactory sedation in between 53% and 77% of children at anesthetic induction (6-9).  
When intranasal dexmedetomidine was used as a primary sedative for transthoracic echo, 
87% of children had satisfactory sedation with intranasal dexmedetomidine 3 μg/kg (4).  
The highest published dose of intranasal dexmedetomidine used for procedural sedation 
is 4 μg/kg for cerebral MRI which resulted in 76.7% of patients separating easily from 
their parents with no reported negative outcomes (10).  This data would indicate that the 
1 ug/kg dose produces a low incidence of satisfactory sedation and that the 2 ug/kg dose 
has a more acceptable incidence of satisfactory sedation with minimal side effects.  There 
is some data supporting that the 4 μg/kg dose produces a higher incidence of adequate 
sedation, still with an adequate side effect profile.   
 
The objective of this study is to determine Cmax and associated Tmax.  In the adult study 
of intranasal dexmedetomidine (1) where 84 μg was given, the cmax, average and sd 
were mean =0.38 ng/ml; sd=0.15 ng/ml; and cv% = 40%.  We originally planned to give 
the following doses: 2 μg/kg, 4 g/kg or 5 or 6 μg/kg. Based on the CV%, differentiating 
between the doses will be problematic because the upper range of the 2 μg/kg dose 
(0.644) will fall within the range of the 4 μg/kg dose (0.552-1.288).  This comparison 
would be even more challenging using a 5 μg/kg dose.  We have determined that based 
on an estimated inter-subject variability of 40% for Cmax, a sample size of 21 subjects (7 
per group) will be sufficient to detect a difference (alpha 0.05, power 0.8)  in Cmax 
between the three dosing groups if they are given doses of 2,4 and 6 μg/kg. 
 
The older patient population, age >2 yo and ≤ 6 yo, in each dosing cohort will complete 
enrollment and have PK and safety analysis performed prior to the enrollment of the 
younger patient population, age ≥1 mo and ≤2 yo.  Interim PK and safety analysis will 
also be performed at the completion of each dosing cohort before enrollment in the next 
higher dose. The older age group can escalate to the next dosing cohort prior to 
completing enrollment of the younger age group.  An independent Medical Monitor who 
is an anesthesiologist that is not an investigator on the study will be responsible for 
assessing and monitoring study safety.  Dose-limiting toxicities (DLT) include 
bradycardia, hypotension, new intraventricular conduction abnormality or any serious 
adverse event possibly, probably, or definitely related to intranasal dexmedetomidine 
administration that occurs after the administration of the intranasal dexmedetomidine and 
through the completion of PK sampling.  In particular, bradycardia, hypotension, or new 
intraventricular conduction abnormalities that occur after the administration of 
intravenous dexmedetomidine given by the primary anesthesia team as part of usual 
clinical care will not be considered DLTs.   Bradycardia is defined as heart rate <80 BPM 
in subjects < 1 yo and < 60 BMP in subjects > 1 yo.  Hypotension is defined as a mean 
arterial blood pressure that is >30% lower than baseline. An intraventricular conduction 
abnormality is defined as second or third degree heart block.  Any of these events that 
cannot be readily explained by the intervention that the patient is undergoing will be 

 
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assumed to be related to the effects of the study drug.  The clinical team will render an 
opinion as to whether the hemodynamic change is likely related to intranasal 
dexmedetomidine.   
 
The maximum tolerated dose (MTD) is defined as the highest dose at which no more than 
1 of 7 subjects in a cohort experiences a dose-limiting toxicity OR no more than 1 of 7 
subjects in a cohort has a blood level in excess of 1000 pg/mL.  This later MTD comes 
from the intravenous pK data that has been obtained in our studies looking at IV 
dexmedetomidine administration in infants and neonates undergoing cardiac surgery (14-
16).  We found that the incidence of bradycardia increased significantly above this 
concentration level.  This MTD was determined with FDA guidance under our current 
IND (#69758). If a MTD is reached, we will de-escalate the next dosing cohort by 25% 
of the dose in which the cohort achieved the MTD. 
 
1.5 
Relevant Literature and Data 
See Section 1.3 for relevant literature. 
1.6 
Compliance Statement 
This study will be conducted in full accordance with all applicable Children’s Hospital of 
Philadelphia Research Policies and Procedures and all applicable Federal and state laws 
and regulations including 45 CFR 46, 21 CFR Parts 50, 54, 56, 312, 314 and 812 and the 
Good Clinical Practice: Consolidated Guideline approved by the International 
Conference on Harmonisation (ICH). All episodes of noncompliance will be documented. 
The investigators will perform the study in accordance with this protocol, will obtain 
consent, and will report unanticipated problems involving risks to subjects or others in 
accordance with The Children’s Hospital of Philadelphia IRB Policies and Procedures 
and all federal requirements. Collection, recording, and reporting of data will be accurate 
and will ensure the privacy, health, and welfare of research subjects during and after the 
study.  
2 
STUDY OBJECTIVES 
The purpose of the study is to determine the pharmacokinetics of atomized intranasally 
administered dexmedetomidine in the pediatric patient with congenital heart disease 
undergoing diagnostic or interventional cardiac catheterization. 
2.1 
Primary Objective (or Aim) 
The primary objective of this study is to determine the peak drug concentration level of 
dexmedetomidine and the corresponding time of peak concentration level following 
intranasal administration to the pediatric patient. 
2.2    Secondary Objectives (or Aim) 
• 
To perform inter-subject cohort dose escalation of intranasal dexmedetomidine 
guided by associated dose-limiting adverse events. 

 
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• 
To determine if dexmedetomidine pharmacokinetics are age dependent. 
• 
To determine if dexmedetomidine pharmacokinetics are different when administered 
intranasally to patients who are spontaneously ventilating versus those that are 
mechanically ventilated via an oral endotracheal tube. 
 
3 
INVESTIGATIONAL PLAN 
3.1 
General Schema of Study Design 
This is a prospective open-label inter-subject cohort dose-escalation pharmacokinetic 
study.  The subjects will receive intranasal dexmedetomidine after the induction of 
anesthesia or sedation and the placement of intravascular lines to conduct the 
catheterization.   Up to ten serum levels of dexmedetomidine will be obtained by 
accessing the intravenous lines placed for the heart catheterization.   Subjects are age ≥1 
mo and ≤ 6 yo undergoing elective diagnostic or interventional cardiac catheterizations. 
3.1.1 
Screening Phase 
The principal investigator will review the Cardiac Center Intake Center appointment 
schedule approximately 2 weeks in advance of scheduled outpatient procedure.  Patients 
who meet the inclusion criteria will be identified and their charts will be reviewed to 
determine eligibility. The nurse practitioners in the Intake Center will be notified of 
potential eligible subjects.  On the day of the Intake Center visit, potentially eligible 
subjects will be approached by one of the physician study team members for enrollment 
in the study and consent will be obtained.  The patient’s history will then be reviewed 
with the family for any exclusion criteria, and if ineligible, the subject will be withdrawn 
from further study participation.  The principal investigator will also review the inpatient 
procedure schedule one day in advance to identify inpatients who may be eligible for the 
study. The subject will be approached and consent will be obtained the day before the 
procedure.  Subjects will be recruited into two strata: children ≥1 month up to ≤24 
months, and children >2 up to ≤6 years of age with a goal of 50% of subjects per age 
strata.  Parental/guardian permission (informed consent) will be obtained prior to any 
study related procedures being performed.  
 
3.1.2  Study Treatment Phase (start of the study intervention) 
Once consent has been obtained, the patient undergoing general anesthesia will receive 
premedication at the discretion of the primary anesthesia team caring for the patient.  The 
patient will undergo standard and routine monitoring throughout the heart catheterization 
procedure as defined by the ASA and the CHOP division of cardiac anesthesia at the 
direction of the assigned anesthesia providers.  Following induction of anesthesia, 
intravascular access necessary for the heart catheterization will be placed by the 
interventional cardiologist.  The study drug will be obtained from the IDS pharmacy and 
will be administered via atomizer (Teleflex® LMA® MAD Nasal™ Intranasal Mucosal 
Atomization Device, MAD300) intranasally by 1 of 2  physician members of the study 
team.  The drug will be administered in one nostril if drug volume is < 1 ml and in both 
nostrils if total volume is > 1 ml.  If the drug volume is > 1 ml, the volume with be split 

 
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evenly and administered to both nostrils.  No more than 2 ml of study drug will be 
administered.  Serum dexmedetomidine levels will be drawn at approximately 0, 10, 15, 
20, 30, 45, 60, 90, 120, 180, 240, and 300 minutes post drug administration. The 1 mL 
samples will be drawn by the cardiologist performing the catheterization at the direction 
of the study team member and will be processed by a study team member.  Intraoperative 
heart rate, rhythm and pulse oximetry will be monitored continuously by the anesthesia 
team for the duration of the heart catheterization.  Blood pressure will be monitored at 
least every 5 (±3) minutes by non-invasive blood pressure monitoring, and continuously 
if an arterial line is placed, by the anesthesia team for the duration of the heart 
catheterization.  The attending anesthesiologist may give intravenous dexmedetomidine 
as a bolus or infusion if desired as part of their normal anesthesia care once the procedure 
is complete and the intravenous access placed by the interventional cardiologist for the 
heart catheterization has been removed.  At the completion of the procedure, the patient 
will be transported to the PACU or ICU for recovery.  The patient will undergo normal 
postoperative monitoring and care per standard CHOP CPRU or CICU management.  
The total duration of monitoring will be for 6 hours from the time of study drug 
administration. 
For the patient undergoing sedation for their cardiac catheterization procedure, the patient 
will receive sedation by the catheterization lab nurse under the direction of the 
cardiologist performing the procedure based on CHOP sedation guidelines.  The patient 
will undergo standard and routine monitoring throughout the procedure as defined by the 
CHOP sedation guidelines.  The administration of study drug and drug sampling will be 
no different than described above and a member of the study team will be present 
throughout the study duration. 
 
3.2 
Allocation to Treatment Groups and Blinding 
There is no randomization and there is no blinding. 
3.3 
Study Duration, Enrollment and Number of Sites 
3.3.1 
Duration of Study Participation 
Once consent has been obtained, the study duration is for up to 6 hours from the time of 
drug administration. 
3.3.2 
Total Number of Study Sites/Total Number of Subjects Projected 
The study will be conducted at 1 investigative site in the United States. 
Recruitment will stop when the following subjects have been enrolled: 
Cohort 1A: 
• 
Dexmedetomidine 2 μg/kg 
• 
Under general oral endotracheal anesthesia 
• 
7 evaluable subjects age >2 yo and ≤ 6 yo 
• 
7 evaluable subjects age ≥1 mo and ≤2 yo  

 
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Cohort 1B: 
• 
Dexmedetomidine 2 μg/kg 
• 
Under sedation with a natural airway 
• 
7 evaluable subjects age >2 yo and ≤ 6 yo 
• 
7 evaluable subjects age ≥1 mo and ≤2 yo  
Cohort 2: 
• 
Dexmedetomidine 4 μg/kg 
• 
Under general oral endotracheal anesthesia 
• 
7 evaluable subjects age >2 yo and ≤ 6 yo 
• 
7 evaluable subjects age ≥1 mo and ≤2 yo  
 
It is expected that approximately 65 subjects will be enrolled to produce 42 evaluable 
subjects.  Evaluable subjects are defined as subjects who received study drug and have 
completed at least 90 minutes of PK sampling.  All subjects who receive study drug will 
be included in data analysis.   
Additional subjects may be required: 
• 
If there is a statistically significant difference in the pharmacokinetics (>30%) 
between patients who received study drug while under general anesthesia versus 
those under sedation with a natural airway.  If there is a statistically significant 
difference between Cohort 1A and 1B, we will add a spontaneously ventilating 
cohort to dosing group 2 as well after IRB and FDA approval.  If a statistically 
significant difference is seen in this group as well, we will request that the 
remaining dosing cohorts only occur in subjects undergoing sedation with a 
natural airway. 
• 
For additional dosing cohorts based on defined MTD. 
The older patient population, age >2 yo and ≤ 6 yo, in each dosing cohort will complete 
enrollment and have PK and safety analysis performed prior to the enrollment of the 
younger patient population, age ≥1 mo and ≤2 yo.  Interim PK and safety analysis will 
also be performed at the completion of each dosing cohort before enrollment in the next 
higher dose. The older age group can escalate to the next dosing cohort prior to 
completing enrollment of the younger age group.  
 
3.4 
Study Population 
3.4.1 
Inclusion Criteria 
1. Male or female subjects age ≥1 mo to ≤6 yo. 
2. Subjects must have congenital heart disease. 
3. ASA status 1 to 3. 

 
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4. Subjects mechanically ventilated via an oral endotracheal tube scheduled for 
elective cardiac interventional or diagnostic catheterization anticipated to last ≥ 
3hours. 
5. Subjects spontaneously ventilating with a natural airway scheduled for elective 
cardiac interventional or diagnostic catheterization anticipated to last ≥ 2hours. 
6. Subjects much have reliable intravascular access from which to draw blood 
samples. 
3.4.2 
Exclusion Criteria 
1. History of allergic reaction or sensitivity to dexmedetomidine. 
2. Nasal pathology preventing the administration of drug. 
3. Patients that are on maintenance medications that could inhibit or induce the 
CYP2A6 enzyme (See Appendix I for full list of CYP2A6 inhibitors and 
inducers). 
4. Cardiac conduction abnormalities defined as second or third degree heart block or 
pacemaker dependence. 
5. Bradycardia, defined by age, upon arrival in the preoperative care area. 
6. Hepatic dysfunction defined as a history of hepatic dysfunction and an ALT value 
greater than 2 times normal in the 6 months prior to study drug administration. 
7. The subject has received dexmedetomidine or clonidine within 1 week of the 
study date. 
8. BMI >30. 
9. Patients previously enrolled in this study. 
10. Any investigational drug use within 30 days prior to enrollment. 
11. Wards will not be eligible. 
Subjects that do not meet all of the enrollment criteria will not be enrolled. Any 
violations of these criteria must be reported in accordance with IRB Policies and 
Procedures.  
4 
STUDY PROCEDURES 
4.1 
Screening Visit 
• 
Informed Consent 
• 
Medical Record Review 
• 
Medication review 
• 
Medication allergy review 
• 
Verification that subject meets study inclusion/exclusion criteria 
 

 
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4.2 
Study Treatment Phase 
4.2.1 
Visit 1 
• 
EKG rhythm strip 
• 
Medical record review 
• 
Dispense study drug 
• 
Administer study drug 
• 
Obtain serum samples at approximately 0, 10, 15, 20, 30, 45, 60, 90, 120, 180, 
240, and 300 minutes from the time of study drug administration. 
4.3 
Concomitant Medication 
All prior and concomitant medications used within 7 days prior to the screening visit and 
through the end of the study will be recorded. The dates of administration, dosage, and 
reason for use will be included.  
4.4 
Rescue Medication Administration 
The subject will be monitored by the primary anesthesia team or the sedation team 
throughout the entire study period.  Hemodynamic management and medication 
administration will be at the sole discretion of the primary team caring for the patient.  At 
any time, the primary care team may administer medications for the management of 
hemodynamic perturbations, including bradycardia or hypotension, as clinically 
indicated.  Possible interventions may include the administration of atropine, 
glycopyrrolate, dopamine or epinephrine.  A member of the research team will be present 
from the time of study drug administration until the study period is complete.  Adverse 
reactions to the study medications will be managed by the clinical team caring for the 
subject.  The teams will not be blinded to study drug administration.  Dexmedetomidine 
is a medication frequently administered by anesthesiologists who are familiar with its use 
and management.  Bradycardia is the most likely effect to be observed.  
4.5 
Subject Completion/Withdrawal 
Subjects may withdraw from the study at any time without prejudice to their care.  The 
Investigator may withdraw subjects to protect the subject for reasons of safety or for 
administrative reasons.  It will be documented whether or not each subject completes the 
clinical study. If the Investigator becomes aware of any serious, related adverse events 
after the subject completes or withdraws from the study, they will be recorded in the 
source documents and on the CRF. 
4.5.1 
Early Termination Study Visit 
Subjects that withdraw from the study will not be evaluable and will not be included in 
the analysis.  No study procedures will be performed following subject withdrawal.   

 
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5 
STUDY EVALUATIONS AND MEASUREMENTS 
5.1 
Screening and Monitoring Evaluations and Measurements 
5.1.1 
Medical Record Review 
• 
Date of procedure 
• 
Date of birth 
• 
Age 
• 
Weight 
• 
Height 
• 
Gender 
• 
Race, ethnicity 
• 
American Society of Anesthesia (ASA) Physical Status 
• 
Physical examination 
• 
Scheduled catheterization procedure 
• 
Catheterization procedure performed 
• 
Allergies 
• 
Medical history  
• 
Single or double ventricle physiology defined 
• 
Current medications 
• 
ECG within 6 months if available 
• 
Premedication administered (drug, dose and route) if applicable 
• 
Duration of anesthesia 
• 
Duration of cardiac catheterization 
• 
Dose of dexmedetomidine provided for post procedure sedation, if applicable 
• 
Intraoperative heart rate, rhythm and pulse oximetry will be monitored 
continuously by the anesthesia team or the sedation team for the duration of the 
heart catheterization. 
• 
Blood pressure will be monitored at least every 5 (±3) minutes by non-invasive, 
automated blood pressure monitoring, and continuously if an arterial line is 
placed, by the anesthesia team or sedation team for the duration of the heart 
catheterization. 
5.1.2 
Vital Signs 
While the patient is lying down for the procedure:  
• 
EKG rhythm prior to the administration of the study  
 
5.2 
Pharmacokinetic Evaluation 
Samples of 0.5 -1 ml of blood, totaling less than 1 tablespoon of blood, will be drawn at 
approximately 0, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, and 300 minutes from the time 
of intranasal drug administration. Once invasive monitoring lines have been removed, 
samples will only be collected if either vascular access that permits blood draws exists or 

 
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a scheduled phlebotomy is performed for clinical indications and the subject has not 
received intravenous dexmedetomidine as part of their normal anesthesia care.  
Dexmedetomidine plasma concentration will be determined using a selective and highly 
sensitive, validated high-performance liquid chromatography-tandem mass spectrometry 
(LC-MS/MS) assay used for analysis of pediatric plasma with a lower limit of 
quantitation of 5 pg/mL (20).  The assay will be performed in an academic laboratory 
setting and clinical decisions will not be made based on the results. Plasma will be 
separated by centrifugation and stored at -80° C.  Dexmedetomidine will be extracted 
from 200 microliters of plasma by solid-phase extraction.   Method validation will be 
performed according to guidelines set by the United States Food and Drug 
Administration (FDA) for bioanalytical method validation (21). Based on prior 
experience with this assay (20) this method will again be validated in terms of linearity, 
specificity, lower limit of quantitation (LLOQ), recovery, intra- and inter-day accuracy 
and precision, and stability of analyte during the sample storage and processing 
procedures. Each analytical run will include blanks, nine standard concentrations for 
calibration, and replicate sets (n = 6) of QC samples (LQC, MQC and HQC).  
Samples will be run in batch following each dosing cohort and the data will be analyzed. 
One- and 2-compartment models will be investigated. The model deemed optimal to 
define the dexmedetomidine plasma concentration profile based on the results from the 
model-building process will be used.   
Investigators will adhere to the NIH “Guidelines for Limits of Blood Drawn for Research 
Purposes” which states that for pediatric patients, no more than 5 mL/kg may be drawn 
for research purposes in a single day and no more than 9.5 mL/kg may be drawn over any 
eight-week period. 
5.3 
Safety Evaluation 
Patients will be monitored by continuous heart rate and rhythm monitoring, continuous 
oxygen saturation monitoring, and at least every 5 (±) minute SBP, DBP and mean BP 
monitoring by automated non-invasive blood pressure monitoring.  If an invasive arterial 
line is placed, continuous blood pressure monitoring will occur.  Continuous ECG 
monitoring will be conducted to evaluate for evidence of cardiac ischemia.  Ischemia is 
defined as widened Q-waves (>0.035 seconds) or new T-wave inversion.  This 
monitoring will continue for the duration of the heart catheterization. At the completion 
of the procedure, the patient will be transported to the PACU or ICU for recovery.  The 
patient will undergo normal postoperative monitoring and care per standard CHOP 
CPRU or CICU management. The total duration of monitoring will be for 6 hours from 
the time of study drug administration. 
Interim PK and safety analysis will be performed at the completion of each dosing cohort 
before enrollment in the next cohort.   The older patient population, age >2 yo and ≤ 6 yo, 
in each dosing cohort will complete enrollment and have PK and safety analysis 
performed prior to the enrollment of the younger patient population, age ≥1 mo and ≤2 
yo. An independent Medical Monitor who is an anesthesiologist that is not an investigator 
on the study will be responsible for assessing and monitoring study safety. 

 
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In this particular clinical setting, a number of the research subjects will receive usual 
clinical care IV dexmedetomidine for sedation management in addition to the initial 
research IN dexmedetomidine. AEs may occur in some subjects early, following the 
administration of research IN drug and during sample collection, prior to administration 
of usual clinical care IV dexmedetomidine.  AEs may also occur later in some subjects, 
following the usual clinical care intravenous dexmedetomidine (and well after the initial 
IN dexmedetomidine). In this latter circumstance, the medical monitor will adjudicate 
whether the AE is attributable to IN dexmedetomidine, or whether IN dexmedetomidine 
contributed to the AE resulting after usual clinical care dexmedetomidine. In both 
circumstances (following initial research IN drug, and later, following both research IN 
as well as usual clinical care drug) AEs will be reported as either unlikely, possibly, 
probably or likely related to the research IN dexmedetomidine.  
 
Dose-limiting toxicities (DLT) include bradycardia, hypotension, new intraventricular 
conduction abnormality, or any serious adverse event possibly, probably, or definitely 
related to intranasal dexmedetomidine administration that occur after the administration 
of the intranasal dexmedetomidine and through the completion of PK sampling.  In 
particular, bradycardia, hypotension, or new intraventricular conduction abnormalities 
that occur after the administration of intravenous dexmedetomidine given by the primary 
anesthesia team as part of usual clinical care will not be considered DLTs.  Bradycardia is 
defined as  <80 BPM in subjects < 1 yo and <60 BPM in subjects > 1yo.  Hypotension is 
defined as a mean arterial blood pressure that is >30% lower than baseline.  New 
intraventricular conduction abnormality is defined as second or third degree heart block.  
The MTD is defined as the highest dose at which no more than 1 of 7 subjects in a cohort 
experiences a dose-limiting toxicity OR no more than 1 of 7 subjects in a cohort has a 
blood level in excess of 1000 pg/mL. This later MTD comes from the intravenous pK 
data that has been obtained in our studies looking at IV dexmedetomidine administration 
in infants and neonates undergoing cardiac surgery (14-16).  We found that the incidence 
of bradycardia increased significantly above this concentration level.  This MTD was 
determined with FDA guidance under our current IND (#69758). If a MTD is reached, 
we will de-escalate the next dosing cohort by 25% of the dose in which the cohort 
achieved the MTD. 
 
 
 

 
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6    STATISTICAL CONSIDERATIONS 
6.1   Primary Endpoint 
The primary endpoint of this study is to determine the peak drug concentration (Cmax)  
of inhaled dexmedetomidine and the corresponding time of peak concentration (Tmax)  
following intranasal administration to the pediatric patient with congenital heart disease. 
 
6.2   Secondary Endpoints 
Secondary endpoints will include the following: 
• 
Compare dexmedetomidine pharmacokinetics between two age ranges receiving 
the same intranasal dexmedetomidine dosing. 
• 
Compare dexmedetomidine pharmacokinetics in patients who received the 
intranasal dose while spontaneously ventilating versus those that are mechanically 
ventilated via an oral endotracheal tube to see if there is a difference in 
absorption. 
• 
To perform inter-subject cohort dose escalation of intranasal dexmedetomidine 
guided by associated dose-limiting toxicities. 
 
6.3   Statistical Methods 
6.3.1    Baseline Data  
Baseline and demographic characteristics will be summarized by standard descriptive 
summaries (e.g. means and standard deviations for continuous variables such as age and 
percentages for categorical variables such as gender). 
6.3.2   Pharmacokinetic/Pharmacodynamic Analysis 
Description of pharmacokinetic parameters to be assessed and methods to be employed to 
calculate those parameters:   
Nonparametric analytical methods will be used due to small sample sizes that are not 
uniformly distributed, to compare the Cmax and Tmax between age groups, and also 
between spontaneous breathing subjects and those that are mechanically ventilated.  
The PK of dexmedetomidine is well described. Bayesian parameter estimates from prior 
studies will be used to perform a two-compartment open model with first-order 
elimination from the central compartment to fit to the concentration-time data from all 
evaluable subjects. This approach will allow for a model-based approach to determine the 
PK parameters of this population in the event that our sampling does not extend past one 
half life (120 minutes) for some subjects. 
 

 
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Comparisons between pharmacodynamics measures before receiving dexmedetomidine 
and following the administration of intranasal dexmedetomidine will be made using each 
patient as his/her own control.  These comparisons will be stratified by individual dosing 
cohorts as well as the entire population collectively.  The following pharmacodynamics 
measures will be evaluated:  HR, heart rhythm SBP, DBP, and MAP.  A Wilcoxon signed 
rank test will be used for comparison of continuous variables at baseline and after the 
administration of intranasal dexmedetomidine for approximately 6 hours. 
The following pharmacodynamics measures will be compared between dosing cohorts 
following the administration of intranasal dexmedetomidine: HR, SBP, DBP, and MAP. 
The following variables will be assessed for correlation with plasma concentration: HR, 
heart rhythm, SBP, DBP, and MAP.  Nonparametric Spearman rank correlation will be 
used to evaluate the correlation of variables to plasma concentrations.   
Plasma concentration will be assessed for correlation with anesthetic method (ie, sedation 
in the spontaneously ventilating patient versus general oral endotracheal intubation) in 
the first dosing cohort.  If a greater than 30% difference in plasma concentration is seen 
between these 2 populations, the following dosing cohort will expand to include patients 
who are both spontaneously ventilating versus those receiving general oral endotracheal 
intubation.  If a greater than 30% difference in plasma concentration is again seen, the 
remaining dosing cohorts will only occur in patients who are under sedation and 
spontaneously ventilating at the time of drug administration. 
6.3.3   Safety Analysis 
All subjects entered into the study at Visit 1 will be included in the safety analysis. The 
frequencies of AEs by type, body system, severity and relationship to study drug will be 
summarized. SAEs (if any) will be described in detail. 
AE incidence will be summarized along with the corresponding exact binomial 95% two-
sided confidence intervals. 
6.4   Sample Size and Power 
The primary objective of this study is to determine the Cmax and corresponding Tmax 
after the administration of intranasal dexmedetomidine.  The sample size is based on this 
objective.  In the adult study of intranasal dexmedetomidine (1) where 84 μg was 
administered, the cmax, average and standard deviation were mean = 0.38 ng/ml; sd 0.15 
ng/ml; and cv% = 40%.  Based on an estimated inter-subject variability of 40% for 
Cmax, a sample size of 21 subjects (7 per group) will be sufficient to detect a difference 
(alpha 0.05, power 0.8) in each age cohort.  Fourteen evaluable patients will be enrolled 
at each dose group.  An additional 14 patients will be added in the first cohort to see if 
there is any difference in the pharmacokinetics of a patient who is under general 
anesthesia with an oral endotracheal tube versus a patient who is spontaneously 
ventilating at the time of intranasal drug administration.  Based on heart catheterization 
lab patient census, it is estimated that 15 months will be required to complete enrollment. 

 
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6.5   Interim Analysis 
Interim PK and safety analysis will be performed at the completion of each dosing cohort 
before enrollment in the next higher dose.   The older patient population, age >2 yo and ≤ 
6 yo, in each dosing cohort will complete enrollment and have PK and safety analysis 
performed prior to the enrollment of the younger patient population, age ≥1 mo and ≤2 
yo. An independent Medical Monitor who is an anesthesiologist that is not an investigator 
on the study will be responsible for assessing and monitoring study safety.  
Dose-limiting toxicities (DLT) include bradycardia, hypotension, new intraventricular 
conduction abnormality, or any serious adverse event possibly, probably, or definitely 
related to intranasal dexmedetomidine administration that occur after the administration 
of the intranasal dexmedetomidine and through the completion of PK sampling.  In 
particular, bradycardia, hypotension, or new intraventricular conduction abnormalities 
that occur after the administration of intravenous dexmedetomidine given by the primary 
anesthesia team as part of usual clinical care will not be considered DLTs.  Bradycardia is 
defined as heart rate <80 BPM in children <1 yo and a heart rate <60 BPM in subjects > 1 
yo. Hypotension is defined as a mean arterial blood pressure that is >30% lower than 
baseline.  A new intraventricular conduction abnormality is defined as second or third 
degree heart block.  The MTD is defined as the highest dose at which no more than 1 of 7 
subjects in a cohort experiences a dose-limiting toxicity OR no more than 1 of 7 subjects 
in a cohort has a blood level in excess of 1000 picograms/mL (14-16).  If a MTD is 
achieved, the next dosing cohort will be at a dose 25% lower than the cohort at which the 
MTD occurred.   
7   STUDY MEDICATION (STUDY DEVICE OR OTHER STUDY 
INTERVENTION) 
7.1   Description 
Dexmedetomidine is a selective alpha-2 adrenergic agonist that is indicated for sedation 
in the perioperative and intensive care setting, as it has sedative, anxiolytic and analgesic 
properties. At the cellular level, dexmedetomidine binds to an alpha-2 adrenergic 
receptor. After binding to the receptor, there is a subsequent decrease in calcium influx to 
the cell and increase in potassium efflux from the cell, thereby decreasing the action 
potential of the neuron. This results in membrane hyperpolarization, decreasing the 
chances of it firing, which decreases norepinephrine release. Ultimately this elicits the 
pharmacologic action, a hypnotic response pattern that mimics the natural sleep pathway. 
After administration, patients are effectively sedated but are still easily arousable. By 
decreasing sympathetic activity, the effect is decreases in blood pressure and heart rate, 
sedation and anxiolysis. Binding of dexmedetomidine to alpha-2 adrenergic receptors in 
the spinal cord results in analgesia.  
7.1.1   Packaging 
Dexmedetomidine is supplied as a 100 μg/mL solution (2 mL).  The study drug will be 
obtained from Pfizer pharmaceuticals. 

 
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7.1.2.   Labeling 
Dexmedetomidine vials will be clearly marked with their contents from the original 
manufacturer. They will be dispensed from the CHOP Investigational Drug Service in 
accordance with FDA guidelines with a patient specific label immediately prior to the 
procedure. An example of the label will be included with the IND application submission 
to the FDA.  
7.1.3   Dosing 
Administration of intranasal dexmedetomidine has been reported in the literature with 
doses ranging from 1-4 μg/kg/dose. For the purposes of a pharmacokinetic analysis in 
pediatric patients and determination of a maximum tolerated dose, dexmedetomidine 2 
μg/kg/dose, 4 μg/kg/dose and 6 μg/kg/dose (based on interim analysis) will be 
administered to patients undergoing cardiac catheterization.  Dexmedetomidine will be 
administered intranasally via the Teleflex® LMA® MAD Nasal™ Intranasal Mucosal 
Atomization Device, MAD300  (See Attachment) which will be used as directed and 
instructed by the CHOP clinical pharmacy.  This atomizer is currently approved for use at 
CHOP.  The drug will be administered in one nostril if drug volume is < 1 ml and in both 
nostrils if total volume is > 1 ml.  If the drug volume is > 1 ml, the volume with be split 
evenly and administered to both nostrils.  No more than 2 ml of study drug will be 
administered.  The drug will be administered by 1 of 2 physician members of the research 
study to provide consistency in administration. Since the patients will be under general 
anesthesia or moderate sedation at the time of administration, issues such as sneezing 
should be limited.   If there should be a concern with the quality of administration in a 
given patient, the data would still be collected and interpreted in the context of the 
administration concerns. 
 
We chose to us an atomizer as opposed to drops because it produces fine particles of drug 
that are thought to optimize drug absorption, hasten onset, and provide more efficient 
sedation (22,23).  Li and colleagues (19) compared intranasal delivery of 
dexmedetomidine in a dose of 3 mcg/kg by either atomizer or drops from a syringe in 
children less than 3 years old undergoing transthoracic echocardiography.  They found 
both modes of administration equally effective.  This has also been seen with the 
administration of ketamine and midazolam, (24,25) supporting the concept that the drug 
could be administered effectively by either technique.  However, these studies also found 
improved patient acceptance of the drug when administered by atomizer.  Also, larger 
volumes of drug administration when given by dropper technique may lead to partial oral 
administration making the PK data difficult to interpret.  Oral dexmedetomidine has poor 
oral bioavailability (26). Finally, the one adult study that looked at intranasal PK data (1) 
used an atomizer for administration. 
 
7.1.4   Treatment Compliance and Adherence 
Medications will be administered in the operating room and each subject’s participation 
will last for up to 6 hours from the time of drug. 
 

 
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7.1.5   Drug Accountability 
Adequate records of study drug receipt and disposition will be maintained by the CHOP 
Investigational Drug Service (IDS), including records of receipts, investigational drug 
orders, dispensing records, and disposition forms that will be examined during the course 
of the study.  Dexmedetomidine lot number and expiration date will be included in the 
IDS records. The purpose of these records is to ensure regulatory authorities and the 
Sponsor that the investigational new drug will not be distributed to any person who is not 
a study subject under the terms and conditions set forth in this protocol.  The study 
medication is to be prescribed by the Investigator or designee and may not be used for 
any purpose other than that described in this protocol. At the completion of each subject, 
all drug supplies will be wasted in a hospital approved drug disposal box and witnessed 
by 2 members of the study team.  Drug supplies include partially used or empty vials as 
well as used atomizers.  At study completion, all remaining unused drug will be 
destroyed in accordance with CHOP IDS policies. 
 
8    SAFETY MANAGEMENT 
8.1   Clinical Adverse Events 
Clinical adverse events (AEs) and study stopping criteria will be monitored throughout 
the study.  
8.2   Adverse Event Reporting 
Unanticipated problems related to the research involving risks to subjects or others that 
occur during the course of this study (including SAEs) will be reported to the IRB in 
accordance with CHOP IRB SOP 408: Unanticipated Problems Involving Risks to 
Subjects. AEs that are not serious but that are notable and could involve risks to subjects 
will be summarized in narrative or other format and submitted to the IRB at the time of 
continuing review.  
8.3    Definition of an Adverse Event 
An adverse event is any untoward medical occurrence in a subject who has received an 
intervention (drug, biologic, or other intervention).  The occurrence does not necessarily 
have to have a causal relationship with the treatment.  An AE can therefore be any 
unfavorable or unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product, whether 
or not considered related to the medicinal product. 
All AEs (including serious AEs) will be noted in the study records and on the case report 
form with a full description including the nature, date and time of onset, determination of 
non-serious versus serious, intensity (mild, moderate, severe), duration, causality, and 
outcome of the event. 

 
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8.4    Definition of a Serious Adverse Event (SAE) 
An SAE is any adverse drug experience occurring at any dose that results in any of the 
following outcomes:  
• 
death, 
• 
a life-threatening event (at risk of death at the time of the event),  
• 
requires inpatient hospitalization or prolongation of existing hospitalization, 
• 
a persistent or significant disability/incapacity, or 
• 
a congenital anomaly/birth defect in the offspring of a subject.   
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug event when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition. 
A distinction should be drawn between serious and severe AEs.  A severe AE is a major 
event of its type.  A severe AE does not necessarily need to be considered serious.  For 
example, nausea which persists for several hours may be considered severe nausea, but 
would not be an SAE.  On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke, but would be an SAE.  
8.4.1  Relationship of SAE to study drug or other intervention 
The relationship of each SAE to the study intervention should be characterized using one 
of the following terms in accordance with CHOP IRB Guidelines: definitely, probably, 
possibly, unlikely or unrelated.  
TABLE 2: CAUSALITY CATEGORY DEFINITIONS 
Causality Term 
Assessment Criteria 
Definitely/ 
Certain 
• 
Event abnormality with plausible time relationship to drug intake 
• 
Cannot be explained by disease or other drug or intervention 
• 
Response to withdrawal plausible (pharmacologically, 
pathologically) 
Probably/ 
Likely 
• 
Event abnormality with reasonable time relationship to drug intake 
• 
Unlikely to be attributed to disease or other drug or intervention 
• 
Response to withdrawal clinically reasonable 
Possibly 
• 
Event abnormality with reasonable time relationship to drug intake 
• 
Could also be explained by disease or other drug or intervention 
• 
Information on drug withdrawal may be lacking or unclear 
Unlikely 
• 
Event abnormality with time to drug intake that makes a relationship 
improbable (but not impossible) 

 
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• 
Disease or other drug provide plausible explanations 
 
8.5    IRB/IEC Notification of SAEs and Other Unanticipated Problems 
The Investigator will promptly notify the IRB of all on-site unanticipated, serious 
Adverse Events that are related to the research activity. Other unanticipated problems 
related to the research involving risk to subjects or others will also be reported promptly. 
Written reports will be filed using the eIRB system and in accordance with the timeline 
below. External SAEs that are both unexpected and related to the study intervention will 
be reported promptly after the investigator receives the report.  
 
Type of Unanticipated 
Problem 
Initial Notification  
(Phone, Email, Fax) 
Written Report 
Internal (on-site) SAEs 
Death or Life Threatening  
24 hours 
Within 2 calendar days 
Internal (on-site) SAEs 
All other SAEs 
7 days 
Within 7 business days 
Unanticipated Problems 
Related to Research 
7 days  
Within 7 business days 
All other AEs 
N/A 
Brief Summary of important 
AEs may be reported at time 
of continuing review 
8.5.1  Follow-up report 
If an SAE has not resolved at the time of the initial report and new information arises that 
changes the investigator’s assessment of the event, a follow-up report including all 
relevant new or reassessed information (e.g., concomitant medication, medical history) 
should be submitted to the IRB. The investigator is responsible for ensuring that all SAE 
are followed until either resolved or stable.  
8.6    Investigator Reporting Requirements to Sponsor 
The PI will promptly notify the Sponsor of all unexpected fatal or life-threatening events 
that are related to the research activity within 24 hours by telephone or by email.  A 
follow-up email will be provided to the Sponsor within 48 hours of the event and a PDF 
document of this email exchange will be created and stored electronically.  Other 
unexpected, non-life threatening SAEs related to the research involving risk to the 
subjects or others will also be reported by the PI to the Sponsor via email within 48 hours 
of the event and a PDF document of this email exchange will be created and stored 
electronically.  All other SAEs that are determined by the PI to not be related to the study 
intervention and non-serious AEs will be reported to the Sponsor at the monthly research 
meetings. 

 
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8.7    FDA Notifications of SAEs/IND Safety Reports to the FDA 
(Refer to 21 CFR 312.32) 
Any unexpected fatal or unexpected life-threatening event that occurs while the subject is 
on study and is determined by the PI to possibly be due to investigational drug 
administration, will be reported to the FDA as soon as possible, but no later than 7 
calendar days after the PI has been notified of the event. 
Unexpected, non-life-threatening SAEs that occur while the subject is on study, and are 
determined by the PI to be due to investigational drug administration, will be reported to 
the FDA as soon as possible but no later than 15 calendar days after PI has been notified 
of the event. 
All other SAEs that are determined by the PI to be not related to the study intervention 
and non-serious AEs will be reported to the FDA at or by the time of the Annual Report. 
8.8    Study Stopping Criteria 
The study will be stopped and reassessed if any of the following criteria are met: 
• 
A single adverse event requiring unanticipated admission to the hospital 
• 
Greater than 20% of subjects experiencing hypotension as defined by 30% 
decreased in blood pressure from baseline. 
• 
Greater than 10% of subjects experiencing severe hypotension as defined by 50% 
decreased from baseline and that requires treatment beyond fluid replacement 
with IV isotonic solution. 
• 
Greater than 20% of subjects experiencing bradycardia as defined as heart rate 
<80 BPM in children <1 yo and a heart rate <60 BPM in subjects > 1 yo and/or 
requiring rescue medications such as atropine, glycopyrrolate, epinephrine or 
dopamine that the practitioner attributes to the administration of study drug. 
• 
One subject who experiences a serious adverse event, with serious adverse event 
defined as death, life-threatening adverse event (e.g. cardiac arrest), inpatient 
hospitalization or prolongation of existing hospitalization, a persistent or 
significant incapacity or substantial disruption of the ability to conduct normal life 
functions. 
Stopping criteria, just like adverse events, will be assessed continuously, starting with the 
first patient enrollment and until study completion. 
9   STUDY ADMINISTRATION 
9.1   Treatment Assignment Methods 
Not applicable. 

 
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9.2 
Data Collection and Management 
Data will be collected and recorded by the PI and co-investigators. The inpatient chart and 
patient records contained within EPIC systems will be reviewed for relevant data. The 
information will be recorded in an electronic database. 
1. Confidentiality.  A master list containing PHI and subject ID number will be kept 
separate from data forms (paper and electronic) that have only a study ID number. 
The master list will be on a separate computer. This form of data is considered 
“coded” not de-identified. As long as the data can be re-linked to identifiers, the 
data is coded. Only when the key to the code or the Master List is destroyed are 
the data considered de-identified.  
2. Security.  A copy of the password-protected file will be kept on the primary 
investigators office computer and the original will be kept in one of the Hospital’s 
secure servers. 
3. As this is an FDA-regulated study, data collected from this study will be 
destroyed 2 years after a marketing application has been approved or 2 years after 
all research of the study has been completed, and as approved by the Sponsor, and 
in accordance with all local policies regarding data retention.  
9.3 
Confidentiality 
All data and records generated during this study will be kept confidential in accordance 
with institutional policies and HIPAA on subject privacy and investigators will not use 
such data and records for any purpose other than conducting the study. Safeguards are 
described under “9.2 Data Collection and Management.” 
 
No identifiable data will be used for future study without first obtaining IRB approval. 
The investigator will obtain a data use agreement between the provider (the PI) of the 
data and any recipient researchers (including others at CHOP) before sharing a limited 
dataset (PHI limited to dates and zip codes).  
9.4 
Regulatory and Ethical Considerations 
9.4.1 
Data and Safety Monitoring Plan 
The study will be monitored by the sponsor and co-investigators. Prior to trial initiation, 
trial readiness will be confirmed by the Office of Research Compliance (ORC) of CHOP, 
as assessed by the Pre-Trial Monitoring Visit.  Periodic institutional monitoring will also 
be conducted according to ORC guidelines.  
After enrolling and starting administration of the investigational agent to the first subject, 
the sponsor (or CHOP PI) will contact the ORC to arrange a monitoring visit.  Thereafter, 
ORC will monitor the study at least annually. 
The principal investigator will be responsible for data safety. Information will be 
collected from patient blood sampling and the anesthesia record in EPIC and will be 

 
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stored in a password protected electronic database. Access to this database will only be 
granted to members of the study team. Safety signals requiring reporting to the IRB and 
FDA will be submitted according to whether the reporting is expedited (in the event of 
serious adverse events) or non-serious, which will be reported as part of the IRB 
continuing review and FDA annual report, as outlined in protocol Section 8.   
An independent Medical Monitor who is an anesthesiologist that is not an investigator on 
the study will be responsible for assessing and monitoring study safety.  Interim PK and 
safety analysis will be performed at the completion of each dosing cohort before 
enrollment in the next higher dose.   
9.4.2 
Risk Assessment 
Risks during this study are considered a minor increase above minimal risk. Patients 
undergoing these procedures regularly receive dexmedetomidine intravenously as part of 
their anesthetic. Attending anesthesiologists or the sedation team administering the study-
assigned analgesic(s) will not be blinded and will be able to manage side-effects or 
complications accordingly, which is consistent with how side effects or complications 
would be managed when these medications are administered in routine clinical practice. 
Study interventions other than administration of the study drug include data collection 
and medical chart review. An additional risk to subjects in this study is the potential loss 
of confidentiality that would occur if identifiable subject information were to be 
distributed to those not authorized to access it. This is highly unlikely to occur as only the 
master list will contain any identifiable subject information, and the identifiable 
information will be limited to the subject’s name, medical record number, date of birth 
and date of the procedure. The master list will be kept in a password-protected file in one 
of the Hospital’s secure servers and a backup copy of this password-protected file will be 
kept on the principal investigator’s password-protected office computer. 
 
9.4.3 
Potential Benefits of Trial Participation 
There are no direct patient benefits. However, the results of this study could provide 
potential future guidance for use of intranasal dexmedetomidine as pre-procedure 
anxiolysis in pediatric patients. 
9.4.4 
Risk-Benefit Assessment 
Risks during this study are considered a minor increase above minimal risk. Patients 
undergoing these procedures are often exposed to dexmedetomidine intravenously.  
Defining the pharmacokinetics of intranasal dexmedetomidine may benefit future patients 
at CHOP and other institutions.  For these reasons the potential benefits to study subjects 
and future patients coupled with no significant increased risk favor both trial participation 
for subjects and conduct of the trial. 
 
9.5 
Recruitment Strategy 
The principal investigator will review the Cardiac Center Intake Center appointment 
schedule approximately 2 weeks in advance of scheduled outpatient procedure.  Patients 

 
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who meet the inclusion criteria will be identified and their charts will be reviewed to 
determine eligibility.  The nurse practitioners in the Intake Center will be notified of 
potential eligible subjects.  On the day of the Intake Center visit, potentially eligible 
subjects will be approached by one of the physician study team members for enrollment 
in the study and consent will be obtained.  The patient’s history will then be reviewed 
with the family for any exclusion criteria, and if ineligible, the subject will be withdrawn 
from further study participation. The principal investigator will also review the inpatient 
procedure schedule one day in advance to identify inpatients who may be eligible for the 
study. The subject will be approached and consent will be obtained the day before the 
procedure.   
 
Subjects will be recruited into two strata: children ≥1 month up to ≤24 months, and 
children >2 up to ≤6 years of age with a goal of 50% of subjects per age strata.  
Parental/guardian permission (informed consent) will be obtained prior to any study 
related procedures being performed.  
 
 
9.6 
Informed Consent/Assent and HIPAA Authorization 
Eligible subjects will be approached by one of the physician study members for 
enrollment in the study.  For outpatients, consent will take place in the Cardiac Center 
Intake Center.  For inpatients, consent will take place in the subject’s hospital room.  If 
subjects are unsure if they would like to consent to the study at this initial meeting, they 
will be re-approached the day of their scheduled procedure for potential participation.  
The discussion and consent will outline the purpose of the study, including that the 
subject will not have a direct benefit from the drug administration and that risks during 
this study are considered to be a minor increase above minimal risk.  Subjects will also be 
informed that their decision to participate or not in the study will in no way affect their 
care.  Subjects/families will sign a combined consent-authorization document. 
9.6.1 
Waiver of Assent 
Waiver of assent is requested for all subjects in this study based on their ages.  No 
child 7 years old or older is eligible for enrollment, and therefore subjects will not 
have the capability to be consulted for assent. 
9.7 
Payment to Subjects/Families 
There will be no payment to subjects or families for study participation. 
10 PUBLICATION 
After collection, review, and analysis of data, the results of this study will be submitted 
for publication in a peer-reviewed scientific journal.  The study will only be conducted at 
CHOP, and the PI will have access to all data.  Anticipated time of submission is 18 
months after the start of the study 
 

 
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11  REFERENCES 
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APPENDIX I 
CYP2A6 Inhibitors and Inducers 
CYP2A6 Inhibitors 
CYP2A6 Inducers 
Amiodarone 
Amlodipine 
Desipramine 
Fenofibrate 
Isoniazid 
Ketoconazole 
Gabapentin 
Pilocarpine 
Pregabalin 
Selegiline 
Barbiturates 
Rifampin 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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