Intranasal Dexmedetomidine for Laceration Repair in Children: a Dose-finding Study
Phase: PHASE2
Conditions: Laceration Repair
Sponsor: London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's

Study: Intranasal dexmedetomidine for laceration repair in children: a dose finding study 
Protocol: Dose Finding Study 
Version 3.5 – November 1, 2019 
 
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Intranasal dexmedetomidine for laceration repair 
in children: a dose finding study 
 
      
 
Trial registration: 
Clinicaltrials.gov Identified Number: NCT03957304  
Protocol number: DFS05081977 
 
Protocol Version Number: V 3.5, 2019-11-01 
 
Funding: 
Children’s Health Research Institute and Lawson Internal Research Fund. The funders have no 
role or authority in study design, collection, management, analysis, and interpretation of data, 
writing of the report, or the decision to submit the report for publication. 
 
Study Sponsor: 
Dr. Naveen Poonai, MSc MD FRCPC 
Associate Professor of Pediatrics & Internal Medicine 
Schulich School of Medicine & Dentistry 
Associate Scientist, Child Health Research Institute Research Director 
Division of Paediatric Emergency Medicine 
800 Commissioners Road East, Room E1-106, London, Ontario, N6A 5W9 
Phone: 519 694 5309/ Fax: 519 667 6769 Alternate email: naveen.poonai@lhsc.on.ca 
 
Qualified Principal Investigator: 
Dr. Naveen Poonai 
 
Co-Investigators (Name and Department): 
Dr. Vikram Sabhaney, MD, Assistant Professor, Paediatrics, University of British Columbia 
Dr. Samina Ali, MDCM, Professor, Paediatrics, University of Alberta 
Dr. Kamary Coriolano, PhD, Clinical Research Coordinator, London Health Sciences Centre 
Dr. Maala Bhatt, MD, Associate Professor, Paediatrics, University of Ottawa 
Dr. Evelyne Doyon-Trottier, MD, Associate Professor, Paediatrics, Universite de Montreal 
Dr. Amit Shah, MD, Associate Professor, Internal Medicine, Western University 
Dr. Anna Heath, PhD, The Hospital for Sick Children, Assistant Professor 
 
Collaborators: 
Ms. Kyna Patterson, Child Life Specialist, London Health Sciences Centre 
 
Roles and Responsibilities: 
Dr. Poonai is the lead investigator responsible for trial oversight. Dr. Coriolano is the project 
coordinator. Dr. Heath is the biostatistician responsible for data analysis. All other investigators 

Study: Intranasal dexmedetomidine for laceration repair in children: a dose finding study 
Protocol: Dose Finding Study 
Version 3.5 – November 1, 2019 
 
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are knowledge experts that will contribute to the design, protocol, results interpretation, and 
manuscript preparation. 
 
 
INTRODUCTION 
 
Lay Summary 
The most common injury prompting an emergency department (ED) visit in children is a cut 
(laceration) that requires repair using stitches or skin glue. Despite anesthetic (freezing), laceration 
repair is often very distressful because in young children, most occur on the face. Distraction 
techniques are difficult and restraint is often necessary to achieve a cosmetically appealing repair. 
Although pain can usually be minimized, distress is very difficult to manage in children. Drugs to 
reduce anxiety in adults such as lorazepam (AtivanTM) often produce greater anxiety in children. 
There is currently no effective drug to relieve the distress of laceration repair in children. Untreated 
pain and distress in children results in slower healing, poor appetite and sleep, fear of medical care, 
and chronic pain. Parents are significantly affected by witnessing their child’s discomfort and look 
to health providers to relieve pain and distress. Our goal is to find a safe and effective drug to reduce 
distress in children undergoing laceration repair. Dexmedetomidine is a new drug that safely 
provides mild sedation and can be given as a painless nasal spray. Intranasal dexmedetomidine 
(IND) has been shown to reduce distress in children undergoing painful procedures such as dental 
work and intravenous insertion. However, no large study has explored IND for laceration repair. In 
order for research to change the way we care for children, a large study that enrolls children across 
many paediatric EDs needs to be performed. The first step is to conduct a smaller study to identify 
the safest and most effective dose. Our proposed study plans to enroll 55 children age 1-10 years 
who require laceration repair. Each participant will receive a weight-based dose of IND with 1-2 
pairs of nasal sprays. Different doses will be used until the most effective and safe dose is found. 
All children will receive local anesthetic (freezing) and undergo laceration repair according to 
standard practice. The two most important outcomes during the procedure are sedation and anxiety. 
We will record a video of the child during laceration repair and to reduce bias, videos will be scored 
by research assistants who are not in the ED. The parent, child, nurse, and doctor will rate their 
satisfaction with the procedure using a 5-point scale. Following discharge, at 24-48 hours, the 
family will receive a 10-minute Internet-based survey to identify delayed adverse behaviors and at 
14 days, a 3-minute survey to record complications related to laceration repair. Our results will be 
used to design a larger study which may potentially lead to a much less distressing experience for 
children that require laceration repair. Perceived distress in children is closely tied to caregiver 
satisfaction and an improved ED experience will lead to a more positive view of the health care 
team. A more relaxed child will enhance the ability of doctors and trainees to achieve a good 
cosmetic repair. Given our links with surrounding hospitals where most children with lacerations 
attend, our results can easily be shared to improve the care of children across Southwestern Ontario 
and eventually Canada-wide. 
 
Background and Rationale 
Lacerations are the most common injury for which children seek care in the emergency 
department (ED) (1). In Canada, lacerations are one of the top ten presenting complaints in 

Study: Intranasal dexmedetomidine for laceration repair in children: a dose finding study 
Protocol: Dose Finding Study 
Version 3.5 – November 1, 2019 
 
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children under 10 years, comprising nearly 8% of paediatric ED visits (2). Despite the routine 
application of topical lidocaine-epinephrine-tetracaine (LET) for analgesia, young children 
routinely resist laceration repair. While distraction may help in older children, in younger 
children, most lacerations occur on the face (3), making distraction difficult. Untreated pain in 
childhood can lead to short-term problems such as slower healing and long-term issues such as 
anxiety, needle phobia, and fear of medical care as adults (4). In 2016, the American Academy of 
Pediatrics and American Academy of Pediatric Dentistry recommended a goal of minimizing 
discomfort and pain and controlling behavior and movement during procedures (5). Local or 
topical anesthetics may reduce pain but do nothing to alleviate procedural distress (6). Many 
children require light sedation to provide comfort, promote compliance with positioning 
requirements, and facilitate a timely and cosmetically appealing repair (6). Intranasal midazolam 
is the most commonly used anxiolytic in children, however, a systematic review found little 
evidence of benefit (7). Moreover, midazolam has unpredictable efficacy and discomfort with 
nasal administration is a common complaint (8, 9).  Dexmedetomidine is a relatively new alpha-2-
adrenergic receptor agonist with anxiolytic, sedative, and analgesic properties (10). Three 
systematic reviews have suggested intravenous dexmedetomidine is effective for procedural 
distress in children (10-12). However, intranasal therapies are gaining popularity among health 
care providers due to ease of administration and less distress. Consequently, our team performed a 
systematic review of intranasal dexmedetomidine (IND). The review included 18 trials of 2037 
children undergoing distressing procedures including intravenous insertion, dental extraction, 
ophthalmologic examination, and diagnostic imaging (Appendix A). Across trials, IND had an 
onset and duration of sedation of 7-31 and 41-92 minutes, respectively. IND 1-4 mcg/kg provided 
adequate sedation in a significantly greater proportion of children (79%, range 55-98%) versus 
other anxiolytics (midazolam, chloral hydrate) (60%, range 0-96%). There were no serious 
adverse events and IND was well tolerated in 88% of participants (13). However, heterogeneity in 
dose and vehicle (mucosal atomizer versus nasal drops) underscored the wide range in 
effectiveness we observed. Optimizing these factors may produce more consistent and effective 
sedation. Due to heterogeneity, we were unable to characterize a dose-response relationship and 
an area of uncertainty is the optimal dose of IND. Only one trial has investigated IND in children 
for positioning prior to laceration repair. 70% (n=20) of participants were deemed “not anxious” 
compared to intranasal midazolam (11%, n=18) (3). However, the small sample size and focus on 
pre-procedural anxiety have limited clinical uptake. A large multicentre trial with an optimized 
dosing protocol will yield the best estimate of IND’s effectiveness. The results will be more likely 
to improve how the distress of laceration repair is managed. However, this is predicated upon 
determining recruitment feasibility, protocol compliance, and the most effective dose of IND.  
Purpose of the study 
Currently, an effective drug to relieve the distress of laceration repair in children is not known. 
Therefore, purpose of this study is to find a safe and effective drug to reduce distress in children 
undergoing laceration repair.  
 
Expected Results and Significance 
We believe that our study will identify the most efficacious and safe dose of IND, logistic 
obstacles to recruitment, and a realistic expectation of maximal sedation efficacy. The results will 

Study: Intranasal dexmedetomidine for laceration repair in children: a dose finding study 
Protocol: Dose Finding Study 
Version 3.5 – November 1, 2019 
 
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inform the design of a much larger multicentre randomized trial that will hopefully change 
practice and improve care. 
 
Objectives 
Primary Objective:  
In children aged 1 to 10 years who requires a laceration repair using stitches or skin glue, our 
objective is to determine the most efficacious dose of intranasal dexmedetomidine (IND) in terms 
of adequate sedation for laceration repair. Adequate sedation for the duration of the laceration 
repair is measured using the Pediatric Sedation State Scale (PSSS) (14). 
Secondary Objectives: 
1. To determine how well participants were able to tolerate the IND sprays. 
2. To determine the degree of satisfaction with laceration repair on the part of participants and 
health care providers 
3. To determine the feasibility of recruitment 
4. To determine the logistic obstacles to implementation 
 
We hypothesize that adequate sedation will be seen at higher doses of IND (3-4 mcg/kg) 
compared to lower doses (1-2 mcg/kg). Our objectives are to determine: (i) the most efficacious 
dose of IND in terms of adequate sedation for laceration repair, (ii) tolerability of IND sprays, (iii) 
patient and provider satisfaction with laceration repair, (iv) feasibility of recruitment, (v) logistic 
obstacles to implementation 
 
Limitations 
Scoring of sedation and anxiolysis are subjective which may lead to an inaccurate determination 
of the optimal dose. To minimize this risk, the training protocol used in prior studies employing 
the PSSS will be followed. In addition, a kappa statistic < 0.7 will prompt a re-review of the 
videos by the PI. Blinding of the different doses will be difficult to accomplish and may be a 
source of bias. To overcome this, the outcome assessors scoring the videos for sedation (PSSS) 
and anxiety (YPAS) will be remote from the clinical encounter and the video segment will 
commence following intranasal drug administration.  
 
Trial Design  
This study will be designed as a phase II single-arm dose ranging pilot study using an adapted 
version of the Continual Reassessment Method (15). CRM is a model-based design that is more 
likely to determine the correct dose compared to standard 3+3 designs (16). The adapted method 
adjusts for potential over-sedation (as measured by the PSSS) for higher doses of IND. 
 
 
METHODS: PARTICIPANTS, INTERVENTIONS, AND OUTCOMES 
 
Study Setting 
This study will be carried out in the paediatric emergency department (ED) of the Children’s 
Hospital in London, Ontario, Canada.  
 

Study: Intranasal dexmedetomidine for laceration repair in children: a dose finding study 
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Eligibility criteria 
 
Inclusion Criteria  
We will include (i) children age 1-10 years who present to the ED with a single isolated laceration 
< 5 cm deemed to require single-layer closure using sutures based on the opinion of the treating 
physician, (ii) predicted to resist positioning for laceration repair based on the opinion of the 
caregiver, treating physician, child life specialist, or bedside nurse, (iii) 
lidocaine/epinephrine/tetracaine (LET) used as sole initial topical anesthetic agent 
 
Exclusion Criteria 
We will exclude children with (i) laceration repair requiring procedural sedation (without IND) or 
local nerve block, (ii) other injuries requiring reduction (fracture or dislocation) or repair (nailbed 
injury or laceration), (iii) lacerations containing foreign body material (including dirt and debris), 
(iv) history of hypersensitivity to dexmedetomidine, (v) occlusion of at least one nare due to 
mucus, polyps, septal deviation, etc., (vi) concomitant use of an a2-adrenergic receptor agonist, 
(vii) bradycardia or hypotension for age (possible transient but clinically insignificant adverse 
effects of dexmedetomidine), (viii) we will exclude caregivers if they are not the primary care 
provider, (ix) are unable to read or understand English above at least a grade 8 literacy level, (x) 
concomitant upper respiratory tract infection or allergic rhinitis with at least one non-patent nare, 
(xi) known renal insufficiency, (xii) uncorrected mineralocorticoid deficiency, (xiii) congenital 
heart disease or cardiac conduction disorder  
 
Intervention 
 
Description of intervention 
Participants will be consecutively screened for eligibility during the hours of study recruitment 
(1700 to 2300 hours, 7 days per week) by trained research assistants (RA) prior to being seen by a 
physician but after nursing assessment. If eligible, the RA will obtain informed consent and assent 
(when applicable) and the physician will confirm eligibility and order the study intervention on 
Cerner. Participants will be administered IND 100 mcg/mL [Precedex®, Pfizer Canada Inc, 
Kirkland, Québec 1-4 mcg/kg (max 200 mcg or 2 mL)]. The weight-based dose will be calculated 
by REDCap and confirmed by the nurse and physician. The intervention will be drawn into a 
mucosal atomizer device (MAD) by the bedside nurse using a 1 mL syringe. An extra 0.15 mL 
will be drawn into the atomizer upon first use to account for dead space. No more than 0.5 mL per 
nare will be administered at once because volumes exceeding 0.5 mL result in oropharyngeal 
deposition (17). If two sprays are required (one per nare), they will be administered either 
simultaneously or in rapid succession. IND will be administered by the bedside nurse with the 
participant positioned supine with the head at 45o. In our ED, topical anesthetic (LET) is placed 
on the wound 30 minutes prior to laceration repair once the nurse has obtained a physician’s 
order. IND has a time to peak plasma concentration of 38 minutes (17) and an onset of sedation in 
children of 25 minutes (18). IND will be given at the same time as LET placement so that the 
onset of sedation is coincident with positioning for laceration repair. The physician or their 
designate will be asked to perform suture repair after at least 30 minutes has elapsed following 
IND administration.  

Study: Intranasal dexmedetomidine for laceration repair in children: a dose finding study 
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Version 3.5 – November 1, 2019 
 
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The RA will conduct two follow-ups with participants by email or telephone, depending on the 
preference of the participant. The RA will contact the participant 24-48 hours post-discharge to 
identify the presence of delayed maladaptive behaviors using the Post-Hospital Behavior 
Questionnaire (PHBQ); The PHBQ will take approximately 10 minutes to complete. At 14 days 
post-laceration repair, participants will be contacted to determine the presence or absence of 
complications (infection; dehiscence; contracture; retained suture material). This survey will take 
approximately 3 minutes to complete. If the latter survey cannot be obtained, the medical record 
of the participant will be examined for the presence of an emergency department visit for wound-
related complications. 
 
Criteria for discounting or modifying allocated interventions 
 
An investigator may discontinue or withdraw a participant from the study for the following 
reasons: 
1. 
If any clinical adverse event (AE), laboratory abnormality, or other medical 
condition or situation occurs such that continued participation in the study would 
be detrimental to the health of the participant. 
2. 
If the participant is found to meet exclusion criteria (either newly developed or not 
previously recognized) that precludes further study participation. 
 
Concomitant care and interventions that are permitted or prohibited during the trial 
 
Permissible co-interventions include topical and subcutaneous anesthetic, oral or IV analgesics, 
and non-pharmacologic strategies for pain and distress. 
 
Outcomes 
 
All data will be recorded using Research Electronic Data Capture (REDCap) by RAs. We will 
collect demographic data: age; sex; size and location of laceration; number of sutures; trainee 
level (if repair is not performed by attending physician); type of local anesthetic; presence or 
absence of a child life specialist; distraction techniques; data pertaining to primary and secondary 
outcomes. The primary outcome is adequate sedation (PSSS 2 or 3) for the duration of the 
measurement period (initial positioning to tying of the last suture). Secondary outcomes include: 
onset and duration of sedation; adverse effects as defined by the Quebec Guidelines (16); 
anxiolysis during the study period measured using the Yale Preoperative Anxiety Scale; 
compliance (yes/no) with IND administration; satisfaction with laceration repair using a 5-item 
Likert scale obtained from the caregiver, child (if > 7 years), individual performing the repair, and 
bedside nurse; nasal irritation from children age > 4 years using the Faces Pain Scale – Revised 
(FPS-R); length of stay; consent rate; heart rate (HR), systolic blood pressure (SBP), diastolic 
blood pressure (DBP) and oxygen saturation (SpaO2), respiratory rate (RR) recorded at baseline 
and every 5 minutes until 60 minutes after last pair of sprays is administered, delayed maladaptive 
behaviors using the Post-Hospital Behavior Questionnaire (PHBQ) assessed 24-48 hours post 

Study: Intranasal dexmedetomidine for laceration repair in children: a dose finding study 
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discharge; complications within 14 days of discharge (infection; dehiscence; contracture; retained 
suture material).  
 
 
Patient Engagement 
 
Study outcomes were identified and agreed upon by a five-member focus group involving the PI, 
a child life specialist, and three parents of children who have undergone laceration repair. The 
study design therefore reflects their concerns about length of stay and topical analgesia. 
 
 
 
 

Study: Intranasal dexmedetomidine for laceration repair in children: a dose finding study 
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Participant timeline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total of N patients will be screened as potential participants. 
Assessment of eligibility by inclusion/exclusion criteria; obtain informed consent 
Screening - ED 
 
Enrollment/Baseli
ne Evaluation - ED 
Obtain demographics: age, sex, medical history, weight, size of laceration, 
location of laceration and vital signs  
The maximum dose for the IND intervention is of 1mL to be administered in 
0.5mL doses in each nostril by at least 60 seconds.  
Post-Intervention 
Assessment 
Research assistant records satisfaction from caregiver bedside nurse, health care 
provider performing repair a 5-item Likert scale.  
Nasal Irritation 
Complete all End of study form, Research 
nurse records PHBQ Questionnaire by 
telephone or internet survey 
_____ mcg /kg x _____kg / 100mcg/mL =_____ mL 
Dose calculation/ 
ED 
Intervention 
Research assistant records nasal irritation from children age > 4 years using the 
Faces Pain Scale – Revised (FPS-R) 
Follow Up: complete 
PHBQ +/- 24 to +/- 48 
hours  
Outcome Assessor 
Outcome assessor will score the videos for Pediatric Sedation State Scale (PSSS)  
and Yale Preoperative Anxiety Scale (YPAS) 
Vital signs  
Heart rate, systolic and diastolic blood pressure, oxygen saturation and 
respiratory rate will be recorded every 5 min until 60 min after last pair of sprays 
is administered. 

Study: Intranasal dexmedetomidine for laceration repair in children: a dose finding study 
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Sample Size 
This was calculated using the Bayesian Continual Reassessment Method (18). Based on an 
adverse event rate of 20%, an “effect size" of 1.6 (i.e. the odds ratio between consecutive 
increasing doses), and a phase II trial accuracy level of 60%, we estimated a sample size of 50 
participants. With increasing the sample size by 10% to account for dropouts, the final sample size 
is 55 participants. 
 
Feasibility 
An existing team of 12 research assistants (RAs) with REDCap and clinical trial recruitment 
experience are available to recruit during the peak visit period of 1700-2300 hours, 7 days a week, 
50 weeks a year. A 2018 clinical informatics search revealed that 1332 laceration repairs were 
performed, of which 472 met our inclusion criteria and presented between 1700-2300 hours. With 
an expected 50% consent rate, recruitment of 50 participants is feasible in 12 months.  
 
Recruitment 
 
METHODS: ASSIGNMENT OF INTERVENTIONS   
 
Allocation 
 
Not applicable 
 
Sequence generation 
 
A list will be provided to  
 
Allocation concealment mechanism 
 
Not applicable 
 
Implementation 
 
Participants will be assigned to each dosing level by pharmacy based on the continual 
reassessment method’s study design. Research assistants will enroll participants.  
 
Blinding 
 
Blinding of dose levels will not be possible for clinical and research personnel in the ED. 
However, outcome assessors will be blinded by virtue of being remote from the clinical 
encounter. Furthermore, video segments will commence immediately after intranasal sprays are 
given so outcome assessors will not see what volume is administered. Two independent assessors 
will score each video and an inter-rater agreement (kappa) will be calculated. Disagreements on 

Study: Intranasal dexmedetomidine for laceration repair in children: a dose finding study 
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scoring for the purposes of estimating the Bayesian dose response model will be resolved by 
discussion.  
 
METHODS: DATA COLLECTION, MANAGEMENT, AND ANALYSIS 
 
Data collection methods 
 
Sedation will be measured using the Pediatric Sedation State Scale (PSSS) (Appendix B), an 
instrument validated for video scoring of children undergoing painful procedures. The PSSS is 
scored from 0 to 5 easily by non-medical personnel. The PSSS assesses pain as well as over 
sedation and under sedation. Adequate sedation is a score of 2 or 3, over sedation is a score of 0 or 
1 and under sedation is a score of 4 or 5 (14). Participants will be assigned to doses of IND from 
1-4 mcg/kg, increasing in whole number increments. Initially three participants will receive 
1mcg/kg and the number of participants at each dose of IND will be recorded. Data from these 
participants will be used to update a Bayesian model for the dose-response curve for all three 
categories of sedation. The following three participants will be assigned the dose with the highest 
posterior probability of an efficacy close to 0.8. This balances the need to determine the most 
efficacious dose but prevents an excessive number of over-sedations. For the Bayesian dose 
response model, a determination will be made as to the overall score category for each participant 
(“adequate”, “over”, or “under sedated” based on the PSSS). To be scored as “adequate”, a 
participant must have a PSSS score of 2 or 3 for at least 90% of observations from initial 
positioning to tying of the last suture. If a participant does not retain a PSSS score of 2 or 3 for at 
least 90% of the observations, they will be categorized as either over or under-sedated, if the 
majority of the remaining PSSS scores are 0 or 1 or 4 or 5, respectively. Furthermore, if the 
participant remains awake, but not distressed during the procedure, they will be scored as a 2 
based on the PSSS. However, for the purposes of the Bayesian dose response model, they will be 
scored as “under sedated” to avoid concluding that a lower dose of IND is effective based on the 
outcomes for participants that did not require sedation. Finally, participants who are noncompliant 
with IND will be categorized as an over-sedation as it is assumed that this dose was not well 
tolerated by the participant and dose escalation should be avoided. 
 
Preliminary results indicate that, conditional on suitable priors, this method has an approximately 
83% chance of selecting the most effective dose. Serious adverse events as defined by the Quebec 
Guidelines on paediatric procedural sedation (19) will be reported as per Good Clinical Practices. 
Data will be reviewed after each dose by a data safety monitoring board (DSMB), who will 
confirm it is safe to escalate to the dose proposed using the Bayesian dose response model. The 
DSMB will be comprised of two emergency physicians and will be independent from the sponsor 
and reporting structure. Permissible co-interventions include topical and subcutaneous anesthetic, 
oral or IV analgesics, and non-pharmacologic strategies for pain and distress.  
 
Data management 
 
The site investigator will be responsible for retaining (archiving) their own essential study 
documents that individually or collectively permit the evaluation and conduct of the study and the 

Study: Intranasal dexmedetomidine for laceration repair in children: a dose finding study 
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quality of data, in accordance with ICH-GCP and applicable regulatory requirements. All study 
documents, including source, are to be stored in a confidential location with secured and limited 
access. All electronic records and data sets will be encrypted and password protected with access 
only permitted by the PI, site coordinator(s), and research team members. Paper data (e.g. copies 
of consent and assent forms) will be stored exclusively in the Participating Site Investigator’s 
research office in a locked cabinet. Results will not be reported in a way that identifies any 
individuals. 
 
All study related documentation will be retained in accordance with Health Canada’s Food and 
Drug Regulations for 25 years and per the investigational site’s institutional record management 
and retention policies. No records will be destroyed without the written consent of the Qualified 
Investigator and/or Sponsor. 
 
Statistical methods  
 
For demographic data and all secondary outcomes, we will summarize the data using  
i) 
proportions for discrete variables 
ii) 
means, medians, standard deviation, interquartile range and range for continuous variables 
For the primary outcome, we will also provide the Bayesian credible interval for the probability of 
a successful sedation, estimated from the Bayesian dose response curve. We will provide a 
graphical summary of patient flow and the dose escalation process. No imputation is planned for 
missing data and, unless unexpectedly high levels of missingness are observed, data will be 
assumed to be missing at random and missing data points will be excluded from the analysis. 
Available data for the primary outcome will be a requirement for all 3 patients at each dosing 
level before proceeding with the next dose. In keeping with methodologic guidelines for dose-
finding studies, inferential analyses will not be performed and will focus instead on a non- 
frequentist confidence interval estimation approach. 
 
Data monitoring 
 
Data will be reviewed after each dose by a data safety monitoring board (DSMB), who will 
confirm it is safe to escalate to the dose proposed using the Bayesian dose response model. The 
DSMB will be comprised of two emergency physicians and will be independent from the sponsor 
and reporting structure.  
 
METHODS: MONITORING 
 
Harms 
 
Study Assessment and Procedures Assessment of Safety 
 
The onset of sedation, duration of sedation, maladaptive behaviors due to sedation, nasal irritation, 
vital signs are also important measures used to assess safety. 
 

Study: Intranasal dexmedetomidine for laceration repair in children: a dose finding study 
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Onset of sedation: This will be defined as the time interval from administration of the first pair of 
IN sprays to the time when a PSSS score of 2 or 3 is achieved, whether or not all of the 
intervention has been administered. This will be ascertained by the outcome assessors. 
 
Duration of sedation: This will be defined as the duration of time between the first PSSS score of 
2 or 3 to the last PSSS score of 2 or 3 post- laceration repair. This will be ascertained by the 
outcome assessors. 
 
Maladaptive behaviors due to sedation: This will be assessed by the research associate using the 
Post-Hospital Behavior Questionnaire (PBHQ) administered by phone or email survey 24 to 48 
hours following discharge. This will be done in order to screen for any delayed behavioral adverse 
effects. This information will be recorded using REDCap (Dose Finding Study PHBQ form). 
 
Nasal irritation: The research assistant will ask participants age > 4 years using the Faces Pain 
Scale – Revised (FPS-R) to rate their nasal irritation related to the IN sprays. Nasal irritation has 
not been described with IN dexmedetomidine but is theoretically possible and needs to be 
identified in order to provide appropriate anticipatory guidance.  
 
Vital Signs:  Heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP) and 
oxygen saturation (SpaO2), respiratory rate (RR) will be recorded at baseline and every 5 minutes 
until 60 minutes after last pair of sprays is administered. Data will be collected using REDCap 
(Vital signs CRF form). 
   
Adverse events (AEs): The research associate will be trained on the recognition and definition of 
all expected and unexpected AEs. AEs are document medical events that occur to a 
participant/subject once enrolled in a study. AEs are the construct through which the safety of an 
intervention is recorded and assessed during the study period.  
 
Data will be collected using REDCap (Dose finding Study AE form). The form includes the 
definitions and AE descriptions that could be related to sedation. Uncertainty regarding the 
presence of AEs will be clarified with the sedating physician (if it occurs while participant is in 
the paediatric emergency department) and with PI for all AE cases reported. All AEs will be 
recorded.  
 
Monitoring of Adverse Events During Sedation 
 
In two systematic reviews (11, 13) of intranasal dexmedetomidine in children (29 trials, 3134 
participants), adverse cardiorespiratory events requiring intervention have not been described. 
This is in contrast to the use of IV dexmedetomidine and may be explained by the reduced 
bioavailability of the intranasal route (median 65%). However, to monitor the presence of serious 
adverse effects, several measures will be in place. Commencing immediately prior to 
administration of the intervention and continuing until the participant is awake, all participants 
will receive continuous cardiorespiratory monitoring. In accordance with our institutional policies 

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and recommendations from the American College of Emergency Physicians’ Guidelines, this 
consists of: 
 
1. 
Five-lead continuous ECG to assess for the presence of bradycardia, dysrhythmias, and 
early changes suggestive of hypokalemia (< 3 mEq/L) (flattened or inverted T waves 
progressing to QT prolongation, ST depression, and U waves). If suggestive ECG 
changes are present, the participant will have a stat capillary puncture to measure the 
serum potassium.  
2. 
Oxygen saturation to assess for the presence of desaturation  
3. 
Blood pressure assessments using a Dynamap every 5 minutes to assess for the 
presence of hypotension or hypertension 
 
A staff anesthetist is in house 24-7 in our institution. In the event that an adverse electrolyte or 
cardiopulmonary event is identified, the appropriate resuscitative measures will be provided based 
on the opinion and direction of the treating paediatric emergency physician. In our institution, 
resuscitative measures in the emergency department fall under the responsibility of the treating 
paediatric emergency physician. In the event of clinically significant hypokalemia, this may 
include but is not restricted to oral potassium chloride. In the event of clinically significant 
hypotension or bradycardia, this may include but is not restricted to reverse Trendelenberg 
positioning, placement of an intravenous line and administration of crystalloid fluids, and other 
measures consistent with the Paediatric Advanced Life Support algorithm.    
 
Serious Adverse Event and Unexpected Drug Reactions 
 
A Serious Adverse Event (SAE) will be defined as - any adverse occurrence of a clinical trial 
subject who is administered a drug at any dose, or placebo that may or may not be caused by the 
administration of the drug or placebo that results in: 
 
1. 
Hospitalization due to a sedation related event 
2. 
Prolongation of existing hospitalization  
3. 
Congenital malformation or birth defect  
4. 
Persistent or significant disability or incapacity  
5. 
An outcome that is life-threatening  
6. 
Death 
 
Important medical events that may not result in death, be life-threatening, substantially disrupt 
one’s ability to conduct normal life functions or require hospitalization may be considered serious 
when, based upon appropriate medical judgment, they may jeopardize the participant and may 
require medical or surgical intervention to prevent one of the outcomes listed in this definition.   
 
All serious, unexpected AEs and drug reactions will be reported to Health Canada by the 
Qualified Principal Investigator within 15 calendar days after the Qualified Principal Investigator 
becomes aware of the event. For death or life-threatening events, this report must be done within 7 
calendar days after the Qualified Principal Investigator becomes aware of the event. In the latter 

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13 
 
case, a follow-up report must be filed within 8 calendar days. All AEs will also be submitted, in 
accordance with the DSMB safety monitoring plan to the independent DSMB assigned to this 
study. 
 
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the PI 
deems the event to be chronic or the participant is stable. The Qualified Principal Investigator will 
also, within 8 days after having informed Health Canada of the adverse drug reaction, submit as 
complete as possible, a report which includes an assessment of the importance and implication of 
any findings.  
 
A completed Adverse Drug Reaction (ADR) Expedited Reporting Summary Form should be 
attached to the front of the completed ADR report (suggested ADR report format: Suspect 
Adverse Reaction Report - CIOMS form of the Council for International Organizations of 
Medical Sciences (CIOMS)). Please find the form attached as Appendix C.  
Adverse Events Reporting 
 
All adverse events (AEs) will be reported to the Research Ethics Board in accordance with site’s 
AE reporting guidelines. The PI will assess each AE in terms of its expectedness and relationship 
to the study drug. Information to be collected will include an event description, date of onset, 
clinician’s assessment of severity, relationship to study intervention (assessed only by those with 
the training and authority to make a diagnosis), and date of resolution/stabilization of the event 
and event outcome (resolved/recovered, recovered with sequalae, not recovered/not resolved, 
death, or unknown). 
 
Study Discontinuation and Closure 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause based on the findings of the DSMB of safety issues. The latter include 
determination by the DSMB of significant adverse events that pose an unacceptable risk to 
participants such as complications due to treatment or related adverse events at rates above 
expected. Serious adverse events as defined by the Quebec Guidelines (16) on paediatric 
procedural sedation will be reported as per Good Clinical Practices. Data will be reviewed by the 
two-member DSMB prior to each planned dose increase. The two members will need to 
unanimously agree that it is safe to increase the dose. Written notification, documenting the 
reason for study suspension or termination, will be provided by the suspending or terminating 
party (DSMB) to study participants, funding agency (if applicable), the Sponsor, responsible REB 
and Health Canada. The Study participants will be contacted by Qualified Principal Investigator, 
as applicable, and be informed of changes to study visit schedule (if applicable). The study may 
resume once concerns about safety, protocol compliance, and data quality are addressed, and 
satisfy the Sponsor, REB and/or Health Canada. 
 
Withdrawal / Discontinuation Criteria 
 

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Participants are free to withdraw from participation in the study at any time upon request. 
However, data accrued from the participant to the time of withdrawal will be retained by the 
investigators for analysis. Example, if participant decided to withdraw the study before receiving 
the intranasal sprays. All data up to the point participant requested to be withdrawn will be kept.   
An investigator may discontinue or withdraw a participant from the study for the following 
reasons: 
1. 
If any clinical adverse event (AE), laboratory abnormality, or other medical 
condition or situation occurs such that continued participation in the study would 
be detrimental to the health of the participant. 
2. 
If the participant is found to meet exclusion criteria (either newly developed or not 
previously recognized) that precludes further study participation. 
 
The reason for participant discontinuation or withdrawal from the study will be recorded on the 
Dose Finding Study Case Report Form (CRF- End of Study Form). For the purposes of this trial, a 
protocol violation will be defined as any accidental or unintentional change or non-compliance 
with the REB approved protocol which increases or decreases benefit, affects the subject’s rights, 
safety or welfare or the integrity of the study. In the event that a participant is found to meet 
exclusion criteria (either newly developed or not previously recognized), this constitutes a 
protocol violation and the protocol will be discontinued. However, the participant will be followed 
for the study period for AEs. A protocol violation report must be completed as per local REB 
requirements and notification should be sent to the local REB (Western University - Research 
ethics board) by email. A note to file signed by the site PI should be completed and if any clinical 
adverse event (AE) occurs, an AE should also be completed and signed by PI and research staff. A 
copy of all documents must be sent to the local REB. 
 
Follow up for participants withdrawn from investigational product: All participants who receive 
the interventional drug, including those who withdrawn, will be asked to remain in the emergency 
department until they are fully recovered from sedation as per the treating physician. Participants 
who are withdrawn after receiving interventional product will be contacted approximately 24 to 
48 hours after discharge by a research associate via telephone. These participants will be asked an 
open-ended question such as: do you have any health concern since you were discharged from 
paediatric emergency department? If they return to the emergency department within 24 hours, the 
participant’s medical record will be scrutinized by the research associate for adverse events as 
defined by the Quebec Guidelines (16) on paediatric procedural sedation.    
 
Caregivers and participants will be advised at discharge and during the follow-up phone call that 
if they (or their child as applicable) experience adverse effects that they believe require a hospital 
visit, it is important that they make every effort to return to the hospital where procedure was 
performed. If they need immediate treatment and are unable to return to the hospital, they should 
proceed to the nearest emergency as soon as possible 
 
Quality Assurance and Quality Control 
 

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15 
 
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution. 
 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical 
trial is conducted and data are generated, documented (recorded), and reported in compliance with 
the protocol, International Conference on Harmonisation Good Clinical Practice (ICH GCP), and 
applicable regulatory requirements.  
 
The investigational site will provide direct access to all trial-related source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 
 
All individuals from the research team such as site Investigator, site coordinators, and other 
research personnel will be required to complete the Tri-Council Policy Tutorial: Ethical Conduct 
for Research Involving Humans, the Good Clinical Practices course, and the division 5 Health 
Canada module. Completion will be documented prior to implementation of the study. Privacy 
and confidentiality policy and procedure will also be reviewed at the study recruitment training 
session for all study personnel. 
 
Auditing 
 
The investigational site will provide direct access to all trial-related source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 
 
 
 
 

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16 
 
ETHICS AND DISSEMINATION 
  
Statement of Compliance 
 
The trial will be conducted in accordance with Good Clinical Practice (GCP) as described in 
Health Canada’s section C.05.010/Division 5 of the Food and Drugs Regulations, International 
Conference on Harmonization-Good Clinical Practice (ICH-GCP E6 R2), Tri-Counsel Policy 
Statement (TCPS2, 2014); applicable federal, provincial and local regulatory and legislative 
requirements. The Qualified and Participating Site Investigator(s) will assure that no deviation 
from, or changes to the protocol will take place without prior documented authorization (no 
objection letter - NOL) from Health Canada (Therapeutic Products Directorate) and documented 
approval from a duly constituted Research Ethics Board (REB), except where necessary to 
eliminate an immediate hazard(s) to the trial participants. All personnel involved in the conduct of 
this study have completed Human Subjects Protection and ICH-GCP Training. 
 
Research ethics approval 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the REB for review and approval. Approval of both the protocol and the consent 
form must be obtained before any participant is enrolled.  
Protocol amendments 
 
Any amendment to the protocol will require review and approval by the REB before the changes 
are implemented to the study as well as authorization form Health Canada. All changes to the 
consent form will be REB approved; a determination will be made regarding whether a new 
consent needs to be obtained from participants who provided consent, using a previously 
approved consent form 
 
Consent or assent 
 
If a patient is eligible, the Research Assistant will obtain informed consent and assent (when 
applicable). 
 
Confidentiality 
 
Please refer to the data management section. All identifying participant information will be kept 
confidential in accordance with our REB requirements. The REDCap project will contain no 
identifying information. 
 
Declaration of interests 
 
None 
 
Access to data 

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17 
 
All electronic records and data sets will be encrypted and password protected with access only 
permitted by the PI, site coordinator(s), and research team members. The investigational site will 
provide direct access to all trial-related source data/documents, and reports for the purpose of 
monitoring and auditing by the sponsor, and inspection by local and regulatory authorities 
 
Ancillary and post-trial care 
 
Post-sedation care and monitoring will be in accordance with local institutional policies for 
sedated patients. Discharge instructions appropriate to laceration repair will be provided. 
 
Dissemination policy 
 
Trial results in the form of an abstract will be presented at local research days and national 
scientific meetings. The manuscript will be submitted to a peer reviewed medical journal. Results 
will be disseminated informally to the study team and health care personnel at the participating 
site. There are no plans for dissemination of results directly to participants.  
 
 
 

Study: Intranasal dexmedetomidine for laceration repair in children: a dose finding study 
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18 
 
References   
 
1. 
Services USDoHaH. Centers for Disease Control and Prevention. National Survey of 
Ambulatory Surgery. 2015 [Available from: https://www.cdc.gov/nchs/nsas/nsas_products.htm. 
2. 
O’Donnell M WJ. Children’s Emergency Department Services: Setting the Stage for Tiers 
Development Vancouver, BC.2016 [Available from: 
https://www.childhealthindicatorsbc.ca/sites/default/files/16%2010%2001%20ED%20Tiers%20S
etting%20the%20Stage_1.pdf. 
3. 
Neville DNW, Hayes KR, Ivan Y, McDowell ER, RD P. Double-blind randomized controlled 
trial of intranasal dexmedetomidine versus intranasal 
midazolam as anxiolysis prior to pediatric laceration repair in the emergency department. Acad 
Emerg Med. 2016;23:910-7. 
4. 
Taddio A, McGrath P, A. F. Effects of early pain experience: The human literature. 
Progress in Pain Research and Management. 1999;13:57-74. 
5. 
Coté CJ, Wilson S, American Academy of Pediatrics, Dentistry AAoP. Guidelines for 
monitoring and management of pediatric patients before, during, and after sedation for 
diagnostic and therapeutic procedures: update 2016,. Pediatrics. 2016;138(1):e1-e31. 
6. 
Miller JL CA, Thomas A, Couloures K, Johnson PN. Sedation and analgesia using 
medications delivered via the extravascular route in children undergoing laceration repair. J 
Pediatr Pharmacol Ther. 2018;23:72-83. 
7. 
Conway A, Rolley J, JR S. Midazolam for sedation before procedures. Cochrane Database 
Syst Rev. 2016;5:CD009491. 
8. 
Kogan A, Katz J, Efrat R, al. e. Premedication with midazolam in young children: a 
comparison of four routes of administration. Paediatr Anaesth. 2002;12:685-9. 
9. 
Fantacci C, Fabrizio GC, Ferrara P, Franceschi F, A C. Intranasal drug administration for 
procedural sedation in children admitted 
to pediatric emergency room. Eur Rev Med Pharmacol Sci. 2018;22:217-22. 
10. 
ter Bruggen FFJA, Eralp I, Jansen CK, Stronks DL, FJPM H. Efficacy of dexmedetomidine as 
a sole sedative agent in small diagnostic and therapeutic 
procedures: a systematic review. Pain Pract. 2017;17(6):829-40. 
11. 
Kim HJ, Shin WJ, Park S, Ahn HS, JH O. The sedative effects of the intranasal 
administration of dexmedetomidine in children undergoing surgeries compared to other 
sedation methods: A systematic review and meta-analysis. J Clin Anesth. 2017;38:33-9. 
12. 
Hayden JC, Breatnach C, Doherty DR, Healy M, Howlett MM, Gallagher PJ, et al. Efficacy 
of α2-agonists for sedation in pediatric critical care: a systematic review. Pediatr Crit Care Med. 
2016;17(2):e66-75. 
13. 
Spohn J, Hendrikx S, Doyon-Trottier E, Sabhaney V, Ali S, Shah A, et al. Intranasal 
dexmedetomidine for procedural distress in children: a systematic review and meta-analysis. 
CJEM. 2019;21(Suppl 1):S30. 
14. 
Cravero JP AN, Sriswasdi P, Tsze DS, Zurakowski D, Sinnott S. Validation of the Pediatric 
Sedation State Scale. Pediatrics. 2017;139(5):e20162897. 

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Protocol: Dose Finding Study 
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19 
 
15. 
O'Quigley H, Pepe M, Fisher L. Continual reassessment method: a practical design for 
phase 1 clinical trials in cancer. Biometrics. 1990;46(1):33-48. 
16. 
Berry DA, Berry SM, Carlin BP, Lee JJ, Muller P. Bayesian Adaptive Methods for Clinical 
Trials. CRC Press LLC; 2010. 
17. 
Yuen VM, Hui TW, Irwin MG, Yao TJ, Wong GL, MK Y. Optimal timing for the 
administration of intranasal dexmedetomidine for premedication in children. Anaesth. 
2010;65(9):922-9. 
18. 
Cheung YK. Sample size formulae for the Bayesian continual reassessment method. Clin 
Trials. 2013;10(6):852-61. 
19. 
Bhatt M, Kennedy RM, Osmond MH, al. e, Network. CPoSRoPERCatPECAR. Consensus-
based recommendations for standardizing terminology and reporting adverse events for 
emergency department procedural sedation and analgesia in children. Ann Emerg Med. 
2009;53(4):426-35.e4. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDICES 
 
Appendix A 
 
 
 
 
 
 

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Appendix B Pediatric Sedation State Scale (PSSS)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix C 
The Council for International Organizations of Medical Sciences (CIOMS) 
 

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Appendix D  
 
 
Post-Hospital Behavior Questionnaire (PHBQ)- Follow up between 24 to 48 hours after discharge (Hilly J, 2015) 
1. Does your child make a fuss about going to bed at night? 
 
               
2. Does your child make a fuss about eating? 
 
               
3. Does your child spend time just sitting or lying and doing nothing?  
 
              
4. Does your child need a pacifier? 
 
               
5. Does your child seem to be afraid of leaving the house with you? 
                                      
                
Much less than before (1) 
Less than before (2) 
Same as before (3) 
More than before (4) 
Much more than before (5) 
Much less than before (1) 
Less than before (2) 
Same as before (3) 
More than before (4) 
Much more than before (5) 
Much less than before (1) 
Less than before (2) 
Same as before (3) 
More than before (4) 
Much more than before (5) 
Much less than before (1) 
Less than before (2) 
Same as before (3) 
More than before (4) 
Much more than before (5) 
Much less than before (1) 
Less than before (2) 
Same as before (3) 
More than before (4) 
Much more than before (5) 

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6. Is your child uninterested in what goes on around him (or her)? 
 
               
7. Does your child wet the bed at night? 
 
                
8. Does your child bite his (or her) finger nails? 
 
                 
9. Does your child get upset when you leave him (or her) alone for a few minutes? 
 
               
10. Does your child need a lot of help doing things? 
 
               
11. Is it difficult to get your child interested in doing things (like playing games with toys/ video games)? 
 
               
Much less than before (1) 
Less than before (2) 
Same as before (3) 
More than before (4) 
Much more than before (5) 
Much less than before (1) 
Less than before (2) 
Same as before (3) 
More than before (4) 
Much more than before (5) 
Much less than before (1) 
Less than before (2) 
Same as before (3) 
More than before (4) 
Much more than before (5) 
Much less than before (1) 
Less than before (2) 
Same as before (3) 
More than before (4) 
Much more than before (5) 
Much less than before (1) 
Less than before (2) 
Same as before (3) 
More than before (4) 
Much more than before (5) 
Much less than before (1) 
Less than before (2) 
Same as before (3) 
More than before (4) 
Much more than before (5) 

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12. Does your child seem to avoid or be afraid of new things? 
 
              
13. Does your child have difficulty making up his (or her) mind? 
 
               
14. Does your child have temper tantrums? 
 
               
15. Is it difficult to get your child to talk to you? 
 
             
16. Does your child seem to get upset when someone mentions doctors or hospitals? 
 
             
17. Does your child follow you everywhere around the house? 
 
               
 
Much less than before (1) 
Less than before (2) 
Same as before (3) 
More than before (4) 
Much more than before (5) 
Much less than before (1) 
Less than before (2) 
Same as before (3) 
More than before (4) 
Much more than before (5) 
Much less than before (1) 
Less than before (2) 
Same as before (3) 
More than before (4) 
Much more than before (5) 
Much less than before (1) 
Less than before (2) 
Same as before (3) 
More than before (4) 
Much more than before (5) 
Much less than before (1) 
Less than before (2) 
Same as before (3) 
More than before (4) 
Much more than before (5) 
Much less than before (1) 
Less than before (2) 
Same as before (3) 
More than before (4) 
Much more than before (5) 

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18. Does your child spend time trying to get or hold your attention?      
                                 
              
19. Is your child afraid of the dark? 
 
               
20. Does your child have bad dreams at night or wake up and cry? 
 
               
21. Does your child have irregular bowel movements? 
 
               
22. Does your child have trouble getting to sleep at night? 
                              
             
23. Does your child seem to be shy around strangers? 
 
               
 
Much less than before (1) 
Less than before (2) 
Same as before (3) 
More than before (4) 
Much more than before (5) 
Much less than before (1) 
Less than before (2) 
Same as before (3) 
More than before (4) 
Much more than before (5) 
Much less than before (1) 
Less than before (2) 
Same as before (3) 
More than before (4) 
Much more than before (5) 
Much less than before (1) 
Less than before (2) 
Same as before (3) 
More than before (4) 
Much more than before (5) 
Much less than before (1) 
Less than before (2) 
Same as before (3) 
More than before (4) 
Much more than before (5) 
Much less than before (1) 
Less than before (2) 
Same as before (3) 
More than before (4) 
Much more than before (5) 

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24. Does your child have a poor appetite? 
 
              
25. Does your child tend to disobey you? 
 
              
26. Does your child break toys or other objects? 
 
               
27. Does your child suck his (or her) fingers or thumbs? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Much less than before (1) 
Less than before (2) 
Same as before (3) 
More than before (4) 
Much more than before (5) 
Much less than before (1) 
Less than before (2) 
Same as before (3) 
More than before (4) 
Much more than before (5) 
Much less than before (1) 
Less than before (2) 
Same as before (3) 
More than before (4) 
Much more than before (5) 
Much less than before (1) 
Less than before (2) 
Same as before (3) More than before (4) 
Much more than before (5) 

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Appendix E 
 
 
 
 
 
 
 

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