Oral Dexamethasone for the Treatment of Acute Migraine Recurrence in Pediatric Patients Presenting to the Emergency Department With Migraine: A Pilot Randomized Controlled Trial
Phase: PHASE3
Conditions: Migraine
Sponsor: Children's Hospital of Eastern Ontario

 
Protocol version: #1, May 30th 2016 
Protocol # and Investigator Initials: #1, RZ 
 
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Protocol Title: Oral Dexamethasone for the Treatment of Acute Migraine 
Recurrence in Pediatric Patients Presenting to the Emergency Department with 
Migraine: A Pilot Randomized Controlled Trial 
 
Principal Investigator:  
Roger Zemek, MD, FRCPC 
Division of Emergency Medicine 
Children’s Hospital of Eastern Ontario 
401 Smyth Road 
Ottawa, Ontario 
K1H 8L1 
Phone: (613) 737-7600 ext. 3963 
 
Co-Investigators:  
Serena L. Orr, MD, MSc Candidate (Epidemiology) 
Co-Investigator 
Children’s Hospital of Eastern Ontario, Division of Neurology 
401 Smyth Road 
Ottawa, ON, K1H 8L1 
Phone: (613) 737-7600 ext. 1605 
 
Lawrence Richer MD, MSc (Clinical Epidemiology) 
Principal Investigator 
4-588 Edmonton Clinic Health Academy (ECHA) 
11405-87 Avenue 
Edmonton, AB T6G 1C9 
Phone: (780) 248-5568 
 
Funded by: Physicians Services Incorporated Foundation 
 
Date: June 4th 2016 
 
Protocol Version Number: 1 
 
 
 
 
 
 
 
 
 
 
 

 
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Table of Contents  
 
1. 
GENERAL INFORMATION .............................................................................................................. 4 
1.1. 
NAME AND ADDRESS OF THE SPONSOR ................................................................................................... 4 
1.2. 
NAME AND ADDRESS OF THE PERSON AUTHORIZED TO SIGN THE PROTOCOL AND AMENDMENTS
 
4 
1.3. 
NAME AND ADDRESS OF THE STUDY’S MEDICAL EXPERT .................................................................... 4 
1.4. 
NAME AND TITLE OF INVESTIGATORS RESPONSIBLE FOR THE TRIAL AND THE ADDRESS AND 
TELEPHONE NUMBERS FOR THE TRIAL SITE ...................................................................................................... 4 
1.5. 
NAME AND ADDRESS OF THE QUALIFIED PHYSICIAN WHO IS RESPONSIBLE FOR TRIAL-RELATED 
MEDICAL DECISIONS ................................................................................................................................................ 5 
1.6. 
NAME AND ADDRESS OF THE CLINICAL LABORATORY AND RESEARCH PHARMACY INVOLVED IN 
THE TRIAL ................................................................................................................................................................. 5 
2. 
ABBREVIATIONS .............................................................................................................................. 7 
3. 
STUDY SUMMARY ............................................................................................................................ 8 
4. 
BACKGROUND INFORMATION AND CLINICAL DATA .......................................................... 9 
4.1. 
NAME AND DESCRIPTION OF INVESTIGATIONAL AGENT ................................................................... 11 
4.2. 
PRE-CLINICAL DATA ON DEXAMETHASONE ........................................................................................ 12 
4.3. 
KNOWN RISKS AND BENEFITS OF DEXAMETHASONE TO HUMAN SUBJECTS ................................. 12 
4.4. 
DESCRIPTION AND RATIONALE FOR DOSE, ROUTE OF ADMINISTRATION AND SINGLE 
ADMINISTRATION OF DEXAMETHASONE FOR THIS INDICATION ................................................................... 14 
4.5. 
CONDUCT OF THE TRIAL .......................................................................................................................... 15 
5. 
TRIAL OBJECTIVES AND PURPOSE ......................................................................................... 15 
5.1 
OBJECTIVES ................................................................................................................................................. 15 
5.2 
PRIMARY RESEARCH QUESTION ............................................................................................................. 16 
5.3 
SECONDARY RESEARCH QUESTIONS ...................................................................................................... 16 
5.4 
HYPOTHESIS ............................................................................................................................................... 16 
6. 
ELIGIBILITY CRITERIA ............................................................................................................... 16 
6.1. 
INCLUSION CRITERIA ............................................................................................................................... 16 
6.2 
EXCLUSION CRITERIA ................................................................................................................................ 17 
7. 
STUDY DESIGN ............................................................................................................................... 18 
7.1. 
DESCRIPTION ............................................................................................................................................. 18 
7.2 
DESCRIPTION OF THE STUDY STAGES .................................................................................................... 18 
7.3 
SCREENING.................................................................................................................................................. 19 
7.4 
RANDOMIZATION ....................................................................................................................................... 21 
7.5 
BASELINE ASSESSMENT ............................................................................................................................ 22 
7.6 
STUDY INTERVENTION ADMINISTRATION AND EFFICACY ASSESSMENTS ....................................... 22 
7.7. 
FOLLOW-UP ............................................................................................................................................... 23 
7.8. 
CHART REVIEW ......................................................................................................................................... 24 
7.9. 
STUDY ENDPOINTS ................................................................................................................................... 24 
7.8.1 Primary Outcome ...................................................................................................................................... 24 
7.8.2 Secondary Outcomes ................................................................................................................................ 25 
8. 
EXPECTED DURATION OF PARTICIPANT PARTICIPATION ........................................... 25 
9. 
STUDY MEDICATION ................................................................................................................... 26 

 
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9.1 
STUDY MEDICATION DESCRIPTION ........................................................................................................ 26 
9.2 
PLACEBO DESCRIPTION ............................................................................................................................ 26 
9.3 
ACCOUNTABILITY PROCEDURES AND STORING .................................................................................... 26 
9.4 
MONITORING FOR SUBJECT COMPLIANCE ............................................................................................. 28 
10. 
STATISTICAL PROCEDURES ................................................................................................... 28 
10.1 
SAMPLE SIZE ............................................................................................................................................ 28 
10.2 
OUTCOME ANALYSIS PLAN .................................................................................................................... 28 
11. 
SAFETY AND ADVERSE EVENTS ............................................................................................ 29 
11.1 
SAFETY ASSESSMENTS ........................................................................................................................... 29 
11.2 
METHODS AND TIMING OF SAFETY ASSESSMENTS AND FOLLOW-UP ........................................... 32 
11.3 
DEFINITIONS PERTAINING TO ADVERSE EVENTS.............................................................................. 33 
11.4 
RECORDING AND REPORTING OF ADVERSE EVENTS ......................................................................... 35 
11.5 
TREATMENT DISCONTINUATION .......................................................................................................... 36 
11.6 
PREMATURE STUDY DISCONTINUATION FOR INDIVIDUAL PARTICIPANTS ................................... 36 
11.7 
PROTOCOL DEVIATIONS AND VIOLATIONS ......................................................................................... 37 
12. 
DATA HANDLING AND RECORD KEEPING ......................................................................... 37 
12.1 
DATA COLLECTION ................................................................................................................................. 37 
12.2 
CONFIDENTIALITY................................................................................................................................... 38 
12.3 
RECORD RETENTION .............................................................................................................................. 38 
13. 
QUALITY CONTROL AND QUALITY ASSURANCE ............................................................. 38 
13.1 
STUDY MONITORING PLAN ................................................................................................................... 38 
13.2 
DATA SAFETY AND MONITORING BOARD ........................................................................................... 40 
13.3 
ETHICAL CONSIDERATIONS ................................................................................................................... 40 
13.3.1 
General Principles .............................................................................................................................. 40 
13.3.2 
Clinical Equipoise ............................................................................................................................... 41 
13.3.3 
Informed Consent ............................................................................................................................... 41 
13.3.4 
Privacy and Confidentiality ........................................................................................................... 41 
14. 
BUDGET AND FINANCE ............................................................................................................ 42 
15. 
PUBLICATION PLAN .................................................................................................................. 42 
16. 
REFERENCES ................................................................................................................................ 42 
 
 
 
 
 
 
 
 
 
 

 
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1. General Information 
 
1.1. Name and Address of the Sponsor 
 
Children’s Hospital of Eastern Ontario 
401 Smyth Road 
Ottawa, Ontario 
K1H 8L1 
1.2. Name and Address of the Person Authorized to Sign the Protocol 
and Amendments 
 
Roger Zemek, MD, FRCPC 
Division of Emergency Medicine 
Children’s Hospital of Eastern Ontario 
401 Smyth Road 
Ottawa, Ontario 
K1H 8L1 
Phone: (613) 737-7600 ext. 3963 
1.3. Name and Address of the Study’s Medical Expert 
 
Roger Zemek, MD, FRCPC 
Division of Emergency Medicine 
Children’s Hospital of Eastern Ontario 
401 Smyth Road 
Ottawa, Ontario 
K1H 8L1 
Phone: (613) 737-7600 ext. 3963 
1.4. Name and Title of Investigators Responsible for the Trial and The 
Address and Telephone Numbers for the Trial Site 
 
Roger Zemek, MD, FRCPC 
Qualified Investigator 
Division of Emergency Medicine 
Children’s Hospital of Eastern Ontario 
401 Smyth Road 
Ottawa, Ontario 
K1H 8L1 
Phone: (613) 737-7600 ext. 3963 
 
Serena L. Orr, MD, MSc Candidate (Epidemiology) 
Co-Investigator 

 
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Children’s Hospital of Eastern Ontario, Division of Neurology 
401 Smyth Road 
Ottawa, ON, K1H 8L1 
Phone: (613) 737-7600 ext. 1605 
 
Lawrence Richer MD, MSc (Clinical Epidemiology) 
Co-Investigator 
4-588 Edmonton Clinic Health Academy (ECHA) 
11405-87 Avenue 
Edmonton, AB T6G 1C9 
Phone: (780) 248-5568 
1.5. Name and Address of the Qualified Physician who is Responsible 
for Trial-Related Medical Decisions 
 
Roger Zemek, MD, FRCPC 
Division of Emergency Medicine 
Children’s Hospital of Eastern Ontario 
401 Smyth Road 
Ottawa, Ontario 
K1H 8L1 
Phone: (613) 737-7600 ext. 3963 
 
1.6. Name and Address of the Clinical Laboratory and Research 
Pharmacy Involved in the Trial 
 
Children’s Hospital of Eastern Ontario  
Pharmacy Department 
401 Smyth Road 
Ottawa, Ontario 
K1H 8L1 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Investigator Agreement 
 
 
By signing below, I confirm that I have read this protocol and agree to conduct this 
study in accordance with the procedures described in this protocol, with Good Clinical 
Practice and 
Health Canada Food & Drug Act, Part C, Division 5 of the Regulations: Drugs Trials 
Involving Human participants 
 
Name of Principal Investigator (Print)  _________________________________ 
 
 
Signature of Principal Investigator _______________________________  
                                                
                                                 Date  _______________ 
 
 
Site Address 
 
______________________________________________ 
 
____________________________________________ 
 
______________________________________________ 
 
_____________________________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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2. Abbreviations 
 
AE – Adverse event 
 
CHEO – Children’s Hospital of Eastern Ontario 
 
CRF – Case report form 
 
ED – Emergency Department 
 
ICH – International Conference on Harmonization 
 
MICYRN – Maternal, Infant, Child and Youth Research Network 
 
REB – Research Ethics Board 
 
REDCaP – Research Electronic Data Capture 
 
SOP – Standard Operating Procedures 
 
SUPPORT – Students Undertaking a Pediatric Program of Research Training  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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3. Study Summary 
 
Title 
Oral Dexamethasone for the Treatment of Acute Migraine 
Recurrence in Pediatric Patients Presenting to the 
Emergency Department with Migraine: A Pilot Randomized 
Controlled Trial  
Short Title 
A Pilot Trial on the Use of Oral Dexamethasone for 
Preventing Pediatric Migraine Recurrence 
 
Protocol Number 
N/A 
 
Phase 
Phase 3 
 
Methodology 
Randomized, double-blind, 2-arm parallel group trial 
 
Study Duration 
6 months 
 
Study Center(s) 
Single center: Children’s Hospital of Eastern Ontario 
 
Objectives 
To determine the feasibility of carrying out a multicenter 
randomized controlled trial to assess the efficacy of oral 
dexamethasone for preventing migraine recurrence in the 
pediatric ED through the implementation of a pilot 
randomized trial. The primary scientific objective will be to 
determine if oral dexamethasone is superior to placebo in 
preventing migraine recurrence within 48 hours of ED 
discharge amongst pediatric patients presenting to the ED 
with migraine. 
Number of 
Participants 
20 
 
Diagnosis and 
Main Inclusion 
Criteria 
Children and adolescents aged 8-18 years with migraine 
according to modified International Classification of 
Headache Disorders 3rd edition (beta version) criteria 
 
Study Product, 
Dose, Route, 
Regimen 
Dexamethasone 0.6mg/kg PO as a one time dose given in 
the emergency department (maximum of 15mg) 
 
Duration of 
administration 
Single dose in the emergency department 
 
Reference 
therapy 
Placebo 
 

 
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Statistical 
Methodology 
The primary outcome pertains to comparing the proportion 
of patients in each group with headache recurrence. A 
Fisher’s exact test will be used to compare the two groups 
on the primary outcome and on the secondary outcomes 
that involve proportions. Adverse events will be presented 
descriptively in tabular form, with the frequency and 
percentage of each adverse event listed by the 
corresponding group. 
 
4. Background Information and Clinical Data 
 
Headache is very common in the pediatric population, with an estimated 
worldwide prevalence of 58.4% amongst children and adolescents(1). Given its 
prevalence, it is not surprising that it accounts for a significant proportion of 
pediatric emergency department (ED) visits: anywhere from 0.8-1.3% of all 
pediatric ED visits are due to headache(2–5). Although the majority of pediatric 
ED visits for headache are due to secondary causes, migraine accounts for 
between 5.4% and 28.7% of these visits(2–6).  
 
Relapse of migraine shortly after the initial ED visit appears to be a very 
common phenomenon. Studies report that anywhere from 26% to 68% of 
pediatric migraine patients have relapse of their migraine within one week of ED 
discharge, even when the pain was initially successfully treated in the ED(7–9). A 
recent study of 32,124 pediatric patients presenting to the ED with migraine 
found that 5.5% of these patients had a return visit to the ED within 3 days(10). 
Although the proportion of patients with return visits is relatively small, when 
considered in the context of the volume of pediatric ED visits for migraine, it 
represents a significant burden to the health case system. In addition, migraine 
relapse is recognized as being a very important outcome to consider in the 
design of acute migraine therapy trials. The International Headache Society 
guidelines for controlled trials of drugs in migraine list incidence of recurrence 
second in the their list of recommended outcomes, immediately after the 
recommended primary outcome, and state that it “should be recorded as an 
important efficacy index”(11). Thus, migraine recurrence is an important 
outcome for migraine patients and it is, unfortunately, exceedingly common even 
after successful acute treatment of migraine in the pediatric ED.  
 
Although migraine recurrence after pediatric ED discharge is common and is 
believed to have negative implications for patients and the healthcare system, 
there are no evidence-based treatments to prevent recurrence in this 
population. The literature is devoid of high quality intervention studies with a 
primary outcome related to migraine recurrence after pediatric ED discharge. A 
few studies have assessed migraine recurrence as a secondary outcome in this 

 
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setting(8,9,12), but have failed to yield evidence for an effective therapy. 
Furthermore, a retrospective study in a pediatric ED failed to show an 
association between the specific migraine treatment administered and rates of 
migraine recurrence within one month of ED discharge(13). Therefore, despite 
the commonality of the problem, there is no evidence to guide clinicians seeking 
to prevent migraine recurrence after ED discharge in pediatric patients. 
There is a well-established literature supporting the efficacy of steroids for the 
prevention of migraine recurrence in adults presenting both to outpatient 
settings and to the ED with migraine. A recent systematic review identified 25 
studies on the efficacy of steroids for a variety of primary headache disorders in 
several different settings(14). The conclusion of the review was that steroids are 
effective for both the acute treatment of headache and for the prevention of 
headache recurrence. The most commonly studied steroid in the ED setting is 
dexamethasone. Three systematic reviews with meta-analyses(15–17) and one 
systematic shortcut review(18) have independently shown that dexamethasone 
reduces migraine recurrence in this setting. It also appears that dexamethasone 
is safe and well tolerated amongst adults for this indication, with dizziness being 
the most common symptom(15,17) and no serious adverse events reported in 
any of the trials(15–18). Furthermore, dexamethasone has a plausible 
mechanism of action in preventing migraine recurrence in that it attenuates the 
inflammatory response, and in some theoretical frameworks migraine is 
believed to be associated with neurogenic inflammation(19). 
Of the thirteen dexamethasone trials carried out in the ED(20–32), two of the 
studies assessed the efficacy of oral dexamethasone(23,27), and the remainder 
randomized patients to intravenous dexamethasone. Unfortunately, neither of 
the studies on oral dexamethasone was powered to detect the expected minimal 
clinically important difference seen when comparing dexamethasone to placebo 
for the endpoint of migraine recurrence. The three meta-analyses that have 
pooled the dexamethasone studies have consistently found that dexamethasone 
results in a 10% lower migraine recurrence rate as compared to placebo(15–17). 
However, the two studies assessing oral dexamethasone selected their sample 
sizes based on the assumption of a 27% difference in recurrence rates(23) and a 
30% difference in recurrence rates(27) when comparing dexamethasone to 
placebo. Thus, neither of these studies found statistically significant differences 
in recurrence rates, despite finding differences consistent with the pooled 
recurrence rates from the meta-analyses: one of the studies found that the 
dexamethasone group had a 10% lower recurrence rate(23) and the other found 
a 12% lower recurrence rate(27) for dexamethasone relative to placebo. We 
carried out a small meta-analysis using a Mantel-Haenszel fixed effects model in 
order to generate an estimate of the odds ratio and 95% confidence interval for 
migraine recurrence when comparing oral dexamethasone to placebo. When the 
results of these two small studies are pooled together, there is a trend towards 
significance for the efficacy of oral dexamethasone in reducing migraine 

 
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recurrence rates (OR=0.60, 95% CI: 0.34-1.06, see Figure 1). Thus, although the 
vast majority of the adult ED studies have assessed the efficacy of intravenous 
dexamethasone for the prevention of migraine recurrence, there is preliminary 
evidence to suggest that oral dexamethasone has the same direction and 
magnitude of effect for this indication. 
 
Figure 1. Meta-analysis on the efficacy of oral dexamethasone for the 
prevention of migraine recurrence in adults visiting the ED with acute 
migraine 
 
 
Based on the adult evidence, dexamethasone presents the most promise as a 
potential therapy for preventing migraine recurrence in children presenting to 
the ED with migraine.  The proposed study intends to explore the gap in the 
literature regarding the treatment of migraine recurrence in the pediatric ED 
population. The long-term objective will be to decipher if oral dexamethasone is 
superior to placebo in preventing short-term migraine recurrence after ED 
discharge in a sample of pediatric patients visiting the ED for migraine. The 
proposed project aims to implement the protocol in a pilot design, which will 
inform the feasibility and implementation of a multi-center randomized 
controlled trial. 
4.1. 
Name and Description of Investigational Agent 
 
This study will assess the efficacy and safety of oral dexamethasone for the 
prevention of migraine recurrence in children and adolescents visiting the ED 
with migraine. Dexamethasone is a synthetic glucocorticoid medication used for 
a variety of indications, which has anti-inflammatory action. Patients 
randomized to the intervention group will receive dexamethasone at a dose of 
0.6mg/kg orally, for a maximum of 15mg. The oral dexamethasone solution will 
be compounded at CHEO from a 10mg/mL intravenous suspension prepared by 
Omega Laboratories Limited and an oral suspension vehicle by the name of Ora-
Blend®. The suspension will have a concentration of 1mg/mL. Patients 
randomized to the placebo group will receive an oral solution comprised of Ora-
Blend® of matched placebo at a volume of 0.6mL/mg, for a maximum of 15mL.  

 
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4.2. 
Pre-Clinical Data on Dexamethasone 
 
Although the pathophysiology of migraine has not been fully elucidated, it is 
believed that a component of migraine pathogenesis involves inflammation at 
the level of the meninges in the brain (33–35). There is no preclinical data 
specifically investigating how dexamethasone may attenuate meningeal 
inflammation in animal models of migraine. However, several studies have 
shown that dexamethasone can attenuate meningeal inflammation in the context 
of animal models of meningitis. In a rabbit model of meningitis, intravenous 
dexamethasone has been shown to attenuate lipopolysaccharide-induced 
inflammation in the subarachnoid space of the brain meninges by reducing 
tumor necrosis factor and preventing ongoing pleocytosis (36). Another study 
found that intravenous dexamethasone inhibited tumor necrosis factor-alpha 
elevations in cerebrospinal fluid after inoculation of rabbits with pneumococcal 
meningitis regardless of antibiotic timing (37). Other studies have found similar 
effects of administering dexamethasone in experimental meningitis models. For 
example, one study found that intravenous dexamethasone reduced brain edema 
in rabbits with meningitis (38). Therefore, it is known, from animal models, that 
dexamethasone is capable of producing a significant anti-inflammatory effect in 
the brain, and it is therefore possible that it may play a role in alleviating 
migraine or preventing recurrence of migraine given that meningeal 
inflammation is thought to play a role in migraine pathogenesis. 
 
4.3. 
Known Risks and Benefits of Dexamethasone to Human 
Subjects 
 
The vast majority of the side effects reported with the use of dexamethasone are 
associated with chronic use as opposed to single use. The many potential 
adverse drug reactions associated with dexamethasone are listed in the product 
monograph. Possible adverse drug reactions include: hypersensitivity reaction 
or anaphylaxis, electrolyte disturbances, hypertension, osteoporosis, fractures, 
gastric or peptic ulcers, pancreatitis, esophagitis, thinning of the skin, increased 
susceptibility to infection, impaired wound healing, headache, convulsions, 
increased intracranial pressure, Cushing syndrome, menstrual irregularities, 
insulin resistance, adrenal suppression, growth suppression, cataracts, 
glaucoma, weight gain, increased appetite and psychological disturbances (see 
product monograph for details).  
 
In the studies where oral dexamethasone was used to prevent the recurrence of 
migraine in adults visiting the ED (23,27), the following adverse events were 
reported in less than 10% of the patients: flushing, diarrhea, transient tingling 
sensations in the extremities, nausea, blurred vision and a hot sensation in the 
legs. In studies where intravenous dexamethasone was used to prevent the 
recurrence of migraine in adults visiting the ED, restlessness was reported in up 

 
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to 31% of patients(25). The following adverse events were reported in less than 
25% of the patients: drowsiness(24,25), dizziness(21,24,25), 
nausea/vomiting(21,25,29). In these studies, the following adverse events were 
reported in less than 10% of the patients: acute medication reactions(24), 
transient tingling sensations in the extremities(20), flushing(29), insomnia(20), 
hiccups(20), swelling/weight gain(21), mood change(21,25), muscle 
cramps(21). A rash was reported by one patient in one of the intravenous 
dexamethasone studies(29). 
 
Several studies have assessed the efficacy of single dose oral dexamethasone for 
other indications in the pediatric population. Overall, dexamethasone has been 
well tolerated in single oral doses in the pediatric population. Three studies did 
not report any significant adverse events associated with one dose of oral 
dexamethasone (39–41). The following adverse events have been reported in 
less than 10% of patients in pediatric trials of single use oral dexamethasone: 
vomiting(42) and abdominal pain(43). The following adverse event has been 
reported in less than 1% of patients in pediatric trials: pneumonia(42,44). In one 
study, a transient increase in blood pressure was noted, though only the average 
blood pressure increase was reported and the number of affected patients was 
not included (45). The range of doses used in these studies was between 
0.15mg/kg and 1mg/kg and therefore was comparable to the dose planned for 
the proposed trial. 
 
One potential idiosyncratic reaction to dexamethasone is aseptic necrosis of the 
femoral and/or humeral heads. This has not been reported in the ED migraine 
studies with single use of dexamethasone nor in the pediatric studies on single 
use oral dexamethasone for other indications. However, there are reports in the 
literature where aseptic necrosis of the femoral and/or humeral heads occurred 
in the context of a single dose of a corticosteroid(46,47). Although this adverse 
event is theoretically possible, it is exceedingly rare.  
 
As per the product monograph (see product monograph), the use of 
dexamethasone in pregnancy, lactation and in women of childbearing potential 
has not been well studied, and a risk/benefit analysis is required prior to 
suggesting its use in this population. Prolonged and substantial use of steroids in 
pregnant women can be associated with hypoadrenalism in the infant once born 
(see product monograph). This is not a concern with a single and relatively small 
oral dose of dexamethasone. 
 
Given the data presented above, it is anticipated that a single dose of 0.6mg/kg  
oral dexamethasone will be well tolerated in the pediatric migraine population. 
 

 
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4.4. 
Description and Rationale for Dose, Route of Administration 
and Single Administration of Dexamethasone for this 
Indication 
 
The dexamethasone dosing was chosen based on both the range of 
dexamethasone doses administered for this indication in the adult literature, 
which range from 8-24mg IV(15–17), and based on the doses used in pediatric 
patients for other indications, which range from 0.03-2mg/kg/dose(48).  
The oral route of administration was chosen based on feedback from experts. 
We presented this study protocol to the Pediatric Emergency Research Canada 
(PERC) group recently at the PERC 2015 meeting (PERC Staff Research Meetings, 
Banff, Alberta, February 3rd 2015). The group felt strongly that the intervention 
should consist of oral dexamethasone as opposed to intravenous 
dexamethasone. The reasons given for this penchant were two-fold: 1) there is 
an ongoing study at the Ste-Justine Hospital in Montreal where children are 
being randomized to intravenous dexamethasone vs. placebo for this indication, 
2) oral dexamethasone, if proven to be effective for this indication, would benefit 
a greater number of patients given that many pediatric patients chose to have 
their migraine managed with oral therapies rather than intravenous therapies. 
Another reason for which dexamethasone is a promising and pragmatic 
intervention to study in this setting pertains to the frequency of its use for other 
indications in the pediatric ED.  For example, clinical practice guidelines 
recommend the use of dexamethasone in the management of croup(49), which is 
a very common pediatric ED presentation. Thus, oral dexamethasone is an 
auspicious and pragmatic intervention to study for reducing pediatric migraine 
recurrence in the ED and has the potential to change practice without major 
barriers to its uptake. 
The pharmacokinetic properties of dexamethasone in children support the 
rationale for using a single dose to prevent short term migraine recurrence. In 
children, dexamethasone has a median half life of 3.75 hours, with a reported 
range of 2.33 to 9.54 hours(50). In addition, it has a duration of action of up to 
72 hours(48), making it plausible that it may act long enough to reduce the risk 
of migraine recurrence. Other pertinent pharmacokinetic properties of 
dexamethasone are displayed in Figure 2. This data is derived from a study 
carried out in twelve pediatric patients receiving intravenous dexamethasone 
for croup or head injury(50). 
 
 
 

 
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Figure 2. Pharmacokinetic properties of dexamethasone 
 
4.5. 
Conduct of the Trial 
 
The trial will be conducted in compliance with the protocol submitted to the 
CHEO Research Ethics. It will follow the International Conference on 
Harmonization Good Clinical Practice standards(51) as described in the 
protocol. Any protocol deviation will only be implemented after approval from 
the CHEO Research Ethics Board (REB), with the exception of situations where 
immediate implementation of a protocol deviation is necessary to protect the 
trial participants from hazards or where the protocol deviation is logistic or 
administrative in nature, in which case the CHEO REB will be notified as soon as 
possible.  
 
5. Trial Objectives and Purpose 
 
5.1 
Objectives 
 
To determine the feasibility of carrying out a multicenter randomized 
controlled trial to assess the efficacy of oral dexamethasone for preventing 
migraine recurrence in the pediatric ED through the implementation of a pilot 
randomized trial in the ED of the Children’s Hospital of Eastern Ontario (CHEO). 
Specifically, with this pilot trial, we will aim to determine: 1) acceptability of the 
protocol to ED staff, 2) acceptability of the study to the participants and their 
families, 3) the number of patients meeting eligibility criteria, 4) recruitment 
rates and 5) estimates of the proportion of participants from each group who 
achieve the primary outcome (ie. migraine recurrence within 48 hours).  

 
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5.2 
Primary Research Question 
 
To determine if oral dexamethasone is superior to placebo in preventing 
migraine recurrence within 48 hours of ED discharge amongst pediatric 
patients presenting to the ED with migraine. 
5.3 
Secondary Research Questions 
 
1. To determine if oral dexamethasone is superior to placebo in preventing 
migraine recurrence within 7 days of ED discharge amongst pediatric 
patients presenting to the ED with migraine. 
2. To determine if oral dexamethasone is superior to placebo in preventing 
return ED visits within 7 days of ED discharge amongst pediatric patients 
presenting to the ED with migraine. 
3. To determine if oral dexamethasone is superior to placebo in terms of the 
proportion of patients achieving persistent pain freedom 48 hours after 
ED discharge amongst pediatric patients presenting to the ED with 
migraine. 
4. To determine if oral dexamethasone is associated with differential rates 
of patient satisfaction as compared to placebo amongst pediatric patients 
presenting to the ED with migraine. 
5.4 
Hypothesis 
 
We hypothesize that oral dexamethasone will be superior to placebo in 
preventing migraine recurrence within 48 hours of ED discharge amongst 
pediatric patients presenting to the ED with migraine. It is anticipated that oral 
dexamethasone will be safe, well tolerated and simple to use for this indication. 
6. Eligibility Criteria 
6.1. 
Inclusion Criteria 
 
Patients will be eligible for the study if: 
 
1. Between the ages of 8 and 18 years (ie. > 8.0 years and < 18.0 years) 
2. Diagnosed with migraine according to a modified version of International 
Classification of Headache Disorders 3rd edition (ICHD-3, beta version, see 
Table 1) diagnostic criteria for pediatric migraine(52) 
 
NB. The use of the International Classification of Headache Disorders for 
migraine diagnosis is the standard for trials assessing both acute and 
prophylactic medications for migraine, according to the 2012 International 
Headache Society guidelines for controlled trials of drugs in migraine (3rd 

 
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edition)(11). However, there has been controversy about the application of 
these criteria to trials in the ED and many ED trials have used other criteria 
for migraine diagnosis. Both an adult(53) and a pediatric study(54) have 
shown that the ICHD criteria lack sensitivity for migraine diagnosis in the ED. 
Criterion A, which establishes that patients must have had five headaches 
meeting ICHD migraine criteria, is particularly problematic in the ED setting 
for several reasons, one of which is that patients commonly present to the ED 
with their first migraine and will therefore not meet this criterion. It has 
been shown that removal of criterion A increases the sensitivity of the ICHD 
criteria in the ED setting(54,55).  Hence, for the proposed study, criterion A 
will be modified to increase the sensitivity of the criteria: criterion A will 
only require that the current headache meet ICHD-3 (beta) criteria, as 
opposed the requirement for five headaches meeting criteria (see Table 1).  
 
Table 1. International Classification of Headache Disorders 3rd edition (beta 
version) criteria for pediatric migraine(52) and modified criteria for proposed 
study 
Criterion 
ICHD-3 (beta) Migraine Criteria 
Modified Criteria for Proposed Study 
A 
At least 5 attacks fulfilling criteria B-D 
Present attack fulfilling criteria B-D 
B 
Attacks last 2-72 hours if untreated or 
unsuccessfully treated 
 
Attack lasting 2-72 hours if untreated 
or unsuccessfully treated 
C 
At least 2 of the following 4 characteristics are 
present: 
 
Unilateral or bilateral in children and 
adolescents, most often 
frontotemporal 
 
Pulsating quality 
 
Moderate or severe pain intensity 
 
Aggravated by or causing avoidance 
of routine physical activity such as 
walking or climbing stairs 
At least 2 of the following 4 characteristics are 
present: 
 
Unilateral or bilateral in children and 
adolescents, most often 
frontotemporal 
 
Pulsating quality 
 
Moderate or severe pain intensity 
 
Aggravated by or causing avoidance 
of routine physical activity such as 
walking or climbing stairs 
D 
At least one of the following is present: 
1. Nausea and/or vomiting 
2. Photophobia and phonophobia 
At least one of the following is present: 
1. Nausea and/or vomiting 
2. Photophobia and phonophobia 
E 
Not better accounted for by another ICHD-3 
diagnosis 
Not better accounted for by another ICHD-3 
diagnosis 
 
 
6.2 Exclusion Criteria 
Patients will be excluded for the following reasons:  
1. Received a dose of a steroid medication in the past 7 days 
2. Known allergy to dexamethasone  
3. Immunosuppressed 

 
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4. Cushing’s syndrome 
5. Known diabetes mellitus 
6. Known peptic or duodenal ulcer or other major gastrointestinal illness (ex. 
ulcerative colitis) 
7. Known myasthenia gravis 
8. Glaucoma 
9. Febrile at triage 
10. History of head trauma in the past 7 days 
11. Presence of any known active infection (eg. on antibiotics or antivirals, 
diagnosed with active infection in the ED, etc) 
12. Current secondary headache (as per the treating physician’s clinical 
impression) 
7. Study Design 
7.1. 
Description 
 
The proposed study will be a Phase III pilot trial, designed as a 2-arm, parallel-
group, randomized, placebo-controlled, double-blind study.  
7.2 
Description of the Study Stages 
 
Twenty children and adolescents will be enrolled into this trial. The expected 
duration of the study will vary from patient-to-patient based on how many 
interventions for acute migraine pain will be administered, and these decisions 
will be made at the discretion of the treating physician. On average, it is 
expected that the duration of study participation in the ED will vary between 2 
and 6 hours.  There will be either a telephone follow-up with a research 
assistant approximately 48 hours after discharge and then a second telephone 
follow-up 7 days after discharge, or an email follow-up at 48 hours and 7 days 
with electronic questionnaires sent directly to participants, depending on 
participant preference. 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Figure 3. Study Flow Diagram 
 
 
 
 
7.3 
Screening 
 
Patients presenting to the CHEO ED with a triage diagnosis of headache, 
migraine or a related term (eg. head pain) who are interested in discussing the 
study will be screened for eligibility by SUPPORT (Students Undertaking a 
Pediatric Program of Research Training) volunteers. The SUPPORT program is a 
specialized volunteer program at CHEO that trains volunteers to assist in 
recruiting patients to clinical studies based in the ED. Prior to approaching 
potentially eligible patients, the SUPPORT volunteer will ask the patient if they 
are willing to discuss the study with them. Should a patient agree, the SUPPORT 

 
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volunteer will introduce the patient and their family to the study and if they are 
interested, they will carry out the eligibility screening (see Appendix A for 
screening questionnaire). If a participant is deemed eligible from the screening 
questionnaire administered by the SUPPORT volunteer, the volunteer will first 
ask the treating physician to verbally confirm that they agree with the diagnosis 
of migraine and that secondary headache is not present, and if the physician 
agrees, the volunteer will then notify the research assistant about the potential 
participant.  
 
The research assistant will then meet with the potential participant to initiate 
the consent process. For patients over the age of 16, verbal and written consent 
will be sought from patients and their parent or guardian by the study assistant. 
For patients under the age of 16, verbal and written assent will be sought from 
the patient, and verbal and written consent will be sought from the parent or 
guardian. Study packages including consent forms, informational brochures and 
pre-printed orders for enrolled participants will be stored in the ED. There will 
be three sets of packages, one for each stratum, and the packages will be pre-
labeled with a numeric randomization code from the randomization scheme 
which will also serve as the participant identification number. 
 
The Maternal, Infant, Child and Youth Research Network (MICYRN) tool, an 
instance of Research Electronic Data Capture (REDCaP)(56), is a secure, web-
based, encrypted application and will be used for screening potentially eligible 
participants and for all data entry for enrolled participants. Basic demographic 
characteristics of patients who were screened for enrollment and who were 
ultimately excluded will also be recorded in MICYRN by the SUPPORT 
volunteers, along with the reason for exclusion (eg. declined, ineligible, etc; see 
Appendix B). The demographic characteristics that will be recorded for excluded 
patients will be the following: sex, age, Canadian Triage and Acuity Scale (CTAS) 
score and time of presentation (time of day) (see Appendix B).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Table 2. Study Schedule 
 
Procedure 
Screening 
Baseline 
Randomization/ 
Treatment 
2 
hours  
Discharge 
48 hour 
follow up 
7 day 
follow up 
Recording of 
reasons for refusal, 
missed enrollment, 
etc 
x 
 
 
 
 
 
 
Assessment of 
eligibility criteria 
x 
 
 
 
 
 
 
Contact information 
 
x 
 
 
 
 
 
Vital signs 
 
x 
 
 
 
 
 
Demographics and 
migraine history 
 
x 
 
 
 
 
 
Physical exam 
 
x 
 
 
 
 
 
Urine pregnancy 
test (where 
applicable) 
 
x 
 
 
 
 
 
Pharmacy carries 
out randomization 
 
 
x 
 
 
 
 
Dispense study 
intervention 
 
 
x 
 
 
 
 
Assessment of pain 
intensity  
 
x 
 
x 
x 
x 
x 
Assessment of 
patient satisfaction 
 
 
 
x 
x 
x 
x 
Assessment of 
missed time at work 
or school 
 
 
 
 
 
x 
x 
Assessment of 
adverse events 
 
 
 
x 
x 
x 
x 
Assessment of 
headache 
recurrence 
 
 
 
 
 
x 
x 
 
7.4 Randomization 
 
Patients consenting to participation and meeting eligibility criteria will be 
randomly assigned to receive either dexamethasone or placebo in a 1:1 ratio. 
Prior to randomization, the research assistants will ensure that the baseline 
assessment is complete (see case report form in Appendix C) and that contact 
information is collected for the purposes of follow-up (see paper-based contact 
information form in Appendix D). Randomization will be stratified according to 
the length of current migraine duration (less than 2 hours, >2 and <24 hours or 
>24 hours). Within each stratum, randomization will be blocked in blocks of 
four.  A statistician will create the randomization scheme. The statistician will 
generate a list of random numbers for each stratum that will correspond to 

 
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specific group assignments. Group assignment will be encoded using a digit 
numeric coding system rather than a dichotomous group A or B system to better 
ensure blinding. The list will be sent to the research pharmacy and will not be 
accessible to anyone involved with the study outside of the pharmacy. The 
allocation will remain concealed to all study participants, study personnel and 
clinical staff.  
 
The research pharmacists will maintain a password-protected list of the 
patients’ names, their assigned numeric codes, their hospital identification 
numbers and their group allocations. Only the research pharmacists will have 
access to the list linking the assigned numeric code and group allocation to the 
patient’s name and identifying information.  In addition, the data safety 
monitoring board, or, where necessary, clinical staff or study investigators, will 
be given access to specific pertinent data from the list if safety issues or adverse 
events occur.  
7.5 
Baseline Assessment 
 
The baseline assessment will involve a physical exam, which will be carried out 
by the ED physician as part of routine clinical care. After eligibility screening, 
the SUPPORT volunteers will confirm with the physician that a physical exam 
was done and that secondary headache was ruled out on physical exam. At this 
time, should the SUPPORT volunteer have any concerns about exclusion criteria 
(eg. presence of active infection) that were not resolved after talking to the 
patient and family, they can also ask the ED physician about their opinion 
regarding exclusion criteria given data acquired from the physician’s history 
and physical exam.  
 
In addition to the physical exam, the research assistant will take a targeted 
migraine history, record the patient’s past medical history, record the vital signs 
from the chart and identify the baseline pain level of the patient using a 4-point 
scale where 0=no headache, 1=mild headache, 2=moderate headache and 
3=severe headache (see Appendix C). The headache history will include 
questions pertaining to migraine diagnosis, presence of aura, headache 
duration, headache frequency, headache intensity, baseline migraine-related 
disability as measured by the Pediatric Migraine Disability Assessment 
(PedMIDAS) questionnaire (see Appendices C and E), and treatment of the 
headache prior to presentation to the ED (see Appendix C). The four point pain 
rating scale is being used in accordance with the recommendation set out in the 
International Headache Society guidelines for controlled trials of drugs in 
migraine(11).  
7.6 
Study Intervention Administration and Efficacy Assessments 
 

 
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Once the baseline assessment is completed, the study intervention will be 
administered. Acute pain interventions will also be administered at the 
discretion of the treating physician. Pre-printed orders will be prepared by the 
research pharmacy in order to simplify study procedures and prevent errors. 
The pre-printed orders will be stored in study packages along with the consent 
forms and the informational brochures (see Appendix F). Three sets of study 
packages will be stored in the ED: one for each randomization stratum. The 
study intervention will be administered by the treating nurse.  
 
A research assistant will assess pain 2 hours post-intervention and at the time 
of discharge, using the 4-point rating scale described above. Should the patient 
be discharged prior to the 2 hour post-intervention time point, the discharge 
pain assessment will replace the 2 hour post-intervention assessment. At the 
time of discharge, patient satisfaction will also be assessed by the research 
assistant, using a 5-point Likert scale where 5=very satisfied, 4=satisfied, 
3=neutral, 2=unsatisfied, 1=very unsatisfied. In the event where a participant is 
discharged prior to having an efficacy assessment by the research assistant, an 
electronic questionnaire will be sent to the participant as a proxy for the in-
person ED discharge assessment. If adverse events are reported on the 
electronic questionnaire, then the participant will be called to further assess the 
adverse event(s). 
7.7. Follow-Up 
 
In the ED, study participants will receive a brochure (see Appendix F) about the 
study from the research assistant at the time of enrollment. The brochure will 
briefly describe the aims of the study, and will detail the timing and options for 
follow-up. 
 
Participants will be offered the option of completing their follow-up via a self-
administered electronic questionnaire sent through MICYRN, or over the phone 
with a research assistant. If they chose the option of the self-administered 
electronic questionnaire, they will receive an email with a link to the MICYRN-
based questionnaire at 48 hours and 7 days post-intervention. Should they not 
complete the given questionnaire within 24 hours of their first notification, a 
second email will be sent. Should they fail to complete the given questionnaire 
within 24 hours of the second notification, the research assistant will contact 
them over the telephone for the given follow-up. 
 
For participants selecting the option of telephone follow-up, the research 
assistant will call the patient for a follow-up telephone-administered 
questionnaire approximately 48 hours after discharge and 7 days after 
discharge (see Appendix C). In the event where it is not possible to contact a 
patient for follow-up over the telephone after several attempts, follow-up 

 
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questionnaires will be emailed to the participant through MICYRN with 24 
hours reminders as above. 
 
When an adverse event is reported during follow-up on one of the electronic 
questionnaires, the participant will be contacted over the telephone in order to 
clarify details pertaining to the adverse event.  
 
Participants who complete both follow-up questionnaires will be sent electronic 
gift cards for Chapters Indigo in the amount of 10$ via email.  
7.8. Chart Review 
 
The research assistant will review the chart 7 days after admission or later in 
order to record any return visits to the ED. Return visits will be coded as either 
headache-related or unrelated (see CRF in Appendix C). 
7.9. Study Endpoints 
7.8.1 Primary Outcome 
 
The primary outcome will be headache recurrence 48 hours after discharge. 
Headache recurrence will be defined as: for patients who were pain-free at ED 
discharge (ie. pain intensity of 0), any return of head pain (ie. pain intensity of 1 
or greater) will be coded as a recurrence, and for patients who had persistent 
head pain at discharge, an increase in head pain since ED discharge will be 
coded as recurrence as well (ie. an increase in their score on the 4-point scale as 
compared to their score at ED discharge). Therefore, the primary outcome will 
involve the comparison of the proportion of patients with headache recurrence 
in each group within 48 hours of ED discharge. Although formal statistics on 
reliability and validity are unavailable, assessment of the primary outcome, as 
described above, is congruent with prior studies on the efficacy of 
dexamethasone for this indication in adults(24,29). 
 
The rationale for using headache recurrence as the primary outcome is derived 
from evidence from adult studies that have established efficacy for 
dexamethasone in preventing migraine recurrence in the short-term(15–18), 
but found no apparent impact on acute pain relief in the ED setting(57). The 
rationale for measuring recurrence of headache at 48 hours is three-fold: 1) the 
International Headache Society guidelines for controlled trials of drugs in 
migraine(11) defines recurrence as “any headache pain from 2 to 48 hours after 
drug administration, regardless of its severity”, 2) prior studies assessed the 
efficacy of steroids (including dexamethasone) in preventing migraine 
recurrence anywhere from 24 to 72 hours after treatment, with the 48 hour 
mark being used most commonly(20,22,24–26,29,58–60), 3) the half-life of 
dexamethasone in children and adolescents is somewhere between 2.33 and 
9.54 hours(50), meaning that it is cleared from the body between 11.7 and 47.7 

 
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hours after ingestion (after 5 half-lives only 3.1% of the drug remains in the 
body). 
 
7.8.2 Secondary Outcomes 
 
Several secondary outcomes are of interest: 
 
1. Pain intensity will be assessed at baseline, 2 hours after having received the 
study intervention (or at the time of ED discharge if prior to 2 hours) and at 
the time of ED discharge. As is suggested in the International Headache 
Society guidelines for controlled trials of drugs in migraine(11), pain 
intensity will be measured using a 4-point scale where 0=no headache, 
1=mild headache, 2=moderate headache and 3=severe headache. 
2. Persistent pain freedom, defined as the proportion of patients in each group 
who achieved pain freedom at 2 hours (or at the time of ED discharge if prior 
to 2 hours) and were free of pain without the use of rescue medication at 48 
hours(11), will be assessed.  
3. Patient satisfaction will be assessed at discharge and again at follow-up with 
the following 5-point Likert scale: 5=very satisfied, 4=satisfied, 3=neutral, 
2=unsatisfied, 1=very unsatisfied. 
4. The proportion of patients in each group with recurrence within the 7 days 
following ED discharge will be assessed. The 7 day time point was selected 
based on its use in a previous study(29) and given our interest in exploring 
potential longer treatment effects of dexamethasone for this indication.  
5. The number of patients with return ED visits within 7 days of ED discharge 
will be assessed through chart review. 
6. Adverse events will also be queried at 2 hours (or at the time of ED discharge 
if prior to 2 hours), at discharge and in the follow-up questionnaires.  
8. Expected Duration of Participant Participation 
 
Participants will remain in the ED for variable lengths of time depending on the 
time required for the acute pain interventions to alleviate the migraine pain. It is 
anticipated that participants will remain in the ED for 1.5-6 hours on average. 
Participants will also be asked to complete two electronic or telephone follow-up 
questionnaires, which are expected to last a maximum of 5 minutes per follow-
up. Participation in the study will end after the second follow-up electronic or 
telephone questionnaire, that is, 7 days following discharge. 

 
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9. Study Medication 
9.1 Study Medication Description 
 
The study intervention will consist of an oral compound of dexamethasone, given 
orally at a one time dose of 0.6mg/kg to a maximum of 15mg.  The 
dexamethasone will be compounded at the CHEO research pharmacy using a 
combination of dexamethasone sodium phosphate USP injection 10mg/mL 
(PRDexamethasone Omega Unidose; see product monograph) manufactured by 
Omega Laboratories Ltd. and Ora-Blend®, a flavored oral suspending vehicle 
manufactured by Galenova Inc.  The compound is created by combining 10mL of 
the dexamethasone 10mg/mL sodium phosphate USP and 90mL of Ora-Blend®. 
The final oral suspension has a concentration of 1mg/mL of dexamethasone and 
a pinkish hue with a milky consistency. The appropriate dose for the participant 
will be drawn up into an oral syringe, which will be labeled for investigational 
use. The commercial label will not be present given that this study is blinded.  
9.2 Placebo Description 
 
The placebo will comprise Ora-Blend®, a flavored oral suspending vehicle 
manufactured by Galenova Inc. Participants randomized to the placebo group will 
be given Ora-Blend® 0.6mL/kg for a maximum of 15mL. Ora-Blend® has a 
pinkish hue and a milky consistency. The appropriate volume for the participant 
will be drawn up into an oral syringe, which will be labeled for investigational 
use. The commercial label will not be present given that this study is blinded. 
9.3 
Accountability Procedures and Storing 
 
The dexamethasone oral suspension will be stored in the Pharmacy Department 
in amber plastic bottles at room temperature, between 20°C and 25°C. The Ora-
Blend placebo suspension will also be stored in the Pharmacy Department, in 
white opaque bottles at room temperature, between 20°C and 25°C.  The 
compound maintains stability for 91 days(61,62) and the vials will be labeled 
with the expiration date. After the expiration date, remaining vials will be 
destroyed in compliance with the Pharmacy Department’s standard operating 
procedures (SOP) for the destruction of investigational drugs, which are 
compliant with the guidelines as set out in ICH(51).  
 
The dexamethasone and placebo vial labeling will be compliant with Health 
Canada Division 5 Food and Drug Regulation clinical trial labeling guidelines (see 
Figures 4 and 5 for labels). 
 
 
Figure 4. Labels for dexamethasone vials 

 
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Figure 5. Labels for placebo vials 
 
 
When a patient is randomized to the study, pre-printed orders with the 
participant’s identification number (corresponding to the randomization code, 
see above), and their identifying information (ie. name, hospital identification 
number, etc) will be sent to the Pharmacy. The research pharmacist will then 
check the randomization scheme and prepare the appropriate intervention, 
either dexamethasone or placebo, according to the participant’s identification 
number/randomization code. At this time, the patient’s identifying information 
will be entered into the research pharmacy’s password-protected group 
assignment list along with their study identification number and assigned 
intervention, so that this data is recorded in case unblinding is required for safety 
reasons.  
 
The study intervention will be drawn into a syringe, which will be capped and 
labeled in compliance with Health Canada Division 5 Food and Drug Regulation 
clinical trial labeling guidelines and the guidelines of the Ontario College of 
Pharmacists. Once the syringe is filled, capped, and labeled, a research 
pharmacist or technologist will bring it to the ED and deliver it to the treating 
nurse.  
 
Dexamethasone 
1mg/mL oral suspension- X mL 
Expiration: DD-MMM-YYYY 
Store at room temperature +20°C and +25°C, 
protected from light in amber plastic bottles 
Lot # ------- 
Protocol Code: ---------- 
Sponsor: Children’s Hospital of Eastern Ontario, 401 
Smyth Road, Ottawa, Ontario, K1H 8L1 
Investigational drug to be used only by a qualified 
Investigator 
Dexamethasone 
Suspension 1mg/mL orale- X mL 
Expiration: DD-MM-YYYY 
Conserver à temperature ambiente entre +20°C and 
+25°C, à l’abri de la lumière dans des bouteilles en 
plastique couleur ambre et opaques 
Lot # ------- 
Code du Protocole: ------------ 
Commenditaire: Centre Hospitalier Pour Enfants de 
L’Est de L’Ontario, 401 Smyth Road, Ottawa, Ontario, 
K1H 8L1 
Médicament expérimental à être utilisé seulement par 
un Investigateur qualifié 
Placebo (Ora-Blend®) 
1mg/mL oral suspension- X mL 
Expiration: DD-MMM-YYYY 
Store at room temperature +20°C and +25°C, 
protected from light in white opaque bottles 
Lot # ------- 
Protocol Code: ---------- 
Sponsor:  Children’s Hospital of Eastern Ontario, 
401 Smyth Road, Ottawa, Ontario, K1H 8L1 
Investigational drug to be used only by a qualified 
Investigator 
Placebo (Ora-Blend®) 
Suspension 1mg/mL orale 
Expiration: DD-MM-YYYY 
Conserver à temperature ambiente entre +20°C and 
+25°C, à l’abri de la lumière dans des bouteilles 
blanches et opaques  
Lot # ------- 
Code du Protocole: ------------ 
Commenditaire:  Centre Hospitalier Pour Enfants de 
L’Est de L’Ontario, 401 Smyth Road, Ottawa, Ontario, 
K1H 8L1 
Médicament expérimental à être utilisé seulement par 
un Investigateur qualifié 

 
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Syringes that are not administered to patients will be sent back to the Pharmacy 
Department for destruction according to the Pharmacy’s SOPs for destruction of 
investigational products.  
 
Drug accountability forms will be completed and stored in the Pharmacy and 
records will be maintained in accordance with Health Canada Division 5 Food 
and Drug Regulation guidelines. 
9.4 
Monitoring for Subject Compliance 
 
Given that this study will involve a one time oral dose of either dexamethasone or 
placebo given in the ED, no compliance issues are anticipated. Loss to follow-up 
will likely occur. Given that this is a pilot randomized controlled trial, monitoring 
of the rate of loss to follow-up is one of the goals of the study.  
10. Statistical Procedures 
10.1 Sample Size 
 
As described above, the proposed study will be a pilot study. The goal will 
eventually be to use this pilot data to inform the design and implementation of a 
large, multi-center trial on the efficacy of dexamethasone for preventing migraine 
recurrence in the pediatric ED. For the purposes of the proposed pilot study, 20 
patients will be recruited. The recruitment period will be over 6 months. The CHEO 
ED has over 300 migraine visits per year, and 6 months is thus expected to be a 
sufficiently long period to capture 20 eligible migraine patients. 
10.2 Outcome Analysis Plan 
 
Demographic characteristics for each group will be presented descriptively in 
tabular form. The primary outcome pertains to comparing the proportion of 
patients in each group with headache recurrence. Because of the small sample size, 
we will use a Fisher’s exact test to compare the two groups on the primary outcome. 
A two-sided p-value less than 0.05 will be considered statistically significant. The 
relative risk of headache recurrence, together with a 95% confidence interval, will 
be computed. 
 
The secondary outcomes will be analyzed in the same fashion as the primary 
outcome. The proportion of migraine recurrence at 7 days, the proportion of 
patients with return ED visits and the proportion of patients who achieve persistent 
pain freedom at 48 hours are all binary outcomes where the interest lies in 
comparing proportions between the two groups. The patient satisfaction outcome is 
an ordinal categorical variable with five possible responses graded on a Likert scale 
(see Appendix C). We will dichotomize this variable into two possible outcomes: 1) 
satisfied (coded as 1), where the sum of the frequencies for ‘very satisfied’ and 

 
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‘satisfied’ will be added together, 2) not satisfied (coded as 0), where the sum of the 
frequencies for ‘neutral’, ‘unsatisfied’ and ‘very unsatisfied’ will be added.  Again, 
due to the small sample size, we will use a Fisher’s exact test to compare the 
proportions between the groups for each secondary outcome.  
 
Adverse events will be presented descriptively in tabular form, with the frequency 
and percentage of each adverse event listed by the corresponding group. 
11. Safety and Adverse Events 
11.1 Safety Assessments 
 
As is described above, few adverse events are anticipated with single use of oral 
dexamethasone. The following are potential adverse events that could occur from 
single use of dexamethasone, as has been reported in the adult migraine literature 
as well as the pediatric literature where oral dexamethasone was used as a one time 
dose for other indications: 
 
 Abdominal pain: In one pediatric study on single use oral dexamethasone in 
the pediatric population, 3.5% of patients reported abdominal pain. Should a 
patient experience significant abdominal pain after the administration of 
dexamethasone, the treating physician will administer analgesics at his or 
her discretion. 
 
 Anaphylaxis/hypersensitivity reaction: Hypersensitivity reactions and 
anaphylaxis are listed as possible adverse drug reactions in the product 
monograph. In one of the adult intravenous dexamethasone studies, acute 
medication reactions occurred in less than 10% of the patients(24), and in 
one study a patient reported a rash(29). As per the product monograph, 
patients with anaphylaxis to dexamethasone will be managed in the ED with 
close monitoring of vital signs, airway support where required, appropriate 
doses of epinephrine and aminophylline if needed. Patients with 
hypersensitivity reactions will be closely monitored in the ED until the 
treating physician deems that discharge is safe. Treatment for 
hypersensitivity reactions will depend on the nature and severity of the 
reaction and will be administered at the discretion of the treating physician. 
 
 Aseptic necrosis of the femoral and/or humeral head: Limited case reports 
have identified the possibility of aseptic necrosis of the femoral and/or 
humeral head following single doses of corticosteroids(46,47). Although this 
adverse event is exceedingly rare with single doses of corticosteroids, any 
patient reporting hip or shoulder pain in the ED will have anteroposterior 
and frog-leg radiographs of the hip(63) and/or shoulder radiographs to 
screen for aseptic necrosis of the affected joint. Should the radiographs not 

 
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reveal evidence of aseptic necrosis, an MRI will be pursued(63). Patients 
reporting the new onset of shoulder or hip pain during telephone follow-up 
will be instructed to return to the ED for an assessment. Patients with 
evidence of avascular necrosis will be urgently referred to Orthopedics for 
management. 
 
 Blood pressure increase: Although blood pressure increase has been 
reported in one study on single use oral dexamethasone in the pediatric 
population, this increase did not require treatment and was clinically 
insignificant, with an average change in systolic blood pressure from 
96.1mmHg + 8.8mmHg to 99.5mmHg + 14.8mmHg(45). We therefore do not 
anticipate that changes in blood pressure will constitute clinically significant 
events in our proposed study.  
 
 Blurred vision: One adult patient reported blurred vision following a one 
time dose of oral dexamethasone in one of the randomized controlled 
trials(27). Although we do not anticipate that this will occur in our 
population, if a patient reports blurred vision while in the ED, the treating 
physician will reassess the patient and determine a plan of action. Should a 
patient report blurred vision during telephone follow-up, that patient will be 
instructed to return to the ED for an assessment. 
 
 Diarrhea: Amongst the studies on single use oral dexamethasone reviewed, 
only one adult patient reported diarrhea in this context(27). If significant 
diarrhea occurs amongst one of the study patients, instructions will be given 
to the patient to return to the ED for an assessment.  
 
 Drowsiness: In two of the adult intravenous dexamethasone studies, 
drowsiness was reported in under 25% of participants(24,25).  Should a 
patient report drowsiness persisting beyond 24 hours, they will be 
instructed to discuss the symptom with their primary care provider or to 
return to the ED if the drowsiness is impairing or severe. 
 
 Facial flushing: One adult patient given a single oral dose of dexamethasone 
to prevent migraine recurrence reported facial flushing(27). Although this 
will be recorded as an adverse event, it is a transient phenomenon that is not 
associated with any harm to the patient and does not require specific 
treatment. 
 
 Hiccups: In one adult study of intravenous dexamethasone, hiccups were 
reported in one participant(20). This is expected to be a self-limited 
symptom. If hiccups persist or are disruptive to the participant, they will be 
asked to follow-up with their primary care provider. 
 

 
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 Muscle cramps: In one of the adult studies on intravenous dexamethasone in 
adults, one participant reported muscle cramps(21). Because muscle cramps 
may indicate an underlying electrolyte imbalance which is an adverse drug 
reaction reported in the product monograph, participants experiencing 
muscle cramps persisting beyond 7 days of discharge or which are 
continuous for more than 24 hours will be asked to return to the ED for an 
assessment. 
 
 Nausea: Nausea does not appear to be a common side effect with single use 
oral dexamethasone, as it was reported by one adult in the studies reviewed. 
Should nausea occur in the ED setting, the treating physician will discuss 
treatment options with the patient. Should nausea occur after discharge and 
be reported in the telephone follow-ups, the patient will be instructed to 
return to the ED if symptoms are not responding to therapies at home. 
 
 Pneumonia: In two of the pediatric studies, one where dexamethasone was 
given for croup(44) and the other where it was given for bronchiolitis(42), 
pneumonia was reported in less than 1% of patients. Although it is not 
anticipated that pneumonia will occur in our patient population, should any 
new respiratory symptoms or fever develop in the days following 
administration as reported on telephone follow-up, then patients will be 
instructed to return to the ED for a visit.  
 
 Psychic derangements: Psychic derangements are listed as possible adverse 
drug reactions in the product monograph and have been reported in some of 
the studies reviewed. These include insomnia(20), mood changes (21,25), a 
feeling of restlessness(25), depression and euphoria. These derangements 
are expected to be self-limited if they occur. Participants reporting any of 
these symptoms will be instructed to discuss the symptom with their 
primary care provider if it persists for more than a week and is bothersome. 
In the case of severe psychic derangements (eg. severe depression with 
suicidal ideation), the participant will be instructed to return immediately to 
the ED. 
 
 Swelling/weight gain: In one of the adult intravenous dexamethasone 
studies, less than 5% of participants reported swelling/weight gain(21). 
Weight gain is also listed in the product monograph in possible adverse drug 
reactions (see product monograph). Should a patient experience weight gain, 
they will be asked to follow-up with the primary care provider, unless the 
degree of weight gain is excessive in a short time frame indicating the need to 
have a more urgent assessment. Because significant weight gain may indicate 
an underlying electrolyte imbalance which is an adverse drug reaction 
reported in the product monograph, participants gaining more than 5% of 
their body weight within a week of discharge will be asked to return to the 
ED for an assessment. 

 
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 Unusual sensations in the extremities: Two adults have reported transient 
tingling sensations in the hands or feet in one of the adult studies or oral 
dexamethasone(27) and one adult reported a “hot sensation in the legs”.. 
Should this type of symptom occur while a patient is in the ED, the treating 
physician will reassess the patient. Should a patient report this type of 
symptom at follow-up, they will be instructed to discuss the symptom with 
their primary care provider if it persists for more than 24 hours. 
 
 Vomiting: In one of the pediatric studies, 5.5% of the patients receiving 
dexamethasone reported vomiting within 20 minutes of the administration 
of oral dexamethasone(42). Should this occur in our population, the treating 
physician will reassess the patient for management of vomiting and 
hydration status. Management changes will be at the discretion of the 
treating physician. 
11.2 Methods and Timing of Safety Assessments and Follow-Up 
 
As is described above, assessment of adverse events will occur during the ED visit at 
2 hours post-intervention (or at the time of ED discharge if prior to 2 hours) and at 
discharge. During the 48 hour and 7 day electronic or telephone follow-ups, 
participants will again be asked if any adverse events have occurred. In the events 
where a participant indicates that an adverse event has occurred, they will be asked 
to describe those adverse events either in written form (for those completing 
electronic questionnaires) or verbally (for those completing telephone 
questionnaires). Participants completing electronic questionnaires and endorsing 
adverse events at follow-up will also be contacted over the telephone to clarify the 
nature of the adverse events. The Qualified Investigator or co-investigator will 
assess the potential relatedness of each AE to the investigational product during the 
trial. 
 
All participants experiencing adverse events in the ED will be contacted over the 
telephone for follow-up (as opposed to being offered the option of electronic follow-
up). Follow-up of adverse events occurring in the ED will also occur during the 48 
hour and 7 day telephone follow-ups. In instances where the adverse event is first 
reported at the 7 day follow-up, an additional telephone follow-up 48 hours after 
the 7 day follow-up will be scheduled.  
 
Although general follow-up timeframes are described above, extended follow-up 
will occur as required when the event does not resolve or stabilize within the above 
timeframes and the frequency, nature and timing of the extended follow-up will be 
determined by the Qualified Investigator. In addition, the Qualified Investigator may 
choose to schedule in-person follow-up in lieu of telephone follow-up when deemed 
necessary for participant safety. 

 
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11.3 Definitions Pertaining to Adverse Events 
Adverse events (AEs) will be reported from the time the informed consent is 
obtained until the subject completes the last study procedure. 
 
We will define AEs in accordance with the definitions set out by the International 
Conference on Harmonization (ICH E2A topic) and the CHEO REB SOP #REB-005: 
 
Adverse event: Any symptom, sign, illness or experience that develops or worsens in 
severity during the course of the study.  Intercurrent illnesses or injuries will be 
regarded as adverse events.  Abnormal results of diagnostic procedures are 
considered to be adverse events if the abnormality: 
 results in study withdrawal 
 is associated with a serious adverse event 
 is associated with clinical signs or symptoms 
 leads to additional treatment or to further diagnostic tests 
 is considered by the investigator to be of clinical significance 
 
Adverse drug reaction: Any response to a drug, biologic, or natural health product 
which is noxious and unintended, which occurs at doses normally used or tested for 
the diagnosis, treatment or prevention of a disease or the modification of an organic 
function. A reaction, as opposed to an adverse event, is characterized by the fact that 
a causal relationship between the product and the occurrence is suspected (i.e. 
judged to be at least a reasonably possibility). 
 
Important medical events are those that may not be immediately life threatening, but 
are clearly of major clinical significance.   They may jeopardize the subject, and may 
require intervention to prevent one of the other serious outcomes noted above.  For 
example, drug overdose or abuse, a seizure that did not result in in-patient 
hospitalization, or intensive treatment of bronchospasm in an emergency department 
would typically be considered serious.  
 
Unexpected adverse drug reaction: An adverse reaction, the nature or severity of 
which is not consistent with the applicable product information (e.g. the 
Investigator’s Brochure for an unapproved investigational product or package 
insert/summary of product characteristics for an approved product). 
 
Unanticipated problem: Any incident, experience, or that meets all of the following 
criteria:  
 
 Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
REB-approved research protocol and informed consent document, or the 

 
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Investigator Brochure; and (b) the characteristics of the research participant 
population being studied; and 
 Related or possibly related to participation in the research (possibly related 
means there is a reasonable possibility that the incident, experience, or 
outcome may have been caused by the [investigational product(s)] or 
procedures involved in the research); and 
 Suggests that the research places research participants or others at a greater 
risk of harm (including physical, psychological, economic, or social harm) 
than was previously known or recognized.  
 
Serious adverse event: Adverse events will be classified as serious or non-serious.  A 
serious adverse event is defined as any AE that is:  
 fatal 
 life-threatening 
 requires or prolongs hospital stay 
 results in persistent or significant disability or incapacity 
 a congenital anomaly or birth defect 
 an important medical event 
 
The severity of an adverse event will be determined by the investigator, who should 
use the following definitions when assessing the intensity of an adverse event: 
 
1. MILD: Participant is aware of symptoms or has minor findings but tolerates them 
well and no or minimal intervention required 
2. MODERATE: Participant experiences enough symptoms or findings to require 
intervention 
3. SEVERE: Participant experiences symptoms or findings that require significant 
intervention 
 
An event will be qualified as unexpected when the specificity or severity of the 
event is not consistent with the package inserts or investigational brochure for the 
drugs under study. 
 
Causality will be determined by the following question, where an affirmative answer 
designates the event as a suspected adverse reaction: Is there a reasonable possibility 
that the drug caused the event? ‘‘Reasonable possibility’’ means there is evidence to 
suggest a causal relationship between the drug and the specific adverse event being 
assessed. 
 
In relation to the identification of adverse events, some participants in this study 
will have pre-existing medical conditions and those pre-existing conditions will not 
be considered as adverse events. New events that occur or the worsening in 
frequency or intensity of pre-existing conditions will be reported as adverse events 
(Schedule of Events). All reportable events as defined above, determined to be an 
AE based on physical examination, laboratory findings, or other means will be 

 
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recorded in the source documents and entered in the CRF. Each event will be 
recorded on an AE CRF starting after first dose of study drug has been delivered. The 
investigator will provide date of onset and resolution, severity, action(s) taken, 
changes in study drug dosing, causality to study drug, and outcome. 
 
For follow-up of AEs, any safety event that is identified at the last assessment (or 
an early termination) will be recorded on the CRF with the status of the safety event 
noted. All serious suspected adverse reactions and serious adverse reactions will be 
followed until resolution or until the patient is medically stable.  
 
11.4 Recording and Reporting of Adverse Events 
 
All adverse events, adverse drug reactions and unanticipated problems will be 
recorded on the electronic adverse event form (see Appendix G), which will be 
stored in MICYRN.  
Only adverse drug reactions that are both serious and unexpected are subject to 
expedited reporting to Health Canada. Expedited reporting of reactions which are 
serious but expected is not required. Expedited reporting is also inappropriate for 
serious events from clinical investigations that are considered unrelated to the 
study product, whether or not the event is expected. 
During this trial, the sponsor (The Children’s Hospital of Eastern Ontario) will 
inform Health Canada of any serious, unexpected adverse drug reaction that has 
occurred inside or outside Canada: 
a. 
where it is neither fatal nor life-threatening, within 15 days after becoming 
aware of the information; 
b. 
where it is fatal or life-threatening, immediately where possible and, in any 
event, within 7 days after becoming aware of the information; and 
c. 
within 8 days after having informed Health Canada of the ADR, submit as 
complete a report as possible which includes an assessment of the 
importance and implication of any findings. 
Each ADR which is subject to expedited reporting will be reported individually in 
accordance with the data element(s) specified in the Health Canada / ICH Guidance 
Document E2A: Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting. 
In situations when causality assessment and determination of expectedness is not 
straightforward, the report will be submitted in the expedited manner and the 
relevant issues will be outlined in a cover letter. 

 
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Final reports of fatal or life-threatening reactions will include an assessment of the 
importance and implication of the findings, including relevant previous experience 
with the same or similar drugs. 
In addition to the above, if any additional situations arise, appropriate scientific and 
medical judgment will be applied to to determine if rapid communication to Health 
Canada is required. For example, information that might influence the risk-benefit 
assessment of a drug, or that would be sufficient to consider changes in drug 
administration, or in the overall conduct of a clinical trial, represent such situations 
where rapid communication to Health Canada will occur; including: 
a. 
for an "expected" serious ADR, an increase in the rate of occurrence which is 
judged clinically important; 
b. 
a significant hazard to the patient population, such as lack of efficacy with a 
drug used in treating a life-threatening disease; and 
c. 
a major safety finding from a newly completed animal study. 
As per the ICH Good Clinical Practice Guidelines stipulations, the Children’s Hospital 
of Eastern Ontario Research Ethics Boards will establish, document in writing and 
follow procedures for: 
 
 Determining the frequency of continuing review as appropriate (including 
adverse drug reactions and adverse events) and  
 Requiring that the Investigator should promptly report to the REB  
o Changes increasing the risk to subjects and/or affecting significantly 
the conduct of the trial; 
o All adverse drug reactions that are both serious and unexpected  
o New information may affect adversely, the safety of the subjects or the 
conduct of the trial. 
 
In additions to the reporting to Health Canada as described above, all serious 
adverse events that occur at CHEO along with any adverse events that are 
both serious and unexpected, will be reported to the CHEO Research Ethics 
Board. 
11.5 Treatment Discontinuation 
 
Although this is a one time dose of oral dexamethasone, participants can decide to 
withdraw from the study at any time point. Participants withdrawing from the study 
will continue with the planned study follow-ups if they provide permission for 
ongoing follow-up.  
11.6 Premature Study Discontinuation for Individual Participants 
 
A participant will be permanently discontinued from the study when: 

 
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 Consent is withdrawn by the participant (ie. the participant requests 
to discontinue the trial) 
 The investigator believe that ongoing participation in the trial will 
either pose a significant risk to the participant, invalidate the results 
of the study or involve a high risk of self-harm 
 Loss to follow-up involving absence of all efficacy assessments and 
follow-up assessments for any reason 
11.7 Protocol Deviations and Violations 
 
A protocol deviation is defined as any modification or alteration of the REB 
approved protocol. A major deviation is defined as a modification or alteration of 
the REB approved protocol involving a potential impact on the participants’ safety, 
rights, welfare or a potential impact on the integrity of the data. A minor deviation is 
defined as a modification or alteration of the REB approved protocol involving no 
significant impact on the study.  
 
No deviations from the protocol will occur prior to having received written 
permission from the CHEO REB, except where required to protect participants from 
hazards or where the deviation is limited to a logistical or administrative aspect of 
the trial. In such instances, the REB will be notified as soon as possible about the 
deviation. 
12. Data Handling and Record Keeping 
12.1 Data Collection 
 
All data in the ED will be collected by the research assistants. Follow-up data will 
either be self-reported through electronic questionnaires for participants selecting 
this option, or will be captured over the telephone by the research assistants. The 
participants and research assistants will remain blinded to group assignment and 
will assess and report all outcomes. Data will be inputted directly into an electronic 
CRF on the MICYRN instance of the Research Electronic Data Capture (REDCaP)(56) 
application (see Appendix C).  
 
REDCap is a secure, web-based application hosted by the Women’s and Children’s 
Health Research Institute’s Clinical Research Informatics Core that is compliant with 
ICH Good Clinical Practice Guidelines section 5.5.3. REDCaP is designed for the 
purposes of capturing data for research studies. REDCap provides: 1) an intuitive 
interface for data entry (with data validation); 2) 128 bit encryption between the 
data entry client and the server (https); 3) audit trails for tracking data 
manipulation and export procedures; 4) automated export procedures for seamless 
data downloads to common statistical packages (SPSS, SAS, Stata, R); 5) procedures 

 
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for importing data from external sources; and 6) advanced features, such as 
branching logic and calculated fields.  
 
The Maternal Infant Child Youth Research Network (MICYRN), a network of 
academic health centres, was founded in 2006 as a collaborative national initiative 
to build capacity for high quality clinical research in Canada. Recognizing the need 
to establish and support standards in clinical research MICYRN has adopted the 
REDCap application to provide a shared data capture platform. The application is 
installed in a secure data centre provided by the Faculty of Medicine and Dentistry 
at the University of Alberta. It is managed and supported by the Women and 
Children’s Health Research Institute’s Clinical Research Informatics Core. The 
application has been validated by MICYRN members and is operated according to 
established standard operating procedures. 
12.2 Confidentiality 
 
All participant information will be kept strictly confidential. The only paper-based 
forms that will be completed for the purposes of this study will be the consent form 
and the Participant Contact Information Form (see Appendix D). The paper-based 
forms will be kept separate from all other study data, in a locked, secure location. 
Study data will be entered into an electronic data capture system, MICYRN, as 
described above. Data entered into MICYRN will be de-identified and coded using a 
numeric code only. The electronic data in MICYRN will be encrypted and password-
protected. 
 
Upon request, participant records will be made available to the sponsor (the CHEO 
Research Institute), Health Canada or other applicable regulatory agencies. 
12.3 Record Retention 
 
Study records will be retained for 25 years in accordance with Division 5 of Health 
Canada’s Food and Drug Regulations. 
13. Quality Control and Quality Assurance 
13.1 Study Monitoring Plan 
 
The study will comply with the ICH Good Clinical Practice Guidelines, the 
requirements of the CHEO REB and Division 5 of Health Canada’s Food and Drug 
Regulations. 
 
A study binder detailing all standard operating procedures and including a copy of 
the protocol will be kept on site and accessible to all research personnel. Prior to 
trial commencement, the site investigators will give a presentation to the research 
personnel outlining the study protocol, documentation and reporting procedures. In 

 
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order to keep ED physicians informed about the study and engaged, the site 
investigators will also carry out a presentation at the CHEO ED grand rounds in the 
weeks leading up to study initiation to present the purposes of the study, its design 
and recruitment processes. ED physicians will have the opportunity to enter a prize 
draw for a Starbucks® gift card by completing a paper ballot in the ED. After every 
fifth participant is recruited, a draw will be carried out for the ED physicians and a 
gift card will be awarded. Information about the study will be sent to ED nurses over 
email in an electronic newsletter.  
 
Research personnel will maintain study records that are complete, legible and 
accurate so as to allow for appropriate interpretation, reporting and verification of 
study records. 
 
Monitoring for this protocol will be coordinated by the sponsor - investigator.   A 
Peer Monitor will monitor the study regularly. The plan will consist of monitoring 
for REB and regulatory compliance on-site and remotely through MICYRN, to ensure 
that the rights and well-being of participants are protected and reported data are 
accurate, complete and verifiable from source documents, along with the trial being 
conducted in compliance with the currently approved protocol and other applicable 
regulatory requirements.  The peer monitoring activities will consist of, but not be 
limited to verification of:  
 
the investigator has adequate qualifications and resources, 
 
the investigational product(s) are stored, supplied, returned/disposed as 
per protocol and applicable regulatory requirement(s), 
 
the investigator follows the approved protocol and all protocol 
amendments, 
 
the written informed consent was obtained before each subject’s 
participation, and was re-consented when amendments were made in the 
trial, 
 
the investigator receives current protocol amendments, all documents, 
and all trial supplies needed to conduct the trial properly, 
 
the investigator and the investigator’s trial staff are adequately informed 
about the trial, 
 
the investigator and the investigator’s trial staff are performing the 
specified trial functions in accordance with the protocol and written 
agreements, 
 
the investigator is enrolling only eligible subjects, 
 
the subject recruitment rate, 
 
the source documents and the other trial records are accurate, complete, 
and kept up-to-date and maintained, 
 
the investigator provides all of the required reports, notification, 
applications, and submissions, and that these documents are accurate, 
complete, timely, legible, dated and identify the trial 
 
Checking the accuracy and completeness of the electronic CRF entries, 
source documents and other trial-related material, 

 
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 
Informing the investigator of any electronic CRF entry error, omission, or 
illegibility in writing, 
 
Determining whether all adverse events are appropriately reported 
within the time periods required by GCP, the protocol, the REB, the 
sponsor, and applicable regulatory requirements, 
 
Determining whether the investigator is maintaining the essential 
documents, 
 
Communicating deviations from the protocol, SOPs, GCP, and the 
applicable regulatory requirements to the investigator and taking 
appropriate action designed to prevent recurrence of the detected 
deviations. 
13.2 Data Safety and Monitoring Board 
 
The data safety monitoring board (DSMB) will comprise three individuals: 1) a 
biostatistician from the CHEO research institute, 2) an epidemiologist from the 
CHEO research institute and, 3) an external emergency physician. The DSMB 
members will individually review the protocol prior to initiation of recruitment. 
Should any of the DSMB members have concerns about the protocol, a meeting will 
be called prior to initiating recruitment during which the DSMB members will make 
a decision about protocol approval. After the DSMB has approved the protocol and 
recruitment has begun, the DSMB will convene as necessary thereafter if and when 
safety issues arise. 
 
Any safety concerns raised by clinical or research staff will be reported to the DSMB 
by the investigators in a written report as soon as possible. All serious adverse 
events will be brought to the attention of the DSMB immediately by the Qualified 
Investigator, who will also send a report to Health Canada (see section 11.4). Once 
safety issues have been brought to the attention of the DSMB, a meeting will be 
scheduled as soon as possible. Should the DSMB identify concerning trends in 
adverse events or should a serious adverse event requiring unblinding occur, they 
will contact the research pharmacists, at their discretion, to access participant 
information if required for safety reasons. The DSMB will make decisions regarding 
early trial termination. Should the DSMB make a decision for early trial termination 
or should the DSMB identify major concerns relating to safety in relation to the trial, 
the DSMB chair will prepare a written report and communicate the plans or findings 
both verbally and in written form to the study investigators. 
13.3 Ethical Considerations 
13.3.1 General Principles 
 
This trial will be carried out according to the principles outlined in the Declaration 
of Helsinki(64), the ICH Good Clinical Practice Guidelines(51) and the Division 5 of 
Health Canada’s Food and Drug Regulations. The institutional policies of the CHEO 
REB will also be followed. 

 
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Prior to initiating the study, written approval from the CHEO REB will be sought. 
Protocol deviations will only be implemented following approval from the CHEO 
REB, except where the investigators are concerned about potential hazards to the 
participants or where the deviations are logistical or administrative in nature. 
13.3.2 Clinical Equipoise  
Although there is a large body of evidence to support the use of dexamethasone in 
adults for the prevention of migraine recurrence, there are no studies to date that 
have addressed the use of dexamethasone for this indication in children and 
adolescents. It is not uncommon that pediatric patients respond differently to 
medications than adults. Therefore, before clinicians adopt the use of medications 
with proven efficacy in the adult population, it is preferable to assess efficacy and 
safety in the pediatric population. For this reason, there is definite clinical equipoise 
regarding the use of dexamethasone for the prevention of migraine recurrence in 
the pediatric population. In addition, it is justifiable to use placebo as a comparison 
in this setting given that there are no known effective therapies for this indication. 
13.3.3 Informed Consent 
Informed consent will be sought from all parents and participants aged 16 years and 
older. Additionally, informed assent will be sought from participants under the age 
of 16 years, or from those deemed by their physician and the research assistant to 
be cognitively unable to provide informed consent. All elements pertinent to 
consent and assent will be explained verbally to the parents and participants by the 
research assistant. Parents and participants will also be provided with a written 
informed consent form, and in applicable cases, with a written assent form. The 
consent and assent forms comply with the Tri-Council Policy Statement: Ethical 
Conduct for Research Involving Humans(65) (see Appendices H, I and F). The 
consent discussions and forms use simple language, written and expressed at the 
grade 6 level. Language at the grade 3 level will be used for the assent process. 
Participants and their parents will receive a detailed explanation about potential 
harms incurred by the study, namely about potential side effects of dexamethasone 
and the inconvenience of the follow-up process with regards to time commitment.  
Anticipated benefits will also be discussed: 1) direct benefits: potential efficacy of 
dexamethasone in preventing migraine recurrence, the potential for a 10$ gift card 
to Chapters Indigo should the participant complete all follow-up 2) indirect benefits: 
potential to be involved in research that might ameliorate the care of pediatric 
migraine patients in the ED. 
13.3.4 Privacy and Confidentiality 
Participant information will be coded using study identification numbers. 
Participant data will be entered into the MICYRN study database using the study 
identification numbers, and will therefore be de-identified. Consent forms and 
contact information collected for the purposes of telephone follow-up will be stored 
separately from the rest of the data in a paper-based file that will be kept in a 
secure, locked area. Only the pharmacists carrying out randomization will have 

 
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access to the participants’ group assignments in case there are adverse reactions 
that require unblinding. The names and their associated study identification 
numbers will be stored in a password-protected electronic file.  
14. Budget and Finance 
 
This study will be funded through a Physicians’ Services Incorporated Foundation 
grant.  
15. Publication Plan 
 
A manuscript will be submitted for publication to a peer-reviewed medical journal 
and at least one conference abstract will be submitted for presentation. The listed 
investigators will participate in the drafting, review and dissemination of the 
manuscript and abstracts. Authors will be required to meet authorship criteria as 
laid out in the International Committee of Medical Journal Editors Guidelines 
(ICMJE).  
16. References 
 
 
1.  
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migraine in children and adolescents: a systematic review of population-
based studies. Dev Med Child Neurol. 2010;52(12):1088–97.  
2.  
Kan L, Nagelberg J, Maytal J. Headaches in a pediatric emergency department: 
etiology, imaging, and treatment. Headache. 2000;40(1):25–9.  
3.  
Burton LJ, Quinn B, Pratt-Cheney JL, Pourani M. Headache etiology in a 
pediatric emergency department. Pediatr Emerg Care; 1997;13(1):1–4.  
4.  
Conicella E, Raucci U, Vanacore N, Vigevano F, Reale A, Pirozzi N, et al. The 
Child With Headache in a Pediatric Emergency Department. Headache. 
2008;48(7):1005–11.  
5.  
Hsiao HJ, Huang JL, Hsia SH, Lin JJ, Huang IA, Wu CT. Headache in the pediatric 
emergency service: a medical center experience. Pediatr Neonatol. 
2014;55(3):208–12.  
6.  
Lewis DW, Qureshi F. Acute headache in children and adolescents presenting 
to the emergency department. Headache. 2000;40(3):200–3.  
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Trottier ED, Bailey B, Dauphin-Pierre S, Gravel J. Clinical outcomes of children 
treated with intravenous prochlorperazine for migraine in a pediatric 
emergency department. J Emerg Med. 2010;39(2):166–73.  
8.  
Brousseau DC, Duffy SJ, Anderson AC, Linakis JG. Treatment of Pediatric 
Migraine Headaches: A Randomized, Double-Blind Trial of Prochlorperazine 
Versus Ketorolac. Ann Emerg Med. 2004;43(2):256–62.  

 
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9.  
Richer L, Craig W, Rowe B. Randomized Controlled Trial of Treatment 
Expectation and Intravenous Fluid in Pediatric Migraine. Headache. 
2014;59(4):1496-505  
10.  
Bachur RG, Monuteaux MC, Neuman MI. A comparison of acute treatment 
regimens for migraine in the emergency department. Pediatrics. 
2015;135(2):232–8.  
11.  
Tfelt-Hansen P, Pascual J, Ramadan N, Dahlof C, D’Amico D, Diener H-C, et al. 
Guidelines for controlled trials of drugs in migraine: Third edition. A guide for 
investigators. Cephalalgia. 2012;32(1):6–38.  
12.  
Trottier ED, Bailey B, Lucas N, Lortie A. Prochlorperazine in children with 
migraine: a look at its effectiveness and rate of akathisia. Am J Emerg Med.; 
2012;30(3):456–63.  
13.  
Legault G, Eisman H, Shevell MI. Treatment of pediatric status migrainosus: 
can we prevent the “bounce back”? J Child Neurol. 2011;26(8):949–55.  
14.  
Woldeamanuel Y, Rapoport A, Cowan R. The place of corticosteroids in 
migraine attack management: A 65-year systematic review with pooled 
analysis and critical appraisal. Cephalalgia. 2015;35(11):996-1024.  
15.  
Colman I, Friedman BW, Brown MD, Innes GD, Grafstein E, Roberts TE, et al. 
Parenteral dexamethasone for acute severe migraine headache: meta-analysis 
of randomised controlled trials for preventing recurrence. BMJ. 
2008;336(7657):1359–61.  
16.  
Singh A, Alter HJ, Zaia B. Does the addition of dexamethasone to standard 
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