Clinical trial NCT02358681
Conditions: Migraine
Keywords: Intranasal Ketorolac Pediatric Migraine Headache
Sponsor: Columbia University
Start date: 2015-06-16; Completion date: 2021-03-31
Enrollment: 59 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Ketorolac is an evidence-based, first-line acute migraine therapy that is commonly used in the pediatric population; however, it is typically administered by the intravenous (IV) or intramuscular (IM) routes, both of which require a painful and distressing needle stick to administer.

The intranasal (IN) route is a painless and effective way of administering analgesics, including ketorolac: IN ketorolac has been shown to be an effective analgesic in adults for painful conditions, including acute migraine headaches. However, IN ketorolac has been understudied in children, and it is not known how effective it is compared to IV ketorolac, which is currently the most common way of administering ketorolac to children. If IN ketorolac is shown to be no less effective than IV ketorolac, IN ketorolac may be a viable and painless alternative to effectively treat acute migraine headaches in children.

Therefore, our primary aim is to demonstrate that IN ketorolac is non-inferior to IV ketorolac for reducing pain in children with acute migraine headaches.

Detailed description:
Primary Aim: Determine whether intranasal (IN) ketorolac is non-inferior to intravenous (IV) ketorolac for reducing pain in children with acute migraine headaches. We hypothesize that IN ketorolac is non-inferior to IV ketorolac in reducing acute migraine headache pain by a minimum clinically significant difference within 60 minutes of administration.

Secondary Aim: Determine whether there is a difference in time to achieve a clinically significant reduction in pain after receiving IN ketorolac compared to IV ketorolac. We hypothesize that there is no difference between IN ketorolac and IV ketorolac in the time it takes to achieve a clinically significant reduction in pain.

We will conduct a prospective, double-blinded, randomized, non-inferiority, parallel 1:1 clinical trial of eligible children in a single urban pediatric ED. We will block randomize patients to receive either 1 mg/kg IN ketorolac and an IV placebo (study group A), or 0.5 mg/kg IV ketorolac and an IN placebo (study group B).

We will assess the patient's pain at baseline, and then at 10 minutes, 30 minutes and 60 minutes after administration of the study drug. The patient will then be assessed at 2 hours and 24 hours after study drug administration for outcomes related to efficacy, function, and safety.

Arms: arm 1: 1. Ketorolac 1 mg/kg, maximum dose 30 mg. To be administered by intranasal route, single dose.
2. Placebo, intravenous. arm 2: 1. Ketorolac 0.5 mg/kg, maximum dose 30 mg. To be administered by intravenous route, single dose.
2. Placebo, intranasal.
Interventions: intervention 1: Ketorolac, intranasal intervention 2: Ketorolac, intravenous intervention 3: Placebo, intravenous intervention 4: Placebo, intranasal
Intervention descriptions: intervention 1: Ketorolac 1 mg/kg, maximum dose 30 mg. To be administered by intranasal route. intervention 2: Ketorolac 0.5 mg/kg, maximum dose 30 mg. To be administered by intravenous route. intervention 3: Placebo of equal volume to IV ketorolac, to be administered by intravenous route. intervention 4: Placebo of equal volume to IN ketorolac, to be administered by intranasal route.

Protocol documents:
Prot_SAP_000.pdf: 
PI: Daniel S. Tsze MD MPH 
 
Page 1 of 12
Intranasal Ketorolac versus Intravenous Ketorolac for Treatment of Migraine Headaches in 
Children: A Randomized Clinical Trial 
NCT02358681 
November 25th 2021 
 
 


PI: Daniel S. Tsze MD MPH 
 
Page 2 of 12
Study Purpose and Rationale: 
Acute migraine headaches are common in children and adolescents, accounting for approximately 85,000 
emergency department (ED) visits annually in the United States.(7) However, there has been a surprising lack 
of investigation of non-oral abortive treatment for migraine headaches in children, resulting in substantial 
variation in practice and undertreatment.(8) Ketorolac is a nonsteroidal anti-inflammatory drug (NSAID) that is 
frequently administered by the intramuscular (IM) or intravenous (IV) routes in the ED, and is one of the most 
common treatments administered to children who present to an ED with a migraine or headache.(7) Ketorolac 
is considered an evidence-based, first-line acute migraine therapy, with most studies completed in adults.(9) 
The intranasal (IN) administration of ketorolac may provide an efficacious and painless means of treating acute 
migraine headaches in children, as this route uniquely uses the nose-brain pathway. The nose-brain pathway 
is the transport of medications directly to the brain through the olfactory and trigeminal nerves exposed in the 
nasal cavity. This pathway circumvents the blood-brain barrier and has been shown to produce both faster 
central nervous system (CNS) effects and higher drug concentrations of other medications in the CNS than 
that achieved after IV administration alone.(10-13) In addition to the nose-brain pathway, administration of 
medications by the IN route takes advantages of the highly vascularized respiratory epithelium. Absorption by 
this means facilitates rapid uptake into the systemic circulation, bypassing first-pass metabolism, and resulting 
in plasma concentrations comparable to those achieved by IV administration.(14) Both of these mechanisms 
have been credited as reasons for IN administration’s ability to produce clinical effects approaching that of IV 
administration for different medications. (12,15-17) Although IN ketorolac has similarly been studied and shown 
to be effective for providing analgesia in adults, there is a gap of knowledge regarding the efficacy of IN 
ketorolac in treating migraines in children and adolescents.(2,3,6,18-21) 
IN ketorolac administration may allow children to receive effective analgesia in an expeditious and painless 
manner in the ED, as well as in a broader number of settings. The implementation of IN medications decreases 
the time it takes for a child to receive analgesics in the ED compared to those receiving IV analgesics, as the 
IN route does not require the additional, technically more challenging step of obtaining IV access.(22) Effective 
analgesics such as ketorolac are typically administered by the IV and IM route and require children to receive a 
painful needle stick, an experience that has been identified by them as amongst the medical experiences that 
they most fear, causing high levels of pain and distress.(23-28) The IN route is a completely needle-free 
technique, and saves children from both the short and long term consequences of inadequately managed 
needle stick pain.(29-33) Finally, eliminating the need for IV access to administer analgesics creates the 
potential opportunity for children to receive more potent and effective analgesics at home or in the office 
setting, rather than the hospital. 
Our overall goal is to determine best-practice management of children with acute migraines. Our specific aims 
for this study are as follows: 
Primary Aim: Determine whether intranasal (IN) ketorolac is non-inferior to intravenous (IV) ketorolac for 
reducing pain in children with acute migraine headaches. We hypothesize that IN ketorolac is non-inferior to IV 
ketorolac in reducing acute migraine headache pain by a minimum clinically significant difference within 60 
minutes of administration. 
Secondary Aim: Determine whether there is a difference in the time to achieve a clinically significant reduction 
in pain after receiving IN ketorolac compared to IV ketorolac. We hypothesize that there is no difference 
between groups in the time it takes to achieve a clinically significant reduction in pain. If we can demonstrate 
that IN ketorolac is as efficacious as IV ketorolac, this would support the clinical implementation of this novel 
modality for effectively treating migraine pain, in addition to incurring additional benefits (such as eliminating 


PI: Daniel S. Tsze MD MPH 
 
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unnecessary needle pain and decreasing time to receiving analgesics) that would improve the overall care of 
children with migraines. 
As a sub-study, some of the data obtained will be used to analyze the validity and clinically significant 
differences between FPS-R and vNRS pain scales for children with migraines. 
Study Design: 
We will conduct a prospective, double-blinded, randomized, non-inferiority, parallel 1:1 clinical trial of 80 
children in a single urban pediatric ED. We will block randomize patients to receive either IN ketorolac (1 
mg/kg) and an IV placebo (study group A), or IV ketorolac (0.5 mg/kg, maximum single dose of 30 mg) and an 
IN placebo (study group B). The volume of the IN placebo will be the same volume the patient would have 
received if they were receiving IN ketorolac; similarly, the volume of IV placebo will be the same volume the 
patient would have received if they were receiving IV ketorolac. Normal saline will be used as the placebo for 
both IN and IV administration. IN administration will be performed in a standardized fashion using a mucosal 
atomization device (MAD), which is a small plastic device that attaches to the end of a syringe.(47) The MAD 
converts any solution that is expressed from the syringe through the MAD into an atomized spray that is more 
readily absorbed and easier to deliver than if the solution was given as drops. All patients will receive an IV line 
to receive IV fluids as is typical in our ED. 
The permuted, block randomization scheme will be predetermined by a third-party uninvolved with any study 
procedures (KB) using an online randomization program.  Study group assignment will be concealed in 
sequentially-numbered sealed opaque envelopes which will not be opened until a patient has been enrolled.   
The members of the study team performing the pain assessments, those conducting the 24-hour follow up call, 
and the patient, will all be blinded to the study group assignment. 
The chosen dosage and maximum dose of IV ketorolac are the standard of care for children.(48- 50) The 
maximum single dose of ketorolac which has been administered by the IN route is 30 mg; this is the maximum 
single dose of IV ketorolac, as well as the maximum dose of IN ketorolac that has been studied in both adults 
and children.(3,51) This practice is also consistent with the dosing of other IN sedatives and analgesics, in 
which the maximum single dose given by the IN route is the same as the as that given by the IV route.(12) The 
dosage of 1 mg/kg for IN ketorolac was selected based on rationale as explained as follows: 
- First, we expect the maximum serum concentration achieved by IN administration to be less than that 
achieved by IV administration. This is because the maximum serum concentrations after IN administration of 
ketorolac has been shown to be 60% of those that occur with the same dose administered intramuscularly. 
Given that intramuscular administration typically achieves serum concentrations less than those achieved after 
IV administration, it would follow that maximum serum concentrations achieved after IN administration would 
be even less than those achieved by IV administration (i.e. no more than 60%). 
- Second, the dose of medications commonly administered by the IN route are at least double the dose when 
the medication is given by the IV route. This is due in part to the decreased serum bioavailability of IN 
administration compared to IV administration. For example, the sedative midazolam is typically dosed 0.1 
mg/kg when administered IV, but is dosed 0.2 to 0.5 mg/kg when given by the IN route.10-18. The analgesic 
fentanyl is typically dosed 1 mcg/kg when administered IV, but is dosed 1.5 to 2 mcg/kg when given by the IN 
route. 
Importantly, there is no increased incidence of adverse events reported with these higher doses when 
administered by the IN route for other medication, and there is nothing from a molecular perspective that 
makes the IN absorption of ketorolac significantly different from midazolam or fentanyl. In addition, ketorolac is 


PI: Daniel S. Tsze MD MPH 
 
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less lipophilic than midazolam and fentanyl, which means that we do not anticipate adverse events related to 
over-absorption through the nose-brain pathway to occur when using this increased dose. 
- Third, ketorolac may be administered by the IV route at doses of 1 mg/kg. Giving 1 mg/kg of IV ketorolac is 
also a well-documented practice when providing analgesia in infants and children. Given that 1 mg/kg is a dose 
which is already in use for IV administration, it would support the acceptability of also administering ketorolac 
at 1 mg/kg by the IN route. 
Study Procedures: We will assess the patient’s pain in a standardized fashion using the FPS-R, administered 
in the patient’s primary language. We will assess the FPS-R and vNRS at baseline (within 15 minutes prior to 
receiving the study drug) and then at 10 minutes, 30 minutes, and 60 minutes (or within 5 minutes of each 
mark to allow for unpredictable setting of the emergency department) after administration of the study drug for 
60 minutes. We will assess pain associated with nasal administration using the same two scales within 15 
minutes of study drug administration. The patient will then be assessed at 2 hours (or within 10 minutes) after 
administration of the study drug and at 24 hours after study drug administration. Pain assessment not required 
if a valid documented reason is provided.  Such reasons may include, but are not limited to: patient is asleep, 
having a procedure done, or other medically indicated reason that prohibits a pain assessment from being 
performed.  The Data Collection Form will serve as source document for study drug administration time. The 
Study Physician will sign on the Data Collection Form as a witness. 
If the 24-hour mark is during a timeframe that is inconvenient for the patient (e.g. during sleeping hours), the 
assessment will be made at a point greater than, but as close to as possible to, the 24-hour mark, within 48-
hours of study drug administration. We will conduct the 24-hour follow up by telephone if the patient is 
discharged from the ED, or in person if the patient is hospitalized (the decision to hospitalize will not be 
dictated by the study). Patients will be reimbursed $10 for the time and effort spent participating in this study. 
Outcomes: Primary Aim: To demonstrate that IN ketorolac is non-inferior to IV ketorolac in reducing pain in 
children with acute migraine headaches, we will compare the mean decrease in pain score of both study 
groups at 60 minutes after administration of the study drug to each other. The outcome we will use to measure 
this decrease in pain will be the Faces Pain Scale – Revised (FPS-R). The FPS-R is a 10 point pain scale that 
has been validated for the use in children greater than 4 years of age in the ED; is one of the self-report 
measures of pain recommended for research in children; and is commonly used as the primary outcome in ED 
research.(56,57) IN ketorolac will be considered non-inferior to IV ketorolac if the difference between the mean 
decreases in pain score of both groups is less than a clinically meaningful difference in pain. The minimum 
clinically meaningful difference in pain in children when using the FPSR has been shown to be 2 out of 10, and 
is consistent across all categories of age, sex, ethnicity, and primary language; (58) therefore, the non-
inferiority margin (delta) will be set at 2/10. In addition to the FPS-R, we will also assess pain using a 
descriptive ordinal scale frequently used in headache research.(59) Using this scale, we will ask the patient to 
describe their headache pain as severe, moderate, mild, or none. We will also use the verbal numeric rating 
scale (vNRS), which involves asking the patient how much pain they have on a scale from zero to ten. We 
selected the reduction in pain, rather than pain freedom as recommended by the IHS guidelines, as pain 
freedom is very seldom achieved in the ED, with only approximately 20% of patients reportedly being pain free 
upon discharge. (59-61) Prior comparative trials of abortive migraine and headache therapies in the ED have 
similarly shown that as few as 15% of adults and 7% of children achieve headache freedom after treatment, 
but greater than 60% experience headache relief.(40,62) As a result, pain freedom from migraine or 
headaches has been infrequently used as the primary outcome for studies in the ED setting; instead, degree of 
pain relief has been used.(37-40,63-66) Additionally, we chose the one hour end point based on the IHS 
recommendations that a time point earlier than two hours should be considered for parenteral study 
medications (which would apply to both IV and IN routes).(59) 


PI: Daniel S. Tsze MD MPH 
 
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Secondary Aim: To determine if there is a difference in time to achieve a clinically significant reduction in pain 
after receiving IN ketorolac compared to IV ketorolac, we will use the outcome of time (in minutes) and 
compare, as appropriate, the mean or median time it takes after administration of study drug in each group to 
achieve a minimum clinically significant difference in pain (i.e. 2/10 on the FPS-R).  
Note that a prior iteration of the protocol stated that this secondary aim was to determine if IN ketorolac was 
non-inferior to IV ketorolac, with a non-inferiority margin for this aim of 10 minutes.  This secondary aim was 
changed prior to starting patient enrollment (i.e. no patients were enrolled yet) because the number of pain 
assessments was decreased from assessments at 10, 20, 30, 40, 50, 60, and 120 minutes to 10, 30, 60, and 
120 minutes for feasibility reasons.  Since we would then no longer be able to assess change in pain score in 
10 minute increments, it would not have been possible to accurately assess for non-inferiority based on a non-
inferiority margin of 10 minutes.  Therefore, the aim was changed to as is currently stated. 
Additional efficacy outcomes will include those that are ED-based, and those assessed at a 24- hour follow up: 
i) 
ED-based outcomes: 1) Receipt of rescue medications at any time during the ED visit; 2) Headache 
relief in the ED, defined as change within 2 hours of the patient’s description of headache from 
severe or moderate to either mild or none, on the severe/moderate/mild/none pain scale, without 
the use of rescue medications; 3) Headache freedom in the ED, defined as achieving a headache 
level of none within 2 hours without the use of rescue medications; and 4) Percentage improvement 
in pain score between baseline and one hour, defined as (baseline pain score – one hour pain 
score)/baseline pain score. 
ii) 
24-hour follow up outcomes: 1) The patient’s overall assessment of efficacy and tolerability, 
expressed as a dichotomous response to the question, “The next time you come to the emergency 
department with a headache or migraine, do you want to be given the same medication (that is, the 
medicine you received first)?”; 2) Sustained headache freedom, defined as achieving a level of 
none on the severe/moderate/mild/none within 2 hours of medication administration and 
maintaining this level continuously for 24 hours without the use of rescue medications; 3) Sustained 
headache relief, defined as change within 2 hours of the patient’s description of headache from 
severe or moderate to either mild or none without the use of rescue medication, and maintaining 
this level of relief continuously for 24 hours without the use of rescue medications; and 4) Use of 
rescue medications, if any, during the 24-hour period after initial medication administration after 
discharge from the emergency department (if yes, which one). 
 
Functional outcomes will be assessed during their ED stay and at the 24-hour follow up. We will use a question 
standard in headache research, but modified to suit the pediatric population: 
 
"Do you think you could do all of your usual daily activities? Usual daily activities can include things like going 
to school, doing your homework, doing your chores, playing games (including video games), reading, or 
playing sports." Available responses will include: a) I think I could do everything I usually do without any 
problems (or difficulty). b) I think it would be a little bit hard (or difficult) to do everything that I usually do. c) I 
think it would be very hard (or difficult) to do everything that I usually do, and I could only do the easiest things. 
d) I don’t think I could do any of the things I usually do at all. (59) Safety outcomes will be assessed at the 1- 
and 2-hour assessments and the 24-hour follow up. We will ask the patient whether they have experienced any 
new or different symptoms.  If they answer in the affirmative, their symptoms will be elicited with an open-
ended question. 
 
The procedure for breaking the blind in this study is as follows: In the event of a serious adverse event (defined 
as a medical occurrence that results in death, is life-threatening, requires inpatient hospitalization, results in 


PI: Daniel S. Tsze MD MPH 
 
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persistent of significant disability/incapacity), not only will this event be reported to the IRB, but it will be 
reported to the study DSMB within 7 days of the event occurrence for consideration of unblinding.  The DSMB 
will decide whether or not to break the blind based on whether or not they deem it necessary for the care of the 
subjects or conduct of the study. 
 
We will be conducting a retrospective medical record review to identify a missed eligible population (i.e. 
patients who are eligible, but are not screened or enrolled).  The reason for this review is to ensure scientific 
credibility by showing that we are not enrolling a biased sample of children.  This review is necessary because 
as patients come to the emergency department 24/7, it is inevitable that some eligible patients will be missed.  
This population of missed eligible patients will not be subjected to study procedures or interventions.  The data 
points collected for these patients will be retrieved from existing medical records and are both limited and 
specific.  These data points include: age; sex; initial pain score; medications received in the emergency 
department; and disposition (e.g. home, admission).  No personal identifiers will be collected for this population 
of missed eligible patients.  Each of these patients will be de-identified and assigned a unique subject number 
at the point of data entry.  There will be no key that will link the subject number to the patient. 
 
Study Drugs and Devices: Ketorolac is a commonly administered NSAID that is used to treat pain in both 
adults and children, for conditions ranging from headaches, back pain, kidney stones, and fractures. It is 
typically administered by the IV or IM route, but has been studied when administered IN, mainly in adults, with 
both its clinical effects and pharmacokinetic properties well described. Ketorolac is commonly administered as 
part of clinical care for pediatric emergency department patients, and is stored in the usual pharmacy-
controlled areas in the pediatric emergency department. The ketorolac which will be administered is the same 
formulation, and patients being enrolled in this study have already been determined by their treating physician 
to require ketorolac as part of their usual care. 
 
The mucosal atomization device (MAD) is a plastic device with a foam applicator that aerosolizes a solution 
into a fine mist into the nasal mucosa. We do not believe that the MAD requires an IND because it does not 
increase the risk of adverse events associated with IV ketorolac. The MAD has been considered IND-exempt 
by this IRB in other studies conducted by our group (IRB-AAAI0699 and IRB-AAAL7510). We do not believe 
that an IND is required. The IND Assistance Program was consulted, and their opinion was that no IND was 
required (note reflecting this decision has been attached to this submission). 
 
We also do not believe that the intranasal route of administration significantly increases the risk associated 
with the drug product (i.e. ketorolac). Similar determinations for midazolam and fentanyl (both of which are also 
not approved for intranasal administration in children) to be suitable for an IND waiver were made by CUMC 
IRBs 1 and 2 in the aforementioned protocols, and to our knowledge and review of the literature, there is 
nothing about ketorolac that makes it more likely than midazolam or fentanyl to increase the risk of adverse 
events when administered intranasally. 
 
Study Subjects: Eligible patients will be children 8 to 17 years of age, inclusive, who present to the pediatric 
ED with a migraine headache as defined by the modified Irma criteria.(43) The Irma criteria are essentially the 
same as the International Headache Society (IHS) ICHD II criteria with annotation for children, except that the 
requirement for a minimal number of headache episodes was removed. The reason for this modification, and 
development of the Irma criteria, was in response to concerns that the ICHD II criteria for diagnosing 
migraines, even with the annotation for children, still lacked sensitivity not only when used in the pediatric 
population, but particularly when they presented to the ED. (44,45) This is because many children who are 
seen in the ED with a headache may present with one of their first episodes; they may indeed have migraines 


PI: Daniel S. Tsze MD MPH 
 
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but will not be diagnosed as such because they cannot fulfill the IHS criteria of requiring five distinct headache 
events over time.(46) 
 
To demonstrate the appropriateness of using the Irma criteria for diagnosing migraines in children in the ED, 
one prior study has shown that the original iteration of the Irma criteria is almost twice as sensitive as the 
ICHD-II criteria with annotation for children for diagnosing migraine headaches in children in the ED 
setting.(43) Although the original iteration of the Irma criteria requires fulfillment of four criteria, decreasing the 
requirement to three (i.e. the modified Irma criteria) increased the sensitivity to 95%.(43) We have chosen to 
use the modified version so that it would be possible to study a more generalizable population of children who 
present to the ED with likely migraine headaches. 
 
Per the modified Irma criteria, children in our study will be eligible if they have a headache that fulfills at least 
three of the six following criteria: i) moderate to severe episode of impaired daily activities; ii) focal localization 
of headache (focal meaning unilateral, bifrontal, bitemporal, or biparietal); iii) pulsatile description; iv) nausea or 
vomiting or abdominal pain; v) photophobia or phonophobia or avoidance of light and noise; and vi) symptoms 
increasing with activity or resolving by rest. Additionally, the eligible child must have a headache of moderate 
to severe pain (defined as 4/10 on the validated Faces Pain Scale – Revised (FPS-R) pain scale) and require 
any IV medication for treatment of their migraine headache (e.g. ketorolac, metoclopramide, prochlorperazine), 
as decided by their attending ED physician.  We will enroll patients with a headache duration between 1 and 
168 hours (i.e. 7 days). 
 
We will exclude patients for any of the following: any contraindication to receiving ketorolac (e.g. known allergy, 
known peptic ulcer disease, gastrointestinal bleeding, renal impairment, known bleeding disorders); receipt of 
an NSAID (e.g. ibuprofen) within previous six hours; presence of intranasal obstruction (e.g. mucous or blood) 
that cannot be readily cleared using suction or nose blowing; inability to speak English or Spanish; unable to 
complete self-report measures of pain or questionnaires (e.g. developmental delay, neurologic impairment); 
known underlying hepatic impairment; critical illness; and frequent use of drugs for headache (defined as 
regular intake of analgesics for acute headaches on more than 10 days per month). 
 
The Data Collection Form will serve as source document for subject eligibility. The Study Physician will sign on 
the Data Collection Form as a witness. 
 
Statistical Procedures: 
We will enroll 80 children (40 in each group) ages 8 to 18 years. We based our sample size on the ability to 
demonstrate non-inferiority between the IN and IV ketorolac groups’ ability to reduce pain. It has been shown 
that a reduction of 2 on the FPS-R score is the minimum clinically significant difference in pain in children.56 
Therefore, our predetermined margin of non-inferiority is 2.  In order to be conservative for the sample size 
calculation, we based the calculation on a margin of 10% less than our predetermined margin of non-inferiority 
of 2. The resulting sample size of 80 children, therefore, is based on a margin of 1.8 on the FPS-R pain scale. 
Using a standard deviation of 2.725 (again, selected using conservative assumptions), a sample size of 40 
patients per group provides 90% power to detect non-inferiority using a one-sided two sample t-test with an 
alpha of 0.05. 
 
We will conduct an intention to treat analysis for all enrolled randomized subjects. We will conduct a one-sided 
t-test to evaluate the difference between the mean decreases in pain score of the two study groups (primary 
outcome). The difference between groups, with its 95% CI, will be compared to the pre-determined non-
inferiority margin (i.e. 2/10) to establish whether IN ketorolac is noninferior to IV ketorolac. For our secondary 
outcome (time to clinically significant reduction in pain), we will also compare groups using a two-sample one-


PI: Daniel S. Tsze MD MPH 
 
Page 8 of 12
sided t-test. Similar to the analysis for the primary outcome, the difference between groups in the time to 
clinically significant reduction in pain, with its 95% CI, will be compared to the pre-determined non-inferiority 
margin of 10 minutes. A Kaplan-Meier distribution analysis will also be used to compare the time to meaningful 
pain relief in the two treatment groups. For other secondary outcomes, we will compare groups using standard 
bivariate analyses for categorical and continuous variables and a table describing adverse events by treatment 
will be reported.  
 
Study Medication: 
IND-Exempt 
Ketorolac  - 1 mg/kg, maximum single dose of 30 mg; Route of administration: Inhalation. 
Ketorolac - 0.5 mg/kg, single maximum dose of 30 mg. Route of administration: Intravenous. 
 
Potential Risks: 
There are no risks in addition to the usual risks associated with receiving ketorolac for analgesia. There is a 
chance that a patient may not experience the same degree of pain relief that they may have experienced if 
they had received IV ketorolac. However, patients will have their pain assessed as per usual standard care, 
and can receive any additional required analgesics at any point in time if their pain relief is inadequate. The 
procedures involved in this study do not increase the risk for adverse events normally associated with receiving 
ketorolac. 
 
Potential Benefits: 
There are no potential direct benefits to participating in this study. 
 
Alternatives: 
An alternative to participation in this study is to choose not to participate. 
 
Data and Safety Monitoring: 
Data will be reviewed on an ongoing basis by the PI with each patient enrolled. On an ongoing basis, the 
investigators will monitor accrual of study subjects, assess adherence to study protocol, assess data quality, 
and collect and review adverse events and other subject safety matters. We will submit to the IRB protocol 
deviations and any requested protocol modifications. 
 
A data safety monitoring board (DSMB) consisting of two physicians unrelated to the study will be formed to 
evaluate safety and adherence to the protocol. The two physicians will consist of one emergency physician 
clinician scientist who is familiar with the clinical management of migraine headaches in the emergency 
department (Dr. Bernard Chang, Department of Emergency Medicine); and a pediatric neurologist who is 
qualified to understand the management of pediatric migraine headaches (Dr. Robert Fryer, Department of 
Pediatrics, Division of Neurology). The DSMB will convene after the first 5 subjects have been enrolled. After 
the first meeting, they will convene on an annual basis. The schedule will be dependent on the rate of 
enrolment of the first 5 patients. 
 
Adverse Event Reporting: An adverse event is any untoward medical occurrence by a subject. For each 
patient, the investigators will evaluate adverse events after completion of enrollment. All unanticipated 
problems (i.e. unexpected events, outcomes, or occurrences, at least possibly related to the research, and 
suggest an increase in risk of harm to subjects or others) will be reported to the IRB. This reporting will be 
done promptly, but no later than one week after the occurrence or after the PI acquiring knowledge of the 
unanticipated problem, and will also be reported at time of continuing review. 
 


PI: Daniel S. Tsze MD MPH 
 
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All data will be maintained on password-protected computers and in locked file cabinets in a locked room to 
which only authorized study personnel will have access. Only approved research staff will view the clinical 
information of children enrolled in this study. We will retain study records and documentation for 3 years after 
the last enrolled patient has completed all study procedures. 
History of Changes to Protocol: https://www.clinicaltrials.gov/ct2/history/NCT02358681 
 
 
 


PI: Daniel S. Tsze MD MPH 
 
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