Migraine
Conditions
Keywords
Intranasal, Ketorolac, Pediatric, Migraine, Headache
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.
Interventions
DRUGKetorolac, intranasal
Ketorolac 1 mg/kg, maximum dose 30 mg. To be administered by intranasal route.
DRUGKetorolac, intravenous
Ketorolac 0.5 mg/kg, maximum dose 30 mg. To be administered by intravenous route.
DRUGPlacebo, intravenous
Placebo of equal volume to IV ketorolac, to be administered by intravenous route.
Placebo of equal volume to IN ketorolac, to be administered by intranasal route.
Sponsors
Migraine Research Foundation
Columbia University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
8 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Present to the emergency department with a migraine headache as defined by the modified Irma criteria. The modified Irma criteria are as follows: Headache episodes of 1-168 hours (7 days) presenting with at least 3 of the following 6 criteria: moderate to severe episode of impaired daily activities; focal localization of headache; pulsatile description; nausea or vomiting or abdominal pain; photophobia or phonophobia or avoidance of light and noise; symptoms increasing with activity or resolving by rest. * Headache severity of moderate to severe pain (i.e. at least 4/10 on the Faces Pain Scale - Revised) * Requiring IV fluids and any IV medication (for example: ketorolac, metoclopramide, prochlorperazine, ondansetron) as part of their headache treatment, as per their treating attending physician
Exclusion criteria
* Contraindication to receiving ketorolac * Receipt of an NSAID within six hours of study drug administration * Presence of an intranasal obstruction that cannot be readily cleared * Inability to speak English or Spanish * Unable to complete self-report measures of pain or questionnaires * Critical illness * Frequent use of drugs for headache (i.e. regular intake of analgesics for acute headaches on more than 10 days per month).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Pain Score After Analgesic Administration (Faces Pain Scale - Revised (FPS-R) | 60 minutes | Measure the change in pain score after administration of analgesic using the Faces Pain Scale - Revised (FPS-R) at 60 minutes after analgesic administration. The FPS-R is scored from 0 (no pain) to 10 (maximum pain intensity, i.e. worst outcome). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Achieve Clinically Significant Reduction in Pain After Analgesic Administration (Pain Score) | 10, 30, 60 and 120 minutes | Pain score will be assessed at 10, 30, 60 and 120 minutes after analgesic administration, until pain score decreases by 2/10 on the Faces Pain Scale - Revised (FPS-R). The FPS-R is scored from 0 (no pain) to 10 (maximal pain, i.e. worst outcome) |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced Headache Relief During Emergency Department Visit | 2 hours | Headache relief defined as change of the patient's headache pain intensity from severe to moderate to either mild or none, without receipt of rescue medications. |
| Number of Participants Who Experienced Headache Freedom During Emergency Department Visit | 2 hours | Headache freedom defined as achieving a headache pain intensity of none, without receipt of rescue medications. |
| Percentage Change in Pain Score Between Baseline and One Hour | 1 hour | Percentage change in pain score between baseline and one hour after study medication administration. Pain measured using the Faces Pain Scale - Revised (FPS-R), which is scored from 0 (no pain) to 10 (maximum pain intensity, i.e. worst outcome). Positive values (i.e. percentage change) indicate a DECREASE (i.e. improvement) in pain intensity. |
| Adverse Events | 24 hours | Adverse events will be assessed at the 1- and 2-hour assessments and the 24-hour follow up. |
| Number of Participants Who Reported Sustained Headache Freedom at 24-hour Follow-up | 24 hours | Sustained headache freedom defined as achieving headache freedom (i.e. headache pain intensity of none), and maintaining this level for 24 hours without the use of rescue medications after emergency department discharge. |
| Number of Participants Who Reported Sustained Headache Relief at 24-hour Follow-up | 24 hours | Sustained headache relief defined as achieving headache relief (i.e. headache pain intensity of mild or none) and maintaining this level for 24 hours without the use of rescue medications after emergency department discharge. |
| Number of Participants Who Used Rescue Medication(s) Within 24 Hours After Emergency Department Discharge | 24 hours | Rescue medications used after emergency department discharged defined as an analgesic taken by the participant at home to reduce pain associated with their headache. |
| Number of Participants Who Reported Positive Overall Efficacy and Tolerability at 24-hour Follow-up | 24 hours | Patient's assessment of overall efficacy and tolerability was assessed by asking 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?. A yes response was considered positive assessment of overall efficacy and tolerability. |
| Number of Participants Who Received Rescue Medications During Emergency Department Visit | 12 hours | Rescue medication defined as an additional parenteral analgesic administered in response to inadequate improvement in pain. Rescue medication was administered when deemed clinically indicated by the treating clinician. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ketorolac, Intranasal 1. Ketorolac 1 mg/kg, maximum dose 30 mg. To be administered by intranasal route, single dose.
2. Placebo, intravenous.
Ketorolac, intranasal: Ketorolac 1 mg/kg, maximum dose 30 mg. To be administered by intranasal route.
Placebo, intravenous: Placebo of equal volume to IV ketorolac, to be administered by intravenous route. | 27 |
| Ketorolac, Intravenous 1. Ketorolac 0.5 mg/kg, maximum dose 30 mg. To be administered by intravenous route, single dose.
2. Placebo, intranasal.
Ketorolac, intravenous: Ketorolac 0.5 mg/kg, maximum dose 30 mg. To be administered by intravenous route.
Placebo, intranasal: Placebo of equal volume to IN ketorolac, to be administered by intranasal route. | 29 |
| Total | 56 |
Baseline characteristics
| Characteristic | Ketorolac, Intravenous | Total | Ketorolac, Intranasal |
|---|---|---|---|
| Age, Continuous | 15 years | 14.5 years | 14 years |
| Race/Ethnicity, Customized Black | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Don't know | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Hispanic | 26 Participants | 50 Participants | 24 Participants |
| Race/Ethnicity, Customized White | 3 Participants | 3 Participants | 0 Participants |
| Sex: Female, Male Female | 21 Participants | 38 Participants | 17 Participants |
| Sex: Female, Male Male | 8 Participants | 18 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 27 | 0 / 29 |
| other Total, other adverse events | 5 / 27 | 6 / 29 |
| serious Total, serious adverse events | 0 / 27 | 0 / 29 |
Outcome results
Primary
Change in Pain Score After Analgesic Administration (Faces Pain Scale - Revised (FPS-R)
Measure the change in pain score after administration of analgesic using the Faces Pain Scale - Revised (FPS-R) at 60 minutes after analgesic administration. The FPS-R is scored from 0 (no pain) to 10 (maximum pain intensity, i.e. worst outcome).
Time frame: 60 minutes
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ketorolac, Intranasal | Change in Pain Score After Analgesic Administration (Faces Pain Scale - Revised (FPS-R) | 4.2 units on a scale |
| Ketorolac, Intravenous | Change in Pain Score After Analgesic Administration (Faces Pain Scale - Revised (FPS-R) | 4.4 units on a scale |
Secondary
Time to Achieve Clinically Significant Reduction in Pain After Analgesic Administration (Pain Score)
Pain score will be assessed at 10, 30, 60 and 120 minutes after analgesic administration, until pain score decreases by 2/10 on the Faces Pain Scale - Revised (FPS-R). The FPS-R is scored from 0 (no pain) to 10 (maximal pain, i.e. worst outcome)
Time frame: 10, 30, 60 and 120 minutes
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ketorolac, Intranasal | Time to Achieve Clinically Significant Reduction in Pain After Analgesic Administration (Pain Score) | 21.9 Minutes |
| Ketorolac, Intravenous | Time to Achieve Clinically Significant Reduction in Pain After Analgesic Administration (Pain Score) | 18.6 Minutes |
Other Pre-specified
Adverse Events
Adverse events will be assessed at the 1- and 2-hour assessments and the 24-hour follow up.
Time frame: 24 hours
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ketorolac, Intranasal | Adverse Events | 0 Participants |
| Ketorolac, Intravenous | Adverse Events | 1 Participants |
Other Pre-specified
Number of Participants Who Experienced Headache Freedom During Emergency Department Visit
Headache freedom defined as achieving a headache pain intensity of none, without receipt of rescue medications.
Time frame: 2 hours
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ketorolac, Intranasal | Number of Participants Who Experienced Headache Freedom During Emergency Department Visit | 11 Participants |
| Ketorolac, Intravenous | Number of Participants Who Experienced Headache Freedom During Emergency Department Visit | 17 Participants |
Other Pre-specified
Number of Participants Who Experienced Headache Relief During Emergency Department Visit
Headache relief defined as change of the patient's headache pain intensity from severe to moderate to either mild or none, without receipt of rescue medications.
Time frame: 2 hours
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ketorolac, Intranasal | Number of Participants Who Experienced Headache Relief During Emergency Department Visit | 25 Participants |
| Ketorolac, Intravenous | Number of Participants Who Experienced Headache Relief During Emergency Department Visit | 26 Participants |
Other Pre-specified
Number of Participants Who Received Rescue Medications During Emergency Department Visit
Rescue medication defined as an additional parenteral analgesic administered in response to inadequate improvement in pain. Rescue medication was administered when deemed clinically indicated by the treating clinician.
Time frame: 12 hours
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ketorolac, Intranasal | Number of Participants Who Received Rescue Medications During Emergency Department Visit | 6 Participants |
| Ketorolac, Intravenous | Number of Participants Who Received Rescue Medications During Emergency Department Visit | 5 Participants |
Other Pre-specified
Number of Participants Who Reported Positive Overall Efficacy and Tolerability at 24-hour Follow-up
Patient's assessment of overall efficacy and tolerability was assessed by asking 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?. A yes response was considered positive assessment of overall efficacy and tolerability.
Time frame: 24 hours
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ketorolac, Intranasal | Number of Participants Who Reported Positive Overall Efficacy and Tolerability at 24-hour Follow-up | 19 Participants |
| Ketorolac, Intravenous | Number of Participants Who Reported Positive Overall Efficacy and Tolerability at 24-hour Follow-up | 21 Participants |
Other Pre-specified
Number of Participants Who Reported Sustained Headache Freedom at 24-hour Follow-up
Sustained headache freedom defined as achieving headache freedom (i.e. headache pain intensity of none), and maintaining this level for 24 hours without the use of rescue medications after emergency department discharge.
Time frame: 24 hours
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ketorolac, Intranasal | Number of Participants Who Reported Sustained Headache Freedom at 24-hour Follow-up | 7 Participants |
| Ketorolac, Intravenous | Number of Participants Who Reported Sustained Headache Freedom at 24-hour Follow-up | 12 Participants |
Other Pre-specified
Number of Participants Who Reported Sustained Headache Relief at 24-hour Follow-up
Sustained headache relief defined as achieving headache relief (i.e. headache pain intensity of mild or none) and maintaining this level for 24 hours without the use of rescue medications after emergency department discharge.
Time frame: 24 hours
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ketorolac, Intranasal | Number of Participants Who Reported Sustained Headache Relief at 24-hour Follow-up | 7 Participants |
| Ketorolac, Intravenous | Number of Participants Who Reported Sustained Headache Relief at 24-hour Follow-up | 12 Participants |
Other Pre-specified
Number of Participants Who Used Rescue Medication(s) Within 24 Hours After Emergency Department Discharge
Rescue medications used after emergency department discharged defined as an analgesic taken by the participant at home to reduce pain associated with their headache.
Time frame: 24 hours
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ketorolac, Intranasal | Number of Participants Who Used Rescue Medication(s) Within 24 Hours After Emergency Department Discharge | 12 Participants |
| Ketorolac, Intravenous | Number of Participants Who Used Rescue Medication(s) Within 24 Hours After Emergency Department Discharge | 8 Participants |
Other Pre-specified
Percentage Change in Pain Score Between Baseline and One Hour
Percentage change in pain score between baseline and one hour after study medication administration. Pain measured using the Faces Pain Scale - Revised (FPS-R), which is scored from 0 (no pain) to 10 (maximum pain intensity, i.e. worst outcome). Positive values (i.e. percentage change) indicate a DECREASE (i.e. improvement) in pain intensity.
Time frame: 1 hour
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ketorolac, Intranasal | Percentage Change in Pain Score Between Baseline and One Hour | 69.8 percentage of initial pain intensity |
| Ketorolac, Intravenous | Percentage Change in Pain Score Between Baseline and One Hour | 71.8 percentage of initial pain intensity |