A Pilot Clinical Trial of a New Neuromodulation Device for Acute Attacks of Migraine in Children and Adolescents

Study Overview
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Brief Summary
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Migraine is a neurological disease characterized by severe and recurrent headaches. Children and adolescents with migraine often present to the emergency department (ED) with acute attacks, where migraine accounts for up to  30% of all pediatric ED visits for headache. Based on the limited evidence, many centers have adopted protocols whereby children and adolescents who visit the ED with acute attacks of migraine are treated with an IV neuroleptic (metoclopramide or prochlorperazine) and an IV non-steroidal anti-inflammatory (ketorolac). This combination of interventions is largely considered to be standard of care despite no rigorous evidence to support this practice. Side effect rates with the neuroleptics (metoclopramide or prochlorperazine) are considerable, and IV catheters are associated with high adverse event and failure rates in children and adolescents. Therefore, the current standard of care for managing children and adolescents visiting the ED with acute attacks of migraine poses concern to patients and is associated with significant pain and frequent side effects. Emerging neuromodulation devices show promise for expanding acute treatment options. Over the past few years, there has been a growth in research investigating the efficacy and safety of non-invasive neuromodulation, which delivers electrical or magnetic stimulation to nerves or neural tissue, for the management of acute attacks of migraine. At present, there are 3 commercially available, non-invasive neuromodulation devices that effectively and safely treat acute attacks of migraine in adults. Because none of these devices have a high level evidence in children, adolescents, nor in the ED setting, there is clinical equipoise as to which device would be most appropriate to study for treating children and adolescents visiting the ED with acute attacks. Throughout our patient engagement work, children and adolescents with migraine have identified that they are interested in trying remote electrical neuromodulation for treating migraine attacks in the ED. The investigators propose a pilot randomized controlled trial (RCT) that will determine the feasibility and acceptability of executing a phase III RCT, in which children and adolescents visiting the ED with acute attacks of migraine will be randomized to REN or standard of care IV treatment, and then crossed over to the other treatment arm if the initial intervention is not effective.

Detailed Description
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One in ten Canadian children and adolescents suffer from migraine, and visits to the pediatric emergency department (ED) for acute attacks are common, with over 2,500 annual visits in Alberta alone. Evidence-based acute management options for children and adolescents presenting to the ED with acute attacks of migraine are limited. The current standard of care, which comprises a combination of a neuroleptic (metoclopramide) and a non-steroidal anti-inflammatory (ketorolac), has a low level of evidence and is administered through an intravenous (IV) cannula. However, at least half of children and adolescents presenting to the ED with acute attacks of migraine would prefer to avoid an IV, and these standard of care migraine interventions have substantial side effects and costs. The Nerivio remote electrical neuromodulation (REN) device is a novel, non-invasive, wearable REN device that is applied to the arm using an armband and wirelessly controlled by a smartphone software application. REN has established efficacy and safety for the treatment of acute attacks of migraine in adults, and preliminary open-label efficacy and safety data for use in adolescents. Through user engagement efforts, the investigators have identified that children and adolescents with migraine and ED providers are interested in trying REN to treat refractory acute attacks in the ED. The investigators are proposing a pilot randomized controlled trial (RCT) that will aim to determine the feasibility and acceptability of implementing a phase III RCT, in which children and adolescents visiting the ED with acute attacks of migraine will be randomized to REN, or to standard of care IV treatment in a double-dummy crossover design. Participants will be crossed over to the other treatment arm if the initial intervention is not effective. The objectives of the investigators are: To determine the feasibility of comparing REN to the standard of care IV intervention (i.e., a combination of metoclopramide and ketorolac) for the treatment of children and adolescents visiting the ED with acute attacks of migraine. To determine the acceptability of the study design and of using REN to treat children and adolescents visiting the ED with acute attacks of migraine. To gather preliminary efficacy and safety data on the use of REN to treat children and adolescents visiting the ED with acute attacks of migraine (for both the initial assigned intervention and the crossover intervention where applicable). The investigators propose to carry out a pilot RCT to determine the feasibility and acceptability of implementing a double-dummy, crossover RCT protocol. In this pilot study, children and adolescents visiting the ED with acute attacks of migraine will be randomized to initially receive either REN or standard of care IV treatment (i.e. a combination of metoclopramide and ketorolac). Each group will also receive a blinded control (either normal saline through the IV for the REN group, or sham stimulation for the standard of care IV group). Consenting participants will be randomized at a 1:1 ratio to either REN or standard of care IV treatment. The allocation sequence will be sent to the research pharmacy and will not be accessible to anyone involved in the study or patient care. The REN group will receive active stimulation and normal saline placebo that will appear identical in appearance and volume to the medications given to the comparison group. The comparison group will receive a combination of pharmaceutical interventions that are considered to be the standard of care for treating children and adolescents visiting the ED with migraine: IV metoclopramide and IV ketorolac. The comparison group will also receive sham stimulation that will be low enough that it cannot induce conditioned pain modulation, the mechanism of action of REN, but it will be perceptible and similar to the sensation induced by the REN device. Stimulation for both groups occurs over 45 minutes. Participants will be assessed 120 minutes following the initial intervention and will be crossed over to the other treatment arm if the initial intervention is not effective. Efficacy and safety outcomes will be measured at baseline, 60 minutes, and 120 minutes (for both the initial and crossover study interventions as applicable), as well as 48 hours post-intervention.

Official Title
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A Pilot Clinical Trial of a New Neuromodulation Device for Acute Attacks of Migraine in Children and Adolescents Visiting the Emergency Department

Conditions
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Migraine Disorders

Intervention / Treatment
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* Drug: Ketorolac
* Drug: Metoclopramide
* Device: Active Remote Electrical Neuromodulation Device
* Drug: Placebo
* Device: Sham Remote Electrical Neuromodulation Device


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged 8-18 years visiting the Alberta Children's Hospital Emergency Department (ED) with an acute attack of migraine as per criteria B-E of the International Classification of Headache Disorders-3 criteria (ICHD-3): B. Headache attacks lasting at least 2 hours (untreated or unsuccessfully treated) C. Headache has at least two of the following four characteristics: unilateral location pulsating quality moderate or severe pain intensity aggravation by or causing avoidance of routine physical activity (eg, walking or climbing stairs) D. Also has least one of the following: nausea and/or vomiting photophobia and phonophobia E. Not better accounted for by another diagnosis in the opinion of the treating physician Criterion A (at least 5 attacks) is not being used in this study because prior research has shown that removing criterion A increases the sensitivity of these criteria in the ED. The patient and their caregiver will also be required to understand spoken and written English. In addition, potential participants will be required to have an upper arm circumference of at least 20 cm to ensure optimal device fit and safety. Exclusion Criteria: Exclusion criteria include the following: allergy or contraindication to metoclopramide, ketorolac, or non-steroidal anti-inflammatories; implanted electrical device, congestive heart failure, severe cardiac or cerebrovascular disease, uncontrolled epilepsy (2 or more unprovoked seizures per year), abnormal skin on both upper arms (e.g., cancerous lesion on both upper arms, metallic implants on both upper arms, or abnormal physical sensation in both upper arms), febrile at triage, head trauma in the past 7 days, current secondary headache, previously enrolled in the study, pregnant or lactating.

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: The investigators will carry out a pilot randomized controlled trial (RCT) to determine the feasibility and acceptability of implementing a double-dummy, crossover RCT protocol.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Standard-of-Care IV Group<br>Patients randomised to the standard of care IV group will receive a single, 45-minute stimulation from a sham remote electrical neuromodulation (REN) device, which will not administer the typical electrical stimulation (modulated frequency of   0.083 Hz and a modulated pulse width of 40-550 µs), and will be given a single dose IV ketorolac and IV metoclopramide, at a dose of 0.5 mg/kg (for a maximum 30 mg) and 0.15 mg/kg (for a maximum 10mg), respectively. Metoclopramide will be infused over 15-30 minutes and ketorolac will be administered as a direct IV push over 1-5 minutes. | Drug: Ketorolac<br>* Intervention in syringe for target dose of 0.5 mg/kg, maximum 30 mg of ketorolac (1 mL), and administer as a direct IV push over 1-5 minutes<br>* Other names: Toradol;Drug: Metoclopramide<br>* Intervention in 50 mL mini bag of normal saline (0.9% NaCl) for target dose of 0.15 mg/kg, maximum 10 mg of metoclopramide (2 mL), and administer as infusion over 15-30 minutes<br>* Other names: Maxeran;Device: Sham Remote Electrical Neuromodulation Device<br>* The sham REN device is identical to the active REN device but the stimulation parameters are different, administering a modulated symmetrical biphasic square electrical pulse, modulated frequency of  0.083 Hz and a modulated pulse width of 40-550 µ. These sham parameters are designed to induce a sensation that will be perceptible to participants, similar to stimulation from the active REN device, but at a frequency that is low enough so as to not modulate the nociceptive sensory nerves.<br>* Other names: Sham REN (Sham Nerivio);|
| Other: REN Group<br>Patients randomised to the REN group will receive a single 45-minutes stimulation from the REN device (modulated frequency of 100-120 Hz and a pulse width of 400 µs) and will also receive two doses of normal saline though an IV. Two doses of saline will be used to match the dosage, route of administration, and duration to ketorolac and metoclopramide, as described above in the standard-of-care IV group. | Device: Active Remote Electrical Neuromodulation Device<br>* The REN device is a battery-powered, wirelessly controlled neuromodulation device that attaches via armband to the upper arm. The REN device is controlled by a smartphone application and administers electrical stimulation to the local C and Aδ nociceptive sensory nerves of the upper arm. This stimulation is achieved using a symmetrical, biphasic, square pulse, modulated at a frequency between 100-120 Hz. Each pulse has a width of 400 µs and the user, via the smartphone application, can adjust the output current to apply a maximum of 40 mA. Each stimulation session occurs over 45 minutes and each device can administer up to 12 stimulation sessions.<br>* Other names: Active REN (Nerivio);Drug: Placebo<br>* 0.9% NaCl will be administered to participants through IV in identical dosages, methods, and duration as the ketorolac and metoclopramide interventions described above.<br>* Other names: Saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of recruitment rate | The primary outcome for this pilot study involves assessment of the feasibility of using the REN device to treat children and adolescents suffering from acute migraine attacks in the ED. The primary feasibility outcome will be determined based on the recruitment rate, defined as the number of participants enrolled per month. Our target is to have an average recruitment rate of 1.5 participants per month. Feasibility will be used as the primary outcome, along with the secondary outcomes, to provide preliminary data to help design and optimize a fully powered, phase III RCT. | Evaluated monthly and at the end of recruitment (i.e., 2 years or once the final participant has completed the study) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of eligible participants who are screened, enrolled, and complete all assessments | These secondary feasibility outcomes will involve the following: The proportion of participants who complete all assessments at each time point (baseline, 60, 120 minutes or at discharge if before 120 minutes, and 48-hours; for both the initial assigned intervention and the crossover intervention where applicable). The proportion of screened eligible participants who are subsequently enrolled in the study. The proportion of approached potential participants who subsequently decide to enroll in the study. | Evaluated monthly and at the end of recruitment (i.e., 2 years or once the final participant has completed the study) | 
| Global impression of change | This acceptability outcome will involve the following: -The proportion of participants who report a global impression of change as very much improved or much improved. | Evaluated for each participant at 2-hours post-intervention, and 48-hours post-intervention | 
| Study feedback from participants and staff | This acceptability outcome will involve the following: Participant feedback regarding study acceptability. Emergency department staff feedback provided | Clinical staff feedback evaluated after each participant's enrollment; participant feedback evaluated at 48 hours post-intervention | 
| Pain freedom | Pain freedom post-intervention | 2 hours post-intervention | 
| Sustained pain freedom | Pain freedom 2-hours post-intervention and maintaining pain freedom to 48 hours post-intervention | 48 hours post-intervention | 
| Pain relief | Change from baseline moderate to severe pain to mild or no pain, or change from baseline mild pain to no pain 2 hours post-intervention | 2 hours post-intervention | 
| Sustained pain relief | Change from baseline moderate to severe pain to mild or no pain, or change from baseline mild pain to no pain 2 hours post-intervention, which is sustained to 48 hours post-intervention | 48 hours post-intervention | 
| Adverse events | Experiencing adverse events and serious adverse events following intervention | Evaluated from time of intervention to 48 hours post-intervention | 
| Freedom from most bothersome symptom | Experienced freedom from most bothersome symptom (nausea, vomiting, sensitivity to light, or sensitivity to sound) | 2 hours post-intervention | 
| Discharged from the emergency department with no further intervention | Discharged from the emergency department with no further intervention other than study intervention | 2 hours post-intervention | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Migraine, Pediatric, Emergency Department, Remote Electrical Neuromodulation