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

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

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. 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.

Over the past few years, there has been a growth in research investigating the efficacy and safety of non-invasive neuromodulation for the management of acute attacks of migraine. At present, there are several 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 completed a pilot randomized controlled trial (RCT) to determine the feasibility and acceptability of executing a phase III RCT, in which children and adolescents visiting the ED with acute attacks of migraine were randomized to REN or standard of care IV treatment. The trial had two phases: initially the design was a parallel-group design, and after 14 months of recruitment to that design, an amendment was made to allow participants to cross over to the other treatment arm if the initial intervention was not effective, in a crossover design. This change was made in response to participant and staff feedback around the parallel-group design.

Study Overview

• Status: Completed
• Conditions: Migraine Disorders
• Intervention / Treatment: Drug: Ketorolac; Drug: Metoclopramide; Device: Sham Remote Electrical Neuromodulation Device; Device: Active Remote Electrical Neuromodulation Device; Drug: Placebo

Detailed Description

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 completed a pilot randomized controlled trial (RCT) that aimed 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 were randomized to REN, or to standard of care IV treatment in a double-dummy parallel group design phase, followed by a crossover design phase. During the crossover phase, participants were crossed over to the other treatment arm if the initial intervention is not effective. The objectives of the investigators were:

1. 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.
2. 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.
3. 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 employed a pilot RCT to determine the feasibility and acceptability of implementing a double-dummy, parallel and crossover RCT protocol. The controlled trial was completed with two design phases: 1) a parallel-group phase from February 22, 2022 to May 15, 2023, and 2) a crossover design phase from May 16, 2023 to March 1, 2024. The design was switched to a crossover design mid-way through the trial based on feedback from participants and clinical staff around concerns with not being able to receive typical care in a timely manner if randomized to the REN arm in the parallel-group design.

In this pilot study, children and adolescents visiting the ED with acute attacks of migraine were randomized to initially receive either REN or standard of care IV treatment (i.e. a combination of metoclopramide and ketorolac). Each group also received 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 were randomized at a 1:1 ratio to either REN or standard of care IV treatment. The allocation sequence was sent to the research pharmacy and was not accessible to anyone involved in the study or patient care. The REN group received active stimulation and normal saline placebo that appeared identical in appearance and volume to the medications given to the comparison group. The comparison group received a combination of pharmaceutical interventions 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 also received sham stimulation that was low enough that it did not induce conditioned pain modulation, the mechanism of action of REN, but it was perceptible and similar to the sensation induced by the REN device. Stimulation for both groups occurred over 45 minutes. In the crossover design phase, participants were assessed 120 minutes following the initial intervention and were crossed over to the other treatment arm if the initial intervention was not effective. Efficacy and safety outcomes were 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.

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T3B 6A8
      • Alberta Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Standard-of-Care IV Group; 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; 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; Other Names: Toradol; Drug: Metoclopramide; 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; Other Names: Maxeran; Device: Sham Remote Electrical Neuromodulation Device; 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.; Other Names: Sham REN (Sham Nerivio)
Other: REN Group; 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; 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.; Other Names: Active REN (Nerivio); Drug: Placebo; 0.9% NaCl will be administered to participants through IV in identical dosages, methods, and duration as the ketorolac and metoclopramide interventions described above.; Other Names: Saline

What is the study measuring?

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. Recruitment rate for both phases of the study are reported to understand if changing to crossover design improved recruitment. We switched to a crossover design strictly to address participant and recruitment concerns around not receiving standard of care migraine treatment if initially randomized to receive REN treatment and such treatment was unsuccessful.	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
Reduction in Pain Severity	Reduction in pain severity between baseline and 1-hour, 2 hours, and 48 hours post-interventions. Pain measured on an 11-point Likert scale where 0 = no pain and 10 = worst pain possible, with lower values indicating no/less pain and higher values indicating more pain. Headache pain was only assessed at 48 hours if participants indicated they were currently experiencing a headache and the 48 hours reduction in pain severity outcome does not include participants who crossed over and were exposed to both interventions as we expected them to become unblinded after being exposed to both study treatments; Standard of Care (Initial Treatment) n = 7, REN (Initial Treatment) n = 5.	Difference between baseline and 1 hour, 2 hours, and 48 hours post-intervention.
Number of Eligible Participants Who Are Screened, Enrolled, and Complete All Assessments	This secondary feasibility outcome involves the following: The number 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).	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 involves the following: The proportion of participants who report a global impression of change as "very much improved" or "much improved".; Measured on a 7-point Likert scale (Patient Global Impression scale in clinical status; PGI-C) where 1 = "Very much improved", 4 = "No change", and 7 = "Very much worse"; Smaller values indicate improvement of overall change while larger values indicate worsening of overall change.	Evaluated for each participant at 2-hours post-intervention, and 48-hours post-intervention
Study Feedback From Participants and Staff	This acceptability outcome involves the following: - Participant feedback regarding study acceptability. Participant feedback measured on 5-point Likert scale (1 = strongly disagree, 5 = strongly agree), where higher values indicate agreement and lower values indicate disagreement. Feedback questions related to study treatments is reported for both treatment groups and combined across treatment groups. Feedback questions related to the research staff and overall study experience is only combined and reported across both groups, rather than being reported for each group separately since these questions don't relate to specific study treatments. Feedback from clinical staff was collected after each participant's enrollment but not analyzed as this feedback was free-form and not collected using a scale.	Participant feedback evaluated at 48 hours post-intervention
Number of Participants Reporting Pain Freedom	Number of participants who indicated they were pain free 2-hours post-intervention. Pain measured on an 11-point Likert scale where 0 = no pain and 10 = worst pain possible, with lower values indicating no/less pain and higher values indicating more pain.	2 hours post-intervention
Number of Participants Reporting Sustained Pain Freedom	Number of participants who indicated they were pain free 2-hours post-intervention and again 48-hours post-intervention. Pain measured on an 11-point Likert scale where 0 = no pain and 10 = worst pain possible, with lower values indicating no/less pain and higher values indicating more pain.	48 hours post-intervention
Numbers of Participants Reporting a Change in 4-point Pain Severity Scale Between Baseline and 2 Hours Post-intervention	Number of participants who experienced a pain reduction from "severe" or "moderate" severity down to a "mild" or "no pain" severity, or those participants who experienced a pain reduction from "mild" to "no pain" severity between baseline and 2 hours post-intervention. Measured using the 4-point pain severity scale where 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe. Smaller values indicate no/less severe pain and higher values indicate more severe pain.	2 hours post-intervention
Number of Participants Reporting 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. Measured using the 4-point pain severity scale where 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe. Smaller values indicate no/less severe pain and higher values indicate more severe pain. Participants who reported they did not have a headache between 2 hours and 48 hours post-intervention were not asked to rate their pain severity and were considered to have no headache pain at 48 hours.	48 hours post-intervention
Number of Participants Reporting Adverse Events	The number of participants who reported experiencing adverse events and serious adverse events following intervention	Evaluated from time of intervention to 2 hours and 48 hours post-intervention
Number of Participants Reporting Freedom From Most Bothersome Symptom	The number of participants who experienced freedom from their most bothersome symptom (nausea, vomiting, sensitivity to light, or sensitivity to sound).	2 hours post-intervention
Number of Participants Discharged From the Emergency Department With no Further Intervention	The number of participants discharged from the emergency department with no further intervention other than study intervention	2 hours post-intervention (after last intervention, following ED discharge)

Collaborators and Investigators

• Sponsor: University of Calgary
• Investigators: Principal Investigator: Serena L Orr, MD, MSc, FRCPC, University of Calgary

Study record dates

Study Major Dates

• Study Start (Actual): February 22, 2022
• Primary Completion (Actual): March 1, 2024
• Study Completion (Actual): August 29, 2024

Study Registration Dates

• First Submitted: September 28, 2021
• First Submitted That Met QC Criteria: October 20, 2021
• First Posted (Actual): November 1, 2021

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 21, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: Pediatric; Migraine; Emergency Department; Remote Electrical Neuromodulation
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Headache Disorders, Primary; Headache Disorders; Migraine Disorders; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Gastrointestinal Agents; Enzyme Inhibitors; Antirheumatic Agents; Sensory System Agents; Analgesics, Non-Narcotic; Analgesics; Neurotransmitter Agents; Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase Inhibitors; Dopamine Agents; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Ketorolac; Metoclopramide
• Other Study ID Numbers: REB21-0408

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: Yes