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

NCT05102591 | Completed Phase 3 Results FDA Drug FDA Device

• 1 other identifier: REB21-0408
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Migraine Disorders

Keywords

Migraine; Pediatric; Emergency Department; Remote Electrical Neuromodulation

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (11)

• Reduction in Pain Severity

  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

  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

  Evaluated for each participant at 2-hours post-intervention, and 48-hours post-intervention

• Study Feedback From Participants and Staff

  Participant feedback evaluated at 48 hours post-intervention

• Number of Participants Reporting Pain Freedom

  2 hours post-intervention

Study Arms (2)

Standard-of-Care IV Group

OTHER

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; Drug: Metoclopramide; Device: Sham Remote Electrical Neuromodulation Device

REN Group

OTHER

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; Drug: Placebo

Interventions

Ketorolac DRUG

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

Also known as: Toradol

Standard-of-Care IV Group

Metoclopramide DRUG

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

Also known as: Maxeran

Standard-of-Care IV Group

Active Remote Electrical Neuromodulation Device 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.

Also known as: Active REN (Nerivio)

REN Group

Placebo DRUG

0.9% NaCl will be administered to participants through IV in identical dosages, methods, and duration as the ketorolac and metoclopramide interventions described above.

Also known as: Saline

REN Group

Sham Remote Electrical Neuromodulation Device 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.

Also known as: Sham REN (Sham Nerivio)

Standard-of-Care IV Group

Eligibility Criteria

• Age: 8 Years - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.

Sponsors & Collaborators

• University of Calgary: lead

Study Sites (1)

Alberta Children's Hospital

Calgary, Alberta, T3B 6A8, Canada

Location

Related Publications (1)

• Orr SL, Kuziek J, Ali S, Anderson E, Birnie KA, Hershey AD, Khanna P, Kirton A, Sajobi T, Freedman SB. Remote electrical neuromodulation to treat children and adolescents with migraine in the emergency department: A randomized double-dummy pilot trial. Headache. 2025 Jun;65(6):1015-1026. doi: 10.1111/head.14838. Epub 2024 Sep 17.

  PMID: 39290050 DERIVED

MeSH Terms

Conditions

Migraine Disorders; Emergencies

Interventions

Ketorolac; Ketorolac Tromethamine; Metoclopramide; Sodium Chloride

Condition Hierarchy (Ancestors)

Headache Disorders, Primary; Headache Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Indomethacin; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Benzamides; Amides; Organic Chemicals; para-Aminobenzoates; Aminobenzoates; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Chlorobenzoates; Hydroxybenzoate Ethers; Hydroxybenzoates; Hydroxy Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Phenyl Ethers; Phenols; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Limitations and Caveats

Our study was conducted during the COVID19 pandemic, the Fall of 2022 "tripledemic", and a shiga-toxin E. Coli outbreak. These events hampered recruitment and our recruitment estimate is likely lower than what we anticipate under 'normal' conditions. Due to delays in the approval process, we had a shorter crossover than the parallel-group phase (9 vs. 15 months). Lastly, 90% of our study participants were White, as such the generalizability of our results is limited.

Results Point of Contact

• Title: Dr. Serena Orr
• Organization: University of Calgary/Alberta Health Services

serena.orr@albertahealthservices.ca

403-955-7728

Study Officials

• Serena L Orr, MD, MSc, FRCPC

  University of Calgary

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: Participants, research staff, and clinical staff, including the investigator, research assistant, research nurse, and attending physician, will remain blind to the study interventions.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Model Details: The investigators will carry out a pilot randomized controlled trial (RCT) to determine the feasibility and acceptability of implementing a double-dummy, parallel and crossover RCT protocol. The parallel-group phase was completed from February 22, 2022 to May 15, 2023, and the crossover design phase was completed from May 16, 2023 to March 1, 2024.

Study Record Dates

• First Submitted: September 28, 2021
• First Posted: November 1, 2021
• Study Start: February 22, 2022
• Primary Completion: March 1, 2024
• Study Completion: August 29, 2024
• Last Updated: March 12, 2025
• Results First Posted: March 12, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)