Neuromodulation During the Prodrome to Prevent Disabling Migraine Attacks in Youth

NCT07772427 | Not Yet Recruiting

• 1 other identifier: REB26-1157
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

Background \& Rationale: One in ten Canadian youth have migraine, a disabling neurological disease that is more common in females and characterized by moderate-severe disabling headaches. Migraine attacks occur in a cycle that begins with a prodromal phase, followed by aura, a pain phase (headache), and finally a postdrome phase when the pain is resolved but other symptoms persist. The prodrome is recognized by \~90% of all youth with migraine, occurs up to 24 hours before headache onset, and consists of a variety of symptoms including, but not limited to, food cravings, fatigue, yawning, mood changes, and sensory hypersensitivity (e.g., light sensitivity). Prodromal symptoms are disabling and frequently graded as moderate to severe. All acute migraine treatments for youth have been studied for use in the pain phase, with the greatest treatment success early in this phase. Unfortunately, only \~1/3 of youth achieve pain freedom within two hours. Recently, a groundbreaking trial found that treatment during the prodrome could prevent the pain phase, although prodromal treatment does not exist for youth. In considering the most innovative, safe, and patient-centered prodromal intervention, remote electrical neuromodulation (REN) is the obvious choice. The investigator's engagement with 175 youth with migraine and their caregivers shows that REN is preferred when pill-based interventions are ineffective or impractical. REN has none of the limitations of pill-based prodromal treatment. The REN device is wearable, battery-operated, worn on the upper arm, and controlled wirelessly by a smartphone application. REN electrically stimulates sensory nerves in the arm below their perceived pain thresholds, but above their depolarization thresholds, to induce a conditioned pain modulation response in the brain to modulate incoming migraine pain signals. Clinical trial and observational studies in youth with migraine have shown REN's safety and efficacy for home-based treatment during the pain phase and led the FDA to clear its use in youth \>8 years. In the adolescent trial, 71% of participants had pain relief at two hours, there were no serious adverse events (AE), and only one device-related AE (transient arm pain) occurred. Also, emerging data show that adults with migraine in the prodrome phase display pain facilitation due to a deficit in pain modulation. Thus, REN's mechanism of action is likely to be more effective during the prodrome vs. the pain phase as it can "turn on" deficient pain modulatory areas earlier when they are most impaired. Research Question \& Objectives: The investigators aim to determine the feasibility of implementing REN treatment during the prodrome to prevent migraine pain in youth with migraine, and hypothesize that:

1. 1.trial design will be feasible
2. 2.REN will be feasible for prodromal treatment, with \>80% of participants using their assigned device to treat a qualifying prodrome.
3. 3.proportion of eligible youth that are enrolled into the screening period, subsequently randomized, and treat a qualifying prodrome with REN.
4. 4.recruitment rate, retention, and withdrawals.
5. 5.participant feedback.

Conditions

Migraine; Migraine Headache

Keywords

pediatric; migraine; headache; neuromodulation; prodrome; treatment; REN

Outcome Measures

Primary Outcomes (4)

• Feasibility - Proportion of Youth Enrolled Into Study

  Proportion of eligible youth enrolled into screening period (target=50%).

  From enrollment to completion of the feedback form (between 60 and 120 days later).

• Feasibility - Proportion of Participants Randomized to Study Treatment

  Proportion of youth enrolled into screening period subsequently randomized (target=33%).

  From enrollment to completion of the feedback form (between 60 and 120 days later).

• Feasibility - Proportion of Participants Using REN Treatment

  Proportion of randomized youth treating a qualifying prodrome event (target=80%).

  From enrollment to completion of the feedback form (between 60 and 120 days later).

• Study Acceptability Based on Participant Feedback

  Participant feedback will be assessed based on the completion of multiple choice and free text items in a feedback form. Multiple choice responses will be "Strongly Disagree", "Disagree", "Neutral", "Agree", and "Strongly Agree", with "Agree" and "Strongly Agree" suggesting the study is acceptable to participants. Multiple choices items will be from previously published work (PubMed ID: 27390769). Free text responses will be reviewed to determine overall positive or acceptable aspects of the study and negative or not acceptable aspects of the study.

  60 to 120 days after successful enrollment.

Secondary Outcomes (1)

• Effect Size Estimate

  From enrollment to completion of the feedback form (between 60 and 120 days later).

Study Arms (2)

Active REN

ACTIVE COMPARATOR

45 minutes of a modulated symmetrical biphasic square electrical pulse, modulated frequency of 100-120 Hz, pulse width of 400 µs, maximum of 40 mA, which modulates the pain response in the brain using conditioned pain modulation to trigger an analgesic effect.

Device: Active Remote Electrical Neuromodulation

Sham REN

SHAM COMPARATOR

45 minutes of modulated symmetrical biphasic square electrical pulse, modulated frequency of \~0.083 Hz and a modulated pulse width of 40-550 µs. The sham device produces sensations comparable to the active device, appears identical to the active device, is also controlled wirelessly by a smartphone application, but uses lower stimulation parameters which were ineffective in adult trials.

Device: Sham Remote Electrical Neuromodulation

Interventions

Active Remote Electrical Neuromodulation DEVICE

The REN device modulates the pain response in the brain using conditioned pain modulation to trigger an analgesic effect. This mechanism is achieved by electrically stimulating the C and Aδ nociceptive sensory nerves in the upper arm, just below the perceived pain threshold and above the depolarization threshold. Precise activation of these sensory nerves further triggers ascending pain pathways within the spinothalamic tract and brain stem. These pathways further activate descending pain inhibitory pathways within the brain stem to modulate incoming pain signals and produce an analgesic effect. The active REN device involves 45 minutes of a modulated symmetrical biphasic square electrical pulse, modulated frequency of 100-120 Hz, pulse width of 400 µs, maximum of 40 mA, which modulates the pain response in the brain using conditioned pain modulation to trigger an analgesic effect.

Also known as: REN

Active REN

Sham Remote Electrical Neuromodulation DEVICE

The sham REN device produces sensations comparable to the active REN device, appears identical to the active REN device, is also controlled wirelessly by a smartphone application, but uses lower stimulation parameters which were ineffective in adult trials. The sham REN device involves 45 minutes of modulated symmetrical biphasic square electrical pulse, modulated frequency of \~0.083 Hz and a modulated pulse width of 40-550 µs.

Sham REN

Eligibility Criteria

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

You may qualify if:

• youth aged 8-\<18 years with a diagnosis of migraine using gold standard International Classification of Headache Disorders criteria
• self-reporting 2-14 headache days/month in the last 3 months
• reporting prodromal symptoms that predict a headache within six hours \>75% of the time.
• To proceed past the 60-day screening period to randomization, participants will need to report 3-28 qualifying prodrome events with \>75% of these events followed by a headache within 6 hours.

You may not qualify if:

• the inability to read or understand English
• a diagnosis of psychosis, schizophrenia, or moderate-severe autism, moderate-severe developmental delay or moderate-severe intellectual disability
• implanted electrical device
• uncontrolled epilepsy (i.e., \>2 seizures in the past year)
• abnormal skin on both upper arms
• arm circumference \<20 cm
• severe cardiac or cerebrovascular disease
• prior participation in the trial

Sponsors & Collaborators

• University of Calgary: lead

Study Sites (1)

Alberta Children's Hospital

Calgary, Alberta, T3B 6A8, Canada

Location

Related Publications (7)

• Hershey AD, Irwin S, Rabany L, Gruper Y, Ironi A, Harris D, Sharon R, McVige J. Comparison of Remote Electrical Neuromodulation and Standard-Care Medications for Acute Treatment of Migraine in Adolescents: A Post Hoc Analysis. Pain Med. 2022 Apr 8;23(4):815-820. doi: 10.1093/pm/pnab197.

  PMID: 34185084 BACKGROUND

• Hershey AD, Lin T, Gruper Y, Harris D, Ironi A, Berk T, Szperka CL, Berenson F. Remote electrical neuromodulation for acute treatment of migraine in adolescents. Headache. 2021 Feb;61(2):310-317. doi: 10.1111/head.14042. Epub 2020 Dec 21.

  PMID: 33349920 BACKGROUND

• Martin EG, Rasiah J, Claassen CS, Waywitka J, Merritt AM, Pringsheim TM, Shearer KA, Tsang VWL, Stevens KE, Sheehan-Klassen CE, Suddaby P, Orr SL. Engaging youth and parents in clinical pediatric research: A case-based example. Paediatr Child Health. 2023 Mar 31;28(4):235-240. doi: 10.1093/pch/pxac111. eCollection 2023 Jul.

  PMID: 37287482 BACKGROUND

• Goadsby PJ, Zanchin G, Geraud G, de Klippel N, Diaz-Insa S, Gobel H, Cunha L, Ivanoff N, Falques M, Fortea J. Early vs. non-early intervention in acute migraine-'Act when Mild (AwM)'. A double-blind, placebo-controlled trial of almotriptan. Cephalalgia. 2008 Apr;28(4):383-91. doi: 10.1111/j.1468-2982.2008.01546.x. Epub 2008 Feb 20.

  PMID: 18294251 BACKGROUND

• Dodick DW, Goadsby PJ, Schwedt TJ, Lipton RB, Liu C, Lu K, Yu SY, Severt L, Finnegan M, Trugman JM. Ubrogepant for the treatment of migraine attacks during the prodrome: a phase 3, multicentre, randomised, double-blind, placebo-controlled, crossover trial in the USA. Lancet. 2023 Dec 16;402(10419):2307-2316. doi: 10.1016/S0140-6736(23)01683-5. Epub 2023 Nov 15.

  PMID: 37979595 BACKGROUND

• Coppola G, Bracaglia M, Di Lenola D, Iacovelli E, Di Lorenzo C, Serrao M, Evangelista M, Parisi V, Schoenen J, Pierelli F. Lateral inhibition in the somatosensory cortex during and between migraine without aura attacks: Correlations with thalamocortical activity and clinical features. Cephalalgia. 2016 May;36(6):568-78. doi: 10.1177/0333102415610873. Epub 2015 Oct 6.

  PMID: 26442930 BACKGROUND

• Cho LY, Bell TK, Craddock L, Godfrey KJ, Hershey AD, Kuziek J, Stokoe M, Millar K, Orr SL, Harris AD. Region-specific changes in brain glutamate and gamma-aminobutyric acid across the migraine attack in children and adolescents. Pain. 2024 Dec 1;165(12):2749-2761. doi: 10.1097/j.pain.0000000000003289. Epub 2024 Jun 4.

  PMID: 38833578 BACKGROUND

MeSH Terms

Conditions

Migraine Disorders; Headache

Condition Hierarchy (Ancestors)

Headache Disorders, Primary; Headache Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Pain; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Officials

• Serena L Orr

  University of Calgary

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Serena L Orr, MD, MSc, FRCPC

CONTACT

(403) 955-7728; serena.orr@albertahealthservices.ca

Jonathan WP Kuziek, MSc

CONTACT

(780)446-1851; jonathan.kuziek@ucalgary.ca

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Model Details: The proposed study will be a pilot randomized, single centre, double-blind, parallel group, sham-controlled trial comparing active to sham REN for the prevention of headache within 24 hours of treating prodromal symptoms in children and adolescents with migraine.

Study Record Dates

• First Submitted: July 31, 2026
• First Posted: August 19, 2026
• Study Start (Estimated): October 1, 2026
• Primary Completion (Estimated): October 1, 2027
• Study Completion (Estimated): September 1, 2028
• Last Updated: August 19, 2026

Record last verified: 2026-08

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)