Migraine, Migraine Headache
Conditions
Keywords
pediatric, migraine, headache, neuromodulation, prodrome, treatment, REN
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. trial design will be feasible 2. REN will be feasible for prodromal treatment, with \>80% of participants using their assigned device to treat a qualifying prodrome. The following feasibility and acceptability outcomes will be measured: 1. proportion of eligible youth that are enrolled into the screening period, subsequently randomized, and treat a qualifying prodrome with REN. 2. recruitment rate, retention, and withdrawals. 3. participant feedback. All secondary outcomes will be reported descriptively, and adverse events will be recorded and reported. Methods: This 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 youth with migraine. Participants will be recruited from headache and neurology clinics at the Alberta Children's Hospital. Eligible and consenting participants will complete an intake visit and enter a 60-day screening period where they will complete electronic daily diaries to determine prodrome or headache occurrence and features. Participants with 3-28 qualifying prodromes during screening, where \>75% are followed by a headache within 6 hours, will be randomized 1:1 to treat one qualifying prodrome with active or sham REN over a 60-day treatment period. Participants will be trained on device use and will be instructed to not use any co-interventions during the qualifying prodrome; if headache onsets after the prodrome, participants will be instructed to use their typical acute treatment. During the treated prodrome, a survey will determine the presence, type, and number of prodromal symptoms. Surveys at 2, 24, and 48 hours post-treatment will record the presence or absence of headache, its characteristics, and AEs. The randomization sequence will be prepared by a biostatistician and will follow randomly ordered blocks of four and six, with variable block sizes. Only research pharmacists will have access to this sequence to prepare consecutively numbered blinded and matched study kits. These kits will contain a restricted mobile phone with only the REN software application pre-installed.
Interventions
DEVICEActive Remote Electrical Neuromodulation
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.
DEVICESham Remote Electrical Neuromodulation
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.
Sponsors
University of Calgary
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
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.
Eligibility
Sex/Gender
ALL
Age
8 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
* 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.
Exclusion criteria
* 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Feasibility - Proportion of Youth Enrolled Into Study | From enrollment to completion of the feedback form (between 60 and 120 days later). | Proportion of eligible youth enrolled into screening period (target=50%). |
| Feasibility - Proportion of Participants Randomized to Study Treatment | From enrollment to completion of the feedback form (between 60 and 120 days later). | Proportion of youth enrolled into screening period subsequently randomized (target=33%). |
| Feasibility - Proportion of Participants Using REN Treatment | From enrollment to completion of the feedback form (between 60 and 120 days later). | Proportion of randomized youth treating a qualifying prodrome event (target=80%). |
| Study Acceptability Based on Participant Feedback | 60 to 120 days after successful enrollment. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effect Size Estimate | From enrollment to completion of the feedback form (between 60 and 120 days later). | The main outcome that we will obtain an effect size estimate for will be the proportion of participants with absence of moderate-severe headache within 24 hours of prodromal treatment. All secondary outcomes will be reported descriptively, with a focus on describing the prevalence and consistency of prodromal symptoms as reported for the adult trial. For headache, pain severity will be measured using the 11-point pain numerical rating scale where 0 = no pain and 10 = the most intense pain imaginable (where a higher rating equals worse pain and worse outcomes). To align with International Headache Society and FDA guidelines for migraine trials, we will also use the 4-point pain severity scale (0=none, 1=mild, 2=moderate, 3=severe; higher ratings equal worse severity and outcomes), and participants will be asked about their most bothersome migraine associated symptom, and whether it is present or not. |
Countries
Canada
Contacts
CONTACTSerena L Orr, MD, MSc, FRCPC
CONTACTJonathan WP Kuziek, MSc
PRINCIPAL_INVESTIGATORSerena L Orr
University of Calgary
Outcome results
None listed