Remote Electrical Neuromodulation for Acute Treatment of Migraine in Adolescents

Andrew D. Hershey MD, PhD, FAAN, FAHS; Tamar Lin PhD; Yaron Gruper MSc; Dagan Harris PhD; Alon Ironi MSEE; Thomas Berk MD; Christina L. Szperka MD, MSCE; Frank Berenson MD, FAHS

Disclosures

Headache. 2021;61(2):310-317. 

In This Article

Methods

Standard Protocol Approvals, Registrations, Patient Assents, and Parents/Guardian Consents

The study protocol was reviewed and approved by the appropriate institutional review board for each site and was conducted according to Good Clinical Practice and the Declaration of Helsinki guidelines. Before undergoing any study procedures, patients provided written informed assent and their parents/guardian provided written informed consent. The study is registered with ClinicalTrials.gov (NCT04089761).

Study Design and Participants

Adolescents with migraine with or without aura participated in this prospective, open-label, single arm, multicenter study conducted at 12 sites in the USA. Patients were eligible to participate if they were 12–17 years old at the time of informed consent (inclusive), met the International Classification of Headache Disorders, 3rd edition criteria for migraine with or without aura,[17] had history of at least three migraine attacks per month for each of the 2 months preceding study enrolment with any number of headache days per month (i.e., the study included both patients with episodic migraine and patients with chronic migraine), reported typical headache duration of at least 3 hours (when untreated or unsuccessfully treated), and were on either no, or stable migraine preventive medications in the last 2 months prior to recruitment. Exclusion criteria were: (a) pregnancy, nursing, trying to conceive, (b) implanted electrical and/or neurostimulator device, (c) congestive heart failure, severe cardiac or cerebrovascular disease, (d) epilepsy, (e) use of cannabis 1 month prior to enrollment, (f) undergoing nerve block in the head or neck within the last 2 weeks, (g) treatment with onabotulinumtoxinA (Botox) to the head and/or neck for 3 months before enrollment and/or during the study, (h) any history of anti-calcitonin gene-related peptide antibody treatment, (i) pure menstrual migraine, (j) parenteral treatments for migraine within the previous 2 weeks, (k) other significant illness that in the opinion of the investigator may confound the study assessments, (l) unable to use a smartphone, (m) previous experience with the device, (n) participating in any other interventional clinical study, and (o) arm circumference below 7.9 in.

The REN Device

The REN device is a wireless, wearable, noninvasive stimulation device applied to the lateral upper arm between the bellies of the lateral deltoid and the triceps for 45 minutes. The device stimulates small skin nerves using a proprietary electrical signal comprising a modulated, symmetrical, biphasic, square pulse with a modulated frequency of 100–120-Hz, pulse width of 400 μs, and up to 40 mA output current (adjusted by the patient). The pulse is designed to stimulate C and Aδ noxious sensory fibers above their depolarization thresholds, yet the stimulation energy is low enough to maintain the overall sensory experience below the perceptual pain threshold. Since REN induces a global pain inhibition mechanism, the device can be used on either arm independently from the side of a unilateral headache.

Procedures

After enrollment, participants were trained to use the electronic diary application, installed on their smartphones, and then completed a 4-week run-in phase. Participants who did not have at least three migraine attacks or did not report the pain level at 2 hours post-treatment in at least 66.7% of the attacks were excluded from the study. Eligible participants continued to an 8-week treatment phase. During this visit, participants and their parents/guardian were trained to use the REN device, including finding the optimal intensity level (perceptible but not painful). Participants were instructed to use the device at home for the treatment of four qualifying migraine attacks during a period of up to 8 weeks. A qualifying migraine attack is defined as a migraine attack that: (a) was not preceded by another migraine or other headache within the preceding 24 hours, (b) was not preceded by the use of specific or nonspecific acute migraine medications within the previous 24 hours, and (c) occurred in a setting in which the patient could properly administer the treatment within 60 minutes of onset and complete the migraine diary at 2 hours.

Participants were instructed to avoid taking rescue medications within 2 hours post-treatment. Pain scores (none, mild, moderate, or severe), absence/presence of associated symptoms (nausea/vomiting, photophobia and phonophobia), and functional disability were recorded at baseline, and 2 and 24 hours post-treatment. To assess functional disability, participants recorded at baseline, and 2 and 24 hours post-treatment their response to the following question in their diary: "How do you rate your ability to do school-work or perform your usual activities?" using a 4-point scale ("as usual," "some ability," "a little ability," and "no ability at all").

Participants who did not achieve satisfactory relief at 2 hours or had headache recurrence could treat again with the device or with usual care. Adverse events reported throughout this phase of the study were recorded.

Outcomes

The primary endpoints of this study were related to the safety and tolerability of REN. Safety was assessed by the incidence of adverse events in general and by seriousness, severity, and association to the device. Treatment tolerability was assessed by the percent of subjects who fail to complete the study because of adverse events. The secondary endpoints were related to device efficacy and included the proportion of participants who achieved pain relief at 2 hours post-treatment, defined as improvement from severe or moderate pain to mild or none, or improvement from mild pain to none; proportion of participants who achieved pain-free (improvement from mild, moderate, or severe pain to none) at 2 hours, and disappearance of associated symptoms (nausea/vomiting, photophobia, and phonophobia) at 2 hours. Exploratory endpoints included sustained pain relief at 24 hours, sustained pain-free at 24 hours, and improvement in functional ability at 2 hours (defined a reduction of at least one grade). Within-subject consistency of pain relief and pain-free responses, defined as the proportion of participants achieving pain relief/pain-free at 2 hours in at least 50% of their treated headaches, were also assessed.

Additional outcome was improvement in migraine-related disability, assessed by the Pediatric Migraine Disability Assessment (PedMIDAS) questionnaire,[18] which asks how migraine interfered with school and daily activities.[19] The questionnaire was administered at baseline (enrollment visit) and at the end of the treatment phase. Although typically the PedMIDAS asks about the last 3 months, in this study participants were asked to refer to the last 2 months since the REN device was used for 8 weeks and the aim was to assess its effect on disability within the intervention period.

Data Analysis

This is the primary analysis of the data obtained from this study. The sample size was calculated on the efficacy endpoint of pain relief at 2 hours. Initial calculations show that a sample size of 110 participants would provide 80% power to determine that 60% (±6%) of the participants will achieve pain relief at 2 hours. To account for a potential ~15% drop-out rate and/or missing data, it was determined that the sample size may be increased to up to 130 participants. Although the power calculation was conducted on the secondary efficacy endpoint, it also accounts for the safety and tolerability primary endpoints, for which a smaller sample size was estimated to suffice to ensure that the majority of safety and tolerability issues would be revealed, as typical with device studies conducted on adolescents following a pivotal adult study.[20] The power calculation was, thus, conducted on the pain relief outcome to make sure the study will not be underpowered study to assess the efficacy endpoints, which are an important aspect of the objective of the study even though they were defined as secondary endpoints. Due to the outbreak of the coronavirus disease 2019 pandemic in the United States in March 2020, all study sites stopped enrolling patients to the study. An interim analysis was conducted to assess the statistical power of the data accumulated from the 60 patients enrolled which is approximately 50% of the planned sample size. Based on the results of this analysis, the data monitoring committee determined that the study can be deemed completed for benefit since pain relief at 2 hours was achieved by more than 60% of participants. Stopping enrollment with a final analysis set of ~40 participants is further supported by an additional power analysis in which the margin of error was increased from 6% in the initial calculation to 10%. Calculations show that a sample size of 40 participants provides statistical power of 80% to determine that 60% (±10%) of the participants will achieve pain relief at 2 hours.

The intention-to-treat population included all participants who received the device and was used for the efficacy and safety analyses. The first reported treatment of each participant was considered a training treatment and was only included in the safety analyses. The efficacy evaluation was based on the first treated qualifying migraine headaches with baseline and 2 hours assessment following the training treatment (hereby termed test treatment). The use of rescue medication before the 2-hours assessment was considered a treatment failure. Treatments with missing data were excluded from all analyses.

For the associated symptoms outcomes, patients with presence of a symptom at baseline and data at 2 hours are included in the analyses. For functional disability endpoints, all patients with baseline values of "some limitation," "moderate limitation," or "severe limitation," and data at 2 hours were included in the analyses.

For continuous variables, mean and standard deviation are provided. The assumptions of normality of the age and PedMIDAS variables were verified using the normal quantile–quantile (Q–Q) plot. Interquartile range of these variables is also presented. The analyses of the categorical variables focused on estimating the event rates with corresponding uncertainty, and there were no formal statistical tests and no null hypothesis testing. In this analysis, the number and percentage of patients in each category are provided with 95% confidence intervals calculated using the binomial (Clopper–Pearson) exact method.[21] Data were analyzed with IBM SPSS statistics software version 25.0. (SPSS Inc., USA).

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