Safety and Efficacy of Nerivio™ for the Acute Treatment of Migraine in Adolescents

A Single Arm, Open Label, Multicenter Study of the Safety and Efficacy of Nerivio™ for the Acute Treatment of Migraine in Adolescents

Due to the outbreak of the COVID-19 pandemic in the USA on March 2020, all study sites stopped enrolling patients to the study

Nerivio™ is an FDA-authorized remote electrical neuromodulation (REN) device for the acute treatment of migraine with or without aura in patients 18 years old or above who do not have chronic migraine. The device delivers transcutaneous electrical stimulation to the upper arm to induce conditioned pain modulation (CPM) that activates a descending endogenous analgesic mechanism. This is a prospective, single arm, open label, multicenter trial of the safety and efficacy of Nerivio™ for the acute treatment of migraine in adolescents The study will be conducted in three phases: Phase I - Run-in: Phase II - Treatment phase: Phase III (optional) - Free-use

This open label study includes 3 phases and up to 4 visits. All visits will be conducted in the presence of a parent/guardian. First visit - enrollment: The first visit will include screening, enrollment and training on the application in diary mode. The screening process will include an eligibility assessment and a urine pregnancy test. Following successful screening, enrollment interview and signing an informed consent by the parent/guardian and an informed assent by the participant. The participants will be trained to use the electronic diary application, installed on their own smartphones. The site personnel will be required to document the training session in the CRF. During this visit, participants will complete baseline questionnaires that included information on the frequency and severity of their migraine attacks, typical associated symptoms, use of preventive and acute treatments, and the effect that their migraine attacks have on their daily routine and quality of life. Phase 1 - run-in phase: After the enrollment visit, participants will undergo a 4-week migraine diary phase aimed to collect baseline migraine characteristics and further assess eligibility. Participants will be asked to report in the application each migraine attack. These reports will be transferred by the application to the electronic data collection (EDC) system, where they will be collected and registered. Participants who did not have at least 3 migraine attacks will be excluded from the study. Eligibility will also be determined based on the compliance of participants to report the attacks within one hour from attack onset and report the pain level at 2 hours post-treatment in at least 66.7% of the reported attacks. Second visit - Device training visit: Eligible participants who meet the run-in requirements will receive the Nerivio™ device. The device will be registered and connected by Bluetooth to their smartphone. During this visit, participants and their parent/guardian will be trained to use the device, including finding the optimal individual stimulation intensity level (perceptible but not painful). The site will also carefully review with the patient and parent/caregiver how to identify a qualifying migraine attack (see below) and provide detailed instructions on study procedures. The individual intensity level identified during this visit will be recorded, and the participants will be asked to treat their migraine headaches with the device using the identified intensity. If the research staff recognizes that the participant cannot tolerate the feeling of the electrical stimulation, the participant may be withdrawn from the study. Phase 2 -Treatment phase: Participants will be instructed to use the device for the treatment of 4 qualifying migraine attacks (see below) as soon as possible and always within 60 minutes of onset during a period of up to 8 weeks. Participants will be instructed to use the device with the intensity level identified during the device training visit (with a range of ±5 units) and make sure the stimulation is perceptible but not painful. Participants will be instructed to avoid taking rescue medications within 2 hours post-treatment. If medications are used, participants will be instructed to record in the app when and which medication was taken. The participants will use the app to record pain intensity levels (none, mild, moderate, or severe) at baseline, 2- and 24-hours post-treatment, and to record the presence/absence of associated migraine symptoms (nausea, photophobia, phonophobia) at baseline and 2 hours post-treatment. To assess functional disability, participants will also record at baseline, 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', 'no ability at all'). At the beginning of each treatment, participants will also be asked to report the time elapsed from attack onset. Adverse events will be reported throughout this phase of the study. Participants who do not achieve satisfactory relief at 2 hours post-treatment may treat again with the Nerivio™ device or may treat with usual care at that time or any time thereafter if the headache does not resolve. Participants will also be able to treat headache recurrence with the device. Attacks that are not treated with the device may be treated with usual care. The first reported treatment will be considered a "training" treatment, aimed to verify that the participants use the device properly, and will only be included in the safety analysis. The efficacy evaluation will be performed on the first treatment of a qualifying attack (see below) following the training treatment (hereby termed "test treatment"). Third visit - Termination of the treatment phase and free-use phase initiation: Following the 8-week period of the treatment phase, participants will return to the clinic to return the device and fill questionnaires assessing satisfaction and user experience. All participants who complete the treatment phase will be offered to participate in an additional 8-week phase in which the device can be incorporate into usual care. Phase 3 - Free-use phase: Participants will continue in an 8-week phase in which they will be able to use the device according to their preferences for the treatment of their migraine attacks. Fourth (final) visit - End of study: Participants will return to the clinic following the end of the 8-week free-use phase, at which time they will return the device.

Nerivio™ is an FDA-authorized remote electrical neuromodulation (REN) device for the acute treatment of migraine with or without aura in patients 18 years old or above who do not have chronic migraine. The device delivers transcutaneous electrical stimulation to the upper arm to induce conditioned pain modulation (CPM) that activates a descending endogenous analgesic mechanism. The treatment is self-administered and controlled by a smartphone application.

The percentage of subjects reporting, for the test treatment, pain relief at 2 hours post-treatment without the use of rescue medication. Pain relief is defined as an improvement from severe or moderate pain to mild or no pain, or from mild pain to no pain. Pain level was reported using a 4-point Likert scale (0 -No pain, 1 - Mild pain, 2 - Moderate pain, 3- Severe pain)

The percentage of subjects reporting, for the test treatment, no pain at 2 hours post-treatment without the use of rescue medication. Pain-free is defined as improvement from mild, moderate, or severe pain to no pain. Pain level was reported using a 4-point Likert scale (0 - No pain, 1 - Mild pain, 2 - Moderate pain, 3- Severe pain)

The percentage of subjects presented nausea at the baseline (T=0 hours) and reported disappearance of nausea at 2 hours post-treatment of the test treatment

The percentage of subjects presented photophobia at baseline (T=0 hours) and reported disappearance of photophobia at 2 hours post-treatment of the test treatment

The percentage of subjects presented phonophobia at baseline (T=0 hours) and reported disappearance of phonophobia at 2 hours post-treatment of the test treatment

The percentage of subjects achieving, for the test treatment, pain relief at 2 hours post-treatment without the use of rescue medication and no relapse of headache pain within 24 hours

The percentage of subjects achieving, for the test treatment, freedom from pain at 2 hours post-treatment without the use of rescue medication and no relapse of headache pain within 24 hours

The percentage of subjects achieving improvement of at least one grade in functional disability in the test treatment at 2 hours post-treatment with no use of rescue medication

The percentage of subjects achieving improvement of at least one grade in functional disability in the test treatment at 24 hours post-treatment with no use of rescue medication

Inclusion Criteria: 1. Participants age 12-17 years old at the time of informed consent, inclusive. 2. Participants have at least a 6-month history of headaches that meet the ICHD-3 diagnostic criteria for migraine with or without aura 3. History of at least 3 migraine attacks per month for each of the 2 months preceding study enrolment 4. Typical headache duration of at least 3 hours (when untreated or unsuccessfully treatment) 5. Stable migraine preventive medications during the 2 months prior to enrollment (no change in usage or dosage). 6. Participants have personal access to a smartphone (24/7) 7. Participants must be able and willing to comply with the protocol 8. Parents/Guardians must be able and willing to provide written informed consent 9. Participants must be able and willing to provide informed assent Exclusion Criteria: Participants with an implanted electrical and/or neurostimulator device (e.g. cardiac pacemaker, cochlear implant). Participants with congestive heart failure (CHF), severe cardiac or cerebrovascular disease. Participants with epilepsy. Medical use of cannabis or recreational use one month prior to enrollment. Participants who have undergone nerve block (occipital or other) in the head or neck within the last 2 weeks Treatment with onabotulinum toxin A (Botox) to the head and/or neck for 3 months before enrollment and/or during the study Any history of anti-CGRP antibody treatment Current participation in any other clinical study that includes treatment Participants without basic cognitive and motor skills required for operating a smartphone. Pregnant or breastfeeding females Pure menstrual migraine Participants who received parenteral treatments for migraine within the previous 2 weeks. Participants with other significant pain, medical or psychological problems that in the opinion of the investigator may confound the study assessments Participants who have previous experience with the device Participants with arm circumference below 7.9 inches (20 cm)

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.