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

 1. Participants with an implanted electrical and/or neurostimulator device (e.g. cardiac
 pacemaker, cochlear implant).

 2. Participants with congestive heart failure (CHF), severe cardiac or cerebrovascular
 disease.

 3. Participants with epilepsy.

 4. Medical use of cannabis or recreational use one month prior to enrollment.

 5. Participants who have undergone nerve block (occipital or other) in the head or neck
 within the last 2 weeks

 6. Treatment with onabotulinum toxin A (Botox) to the head and/or neck for 3 months
 before enrollment and/or during the study

 7. Any history of anti-CGRP antibody treatment

 8. Current participation in any other clinical study that includes treatment

 9. Participants without basic cognitive and motor skills required for operating a
 smartphone.

 10. Pregnant or breastfeeding females

 11. Pure menstrual migraine

 12. Participants who received parenteral treatments for migraine within the previous 2
 weeks.

 13. Participants with other significant pain, medical or psychological problems that in
 the opinion of the investigator may confound the study assessments

 14. Participants who have previous experience with the device

 15. Participants with arm circumference below 7.9 inches (20 cm)