Efficacy and Safety of Nerivio Device for Acute Treatment of Migraine in People With Chronic Migraine
Efficacy and Safety of Nerivio Device for Acute Treatment of Migraine in People With Chronic Migraine
A prospective, single arm, open-label, multicenter trial to assess the efficacy and safety of
 the Nerivio device in chronic migraine patients. This study will be conducted in three
 phases:

 Phase I - Run-in:

 Eligible participants will be trained to use a smartphone migraine diary application. During
 the 4 weeks of this phase, participants will be instructed to report all their migraines and
 headaches at onset, 2 hours and 24 hours post report .

 Phase II - Treatment:

 A 4-week treatment phase in which participants will be asked to treat their migraine
 headaches with the Nerivio device and report it using the smartphone application at baseline,
 2 hours and 24 hours post-treatment.

 Phase III - Follow-up:

 An 8-week follow-up phase in which participants will incorporate the Nerivio device into
 their usual care according to their preference (Nerivio only, medication only, both or none).
 Participants will be asked to report all their migraines or headaches at onset, 2 hours post
 report and 24 hours post report.
This open label study includes up to four visits. The enrollment and application training may
 occur in two separate visits instead of one.

 First visit - The first visit will include screening, enrollment and training on the
 application.

 Enrollment: The screening process will include an eligibility assessment and a urine
 pregnancy test. Following successful screening, the site staff will provide the participants
 with study related information, perform an enrollment interview and receive an informed
 consent from the participants. 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.

 Application training: Eligible participants who enroll to the study will be trained to use
 the diary mode of the application that is installed on their own smartphones. The
 participants will be instructed to report the onset of all their migraines and headaches and
 complete a migraine diary questions regarding their pain intensity levels, the
 presence/absence of aura and associated migraine symptoms (nausea, photophobia, phonophobia,
 and allodynia) as well as rate their stress level and functional disability at baseline, 2-
 and 24-hours post-treatment. At the beginning of each treatment, participants will also be
 asked to report the time elapsed from attack onset. The site personnel will be required to
 document the training session in the Case Report Form (CRF).

 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. The
 participants will use the app to record pain intensity levels, the presence/absence of aura
 and associated migraine symptoms (nausea, photophobia, phonophobia, and allodynia) as well as
 the effect that their migraine attacks have on their daily routine and quality of life, at
 baseline, 2- and 24-hours post-treatment. These reports will be transferred by the
 application to the electronic data capture (EDC) system, where they will be collected and
 registered.

 Participants who report at least 6 qualifying migraine headaches with pain data at baseline
 and 2 hours post-treatment will continue to the treatment phase.

 Second visit- Device training: Eligible participants who successfully complete the run-in
 phase will receive the Nerivio™ device. The device will be registered and connected by
 Bluetooth to their smartphone. During this visit, participants will be trained to use the
 device. Device training will include finding the optimal individual stimulation intensity
 level (perceptible but not painful), that will be subject to change during the treatment
 phase. The site staff will also carefully review with the patient how to identify a
 qualifying migraine headache (see below) and provide detailed instructions on study
 procedures.

 If the research staff recognizes that the participant cannot tolerate the feeling of the
 electrical stimulation, the participant may be withdrawn from the study.

 During the training, participants will also be informed on the key elements which are
 critical for the successful conduct of the study:

 -  Treatments of migraine and headaches with Nerivio™ should be performed as soon as
 possible after migraine headache or aura began and always within one hour of symptoms
 onset. Treatments of mild headaches are accepted.

 -  Avoid taking rescue medications within two hours post-treatment (2 hours from start of
 treatment), if possible.

 -  The treatment should be performed for at least 30 minutes (the recommended treatment
 duration is 45 minutes).

 The site personnel will be required to document the training session in the CRF.

 Treatment phase: Participants will be instructed to use the device for the treatment of
 migraine and/or headaches (see below) as soon as possible and always within 60 minutes of
 onset during a period of up to 4 weeks. Participants will be instructed to use the device
 with the intensity level identified during the device training visit (and adjust as
 necessary) 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 at 2- and 24-hours post treatment. The participants will use the app to record pain
 intensity levels, the presence/absence of aura and associated migraine symptoms (nausea,
 photophobia, phonophobia, and allodynia) as well as the effect that their migraine attacks
 have on their daily routine and quality of life, at baseline, 2- and 24-hours post-treatment.
 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
 directly to the site staff.

 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. Migraine headaches 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- Follow-up phase:

 Following the 4-week period of the treatment phase, participants will return to the clinic to
 fill questionnaires assessing satisfaction and user experience. All participants who complete
 the treatment phase will enter an additional 8-week phase in which the device can be
 incorporate into their usual care. Participants will treat their migraines and headaches
 according to their preference- treatment with Nerivio only, treatment with medication only,
 both treatment options, or none. Participants will be asked to report all their migraine
 headaches at onset (migraines or headache), regardless if they are using the device or not.
 The participants will use the app to record pain intensity levels, the presence/absence of
 aura and associated migraine symptoms (nausea, photophobia, phonophobia, and allodynia) as
 well as the effect that their migraine attacks have on their daily routine and quality of
 life, at baseline, 2- and 24-hours post-treatment.

 Fourth (final) visit - End of study:

 Participants will return to the clinic following the end of the follow-up phase, at which
 time they will return the device. The participants will have the option of returning the
 device by mail instead of an on-site visit. Participants may be asked to fill additional
 questionnaires on their migraine and their experience with the device.
Inclusion Criteria:

 1. Participants aged 18-75 years old.

 2. Participants meeting the International Classification of Headache Disorders-3 (ICHD-3)
 diagnostic criteria for chronic migraine

 3. Participants experiencing between 15 to 23 headache days per month, with at least 8
 headache days (per month) with migraine phenotype presentation

 4. Participants have personal access to a smartphone

 5. Participants must be able and willing to comply with the protocol

 6. Participants must be able and willing to provide written informed consent

 Exclusion Criteria:

 1. Participants with an active 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 uncontrolled epilepsy.

 4. Lack of efficacy, after an adequate therapeutic trial, of at least two migraine
 specific acute medications.

 5. Change in migraine preventive medications (type or dose) in the last two months prior
 to recruitment and/or during the study

 6. Pregnant, trying to get pregnant or breastfeeding female participants

 7. Subjects participating in any other interventional clinical study.

 8. Participants without basic cognitive and/or motor skills needed to operate a
 smartphone

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

 10. Participants who have previous experience with the device