Assessment of Safety and Efficacy of Nerivio for the Migraine Prevention
Assessment of Safety and Efficacy of Nerivio for the Migraine Prevention
Migraine is a common neurologic with attacks of headache and associated symptoms such as
 nausea, vomiting, phono and photophobia. Migraine can lead to substantial functional
 impairment. This study intends to demonstrate the safety and efficacy of the Nwrivio for
 migraine prevention.

 The study is a prospective, randomized, double-blind, sham-controlled, multicenter study,
 conducted in three phases.

 The study will consist of a screening/enrollment visit, followed by a 4-week (28 days)
 baseline phase, an 8-week double-blind preventive treatment phase, and a 4-week open-label
 phase.

 Patients will complete an electronic diary throughout the study; this includes a daily
 evening report (completed regardless of whether the patient had a headache) and treatment
 feedback during the follow-up pre-emptive phase.

 The primary endpoint is the mean change in the average of migraine headache days per month
 comparing the 4-week baseline phase (weeks 1 through 4) with the last 28 days of the
 treatment phase (weeks 9 through 12).
Nerivio is a neuromodulation device approved for the acute treatment of migraine with or
 without aura in patients 12 years of age or older. The device utilizes electro stimulation to
 achieve conditioned pain modulation (CPM). CPM stimulate endogenous analgesic mechanism.
 Treatments are self-administered by the user at the onset of a migraine attack. this study
 intends to demonstrate the safety and efficacy of the Nwrivio for migraine prevention.

 The study is a prospective, randomized, double-blind, sham-controlled, multicenter trial,
 conducted in three phases. The ratio between treatment and control groups will be 1:1,
 stratified by center and patient type (chronic/non-chronic). The study will consist of a
 screening/enrollment visit, followed by a 4-week (28 days) baseline phase. Eligible
 participants will enter an 8-week double-blind preventive treatment phase. Following the
 preventive treatment phase, patients will be offered to participate in a 4-week open-label
 pre-emptive treatment phase or continue their prevention treatment with an active device,
 according to their eligibility.

 Patients will complete an electronic diary throughout the study; this includes a daily
 evening report (completed regardless of whether the patient had a headache) and treatment
 feedback during the follow up pre-emptive phase

 Phase I - Baseline - 4 weeks (weeks 1 through 4):

 Eligible participants will install the Nerivio app on their smartphones and will be
 instructed to record daily their migraine/headaches symptoms and medication use on the
 Nerivio app.

 Transition to the treatment phase: Participants who meet the following criteria in the
 baseline phase will be eligible to continue to the treatment phase:

 -  Complete the diary in at least 22 out of the 28 days during the baseline phase (80%)

 -  Have between 6 to 24 headache days during the 28-day baseline period

 -  At least 4 of their headache days during the baseline phase fulfill the ICHD-3 criteria
 for migraine (migraine without aura [code 1.1; C and D] or with aura [code 1.2; B and
 C], or probable migraine, or headaches requiring the use of migraine-specific
 medications including triptans, gepants or ergot derivatives).

 Phase II - treatment phase (prevention) - 8 weeks (weeks 5 through 12):

 Participants who meet the baseline phase requirements will be randomized in a 1:1 ratio to
 active and sham groups. Participants will be instructed to complete a daily diary (in the
 Nerivio app) about their headaches, associated symptoms, and medication use. They will also
 be instructed to conduct a 45-minute treatment with Nerivio every other day.

 Transition to the follow-up phase (open label):

 At the end of the treatment phase, participants from both arms (active and sham) may continue
 to a follow-up phase in which they will receive an active device that can be used during this
 phase. The data of all participants will be used for safety analyses.

 The data of participants from the baseline and treatment phases will be used to assess their
 eligibility to participate in the pre-emptive follow-up phase. Participants eligible for the
 follow-up phase meet the following conditions:

 -  Between 6-16 headache days during the baseline phase.

 -  Participants experience prodrome symptoms within 24 hours prior to the onset of their
 migraine headache in at least half of their migraine attacks during the baseline phase.

 -  Participants completed the daily questionnaires in at least 70% of the days during the
 treatment phase.

 -  Treated every other day in at least 24 and less than 33 days during the 56 days of the
 treatment phase.

 All adverse events will be reported.

 Phase III - Follow-up phase (open label) - 4 weeks (weeks 13 through 16):

 All participants will receive an active Nerivio device to use during the follow-up phase.
 Participants who do not meet the above requirements will be able to enter into the safety
 follow-up and continue to use Nerivio every other day for the preventive treatment of
 migraine. They will be instructed to compete a daily diary as was done in the treatment
 phase.

 Participants who meet the above requirements will enter the pre-emptive follow-up phase and
 be instructed to conduct a 45-minute device treatment within 60 minutes of prodrome symptom
 onset. Participants will be instructed to complete questionnaires regarding their headache,
 prodrome symptoms, and medication use at baseline (start of treatment), 2 hours
 post-treatment, and 24 hours post-treatment. In addition, participants will be instructed to
 continue to report the daily diary, as performed in the other phases of the study.

 All adverse events will be reported.
Inclusion Criteria:

 1. Age 18-75 years old.

 2. Must have at least a 6-month history of headaches that meet the ICHD-3 diagnostic
 criteria for migraine with or without aura, either chronic (at least 15 days of HA/
 month with migraine days (migraine with and without aura) at least 8 days/ month for >
 3 months) or non-chronic migraine.

 3. History of 6 to 24 headache days per 28-day period for each of the 3 months preceding
 study enrolment (based on participant report).

 4. Subject on prophylactic migraine treatment are permitted to remain on 1 medication
 with possible migraine-prophylactic effects if the dose has been stable for at least 2
 months prior to the screening visit, and the dose is not expected to change during the
 course of the study.

 5. Have personal access to a smartphone (24/7).

 6. Must be able and willing to comply with the protocol.

 7. Must be able and willing to provide informed consent..

 Exclusion Criteria:

 1. An active implanted electrical and/or neurostimulator device (e.g. cardiac pacemaker,
 cochlear implant).

 2. Uncontrolled epilepsy.

 3. History of use of opioids or barbiturates on more than 4 days a month in the last 6
 months.

 4. Current participation in any other interventional clinical study

 5. Subject without basic cognitive and motor skills required for operating a smartphone.

 6. Pregnant or breastfeeding.

 7. Other significant pain, medical or psychological problems that in the opinion of the
 investigator may confound the study assessments.

 8. Prior experience with the Nerivio device.