Assessment of Safety and Efficacy of Nerivio for the Migraine Prevention

A Prospective, Randomized, Double-blind, Sham-controlled Multi-center Clinical Study Assessing the Safety and Efficacy of Nerivio for the Preventive Treatment of Migraine

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 Nerivio 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 International Classification of Headache Disorders 3rd edition (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.

Participants will treat with a sham (placebo) Nerivio device every other day for migraine prevention.

The mean reduction in the number of migraine days per month during the last 28 days (4 weeks) of the treatment phase (weeks 9 through 12) compare to the 4-week baseline phase (weeks 1 through 4) A migraine day is defined as a calendar day with a headache that is accompanied by at least one of the following symptoms: aura, photophobia, phonophobia, nausea and/or vomiting; or a calendar day with a headache that is treated with a migraine-specific acute medication.

Number of participants with Adverse Events (AE), Serious Adverse Events (SAE) and Device-related Adverse Events

The mean reduction in the number of moderate/severe headache days per month during the last 28 days (4 weeks) of the treatment phase (weeks 9 through 12) compare to the 4-week baseline phase (weeks 1 through 4) A moderate/severe headache day is defined as a calendar day with a moderate or severe headache.

The mean reduction in the number of headache days per month during the last 28 days (4 weeks) of the treatment phase (weeks 9 through 12) compare to the 4-week baseline phase (weeks 1 through 4) A headache day is defined as a calendar day with headache (at any severity).

Percentage of patients achieving at least 50% reduction from baseline in the mean number of headache days (all severities) per month in the last 4 weeks of the treatment phase (weeks 9 through 12).

Increase in Headache Impact Test-6 (HIT-6) Score at the End of the Last 28 Days (4 Weeks) of the Treatment Phase (Weeks 9 Through 12) Compare to the HIT-6 Score at the End of the 4-week Baseline Phase (Weeks 1 Through 4)

Headache Impact Test-6 (HIT-6) questionnaire is a tool used to measure the impact headaches have on your ability to function on the job, at school, at home, and in social situations. the questionnaire contains 6 questions with a total score between 36 to 78. Higher score interpret as better patient outcome.

Reduction in Migraine-Specific Quality-of-Life (MSQ) Questionnaire Score at the End of the Last 28 Days (4 Weeks) of the Treatment Phase (Weeks 9 Through 12) Compare to the MSQ Score at the End of the 4-week Baseline Phase (Weeks 1 Through 4)

The migraine Specific Quality-of-Life questionnaire (MSQ) is a tool to measure the impact of migraine on your ability to function on the job, at school, at home, and in social situations. The questionnaire contains 14 questions with a total score between 0 to 84. Lower score interprets as better patient outcome.

Reduction in the mean number of acute headache/migraine medication days per month in the last 4 weeks of the treatment phase (weeks 9 through 12) compared to baseline (weeks 1 through 4).

Percentage of participants who treat for the first treatment in the pre-emptive phase, during the prodrome, when they are pain-free, and remain pain-free during the following 2 hours after the treatment, without use of acute medication.

Percentage of participants who treat for the first treatment in the pre-emptive phase, during the prodrome, when they are pain-free, and remain pain-free during the following 24 hours after the treatment, without use of acute medication.

Percentage of patients who treat during the prodrome, when they are pain free, and remain either pain free or with mild pain during the following 24 hours after the treatment without use of acute medication.

Analysis of the daily information provided by the participants for the purpose of predicting their migraine days

Health economics analysis of the difference between subjects using Nerivio as a therapy and those who do not with respect to: Absenteeism - number of missed work/school days Presenteeism - number of work/school days with moderate/severe functional disability Healthcare provider appointments ED visits Brain MRI/CT scans

Inclusion Criteria: Age 18-75 years old. 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 Headache Days(HD)/ month with migraine days (migraine with or without aura) at least 8 days/ month for > 3 months) or non-chronic migraine. History of 6 to 24 headache days per 28-day period for each of the 3 months preceding study enrolment (based on participant report). 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. Have personal access to a smartphone (24/7). Must be able and willing to comply with the protocol. Must be able and willing to provide informed consent.. Exclusion Criteria: An active implanted electrical and/or neurostimulator device (e.g. cardiac pacemaker, cochlear implant). Uncontrolled epilepsy. History of use of opioids or barbiturates on more than 4 days a month in the last 6 months. Current participation in any other interventional clinical study Subject without basic cognitive and motor skills required for operating a smartphone. Pregnant or breastfeeding. Other significant pain, medical or psychological problems that in the opinion of the investigator may confound the study assessments. Prior experience with the Nerivio device.