Efficacy and Safety of Nerivio Device for Acute Treatment of Migraine in People With Chronic Migraine

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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.

Official Title
-----------------
An Open Label, Single Arm, Multicenter Study Assessing the Efficacy and Safety of Nerivio, a Remote Electrical Neuromodulation Device, for Acute Treatment of Migraine in People With Chronic Migraine

Conditions
-----------------
Chronic Migraine

Intervention / Treatment
-----------------
* Device: Nerivio


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participants aged 18-75 years old. Participants meeting the International Classification of Headache Disorders-3 (ICHD-3) diagnostic criteria for chronic migraine Participants experiencing between 15 to 23 headache days per month, with at least 8 headache days (per month) with migraine phenotype presentation Participants have personal access to a smartphone Participants must be able and willing to comply with the protocol Participants must be able and willing to provide written informed consent Exclusion Criteria: Participants with an active 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 uncontrolled epilepsy. Lack of efficacy, after an adequate therapeutic trial, of at least two migraine specific acute medications. Change in migraine preventive medications (type or dose) in the last two months prior to recruitment and/or during the study Pregnant, trying to get pregnant or breastfeeding female participants Subjects participating in any other interventional clinical study. Participants without basic cognitive and/or motor skills needed to operate a smartphone 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nerivio device treatment<br>Treatment with active Nerivio device | Device: Nerivio<br>* A remote electrical neuromodulation (REN) device for the acute treatment of migraines.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.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain Relief at 2 Hours Post-treatment | The proportion 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 will be reported using a 4-point Likert scale (0 - No pain, 1 - Mild pain, 2 - Moderate pain, 3- Severe pain) | 2 hours post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain-free at 2 Hours Post-treatment | The proportion 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 none. Pain level will be reported using a 4-point Likert scale (0 - No pain, 1 - Mild pain, 2 - Moderate pain, 3- Severe pain) | 2 hours post-treatment | 
| Disappearance of Nausea at 2 Hours Post-treatment | The proportion of subjects presented nausea at the migraine onset and reported disappearance of nausea at 2 hours post-treatment of the test treatment | 2 hours post treatment | 
| Disappearance of Photophobia at 2 Hours Post-treatment | The proportion of subjects presented photohobia at the migraine onset and reported disappearance of photophobia at 2 hours post-treatment of the test treatment | 2 hours post treatment | 
| Disappearance of Phonophobia at 2 Hours Post-treatment | The proportion of subjects presented phonophobia at the migraine onset and reported disappearance of phonophobia at 2 hours post-treatment of the test treatment | 2 hours post treatment |