Evaluation of a Novel Device for Treatment of Migraine Headache

A Randomized, Double Blinded, Sham Controlled Clinical Study to Evaluate the Safety and Efficacy of the Nerivio Migra 1, a Neuromodulation Device, for the Acute 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. Recent evidence suggests that electro stimulation is effective in providing relief for chronic headaches including migraine. It is tolerable by patients and associated with no adverse effects. The device utilizes electro stimulation to achieve conditioned pain modulation (CPM). CPM an stimulate endogenous analgesic mechanism. The modulatory effect is over the whole body, and can be induced anywhere. This is a prospective, randomized, double-blind, sham controlled multi-center trial. Ratio between treatment and control groups will be 1:1, stratified by center and use of preventive medications. The study objectives is to demonstrate the safety and effectiveness of the Nerivio Migra electro stimulation device for the reduction of migraine headache during an attack of migraine with or without aura. The study is intended for subject with 2-8 migraine episodes per month. patients will receive the device, either an active or a placebo type, and will be asked to use the device at home or in any location that they will be when the migraine starts. The study hypothesis is that electro stimulation delivered transcutaneously to the peripheral nervous system at onset of a migraine attack significantly reduce headache pain demonstrated by a significant difference between proportions of responders to the active treatment stimulation in comparison to proportion of responders that will use a placebo device.

Nerivio Migra is intended for the acute treatment of migraine with or without aura in patients 18 years of age or older. It is self-applied to the upper arm. Treatments are self-administered by the user at the onset of a migraine attack. The device delivers extra cephalic transcutaneous electrical stimulation below the pain threshold to the skin of the upper arm at the onset of a migraine attack. Nerivio Migra is operated via a mobile application. This is a prospective, randomized, double-blind, sham controlled multi-center clinical trial to test the ability of the Nerivio Migra neuromodulation device to relieve the patient's migraine pain during a migraine attack. The study will enroll up to 270 patients diagnosed with migraine with or without aura, per the inclusion and exclusion criteria. These patients will be individually and randomly assigned to either treatment group or control group. For sham control, electrical pulses of similar width and intensity, but much lower frequency compared to the active device will be administered. This sham program produces pulses that are perceivable by the user, thus maintaining the blinding, but on the other hand do not have therapeutic qualities, based on existing knowledge of parameters range of electro stimulation treatments. st visit - screening, enrollment and training on the application in diary mode Following successful screening, enrollment interview and signing of informed consent, participants will be provided with the Nerivio Migra application (either installed on their own smartphone, or on a smartphone provided by the study coordinator). The participants will be trained how to operate the application and report their migraine attacks in the patient diary mode, which is part of the application. The site personnel will be required to approve the training session in the CRF. Stage 1 - Roll in phase The Roll-in is a period of 15 - 30 days in which at least two (2) and no more of eight (8) migraine attacks has been occurred. During this period, baseline information including mean frequency and severity of migraine attacks, occurrence of other headaches, presence of ICHD-3 diagnostic criteria for migraine with or without aura and use of preventive and rescue medications will be recorded. nd visit Following the Roll-in phase, the participants will arrive to the clinic and their compliance to the study procedures and eligibility to continue to the next phase will assessed. Participants that will be eligible to continue to the treatment phase will undergo the following: Participant will be randomized into one of the two study group (Active or Sham device) Investigational devices will be programmed in active or sham mode with a 1:1 ratio, in order to achieve the desired ratio between active and control groups sizes, stratified with by use of preventive medications. Participant will be trained on the device, the application (in diary and treatment modes), the treatment procedures and the key elements critical for the success of the study: Apply the Nerivio Migra as soon as possible following the onset of the migraine symptoms and NO LATER than 60 min from onset Refrain from taking any rescue medication 2 hours following the start of treatment. Perform the treatment for a period of at least 30 minutes (recommended treatment time is 45 minutes). Stage 2 - Parallel arms, double- blind treatment phase. Participants will be instructed to activate the device at onset of a qualifying migraine attack and manually adjust stimulation intensity to a level within the pre-defined range, where it is well perceived but not painful. A qualifying migraine attack shall be preceded by at least 48 hours of freedom from migraine. Patients will be requested to refrain from use of rescue medications prior to and during the first two hours after treatment with the device, and if they cannot comply with this, record their use of rescue medications (migraine specific drugs or other medications or therapies that may be used to treat pain, from a pre-specified list) in the mobile application. Via the smartphone application, each participant will be asked to rate his/her migraine pain level three times using Pain Grades Scale (0 - no pain, 1- mild pain, 2- moderate pain, 3 - severe pain): (1) upon starting the treatment, (2) two hours after start of treatment, (3) 48 hours after start of attack. At the start of each treatment, participants will be also asked to provide time elapsed from start of migraine symptoms to start of the treatment. Participants will be also asked to provide feedback regarding their use of medication (migraine specific drugs or other medications or therapies that may be used to treat pain, from a pre-specified list), presence of nausea, photophobia, phonophobia or allodynia, and treatment perception. After providing feedback at two hours after start of treatment and in case of pain recurrence, participants will be allowed to re-treat the attack using Nerivio Migra device. Adverse events will be reported. Stage 3 (optional, by subject request only) - Open label extended treatment: Following the completion of double-blind stage of the study, all subjects will be offered a 2-month open label period using the active device.

For sham control, electrical pulses of similar width and intensity, but much lower frequency compared to the active device will be administered. This sham program produces pulses that are perceivable by the user, thus maintaining the blinding, but on the other hand do not have therapeutic qualities. The devices will be delivered with an identifying number, without exposing to the investigator or participant if it is an active or a pacebo/sham device

The device is placed on the subject upper arm. when activated, stimulus is applied to influence the subject's perception of a painful stimulus, delivered (or originating) at a different location. Based on diffused noxious inhibitory control mechanism, sometimes referred to as "pain inhibits pain" principle, conditioned pain modulation evokes an endogenous analgesic mechanism. The modulatory effect is over the whole body, and can be induced anywhere in the body. This approach allows applying the conditioning stimuli away from the painful site.

The device is placed on the subject upper arm. when activated, the stimulus is applied is not sufficient to influence the subject's perception of a painful stimulus.

The percentage of patients reporting reduction in their pain level 2 hours post-treatment without rescue medications from severe or moderate to mild or no pain, or from mild to no pain, in their first treated migraine attack (excluding the "run-in test" treatment).

Percentage of Participants With Reduction of Most Bothersome Migraine-associated Symptom (MBS) Relief at 2 Hours Post Treatment

The percentage of patients reporting, 2 hours post-treatment, freedom from their most bothersome migraine-associated symptom (MBS) other than a headache, in their first treated migraine attack (excluding the "run-in test" treatment). MBS may be nausea, photophobia, phonophobia or allodynia - as defined by each subject at the beginning of the treatment

The percentage of patients reporting, 2 hours post treatment response to both the primary and the first secondary endpoints

The percentage of subjects reporting freedom from migraine pain at 2 hours post-treatment without medications in their first treated migraine attack

The number of Adverse events related to the study device. Safety analyses were performed on all participants from the ITT population (126 participants in each group).

Within-patient Consistency - Percentage of Participants With Reduction in Headache Pain in at Least 50% of Their Treatments

The repeatability of migraine headache reduction, as described in the primary endpoint definition, in subsequent treated attacks. Thus, this endpoint measures the % of patient responding to the primary endpoint in at least 50% of their treated attacks (excluding the run-in attack

The proportion (%) of subjects reporting pain-free at 2 hours, and no return of any pain or use of rescue/acute medication, or reuse of device between 2 hours and 48 hours, in their first treated migraine attack

Percentage of Participants With Sustained Headache Reduction for 48 Hours With Single Use of the Device

The proportion (%) of subjects reporting treatment response 2 hours post-treatment without rescue medications, and no return to baseline level of pain at time of treatment, or use of rescue/acute medication, or reuse of device between 2 hours and 48 hours, in their first treated migraine attack

Inclusion Criteria: Subjects age 18-75 years old. Subjects meet the ICHD-3 diagnostic criteria for migraine with or without aura Subjects report 2-8 migraine attacks per month. Stable migraine preventive medications in the last two months prior to recruitment (No change in usage or dosage). Subjects must be able and willing to comply with the protocol Subjects must be able and willing to provide written informed consent Exclusion Criteria: Subject has other significant pain, medical or psychologic problems that in the opinion of the investigator may confound the study assessments Subject has an implanted electrical and/or neurostimulator device (e.g. cardiac pacemaker or defibrillator, vagus nerve neurostimulator, deep brain stimulator, spinal stimulator, bone growth stimulator cochlear implant, Sphenopalatine ganglion stimulator or Occipital nerve stimulator). Subject has known uncontrolled epilepsy. Any use of Cannabis including medical use. Subject has >10 headache days per month. Subject has undergone nerve block (occipital or other) in the head or neck within the last 2 weeks. Subject is participating in any other clinical study. The subject does not have the basic cognitive and motor skills needed to operate a smartphone. Pregnant, or trying to get pregnant Subject is experiencing a menstrually related migraine Received OnabotulinumtoxinA or any botulinum toxin injections for migraine within the previous month Received parenteral infusions for migraine within the previous 2 weeks. Subject participated in a previous study with the Nerivio Migra 1 device

Rapoport AM, Bonner JH, Lin T, Harris D, Gruper Y, Ironi A, Cowan RP. Remote electrical neuromodulation (REN) in the acute treatment of migraine: a comparison with usual care and acute migraine medications. J Headache Pain. 2019 Jul 22;20(1):83. doi: 10.1186/s10194-019-1033-9.

Yarnitsky D, Dodick DW, Grosberg BM, Burstein R, Ironi A, Harris D, Lin T, Silberstein SD. Remote Electrical Neuromodulation (REN) Relieves Acute Migraine: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial. Headache. 2019 Sep;59(8):1240-1252. doi: 10.1111/head.13551. Epub 2019 May 9.