Evaluation of a Novel Device for Treatment of Migraine Headache
Evaluation of a Novel Device for Treatment of Migraine Headache
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.

 1. 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.

 2. 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:

 1. 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.

 2. 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.
Inclusion Criteria:

 1. Subjects age 18-75 years old.

 2. Subjects meet the ICHD-3 diagnostic criteria for migraine with or without aura

 3. Subjects report 2-8 migraine attacks per month.

 4. Stable migraine preventive medications in the last two months prior to recruitment (No
 change in usage or dosage).

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

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

 Exclusion Criteria:

 1. Subject has other significant pain, medical or psychologic problems that in the
 opinion of the investigator may confound the study assessments

 2. 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).

 3. Subject has known uncontrolled epilepsy.

 4. Any use of Cannabis including medical use.

 5. Subject has >10 headache days per month.

 6. Subject has undergone nerve block (occipital or other) in the head or neck within the
 last 2 weeks.

 7. Subject is participating in any other clinical study.

 8. The subject does not have the basic cognitive and motor skills needed to operate a
 smartphone.

 9. Pregnant, or trying to get pregnant

 10. Subject is experiencing a menstrually related migraine

 11. Received OnabotulinumtoxinA or any botulinum toxin injections for migraine within the
 previous month

 12. Received parenteral infusions for migraine within the previous 2 weeks.

 13. Subject participated in a previous study with the Nerivio Migra 1 device