Non-invasive Vagus Nerve Stimulation for the Prevention of Migraines

The study is a prospective randomized, multi-center, double-blind, parallel, sham-controlled
study, designed for comparison of two parallel groups, gammaCore®-Sapphire (active treatment)
and a sham (inactive) treatment.

The study period will begin with a four-week run-in period, during which there is no
investigational treatment. The purpose of the run-in period will be to establish a baseline
of the subject's headache/migraine history for longitudinal comparison.

The run-in period will be followed by a 12-week randomized period when the subjects will be
randomized (1:1) to either active treatment or sham (inactive) treatment.

Subjects will dose themselves 3 times per day for 12 weeks.

Inclusion Criteria:

1. Between the ages of 18 and 75 years

2. Been previously diagnosed with migraine (with or without aura), in accordance with the
ICHD-3 criteria

3. Experiences between 8 to 20 headaches days per month (during the last 3 months), with
at least 2 of them being migraine days during which the migraines lasted more than 4
hours

4. Onset of migraine at age 50 years or younger

5. Agrees to refrain from initiating or changing the type, dosage, or frequency of any
prophylactic medications for indications other than migraine that, in the opinion of
the clinician may interfere with the study objectives (e.g., antidepressants,
anticonvulsants, beta-adrenergic blockers, etc.)

6. Agrees to use nVNS as intended, follow all of the requirements of the study including
Follow-up Visit requirements, and record required study data in the subject e-diary

7. Able to provide written informed consent

Exclusion Criteria:

1. Concomitant medical condition that will require oral or injectable steroids during the
study

2. Currently on a stable regime of more than 1 migraine preventative therapy

3. History of intracranial aneurysm, intracranial hemorrhage, brain tumor, or significant
head trauma

4. Structural abnormality at the nVNS treatment site (e.g., lymphadenopathy, previous
surgery, abnormal anatomy)

5. Pain at the nVNS treatment site (e.g., dysesthesia, neuralgia, cervicalgia)

6. Other significant pain problem (e.g., cancer pain, fibromyalgia, other head or facial
pain disorder) that, in the opinion of the Investigator, may confound the study
assessments

7. Known or suspected severe cardiac disease (e.g., symptomatic coronary artery disease,
prior myocardial infarction, congestive heart failure)

8. Known or suspected cerebrovascular disease (e.g., prior stroke or transient ischemic
attack, symptomatic carotid artery disease, prior carotid endarterectomy or other
vascular neck surgery) or an abnormal baseline electrocardiogram (ECG) within the last
year (e.g., second or third-degree heart block, prolonged QT interval, atrial
fibrillation, atrial flutter, history of ventricular tachycardia or ventricular
fibrillation, clinically significant premature ventricular contraction)

9. Previous cervical vagotomy

10. Uncontrolled high blood pressure (systolic >160 mm HG, diastolic >100 mm Hg) after 3
measurements within 24 hours

11. Currently implanted with an electrical and/or neurostimulator device (e.g., cardiac
pacemaker or defibrillator, vagal neurostimulator, deep brain stimulator, spinal
stimulator, bone growth stimulator, cochlear implant, sphenopalatine ganglion
stimulator, occipital nerve stimulator)

12. Been implanted with metal cervical spine hardware or has a metallic implant near the
nVNS stimulation site

13. Known history or suspicion of secondary headache

14. History of syncope (within the last 2 years)

15. History of seizure (within the last 2 years)

16. Known history or suspicion of substance abuse or addiction (within the last 5 years)

17. Currently using marijuana (including medical marijuana) or has used marijuana
(including medical marijuana) or cannabidiol oil within the last 1 year

18. Currently takes simple analgesics or NSAIDs >15 days per month or triptans, ergots, or
combined analgesics >10 days per month for headaches or other body pain

19. Currently takes prescription opioids more than 2 days per month for headaches or body
pain

20. Previous diagnosis of medication overuse headache, which has reverted to migraine
within the last 3 months

21. Failed an adequate trial (2 months or greater), or based on the decision of the
clinician, of at least 3 classes of a drug therapy for migraine prevention

22. Surgery for migraine prevention

23. Undergone nerve block (occipital or other) in the head or neck within the last 3
months

24. Received Botox or CGRP mAb injections within the last 6 months

25. Pregnant or thinking of becoming pregnant during the study period, or of childbearing
years and unwilling to use an accepted form of birth control

26. Participating in any other therapeutic clinical investigation or has participated in a
clinical trial in the preceding 30 days

27. Belongs to a vulnerable population or has any condition such that his or her ability
to provide informed consent, comply with the follow-up requirements, or provide self-
assessments is compromised (e.g., homeless, developmentally disabled, prisoner)

28. A relative of or an employee of the Investigator or the clinical study site

29. Psychiatric or cognitive disorder and/or behavioral problems that, in the opinion of
the clinician, may interfere with the study

30. Previously used gammaCore