RCT of Non-Invasive Vagus Nerve Stimulation (nVNS) With gammaCore®, for the Acute Treatment of Migraine Attacks

Study Overview
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Brief Summary
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This study is a prospective, multi-centre, randomised, double-blind, sham-controlled investigation designed for comparison of two parallel treatment groups: gammaCore (active nVNS treatment) and a Sham device (control treatment), for the acute treatment of migraine attacks

Detailed Description
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Period 1: 4-week observational run-in period; no stimulation treatment. Subjects use standard of care (SoC) medication to treat their migraine attacks, according to their individual prescriptions. Period 2: 4-week randomized/controlled period. After the run-in period, subjects are randomized (1:1) to receive either an nVNS device or a sham device to treat up to 5 migraine attacks. Period 3: 4-week open-label (active treatment) period. After the randomized period, subjects continue to the open-label period where all subjects receive an active gammaCore device to treat up to 5 migraine attacks.

Official Title
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A Prospective, Multi-centre, Randomized, Double-blind, Sham-controlled Study of gammaCore® Non-invasive Vagus Nerve Stimulator (nVNS), for the Acute Treatment of Migraine

Conditions
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Migraine

Intervention / Treatment
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* Device: gammaCore-S
* Device: gammaCore-S Sham


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Is 18-75 years old. Has been previously diagnosed with migraine (with or without aura) in accordance with the ICHD-3 Beta classification criteria. Age of onset of migraines < 50 years old. Experiences between 3-8 migraine attacks per month of moderate or severe intensity, and less than 15 headache days per month over the last 6 months. Is able to distinguish migraine headaches from other headaches (e.g. tension type headache). Agrees to withhold usual acute migraine medications until 2 hours after stimulation treatment with the study device. Agrees not to initiate new or change existing migraine prophylaxis medication for the duration of the study, or receive nerve blocks or injections. Agrees not to initiate new or change existing prophylactic medication for indications other than migraine that in the opinion of the Investigator may interfere with the study objectives (e.g. antidepressant, anti-convulsant, beta blockers, etc). Has internet/web access for web-based e-Diary completion. Agrees to use the study device as intended, comply with all study requirements including treatment, follow-up visits, record required study data in the subject diary, and complete study self-assessment questionnaires. Is able to provide written informed consent. Exclusion Criteria: Experiences ≥ 15 headache days per month, including migraine, tension type headache, medication overuse headache, and other types of headache as defined in the ICHD-3 Beta classification. Has a known history or suspicion of secondary headache. Has previous diagnosis of medication overuse headache (MoH), which has reverted to episodic migraine within the last 6 months. Has had surgical intervention for migraine prevention. Has had a cervical vagotomy. Has a structural abnormality (e.g. lymphadenopathy, neoplasm, previous surgery or abnormal anatomy), or pain (e.g. dysesthesia, neuralgia and/or cervicalgia) at the stimulation treatment site. Has other significant pain problem (e.g. cancer pain, fibromyalgia or other head or facial disorder) that in the opinion of the Investigator may confound the study assessments. Is 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, or occipital nerve stimulator). Has been implanted with metal cervical spine hardware or has a metallic implant near the stimulation treatment site. Has failed an adequate trial (two months or greater) of at least 3 classes of a drug therapy for acute treatment of migraine. Has initiated new, or changed existing medications for migraine prophylaxis in the previous 2 months. Is using marijuana (including medical marijuana) for any indications, more than twice a month. Currently takes simple analgesics or non-steroidal anti-inflammatory drugs (NSAIDS) greater than 15 days per month, or triptans, ergots or combined analgesics greater than 10 days per month. Currently takes opioids greater than 2 days per month for headache relief or body pain. Has undergone nerve block (occipital or other) in the head or neck within the last 2 months, or Botox injections within the last 6 months. Has a concomitant medical condition that will require oral or injectable steroids during the study. Has a history of intracranial aneurysm, intracranial haemorrhage, brain tumour or significant head trauma. Has known or suspected severe cardiac disease (e.g. symptomatic coronary artery disease, prior myocardial infarction, congestive heart failure(CHF), cerebrovascular disease (e.g. prior stroke or transient ischemic attack symptomatic carotid artery disease, prior carotid endarterectomy or other vascular neck surgery), or uncontrolled high blood pressure (systolic >160, diastolic >100 after 3 repeated measurements within 24 hours). Has a history of syncope or seizure (within the last 5 years). Has a known history or suspicion of substance abuse or addiction (within the last 5 years). Has psychiatric or cognitive disorder and/or behavioural problems which in the opinion of the clinician may interfere with the study. 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). Is pregnant or thinking of becoming pregnant during the study period, or of childbearing years and is unwilling to use an accepted form of birth control. Is a relative or employee of the Investigator or the clinical study site. Is participating in any other therapeutic clinical investigation or has participated in a clinical trial in the preceding 30 days. Has previously used the gammaCore device.

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: gammaCore-S<br>Treatment of up to 5 migraine attacks with the Active gammaCore-S non-invasive vagus nerve stimulator device which delivers a mild electrical signal in the vicinity of the vagus nerve | Device: gammaCore-S<br>* At onset of migraine pain, the subject self-administers a bilateral treatment with the gammaCore nVNS device (2 minutes on the right side, and 2 minutes on the left side). If their headache pain has not improved after 15 minutes, they administer another bilateral treatment. If they are not pain-free at 2 hours, they have the option to administer a third bilateral treatment, or take their usual rescue medication.<br>* Other names: nVNS;|
| Sham Comparator: gammaCore-S Sham<br>Treatment of up to 5 migraine attacks with the Sham gammaCore-S non-invasive vagus nerve stimulator device which delivers a mild electrical signal in the vicinity of the vagus nerve | Device: gammaCore-S Sham<br>* At onset of migraine pain, the subject self-administers a bilateral treatment with the gammaCore nVNS Sham device (2 minutes on the right side, and 2 minutes on the left side). If their headache pain has not improved after 15 minutes, they administer another bilateral treatment with the Sham device. If they are not pain-free at 2 hours, they have the option to administer a third bilateral treatment with the Sham device, or take their usual rescue medication.<br>* Other names: sham nVNS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment Response - No Pain | The primary objective is to compare the treatment response for nVNS and Sham therapies at two hours post-treatment, for the first treated migraine attack during study Period 2. Treatment response is defined as no pain at 2 hours post-treatment and no rescue medication use by 2 hours post-treatment. | 2 hours post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Absence of Nausea/Vomiting, Photophobia, Phonophobia | Presence or absence of nausea/vomiting, photophobia and phonophobia for nVNS and sham therapies for the first treated migraine attack at 120 minutes during study Period 2. | 2 hours post-treatment study - period 2 (each study period was 4 weeks) | 
| Number of Participants With Treatment Response - No Pain or Mild Pain | Response to treatment was assessed by the subjects using the 4 point headache scale, where 0 = No pain, 1 = Mild pain, 2 = Moderate pain and 3 = severe pain. Results show count of participants with a response of no pain (score = 0) or mild pain (score = 1) on the 4-point headache pain scale for the nVNS and sham therapies at 2 hours post-treatment and no rescue medication use by 2 hours post-treatment for the first treated migraine attack during study Period 2. | 2 hours post-treatment | 
| Number of Participants With Treatment Response no Pain or Mild Pain at 24 and 48 Hours. | Response to treatment was assessed by the subjects using the 4 point headache scale, where 0 = No pain, 1 = Mild pain, 2 = Moderate pain and 3 = severe pain. Results show count of participants with a response of no pain or mild pain on the 4-point headache pain scale at 24, and 48 hours post-treatment (and no rescue medication use) for nVNS and sham therapies for the first treated migraine attack during study Period 2. | 24 and 48 hours post-treatment | 
| Number of Migraine Attacks With Treatment Response 'No Pain' in Study Period 2 All Attacks | Response to treatment was assessed by the subjects using the 4 point headache scale, where 0 = No pain, 1 = Mild pain, 2 = Moderate pain and 3 = severe pain. Results show % Treatment response 'No pain' for the nVNS and sham therapies at 30, 60 and 120 minutes calculated for all treated attacks during study Period 2. | 30, 60, 120 minutes; Study Period 2 (each study period was 4 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Migraine, Non-invasive vagus nerve stimulation, Vagus nerve stimulation, Vagal nerve stimulation, gammaCore, episodic migraine