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

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

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

Study Overview

• Status: Completed
• Conditions: Migraine
• Intervention / Treatment: Device: gammaCore-S; Device: gammaCore-S Sham

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 285
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Italy
  • Bari, Italy
    • University Aldo Moro, Ospedale Pediatrico
  • Bologna, Italy
    • IRCCS Istituto delle Scienze Neurologiche di Bologna, Ospedale Bellaria
  • Florence, Italy
    • University Hospital of Careggi
  • Milan, Italy
    • Fondazione IRCCS Istituto Neurologico C. Besta
  • Pavia, Italy
    • IRCSS "National Neurological Institute C. Mondino" Foundation
  • Perugia, Italy
    • S. Maria della Misericordia Hospital
  • Pozzilli, Italy
    • INM Neuromed IRCCS
  • Rome, Italy
    • IRCCS San Raffaele Pisana
  • Rome, Italy
    • Sant'Andrea Hospital, Sapienza University of Rome
  • Turin, Italy
    • University of Turin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Is 18-75 years old.
2. Has been previously diagnosed with migraine (with or without aura) in accordance with the ICHD-3 Beta classification criteria.
3. Age of onset of migraines < 50 years old.
4. 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.
5. Is able to distinguish migraine headaches from other headaches (e.g. tension type headache).
6. Agrees to withhold usual acute migraine medications until 2 hours after stimulation treatment with the study device.
7. Agrees not to initiate new or change existing migraine prophylaxis medication for the duration of the study, or receive nerve blocks or injections.
8. 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).
9. Has internet/web access for web-based e-Diary completion.
10. 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.
11. Is able to provide written informed consent.

Exclusion Criteria:

1. 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.
2. Has a known history or suspicion of secondary headache.
3. Has previous diagnosis of medication overuse headache (MoH), which has reverted to episodic migraine within the last 6 months.
4. Has had surgical intervention for migraine prevention.
5. Has had a cervical vagotomy.
6. 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.
7. 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.
8. 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).
9. Has been implanted with metal cervical spine hardware or has a metallic implant near the stimulation treatment site.
10. Has failed an adequate trial (two months or greater) of at least 3 classes of a drug therapy for acute treatment of migraine.
11. Has initiated new, or changed existing medications for migraine prophylaxis in the previous 2 months.
12. Is using marijuana (including medical marijuana) for any indications, more than twice a month.
13. 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.
14. Currently takes opioids greater than 2 days per month for headache relief or body pain.
15. 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.
16. Has a concomitant medical condition that will require oral or injectable steroids during the study.
17. Has a history of intracranial aneurysm, intracranial haemorrhage, brain tumour or significant head trauma.
18. 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).
19. Has a history of syncope or seizure (within the last 5 years).
20. Has a known history or suspicion of substance abuse or addiction (within the last 5 years).
21. Has psychiatric or cognitive disorder and/or behavioural problems which in the opinion of the clinician may interfere with the study.
22. 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).
23. 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.
24. Is a relative or employee of the Investigator or the clinical study site.
25. Is participating in any other therapeutic clinical investigation or has participated in a clinical trial in the preceding 30 days.
26. Has previously used the gammaCore device.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: gammaCore-S; 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; 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.; Other Names: nVNS
Sham Comparator: gammaCore-S Sham; 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; 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.; Other Names: sham nVNS

What is the study measuring?

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)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Migraine Attacks With Treatment Response 'No Pain' in Study Period 3	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. Number of migraine attacks with treatment response 'no pain' for the nVNS and sham therapies at 30, 60 and 120 minutes calculated for all treated attacks during study Period 3.	30, 60, 120 minutes; Period 3 (each study period was 4 weeks)
Number of Migraine Attacks 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. Number of migraine attacks with treatment response 'no pain' or 'mild pain' on the 4-point headache pain scale for the nVNS and sham therapies at 30, 60 and 120 minutes calculated for all treated attacks during study Periods 2 and 3 (separately)	30, 60, 120 minutes; Study Periods 2 and 3 (each study period was 4 weeks)
Number of Migraine Attacks With Absence of Nausea, Vomiting, Photophobia and Phonophobia	Number of Attacks with Absence of Nausea, Vomiting, Photophobia and Phonophobia at 120 minutes for nVNS and sham therapies calculated for all treated attacks during study Periods 2 and 3 (separately).	Study Periods 2 and 3 (each study period was 4 weeks)
Number of Attacks With Sustained Treatment Response	Number of migraine attacks with sustained treatment response (mild or no pain at 24 and 48 hours post-treatment) for nVNS and sham therapies calculated for all treated attacks during study Periods 2 and 3 (separately).	24 and 48 hours; Study Periods 2 and 3 (each study period was 4 weeks)
Number of Subjects With Consistency of Response	Consistency of response, defined as the number of subjects who achieve no pain or mild pain in 50% or greater of their attacks, in subjects treating at least two attacks, for nVNS and sham therapies for all treated attacks during study Periods 2 and 3 (separately).	Study Periods 2 and 3 (each study period was 4 weeks)
Quality of Life Measured by EuroQol-5D-5L (EQ-5D-5L)	Treatment effect on quality of life: EQ-5D-5L is assessed at end of the run-in period and at the end of each 4-week period for nVNS and sham therapies. EQ-5D-5L descriptive system comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: 1 = no problems, 2 = slight problems, 3= moderate problems, 4 = severe problems and 5 = extreme problems. Subjects indicate health state by ticking choosing appropriate statement in each dimension. The 5 dimensions scores are combined into a score, where a lower score indicates less problems. Scores across all 5 dimensions are averaged resulting in a total theoretical score of 1 to 5 with lower scores indicating less problems	End of each study period (each study period was 4 weeks)
Bang Blinding Index Scores	After the first treated attack and at the end of the double blind period (period 2) subjects were asked to guess if they were had received 'gammaCore-S', ''sham' or 'do not know'. Bang blinding index estimated are presented for the gammaCore-S and sham. Bang Blinding Index shows the success of blinding. The blinding index proposed is scaled to an interval of -1 to 1, 1 being complete lack of blinding, 0 being consistent with perfect blinding and -1 indicating opposite guessing which may be related to unblinding. A score of one means they guess correctly, -1 incorrectly. If the bang index includes 0 it indicates that the guesses were consistent for the sham and active and the study was appropriately blinded	Study Period 2 (4 weeks)
Subject Satisfaction	Subject satisfaction with the study devices Subjects were asked to rate their satisfaction with the device from the following options: Extremely satisfied, Very satisfied, Satisfied, A little satisfied or Not at all satisfied	End of Study Periods 2 and 3 (each study period was 4 weeks long)
Mean Change in Pain Score From Baseline to 120 Minutes	Subjects rated pain at onset of migraine attack (baseline) and at 120 minutes using a 4 point headache pain scale where 0 = no pain, 1 = mild pain, 3 = moderate pain and 4 = severe pain. A lower score indicates less pain. Mean change in pain score from baseline to 120 minutes for all attacks in study period 2	120 minutes, Study Period 2 (each study period was 4 weeks long)
Ease of Use	Ease of use of the study devices - Subjects were asked to rate the ease of use of the device from the following options: Very easy, somewhat easy, difficult, very difficult.	End of Study Periods 2 and 3 (each study period was 4 weeks long)
Quality of Life Measured by Headache Impact Test (HIT-6)	The HIT-6 measures impact of headaches on ability to function at work, at home and in social situations. Subjects answer 6 questions about ability to function and normal daily life and for each question they rate the impact of their headaches as 'never' (6 points) or 'rarely' (9 points) or 'sometimes' (10 points) or 'very often' (11 points) or 'always' (13 points). Minimum score = 36, maximum score = 78. Higher score is worse and lower score is better quality of life	End of each study period (each study period was 4 weeks)

Collaborators and Investigators

• Sponsor: ElectroCore INC
• Investigators: Study Chair: Cristina Tassorelli, MD, PhD, IRCSS "National Neurological Institute C. Mondino" Foundation

Publications and helpful links

General Publications

• Martelletti P, Barbanti P, Grazzi L, Pierangeli G, Rainero I, Geppetti P, Ambrosini A, Sarchielli P, Tassorelli C, Liebler E, de Tommaso M; PRESTO Study Group. Consistent effects of non-invasive vagus nerve stimulation (nVNS) for the acute treatment of migraine: additional findings from the randomized, sham-controlled, double-blind PRESTO trial. J Headache Pain. 2018 Nov 1;19(1):101. doi: 10.1186/s10194-018-0929-0. Erratum In: J Headache Pain. 2018 Dec 18;19(1):120.
• Grazzi L, Tassorelli C, de Tommaso M, Pierangeli G, Martelletti P, Rainero I, Geppetti P, Ambrosini A, Sarchielli P, Liebler E, Barbanti P; PRESTO Study Group. Practical and clinical utility of non-invasive vagus nerve stimulation (nVNS) for the acute treatment of migraine: a post hoc analysis of the randomized, sham-controlled, double-blind PRESTO trial. J Headache Pain. 2018 Oct 19;19(1):98. doi: 10.1186/s10194-018-0928-1. Erratum In: J Headache Pain. 2019 Jan 7;20(1):1.
• Tassorelli C, Grazzi L, de Tommaso M, Pierangeli G, Martelletti P, Rainero I, Dorlas S, Geppetti P, Ambrosini A, Sarchielli P, Liebler E, Barbanti P; PRESTO Study Group. Noninvasive vagus nerve stimulation as acute therapy for migraine: The randomized PRESTO study. Neurology. 2018 Jul 24;91(4):e364-e373. doi: 10.1212/WNL.0000000000005857. Epub 2018 Jun 15.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2016
• Primary Completion (Actual): December 1, 2016
• Study Completion (Actual): March 1, 2017

Study Registration Dates

• First Submitted: February 15, 2016
• First Submitted That Met QC Criteria: February 18, 2016
• First Posted (Estimate): February 19, 2016

Study Record Updates

• Last Update Posted (Actual): August 2, 2019
• Last Update Submitted That Met QC Criteria: June 11, 2019
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Keywords: Migraine; episodic migraine; Vagus nerve stimulation; Vagal nerve stimulation; Non-invasive vagus nerve stimulation; gammaCore
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Headache Disorders, Primary; Headache Disorders; Migraine Disorders
• Other Study ID Numbers: GM-16

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No