Non-invasive Vagus Nerve Stimulation for the Prevention of Migraines

A Randomized, Multicenter, Double-blind, Parallel, Sham-controlled Study of Non-invasive Vagus Nerve Stimulation for the Prevention of Migraines. (Premium II)

The purpose of the study is to investigate if the use of gammaCore Sapphire™ device reduces the number of migraines preventatively.

Study Overview

• Status: Completed
• Conditions: Migraine Disorders
• Intervention / Treatment: Device: gammaCore Sapphire active; Device: gammaCore Sapphire Sham

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 231
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic
  • California
    • Carlsbad, California, United States, 92011
      • The Research Center of Southern California
    • Palo Alto, California, United States, 94304
      • Stanford University Medical Center Hoover Pavilion
    • San Francisco, California, United States, 94115
      • UCSF Headache Center
    • Santa Monica, California, United States, 90404
      • California Medical Clinic for Headache
  • Colorado
    • Englewood, Colorado, United States, 80113
      • Summit Headache and Neurologic Institute, PC
  • Connecticut
    • Stamford, Connecticut, United States, 06905
      • New England Institute for Neurology and Headache
    • West Hartford, Connecticut, United States, 06107
      • Hartford HealthCare Headache Center
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami, Miller School of Medicine
  • Illinois
    • Chicago, Illinois, United States, 60642
      • Diamond Headache Clinic
    • Glenview, Illinois, United States, 60026
      • NorthShore Ambulatory Care Center
  • Kentucky
    • Louisville, Kentucky, United States, 40207
      • Norton Neurology
  • Louisiana
    • Chalmette, Louisiana, United States, 70043
      • Crescent City Headache and Neurology Center
    • Covington, Louisiana, United States, 70433
      • Ochsner North Shore Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215-5400
      • Beth Israel Deaconess Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48104
      • Michigan Head Pain & Neurological Institute (MHNI)
  • Mississippi
    • Ridgeland, Mississippi, United States, 39157
      • Headache Neurology Research Institute
  • Missouri
    • Saint Peters, Missouri, United States, 63303
      • StudyMetrix, LLC
    • Springfield, Missouri, United States, 65810
      • Clinvest Research
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03766
      • Dartmouth-Hitchcock Medical Center
  • New York
    • Amherst, New York, United States, 14226
      • Dent Neurologic Institute
    • Bronx, New York, United States, 10461
      • Montefiore Headache Center
    • New York, New York, United States, 10003
      • NY Neurology Associates
    • Plainview, New York, United States, 11803
      • Island Neurological Associates
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospitals of Cleveland
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
    • Waxahachie, Texas, United States, 75165
      • ClinPoint Trials LLC
  • Virginia
    • McLean, Virginia, United States, 22101
      • MedStar Georgetown University Hospital
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • West Virginia University Hospitals - Department of Neurology

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

Key Inclusion Criteria:

• Between the ages of 18 and 75 years
• Been previously diagnosed with migraine (with or without aura), in accordance with the ICHD-3 criteria
• Experiences between 8 to 20 headaches days per month (during the last 3 months), with at least 5 of them being migraine days
• Onset of migraine at age 50 years or younger
• Agrees to refrain from initiating or changing any prophylactic medications for indications other than migraine

Key Exclusion Criteria:

• Concomitant medical condition that will require oral or injectable steroids during the study
• Currently on a stable regime of more than 1 migraine preventative therapy
• Other significant pain problem (e.g., cancer pain, fibromyalgia, other head or facial pain disorder)
• Known or suspected severe cardiac disease (e.g., symptomatic coronary artery disease, prior myocardial infarction, congestive heart failure)
• Known or suspected cerebrovascular disease
• Previous cervical vagotomy
• Currently implanted with an electrical and/or neurostimulator device
• Been implanted with metal cervical spine hardware or has a metallic implant near the nVNS stimulation site
• Known history or suspicion of secondary headache
• Currently using marijuana (including medical marijuana) or has used marijuana (including medical marijuana) or cannabidiol oil within the last 6 months
• 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
• Currently takes prescription opioids more than 2 days per month for headaches or body pain
• Failed an adequate trial (2 months or greater) of at least 3 classes of a drug therapy for migraine prevention
• Surgery for migraine prevention
• Undergone nerve block (occipital or other) in the head or neck within the last 3 months
• Received Botox or CGRP mAb injections within the last 6 months
• Pregnant or thinking of becoming pregnant during the study period, or of childbearing years and unwilling to use an accepted form of birth control
• Previously used gammaCore

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: gammaCore Sapphire active; Treatment 3 times per day, every day for the 12-week treatment period Each of the 3 daily treatments comprises 2 consecutive 120-second stimulations on 1 side, ipsilateral (2 stimulations) to the side of predominate pain, upon waking, lunch time (i.e., between 11:00 AM and 2:00 PM), and prior to sleep, for a total of 6 stimulations per day	Device: gammaCore Sapphire active; GammaCore Sapphire™ is a handheld, non-invasive, low voltage electrical device which stimulates the vagus nerve by producing weak 120 second electrical stimulation cycles that may help reduce, ease, lessen or stop your migraine symptoms. GammaCore Sapphire™ has been approved for the treatment of headache, including migraine by the United States Food and Drug Administration (FDA).
Sham Comparator: gammaCore Sapphire Sham; Treatment 3 times per day, every day for the 12-week treatment period Each of the 3 daily treatments comprises 2 consecutive 120-second stimulations on 1 side, ipsilateral (2 stimulations) to the side of predominate pain, upon waking, lunch time (i.e., between 11:00 AM and 2:00 PM), and prior to sleep, for a total of 6 stimulations per day	Device: gammaCore Sapphire Sham; The sham device is a hand-held portable device that appears identical to gammaCore Sapphire, in look, weight, visual and audible feedback, user application, and control. Like gammaCore Sapphire, the sham device is a multi-use device.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and effectiveness of gammaCore Sapphire as a treatment for the prevention of a migraine during the double-blind period measured by Incidence of Unexpected Adverse Events.	The primary outcome measurement for effectiveness is the difference between the active and sham treatment groups in the mean reduction in number of migraine days during the last 4 weeks of the 12-week double-blind period (versus during the 4-week run-in period).	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Responder rate in the nVNS group compared to the sham group	A subject who reports at least a 50% decrease in the number of migraine days during the last 4 weeks in the 12-week double-blind period	Last 4 weeks of the 12 week double-blind
Mean reduction in the number of headache days	Difference between the nVNS and sham treatment groups in mean reduction in the number of headache days during the last 4 weeks of the 12-week double-blind period	Last 4 weeks of the 12 week double-blind
Mean reduction in days on which acute migraine medication	Difference between the nVNS and sham treatment groups in the mean reduction in days on which acute migraine medication was taken during the last 4 weeks of the 12 week double-blind period	Last 4 weeks of the 12 week double-blind

Collaborators and Investigators

• Sponsor: ElectroCore INC
• Investigators: Study Director: Peter Staats, MD, Chief Medical Officer

Publications and helpful links

General Publications

• Najib U, Smith T, Hindiyeh N, Saper J, Nye B, Ashina S, McClure CK, Marmura MJ, Chase S, Liebler E, Lipton RB. Non-invasive vagus nerve stimulation for prevention of migraine: The multicenter, randomized, double-blind, sham-controlled PREMIUM II trial. Cephalalgia. 2022 Jun;42(7):560-569. doi: 10.1177/03331024211068813. Epub 2022 Jan 9.

Study record dates

Study Major Dates

• Study Start (Actual): November 2, 2018
• Primary Completion (Actual): September 9, 2020
• Study Completion (Actual): September 9, 2020

Study Registration Dates

• First Submitted: October 10, 2018
• First Submitted That Met QC Criteria: October 19, 2018
• First Posted (Actual): October 23, 2018

Study Record Updates

• Last Update Posted (Actual): September 11, 2020
• Last Update Submitted That Met QC Criteria: September 10, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: Prevention; Chronic; Episodic
• 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-US-10

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: Yes