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

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ClinicalTrials.gov Identifier: NCT02686034
Recruitment Status : Completed
First Posted : February 19, 2016
Results First Posted : August 2, 2019
Last Update Posted : August 2, 2019
Sponsor:
Information provided by (Responsible Party):
ElectroCore INC

Brief Summary:
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

Condition or disease Intervention/treatment Phase
Migraine Device: gammaCore-S Device: gammaCore-S Sham Not Applicable

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 285 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Prospective, Multi-centre, Randomized, Double-blind, Sham-controlled Study of gammaCore® Non-invasive Vagus Nerve Stimulator (nVNS), for the Acute Treatment of Migraine
Actual Study Start Date : January 2016
Actual Primary Completion Date : December 2016
Actual Study Completion Date : March 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Migraine

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 Name: 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 Name: sham nVNS




Primary Outcome Measures :
  1. Number of Participants With Treatment Response - No Pain [ Time Frame: 2 hours post-treatment ]
    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.


Secondary Outcome Measures :
  1. Number of Participants With Absence of Nausea/Vomiting, Photophobia, Phonophobia [ Time Frame: 2 hours post-treatment study - period 2 (each study period was 4 weeks) ]
    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. Number of Participants With Treatment Response - No Pain or Mild Pain [ Time Frame: 2 hours post-treatment ]

    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.


  3. Number of Participants With Treatment Response no Pain or Mild Pain at 24 and 48 Hours. [ Time Frame: 24 and 48 hours post-treatment ]

    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.


  4. Number of Migraine Attacks With Treatment Response 'No Pain' in Study Period 2 All Attacks [ Time Frame: 30, 60, 120 minutes; Study Period 2 (each study period was 4 weeks) ]

    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.



Other Outcome Measures:
  1. Number of Migraine Attacks With Treatment Response 'No Pain' in Study Period 3 [ Time Frame: 30, 60, 120 minutes; Period 3 (each study period was 4 weeks) ]

    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.


  2. Number of Migraine Attacks With Treatment Response no Pain or Mild Pain [ Time Frame: 30, 60, 120 minutes; Study Periods 2 and 3 (each study period was 4 weeks) ]

    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)


  3. Number of Migraine Attacks With Absence of Nausea, Vomiting, Photophobia and Phonophobia [ Time Frame: Study Periods 2 and 3 (each study period was 4 weeks) ]
    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).

  4. Number of Attacks With Sustained Treatment Response [ Time Frame: 24 and 48 hours; Study Periods 2 and 3 (each study period was 4 weeks) ]
    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).

  5. Number of Subjects With Consistency of Response [ Time Frame: Study Periods 2 and 3 (each study period was 4 weeks) ]
    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).

  6. Quality of Life Measured by EuroQol-5D-5L (EQ-5D-5L) [ Time Frame: End of each study period (each study period was 4 weeks) ]

    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


  7. Bang Blinding Index Scores [ Time Frame: Study Period 2 (4 weeks) ]

    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


  8. Subject Satisfaction [ Time Frame: End of Study Periods 2 and 3 (each study period was 4 weeks long) ]
    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

  9. Mean Change in Pain Score From Baseline to 120 Minutes [ Time Frame: 120 minutes, Study Period 2 (each study period was 4 weeks long) ]
    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

  10. Ease of Use [ Time Frame: End of Study Periods 2 and 3 (each study period was 4 weeks long) ]
    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.

  11. Quality of Life Measured by Headache Impact Test (HIT-6) [ Time Frame: End of each study period (each study period was 4 weeks) ]

    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




Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02686034


Locations
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Italy
University Aldo Moro, Ospedale Pediatrico
Bari, Italy
IRCCS Istituto delle Scienze Neurologiche di Bologna, Ospedale Bellaria
Bologna, Italy
University Hospital of Careggi
Florence, Italy
Fondazione IRCCS Istituto Neurologico C. Besta
Milan, Italy
IRCSS "National Neurological Institute C. Mondino" Foundation
Pavia, Italy
S. Maria della Misericordia Hospital
Perugia, Italy
INM Neuromed IRCCS
Pozzilli, Italy
IRCCS San Raffaele Pisana
Rome, Italy
Sant'Andrea Hospital, Sapienza University of Rome
Rome, Italy
University of Turin
Turin, Italy
Sponsors and Collaborators
ElectroCore INC
Investigators
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Study Chair: Cristina Tassorelli, MD, PhD IRCSS "National Neurological Institute C. Mondino" Foundation

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: ElectroCore INC
ClinicalTrials.gov Identifier: NCT02686034     History of Changes
Other Study ID Numbers: GM-16
First Posted: February 19, 2016    Key Record Dates
Results First Posted: August 2, 2019
Last Update Posted: August 2, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by ElectroCore INC:
Migraine
Non-invasive vagus nerve stimulation
Vagus nerve stimulation
Vagal nerve stimulation
gammaCore
episodic migraine
Additional relevant MeSH terms:
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Migraine Disorders
Headache Disorders, Primary
Headache Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases