Migraine
Conditions
Keywords
Migraine, Non-invasive vagus nerve stimulation, Vagus nerve stimulation, Vagal nerve stimulation, gammaCore, episodic migraine
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
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.
Interventions
DEVICEgammaCore-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.
DEVICEgammaCore-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.
Sponsors
ElectroCore INC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Response - No Pain | 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
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Absence of Nausea/Vomiting, Photophobia, Phonophobia | 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. |
| Number of Participants With Treatment Response - No Pain or Mild Pain | 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. |
| Number of Participants With Treatment Response no Pain or Mild Pain at 24 and 48 Hours. | 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. |
| Number of Migraine Attacks With Treatment Response 'No Pain' in Study Period 2 All Attacks | 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
| Measure | Time frame | Description |
|---|---|---|
| Quality of Life Measured by EuroQol-5D-5L (EQ-5D-5L) | 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 |
| Bang Blinding Index Scores | 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 |
| Subject Satisfaction | 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 |
| Number of Migraine Attacks With Treatment Response 'No Pain' in Study Period 3 | 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. |
| Ease of Use | 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. |
| Quality of Life Measured by Headache Impact Test (HIT-6) | 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 |
| Mean Change in Pain Score From Baseline to 120 Minutes | 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 |
| Number of Migraine Attacks With Treatment Response no Pain or Mild Pain | 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) |
| Number of Migraine Attacks With Absence of Nausea, Vomiting, Photophobia and Phonophobia | 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). |
| Number of Attacks With Sustained Treatment Response | 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). |
| Number of Subjects With Consistency of Response | 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). |
Countries
Italy
Participant flow
Pre-assignment details
37 patients were excluded from the study at the end of the 4-week Run-In/Observational period because they did not continue to meet the study eligibility criteria, were lost to follow-up, or they chose not to continue in the study.
Participants by arm
| Arm | Count |
|---|---|
| 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
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. | 120 |
| 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
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. | 123 |
| Total | 243 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Open Label Period 3 | Lost to Follow-up | 0 | 1 |
| Randomized Controlled Period 2 | Adverse Event | 0 | 2 |
| Randomized Controlled Period 2 | Lost to Follow-up | 1 | 2 |
| Randomized Controlled Period 2 | Spontaneous reduction in migraines | 1 | 0 |
| Randomized Controlled Period 2 | Withdrawal by Subject | 3 | 0 |
| Run-In Period 1 | Eligibility | 12 | 10 |
| Run-In Period 1 | Lost to Follow-up | 4 | 4 |
| Run-In Period 1 | Withdrawal by Subject | 4 | 3 |
Baseline characteristics
| Characteristic | gammaCore-S | Total | gammaCore-S Sham |
|---|---|---|---|
| Age, Continuous | 38.8 Years STANDARD_DEVIATION 11 | 39.2 Years STANDARD_DEVIATION 11.38 | 39.6 Years STANDARD_DEVIATION 11.78 |
| Age of Onset of Migraine Attacks | 29.42 years STANDARD_DEVIATION 11.2 | 28.96 years STANDARD_DEVIATION 11.35 | 28.51 years STANDARD_DEVIATION 11.52 |
| Currently Taking Migraine Prevention Medication | 42 Participants | 77 Participants | 35 Participants |
| Days Per Month Acute Migraine Medication Taken | 5.6 Days per month STANDARD_DEVIATION 1.69 | 5.5 Days per month STANDARD_DEVIATION 1.68 | 5.3 Days per month STANDARD_DEVIATION 1.66 |
| Migraine with Aura Diagnosis | 8 Participants | 17 Participants | 9 Participants |
| Number of Migraine Attacks Per Month in Last 6 Months | 5.4 Attacks per month STANDARD_DEVIATION 1.51 | 5.4 Attacks per month STANDARD_DEVIATION 1.49 | 5.4 Attacks per month STANDARD_DEVIATION 1.48 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 120 Participants | 243 Participants | 123 Participants |
| Region of Enrollment Italy | 120 Participants | 243 Participants | 123 Participants |
| Sex: Female, Male Female | 95 Participants | 186 Participants | 91 Participants |
| Sex: Female, Male Male | 25 Participants | 57 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 122 | 0 / 126 |
| other Total, other adverse events | 22 / 122 | 23 / 126 |
| serious Total, serious adverse events | 0 / 122 | 0 / 126 |
Outcome results
Primary
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.
Time frame: 2 hours post-treatment
Population: Sensitivity analysis, Intent to Treat population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| gammaCore-S | Number of Participants With Treatment Response - No Pain | 36 Participants |
| gammaCore-S Sham | Number of Participants With Treatment Response - No Pain | 26 Participants |
Secondary
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.
Time frame: 30, 60, 120 minutes; Study Period 2 (each study period was 4 weeks)
Population: Intent to Treat
| Arm | Measure | Group | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| gammaCore-S | Number of Migraine Attacks With Treatment Response 'No Pain' in Study Period 2 All Attacks | 30 Minutes | 43 Attacks |
| gammaCore-S | Number of Migraine Attacks With Treatment Response 'No Pain' in Study Period 2 All Attacks | 60 Minutes | 69 Attacks |
| gammaCore-S | Number of Migraine Attacks With Treatment Response 'No Pain' in Study Period 2 All Attacks | 120 Minutes | 93 Attacks |
| gammaCore-S Sham | Number of Migraine Attacks With Treatment Response 'No Pain' in Study Period 2 All Attacks | 30 Minutes | 28 Attacks |
| gammaCore-S Sham | Number of Migraine Attacks With Treatment Response 'No Pain' in Study Period 2 All Attacks | 60 Minutes | 41 Attacks |
| gammaCore-S Sham | Number of Migraine Attacks With Treatment Response 'No Pain' in Study Period 2 All Attacks | 120 Minutes | 66 Attacks |
Secondary
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.
Time frame: 2 hours post-treatment study - period 2 (each study period was 4 weeks)
Population: Intent to treat population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| gammaCore-S | Number of Participants With Absence of Nausea/Vomiting, Photophobia, Phonophobia | No Nausea at 120 minutes | 83 Participants |
| gammaCore-S | Number of Participants With Absence of Nausea/Vomiting, Photophobia, Phonophobia | No Vomiting at 120 minutes | 110 Participants |
| gammaCore-S | Number of Participants With Absence of Nausea/Vomiting, Photophobia, Phonophobia | No Photophobia at 120 minutes | 76 Participants |
| gammaCore-S | Number of Participants With Absence of Nausea/Vomiting, Photophobia, Phonophobia | No Phonophobia at 120 minutes | 75 Participants |
| gammaCore-S Sham | Number of Participants With Absence of Nausea/Vomiting, Photophobia, Phonophobia | No Phonophobia at 120 minutes | 74 Participants |
| gammaCore-S Sham | Number of Participants With Absence of Nausea/Vomiting, Photophobia, Phonophobia | No Nausea at 120 minutes | 86 Participants |
| gammaCore-S Sham | Number of Participants With Absence of Nausea/Vomiting, Photophobia, Phonophobia | No Photophobia at 120 minutes | 72 Participants |
| gammaCore-S Sham | Number of Participants With Absence of Nausea/Vomiting, Photophobia, Phonophobia | No Vomiting at 120 minutes | 109 Participants |
Secondary
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.
Time frame: 2 hours post-treatment
Population: Intent to Treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| gammaCore-S | Number of Participants With Treatment Response - No Pain or Mild Pain | 62 Participants |
| gammaCore-S Sham | Number of Participants With Treatment Response - No Pain or Mild Pain | 50 Participants |
Secondary
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.
Time frame: 24 and 48 hours post-treatment
Population: Intent to Treat
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| gammaCore-S | Number of Participants With Treatment Response no Pain or Mild Pain at 24 and 48 Hours. | 24 Hours | 46 Participants |
| gammaCore-S | Number of Participants With Treatment Response no Pain or Mild Pain at 24 and 48 Hours. | 48 Hours | 43 Participants |
| gammaCore-S Sham | Number of Participants With Treatment Response no Pain or Mild Pain at 24 and 48 Hours. | 24 Hours | 37 Participants |
| gammaCore-S Sham | Number of Participants With Treatment Response no Pain or Mild Pain at 24 and 48 Hours. | 48 Hours | 33 Participants |
Other Pre-specified
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
Time frame: Study Period 2 (4 weeks)
Population: Intent to treat
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| gammaCore-S | Bang Blinding Index Scores | First Treated Attack | 0.07 Bang Blinding Index Score |
| gammaCore-S | Bang Blinding Index Scores | End of Period 2 | -0.03 Bang Blinding Index Score |
| gammaCore-S Sham | Bang Blinding Index Scores | First Treated Attack | 0.00 Bang Blinding Index Score |
| gammaCore-S Sham | Bang Blinding Index Scores | End of Period 2 | 0.23 Bang Blinding Index Score |
Other Pre-specified
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.
Time frame: End of Study Periods 2 and 3 (each study period was 4 weeks long)
Population: Intent to treat
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| gammaCore-S | Ease of Use | Visit 7 Very Difficult | 0 Participants |
| gammaCore-S | Ease of Use | Visit 7 Very Easy | 92 Participants |
| gammaCore-S | Ease of Use | Visit 5 Very Easy | 90 Participants |
| gammaCore-S | Ease of Use | Visit 5 Easy | 23 Participants |
| gammaCore-S | Ease of Use | Visit 5 Difficult | 5 Participants |
| gammaCore-S | Ease of Use | Visit 5 Very Difficult | 0 Participants |
| gammaCore-S | Ease of Use | Visit 7 Easy | 18 Participants |
| gammaCore-S | Ease of Use | Visit 7 Difficult | 5 Participants |
| gammaCore-S Sham | Ease of Use | Visit 7 Very Difficult | 0 Participants |
| gammaCore-S Sham | Ease of Use | Visit 5 Very Difficult | 1 Participants |
| gammaCore-S Sham | Ease of Use | Visit 7 Very Easy | 98 Participants |
| gammaCore-S Sham | Ease of Use | Visit 5 Very Easy | 97 Participants |
| gammaCore-S Sham | Ease of Use | Visit 7 Difficult | 3 Participants |
| gammaCore-S Sham | Ease of Use | Visit 5 Easy | 20 Participants |
| gammaCore-S Sham | Ease of Use | Visit 7 Easy | 17 Participants |
| gammaCore-S Sham | Ease of Use | Visit 5 Difficult | 4 Participants |
Other Pre-specified
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
Time frame: 120 minutes, Study Period 2 (each study period was 4 weeks long)
Population: Intent to Treat
| Arm | Measure | Value (MEAN) |
|---|---|---|
| gammaCore-S | Mean Change in Pain Score From Baseline to 120 Minutes | -0.4954 score on a scale |
| gammaCore-S Sham | Mean Change in Pain Score From Baseline to 120 Minutes | -0.2769 score on a scale |
Other Pre-specified
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).
Time frame: 24 and 48 hours; Study Periods 2 and 3 (each study period was 4 weeks)
Population: Intent to treat Period 2 373/347 attacks treated Period 3 286/309 attacks treated
| Arm | Measure | Group | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| gammaCore-S | Number of Attacks With Sustained Treatment Response | 24 Hours, Period 2 | 132 Attacks |
| gammaCore-S | Number of Attacks With Sustained Treatment Response | 48 Hours, Period 2 | 121 Attacks |
| gammaCore-S | Number of Attacks With Sustained Treatment Response | 24 Hours, Period 3 | 100 Attacks |
| gammaCore-S | Number of Attacks With Sustained Treatment Response | 48 Hours, Period 3 | 96 Attacks |
| gammaCore-S Sham | Number of Attacks With Sustained Treatment Response | 48 Hours, Period 3 | 111 Attacks |
| gammaCore-S Sham | Number of Attacks With Sustained Treatment Response | 24 Hours, Period 2 | 103 Attacks |
| gammaCore-S Sham | Number of Attacks With Sustained Treatment Response | 24 Hours, Period 3 | 117 Attacks |
| gammaCore-S Sham | Number of Attacks With Sustained Treatment Response | 48 Hours, Period 2 | 95 Attacks |
Other Pre-specified
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).
Time frame: Study Periods 2 and 3 (each study period was 4 weeks)
Population: Intent to Treat population Period 2 373/347 attacks treated Period 3 286/309 attacks treated
| Arm | Measure | Group | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| gammaCore-S | Number of Migraine Attacks With Absence of Nausea, Vomiting, Photophobia and Phonophobia | No Nausea Period 2 | 253 Attacks |
| gammaCore-S | Number of Migraine Attacks With Absence of Nausea, Vomiting, Photophobia and Phonophobia | No Vomiting Period 2 | 342 Attacks |
| gammaCore-S | Number of Migraine Attacks With Absence of Nausea, Vomiting, Photophobia and Phonophobia | No Photophobia Period 2 | 233 Attacks |
| gammaCore-S | Number of Migraine Attacks With Absence of Nausea, Vomiting, Photophobia and Phonophobia | No Phonophobia Period 2 | 223 Attacks |
| gammaCore-S | Number of Migraine Attacks With Absence of Nausea, Vomiting, Photophobia and Phonophobia | No Nausea Period 3 | 195 Attacks |
| gammaCore-S | Number of Migraine Attacks With Absence of Nausea, Vomiting, Photophobia and Phonophobia | No Vomiting Period 3 | 268 Attacks |
| gammaCore-S | Number of Migraine Attacks With Absence of Nausea, Vomiting, Photophobia and Phonophobia | No Photophobia Period 3 | 158 Attacks |
| gammaCore-S | Number of Migraine Attacks With Absence of Nausea, Vomiting, Photophobia and Phonophobia | No Phonophobia Period 3 | 154 Attacks |
| gammaCore-S Sham | Number of Migraine Attacks With Absence of Nausea, Vomiting, Photophobia and Phonophobia | No Phonophobia Period 3 | 203 Attacks |
| gammaCore-S Sham | Number of Migraine Attacks With Absence of Nausea, Vomiting, Photophobia and Phonophobia | No Nausea Period 2 | 228 Attacks |
| gammaCore-S Sham | Number of Migraine Attacks With Absence of Nausea, Vomiting, Photophobia and Phonophobia | No Nausea Period 3 | 226 Attacks |
| gammaCore-S Sham | Number of Migraine Attacks With Absence of Nausea, Vomiting, Photophobia and Phonophobia | No Vomiting Period 2 | 312 Attacks |
| gammaCore-S Sham | Number of Migraine Attacks With Absence of Nausea, Vomiting, Photophobia and Phonophobia | No Photophobia Period 3 | 195 Attacks |
| gammaCore-S Sham | Number of Migraine Attacks With Absence of Nausea, Vomiting, Photophobia and Phonophobia | No Photophobia Period 2 | 202 Attacks |
| gammaCore-S Sham | Number of Migraine Attacks With Absence of Nausea, Vomiting, Photophobia and Phonophobia | No Vomiting Period 3 | 288 Attacks |
| gammaCore-S Sham | Number of Migraine Attacks With Absence of Nausea, Vomiting, Photophobia and Phonophobia | No Phonophobia Period 2 | 203 Attacks |
Other Pre-specified
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.
Time frame: 30, 60, 120 minutes; Period 3 (each study period was 4 weeks)
Population: Intent to Treat Period 2 373/347 attacks treated Period 3 286/309 attacks treated
| Arm | Measure | Group | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| gammaCore-S | Number of Migraine Attacks With Treatment Response 'No Pain' in Study Period 3 | 30 Minutes | 35 Attacks |
| gammaCore-S | Number of Migraine Attacks With Treatment Response 'No Pain' in Study Period 3 | 60 Minutes | 47 Attacks |
| gammaCore-S | Number of Migraine Attacks With Treatment Response 'No Pain' in Study Period 3 | 120 Minutes | 63 Attacks |
| gammaCore-S Sham | Number of Migraine Attacks With Treatment Response 'No Pain' in Study Period 3 | 30 Minutes | 41 Attacks |
| gammaCore-S Sham | Number of Migraine Attacks With Treatment Response 'No Pain' in Study Period 3 | 60 Minutes | 61 Attacks |
| gammaCore-S Sham | Number of Migraine Attacks With Treatment Response 'No Pain' in Study Period 3 | 120 Minutes | 83 Attacks |
Other Pre-specified
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)
Time frame: 30, 60, 120 minutes; Study Periods 2 and 3 (each study period was 4 weeks)
Population: Intent to Treat Period 2 373/347 attacks treated Period 3 286/309 attacks treated
| Arm | Measure | Group | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| gammaCore-S | Number of Migraine Attacks With Treatment Response no Pain or Mild Pain | Period 2 30 Minutes | 149 Attacks |
| gammaCore-S | Number of Migraine Attacks With Treatment Response no Pain or Mild Pain | Period 2 60 Minutes | 160 Attacks |
| gammaCore-S | Number of Migraine Attacks With Treatment Response no Pain or Mild Pain | Period 2 120 Minutes | 165 Attacks |
| gammaCore-S | Number of Migraine Attacks With Treatment Response no Pain or Mild Pain | Period 3 30 Minutes | 105 Attacks |
| gammaCore-S | Number of Migraine Attacks With Treatment Response no Pain or Mild Pain | Period 3 60 Minutes | 117 Attacks |
| gammaCore-S | Number of Migraine Attacks With Treatment Response no Pain or Mild Pain | Period 3 120 Minutes | 124 Attacks |
| gammaCore-S Sham | Number of Migraine Attacks With Treatment Response no Pain or Mild Pain | Period 3 60 Minutes | 140 Attacks |
| gammaCore-S Sham | Number of Migraine Attacks With Treatment Response no Pain or Mild Pain | Period 2 30 Minutes | 123 Attacks |
| gammaCore-S Sham | Number of Migraine Attacks With Treatment Response no Pain or Mild Pain | Period 3 30 Minutes | 122 Attacks |
| gammaCore-S Sham | Number of Migraine Attacks With Treatment Response no Pain or Mild Pain | Period 2 60 Minutes | 130 Attacks |
| gammaCore-S Sham | Number of Migraine Attacks With Treatment Response no Pain or Mild Pain | Period 3 120 Minutes | 147 Attacks |
| gammaCore-S Sham | Number of Migraine Attacks With Treatment Response no Pain or Mild Pain | Period 2 120 Minutes | 136 Attacks |
Other Pre-specified
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).
Time frame: Study Periods 2 and 3 (each study period was 4 weeks)
Population: Intent to Treat
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| gammaCore-S | Number of Subjects With Consistency of Response | Period 2 | 57 participants |
| gammaCore-S | Number of Subjects With Consistency of Response | Period 3 | 44 participants |
| gammaCore-S Sham | Number of Subjects With Consistency of Response | Period 2 | 46 participants |
| gammaCore-S Sham | Number of Subjects With Consistency of Response | Period 3 | 44 participants |
Other Pre-specified
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
Time frame: End of each study period (each study period was 4 weeks)
Population: Intent to treat
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| gammaCore-S | Quality of Life Measured by EuroQol-5D-5L (EQ-5D-5L) | EQ5D5L - Visit 1 Start of run-in period | 0.885 Score | Standard Deviation 0.1028 |
| gammaCore-S | Quality of Life Measured by EuroQol-5D-5L (EQ-5D-5L) | EQ5D5L - Visit 3 End of run-in period | 0.896 Score | Standard Deviation 0.0903 |
| gammaCore-S | Quality of Life Measured by EuroQol-5D-5L (EQ-5D-5L) | EQ5D5L -Visit 5 End of randomised period | 0.911 Score | Standard Deviation 0.098 |
| gammaCore-S | Quality of Life Measured by EuroQol-5D-5L (EQ-5D-5L) | EQ5D5L - Visit 7 End of open label period | 0.923 Score | Standard Deviation 0.0924 |
| gammaCore-S Sham | Quality of Life Measured by EuroQol-5D-5L (EQ-5D-5L) | EQ5D5L - Visit 7 End of open label period | 0.931 Score | Standard Deviation 0.091 |
| gammaCore-S Sham | Quality of Life Measured by EuroQol-5D-5L (EQ-5D-5L) | EQ5D5L - Visit 1 Start of run-in period | 0.912 Score | Standard Deviation 0.0969 |
| gammaCore-S Sham | Quality of Life Measured by EuroQol-5D-5L (EQ-5D-5L) | EQ5D5L -Visit 5 End of randomised period | 0.926 Score | Standard Deviation 0.0951 |
| gammaCore-S Sham | Quality of Life Measured by EuroQol-5D-5L (EQ-5D-5L) | EQ5D5L - Visit 3 End of run-in period | 0.917 Score | Standard Deviation 0.098 |
Other Pre-specified
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
Time frame: End of each study period (each study period was 4 weeks)
Population: Intent to treat
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| gammaCore-S | Quality of Life Measured by Headache Impact Test (HIT-6) | HIT6 - Visit 1 Start of run-in period | 63.250 Score | Standard Deviation 5.0581 |
| gammaCore-S | Quality of Life Measured by Headache Impact Test (HIT-6) | HIT6 - Visit 3 End of run-in period | 63.275 Score | Standard Deviation 5.4618 |
| gammaCore-S | Quality of Life Measured by Headache Impact Test (HIT-6) | HIT6 - Visit 5 End of randomised period | 61.897 Score | Standard Deviation 5.59 |
| gammaCore-S | Quality of Life Measured by Headache Impact Test (HIT-6) | HIT6 - Visit 7 End of open label period | 61.128 Score | Standard Deviation 5.5871 |
| gammaCore-S Sham | Quality of Life Measured by Headache Impact Test (HIT-6) | HIT6 - Visit 7 End of open label period | 60.750 Score | Standard Deviation 5.7149 |
| gammaCore-S Sham | Quality of Life Measured by Headache Impact Test (HIT-6) | HIT6 - Visit 1 Start of run-in period | 63.179 Score | Standard Deviation 5.2977 |
| gammaCore-S Sham | Quality of Life Measured by Headache Impact Test (HIT-6) | HIT6 - Visit 5 End of randomised period | 60.959 Score | Standard Deviation 5.6604 |
| gammaCore-S Sham | Quality of Life Measured by Headache Impact Test (HIT-6) | HIT6 - Visit 3 End of run-in period | 61.894 Score | Standard Deviation 5.5704 |
Other Pre-specified
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
Time frame: End of Study Periods 2 and 3 (each study period was 4 weeks long)
Population: Intent to treat
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| gammaCore-S | Subject Satisfaction | Visit 5 Extremely Satisfied | 7 Participants |
| gammaCore-S | Subject Satisfaction | Visit 5 Very Satisfied | 18 Participants |
| gammaCore-S | Subject Satisfaction | Visit 5 Satisfied | 27 Participants |
| gammaCore-S | Subject Satisfaction | Visit 5 A Little Satisfied | 33 Participants |
| gammaCore-S | Subject Satisfaction | Visit 5 Not at All Satisfied | 33 Participants |
| gammaCore-S | Subject Satisfaction | Visit 7 Extremely Satisfied | 10 Participants |
| gammaCore-S | Subject Satisfaction | Visit 7 Very Satisfied | 19 Participants |
| gammaCore-S | Subject Satisfaction | Visit 7 Satisfied | 23 Participants |
| gammaCore-S | Subject Satisfaction | Visit 7 A Little Satisfied | 32 Participants |
| gammaCore-S | Subject Satisfaction | Visit 7 Not at All Satisfied | 31 Participants |
| gammaCore-S Sham | Subject Satisfaction | Visit 7 Satisfied | 34 Participants |
| gammaCore-S Sham | Subject Satisfaction | Visit 5 Extremely Satisfied | 8 Participants |
| gammaCore-S Sham | Subject Satisfaction | Visit 7 Extremely Satisfied | 12 Participants |
| gammaCore-S Sham | Subject Satisfaction | Visit 5 Very Satisfied | 12 Participants |
| gammaCore-S Sham | Subject Satisfaction | Visit 7 Not at All Satisfied | 28 Participants |
| gammaCore-S Sham | Subject Satisfaction | Visit 5 Satisfied | 22 Participants |
| gammaCore-S Sham | Subject Satisfaction | Visit 7 Very Satisfied | 18 Participants |
| gammaCore-S Sham | Subject Satisfaction | Visit 5 A Little Satisfied | 36 Participants |
| gammaCore-S Sham | Subject Satisfaction | Visit 7 A Little Satisfied | 26 Participants |
| gammaCore-S Sham | Subject Satisfaction | Visit 5 Not at All Satisfied | 44 Participants |