Clinical trial NCT02378844: A Randomized, Sham-controlled Study of gammaCore ® (nVNS) for Prevention of Episodic Migraine
Official title: A Randomized, Multicentre, Double-blind, Parallel, Sham-controlled Study of gammaCore®, a Non-invasive Vagal Nerve Stimulator (nVNS), for Prevention of Episodic Migraine
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Migraine
Lead sponsor: ElectroCore INC
Sponsor class: INDUSTRY
First posted: 2015-03-04
Enrollment: 477
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: A prospective, double-blind, randomized, sham-controlled, multicentre investigation.

Detailed description: 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 observation for baseline 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.

The randomized period will be followed by a 24 week open label period, where the subjects in the sham treatment group will switch in treatment assignment and receive a gammaCore®-R and the gammaCore®-R will continue to receive an active treatment.

Eligibility criteria: Inclusion Criteria:

1. Is between the ages of 18 and 75 years.
2. Has been previously diagnosed with migraine (with or without aura) in accordance with the International Classification of Headache Disorders (ICHD)-3 Beta Classification criteria.
3. Experience between 5 and 12 migraine days per month (over the last 4 months) with at least 2 of the migraines lasting more than 4 hours.
4. Has age of onset of migraine less than 50 years old.
5. Agrees not to use any migraine prevention treatments (including Botox injections) and/or medications (exclusive of medications taken for acute relief of migraine symptoms).
6. Agrees to refrain from initiating or changing the type, dosage or frequency of any prophylactic medications for indications other than migraine that in the opinion of the clinician may interfere with the study objectives (e.g. antidepressant, anti convulsant, beta blockers, etc.).
7. Agrees to use the gammaCore®-R device as intended, follow all of the requirements of the study including follow-up visit requirements, record required study data in the subject dairy, and other self-assessment questionnaires.
8. Is able to provide written Informed Consent.

Exclusion Criteria:

1. Has a concomitant medical condition that will require oral or injectable steroids during the study.
2. Has a history of any intracranial aneurysm, intracranial haemorrhage, brain tumour or significant head trauma.
3. Has a structural abnormality at the gammaCore®-R treatment site (e.g lymphadenopathy previous surgery or abnormal anatomy).
4. Has pain at the gammaCore®-R treatment site (e.g.dysesthesia, neuralgia and/or cervicalgia).
5. 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
6. Has know or suspected severe cardiac disease(e.g. symptomatic coronary artery disease, prior myocardial infarction, congestive heart failure (CHF)).
7. Has known or suspected severe cerebrovascular disease, (e.g. prior stroke or transient ischemic attack, symptomatic carotid artery disease, prior carotid endarterectomy or other vascular neck surgery).
8. Has an abnormal baseline Electrocardiogram (ECG) e.g. second and third degree heart block, prolonged QT interval, atrial fibrillation, atrial flutter, history of ventricular tachycardia or ventricular fibrillation, or clinically significant premature ventricular contraction).
9. Has had a cervical vagotomy.
10. Has uncontrolled high blood pressure (systolic \>160 diastolic \> 100 after 3 repeated measurements within 24 hours).
11. 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).
12. Has been implanted with metal cervical spine hardware or has a metallic implant near the gammaCore®-R stimulation site.
13. Has a known history of suspicion of secondary headache.
14. Has a history of syncope (within the last five years).
15. Has a history of seizures (within the last five years).
16. Has a known or suspicion of substance abuse or addiction (within the last 5 years).
17. Is using marijuana (including medical marijuana) for any indications, more than twice a month.
18. 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 for headaches or other body pain.
19. Currently takes prescription opioids greater than 2 days per month for headaches or body pain.
20. Has taken medications for migraine prophylaxis in the previous 30 days.
21. Has previous diagnosis of medication overuse headache (MoH) , which has reverted to episodic migraine within the last 6 months.
22. Meets the ICHD-3 Beta Classification criteria for chronic migraine (\> 15 headache days per month).
23. Has failed an adequate trial (two months or greater) of at least 3 classes of a drug therapy for the prophylaxis of migraine .
24. Has had surgery for migraine prevention.
25. Has undergone nerve block (occipital or other) in the head or neck within the last 2 months.
26. Has received Botox injections within the last 6 months.
27. Is pregnant or thinking of becoming pregnant during the study period, or of childbearing years and is unwilling to use and accepted form of birth control.
28. Is participating in any other therapeutic clinical investigation or has participated in a clinical trial in the preceding 30 days.
29. 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 and prisoner).
30. Is a relative of or an employee of the investigator or the clinical study site.
31. Has psychiatric or cognitive disorder and/or behavioural problems which in the opinion of the clinician may interfere with the study.
32. Has previously used the gammaCore® device.

Primary outcomes:
measure: Change in the Number of Migraine Days
timeFrame: last 4 weeks of the randomized/controlled period compared to the subject's own 4-week run-in period.
Secondary outcomes:
measure: Number of Participants With 50% Responder Rate
timeFrame: The last four weeks in the randomization period compared to the four week run-in period.
measure: Mean Change in Number of Headache Days
timeFrame: The last four weeks in the randomization period compared to the four week run-in period.
measure: Change in Number of Acute Medication Days
timeFrame: The last four weeks in the randomization period compared to the four week run-in period.
measure: Change in Headache Disability Using Headache Impact Test-6
timeFrame: From four week run-in period to last four weeks in the randomization period
measure: Number of Participants According to Grade on the Migraine Disability Assessment (MIDAS) Before and After Randomized Period
timeFrame: 3 months - end of run-in period to end of randomized period
measure: Compare Changes in Quality of Life EuroQol Questionnaire 5 Dimensions and 5 Levels (EQ-5D-5L)
timeFrame: From four week run-in period to last four weeks in the randomization period
measure: Change in Migraine Days in the Open Label Period (Adjusted ANCOVA)
timeFrame: The 6 month open-label period compared to the four week run-in period
measure: Number of Participants With Adverse Events
timeFrame: up to Week 36
measure: Change in Headache Days in the Open Label Period
timeFrame: The 6 month open-label period compared to the four week run-in period
Other outcomes:
Locations:
city: Liège
country: Belgium
facility: Neurology Department, University of Liège
city: Glostrup
country: Denmark
facility: Danish Headache Center
city: Berlin
country: Germany
facility: Neurologische Klinik und Poliklinik, Charité Campus Mitte
city: Essen
country: Germany
facility: Klinik für Neurologie, Universitätsklinikum Essen
city: Hamburg
country: Germany
facility: CTC, University Medical Center Hamburg-Eppendorf
city: Königstein
country: Germany
facility: Migräne- und Kopfschmertzklinik Königstein
city: München
country: Germany
facility: Klinik für Neurologie, Ludwig-Maximilliams-Universität, Klinikum Grosshadern
city: Tübingen
country: Germany
facility: Zentrum für Neurologie und Epileptologie, Hertie-Institut für Klinische Hirnforschung
city: Wiesbaden
country: Germany
facility: DKD HELIOS Klinik Wiesbaden
city: Athens
country: Greece
facility: Neurology Department, Athens Naval Hospital
city: Leiden
country: Netherlands
facility: Neurology Department, Leiden University Center
city: Sandvika
country: Norway
facility: Sandvika Nevrosenter AS
city: Barcelona
country: Spain
facility: Headache Unit, University Hospital Vall d'Hebron
city: Madrid
country: Spain
facility: Servicio de Neurologia, Hospital Ruber Internacional
city: Pamplona
country: Spain
facility: Servicio de Neurologia, Clinica Universidad de Navarra
city: Valencia
country: Spain
facility: Servicio de Neurologia, Hospital Clinico Universitario de Valencia
city: Basildon
country: United Kingdom
facility: Basildon University Hospital
state: Essex
city: Birmingham
country: United Kingdom
facility: School of Clinical and Expermental Medicine
city: Glasgow
country: United Kingdom
facility: Neurology Department, The Southern Hospital
city: Hull
country: United Kingdom
facility: Neurology Department, Hull Royal Infirmary
city: Liverpool
country: United Kingdom
facility: Neurology Department, The Walton Center
city: London
country: United Kingdom
facility: Neurology Department, King's College London
Study officials:
affiliation: Universtätsklinikum Essen
name: Hans-Christoph Diener, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Diener HC, Goadsby PJ, Ashina M, Al-Karagholi MA, Sinclair A, Mitsikostas D, Magis D, Pozo-Rosich P, Irimia Sieira P, Lainez MJ, Gaul C, Silver N, Hoffmann J, Marin J, Liebler E, Ferrari MD. Non-invasive vagus nerve stimulation (nVNS) for the preventive treatment of episodic migraine: The multicentre, double-blind, randomised, sham-controlled PREMIUM trial. Cephalalgia. 2019 Oct;39(12):1475-1487. doi: 10.1177/0333102419876920. Epub 2019 Sep 15.