A Randomized, Multicentre, Double-blind, Parallel, Sham-controlled Study of gammaCore®, a Non-invasive Vagal Nerve Stimulator (nVNS), for Prevention of Episodic Migraine
Phase: NA
Conditions: Migraine
Sponsor: ElectroCore INC

Clinical Investigation Plan 
Sponsor: electroCore LLC 
Version:  3.0 
Clinical Investigation Plan Code: GM-11 
Date: 1st September 2017  
 
This clinical investigation will be performed in compliance with ISO 14155:2011(E), Medical Device 
Directive (MDD) and the Declaration of Helsinki and applicable regulatory requirements. 
 
CONFIDENTIAL 
This Clinical Investigation Plan contains privileged or confidential information, which is the property of the 
Sponsor. Information may not be disclosed to a third party without written authorisation from the Sponsor. 
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CONFIDENTIAL 
CLINICAL INVESTIGATION PLAN (CIP) 
 
 
 
Title: A randomized, multicentre, double-blind, parallel, sham-controlled study of 
the gammaCore®-R, a non-invasive neurostimulator device, for the prevention of 
episodic migraine 
Clinical Investigation Plan Code: 
GM-11 
Clinical Investigation Medical Device: 
gammaCore®-R 
Indication: 
Episodic migraine 
Device Class: 
IIa 
Version: 
3.0 
Date: 
1st September 2017  
Coordinating/Principle Clinical 
Investigator: 
Prof. Hans Christoph Diener 
Klinik für Neurologie, Universitätsklinikum 
Essen, Hufelandstr. 55, D-45147 Essen, 
Germany 
Sponsor: 
electroCore LLC 
150 Allen Road, Suite 201 
Basking Ridge, NJ 07920 
USA 

Clinical Investigation Plan 
Sponsor: electroCore LLC 
Version: 3.0   
CIP Code: GM-11 
Date: 1st September 2017 
 
Confidential 
 
 
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1 
SYNOPSIS 
NAME OF THE SPONSOR: 
electroCore LLC 
 
CLINICAL INVESTIGATION CODE:   
GM-11 
 
CLINICAL INVESTIGATION TITLE:  
A randomized, multicentre, double-blind, parallel, sham-controlled study of the gammaCore®-
R, a non-invasive neurostimulator device, for the prevention of episodic migraine 
 
CLINICAL INVESTIGATIONAL MEDICAL DEVICE(S):  
gammaCore®-R 
 
OBJECTIVES: 
Primary objective: 
The primary objective is the difference between the gammaCore®-R and the sham 
treatment groups in mean reduction in number of migraine days during the last four weeks 
in the twelve-week randomized period compared with the four week run-in period  
 
Secondary objectives: 
 
 To evaluate rate of responders for the gammaCore®-R group compared to the sham 
group. A responder is defined as recording at least 50% reduction in migraine days 
during the last four weeks in the twelve-week randomization period compared to the 
four week run-in period. 
 
To evaluate the difference between the gammaCore®-R and sham treatment groups in 
mean reduction in number of headache days during the last four weeks in the twelve-
week randomized period compared to the four week run-in period.  
 
 
To evaluate difference between the gammaCore®-R and the sham treatment groups in 
the mean reduction in acute headache medications taken during the last four weeks in 

Clinical Investigation Plan 
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Version: 3.0   
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Date: 1st September 2017 
 
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the twelve-week randomized period compared to the four week run-in period. 
 
Compare improvement in headache disability using Headache Impact Test-6 (HIT-6) 
 
Compare improvement in Migraine Disability Assessment (MIDAS)  
 
Compare Quality of Life  EQ-5D-5L 
 
Reduction of number of headache/migraine days in the open label period compared to 
baseline run-in period 
 
Adverse events 
Other: 
 
Blinding questions 
 
Subject satisfaction question; and 
 
Ease of use 
 
OVERALL CLINICAL INVESTIGATION DESIGN:  
 
The study is a prospective double blind, randomized, sham-controlled, multi-center 
investigation designed for comparison of two parallel groups, gammaCore®-R (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 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 group will continue to receive an active treatment (see Protocol 
Section 7.1 for details). 
 
 
 
 
 
 
 
 

Clinical Investigation Plan 
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Version: 3.0   
CIP Code: GM-11 
Date: 1st September 2017 
 
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   4 weeks                                    12 weeks                           24 weeks 
                                                    Randomized period           Open label period 
 
INCLUSION AND EXCLUSION 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 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   
Subjects meeting any of the following criteria cannot be included in this research study  
 
Run-in 
Period 
gammaCore®-R 
Sham 
Open Label 

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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 coronay 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 cartoid 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, Spehnopalatine ganglion stimulator  
or Occiptial 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) 

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Date: 1st September 2017 
 
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greater than 15 days per month or triptans, ergots or combinedanalgesics greater than 
10 days per month for headaches or other body pain.  
19.  Currently takes  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 abilitity 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. 
 
Visit 2 Inclusion/Exclusion Criteria (randomization visit) 
Before randomization into the study patient must meet all of the following inclusion criteria and 
none of the following exclusion criteria. 
 
Inclusion criteria 
The subject: 
1. Continues to meet all Baseline (Visit 1) Eligibility Criteria.  
2. Has experienced between 5-12 migraine days and less than 15 headache days during 
the 4 week run-in period. 

Clinical Investigation Plan 
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Version: 3.0   
CIP Code: GM-11 
Date: 1st September 2017 
 
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Exclusion criteria 
The subject: 
1. Has initiated or changed the type, dose or frequency of any prophylactic medication for 
indications other than migraine that in the opinion of the clinician may interfere with the 
study objectives during the 4-week run-in period.  
PERFORMANCE AND SAFETY ENDPOINTS:  
Primary Endpoint 
Diary- number of migraine/headache days 
Secondary Endpoints 
HIT-6 
MIDAS 
EQ-5D-5L 
Medication use and change 
Adverse event 
 
Primary and Secondary Performance analysis 
 
Primary Performance Analysis 
The primary efficacy analyses will be based on the ITT and repeated in the PPS, when the 
groups differ by more than 5%.  
Summary statistics for the primary variable will be presented by device group, strata/centre 
and visit. The total for each device group will be calculated. 
 
The primary outcome measurement is the change in the number of 
migraine days during the last 4 weeks of the 12-week 
randomized/controlled period compared to the subject's own 4-week run-
in period.  
 
Let µActive be the mean change (from 4-week run-in period) in the number 
of migraine days for the active treatment group and µSham be the mean 
change in the number of migraine days for the sham treatment group.  
Then the effectiveness of the gammaCore-R-R device can be measured 
by testing the difference in mean changes, µActive - µSham. The null and 
alternative hypotheses of interest are: 
Hnull: µActive - µSham = 0  versus  Halt: µActive - µsham ≠ 0 

Clinical Investigation Plan 
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Version: 3.0   
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Date: 1st September 2017 
 
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The number of migraines will be summarized descriptively for each 4-week interval by period 
and by treatment group. The absolute value and change from 4-week run-in period will be 
summarized using number of non-missing values, mean, standard deviation, median, 
minimum, and maximum. 
The difference between the two groups in change from 4-week run-in period will be compared 
using a two-group t-test.  The directionality of the difference as well as the p-value will be 
evaluated in order to make conclusions about the effectiveness of the active treatment. 
As sensitivity analyses, the two treatment groups will be compared using analysis of 
covariance (ANCOVA) models with change from 4-week run-in period as the dependent 
variable and treatment group and center as fixed effects with the number of migraine days in 
the 4-week run-in period as a covariate and again with treatment group, center, and aura as 
fixed effects with number of migraine days in the 4-week run-in period as a covariate. The 
adjusted means, adjusted mean difference and 95% confidence interval for the adjusted mean 
difference based on the ANCOVA models will be reported. The p-values tests that the adjusted 
mean difference between groups at Month 3 equals zero will be reported. 
The above procedures will be used for the analysis of the primary and secondary effectiveness 
outcome measures.  Additional sensitivity analyses, including details on the handling of the 
missing assessments, will be specified in the SAP. 
 
Secondary Performance Analyses 
The secondary efficacy analyses will be based on the ITT. 
 
The outcome measurement for responders is the percentage of subjects 
with a reduction of 50% or more in the number of migraine days during 
the last 4 weeks of the 12-week randomized/controlled period compared 
to the subject's own 4-week run-in period.  
 
Let pActive be the proportion of patients in the active treatment group with 
at least a 50% reduction and let pSham be the proportion of patients in the 
sham treatment group with at least a 50% reduction. Then the 
effectiveness of the gammaCore-R device can be measured by testing 
the difference in proportions, pActive - pSham. The null and alternative 
hypotheses of interest are: 
Hnull: pActive – pSham = 0  versus  Halt: pActive – pSham ≠ 0 
The number and percentage of responders (>=50% reduction in number of migraine days per 
4-week interval) will be summarized for each treatment group for period 2.  The difference 
between treatment groups and the corresponding 95% interval for the difference will be 
provided.  A chi-square test for comparing the two treatment groups will be performed and the 
p-value reported. 
As sensitivity analyses, the two groups will be compared using Logistic Regression models 
with the number of migraines in the 4-week run-in period, treatment group, and center  as 

Clinical Investigation Plan 
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Version: 3.0   
CIP Code: GM-11 
Date: 1st September 2017 
 
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covariates and again with the number of migraines in the 4-week run-in period, treatment 
group, center, and aura as covariates. 
 
 

Clinical Investigation Plan 
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Version: 3.0   
CIP Code: GM-11 
Date: 1st September 2017 
 
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2 
TABLE OF CONTENTS 
Section Page 
1 
SYNOPSIS .................................................................................................................... 2 
Inclusion Criteria .................................................................................................. 4 
Exclusion Criteria ................................................................................................. 4 
Primary Endpoint .................................................................................................. 7 
Secondary Endpoints ........................................................................................... 7 
Secondary Performance Analyses ....................................................................... 8 
2 
TABLE OF CONTENTS .............................................................................................. 10 
3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................... 13 
3.1 
List of Abbreviations ........................................................................................ 13 
4 
CLINICAL INVESTIGATORS AND CLINICAL INVESTIGATION ADMINISTRATIVE 
STRUCTURE .............................................................................................................. 14 
5 
INTRODUCTION ......................................................................................................... 24 
5.1 
Background ...................................................................................................... 24 
6 
CLINICAL INVESTIGATION OBJECTIVES ................................................................ 29 
6.1 
Primary Objective ............................................................................................. 29 
6.2 
Secondary Objective ........................................................................................ 29 
7 
DESIGN OF THE CLINICAL INVESTIGATION .......................................................... 30 
7.1 
Overall Clinical Investigation Design .............................................................. 30 
7.2 
Clinical Investigation Procedures and Definitions......................................... 31 
7.2.1 
Schedule of Clinical Investigation Events ......................................... 31 
7.2.1.1 
Definition of headache/migraine day ................................................ 31 
7.2.1.2 
Visit 1, Day -28 (start of four week run-in period) ............................. 31 
7.2.1.3 
Visit 2, Day 0 (4 weeks +/-3 days after run-in period) ....................... 32 
7.2.1.4 
Visit 3, Day 7 Phone call (1 week +/- 3 days after visit 2) ................. 33 
7.2.1.5 
Visit 4, Day 28 (+/- 3 days ) .............................................................. 33 
7.2.1.6 
Visit 5, Day 56 Phone call ( +/- 5 days ) ........................................... 34 
7.2.1.7 
Visit 6, Day 84 (+/- 5 days ) .............................................................. 34 
7.2.1.8 
Visit 7, Day 91 Phone call (+/- 3) ...................................................... 35 
7.2.1.9 
Visit 8, Day 112 (+/-3 days) .............................................................. 35 
7.2.1.10 
Visit 9, Day 140 Phone call (+/- 5 days) ........................................... 36 
7.2.1.11 
Visit 10, Day 168 ( +/- 5 days) .......................................................... 36 
7.2.1.12 
Visit 11, Day 210 (+/- 5 days) ........................................................... 37 
7.2.1.13 
Visit 12 Day 252 ( +/- 5 days ) .......................................................... 37 
7.2.2 
Clinical Investigation Flow Chart ...................................................... 38 
7.3 
Discussion and Justification of Clinical Investigation Design, Including the 
Choice of Control Groups ................................................................................ 40 
7.3.1 
Prior and Concomitant Medication and Procedures ......................... 40 
7.4 
Selection of Population for the Clinical Investigation ................................... 41 
7.4.1 
Number of Subjects ......................................................................... 41 
7.4.2 
Inclusion Criteria .............................................................................. 41 
7.4.3 
Exclusion Criteria ............................................................................. 42 
7.4.4 
Removal of Subjects from the Clinical Investigation ......................... 44 

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7.5 
Identification and Description of the Clinical Investigational Medical Device
 ........................................................................................................................... 45 
7.5.1 
Identification of the Clinical Investigational Medical Device .............. 45 
7.5.2 
Packaging and Labelling of the Clinical Investigational Medical Device
 ........................................................................................................ 47 
7.5.3 
Installation and Use of the Clinical Investigational Medical Device ... 47 
7.5.4 
Methods of Assigning Subjects to Device Groups ............................ 47 
7.5.5 
Blinding ............................................................................................ 47 
7.5.6 
Compliance with Device Usage ........................................................ 48 
7.6 
Risk and Benefits of the investigational device and clinical investigation .. 48 
7.7 
Performance and Safety Endpoints, Variables and Measurements ............. 49 
7.7.1 
Subject Characteristics .................................................................... 49 
7.7.2 
Primary and Secondary Endpoints ................................................... 49 
7.7.3 
Performance Variables and Measurements ..................................... 49 
7.7.4 
Safety Variables and Measurements ................................................ 50 
7.7.5 
Other Variables and Measurements ................................................. 50 
7.7.6 
Appropriateness of Measurements ................................................... 50 
7.8 
Adverse Events/Adverse Device Effects and Device Deficiencies ............... 50 
7.8.1 
Adverse Event/Adverse Device Effect Definitions ............................ 50 
7.8.2 
Serious Adverse Event/Serious Adverse Device Effect/Unanticipated 
Adverse Device Effect Definitions .................................................... 51 
7.8.3 
Unanticipated serious adverse device effect (USADE) ..................... 52 
7.8.4 
Reporting of Adverse Events/Adverse Device Effects ...................... 52 
7.8.4.1 
Methods for Eliciting Adverse Events/Adverse Device Effects .......... 52 
7.8.4.2 
Follow-up of Subjects with Adverse Events ...................................... 53 
7.8.5 
Reporting of Serious Adverse Event/Serious Adverse Device Effects
 ........................................................................................................ 53 
7.8.6 
Device deficiencies .......................................................................... 54 
7.9 
Data Quality Assurance ................................................................................... 54 
7.9.1 
Monitoring, Audits and Inspections ................................................... 54 
7.9.2 
Subject Records and Source Data ................................................... 55 
7.9.3 
Access to Source Data and Documentation ..................................... 55 
7.9.4 
Training of Staff ................................................................................ 55 
7.9.5 
Data and Quality Management ......................................................... 56 
7.10 Statistical Methods and Determination of Sample Size ................................. 56 
7.10.1 
Statistical Evaluation of Performance and Safety Variables ............. 56 
7.10.1.1 
Data Sets to be Analysed ................................................................. 56 
7.10.1.2 
Definitions ........................................................................................ 57 
7.10.1.3 
Summary Statistics .......................................................................... 57 
7.10.1.4 
Primary Performance Analysis ......................................................... 57 
7.10.1.5 
Secondary Performance Analyses ................................................... 58 
7.10.1.6 
Demographic and Other Baseline Characteristics ............................ 59 
7.10.1.7 
Extent of Device Usage .................................................................... 59 
7.10.1.8 
Concomitant Treatment .................................................................... 59 
7.10.1.9 
Adverse Events/Adverse Device Effects .......................................... 59 
7.10.1.10 Other Safety Assessments (if applicable) ......................................... 60 
7.10.1.11 Other Variables (if applicable) .......................................................... 60 
7.10.2 
Handling of Drop-outs and Missing Data .......................................... 60 

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7.10.3 
Determination of Sample Size .......................................................... 60 
7.10.4 
Interim Analysis ................................................................................ 61 
7.10.5 
Procedures for Reporting any Deviations from the Original Statistical 
Analysis Plan ................................................................................... 61 
7.11 Amendments to the Clinical Investigation Plan ............................................. 61 
7.12 Deviations from the Clinical Investigation Plan ............................................. 61 
7.13 Report and Publication .................................................................................... 62 
8 
ETHICS ....................................................................................................................... 63 
8.1 
Institutional Ethics Review .............................................................................. 63 
8.2 
Ethical Conduct of the Clinical Investigation ................................................. 63 
8.3 
Subject Information and Consent ................................................................... 63 
9 
SUBJECT PROTECTION PROCEDURES ................................................................. 64 
9.1 
Procedures in Case of Medical Emergency.................................................... 64 
9.2 
Subject Data Protection ................................................................................... 64 
9.3 
Insurance .......................................................................................................... 64 
10 
CLINICAL INVESTIGATION TIME TABLE AND TERMINATION ............................... 65 
11 
REFERENCES ............................................................................................................ 66 
12 
SIGNATURES ............................................................................................................. 68 
13 
CLINICAL INVESTIGATION PLAN AGREEMENT FORM ......................................... 69 
14 
APPENDICES ............................................................................................................. 70 
14.1 Helsinki Declaration ......................................................................................... 71 
 
 

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3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
3.1 
List of Abbreviations 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
CIP 
Clinical Investigation Plan 
CRF 
Case Report Form 
DMC 
FAS 
Data Monitoring Committee 
Full analysis set 
IEC 
PPS 
Independent Ethics Committee 
Per protocol set 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
IRB 
Institutional Review Board 
UAE 
UADE 
USADE 
Unanticipated Adverse Event 
Unanticipated Adverse Device Effect 
Unanticipated Serious Adverse Device Effect  
 
 
 
 
 
 
 
 
 
 
 
 
 

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4 
CLINICAL INVESTIGATORS AND CLINICAL INVESTIGATION 
ADMINISTRATIVE STRUCTURE 
COORDINATING CLINICAL INVESTIGATOR 
Name: 
Prof. Hans Christoph Diener 
Address: 
Klinik für Neurologie, Universitätsklinikum Essen. Hufelandstr. 55,  
D-45147 Essen, Germany 
Phone: 
+49 (0)201 723 2460 
Fax:  
+49 (0)201 723 5901 
E-mail: 
hans.diener@uk-essen.de 
 
CLINICAL INVESTIGATION SITE(S) 
SITE NO: 1 
 
Name: 
Prof. Hans Christoph Diener 
Address: 
Klinik für Neurologie, Universitätsklinikum Essen. Hufelandstr. 55,  
D-45147 Essen, Germany 
Phone: 
+49 (0)201 723 2460 
Fax:  
+49 (0)201 723 5901 
E-mail: 
hans.diener@uk-essen.de 
 
SITE NO: 2 
Name: 
Prof. Andreas Straube 
Address: 
Klinik für Neurologie, Ludwig-Maximilians-University Munich, Klinikum        
Grosshadern, Marchioninistr. 15, D-81377 Munich, Germany 
Phone: 
+49 (0)89 4400 73900 
Fax:  
+49 (0)89 4400 73677  
E-mail: 
Andreas.Straube@med.uni-muenchen.de 
 
 

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SITE NO: 3   
Name: 
Priv.-Doz. Dr. Charly Gaul 
Address: 
Migräne- und Kopfschmertzklinik Königstein, Ölhühlweg 31, D-61462 
Königstein im Taunus, Germany 
Phone: 
+49 (0)6174 29040 
Fax:  
+49 (0)6174 2904100 
E-mail: 
c.gaul@migraine-klinik.de 
 
   SITE NO: 4 
Name: 
Dr. Uwe Reuter 
Address: 
Neurologische Klinik und Poliklinik, Charité Campus Mitte, Schumanstr. 20/21, 
D-10117 Berlin, Germany 
Phone: 
+49 304 50560274 
Fax:  
+49 304 504560932 
E-mail: 
uwe.reuter@charite.de 
 
   SITE NO: 5 
Name: 
Prof. Arne May 
Address: 
Institut für Systemische Neurowissenschafte, Universitätsklinikum Hamburg-
Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany 
Phone: 
+49 40 7410 59189 
Fax:  
+49 40 7410 59955 
E-mail: 
a.may@uke.uni-hamburg.de 
   SITE NO: 6 
Name: 
Prof. Peter J. Goadsby 
Address: 
Neurology dept., Wellcome Foundation Building, King’s College London, 
Denmark Hill Campus, London SE5 9PJ, UK 
Phone: 
+44 (0) 20 3299 3106 (PA) 
E-mail: 
profgoadsby.research@gmail.com 

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   SITE NO: 7 
Name: 
Dr. Fayyaz Ahmed 
Address: 
Neurology dept., Hull Royal Infirmary, Anlaby Road, Hull HU3 2JZ, UK 
Phone: 
+44 (0)1482 875875 
Fax:  
+44 (0)1482 675213 
E-mail: 
fayyaz.ahmed@hey.nhs.uk 
 
  SITE NO: 8 
Name: 
Dr. Alok Tyagi 
Address: 
Neurology dept., The Southern Hospital, 1345 Govan Road, Glasgow G51 
4TF, UK 
Phone: 
+44 (0)141 201 7542 
Fax:  
+44 (0)141 201 2999 
E-mail: 
alok.tyagi@nhs.net 
 
  SITE NO: 9 
Name: 
Dr. Nicholas Silver 
Address: 
Neurology dept.,The Walton Centre, Lower Lane, Fazakerley, Liverpool L9 7LJ, 
UK 
Phone: 
+44 (0)151 525 3611 
Fax:  
+44 (0)151 529 5500 
E-mail: 
nicholas.silver@thewaltoncentre.nhs.uk 
 
   SITE NO: 10 
Name: 
Dr. Alexandra Sinclair 
Address: 
School of Clinical and Expermental Medicine, College of Medical and Dental 
Sciences, Room WX2.19, Institue of Biomedial Research (West), The 
University of Birmingham, Wolfson Drive, Edgbaston, Birmingham B15 2TT, 
UK 

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Phone: 
+44 (0)121 414 8857 
Fax:  
 
E-mail: 
A.B.Sinclair@bham.ac.uk 
 
   SITE NO: 11 
Name: 
Dr. Messoud Ashina 
Address: 
Danish Headache Center, Nordre Ringvej 67, Area North, House 14, DK-2600  
Glostrup, Denmark 
Phone: 
+45 38 63 22 75 
Fax:  
+45 38 63 30 71 
E-mail: 
ashina@dadlnet.dk 
 
   SITE NO: 12 
Name: 
Dr. Anne Christine Buckley Poole 
Address: 
Sandvika Nevrosenter AS, Postboks 223, NO-1300 Sandvika, Norway 
Phone: 
+47 67 522080 
Fax:  
+47 67 522081 
E-mail: 
tine@poole.no 
 
   SITE NO: 13 
Name: 
Prof. Till Sprenger 
Address: 
DKD HELIOS Klinik Wiesbaden, Aukammallee 33, D-65191, Wiesbaden, 
Germany 
Phone: 
+49 (0) 611 577-430  
Fax:  
+ 49 611 577-311  
E-mail: 
Till.Sprenger@helios-kliniken.de  
 
 
 

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   SITE NO: 14  
Name: 
Dr. Miguel JA Làinez 
Address: 
Dept. of Neurology, University Clinic Hospital, Catholich University of 
Valencia, Avda Blasco Ibànez 17, ES-46010 Valencia, Spain 
Phone: 
+34 963 868863 
Fax:  
+34 963 900321 
E-mail: 
miguel.lainez@sen.es 
 
   SITE NO: 15      
Name: 
Prof. Michel D. Ferrari 
Address: 
Dept. of Neurology, K5-Q-104, Leiden University Center, Albindusdreef 2, NL-
2333 ZA Leiden, The Netherlands 
Phone: 
+31 71 5262895 
Fax:  
+31 71 5248253 
E-mail: 
m.d.ferrari@lumc.nl 
 
SITE NO: 16 
Name: 
Dr. Delphine Magis 
Address: 
Neurology dept. University of Liège, CHR Citadelle, Boulevard du 12ème de 
Ligne 1, B-4000 Liège, Belgium 
Phone: 
+32 4230 7811 
E-mail: 
dmagis@chu.ulg.ac.be 
 
SITE NO: 17    
Name: 
Dr. Dimos Mitsikostas 
Address: 
Neurology Clinic, Aginition Hospital, 72-74 Vas. Sofias Avenue, GR-11528  
Athens, Greece 
Phone: 
+30 2107 2611148 
Fax:  
+30 2017 261369 
E-mail: 
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SITE NO: 18   
Name: 
Dr. Pablo Irimia Sieira 
Address: 
Planta 5, Servicio de Neurologica, Av. Pio XII, 36 ES-31008 Pamplona, Spain 
Phone: 
+32 948 255 400 
Fax:  
+32 948 296 500 
E-mail: 
pirimia@unav.es 
SITE NO:  19   
Name: 
Dr. Farooq Maniyar 
Address: 
Basildon University Hospital, Nethermayne, Basildon, Essex, SS16 5NL, UK 
Phone: 
+44 (0) 1268 524900 
E-mail: 
farooq.maniyar@buth.nhs.uk 
 
SITE NO:  20   
Name: 
Dr. Tobias Freilinger 
Address: 
Zentrum für Neurologie und Epileptologie, Hertie-Institut für Klinische 
Hirnforschung, Universitätsklinikum Tübingen, Hoppe-Seyler-Str. 3, D-72076 
Tübingen, Germany 
Phone: 
+49 (0)7071 298-2141 
E-mail: 
tobias.freilinger@uni-tuebingen.de 
 
 
SITE NO:  21   
Name: 
Dr. Margarita Sánchez del Rio 
Address: 
Servicio de Neurologia, Hospital Ruber Internacional, Calle de la Máso, 38, 
ES-28034 Madrid, Spain 
Phone: 
+34 91 387 52 50 
E-mail: 
msanchezdelrio@ruberinternacional.es 
 
 

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SITE NO:  22   
Name: 
Dr. Patricia Pozo Rosich 
Address: 
Headache Unit, University Hospital Vall d'Hebron; Passeig de la Vall d'Hebron, 
119-129, ES-08035 Barcelona, Spain 
Phone: 
+34 934 89 30 
E-mail: 
ppozorosich@yahoo.com 
 
SPONSOR REPRESENTATIVE & PROJECT LEADER 
Name: 
Annelie Andersson, Sr. Director, Clinical Affairs, EU 
Address: 
electroCore, Skårs Led 3, 412 63 Göteborg, Sweden 
Mobile: 
+46 (0)721 803076 
Fax:  
+46 (0)31 7037101 
E-mail: 
annelie.andersson@electrocorellc.com 
OTHER SPONSOR REPRESENTATIVE 
Name: 
Matina Nouni-Starck, Clinical Trial Coordinator, Clinical Affairs, EU 
Address: 
electroCore, Skårs Led 3, 412 63 Göteborg, Sweden 
Phone: 
+46 (0)31 7037127 
Mobile: 
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Fax:  
+46 (0)31 7037101 
E-mail: 
matina.nouni-starck@electrocorellc.com 
BIOSTATISTICIAN 
Name: 
NAMSA        
Address: 
St Louis Park 
400 Highway 169 South, suite 500 
Minneapolis, Minnesota, USA 55426 
 
Phone: 
+1 763 287 3830 
Fax:  
+1 763 287 3836 
 
 

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SAFETY OFFICER 
Name: 
Juana Marin 
E-mail: 
jcamarin@hotmail.co.uk 
 
CLINICAL DATA MANAGER(S) 
Name: 
Arde Montasser, Consultant 
E-mail: 
arde.montasser@electrocorellc.com 
 
LEAD CLINICAL INVESTIGATION MONITOR  
Name: 
Emma de Launay  
Mobile: 
+44 (0)7967 025866 
E-mail: 
emma.delaunay@electrocorellc.com 
BELGIUM & THE NETHERLANDS 
Name: 
Marcel van den Heuvel,  
Phone: 
+31 (0) 6 42228422 
E-mail: 
marcelvandenheuvel@me.com 
 
   
GERMANY  
Name: 
Sven Wachlin   
Phone: 
+49 (0) 6083 9589810 
Mobile: 
+49 (0) 179 5412291 
Fax:  
+49 (0) 6083 9589811  
E-mail: 
sven.wachlin@climoserv.com 
 
 
 GREECE 
 Name: 
Marinos Xagoraris 
 Email: 
marxagoraris@yahoo.gr 
 

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 NORWAY AND DENMARK 
Name: 
Annelie Andersson, Sr. Director, Clinical Affairs, EU 
Address: 
electroCore, Skårs Led 3, 412 63 Göteborg, Sweden 
Mobile: 
+46 (0)721 803076 
 
 SPAIN 
Name: 
Sergio Sevilla 
Phone: 
+34 658 27 1136 
Fax: 
+34 93 198 02 33 
Email: 
Sergio.sevilla@bcnconsultant.com 
 
UK  
Site 6,7,9,10 and 19 
Name:              Emma de Launay 
Mobile:           +44 (0)796 7025866 
Email:               emma.delaunay@electrocorellc.com 
 
Site 8 
Name:               Annelie Andersson 
Phone:            +46 (0)721 803076 
E-mail:            annelie.andersson@electrocorellc.com 
 
 
AUTHOR(S) 
Name: 
Annelie Andersson, Sr. Director, Clinical Affairs, EU 
Address: 
electroCore, Skårs Led 3, 412 63 Göteborg, Sweden 
Mobile: 
+46 (0)721 803076 
Fax:  
+46 (0)31 7037101 
E-mail: 
annelie.andersson@electrocorellc.com 
 
DATA MONITORING COMMITTEE (DMC) 

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Not applicable 

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5 
INTRODUCTION 
 
5.1 
Background 
Migraine headache is a common and potentially debilitating disorder. The World Health 
Organization (WHO) estimates a worldwide prevalence of current migraine of 10%, and a 
lifetime prevalence of 14%. Approximately 3,000 migraine attacks occur every day for each 
million persons within the general population worldwide, and the number of workdays lost in 
the United States attributable to migraine has been estimated at more than 150 million per 
year.1 
The International Headache Society (IHS) defines migraine as a recurrent headache disorder 
manifesting in attacks lasting 4-72 hours. Typical characteristics of the headache are unilateral 
location, pulsating quality, moderate or severe intensity, aggravation by routine physical 
activity, and association with nausea, allodynia, and/or photophobia and phonophobia. It may 
occur with or without prodromal symptoms (including personality changes, irritability, changes 
in appetite, dizziness, etc.)  Some patients may also experience aura, which may consist of 
neurologic symptoms, such as scotomas and/or or visual scintillations, which, when present, 
typically occur within 60 minutes of the onset of the pain phase of the migraine.  The 
pathophysiology of migraine headaches is not clearly understood. Initially migraine headaches 
were thought to be of vascular origin. Evidence now supports a neurogenic cause, with 
vascular changes occurring as more of an epiphenomenon.2 
Migraines present with varying frequency and intensity, and with and without identifiable 
triggers such as foods, stress, alcohol, odors, and sleeplessness.  Migraineurs who suffer with 
headache pain on more than fifteen days per month are referred to as “chronic migraineurs”, 
while those suffering fewer days per month are referred to as “episodic”.  There is no 
consensus among headache specialists regarding what causes an individual to be a chronic 
versus episodic migraineur, and there is no single standard of care for patients presenting with 
migraine symptoms, independent of triggers, if known.  Typically, however, the more severe, 
and more frequent the sufferer experiences migraines, the more likely that individual will seek 
out, or be referred to a neurologist for specialized treatment. 
  
                                               
 
 
 
1 Von Korff M, Stewart W, Simon D, Lipton R. Migraine and Reduced Work Performance: A Population-
Based Diary Study. Neurology. 1998; 50:1741-1745. 
2 Cutrer FM, Charles A. The neurogenic basis of migraine. Headache. Oct 2008;48(9):1411-4. 

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Treatment choices for acute migraine are based on headache severity, migraine frequency, 
associated symptoms, and co-morbidities.  However, achieving satisfactory treatment 
outcomes is challenging because of substantial rates of inadequate response to medications 
and difficulty in predicting individual response to a specific agent or dose. 
Abortive therapy is used as early as possible after the onset of symptoms.  Effective first-line 
therapies for mild to moderate migraine are non-prescription aspirin, acetaminophen, non-
steroidal anti-inflammatory drugs and combination analgesics containing acetaminophen, 
aspirin, and caffeine.  Migraine specific medications, a class of which are termed triptans 
(serotonin (5-HT) receptor agonists), are first-line therapies for moderate to severe migraine, or 
mild to moderate migraine that has not responded to adequate doses of simple 
analgesics.  However, triptans have to be avoided in patients with vascular disease, 
uncontrolled hypertension, or hemiplegic migraine. While different formulations of a specific 
triptan may be used in the same 24-hour period, only one type of triptan may be used during 
this time frame. Triptan overuse can lead to increased frequency of headache in some 
patients, a phenomenon termed medication overuse headache. Additionally, triptan 
administration can elicit a behavioural syndrome of enhanced sensitivity to surrogate triggers of 
migraine that is maintained for weeks following discontinuation of drug, a phenomenon termed 
“triptan-induced latent sensitization”. 3 
Anticonvulsants that interact with the GABAergic system seem to have a positive effect in 
reducing the frequency of migraine attacks. Divalproex sodium (Depakote) and topiramate 
(Topamax) are most commonly used, and are FDA-approved for migraine prophylaxis. Both 
drugs have class I evidence supporting their effectiveness in decreasing the frequency of 
migraine attacks.  
Despite advances in the medical and surgical management of this challenging disorder, clinical 
data have revealed a significant proportion of patients who do not adequately respond to 
pharmacologic intervention and remain symptomatic.  Approximately 40% of all migraine 
attacks do not adequately respond to a given triptan or any other substance.4  In addition, 
many of the current therapeutic options come with significant risks ranging from GI and 
vascular injury to birth defects and surgical complications.  
Alternative therapy that may be effective for treating migraines could involve electrical 
stimulation of vagal neural pathways involved in mediating the causes and symptoms of 
migraine. Cyberonics, Inc., markets an implanted vagus nerve stimulator for treatment of 
epilepsy and long-term adjunctive treatment for treatment-resistant depression. Published 
reports of studies of these indications also describe positive effects on headache and migraine 
                                               
 
 
 
3 De Felice M., Triptan-induced enhancement of neuronal nitric oxide synthase in trigeminal 
ganglion dural afferents underlies increased responsiveness to potential migraine triggers. Brain 
(2010 Aug) 133(Pt 8):2475-88  
4 Edwards KR, Norton J, Behnke M. Comparison of intravenous valproate versus intramuscular 
dihydroergotamine and metoclopramide for acute treatment of migraine headache. Headache. Nov-
Dec 2001;41(10):976-80. 

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pain5,6,7.  Additionally two non-invasive devices were recently approved by FDA and are 
available for the treatment of migraine.  The Cefaly® device, which applies electric current to 
the skin and underlying body tissues to stimulate branches of the trigeminal nerve, is indicated 
for the prevention of migraine. The eNeura device is a non-invasive device that uses single-
pulse Transcranial Magnetic Stimulation to include very mild current that can depolorize 
neurons in the brain and is indicated for the acute treatment of pain associated with migraine 
with aura. 
There remains a considerable unmet need for a novel, non-pharmaceutical, non-invasive way 
to prevent migraine symptoms.  Such a treatment has the potential to not only improve patient 
quality of life, but also to reduce lost workdays and reduce healthcare expenditure for the large 
number of people who suffer from migraines. 
ElectroCore® has designed a non-invasive vagus nerve stimulation (nVNS) device called the 
gammaCore® device. The gammaCore® device is a hand-held, battery-powered unit that 
produces a proprietary electrical waveform in the vicinity of the vagus nerve in the neck.  Each 
treatment, or dose, is relatively brief (120 seconds) and the user maintains control over the 
stimulation intensity.  The gammaCore® device was the subject of a home-use pilot study for 
the acute relief of migraine under Investigational Device Exemption G110224.  Of 30 enrolled 
patients (25 females, five males, median age 39), two treated no attacks, and one treated aura 
only, leaving a Full Analysis Set of 27 treating 80 attacks with pain. Four of 19 (21%) who 
treated that was moderate or severe headache at baseline, were pain-free rate at two hours 
post-stimulation treatment. The pain-free rate for all baseline moderate or severe attacks was 
12/54 (22%). No unanticipated, serious or severe adverse events were reported.8 
GammaCore® was further studied in a home-use randomized sham-controlled pilot study for 
the prevention of chronic migraine attacks under Investigational Device Exemption G120120.  
Of the 59 enrolled patients, (53 females, 6 males, average age of 40 years), forty-eight patients 
(26 in the active group and 23 in the sham group) completed both the 1-month baseline period 
and the two-month randomized period per protocol.  The average number of headache attacks 
experienced in the active group by 2 days compared to a decrease of 0.1 days in the sham 
group, per a 28 day period.  After the two-month randomised/controlled period, all patients 
were then permitted to roll over to active (open label) therapy for 6 months, with headache 
days per month tracked on a bimonthly basis.  Increased improvement in headache days per 
                                               
 
 
 
5 Cecchini AP, Mea E, Tullo V, Curone M, Franzini A, Broggi G, Savino M, Bussone G, Leone 
M. Vagus nerve stimulation in drug-resistant daily chronic migraine with depression: preliminary data. 
Neurol Sci. 2009 May;30 Suppl 1:S101-4. 
6 Lenaerts ME, Oommen KJ, Couch JR, Skaggs V. Can vagus nerve stimulation help migraine? 
Cephalalgia. 2008 Apr;28(4):392-5 
7 Mauskop A. Vagus Nerve Stimulation Relieves Chronic Refractory Migraine and Cluster Headaches. 
Cephalalgia 2005;25:82-86 
8 Goadsby, P. J., et al. "Effect of noninvasive vagus nerve stimulation on acute migraine: An open-label 
pilot study." Cephalalgia (2014): 0333102414524494. 

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month was experienced across the combined cohorts during the open label period.  No 
unanticipated or serious device related adverse events were reported. 
With respect to the theoretical cardiac and respiratory side effects of non-invasive treatment, 
historically, stimulation of the vagus nerve is associated with adverse side effects, including 
bradycardia and bronchoconstriction. These effects were shown to be the result of in 
discriminant stimulation of all fibers in the vagal bundle (the vagus nerve is primarily comprised 
of A and C fibers), which could be avoided by specifically tuning the electrical signals to 
selectively stimulate only the A fibers.  This is possible because of the difference in electric 
field strengths necessary to activate the different fiber types. 9,10 
The intensity, pulse duration and frequency of gammaCore® VNS stimulation parameters have 
been optimized to induce signals in the large, myelinated Aβ fibers of the cervical branch of the 
vagus nerve. Since gammaCore activates only the low threshold afferent Aβ fibers, versus the 
high threshold efferent C-fibers that innervate the heart, there is no known risk for adverse 
cardiac or other systemic parasympathetic effects. 
Even so, electroCore has conducted pre-clinical studies to assess the potential risk of vagus 
nerve overstimulation on the heart and airways. Several studies were conducted in Beagles 
with hypersensitized airways (worst case for airway reactivity) at maximum stimulation output 
for 2 minutes.  Review of heart rate and airway resistance before, during and after stimulation 
indicated that there were no significant adverse changes associated with stimulation.  These 
results are consistent with the human clinical experience with the gammaCore® device. 
Regarding the theorized mechanism of action, afferent fibers from the vagus nerve enter the 
brain and synapse onto the nucleus tractus solitarius (NTS) in the brain stem11, making 
connections with many structures in the brain including the locus coeruleus (LC), the 
periaqueductal gray (PAG) and the raphe nucleus (RN).12 These structures are known to 
control the release of key inhibitory neurotransmitters.  Numerous animal and clinical studies 
over the last 25 years have implicated the activity of these structures, in particular the LC, in 
the mechanism of action of VNS to inhibit seizures.  Indeed, VNS has been shown to increase 
levels of norepinephrine (NE), serotonin and GABA.13 These structures also make projections 
                                               
 
 
 
9 Castoro, Mark A., et al. "Excitation properties of the right cervical vagus nerve in adult dogs." 
Experimental neurology 227.1 (2011): 62-68. 
10 Yoo, Paul B., et al. "High-resolution measurement of electrically-evoked vagus nerve activity in the 
anesthetized dog." Journal of neural engineering 10.2 (2013): 026003. 
 
11  Bonham, Ann and Chao-Yin Chen. Synaptic Transmission in the Nucleus Tractus Solitarius 
(NTS).  Advances in Vagal Afferent Neurobiology.  Bradley J. Undem and Daniel Weinreich, eds. 
CRC Press, 2005.193. 
12 Ruffoli R, Giorgi FS, Pizzanelli C, Murri L, Paparelli A, Fornai F: The chemical neuroanatomy of vagus 
nerve stimulation. J Chem Neuroanat; 2011 Dec;42(4):288-96 
13 Beekwilder JP, Beems T.Overview of the clinical applications of vagus nerve stimulation. J Clin 
Neurophysiol. 2010 Apr;27(2):130-8 

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to the TNC where they inhibit glutamate release.14 In an animal study, described below, high 
levels of glutamate in the TNC were prevented and/or reversed following acute nVNS with 
gammaCore®. It has been hypothesized that the acute relief of headache pain resulting from 
nVNS is due to this inhibition, and that the modulation of activity among the cells in the TNC 
(neurons and astrocytes) may inhibit the ability of these cells to subsequently over-express 
glutamate, potentially providing a prophylactic benefit. 
The mechanism of action of non-invasive vagus nerve stimulation (nVNS) for the treatment of 
trigeminal allodynia was studied in an accepted animal model of migraine. Rats were 
repeatedly infused with inflammatory mediators directly onto the dura, which led to chronic 
trigeminal allodynia. Administration of nVNS for 2 minutes decreased periorbital sensitivity in 
rats with periorbital trigeminal allodynia for up to 3.5 hours after stimulation. Using 
microdialysis, levels of extracellular neurotransmitters in the trigeminal nucleus caudalis (TNC) 
were quantified allodynic rats showed a 7.7 ± 0.9-fold increase in extracellular glutamate in the 
TNC after i.p. administration of the chemical headache trigger glyceryl trinitrate (GTN; 0.1 
mg/kg). Allodynic rats that received nVNS had only a 2.3 ± 0.4-fold increase in extracellular 
glutamate after GTN, similar to the response in control naive rats. When nVNS was delayed 
until 120 minutes after GTN treatment, the high levels of glutamate in the TNC were reversed 
after nVNS. The nVNS stimulation parameters used in this study did not produce significant 
changes in blood pressure or heart rate. These data suggest that nVNS may be used to treat 
trigeminal allodynia.15 
 
The device, gammaCore®, is CE-marked and currently commercially available for the 
treatment of migraine. 
 
The purpose of this multi-center, prospective, double-blind, randomized, sham-controlled study 
is to collect further clinical data related to the extended safety and maintance of effect of non-
invasive vagus nerve stimulation with the gammaCore device for the prophylactic treatment of 
episodic migraine. The study is one of two identical studies (North America and EU) to 
compare the gammaCore-R against a sham treatment for the prophylactic treatment of 
episodic migraine. At the conclusion of both studies, the data will be combined for further 
analysis. 
 
 
                                               
 
 
 
14 Travagli, R.A. and Williams, J.T. (1996) Endogenous monoamines inhibit glutamate transmission in 
the spinal trigeminal nucleus of the guinea-pig. J. Physiol. 491, 177–185 
15 Oshinsky, Michael L., et al. "Noninvasive vagus nerve stimulation as treatment for trigeminal 
allodynia." PAIN® 155.5 (2014): 1037-1042. 
 

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6 
CLINICAL INVESTIGATION OBJECTIVES  
6.1 
Primary Objective 
The primary objective is the difference between the gammaCore®-R and the sham 
treatment groups in mean reduction in number of migraine days during the last four 
weeks in the twelve-week randomized period compared with the four week run-in 
period  
 
 
6.2 
Secondary Objective 
 
To evaluate rate of responders for the gammaCore®-R group compared to the sham 
group. A responder is defined as recording at least 50% reduction in migraine days 
during the last four weeks in the twelve-week randomization period compared to the 
four week run-in period. 
 
To evaluate difference between the gammaCore®-R and sham treatment groups in 
mean reduction in number of headache days during the last four weeks in the twelve-
week randomized period compared to the four week run-in period.  
 
 
To evaluate difference between the gammaCore®-R and the sham treatment groups in 
the mean reduction in acute headache medications taken during the last four weeks in 
the twelve-week randomized period compared to the four week run-in period. 
 
Compare improvement in headache disability using Headache Impact Test-6 (HIT-6) 
 
Compare improvement in Migraine Disability Assessment (MIDAS)  
 
Compare Quality of Life  EQ-5D-5L 
 
Reduction of number of headache/migraine days in the open label period compared to 
baseline run-in period 
 
Adverse events 
Other: 
 
Blinding questions 
 
Subject satisfaction question; and 
 
Ease of use 

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7 
DESIGN OF THE CLINICAL INVESTIGATION 
7.1 
Overall Clinical Investigation Design 
The study is a prospective double blind, randomized, sham-controlled, multi-center 
investigation designed for comparison of two parallel groups, gammaCore®-R (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 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 group will continue to receive an active treatment. 
 
Figure 1 
Overall Design 
 
 
 
 
 
 
 
 
 
 
   4 weeks                            12 weeks                   24 weeks 
                                        Randomized  period        Open label period 
 
 
 
Run-in 
Period 
gammaCore®-
R 
Sham 
Open Label 

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7.2 
Clinical Investigation Procedures and Definitions 
 
7.2.1 
Schedule of Clinical Investigation Events 
7.2.1.1 
Definition of headache/migraine day 
The subject will record a headache event that occurs in a 24 hour period as “a migraine day” if 
it fulfils one of the following: 
• Meets criteria for 1.1 Migraine without aura 
• Meets criteria for 1.2 Migraine with aura  
• Believed by the patient to be migraine at onset and relieved by a triptan, ergot derivative or 
high dose NSAID 
The subject will record a “headache day” in the subject diary if it does not meet the ICHD-3 
beta definition of a migraine headache.  Only headache’s that last more than 30 minutes 
should be considered a headache day. 
For a headache day, a “day” will be defined as any event that occurs within the calendar 
day.  For a migraine day, a “day” will be defined as any migraine event that occurs within a 24 
hour period. For example, if a subject’s migraine starts at 09.00 in the morning and ends at 
08.30 in the morning the next day, it is considered one migraine day and two headache days. 
 
 
7.2.1.2 
Visit 1, Day -28 (start of four week run-in period) 
At Visit 1, the following assessments will be performed after the subject and the Investigator 
have signed the Consent form:  
 
Demographics  
o Age 
o Sex 
o Race 
 
Concomitant medication 
 
Inclusion and exclusion criteria 
 
Medical and Surgical history 
 
History of migraine 
 
Physical examination 

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 
Blood pressure and weight 
 
Urine pregnancy test for fertile women 
 
ECG 
 
Subject will be instructed how to complete the daily migraine/headache diary. The diary 
captures the following information: 
o Start date and time of migraine/headache attack 
o  Medication taken for the attack 
o  If the attack was accompanied with an aura 
o  Any adverse events 
 
Provide subject diary guidance handout 
Book a visit 2 appointment 4 weeks +/- 3 days from visit 1. 
 
7.2.1.3 
Visit 2, Day 0 (4 weeks +/-3 days after run-in period) 
At visit 2 the following assessment will be performed: 
 
Check diary from the run-in period 
 
Re-check inclusion and exclusion criteria 
 
Concomitant medication 
 
If still fulfilling all criteria, randomize patient 
 
Complete HIT-6, MIDAS and EQ-5D-5L (paper form) 
 
Device training by un-blinded trainer 
 
Instruct the subject how to complete the diary information 
 
Adverse events 
 
Subject will be instructed to fill in a migraine/headache diary daily. The diary captures 
the following information: 
o Prophylactic stimulation three times per day 
o Start date and time of migraine/headache attack 
o Any medication taken for the attack 
o If the attack was accompanied with an aura 
o Any adverse events 

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Subjects will be instructed to treat three times per day, 2 consecutive bilateral 
stimulations, upon waking, six to eight hours following the first daily treatment, and six 
to eight hours following the second daily treatment (one stimulation on the right side 
immediately followed by a second stimulation on the left side). 
 
Book a phone call 1 week +/- 3 days from visit 2.  
7.2.1.4 
Visit 3, Day 7 Phone call (1 week +/- 3 days after visit 2)  
During the phone call visit the un-blinded trainer will discuss the following with the subject: 
 
Any new or change in medication 
 
Use of the device 
 
Remind subject to enter information into migraine/headache diary 
 
Any Adverse event 
 
Blinding question 
Book a visit 4 appointment day 28 (+/- 3 days) . 
 
7.2.1.5 
Visit 4, Day 28 (+/- 3 days) 
At visit 4 the following assessment will be performed: 
 
 
Check diary from the first 28 days of the randomized period 
 
Concomitant medication 
 
Complete HIT-6  and EQ-5D-5L 
 
Un-blinded trainer shall follow-up the use of the device 
 
Review the entry in the diary and instruct the subject to continue to enter information 
 
Adverse events 
 
Subject will be instructed to fill in a migraine/headache diary daily. The diary captures 
the following information: 
o Prophylactic stimulation three times per day 
o Start date and time of migraine/headache attack 
o Any medication taken for the attack 
o If the attack was accompanied with an aura 
o Any adverse events 

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Subjects will be instructed to treat three times per day, 2 consecutive bilateral 
stimulations, upon waking, six to eight hours following the first daily treatment, and six 
to eight hours following the second daily treatment. 
Book a visit 5 phone call, day 56 (+/- 5 days).  
 
7.2.1.6 
Visit 5, Day 56 Phone call (+/- 5 days)  
During the phone call visit the un-blinded trainer will discuss the following with the subject: 
 
 
Any new or change in medication 
 
Use of the device 
 
Remind subject to enter information into migraine/headache diary 
 
Any adverse event 
 
Remind subject to complete HIT-6 and EQ-5D-5L 
 
Book a visit 6 appointment, day 84 (+/- 5 days) . 
 
7.2.1.7 
Visit 6, Day 84 (+/- 5 days) 
At visit 6 the following assessment will be performed: 
 
 
Collect the device(s) from the randomized period 
 
Complete HIT-6, MIDAS and EQ-5D-5L (paper form) 
 
Blood pressure and weight 
 
Concomitant medication 
 
Blinding question 
 
Satisfaction question 
 
Easy to use 
 
Device training with gammaCore®-R (active treatment) by un-blinded trainer 
 
Hand out gammaCore®-R 
 
Review the entry in the diary and instruct the subject to continue to enter information 
 
Adverse events 

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 
Subject will be instructed to fill in a migraine/headache diary daily. The diary captures 
the following information 
o Prophylactic stimulation three times per day 
o Start date and time of migraine/headache attack 
o Any medication taken for the attack 
o If the attack was accompanied with an aura 
o Any adverse events 
Subjects will be instructed to treat three times per day, 2 consecutive bilateral 
stimulations, upon waking, six to eight hours following the first daily treatment, and six 
to eight hours following the second daily treatment. 
 
Book a visit 7 phone call, day 91 (+/- 3 days) . 
 
7.2.1.8 
Visit 7, Day 91 Phone call (+/- 3 days) 
During the phone call visit the following will be discussed with the subject: 
 
Any new or change in medication 
 
Use of the device 
 
Remind subject to enter information into headache diary 
 
Any adverse event 
Book a visit 8 appointment, day 112  (+/- 3 days) . 
 
7.2.1.9 
Visit 8, Day 112 (+/-3 days)  
At visit 8 the following assessment will be performed: 
 
 
Complete HIT-6 and EQ-5D-5L 
 
Concomitant medication 
 
Review the entry in the diary and instruct the subject to continue to enter information 
 
Adverse events 
 
Subject will be instructed to fill in a migraine/headache diary daily. The diary captures 
the following information 
o Prophylactic stimulation three times per day 

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o Start date and time of migraine/headache attack 
o Any medication taken for the attack 
o If the attack was accompanied with an aura 
o Any adverse events 
 
Subjects will be instructed to treat three times per day, 2 consecutive bilateral 
stimulations, upon waking, six to eight hours following the first daily treatment, and six 
to eight hours following the second daily treatment. 
Book a visit 9 phone call, day 140 (+/- 5 days) . 
 
7.2.1.10 
Visit 9, Day 140 Phone call (+/- 5 days) 
During the phone call visit the following will be discussed with the subject: 
 
Any new or change in medication 
 
Remind subject to enter information into migraine/headache diary 
 
Adverse event 
 
Remind subject to complete HIT-6 and EQ-5D-5L 
 
Book a visit 10 appointment, day 168 (+/- 5 days). 
 
7.2.1.11 
Visit 10, Day 168 (+/- 5 days) 
At visit 10 the following assessment will be performed: 
 
 
Complete HIT-6, MIDAS and EQ-5D-5L 
 
Concomitant medication 
 
Review the entry in the diary and instruct the subject to continue to enter information 
 
Adverse events 
 
Subject will be instructed to fill in a migraine/headache diary daily. The diary captures 
the following information 
o Prophylactic stimulation three times per day 
o Start date and time of migraine/headache attack 
o Any medication taken for the attack 
o If the attack was accompanied with an aura 

Clinical Investigation Plan 
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o Any adverse events 
 
Subjects will be instructed to treat three times per day, 2 consecutive bilateral 
stimulations, upon waking, six to eight hours following the first daily treatment, and six 
to eight hours following the second daily treatment. 
 
Book a visit 11 appointment, day 210 (+/- 5 days). 
 
7.2.1.12 
Visit 11, Day 210 (+/- 5 days) 
At visit 11 the following assessment will be performed: 
 
 
Concomitant medication 
 
Review the entry in the diary and instruct the subject to continue to enter information 
 
Adverse events 
 
Subject will be instructed to fill in a migraine/headache diary daily. The diary captures 
the following information 
o Prophylactic stimulation three times per day 
o Start date and time of migraine/headache attack 
o Any medication taken for the attack 
o If the attack was accompanied with an aura 
o Any adverse events 
Subjects will be instructed to treat three times per day, 2 consecutive bilateral 
stimulations, upon waking, six to eight hours following the first daily treatment, and six 
to eight hours following the second daily treatment. 
Book a visit 12 appointment, day 252 (+/- 5 days).  
 
7.2.1.13 
Visit 12 Day 252 (+/- 5 days ) 
At visit 12 the following assessment will be performed: 
 
 
Review the entry in the diary 
 
Collect gammaCore®-R 
 
Complete HIT-6, MIDAS and EQ-5D-5L 
 
Blood pressure and weight 

Clinical Investigation Plan 
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Version: 3.0   
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Date: 1st September 2017 
 
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 
Satisfaction questions 
 
Easy to use 
 
Review medications and complete any medication page in the electronic case report 
form (e-CRF) 
 
Follow-up and complete any ongoing AE’s 
 
Fill out termination page in e-CRF 
 
7.2.2 
Clinical Investigation Flow Chart 
Procedures and outcome measures will be collected as described in the clinical investigation 
flow chart shown in  
Table 1 Clinical Investigation Flow Chart 
Period 
Run-
in 
Randomized 
Open label 
Visit number 
V1 
V2 
V3* 
V 4 
V5 
** 
V 6 
V7 * 
V 8 
V9  
** 
V 10 
V11 
V 12 
Week 
-4 
0 
1 
4 
8 
12 
13 
16 
20 
24 
30 
36 
 
Day 
-28 
1  
+/-3 
7  
+/-3 
28 
+/-3 
56 
+/- 5 
84 
+/-5 
91 
+/-3 
112 
+/- 3 
140
+/-5 
168
+/-5 
210 
+/-5 
252
+/-5 
Signed 
Consent Form 
  
 
 
 
 
 
 
 
 
 
 
Demographics  
  
 
 
 
 
 
 
 
 
 
 
Blood pressure 
and weight 
  
 
 
 
  
 
 
 
 
 
Inclusion/ 
Exclusion 
criteria 
 
  
 
 
 
 
 
 
 
 
 
History of 
migraine 
  
 
 
 
 
 
 
 
 
 
 
Concomitant 
medication 
 
 
 
 
 
 
 
 
 
 
 
 

Clinical Investigation Plan 
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Medical and 
surgical history 
  
 
 
 
 
 
 
 
 
 
 
Physical 
examination 
  
 
 
 
 
 
 
 
 
 
 
ECG 
  
 
 
 
 
 
 
 
 
 
 
Urine 
pregnancy 
test1 
  
 
 
 
 
 
 
 
 
 
 
Diary 
completion  
 
 
 
 
 
 
 
 
 
 
 
 
Device training 
and placement 
 
 
 
  
  
 
 
 
 
 
Collect  
device/ 
gammaCore®-
R 
 
 
 
 
 
  
 
 
 
 
 
HIT-63 
 
  
 
 
  
 
 
 
 
 
MIDAS3 
 
  
 
 
  
 
 
  
 
EQ-5D-5L3 
 
  
 
 
  
 
 
 
 
 
Adverse 
Event2 
 
 
 
 
 
 
 
 
 
 
 
 
Study 
Termination 
 
 
 
 
 
 
 
 
 
 
 
 
Blinding 
question 
 
 
  
 
  
 
 
 
 
 
Subject 
satisfaction 
question 
 
 
 
 
 
  
 
 
 
 
 
Easy to use 
question 
 
 
 
 
 
  
 
 
 
 
 
1 Fertile woman only 
2 All new events during the run-in will be reported under adverse events 
Call* - One week after the previous visit 
Call **- One month after the previous visit 
3 At visit 2 and 6 these questionnaires will be completed by the subjects on paper forms during the visit 

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7.3 
Discussion and Justification of Clinical Investigation Design, Including 
the Choice of Control Groups 
The study design (randomized, sham-controlled, parallel group) was chosen to evaluate the 
usefulness of the gammaCore®-R device for symptom improvement in subjects suffering 
migraine attacks compared to treatment with sham device.  
 
During the 4 week run-in (baseline) period and through the whole study the subjects will 
continue using their existing prescribed or over the counter (OTC) treatments for acute 
treatment. Preventive medications are not allowed throughout the study. 
 
Following the run-in period the subjects will be randomized to a 12 weeks self-treatment period 
with either an active or sham device. 
 
During the final 24 weeks (open label period) the study subjects randomized to the sham 
treatment group will be eligible to receive an active device. The subjects will be instructed to 
treat with the gammaCore®-R device three times daily with 6-8 hours between treatments. The 
subject will continue to record any medication taken to manage their migraine attacks.  
The primary objective is to compare the reduction of migraine days during the randomized 
period with the run-in period. 
 
7.3.1 
Prior and Concomitant Medication and Procedures 
Medication, which is considered necessary for the subject safety and well-being, may be given 
at the discretion of the Investigator.  
 
Subjects will document all medication usage during the investigation in the diary. The Clinical 
Investigator will check for any changes and update the e-CRF accordingly. 
 
Subjects may use abortive or pain relieving medications, prescribed or OTC, to relieve 
headache pain, if needed.  Subjects taking medication as preventative care for migraine are 
excluded from this study; thus eligible patients will not be asked to withhold any medication.  If 
after enrollment into the study it is determined that preventative medication is clinically 
indicated for a subject, the subject is permitted to take these medications as prescribed starting 
at week 24 of the study.  Subjects taking prophylactic medications for indications other than 
migraine that in the opinion of the clinician may interfere with the study, must refrain from 
changing the type, dose or frequency of medication for the duration of the study.  Examples 
include but are not limited to:  
 
Antidepressants – e.g. Tricyclics such as amitriptyline (Elavil) 
 
Beta Blockers – e.g. Propanolol (Inderal)  

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 
Anticonvulsants – e.g.Valproic Acid (Depakote) and Topiramate (Topamax).   
 
Subjects will document all medication usage during the treatment periods, including but not 
limited to migraine relief medications. 
 
 
7.4 
Selection of Population for the Clinical Investigation 
7.4.1 
Number of Subjects 
Up to 400 subjects will be screened / enrolled (informed consent signed) to obtain 
approximately 320 randomized subjects.  Up to 20 sites will participate. Enrolment is 
competitive, and the total enrolment at each site will depend on subject availability and, 
therefore, may not be evenly distributed among the sites.  However, no single site may 
randomize more than 15% (48 subjects) of the total patient population. 
 
 
7.4.2 
Inclusion Criteria 
The subjects have to meet all of the following criteria to be eligible to enter the investigation: 
 
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 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. 

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8. Is able to provide written Informed Consent. 
 
7.4.3 
Exclusion Criteria  
 
Subjects meeting any of the following criteria cannot be included in this research study  
 
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 coronay 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 cartoid 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, Spehnopalatine ganglion stimulator  
or Occiptial nerve stimulator). 
12. Has been implanted with metal cervical spine hardware or has a metallic implant near 
the gammaCore®-R stimulation site. 

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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 combinedanalgesics greater than 
10 days per month for headaches or other body pain.  
19.  Currently takes  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 abilitity 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. 
 

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Visit 2 Inclusion/Exclusion Criteria (randomization visit) 
Before randomization into the study patient must meet all of the following inclusion criteria and 
none of the following exclusion criteria. 
 
Inclusion criteria 
The subject: 
1. Continues to meet all Baseline (Visit 1) Eligibility Criteria.  
2. Has experienced between 5-12 migraine days and less than 15 headache days during 
the 4 week run-in period. 
 
Exclusion criteria 
The subject: 
Has initiated or changed the type, dose or frequency of any prophylactic medication for 
indications other than migraine that in the opinion of the clinician may interfere with the 
study objectives during the 4-week run-in period. 
7.4.4 
Removal of Subjects from the Clinical Investigation 
Subjects are free to discontinue participation in the investigation at any time, without prejudice 
to further treatment. Subjects who discontinue the investigation should always be asked about 
the reason(s) for their discontinuation and about the presence of any adverse event 
(AE)/adverse device effect (ADE) and, if possible, be assessed by a Clinical Investigator. 
Subjects may be withdrawn from investigation treatment and assessments at any time, if 
deemed necessary by the Clinical Investigator.  
Specific reasons for withdrawal of subjects from this investigation are:  
 
The decision of a subject to withdraw from the investigation (including if the subject 
withdraws informed consent) 
 
Unacceptable adverse event 
 
Subject lost to follow-up; or 
 
Subject is non-compliant with study procedure 
In case of withdrawal, AEs/ADEs should be followed up. The device and any other study 
material should be returned by the subject. 
Incorrectly enrolled or randomised subjects will be withdrawn from further investigation and 
assessments. A subject may, however, continue the investigation under exceptional 
circumstances (i.e. if continuation of investigation or follow-up are necessary for the subject’s 
safety and well-being, or if only a follow-up period remains, and the continuation of the 
investigation is not expected to be associated with any risk or discomfort for the subject). 
 

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Early Termination of the Clinical Investigation 
If the investigation is terminated prematurely or suspended, the Sponsor will promptly inform 
the Clinical Investigators/investigation sites of the termination or suspension and the reason(s) 
for this. The Institutional Review Board (IRB)/Independent Ethics Committee (IEC) will also be 
informed promptly and provided with the reason(s) for the termination or suspension by the 
Sponsor or by the Clinical Investigator/investigation sites. 
7.5 
Identification and Description of the Clinical Investigational Medical 
Device 
7.5.1 
Identification of the Clinical Investigational Medical Device 
 
gammaCore®-R Device 
 
The gammaCore-R device (Fig 2) is a multi-use, hand-held, rechargeable, portable device 
consisting of a rechargeable battery, signal generating and amplifying electronics, two buttons 
to power on the device and for operator control of the stimulation intensity (relative range 0-40 
continuous), a status indicating LED, and a 3-character LCD display with icons. The device can 
be recharged by using the charging station.  The device provides visible (display and light) and 
audible feedback on device and stimulation status. A pair of stainless steel round discs, which 
are the skin contact surfaces (“stimulation surfaces”), allow the delivery of a proprietary 
electrical signal. The user/operator applies conductive gel to the stimulation surfaces to 
maintain an uninterrupted conductive path from the stimulation surfaces to the skin on the 
neck.  Conductive gel is provided with each unit for this purpose.  The stimulation surfaces are 
capped when not in use.  
 
 
 
Figure 2. gammaCore®-R Device 
 

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The gammaCore®-R is a multi-use rechargeable device designed for intermittent external 
stimulation of the vagus nerve, capable of delivering six daily 120-second treatments (the 
stimulation automatically stops 120 seconds after the device is powered on). The gammaCore-
R device will be programmed with a maximum number of treatments per 24-hour period.  Once 
the maximum daily number of treatments has been reached, the device will not deliver any 
more treatments until the following 24-hour period.. The gammaCore-R device includes a 
charging station to hold and charge the device (Fig 3).  
 
 
 
 
 
 
 
Figure 3.  gammaCore®-R with charging station 
 
The user applies conductive gel (supplied with the device) to the stimulation surfaces and then 
holds the gammaCore-R device on the skin over the vagus nerve on the neck (between the 
trachea and the sternocleidomastoid muscle, over the carotid pulse). Details of device 
placement and operation are provided in Instructions for Use (IFU) 
The gammaCore®-R device produces a proprietary, low voltage electric signal that generates 
an electric field in the vicinity of the vagus nerve when the device is placed in the intended 
location.  The strength of the stimulation is lower than that required to activate efferent vagus 
nerve stimulation that mediates cardiac-specific effects.   
 
Sham device 
The sham device is a hand-held portable device that appears identical to the gammaCore®-R, 
in look, weight, visual and audible feedback, user application and control. It passes a low 
frequency (0.1 Hz) biphasic DC signal into the tissue, which can be felt as a tingling sensation 
but does not stimulate the vagus nerve or cause muscle contraction. As the amplitude is 
increased, the sensation becomes more pronounced, until it is uncomfortable, at which point 
the amplitude is decreased slightly until it is tolerable. 
Like the active device, the sham device is a multi-use device and will be programmed with a 
maximum number of treatments per 24-hour period.  Once the maximum daily number of 
treatments has been reached, the device will not deliver any more treatments until the following 

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24-hour period. The sham device will be programmed to expire based on the number of days 
per period. The sham device includes a charging station to hold and charge the device (Fig 3).  
 
7.5.2 
Packaging and Labelling of the Clinical Investigational Medical Device 
The commercial packages will be used in this Clinical Investigation, all device packaging will be 
marked “For Clinical Investigation Only”. 
 
7.5.3 
Installation and Use of the Clinical Investigational Medical Device 
Use of the device will be according to the IFU; a qualified member of the team will train the 
study subjects at the site before they can start home use. For the randomization period there 
will be an un-blinded trainer. 
 
7.5.4 
Methods of Assigning Subjects to Device Groups 
Subjects will be randomized to either the active treatment arm or sham control arm (allocation 
1:1) under a randomized variable block design, stratified by study centre. 
 
Subjects will be randomized using Merge eClinical OS Interactive Web Response system 
(IWRS) via computer key board data entry for a web based interface.   
The site personnel (the investigator or his designee) will enter the required study and subject 
information and will then be provided with a subject randomization number and device serial 
number. Once subject numbers, serial numbers, and randomization numbers have been 
assigned, they cannot be reassigned. 
The IWRS will provide the site personnel confirmation of the randomization number and device 
serial number assigned to each subject.  
   
A sponsor designee will also have a copy of the randomization schemes for each study centre 
and will be responsible for providing the un-blinded trainer with the randomization schemes.   
 
 
7.5.5 
Blinding 
 
The subjects and Investigator will be blinded to treatment assignment.  
 
The un-blinded trainer will open the study device, and use it to train the subject and provide it 
to the subject after training. The subject, investigator and study coordinator will remain blinded 
to randomised period treatment assignment for the duration of the study. The study subject will 
complete blinding questionnaires at 1-week into randomised period and at the completion of 

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randomised period as part of the data collection requirements. The blinding questionnaire will 
ask both treatment and sham patients which treatment they think they received (“Active 
Stimulation”, “Sham Control”, or “Don’t know”). The Bang blinding index will be evaluated 
based on methods described by Bang et al16. 
Subjects, study coordinators and clinicians will be told their actual randomised period treatment 
assignment at the conclusion of the study when the results are formally un-blinded. 
 
7.5.6 
Compliance with Device Usage 
Subject will record all use of the device in an electronic diary. Compliance will be assessed by 
the diaries.  
 
7.6 
Risk and Benefits of the investigational device and clinical investigation 
The gammaCore®-R is being trialled for the prophylactic treatment of episodic migraine. The 
anticipated benefits include:  
  
 
Significant reduction of number of migraine/headache days 
 
Improved quality of life. 
 
Reduced medication for acute migraine rescue medication 
 
There are no significant risks identified with the participation in this study however study 
subjects can rarely experience transient symptoms such as: 
 
 
Shortness of breath (dyspnoea), hoarseness or change in voice during treatment 
 
Muscle twitching, discomfort, or pain during stimulations  
 
Tingling, pricking or a feeling of “pins and needles” on the skin where the device is 
applied (paraesthesia or dysaesthesia) lasting beyond the treatment period  
 
Skin irritation/inflammation 
 
Fainting (Syncope) during treatment 
 
Dizziness 
 
Abnormal or change in taste (Dysgeusia) 
 
 
 

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The product will be used at home so specific caution should be taken for the storage of the 
device (temperature, out of reach for children etc.). 
 
All subjects must undergo training at the clinic before starting treatment with the device in order 
to learn and optimize where and how to stimulate. Written information will also be provided.   
 
Subjects will also be instructed to contact the site immediately if the product malfunctions and 
does not work as expected or if the device have been damaged or is expected to have been 
damaged in some way. 
 
The benefits of this study are estimated to outweigh the risks as the subject’s improvement is 
expected to be considerably greater than any expected side effects. The goal of this study is to 
decrease number of headache days resulting in a better quality of life for the subject.    
A risk analysis was performed for the sham device. As a result, there were no major or 
moderate risks and/or hazards identified regarding vagus nerve stimulation with the sham 
device that are not identified above 
7.7 
Performance and Safety Endpoints, Variables and Measurements 
7.7.1 
Subject Characteristics 
Age, Sex and Race 
Migraine history 
 
7.7.2 
Primary and Secondary Endpoints 
Diary- number of migraine/headache days 
HIT-6 
MIDAS 
EQ-5D-5L 
Medication use and change 
Adverse event 
 
7.7.3 
Performance Variables and Measurements 
Diary-Use of the gammaCore®-R prophylactic 
 

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7.7.4 
Safety Variables and Measurements 
Physical examination 
Blood pressure 
 
Additionally, the following will be obtained at baseline: 
Pregnancy test for fertile women 
Medical and Surgical history 
ECG 
 
7.7.5 
Other Variables and Measurements 
Blinding question 
Satisfaction question 
Easy to use question 
 
7.7.6 
Appropriateness of Measurements 
The primary and secondary endpoint measurements are using instruments commonly used to 
evaluate the maintenance of efficacy of migraines and headaches and the impact on the 
subject’s quality of life.  These will permit evaluation of the primary and secondary objectives 
for the study. 
The safety measurements are typical for a clinical trial and permit evaluation of the safety of 
the device. 
 
7.8 
Adverse Events/Adverse Device Effects and Device Deficiencies  
The definitions and procedures for reporting adverse events (AE), adverse device effects 
(ADE), serious adverse events (SAE), serious adverse device effects (SADE) and are 
presented in the sections below. It is of utmost importance that all staff involved in the 
investigation are familiar with the definitions and procedures and it is the responsibility of the 
Clinical Investigator to ensure this.  
7.8.1 
Adverse Event/Adverse Device Effect Definitions 
Adverse Event 

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Any untoward medical occurrence, unintended disease or injury, or untoward clinical signs 
(including abnormal findings) in subjects, users or other persons, whether or not related to the 
investigational medical device. 
Note1: This definition includes events related to the investigational medical device or 
comparator. 
Note 2: This definition includes events related to the procedures involved 
Note 3: For users or other persons, this definition is restricted to events related to 
investigational medical device 
Adverse Device Effect 
Adverse event related to the use of an investigational medical device  
Note 1: This definition includes any event resulting from insufficiencies or inadequate 
instructions for use, deployment, implantation, installation, or operation, or any malfunction of 
the investigational medical device. 
Note 2: This definition includes any event that is a resulting from a user error or from intentional 
misuse of the investigational medical device. 
7.8.2 
Serious Adverse Event/Serious Adverse Device Effect/Unanticipated 
Adverse Device Effect Definitions 
Serious Adverse Event 
Adverse event that: 
a) Leads to a death 
b) Led to a serious deterioration in the health of the subject that either resulted in: 
1. a life-threatening illness or injury or 
2. a permanent impairment of a body structure or a body function, or 
3. in-patient hospitalisation or prolonged  hospitalisation,  
4. medical or surgical intervention to prevent life-threatening illness or permanent         
impairment to a body structure or a body function 
c) Led to foetal distress, foetal death or a congenital abnormality or birth defect 
Serious Adverse Device Effect 
A SADE is an ADE that results in any of the consequences characteristic of an SAE or that 
might lead to any of these consequences if suitable action is not taken, if intervention is not 
made or if circumstances are less opportune.  

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7.8.3 
Unanticipated serious adverse device effect (USADE) 
Serious adverse device effect which by its nature, incidence, severity or outcome has not been 
identified in the current version of the risk analysis report. 
Note: Anticipated serious adverse device effect (ASADE) is an effect which by nature, 
incidence, severity or outcome has been identified in the risk analysis report. 
 
7.8.4 
Reporting of Adverse Events/Adverse Device Effects 
7.8.4.1 
Methods for Eliciting Adverse Events/Adverse Device Effects 
All subjects will be carefully monitored for the occurrence of AEs during the investigation period 
from the run-in to the completion of follow up.  The Clinical Investigator will collect AE 
information using non-leading questions such as “have you experienced any new health 
problems or worsening of existing conditions”. Events directly observed or spontaneously 
volunteered by subjects will also be recorded. 
Clearly related signs, symptoms and abnormal diagnostic procedure results should be grouped 
together and reported as a single diagnosis or syndrome whenever possible. 
All AEs including but not limited to events reported by the subject or reported in response to an 
open question by the Clinical Investigator or member of this team, which fall into any of the 
above definitions must be recorded as an AE in the CRF and should include the following 
information. 
 
Brief description of the event (diagnosis) 
 
Start date (and time, if relevant) 
 
Stop date (and time, if relevant) (or resolution) 
 
Severity 
 
Action taken regarding the medical device 
 
Opinion on causality 
 
Seriousness 
 
Outcome 
Severity 
Severity describes the intensity of an event and will be assessed as: 
 
Mild 
The AE does not interfere in a significant manner with the subject’s normal functioning level. It 
may be an annoyance. 
 

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Moderate 
The AE produces some impairment of function but not hazardous to health. It is uncomfortable 
and/or an embarrassment. 
 
Severe 
The AE produces significant impairment of functioning or incapacitation and/or it is a hazard to 
the subject. 
 
If an AE changes in severity, it should be reported as an AE of new severity but with the same 
description. 
Causality (Adverse Device Effects/ADE) 
Causality will be assessed as: 
 
Related (definitely, possible or probable) 
 
A causal relationship between the clinical investigational medical device and the AE is at least 
a reasonable possibility, i.e. there is evidence or argument suggesting a causal relationship.  
 
Not related 
There is no indication that the AE was caused by the clinical investigational medical device. 
 
ADEs will be reported by ticking the “yes” box for ADEs on the CRF page for AEs/ADEs.  
The procedures described for AEs above will be followed for documenting ADEs.  
7.8.4.2 
Follow-up of Subjects with Adverse Events 
Any AE that is ongoing when the subject is withdrawn from the investigation should be 
followed-up until the AE is resolved or the Clinical Investigator decides that the AE is stable 
and needs no further follow-up. The date when the Clinical Investigator considers one of these 
outcomes to have occurred for the last ongoing AE for a subject will be considered the last visit 
for this subject, and the outcome should be recorded in the CRF. 
 
 
7.8.5 
Reporting of Serious Adverse Event/Serious Adverse Device Effects 
SAEs/SADEs must be reported to the Sponsor within 24 hours of learning about the event, 
regardless of the time that may have elapsed from the time the event occurred. The initial 
report should contain as much information as possible, but as a minimum the following 
information: 
 
Subject identification 

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 
Treatment specification 
 
AE diagnosis 
 
Time specification for the medical event 
 
Name of the Clinical Investigator 
 
Causality assessment 
 
Seriousness criteria 
The Sponsor must also receive a completed SAE/SADE Form within 5 calendar days of the 
occurrence. All SAEs have to be reported, whether or not they are considered causally related 
to the investigation medical device.  
All SAEs and SADEs that are related to the investigational medical device will be subject to 
expedited reporting. 
The Sponsor should inform the IEC and Competent Authorities about SAEs and SADEs 
associated with the use of the device, as per local requirements. 
SAE EMERGENCY CONTACT DETAILS 
Sponsor’s Medical Monitor: Annelie Andersson 
Fax: +46 (0)31 703 7101 
 
Email: annelie.andersson@electrocorellc.com 
Phone: +46 (0)721 803076 
 
7.8.6 
Device deficiencies 
All device deficiencies related to the identity, quality, durability, reliability, safety or performance 
of an investigational medical device shall be documented on the separate DD form. 
7.9 
Data Quality Assurance 
7.9.1 
Monitoring, Audits and Inspections 
During the investigation, the monitor will have regular contacts with the investigation site. 
These contacts will include visits to confirm that the facilities remain adequate to specified 
standards and that the investigation team is carrying out the procedure stated in the Clinical 
Investigation Plan (CIP). All data must be accurately recorded in the CRF. Source data 
verification (a comparison of data in the CRF with the subject’s medical records and other 
records at the investigation site) with access to records will also be performed.  
The monitor and Sponsor personnel will be available between visits if the Clinical Investigator 
or other staffs at the site needs information and/or advice. 

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Authorised representatives of the Sponsor and/or Regulatory agencies may visit the site to 
perform audits/inspections, including source data verification. 
7.9.2 
Subject Records and Source Data 
Data may be recorded directly in the e-CRF, which will then be considered as source data. 
This must documented in the Monitoring manual or a file note before the study starts. 
The origin of source data in the investigation will be further specified in the monitoring manual 
(“Origin of Source Data”).  
It is the responsibility of the Clinical Investigator to record essential information in the medical 
records in accordance with national regulations and requirements, including: 
 
Investigation code 
 
Subject screening number and/or subject number 
 
That informed consent for participating in the study was obtained 
 
Diagnosis 
 
All visits during the investigation period 
 
All AEs/ADEs 
 
All DD 
 
Treatments and medications 
 
The SN number of the device 
 
Subject health service identification number if applicable 
The Clinical Investigator is responsible for ensuring the accuracy, completeness, legibility and 
timeliness of the data recorded in the CRFs. Signed sections of CRFs will be monitored and 
collected on a regular basis. 
7.9.3 
Access to Source Data and Documentation 
The Clinical Investigator should guarantee access to source documents for the monitor and 
auditors as well as for inspection by appropriate regulatory agencies, and the IRB/IEC, if 
required. 
7.9.4 
Training of Staff 
The Clinical Investigator will ensure that appropriate training relevant to the investigation is 
given to the medical, nursing and other staff involved and that new information of relevance to 
the performance of this investigation is forwarded to the staff involved. 

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7.9.5 
Data and Quality Management 
The data collection tool for this trial will be a validated electronic data capture (EDC) system 
using eCRF’s.  Subject data necessary for analysis and reporting will be entered into a 
validated database or data system.  Data management and handling will be conducted 
according to the investigation specific Data Management Plan in accordance with applicable 
guidelines and Sponsor’s operating procedures (SOP). 
Any deviations, i.e. discrepancies and additions from the process defined in the Data 
Management Plan will be described in an investigation specific Data Management report. 
 
7.10 
Statistical Methods and Determination of Sample Size 
7.10.1 
Statistical Evaluation of Performance and Safety Variables 
7.10.1.1 
Data Sets to be Analysed 
The following analysis sets will be used for the statistical analysis and presentation of data:  
 
The safety set will consist of all subjects who sign informed consent and are thus 
enrolled. 
 
The Intention to treat (ITT) will include subjects who fulfil the following criteria: 
o included in the safety set 
o are randomized with at least one verified treatment post-training during the 12 
week randomized period 
 
 
The per protocol set (PPS) will include subjects who fulfil the following criteria: 
o included in the ITT 
o do not have any other major protocol violations which will affect the assessment 
of efficacy. Major protocol violations include but are not limited to the following:  
 
The subject must have reached the visit 6. 
 
Compliance to treatment 67% per four week interval in the randomized 
period. 
 
The final criteria for PPS, regarding which protocol deviations that warrant exclusions, 
will be determined when all data on protocol violations/deviations are available and 
before breaking the blind. 
 
The baseline and safety presentations will be based on the safety set.  

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The ITT is considered as the primary analysis dataset, and will be used for all primary and 
secondary efficacy analyses. If the difference between ITT and PPS is more than 5%, the 
primary efficacy analyses will be repeated using the PPS. Otherwise, only the ITT will be used 
for the presentations. 
Subjects screened but not included in the study will not be presented in any listings or tables. 
 
7.10.1.2 
Definitions 
Generally, a baseline measurement refers to the last non-missing assessment made before the 
first administration of study treatment (at e.g. screening and baseline). 
 
7.10.1.3 
Summary Statistics 
In general, data will be summarized by means of summary statistics. Continuous data will be 
presented with the number of observations, mean value, standard deviation, minimum, Q1, 
median, Q3 and maximum value. Categorical data will be presented as counts and 
percentages. The data will be presented for each device group by visit. In certain tables, data 
will be presented by site and in total.   
7.10.1.4 
Primary Performance Analysis 
The primary efficacy analyses will be based on the ITT and repeated in the PPS, when the 
groups differ by more than 5%.  
Summary statistics for the primary variable will be presented by device group, strata/centre and 
visit. The total for each device group will be calculated. 
 
The primary outcome measurement is the change in the number of 
migraine days during the last 4 weeks of the 12-week 
randomized/controlled period compared to the subject's own 4-week run-
in period.  
 
Let µActive be the mean change (from 4-week run-in period) in the number 
of migraine days for the active treatment group and µSham be the mean 
change in the number of migraine days for the sham treatment group.  
Then the effectiveness of the gammaCore-R-R device can be measured 
by testing the difference in mean changes, µActive - µSham. The null and 
alternative hypotheses of interest are: 
Hnull: µActive - µSham = 0 versus  Halt: µActive - µsham ≠ 0 

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The number of migraines will be summarized descriptively for each 4-week interval by period 
and by treatment group. The absolute value, change from 4-week run-in period and percentage 
change from 4-week run-in period will be summarized using number of non-missing values, 
mean, standard deviation, median, minimum, and maximum. 
The difference between the two groups in change from 4-week run-in period will be compared 
using a two-group t-test.  The directionality of the difference as well as the p-value will be 
evaluated in order to make conclusions about the effectiveness of the active treatment. 
As sensitivity analyses, the two groups will be compared using analysis of covariance 
(ANCOVA) models with change from 4-week run-in period as the dependent variable and 
treatment group and center as fixed effects with the number of migraine days in the 4-week 
run-in period as a covariate and again with treatment group, center, and aura as fixed effects 
with number of migraine days in the 4-week run-in period as a covariate. The adjusted means, 
adjusted mean difference and 95% confidence interval for the adjusted mean difference based 
on the ANCOVA models will be reported. The p-values tests that the adjusted mean difference 
between groups at Month 3 equals zero will be reported. 
The above procedures will be used for the analysis of the primary and secondary effectiveness 
outcome measures.  Additional sensitivity analyses, including details on the handling of the 
missing assessments, will be specified in the SAP. 
 
7.10.1.5 
Secondary Performance Analyses 
The secondary efficacy analyses will be based on the ITT. 
 
The outcome measurement for responders is the percentage of subjects 
with a reduction of 50% or more in the number of migraine days during 
the last 4 weeks of the 12-week randomized/controlled period compared 
to the subject's own 4-week run-in period.  
 
Let pActive be the proportion of patients in the active treatment group with 
at least a 50% reduction and let pSham be the proportion of patients in the 
sham treatment group with at least a 50% reduction. Then the 
effectiveness of the gammaCore-R device can be measured by testing 
the difference in proportions, pActive - pSham. The null and alternative 
hypotheses of interest are: 
Hnull: pActive – pSham = 0  versus  Halt: pActive – pSham ≠ 0 
The number and percentage of responders (>=50% reduction in number of migraine days per 
4-week interval) will be summarized for each treatment group for period 2. The difference 
between treatment groups and the corresponding 95% interval for the difference will be 

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provided.  A chi-square test for comparing the two treatment groups will be performed and the 
p-value reported. 
As sensitivity analyses, the two groups will be compared using a Logistic Regression models 
with the number of migraines in the 4-week run-in period, treatment group, and center  as 
covariates and again with the number of migraines in the 4-week run-in period, treatment 
group, center, and aura as covariates. 
7.10.1.6 
Demographic and Other Baseline Characteristics 
Subject disposition, demographic and other baseline data will be presented using summary 
statistics.  
The number and percentage of subjects randomized, treated, completing/withdrawing from the 
study overall, and each period, as well as those included/excluded from safety and efficacy 
analyses will be tabulated. 
 
Descriptive statistics of demographic variables (e.g. age, gender and race), and other baseline 
characteristics will be presented for the safety and ITT populations by treatment group and 
overall. For quantitative variables, all summaries will include the number of non-missing 
observations, mean, median, standard deviation, minimum, and maximum. For qualitative 
variables, the summaries will include the number and percentage of subjects within each 
category for the outcome. 
 
7.10.1.7 
Extent of Device Usage 
Exposure to treatment/device will be presented by using summary statistics for number of days 
with study treatment by each device group. 
 
7.10.1.8 
Concomitant Treatment 
The concomitant medication and concomitant therapy will be summarised and sorted as text 
fields per subject. The safety set will be used for this presentation.  
7.10.1.9 
Adverse Events/Adverse Device Effects 
The total number of subjects with at least one AE/ADE and the number of AEs/ADEs will be 
derived. 
If more than one AE/ADE with the same preferred term occurs within a subject during the 
investigation period, they will be counted only once for that subject using the worst reported 
severity and causal relationship to treatment. AEs/ADEs will also be tabulated versus worst 
severity and worst relationship to treatment. In this table, subjects having AEs will be identified 
by their subject number.  

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Symptoms, AEs recorded before administration of treatment will only be presented in listings.  
7.10.1.10 
Other Safety Assessments (if applicable) 
Not Applicable 
7.10.1.11 
Other Variables (if applicable) 
Not Applicable 
 
7.10.2 
Handling of Drop-outs and Missing Data 
Outliers will be included in summary tables and listings, and will not be handled separately. 
Available data from prematurely withdrawn subjects will be included in the analysis as far as 
possible. If data are only partially completed for either the 4-week run-in period or the last 4 
weeks in the 12-week randomized/controlled period, the available data will be converted to a 4-
week interval.  That is, if data are collected for 2 weeks within a 4-week interval, then to 
convert to a 4-week period the data will be multiplied by 2.  Missing data will be analysed and 
imputed with appropriate method. The SAP will include additional details on the handling of 
missing data. 
7.10.3 
Determination of Sample Size 
Table 1 provides the required sample size per treatment group when the number of migraine 
days per 28-day period is used as the primary outcome measure.  Sample size calculations are 
based on the difference between active and sham treatment groups in change from baseline.  
Assuming a type I error of 5% (two-sided) and 90% power, Table 1 displays the required 
sample sizes for different values of the common standard deviation (2.0, 2.5, 3.0 and 3.5) and 
the presumed difference between treatment groups (1, 1.5 and 2 days).  Selecting an 
improvement of 1 day and a common standard deviation of 2.5 requires 133 subjects per 
treatment group.  With 15% drop-out during the randomized treatment period, a total of 160 
subjects per treatment group (or 320 subjects total) would need to be randomized. 
 
Table 1:  Required Sample Size per Treatment Group  
Assuming Type I Error (α) = 5% (two-sided) and 90% Power 
Variability 
(Common SD*, ) 
Clinically Significant Improvement:  
Active – Sham = ∆ 
1-day 
1.5-day 
2-day 
2.0 
86 
-- 
-- 
2.5 
133 
60 
34 
3.0 
191 
86 
49 
3.5 
259 
115 
66 
*Estimated standard deviation for change from baseline.  Standard 
deviations for baseline and post treatment scores are between 2.0 to 
3.5. 

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7.10.4 
Interim Analysis  
The analysis of the primary and secondary efficacy endpoints will occur after all subjects have 
completed the randomized/controlled period and their data is deemed clean; and, before the 
formal completion of the study (at the end of the open-label period).  As this is the final analysis 
for the primary objective of the study, no adjustment of alpha will be performed. Further details 
of this final analysis will be detailed in the SAP. 
 
7.10.5 
Procedures for Reporting any Deviations from the Original Statistical 
Analysis Plan 
Any deviation(s) from the original statistical analysis plan will be described and justified in a 
CIP Amendment and/or in a revised statistical analysis plan and/or in the final report, as 
appropriate.  
7.11 
Amendments to the Clinical Investigation Plan 
Any change to the approved CIP must be documented in a written and numbered CIP 
amendment with a justification for the amendment. Changes to the CIP will only be 
implemented after written agreement has been obtained between the Principal/Coordinating 
Clinical Investigator and the Sponsor. 
An amendment to the CIP may require notification or approval from IRB/IEC and, in many 
countries, the Competent Authority before implementation. Local requirements shall be 
followed. 
The Sponsor will distribute CIP amendments to the Clinical Investigator, who is responsible for 
the distribution of these documents to the IRB/IEC and to staff concerned at his/her site. The 
distribution of these documents to the FDA/Competent Authority will be handled according to 
local practice. 
7.12 
Deviations from the Clinical Investigation Plan 
Every effort should be made to comply with the requirements of the protocol.  Prior approval by 
the Sponsor is required for changes in or deviations from the CIP, except in an emergency.  If 
the changes or deviations may affect the rights, safety, or welfare of participants, IRB/IEC 
approval is required. Deviations will be recorded with an explanation for the change. The 
Sponsor is responsible for analysing the deviations and assessing their significance.  
Corrective action will be implemented to avoid repeat deviations.   
The reasons for any subject’s withdrawal and discontinuation from the investigation will be 
recorded. If such discontinuation is because of problems of safety or lack of effectiveness, the 
subject will still be followed up in the investigation, if possible. 

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7.13 
Report and Publication 
The CIP shall specify whether the results of the investigation will be submitted for publication or 
the extent to which and conditions under which the results of the clinical investigation will be 
offered for publication. 
A final report of the investigation (a “Clinical Investigation Report”) should be completed, even 
if the investigation is prematurely terminated. The report will be prepared by the sponsor 
according to the guideline presented in Annex C of ISO 14155-1:2003(E).  
All publications and presentations must be based upon the clinical investigation report. 
All information supplied by the Sponsor in connection with this investigation will remain the sole 
property of the Sponsor and is to be considered confidential information. No confidential 
information will be disclosed to others without obtaining prior written consent from the Sponsor 
and will not be used except in the performance of this investigation. 
The Clinical Investigator may publish results from this investigation; however as some of the 
information regarding the investigational medical device and development activities may be of 
a strictly confidential nature, the Sponsor must first be given the opportunity to review any 
publication manuscript prior to submission to journals, meetings or conferences. 
The Sponsor may choose to publish or present data from this investigation. If a Clinical 
Investigator is offered first authorship, he/she will be asked to comment and approve the 
publication. The Sponsor has the right to use the results for registration and internal 
presentation and for promotion. 
 

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8 
ETHICS 
8.1 
Institutional Ethics Review 
The final CIP, including the final version of the Subject Information and Consent Form, must be 
approved or given a favourable opinion in writing by an IRB/IEC before enrolment of any 
subject into the investigation. The Clinical Investigator is responsible for informing the IRB/IEC 
of any amendment to the CIP as per local requirements. 
8.2 
Ethical Conduct of the Clinical Investigation 
The investigation will be conducted in compliance with applicable regulatory requirements and 
with the ethical principles of the latest revision of the Declaration of Helsinki as adopted by the 
World Medical Association (Appendix A).   
8.3 
Subject Information and Consent 
All subjects will receive written and verbal information regarding the investigation prior to any 
investigation-related procedures. This information will emphasise that participation in the 
investigation is voluntary and that the subject may withdraw from the investigation at any time 
and for any reason. All subjects will be given the opportunity to ask questions about the 
investigation and will be given sufficient time to decide whether to participate in the 
investigation. 
Before any investigation-related procedures, the informed consent will be signed and dated by 
the subject (or their legally acceptable representative and/or witness, as applicable) and by the 
Clinical Investigator who gave the subject the verbal and written information. 
The consent specifies that data will be recorded, collected, processed and may be transferred 
(to either EEA countries and/or non-EEA countries). In accordance with the EU Data Protection 
Directive (95/46/EC), the data will not identify any persons taking part in the investigation. 

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9 
SUBJECT PROTECTION PROCEDURES 
9.1 
Procedures in Case of Medical Emergency 
The Clinical Investigator is responsible for ensuring that procedures and expertise are available 
to cope with medical emergencies during the investigation. 
9.2 
Subject Data Protection 
The written subject information explains that the data will be stored in a computer database, 
maintaining confidentiality in accordance with national data legislation, and that authorised 
representatives of the Sponsor, FDA, a Competent Authority or an IRB/IEC require direct 
access to those parts of the medical records relevant to the investigation, including medical 
history, for verification of data. 
All computerised data will be identified by subject number only. 
9.3 
Insurance 
ElectroCore LLC has product insurance that also covers Clinical Investigation. If required 
according to local/national laws, insurance will be subscribed for that specific country. 
 
 

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10 
CLINICAL INVESTIGATION TIME TABLE AND TERMINATION 
Clinical investigation start (first subject first visit): Q2 2015 
Interim analysis: At completion of the randomized period for all subjects 
Inclusion completed (last subject first visit): 31st January 2017 
Last subject out (last subject last visit): Q4 2017 
 
 

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11 
REFERENCES 
In order to determine the scientific background for this clinical investigation as well as to 
assess risks/benefits of the device, a literature review was conducted and a Clinical evaluation 
has been performed according to MDD.  
The literature listed below was critically evaluated before serving as background information 
 
1 Von Korff M, Stewart W, Simon D, Lipton R. Migraine and Reduced Work Performance: A 
Population-Based Diary Study. Neurology. 1998; 50:1741-1745. 
 
2 Cutrer FM, Charles A. The neurogenic basis of migraine. Headache. Oct 2008;48(9):1411-4. 
 
3  De Felice M., Triptan-induced enhancement of neuronal nitric oxide synthase in 
trigeminal ganglion dural afferents underlies increased responsiveness to potential 
migraine triggers. Brain (2010 Aug) 133(Pt 8):2475-88  
 
 
4 Edwards KR, Norton J, Behnke M. Comparison of intravenous valproate versus 
intramuscular dihydroergotamine and metoclopramide for acute treatment of migraine 
headache. Headache. Nov-Dec 2001;41(10):976-80. 
 
5 Cecchini AP, Mea E, Tullo V, Curone M, Franzini A, Broggi G, Savino M, Bussone G, Leone 
M. Vagus nerve stimulation in drug-resistant daily chronic migraine with depression: 
preliminary data. Neurol Sci. 2009 May;30 Suppl 1:S101-4. 
6 Lenaerts ME, Oommen KJ, Couch JR, Skaggs V. Can vagus nerve stimulation help 
migraine? Cephalalgia. 2008 Apr;28(4):392-5 
 
7 Mauskop A. Vagus Nerve Stimulation Relieves Chronic Refractory Migraine and Cluster 
Headaches. Cephalalgia 2005;25:82-86 
 
8 Goadsby, P. J., et al. "Effect of noninvasive vagus nerve stimulation on acute migraine: An 
open-label pilot study." Cephalalgia (2014): 0333102414524494. 
 
9 Castoro, Mark A., et al. "Excitation properties of the right cervical vagus nerve in adult dogs." 
Experimental neurology 227.1 (2011): 62-68. 
 
10 Yoo, Paul B., et al. "High-resolution measurement of electrically-evoked vagus nerve activity 
in the anesthetized dog." Journal of neural engineering 10.2 (2013): 026003. 
 
11  Bonham, Ann and Chao-Yin Chen. Synaptic Transmission in the Nucleus Tractus Solitarius 
(NTS).  Advances in Vagal Afferent Neurobiology.  Bradley J. Undem and Daniel Weinreich, 
eds. 
CRC Press, 2005.193. 
 

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12  Ruffoli R, Giorgi FS, Pizzanelli C, Murri L, Paparelli A, Fornai F: The chemical 
neuroanatomy of vagus nerve stimulation. J Chem Neuroanat; 2011 Dec;42(4):288-96 
 
13 Beekwilder JP, Beems T.Overview of the clinical applications of vagus nerve stimulation. J 
Clin Neurophysiol. 2010 Apr;27(2):130-8 
 
14 Travagli, R.A. and Williams, J.T. (1996) Endogenous monoamines inhibit glutamate 
transmission in the spinal trigeminal nucleus of the guinea-pig. J. Physiol. 491, 177–185 
 
15  Oshinsky, Michael L., et al. "Noninvasive vagus nerve stimulation as treatment for 
trigeminal allodynia." PAIN® 155.5 (2014): 1037-1042. 
16 Bang H., et al. Assessment of blinding in clinical trials “Contemporary Clinical Trials, 25, 
143-156. 

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12 
SIGNATURES 
 
SPONSOR’S REPRESENTATIVE: 
 
 
 
 
 
 
 
 
 
 
 
 
 
DATE: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COORDINATING/PRINCIPAL 
CLINICAL INVESTIGATOR:  
 
 
 
 
 
 
 
 
 
 
 
 
 
DATE: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 

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13 
CLINICAL INVESTIGATION PLAN AGREEMENT FORM 
I agree to the terms of this CIP. I will conduct the investigation according to the procedures 
specified herein.  
 
Clinical investigation code: GM-11 
 
 
Site No.:  
Principal Clinical Investigator 
Name:  
 
 
Signature: _____________________ Date: ______________ 
 

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14 
APPENDICES 
14.1  Helsinki Declaration 

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14.1 
Helsinki Declaration 
 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53th WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 added) 
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added) 
59th WMA General Assembly, Seoul, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
Preamble 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including research 
on identifiable human material and data. 
The Declaration is intended to be read as a whole and each of its constituent paragraphs should 
not be applied without consideration of all other relevant paragraphs. 
2. Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians. The WMA encourages others who are involved in medical research involving human 
subjects to adopt these principles.  
General Principles 
3. The Declaration of Geneva of the WMA binds the physician with the words, “The health of my 
patient will be my first consideration,” and the International Code of Medical Ethics declares that, 
“A physician shall act in the patient's best interest when providing medical care.” 
4. It is the duty of the physician to promote and safeguard the health, well-being and rights of 
patients, including those who are involved in medical research. The physician’s knowledge and 
conscience are dedicated to the fulfilment of this duty.  
5. Medical progress is based on research that ultimately must include studies involving human 
subjects. 
6. The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures and treatments). Even the best current 
interventions must be evaluated continually through research for their safety, effectiveness, 
efficiency, accessibility and quality. 
7. Medical research is subject to ethical standards that promote and ensure respect for all 
human subjects and protect their health and rights.  
8. While the primary purpose of medical research is to generate new knowledge, this goal can 
never take precedence over the rights and interests of individual research subjects. 

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9. It is the duty of physicians who are involved in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal information of 
research subjects. The responsibility for the protection of research subjects must always rest 
with the physician or other health care professionals and never with the research subjects, even 
though they have given consent 
10. Physicians must consider the ethical, legal and regulatory norms and standards for research 
involving human subjects in their own countries as well as applicable international norms and 
standards. No national or international ethical, legal or regulatory requirement should reduce or 
eliminate any of the protections for research subjects set forth in this Declaration. 
11. Medical research should be conducted in a manner that minimizes possible harm to the 
environment.  
12. Medical research involving human subjects must be conducted only by individuals with the 
appropriate ethics and scientific education, training and qualifications. Research on patients or 
healthy volunteers requires the supervision of a competent and appropriately qualified physician 
or other health care professional.  
13. Groups that are underrepresented in medical research should be provided appropriate 
access to participation in research. 
14. Physicians who combine medical research with medical care should involve their patients in 
research only to the extent that this is justified by its potential preventive, diagnostic or 
therapeutic value and if the physician has good reason to believe that participation in the 
research study will not adversely affect the health of the patients who serve as research 
subjects.   
15. Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured. 
Risk, Burdens and Benefits 
16. In medical practice and in medical research, most interventions involve risks and burdens. 
Medical research involving human subjects may only be conducted if the importance of the 
objective outweighs the risks and burdens to the research subjects. 
17. All medical research involving human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and groups involved in the research in 
comparison with foreseeable benefits to them and to other individuals or groups affected by the 
condition under investigation. 
Measures to minimize the risks must be implemented. The risks must be continuously 
monitored, assessed and documented by the researcher. 
18. Physicians may not be involved in a research study involving human subjects unless they 
are confident that the risks have been adequately assessed and can be satisfactorily managed.  
When the risks are found to outweigh the potential benefits or when there is conclusive proof of 
definitive outcomes, physicians must assess whether to continue, modify or immediately stop the 
study. 
Vulnerable Groups and Individuals 
19. Some groups and individuals are particularly vulnerable and may have an increased 
likelihood of being wronged or of incurring additional harm. 

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All vulnerable groups and individuals should receive specifically considered protection. 
20. Medical research with a vulnerable group is only justified if the research is responsive to the 
health needs of priorities of this group and the research cannot be carried out in a non-
vulnerable group. In addition, this group should stand to benefit from the knowledge, practices or 
interventions that result from the research.  
Scientific Requirements and Research Protocols 
21. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources 
of information, and adequate laboratory and, as appropriate, animal experimentation. The 
welfare of animals used for research must be respected.. 
22. The design and performance of each research study involving human subjects must be 
clearly described and justified in a research protocol. 
The protocol should contain a statement of the ethical considerations involved and should 
indicate how the principles in this Declaration have been addressed. The protocol should include 
information regarding funding, sponsors, institutional affiliations, potential conflicts of interest, 
incentives for subjects and information regarding provisions for treating and/or compensating 
subjects who are harmed as a consequence of participation in the research study. 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial 
provisions. 
Research Ethics Committees 
23. The research protocol must be submitted for consideration, comment, guidance and 
approval to the concerned research ethics committee before the study begins. This committee 
must be transparent in its functioning, must be independent of the researcher, the sponsor and 
any other undue influence and must be duly qualified. It must take into consideration the laws 
and regulations of the country of countries in which the research is to be performed as well as 
applicable international norms and standards but these must not be allowed to reduce or 
eliminate any of the protections for research subjects set forth in this Declaration. 
The committee must have the right to monitor ongoing studies. The researcher must provide 
monitoring information to the committee, especially information about any serious adverse 
events. No amendment to the protocol may be made without consideration and approval by the 
committee. After the end of the study, the researchers must submit a final report to the 
committee containing a summary of the study’s findings and conclusions. 
Privacy and Confidentiality 
24. Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information. 
Informed Consent 
25. Participation by individuals capable of giving informed consent as subjects in medical 
research must be voluntary. Although it may be appropriate to consult family members or 
community leaders, no individual capable of giving informed consent may be enrolled in a 
research study unless he or she freely agrees. 
 26. In medical research involving human subjects capable of giving informed consent, each 
potential subject must be adequately informed of the aims, methods, sources of funding, any 

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possible conflicts of interest, institutional affiliations of the researcher, the anticipated benefits 
and potential risks of the study and the discomfort it may entail, post-study provisions and any 
other relevant aspects of the study. The potential subject must be informed of the right to refuse 
to participate in the study or to withdraw consent to participate at any time without reprisal. 
Special attention should be given to the specific information needs of individual potential 
subjects as well as to the methods used to deliver the information. 
After ensuring that the potential subject has understood the information, the physician or another 
appropriately qualified individual must then seek the potential subject’s freely-given informed 
consent, preferably in writing. If the consent cannot be expressed in writing, the non-written 
consent must be formally documented and witnessed. 
All medical research subjects should be given the option of being informed about the general 
outcome and results of the study. 
27. When seeking informed consent for participation in a research study the physician must be 
particularly cautious if the potential subject is in a dependent relationship with the physician or 
may consent under duress. In such situations the informed consent must be sought by an 
appropriately qualified individual who is completely independent of this relationship. 
28. For a potential research subject who is incapable of giving informed consent, the physician 
must seek informed consent from the legally authorized representative. These individuals must 
not be included in a research study that has no likelihood of benefit for them unless it is intended 
to promote the health of the group represented by the potential subject, the research cannot 
instead be performed with persons capable of providing informed consent, and the research 
entails only minimal risk and minimal burden. 
29. When a potential research subject who is deemed incapable of giving informed consent is 
able to give assent to decisions about participation in research, the physician must seek that 
assent in addition to the consent of the legally authorized representative. The potential subject’s 
dissent should be respected. 
30. Research involving subjects who are physically or mentally incapable of giving consent, for 
example, unconscious patients, may be done only if the physical or mental condition that 
prevents giving informed consent is a necessary characteristic of the research group. In such 
circumstances the physician must seek informed consent from the legally authorized 
representative. If no such representative is available and if the research cannot be delayed, the 
study may proceed without informed consent provided that the specific reasons for involving 
subjects with a condition that renders them unable to give informed consent have been stated in 
the research protocol and the study has been approved by a research ethics committee. 
Consent to remain in the research should be obtained as soon as possible from the subject or a 
legally authorized representative. 
31. The physician must fully inform the patient which aspects of their care are related to the 
research. The refusal of a patient to participate in a study or the patient’s decision to withdraw 
from the study must never adversely affect the patient-physician relationship. 
32. For medical research using identifiable human material or data, such as research on material 
or data contained in biobanks or similar repositories, physicians must seek informed consent for 
its collection, storage and/or reuse. There may be exceptional situations where consent would 

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be impossible or impracticable to obtain for such research. In such situations the research may 
be done only after consideration and approval of a research ethics committee. 
Use of placebo 
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested against 
those of the best proven intervention(s), except in the following circumstances: 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable 
or 
Where for compelling and scientifically sound methodological reasons the use of any 
intervention less effective than the best proven one, the use of placebo, or no intervention is 
necessary to determine the efficacy or safety of an intervention 
and the patients who receive any intervention less effective than the best proven one, placebo, 
or no intervention will not be subject to additional risks of serious or irrever4sible harm as a 
result of not receiving the best proven intervention. 
Extreme care must be taken to avoid abuse of this option. 
Post-Trial Provisions 
34. In advance of a clinical trial, sponsors, researchers and host country governments should 
make provisions for post-trial access for all participants who still need an intervention identified 
as beneficial in the trial. This information must also be disclosed to participants during the 
informed consent process. 
Research Registration and Publication and Dissemination of Results 
35. Every research study involving human subjects must be registered in a publicly accessible 
database before recruitment of the first subject. 
36. Researcher, authors, sponsors, editors and publishers all have ethical obligations with 
regard to the publication and dissemination of the results of research. Researchers have a duty 
to make publicly available the results of their research on human subjects and are accountable 
for the completeness and accuracy of their reports. All parties should adhere to accepted 
guidelines for ethical reporting. Negative and inconclusive as well as positive results must be 
published or otherwise made publicly available. Sources of funding, institutional affiliations and 
conflicts of interest must be declared in the publication. Reports of research not in accordance 
with the principles of this Declaration should not be accepted for publication. 
Unproven Interventions in Clinical Practice 
37. In the treatment of an individual patient, where proven interventions do not exist or other 
known interventions have been ineffective, the physician, after seeking expert advice, with 
informed consent from the patient or a legally authorized representative, may use an unproven 
intervention if in the physician’s judgement it offers hope of saving life, re-establishing health or 
alleviating suffering. This intervention should subsequently be made the object of research, 
designed to evaluate its safety and efficacy. In all cases, new information must be recorded and, 
where appropriate, made publicly available.