A Randomized, Double Blinded, Sham Controlled Clinical Study to Evaluate the Safety and Efficacy of the Nerivio Migra 1, a Neuromodulation Device, for the Acute Treatment of Migraine
Phase: NA
Conditions: Migraine Without Aura, Migraine With Aura
Sponsor: Theranica

 
A Randomized, Double Blinded, Sham controlled Clinical Study to Evaluate 
the Safety and Efficacy of the Nerivio Migra 1, a Neuromodulation Device, 
for the acute treatment of Migraine 
Protocol number:  TCH-003 
Page 1 of 94 
 
Confidential 
 
 A Randomized, Double Blinded, Sham controlled Clinical Study 
to Evaluate the Safety and Efficacy of the Nerivio Migra 1, a 
Neuromodulation Device, for the acute treatment of Migraine 
 
Pivotal prospective multi-center clinical trial 
Clinical Investigation Plan 
NCT03361423 
01/Nov/2017 
 
 
Confidentiality statement: 
The following confidential information is the property of Theranica Bioelectronics. It may only be used 
when permission has been obtained from Theranica Bioelectronics in writing.  It is not permitted to 
make reproductions of all or sections of this protocol.   
 

 
A Randomized, Double Blinded, Sham controlled Clinical Study to Evaluate 
the Safety and Efficacy of the Nerivio Migra 1, a Neuromodulation Device, 
for the acute treatment of Migraine 
Protocol number:  TCH-003 
Page 2 of 94 
 
Confidential 
CLINICAL CLINICAL INVESTIGATION PLAN  
STUDY TITLE:  
A Randomized, Double Blinded, Sham controlled Clinical Study to 
Evaluate the Safety and Efficacy of the Nerivio Migra 1, a 
Neuromodulation Device, for the acute treatment of Migraine  
PROTOCOL NUMBER: 
 
TCH-003 
REVISION: 
 
 
1.0 
RELEASE DATE:  
 
01/Nov/2017 
DEVICE: 
Nerivio Migra 1, a Neuromodulator device for the acute 
treatment of migraine  
PRINCIPAL INVESTIGATORS:    
TBD 
SPONSOR:  
 
 
Theranica Bioelectronics 
 
 
 
 
45 HaMelakha st, Netanya, Israel 
CONTACT DETAILS: 
  
Dagan Harris, VP Clinical & Regulatory 
Tel: +972.72.390.9758 
Fax: + 972.72.390.9762 
Mobile: +972-0542220121 
EMAIL: daganh@theranica.com 
 
APPROVED BY: 
POSITION: 
DATE: (DDMMYY) 
SIGNATURE: 
___________ 
____________ 
  _ _ /_ _ /_ _ 
 
______________ 
___________  
____________ 
  _ _ /_ _ /_  
______________ 

 
A Randomized, Double Blinded, Sham controlled Clinical Study to Evaluate 
the Safety and Efficacy of the Nerivio Migra 1, a Neuromodulation Device, 
for the acute treatment of Migraine 
Protocol number:  TCH-003 
Page 3 of 94 
 
Confidential 
Version control table 
 
 
Rev. 
no. 
Change rationale 
Date 
1.0 
 initial version for FDA pre-submission review 
Oct, 1, 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
A Randomized, Double Blinded, Sham controlled Clinical Study to Evaluate 
the Safety and Efficacy of the Nerivio Migra 1, a Neuromodulation Device, 
for the acute treatment of Migraine 
Protocol number:  TCH-003 
Page 4 of 94 
 
Confidential 
The sponsor of this study, Theranica Bioelectronics Ltd, manufacturer of the Nerivio 
Migra device for the acute treatment of migraine, states the following: 
a) 
This study will be conducted in compliance with the protocol (after being 
approved by the local IRB/EC and, if required, by the relevant health care 
agencies), US 21 CFR Parts 50, 54, 56 and 812, 45 CFR Part 46, national laws 
and regulation concerning clinical trials, the Good Clinical Practices (GCP) 
set forth in ISO 14155 (2011) standard and the ethical principles that have 
their origin in the Declaration of Helsinki. 
b) 
The Protocol, Informed Consent Form (ICF), patient's information material, 
and advertising material (if applicable) will be submitted and approved by 
the ethics and regulatory authorities, and any request by the IRB/EC or 
regulatory agencies will be complied with. Approval will be obtained prior 
to enrollment of any patients. 
c) 
Adequate insurance policy will be held valid for the entire study duration 
as well as for the discovery period required per local regulation.  
d) 
The study will be registered with CLINICALTRAIL.GOV 
 
 
 

 
A Randomized, Double Blinded, Sham controlled Clinical Study to Evaluate 
the Safety and Efficacy of the Nerivio Migra 1, a Neuromodulation Device, 
for the acute treatment of Migraine 
Protocol number:  TCH-003 
Page 5 of 94 
 
Confidential 
Protocol Signature Page for Principal Investigator 
The signing of this Clinical Investigation Plan (CIP) by the Principal Investigator signifies that 
the contents have been laid down in full agreement and that the study will be conducted per 
this CIP, its amendments, the clinical trial agreement and the applicable regulatory 
requirements.  
 
The Principal Investigator confirms that written Institutional Review Board (IRB) Ethics 
Committee approval for the amended CIP will be obtained prior to commencing with data 
collection. This approval must be in the Principal Investigator’s name and a copy sent to 
Theranica Bioelectronics. Additionally, the Principal Investigator must sign the declaration 
below: 
 
I will provide copies of this CIP and all pertinent information to the study personnel under 
my supervision. I will discuss this material with them and ensure they are fully informed 
regarding the conduct of the Study. 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
 
 
 
 
 
 
 
 
 
Principal Investigator’s Printed Name 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Site Name 
 
Site # 
 
 
  

 
A Randomized, Double Blinded, Sham controlled Clinical Study to Evaluate 
the Safety and Efficacy of the Nerivio Migra 1, a Neuromodulation Device, 
for the acute treatment of Migraine 
Protocol number:  TCH-003 
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Confidential 
Contents 
1 
SYNOPSIS ........................................................................................................................................... 9 
2 
BACKGROUND ................................................................................................................................18 
2.1 
INTRODUCTION ....................................................................................................................................18 
3 
IDENTIFICATION AND DESCRIPTION OF THE DEVICE .....................................................19 
3.1 
INTENDED USE .....................................................................................................................................20 
3.2 
THE DEVICE.........................................................................................................................................20 
3.3 
THE APPLICATION .................................................................................................................................22 
3.4 
ENERGY OUTPUT ..................................................................................................................................23 
3.5 
VERIFICATION AND VALIDATION ...............................................................................................................24 
3.5.1 
Performance testing ...............................................................................................................24 
3.5.2 
Software validation ................................................................................................................24 
3.6 
PRINCIPLE OF OPERATION ......................................................................................................................25 
3.7 
IDENTIFICATION OF THE MEDICAL DEVICE .................................................................................................26 
3.8 
INSTRUCTIONS FOR USE .........................................................................................................................26 
3.9 
SUMMARY OF NECESSARY TRAINING ........................................................................................................27 
4 
PRELIMINARY INVESTIGATIONS AND JUSTIFICATION FOR THE STUDY DESIGN ..28 
4.1 
PREVIOUS PRE-CLINICAL EXPERIENCE .......................................................................................................28 
4.2 
PREVIOUS CLINICAL EXPERIENCE .............................................................................................................28 
4.3 
CLINICAL INVESTIGATION RISKS AND BENEFITS ...........................................................................................32 
5 
OBJECTIVES & HYPOTHESES ....................................................................................................34 
5.1 
OBJECTIVE ..........................................................................................................................................34 
5.2 
HYPOTHESIS ........................................................................................................................................34 
6 
DESIGN OF THIS CLINICAL STUDY ..........................................................................................35 
6.1 
DESCRIPTION .......................................................................................................................................35 
6.2 
MEASURES TO MINIMIZE BIAS ................................................................................................................38 
6.2.1 
RANDOMIZATION ............................................................................................................................39 
6.2.2 
PROCEDURES TO ENSURE BLINDING .....................................................................................................39 
6.3 
STUDY ENDPOINTS ...............................................................................................................................39 
6.4 
METHODS AND TIMING OF ASSESSING, RECORDING AND ANALYZING VARIABLES ..............................................41 
6.4.1 
TYPES OF DATA ...............................................................................................................................41 
6.4.2 
CLINICAL STUDY VARIABLES AND DATA CAPTURE TOOLS .........................................................................42 
6.4.2.1 
Start attack/episode PRO feedback data ..........................................................................42 
6.4.2.2 
2h PRO ..............................................................................................................................43 
6.4.2.3 
48h PRO ............................................................................................................................43 
6.4.3 
METHODS AND TIMING OF ASSESSING, RECORDING AND ANALYZING VARIABLES .........................................44 
6.4.4 
DATA FLOW AND MANAGEMENT .......................................................................................................44 
6.4.5 
PROCEDURES FOR REVIEW OF DATA ....................................................................................................46 
6.4.6 
DATA MONITORING COMMITTEE .......................................................................................................46 
6.4.7 
TOTAL EXPECTED DURATION OF THE CLINICAL INVESTIGATION .................................................................47 
6.5 
SUBJECTS ............................................................................................................................................47 
6.5.1 
INCLUSION CRITERIA ........................................................................................................................47 
6.5.2 
EXCLUSION CRITERIA ........................................................................................................................47 
6.5.3 
CONTRAINDICATIONS .......................................................................................................................48 
6.5.4 
NUMBER OF SUBJECTS ......................................................................................................................48 
6.5.5 
EXPECTED STUDY DURATION FOR EACH SUBJECT ...................................................................................48 
6.5.6 
POINT OF ENROLLMENT ....................................................................................................................48 
6.5.7 
PATIENT WITHDRAWAL CRITERIA .......................................................................................................48 
6.5.8 
HANDLING OF WITHDRAWALS ...........................................................................................................49 

 
A Randomized, Double Blinded, Sham controlled Clinical Study to Evaluate 
the Safety and Efficacy of the Nerivio Migra 1, a Neuromodulation Device, 
for the acute treatment of Migraine 
Protocol number:  TCH-003 
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6.5.9 
PATIENT LOST TO FOLLOW-UP ............................................................................................................49 
6.5.10 
ENROLLMENT PERIOD ..................................................................................................................49 
6.5.11 
PROCEDURES FOR REPLACEMENT OF SUBJECTS .................................................................................49 
6.6 
STUDY RELATED PROCEDURES .................................................................................................................50 
6.6.1 
GENERAL .......................................................................................................................................50 
6.6.2 
VISIT AND ASSESSMENT SCHEDULE ......................................................................................................50 
6.6.3 
ACTIVITIES PERFORMED BY SPONSOR REPRESENTATIVES ...........................................................................50 
6.7 
MONITORING PLAN ..............................................................................................................................51 
7 
STATISTICAL CONSIDERATIONS .............................................................................................52 
7.1 
STUDY DESIGN AND AIM........................................................................................................................52 
7.2 
STUDY VARIABLES ................................................................................................................................52 
7.2.1 
PRIMARY PERFORMANCE VARIABLE .....................................................................................................52 
7.2.2 
SECONDARY PERFORMANCE VARIABLES ................................................................................................52 
7.2.3 
EXPLORATORY PERFORMANCE VARIABLES .............................................................................................52 
7.2.4 
SAFETY VARIABLES ...........................................................................................................................52 
7.3 
STUDY HYPOTHESIS ..............................................................................................................................52 
7.4 
SAMPLE SIZE ESTIMATION ......................................................................................................................53 
7.5 
DEFINITION OF ELIGIBLE TREATMENT ........................................................................................................53 
7.6 
INTERIM ANALYSIS ................................................................................................................................53 
7.7 
RANDOMIZATION .................................................................................................................................54 
7.8 
ANALYSIS SETS .....................................................................................................................................54 
7.9 
STATISTICAL ANALYSES – (TBD) ..............................................................................................................55 
7.9.1 
GENERAL CONSIDERATIONS ...............................................................................................................55 
7.9.2 
SIGNIFICANCE LEVELS AND HANDLING OF TYPE I ERROR ............................................................................55 
7.9.2.1 
TYPE I ERROR .............................................................................................................................55 
7.9.2.2 
HIERARCHY APPROACH FOR SECONDARY ENDPOINTS ANALYSIS ...........................................................55 
7.9.3 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .........................................................................55 
7.9.4 
DISPOSITION OF PATIENTS .................................................................................................................56 
7.9.5 
PERFORMANCE ANALYSES .................................................................................................................56 
7.9.6 
SAFETY ANALYSIS: ...........................................................................................................................57 
7.9.7 
HANDLING OF MISSING DATA ............................................................................................................57 
7.10 
POOLING .......................................................................................................................................57 
8 
DATA MANAGEMENT ...................................................................................................................58 
8.1 
DATA CAPTURE ....................................................................................................................................58 
8.1.1 
DIRECT DATA ENTRY ........................................................................................................................58 
8.2 
DATA QUALITY ASSURANCE ....................................................................................................................58 
8.3 
ELECTRONIC SIGNATURES.......................................................................................................................58 
8.4 
VERIFICATION, VALIDATION AND SECURING OF ELECTRONIC DATA CAPTURE SYSTEM ...........................................59 
8.5 
RECORDS AND DATA RETENTION .............................................................................................................59 
8.6 
OTHER ASPECTS OF CLINICAL QUALITY ASSURANCE ....................................................................................59 
9 
AMENDMENTS TO THE CLINICAL INVESTIGATION PLAN ..............................................60 
10 
CLINICAL INVESTIGATION PLAN DEVIATIONS ..................................................................61 
10.1 
PROCEDURES FOR RECORDING, REPORTING AND ANALYZING PROTOCOL DEVIATIONS ...................................61 
10.2 
NOTIFICATION REQUIREMENT AND TIMELINES ......................................................................................62 
11 
DEVICE ACCOUNTABILITY ........................................................................................................63 
12 
STATEMENTS OF COMPLIANCE ...............................................................................................64 
13 
INFORMED CONSENT PROCESS ................................................................................................65 
14 
ADVERSE EVENTS .........................................................................................................................66 
14.1 
CHARACTERISTICS OF AN ADVERSE EVENT ............................................................................................66 

 
A Randomized, Double Blinded, Sham controlled Clinical Study to Evaluate 
the Safety and Efficacy of the Nerivio Migra 1, a Neuromodulation Device, 
for the acute treatment of Migraine 
Protocol number:  TCH-003 
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14.1.1 
Severity of the Adverse Event ............................................................................................66 
14.1.2 
Relationship of an AE and SAE to the Study Device ..........................................................66 
14.2 
DEFINITIONS OF ADVERSE EVENT AND ADVERSE DEVICE EFFECT ...............................................................66 
14.3 
DEFINITION OF SERIOUS ADVERSE EVENT .............................................................................................67 
14.4 
DEVICE DEFICIENCY ..........................................................................................................................67 
14.5 
TIME-FRAME FOR INVESTIGATOR REPORTING AE TO SPONSOR, EC, RA .....................................................67 
14.6 
ADVERSE EVENT REPORTING FORMS ...................................................................................................68 
14.7 
FORESEEABLE COMPLICATIONS AND ANTICIPATED ADVERSE DEVICE RELATED EFFECTS. .................................68 
14.8 
SAFETY MONITORING AND ADJUDICATION OF ADVERSE EVENTS ...............................................................69 
15 
VULNERABLE POPULATION ......................................................................................................70 
16 
EARLY TERMINATION OF THE CLINICAL INVESTIGATION ...........................................71 
16.1 
CRITERIA AND ARRANGEMENTS ..........................................................................................................71 
16.2 
REQUIREMENTS FOR PATIENT FOLLOW-UP IN CASE OF WITHDRAWAL ........................................................71 
17 
PUBLICATION POLICY .................................................................................................................72 
18 
PATIENT CONFIDENTIALITY & DATA PROTECTION.........................................................73 
19 
GUIDELINES AND APPLICABLE DOCUMENTS .....................................................................74 
20 
REFERENCES ...................................................................................................................................75 
21 
ACRONYM LIST ..............................................................................................................................77 
APPENDIX A. STIMULATION PROGRAMS ........................................................................................79 
APPENDIX B. CASE REPORT FORMS LIST AND DRAFT CRF QUESTONS ...............................80 
 

 
A Randomized, Double Blinded, Sham controlled Clinical Study to Evaluate 
the Safety and Efficacy of the Nerivio Migra 1, a Neuromodulation Device, 
for the acute treatment of Migraine 
Protocol number:  TCH-003 
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Confidential 
1  SYNOPSIS 
 
Title 
A Randomized, Double Blinded, Sham controlled Clinical Study to Evaluate the 
Safety and Efficacy of the Nerivio Migra 1, a Neuromodulation Device, for the 
acute treatment of Migraine 
Sponsor 
Theranica Bioelectronics Ltd. 45 HaMelakha st, Netanya, Israel 
Investigational 
Device 
Nerivio Migra, a neurostimulation device, is intended for the acute treatment of 
migraine with or without aura in patients 18 years of age or older.  
The device delivers transcutaneous electrical stimulation below pain threshold 
to the patient's upper arm. The level of generated stimuli is similar to other FDA 
approved electro- stimulation devices. The treatment is self-administered and 
controlled by a dedicated smartphone application. It is believed to alleviate pain 
through conditioned pain modulation. 
Study Design 
A prospective, randomized (1:1), double-blind, sham-controlled trial.  
The study will be conducted in three stages; two mandatory stages, and one 
optional stage. 
Stage One - Roll-in: 
Eligible participants will be trained to use a smartphone migraine diary 
application.  After the enrollment visit, participants who successfully completed 
training will report all their migraine attacks using the smartphone application 
for up to one month. Only patients who properly report at least 2 and no more 
than 8 migraine attacks, with a compliance rate as defined in section 6.1, will 
continue to the next stage. 
 
Stage Two - Parallel arm, double-blind treatment stage:  
Participants who meet the entry requirements will be randomized to an active 
Nerivio Migra or an identically looking sham device. They will be trained to use 
the device for treatment and provide feedback via the smartphone application. 
The active/sham ratio is 1:1.  
Following successful completion of training, subjects will be asked, to apply the 
device and administer treatment for every migraine attack they experience, at 
the onset of their migraine attack. Subjects will be asked to report the results of 
every treatment, using the smartphone application, at the times preset in the 
application. 
Subjects will be asked to carry the device and their smartphones with them at 
all times, and to make a reasonable effort to keep their smartphone charged 
and connected to the Internet at all times.  

 
A Randomized, Double Blinded, Sham controlled Clinical Study to Evaluate 
the Safety and Efficacy of the Nerivio Migra 1, a Neuromodulation Device, 
for the acute treatment of Migraine 
Protocol number:  TCH-003 
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The first treated attack in the double-blind treatment stage is considered a "run-
in test" treatment; its purpose is to verify compliance. This "run-in test" is only 
included in the safety endpoint analysis. It will not be included in the primary 
and secondary performance endpoints analysis. 
Stage Two will end after four (separate) treated migraine attacks, (excluding the 
"run-in test" attack), or one month (whichever is achieved first).  
Stage Three (optional, by subject request only) - Open label extended 
treatment: 
Following the completion of double-blind stage of the study, all subjects will be 
offered a 2-month open label period using the active device. 
Objectives 
To demonstrate the safety and effectiveness of the Nerivio Migra electro 
stimulation device for the reduction of migraine headache during an attack of 
migraine with or without aura. 
Safety Endpoints 
1. Adverse events related or unrelated to the study device. 
2. Treatment tolerability 
Primary 
Performance 
Endpoint 
Reduction of migraine headache: 
The proportion (%) of patients reporting reduction in their pain level 2 hours post-
treatment without rescue medications from severe or moderate to mild or no 
pain, or from mild to no pain, in their first treated migraine attack (excluding the 
"run-in test" treatment).   
Secondary 
Performance 
Endpoints 
 
1. MBS Relief: 
Proportion (%) of patients reporting, 2 hours post-treatment, freedom from 
their most bothersome migraine-associated symptom (MBS) other than a 
headache, in their first treated migraine attack (excluding the "run-in test" 
treatment).  MBS may be nausea, photophobia, phonophobia or allodynia – 
as defined by each subject at the beginning of the treatment.  
 
2. Reduced Migraine Headache AND MBS Relief: 
Proportion (%) of patients reporting, 2 hours post treatment response to 
both the primary and the first secondary endpoints. 
 
3. Pain-free at 2 hours: 
The proportion (%) of subjects reporting freedom from migraine pain at 2 
hours post-treatment without medications in their first treated migraine 
attack (excluding the "run-in test" treatment). 
 

 
A Randomized, Double Blinded, Sham controlled Clinical Study to Evaluate 
the Safety and Efficacy of the Nerivio Migra 1, a Neuromodulation Device, 
for the acute treatment of Migraine 
Protocol number:  TCH-003 
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Exploratory 
Performance 
Endpoints 
 
1. 
Sustained pain-free 48 hours with single use of the device: 
The proportion (%) of subjects reporting pain-free at 2 hours, and no 
return of any pain or use of rescue/acute medication, or reuse of device 
between 2 hours and 48 hours, in their first treated migraine attack 
(excluding the "run-in test" treatment).   
 
2. 
Sustained Headache Reduction for 48 hours with single use of the device: 
The proportion (%) of subjects reporting treatment response 2 hours post-
treatment without rescue medications, and no return to baseline level of 
pain at time of treatment, or use of rescue/acute medication, or reuse of 
device between 2 hours and 48 hours, in their first treated migraine attack 
(excluding the "run-in test" treatment).  
Treatment response is defined as: 
o  pain level reduction from moderate or severe at baseline 
to mild or none, OR: 
o pain level reduction from mild to no pain. 
 
3. 
Sustained pain-free 48 hours with reuse of device 
The proportion (%) of subjects reporting pain-free at 2 hours, and no 
return of any pain or use of rescue/acute medication except for reuse of 
device between 2 hours and 48 hours, in their first treated migraine attack 
(excluding the "run-in test" treatment).   
 
4. 
Sustained Headache Relief 48 hours with reuse of the device: 
The proportion (%) of subjects reporting Treatment Response at 2 hours, 
and no return to baseline level of pain at time of treatment, or use of 
rescue/acute medication except for reuse of device between 2 hours and 
48 hours, in their first treated migraine attack (excluding the "run-in test" 
treatment).   
Treatment response is defined as: 
o  pain level reduction from moderate or severe at baseline 
to mild or none, OR: 
o pain level reduction from mild to no pain. 
 
5. 
Sustained relief of MBS with a single use of the device  
The proportion (%) of subjects reporting freedom from MBS at 2 hours, 
and no return of MBS, or use of rescue/acute medication between 2 hours 
and 48 hours, in their first treated migraine attack (excluding the "run-in 
test" treatment). 
 

 
A Randomized, Double Blinded, Sham controlled Clinical Study to Evaluate 
the Safety and Efficacy of the Nerivio Migra 1, a Neuromodulation Device, 
for the acute treatment of Migraine 
Protocol number:  TCH-003 
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Confidential 
6. 
Sustained relief of the MBS with reuse of the device: 
Proportion (%) of patients reporting, 48 hours post the first treatment, 
freedom from their most bothersome migraine-associated symptom other 
than headache (MBS), possibly with reuse of the device, in their first 
treated migraine attack (excluding the "run-in test" treatment).  
 
7. 
Within-patient consistency of the primary endpoint in subsequent 
treatments: 
The repeatability of migraine headache reduction, as described in the 
primary endpoint definition, in subsequent treated attacks.  
Thus, this endpoint measures the % of patient responding to the primary 
endpoint in at least 50% of their treated attacks (excluding the run-in 
attack 
 
Patient 
Population 
Adults 18-75 years old meeting International Headache Society criteria (ICDH3) 
for migraine with and without aura, who are reporting 2-8 migraine attacks per 
month. 
Number of 
Patients 
up to 270 patients with evaluable data, equally distributed between US and 
non-US sites 
Inclusion Criteria 
 
1. Subjects age 18-75 years old. 
2. Subjects meet the ICHD-3 diagnostic criteria for migraine with or without 
aura 
3. Subjects report 2-8 migraine attacks per month. 
4. Stable migraine preventive medications in the last two months prior to 
recruitment (No change in usage or dosage). 
5. Subjects must be able and willing to comply with the protocol 
6. Subjects must be able and willing to provide written informed consent 
Exclusion Criteria 
1. Subject has other significant pain, medical or psychologic problems that 
in the opinion of the investigator may confound the study assessments 
2. Subject has an implanted electrical and/or neurostimulator device (e.g. 
cardiac pacemaker or defibrillator, vagus nerve neurostimulator ,deep 
brain stimulator, spinal stimulator, bone growth stimulator  cochlear 
implant, Sphenopalatine ganglion stimulator  or Occipital nerve 
stimulator). 
3. Subject has known uncontrolled epilepsy. 
4. Any use of Cannabis including medical use.  
5. Subject has >10 headache days per month . 

 
A Randomized, Double Blinded, Sham controlled Clinical Study to Evaluate 
the Safety and Efficacy of the Nerivio Migra 1, a Neuromodulation Device, 
for the acute treatment of Migraine 
Protocol number:  TCH-003 
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6. Subject has undergone nerve block (occipital or other) in the head or 
neck within the last 2 weeks . 
7. Subject is participating in any other clinical study. 
8. The subject does not have the basic cognitive and motor skills needed to 
operate a smartphone. 
9. Pregnant, or trying to get pregnant 
10. Subject is experiencing a menstrually related migraine  
11. Received OnabotulinumtoxinA or any botulinum toxin injections for migraine 
within the previous month 
12. Received parenteral infusions for migraine within the previous 2 weeks.  
13. Subject participated in a previous study with the Nerivio Migra 1 device  
 
Note - Females of child bearing potential must have a negative pregnancy test 
and must be willing to use adequate contraception during the study 
Study Procedures 
Enrollment visit: 
Following successful eligibility screening, enrollment interview and 
signing of informed consent, participants will be trained in the Nerivio 
Migra software application in its “diary” mode.  The application will be 
installed on their smartphones (or smartphones provided by the clinic, if 
the patient does not have a compatible smartphone).  
Subjects will complete a baseline questionnaire including the frequency 
and severity of migraine attacks, usual most bothersome symptom, usage 
of preventive and acute medications and devices.  
Roll-in stage: 
After the enrollment visit, patients will be asked to report each and every 
migraine attack with the application. (These reports will be collected). 
Participants who successfully complete the roll-in stage with at least 2 
but no more than 8 migraine attacks, with complete and prompt 
reporting and compliance rates as defined in section 6.1, will be eligible for 
randomization.  
Randomization visit: 
Patients will be randomized and provided with an active Nerivio Migra or 
an identically looking sham device. Then they will be trained to use the 
device and provide feedback via the smartphone application.  

 
A Randomized, Double Blinded, Sham controlled Clinical Study to Evaluate 
the Safety and Efficacy of the Nerivio Migra 1, a Neuromodulation Device, 
for the acute treatment of Migraine 
Protocol number:  TCH-003 
Page 14 of 94 
 
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Treatment stage: 
After the randomization visit, patients will be asked to treat all their 
migraine attacks with the device, if, and only if, they can apply the device 
immediately after the onset of the migraine attack symptoms and no 
later than 60 min, and report through the application, at the preset times 
on the application. Patients will be asked to keep the device and their 
smartphone with them at all times and make a reasonable effort to keep 
the smartphone charged and connected to the Internet.  
Patients will be asked not to use rescue medications during the first two 
hours after the start of treatment. Taking rescue medication in this time 
period is considered a major protocol violation. Patients will record their 
medication use in the smartphone application.  
At the beginning of treatment, two, and 48 hours later, each participant 
will be prompted by the application to rate their migraine pain level using 
Pain Grades Scale with values 0-3 (no pain, mild, moderate, severe), and 
other symptoms of the migraine attack: aura, nausea, photophobia, 
phonophobia and allodynia.   
In case of failure to provide feedback regarding pain level post-
treatment, alerts will be generated by the Electronic Data Collection 
system, and telephone follow-up inquiries will be performed by study 
investigator staff.  
Two hours after treatment and completing the post two-hour feedback, 
subjects will be able re-treat the attack – if they choose so - by re-using 
the Nerivio Migra device as often as they want. 
After completing up to 4 qualified treatment, or 1 month from the 
randomization visit (whichever happens first) subjects will stop using 
their device until their next visit.  
Open Label visit: 
Subjects will fill an end of study questionnaire, which includes patient 
global impression of the change in their migraine experience with the 
device, blinding questionnaire, and usability assessment. 
After completing the questionnaire, subjects will be offered an active 
which they will be able to use for the next two months.  

 
A Randomized, Double Blinded, Sham controlled Clinical Study to Evaluate 
the Safety and Efficacy of the Nerivio Migra 1, a Neuromodulation Device, 
for the acute treatment of Migraine 
Protocol number:  TCH-003 
Page 15 of 94 
 
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Open Label extension: 
All treatments will be recorded and monitored (identical to the dual-arm 
treatment phase).  Adverse events will also be recorded.  
Final visit: (This can occur at the open label visit if patients do not want to 
continue to use the device): 
At the end of the Open-Label extension, patients will return the device to 
the clinic. 
Adverse events will be collected throughout the study. 
Study Duration 
Duration for each patient will be approximately two months – up to one 
month of roll-in stage and up to one month or treatment of up to four 
qualified migraine attacks (whichever is achieved first). 
An optional open-label extension of two months is available. 
Qualified 
Treatments 
Qualified treatments must meet ALL the following criteria: 
1. The patient had at least 48 consecutive hours without migraine 
headache prior to treatment.  
2. Treatment is started no later than 60 minutes post the onset of 
migraine symptoms. 
3. Treatment lasted at least 30 (continuous) minutes.  
4. No pain medications were used from 24 hours prior the onset of 
the migraine, until 2 hours after the start of the treatment. 
5. The patient completed and reported the post 2-hour treatment 
questionnaire through the application. 
Major Protocol 
Violations 
The following will be considered major protocol violations: 
1. Taking rescue medication within the two hours of starting 
treatment. Such treatments will be considered non-qualified. 
2. Starting the treatment more than 60 mins after the onset of 
migraine symptoms. Such treatments will be considered non-
qualified. 
3. Not completing 30 minutes of treatment. Such treatments will be 
considered non-qualified. 
Sample Size  
Up to 270 subjects will be recruited to this study 
Data Analysis 
Data management function will be supported by a cloud-based EDC system 
(Clear Clinica, Modi’in, Israel). Clear Clinica provides services for collection 

 
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and remote monitoring of clinical trials data, compliant with HIPAA and 21 
CFR Part 11. 
EDC portals with secure authorized access will be made available to the 
site personnel, as well as to the study monitor.  
Data captured by clinical personnel will be entered directly into pre-
specified eCRF screens by site personnel.  Data from paper sources will be 
entered into the study database. Automatic data checks will be 
implemented for the majority of entry fields to provide an opportunity for 
resolving data inconsistencies as close as possible to real time.  
 
Data collected onto the smartphone application will be directed to a 
secure cloud-based database where it will undergo analysis aimed at 
detection of missing data and other inconsistencies.  
Activities such as repeatedly aborted programs, missing feedbacks, 
inconsistent stimulation intensity adjustments, and similar, will be 
communicated to research coordinator of the corresponding site, using 
participants’ ID codes. Missing data will be identified automatically, and 
queries will be generated to participants and corresponding site study 
coordinator.  
Statistical analysis 
Analysis Sets 
1. Intent to Treat analysis set (ITT) 
The ITT analysis set includes all patients who are randomized and 
treat at least one attack. 
  
2. Modified Intend to Treat analysis set (mITT) 
The mITT analysis set includes all patients who are randomized and 
treat at least one attack (excluding the" run-in test" attack) within 
1 hour from the attack onset.  
 
3. Per-Protocol analysis set (PP) 
The PP analysis set includes patients who are randomized and treat 
at least one attack (excluding the "run-in test" attack), which 
conforms with the protocol instructions: 
• 
Treatment starts within one hour from attack onset. 
• 
No rescue medication (or pain medication) is consumed 
within the 2 hours after start of treatment. 
• 
The treatment is not aborted prematurely (i.e., before the 
first 30 minutes).  
• 
No Pain medication 24h prior migraine onset 

 
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Statistical Analysis of Analysis Sets 
The ITT analysis set will serve as the main set for safety assessments.  
 
The mITT analysis set for all performance assessments. 
 
The primary and secondary performance assessments will also be 
performed on the PP analysis set as a sensitivity analysis. 
 

 
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2 BACKGROUND 
2.1 Introduction 
Migraine is a common neurologic with attacks of headache and associated symptoms such as 
nausea, vomiting, phono and photophobia. Migraine can lead to substantial functional 
impairment [1]. The recent Global Burden of Disease Study 2010 (GBD2010), conducted by the 
World Health Organization, estimates a worldwide prevalence of migraine of 14.7%, ranking it 
third place among the most common diseases and at the seventh place among specific causes of 
disability and top of all neurological disorders as cause of total years lived with disability [1]. The 
pathophysiology of migraine is becoming understood [2]. Current approach to migraine treatment 
is predominantly pharmacological [3].  
Transcutaneous electrical stimulation (ES) is a non-invasive technique that delivers series of weak 
electrical pulses to patient’s skin.  ES has been used for decades for treatment of many painful 
conditions [3, 4]. In general, the stimulation is applied adjacent to, or at least within the 
dermatome of the painful body site. Recent evidence suggests that electro stimulation is effective 
in providing relief for chronic headaches including migraine. It is tolerable by patients and 
associated with no adverse effects [4-6]. There are currently two approved non-invasive devices 
intended for providing migraine relief via transcutaneous electro stimulation. The first device, 
Cefaly, is used for acute and preventive treatment migraines, was developed by STX-Med [4]. The 
device applies electro stimulation to the forehead, within the trigeminal nerve territory. The 
second device, GammaCore, developed by ElectroCore [6], vagus nerve stimulation is approved 
for marketing in Europe and is used for treatment of migraine pain. It is approved in the US for 
the acute treatment of episodic cluster headache. Both devices deliver stimulation at relatively 
low intensity (16mA).  Both devices target electro stimulation to major specific nerves in close 
proximity to patient’s head. Both trigeminal and vagus nerves are responsible for multiple 
functions of major importance. The list includes, but is not limited to, facial sensation, biting, 
chewing for trigeminal nerve; heart rate, sweating and speech for vagus nerve. 
These commercially available treatment approaches are associated with some usability 
challenges (Cefaly device is mounted on forehead and the GammaCore is hand held throughout 
the treatment session but only 90 seconds).  
There exists a need for additional non-pharmacological solutions for migraine treatment. 

 
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3 IDENTIFICATION AND DESCRIPTION OF THE DEVICE 
Theranica has developed Nerivio Migra (“Migra” or “the device”).  Nerivio Migra is intended for 
the acute treatment of migraine with or without aura in patients 18 years of age or older. It is self-
applied to the upper arm. Treatments are self-administered by the user at the onset of a migraine 
attack. The device delivers extra cephalic transcutaneous electrical stimulation below the pain 
threshold to the skin of the upper arm at the onset of a migraine attack.  Nerivio Migra is operated 
via a mobile application.   
Nerivio Migra utilizes electro stimulation to achieve conditioned pain modulation (CPM). 
Conditioned Pain Modulation (CPM) [7] is a paradigm used in pain research, in which a 
“conditioning” (also referred to as secondary) stimulus is applied to influence the subject’s 
perception of a “conditioned” (primary) painful stimulus, delivered (or originating) at a different 
y location. Based on diffused noxious inhibitory control (DNIC) mechanism [14], and sometimes 
referred to as “pain inhibits pain” principle, CPM evokes an endogenous analgesic mechanism. 
The modulatory effect is over the whole body, and can be induced anywhere in the body. This 
approach allows applying the conditioning stimuli away from the painful site.  
The conditioning stimulus is given at an intensity which is well felt, but below the pain threshold. 
Experimental human data shows that in the majority of tested subjects, a conditioning stimulus 
which is slightly lower than pain threshold is sufficient to activate CPM [8, 9]. This is probably due 
to different summation requirements of the brainstem pain modulation centers and of the cortex; 
more intensive peripheral nociceptive activity is needed for the cortex than for the brainstem.  
The 'inhibitory power' activated by CPM via this peripheral non-painful stimulation is limited. It is 
most effective when used migraine headache onset, when activity of the nociceptive pathways is 
still just starting, and may be related to lack of central sensitization.  Central sensitization often 
develops during the first two hours of the migraine attack; this explains the benefit of early 
treatment. [10] Thus, treatment early in the attack is expected to be more effective. 
The device delivers electrical currents that are within the range of FDA approved battery operated 
Transcutaneous electrical nerve stimulation (TENS) devices to treat pain [18, 19].  
The use of TENS has proved effective in clinical studies and its safety is well established [15-17]. 
Multiple TENS devices are being marketed for over-the-counter use for a wide range of indications 
and anatomical locations. Many approved devices are used to treat chronic conditions.   
Two main groups of electro stimulation protocols have been described and evaluated for pain 
relief: high frequency (80-200Hz) and low frequency (1-5Hz) [18]. Nerivio Migra operates in high 
frequency domain.  
To the best of our knowledge this is the first device based on application of electrical stimulation 
to treat migraine headache through conditioned pain modulation allowing for the application of 
the stimulator remotely to head and neck.  
 
The device is comprised of 3 main components: (1) Arm-band with attached electrodes, (2) 
Electronics case and (3) Software including Firmware and Mobile Application software to be run 
on a mobile platform.  Each of these components is briefly described below.    

 
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3.1 Intended Use 
The Nerivio Migra device is intended for the acute treatment of migraine with or without aura in 
patients 18 years of age or older.  
The Nerivio Migra is indicated to be applied within no more than 60 minutes from migraine 
symptoms onset. The Nerivio Migra is indicated for self-administration in home setting. 
 
3.2 The Device 
The Device is a fully integrated unit similar in appearance to an armband.  The device includes an 
arm band, electronic circuitry and battery contained in a plastic case, and a pair of electrodes with 
hydrogel (Figure 1). 
 
 
The armband is based on biocompatible materials and comply with the biocompatibility 
requirements (according to ISO 10993 part 1- biological evaluation for medical devices).  It is thin 
and stretchable, as to not impede the user’s movement. The Velcro strip allows convenient 
placement of the device at intended arm area for variety of arm sizes. 
A pair of electrodes is attached to the internal side of the armband. The 5cm x 5cm Ultra Slim 
Electrodes with multistick gel (Model SN2020) are manufactured by Axelgaard Manufacturing Co. 
Ltd (Fallbrook CA, USA).  The electrodes are incorporated into the armband and are not to be 
replaced by participants throughout the course of the study.   
Figure 1. - Internal side of Nerivio Migra device 

 
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The plastic case, made of non-flammable ABS type plastic, is placed on the armband in a manner 
that does not result in its contact with the body. The plastic case contains the device’s electronics 
circuitry.  It is attached to the external surface of the armband and wired to the electrodes that 
are housed on the inside of the armband.  The case dimensions are 10cm x 5cm x 1.5cm.  
The electronic circuitry housed within the plastic case contains a small printed circuit board (PCB) 
with the electronics components that are needed to generate and operate the electro stimulation 
functions (delivered via the electrodes) as well as the wireless communication with the user’s 
smartphone or tablet (via standard Bluetooth protocol).  The PCB connects to a battery located 
inside the case, and is wired to the pair of stimulation electrodes. 
The outer part of the case contains an on/off switch and LED indicator of working mode (Figure 
2). 
 
Figure 2. - External side of Nerivio Migra device 
The device includes current source circuitry that ensures steady stimulation current output.  The 
current output is limited by the current source hardware design to 60mA.  The output voltage is 
further limited by the power supply hardware design to 60V.  
The device uses a controlled current source to output steady and controlled current via a pair of 
electrodes.  The stimulation program is stored in device memory.  The waveform is generated by 
the Pulse Generator unit and controlled by a programmable microcontroller (μCPU) to follow pre-
set stimulation program parameters.  Intensity of the output current can be controlled via mobile 
app software by Bluetooth wireless connection (BT/BLE).  Once stimulation has been started by 
user, the device can operate in a stand-alone fashion without wireless connection to the mobile 
app software and will automatically cease stimulation after reaching the program’s time limit. 
The provided battery is sufficient to provide power required for stimulation throughout the 
duration of the whole experiment. The device will not be connected to power outlet by study 
participants. 
An ID sticker used to uniquely identify the device, as well as assist with a quick Bluetooth pairing 
is placed on the external side of the device. 

 
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3.3 The Application 
Activation, control over stimulation intensity and termination of stimulation are performed via a 
dedicated smartphone application developed by Theranica and installed on the user’s cell phone.  
The Nerivio Migra Application provides user interface for operating and managing the device, 
means for collecting Patient Reported Outcomes (PRO) and the link to the secure cloud and study 
database (DB). Captures of main Application screens are shown in figure 3.  
The Application is installed from a standalone APK file, fully independent and distributable; 
implementation for Android only (4.1 and above). 
• 
Upon activation, the Application shows the main window with the following options for 
the user to select: 
o Connection – handles the Bluetooth connection to the device 
o Diary/Treatment – collects information regarding migraine symptoms, controls 
the stimulation programs, as well as user feedback regarding the treatment 
o Help – provides online help to the user 
o Switch to treatment – register the patient and the device for the treatment stage 
 
• 
The Application logs and records every operation of the device into NVM on the 
Smartphone. Subsequently, this information is also relayed to the Cloud (see Figure 7). 
• 
The Application is able to query device battery status and notify the user of its condition.  
• 
Supports menus and display language in Hebrew and English (according to phone’s 
language set) 
• 
Supports PRO collection 
• 
Keeps logs of the actions performed by the user, including: 
o Device’s connection and disconnection 
o Activation and deactivation periods 
o User stimulation intensity adjustments 
o Feedback from the user (before, during and after activation) 
 
Figure 3. - Application screens. Left to right: start screen, main menu, connectivity screen, treatment 
management screen 

 
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3.4 Energy output 
Output parameters of the Migra are similar to those of other TENS devices previously cleared by 
the FDA and currently marketed for variety of indications for over the counter use. 
The Nerivio Migra output parameters and its comparison to other approved devices are 
described in table 1 
 
Parameter 
Nerivio Migra 1 
Cefaly 
Sys*Stim TENS 
Mode 
or 
Program 
name 
TENS 
TENS 
TENS 
Waveform 
Biphasic, 
symmetrical 
Biphasic, 
symmetrical 
Asymmetrical 
biphasic with zero net 
DC 
Shape 
Rectangular 
Rectangular 
Rectangular 
Maximum 
output 
voltage (V)  
  
  
  
500Ω 
30 
8 
92 ±20% 
2KΩ 
60 
32 
144 ±20% 
10KΩ 
60 
60 
166 ±20% 
Maximum 
output 
current (mA)  
  
  
  
500Ω 
60 
16 
184 ±20% 
2KΩ 
30 
16 
72 ±20% 
10KΩ 
6 
6 
17 ±20% 
Duration of primary 
(depolarizing) phase 
(µsec) 
200 
250 
200µs ±10% 
Frequency (Hz) 
100-120 
60 
1-80Hz ±10% 
Maximum 
average 
power 
density 
(mW/cm²)500Ω 
3.17 
0.017 
12 
Maximum 
phase 
charge (µC) 
  
  
  
500Ω 
12 
4 
33.5u ±10% 

 
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Maximum 
current 
density 
(mA/cm², 
r.m.s) 
  
  
  
500Ω 
0.50 
2.37 
 
Table 1 - Key output parameters comparison 
 
User has control over stimulation intensity within the specified limits.  A dedicated mechanism 
controls speed of intensity adjustment in order to protect the user from unexpectedly strong 
stimulation intensity variations.  
 
3.5 Verification and validation 
The design of the Nerivio Migra device has been verified and validated as per the design control 
requirements (FDA 21 CFR part 820.30 and ISO 13485). The device successfully passed basic safety 
and EMC tests per applicable standards (leakage current, power consumption and radiation 
emission) at Hermon Laboratories. 
3.5.1 Performance testing  
All features and output specifications identified in Table 1 were verified under various loading 
conditions meant to simulate those the device could encounter during use. 
Bench tests of the device included: 
• 
Verification of stimulation programs – pulses characteristics, program duration, and 
stimulation intensity. The tests were performed using e*Scope TDS3012B manufactured 
by Tektronix (USA). 
• 
Mechanical testing 
• 
Bluetooth connectivity – distance and robustness 
• 
Battery lifetime for active and passive states.  
3.5.2 Software validation 
Validation of software (smartphone application) relating to the function of the device was 
performed for variety of use cases providing coverage of device requirements.  
It includes: 
• 
Application in general 
• 
Authorization  
• 
Connectivity with the device 
• 
Help / troubleshooting messages  
• 
Programs execution 

 
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• 
Activation 
• 
Amplitude control 
• 
User feedback 
• 
Battery measurement 
• 
Android version 
• 
Logs 
• 
Application dialogs 
• 
Client/server communication  
• 
Notifications 
• 
User feedback –additional data 
• 
Notification to switch down device 
3.6 Principle of Operation 
Once Migra is placed on the patient’s arm (see Figure 4) at the onset of a migraine attack, the 
user turns the device ON and activates therapy via the Mobile Application.  
 
Figure 4 - Nerivio Migra located on the upper arm 
 
This target location is easily accessed independently by the patient without help and is discrete 
to maintain treatment privacy.  The treatment delivered to the user is a weak electrical current to 
the skin via the electrodes. 
The operation of Migra is controlled by mobile application software that was developed by the 
company. The application is installed and operated from the patient’s smartphone device, and is 
used for the activation, termination and control (e.g. stimulation intensity control, status 
indications and more) of the device. 
The communication between the Migra device and the Application software is performed 
wirelessly via standard Bluetooth protocol. 
Duration of the stimulation program is pre-set to 45 minutes. At any point in time, however, the 
patient is able to stop treatment by one of three methods: 

 
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• 
Terminating the stimulation via the Mobile Application 
• 
Turning off the device on/off switch located on the outer part of the armband 
• 
Carefully removing the armband 
For the study purposes, the Nerivio Migra delivers a single, pre-set, active stimulation program, 
or a sham program. Programs characteristics are given in Appendix A. 
Device operation flow is presented in the figure 5. 
 
Figure 5. - Device operation flow 
At any moment during treatment, user can stop treatment by terminating the stimulation via the 
smartphone application, or by turning off the switch on the wearable unit, or by simply removing 
the armband.  
 
3.7 Identification of the Medical Device 
The medical device will be labeled for clinical investigation use only. The label includes the address 
of the legal manufacturer and all other essential information to allow full traceability of the 
medical device as per the regulatory labeling requirements. 
3.8 Instructions for Use 
Device Instructions for Use are available as a separate document to study personnel. Printed 
instructions for Use are handed to study participants along with the device. Electronic version of 

 
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IFU is accessible from the Application at any time. A brief description of principle of operation can 
be found in sections 3.1- 3.4 above. 
3.9 Summary of Necessary Training  
General instructions and training in device use as peer the IFU will be provided to study 
participants at the participating sites. No specific skills are required from study participants 
beyond basic level of experience with general purpose Android applications. Training will be 
delivered by designated study personnel and will be recorded in a corresponding CRF. In addition, 
records of the training session will be documented in the study DB with label “training”. The 
criteria for training effectiveness will be ability of the participant to run a training treatment 
session independently.  
Training to the investigator and staff will be delivered by sponsor representative in a frontal 
session including demo and training activations. In order to provide additional support to clinical 
personnel, a training video clip was prepared and will be available at all training sessions for staff 
and participants.  

 
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4 PRELIMINARY INVESTIGATIONS AND JUSTIFICATION FOR THE 
STUDY DESIGN  
4.1 Previous Pre-Clinical Experience 
There were no animal studies with the Nerivio Migra device. Since it is applying energy output 
similar to that of FDA approved TENS devices, and in accordance with the application of risk 
management as per EN ISO14791, the necessity for such a study has been precluded. There is no 
valid animal model to test the effectiveness of this device.  
4.2 Previous Clinical Experience 
Sponsor has completed a prospective, randomized, double-blind, sham controlled, cross-over, 
multiple treatment arms single center study “Relief of migraine pain through electro stimulation” 
at the Neurology Department, Rambam Medical Center (Haifa, Israel). A brief summary of this 
pilot study protocol is provided below, along with an overview of the procedures utilized and the 
results observed.   
Pilot Study Objective   
The purpose of the investigation was to evaluate the safety and performance of the Nerivio Migra 
for the relief of headache pain of non-chronic migraine patients with and without aura and 
provide comparative data regarding performance and tolerability of the evaluated treatment 
programs.   
Inclusion and Exclusion Criteria 
Inclusion Criteria 
1. Adult male and female ages 18-75. 
2. Patients meeting International Headache Society criteria for migraine with and without 
aura. 
3. Patients reporting 2-8 migraine attacks per month. 
4. Patient must be able and willing to comply with the required follow-up schedule 
5. Patient must be able and willing to provide written informed consent 
6. Patient was not on preventive medications for at least two months 
Exclusion Criteria 
1. 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 
2. Has severe cardiac or cerebrovascular disease. 
3. Has uncontrolled high blood pressure (systolic > 160 mmHg, diastolic > 100 mmHg after 
3 repeated measurements within 24 hours). 
4. Is currently implanted with an electrical and/or neurostimulator  device (e.g. cardiac 
pacemaker or defibrillator, vagus nerve neurostimulator  ,deep brain stimulator, spinal 
stimulator, bone growth stimulator  cochlear implant, Sphenopalatine ganglion 
stimulator or Occipital nerve stimulator). 
5. Known epilepsy. 

 
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6. Use of Cannabis including medical use.  
7. Has chronic migraine (more than 15 headache days per month) . 
8. Has undergone nerve block (occipital or other) in the head or neck within the last 2 
months. 
9. Has received Botox injections within the last 6 months. 
10. Is pregnant or thinking of becoming pregnant during the study period, or of childbearing 
years and is unwilling to use an accepted form of birth control.   
11. Is participating in another clinical study in Migraine treatment or prevention. 
12. Does not possess the basic cognitive or motor skills needed to operate android cell phone. 
Study Procedures 
Potential patients signed informed consent prior to any study procedure. The patient medical 
history, migraine history, use of concomitant medications and diagnosis were recorded.  Patients 
found eligible by meeting all the inclusion criteria and none of the exclusion criteria received 
documented training whereupon its successful completion the investigational device was 
provided to study participants for home use.  
As per the instructions for use, participants were instructed to activate the device at the onset of 
a migraine attack and manually adjust stimulation intensity to a level where it is perceivable but 
not painful. Patients were requested to refrain from use of rescue medications prior to and during 
the first two hours following treatment by the device, and if they could not comply with this, 
record medications usage in the smartphone application.  
Five 20-minute long stimulation protocols were programmed into each unit; four active programs 
at 100-120 Hz, with primary phase widths of 200 (P200), 150 (P150), 100 (P100) and 50 (P50) 
microseconds, and one placebo stimulation protocol (P0) at 0.1 Hz frequency with 45 
microseconds long pulses.  Stimuli were given at random sequences with the following 
distribution: P0 and P200: probability of 1/3 each, P50, P100, P150: probability of 1/9 each. 
Randomized sequences of programs were generated independently for each participant.  
Both patients and study personnel were blinded to the order of individual treatments. 
Via the smartphone application, each participant was asked to rate his/her migraine pain level 
four times using a Numeric Pain Rating Scale (NPS, values 0-10): (1) upon starting the treatment, 
(2) during (halfway through treatment program), (3) at the end of treatment, as well as (4) two 
hours after treatment.  
At the beginning of each treatment, participants were asked to provide feedback using the 
application regarding the time elapsed from start of migraine attack to start of the treatment. In 
case of failure to provide feedback regarding pain level post-treatment, telephone follow-up was 
performed by study investigator staff to solicit such feedback. Follow up phone calls were 
performed to record changes in medical condition, concomitant medication, migraine therapy 
and adverse effects. Unscheduled visits were recorded, and termination visit were scheduled 
upon the completion of the study as defined by a maximal number of 20 complete treatment 
cycles but no longer than 6 months from enrollment. (whichever is fulfilled first). In the event of 
premature discontinuation an early discontinuation visit was scheduled. End of study interview 

 
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was performed soliciting feedback regarding device usability, burden of treatment, use of 
migraine medications during the study period, as well as free comments. 
Study Endpoints 
• 
The primary efficacy endpoint of the study was the proportion of responders, where a 
responder is defined as subject with clinically significant decrease in pain score measured 
by Numeric Pain Rating Scale (NPS) of at least 50%, 2 hours post treatment as compared 
to baseline in at least 50% of treatments. 
• 
The second primary performance endpoint was relative pain reduction at 2 hours post 
treatment as compared to baseline. 
• 
The primary safety endpoint was evidence of device related adverse effects.   
Burden of treatment was assessed by mean scores of post-study questionnaire.  Success was 
defined as superior performance of active treatments as compared to sham treatment.  The 
protocol provided for enrollment of up to 100 patients.   
Summary of Results 
The pilot study was performed between June 2015 and March 2016.  A total of 86 participants 
were provided with the Nerivio Migra devices for use as part of this clinical study.   
A summary of participants’ demographic characteristics is presented in Table 2 below. 
 
Female 
Male 
N (%) 
69 (80%) 
17 (20%) 
Age mean (min-max, STD) 
45.2 (22-72, 11.7) 
48.8 (26- 67, 11.7) 
Migraine attacks per month, mean (STD) 
5.1 (2.7) 
5.34 (2.3) 
Mean pain intensity during attack 
8.9 
8.6 
Occurrence of aura 
40 (58%) 
11 (65%) 
Table 2 – Pilot Study Population 
 
Seventy-two participants successfully treated at least one migraine attack.  The remainder of 
participants either did not treat their attacks per protocol, or failed to provide complete feedback. 
One participant was excluded from statistical analysis due to repeated use of rescue medications 
concurrently with the electro stimulation treatments. Complete reporting was obtained for 70% 
of activations for P200, P150, P100 programs, 58% of activations of P50 and 28% of placebo 
activations. 
No adverse events related to the device and no side effects were reported. 
Observed outcome measures based on ITT analysis are summarized in Table 3 below. 
  
Sham 
Active programs 

 
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P0 
P200 
P150 
P100 
P50 
Overall active programs 
(p vs. placebo) 
%50% (% 
responders), N=71 
26% 
46% 
(0.04) 
48% 
(0.06) 
39% 
(0.4) 
44% 
(0.14) 
64% 
(significance level 0.005) 
Relative pain 
reduction (%) 
-2 
-20 
NS 
-26 
P=0.02 
-16 
NS 
-18 
NS 
Model p=0.031 
Pain grade 
reduction (% 
responders), N=57 
24% 
58% 
(0.02) 
52% 
(0.08) 
40% 
(0.44) 
48% 
(0.20) 
76% 
(significance level 0.005) 
No pain after two 
hours (% 
responders), N=57 
6% 
30% 
(0.004) 
12% 
(0.56) 
23% 
(0.06) 
26% 
(0.14) 
44% 
(significance level 0.005) 
Table 3 – Pilot Study Results 
Our results show that remote electrical stimulation allowed to achieve significant reduction in the 
migraine pain. Analysis per pain grades, as has been used for triptans, shows results similar to the 
triptans per pain reduction and pain elimination. When taking all active stimulation protocols 
together, 64% of the patients had more than 50% pain reduction, in more than half of their treated 
attacks. Relative pain reduction for the active stimuli ranged between 16 and 26%, while for the 
placebo stimulation the reduction was of 2% only. Mean pain level at device activation point was 
4.6. Overall ANOVA based effect was significant (p=0.031), with significant effect in post hoc 
analyses for the P150 protocol.  
In terms of change in pain grades, reduction from moderate or severe to mild or none was 
reported by 58% of the participants in response to the strongest stimulation program (P200, 
widest pulse), as opposed to 24% for placebo. Overall, 76% of subjects reported such reduction 
to active stimulation (significant at 0.005 level vs. placebo). Reduction to no pain outcome 
occurred in more than 50% of activations for 30% of participants when the strongest program was 
activated, as opposed to 6% for placebo. In the course of the study, 64% of participants who 
provided feedback on at least one active program activation reported at least 50% pain reduction 
in more than half of their activations and are considered responders to the evaluated treatment. 
This is significantly higher than the 26% responder to placebo activations (p=0.005).  
 
In the end-of-trial interviews, subjects indicated (i) Reduction in amount of migraine medications 
during study period (mean questionnaire score was 1.5, where 1 means “same amount”, 2 means 
“less”); (ii) overall burden of treatment was considered very low – mean score was 2.5 (between 
“neutral” and “not at all”); and (iii) the device and application were found easy to use by a majority 
of study participants (mean questionnaire score was 3.85 (between “easy” and “very easy”)).  

 
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4.3 Clinical Investigation Risks and Benefits 
4.3.1 
Anticipated Benefits 
Sponsor's pilot study demonstrated a significant effect of Nerivio Migra in alleviating migraine 
pain (see pilot study results above). It is anticipated that patients will experience similar effect 
under the setting of the current study. 
Another known benefit to patients participating in such a study is the ability to learn more about 
their medical condition through the assessments that will be performed throughout the course of 
the study. Additionally, patients will be closely observed by the study staff throughout their 
participation in the study. Last, all assessments associated with the study, as well as the study 
device, are provided at no charge to the participants. 
4.3.2 
Risks and Adverse Effects 
Technical characteristics and electrical output of Nerivio Migra device are similar to other known 
and approved for personal use TENS devices applying electrical stimulation for pain relief purpose 
(see Table 1). Safety of the Nerivio Migra has been extensively tested and confirmed through 
bench performance testing (see section 3.5.1) as well as throughout sponsor's pilot clinical study 
with the device.  No device related adverse events were recorded in the course of the pilot study, 
and treatment was well tolerated by participants. 
Current study design does not require application of electrical stimulation for unusually prolonged 
periods, or other circumstances where the use of the device has not yet been validated. Hence 
this protocol presents minimal risks to the subjects and adverse events are not anticipated beyond 
those reported for other TENS devices. Potential expected device side effects are listed in section 
14.7. 
No information is available for use of the Nervio Migra and pregnancy. Thus, women who are 
pregnant are not eligible for inclusion in this study.  
As discussed with the FDA at a Pre-submission meeting (September 2016), the Nerivio Migra is 
accepted as a Non-Significant Risk (NSR) device and the proposed clinical study meets the criteria 
of a Non-Significant Risk (NSR) device study.   
4.3.3 
Risk Control and Mitigation 
The following efforts will minimize risks to patients in the study: 
• 
Conduct of the study following successful completion of extensive bench performance testing 
and careful risk analysis. 
• 
Selection of investigators who are experienced and skilled in management of patients with 
migraine. 
• 
Clearly defining the inclusion and exclusion criteria such that only appropriate patients are 
enrolled in the study. 

 
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• 
Establishment of a training program for study staff members (investigators and coordinator) 
and use of tools that will ensure proper training to the patients for home use of the device. 
• 
Maintaining a support team (e.g. technician, call center for massages, etc.) to assist the sites 
and coordinators. 
4.3.4 
Risk-to-Benefit Rationale 
The sponsor believes that the Nerivio Migra device holds great potential to provide an efficient 
and low risk treatment option to the population of migraine sufferers. Assessing the risks against 
the potential benefits of the use of the Nervio Migra for alleviating migraine pain, sponsor and 
the principal investigators (PIs) have determined that there is a high likelihood that the expected 
benefit may outweigh the risk in patients fulfilling the study eligibility criteria. 
 

 
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5 OBJECTIVES & HYPOTHESES 
5.1 Objective 
To demonstrate the safety and effectiveness of the Nerivio Migra electro stimulation device for 
the reduction of migraine headache during an attack of migraine with or without aura. 
5.2 Hypothesis 
Electro stimulation delivered transcutaneously to the peripheral nervous system at onset of a 
migraine attack significantly alleviates headache pain demonstrated by a significant difference 
between proportions of responders to the active treatment stimulation and the sham control 
without unexpected device related adverse effects.  

 
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6 DESIGN OF THIS CLINICAL STUDY 
6.1 Description 
This is a prospective, randomized, double-blind, sham controlled multi-center clinical trial to test 
the ability of the Nerivio Migra neuromodulation device to relieve the patient’s migraine pain 
during a migraine attack.  The study will enroll up to 270 patients diagnosed with migraine with 
or without aura, per the inclusion and exclusion criteria.  These patients will be individually and 
randomly assigned to either treatment group or control group. For sham control, electrical pulses 
of similar width and intensity, but much lower frequency compared to the active device will be 
administered. This sham program produces pulses that are perceivable by the user, thus 
maintaining the blinding, but on the other hand do not have therapeutic qualities, based on 
existing knowledge of parameters range of electro stimulation treatments [5-7, 18]. 
1st visit – screening, enrollment and training on the application in diary mode 
Following successful screening, enrollment interview and signing of informed consent, 
participants will be provided with the Nerivio Migra application (either installed on their own 
smartphone, or on a smartphone provided by the study coordinator). The participants will be 
trained how to operate the application and report their migraine attacks in the patient diary mode, 
which is part of the application. The site personnel will be required to approve the training session 
in the CRF.  
Stage 1 - Roll in phase 
The Roll-in is a period of 15 - 30 days in which at least two (2) and no more of eight (8) migraine 
attacks has been occurred. During this period, baseline information including mean frequency and 
severity of migraine attacks, occurrence of other headaches, presence of ICHD-3 diagnostic 
criteria for migraine with or without aura and use of preventive and rescue medications will 
be recorded.   
2nd visit 
Following the Roll-in phase, the participants will arrive to the clinic and their compliance to the 
study procedures and eligibility to continue to the next phase will assessed. 
For the study purpose, an eligible subject for stage 2 is a subject that comply with the following 
criteria: 
• 
Subject had at least 2 and no more than 8 migraine attacks during the Roll in stage 
• 
Migraine attacks were reported as required by the protocol (within 60 min from onset, 
complete reports at t=0 and t=2 hours) in at least the following attacks percentage: 
o 1 out of 1 attack (100% compliance) 
o 2 out of 2 attacks (100% compliance) 
o 2 out of 3 attacks (67%% compliance) 
o 3 out of 4 attacks (75% compliance) 
o 4 out of 5 attacks (80% compliance) 
o 5 out of 6 attacks (83% compliance) 
o 6 out of 7 or 8 attacks (75-85% compliance) 

 
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Participants that will be eligible to continue to the treatment phase will undergo the following: 
1. Participant will be randomized into one of the two study group (Active or Sham device) 
Investigational devices will be programmed in active or sham mode with a 1:1 ratio, in 
order to achieve the desired ratio between active and control groups sizes, stratified with 
by use of preventive medications. 
2. Participant will be trained on the device, the application (in diary and treatment modes), 
the treatment procedures and the key elements critical for the success of the study: 
o Apply the Nerivio Migra as soon as possible following the onset of the migraine 
symptoms and NO LATER than 60 min from onset 
o Refrain from taking any rescue medication 2 hours following the start of 
treatment. 
o Perform the treatment for a period of at least 30 minutes (recommended 
treatment time is 45 minutes).  
During the training for the treatment phase, participants will operate the device and the 
appropriate intensity range for each individual participant will be defined with the study team in 
a way that the treatment stimulation is "well-perceived but not painful" for the participant. This 
individual Intensity level will be recorded, and the participant will be asked to operate the 
device within this range as a default.  
If the research staff recognizes during the training that the patient cannot tolerate the feeling of 
the electrical stimulation, the patient will be withdrawal from the study, as described in section 
6.5.7 patient withdrawal criteria.  
  
Stage 2 - Parallel arms, double- blind treatment phase.   
Participants will be instructed to activate the device at onset of a qualifying migraine attack and 
manually adjust stimulation intensity to a level within the pre-defined range, where it is well 
perceived but not painful. A qualifying migraine attack shall be preceded by at least 48 hours of 
freedom from migraine. Patients will be requested to refrain from use of rescue medications prior 
to and during the first two hours after treatment with the device, and if they cannot comply with 
this, record their use of rescue medications (migraine specific drugs or other medications or 
therapies that may be used to treat pain, from a pre-specified list) in the mobile application.  
Via the smartphone application, each participant will be asked to rate his/her migraine pain level 
three times using Pain Grades Scale (0 - no pain, 1- mild pain, 2- moderate pain, 3 – severe pain): 
(1) upon starting the treatment, (2) two hours after start of treatment, (3) 48 hours after start of 
attack. At the start of each treatment, participants will be also asked to provide time elapsed from 
start of migraine symptoms to start of the treatment. Participants will be also asked to provide 
feedback regarding their use of medication (migraine specific drugs or other medications or 
therapies that may be used to treat pain, from a pre-specified list), presence of nausea, 
photophobi, phonophobia or allodynia, and treatment perception. After providing feedback at 
two hours after start of treatment and in case of pain recurrence, participants will be allowed to 
re-treat the attack using Nerivio Migra device.  
Adverse events will be reported. 

 
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For the purpose of the study endpoints analysis, the following treatments will be considered for 
both active and placebo groups: 
• 
The 1st reported treatment in the double-blind treatment stage will be considered as a 
"run-in test" treatment, to assess the patient competence to activate the device and 
report his migraine headache level at the required time periods. This treatment will be 
included in the safety endpoint analysis only. It WILL NOT be included in any of the 
primary and secondary performance endpoints analysis. 
• 
The 2nd reported treatment (1st after the "run-in test" treatment) will be considered as a 
valid treatment and will be used for the analysis of the primary performance endpoint, as 
well as for the secondary, exploratory and safety endpoints, as defined in section 6.3. 
• 
The subsequent treatments (3rd, 4th and 5th treatments – if performed) will be considered 
as valid treatments and will be used for the “repeatability” exploratory endpoint analysis 
and the safety endpoint analysis, as defined in section 6.3. 
 
Duration for each patient will be approximately two months – up to one month of roll-in stage 
followed by treatment stage of up to five qualifying attacks (with the first reported attack 
considered as a" run-in test" (pilot) treatment, while the following four reported attacks 
considered as valid treatments for endpoint analysis) over the course of one month (whichever is 
achieved first). An optional open-label extension of two months is available. 
Post study questionnaire will include patient global impression of change [27], blinding and 
usability assessments. 
 
 
Study flow is schematically presented in figure 6 below. 

 
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Figure 6. - Study Design 
 
6.2 Measures to Minimize Bias 
A number of measures are built into the study design and procedures in order to minimize various 
potential sources of bias. 
Implementation of the 2-4 weeks of roll-in period in conjunction with baseline assessment 
(questionnaire) mitigates recall bias and allows more reliable assessment of baseline headaches 
frequency, duration and severity. 
Gender selection bias will be eliminated due to recruiting patients in headache clinics, emergency 
and neurology departments.  
Randomization is employed to avoid bias in participants’ allocation to study arms. 
Double blind design is ensuring collection of bias free efficacy data. Specific measures will be taken 
to ensure blindness (refer to Section 6.2.2). 
Participants will define their intensity working range during the training session, prior to 
treatment phase, to ensure that the intensity level is the appropriate level they require and 
tolerate. 
Detailed statistical analysis plan will be developed prior to study start to mitigate interpretation 
bias. 
 

 
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6.2.1 Randomization 
Randomized allocation of active and sham devices with stratification to use of preventive 
medications will be performed. Every site will be allocated a stock of identically looking, 
numbered devices of both kinds. 
6.2.2 Procedures to ensure blinding 
This is a double-blind study: neither the patient, nor the investigators will be aware of arm 
allocation of each study participant. Maintaining double blind design is a known challenge in non-
invasive neuromodulation devices trials. Several means are planned to ensure the double-blind 
aspect of this trial. 
• 
Selection of identically looking, active sham devices as control means is only a single step 
aimed at maintaining blindness.  
• 
Adherence to randomization procedure by clinical staff is critically important.  
• 
Importance of adherence to study design and procedures will be explained to participants 
in the course of enrollment.  
• 
No information regarding expected stimulation perception will be provided, except for 
the fact that stimulation intensity adjustment control will allow to adjust intensity to 
a ”well perceived but non-painful” level.   
• 
In order to achieve blinding, participants will be trained individually. A training clip will be 
used for training, in order to minimize staff exposure to participants’ reaction to and 
tolerability of treatment intensity. 
• 
In the course of the trial, participants will not be asked directly any questions regarding 
treatment perception. 
• 
The clinical staff will be instructed to not engage in any discussions regarding anticipated 
treatment perception. 
 
End of study questionnaire will include individual blinding assessment to examine whether the 
blinding was well maintained throughout the study. 
6.3 Study Endpoints 
6.3.1 
Primary Endpoint 
Reduction of Migraine Headache: 
The proportion (%) of patients reporting reduction in their pain level 2 hours post-treatment 
without rescue medications from severe or moderate to mild or no pain, or from mild to no 
pain in their first treated migraine attack (excluding the "run-in test" treatment).   
 
For calculating this endpoint, only the 1st reported treatment following the "run-in test" 
treatment will be used.  
 

 
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6.3.2 
Secondary Endpoints 
Secondary Performance Endpoints 
1. MBS Relief: 
Proportion (%) of patients reporting, 2 hours post-treatment, freedom from their most 
bothersome migraine-associated symptom (MBS) other than a headache, in their first 
treated migraine attack (excluding the "run-in test" treatment).  MBS may be nausea, 
photophobia, phonophobia or allodynia – as defined by each subject. 
2. Migraine Headache Relief AND MBS Relief: 
Proportion (%) of patients reporting 2 hours post treatment response to both the 
primary and the first secondary endpoints. 
3. Pain-free at 2 hours: 
The proportion (%) of subjects reporting freedom from migraine pain at 2 hours post-
treatment without medications in their first treated migraine attack (excluding the "run-
in test" treatment) 
 
6.3.3 
Exploratory Endpoints: 
1. 
Sustained pain-free 48 hours with single use of the device: 
The proportion (%) of subjects reporting pain-free at 2 hours, and no return of any 
pain or use of rescue/acute medication, or reuse of device between 2 hours and 48 
hours, in their first treated migraine attack (excluding the "run-in test" treatment).   
 
2. 
Sustained Headache Reduction for 48 hours with single use of the device: 
The proportion (%) of subjects reporting treatment response 2 hours post-treatment 
without rescue medications, and no return to baseline level of pain at time of 
treatment, or use of rescue/acute medication, or reuse of device between 2 hours and 
48 hours, in their first treated migraine attack (excluding the "run-in test" treatment).  
Treatment response is defined as: 
• pain level reduction from moderate or severe at baseline to mild or none, OR: 
• pain level reduction from mild to no pain. 
 
3. 
Sustained pain-free 48 hours with reuse of device 
The proportion (%) of subjects reporting pain-free at 2 hours, and no return of any 
pain or use of rescue/acute medication except for reuse of device between 2 hours 
and 48 hours, in their first treated migraine attack (excluding the "run-in test" 
treatment).   
 
4. 
Sustained Headache Relief 48 hours with reuse of the device: 

 
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The proportion (%) of subjects reporting Treatment Response at 2 hours, and no 
return to baseline level of pain at time of treatment, or use of rescue/acute 
medication except for reuse of device between 2 hours and 48 hours, in their first 
treated migraine attack (excluding the "run-in test" treatment).   
Treatment response is defined as: 
•  pain level reduction from moderate or severe at baseline to mild or none, OR: 
• pain level reduction from mild to no pain. 
 
5. 
Sustained relief of MBS with a single use of the device  
The proportion (%) of subjects reporting freedom from MBS at 2 hours, and no return 
of MBS, or use of rescue/acute medication between 2 hours and 48 hours, in their first 
treated migraine attack (excluding the "run-in test" treatment). 
 
6. 
Sustained relief of the MBS with reuse of the device: 
Proportion (%) of patients reporting, 48 hours post the first treatment, freedom from 
their most bothersome migraine-associated symptom other than headache (MBS), 
possibly with reuse of the device, in their first treated migraine attack (excluding the 
"run-in test" treatment).  
 
7. 
Within-patient consistency of the primary endpoint in subsequent treatments: 
The repeatability of migraine headache reduction, as described in the primary 
endpoint definition, in subsequent treated attacks.  
Thus, this endpoint measures the % of patient responding to the primary endpoint in 
at least 50% of their treated attacks (excluding the "run-in test" attack) 
 
6.3.4 
Safety Endpoints: 
 
Adverse events related or unrelated to the study device. 
 
Treatment tolerability 
 
6.4 Methods and Timing of Assessing, Recording and Analyzing Variables 
Data capture and management are described in detail in the Data Management Plan. 
List and structure of individual eCRFs are also given in the Data Management Plan. 
Data monitoring procedures are described in detail in the study’s Monitoring plan. 
The study will rely to a large degree on electronic data capture methods. 
6.4.1 Types of Data   
Overall, data collected in the course of the study may be divided into three categories:  

 
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1. captured by clinical personnel. This includes demographic characteristics, baseline 
migraine parameters, end of study questionnaires, adverse events reports. Source data 
may be paper worksheets, further transferred into eCRFs maintained by the EDC system. 
2. patient reported outcomes. This includes feedback entered via the smartphone 
application regarding migraine pain level, migraine symptoms, treatment perception, 
rescue medications. These data are used for calculation of study endpoints. Here, source 
data will be electronic, followed by automatic transfer to eCRFs. 
3. additional information and technical data, captured by means of a system of log files by 
the Application. This includes stimulation activation times, applied stimulation intensity, 
device defects information, and other. 
6.4.2 Clinical Study Variables and Data Capture Tools 
This section provides an overview of collected PRO data and its capture tools. 
6.4.2.1 
Start attack/episode PRO feedback data 
The screen provides for collection of the following data: 
Item 
Description 
Control type 
Values range 
Current migraine 
pain level  
Current 
migraine pain 
level in pain 
grade categories 
Dropdown list  
Mild (1), 
Moderate (2),  
Severe (3).  
 
Time from onset 
of migraine pain 
Time from onset 
of migraine pain 
Dropdown list 
1) Within 30 minutes 
2) Between 30 to 60 
minutes 
3) 60 minutes or more 
Nausea 
Presence of 
nausea 
Radio buttons 
Y/N 
Sensitivity to 
light 
Presence of 
photophobia 
Radio buttons 
Y/N 
Sensitivity to 
sound 
Presence of 
phonophobia 
Radio buttons 
Y/N 
Increased skin 
sensation 
Presence of 
allodynia 
Radio buttons 
Y/N 
MBS 
Most bothering 
symptom (other 
than headache) 
Dropdown list 
1) Nausea 
2) Photophobia 
3) Phonophobia 
4) Allodynia 
 

 
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6.4.2.2 
2h PRO 
This feedback dialog appears 2h after the treatment program has started.  
The screen provides for collection of the following data: 
Item 
Description 
Control type 
Values range 
Current 
migraine pain 
level  
Current migraine 
pain level in pain 
grade categories 
Dropdown list 
No pain (0),  
Mild (1),  
Moderate (2), 
 Severe (3).  
Medication 
Whether rescue 
medication was 
taken within 4h 
prior treatment 
until the 2h 
follow-up period. 
Radio buttons 
Y/N 
Medication time If patient 
indicates taking 
medication, she 
needs to insert 
the time when 
medication was 
taken 
Dropdown list 
1) Before start of 
treatment 
2) Less than 2 hours 
after start of 
treatment 
3) 2 hours or more 
from starting the 
treatment 
Medication 
name 
Rescue 
medication  
Dropdown list 
From a pre-defined 
list 
Nausea 
Presence of 
nausea 
Radio buttons 
Y/N 
Sensitivity to 
light 
Presence of 
photophobia 
Radio buttons 
Y/N 
Sensitivity to 
sound 
Presence of 
phonophobia 
Radio buttons 
Y/N 
Increased skin 
sensation 
Presence of 
allodynia 
Radio buttons  
Y/N 
 
6.4.2.3 
48h PRO 
The screen shall provide for collection of the following data: 
Item 
Description 
Control type 
Values range 

 
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Current 
migraine pain 
level  
Current 
migraine pain 
level in pain 
grade categories 
Dropdown list  
No pain (0),  
Mild (1),  
Moderate (2),  
Severe (3).  
Medication 
Whether rescue 
medication was 
taken within the 
last 46h 
Radio buttons 
Y/N 
Medication 
name 
Rescue 
medication  
Dropdown list 
 From a pre-defined 
list 
 
6.4.3 Methods and Timing of Assessing, Recording and Analyzing 
Variables 
Once the last patient will have completed the study and all the queries have been resolved, 
database will be locked, cleaned and exported for final statistical analysis. Study report will be 
issued following final database lock.  
Only data from the first 2h of the 1st treated migraine attack following the "run-in test" attack will 
be used for analysis of the study primary endpoint. A new migraine attack is an attack that that 
had a "freedom from pain" period of at least 48 hours prior the attack. 
 Recurrent treatments within 46 hours from first treatment of an attack are allowed, and are 
collected as exploratory data. Use of rescue medication within the 48 hours from start of 1st 
treatment of the attack is considered a failure for sustained relief assessment. 
6.4.4 Data Flow and Management 
Data management function will be supported by a cloud based EDC system developed by Clear 
Clinica (Modi’in, Israel). Clear Clinica provides services for collection and remote monitoring of 
clinical trials data, compliant with HIPAA and 21 CFR Part 11. 
EDC portals with secure authorized access will be made available to every participating site, as 
well as to the study monitor.  
Data captured by clinical personnel will be entered directly into pre-specified eCRF screens by site 
personnel.   Data from paper sources will be entered into the study database. Automatic data 
checks will be implemented for majority of entry fields to provide opportunity for resolving data 
inconsistencies as close as possible to real time. Effort will be made to identify missing or incorrect 
data and resolve the issues promptly.  
 
Data collected onto the smartphone application will be directed to a secure cloud based database 
where it will undergo analysis aimed at detection of missing data and other inconsistencies. The 
smart phone will transmit PRO and technical data containing activation times, stimulation 
intensity and ePRO via the smartphone to a central electronic database for analysis.  Activities 

 
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such as repeatedly aborted programs, missing feedbacks, inconsistent stimulation intensity 
adjustments, and similar, will be communicated to research coordinator of the corresponding site, 
using participants’ ID codes. Automated means were developed to identify and provide 
corresponding notifications regarding events that may lead to protocol deviations and/or missing 
data, and which resolution may require involvement of study staff. Examples of such events 
include missing PRO data or low device battery level. An automated system was implemented to 
notify the participant, site study coordinator and Sponsor study monitor on the above events. 
Missing data will be identified automatically by a script running on Clear Clinica’s cloud, and 
queries will be generated to participants and corresponding site study coordinator. Near real time 
detection of problems in accumulating data will allow timely generation and resolution of queries. 
Intermediate data processing and translation into eCRF format are performed at this stage. 
Processed data are further pushed into the EDC system. 
 
Schematics of data flow are presented in figure 7. 
 
 
Figure 7. - Schematics of data flow 
 

 
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Back-up of the database is performed daily.  In addition, copy of each participant’s ePROs and 
other activity is stored in his/her smartphone memory and can be retrieved in case such need 
occurs.   
Study database will be locked and exported using EDC tools into SAS compatible format for interim 
and final statistical analyses. 
 
Query resolution will be performed using EDC tools. 
 All paper based source data and relevant medical documents meant to serve also as source 
documents will be maintained by the sites and available as eCRF attachments. Patient 
identification will be blackened from all data. Patients will be identified by their codes. The site 
investigator is responsible for ensuring that eCRFs are filled in a timely manner and relevant paper 
documents are properly stored. Investigator will provide the documents to the sponsor either 
through the sponsor representative or by mail per sponsor request. 
Access to data will be authorized and controlled, in accordance with relevant laws and guidelines. 
Study will be performed according to the protocol. At each site, the PI will appoint staff member(s) 
that will be responsible for completing the Case Report Forms supplied by the sponsor. 
Specifics of data query handling are given in Data Management and Monitoring plans.  
Audit trail for data entry and corrections will be maintained. 
6.4.5 Procedures for Review of Data 
A detailed description of data queries, their resolution and overall data flow can be found in the 
Data Management Plan. 
Missing PRO data will be identified by a dedicated software running on the cloud closely to real 
time. Corresponding queries will be issued to study participants and site study coordinator. Effort 
will be made to resolve such queries as close as possible to real time. 
6.4.6 Data Monitoring Committee  
An independent Data Monitoring Committee (DMC) is charged with the task of providing regular 
oversight of the data monitoring issues as detailed in the document: “DMC”.  These experts will 
periodically review and evaluate the accumulated data for study progress.  The DMC will make 
recommendations concerning continuation, modification, or termination of the study.  The Data 
reviewed by the DMC will include a summary of the following topics:  
• Study progress: Subject recruitment, comparison with targeted recruitment, retention, protocol 
adherence, and quality of data collection procedures.  
• Treatment Monitoring: Data on treatment integrity and adherence.  
• Safety Monitoring: Data related to the safety of the subjects, including any adverse events or 
side effects related to the treatment.  
• Efficacy monitoring: Interim efficacy analysis is to be performed per algorithm presented in 
Section 7.6.   

 
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• Futility monitoring: Futility will be assessed at the time of interim analysis.   
6.4.7 Total Expected Duration of the Clinical Investigation 
The anticipated duration of the study is up to 12 months.  
6.5 Subjects  
6.5.1 Inclusion Criteria 
Patients need to fulfill all the below Inclusion criteria: 
1. 
Subject is 18-75 years old. 
2. 
Subject meeting the ICHD-3 diagnostic criteria for migraine with or without aura 
3. 
Subject reporting 2-8 migraine attacks per month. 
4. 
Stable migraine preventive medications in the last two months prior to recruitment (No 
change in usage or dosage). 
5. 
Subject must be able and willing to comply with the protocol 
6. 
Subject must be able and willing to provide written informed consent 
6.5.2 Exclusion Criteria 
Patients are excluded if they have any of the following: 
1. Subject has other significant pain, medical or psychologic problems that in the 
opinion of the investigator may confound the study assessments 
2. 
Subject is currently implanted with an electrical and/or neurostimulator  device (e.g. 
cardiac pacemaker or defibrillator, vagus nerve neurostimulator ,deep brain stimulator, 
spinal stimulator, bone growth stimulator  cochlear implant, Sphenopalatine ganglion 
stimulator or Occipital nerve stimulator). 
3. 
Subject has known uncontrolled epilepsy. 
4. 
Any use of Cannabis including medical use.  
5. 
Subject has >
 0
1 
headache days per month . 
6. 
Subject has undergone nerve block (occipital or other) in the head or neck within the last 
2 weeks. 
7. 
Subject is participating in any other clinical study. 
8. 
The subject does not have the basic cognitive and motor skills needed to operate a 
smartphone 
9. 
Pregnant, or trying to get pregnant 
10. Subject is experiencing a menstrually related migraine  
11. Received OnabotulinumtoxinA or any botulinum toxin injections for migraine within the 
previous month 
12. Received parenteral infusions for migraine within the previous 2 weeks.  

 
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13. 
Subject participate in a previous study with the Nerivio Migra 1 device  
 
Note - Females of child bearing potential must have a negative pregnancy test and must be willing 
to use adequate contraceptive means during the study 
6.5.3 Contraindications  
Contraindications for the use of the Nerivio Migra device include those known for transcutaneous 
electrical stimulation procedures. In addition to restrictions described in exclusion criteria, Nerivio 
Migra shall not be placed over open wounds or burns, or on irritated skin.  
The Nerivio Migra is NOT intended for use in any other location except the upper arm. 
6.5.4 Number of Subjects  
The total number of patients to be treated in this study is up to 270 eligible patients (see section 
7.6). 
6.5.5 Expected Study Duration for Each Subject 
Study duration per patient is up to 2 months for the roll-in and double-blind stages, and then, 
possibly another 2 months for the open label extension, if required.  
6.5.6 Point of Enrollment 
Patients are formally enrolled in the study once they are found eligible by inclusion and exclusion 
criteria, have signed an informed consent and received training on the use of the device. If the 
patient was not treated with the investigational device, the patient will be excluded from the mITT 
data analysis set.  
6.5.7 Patient Withdrawal Criteria 
Patients may be withdrawn from the study by the PI or sponsor, if any one or more of the following 
events occur: 
• 
The patient wishes to withdraw from the study without providing any explanation. 
• 
Patient is lost to follow-up. 
• 
Refusal of the patient to continue treatment and/or follow-up observations. 
• 
Serious adverse event. 
• 
Subjects who have problems/difficulties with the Investigational Product (IP) and 
cannot handle it independently (e.g. cannot tolerate the treatment, cannot operate 
the application). 
• 
Significant protocol deviation/violation or noncompliance, either on the part of the 
patient or investigator. 
• 
Decision made by the investigator that termination is in the patient’s best medical 
interest. 

 
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• 
Device failure. 
• 
Other ethical or clinical considerations upon investigator discretion. 
6.5.8 Handling of Withdrawals 
In accordance with the Declaration of Helsinki, a patient has the right to withdraw from the study 
at any time, for any reason, without prejudice to any future medical care by the physician or the 
institution. The investigator and the sponsor also have the right to withdraw patients from the 
study in the event of serious adverse events, protocol departures (deviations, violations and 
exemptions), or other reasons. Should a patient (or the patient’s legally authorized 
representative) decide to withdraw, all efforts will be made to collect and report the next visit 
observations, and the reasons for withdrawal, as thoroughly and timely as possible.  
Withdrawals will be recorded, analyzed and reported to local ethical committee according to local 
regulations. 
6.5.9 Patient lost to follow-up 
If a patient does not show for end-of-study visit and cannot be contacted to collect follow-up 
information, he/she will be counted as a ‘missed visit’. Prior to counting the patient as a ‘missed 
visit’ the following will be performed: 
• 
Repeated, documented attempts to contact the patient via all available means. 
• 
Repeated, documented attempts to contact the patient’s general practitioner or referring 
physician. 
• 
If a visit cannot be arranged, obtain as much information as possible through all 
communication means with the patient and/or his/her treating physician.  
If a patient is lost to follow-up, the methods used to attempt to contact the patient should be 
noted. At least three attempts should be made to contact the patient and/or his/her treating 
physician via all available routes, and a certified letter should be sent to the permanent address 
on file. 
6.5.10 Enrollment Period 
The anticipated enrollment rate is expected to be approximately 6-10 patients per month, 
depending on participating site. Enrollment period is expected to be up to six months long.  
6.5.11 Procedures for Replacement of Subjects 
No subject replacement is planned. 

 
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6.6 Study related Procedures 
6.6.1 General 
The potential candidates will be screened to assess whether they are appropriate candidates for 
inclusion in this study. Informed consent will be obtained prior to initiation of any of the following 
clinical procedures that are performed solely for the purpose of determining eligibility for 
research. Pregnancy test for female patients with childbearing potential will be performed. The 
patient medical history, migraine history and diagnosis will be recorded and verified, the use of 
concomitant medication will be recorded in designated case report forms. Eligible patients will 
receive a documented training, and upon its successful completion the application will be installed 
on the participant's phone (or on a dedicated phone supplied by the Sponsor, depend on 
participant's request) during the 1st phase. Investigational device will be handed to study 
participants for home use prior the 2nd phase. As per the IFU, participants are instructed to 
activate the device at the onset of a migraine attack and manually adjust stimulation intensity to 
a level where it is perceivable but not painful, as defined during the Randomization/training visit. 
Participants are requested to refrain from use of rescue medications prior to and during the first 
two hours after treatment and, if could not comply with this, record their use in the cellular 
application. Via the smartphone application, each participant will be asked to rate his/her 
migraine pain level three times: (1) upon starting the treatment, (2) two hours after treatment, 
(3) 48 hours after first treatment corresponding to the current migraine attack, using Pain Grades 
Scale (0 - no pain, 1- mild pain, 2- moderate pain, 3 – severe pain). At the end of each treatment, 
participants will be asked to provide feedback using the application regarding the time elapsed 
from start of migraine attack to start of the treatment, their use of medication. In case of failure 
to provide feedback regarding pain level post-treatment, telephone follow-up will be performed 
by study investigator staff to solicit such feedback. Additional migraine symptoms will be self-
reported using the application. Follow up phone calls will be scheduled to record change in 
medical condition, concomitant medication and migraine therapy. Unscheduled visits will be 
recorded and termination visit will be scheduled upon the completion of the study as defined by 
treatment of four qualifying attacks over the course of one month (whichever is achieved first). 
In the event of premature discontinuation an early discontinuation visit will be scheduled.  
6.6.2 Visit and assessment schedule 
The study requires up to four visits: (1) for screening and migraine diary training and (2) 
randomization and device treatment training (3) end of study, when the device is returned, and 
end of study assessment is performed If the patient chooses to continue to the open-label 
extension, additional visit (4) will be required. 
6.6.3 Activities performed by sponsor representatives 
It is the sponsor’s responsibility to train the site staff and supply the devices in a timely manner.  

 
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It is also the sponsor’s responsibility to communicate to other sites’ representatives in regard to 
serious adverse events, device malfunctioning findings and other relevant information that may 
affect study operation. 
6.7 Monitoring Plan 
A detailed Monitoring Plan was developed for this study by the sponsor.   
Monitoring functions will be performed in compliance with Good Clinical Practices guidelines per 
forth in ISO 14155 (2011). The major function of the clinical monitor is to observe and assess the 
quality of the clinical study and the data generated from it, and to ensure that patients’ welfare 
is being kept.  
Based on implementation of an EDC platform, remote monitoring will be possible and will be 
performed on a regular basis between monitoring visits. The Study Monitor/CRA will access the 
EDC to perform remote review of the data. Attention will be paid (but not limited to) to the 
following: 
• 
Number of patients enrolled, per site. 
• 
Timely data entry. 
• 
Timely resolution of queries. 
• 
AE/SAE and device deficiencies reporting in accordance with the protocol and according to 
the timelines, including adequate follow-up. 
• 
Non-compliances documentation. 
• 
Timely follow-up. 
• 
Devices accountability 
Due to utilization of integrated ePRO tools and EDC platform for data collection and management, 
electronic source data will be considered verified by nature of process validation and verification 
performed jointly by the sponsor and the EDC vendor and documented separately.    
A well planned and prepared Initiation Visit will take place to address and train the site on aspects 
of protocol adherence and data monitoring processes. 
The following monitoring visits are planned in the course of the study: 
• 
After the Site Initiation, a monitoring visit close to the first few (3-5) subjects’ enrollment.  
• 
After the study completion by first few patients  
• 
After completion of study by all planned patients 
In cases where the monitor notices that the PI is performing not according to the protocol or 
relevant regulation, the monitor should notify the sponsor by means of the monitoring report, 
email notification or a separate report if needed (i.e. Deviation Report Form). A follow-up letter 
to the PI should include the key findings. Site revisiting regarding GCP and protocol adherence 
should be done by the monitor in case of repetitive deviations. 
 

 
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7 STATISTICAL CONSIDERATIONS 
7.1 Study Design and Aim 
The study is designed as a prospective, randomized, double-blind, sham controlled multi-center 
clinical trial. The study aim is to demonstrate safety and effectiveness of Nerivio Migra electro 
stimulation device for the acute treatment of migraine attacks with and without aura.   
7.2 Study Variables 
7.2.1 Primary performance variable  
The primary performance endpoint will be measured in the form of a binary variable which will 
be assigned the value of “1” if the subject reports such headache pain reduction without rescue 
medications, and “0” otherwise.  
7.2.2 Secondary performance variables  
The secondary performance endpoints will be measured in the form of a binary variable which 
will be assigned the value of “1” if the subject responds to each specific secondary endpoint, and 
“0” otherwise. 
7.2.3 Exploratory performance variables 
The exploratory performance endpoints will be measured in the form of a binary variable which 
will be assigned the value of “1” if the subject responds to each specific exploratory endpoint, and 
“0” otherwise. 
In addition, patient global impression of change is measured via a questionnaire. 
7.2.4 Safety variables 
Incidence of all adverse events and complications by severity and relationship to study device.  
Treatment tolerability as measured by a questionnaire. 
7.3 Study Hypothesis 
H0: The proportion (%) of subjects reporting reduction of migraine headache at 2 hours post 
treatment without rescue medications from severe/moderate to mild/no-pain or from mild to no-
pain during the 1st migraine attack following the "run-in test" attack in the treated group = The 
proportion (%) of subjects reporting reduction of migraine headache at 2 hours post treatment 
without rescue medications from severe/moderate to mild/no-pain or from mild to no- in the 1st 
migraine attack following the "run-in test" attack in in the sham group. 
HA: The proportion (%) of subjects reporting reduction of migraine headache at 2 hours post 
treatment without rescue medications from severe/moderate to mild/no-pain or from mild to no-
pain in the 1st migraine attack following the "run-in test" attack in in the treated group ≠ The 

 
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proportion (%) of subjects reporting reduction of migraine headache at 2 hours post treatment 
without rescue medications from severe/moderate to mild/no-pain or from mild to no-pain in the 
1st migraine attack following the "run-in test" attack in in the sham group. 
 
If the null hypothesis is rejected in favor of the alternative hypothesis and the proportion (%) of 
subjects responding to this endpoint in the treated group is greater than that of the sham group, 
the study will be deemed successful. 
7.4 Sample Size Estimation 
T The sample size for this study was calculated to test the null hypothesis with a chi-squared 
test, even though the final analysis may employ a regression model or a Fisher’s exact test.  
Sample sizes are calculated for both the primary and secondary endpoints to test the hypothesis 
with 80% power at a 5% level of significance. Sham success rate is assumed to be 32% and the 
sample size calculated for differences ranging between 15% and 20%. 
Primary endpoint:  
We assume that 50% of the subjects in the treatment arm will have successful reduction of 
migraine headache versus 32% in the sham arm. Hence, 234 evaluable subjects are required to 
detect this difference, 117 per group. Allowing for a ~15% drop-out rate, a total of 270 (135 
treated vs. 135 sham) subjects should be enrolled in the study.   
7.5 Definition of eligible treatment 
An eligible patient for statistical analysis is a patient that complete the Roll-in phase and the 
treatment phase. An eligible migraine episode for analysis of primary and secondary endpoints 
includes the following 
• 
The patient had at least 48 consecutive hours without migraine headache prior to 
treatment.  
• 
Treatment is started no later than 60 minutes post the onset of migraine symptoms. 
• 
Treatment lasted at least 30 (continuous) minutes.  
• 
No pain medications were used from 24 hours prior the onset of the migraine, until 2 
hours after the start of the treatment. 
• 
The patient completed and reported the post 2-hour treatment questionnaire through 
the application. 
7.6 Interim Analysis 
An interim analysis will be performed when approximately 20-30% of the subjects reach the 
primary endpoint.  An independent committee will review the results and recommend whether 
the study should be stopped for futility or continue.  Details of the interim analysis will be specified 
in a statistical analysis plan prior to study initiation. 

 
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7.7 Randomization 
Subject will be randomly allocated (with a 1:1 ratio) to one of the following 2 treatment groups 
based on a randomization scheme using the permuted block method stratified by preventive 
medications use and center:  
• 
Sham Control 
• 
Nerivio Migra group 
The randomization scheme will be prepared by the study statistician using the SAS (version 9.4.) 
random number procedure. The block size will be fixed, and study personnel will be blinded to 
the randomization block size. 
7.8 Analysis sets 
Analysis Sets: 
1. Intent to Treat analysis set (ITT) 
The ITT analysis set includes all patients who are randomized and treat at least 
one attack. 
  
2. Modified Intend to Treat analysis set (mITT) 
The mITT analysis set includes all patients who are randomized and treat at least 
one attack (excluding the "run-in test" attack) within 1 hour from the attack 
onset.  
 
3. Per-Protocol analysis set (PP) 
The PP analysis set includes patients who are randomized and treat at least one 
attack (excluding the "run-in test" attack), which conforms with the protocol 
instructions: 
• Treatment starts within one hour from attack onset. 
• No rescue medication (or pain medication) is consumed within the 2 hours 
after start of treatment. 
• The treatment is not aborted prematurely (i.e., before the first 30 
minutes).  
• No Pain medication 24h prior migraine onset 
 
Statistical Analysis of Analysis Sets: 
The ITT analysis set will serve as the main set for safety assessments 
The mITT analysis set for all performance assessments. 
The primary and secondary performance assessments will also be performed on 
the PP analysis set as a sensitivity analysis. 

 
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7.9 Statistical Analyses – (TBD) 
Amendments to the statistical analyses section will not require IRB approval, unless driven by 
protocol or study design change. In that case a standalone SAP will be prepared prior to data lock 
for each analysis milestone.  
7.9.1 General Considerations 
Statistical analyses will be performed using SAS® v9.4 (SAS Institute, Cary NC, USA). 
All statistical tests will be two-sided. The required significance level of findings will be equal 
to or lower than 5%, nominal p-values will be presented. Where confidence limits are 
appropriate, the confidence level will be 95%. 
Continuous variables will be summarized by a mean, standard deviation, minimum, median 
and maximum, and categorical variables by a count and percentage. For comparison of 
means (continuous variables), the two-sample t-test or the Wilcoxon rank sum test will be 
used as appropriate.  For comparison of proportions (categorical variables), the Chi-
squared test or Fisher’s exact test will be used as appropriate.  
If multiple measurements are taken in a single patient, statistics described below will be 
appropriately modified to accommodate the within patient correlation. 
7.9.2 Significance levels and handling of type I error 
7.9.2.1 Type I Error 
The overall significance level for this study is 5% using two-tailed tests, except for 
treatment by site interaction that will be tested at a significance level of 10%. 
7.9.2.2 Hierarchy Approach for Secondary Endpoints Analysis 
The hierarchy approach will be adopted for the primary and secondary endpoints to 
control type I error due to multiple endpoint testing. Thus, the primary endpoint will first 
be analyzed and only if p<0.05, will the secondary endpoints be analyzed. 
7.9.3 Demographic and Other Baseline Characteristics 
Demographic and baseline condition related characteristics will be tabulated and compared 
between the study groups by data type. Continuous variables will be summarized by a mean, 
standard deviation, minimum, median and maximum, and categorical variables by a count and 
percentage. 
This data will include: 
• 
Demographic data 
• 
Medical history 
• 
Migraine preventive medication 
• 
Other concomitant medication  

 
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• 
Migraine attacks characteristics per ICHD-3 diagnostic criteria for migraine with 
and without aura 
• 
Physical examination 
• 
Laboratory (pregnancy) tests for women of childbearing potential 
7.9.4 Disposition of Patients  
The numbers of patients who entered the study and completed each stage of the study 
will be provided per month, as well as the reasons for all post randomization 
discontinuations, grouped by major reason, e.g., lost to follow-up, adverse event, poor 
compliance, did not administer any treatment (with reasons). A list of discontinued 
patients, protocol deviations, and patients excluded from the performance analysis will 
be provided as well. 
7.9.5 Performance Analyses 
Primary performance: 
A count and percentage of subject treatments responding to the primary performance endpoint 
will be calculated and presented for both study groups each with a two-sided 95% exact 
confidence interval. The groups will be compared with a chi-squared test, and a Fisher’s exact 
test. 
If the null hypothesis is rejected in favor of the alternative hypothesis and the proportion (%) 
responders in the treated group is greater than that of the sham group, the study will be deemed 
successful. 
The primary endpoint will also be evaluated stratified by center using a Mantel-Haenszel test to 
assess the center by group interaction. 
A sensitivity analysis of the primary endpoint will be performed to assess the impact of missing 
data on the study outcome. This will be performed using several possible imputation methods. 
A subject who took rescue medication during the 2 hours post treatment is considered as being 
in pain. The PP analysis will be performed without these attacks. 
 
Adjustment for other covariates such as demographics or other baseline patient characteristics 
may be performed by adding these variables into a logistic regression model. 
 
Subgroup analysis according to use of preventive medications, time from onset of attack till 
treatment and intensity of stimulation will be performed and reported by adding these variables 
to a logistic regression model. 
Secondary performance: 
The secondary performance variables will be summarized by a count and percentage and 
compared with a chi-squared test. 
Exploratory performance: 

 
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A count and percentage of patients responding to each of the exploratory performance 
endpoints will be presented. The groups will be compared with a chi-squared test and a Fisher’s 
exact test. 
Patient global impression of change (total score) will be summarized by descriptive statistics per 
treatment group and compared between the groups with a t-test. 
Frequency of use of rescue medication will be summarized by descriptive statistics per 
treatment group and period (roll-in vs. treatment) and compared between the groups with 
Poisson regression. 
7.9.6 Safety Analysis: 
The primary safety variable, the cumulative incidence (and 95% CI) of device related adverse 
events (AEs) throughout the study, will be presented in tabular format and will include incidence 
tables by severity. 
Adverse event rates will be compared between the study groups with a Fisher’s exact test. 
Serious adverse events will be listed and discussed individually. 
Treatment tolerability will be compared between the study groups, the number and percent of 
subjects who fail to complete the study and the number and percent of subjects who fail to 
complete the study because of Adverse Events will be presented as well 
7.9.7 Handling of Missing Data 
A sensitivity analysis of the primary end-point will be performed to assess the impact of 
missing data on the study outcome using possible imputation methods for binary data. A 
“worse case” scenario analysis will be performed as well where subjects with missing data 
for the binary response assessment will be considered as a non-responder/ non-success.  
Imputation of missing data may be performed on secondary and exploratory endpoints as 
well. 
7.10 Pooling 
Subgroup analysis of the primary performance endpoint by center, and US vs OUS, will be 
used to evaluate the poolability of the results. The significance of center-to-center 
variability in treatment effect will be evaluated by including an interaction term of 
treatment group by center in a logistic regression model. In the case that poolability is 
questionable, the reasons for differential treatment effect, such as patient and clinical 
characteristics, will be investigated and reported. 

 
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8 DATA MANAGEMENT 
8.1 Data Capture 
Data capture will be performed using an Electronic Data Collection (EDC) system in conjunction 
with electronic patient reported outcome collection tools implemented in the smartphone 
application. The clinical sites will use electronic case report forms (eCRFs) to document the 
information required by the study CIP. 
The EDC provider is ClearClinica. The EDC allows for the secure collection, transmission, validation, 
monitoring and real-time administration of study data gathered at investigative sites, and by the 
patient via the smartphone application. The system allows password-restricted access to clinical 
trial information based on individuals' roles and responsibilities. The EDC is compliant with 21 CFR 
Part 11 and FDA’s “Guidance: Computerized Systems Used in Clinical Trials.” 
Except for Patient Reported Outcome entered directly by the patient to the smartphone App, data 
reported on the eCRF should be driven from source documents and be consistent with these 
source documents. Editing of data is done under full audit trail. 
PRO data collected from the smartphone applications will be saved in dedicated log files on the 
smartphones for backup purposes and transferred to the EDC system at end of study visit.  
8.1.1 Direct Data Entry 
For several CRF fields Source Data Verification (SDV) may not be possible as entries may not be 
found in source documents (e.g., migraine diary or other Patient Reported Outcome completed 
directly into the smartphone App). Therefore, it is allowed to use the CRF for direct data entry, 
but only for pre-defined fields.  
8.2 Data Quality Assurance 
To ensure the quality of clinical data across all subjects, a clinical data management review will be 
performed by sponsor on patient data submitted in the CRF. During this review, patient data will 
be checked for consistency, omissions, and any apparent discrepancies. In addition, the data will 
be reviewed for adherence to the CIP and relevant regulations. To resolve any questions arising 
from the clinical data management review process, data queries and/or site notifications will be 
issued by sponsor. Discrepancy resolution will be documented within the database audit trail. 
8.3 Electronic Signatures 
The PI will electronically sign each individual eCRF after the data has been cleaned, monitored and 
data reviewed. The electronic signature asserts that the investigator inspected or reviewed the 
data on the eCRF, the data queries, and the site notifications, and agrees with the content. Any 
changes made to the data after electronic signature has been applied will result in invalidation of 
the original signature, and the PI will be required to re-sign the data after reviewing the change(s). 

 
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8.4 Verification, validation and securing of electronic data capture 
system 
Verification and validation of the EDC and eCRFs will be performed by a team comprising 
representatives of the developer, the sponsor and at least one of the participating sites. 
Verification and validation report will be held by the sponsor.  
8.5 Records and Data Retention 
Copy of all records (e.g., informed consent documents, source data, safety reports, study device 
dispensing records, etc.) which support case report forms for this study, will be retained in the 
files of the responsible investigator for a minimum of five (5) years following notification by the 
sponsor that all investigations (not merely the investigator's portion) are completed, terminated 
and/or discontinued.  If the principal investigator retires, relocates, or for other reasons 
withdraws from the responsibility of keeping the study records, custody must be transferred to a 
person who will accept the responsibility.  The sponsor must be notified in writing of the name 
and address of the new custodian within 5 days after such transfer occurs. 
Database will be retained by the EDC system provider for a minimum of 5 years. 
8.6 Other Aspects of Clinical Quality Assurance  
Site PI or a person designated by the site PI is responsible for establishing and maintaining 
adherence to the study protocol. Study PI is responsible for addressing quality assurance issues 
(correcting procedures that are not in compliance with protocol). Study Coordinator is responsible 
for quality control issues (i.e. correcting errors in data entry).  
Sponsor will assign a monitor to monitor the investigational sites throughout the study. All 
outstanding issues and findings that site personnel become aware of will be communicated and 
handled in agreement with Monitoring Plan. 
Sponsor auditing of the site may be done before the completion of the study to ascertain data 
quality and integrity.  
The Food and Drug Administration (FDA) and/or the local state health authorities may request 
access to all study records, including source documents, for inspection. The investigator and site 
staff agree to cooperate with these audits. The investigator must notify the sponsor of any health 
authority audit as soon as notification of such audit is made. A representative or designee of 
sponsor may be present during health authority audit.  
 

 
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9 AMENDMENTS TO THE CLINICAL INVESTIGATION PLAN   
The protocol is not to be amended by the investigator without first obtaining sponsor’s approval. 
Amendments initiated by the sponsor, or initiated by the investigator and then approved by the 
sponsor, will be submitted for approval to local IRB/EC and, if applicable, to the respective 
Regulatory Authority (RA). Protocol amendments should receive the IRB/EC approval, and if 
submitted to the RA, a regulatory approval as well, prior to implementation in the study. For non-
substantial changes (e.g. minor logistical or administrative changes, change of monitor(s), 
telephone numbers, renewal of insurance) not affecting the rights, safety and well-being of 
human subjects or not related to the clinical investigation objectives or endpoints, a simple 
notification to the IRB/ EC and, where appropriate, regulatory authorities can be sufficient. 
The following documents are relevant to the protocol, but are not considered part of the protocol.  
They are stored and modified separately. As such, modifications to these documents do not 
require protocol amendments. 
• 
Site Roster 
• 
Case report forms 
• 
Data Management Plan 
• 
Monitoring Plan 
• 
Statistical Analysis Plan 
• 
DMC  

 
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10 CLINICAL INVESTIGATION PLAN DEVIATIONS 
A protocol deviation is any noncompliance with the clinical study protocol, Good Clinical Practice, 
or related SOPs requirements.  The noncompliance may be on the part of the subject, the 
investigator, or study staff.   
The protocol is not to be deviated by the investigator or the co-investigators without first 
obtaining sponsor approval except in cases where the safety and well-being of a patient will be 
affected, as stated in section 4.5.4 b of the ISO 14155 (2011).  
Compliance to the protocol will be assessed by study monitor during monitoring visits as well as 
remotely, using designated reports provided by the EDC system. 
All deviations from the protocol will be addressed in study subject source documents and 
promptly reported to the site IRB, according to local requirements.   
 
10.1 Procedures for Recording, Reporting and Analyzing Protocol 
Deviations 
All protocol deviations need to be documented in source documents and appropriate eCRF. 
The Study Monitor is responsible for identifying and reviewing protocol deviations with the 
investigator or designee and documenting the issue and action/outcome of the protocol deviation 
in the MVR and any follow up letter / communication to the principal investigator. 
The Study Monitor will ensure that major protocol deviations are discussed with the Investigator. 
Major deviations are those deviations that: 
• 
impact patient safety  
• 
alter the risk/benefit ratio 
• 
compromise the integrity of the study data  
• 
affect willingness of the patient’s participation in the study  
Deviations will be reported to the IRB/EC periodically or as specified by local regulations. Further 
documentation of any changes in research activity should be submitted to the sponsor and the 
IRB/EC if: 
• 
They are related to any instance of serious or continuing non-compliance with governing 
regulations/requirements of the IRB/EC, and/or 
• 
Related to changes in protocol specified patient activity and procedures.  
The Study Monitor will, in addition to the above immediate reporting, document all deviations in 
the monitoring visit report and follow-up letters. The monitor will discuss deviations with relevant 
site personnel. If needed, a Note to File will be issued and filed in the relevant file and a copy sent 
to sponsor. 
Sponsor or its designee will review records of deviations and will consider the need for corrective 
and preventive action and further external reporting to regulatory authorities. Deviations will be 

 
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summarized and included in the study report. Assessment and discussion of their potential impact 
/ lack of impact on study results will be addressed. 
10.2 Notification Requirement and Timelines 
Major deviations should be escalated to the sponsor within 5 business days.  
Protocol deviations must be reported to local IRB/EC per their guidelines. The site PI or other 
designated site staff member is responsible for knowing and adhering to local IRB/EC 
requirements. 

 
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11 DEVICE ACCOUNTABILITY 
 Devices will be provided by Theranica Bioelectronics (sponsor), bearing required labeling. Upon 
being handed to study participant, device number will be documented in CRF and in site log. Each 
batch of devices delivered to clinical sites for allocation to study participants is accompanied by a 
shipment note. Device shipment records are maintained by sponsor and on site. 
Prior to distribution, the devices are stored in a designated locked cabinet. Access to 
investigational devices is controlled by the research staff. The devices are only used in the clinical 
investigation and according to the study protocol. 
Each device has a sticker on it with a unique number. When a device is handed to a study 
participant, it is coupled to the participant’s smartphone by means of Bluetooth connection.  
In the course of device allocation, application installation and device – application connection 
establishment, site allocated User ID is entered by study coordinator via the Application.  
The triplet of IDs (User ID, phone ID, device ID) provides means of identifying technical and PRO 
data from each participant in the electronic database while protecting participant’s privacy.  
The clinical investigator will be responsible for the safe storage of devices in accordance with 
instructions given by Theranica Bioelectronics, with restricted access to the investigational 
materials in their possession, thereby preventing use of any materials by any person not 
participating in the study. Device accountability records will be reviewed during monitoring visits. 
The investigator will be responsible for providing device use training to the patients according to 
the IFU and protocol and for maintaining product inventory and records. 
As part of study closure, all unused devices must be returned in their original packaging to 
Theranica Bioelectronics. 

 
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12 STATEMENTS OF COMPLIANCE 
This study will be conducted in compliance with the protocol (after being approved by the local 
EC and, if required, by the local RA), the Good Clinical Practice (GCP) per ISO 14155 (2011) 
standard and the ethical principles that have their origin in the Declaration of Helsinki. 
The Informed Consent Form (ICF), patient's information material, and advertising material (if 
applicable) must be submitted and approved by the IRB/EC (and RA when needed), and any 
request by the IRB/EC or RA will be followed. Written approval of the protocol, ICF, patient's 
information material, and any advertising material (if applicable) must be obtained from the EC 
and if applicable the corresponding RA prior to any patient enrollment. 
Adequate insurance policy will be held valid for the entire study duration as well as for the 
discovery period required per local regulation.  

 
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13 INFORMED CONSENT PROCESS 
Written informed consent must be obtained from each study patient prior to commencing any 
CIP-specific procedures. A written informed consent (approved by sponsor and the IRB/EC) must 
be signed and dated by the patient, and the person who conducted the informed consent 
discussion. Additionally, the person who conducted the informed consent discussion will indicate 
that Informed Consent has been obtained by noting so in the appropriate section of the. Patients 
will be given a copy of the signed informed consent document. The signed informed consent will 
be retained with the study records at the investigational site. New findings relevant to the 
patient’s continued participation will be made available to the patients after approval of such 
updates by the IRB/EC. 
Informed consent accurately describes all aspects of the clinical investigation that are relevant to 
the subject’s decision to participate in the study. 
 

 
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14 ADVERSE EVENTS 
Capturing of adverse events will serve for safety evaluation.  
Adverse events encountered during treatment will be captured via end of study questionnaire 
and interview. 
This study will use the list in section 14.7 below for nomenclature of adverse events complications 
reported in the CRF for Device related side effects.  
Non-Device adverse events will be graded according to section 14.2.1 below. AE resulting from a 
procedure that is not related to the device, are considered as general AEs. 
On-site visits to investigate adverse events and follow them up will be scheduled at the discretion 
of the principal investigator.  Unscheduled visits and termination visit will be reported using 
designated case report forms. 
If at the last visit there will be a Device related AE/side effect that is still active, the patient will be 
followed to completion or until a steady state is achieved for a continuous period of 2 weeks. 
. 
14.1 Characteristics of an Adverse Event 
14.1.1 Severity of the Adverse Event 
Severity of AEs will be determined using the following scale: 
• 
Mild: The patient is aware of a sign or symptom, but it is easily tolerated 
• 
Moderate: Discomfort or interference with usual activity 
• 
Severe: Incapacitating, with inability to engage in usual activity 
. 
14.1.2 Relationship of an AE and SAE to the Study Device  
The relationship of the adverse event to the study device is defined as follows: 
Definite: An adverse event has a definite determination that it was caused due to the device. 
Probable: An adverse event has a strong temporal relationship to study device or recurs on 
rechallange, and another etiology is unlikely or significantly less likely. 
Possible: An adverse event has a strong temporal relationship to study device, and an alternative 
etiology is equally or less likely compared to the potential relationship to study device. 
Unrelated - The AE is clearly NOT related to the device. 
 
14.2 Definitions of Adverse Event and Adverse Device Effect 
An adverse event (AE) is any untoward medical occurrence, unintended disease or injury or any 
untoward clinical signs (including an abnormal laboratory finding) in study participants, whether 
or not related to the investigational device. This should relate to baseline information whenever 
available. 

 
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An adverse device effect (ADE) is an adverse event related to the use of the investigational device. 
In this study the ADE is refers to "side effect" or “complications”.  
14.3 Definition of Serious Adverse Event 
A serious adverse event (SAE) is an adverse event, that  
a) led to death,  
b) led to 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 or prolonged hospitalization, or  
4) medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function,  
c) led to fetal distress, fetal death or a congenital abnormality or birth defect  
It is responsibility of site PI to report any Serious Adverse Event or Serious Adverse Device Event 
to the sponsor, within 24 hours to: 
 
Theranica Bioelectronics  
Dr. Dagan Harris 
Tel: +972.72.390.9758 
Fax: + 972.72.390.9755 
Email: dagah@theranica.com 
A Serious device related adverse effect (SADE) is an adverse event related to the use of the 
investigational device and that is considered by regulations and definitions as Serious. 
14.4 Device Deficiency 
 Device deficiency is an inadequacy with respect to the device’s identity, quality, durability, 
reliability, safety, or performance, such as a malfunction, failure, use error or inadequate labeling. 
Device deficiencies may or may not be associated with an adverse event.  
All device deficiencies will be entered in the eCRF. Device deficiencies that were associated with 
an SAE or that could have led to an SAE if a) suitable action had not been taken or b) intervention 
had not been made or c) if circumstance had been less fortunate, will be reported within 24 hours 
of occurrence. If possible, the device(s) associated with a malfunction or failure should be retained 
until arrangements for its collection are made by the sponsor. 
Device deficiencies will be summarized and reported in the clinical study report and will be 
reported to the regulatory authorities per country’s applicable reporting requirements. 
14.5 Time-frame for Investigator Reporting AE to Sponsor, EC, RA 
Serious adverse events, whether or not related to the device, and whether anticipated or 
unanticipated, must be reported to the sponsor within 24 hours of learning of the event 
occurrence by the site staff. This requirement is in addition to, and does not replace, other 
investigator responsibilities for adverse event reporting. Notification on a SAE is forwarded to 

 
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sponsor designated contact person.  Additionally, SAEs should be reported by the site to the 
involved IRB/EC and Regulatory Authorities as applicable.  
Unanticipated device related adverse events shall be reported to the sponsor within 48 hours of 
learning of the event occurrence by the site staff.   
In addition, device related side effects shall be reported to the sponsor and documented in 
monitoring visit/phone call summary.   
Any AE that results in withdrawal from observation in the study must be reported to the sponsor 
within 24 hours after the decision to withdraw the patient is made. 
Any death occurring during the study must be reported to the sponsor within 24 hours of 
discovery of the event. “Death” should not be reported as an AE, the cause of death should be 
reported as an AE. The only exception is “Sudden Death” when the cause is unknown. A copy of 
the death records, death certificate and an autopsy report (if performed) must be provided to 
the sponsor as soon as possible. 
The sponsor is responsible for relaying adequate information on SAEs to the regulatory 
authorities per country’s applicable reporting requirements. 
14.6 Adverse Event Reporting Forms 
The eCRFs for AE or SAE will include all relevant information of the AE or SAE with regards to onset 
and resolution time, grade, causality to device, treatment given etc.  
 
14.7 Foreseeable Complications and Anticipated Adverse Device Related 
Effects. 
Possible adverse events associated with Transcutaneous Electrical Nerve Stimulation include, 
but are not limited to the following: 
• 
Anxious mood 
• 
Burn marks 
• 
Increased air temperature sensitivity 
• 
Itching 
• 
Muscle fatigue 
• 
Muscle spasms 
• 
Skin irritation or redness 
• 
Stinging sensations 
 
The following migraine symptoms are foreseeable and will not be considered as device related: 
headache, nausea, light sensitivity, sensitivity to noise or odors, stomach upset, abdominal pain, 
loss of appetite, cold or heat sensation, paleness, fatigue, dizziness, fever (rare), blurred vision, 
vision symptoms such as bright flashing dots or lights, blind spots, wavy or jagged lines (aura). 
 

 
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14.8 Safety Monitoring and Adjudication of Adverse Events 
The sponsor will review submitted AE information and may request supplemental information if 
needed. For SAE, USADE and ADE (as classified by the investigator) a narrative will be prepared 
and adjudicated for assessing the relatedness, seriousness and possible action items required. 
The sponsor may ask for further information or clarification from the investigator. A summary of 
the adjudication results will be issued; if different than investigator’s report, PI will be notified.   
Adjudicated events will serve as a basis for reporting AE/SAE. Differences between site-reported 
events and adjudicated events will also be presented and discussed in the report. 

 
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15 VULNERABLE POPULATION 
No vulnerable population will be enrolled to this study. 

 
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16 EARLY TERMINATION OF THE CLINICAL INVESTIGATION 
16.1 Criteria and Arrangements 
The study may be discontinued if: 
- At any time, in the opinion of study PI, the study represents an unreasonable medical risk to 
patients. 
- The sponsor decides to terminate the study due to company considerations (e.g. Data 
Monitoring Committee recommends study termination based on futility analysis of interim data)  
 
In the event of clinical investigation premature termination or suspension, sponsor will send a 
report outlining the circumstances to the corresponding IRB/EC, regulatory body and all 
investigators. A suspended or terminated clinical investigation may not be re-initiated without 
approval of the corresponding IRB/EC and relevant RA, as applicable. In the event of clinical 
investigation premature termination or suspension, enrolled subjects will be followed up as per 
the institution’s standard of care. 
16.2 Requirements for Patient Follow-Up in case of Withdrawal 
In case of patient withdrawal, all efforts will be made to collect and report the final visit 
observations as thoroughly and timely as possible. 

 
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17 PUBLICATION POLICY 
The publication policy is defined in the sponsor – investigator agreement. 

 
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18 PATIENT CONFIDENTIALITY & DATA PROTECTION 
The privacy of participants and confidentiality of personal data will be maintained in reports and 
publications and will not be otherwise published in any way. 
Privacy will be maintained according to prevailing national data protection, privacy and secrecy 
laws. Each patient will be identified by a unique patient identification number. 
However, the sponsor’s monitor or representative and regulatory representatives, auditors and 
inspectors may have access to medical files in order to verify authenticity of data collected, as 
documented in informed consent form. 

 
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19 GUIDELINES AND APPLICABLE DOCUMENTS 
1. EN ISO 14155; (2011): Clinical investigation of medical devices for human patients  
2. EN ISO 14971; (2012): Medical devices – Application of risk management to medical 
devices. 

 
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20 REFERENCES 
1. Bloudek I. et al. Cost of healthcare for patients with migraine in five European countries: 
results from the International Burden of Migraine Study (IBMS). J Headache Pain (2012) 
13:361–378  
2. Goadsby PJ, Lipton RB, Ferrari MD. Migraine – current understanding and treatment. N 
Engl J Med, 346: 257 
3. Martelletti et al. Neuromodulation of chronic headaches: position statement from the 
European Headache Federation. The Journal of Headache and Pain 2013, 14:86 
4. Schoenen J et al., Migraine prevention with a supraorbital transcutaneous stimulator. 
Neurology 80 February 19, 2013 
5. Magis D. et.al. Safety and patients’ satisfaction of transcutaneous Supraorbital 
NeuroStimulation (tSNS) with the Cefaly® device in headache treatment: a survey of 2,313 
headache sufferers in the general population. The Journal of Headache and Pain 2013, 
14:95 
6. Magis D, Schoenen PGJ, Transcutaneous Vagus Nerve Stimulation (tVNS) for headache 
prophylaxis: initial experience. The Journal of Headache and Pain 2013, 14(Suppl 1):198  
7. Slavin KV, Nersesyan H, Wess C. Peripheral neurostimulation for treatment of intractable 
occipital neuralgia. Neurosurgery 2006; 58:112. 
8. Ristić D, Ellrich J. Innocuous Peripheral Nerve Stimulation Shifts Stimulus–Response 
Function of Painful Laser Stimulation in Man. Neuromodulation 2014; 17: 686  
9. Nir RR et.al. A psychophysical study of endogenous analgesia: the role of the conditioning 
pain in the induction and magnitude of conditioned pain modulation. Eur J Pain. 2011 
May;15(5):491 
10. Burstein R, Cutrer MF, Yarnitsky D. The development of cutaneous allodynia during a 
migraine attack clinical evidence for the sequential recruitment of spinal and supraspinal 
nociceptive neurons in migraine. Brain. 2000 Aug;123 ( Pt 8):1703 
11.  Lipton RB et. al.  Single-pulse transcranial magnetic stimulation for acute treatment of 
migraine with aura: a randomized, double-blind, parallel-group, sham-controlled trial. 
The Lancet 2010; 9:373 
12. Barbanti P et.al. Non-invasive vagus nerve stimulation for acute treatment of high-
frequency and chronic migraine: an open-label study. The Journal of Headache and Pain. 
2015 16:61 
13. Machin, D., Campbell, M.J. Statistical Tables for Design of Clinical Trials Blackwell Scientific  
       Publications, Oxford (1987)  
14.  Fleiss, J.L., Tytun, A., Ury, S.H.K. "A simple approximation for calculating sample sizes for  

 
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        comparing independent proportions" Biometrics 36(1980) pp. 343-346 
15. Allais G, De Lorenzo C, Quirico PE , Lupi G, Airola G, Mana O, Benedetto C. Non-
pharmacological approaches to chronic headaches: transcutaneous electrical nerve 
stimulation, laser therapy and acupuncture in transformed migraine treatment. Neurol 
Sci. 2003 May; 24 Suppl 2: S138-42 
16. Marchand S  et.al. Is TENS purely a placebo effect? A controlled study on chronic low back 
pain Pain. 1993; 54(1):99-106.  
17. Johnson MI, Ashton CH, Thompson JW.  An in-depth study of long-term users of 
transcutaneous electrical nerve stimulation (TENS). Implications for clinical use of TENS. 
Pain. 1991; 44(3):221-9. 
18. J.J. Amer-Cuenca. Programacio´n y aplicacio´n de la estimulacio´n nerviosa ele´ctrica 
transcuta´nea (TENS): guı´a de pra´ctica clı´nica basada en la evidencia. Fisioterapia 
2010;32(6):271–278 
19. Oosterhof J. Outcome of transcutaneous electrical nerve stimulation in chronic pain: 
short-term results of a double-blind, randomised, placebo-controlled trial. J Headache 
Pain (2006) 7:196–205 
20. Chesterton LS et.al. Sensory stimulation (TENS): effects of parameter manipulation on 
mechanical pain thresholds in healthy human subjects. Pain 2002; 99:253-62. 
21. Eton DT et. al. A systematic review of patient-reported measures of burden of treatment 
in three chronic diseases. Patient Related Outcome Measures 2013:4 7–20 
22. Tran VT et. al. Adaptation and validation of the Treatment Burden Questionnaire (TBQ) in 
English using an internet platform. BMC Medicine 2014, 12:109 
23. Lines CR, Vandormael K, Malbecq W. A comparison of visual analog scale and categorical 
ratings of headache pain in a randomized controlled clinical trial with migraine patients. 
Pain 93 (2001) 185±190 
24. CR Mehta and SJ Pocock Adaptive Increase in Sample Size when Interim Results are 
Promising: A Practical Guide with Examples; Statistics in Medicine. 2000; 00:1–6 
25. Chen et al., Increasing the sample size when the unblinded interim result is promising; 
Statistics in Medicine. 2004; 23:1023–1038 
26.  Broberg. Sample size re-assessment leading to a raised sample size does not inflate type 
I error rate under mild conditions; Medical Research Methodology 2013, 13:94 
27. Younger J, McCue R., Mackey S.. Pain Outcomes: A Brief Review of Instruments and 
Techniques, Curr Pain Headache Rep. 2009 February ; 13(1): 39–43 

 
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21 ACRONYM LIST 
 
ADE - Adverse Device Effect 
AE - Adverse Event 
CA – Competent Authority 
CE - Conformité Européenne [CE Mark] 
CI – Confidence Interval  
CIP - Clinical Investigation Plan  
CRF - Case Report Form 
CV - Curriculum Vitae 
d – Day 
DM - Data Management 
DNIC - diffused noxious inhibitory control 
EC - Ethical Committee 
GCP - Good Clinical Practice 
GMP- Good Manufacturing Practice 
IB - Investigator Brochure 
ICF - Informed Consent Form 
ICH - International Conference on Harmonization 
IFU – Instructions for Use 
ISO - International Organization for Standardization 
m - Month 
MDD - Medical Device Directive 
MoH – Ministry of Health 
NPS – Numeric Pain Rating Scale  
PI - Principal Investigator 
PP - Per-Protocol analysis set 
PRO - Patient Reported Outcomes 
RA - Regulatory Authority 
SADE - Serious Adverse Device Effect 
SAE - Serious Adverse Event 

 
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SD - Standard Deviation 
SDV - Source Data Verification 
SOPs - Standard Operating Procedures 
w - Week 

 
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APPENDIX A. STIMULATION PROGRAMS 
 
Active device: 
• 
Modulated waveform:  
• 
Biphasic, rectangular, symmetrical 
• 
Pulse duration (µsec): 400 
• 
Pulse frequency (Hz): 100-120* 
• 
Max output current (mA): 60 
• 
Modulating waveform:  
amplitude modulation at 2 Hz, with amplitude attenuation of 0.75.  
 
Sham device: 
• 
Waveform: rectangular, symmetrical 
• 
Pulse duration (µsec): pseudo-random between 80 to 400 
• 
Pulse frequency (Hz): 0.083 on average 
• 
Max output current (mA): 40 
 
 
 
 

 
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APPENDIX B. CASE REPORT FORMS LIST AND DRAFT CRF QUESTONS 
Electronic CRFs are being implemented, so the tables below provide contents but not 
look of the planned forms. 
 
The CRFs are comprised of the following forms: 
 
  
eCRFs List 
1 Demographics 
2 Medical History 
3 Migraine Assessment 
4 Medical assessment 
5 Eligibility (Incl./Excl.) 
5a Informed consent 
6 Device identification 
    
7 Migraine Diary 
8 Treatments and outcomes 
9 Adverse Events 
9a SAE 
10 Protocol Deviations 
11 Device deficiency 
12 Concomitant Medication  
12a Migraine Medication  
13 End of Study Questionnaire 
13a 
Changes in medication during the 
study period 
14 Study exit form 
 
1. Demographics 
Question 
Type 
Optional input 
Part of eligibility 
criteria (Y/N) 
Date of Birth 
dd/mm/YYYY 
  
  
Age at enrollment 
  
calculated 
Y 
Gender 
  
RadioButton 
  
Male 
  
Female 
  

 
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Race (check one or 
specify other) 
  
  
  
  
  
  
  
  
RadioButton 
  
  
  
  
  
  
  
  
American Indian or Alaskan Native 
  
Asian 
  
African American 
  
Native Hawaiian or other Pacific 
Islander 
  
Caucasian 
  
African Arab 
  
Eastern Arab 
  
Other:   
  
height 
Open text 
(number) 
cm/inches( radio buttons) 
  
weight  
Open text 
(number) 
kg/pounds(radio buttons) 
  
 
2. Medical History 
Question 
 
Type 
Optional input 
Date of assessment 
Date field 
  
Prior surgeries 
Radio buttons 
yes/no 
If yes, year and reason 
Open text 
unknown  
Other prior hospitalizations 
Radio buttons 
yes/no 
If yes, year and reason 
Open text 
unknown  
Which of the following conditions 
was the patient treated for in the 
past? Check all that apply 
Checkbox with multiple 
choices 
Neurological 
Psychiatric 
HEENT 
Respiratory 
Cardiovascular 
Gastrointestinal/Hepatic 
Renal 
Genitourinary 
Musculoskeletal 
 Dermatological 
Hematological 
Metabolic/Endocrine 
Allergy 
Other 
If Other, please specify 
Open text 
  
If any of the above checked, please 
detail year diagnosed and specifics 
Open text 
unknown  
Does the patient currently smoke or 
chew tobacco? 
Radio buttons 
yes/no 

 
A Randomized, Double Blinded, Sham controlled Clinical Study to Evaluate 
the Safety and Efficacy of the Nerivio Migra 1, a Neuromodulation Device, 
for the acute treatment of Migraine 
Protocol number:  TCH-003 
Page 82 of 94 
 
Confidential 
If yes, how many packs per day? 
Open text (number) 
  
If no, had he/she in the past? 
Radio buttons 
yes/no 
If yes, please specify year stopped  
Open text 
  
If yes, please specify how many 
packs per day 
Open text 
  
Does the patient drinks alcohol, 
beer or wine? 
Radio buttons 
yes/no 
If yes, how many drinks per week? 
Open text (number) 
  
If no, had he/she in the past? 
Radio buttons 
yes/no 
If yes, please specify year stopped  
Open text 
  
If yes, please specify  how many 
drinks per week 
Open text 
  
 
 
3. Migraine Assessment 
Question 
Type 
Optional input 
Part of eligibility 
criteria (Y/N) 
Year of migraine diagnosis 
drop down 
list  
unknown 
 
Average number of attacks per 
month 
input field 
 
Y 
Average number of migraine days 
per month 
input field 
 
Y 
Number of other types of 
headaches per month 
radio buttons 
"0" / "1-5" / "6 and 
more" 
 
Use of preventive medication.  
If YES, fill in concomitant 
medication CRF entry 
radio buttons 
yes/no 
 
Any change in use/dose of 
preventive medication in the past 
two months 
radio buttons 
yes/no 
Y 
How often do you experience aura 
preceding a migraine attack 
radio buttons 
Often /  
Rarely /  
None 
 
Average attack duration  w/o 
medication 
dropdown list 
0-2/ 2-6/ 6-12/ 12-
24/ 24-48/ More 
than 48 
 

 
A Randomized, Double Blinded, Sham controlled Clinical Study to Evaluate 
the Safety and Efficacy of the Nerivio Migra 1, a Neuromodulation Device, 
for the acute treatment of Migraine 
Protocol number:  TCH-003 
Page 83 of 94 
 
Confidential 
Maximum pain level for an average 
attack, without medication (pain 
grade) 
radio buttons 
mild/moderate/se
vere 
 
Use of acute medication to treat 
the headache during migraine 
attack 
dropdown list 
always/sometime
s/rarely/never 
 
   If yes, medication name 
dropdown list 
see rescue 
medication list 
sheet 
 
   If yes, medication dose  
fractional 
number 
23.5 
 
   If yes, medication dose units  
radio buttons 
mg/cc/other 
 
"if other, specify" - an input  text 
window  
input field 
  
 
How long after pain start is rescue 
medication taken, on average  
dropdown list 
0-20min/20-
40min, 40-
60min/1-2h/2-
4h/more than 4h 
 
Average attack duration  with 
rescue medication 
dropdown list 
0-2/ 2-6/ 6-12/ 12-
24/ 24-48/ More 
than 48 
 
Typical pain level for an average 
attack, 2 hours after rescue 
medication taken 
None (0) 
Mild (1) 
Moderate (2) 
Severe (3) 
pain grade 
 
  
  
  
 
Migraine pain side 
radio buttons 
left/right/alternatin
g/both 
Y 
Nausea/vomiting during attack   
radio buttons 
yes/no/sometime
s 
Y 
Light sensitivity during attack 
radio buttons 
yes/no/sometime
s 
Y 
Sound sensitivity during attack  
radio buttons 
yes/no/sometime
s 
Y 
Where does your skin become 
more sensitive to touch or pressure 
when you have migraine 
checkboxes 
None 
Scalp 
Eye and/or 
forehead 
Body 
Y 

 
A Randomized, Double Blinded, Sham controlled Clinical Study to Evaluate 
the Safety and Efficacy of the Nerivio Migra 1, a Neuromodulation Device, 
for the acute treatment of Migraine 
Protocol number:  TCH-003 
Page 84 of 94 
 
Confidential 
Most bothersome migraine 
symptom beyond pain 
dropdown list 
nausea/light/nois
e/skin 
sensitivity/none 
 
 
 
4. Medical assessment 
Question 
Type 
Optional input 
Part of eligibility 
criteria (Y/N) 
Open wounds or burns, or irritated 
skin on upper arm area 
Radio buttons 
yes/no 
n 
Pregnancy test taken 
Radio 
buttons 
yes/no/NA 
  
if no, specify reason  
open text  
  
  
Pregnancy test result 
Radio buttons 
positive/negative 
  
General motor and sensory 
function 
Radio buttons 
normal/abnormal 
  
 
5. Eligibility 
Question 
 
Type 
Optional input 
Inclusion criteria 
If any inclusion criterion is checked No, the patient is considered ineligible for this study and 
cannot be enrolled. 
Subject is 18-75 years old 
Radio buttons 
yes/no 
Meets the ICHD-3 diagnostic criteria for migraine 
with and without aura 
Radio buttons 
yes/no 
Subjects report 2-8 migraine attacks per month 
Radio buttons 
yes/no 
Stable migraine preventive medications in the last 
two months prior to recruitment (No change in 
usage or dosage). 
Radio buttons 
yes/no 
Subjects must be able and willing to comply with 
the protocol 
Radio buttons 
yes/no 
Subjects must be able and willing to provide 
written informed consent protocol 
Radio buttons 
yes/no 
Exclusion criteria  
If any Exclusion criterion is checked Yes, the patient is considered ineligible for this study and 
cannot be enrolled. 

 
A Randomized, Double Blinded, Sham controlled Clinical Study to Evaluate 
the Safety and Efficacy of the Nerivio Migra 1, a Neuromodulation Device, 
for the acute treatment of Migraine 
Protocol number:  TCH-003 
Page 85 of 94 
 
Confidential 
Subject has other significant pain, medical or 
psychologic problems that in the opinion of the 
investigator may confound the study assessments 
Radio buttons 
yes/no 
Subject has an implanted electrical and/or 
neurostimulator device (e.g. cardiac pacemaker or 
defibrillator, vagus nerve neurostimulator, deep 
brain stimulator, spinal stimulator, bone growth 
stimulator cochlear implant, Sphenopalatine 
ganglion stimulator or Occipital nerve stimulator). 
Radio buttons 
yes/no 
Subject has known uncontrolled epilepsy. 
Radio buttons 
yes/no 
Any use of Cannabis including medical use.  
Radio buttons 
yes/no 
Subject has >10 headache days per month. 
Radio buttons 
yes/no 
Subject has undergone nerve block (occipital or 
other) in the head or neck within the last 2 weeks. 
Radio buttons 
yes/no 
Radio buttons 
yes/no 
Subject is participating in any other clinical study. 
Radio buttons 
yes/no 
The subject does not have the basic cognitive and 
motor skills needed to operate a smartphone. 
Radio buttons 
yes/no 
Pregnant, or trying to get pregnant 
Radio buttons 
yes/no/NA 
Subject is experiencing a menstrually related 
migraine  
Radio buttons 
yes/no/NA 
Received OnabotulinumtoxinA or any botulinum 
toxin injections for migraine within the previous 
month 
Radio buttons 
yes/no 
Received parenteral infusions for migraine within 
the previous 2 weeks.  
Radio buttons 
yes/no 
Subject participated in a previous study with the 
Nerivio Migra 1 device  
Radio buttons 
yes/no 
Is patient eligible for participating in the study?  
( If NO, patient should not be enrolled) 
Radio buttons 
Yes/No 
 
5a. Informed Consent 
Question 
 
Type 
Optional input 
Has the patient received written and oral explanation 
of the study? 
Radio buttons 
Yes/No 
ICF version : 
integer 
number 1-10 
Date obtained and signed 
dd/mm/YYYY 
  

 
A Randomized, Double Blinded, Sham controlled Clinical Study to Evaluate 
the Safety and Efficacy of the Nerivio Migra 1, a Neuromodulation Device, 
for the acute treatment of Migraine 
Protocol number:  TCH-003 
Page 86 of 94 
 
Confidential 
Has the patient received a copy of the signed ICF ? 
Radio buttons 
Yes/No 
If NO, explain why 
Open text 
  
 
6. Device identification 
Question 
Type 
Optional input 
Smartphone ID 
  
fed from 1st connect event with app 
Phone_ype 
  
fed from 1st connect event with app 
Application Version 
  
fed from 1st connect event with app 
SEW5120Ver 
  
fed from 1st connect event with app 
Training - diary 
radio buttons 
fed from server when executed 
 
7. Migraine Diary 
For each reported attack 
Attack  
start 
  
  
Attack number 
sequential 
number of this 
attack in diary list 
from server 
  
Date and time 
  
from server 
  
time elapsed after 
previous reported 
attack 
dd/hh/mm 
from server 
dd/hh/mm 
Current migraine 
pain level  
Current migraine 
pain level in pain 
grade categories 
Radio buttons 
Mild (1), Moderate (2), 
Severe (3). 
Time from onset of 
migraine pain 
Time from onset 
of migraine pain 
Dropdown list 
under 30 minutes  
30-60 minutes 
over 60 minutes 
Nausea 
Presence of 
nausea 
Radio buttons 
yes/no 
Sensitivity to light 
Presence of 
photophobia 
Radio buttons 
yes/no 
Sensitivity to sound 
Presence of 
phonophobia 
Radio buttons 
yes/no 
Increased skin 
sensation 
Presence of 
allodynia 
Radio buttons 
yes/no 
MBS  
most boresome 
symptoms 
Radio buttons 
Nausea/Photophobia/Pho
nophobia/Allodynia/None 
aura 
  
Radio buttons 
yes/no 

 
A Randomized, Double Blinded, Sham controlled Clinical Study to Evaluate 
the Safety and Efficacy of the Nerivio Migra 1, a Neuromodulation Device, 
for the acute treatment of Migraine 
Protocol number:  TCH-003 
Page 87 of 94 
 
Confidential 
Status 
at 2h 
  
  
  
  
  
  
  
  
  
  
  
Date and time 
date and time 
when record 
received 
  
  
Attack number 
sequential 
number of this 
attack in diary list 
from server 
  
Migraine pain level 2 
hours past attack 
start  
Current migraine 
pain level in pain 
grade categories 
Dropdown list 
No pain (0), Mild (1), 
Moderate (2), Severe (3).  
Medication 
Whether rescue 
medication was 
taken  
Radio buttons 
yes/no 
Rescue medication 
name 
Rescue 
medication name 
Free text from 
App 
See Appendix 5.3 
if medication has 
being used 
  
Radio buttons 
Before start of treatment 
Less than 2 hours after 
start of treatment 
 2 hours or more from 
starting the treatment 
Nausea 
Presence of 
nausea 
Radio buttons 
yes/no 
Sensitivity to light 
Presence of 
photophobia 
Radio buttons 
yes/no 
Sensitivity to sound 
Presence of 
phonophobia 
Radio buttons 
yes/no 
Increased skin 
sensation 
Presence of 
allodynia 
Radio buttons  
yes/no 
Status 
at 48h 
  
  
  
  
Attack number 
sequential 
number of this 
attack in diary list 
from server 
  
Date and time 
date and time 
when record 
received 
from server 
  
Migraine pain level 
48 hours past attack 
start  
Current migraine 
pain level in pain 
grade categories 
Dropdown list  
No pain (0), Mild (1), 
Moderate (2), Severe (3).  
Additional 
medication taken 
(after reported @2h) 
Whether rescue 
medication was 
taken  
Radio buttons 
yes/no 
Rescue medication 
name 
Rescue 
medication name 
Free text from 
App 
See Appendix 5.3 
 
8. Randomization 

 
A Randomized, Double Blinded, Sham controlled Clinical Study to Evaluate 
the Safety and Efficacy of the Nerivio Migra 1, a Neuromodulation Device, 
for the acute treatment of Migraine 
Protocol number:  TCH-003 
Page 88 of 94 
 
Confidential 
Question 
 
Type 
Optional input 
Device ID 
  
fed from 1st connect event with app 
Smartphone ID 
  
fed from 1st connect event with app 
Phone_type 
  
fed from 1st connect event with app 
Application_Version 
  
fed from 1st connect event with app 
SEW5120Ver 
  
fed from 1st connect event with app 
Training - treatment 
radio buttons 
fed from server when executed 
 
9. Treatment 
  
Item 
Description 
Control type 
for PRO 
Values range 
  
Attack number 
sequential number of 
this attack in treated 
attacks list 
from server 
  
Attack  
start 
  
  
  
  
  
  
  
  
  
  
Date and time 
  
from server 
  
time elapsed after 
previous reported 
attack 
dd/hh/mm 
from server 
dd/hh/mm 
Current 
migraine 
pain level  
Current 
migraine 
pain level in pain 
grade categories 
Radio 
buttons 
Mild (1), Moderate (2), 
Severe (3). 
Time from onset of 
migraine pain 
Time from onset of 
migraine pain 
Dropdown 
list 
under 30 minutes  
30-60 minutes 
over 60 minutes 
Nausea 
Presence of nausea 
Radio 
buttons 
yes/no 
Sensitivity to light 
Presence 
of 
photophobia 
Radio 
buttons 
yes/no 
Sensitivity to sound 
Presence 
of 
phonophobia 
Radio 
buttons 
yes/no 
Increased 
skin 
sensation 
Presence of allodynia Radio 
buttons 
yes/no 
Aura 
Presence of aura 
Radio 
buttons 
yes/no 
Status at 
2h 
  
  
  
Date and time 
date and time when 
record received 
  
  
Attack number 
sequential number of 
this attack in treated 
attacks list 
from server 
  

 
A Randomized, Double Blinded, Sham controlled Clinical Study to Evaluate 
the Safety and Efficacy of the Nerivio Migra 1, a Neuromodulation Device, 
for the acute treatment of Migraine 
Protocol number:  TCH-003 
Page 89 of 94 
 
Confidential 
  
  
  
  
  
  
  
  
  
  
Current 
migraine 
pain level  
Current 
migraine 
pain level in pain 
grade categories 
Dropdown 
list 
No pain (0), Mild (1), 
Moderate (2), Severe 
(3).  
Medication 
Whether 
rescue 
medication 
was 
taken  
Free Text 
Yes/No 
Rescue medication 
name 
Rescue 
medication 
name 
Dropdown 
list 
See Appendix 5.3 
if medication has 
being used 
  
Radio 
buttons 
Before 
start 
of 
treatment 
Less than 2 hours after 
start of treatment 
 2 hours or more from 
starting the treatment 
Nausea 
Presence of nausea 
Radio 
buttons 
yes/no 
Sensitivity to light 
Presence 
of 
photophobia 
Radio 
buttons 
yes/no 
Sensitivity to sound 
Presence 
of 
phonophobia 
Radio 
buttons 
yes/no 
Increased 
skin 
sensation 
Presence of allodynia Radio 
buttons 
yes/no 
MBS  
most 
boresome 
symptoms 
Radio 
buttons 
Nausea/Photophobia/P
honophobia/Allodynia/
None 
Status at 
48h 
  
  
  
  
Date and time 
date and time when 
record received 
  
  
Attack number 
sequential number of 
this attack in treated 
attacks list 
from server 
  
Current 
migraine 
pain level  
Current 
migraine 
pain level in pain 
grade categories 
Dropdown 
list  
No pain (0), Mild (1), 
Moderate (2), Severe 
(3).  
Additional 
medication 
taken 
(after 
reported 
@2h) 
Whether 
rescue 
medication 
was 
taken  
Radio 
buttons 
yes/no 
Rescue medication 
name 
Rescue 
medication 
name 
Free Text 
See Appendix 5.3 
 
10. Treatment summary 
Item 
Description 
Control type 
for PRO 
Values range 

 
A Randomized, Double Blinded, Sham controlled Clinical Study to Evaluate 
the Safety and Efficacy of the Nerivio Migra 1, a Neuromodulation Device, 
for the acute treatment of Migraine 
Protocol number:  TCH-003 
Page 90 of 94 
 
Confidential 
qualified 
  
Radio buttons 
yes/no 
treatment status 
  
Radio buttons 
completed/aborted/stopped/unknown 
report status 
  
Radio buttons 
missing data/evaluable/complete 
average 
stimulation 
intensity 
  
from server 
  
max 
stimulation 
intensity 
  
from server 
  
treatment 
duration 
  
from server 
  
 
11. Phone call 
Question 
Type 
Optional input 
Date 
Date field 
  
Time 
time filed 
  
Alert performed for ? 
Radio buttons 
mising 2 hours feedback 
missing 48 hours feedback 
Battery level below 40% 
Battery level below 25% 
Battery level below 10% 
Low stimulation intensity level 
Repeated abort or incompletion of the 
qualified session 
Long inactive/off-line time 
Less than 2 qualified attacks per month 
Subject contacted? 
Radio buttons 
Yes/No 
Call effective? 
Radio buttons 
Yes/No 
Comments 
Open text 
  
 
 
12. End of Study questionnaire  
Question 
 
Type 
Optional input 
Usability assessment: How easy was it 
to administer treatment 
Dropdown 
list 
very easy (1), easy (2),   neutral (3), 
uncomfortable (4), difficult (5) 
Blinding assessment: which group do 
you think you were assigned? 
Dropdown 
list 
active/sham/do not know 
Global impression of change: please 
rate your current status 
Dropdown 
list 
 very much improved  (1),  much 
improved (2), minimally improved 
(3),  no change (4), minimally worse 

 
A Randomized, Double Blinded, Sham controlled Clinical Study to Evaluate 
the Safety and Efficacy of the Nerivio Migra 1, a Neuromodulation Device, 
for the acute treatment of Migraine 
Protocol number:  TCH-003 
Page 91 of 94 
 
Confidential 
(5),  much worse (6), or (7) very much 
worse 
Application log files uploaded 
Radio 
buttons 
yes/no 
 
13. Study exit form 
Question 
 
Type 
Optional input 
Date of study termination 
Date field 
  
Did the patient complete the 
study according to the 
protocol ?  
Radio buttons 
yes 
no 
 If no, select from the list: 
Dropdown list 
Roll in screen failure  
Patient withdrew consent 
Adverse event or SAE 
Noncompliance with the protocol 
 Lost to follow up 
Other 
  
  
If other, please specify 
Open text 
  
Subject received 
compensation 
Radio buttons 
Yes/No 
Additional comments 
Open text 
  
log files copied 
Radio buttons 
Yes/No 
 
 
14. Concomitant medications 
PRIMARY QUESTION 
Is the subject taking any medication that will be 
continued during the study? 
Radio buttons 
yes/no 
GRID 
  
  
Question 
Type 
Optional input 
Migraine related? 
Radio buttons 
yes/no 
Medication name 
Open text 
  
If Related to migraine, Use ? 
Radio buttons 
preventive/rescue 
If Not Related to migraine, Administered for 
Open text 
  

 
A Randomized, Double Blinded, Sham controlled Clinical Study to Evaluate 
the Safety and Efficacy of the Nerivio Migra 1, a Neuromodulation Device, 
for the acute treatment of Migraine 
Protocol number:  TCH-003 
Page 92 of 94 
 
Confidential 
If Related to AE/ SAE then AE/ SAE Number: 
Open text 
(number) 
  
Daily dose 
fractional number 
23.5 
Units 
Radio buttons 
cc, mg, other 
if other unit, specify: 
Open text 
  
Start date 
Date field 
  
Stop/End date 
Date field 
  
on going/unknown 
Checkbox  
  
 
15. AE 
adverse event seq number 
Open text 
  
Date of adverse event 
Date field 
  
Date of report 
Date field 
  
Initial or follow-up data 
Radio 
buttons 
Initial report 
Follow-up data 
Diagnosis  
Open text 
  
Description 
Open text 
  
Severity 
Radio 
buttons 
Mild 
Moderate 
Severe 
Worsened pre-existing condition 
Radio 
buttons 
Yes 
No 
Relationship to study device 
Dropdown 
list 
Not related 
Possibly related 
Probably related 
Definitely related 
Relation to other therapy 
Radio 
buttons 
Not related 
Possibly related 
Probably related 
Definitely related 
If related to other therapy, please explain in the 
description above 
Open text 
  
Action taken 
Checkbox 
None 
Medication 
Intervention 
device treatment 
discontinuation  
Other 
If intervention, please specify 
Open text 
  

 
A Randomized, Double Blinded, Sham controlled Clinical Study to Evaluate 
the Safety and Efficacy of the Nerivio Migra 1, a Neuromodulation Device, 
for the acute treatment of Migraine 
Protocol number:  TCH-003 
Page 93 of 94 
 
Confidential 
If Other, please specify 
Open text 
  
Outcome 
Radio 
buttons 
Resolved 
Resolved with sequelae 
Ongoing, improved 
Ongoing, unchanged 
worsening 
If resolved, date 
Date field 
  
If resolved with sequelae, date 
Date field 
  
Upload supporting information 
Upload 
file 
  
Study discontinued ? 
  
Radio 
buttons 
Yes 
No 
 
16. SAE 
Item 
 
Description 
Values range 
SAE number 
Open text 
  
Date of adverse event 
Date field 
  
End date 
Date field 
ongoing 
Date of report 
Date field 
  
Initial or follow-up data 
Radio buttons 
Initial report 
Follow-up data 
Diagnosis  
Open text 
  
Description 
Open text 
  
Severity 
Radio buttons 
Mild 
Moderate 
Severe 
Was the adverse event serious 
(SAE)? 
Radio buttons 
Yes 
No 
If serious, specify 
Radio buttons 
Fatal 
Immediately life 
threatening 
Required hospitalization or 
prolonged hospitalization 
Persistent or significant 
disability/incapacity 
Congenital anomaly/birth 
defect 
 Other medically important 
serious event 

 
A Randomized, Double Blinded, Sham controlled Clinical Study to Evaluate 
the Safety and Efficacy of the Nerivio Migra 1, a Neuromodulation Device, 
for the acute treatment of Migraine 
Protocol number:  TCH-003 
Page 94 of 94 
 
Confidential 
If selected hospitalized: 
date of hospitalization 
Date field 
date of discharge 
Date field 
If selected  Other medically 
important serious event, Specify: 
Open text 
  
Worsened pre-existing condition 
Radio buttons 
Yes 
No 
Relationship to study device 
Radio buttons 
Not related 
Possibly related 
Probably related 
Definitely related 
Relation to other therapy 
Radio buttons 
Not related 
Possibly related 
Probably related 
Definitely related 
If related to other therapy, please 
explain in the description above 
  
  
Action taken 
Radio buttons 
None 
Medication 
Hospitalization 
Intervention 
Other 
If intervention, please specify 
Open text 
  
If Other, please specify 
Open text 
  
Outcome 
Checkbox 
Resolved 
Resolved with sequelae 
Ongoing, improved 
Ongoing, unchanged 
worsening 
Fatal 
If death, date 
Date field 
  
If resolved, date 
Date field 
  
If resolved with sequelae, date 
Date field 
  
Upload supportive information 
Upload file