A Prospective, Randomized, Double-blind, Sham Controlled Multi-center Clinical Trial, Migraine Headache Treatment With Nerivio Migra Neurostimulation Device
Phase: NA
Conditions: Acute Migraine
Sponsor: Theranica

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“Migraine Treatment with Nerivio Migra 
neurostimulation device” 
Pivotal prospective randomized double-blind, sham controlled multi-
center clinical trial 
Clinical Investigation Plan 
 
 
 
 
 

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CLINICAL CLINICAL INVESTIGATION PLAN  
STUDY TITLE:  
Migraine Treatment with Nerivio Migra Neurostimulation 
device 
PROTOCOL NUMBER: 
 
TCH_002 
REVISION: 
 
 
1.4 
RELEASE DATE:  
 
__/__/__ 
DEVICE: 
Nerivio Migra migraine treatment device, model 1.0. SW 
Final version 1.2, 22 November 2016 
                                                            AMENDMENT 1, 2 February 2017  
AMENDMENT 2, 14 FEB 2017 
version 1.4 
PRINCIPAL INVESTIGATORS:    
TBD 
SPONSOR:  
 
 
Theranica Bioelectronics 
 
 
 
 
45 HaMelakha st, Netanya, Israel 
CONTACT DETAILS: 
  
Alon Ironi, CEO 
Tel: +972.72.390.9758 
Fax: + 972.72.390.9762 
EMAIL: ALONI@THERANICA.COM 
APPROVED BY: 
DATE: 
SIGNATURE: 
____________ 
__/__/__ 
 
_______________________ 
____________  
__/__/__ 
 
_______________________ 
 
 
 
 
 

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Confidentiality statement: 
The following confidential information is the property of Theranica Bioelectronics.  As long as 
the information contained in this protocol has not been published; 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.   
 

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Change control table 
 
 
Rev. 
no. 
Change rationale 
Date 
1.0 
Release for FDA review following pre-sub meeting on Sept. 13, 
2016 
Nov. 06, 2016 
1.1 
Release for IRB submission 
Nov. 15, 2016 
1.2 
Additional amendments: procedures   
Nov. 22, 2016 
1.3 
Correction of mistakes in section 14.7 
Feb 2, 2017 
1.4 
Addition of open label phase, addition of one secondary 
endpoint, a few modifications following comments from FDA 
Feb 14, 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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The sponsor of this study, Theranica Bioelectronics Ltd, manufacturer of the Nerivio 
Migra migraine treatment device, 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.  
 
 
 

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Protocol Signature Page 
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 # 
 
 

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Contents 
1 
SYNOPSIS ..........................................................................................................................................10 
2 
BACKGROUND ................................................................................................................................14 
2.1 
INTRODUCTION ....................................................................................................................................14 
3 
IDENTIFICATION AND DESCRIPTION OF THE DEVICE .....................................................15 
3.1 
INTENDED USE .....................................................................................................................................16 
3.2 
THE DEVICE.........................................................................................................................................16 
3.3 
THE APPLICATION .................................................................................................................................18 
3.4 
ENERGY OUTPUT ..................................................................................................................................19 
3.5 
VERIFICATION AND VALIDATION ...............................................................................................................20 
3.5.1 
Performance testing ...............................................................................................................21 
3.5.2 
Software validation ................................................................................................................21 
3.6 
PRINCIPLE OF OPERATION ......................................................................................................................21 
3.7 
IDENTIFICATION OF THE MEDICAL DEVICE .................................................................................................23 
3.8 
INSTRUCTIONS FOR USE .........................................................................................................................23 
3.9 
SUMMARY OF NECESSARY TRAINING ........................................................................................................23 
4 
PRELIMINARY INVESTIGATIONS AND JUSTIFICATION FOR THE STUDY DESIGN ..24 
4.1 
PREVIOUS PRE-CLINICAL EXPERIENCE .......................................................................................................24 
4.2 
PREVIOUS CLINICAL EXPERIENCE .............................................................................................................24 
4.3 
CLINICAL INVESTIGATION RISKS AND BENEFITS ...........................................................................................28 
5 
OBJECTIVES & HYPOTHESES ....................................................................................................29 
5.1 
OBJECTIVE ..........................................................................................................................................29 
5.2 
HYPOTHESIS ........................................................................................................................................29 
6 
DESIGN OF THIS CLINICAL STUDY ..........................................................................................29 
6.1 
DESCRIPTION .......................................................................................................................................29 
6.2 
MEASURES TO MINIMIZE BIAS ................................................................................................................31 
6.2.1 
RANDOMIZATION ............................................................................................................................31 
6.2.2 
PROCEDURES TO ENSURE BLINDING .....................................................................................................31 
6.3 
STUDY ENDPOINTS ...............................................................................................................................32 
6.4 
METHODS AND TIMING OF ASSESSING, RECORDING AND ANALYZING VARIABLES ..............................................33 
6.4.1 
TYPES OF DATA ...............................................................................................................................33 
6.4.2 
CLINICAL STUDY VARIABLES AND DATA CAPTURE TOOLS .........................................................................33 

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6.4.2.1 
Start attack/episode PRO feedback data ..........................................................................33 
6.4.2.2 
2h PRO ..............................................................................................................................34 
6.4.2.3 
48h PRO ............................................................................................................................35 
6.4.3 
METHODS AND TIMING OF ASSESSING, RECORDING AND ANALYZING VARIABLES .........................................35 
6.4.4 
DATA FLOW AND MANAGEMENT .......................................................................................................36 
6.4.5 
PROCEDURES FOR REVIEW OF DATA ....................................................................................................38 
6.4.6 
DATA MONITORING COMMITTEE .......................................................................................................38 
6.4.7 
TOTAL EXPECTED DURATION OF THE CLINICAL INVESTIGATION .................................................................38 
6.5 
SUBJECTS ............................................................................................................................................38 
6.5.1 
INCLUSION CRITERIA ........................................................................................................................38 
6.5.2 
EXCLUSION CRITERIA ........................................................................................................................39 
6.5.3 
CONTRAINDICATIONS .......................................................................................................................39 
6.5.4 
NUMBER OF SUBJECTS ......................................................................................................................39 
6.5.5 
EXPECTED STUDY DURATION FOR EACH SUBJECT ...................................................................................39 
6.5.6 
POINT OF ENROLLMENT ....................................................................................................................39 
6.5.7 
PATIENT WITHDRAWAL CRITERIA .......................................................................................................39 
6.5.8 
HANDLING OF WITHDRAWALS ...........................................................................................................40 
6.5.9 
PATIENT LOST TO FOLLOW-UP ............................................................................................................40 
6.5.10 
ENROLLMENT PERIOD ..................................................................................................................40 
6.5.11 
PROCEDURES FOR REPLACEMENT OF SUBJECTS .................................................................................41 
6.6 
STUDY RELATED PROCEDURES .................................................................................................................41 
6.6.1 
GENERAL .......................................................................................................................................41 
6.6.2 
VISIT AND ASSESSMENT SCHEDULE ......................................................................................................41 
6.6.3 
ACTIVITIES PERFORMED BY SPONSOR REPRESENTATIVES ...........................................................................42 
6.7 
MONITORING PLAN ..............................................................................................................................42 
7 
STATISTICAL CONSIDERATIONS .............................................................................................43 
7.1 
STUDY DESIGN AND AIM........................................................................................................................43 
7.2 
STUDY VARIABLES ................................................................................................................................43 
7.2.1 
PRIMARY PERFORMANCE VARIABLE .....................................................................................................43 
7.2.2 
SECONDARY PERFORMANCE VARIABLES ................................................................................................43 
7.2.3 
EXPLORATORY PERFORMANCE VARIABLES .............................................................................................43 
7.2.4 
SAFETY VARIABLES ...........................................................................................................................44 
7.3 
STUDY HYPOTHESIS ..............................................................................................................................44 
7.4 
SAMPLE SIZE ESTIMATION ......................................................................................................................44 

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7.5 
INTERIM ANALYSIS ................................................................................................................................44 
7.6 
RANDOMIZATION .................................................................................................................................45 
7.7 
ANALYSIS SETS .....................................................................................................................................46 
7.7.1 
INTENT TO TREAT ANALYSIS SET (ITT) ..................................................................................................46 
7.7.2 
MODIFIED INTENT TO TREAT ANALYSIS SET (MITT) .................................................................................46 
7.7.3 
PER PROTOCOL ANALYSIS SET (PP) ......................................................................................................46 
7.7.4 
STATISTICAL ANALYSIS OF ANALYSIS SETS ..............................................................................................46 
7.8 
STATISTICAL ANALYSES ..........................................................................................................................46 
7.8.1 
GENERAL CONSIDERATIONS ...............................................................................................................46 
7.8.2 
SIGNIFICANCE LEVELS AND HANDLING OF TYPE I ERROR ............................................................................47 
7.8.2.1 
TYPE I ERROR .............................................................................................................................47 
7.8.2.2 
HIERARCHY APPROACH FOR SECONDARY ENDPOINTS ANALYSIS ...........................................................47 
7.8.3 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .........................................................................47 
7.8.4 
DISPOSITION OF PATIENTS .................................................................................................................47 
7.8.5 
PERFORMANCE ANALYSES .................................................................................................................47 
7.8.6 
SAFETY ANALYSIS: ...........................................................................................................................48 
7.8.7 
HANDLING OF MISSING DATA ............................................................................................................49 
7.9 
POOLING ............................................................................................................................................49 
8 
DATA MANAGEMENT ...................................................................................................................49 
8.1 
DATA CAPTURE ....................................................................................................................................49 
8.1.1 
DIRECT DATA ENTRY ........................................................................................................................49 
8.2 
DATA QUALITY ASSURANCE ....................................................................................................................50 
8.3 
ELECTRONIC SIGNATURES.......................................................................................................................50 
8.4 
VERIFICATION, VALIDATION AND SECURING OF ELECTRONIC DATA CAPTURE SYSTEM ...........................................50 
8.5 
RECORDS AND DATA RETENTION .............................................................................................................50 
8.6 
OTHER ASPECTS OF CLINICAL QUALITY ASSURANCE ....................................................................................50 
9 
AMENDMENTS TO THE CLINICAL INVESTIGATION PLAN ..............................................51 
10 
CLINICAL INVESTIGATION PLAN DEVIATIONS ..................................................................51 
10.1 
PROCEDURES FOR RECORDING, REPORTING AND ANALYZING PROTOCOL DEVIATIONS ...................................52 
10.2 
NOTIFICATION REQUIREMENT AND TIMELINES ......................................................................................52 
11 
PROTOCOL DEVIATIONS ............................................................................................................52 
12 
STATEMENTS OF COMPLIANCE ...............................................................................................53 
13 
INFORMED CONSENT PROCESS ................................................................................................53 
14 
ADVERSE EVENTS .........................................................................................................................54 

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14.1 
CHARACTERISTICS OF AN ADVERSE EVENT ............................................................................................54 
14.1.1 
Severity of the Adverse Event ............................................................................................54 
14.1.2 
Relationship of an AE and SAE to the Study Device ..........................................................54 
14.2 
DEFINITIONS OF ADVERSE EVENT AND ADVERSE DEVICE EFFECT ...............................................................54 
14.3 
DEFINITION OF SERIOUS ADVERSE EVENT .............................................................................................55 
14.4 
DEVICE DEFICIENCY ..........................................................................................................................55 
14.5 
TIME-FRAME FOR INVESTIGATOR REPORTING AE TO SPONSOR, EC, RA .....................................................55 
14.6 
ADVERSE EVENT REPORTING FORMS ...................................................................................................56 
14.7 
FORESEEABLE COMPLICATIONS AND ANTICIPATED ADVERSE DEVICE RELATED EFFECTS. .................................56 
14.8 
SAFETY MONITORING AND ADJUDICATION OF ADVERSE EVENTS ...............................................................57 
15 
VULNERABLE POPULATION ......................................................................................................57 
16 
EARLY TERMINATION OF THE CLINICAL INVESTIGATION ...........................................57 
16.1 
CRITERIA AND ARRANGEMENTS ..........................................................................................................57 
16.2 
REQUIREMENTS FOR PATIENT FOLLOW-UP IN CASE OF WITHDRAWAL ........................................................57 
17 
PUBLICATION POLICY .................................................................................................................57 
18 
PATIENT CONFIDENTIALITY & DATA PROTECTION.........................................................58 
19 
GUIDELINES AND APPLICABLE DOCUMENTS .....................................................................58 
20 
REFERENCES ...................................................................................................................................58 
21 
ACRONYM LIST ..............................................................................................................................60 
APPENDIX A. STIMULATION PROGRAMS ........................................................................................61 
APPENDIX B- SUBJECT QUESTIONNAIRES ......................................................................................61 
 
1  SYNOPSIS 
Sponsor 
Theranica Bioelectronics Ltd. 45 HaMelakha st, Netanya, Israel 
Title 
A prospective, randomized, double-blind, sham controlled multi-center clinical 
trial “Migraine Headache Treatment with Nerivio Migra neurostimulation 
device” 
Investigational 
Device 
Nerivio Migra neurostimulation device is intended for acute treatment of 
migraine headache with and without aura via delivery of transcutaneous 
electrical stimulation below pain threshold to patient upper arm at the onset a 
migraine pain. The level of generated stimuli is similar to other FDA approved 
electro stimulation devices. Nerivio Migra treatment is self-administered by the 
patient. It is intended to alleviate pain through conditioned pain modulation. 
The device is controlled by a dedicated smartphone application.  

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Study Design 
A prospective, randomized, double-blind, sham controlled multi-center trial. 
Ratio between treatment and control groups will be 1:1, stratified by center and 
use of preventive medications. 
The study will be conducted in three stages. 
Enrolled participants will be provided with an active Nerivio Migra or an 
identically looking sham device and trained to perform treatment and provide 
feedback via the smartphone application. 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. Following successful 
completion of device and application training, subjects will be discharged. 
Stage One. Roll-in. Participants will be reporting their migraine attacks using an 
electronic migraine diary installed on their smartphones. Duration of this phase 
is one month. 
Stage Two. Parallel arm treatment stage.  Following successful completion of 
Stage 1, the application will be activated in treatment mode. Subjects will be 
asked to apply the device and administer treatment at onset of their migraine 
pain. Subjects will be reporting their feedback via the smartphone application. 
Duration of Stage Two will be determined by treatment of four attacks over the 
course of two months (whichever is achieved first). 
Stage Three. Open label extended treatment. Following the completion of the 
study by all subjects and the return of all study devices, subjects will be offered a 
2-month period of using active device, at no cost.  
Objectives 
The purpose of this study is to evaluate the safety and performance of the 
Nerivio Migra Migraine device for the treatment of non-chronic migraine 
patients with and without aura 
Primary 
Endpoint 
Primary Performance Endpoint. Proportion (%) of patients reporting freedom 
from pain (pain grade 0) 2 hours post treatment without rescue medications in at 
least 50% of treated attacks 
Primary Safety Endpoint. Device related adverse effects 
Secondary & 
Exploratory 
Endpoints 
 
Performance endpoints: 
Secondary: 
1. The proportion (%) of subjects reporting treatment response at 2 hours 
post treatment without medications in at least 50% of treated attacks.  
Treatment response is defined as pain level reduction from moderate or 
severe at baseline to mild or pain level of none if treatment started with 
mild pain. 
2. Proportion (%) of patients reporting, 2 hours post treatment: 
 freedom from pain (pain grade 0) and their most bothersome 
migraine-associated symptom (MBS) in at least 50% of treated 
attacks 
 freedom from nausea in at least 50% of treated attacks 

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 freedom from photophobia in at least 50% of treated attacks 
 freedom from phonophobia in at least 50% of treated attacks 
Exploratory: 
3. The proportion (%) of patients reporting freedom from pain (pain grade 
0) 48 hours post treatment without medications in at least 50% of treated 
attacks 
4. The percent of subjects who are pain-free at 2 hours with no use of rescue 
medication, and either have no relapse of pain within the subsequent 46 
hours, or, if they have a relapse of pain in this time window, it disappears 
every time, after two hours, using the device, with no use of rescue 
medications. 
5. Patient global impression of change, with emphasis on disability and 
quality of life. 
Safety Endpoints 
 
Treatment tolerability  
 
Adverse events and complications whether related or unrelated to 
study device. 
Patient 
Population 
Adults 18-75 years old meeting International Headache Society criteria for 
migraine with and without aura, who are reporting 2-8 migraine attacks per 
month. 
Number of 
Patients 
Up to 248 patients with evaluable data, equally distributed between US and 
non-US sites 
Inclusion Criteria 
 
1. Patient is 18-75 years old. 
2. Patient meeting the ICHD-3 diagnostic 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 protocol 
5. Patient must be able and willing to provide written informed consent 
6. Male or non-pregnant / non-lactating female (NOTE: Females of child bearing 
potential must have a negative pregnancy test and must be willing to use 
adequate contraceptive means during the study 
7. Possesses the basic cognitive and motor skills needed to operate android cell 
phone 
Exclusion 
Criteria 
1. Has other significant pain problem that in the opinion of the investigator may 
confound the study assessments 
2. 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. Known uncontrolled epilepsy. 
4. Use of Cannabis including medical use.  
5. Has chronic migraine (more than
 
15
 
headache days per month). 

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6. Changed usage or dosage of migraine preventive medications in the last two 
months 
7. Has undergone nerve block (occipital or other) in the head or neck within the 
last 2 weeks. 
8. Is participating in any other clinical study. 
 
Study 
Procedures 
Following successful screening, enrollment interview and signing of informed 
consent, participants will be provided with an active Nerivio Migra or identically 
looking sham device and trained to perform treatment and provide feedback via 
the smartphone application.    
Baseline information including mean frequency and severity of migraine attacks, 
occurrence of other headaches, presence of ICHD-3 diagnostic criteria for 
migraine with and without aura and use of preventive and rescue medications 
will be recorded.   
During roll-in stage, migraine status will be recorded and participants will be 
requested to complete a quality of life questionnaire. 
Participants who successfully completed the roll-in stage will continue to the 
stage involving treatment of four qualifying migraine attacks. A qualifying 
migraine attack shall be preceded by at least 48 hours of freedom from headache. 
Participants will be instructed to activate the device at the onset of a qualifying 
migraine attack and manually adjust stimulation intensity to a level within the 
pre-defined range where it is perceivable but not painful. 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 can not comply with this, 
record their use of medications in the smartphone application. Via the 
application, each participant will be asked to rate his/her migraine pain level 
using Pain Grades Scale with values 0-3 (no pain, mild, moderate, severe): (1) 
upon starting the treatment, (2) two hours after starting treatment, (3) 48 hours 
after start of the first treatment corresponding to current migraine attack. 
Participants will be also asked to provide feedback using the application regarding 
the time elapsed from start of migraine attack to start of the treatment. In 
addition, participants will be reporting their use of rescue medication and 
presence of nausea, photophobia, phonophobia and allodynia, as well as 
additional migraine symptoms.   
In case of failure to provide feedback regarding pain level post-treatment, queries 
will be generated via EDC system and telephone follow-up will be performed by 
study investigator staff to solicit such feedback. After providing feedback at two 
hours post start of treatment and in case of pain recurrence, participants will be 
allowed to re-treat the attack using Migra device. 
Adverse events will be reported. 
Post study questionnaire will include patient global impression of change, 
blinding and usability assessments. 

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Unscheduled visits will be recorded and termination visit will be scheduled upon 
the completion of the study. In the event of premature discontinuation an early 
discontinuation visit will be scheduled.  
Study Duration 
Duration of study participation for each subject will be approximately three 
months, one month of roll-in stage and treatment of four qualifying migraine 
attacks over the course of two months (whichever is achieved first). 
Sample Size 
Estimation 
Sample size calculation is based on responders rate, defined as the proportion of 
patients that achieved pain free status (pain grade 0) at two hours post 
treatment. 
Investigational 
Sites and 
Principal 
Investigators 
Current list is kept on file 
 
 
2 BACKGROUND 
2.1 Introduction 
Migraine is a common neurovascular disorder manifesting itself in attacks of headaches that can 
reach a level of severe pain in many patients, leading 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]. Migraine, thus, 
affects millions of people [1]. Up to date, pathophysiology of migraine is not fully 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 variety of painful 
conditions [3, 4], with application of the stimulation adjacent to, or at least within the dermatome 
of the painful body site. Recent clinical data provide evidence that electro stimulation is an 
effective approach providing relief to chronic headaches and, among them, migraine. It is highly 
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 treatment and prophylaxis of chronic migraines, 
was developed by STX-Med [4]. The device applies electro stimulation to the forehead, within 
trigeminal nerve territory. The second device, GammaCore, was developed by ElectroCore [6], 
vagus nerve stimulation is approved for marketing in Europe and is used for treatment of migraine 
pain. Both devices deliver stimulation at relatively low intensity (16mA).  At the same time, 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, 

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sweating and speech for vagus nerve. From this prospective, safety of treatment is of great 
concern. 
These commercially available treatment approaches are associated with significant usability 
challenges due to the bulkiness of the applied devices and their cumbersome self-application 
(Cefaly device is mounted on forehead and the GammaCore is hand held throughout the 
treatment session).  
In addition, burden of treatment with these devices defined as the ‘work’ of being a patient and 
its effect on the quality of life (QOL) including challenges associated with lifestyle changes, 
reaction of others, etc. [21, 22] may be quite high. 
In summary, there exists recognized clinical need for a non-pharmacological solution for acute 
migraine. 
3 IDENTIFICATION AND DESCRIPTION OF THE DEVICE 
Theranica has developed Nerivio Migra (“Migra” or “the device”).  Nerivio Migra is intended for 
acute treatment of non-chronic migraines with and without aura. The device is designed to be 
self-applied to the upper arm. Treatments with Nerivio Migra are intended to be self-administered 
by the user at onset of a migraine headache. The device delivers transcutaneous electrical 
stimulation below pain threshold to peripheral nerve system at the onset of an acute migraine 
attack.  Migra is operated via a mobile application.   
Nerivio Migra utilizes electro stimulation in order to achieve conditioned pain modulation (CPM) 
effect at the onset of a migraine headache. Conditioned Pain Modulation (CPM) [7] is a paradigm 
used in pain research, in which a “conditioning” (also referred to as secondary) stimulus is applied 
such as to influence the subject’s perception of a “conditioned” (primary) painful stimulus, 
delivered (or originating) at a different body location. Based on diffused noxious inhibitory control 
(DNIC) mechanism [14], and sometimes referred to as “pain inhibits pain” principle, CPM allows 
to evoke powerful endogenous analgesic mechanism, by which a painful stimulus may be 
inhibited. The modulatory effect is diffuse, over the whole body, and can be induced by 
conditioning that can be applied anywhere in the body. Thus, use of 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 pain threshold, so 
it is not painful. 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; it seems that more intensive peripheral nociceptive activity is needed 
for the latter than for the former.  Since the 'inhibitory power' activated by the CPM via this 
peripheral non-painful stimulation is limited, the time window at migraine pain onset, where 
activity of the nociceptive pathways is still just starting, seems to be an ideal target for stimulation.  
It is well known [10] that nociceptive pathways undergo a process of sensitization during the first 
two hours or so of the migraine attack, such that it is easier to abort an attack earlier within this 
window, and more difficult later. Thus, application of the stimulation early in the attack is 
expected to alleviate pain substantially, or abort the attack. 
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].  

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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.    
3.1 
Intended Use 
The Nerivio Migra device is intended for acute treatment of adult episodic migraine with and 
without aura.  It is intended for self-administration in home setting.  
3.2 
The Device 
The Device is a fully integrated unit similar in appearance to a sports armband.  The device 
includes an arm band, electronic circuitry and battery contained in a plastic case, and a pair of 
electrodes with hydrogel. 
 

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The armband is based on a standard, off the shelf, smartphone armband made from a durable 
light neoprene material.  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).  The electrodes are incorporated into the armband and are not to be replaced 
by participants throughout the course of the study.   
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 outside of the plastic case contains an on-off switch and LED indicator of working state. 
Figure 1. Internal side of Nerivio Migra device 

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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. 
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 4.  
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: 

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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 
 
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 5). 
 
The Application is able to query device battery status and notify the user of its condition.  
 
Supports menus and display language in Hebrew, English and Russian (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 4. Application screens. Left to right: start screen, main menu, connectivity screen, 
treatment management screen 
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. 
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 

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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% 
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. 

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3.5.1 Performance testing  
All features and output specifications identified in Tables 1-2 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 
 
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 3) at the onset of a migraine headache, the 
user turns the device ON and activates therapy via the Mobile Application.  

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Figure 3 - Nerivio Migra ready for use 
 
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 25 minutes. At any point in time, however, the 
patient is able to stop treatment by one of three methods: 
 
Terminating the stimulation via the Mobile Application 
 
Turning off the device switch located on the outside of the armband 
 
Carefully removing the armband 
Migra delivers a single, pre-set, active stimulation program, or a sham program. Programs 
characteristics are given in Appendix XX. 
Device operation flow is presented in the figure below. 

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Figure 5. Device operation flow 
At any moment in the course of 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 
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, 

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records of the training session will be recorded 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. At the end of the session, the device will be switched into operational mode by 
“sliding off” training mode indicator on the main screen of the application.  
Training to the investigator and staff will be delivered by Theranica representative in a frontal 
session including demo and training activations. In order to provide additional support to clinical 
personnel, a training clip was recorded and will be available at all training sessions for staff and 
participants.  
 
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 
Theranica 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 treatment 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 

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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. 
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 of 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 

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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 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. 

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Sham  
Active programs  
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 
Theranica’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 section3.5.1) as well as throughout Theranica’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, so 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 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. 
 
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. 
 
Clearly defining the inclusion and exclusion criteria such that only appropriate patients are 
enrolled in the study. 

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4.3.4 
Risk-to-Benefit Rationale 
We believe 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, Theranica 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. 
 
5 OBJECTIVES & HYPOTHESES 
5.1 Objective 
The study purpose is to demonstrate safety and effectiveness of the Nerivio Migra electro 
stimulation device for treatment of migraine attacks with and without aura. 
5.2 Hypothesis 
The hypothesis is that the electro stimulation delivered transcutaneously to the peripheral 
nervous system at onset of a migraine headache will abort the attack, as indicated by significant 
difference between proportions of responders to the sham control stimulation and the active 
treatment without unexpected device related adverse effects.  
6 DESIGN OF THIS CLINICAL STUDY 
6.1 Description 
This is a prospective, randomized, double-blind, sham controlled multi-center clinical trial 
“Migraine Treatment with Nerivio Migra electro stimulation device”.  The study will enroll up to 
248 patients diagnosed with migraine with and 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, short electrical pulses of amplitude range similar to that of the 
treatment programs will be administered at very low frequency (0.1-0.5 Hz). The rationale 
underlying selection of sham control settings is that, on the one hand, pulses are perceivable and 
the user is able to manipulate their intensity similarly to the case of treatment programs, while, 
on the other hand, no clinically relevant treatment is delivered, based on existing knowledge of 
parameters range of electro stimulation treatments [5-7, 18]. 
Following successful screening, enrollment interview and signing of informed consent, 
participants will be provided with an active Nerivio Migra or identically looking sham device and 
trained to perform treatment and provide feedback via the smartphone application.   Ratio 
between treatment and control groups will be 1:1. 
Baseline information including mean frequency and severity of migraine attacks, occurrence of 
other headaches, presence of ICHD-3 diagnostic criteria for migraine with and without aura and 
use of preventive and rescue medications will be recorded.   

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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. 
Study flow is schematically presented in the figure below. 
 
Figure 4. Study Design 
Following enrollment, the study will be conducted in three stages. 
Stage One. In stage one (roll-in phase) recruited participants will be reporting their migraine 
attacks per ICHD-3 diagnostic criteria, including presence of aura, using an electronic migraine 
diary installed on their smartphones. Duration of this phase is one month. 
Stage Two. This will be the parallel arm treatment stage.   
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 headache. 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 can not 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 attack 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, 
photophobia and phonophobia, and treatment perception. After providing feedback at two hours 

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after start of treatment and in case of pain recurrence, participants will be allowed to re-treat the 
attack using Migra device.  
Adverse events will be reported. 
Duration of study participation for each patient will be up to three months, determined by one 
month of the roll-in stage followed treatment of four qualifying attacks over the course of two 
months (whichever is achieved first). 
Post study questionnaire will include patient global impression of change [27], blinding and 
usability assessments. 
Stage Three. This part will include open label extended treatment. Following the completion of 
the study by all subjects and the return of all study devices, subjects will be offered a 2-month 
period of using active device, at no cost. 
 
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 one-month 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 ensures collection of bias free efficacy data. Specific measures will be taken 
to ensure blindness (refer to Section 6.2.2). 
Detailed statistical analysis plan will be developed prior to study start to mitigate interpretation 
bias. 
 
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. A number of 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. Each device will be numbered with 3 digit numbers, first digit site 
number and two digit subject numbers. Each new patient will be provided with d next consecutive 
numbered device.  

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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 Endpoints 
Performance  
Proportion (%) of patients reporting freedom from pain (pain grade 0) 2 hours post treatment 
without medications in at least 50% of treated attacks 
6.3.2 
Secondary Endpoints 
Secondary Performance Endpoints 
1. 
The proportion (%) of subjects reporting treatment response at 2 hours post treatment 
without rescue medications in at least 50% of treated attacks.  Treatment response is 
defined as: pain level reduction from moderate or severe at baseline to mild or pain level 
of none if treatment started with mild pain 
 
2. Proportion (%) of patients reporting, 2 hours post treatment: 
 
freedom from pain (pain grade 0) and their most bothersome migraine-associated 
symptom (MBS) in at least 50% of treated attacks 
 
freedom from nausea in at least 50% of treated attacks 
 
freedom from photophobia in at least 50% of treated attacks 
 
freedom from phonophobia in at least 50% of treated attacks 
 
6.3.3 
Exploratory Endpoints: 
1. The proportion (%) of patients reporting freedom from pain (pain grade 0) 48 hours 
post treatment without medications in at least 50% of treated attacks 

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2. The percent of subjects who are pain-free at 2 hours with no use of rescue 
medication, and either have no relapse of pain within the subsequent 46 hours, or, 
if they have a relapse of pain in this time window, it disappears every time, after two 
hours, using the device, with no use of rescue medications. 
3. Patient global impression of change, with emphasis on disability and quality of life. 
6.3.4 
Safety Endpoints: 
 
Treatment tolerability  
 
Adverse events and complications whether related or unrelated to study device. 
 
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:  
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).  
 

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Time from onset 
of migraine pain 
Time from onset 
of migraine pain 
Dropdown list 
under 10 
minutes  
10-20 minutes 
20-60 minutes 
1-2 hours 
2-4 hours 
over 4 hours 
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 
 
6.4.2.2 
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  
Radio buttons 
Y/N 
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 

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Increased skin 
sensation 
Presence of 
allodynia 
Radio buttons  
Y/N 
Arm side where 
device was applied  
Left or right arm 
Radio buttons 
L/R 
Pain location (side) 
 
Dropdown list 
L 
R 
both 
Additional 
feedback 
Additional, free 
style feedback 
Textbox  
Free text, 
optional 
 
6.4.2.3 
48h PRO 
The screen shall provide 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  
Radio buttons 
Y/N 
Medication 
name 
Rescue 
medication  
Dropdown list 
 From a pre-
defined list 
Additional 
feedback 
Additional, free 
style feedback 
Textbox  
Free text, 
optional 
 
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.  
Recurrent treatments within 46 hours from first treatment of an attack are allowed, and are 
collected and analyzed 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. 

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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 
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 5. 
 

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Figure 5. Schematics of data flow 
 
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.  

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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 7.5.   
• 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 18 months.  
6.5 Subjects  
6.5.1 Inclusion Criteria 
Patients need to fulfill all the below Inclusion criteria: 
1. Patient is 18-75 years old. 
2. Patient meeting the ICHD-3 diagnostic criteria for migraine with and without aura 
3. Patient reporting 2-8 migraine attacks per month. 
4. Patient must be able and willing to comply with the protocol 
5. Patient must be able and willing to provide written informed consent 
6. Male or non-pregnant / non-lactating female (NOTE: Females of child bearing 
potential must have a negative pregnancy test and must be willing to use adequate 
contraceptive means during the study) 
7. Possesses the basic cognitive and motor skills needed to operate android cell phone 

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6.5.2 Exclusion Criteria 
Patients are excluded if they have any of the following: 
1. Has other significant pain problem that in the opinion of the investigator may 
confound the study assessments 
2. 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. Known uncontrolled epilepsy. 
4. Use of Cannabis including medical use.  
5. Has chronic migraine (more than
 
15
 
headache days per month). 
6. Changed usage or dosage of migraine preventive medications in the last two months 
7. Has undergone nerve block (occipital or other) in the head or neck within the last 2 
weeks. 
8. Is participating in any other clinical 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 248 eligible patients (see section 
7.5). 
6.5.5 Expected Study Duration for Each Subject 
Study duration per patient is 4 complete treatment cycles and no longer than 3 months from 
enrollment (whichever is fulfilled sooner).  
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: 

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 
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. 
 
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. 
 
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 a 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 6-15 patients per month, 
depending on participating site. Enrollment period is expected to be up to six months long.  

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6.5.11 Procedures for Replacement of Subjects 
No subject replacement is planned. 
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 investigational device will 
be handed to study participants for home use. As per the IFU, participants are instructed to 
activate the device at the onset of a migraine headache and manually adjust stimulation intensity 
to a level where it is perceivable but not painful. 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 two 
months (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 two hospital visits: (1) for screening and device training and (2) end of study 
visit when the device is returned and end of study assessment is performed. 
Screening and enrollment visit 
During the screening visit, the following procedures will be performed: 
 
Review Inclusion /exclusion criteria and evaluate eligibility 
 
Informed consent  signing 
 
Demographics and medical history review. 
 
History of migraines. 

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 
Medication history and concomitant medication(s) review. 
 
Enrollment and randomization.   
 
Patients will receive the Narivio device and smart phone (per need) 
 
Patients will receive training on device and application operation and schedule of 
reporting. 
 
Completion of a questionnaire. 
 
Urine pregnancy test  
 
End of study visit (3 months after enrollment) 
During the screening visit, the following procedures will be performed: 
 
Participants will be asked about changes in concomitant medications and adverse events 
that have occurred during the study.Devices and smartphones will be returned. 
 
Completion of a questionnaire 
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.  
It is also the sponsor’s responsibility to communicate to other sites’ representatives 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 

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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 Theranica 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. 
 
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 treatment of migraine attacks with and without aura.   
7.2 Study Variables 
7.2.1 Primary performance variable  
The primary performance endpoint, the proportion (%) of patients reporting freedom from pain 
(pain grade 0) 2 hours post treatment without rescue medications in at least 50% of treated 
attacks, will be measured in the form of a binary variable which will be assigned the value of “1” 
if the subject reports freedom from pain (pain grade 0) 2 hours post treatment without rescue 
medications in at least 50% of his/her treated attacks, and “0” otherwise.  
7.2.2 Secondary performance variables  
The secondary performance endpoints will all be expressed in the form of binary variables as in 
the representation of the primary performance variable. 
7.2.3 Exploratory performance variables 
The exploratory performance endpoint, the proportion (%) of patients reporting freedom from 
pain (pain grade 0) 48 hours post treatment without rescue medications in at least 50% of treated 
attacks, will be measured in the form of a binary variable which will be assigned the value of “1” 

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if the subject reports freedom from pain (pain grade 0) 48 hours post treatment without rescue 
medications in at least 50% of his/her treated attacks, and “0” otherwise. 
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 freedom from pain at 2 hours post treatment without 
rescue medications in the treated group = The proportion (%) of subjects reporting freedom from 
pain at 2 hours post treatment without rescue medications in the sham group. 
HA: The proportion (%) of subjects reporting freedom from pain at 2 hours post treatment without 
rescue medications in the treated group ≠ The proportion (%) of subjects reporting freedom from 
pain at 2 hours post treatment without rescue medications in the sham group. 
 
7.4 Sample Size Estimation 
The sample size for this study was calculated to test the above described null hypothesis with a 
chi-squared test, even though the final analysis may employ a regression model.  
In the pilot study, the percentage of responders in the relevant treatment arm was 30%, while the 
percentage of responders in the sham group was 6%. The latter result is consistent with sham 
response rates referenced in IHS Guidelines for Migraine Trials. Sample size calculations are based 
on a more conservative estimate of the sham group response rate of 10%, then a sample size to 
detect a difference between treated and sham groups (of 20%) with 80% power at a 5% level of 
significance will result in a total of 124 evaluable subjects, with 62 subjects randomized to the 
treated arm and 62 to the sham arm. Allowing for a ~10% drop-out rate, a total of 136 (68 treated 
vs. 68 sham) subjects may be enrolled in the study.   
Statistical considerations require availability of 124 evaluable subjects, i.e. with data available for 
analyses. The study recruitment will be monitored closely via the EDC system and, as soon as the 
evaluable data target is achieved, the Study Monitor will receive notification. If the number of 
subjects enrolled in the US is at least 50% of the accumulated population, recruitment will be 
stopped. 
7.5 Interim Analysis 
According to [24-26], planning an interim analysis that permits an increase in the sample size as 
described below does not inflate the type I error. In addition, the final analysis is performed using 
the conventional test as appropriate for the statistical hypothesis. 
One interim analysis is planned once 50% of the information is collected, i.e. the interim look will 
be performed after 62 evaluable subjects have been accrued. After all the relevant data will be 

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entered into the database, a soft lock to the database will be performed. An unblinded statistician 
will perform the assessments described below. A designated Data Monitoring Committee will 
recommend whether to stop the study once the interim results are available. 
The study will then either continue to the originally planned sample size if the result is “favorable”, 
stop for futility if the result is “unfavorable”, or an increase will be made to the sample size if the 
result is “promising”. These decisions will be made based on the conditional power (CP), defined 
as the conditional probability that the result will exceed a critical value at the interim given the 
observed effect size  𝛿1
̂ = difference between response rates treated versus control at the interim 
look.  
Notation: 
n1= sample size at interim analysis 
n2= sample size calculated based of effect size obtained at interim 
nmax = the highest sample size the company is willing to use/ can afford, nmax = 248 subjects and 
is calculated based on a smaller effect size of 15% in the same manner as above. 
CPmin=is the calculated minimum CP based on the ratios nmax/n2, n1/n2 and the target study 
power (80%). 
The following are the decision rules for the interim analysis which will be performed upon accrual 
of 50% (n1/n2) of the sample size, i.e. 62 evaluable subjects. These depend on the zone into which 
CP falls at the interim, the calculated CPmin, the maximum sample size designated for the study 
and the % of the originally planned sample size at which the interim analysis will be performed. 
Following this principle does not inflate the Type I error. 
1. If the result is “Unfavorable”, i.e. CP < CPmin = 36% (interim result is so disappointing that 
it is not worth increasing the sample size to retrieve conditional power), continue to the 
original sample size of 124. If the difference between response rates at the interim (Pt-
Pc) is less than 0 (i.e. control is better than treatment) stop the trial for futility. 
2. If the result is “Promising”, i.e. 36% ≤ CP < 80%, the sample size is increased to recover 
the targeted power of 80%. The sample size used will be either the new calculated sample 
size based on the conditional power (as described in Sample size re calculation using 
conditional power Jonathan S. Denne Statist. Med. 2001; 20:2645–2660) or the 
predetermined maximum sample size of 248 subjects whichever lower.  
3. If the result is “Favorable”, i.e. CP ≥ 80% the interim results are sufficiently favorable and 
trial continues to the original sample size planned of 124 without the need to adaptively 
increase the sample size. 
7.6 Randomization 
After a subject meets the eligibility criteria, he/she 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 

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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. 
7.7 Analysis sets 
7.7.1 Intent to treat analysis set (ITT) 
The ITT analysis set will consist of all subjects randomized. In accordance with the ITT principle, 
all subjects randomized will be kept in their originally assigned treatment group. 
7.7.2 Modified intent to treat analysis set (mITT) 
The mITT set will consist of all subjects in the ITT set who completed at least one study 
treatment, assigned a treatment group as treated. 
7.7.3 Per protocol analysis set (PP) 
The Per-Protocol (PP) analysis set includes all patients from the mITT analysis set without any 
major protocol deviation who have evaluable data on at least one qualifying migraine attack. 
7.7.4 Statistical analysis of analysis sets 
The ITT analysis set will serve as the main set for safety assessments and the mITT set for all 
performance assessments. 
The primary performance assessment will also be performed on the PP analysis set as a 
sensitivity analysis. 
7.8 Statistical Analyses 
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.  
7.8.1 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.  

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If multiple measurements are taken in a single patient, statistics described below will be 
appropriately modified to accommodate the within patient correlation. 
7.8.2 Significance levels and handling of type I error 
7.8.2.1 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%. 
7.8.2.2 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. 
7.8.3 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  
 
Migraine attacks characteristics per ICHD-3 diagnostic criteria for migraine 
with and without aura 
 
Physical examination 
 
Laboratory (pregnancy) tests for women of childbearing potential 
7.8.4 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. 
7.8.5 Performance Analyses 
Primary Performance Analyses: 
The primary endpoint is freedom from pain at 2 hours post treatment without rescue medications 
in at least 50% of treated attacks, a count and percentage of subjects free from pain 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.  

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If the null hypothesis is rejected in favor of the alternative hypothesis and the proportion (%) of 
subjects reporting freedom from pain at 2 hours post treatment without rescue medications 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 end-point will be performed to assess the impact of missing 
data on the study outcome. This will be performed using several possible imputation methods. 
Subset analysis: 
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 will be performed and reported by 
adding these variables to a logistic regression model. 
Secondary performance analyses: 
The secondary performance variables will be summarized by a count and percentage and 
compared with a chi-squared test. 
Exploratory performance analyses: 
A count and percentage of patients reporting freedom from pain (pain grade 0) 48 hours post 
treatment without rescue medications in at least 50% of treated attacks will be presented, the 
groups will be compared with a chi-squared test. 
Use of rescue medications will be summarized by descriptive statistics per treatment group and 
compared between the groups with a t-test. 
Patient global impression of change will be summarized by descriptive statistics per treatment 
group and compared between the groups with a t-test. 
 
Ease of use will be summarized by descriptive statistics. 
7.8.6 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 chi-squared 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. 
 

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7.8.7 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. 
7.9 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. 
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.  

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8.2 Data Quality Assurance 
To ensure the quality of clinical data across all subjects, a clinical data management review will be 
performed by Theranica 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 Theranica. 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). 
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).  
Theranica 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. 

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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.  
 
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  
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.   
 

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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 Theranica. 
Theranica 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 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.  
11 PROTOCOL DEVIATIONS  
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.Device Accountability 
 Devices will be provided by Theranica Bioelectronics, 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. 

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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. 
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.  
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 Theranica 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. 

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Informed consent accurately describes all aspects of the clinical investigation that are relevant to 
the subject’s decision to participate in the study. 
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 

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or not related to the investigational device. This should relate to baseline information whenever 
available. 
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 Theranica Bioelectronics, within 24 hours to: 
Theranica Bioelectronics  
Alon Ironi 
Tel: +972.72.390.9758 
Fax: + 972.72.390.9755 
Email: aloni@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 Theranica. 
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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Theranica 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: 
 
Likely 
o Minor skin irritation from wearing the device, which disappears shortly after the 
treatment is over.  
 
Less Likely  
o Red marks at the site of stimulation, that disappear shortly after the treatment 
is over. 
o Possible sensation of slight warmth where the device touches the skin. This 
disappears shortly after the treatment is over.  
o A sensation of itching or tingling or stinging at the site of stimulation, which 
disappears shortly after the treatment is over. 
o Slight muscle fatigue or weakness in arm where the device is applied, which 
disappears shortly after the treatment is over. 
 
Very unlikely 
o Slight muscle spasms in the arm where the device is applied, which disappears 
shortly after the treatment is over. 
 

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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, 
bright flashing dots or lights, blind spots, wavy or jagged lines (aura). 
 
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. 
15 VULNERABLE POPULATION 
No vulnerable population will be enrolled to this study. 
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, Theranica 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. 
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. 
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. 
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 

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Confidential 
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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  
        comparing independent proportions" Biometrics 36(1980) pp. 343-346 
15. 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 

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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 
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 

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MDD - Medical Device Directive 
MoH – Ministry of Health 
NPS – Numeric Pain Rating Scale  
PI - Principal Investigator 
PP - Per-Protocol analysis set 
RA - Regulatory Authority 
SADE - Serious Adverse Device Effect 
SAE - Serious Adverse Event 
SD - Standard Deviation 
SDV - Source Data Verification 
SOPs - Standard Operating Procedures 
w - Week 
APPENDIX A. STIMULATION PROGRAMS 
 
Waveform: Biphasic, rectangular, symmetrical 
 
Duration of primary phase (µsec): 200 
 
Pulse duration (µsec): 400 
 
Pulse frequency (Hz): 100-120* 
 
Max output current (mA): 60 
 
* In order to avoid habituation (i.e., cease of response to the stimulus), Migra employs frequency 
drifting in the following manner – after each 5-minute section of the treatment, the frequency of 
the output will toggle between 100-110-120Hz. 
 
APPENDIX B- SUBJECT QUESTIONNAIRES 
Appendix B. Subjects’ questionnairesNM1 MCT – Start of Study 
Questionnaire 
The Migraine Disability Assessment questionnaire was put together to help you measure 
the impact that migraines (and headaches) on your life.  
Please answer all the following questions regarding ALL the migraines you’ve had in the 
past 2 months. For each question, select one choice. 
Part I – Migraine Disability Assessment 
Establishing baseline 

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1. How many days per month, in the 2 months before the study, did you miss work 
or school because of your migraine? 
1. 0 
2. 1-3 
3. 4-8 
4. More than 8 
2. In how many days per month, in the 2 months before the study, was your 
productivity at work or school significantly reduced because of your migraine (do 
not include days that you indicated in question #1)? 
1. 0 
2. 1-3 
3. 4-8 
4. More than 8 
3. In how many days per month, in the 2 months before the study, did you not do 
household work because of your migraine (such as housework, home repairs or 
maintenance, shopping, caring for children, etc.)? 
1. 0 
2. 1-3 
3. 4-8 
4. More than 8 
4. In how many days per month, in the 2 months before the study, was your 
productivity in household work significantly reduced because of your migraine 
(such as housework, home repairs or maintenance, shopping, caring for children, 
etc.)? 
1. 0 
2. 1-3 
3. 4-8 
4. More than 8 
5. On how many days per month, in the 2 months before the study, did you miss 
family, social or leisure activities because of your migraine? 
1. 0 
2. 1-3 
3. 4-8 
4. More than 8 
6. In general, how would you grade the degradation in your quality of life as a result 
of migraines? 
1. None 
2. Mild effect 
3. Moderate effect 

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4. Severe effect 
7. How much do you typically spend on migraine medication, per month? 
1. Less than $10 
2. $11-$20 
3. $21-$50 
4. More than $50 
NM1 MCT – End of Study Questionnaire 
The Migraine Disability Assessment questionnaire was put together to help you measure 
the impact that migraines (and headaches) on your life.  
Please answer all the following questions regarding ALL the headaches you’ve had in the 
past 2 months. For each question, select one choice. 
1. How many days per month, in the last 2 months, did you miss work or school 
because of your migraine? 
1. 0 
2. 1-3 
3. 4-8 
4. More than 8 
2. In how many days per month, in the last 2 months, was your productivity at work 
or school significantly reduced because of your migraine (do not include days that 
you indicated in question #1)? 
1. 0 
2. 1-3 
3. 4-8 
4. More than 8 
3. In how many days per month, in the last 2 months, did you not do household work 
because of your migraine (such as housework, home repairs or maintenance, 
shopping, caring for children, etc.)? 
1. 0 
2. 1-3 
3. 4-8 
4. More than 8 
4. In how many days per month, in the last 2 months, was your productivity in 
household work significantly reduced because of your migraine (such as 
housework, home repairs or maintenance, shopping, caring for children, etc.)? 
1. 0 
2. 1-3 
3. 4-8 
4. More than 8 

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5. On how many days per month, in the last 2 months, did you miss family, social or 
leisure activities because of your migraine? 
1. 0 
2. 1-3 
3. 4-8 
4. More than 8 
6. In the past two months, how would you grade the degradation in your quality of 
life as a result of migraines? 
1. None 
2. Mild effect 
3. Moderate effect 
4. Severe effect 
7. How much do you typically spend on migraine medication, per month, during the 
3-months study? 
1. Less than $10 
2. $11-$20 
3. $21-$50 
4. More than $50 
Part II – Device Usability and Pricing 
1. If you could purchase the device now, how much would you be willing to pay for 
it, per month? 
1. Less than $10 
2. $11-$20 
3. $21-$50 
4. More than $50 
2. If you had the device permanently in your possession, what would be your 
estimate for additional (extra) spending on medication? 
1. Less than $10 
2. $11-$20 
3. $21-$50 
4. More than $50 
3. If you had the device permanently in your possession, what would be your 
estimate for additional (extra) spending on medication? 
1. Less than $10 
2. $11-$20 
3. $21-$50 
4. More than $50 

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4. How likely are you to recommend using NM1 device for a friend or family 
member that also suffer from migraines? 
1. Not likely 
2. Likely 
3. Very likely 
4. Extremely likely 
5. How likely would you be willing to share the information about your migraine 
episodes with your physician or any other designated care-taker, via the device 
and its App? 
1. Not likely 
2. Likely 
3. Very likely 
4. Extremely likely 
 
Did you experience any inconvenience during the treatment? 
6. Itching at the location of the device? 
1. None 
2. Mild 
3. Moderate 
4. Severe 
7. Skin redness at the location of the device? 
5. None 
6. Mild 
7. Moderate 
8. Severe 
8. Sensation of heat at the location of the device? 
9. None 
10. Mild 
11. Moderate 
12. Severe 
9. Overall, how would you rate the study and your experience with the device? 
1. Excellent 
2. Very good 
3. Good 
4. Fair 
5. Poor 
10. How user friendly and intuitive was the App? 
1. Extremely friendly/intuitive 

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2. Very friendly/intuitive 
3. Somewhat friendly/intuitive 
4. Not so friendly/intuitive 
5. Not friendly/intuitive at all 
 
11. To what extent did you like using the device? 
a. Liked it a lot 
b. Liked it 
c. Did not like it so much 
d. Disliked it very much